|
|
Line 6,500: |
Line 6,500: |
| Zuckerman, S., and McKeown, T. 1938. The | | Zuckerman, S., and McKeown, T. 1938. The |
| canine prostate in relation to normal and abnormal testicular changes. J. Path. & Bact., | | canine prostate in relation to normal and abnormal testicular changes. J. Path. & Bact., |
| 46, 7. | | 46, 7. |
| | |
| | |
| | |
| | |
| | |
| | |
| =The Accessory Reproductive Glands of Mammals=
| |
| | |
| Dorothy Price, Ph.D.
| |
| | |
| Professor Of Zoology, The University Of Chicago
| |
| | |
| and
| |
| | |
| H. Guy Williams- Ashmari, Ph.D.
| |
| | |
| Associate Professor, Ben May Laboratory, The University Of Chicago
| |
| | |
| | |
| | |
| L Gross Structure, Homologies, and I. Gross Structure, Homologies, and
| |
| | |
| Occurrence in Mammalian Orders. 366 Occurrence in Mammalian
| |
| | |
| A. Introduction c566 „ ,
| |
| | |
| B. General Characteristics 367 Ureters
| |
| | |
| C. Survey of the Glands 368 j^ INTRODUCTION
| |
| | |
| 1. Bulbo-urethral and bulbovestibu- ^, • , , ^ , ,
| |
| | |
| la,!- 368 The genital system of male mammals con
| |
| 2. Male and female prostate glands. . 369 sists of three component parts. These are:
| |
| | |
| 3. Seminal vesicles 376 ( 1) paired testes, the primary sex organs in
| |
| | |
| 4. Ampullary glands ■ • ■ • ■ 376 ^^^j^j^j-, spermatozoa are formed and andro
| |
| U. Evolutionarv Historv of Accessory • i j. j /ov
| |
| | |
| Reproductive Glands in Mammals 376 g^nic hormones are secreted; (2) accessory
| |
| | |
| II. Function ofMale Accessory Glands.. 377 reproductive organs, a continuous series of
| |
| | |
| A. Introduction 377 ducts in which spermatozoa are transported
| |
| | |
| B. Volumetric Studies of Secretion 378 fpo^ the testes, stored in the tail of the epi
| |
| 1. Prostatic isolation operation^. 378 .^^^^ ■ ^nd finallv carried to the exterior
| |
| | |
| 2. Prostatic translocation operation. 380 , - . , ,. ' ,
| |
| | |
| C. Chemical Composition of the Glandu- ^^hen ejaculation occurs, and various
| |
| | |
| lar Secretions 380 glands, the secretions of which provide the
| |
| | |
| I). Metabolism of the Prostate and Sem- carrying medium for the spermatozoa at
| |
| | |
| inal Vesicle 394 emission ; ( 3) external genitalia, the penis
| |
| | |
| K. Coagulation of Semen 396 , , , . , ,
| |
| | |
| III. Structure and Function in Relation ^r copuhitory organ and, m most mammals,
| |
| | |
| TO Hormones 398 i^ scrotum in which the testes come to lie
| |
| | |
| A. Introduction 398 more or less permanently, or only periodi
| |
| B. Effects of Androgens 399 p.^Hy during the breeding season.
| |
| | |
| 1. Testicular andn,gens 399 ^^ ^^jj^ -^ ^j^^ epithelial lining of the
| |
| | |
| 2. Adrenal androgens 423 / . i i j r l ^ c
| |
| | |
| 3. Ovarian androgens 424 ^ttcrent, epididymal, and deferent parts of
| |
| | |
| 4. Progesterone 425 the duct system have secretory functions,
| |
| | |
| C. Effects of Estrogens 426 but all male mammals develop discrete and
| |
| | |
| I). Hormonal Control ()f Spontaneous ^^^ specialized glands which are associated with
| |
| | |
| 1. Benign growtU.''""^ '.'.'.'.'.'.'.'.'.'.'.'.'.'. 429 ^Pecific regions of the reproductive tract and
| |
| | |
| 2. Prostatic cancer 430 eject their secretions into it at seminal
| |
| | |
| E. I'^ffects of Carcinogenic Aromatic Hy emission. The degree of development of
| |
| | |
| drocarbons 430 these large, conspicuous glands is a unique
| |
| | |
| F. Effects of Nonsteroid Hormones 433 .ij^r^cteristic of mammals.
| |
| | |
| 1. I'rolactin (LTH) 433 _, i x- i j u
| |
| | |
| 2. Growth hormone (STH) 434 The accessory reproductive glands can be
| |
| | |
| IV. References 435 grouped logically into those ^vhich arise
| |
| | |
| 366
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 367
| |
| | |
| | |
| | |
| embryonically from the mesonephric or
| |
| Wolffian duct (ductus deferens) i.e., the
| |
| ampullary glands (glandula vasis deferentis) and seminal vesicles or vesicular
| |
| glands, and those deriving from the urogenital sinus or urethra, namely the prostate and bulbo-urethral or Cowper's glands
| |
| (see chapter by Burns). The anatomic relationships established in the fetus are retained to a considerable degree postnatally
| |
| so that the ampullary glands and seminal
| |
| vesicles are associated with the ducti deferentes. However, in some mammals the seminal vesicles empty into the pelvic urethra
| |
| close to the openings of the deferent ducts
| |
| but separate from them; no ejaculatory
| |
| ducts are present. The prostatic and bulbourethral glands are associated with the
| |
| proximal and distal urethra, respectively.
| |
| The secretion of the prostate is discharged,
| |
| in most cases, through multiple ducts that
| |
| join the prostatic urethra at the level of
| |
| the colliculus seminalis. The ducts of the
| |
| bulbo-urethral glands drain into the urethra
| |
| in the region of the urethral bulb.
| |
| | |
| In addition to these accessory reproductive glands, there are small mucus-secreting
| |
| glands (of Littre) opening into the urethra
| |
| along its length, and preputial glands
| |
| (which are modified sebaceous glands)
| |
| emi)tying their secretion on the prepuce.
| |
| | |
| In many female mammals, homologues of
| |
| the male prostate and bulbo-urethral glands
| |
| develop in the fetus. These glands may retrogress prenatally, remain vestigial, or develop postnatally and become functionally
| |
| active. These homologues are the female
| |
| prostate glands (para-urethral glands of
| |
| Skene) and the bulbovestibular (major
| |
| vestibular or Bartholin's glands). In addition, there are urethral glands (minor vestibular) which are homologous with the
| |
| male urethral glands of Littre, and female
| |
| preputial or clitoridal glands corresponding
| |
| to the male preputials. The major vestibular, when present, and the minor vestibular
| |
| and clitoridal glands are functional in many
| |
| mature females. In a few cases, well developed prostate glands which are actively secretory have been found in females of four
| |
| mammalian orders.
| |
| | |
| | |
| | |
| B. GENERAL CHARACTERISTICS
| |
| | |
| The male accessory reproductive glands
| |
| of higher mammals have many characteristics in common. Typically, all possess (1)
| |
| a secretory epithelium which is enormously
| |
| increased in effective secretory area by villous infoldings, or by a compound tubuloalveolar structure, (2) an underlying layer
| |
| of connective tissue (the lamina propria)
| |
| and (3) smooth muscle fibers. It is now well
| |
| established that the secretory activity of the
| |
| epithelial cells is normally under the control
| |
| of testicular hormones. The secretions pass
| |
| from the cells into the lumina of the glandular alveoli where they are usually stored
| |
| until ejaculation.
| |
| | |
| The sensory innervation includes various
| |
| types of sensory nerve endings in the connective tissue, and free nerve endings in
| |
| the epithelium. The autonomic innervation
| |
| is parasympathetic (nervi erigentes) and
| |
| sympathetic (hypogastric nerve) from the
| |
| pelvic plexus. If the plexus is resected or
| |
| the sympathetic chain above is interrupted,
| |
| there is no reflex ejection of the glandular
| |
| secretions. When the hypogastric nerve is
| |
| stimulated, peristaltic waves of contraction
| |
| occur in the ductus deferens, and there is
| |
| contraction in the seminal vesicles and prostate which partially empties the stored secretion from the lumina of these glands.
| |
| Stimulation of the parasympathetic system
| |
| or the administration of pilocarpine results
| |
| in an increased output of prostatic secretion.
| |
| | |
| There are marked dissimilarities in gross
| |
| structure, character of the epithelia, and the
| |
| chemical nature of the secretions in the
| |
| various glands — ^prostates, seminal vesicles,
| |
| bulbo-urethral, and ampullary (Mann,
| |
| 19o4a). There are also differences in structure and function between homologous
| |
| glands in related forms. The nomenclature
| |
| that was applied to the glands in early descriptive studies was often based on anatomic relationships and gross morphologic
| |
| structure in adults. This resulted in some
| |
| confusion in classification, but most of the
| |
| disputed points have been clarified and
| |
| some of the homologies have been established by embryologic study. The extensive
| |
| studies of INIann (1954a) show clearly that
| |
| | |
| | |
| | |
| 368
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| TABLE 6.1
| |
| Occurrence of male accessory reproductive glands and their homologues in females"
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Male*
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Female<^
| |
| | |
| | |
| Order
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Bu
| |
| | |
| | |
| Pr
| |
| | |
| | |
| Sv
| |
| | |
| | |
| Am
| |
| | |
| | |
| Bv
| |
| | |
| | |
| Pr
| |
| | |
| | |
| Genera and species with functioning female prostates
| |
| | |
| | |
| Monotremata . . .
| |
| | |
| | |
| +
| |
| | |
| | |
| _?
| |
| | |
| | |
| _
| |
| | |
| | |
| _
| |
| | |
| | |
| +
| |
| | |
| | |
| _
| |
| | |
| | |
| | |
| | |
| Marsupiala
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| | |
| | |
| | |
| | |
| +
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Insectivora
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| ±
| |
| | |
| | |
| ±
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| Erinaceoii.s europeus (Deanesly, 193-4)
| |
| Hemicentetes (Lehmann, 1938)
| |
| Talpa europea (Godet, 1949)
| |
| | |
| | |
| Chiropt era
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| ±
| |
| | |
| | |
| ±
| |
| | |
| | |
| +
| |
| | |
| | |
| =t
| |
| | |
| | |
| Coelura afra (Mathews, 1941)
| |
| Taphozous sp. (Mathews, 1941)
| |
| Nycteris luteola (Mathews, 1941)
| |
| Carioderma cor (Mathews, 1941)
| |
| | |
| | |
| Primates
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| ±
| |
| | |
| | |
| =b
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| Carnivora
| |
| | |
| | |
| ±
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| zb
| |
| | |
| | |
| ±
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| Perissodactyla...
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| _
| |
| | |
| | |
| | |
| | |
| Artiodactyla ....
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| ±
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| Hyracoidea
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Proboscidea
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Sirenia
| |
| | |
| | |
| —
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Cetacea
| |
| | |
| | |
| —
| |
| | |
| | |
| +
| |
| | |
| | |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Edentata
| |
| | |
| | |
| ±
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Pholidota
| |
| | |
| | |
| —
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Rodentia
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| =t
| |
| | |
| | |
| ±
| |
| | |
| | |
| ±
| |
| | |
| | |
| Arvicanthus cinereus (Rant her, 1909)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Rattus norvegicus (Marx, 1931, 1932; Korenchevsky
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| and Dennison, 1936; Korenchevsky, 1937; Witschi,
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Mahoney and Riley, 1938; Price, 1939; Mahoney,
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 1940, 1942; Mahoney and Witschi, 1947)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Mastomys erythroleucus (Brambell and Davis, 1940)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Apodemus sylvaticus (Raynaud, 1942, 1945)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Microtus arvalis (Delost, i953a, 1953b)
| |
| | |
| | |
| Lagomorpha. . . .
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| ±
| |
| | |
| | |
| +
| |
| | |
| | |
| +
| |
| | |
| | |
| ±
| |
| | |
| | |
| Sylvilagus floridanus (Elschlepp, 1952)
| |
| | |
| | |
| | |
| "Compiled from Oudemans, 1892; Engle, 1926a; Retief, 1949; Eckstein and Zuckerman, 1956 and
| |
| others. + indicates the presence of a well developed functioning gland. — indicates either a small vestigial gland or the absence of any rudiment.
| |
| | |
| ^ Bulbo-urethral (Cowper's), prostate, seminal vesicle and ampuUary glands.
| |
| | |
| "^ Bulbovestibular (Bartholin's) and prostate glands (para-urethral glands of Skene); genera and
| |
| species refer only to those in which functioning female prostates have been reported in the listed references.
| |
| | |
| | |
| | |
| homologous organs do not necessarily have
| |
| the same chemical functions.
| |
| | |
| Finally, there is variability among orders
| |
| of mannnals and families within orders, with
| |
| respect to the accessory glands which are
| |
| present (Table 6.1). The prostate is the
| |
| only u;land that is found almost universally.
| |
| | |
| | |
| | |
| C. SURVEY OF THE GL.4NDS
| |
| | |
| | |
| | |
| 1.
| |
| | |
| | |
| | |
| Bulbo-urethral
| |
| Glands
| |
| | |
| | |
| | |
| and Bulbovestihidar
| |
| | |
| | |
| | |
| Bulbo-urethral (Cow^per'.s). The bulbourethral glands are compound tubulo-alveolar glands resembling mucous glands in
| |
| some respects. Their secretion is a viscid
| |
| lubricant which is em])tied into the bulbar
| |
| | |
| | |
| | |
| region of the pelvic urethra. There may be
| |
| a single pair of glands as in the monotremes,
| |
| primates, and rodents, or as many as three
| |
| pairs (Fig. 6.1), as in some marsupials
| |
| (Chase, 1939; Rubin, 1944). Their relative
| |
| size, gross structure, and complexity vary
| |
| widely. For example, they are small, compact, bean-shaped glands in man, relatively
| |
| enormous, complicated glands in squirrels,
| |
| and large, cylindrical glands in the boar.
| |
| | |
| Bulbo-urethral glands are notably lacking
| |
| in Cetacea, Sirenia, and certain carnivores
| |
| such as seals, walruses, sea lions, all raustelids, and the bear and dog (Oudemans, 1892;
| |
| Engle, 1926a; Eckstein and Zuckerman,
| |
| 1956). (Oudemans made a point of the fact
| |
| that they are not present in aciuatic mam
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 369
| |
| | |
| | |
| | |
| mals, but it is rather doubtful if their absence is related to an aquatic environment.
| |
| BuLBOVESTiBULAR (Bartholin's) . The
| |
| bulbovestibular or major vestibular glands
| |
| are also compound tubulo-alveolar glands
| |
| which resemble their male homologues in
| |
| structure and secrete a mucus-like substance. Their secretory function is under
| |
| control of ovarian hormones and they involute when the ovaries are removed. They
| |
| are widely distributed in the various orders
| |
| of mammals although the information is
| |
| fragmentary with respect to some groups.
| |
| A single pair of glands is the general rule
| |
| and they are usually much smaller than the
| |
| bulbo-urethral. In the female opossum, the
| |
| single pair of glands is homologous with the
| |
| smallest of the three pairs of Cowper's
| |
| glands. In the adult, they are well developed
| |
| and filled with colloid (Rubin, 1944). In
| |
| monotremes the ducts open at the base of
| |
| the clitoris, in opossums into the urogenital
| |
| sinus canal, and in hyenas (where they are
| |
| well developed) into the urogenital canal
| |
| close to the base of the clitoris (Eckstein
| |
| and Zuckerman, 1956). In many other females the ducts open into the vestibule. In
| |
| the adult human female, Bartholin's glands
| |
| resem])le Cowper's glands closely in histologic structure.
| |
| | |
| 2. Male and Female Prostate Glands
| |
| | |
| Male prostate. The prostate is a compound tubulo-alveolar gland in which the
| |
| gross structure is variable and may be (1)
| |
| disseminate or diffuse, in which the glandular acini remain within the lamina propria
| |
| around the urethra and do not penetrate
| |
| the voluntary muscle of the urethra, (2)
| |
| a type in which the gland forms a '"body,"
| |
| sometimes lobed, outside the urethral
| |
| muscle, or (3) a combination of both types.
| |
| A disseminate prostate is found in some
| |
| marsupials (Fig. 6.1) and edentates, and
| |
| in sheep, goats, the hippopotamus, and
| |
| the whale. The bull and boar prostates have
| |
| a disseminate region as well as a discrete
| |
| body of the gland. In mammals in which
| |
| there is a glandular body, there may be a
| |
| solid, compact prostate as in the dog and
| |
| man, or several lobes as in rodents (Figs.
| |
| 6.2 and 6.3), lagomorphs (Fig. 6.4), and
| |
| insectivores.
| |
| | |
| | |
| | |
| | |
| Fig. 6.L Male opossum reproductive tract. B,
| |
| bladder; C, Cowper's glands; D, ductus deferens; E,
| |
| epididymis; P, penis; Pr, prostate I, II, III surrounding the urethra; T, Testis; U, ureter. (Redrawn from C. R. Moore, Phj'siol. ZooL, 14, 1-45,
| |
| 194L)
| |
| | |
| A prostate gland has been found in all
| |
| mammals that have been studied except
| |
| monotremes, and is the only accessory gland
| |
| in carnivores such as the ferret, weasel, dog,
| |
| and bear, and in cetaceans — whales, dolphins, and porpoises. Oudemans (1892) considered that monotremes and marsupials
| |
| lack prostate glands but possess well developed urethral glands. His classification
| |
| of glands as "urethral" (glands of Littrei
| |
| or "prostatic" depended on whether the
| |
| glandular acini remained in the urethral
| |
| stroma or penetrated the muscle to form a
| |
| | |
| | |
| | |
| 370
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| COAGULATING GLANDS
| |
| | |
| | |
| | |
| SEMINAL VESICLE
| |
| | |
| | |
| | |
| SEMINAL VESICLE
| |
| | |
| | |
| | |
| ■1%.^
| |
| | |
| | |
| | |
| | |
| AMPULLARY GLAND
| |
| DORSAL PR0STATE
| |
| VENTRAL PROSTATE
| |
| | |
| | |
| | |
| | |
| Fic. 6.2. Mule hamster accessory repidiluri i
| |
| aspect.
| |
| | |
| body outside. It is now recognized that
| |
| marsupials such as the opossum have a disseminate prostate, and in Didelphys Virginian a there are three regions which differ
| |
| | |
| | |
| | |
| 5EMINAL VESICLE
| |
| .- RIGHT
| |
| | |
| | |
| | |
| DORSAL PROSTATE
| |
| | |
| | |
| | |
| ^VENTRAL PROSTATE
| |
| | |
| | |
| | |
| gl.-inds. Above, ventral aspect; below, dor.sal
| |
| | |
| | |
| | |
| clearly in histologic structure (Chase, 1939).
| |
| It may be considered that there are three
| |
| prostatic "lobes" probably differing in function as well as in structure. Although Oude
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 371
| |
| | |
| | |
| | |
| — RIGHT SEMINAL VESICLE
| |
| | |
| | |
| | |
| COAGULATING GLAND
| |
| | |
| | |
| | |
| DORSAl
| |
| PROSTATE
| |
| | |
| LATERAL
| |
| | |
| | |
| | |
| DUCTUS
| |
| -DEFERENS
| |
| | |
| | |
| | |
| BLADDER
| |
| | |
| | |
| | |
| URETHRA
| |
| | |
| | |
| | |
| Fig. 6.3. Male guinea pig accessory reproductive glands. (From E. Ortiz, D. Price, H. G.
| |
| Williams-Ashman and J. Banks, Endocrinology, 59, 479-492, 1956.)
| |
| | |
| | |
| | |
| mans concluded that monotremes lack prostate glands, he described a concentration of
| |
| urethral glands at the neck of the bladder
| |
| in the duckbill platypus. Ornithorhyncus
| |
| poradoxicus. The diagrams in his monograph suggest that this concentration of
| |
| complicated glands is a disseminate type of
| |
| prostate.
| |
| | |
| There has been confusion in the nomenclature of the lobes of the prostate in the
| |
| rat and in the descriptions of the structure
| |
| of the lobes. In early studies the application
| |
| of human anatomic terminology to rodents
| |
| resulted in designation of the lobes as anterior (ventral), middle, and posterior (dorsal). Later terminology, more suitable for
| |
| | |
| | |
| | |
| cfuadrupedal animals, led to anterior (cranial), middle, and posterior (caudal). Unfortunately, combinations of these two systems of nomenclature still occur in the
| |
| literature, and there is uncertainty as to the
| |
| number of histologically distinguishable regions or lobes. In view of the current interest in the chemical composition of the
| |
| glands and their secretions the subject will
| |
| be reviewed.
| |
| | |
| For many years the prostate was usually
| |
| described as being composed of three pairs
| |
| of lobes: cranial or anterior (coagulating
| |
| glands) bound to the seminal vesicles; middle or dorsolateral nearly encircling the
| |
| urethra dorsolaterally, and the ^-entral or
| |
| | |
| | |
| | |
| 372
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 6.4. Rabbit accessory reproductive glands; lateral aspect. Left, domestic male; center,
| |
| cottontail male; right, cottontail female. B, bulbo-urethral gland; C, coagulating gland (vesicular gland); D, ductus deferens; P, paraprostate ; Pr, prostate; V , urethra; VC, urogenital
| |
| canal (vestibulum) ; V, vagina. (Redrawn from J. G. Elschlepp, J. Morphol., 91, 169-198,
| |
| 1952.)
| |
| | |
| | |
| | |
| lio.sterior (Moore, Price and Gallagher,
| |
| 1930; Callow and Deanesly, 1935; Price,
| |
| 1936). Korenchevsky and Dennison (1935)
| |
| noted that the histologic structure of the
| |
| dorsal lobe (or region) is quite similar to
| |
| that of the coagulating glands whereas the
| |
| lateral lobes more nearly resemble the ventral. This has been confirmed in histologic
| |
| and functional studies (Price, Mann and
| |
| Lutwak-Mann, 1955). Gunn and Gould
| |
| (1957a) reported differences in histologic
| |
| structure and functional activity in the two
| |
| lobes.
| |
| | |
| The lateral lobes can be distinguished
| |
| grossly from the dorsal by anatomic relationships and color, but the glandular lobules form a continuous mass and can be
| |
| separated into distinct lateral and dorsal
| |
| lobes only by dissection. This can be accomplished with considerable accuracy in immature males and young adults; in large
| |
| rats it is more difficult because of distention
| |
| of the alveoli and overlap of lobules in
| |
| contiguous regions. The ventral tips of the
| |
| lateral lobes extend down and partially
| |
| underlie the ventral lobes to which they are
| |
| loosely bovmd. The dorsal prostate is somewhat butterfly-shaped with a single cranial
| |
| region and wings extending caudally along
| |
| | |
| | |
| | |
| the urethra much as in the hamster (Fig.
| |
| 6.2). By dissection in the midline, it can be
| |
| divided into right and left lobes. The dorsal
| |
| and lateral prostates are drained by 50 or
| |
| more ducts opening into the roof of the prostatic urethra (Witschi, Mahoney and Riley,
| |
| 1938). Those from the dorsal region open
| |
| more dorsally; those from the lateral lobes,
| |
| laterodorsally.
| |
| | |
| Some of the confusion in prostatic terminology arises from the general application
| |
| of the word "lobe" to (1) organs that are
| |
| grossly anatomically distinct, (2) regions
| |
| that do not form entirely discrete structures
| |
| but can be distinguished histologically, (3)
| |
| ])arts of the gland which contain two histologically different portions, and (4) regions
| |
| that differ, not in histologic structure but
| |
| in response to hormones and in the tendency
| |
| to ])athologic growths (human and dog).
| |
| | |
| The lobation of the human prostate has
| |
| been the subject of controversy for some
| |
| time. It is of especial interest because one
| |
| region, the posterior or dorsal lobe, is commonly the site for prostatic carcinoma and
| |
| another, the more anterior or ventral region,
| |
| for benign prostatic hypertrophy. The lobes
| |
| have been described as posterior, anterior,
| |
| middle, and two lateral, or as posterior and
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 373
| |
| | |
| | |
| | |
| anterior, or outer and inner (medullary).
| |
| The component parts of these regions have
| |
| been discussed extensively (see Moore,
| |
| 1936; Huggins and Webster, 1948; Retief,
| |
| 1949; Franks, 1954). Lowsley (1912)
| |
| studied the embryologic development of the
| |
| human prostate and concluded that the
| |
| gland derives from five independent groups
| |
| of tubules. A cranial posterior or dorsal
| |
| group (lobe) arises from the dorsal wall of
| |
| the prostatic urethra or urogenital sinus;
| |
| right and left lateral lobes originate from
| |
| the prostatic furrows and grow back to form
| |
| the main part of the base of the gland; a
| |
| middle lobe derives dorsally from the urethra between the bladder and ejaculatory
| |
| ducts; a ventral or anterior lobe forms but
| |
| regresses and becomes insignificant.
| |
| | |
| Although these prostatic buds or tubules
| |
| form independent groups in their embryonic
| |
| origin there is no clear separation into such
| |
| groups in the human prostate postnatally.
| |
| However, Huggins and Webster (1948) were
| |
| able to distinguish clearly two different regions, a posterior and an anterior lobe, by
| |
| differential response to estrogen administration. The extent of the anterior or ventral
| |
| lobe, as delimited by them, apparently includes the tubules of the middle and lateral
| |
| lobes as described by Lowsley.
| |
| | |
| The pioneer studies of Walker (1910a) on
| |
| the coagulating function of discrete glands
| |
| of the prostatic complex in rats and guinea
| |
| pigs (Fig. 6.3) were followed by specific
| |
| identification of coagulating glands in several rodents including mice and hamsters
| |
| (Fig. 6.2) and in the rhesus monkey (van
| |
| Wagenen, 1936). However, a copulation
| |
| plug in the vagina of females has been reported in some marsupials, insectivores,
| |
| chiropterans, the chimpanzee among the
| |
| primates (Tinklepaugh, 1930), and several
| |
| genera of rodents in which coagulating
| |
| glands have not been identified. Eadie
| |
| (1948a) found that in an insectivore, Condylura cristata, there is a peculiar prostatic
| |
| secretion from paired ventral lobes. It contains an enormous number of amyloid
| |
| bodies resembling the corpora amylacea
| |
| present in the prostate gland of man and
| |
| some other mammals. These prostatic concretions are generally considered abnormal,
| |
| but Eadie suggested that this unusual se
| |
| | |
| | |
| cretion, which was found in all breeding
| |
| males, might be instrumental in the formation of a unique type of copulation plug.
| |
| A large ''urethral" gland which lies between the prostate and bulbo-urethral
| |
| glands and surrounds the urethra is peculiar
| |
| to certain species of bats. Mathews (1941)
| |
| considered it probable that the presence of
| |
| this gland is correlated with the formation
| |
| of a large copulation plug, but he did not
| |
| ascribe a specific coagulating function to
| |
| the gland (which bears a histologic resemblance to the bulbo-urethral glands in some
| |
| bats).
| |
| | |
| The difficulties of homology and classification can be illustrated by the case of the
| |
| rabbit. Differences of opinion have existed
| |
| concerning the nomenclature and homologies of the seminal vesicles (or prostatic
| |
| utricle), vesicular glands (seminal vesicle
| |
| or prostate), and paraprostate glands (or
| |
| superior Cowper's glands). In studies on
| |
| embryologic development and histologic
| |
| structure, Bern and Krichesky (1943) clarified the problem. They established that the
| |
| domestic rabbit has true seminal vesicles,
| |
| vesicular glands (which are considered as
| |
| probably homologous with the coagulating
| |
| glands of rats), prostates, paraprostates
| |
| (usually similar to the bulbo-urethrals in
| |
| histologic structure but in about one-third
| |
| of the cases, one or more of the paraprostates resembled the prostate histologically),
| |
| bulbo-urethral glands, and glandular ampullae. Elschlepp (1952) compared the accessory glands of the cottontail, Sylvilagus
| |
| floridamis, with those of the domestic rabbit, and concluded that coagulating glands
| |
| (avoiding the usage of "vesicular glands"
| |
| which has often been used synonymously
| |
| with seminal vesicles) , dorsal prostates, and
| |
| bulbo-urethral glands are homologous in
| |
| the two species. The adult cottontail has
| |
| neither paraprostates nor seminal vesicles
| |
| (Fig. 6.4) . Classification of the glands in the
| |
| hedgehog and shrew has also presented
| |
| problems (see discussion in Eckstein and
| |
| Zuckermann, 1956; Eadie, 1947). Among the
| |
| Sciuridae, many possess a bulbar gland
| |
| which differs from their true Cowper's
| |
| glands (Mossman, Lawlah and Bradley,
| |
| 1932). It is evident that among mammals
| |
| | |
| | |
| | |
| 374
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| there are many potentialities for forming
| |
| accessory glands with varied anatomic
| |
| structure, histologic characteristics, and
| |
| functional activities.
| |
| | |
| Female prostate. In fetuses of many female mammals, small cords of cells which
| |
| represent the homologues of the male prostate bud off from the epithelial lining of the
| |
| urethra. These primordia normally retrogress or remain vestigial and only rarely
| |
| continue to develop after birth. In the human female, these rudimentary structures
| |
| are known as para-urethral glands of Skene.
| |
| They have also been referred to as periurethral glands. However, it seems advisable, as Witschi, Mahoney and Riley (1938)
| |
| suggested, to restrict the usage para-urethral and peri-urethral to the aggregations
| |
| of mucus-secreting glands that have short
| |
| ducts opening into the urethra. These clearly
| |
| differ from the true female prostate glands.
| |
| | |
| In contrast to the rudimentary prostate
| |
| glands which are retained postnatally by
| |
| some female mammals, relatively large, well
| |
| developed female prostates have been reported postnatally in some insectivores,
| |
| chiropterans, rodents, and lagomorphs. The
| |
| male accessory glands of many species in
| |
| these orders are exceptionally well developed and the prostates are usually lobed.
| |
| Female prostates are tubulo-alveolar glands,
| |
| as are their male homologues, and they too
| |
| form lobes, but the glands are never as
| |
| large as those of the male. Their secretory
| |
| activity is apparently dependent mainly on
| |
| ovarian androgens, but the function, if any,
| |
| of the secretion is obscure. Extensive research has shown that the administration of
| |
| androgens to rodents, either to pregnant females or fetuses, to fetal lagomorphs, and
| |
| to pouch-young oppossums, results in the
| |
| formation and retention of prostates in females which normally do not have such
| |
| glands (see chapter by Burns).
| |
| | |
| Deanesly (1934) described vaginal glands
| |
| in the female hedgehog and suggested that
| |
| one pair is homologous with the external
| |
| prostates of the male. The female glands extend dorsolaterally on either side of the urethra and a single duct from each lobe opens
| |
| into the vagina. They seem to be active
| |
| during the breeding season and to retrogress
| |
| in the anestrum. In another insectivore,
| |
| | |
| | |
| | |
| Hemicentetes, there is a pair of large
| |
| "paravaginal glands" which are functionally active in the mature female and have
| |
| large acini filled with secretion. They resemble the male prostate in histologic structure and anatomic position, but have no
| |
| ducts (Lehmann, 1938). In adult European
| |
| moles, most females have bilobed ventral
| |
| prostate glands which undergo cyclic
| |
| changes in the epithelium. The prostate of
| |
| the male is also bilobed and ventral in position and the homology in the two sexes is
| |
| clear (Godet, 1949).
| |
| | |
| Mathews (1941) studied the anatomy and
| |
| histophysiology of the male and female genital tracts of nine species of African bats.
| |
| Female prostates are well developed in four
| |
| species, less conspicuous in a fifth, and absent from the remaining four. There is a
| |
| marked tendency for greater development
| |
| of the glands in pregnant and lactating females. In three species, the female prostates
| |
| surround the urethra (as do their male homologues), but in Nycteris luteola the female prostate appears ventrally, whereas
| |
| the male prostate in this species is limited
| |
| to the dorsal aspect of the urethra. Mathews
| |
| considered that the female prostates represent greatly enlarged female urethral glands
| |
| which are homologous with the male ])yostate.
| |
| | |
| The occurrence of female prostates and
| |
| their relation to hormones have been most
| |
| extensively studied in rodents. The first description of a well developed female prostate gland seems to be that of Rauther
| |
| (1909), who found such a gland ventral to
| |
| the neck of the bladder in the African field
| |
| rat, Arvicanthis cinereus. In Rattus norvegicus, Marx (1931, 1932) reported the
| |
| sporadic occurrence of female prostates.
| |
| Korenchevsky and Dennison (1936) and
| |
| Korenchevsky (1937) found prostates in 9
| |
| of 56 females and stated that the glands
| |
| wei'c atrophic, but when androgens were administered, these glands resembled the
| |
| male ventral prostate. On this basis, the
| |
| homology of the glands of the female with
| |
| the \-entral prostate of the male was suggested. Further studies (Witschi, Mahoney
| |
| and Riley, 1938; Mahoney, 1940, 1942; Malioney and Witschi, 1947) showed that the
| |
| female prostate of the rat is homologous
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 375
| |
| | |
| | |
| | |
| with only the most medioventral part of the
| |
| male prostate ; the lobes are bilateral or unilateral, with the right the preferred side;
| |
| each lobe has a single duct which opens into
| |
| the urethra. The incidence of female prostates varies markedly in different strains,
| |
| and can be increased by selective inbreeding, w^iich also increases the occurrence of
| |
| bilateral compared with unilateral lobes.
| |
| The frequency of female prostates was increased in the Wistar stock from 28 to 99
| |
| per cent, but when selective inbreeding was
| |
| stopped, the frequency declined.
| |
| | |
| In young untreated female rats, the prostate, when present, develops a histologic
| |
| structure identical with that of the male
| |
| homologue, but at about 6 weeks of age the
| |
| epithelium undergoes regression (Price,
| |
| 1939; Mahoney, 1940) and becomes histologically well developed again only during
| |
| pregnancy and lactation (Burrill and
| |
| Greene, 1942; Price, 1942). Thus, the female prostate of the rat is not only homologous with a part of the ventral prostate of
| |
| the male on the basis of embryologic development, but during early postnatal development and in periods of pregnancy and
| |
| lactation it resembles its male homologue
| |
| histologically (Fig. 6.46). In addition, it is
| |
| functionally equivalent (see Section II) to
| |
| the male ventral prostate in the secretion
| |
| of citric acid (Price, Mann and LutwakMann, 1949).
| |
| | |
| Brambell and Davis (1940) found large,
| |
| well developed prostate glands in every one
| |
| of 104 female African mice, Mastonujs
| |
| erythroleucus Temm. These glands consist
| |
| of paired lobes, each draining into the
| |
| urethra by a single duct. They resemble the
| |
| ventral prostate of the male in position,
| |
| shape, and histologic structure. On the basis of this evidence it was concluded that
| |
| the female glands are the homologues of the
| |
| male ventral prostate. In some cases, the
| |
| female prostates are nearly as large as their
| |
| male homologues and are actively secretory. Brambell and Davis correlated hypertrophy and secretory activity with the luteal phase of the cycle and gestation.
| |
| | |
| Female prostate glands have also been described in the field mouse, Apodemns sylvaenms sylvaticus. Raynaud (1942, 1945)
| |
| found bilobed prostates in 51 immature and
| |
| | |
| | |
| | |
| adult females collected in the vicinity of
| |
| Vabre (Tarn) and in 3 females from three
| |
| other regions of France. However, the lobes
| |
| were macroscopically visible in only 10 females; in all others, the glands were identified in histologic preparations. There w^as
| |
| great variability in histologic structure, but
| |
| a well developed epithelium showing secretory activity was found during pregnancy
| |
| and lactation. Raynaud established that the
| |
| female prostate is homologous with a part
| |
| of the male ventral prostate. He concluded
| |
| that there is a probability that bilobed female prostates exist normally in all females
| |
| of Apodemus sylvaticus.
| |
| | |
| The prostate glands in adult female field
| |
| voles, Microtiis arvalis P., are considered
| |
| homologous with the ventral lobes and part
| |
| of the lateral lobes of the male prostate
| |
| (Delost, 1953a, b). The lobes in the female
| |
| are lateral in position in part of the gland,
| |
| but in other regions they completely surround the urethra. The structure is identical
| |
| with that of the ventral prostate of the male.
| |
| The epithelium appears secretory in normal
| |
| adult females, and during gestation this activity is intense.
| |
| | |
| Bilobed female prostates were found in
| |
| the 37 adult cottontail rabbits examined by
| |
| Elschlepp (1952). They lie on the dorsal
| |
| wall of the vagina (Fig. 6.4) and are similar histologically to the prostate of the male.
| |
| The glands are larger in pregnant than in
| |
| nonpregnant females and contain more secretion.
| |
| | |
| In summary, well developed female prostate glands are present in immature and
| |
| adult females of many species. They may
| |
| occur as ventral, lateral, or dorsal lobes; the
| |
| lobes may be unilateral or consistently bilateral; their occurrence may be sporadic
| |
| or reach an incidence of 100 per cent; they
| |
| are found both in laboratory strains and in
| |
| wild populations. The genetic studies of
| |
| Witschi and his collaborators show that the
| |
| incidence in rodents can be increased by
| |
| selective inbreeding. In certain populations
| |
| of wild rodents the character has become
| |
| established. A striking example of this is the
| |
| presence of large prostates in all female
| |
| Masto)7iys erythroleucus. The secretory activity of the glands seems to be controlled
| |
| mainly by ovarian androgens (sec Section
| |
| | |
| | |
| | |
| 376
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| III) . No function can be ascribed to the secretion.
| |
| | |
| 3. Seminal Vesicles
| |
| | |
| The seminal vesicles are paired, usually
| |
| elongated glands which may appear relatively simple externally (Figs. 6.2 and 6.3)
| |
| but are subdivided internally by complicated villous projections. The name refers
| |
| to an old misconception that they are sperm
| |
| reservoirs. The seminal vesicles are relatively enormous and distended with secretion in some mammals, for example, the rat,
| |
| guinea pig, and hamster; they are large in
| |
| others such as the boar, and in still others,
| |
| as in man, they are small and compact.
| |
| | |
| Seminal vesicles are absent from the monotremes, marsupials, carnivores, and cetaceans that have been studied, and from some
| |
| insectivores, chiropterans, primates, and
| |
| lagomorphs. Variability exists among the
| |
| edentates ; the sloths and the armadillo have
| |
| seminal vesicles which are well developed
| |
| in the two-toed sloth and armadillo, but
| |
| are very small and rudimentary in the
| |
| three-toed sloth. Among the lagomorphs, the
| |
| seminal vesicle of the domestic male rabbit
| |
| is a large unpaired gland whereas the seminal vesicles in the adult cottontail rabbit
| |
| are vestigial or absent although they develop for a time in the fetus (Elschlepp,
| |
| 1952).
| |
| | |
| 4- Ampullary Glands
| |
| | |
| These organs are glandular enlargements
| |
| arising from the ampullae of the ducti
| |
| cleferentes or the posterior region of the
| |
| ductus if a distinct ampullary enlargement
| |
| is not present. They may be only slight
| |
| glandular enlargements of the wall, or discrete glands which nearly encircle the ductus deferens as in rats, some mice, and hamsters (Fig. 6.2). They are vestigial in
| |
| certain pure line strains of mice (Horning,
| |
| 1947) and lacking in guinea pigs (Fig. 6.3).
| |
| In some bats, they attain very large size. In
| |
| general, they are absent from many mammalian orders and variable in others (Table
| |
| 6.1).
| |
| | |
| D. EVOLUTIONARY HISTORY OF ACCESSORY
| |
| REPRODUCTIVE GLANDS OF MAMMALS
| |
| | |
| The well developed male accessory glands
| |
| which characterize the niamnialiaii class as
| |
| | |
| | |
| | |
| a whole, and form such a conspicuous part
| |
| of the reproductive tract in most mammals,
| |
| are not found in nonmammalian vertebrates.
| |
| These glands appear as anatomically distinct organs in the primitive prototherian
| |
| mammals, the monotremes, which are definitely mammalian but which also retain
| |
| certain anatomic characteristics of their
| |
| reptilian ancestors and still lay shelled eggs.
| |
| However, it has been suggested that in the
| |
| evolution of the three groups of living mammals from mammal-like reptiles, the line of
| |
| descent of monotremes is entirely separate
| |
| from that of marsupials and placentals.
| |
| Furthermore, the last two groups are probably parallel branches of the mannnalian
| |
| stock.
| |
| | |
| The accessory glands of modern mammals represent, then, the parallel evolution
| |
| of discrete glands that probably began their
| |
| development very early in the evolutionary
| |
| history of mammals. In gross structure, size,
| |
| and internal complexity they are unique
| |
| accessory organs among vertebrates. Modern reptiles have no such glands; the seminal plasma is composed mainly of secretions
| |
| from the epididymis and the renal tubules
| |
| of the sexual segment of the long, lobulated
| |
| kidney. Both these regions become highly
| |
| secretory during the breeding season (see
| |
| chapter by Forbes) . Parenthetically, the semen of birds (a later offshoot from the reptilian line than mammals) contains only a
| |
| small amount of seminal plasma (Mann,
| |
| 1954a) which is secreted in the cock almost
| |
| entirely by the seminiferous tubules and
| |
| vasa efferentia (Lake, 1957). In modern
| |
| mammals, the epididymal epithelium is
| |
| still an important accessory secretory area
| |
| (see chapter by Bishop) , but the bulk of the
| |
| seminal plasma comes from glandular elaborations of quite different regions, the urogenital sinus (a derivative of the primitive
| |
| cloaca) and the posterior part of the Wolffian ducts, the ducti deferentes.
| |
| | |
| Modern monotremes are specialized forms
| |
| but in certain characteristics they are primitive. They show almost diagramatically
| |
| some of the first steps in the evolution of
| |
| accessory glands. The bulbo-urethrals are
| |
| already well developed but the concentration of complicated urethral glands at the
| |
| neck of the bladder in the duckbill platypus
| |
| almost certainlv illustrates the derivation
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 877
| |
| | |
| | |
| | |
| of a specialized gland (the prostate) from
| |
| simpler glands which are nmnerous along
| |
| the urethra. The probable evolution of prostates and bulbo-urethral glands from
| |
| smaller, simpler urethral glands has been
| |
| suggested in the past. Observations of
| |
| Bruner and Witschi (1946) support this
| |
| concept. In experiments on fetal hamsters,
| |
| it was found that masculinized females developed prostate glands but the ducts
| |
| joined the collecting ducts of the urethral
| |
| glands and did not open directly into the
| |
| urogenital sinus. According to these workers, this may represent an intermediate
| |
| stage in the development of specialized
| |
| glands.
| |
| | |
| The history of the cloaca may well be important in relation to development of accessory glands (Retief, 1949). The cloaca is
| |
| retained in modern reptiles; in monotremes
| |
| it is subdivided cranially into ventral urodeum or urogenital sinus and a dorsal coprodeum; it is represented by a pocket in marsupials but is lost as a discrete structure in
| |
| all higher mammals. The first development
| |
| of a separate urogenital duct or urethra as
| |
| it occurs in monotremes may be correlated
| |
| with the first appearance of discrete accessory glands from this specific region in
| |
| mammals.
| |
| | |
| The marsupials illustrate a more advanced type of glandular development with
| |
| three histologically distinguishable regions
| |
| in the disseminate prostate and three pairs
| |
| of bulbo-urethral glands. Seminal vesicles
| |
| and ampullary glands are found only among
| |
| higher mammals.
| |
| | |
| The size and structural complexity of
| |
| these unique glands in mammals raises the
| |
| question of the adaptive value of relatively
| |
| large accessory glands associated with the
| |
| mammalian reproductive tract. This is a
| |
| matter only for speculation. The evolution
| |
| of such glands with increased surface for
| |
| secretion and enlarged storage space may,
| |
| perhaps, have been correlated with a tendency for an increase in volume of seminal
| |
| plasma in the ejaculate of mammals. Mann
| |
| (1954a) pointed out the variability in the
| |
| volume of ejaculated semen and in the
| |
| sperm density in various species. With regard to the volume of seminal plasma, he
| |
| stated, "In lower animals it may be so
| |
| scarce that the emitted semen takes the
| |
| | |
| | |
| | |
| form of a very thick lump of spermatozoa,
| |
| closely packed together. There is little seminal plasma in bird semen and even among
| |
| some of the mammals, but on the whole, the
| |
| higher mammals including man, produce a
| |
| relatively dilute semen with a considerable
| |
| l)roportion of seminal plasma." A second
| |
| suggestion, more speculative, is that the
| |
| evolution of large mammalian glands may
| |
| also have compensated for loss of accessory
| |
| reproductive function in the kidney. The
| |
| kidney of mammal-like reptiles and ancestral mammals may have contributed to the
| |
| formation of seminal plasma (as is true in
| |
| modern reptiles, amphibians, and fishes),
| |
| but the compact kidney of warm-blooded,
| |
| metabolically active mammals may be ill
| |
| adapted for such a purpose.
| |
| | |
| II. Function of the Male
| |
| Accessory Glands
| |
| | |
| A. INTRODUCTION
| |
| | |
| The only known function of the male accessory glands is to secrete the seminal
| |
| plasma. The proportion of this fluid which
| |
| originates from the various secretory organs, or even from different lobes of the
| |
| same gland, varies greatly from one species
| |
| to another. There is also remarkable species
| |
| variation in the volume and composition of
| |
| the individual secretions. The functional
| |
| activity of the accessory glands is governed
| |
| primarily by hormones of testicular origin.
| |
| The output of androgens is subject to the
| |
| control of the anterior hypophysis, and
| |
| many factors (e.g., age, light, season, temperature, and diet) affect the secretory activity of the hypophysis and testis. Thus, it
| |
| is not surprising that in a given individual,
| |
| there may be marked fluctuations in the
| |
| cjuantity and chemistry of the secretions of
| |
| the accessory glands, and hence of the seminal plasma.
| |
| | |
| The development by Charles Huggins of
| |
| ingenious surgical procedures enabled the
| |
| secretory activity of the canine prostate to
| |
| be measured by simple volumetric methods.
| |
| Such studies of prostatic secretion in the
| |
| dog established the quantitative relationships between the function of prostatic epithelium and the androgenic status of the
| |
| host. In other species, serial collection of the
| |
| individual secretions in the same animal
| |
| | |
| | |
| | |
| 378
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| has not been achieved for purely technical
| |
| reasons. The use of "split ejaculates" has
| |
| given some insight into the glandular origin
| |
| of various conii)oncnts of the seminal
| |
| plasma, but this techniciue does not provide
| |
| uncontaminated secretions from any one
| |
| gland. However, in the last two decades extensive analyses of the chemical and enzymatic constituents of the individual secretions stored in the accessory glands, and of
| |
| the whole seminal plasma, have been performed. The levels of many of these substances and enzymes are dependent on androgenic hormones. These findings have
| |
| provided a basis for sensitive chemical
| |
| methods for the bioassay of androgens.
| |
| Moreover, knowledge of the biosynthesis of
| |
| these substances by the accessory glands
| |
| may point to the primary biochemical locus
| |
| of action of androgenic steroids. This chemical approach to the study of the accessory
| |
| glands has received great impetus from the
| |
| pioneer studies of Thaddeus Mann.
| |
| | |
| The secretions of the accessory glands of
| |
| many species are a repository for huge
| |
| Cjuantities of substances which are present
| |
| only in trace amounts in other tissues and
| |
| body fluids. It is obvious that the seminal
| |
| plasma must provide an ionically balanced
| |
| and nutritive milieu suitable for the survival of sperm in the vagina and uterus.
| |
| Certain substances secreted by one or more
| |
| of the accessory glands, e.g., fructose, undoubtedly serve as a source of energy for
| |
| the sperm. However, there is no evidence
| |
| that any component of mammalian seminal
| |
| plasma, or any one of the accessory glands,
| |
| is absolutely indispensable for fertility. Artificial insemination is successful in some
| |
| mammals if sperm from the epididymis are
| |
| diluted in a suital)ly prepared medium,
| |
| placed in a female in the correct stage of the
| |
| estrous cycle, and deposited in a region of
| |
| th(; female tract where there is maximal
| |
| opiiortunity for their successful ascent. Removal of the coagulating glands in guinea
| |
| l)igs (Engle, 1926b) , or dorsolateral prostate
| |
| (Gunn and Gould, 1958) in rats does not
| |
| prevent insemination and fertilization. Blandau (1945) extirpated the seminal vesicles
| |
| and coagulating glands of rats and found
| |
| that when these males were mated there was
| |
| no copulation plug and, evidently as a result, the spermatozoa did not penetrate the
| |
| | |
| | |
| | |
| vaginal canals of the females. Thus the secretions of the coagulating gland and seminal vesicles in the rat assist the transport
| |
| of sperm in the female.
| |
| | |
| The following section will consider the
| |
| output and composition of the secretions,
| |
| and their hormonal regulation, primarily
| |
| from a chemical standpoint, rather than in
| |
| relation to the anatomy and embryology of
| |
| the structures from which they originate.
| |
| | |
| B. VOLUMETRIC (STUDIES OF SECRETION
| |
| | |
| 1. Prostatic Isolation Operation
| |
| | |
| Volumetric studies of the secretion of
| |
| canine prostatic fluid have yielded great insight into the factors which determine the
| |
| functional activity of male accessory glands.
| |
| The dog is devoid of both seminal vesicles
| |
| and bulbo-urethral glands, and if the urine
| |
| is suitably deviated, practically pure prostatic secretion can be collected from the
| |
| urethra. Eckhard (1863) ligated the neck
| |
| of the bladder of dogs and obtained prostatic fluid by urethral catheterization. This
| |
| technique was used by a number of investigators to study the secretory activity of the
| |
| i:)rostate gland (Mislawsky and Bormann,
| |
| 1899; Sergijewsky and Bachromejew, 1932;
| |
| Winkler, 19311. A superior modification of
| |
| the operation was introduced by Farrell
| |
| (1931, 1938; Farrell and Lyman, 1937). The
| |
| output of prostatic fluid was increased
| |
| greatly either by electrical stimulation of
| |
| the nervus erigens or by the injection of
| |
| cholinergic drugs such as pilocarpine. These
| |
| early prostatic isolation operations suffered
| |
| from the signal disadvantage that, for
| |
| technical reasons, they permitted only brief
| |
| experiments.
| |
| | |
| In 1939, Huggins, Masina, Eichelberger
| |
| and Wharton developed a simple surgical
| |
| procedure which enabled frequent collection
| |
| of canine prostatic secretion over long
| |
| l)eriods of time. The original technique was
| |
| modified slightly by Huggins and Sommer
| |
| (1953) and is depicted in Figure 6.5. The
| |
| bladdei' is separated from the prostate
| |
| gland, the urine voided through a supral)ubic canula, and the animals circumcised.
| |
| Healing was complete within one week after
| |
| surgery, and the animals were maintained in
| |
| good health. Prostatic fluid could be collected at fre(iucnt intervals for as long as
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 379
| |
| | |
| | |
| | |
| two years. Normal adult dogs were found
| |
| to secrete 0.1 to 0.2 ml. of prostatic fluid per
| |
| hour without external stimulation. Following the administration of pilocarpine, the
| |
| canine prostate secreted as much as four
| |
| times its weight of fluid (60 ml.) in one
| |
| hour. The amount of secretion obtained in
| |
| response to a standard dose of pilocarpine remained relatively constant for three
| |
| months or more, and bore no direct relationship to the weight of the gland. The volume
| |
| and composition of the fluid varied with the
| |
| time and intensity of the cholinergic stimulus. Huggins (1947c) found that, after a
| |
| single intravenous injection of pilocarpine,
| |
| the volume and the content of total protein, certain enzymes (acid phosphatase, fSglucuronidase and fibrinogenase ) , and citrate were maximal in the first 15 minutes,
| |
| then declined progressively in three succeeding quarter-hour periods. But the chloride
| |
| content always rose initially from the low
| |
| values of the resting secretion and reached
| |
| maximal levels after the first 15-minute
| |
| period. If the drug was administered intramuscularly, maximal values for total protein and citrate were found in the first period, whereas those for the volume and
| |
| enzyme content were higher in the second
| |
| and third periods. It was concluded from
| |
| experiments involving the repeated intravenous injection of pilocarpine that acid
| |
| phosphatase and fibrinogenase were definitely secreted and not simply washed out
| |
| of the gland. However, a "washing out"
| |
| process does occur after an initial stimulus
| |
| with respect to total protein and citrate
| |
| levels.
| |
| | |
| It was observed by Huggins, Masina,
| |
| Eichelberger and Wharton (1939) that infectious diseases {e.g., pyelonephritis, distemper) often decreased the volume of
| |
| stimulated fluid. This effect seemed to be
| |
| due to inhibition of the hypophysis, because
| |
| it could be overcome by injection of gonadotrophin. Soon after castration (7 to 23 days)
| |
| the secretion ceased and was restored by the
| |
| administration of testosterone propionate.
| |
| Androgens also initiated secretion in immature animals. In castrate dogs maintained on
| |
| testosterone, neither adrenalectomy nor removal of the thyroid and parathyroid glands
| |
| affected the rate of prostatic secretion.
| |
| Huggins (1947c) observed that in normal
| |
| | |
| | |
| | |
| | |
| Fig. 6.5. The canine prostatic isolation operation.
| |
| The connection of the prostatic urethra with the
| |
| bhulder has been severed and the prostatic secretion is collected by way of the penis. (From C.
| |
| Huggins and J. L. Sommer, J. Exper. Med., 97, 663680, 1953.)
| |
| | |
| animals, secretion was unaffected by injection of either progesterone or desoxycorticosterone.
| |
| | |
| Cystic hyperplasia of the prostate occurs
| |
| in many senile dogs. The volume of fluid
| |
| secreted by such hypertrophied glands in
| |
| response to pilocarpine was smaller than
| |
| that obtained from young adult animals
| |
| (Huggins and Clark, 1940).
| |
| | |
| Injection of diethylstilbestrol into normal
| |
| adult dogs abolishes prostatic secretion. Administration of gonadotrophin restores secretion in such estrogen treated animals,
| |
| which suggests that the primary effect of
| |
| estrogens under these conditions is on the
| |
| hypophysis (Huggins, 1947c). Estrogens
| |
| also antagonize the stimulatory effects of
| |
| injected androgens. In castrate dogs receiving testosterone, injection of large doses
| |
| of diethylstilbestrol decreases the output of
| |
| prostatic fluid to very low levels (Huggins
| |
| | |
| | |
| | |
| 380
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| and Clark, 1940). The neutralization of
| |
| androgen action by estrogens in this situation is pronounced but not complete. Thus
| |
| the acid phosphatase activity of prostatic
| |
| fluid collected from animals treated with
| |
| both testosterone propionate and diethylstilbestrol is of the same order of magnitude
| |
| as that of normal secretion, despite the fact
| |
| that the volume of the secretion is extremely low (Huggins, 1947c). The ratio
| |
| of diethylstilbestrol recjuired to antagonize
| |
| maximally the action of testosterone was
| |
| found to be about 1 : 25. In dogs with either
| |
| normal or cystic prostate glands, injection
| |
| of amounts of estrogen sufficient to decrease
| |
| prostatic secretion leads to shrinkage of the
| |
| prostate. Large doses of estrogen cause the
| |
| canine prostate gland to enlarge ; the dorsal
| |
| segment undergoes squamous metaplasia
| |
| and the ventral lobe becomes atrophic
| |
| (Huggins and Clark, 1940; Huggins, 1947c).
| |
| If both estrogen and androgen are administered simultaneously, the dorsal region becomes squamous and the ventral portion of
| |
| the gland retains its columnar epithelium,
| |
| although the volume of the prostatic secretion may be drastically reduced.
| |
| | |
| | |
| | |
| | |
| Fig. 6.6. The c-anine prostatic translocation operation. (From C. Huggins and J. L. Sommer, J.
| |
| Exper. Med., 97, 663-680, 1953.)
| |
| | |
| | |
| | |
| 2. Prostatic Translocation Operation
| |
| | |
| Huggins and Sommer (1953) transposed
| |
| the prostate gland of the dog from its natural position to the perineum, as depicted in
| |
| Figure 6.6. This procedure permitted the
| |
| size of the prostate to be measured in the
| |
| living animal, and provided prostatic fluid
| |
| quite uncontaminated with other material.
| |
| Pilocarpine was used as a secretory stimulus. Using this technique, Huggins and Sommer found that the effects of androgens and
| |
| estrogens on prostatic size and secretion
| |
| were similar to those obtained with dogs
| |
| that had undergone the prostatic isolation
| |
| operation.
| |
| | |
| C. CHEMICAL COMPOSITION OF THE
| |
| GLANDULAR SECRETIONS
| |
| | |
| Electrolytes. Water is the main constituent of prostatic and seminal vesicle secretions and of seminal plasma, all of which
| |
| are approximately iso-osmotic with respect
| |
| to blood serum. The vesicular secretion is
| |
| usually more alkaline than the prostatic secretion and has a higher dry weight, mainly
| |
| because it contains more protein. The electrolyte content of the secretions varies
| |
| widely between different species (Huggins,
| |
| 1945; Mann, 1954a). In general, sodium is
| |
| the main cation, although this is not true of
| |
| boar vesicular secretion which is very rich
| |
| in potassium. Chloride tends to be the main
| |
| anion in those species whose accessory gland
| |
| secretions do not contain large amounts of
| |
| citrate. In this connection it is instructive
| |
| to compare the resting prostatic fluid of
| |
| man, and the pilocarpine-stimulated prostatic fluid of the dog (Huggins, 1945, 1947c).
| |
| The human secretion has a much greater
| |
| citrate and calcium content, and a much
| |
| smaller chloride level than the corresponding canine fluid, although the total concentration of osmotically active substances is of
| |
| the same order of magnitude in both secretions.
| |
| | |
| Zinc. Berti'aiid and X'hidesco (1921 » found
| |
| large amounts of zinc in human semen. The
| |
| highest concentration of zinc is present in
| |
| the first fraction of the ejaculate, which is
| |
| largely prostatic secretion (Mawson and
| |
| Fischer, 1953). In the rat, the zinc content
| |
| of the dorsolateral prostate is especially
| |
| lii<i;li (.Mawson and Fisclicr, 1951 ). After in
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 381
| |
| | |
| | |
| | |
| tracardiac injection, Zn*'^ is concentrated by
| |
| this tissue 15 to 25 times more than any
| |
| other organ, including the ventral prostate
| |
| (Gunn, Gould, Ginori and Morse, 1955).
| |
| The dorsolateral prostate of the rat consists
| |
| of two parts which are functionally and anatomically distinct, and only the lateral
| |
| portion concentrates Zn*'^ (Gunn and Gould,
| |
| 1956a, 1957a). A rapid uptake of Zn^'s by
| |
| slices of the rat dorsolateral prostate in
| |
| vitro has been noted by Taylor (1957) .
| |
| | |
| The zinc content of the rat dorsolateral
| |
| prostate, and its uptake of Zn*'^, are under
| |
| hormonal control. The concentration of zinc
| |
| in this gland increases 6- to 10-fold between
| |
| the 35th and 100th day of life (Fischer, Tikkala and IMawson, 1955). In the adult rat,
| |
| Gunn and Gould (1956b) observed a
| |
| marked decrease in Zn^^ uptake after castration, which could be prevented by androgen treatment. In immature (Alihar,
| |
| Elcoate and JNIawson, 1957) and hypophysectomized (Gunn and Gould, 1957b) animals, the administration of testosterone or
| |
| gonadotrophin increased the zinc levels and
| |
| the rate of Zn*'^ uptake, whereas estradiol
| |
| was ineffective.
| |
| | |
| The physiologic function of the zinc in
| |
| seminal plasma is problematical. This metal
| |
| is an integral component of the enzyme
| |
| carbonic anhydrase. The distribution of
| |
| carbonic anhydrase among the various lobes
| |
| of the prostate gland was studied by Mawson and Fischer (1952). In the rat, the posterior prostate contains about the same
| |
| amount of carbonic anhydrase as the erythrocytes, whereas the ventral prostate contains very little of this enzyme. The lateral
| |
| portion of the posterior prostate contains
| |
| about 6 times as much zinc as the median
| |
| part. But only a small portion of the zinc
| |
| in the rat dorsolateral prostate, and in human semen, can be accounted for as carbonic anhydrase (Mawson and Fischer,
| |
| 1953). According to Gunn and Gould
| |
| (1958), dorsolateral prostatectomy, which
| |
| removes most of the zinc from semen, is
| |
| without influence upon either fecundity or
| |
| fertility in the rat.
| |
| | |
| Fructose. The presence of a reducing and
| |
| yeast-fermentable sugar in mammalian semen has been known for some time (McCarthy, Stepita, Johnston and Killian, 1928;
| |
| | |
| | |
| | |
| Huggins and Johnson, 1933). It was assumed by early workers that this sugar was
| |
| glucose. Although Yamada (1933) reported
| |
| that human semen contained a sugar which
| |
| reacted as a ketose, it was not until 1945
| |
| that the nature of the main reducing sugar
| |
| in most mammalian semens was elucidated
| |
| by Thaddeus Mann. Using a highly specific
| |
| enzymatic method of estimation, Mann
| |
| (1946) showed that the semen of men and
| |
| many other mammals contains little or no
| |
| glucose. The reducing and yeast-fermentable
| |
| sugar of bull seminal plasma was isolated in
| |
| the pure state and identified as d( — ) -fructose on the basis of its optical rotation and
| |
| formation of methylphenyl fructosazone.
| |
| | |
| Mann (1949) found fructose in the semen
| |
| of the bull, ram, boar, goat, opposum, rabbit, guinea pig, mouse, hamster, and man.
| |
| It is also present in the European mole
| |
| iTalpa) and hedgehog {Erinaceus) (Mann,
| |
| 1956). Table 6.2 shows that the fructose
| |
| content of semen varies greatly from one
| |
| species to another. In the five species indicated, the total fructose accounts for all
| |
| the yeast-fermentable carbohydrate present, but these species also contain nonfermentable sugars. The semen of some animals contains glucose. This is true of the
| |
| rabbit, in which both glucose and fructose
| |
| are detectable (]\lann and Parsons, 1950),
| |
| and the cock (Mann, 1954a), the semen of
| |
| which is devoid of fructose. Ketoses other
| |
| than fructose are found in certain semens.
| |
| For example, the vesicular and ampullar
| |
| secretions of the stallion possess carbohydrates which react in colorimetric tests as
| |
| | |
| TABLE 6.2
| |
| Reducing sugars of semen
| |
| Values obtained from Mann (1946) and expressed in terms of milligrams of fructose per 100
| |
| ml. of semen.
| |
| | |
| | |
| | |
| Species
| |
| | |
| | |
| Total
| |
| | |
| Reducing
| |
| | |
| Sugar
| |
| | |
| | |
| Fructose
| |
| | |
| | |
| Yeast
| |
| Fermentable Sugar
| |
| | |
| | |
| Nonfer
| |
| mentable
| |
| | |
| Sugar
| |
| | |
| | |
| Bull
| |
| | |
| | |
| 937
| |
| 443
| |
| 528
| |
| 295
| |
| 31
| |
| | |
| | |
| 910
| |
| 340
| |
| | |
| 417
| |
| | |
| 141
| |
| | |
| 9
| |
| | |
| | |
| 917
| |
| | |
| 370
| |
| | |
| 411
| |
| | |
| 144
| |
| | |
| 10
| |
| | |
| | |
| 25
| |
| | |
| | |
| Ram
| |
| | |
| | |
| 73
| |
| | |
| | |
| Rabbit"
| |
| | |
| | |
| 117
| |
| | |
| 149
| |
| | |
| | |
| Boar
| |
| | |
| | |
| 21
| |
| | |
| | |
| | |
| " Small amounts of glucose were occasionallj'
| |
| fovmd in rabbit semen by Mann and Par.-ons
| |
| (1950).
| |
| | |
| | |
| ketoses, but cannot be fructose as they are
| |
| not fermented by yeast (Mann, Leone and
| |
| Polge, 1956) .
| |
| | |
| In most mammals, fructose is formed
| |
| mainly in the seminal vesicles (Huggins and
| |
| Johnson, 1933; Davies and Mann, 1947;
| |
| Mann, 1949; Ortiz, Price, Williams-Ashman
| |
| and Banks, 1956). But in the rat, the seminal vesicles secrete little fructose, most of
| |
| which originates from the dorsal prostate
| |
| and coagulating glands (Humphrey and
| |
| Mann, 1949).
| |
| | |
| Metabolic pathways for the biosynthesis
| |
| of seminal fructose by the accessory glands
| |
| have been studied extensively. From the results of experiments on diabetic animals,
| |
| Mann and Parsons (1950) concluded that
| |
| blood glucose was the precursor of seminal
| |
| fructose. The hyperglycemia resulting from
| |
| the administration of alloxan to rabbits was
| |
| accompanied by a parallel increase in the
| |
| fructose content of semen. Injection of insulin into such diabetic animals led to a fall
| |
| in the levels of both blood glucose and seminal fructose. Similarly, the concentration of
| |
| fructose in human semen was found to be
| |
| abnormally high in diabetic patients. Mann
| |
| and Lutwak-Mann (1951b) incubated
| |
| minced accessory gland tissue with glucose
| |
| and observed the formation of small amounts
| |
| of fructose. Cell-free extracts of bull seminal
| |
| vesicle showed marked phosphoglucomutase
| |
| and phosphohexoisomerase activity. The
| |
| same preparations hydrolyzed both glucose
| |
| 6-phosphate and fructose 6-phosphate to the
| |
| corresponding free sugars. Slices of seminal
| |
| vesicle glycolyzed glucose at much greater
| |
| rates than fructose. On the basis of these
| |
| facts, Mann and Lutwak-Mann (1951a, b)
| |
| postulated that the conversion of glucose to
| |
| fructose involved an initial phosphorylation
| |
| of glucose to glucose 6-phosphate by hexokinase, with adenosine triphosphate as the
| |
| ])hosphate donor. After enzymatic isomerization of glucose 6-phosphate to fructose
| |
| 6-phosphate, the latter was dephosphorylated to free fructose. It was assumed that
| |
| any glucose formed by the dephosphorylation of glucose 6-phosphate was rcutilized,
| |
| whereas fructose was not, and hence accumulated in the secretion. This formulation
| |
| is consonant with the properties of the hexokinase of seminal vesicle (Kellerman, 19551
| |
| wliicli, at low sugar concentrations, phosphorylates glucose at much faster rates than
| |
| fructose.
| |
| | |
| It was suggested by Mann and LutwakMann (1951a, b) that the dephosphorylation of hexosemonophosphates by accessory
| |
| glands was catalyzed by an alkaline phosphatase which attacked the 6-phosphate esters of both glucose and fructose. Kuhlman
| |
| (1954) claimed, on histochemical evidence,
| |
| that rat seminal vesicle contains a phosphatase specific for fructose 6-phosphate
| |
| which is most active in the vicinity of pH 7.
| |
| Kellerman (1955) stated that, although the
| |
| microsome-bound alkaline phosphatase of
| |
| guinea pig seminal vesicle hydrolyzes the
| |
| 6-phosphate esters of glucose and fructose
| |
| at approximately the same rate, the mitochondria of this tissue contain a phosphatase
| |
| which, at pH 5.8, hydrolyzes fructose 6-phosphate ten times as rapidly as glucose 6-phosphate. However, Hers (1957a) was unable
| |
| to confirm these observations.
| |
| | |
| An alternative pathway for the conversion of glucose to fructose was suggested by
| |
| Williams-Ashman and Banks (1954a), who
| |
| found that certain fructose-secreting accessory glands of rodents contain an enzyme,
| |
| ketose reductase, which catalyzes the reversible oxidation of sorbitol to fructose.
| |
| This enzyme attacks a number of higher
| |
| polyols and uses diphosphopyridine nucleotide (DPN) as a specific hydrogen acceptor
| |
| (Williams-Ashman, Banks and Wolf son,
| |
| 1957). The presence of an active ketose reductase in male accessory sexual tissues was
| |
| confirmed by Hers (1956, 1957a) who discovered another enzyme, aldose reductase,
| |
| which catalyzes the reduction of glucose to
| |
| sorbitol with dihydrotriphosphopyridine nucleotide (TPNH) as the hydrogen donor.
| |
| Hers suggested that seminal fructose was
| |
| formed from glucose by the combined action
| |
| of ketose and aldose reductases, as follows:
| |
| | |
| Glucose + TPNH + H+ ;^± Sorbitol + TPN+
| |
| | |
| Sorbitol + DPN+ <=^ Fructose + DPNH + H+
| |
| | |
| Glucose + TPNH + DPN+
| |
| | |
| -^ Fructose + TPN^ + DPNH
| |
| | |
| this nu'chanism for fructose biosynthesis
| |
| accounts for the following observations
| |
| ( Hers. 1957a) : (1) extracts of sheep seminal
| |
| vesicle convert C'^-labelcd glucose to fructose without rupture of the carbon chain;
| |
| (2) TPNH and DPN are required for this
| |
| transformation, during which sorbitol is produced, and becomes radioactive; (3) inhibitors of aldose reductase {e.g., glucosonej inhibit the conversion of glucose to fructose
| |
| and sorbitol; and (4j sorbitol is present,
| |
| alongside fructose, in the secretions of sheep
| |
| seminal vesicle and of certain accessory
| |
| glands of other species [vide injra) .
| |
| | |
| The relative importance of these phosphorylative and nonphosphorylative pathways for the biosynthesis of seminal fructose
| |
| remains to be determined.^
| |
| | |
| The fructose content of semen and of the
| |
| accessory glands is strictly controlled by
| |
| testicular hormones. The experiments of
| |
| Mann and Parsons (1950), depicted in Figure 6.7, show that in the sexually mature
| |
| rabbit, seminal fructose levels fell dramatically soon after castration. This decrease
| |
| in seminal fructose was prevented by implantation of a pellet of testosterone. Later
| |
| administration of androgen to the orchidectomized animals restored seminal fructose
| |
| to normal levels. Measurement of the fructose content of ejaculated semen may be
| |
| a sensitive index of androgenic activity,
| |
| and has the signal advantage that the timesequence of changes which result from alterations in the level of circulating androgen
| |
| can be determined without sacrifice of the
| |
| animal. This "fructose test" has been used
| |
| to assess the production of testicular androgen, or the hormonal activity of exogenous
| |
| substances, in man (Harvey, 1948; Landau
| |
| and Longhead, 1951; Tyler, 1955; Nowakowski and Schirren, 1956; Nowakowski,
| |
| 1957) and in other animals (Gassner, Hill
| |
| and Svdzberger, 1952; Branton, D'Arensbourg and Johnston, 1952; ]\Iann and Walton, 1953; Glover, 1956; Davies, Mann and
| |
| Rowson, 1957) .
| |
| | |
| The amounts of fructose in semen and in
| |
| the accessory glands are not determined
| |
| solely by androgenic hormones, as Mann
| |
| (1954a, 1956) has emphasized. The relative
| |
| size and storage capacity of the accessory
| |
| | |
| ^Samuels, Harding and Mann (1960) measured
| |
| the aldose and ketose reductase levels in the various accessory glands of the rat, and in the seminal
| |
| vesicles of the sheep, bull, boar, and horse. They
| |
| found that the level of fructose production could
| |
| be correlated with the activity of the least of the
| |
| two enzymes.
| |
| | |
| | |
| | |
| | |
| Fig. 6.7. Postcastrate fall and testosterone-induced rise of seminal fructose in the rabbit. The
| |
| pellet contained 100 mg. of testosterone. (Redrawn
| |
| from T. Mann, The Biochemistry of Semen,
| |
| Methuen & Co., 1954.)
| |
| | |
| glands play an important role. Another factor which complicates the fructose test is
| |
| frequency of ejaculation. In man and the
| |
| stallion, a single ejaculation largely depletes
| |
| the seminal vesicles (Mann, 1956). In the
| |
| bull, however, the seminal vesicles have a
| |
| remarkable storage capacity such that the
| |
| fructose content of eight consecutive ejaculations obtained within one hour is practically the same (Mann, 1954a) . Blood sugar
| |
| levels can influence seminal fructose, but
| |
| there is no evidence that the abnormally
| |
| large quantities of fructose in diabetic semen
| |
| (Alann and Parsons, 1950) result from increased output of androgenic hormones. Interruption of the blood supply to an accessory gland is another factor which affects the
| |
| amount of fructose it secretes (Clegg, 1953).
| |
| In immature animals, there seems to be a
| |
| short time after birth when the accessory
| |
| glands will not produce fructose in response
| |
| to testosterone (Ortiz, Price, Williams-Ashman and Banks. 1956). Obstruction of the
| |
| ejaculatory ducts will, of course, prevent the
| |
| appearance of fructose in semen, as Young
| |
| (1949) found in a patient with congenital bilateral aplasia of the vas deferens.
| |
| | |
| | |
| | |
| The anterior hypophysis may determine
| |
| indirectly the secretory activity of accessory
| |
| glands, and the amounts of fructose and
| |
| other chemical substances which accumlate
| |
| therein. Mann and Parsons (1950) showed
| |
| that hypophysectomy in the rabbit results
| |
| in a decline in the fructose content of semen,
| |
| and of the prostate gland and glandula vesicularis. These changes were similar to those
| |
| induced by castration, and could be reversed
| |
| by treatment with androgens or with gonadotrophin. The deleterious effect of inanition,
| |
| or a deficiency of certain B vitamins, on
| |
| fructose formation in the accessory glands
| |
| is almost certainly related to a concomitant
| |
| depression of gonadotrophin secretion by the
| |
| anterior pituitary gland (Lutwak-Mann and
| |
| Mann, 1950 ) . In the bull (Davies, Mann and
| |
| Rowson, 1957j, underfeeding leads to a
| |
| greater depression of fructose levels in semen than of sperm formation.
| |
| | |
| Analysis of fructose in excised ]irostate
| |
| gland or seminal vesicle has been used
| |
| widely as an indicator of androgenic activity. This procedure has yielded much information concerning the relationship between
| |
| the time of onset of androgen secretion by
| |
| the testes and the initiation of spermatogenesis. In the rabbit (Davies and Mann,
| |
| 1949), rat (Mann, Lutwak-Mann and Price,
| |
| 1948), bull (Mann, Davies and Humphrey,
| |
| 1949), boar (Mann, 1954b), and guinea pig
| |
| (Ortiz, Price, Williams-Ashman and Banks,
| |
| 1956) , fructose can be detected in the accessory glands before spermatozoa are produced. The androgenic potency of exogenous
| |
| substances can be determined by application
| |
| of the fructose test to the accessory glands
| |
| of animals castrated before or after puberty.
| |
| The increase in fructose content of the coagulating gland of castrated rats in response
| |
| to testosterone is greater than the corresponding change in organ weight (Mann and
| |
| Parsons, 1950) . The prostate gland and seminal vesicle of the rat (Rudolph and Samuels,
| |
| 1949; Rudolph and Starnes, 1955; Rauscher
| |
| and Schneider, 1954) and the seminal vesicle
| |
| of the guinea pig (Levey and Szego, 1955b;
| |
| Ortiz, Price, Williams-Ashman and Banks,
| |
| 1956) behave in a similar fashion. This technique has provided evidence for the slight
| |
| androgenic activity of progesterone (Price,
| |
| Mann and Lutwak-Mann, 1955), and for
| |
| the antagonistic (Parsons, 1950) or synergistic (Gassner, Hill and Sulzberger, 1952)
| |
| influence of estrogens on the action of androgens.
| |
| | |
| Intact vascular and neural links are not
| |
| necessary for the male accessory glands to
| |
| accumulate fructose after androgenic stimulation. Subcutaneous transplants of these
| |
| tissues into male rats will grow and produce
| |
| fructose. After castration, the fructose content falls and can be restored by testosterone
| |
| therapy (Mann, Lutwak-Mann and Price,
| |
| 1948). Fructose secretion was also observed
| |
| in accessory tissues transplanted into female
| |
| hosts which had received androgens (Lutwak-Mann, Mann and Price, 1949), or were
| |
| injected with gonadotrophins. which probably stimulate the secretion of ovarian androgens (Price, Mann and Lutwak-]Mann,
| |
| 1955).
| |
| | |
| The fructose in seminal i^lasma serves as
| |
| a source of energy for spermatozoa under
| |
| both anaerobic and aerobic conditions
| |
| (Mann, 1954a).
| |
| | |
| Sorbitol. Sorbitol has been detected in the
| |
| seminal vesicles of the sheep ( Hers, 1957a,
| |
| b) and the coagulating gland of the rat
| |
| (Wolfson and Williams-Ashman, 1958), as
| |
| well as in the semen of many species ( King,
| |
| Isherwood and Mann, 1958; King and Alann,
| |
| 1958, 1959). The sorbitol content of semen
| |
| tends to be high in those animals which exhibit high levels of seminal fructose, although it is also present in the semens of the
| |
| stallion and cock, which are virtually devoid
| |
| of fructose (Table 6.3). Sorbitol can be synthesized in the accessory glands by the
| |
| action of either ketose reductase (WilliamsAshman and Banks, 1954a; Williams-Ashman, Banks and Wolfson, 1957; Hers, 1956,
| |
| 1957a) or aldose reductase (Hers, 1956,
| |
| 1957a). Under anaerobic conditions, spermatozoa will not glycolyze sorbitol (unlike
| |
| fructose) to lactic acid, but will reduce both
| |
| fructose and glucose to sorbitol. In oxygen,
| |
| spermatozoa readily oxidize sorbitol (Mann
| |
| and White, 1956), and also form sorbitol
| |
| from glucose and fructose. The interconversion of fructose and sorbitol by spermatozoa
| |
| is catalyzed by a DPN-specific ketose re(Uictas(> (sorbitol dehydrogenase) which is
| |
| similar to that of the accessory glands
| |
| (King and ^Nlann, 1959). Although the spermatozoa can affect the ratio of the levels of
| |
| soi'bitol and fi-uctose in seminal plasma, most of the seminal sorbitol is probably derived from the accessory glands.
| |
| | |
| Inositol. During his studies on the vesicular secretion of the boar, Mann (1954b) isolated large amounts of a crystalline, nonreducing carbohydrate which he identified
| |
| rigorously as ?weso-inositol. This cyclic
| |
| polyol was found only in the seminal vesicle, being absent from the epididymis and
| |
| Cowper's gland. The concentration of inositol in boar vesicular secretion was as high
| |
| as 2.6 gm. per 100 ml., and constituted as
| |
| much as 70 per cent of the total dialyzable
| |
| material therein. Using a specific microbiologic method of estimation, Hartree (1957)
| |
| found that in the boar, the inositol content
| |
| of seminal plasma was usually greater than
| |
| 600 mg. per 100 ml., although much smaller
| |
| quantities (less than 60 mg. per 100 ml.)
| |
| were present in the bull, ram, stallion, and
| |
| man. In all of the species examined, the bulk
| |
| of the inositol in seminal plasma was in the
| |
| free state, and in amounts much greater
| |
| than those in blood or cerebrospinal fluid. In
| |
| most animals, seminal inositol originates
| |
| from the seminal vesicles, but it has been
| |
| detected in the prostate gland of the hedgehog, and in the ampullar secretion of the
| |
| stallion.
| |
| | |
| The levels of inositol in human semen, together with those of fructose, are increased
| |
| after the administration of testosterone according to Kimmig and Schirren (1956).
| |
| | |
| The physiologic function, if any, of the
| |
| inositol in seminal plasma is unknown. Since
| |
| boar vesicular secretion, unlike other body
| |
| fluids of the pig, contains immense amounts
| |
| of inositol and very little sodium chloride,
| |
| j\Iann (1954b) suggested that inositol is concerned with the maintenance of the osmotic
| |
| ecjuilibrium of boar seminal plasma.
| |
| | |
| Ascorbic acid. Deproteinized extracts of
| |
| the seminal plasma of many species reduce
| |
| 2,6-dichlorophenol indophenol in the cold.
| |
| This property has been attributed to the
| |
| presence of ascorbic acid in the semen of the
| |
| bull (Phillips, Lardy, Heiser and Ruppel,
| |
| 1940), guinea pig (Zimmet, 1939), and man
| |
| (Nespor, 1939; Berg, Huggins and Hodges,
| |
| 1941; Huggins, Scott and Heinen, 1942).
| |
| However, it is now established that ascorbic
| |
| acid does not always account for the total
| |
| reducing power of semen. In some animals,
| |
| e.g., the boar, ergothioneine is responsible in
| |
| | |
| | |
| | |
| TABLE 6.3
| |
| Sorbitol and fructose content of fresh seminal
| |
| | |
| plasma
| |
| In some oases the .samples represented semen
| |
| which had lieen pooled; the number of individuals
| |
| is given in brackets. (From T. E. King and T.
| |
| Mann, Proc. Roy. Soc. London, ser B, 151, 2262-13, 1959.)
| |
| | |
| | |
| | |
| Number of
| |
| Species \ Samples Sorbitol ; Fructose
| |
| | |
| Analyzed
| |
| | |
| | |
| | |
| | |
| Ram. . .
| |
| Rabbit.
| |
| Bull . . .
| |
| Boar. . .
| |
| Stallion
| |
| Dog .. .
| |
| Cock...
| |
| Man . . .
| |
| | |
| | |
| | |
| mg./lOO ml.
| |
| | |
| 150-600 (12)
| |
| | |
| 40-150 (4)
| |
| | |
| 120-540 (14)
| |
| | |
| 20-40 (4)
| |
| | |
| <1 (4)
| |
| | |
| <1 (5)
| |
| | |
| <1 (14)
| |
| | |
| 154 (3)
| |
| | |
| | |
| | |
| large i^art for the reduction of indophenol
| |
| [vide infra), and bull semen contains sulfite
| |
| and another, unidentified, reducing substance (Larson and Salisbury, 1953) . Nevertheless, ascorbic acid is undoubtedly present
| |
| in seminal plasma. Employing a specific
| |
| analytical method based on the formation
| |
| of its dinitrophenylhydrazone, ]\Iann
| |
| (1954a) found that the seminal vesicle secretion of the rat, bull, guinea pig, and man
| |
| contains ascorbic acid in amounts varying
| |
| from 5 to 12 mg. per 100 ml. Mann's values
| |
| for the ascorbic acid content of human semen (10 to 12 mg. per 100 ml.) agree well
| |
| with those reported by Berg, Huggins and
| |
| Hodges (1941), which were based on indophenol reduction.
| |
| | |
| Amino sugars. After hydrolysis with acid,
| |
| boar semen contains considerable amounts
| |
| of amino sugars (Mann, 1954a). The epididymal "semen" contains more amino
| |
| sugar than the vesicular secretion.
| |
| | |
| Ergothioneine. The vesicular secretion of
| |
| the boar (Leone and Mann, 1951 ; Mann and
| |
| Leone, 1953) is a rich source of ergothioneine. This sulfur-containing base is also
| |
| found in the accessory glands of the European hedgehog and mole (Mann, 1956) , and
| |
| in the ampullar secretion of the stallion
| |
| (Mann, Leone and Polge, 1956). Little or no
| |
| ergothioneine is present in the semen of the
| |
| bull, ram, and man.
| |
| | |
| Experiments with S^^-labeled precursors
| |
| suggest strongly that seminal ergothioneine is not synthesized in the animal V)ody (Alelville, dtken and Kovalenko, 1955; Heath,
| |
| Rimington and Mann, 1957). Because
| |
| orally ingested S'^'"'-labeled ergothioneine
| |
| l)asses into the seminal plasma of the boar
| |
| (Heath, Rimington, Glover, ]Mann and
| |
| Leone, 1953) , it is possible that those accessory glands which secrete ergothioneine
| |
| concentrate this substance from the blood.
| |
| | |
| Mann and Leone (1953) are of the opinion
| |
| that the function of ergothioneine in seminal
| |
| plasma is to protect the spermatozoa from
| |
| the poisonous action of oxidizing agents. It
| |
| is remarkable that the seminal fluids of the
| |
| boar and the stallion, both of which contain
| |
| ergothioneine, have common characteristics
| |
| which would render their spermatozoa especially sensitive to oxidizing agents, viz.,
| |
| large volume, low sperm density, and small
| |
| content of glycolyzable sugars.
| |
| | |
| PoLYAMiNES. Large amounts of spermine
| |
| and spermidine are present in the prostate
| |
| gland of many species (Harrison, 1931 ;
| |
| Rosenthal and Tabor, 1956). The chemical
| |
| structure of these polyamines was elucidated
| |
| by Dudley, Rosenheim and Starling (1926,
| |
| 1927). Human seminal plasma contains as
| |
| much as 300 mg. spermine per 100 ml., most
| |
| of which is derived from the prostate gland.
| |
| If human semen is allowed to stand for a
| |
| few hours at room temperature, the spermine
| |
| present crystallizes in the form of spermine
| |
| phosphate ("Boettcher's crystals").- Both
| |
| spermine and spermidine are oxidized by the
| |
| diamine oxidase of human seminal plasma
| |
| (Zellcr, 1941; Zeller and Joel, 1941). These
| |
| polyamines via their degradation products
| |
| are highly toxic to spermatozoa (Tabor and
| |
| Rosenthal, 1956) , and it seems unlikely that
| |
| | |
| "In a letter written to llie Royal Society of
| |
| London in November 1677, Antoni van Leeuwenhoek described for the fir.'^t time the presence and
| |
| movement of spermatozoa in human semen. In
| |
| the same letter, he also mentioned that "threesided bodies," which were "as bright and clear as
| |
| if they had been crystals," were deposited in the
| |
| aged semen of man. These crystals were undoubtedly composed of spermine phosphate. The liistory of the discovery of spermine in semen is admirably summarized by Mann (1954a), with special
| |
| reference to the contributions of Louis Vauquelin
| |
| (see footnote 3), and also of Alexander von Pcihl,
| |
| whose claims for the therapeutic proiinities' of
| |
| spermine aroused much interest aiul controversy
| |
| at the end of the 19th centurv.
| |
| | |
| | |
| | |
| their presence in seminal plasma is of functional value.
| |
| | |
| Choline DERIVATIVES. Florence (1895) described the formation of brown crystals
| |
| upon the addition of a solution of iodine in
| |
| potassium iodide to semen. This reaction was
| |
| used as the basis of a medico-legal test for
| |
| semen stains. Bocarius (1902) showed that
| |
| choline was responsible for the formation
| |
| of this material. In the rat, the seminal
| |
| fluid is by far the richest source of choline
| |
| of any tissue or body fluid (Fletscher, Best
| |
| and Solandt, 1935). A series of careful studies by Kahane (Kahane and Levy, 1936;
| |
| Kahane, 1937) revealed that human semen
| |
| contains very little free choline immediately
| |
| after ejaculation, but that large amounts of
| |
| the free base are formed if the semen is allowed to stand at room temperature. Lundquist (1946, 1947a, b, 1949) isolated phosphorylcholine from human seminal plasma
| |
| and showed that it was converted to choline
| |
| and inorganic phosphate by seminal acid
| |
| phosphatase. However, the French investigators (Diament, Kahane and Levy, 1952.
| |
| 1953; Diament, 1954) isolated a-glycerophosphorylcholine from the vesicular secretion of rats, and suggested that this substance, rather than phosphorylcholine, was
| |
| the precursor of free choline in aged semen.
| |
| Lundquist (1953) also found glycerophosl^horylcholine in the vc'sicular secretion of
| |
| the rabbit, rat, and guinea pig. WilliamsAshman and Banks (1956) showed that the
| |
| amount of glycerophosphorylcholine in rat
| |
| vesicular secretion falls rapidly after castration, and can be restored to normal levels by
| |
| administration of testosterone. Rezek and
| |
| Sir (1956) found both ]')hosi)liorylcholinf
| |
| and glyceroi)hospliofylclu)line in lunnan
| |
| ejaculates.
| |
| | |
| A thorough study of the wat('i'-s()lul)lf
| |
| choline (lerivati\-cs in seminal plasma was
| |
| made by Dawson, Maiui and White (1957).
| |
| They foimd (Tabh'().4i that in most species,
| |
| gh^cerophosphoryh-holine is the only derivati\'e preseiu, but ill man there are consider■a\)\v (|uantities of phosphoiyh'lioline as well.
| |
| The lattei- substance is rai)idly dephospholylated after ejaculation, but glycerophosphoryh'holine is not degradeil by enzymes
| |
| in seminal phisnia or \'esiculai' secretion. In
| |
| | |
| | |
| | |
| | |
| TABLE 6.4
| |
| | |
| Phosphor ylchoUne and a-glycerophosphorylcholine in semen and in
| |
| secretions of accessory reproductive glands
| |
| | |
| | |
| | |
| Species
| |
| | |
| | |
| | |
| Concentration (mg. per 100 gm.) of:
| |
| | |
| | |
| | |
| Phosphorylcholine a-Glycerophosphorylcholine
| |
| | |
| | |
| | |
| Ram
| |
| | |
| Ram
| |
| | |
| Bull
| |
| | |
| Bull
| |
| | |
| Bull
| |
| | |
| Bull
| |
| | |
| Bull
| |
| | |
| Cioat
| |
| | |
| Boar
| |
| | |
| Boar
| |
| | |
| Boar
| |
| | |
| Stallion. . .
| |
| Stallion. . .
| |
| | |
| Man
| |
| | |
| Rat
| |
| | |
| Rat
| |
| | |
| Rabbit...
| |
| Hedgehog.
| |
| Hedgehog.
| |
| Monkey. . .
| |
| Cock..'....
| |
| | |
| | |
| | |
| Semen
| |
| | |
| Seminal pla.sma
| |
| | |
| Semen
| |
| | |
| Seminal plasma
| |
| | |
| Vesicular secretion
| |
| | |
| Epididymal secretion
| |
| | |
| Ampullar secretion
| |
| | |
| Semen
| |
| | |
| Seminal plasma
| |
| | |
| Vesicular secretion
| |
| | |
| Epididymal secretion
| |
| | |
| Semen
| |
| | |
| Ampidlar secretion
| |
| | |
| Semen
| |
| | |
| Vesicular secretion
| |
| | |
| Seminal vesicle
| |
| | |
| Semen
| |
| | |
| Secretion of "Prostate I and 11"
| |
| | |
| Secretion of "Prostate III"
| |
| | |
| Vesicular secretion
| |
| | |
| Semen
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Present
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 256-380
| |
| | |
| | |
| | |
| | |
| Present
| |
| Present
| |
| Present
| |
| Present
| |
| | |
| | |
| | |
| 1185-1942
| |
| | |
| 1601-2040
| |
| | |
| 237-460
| |
| | |
| 110-496
| |
| | |
| | |
| | |
| 1490
| |
| | |
| 94
| |
| | |
| 1382-1550
| |
| | |
| 108-235
| |
| | |
| 190
| |
| | |
| 3060
| |
| | |
| 38-113
| |
| | |
| 120
| |
| | |
| 59-90
| |
| | |
| 654; 530-765"
| |
| | |
| 190-515"
| |
| | |
| 215-370
| |
| | |
| Present
| |
| | |
| | |
| | |
| | |
| ° Results from Williams-Ashman and Banks (1956); all other values from Dawson, Mann and White
| |
| | |
| lf57).
| |
| | |
| | |
| | |
| the bull and boar, the epidiclymi.^ is the ])rincii)al source of the glyceroiihosi)horylcholine
| |
| of the seminal plasma.
| |
| | |
| Williams-Ashman and Banks (1956) in-ovided evidence that the choline moiety of the
| |
| glycerophosphorylcholine in vesicular secretion is not derived from a direct reaction
| |
| between glycerol and cytidine diphosphate
| |
| choline. The latter nucleotide was shown
| |
| to be a precursor of lecithin in rat seminal
| |
| vesicle tissue. The glycerophosphorylcholine
| |
| of seminal plasma may originate from the
| |
| enzymatic degradation of the choline-containing lipids of the seminal vesicle epithelium.
| |
| | |
| Choline and glycerophosjihorylcholine are
| |
| not metabolized by spermatozoa, and do not
| |
| affect their respiration (Dawson, Mann and
| |
| White, 1957). There is no evidence that the
| |
| water-soluble choline derivatives of seminal
| |
| plasma serve any useful function.
| |
| | |
| Lipids. That lipid-containing granules are
| |
| l^resent in human seminal plasma has been
| |
| known for more than a century. They are
| |
| found in prostatic secretion (Thompson, 1861 1, and were termed "lecithin-kornchen"
| |
| by Fuerbringer (1881). However, Scott
| |
| ( 1945 ) showed that lecithin is absent from
| |
| both of these fluids, and that the majority
| |
| of the phospholipid therein is phosphatidyl
| |
| ethanolamine. Neutral fat is virtually absent from human seminal plasma and prostatic secretion, one-third of the total lipid
| |
| of which can be accounted for as cholesterol.
| |
| | |
| According to Boguth (1952), about onethird of the total plasmalogen in bull semen
| |
| (30 to 90 mg. per 100 ml.) is in the seminal
| |
| plasma. In the ram, only 10 per cent of the
| |
| seminal plasmalogen is found outside the
| |
| spermatozoa (Hartree and ]Mann. 1959).
| |
| | |
| Large amounts of 7-dehydrocholesterol
| |
| were found in the preputial gland and epididymis of the rat (Ward and ]\Ioore, 1953) .
| |
| One gram of the hydrocarbon heptacosane
| |
| (CH3(CHo)o5CH3) was isolated from an alcoholic extract of 18 liters of human semen
| |
| by Wagner-Jauregg (1941). The partition
| |
| of heptacosane, and of steroidal estrogens
| |
| (Diczfalusy, 1954) and androgens (Dirscherl and Kniicliel, 1950) between the sperm and plasma of human semen remains to be
| |
| determined.
| |
| | |
| Citric acid. Citric acid was first detected
| |
| in human semen by Schersten (1929). The
| |
| distribution of citric acid in the semen and in
| |
| the secretions of the accessory glands of various species is summarized in Table 6.5. In
| |
| some animals, {e.g., the rat and man), citric
| |
| acid is produced mainly by the prostate
| |
| gland, and in others {e.g., the bull, boar, and
| |
| guinea pig), most of it originates from the
| |
| seminal vesicles.
| |
| | |
| The citric acid content of the seminal plasma and of the secretions of accessory
| |
| glands depends on androgenic hormones.
| |
| Citric acid disappears from these fluids after
| |
| castration, and is formed again after treatment with testosterone. This ''citric acid
| |
| test" has been used to determine the time of
| |
| onset of secretory function in accessory
| |
| glands (Mann, Davies and Humphrey, 1949;
| |
| Ortiz, Price, Williams- Ashman and Banks,
| |
| 1956), hormonal influences on secretion in
| |
| subcutaneous transplants (Mann, LutwakMann and Price, 1948; Lutwak-jNIann.
| |
| Mann and Price, 1949 L the androgenic ac
| |
| | |
| | |
| TABLE 6.5
| |
| | |
| Citric acid in semen and in the secretions of accessory reproductive glands
| |
| | |
| | |
| | |
| Species
| |
| | |
| | |
| Material
| |
| | |
| | |
| Citric Acid
| |
| | |
| | |
| Reference
| |
| | |
| | |
| | |
| | |
| | |
| | |
| (tng./lOO gm.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Man
| |
| | |
| | |
| Semen
| |
| | |
| | |
| 140-637
| |
| | |
| | |
| Huggins and Xeal (1942)
| |
| | |
| | |
| | |
| | |
| Man
| |
| | |
| | |
| Prostatic secretion
| |
| | |
| | |
| 480-2()88
| |
| | |
| | |
| Huggins and Neal (1942)
| |
| | |
| | |
| | |
| | |
| Man ....
| |
| | |
| | |
| Seminal vesicle secretion
| |
| Hypertrophic adenoma of the
| |
| | |
| | |
| 15-22
| |
| 201-1533
| |
| | |
| | |
| Huggins and Neal (1942)
| |
| Barron and Huggins (1946a)
| |
| | |
| | |
| | |
| | |
| Man
| |
| | |
| | |
| | |
| | |
| | |
| | |
| prostate gland
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Man
| |
| | |
| | |
| Carcinoma of the prostate gland
| |
| | |
| | |
| 12-137
| |
| | |
| | |
| Barron and Huggins (194()a)
| |
| | |
| | |
| | |
| | |
| Bull
| |
| | |
| | |
| Semen
| |
| | |
| | |
| 510-1100
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Bull
| |
| | |
| | |
| Seminal gland secretion
| |
| | |
| | |
| 670
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Bull
| |
| | |
| | |
| Ampullar semen
| |
| | |
| | |
| 550
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Bull
| |
| | |
| | |
| Epididvmal semen
| |
| | |
| | |
| | |
| | |
| | |
| Humphrey and IVIann (1949)
| |
| | |
| | |
| | |
| | |
| Bull
| |
| | |
| | |
| Epididymis
| |
| | |
| | |
| 18
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Boar
| |
| | |
| | |
| Semen
| |
| | |
| | |
| 130
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Boar
| |
| | |
| | |
| Cowper's gland secretion
| |
| Epididymal semen
| |
| Seminal yesicle secretion
| |
| | |
| | |
| | |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Boar
| |
| | |
| | |
| | |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Boar
| |
| | |
| | |
| 580
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Ram
| |
| | |
| | |
| Semen
| |
| Semen
| |
| | |
| | |
| 110-260
| |
| 110-550
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| Himiphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Epididymis
| |
| | |
| | |
| 54
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Prostate (I, II and III)
| |
| | |
| | |
| 62
| |
| | |
| | |
| Himiphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Cowper's Gland
| |
| | |
| | |
| 42
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Ampulla
| |
| | |
| | |
| 273
| |
| | |
| | |
| Himiphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rat
| |
| | |
| | |
| Seminal vesicle
| |
| Coagulating gland
| |
| Ampulla
| |
| Dorsolateral prostate
| |
| | |
| | |
| 39
| |
| | |
| | |
| | |
| Humi)hrey and :\Iann (1949)
| |
| Hunii)hrc\ and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rat
| |
| | |
| | |
| | |
| | |
| Rat
| |
| | |
| | |
| | |
| | |
| | |
| Humplucv and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rat
| |
| | |
| | |
| 20
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| | |
| | |
| | |
| | |
| Rat
| |
| | |
| | |
| Ventral prostate
| |
| Semen
| |
| | |
| | |
| 122
| |
| | |
| | |
| Humphrey and Mann (1949)
| |
| Mann, Leone and Polge (1956)
| |
| | |
| | |
| | |
| | |
| Stallion
| |
| | |
| | |
| 8-53
| |
| | |
| | |
| | |
| | |
| Stallion
| |
| | |
| | |
| Seminal vesicle
| |
| | |
| | |
| 77
| |
| | |
| | |
| Mann, Leone and Polge (1956)
| |
| | |
| | |
| | |
| | |
| Guinea pig. . . .
| |
| | |
| | |
| Seminal vesicle
| |
| | |
| | |
| 153-216
| |
| | |
| | |
| Ortiz, Price, Williams-Ashman
| |
| Banks (195())
| |
| | |
| | |
| | |
| | |
| Guinea pig. . . .
| |
| | |
| | |
| Semiiuil vesicle sec'retion
| |
| | |
| | |
| 320-357
| |
| | |
| | |
| Ortiz, Price, Williams-Ashman
| |
| Baidvs (1956)
| |
| | |
| | |
| | |
| | |
| Guinea pig. . . .
| |
| | |
| | |
| Coagulating gland
| |
| | |
| | |
| 26-40
| |
| | |
| | |
| Ortiz, Price, Williams- Ashman
| |
| Banks (1956)
| |
| | |
| | |
| | |
| | |
| Guinea pig. . . .
| |
| | |
| | |
| Lateral i)rostate
| |
| | |
| | |
| 16-20
| |
| | |
| | |
| Ortiz, Price, Williams- Ashman
| |
| Banks (1956)
| |
| | |
| | |
| | |
| | |
| Guinea i)ig. . . .
| |
| | |
| | |
| Doi'sal ])i(is1at(>
| |
| | |
| | |
| 47-75
| |
| | |
| | |
| Ortiz, Price, Williams-Ashman
| |
| Banks (195(i)
| |
| | |
| | |
| | |
| | |
| Dog
| |
| | |
| | |
| Prostatic secretion
| |
| | |
| | |
| 0-30
| |
| | |
| | |
| Barron and Huggins (1946a)
| |
| Barron and Huggins (1946a)
| |
| Mann, Leone and Polge (1956)
| |
| | |
| | |
| | |
| | |
| Dog
| |
| | |
| | |
| Prostate gland
| |
| Vesicular secretion
| |
| | |
| | |
| 8
| |
| | |
| | |
| | |
| | |
| Jackass
| |
| | |
| | |
| 22-82
| |
| | |
| tivity of various hormones (Mann and Parsons, 1950; Price, Mann and Lutwak-JMann,
| |
| 1955; Ortiz, Price, Williams-Ashman and
| |
| Banks, 1956), and the effect of nutrition on
| |
| the onset of androgen secretion and sperm
| |
| formation in bull calves (Davies, Mann and
| |
| Rowson, 1957).
| |
| | |
| The androgen-induced changes in the citrate levels in semen and various accessory
| |
| glands are reminiscent of similar alterations
| |
| in the fructose content of these tissues. However, the concentrations of these substances
| |
| do not necessarily parallel one another in response to hormonal stimulation. In the postcastrate animal, the fall in citric acid and its
| |
| reappearance after androgen treatment is
| |
| usually more sluggish than that of fructose.
| |
| Also, the seminal fructose of some species
| |
| may not be secreted by the same accessory
| |
| organ (or lobes of the gland ) which produces
| |
| citric acid. Thus in the rat, fructose is secreted by the anterior and dorsolateral prostate, whereas citric acid is derived from the
| |
| seminal vesicles and dorsolateral and ventral prostates, but is totally absent from the
| |
| anterior prostate (Humphrey and Mann,
| |
| 1949). In the guinea pig, however, the seminal vesicles are the principal source of both
| |
| fructose and citric acid (Ortiz, Price, Williams-Ashman and Banks, 1956).
| |
| | |
| Using a strain of rats in which the incidence of the female prostate is very high,
| |
| Price, ]Mann and Lutwak-JVIann (1949)
| |
| showed that the growth of this gland which
| |
| follows the injection of testosterone is accompanied by a tremendous increase in its
| |
| content of citric acid. In this way the female
| |
| prostate resembles the ventral prostate gland
| |
| of the male rat.
| |
| | |
| Citric acid is synthesized in the i)rostate
| |
| gland by the usual reactions of the tricarboxylic acid cycle (Williams-Ashman, 1954;
| |
| Williams-Ashman and Banks, 1954b). No
| |
| other organic acids are present in more than
| |
| trace amounts in the secretions of those accessory glands that accumulate citrate. The
| |
| enzymatic machinery for the degradation of
| |
| citric acid via the tricarboxylic acid cycle is
| |
| jH-esent in the rat ventral prostate gland
| |
| OVilliams-Ashman, 1954; Williams-Ashman
| |
| and Banks, 1954b; Williams-Ashman, 1955)
| |
| and there is no evidence, despite suggestions
| |
| to the contrary (Awapara, 1952a), that citric acid accumulates because it cannot be
| |
| oxidized. It has been suggested that a common denominator affecting the androgendependent accumulation of citric acid and
| |
| fructose in the accessory glands is the intracellular balance between the oxidized and
| |
| reduced forms of DPN and TPN (Talalay
| |
| and Williams-Ashman, 1958).
| |
| | |
| ^lann (1954a) has summarized the ideas
| |
| of various authors concerning the possible
| |
| functional role of citric acid in seminal
| |
| plasma. All of these suggestions are based
| |
| more upon conjecture than experimental
| |
| fact.
| |
| | |
| Catecholamine^. There is evidence for the
| |
| presence of both epinephrine and norepinephrine in seminal pla.sraa (Brochart, 1948;
| |
| Beauvallet and Brochart, 1949). Extracts of
| |
| human prostate and seminal vesicle contain
| |
| a monoamine oxidase which oxidizes catecholamines (Zcller and Joel, 1941). Katsh
| |
| (1959) detected serotonin and histamine in
| |
| human ejaculates.
| |
| | |
| Amino acids. Chromatographic studies
| |
| have revealed the presence of many free
| |
| amino acids in human semen (Jacobbson,
| |
| 1950; Lundquist, 1952), from which crystalline tyrosine was isolated by WagnerJauregg (1941). According to Barron and
| |
| Huggins (1946b), human prostatic adenoma
| |
| is very rich in free glutamic acid, and the
| |
| nonprotein amino-nitrogen of this and dog
| |
| prostatic tissue is high. Bovine seminal
| |
| plasma contains free serine, alanine, glycine,
| |
| and aspartic and glutamic acids (Gassner
| |
| and Hopwood, 1952). A similar distribution
| |
| of amino acids is found in the vesicular and
| |
| ampullary secretions of the bull. The free
| |
| amino acid levels of bull seminal plasma fall
| |
| greatly after castration. In the rat, Marvin
| |
| and Awapara (1949) found that the concentration of free amino acids in the whole prostate decreased markedly following orchidectomy, and could be restored to normal levels
| |
| in the castrate animal by treatment with
| |
| androgen. In this species, Awapara (1952a)
| |
| observed that the content of free amino acids
| |
| in the ventral lobe of the prostate was much
| |
| higher than in the dorsal lobe. After castration, there was a marked drop in the content
| |
| of most amino acids with the exception of
| |
| aspartic and glutamic acids, which seemed to remain at almost normal levels (Awapara,
| |
| 1952b j.
| |
| | |
| Seminal plasma and the secretions of the
| |
| male accessory glands contain a battery of
| |
| proteolytic enzymes [vide infra). For this
| |
| reason, changes in the levels of free amino
| |
| acids in these fluids resulting from hormonal
| |
| treatments should be interpreted with caution. Jacobbson (1950), for example, has
| |
| shown that in human semen, the nonprotein
| |
| nitrogen and amino-nitrogen content increases many fold within 60 minutes after
| |
| ejaculation.
| |
| | |
| Prostaglandin. A vasodepressor substance, designated j^rostaglandin, was found
| |
| by von Euler (1934, 1936) in the prostatic
| |
| and vesicular secretions of man, and also in
| |
| the accessory glands of sheep (von Euler,
| |
| 1939). The prostaglandin of ram prostate
| |
| was i^urified by Bergstrom ( 1949), who suggested that it was an unsaturated fatty acid
| |
| devoid of nitrogen. According to Eliasson
| |
| (1957), the prostaglandin of human semen
| |
| and of the prostate gland of sheep are identical.
| |
| | |
| The pharmacologic effects which result
| |
| from the injection of seminal plasma icf.
| |
| Kurzrok and Lieb, 1931; von Euler, 1934,
| |
| 1936, 1939; Goldblatt, 1935; Cockrill, Miller and Kurzrok, 1935; Asplund, 1947) are
| |
| complex, and are probably due to the combined action of many constituents of this
| |
| fluid. The hypotensive action of protein
| |
| fractions of the secretions of some accessory organs (Freund, Miles, Mill and Wilhelm, 19581 is discussed below.
| |
| | |
| Uric acid. Bull seminal vesicles may contain as much as 70 mg. per cent of uric
| |
| acid (Leone, 1953). The uric acid content of
| |
| the semen of other animals is much lowci'
| |
| (Mann, 1954a).
| |
| | |
| Urea. The urea content of human and
| |
| ram semen is much higlici' than that found
| |
| in the bull, boar, and stallion (Mann.
| |
| 1954a).
| |
| | |
| Major protein constitiiknts. Human
| |
| seminal plasma contains from 3.5 to 5.5
| |
| gm. of protein-like material per 100 niL
| |
| (Huggins, Scott and Heinen, 1942). Less
| |
| than 18 per cent of this material is coagulable by heat, and as much as 68 per cent
| |
| of it is dialyzable. Thus the majority of
| |
| the seminal proteins of man can be classified as proteoses. Electrophoretic analyses of the nondialyzable proteins of human
| |
| seminal plasma have been performed by
| |
| Gray and Huggins ( 1942 1 and by Ross,
| |
| Moore and Aliller (1942). The major components bore some correspondence to those
| |
| of blood serum, although the amount of
| |
| albumin was small. The proteins of bovine
| |
| seminal plasma are less dialyzable, and
| |
| more coagulable by heat, than those of man
| |
| (Larson and Salisbury, 1954). Electrophoretic studies showed the presence of three
| |
| major and eight minor constituents, which
| |
| seemed to be distinct from the proteins of
| |
| bovine blood serum. In this species giycoor lipoproteins were present only in very
| |
| low concentrations. Larson, Gray and Salisbury (1954) found that the bovine seminal
| |
| plasma proteins are highly antigenic. They
| |
| obtained immunologic evidence that the
| |
| major protein constituents of this fluid are
| |
| distinct from any of the main ])rot(>ins of
| |
| either blood or milk.
| |
| | |
| Enzymes, (i) Acid phosphatase. Kutscher and Wolbergs (1935) discovered that
| |
| human semen and prostate contain a very
| |
| active phosphatase which is optimally active at pH 5 to 6. This enzyme is resjjonsible for the greater phosphatase activity of
| |
| male as compared with female urine. Its
| |
| secretion by the prostate accounts for the
| |
| fact that male urine collected from the
| |
| renal pelvis exhibits very little enzyme activity (Scott and Huggins, 1942). Human
| |
| prostatic acid phosjihatase hydrolyzes a
| |
| number of phosphate monoesters (Kutscher
| |
| and Worner, 1936; Kutscher and Pany,
| |
| 1938). The enzyme has been purified extensively (London and Hudson, 1953; Boman, 1954; London, Sommer and Hudson,
| |
| 1955). In addition to hydrolyzing phosphate esters, human prostatic acid phosphatase catalyzes the transfer of phosphate
| |
| from various donors to alcohols such as glucose, fructose, and methanol (London and
| |
| Hudson, 1955; Jeffree, 1957). L-Tartrate
| |
| inliibits the enzyme competitively (AbulKadl and King, ^1948).
| |
| | |
| 'I'hc activity of acid phosphatase in the
| |
| human jjrostate is low in childhood and increases about 20 times at i)uberty (Gutman
| |
| and Gutman, 1938a). In adult men, the
| |
| acid phosphatase content of semen seems
| |
| to reflect the circulating levels of androgenic hoi-niones (Gutman and Gutman, 1940). High levels of acid })hosphatase are
| |
| also present in osteoplastic metastases of
| |
| prostatic carcinoma (Gutman, Sproul and
| |
| Gutman, 1936). Acid phosphatase does not
| |
| seem to enter the circulation from the prostate gland in healthy individuals unless
| |
| they are subject to prostatic massage. But
| |
| in about 65 per cent of men with metastatic
| |
| carcinoma of the prostate, the serum levels
| |
| of this enzyme are abnormally high (Gutman and Gutman, 19381); Robinson, Gutman and Gutman, 1939; Huggins and
| |
| Hodges, 1941). The diagnosis and prognostic evaluation of carcinoma of the prostate
| |
| in men has been aided greatly by measurements of the acid phosphatase levels of
| |
| serum. Inhibition of the acid phosphatase
| |
| activity of blood serum by L-tartrate has
| |
| been used as an index for the outflow of
| |
| prostatic acid phosphatase into the serum
| |
| in neoplastic diseases of the prostate gland
| |
| (Abul-Fadl and King, 1948; Fishman and
| |
| Lerner, 1953).
| |
| | |
| The prostate gland of the monkey (Gutman and Gutman, 1938a) and dog (Huggins and Russell, 1946), and the seminal
| |
| vesicle of the guinea i)ig (Bern and Le\y,
| |
| 1952) exhibit powerful acid phosphatase
| |
| activity, whereas the levels of this enzyme
| |
| in the prostate of the rabbit (Bern and
| |
| Levy, 1952) and rat (Huggins and Webster, 1948) are relatively low. The properties of these enzymes from different species
| |
| are strikingly similar (Novales and Bern,
| |
| 1953) . In the monkey and dog, the prostatic
| |
| acid jihosphatase activities are controlled
| |
| by androgenic hormones. This is also true
| |
| in the rat (Stafford, Rubinstein and Meyer,
| |
| 1949), and guinea pig (Ortiz, Brown and
| |
| Wiley, 1957).
| |
| | |
| {2} Alkaline phosphatase. An enzyme,
| |
| activated by magnesium ions, which hydrolyzes a variety of phosphate monoesters at
| |
| pH 9, is present in the seminal fluid and
| |
| accessory glands. In some species, e.g., the
| |
| l)ull (Reid, Ward and Salisbury, 1948 ) , the
| |
| levels of seminal alkaline phosphatase are
| |
| much greater than those of the acid phosphatase. In the rat, alkaline phosphatase
| |
| activity in the prostate and seminal vesicles
| |
| decreases markedly after castration (Stafford, Rubinstein and Meyer, 1949).
| |
| | |
| (3) 5'-Nucleotidase. Reis (1937, 1938)
| |
| noticed that human seminal plasma dcphosphorylated adenosine 5'-phosphate and inosine 5'-phosphate very rapidly. He proposed
| |
| the term ''5'-nucleotidase" for enzymes
| |
| which specifically hydrolyze the 5'-monophosphates of ribose and its nucleosides.
| |
| Mann (1945) reported that bull seminal
| |
| plasma is exceedingly rich in 5'-nucleotidase. The enzyme was purified from this
| |
| source by Heppel and Hilmoe (1951a). It
| |
| was inactive towards adenosine 2'- and 3'phosphates, but catalyzed the hydrolysis
| |
| of the 5'-monophosphate esters of adenosine, inosine, cytidine, uridine, and ribosyl
| |
| nicotinamide. The 5'-nucleotidase of bull
| |
| semen is optimally active at pH 8.5, and
| |
| requires magnesium ions for maximal activity.
| |
| | |
| (4) Inorganic pyrophosphatase. Heppel
| |
| and Hilmoe (1951b) reported the presence
| |
| of an inorganic pyrophosphatase in bull
| |
| seminal plasma. The enzyme was not purified extensively, and it is not clear whether
| |
| it is different from other in'rophosphatases
| |
| in semen.
| |
| | |
| (5) Nucleotide pyrophosphatases. The
| |
| enzymatic hydrolysis of adenosine triphosphate (ATP) by seminal plasma was observed by Mann (1945) and by MacLeod
| |
| and Summerson (1946). Three distinct
| |
| ATPases were isolated from bull seminal
| |
| plasma by Heppel and Hilmoe (1953). The
| |
| first of these enzymes catalyzed the hydrolysis of ATP to inorganic pyrophosphate
| |
| and adenosine 5'-phosphate. The other two
| |
| catalyzed the liberation of inorganic orthophosphate from ATP, and were active at
| |
| pH 5 and pH 8.5 respectively. The possible
| |
| identity of any of these proteins with other
| |
| enzymes which hydrolyze the pyrophosphate linkage of ]iyridine nucleotides (Williams-Ashman, Liao and Gotterer, 1958)
| |
| and cytidine diphosphate choline (Williams-Ashman and Banks, 1956) remains
| |
| to be established.
| |
| | |
| The physiologic function of any of the
| |
| phosphatases in seminal plasma is unknown.
| |
| | |
| {6) Proteolytic enzymes. The proteolytic
| |
| activity of human semen was first noted by
| |
| Huggins and Neal (1942), and has been
| |
| studied extensively by Lundquist and his
| |
| collaborators. An enzyme similar to pepsinogen, and probably secreted by the seminal vesicles, was discovered in human seminal plasma by Lundquist and Seedorf
| |
| (1952). Three other proteolytic enzymes
| |
| were partially purified from human semen
| |
| by Lundquist, Thorsteinsson and Buus
| |
| (1955). The first enzyme resembled chymotrypsin, and the second was an aminopeptidase. The third enzyme hydrolyzed benzoylarginine ethyl ester, and seems to be
| |
| identical with the arginine ester hydrolyzing enzyme described in male accessory reproductive glands by Gotterer, Banks and
| |
| Williams-Ashman (1956). The relationship
| |
| of these enzymes to the hydrolysis of fibrin
| |
| or fibrinogen by prostatic secretion is discussed below with reference to the coagulation and liquefaction of semen.
| |
| | |
| (7) Glycosidases. Using phenolphthalein
| |
| glucuronide as a substrate, Talalay, Fishman and Huggins (1946) determined the
| |
| /?-glucuronidase activity of the male accessory glands of the rat. The levels of this
| |
| enzyme in the epididymis fall about 50 per
| |
| cent after castration, and can be restored
| |
| to normal levels by the administration of
| |
| testosterone (Conchie and Findlay, 1959).
| |
| When the corresponding phenol- or p-nitrophenol-glycosides were employed as substrates, Conchie, Findlay and Levvy (1956)
| |
| showed that the epididymis of the rat is
| |
| particularly rich in y3-iV-acetylglucosaminidase. The levels of this enzyme were found
| |
| by Conchie and Mann (1957) to be very
| |
| much greater than those of seven other
| |
| glycosidases in male accessory secretions.
| |
| The levels of various glycosidases in the
| |
| epididymis of rodents increases enormously
| |
| at puberty. In adult animals the activity
| |
| of some of these enzymes {e.g., a-mannosidase and /?-iV-acetylglucosaminidase) fell
| |
| to negligible values after castration, and
| |
| were restored only partially by treatment
| |
| with testosterone.
| |
| | |
| (8) Miscellaneous enzipnes. The kneels of
| |
| a number of oxidizing enzymes in human
| |
| seminal plasma were studied by Rhodes and
| |
| Williams-Asluiuiii (1960», who noted the
| |
| presence of a x'cry active TPN-linked isocitric dehydrogenase. The ability of luiinan
| |
| semen to hydrolyze acetylclioline is rather
| |
| fe(>!)le, and the bulk of the activity resides
| |
| in the seminal plasma (Zeller and Joel,
| |
| 1941). According to Sekine (1951), boar
| |
| semen exhibits powerful choline esterase
| |
| activity, wliicli is confined mainly to the s])ermatozoa. The activity of phosphohexoisomerase (Wiist, 1957) and lactic dehydrogenase (MacLeod and Wroblewski,
| |
| 1958) in human seminal plasma has been
| |
| documented.
| |
| | |
| The levels of the following soluble enzymes have been determined in the accessory glands of male rodents: phenol sulfatase (Huggins and Smith, 1947). nonsi)ecific
| |
| esterase (Huggins and ]\Ioulton, 1948),
| |
| enolase, and dehydrogenases for lactate,
| |
| malate, glucose 6-phosphate, 6-phosphogluconate and isocitrate (Williams- Ashman,
| |
| 1954; Rudolph, 1956), aldolase and a-glycero])hosphate dehydrogenase (Butler and
| |
| Schade, 1958). The nucleoside phosphorylase and adenosine deaminase activities of
| |
| bull seminal vesicle were measured by
| |
| Leone and Santoianni (1957). The vesicular secretion of the bull is rich in flavins,
| |
| and exhibits strong xanthine oxidase activity (Leone, 1953). Leone and Bonaduce
| |
| (1959) described a very active diphospho]5yridine nucleotidase in the vesicular secretion of the bull.
| |
| | |
| Conclusions. The foregoing survey indicates that, just as the size and morphology
| |
| of the accessory glands differ profoundly,
| |
| so there are wide species variations in the
| |
| chemistry of their secretions, which comprise the seminal plasma. Some seminal
| |
| constituents {e.g., fructose) are found in
| |
| many mammals. Other substances, such as
| |
| ergothioneine, are present in appreciable
| |
| amounts in the seminal plasma of only a
| |
| few species. The biochemistry of the accessory glands is still in its infancy, and it
| |
| may be expected that future research will
| |
| disclose other species-restricted comjionents
| |
| of seminal plasma. Mann (1954a, 1956)
| |
| I'ightly emphasizes that the finding of substantial concentrations of certain substances in the semen of only relatively few
| |
| species does not necessarily detract from
| |
| their physiologic value. The high levels of
| |
| ci-gotliioneine in the seminal plasma of the
| |
| boar and stallion is a case in point. The
| |
| cjacuhitcs of these species have peculiarities
| |
| which may render their spermatozoa particularly susceptible to the immobilizing
| |
| action of oxidizing agents, and the suggestion (Mann and Leone, 1953; IMann, Leone
| |
| and Polge, 1956) that ergothioneine, in virtue of its reducing properties, serves a protective function in boar and stallion semen
| |
| seems an eminently reasonable one. However, the accessory glands of many animals
| |
| secrete certain substances {e.g., glycerophosphorylcholine, spermine, citric acid)
| |
| that do not appear to be of any particular
| |
| value for the survival of spermatozoa in
| |
| the male or female genital tracts. Perhaps
| |
| these substances are simply by-products
| |
| of the secretory mechanisms of the glands
| |
| from which they originate, or represent biochemical vestiges.
| |
| | |
| The widespread occurrence of fructose in
| |
| accessory gland secretions deserves further
| |
| comment. The only other situation where
| |
| large amounts of fructose are present in
| |
| mammalian extracellular fluids under normal physiologic conditions is in the fetal
| |
| blood of ungulates (Bernard, 1855; Bacon
| |
| and Bell, 1948; Alexander, Huggett, Nixon
| |
| and Widdas, 1955). Mammalian spermatozoa metabolize glucose just as well as fructose as a source of energy under anaerobic
| |
| and aerobic conditions. Indeed, glucose has
| |
| been used widely as the sole glycolyzable
| |
| sugar in artifi^l diluents employed in the
| |
| storage of semen for artificial insemination
| |
| (Mann, 1954a). Thus fructose does not
| |
| seem to be more beneficial than glucose
| |
| to the well being of spermatozoa. There is
| |
| evidence that the utilization of fructose, in
| |
| contrast to glucose, is not impaired in the
| |
| diabetic state (Chernick, Chaikoff and
| |
| Abraham, 1951 ; Renold, Hastings and Nesbett, 1954) . It is conceivable that the presence of fructose in semen w^ould render the
| |
| spermatozoa relatively insensitive to insulin. But it would seem more probable that
| |
| the physiologic value of seminal fructose
| |
| is related to factors other than the maturation or survival of spermatozoa. Mann
| |
| (1954a) has pointed out that if glucose
| |
| were the only glycolyzable sugar in semen,
| |
| its concentration would not be expected to
| |
| exceed that of blood. The transformation of
| |
| blood glucose into seminal fructose by the
| |
| accessory glands permits the establishment
| |
| of very high levels of fructose in semen.
| |
| Furthermore, the formation of seminal fructose is strictly controlled by androgenic
| |
| hormones, and it would be hard to conceive
| |
| of a similar hormonal dependence of glucose levels in semen.
| |
| | |
| Although the volume and chemical composition of seminal plasma are influenced
| |
| by many factors, androgenic hormones are
| |
| undoubtedly the principal determinants of
| |
| the secretory activity of the accessory
| |
| glands. Chemical and enzymatic constituents of accessory gland secretions such
| |
| as fructose, citric acid, and acid phosphatase have proved to be exquisitely sensitive
| |
| indicators of androgenic activity. The application of such "chemical tests" for androgen action has provided important
| |
| corroborative evidence for previous conclusions, based on purely morphologic
| |
| studies, that the initiation of mature secretory function of the accessory glands precedes the appearance of sperm in the seminiferous tubules, and also that the adverse
| |
| effects of malnutrition on the functional
| |
| activity of the prostate gland and seminal
| |
| vesicle are mediated via the hypophysis.
| |
| Chemical investigations have established
| |
| that the major portion of certain components (glycerojihosphorylcholine, glycosidases ) of the seminal plasma of some species
| |
| originates from the epididymis. The way
| |
| to the successful treatment of metastatic
| |
| carcinoma of the prostate in man by antiandrogenic measures was paved by the
| |
| availability of a chemical systemic index
| |
| of the hormonal dependence of many of
| |
| these neoplasias, viz., the acid phosphatase
| |
| of blood serum. Changes in the chemistry
| |
| of some accessory organs (e.g., the fructose
| |
| content of the rat coagulating glandj seem
| |
| to l)e more sensitive indicators of the action of exogenous androgens in castrated
| |
| animals than the weights or histologic
| |
| structure of these organs. The application of
| |
| such chemical methods to the bioassay of androgens holds much promise for the future.
| |
| Finally, it may be mentioned that chemical studies of the secretions of the accessory
| |
| glands have given insight into the homology
| |
| of these organs. The finding of high concentrations of citric acid, but not of fructose, in the rat female prostate after stimulation with androgens shows that the
| |
| secretion of this tissue resembles that of the
| |
| ventral prostate gland of the male rat. On
| |
| the other hand, structures which are usually considered to be anatomically and
| |
| functionally homologous may secrete quite
| |
| different substances. Thus in the guinea
| |
| pig and bull, both citric acid and fructose are secreted by the seminal vesicles,
| |
| whereas in the rat, citric acid is produced
| |
| by the seminal vesicles and fructose is
| |
| formed only in the dorsolateral prostate
| |
| and coagulating glands.
| |
| | |
| ===D. Metabolism of the Prostate and Seminal Vesicle===
| |
| | |
| The metabolism of the male accessory
| |
| reproductive glands, and the activity of
| |
| many enzymes therein, are influenced profoundly by steroid hormones. In adult animals, excision of the testes results in a
| |
| rapid decline in the respiration, but not of
| |
| the anaerobic glycolysis, of slices of the
| |
| prostate gland of the dog (Barron and
| |
| Huggins, 1944), and of the rat prostate
| |
| (Homma, 1952; Nyden and Williams-Ashman, 1953; Bern, 1953; Rudolph and
| |
| Starnes, 1954; Butler and Schade, 1958)
| |
| and seminal vesicle (Rudolph and Samuels,
| |
| 1949; Porter and Melampy, 1952; Rudolph
| |
| and Starnes, 1954j. The post-castrate fall
| |
| in oxygen consumption by these tissues can
| |
| be reversed by the administration of testosterone. The respiration of the epithelium
| |
| (but not of the muscle) of the guinea pig
| |
| seminal vesicle responds in a similar way to
| |
| androgen deprivation (Levey and Szego,
| |
| 1955b). The stimulatory effect of testosterone on the respiration of the prostate
| |
| gland and seminal vesicle of castrated rats
| |
| is not prevented by the simultaneous administration of hydrocortisone (Rudolph
| |
| and Starnes, 1954).
| |
| | |
| The activity of a number of respiratory
| |
| enzymes in the rat prostate gland is decreased by castration to about the same
| |
| extent as the respiration of slices of this
| |
| tissue. This is true for the succinic and cytochrome oxidase systems (Davis, Meyer
| |
| and McShan, 1949), and for fumarase,
| |
| aconitase, and malic dehydrogenase (Williams-Ashman, 1954). But the succinic oxidase levels in two other androgen-sensitive
| |
| tissues are uninfluenced by castration, viz.,
| |
| the epithelium of the guinea pig seminal
| |
| vesicle (Levey and Szego, 1955b), and the
| |
| levator ani muscle of the rat (Leonard,
| |
| 1950). In the rat prostate, androgens have
| |
| little influence on the activity of the glycolytic enzymes enolase and lactic (l(>hydrogenase, and of the TPN-specific enzymes
| |
| which oxidize isocitrate, glucose 6-phosphate and 6-phosphogluconate (WilliamsAshman, 1954; Rudolph, 1956). The enzymatic machinery responsible for the respiration of the male accessory glands seems to
| |
| be similar to that of other mammalian tissues (Barron and Huggins, 1946a, b; Nyden
| |
| and Williams-Ashman, 1953; WilliamsAshman, and Banks, 1954b; Williams-Ashman, 1954, 1955; Levey and Szego, 1955a).
| |
| Glock and McLean (1955) have shown
| |
| that, as in most other mammalian tissues,
| |
| the levels of DPN in rodent prostate and
| |
| seminal vesicle are higher than those of
| |
| DPNH, whereas the content of TPNH is
| |
| much greater than that of TPN.
| |
| | |
| Nyden and Williams-Ashman (1953)
| |
| found that the respiration-coupled synthesis of long-chain fatty acids from acetate
| |
| by ventral prostate slices m viti'o was depressed by castration to a greater extent
| |
| than the respiration, and could be restored
| |
| to normal levels by testosterone therapy.
| |
| Certain other synthetic reactions (the incorporation of P^--labeled inorganic phosphate into phospholipids, total nucleic
| |
| acids, and phosphoproteins) were less sensitive to androgens under these conditions.
| |
| However, in experiments involving the injection of P-^--labeled inorganic phosphate
| |
| into animals, the administration of androgen increased the turnover of various acidinsoluble phosphorus containing fractions.
| |
| Thus Levin, Albert and Johnson (1955)
| |
| observed that testosterone increases the
| |
| turnover of various phospholipids in the
| |
| lirostate gland and seminal vesicle. In the
| |
| seminal vesicle, Fleischmann and Fleischmann (1952) found that the entry of P-'into the desoxyribonucleic acid fraction
| |
| was increased 100-fold by androgen administered to castrate rats, whereas the
| |
| sjiecific radioactivity of the ribonucleic
| |
| acid was increased only 2-fold. Cytoplasmic basophilia in the rat seminal vesicle
| |
| (Melampy and Cavazos, 1953), and the
| |
| endoplasmic reticulum of the ventral prostate gland (Harkin, 1957a), which are intimately associated with cytoi)lasmic ribonucleic acid, are influenced profoundly by
| |
| androgenic hormones.
| |
| | |
| Transamination bet^^■een glutamate and
| |
| cither pyruvate or a-ketoglutarate was
| |
| shown by Barron and Huggins (1946b) to
| |
| proceed rapidly in canine and human prostate tissues. Awapara (1952a. bl reported
| |
| that the ahmine (but not aspartic) transaminase activities of the ventral prostate
| |
| gland of the rat were decreased by castration, and increased by testosterone therapy.
| |
| | |
| Rudolph and Starnes (1954) studied the
| |
| water distribution in the rat accessory
| |
| glands. The extracellular water in normal
| |
| seminal vesicles and prostates was 13.8 per
| |
| cent and 8.5 per cent, respectively. The
| |
| corresj^onding values in castrate animals
| |
| were 37.0 per cent and 31.8 per cent. The
| |
| growth of the glands which resulted from
| |
| treatment with testosterone was accompanied by a greater increase in the intracellular water than in extracellular water.
| |
| Rudolph and Samuels (1949) provided evidence that changes in the water content of
| |
| seminal vesicles induced by treatment of
| |
| castrate rats with testosterone did not \)recede metabolic changes (e.g., fructose synthesis) in this tissue.
| |
| | |
| The pronounced effects of androgen administration in vivo on the metabolism and
| |
| enzymatic activity of the accessary glands
| |
| cannot be mimicked by the addition of androgens in vitro. Dirscherl, Breuer and
| |
| Scheller (1955) reported that low levels of
| |
| testosterone stimulated the respiration of
| |
| mouse seminal vesicles if the control respiration was low. But others have found that
| |
| the respiration and glycolysis of male accessory glands are uninfluenced by the direct addition of androgens /// I'itro except
| |
| at high concentrations (>5 X 10~^ m), at
| |
| which testosterone is inhibitory (Bern,
| |
| 1953; McDonald and Latta, 1954, 1956; Andrewes and Taylor, 19551. According to
| |
| Farnsworth (1958), the direct addition of
| |
| testosterone to prostate tissue impedes citrate synthesis to a greater extent than oxygen consumption. Williams-Ashman (1954)
| |
| found that the in vitro addition of testosterone did not affect the activity of a number of respiratory and glycolytic enzymes
| |
| in the rat A-entral prostate gland.
| |
| | |
| The mechanism of action of androgenic
| |
| hormones at a molecular level is not known.
| |
| There is no evidence that androgens are directly involved in the large changes in the
| |
| activity of some enzyme systems in accessory glands which follow the administration
| |
| or deprivation of these hormones. Recent
| |
| studies wliich indicate that minute concentrations of certain steroid hormones can
| |
| stimulate the transfer of hydrogen between
| |
| pyridine nucleotides by isolated enzyme
| |
| systems deserve further comment. A soluble
| |
| enzyme in human placenta catalyzes an
| |
| estradiol- 17y8-dependent exchange of hydrogen between TPNH and DPN (Talalay
| |
| and Williams-Ashman, 1958). There is evidence in favor of the hypothesis (Talalay,
| |
| Hurlock and Williams-Ashman, 1958; Talalay and Williams-Ashman, 1960) that estradiol- 17^ transports hydrogen in this reaction by undergoing reversible oxidation
| |
| to estrone:
| |
| | |
| Estrone + TPNH + H+ ^ Estradiol-17/3 + TPN
| |
| EstradioI-17/3 + DPN ^
| |
| | |
| Estrone + DPNH + H+
| |
| TPNH + DPN ^ TPN + DPNH
| |
| | |
| Hagerman and Villee (1959), however,
| |
| believe that estradiol- 17/;^ and estrone mediate transhydrogenation between TPXH
| |
| and DPN by a mechanism which does not
| |
| involve oxido-reduction of the steroids.
| |
| Hurlock and Talalay (1958) showed that
| |
| a soluble 3a-hydroxysteroid dehydrogenase
| |
| isolated from rat liver catalyzes hydrogen
| |
| transfer between pyridine nucleotides in the
| |
| presence of catalytic levels of androsterone
| |
| and some other 3a-hydroxysteroids. In this
| |
| instance also, it seems that the steroids act
| |
| in a coenzyme-like manner by undergoing
| |
| alternate oxidation and reduction. However,
| |
| biologically inactive steroids such as etiocholan-3a-ol-17-one are even more active
| |
| than androgenic substances such as anch'osterone in this isolated enzyme system.
| |
| Hurlock and Talalay (1959) reported that
| |
| the particle-bound 3a- and 11^-hydroxysteroid dehydrogenases of rat liver react at
| |
| comparable rates with both TPX and DPN,
| |
| and they suggest that these dehydrogenases
| |
| might function as transhydrogenases in the
| |
| presence of their appropriate steroid substrates. The hydroxy steroid dehydrogenases
| |
| for which there is direct or circumstantial
| |
| evidence for their ability to function as
| |
| transhydrogenases are localized either in
| |
| the microsomes (endoplasmic reticulum) or
| |
| in the soluble cell sap. Other enzymes that
| |
| catalyze the transfer of hydrogen between
| |
| pyridine nucleotides are bound to the mitochondria of many animal tissues (Stein,
| |
| | |
| | |
| Kaplan and Ciotti, 1959; c/. Talalay, Hurlock and Williams-Ashman, 1958). These
| |
| mitochondrial transhydrogenases do not require steroid hormones as cof actors. According to Hmiiphrey (1957), the large cytoplasmic particles of rat prostate gland and
| |
| seminal vesicle are devoid of transhydrogenase activity. Slices of human prostate
| |
| gland convert testosterone to androst-4ene-3,17-dione (and other metabolites)
| |
| (Wotiz and Lemon, 1954; Wotiz, Lemon
| |
| and Voulgaropoulos, 1954). This suggests
| |
| that the human prostate contains a 17/3hydroxysteroid dehydrogenase which could
| |
| conceivably function as a transhydrogenase
| |
| in the presence of low levels of testosterone.
| |
| Baron, Gore and Williams (1960) reported
| |
| the presence of androsterone-stimulated
| |
| transhydrogenase reactions in the prostate
| |
| gland of rodents and man. On the contrary,
| |
| Williams-Ashman, Liao and Gotterer
| |
| (1958), and Samuels, Harding and Mann
| |
| (1960) were unable to demonstrate any activation by testosterone of hydrogen transfer between TPNH and DPN in rat prostatic tissue. DPNH and TPNH serve
| |
| rather different metabolic functions (c/.
| |
| Talalay and Williams-Ashman, 1958), and
| |
| it is possible that steroid-mediated transhydrogenations might exert a controlling
| |
| influence over the balance between the oxidized and reduced forms of pyridine nucleotides in the extramitochondrial regions of
| |
| certain cells. However, at present there is no
| |
| direct evidence in support of this hypothesis
| |
| (cf. Talalay and Williams-Ashman, 1960).
| |
| | |
| ===E. Coagulation of Semen===
| |
| | |
| Mammalian semen is emitted from the
| |
| urethra as a liquid. In some species, e.g.,
| |
| the bull and the dog, the semen remains
| |
| permanently in the liquid state. But the
| |
| seminal fluid of many other mammals may
| |
| undergo remarkable changes in its physical
| |
| IM^operties on standing. Rodent semen clots
| |
| rapidly and, if ejaculated into the vagina,
| |
| forms a solid vaginal plug. This structure
| |
| assists fertilization by preventing an outflow of semen from the vagina after copulation (Blandau, 1945). The subsequent
| |
| dissolution of the vaginal plug, probably
| |
| as the result of the action of leukocytic enzymes, was studied by Stockard and Pajianicolaou (1919). A copulatory plug lias also been described in certain Insectivora,
| |
| Chiroptera, and Marsupiala (Camus and
| |
| Gley, 1899; Engle, 1926a; Courrier, 1925;
| |
| Eaclie, 1948a, bj.
| |
| | |
| It has been stated that in the opposum
| |
| (Hartman, 1924) and in the bat (Courrier,
| |
| 1925), the vaginal plug results from the
| |
| coagulation of the female secretions by
| |
| seminal plasma. However, the semen of
| |
| many other species clots on its own accord.
| |
| Camus and Gley (1896, 1899) were the
| |
| first to recognize that in the rat and guinea
| |
| pig, the clotting process involves the solidification of the vesicular secretion by an
| |
| enzyme of prostatic origin, which they
| |
| termed vesiculase. The classical experiments of Walker (1910a, b) showed that
| |
| this enzyme is secreted solely by the anterior prostate or "coagulating" gland. In
| |
| the rhesus monkey, the secretion of the
| |
| cranial lobe (but not of the caudal lobe) of
| |
| the prostate gland coagulates the vesicular
| |
| secretion (van Wagenen, 1936) . The "soft
| |
| calculus" frequently present in the urinary
| |
| bladder of male but not female rats is
| |
| l^robably formed by clotting of the seminal
| |
| vesicle secretion by the action of enzymes
| |
| from the coagulating gland (Vulpe, Usher
| |
| and Leblond, 1956) .
| |
| | |
| More recently, the mechanism of action
| |
| of vesiculase has been studied in considerable detail. A crude preparation of the proteins of the vesicular secretion that are
| |
| clotted by this enzyme can be obtained in
| |
| a stable form, and the clotting process may
| |
| l)e measured quantitatively by simple spectrophotometric procedures (Gotterer, Ginsburg, Schulman, Banks and Williams-Ashman, 1955; Gotterer and Williams-Ashman,
| |
| 1957; Zorgniotti and Brendler, 1958). The
| |
| over-all coagulation process is extremely
| |
| sensitive to the ionic strength of the solution in which it takes place, and is abolished
| |
| by the addition of metal chelating agents
| |
| such as Versene (ethylcnediaminetetraacetic acid), o-i)henanthroline, and a,adipyridyl, and also by heavy metals such
| |
| as mercuric ions. The inhibitory action of
| |
| Versene can be overcome by manganous
| |
| ions, or by somewhat higher concentrations
| |
| of calcium ions. Experiments involving the
| |
| delayed addition of either heavy metal ions
| |
| or of metal chelating agents established that
| |
| till' coagulation process can be separated into two distinct phases (Gotterer and
| |
| AVilliams-Ashman, 1957). The first of these
| |
| requires a metal ion such as Mn++, is inhibited by Versene, and does not necessarily
| |
| involve the precipitation of insoluble material. The second phase, which is insensitive to the action of metal chelating agents,
| |
| is inhibited by mercuric ions and leads to
| |
| the formation of a coagulum. The coagulated material is protein in nature.
| |
| | |
| Further fractionation of the vesicular
| |
| secretion by Speyer (1959) led to the isolation of a heat-stable protein, coagulinogen, which is the precursor of the insoluble
| |
| material of the vaginal plug, but is not
| |
| clotted by vesiculase. Speyer (1959) isolated another, heat-labile protein from
| |
| vesicular secretion which he designated
| |
| procoagulase, and which is converted into
| |
| a clotting enzyme coagulase by the action
| |
| of vesiculase. The coagulation of the seminal vesicle secretion by the prostatic enzyme vesiculase thus seems to take place
| |
| by the following reactions:
| |
| | |
| „ , Vesiculase „ ,
| |
| | |
| rrocoagulase > Coagulase
| |
| | |
| Coagulinogen °^^" '^^^ — ^ Coagulated protein
| |
| | |
| Only the first reaction is inhibited by
| |
| Versene.
| |
| | |
| Partial purification of vesiculase has
| |
| l>een achieved (Gotterer, Ginsburg, Schulman. Banks and Williams-Ashman, 1955).
| |
| Vesiculase is quite distinct from another
| |
| enzyme in the secretion of the coagulating
| |
| gland of guinea pigs which hydrolyzes, inter alia, tosyl-L-arginine methyl ester
| |
| (TAMe) (Gotterer, Banks and WilliamsAshman, 1956). Unlike thrombin, vesiculase does not hydrolyze TAMe and does not
| |
| clot fibrinogen. The dissimilarity between
| |
| the coagulation of blood and of semen is
| |
| further borne out by the failure of thrombin
| |
| to clot the proteins of the vesicular secretion, and by the inability of TA]\Ie (which
| |
| depresses the action of thrombin) to inhibit
| |
| vesiculase action.
| |
| | |
| Electrical stimulation of the head of the
| |
| guinea pig induces ejaculation without
| |
| voiding of either urine or feces (Batelli,
| |
| 1922). Ejaculates obtained in this manner
| |
| from normal, sexually mature guinea pigs
| |
| coagulate rapidly. After castration, the semen is no longer coagulable, but becomes so a few days after treatment with androgens (Moore and Gallagher, 1930). This
| |
| "electric ejaculation test" can be used as
| |
| an indicator for androgenic activity (c/.
| |
| Sayles, 1939, 1942).
| |
| | |
| It is generally believed that human semen is ejaculated as a fluid, and then coagulates (Lane-Roberts, Sharman, Walker
| |
| and Wiesner, 1939; Joel, 1942; Huggins
| |
| and Neal, 1942; Lundquist, 1949), although
| |
| some authors state that it is emitted in a
| |
| gelatinous form (Pollak, 1943; Hammen,
| |
| 1944; Oettle, 1954). But there is no doubt
| |
| that the semen from normal men subsequently liquifies if kept at room temperature.^ Human semen possesses strong fibrinolytic activity (Huggins and Neal,
| |
| 1942; Harvey, 1949; Ying, Day, Whitmore
| |
| and Tagnon, 1956). The prostate gland of
| |
| men secretes a proteolytic enzyme, fibrinolysin, which is probably responsible for the
| |
| phenomenon of liquefaction. Prostatic fibrinolysin is produced in large amounts by
| |
| certain cancers of the prostate in man, and
| |
| seems to enter the circulation since there
| |
| is a pronounced bleeding tendency in such
| |
| patients (Tagnon, Schulman, Whitmore
| |
| and Leone, 1953; Scott, Matthews, Butterworth and Frommeyer, 1954; Swan, Wood
| |
| and Owen, 1957). Canine semen, which
| |
| does not clot, contains little fibrinolysin,
| |
| but is rich in another proteolytic enzyme,
| |
| fibrinogenase, which hydrolyzes fibrinogen.
| |
| Little fibrinogenase is present in human
| |
| semen (Huggins and Neal, 1942). The presence of related proteolytic enzymes in the
| |
| secretions of the male accessory glands is
| |
| described above.
| |
| | |
| ^ Louis Nicolas Vauquelin published the first
| |
| paper on the chemistry of seminal fluid (Vauquelin, 1791). This remarkable study includes a
| |
| detailed and accurate account of the liquefaction
| |
| of human semen which is quite unexcelled by later
| |
| writings. It also describes the formation, in ejaculates which had stood for three or four days, of
| |
| "cristaux transparens, d'environ une hgne de long,
| |
| tres-minces, et qui se croisent souvent de maniere
| |
| a representer les rayons d'une roue. Ces cristaux
| |
| isoles nous ont offer, a I'aide d'un verre grossissant,
| |
| la forme d'un solide a quatre pans, termines par
| |
| des pyramides tres-allongees, a quatre faces." Although Vauquelin believed that these crystals were
| |
| composed of calcium phosphate, Mann (1954a)
| |
| has pointed out that he had, in reality, obser\ed
| |
| the deposition of spermine phosphate in aged
| |
| semen.
| |
| | |
| | |
| Freund and Thompson (1957) reported
| |
| that intravenous injection of crude guinea
| |
| pig coagulating gland secretion into rabbits or guinea pigs induces hypotensive
| |
| shock. Edema results if the secretion is
| |
| injected locally. The secretion of the coagulating gland of the rat does not possess
| |
| these properties. Further studies by Freund,
| |
| Miles, Mill and Wilhelm (1958) showed
| |
| that two main protein fractions can be separated from the secretion of the guinea pig
| |
| coagulating gland by preparative starch
| |
| electrophoresis. Fraction I was hypotensive
| |
| and a potent permeability factor in rabbits
| |
| and guinea pigs. It hydrolyzed TAMe rapidly and may be identical with the TAMehydrolyzing enzyme described in guinea
| |
| pig coagulating gland l)y Gotterer, Banks
| |
| and Williams-Ashman (1956). The latter
| |
| enzyme is not present in the coagulating
| |
| gland of the rat. Fraction II isolated by
| |
| Freund and his associates is ]n"obably vesiculase.
| |
| | |
| III. Structure and Function in
| |
| Relation to Hormones
| |
| | |
| A. INTRODUCTION
| |
| | |
| Some of the effects of removal of the
| |
| testes in males have been recognized ever
| |
| since castration was first practiced on man
| |
| and domestic animals. Aristotle's writings
| |
| include accurate descriptions of the effects
| |
| of castration on secondary sex characters
| |
| in birds and in man. The classical studies
| |
| of John Hunter (1792) laid the basis for
| |
| an understanding of the relation between
| |
| the presence of the testes and the size and
| |
| functional state of the accessory reproductive glands of mammals, although he did
| |
| not postulate the existence of testicular
| |
| hormones.
| |
| | |
| Hunter demonstrated experimentally
| |
| that the seminal vesicles of guinea pigs are
| |
| not reservoirs for semen and concluded that
| |
| this a])plies to the seminal vesicles in man
| |
| and in other mammals. He not only described the gross anatomy of the seminal
| |
| vesicles in many species (hedgehog, iiiole.
| |
| man, boar, bull, horse, buck, mouse, rat,
| |
| beaver, guinea pig) and their absence fi'om
| |
| others, but he observed tliat they arc smaller
| |
| in the gelding than in the stallion. In
| |
| refei'ence to other glands, he generalized
| |
| | |
| | |
| | |
| that "the prostate gland, Cowper's glands
| |
| and the glands along the urethra . . . are in
| |
| the perfect male large and pulpy, secreting
| |
| a considerable quantity of slimy mucus
| |
| which is salt to the taste . . . while in the
| |
| castrated animal these are small, flabby,
| |
| tough and ligamentous, and have little secretion." In addition, he made the equally
| |
| important discovery that the testes of
| |
| mammals (and birds as well) are very
| |
| small in winter in animals ''which have
| |
| their seasons of copulation" and the seminal vesicles and prostates are "hardly discernable." He concluded that "from these
| |
| observations it is reasonable to infer that
| |
| the use of the vesiculae in the animal
| |
| oeconomy must, in common with many
| |
| other parts, be dependent upon the testicles."
| |
| | |
| Over 100 years later, many of his observations were rediscovered, extended, and
| |
| interpreted in the light of the first demonstration that the testis is an endocrine organ (Berthold, 1849). In the early part of
| |
| the 20th century the interest in attempting
| |
| to isolate and characterize androgens from
| |
| testis tissue and urine led to a search for
| |
| rapid and dependable bioassay methods.
| |
| The cock's comb provided a sensitive and
| |
| convenient test object (Pezard, 1911). In
| |
| addition, some of the accessory reproductive glands of mammals were found to
| |
| atrophy rapidly after castration and proved
| |
| also to be sensitive indicators for the presence of androgenic hormones. Cytologic
| |
| tests using the rat prostate, seminal vesicles, and Cowper's glands were developed
| |
| and an electric ejaculation test in the guinea
| |
| l)ig was devised (Moore, 1932, 1939).
| |
| Weights, sizes, cytologic structure, and mitotic activity in mouse seminal vesicles
| |
| were suggested as bioassay methods for androgenic hormones (Deaneslv and Parkes.
| |
| 1933).
| |
| | |
| After th(> successful isolation and chemical characterization of androgens and estrogens from various sources, interest centered on the fundamental relationships of
| |
| androgens to normal develojjment, histologic structure, and secretory activity of
| |
| the accessory glands in many species of
| |
| inainmals. The effects of estrogens and gestagens and the competitive and synergistic
| |
| i'elationshii)s of steroid hormones were examined. The results of this early work
| |
| contributed extensively to the fields of biochemistry, biology, and medicine. More
| |
| recently there have been studies on the relation of hormones to the ultrastructure, histochemistry, and metabolism of the glands,
| |
| and to the chemical composition of their
| |
| secretions ( Section II I .
| |
| | |
| In the following section, the hormonal
| |
| control of structure and function will be
| |
| discussed with particular reference to the
| |
| luniierous studies on the prostate glands
| |
| and seminal vesicles of rats and mice.
| |
| | |
| B. EFFECTS OF ANDROGENS
| |
| | |
| The term androgen will be used in the
| |
| collective sense for substances that are
| |
| capable of stimulating accessory reproductive glands in castrated animals and
| |
| maintaining normal histologic structure and
| |
| secretory activity in the epithelium. Androgenic substances are formed by the testes,
| |
| ovaries, and adrenal cortex. All androgens
| |
| which have been characterized are steroids.
| |
| The urine contains many androgen metabolites, mainly in the form of their conjugates
| |
| with either glucuronic or sulfuric acids.
| |
| Testosterone is the principal androgen secreted by the testis and this substance, or
| |
| tiie longer acting testosterone propionate,
| |
| is most commonly used as a replacement
| |
| for testicular androgen. In the last two
| |
| decades a number of unnatural androgens
| |
| [e.g., 17a-methyl testosterone) have been
| |
| synthesized and found to possess strong
| |
| biologic activity. The relationship between
| |
| chemical structure of steroids and andro
| |
| | |
| | |
| genic activity in a variety of bioassay procedures is discussed by Dorfman and Shipley (1956).
| |
| | |
| 1. Testicular Androgens
| |
| | |
| The effects of endogenous and exogenous
| |
| androgen on weight, histologic structure,
| |
| and secretory activity of the accessory
| |
| glands have been reviewed by Moore
| |
| (1939), Price (1947), Burrows (1949),
| |
| Dorfman (1950), Dorfman and Shipley
| |
| (1956) and many others. Aspects of metabolic activity have been treated by Roberts
| |
| and Szego (1953) and Mann (1954a).
| |
| | |
| The first detailed cytologic studies of
| |
| male accessory glands and the changes following castration and hormone administration were made on the prostates, coagulating glands, and seminal vesicles of adult
| |
| rats (Moore, Price and Gallagher, 1930;
| |
| Moore, Hughes and Gallagher, 1930). Extensive research on structure and function
| |
| of these and other accessory glands in many
| |
| species followed this early work, but the
| |
| cytologic structure of prostates and seminal
| |
| vesicles of rats and mice remains one of the
| |
| most sensitive indicators for androgenic
| |
| hormones.
| |
| | |
| Rat PROSTATE AND SEMINAL VESICLES. Ventral prostate. In the normal adult gland, the
| |
| columnar secretory epithelium has basal
| |
| nuclei with conspicuous nucleoli and chromatin particles, and a supranuclear clear
| |
| zone or light area in the cytoplasm corresponding to the position of the Golgi zone
| |
| (Figs. 6.8, 6.9, and 6.14). In osmium preparations, the Golgi apparatus appears as
| |
| | |
| | |
| | |
| | |
| Fics. (3.8 Axn 6.9. Rat ventral prostate from a normal adult male. X 5UU and lOUU. Boinnhematoxylin preparations. (From C. R. Moore, D. Price and T. F. Gallagher, Am. J. Anat.,
| |
| 45, 71-107, 1930.)
| |
| | |
| | |
| | |
| 400
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| heavy strands or networks (Figs. 6.19 and
| |
| 6.22) which do not conform precisely to
| |
| the shape or area of the cytoplasmic clear
| |
| zone. Mitochondria are distributed as rods
| |
| or granules in all parts of the cell. The secretion in the lumina of the alveoli is eosinophilic and mainly granular. A basement
| |
| membrane rests on a stroma of connective
| |
| tissue containing smooth muscle strands
| |
| and blood vessels. Occasional small basal
| |
| cells are wedged between the tall secretory
| |
| cells. These observations were made by
| |
| light microscopy of tissues fixed and stained
| |
| by routine methods (Moore, Price and Gallagher, 1930).
| |
| | |
| | |
| | |
| Electron microscopy (Harkin, 1957a)
| |
| shows that the epithelial cells have an endoplasmic reticulum or ergastoplasm composed of membrane-lined sacs with a finely
| |
| granular component in the spaces between
| |
| them (Figs. 6.27 to 6.29) ; the outside of
| |
| the thin membrane is studded with Palade's
| |
| granules (Palade, 1955). The arrangement
| |
| of the sacs tends to parallel the long axis
| |
| of the cells, but in cross section the pattern
| |
| ai)pears concentric or lamellar, particularly
| |
| in the supranuclear region (Fig. 6.29). The
| |
| ergastoplasmic sacs occupy more space than
| |
| the matrix apically, but basally the two are
| |
| equally prominent (Fig. 6.28). The mem
| |
| | |
| | |
| TABLE 6.6
| |
| | |
| Summary of the effects of testicular androgen, on the rat prostate and coagulating glands
| |
| | |
| | |
| | |
| Normal Males
| |
| | |
| | |
| | |
| Castrated Males
| |
| | |
| | |
| | |
| General Characteristics
| |
| | |
| | |
| | |
| All lobes
| |
| alveoli witli folded inueosa; secretion in the lumina..
| |
| columnar epithelial cells: cytoplasm granular or foamy.
| |
| supranuclear clear zone in cytoplasm (ventral lobe)
| |
| | |
| Golgi supranuclear networks
| |
| | |
| mitochondria as rods or granules
| |
| | |
| nuclei basal or central
| |
| | |
| stroma of connective tissue and smooth muscle
| |
| | |
| | |
| | |
| Size reduced; villi lost; secretion reduced
| |
| | |
| Size reduced; pseudostratified; cytoplasm less dense
| |
| | |
| Clear zone lost
| |
| | |
| Reduced in amount; fragmented
| |
| | |
| Still numerous but reduced in relative numbers
| |
| | |
| Shrunken and pyknotic
| |
| | |
| Increased fibromuscular tissue
| |
| | |
| | |
| | |
| Specific Characteristics
| |
| | |
| | |
| | |
| Ventral lobes
| |
| | |
| Histochemical observations:
| |
| | |
| secretion in lumina strongly PAS- and alkaline phosphatase-positive . . .
| |
| | |
| cytoplasm weak PAS, strong alkaline phosphatase activity;
| |
| | |
| basophilic reaction except in clear zone
| |
| | |
| Golyi accumulations of PAS-positive granules
| |
| | |
| stroma some alkaline phosphatase activity
| |
| | |
| Electron microscopic observations:
| |
| | |
| cytoplasm moderately distended ergastoplasmic sacs
| |
| | |
| Golgi supranuclear microvesicular complex
| |
| | |
| mitochondria numerous, prominent apically
| |
| | |
| Lateral lobes
| |
| | |
| Histochemical observations:
| |
| | |
| cyioplasm luminal border organelle with high concentrations of zinc and
| |
| basophilic material; osmiophilic, argentophilic
| |
| | |
| nucleoli high concentrations of zinc and marked basophilia
| |
| | |
| stroma high concentrations of zinc; basojihilic material (jresent
| |
| Dorsal lobes
| |
| Histochemical observations:
| |
| | |
| cytoplasm in apical region strongly basophilic; basally, some zinc
| |
| | |
| nucleoli high concentrations of zinc and marked basophilia
| |
| | |
| stroma basophilic material; strong alkaline i)hosphatase reaction
| |
| | |
| Electron microscopic observations:
| |
| | |
| cytoplasm distended ergastoplasmic cisternae;
| |
| | |
| Coagulating glands (anterior prostate)
| |
| Histocheinical observations:
| |
| | |
| secretion strongly PAS-positive
| |
| | |
| cytoplasm weak P.\S reaction
| |
| | |
| stroma some alkaline phosphatase activity
| |
| | |
| Electron microscopic observations:
| |
| | |
| cyioplasm extremely dilated ergastoplasmic cisternae
| |
| | |
| | |
| | |
| Some phosphatase activity retained
| |
| Phosphatase activity low
| |
| | |
| | |
| | |
| Sacs collapsed; granvilar component reduced
| |
| | |
| Reduced in size
| |
| | |
| Reduced in relative numbers
| |
| | |
| | |
| | |
| Cisternae collapse
| |
| | |
| | |
| | |
| granules reduced
| |
| | |
| | |
| | |
| pears unalterc
| |
| | |
| | |
| | |
| Cisternae collapsed; granules reduced
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 401
| |
| | |
| | |
| | |
| hrane is continuous with the outer nuclear
| |
| membrane. The Golgi complex is conspicuous as microvesicles midway between nucleus and lumen. Mitochondria lie in the
| |
| matrix between the sacs and are very prominent in the most apical region. Microvilli
| |
| project into the lumina of the alveoli with
| |
| no interruption of the cytoplasmic, or
| |
| plasma, membrane. The membrane at the
| |
| base of the cell is double (see Fig. 6.28) ;
| |
| one component, the basement membrane,
| |
| continues unbroken under adjacent cells;
| |
| the second forms a part of the double
| |
| plasma membrane between cells. Brandes
| |
| and Groth (1961) have confirmed Harkin's findings and added further observations. Nuclei contain patches of granules
| |
| which are frequently along the inner nuclear membrane; the Golgi complex consists
| |
| of vesicles, vacuoles, and parallel meml)ranes; vesicles and granules surrounded
| |
| by smooth-surfaced membranes are disposed in the cytoplasmic matrix and are
| |
| more numerous apically; the dilated sacs
| |
| or cisternae of the supranuclear region
| |
| seem to intercommunicate.
| |
| | |
| Histochemical studies of basophilia, alkaline phosphatase activity, and the localization of i^eriodic acid-reactive carbohydrates (Periodic acid-Schiff or PAS
| |
| reaction) add further information (Table
| |
| 6.6). Davey and Foster (1950) found basophilia (which was abolished by ribonuclease) distributed through the cytoplasm
| |
| except in the clear area described by Moore,
| |
| Price and Gallagher (1930) as corresponding to the position of the Golgi zone. Stroma
| |
| of the ventral prostate shows some degree
| |
| of alkaline phosphatase activity but luminal secretion and epithelial cells are
| |
| strongly positive (Bern, 1949a), especially
| |
| at the luminal and basal borders (Stafford,
| |
| Rubenstein and Meyer, 1949). The secretion also gives a fairly intense PAS reaction whereas the epithelial cells are only
| |
| slightly reactive; occasionally the Golgi
| |
| apparatus is visible as PAS-positive granules (Leblond, 1950).
| |
| | |
| After castration, there is reduction in cell
| |
| height and loss of the cytoplasmic clear
| |
| zone (Fig. 6.15) within 4 days. On subsecjuent days, cell size continues to decrease
| |
| and nuclei become small and pyknotic
| |
| (Figs. 6.10. 6.16 to 6.18). The Golgi ap
| |
| | |
| | |
| paratus begins to fragment by 10 days; by
| |
| 20 days it consists of granules much reduced in amount (Fig. 6.20) and the basement membrane of the cells disappears
| |
| (Moore, Price and Gallagher, 1930).
| |
| | |
| Harkin (1957a) reported changes observable by electron microscopy within 24
| |
| hours after castration; distention of apical
| |
| ergastoplasmic sacs and reduction in size
| |
| and number of microvilli. By 2 days, there
| |
| is dilation of Golgi microvesicles, collapse
| |
| of the apical ergastoplasmic sacs, and reduction in mass of apical cytoplasm; at 4
| |
| days, massive collapse of sacs, reduction
| |
| in mitochondrial number, and increase in
| |
| electron-dense bodies (Fig. 6.30). The
| |
| granular component is not reduced until 8
| |
| days after castration or longer. Brandes and
| |
| Portela (1960a) noted, briefly, collapse in
| |
| the cisternae of the ergastoplasm, loss of
| |
| the ribonucleic acid- (RNA) rich granules
| |
| from the membranes of the endoplasmic reticulum, and apparent increase in mitochondria but with a reduction in their size
| |
| (Table 6.6).
| |
| | |
| The distribution of alkaline phosphatase
| |
| in the stroma, epithelium, and secretion is
| |
| unchanged 32 days after castration; the
| |
| stroma is still reactive at 120 days but the
| |
| epithelium is completely atrophic (Bern
| |
| and Levy, 1952). (Quantitative determinations of alkaline and acid phosphatases
| |
| showed, however, that activities of both
| |
| enzymes are reduced markedly by 8 days
| |
| (Stafford, Rubenstein and Meyer, 1949).
| |
| The epithelium loses the ability to secrete
| |
| citric acid (see Section IT).
| |
| | |
| Changes after gonadectomy are prevented or reversed by administration of
| |
| androgenic substances. Extracts of bull
| |
| testes (:\Ioore, Price and Gallagher, 1930)
| |
| prevented involution of the epithelium in
| |
| castrates (Fig. 6.11 and 6.21) and androsterone, testosterone, and testosterone propionate prevented or repaired castration
| |
| changes CMoore and Price, 1937, 1938).
| |
| The response of the castrate to androgen
| |
| is rapid; cell hypertrophy begins within
| |
| 23 hours after a single injection of testosterone propionate into males castrated for
| |
| 40 days ; at 35 hours mitotic activity begins
| |
| and reaches a maximum at 43 hours (Burkhart, 1942).
| |
| | |
| Ergastoplasmic sacs in the epithelial cells
| |
| | |
| | |
| | |
| 402
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| ;;^.. Da .^.^^
| |
| | |
| | |
| | |
| | |
| | |
| | |
| I I'- <; II) 0.13. Rat ventr;il lu-o-tatc (Figs. 6 10. H.U) and coagulal iim aland ( Fm- C) 12,
| |
| (i.lo). All pliotomicrographs , lOUU. Fig. 6.10. 20-day cabtiatc. Fig. 6.11. 20-day ca.^tratf injected with testis extract. Fig. 6.12. 20-day castrate. Fig. 6.13. 20-day castrate injected with
| |
| testis extract. (From C. R. Moore, D. Price and T. F. Gallagher, Am. J. Anat., 45, 71-107,
| |
| 1930.)
| |
| | |
| | |
| | |
| are prevented from collapsing by treatment
| |
| of castrates with testosterone and the process is reversed if the androgen is given after
| |
| castration changes have developed (J. C.
| |
| Harkin, personal communication). Alkaline and acid phosphatase levels are essentially normal in castrates injected with
| |
| testost(M'one propionate (Stafford, Rubinstein and Meyer, 1949).
| |
| | |
| Lateral prostate. The epithelial cells in
| |
| normal adult glands are columnar and the
| |
| nuclei are basal, but cell size and nuclear
| |
| position arc more variable than in the ventral prostate ( Korenchevsky and Dcnnison.
| |
| 193.51. The Golgi apparatus appears as
| |
| | |
| | |
| | |
| l^rominent supranuclear networks in osmium stainecl preparations (Rixon and
| |
| Whitfield, 1959).
| |
| | |
| Histochemical studies employing a dithizone zinc stain demonstrated high concentrations of zinc in the apical jiart of the
| |
| cells (Gunn and Gould, 19o6a). Fleischhauer (1957) observed (macroscopically)
| |
| heavy staining that was visible in this lobe
| |
| after intravenous or subcutaneous injections of dithizone. In mifix(Hl frozen sections,
| |
| he found in tlic basal regions of all epithelial cells numerous stained granules
| |
| which lie interpreted as zinc-positive material. 'Hie nature of a rather wide diffusely
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 403
| |
| | |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| IB
| |
| | |
| | |
| | |
| | |
| | |
| | |
| IB
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| 0'^
| |
| | |
| | |
| | |
| | |
| | |
| | |
| IE
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| Figs. 6.14-6.26
| |
| | |
| | |
| | |
| | |
| Figs. 6.14-6.22. Rat ventral prostate. Figs. 6.14-6.21. Camera lucida drawings X 3000. Figs.
| |
| 6.19-6.22. Mann-Kopsch preparations for Golgi apparatus. Fig. 6.14. Normal male. Figs. 6.156.18. From males castrated for 4, 10, 20 and 90 days. Fig. 6.19. Normal male. Fig. 6.20. 20-day
| |
| castrate. Fig. 6.21. 20-day castrate injected with testis extract. Fig. 6.22. Normal male ; photomicrograph X 1000. (From C. R. Moore, D. Price and T. F. Gallaglier, Am. J. Anat., 45, 71107, 1930.)
| |
| | |
| Figs. 6.23-6.26. Rat coagulating gland. Figs. 6.23-6.25. Camera lucida drawings X 3000.
| |
| Fig. 6.23. Normal male. Fig. 6.24. 20-day castrate. Fig. 6.25. 20-day castrate injected with testis
| |
| extract. Fig. 6.26. Normal male; photomicrogaph X 1000; Mann-Kopsch preparation for
| |
| Golgi apparatus. (From C. R. Moore, D. Price and T. F. Gallagher, Am. J. Anat.. 45, 71-107,
| |
| 1930.)
| |
| | |
| | |
| | |
| 404
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| ■^f
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| «#
| |
| | |
| | |
| | |
| Fig. 6.27. R:it xcniinl |.in~i,ii( ikhihiI mil. I ,li . 1 1 uiiiuicrograpli X 8500; LuftV ])prmanganate fixative. Aliciuvilli lxIlikI a^ i)iul()n^atioii.-. ol the cytoplasm into the lumen; a major
| |
| part of the cytoplasm is a labyrinth of ergastoplasmic sacs with scattered mitochondria ; nuclei are basal ; half-way between nucleus and cell apex is a zone of small vesicles and canals,
| |
| the Golgi complex (From J. C. Harkin, un])u})lishe(l.)
| |
| | |
| | |
| | |
| | |
| stained area in the ai)ical cytoi)lasin was
| |
| not clear. Ki.xoii and Whitfield 11959) reported high concentrations of zinc in the
| |
| apical cytoplasm, nucleoli, and stroma in
| |
| fixed tissues stained with dithizone. Tn the
| |
| apical cytoplasm, the zinc is conccnti atcd
| |
| at the tip of the cells in a "luminal l)order
| |
| organelle" which is osmiophilic (distinct
| |
| from the (Jo].o;i apparatus), argent()i)hilic,
| |
| | |
| | |
| | |
| and basophilic. Nucleoli and subepithelial
| |
| sti'oma are basophilic.
| |
| | |
| Castration results in a typical pattern
| |
| of involution in the epithelial cells: size is
| |
| !•(■( bleed, nuclei become small and jwknotic,
| |
| and changes occur in the density of the cytoplasm (Korenchevsky and Dennison,
| |
| 1935; Price, Mann and Lutwak-Mann,
| |
| 1955). The zinc content of the gland (dor
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 405
| |
| | |
| | |
| | |
| solatcral or lateral prostate) and the rate
| |
| of Zn*^^ uptake decrease after gonadectomy
| |
| as does the secretion of citric acid and fructose (see Section II).
| |
| | |
| Dorsal prostate. The epithelium in the
| |
| dorsal prostate of normal rats is columnar
| |
| or cuboidal depending on distention of the
| |
| alveoli; nuclei are basal and stain heavily;
| |
| there is cytoplasmic vacuolization which is
| |
| usually limited to the basal region (Korenchevsky and Dennison, 1935) .
| |
| | |
| Brandes and Groth (1961) described the
| |
| ultrastructure of two different cell types
| |
| in the dorsolateral (or dorsal) lobe. These
| |
| types differ in the relation of cytoplasmic
| |
| matrix to endoplasmic reticulum. In both,
| |
| the matrix is moderatelv homogeneous and
| |
| | |
| | |
| | |
| contains small particles, but in cell type 1,
| |
| the matrix appears as separate profiles and
| |
| the reticulum as membrane-bounded individual cavities. In cell type 2, the reticulum
| |
| forms dilated membrane-bounded cisternae
| |
| which are intercommunicating and the cytoplasmic matrix is reduced mainly to thin
| |
| strands appearing isolated within the cisternae.
| |
| | |
| Gunn and Gould (1956a) reported a
| |
| zinc-negative histochemical reaction in the
| |
| epithelium of the dorsal prostate. Fleischhauer (1957) observed a slight dithizonestain macroscopically, and in unfixed frozen
| |
| sections, individual groups of cells contain
| |
| the distinctive basal zinc-positive granules
| |
| that are characteristic of all epithelial cells
| |
| | |
| | |
| | |
| ...\
| |
| | |
| | |
| | |
| Fl(.i. li..'N. l;;il v,l,ii;,l |Mm-;;:h, n,uM,:,l in.ih. 1 ,1. r i ,, ,i i li i in . ,-i:i [ .1, . 2(;,()()(); 1 ),-| ll ( )ll's
| |
| chrome o^niic and hxatixi . Il;i>:il pari ot epithelial cell to show the character of the granular
| |
| component and ergastopla>iiiic -acs which are essentially equal in amount in this region.
| |
| Double basement membrane indicated by arrow. (From J. C. Harkin, Endocrinology, 60,
| |
| 185-199, 1957.)
| |
| | |
| | |
| | |
| 406
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| ■:^lVi4
| |
| | |
| | |
| | |
| l'"i(..G.2U. Rat \(;iilial lUo.-Uilu, iiuinial iiiak;. I'^lcctionnu'
| |
| acid fixative with sucrose. Supranuclear region of epithelia
| |
| plasmic sacs. (From J. C. Harkin, unpublished.)
| |
| | |
| | |
| | |
| .-laph Is.iiOO; Paladps osmic
| |
| •ell sliowing laniellatetl ergasto
| |
| | |
| | |
| in the lateral lolje. Tiiere is no diffuse staining of the apical cytoplasm. Nucleoli arc
| |
| intensely zinc-positive after fixation and
| |
| staining with dithizone; nucleoli, apical cytoplasm and stroma are basophilic fRixon
| |
| and Whitfield, 1959). The stroma is also
| |
| strongly alkaline phosphatase - positive
| |
| (Bern, 1949a).
| |
| | |
| Epithelial cells respond to castration l»y
| |
| reduction in cell and nuclear size, and loss
| |
| of granulation in the cytoplasm (Korenchevsky and Dennison, 1935). Brandes and
| |
| Portela (1960a) observed in electron micrographs the V)eginning of collapse of the
| |
| | |
| | |
| | |
| cisternae of the endoi)lasmic reticulum, reduction in RNA-rich particles, and changes
| |
| in mitochondria. Histochemical studies
| |
| ( Iicni and Levy, 1952) indicate that distribution of alkaline phosphatase activity remains unchanged. Fructose content is reduced in the gland after castration (Price,
| |
| Mann and Lut\vak-]\Iann, 1955).
| |
| | |
| CocKjulating gland {anterior prostdte) . In
| |
| normal males, the ei)ithelium is columnar
| |
| and rests on a well marked basement membrane; nuclei stain heavily and homogeneously and ai'e situated midway between the
| |
| basement meml)i';iiie and lumen. The cvto
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCriVE GLANDS
| |
| | |
| | |
| | |
| 407
| |
| | |
| | |
| | |
| plasm is not as granular as in the ventral
| |
| prostate and appears vacuolated, particularly in the basal region and around the
| |
| nuclei; the apical cytoplasm is condensed
| |
| and granular (Fig. 6.13, a gland from a
| |
| castrated male injected with testicular extract, illustrates essentially the characteristics of the normal epithelium). Golgi bodies
| |
| ( Fig. 6.26) form large networks close to the
| |
| | |
| | |
| | |
| luminal end of the cells (Moore, Price and
| |
| Gallagher, 1930).
| |
| | |
| The striking characteristic of these cells
| |
| in electron microscopy (Brandes, Belt and
| |
| Bourne, 1959; Brandes and Groth, 1961)
| |
| is the great dilation of the cisternae of the
| |
| endoplasmic reticulum (Fig. 6.31) which
| |
| fill the greatest part of the cell and are particularly distended in the basal region. The
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 6.30. Rut \entral prostate, 4-day castrate. Electronmicrograph X 26,000; Dalton's
| |
| chrome osmic acid fi.xative. Portion of nucleus and di.stal region of epithelial cell. An electron
| |
| dense body lies above the nucleus and below dilatated Golgi microvesicles. Arrow points to
| |
| collapsed ergastoplasmic sacs. (From J. C. Harkin, Endocrinology, 60, 185-199, 1957.)
| |
| | |
| | |
| | |
| 408
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 6.31. Rat coagulating gland, normal male. Electronmiciogiaplis, lefl X 7200; upper and
| |
| lowei- right X 39,000. Caulfield's modification of Palade's osmic acid fixative. Left, ba.sal portions of two epithelial cells; right, details of basal region: bni, basement membrane; ci,
| |
| dilated cisternae; cm, plasma membrane; cy, cytoplasmic matrix; G, Golgi complex; bn,
| |
| limiting membrane of endoplasmic reticulum; w, mitochondria; n, nucleus. (From D.
| |
| Brandes, unpublished.)
| |
| | |
| | |
| | |
| cytoplasmic matrix appears as strands
| |
| within the cisternae. The Golgi complex
| |
| is represented by parallel rows of membranes, vacuoles, and smaller vesicles.
| |
| | |
| Histochemically (Table 6.6), the secretion is intensely PAS-positive and the cytoplasm is slightly reactive (Leblond, 19501.
| |
| The stroma is strongly alkaline phosphatase-positive (Bern, 1949a).
| |
| | |
| The effects of castration arc not ai)i)arent
| |
| by light microscopy as early as in the ventral prostate and seminal vesicles. At 10
| |
| days after castration the cells are slightly
| |
| smaller and the cytoplasm less dense; by
| |
| 20 days, the cells are markedly reduced in
| |
| size, nuclei smaller, cytoplasm clear, basement membrane absent or less well defined
| |
| (Figs. 6.12 and 6.24). The Golgi apparatus
| |
| is reduced in amount but not fragmontcnl.
| |
| It still retains the shape of strands or
| |
| threads which cap around tlic nucleus at
| |
| | |
| | |
| | |
| 90 days of castration but the mass is reduced (Moore, Price and Gallagher, 1930).
| |
| | |
| Brandes and Portela (1960a) state that
| |
| castration produces gradual and slow collapse of cisternae in the endoplasmic reticulum, changes in mitochondria, and reduction and loss of RNA-rich particles from
| |
| the membranes. Studies of functional activity show that the ability to secrete fructose and vesiculase is lost (see Section II).
| |
| | |
| Depending on the length of the interval
| |
| between the operation and administration
| |
| of the hormone, treatment of castrates with
| |
| testis extracts (Figs. 6.13 and 6.25) or
| |
| testosterone prevents or repairs histologic
| |
| and functional changes.
| |
| | |
| Seminal vc.'iicles. The secretory epithelium is colunuiar in normal males; nuclei
| |
| are basal and contain one or two conspicuous nucleoli and smaller chromatin masses
| |
| (Table 6.7). Seci-etion granules, surrounded
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 409
| |
| | |
| | |
| | |
| TABLE 6.7
| |
| Summary of the effects of testicular androgen on rat and mouse seminal vesicles
| |
| | |
| | |
| | |
| Normal Males
| |
| | |
| | |
| | |
| Castrated Males
| |
| | |
| | |
| | |
| General Characteristics
| |
| | |
| | |
| | |
| Rat and mouse
| |
| | |
| mucosa folded; acidophilic secretion in lumen Villous folding reduced; secretion greatly reduced
| |
| | |
| columnar epithelial cells: secretion granules supranuclear Cell size reduced; granules lost
| |
| | |
| Golgi supranuclear networks \ Reduced in volume; fragmented
| |
| | |
| mitochondria as rods or granules ' Apparently reduced in relative numbers (rat)
| |
| | |
| nuclei basal; nucleoli prominent I Nuclei shrunken and pyknotic; nucleoli disappear
| |
| | |
| stroma of connective tissue and smooth muscle Amount appears increased
| |
| | |
| | |
| | |
| Specific Characteristics
| |
| | |
| | |
| | |
| Rat
| |
| Histochemical observations :
| |
| secretion in lumen PAS-positive, intensity variable; acidophilic
| |
| | |
| ci//opZasm slight PAS reaction; strongly acid phosphatase-positive;
| |
| | |
| strongly basophilic
| |
| | |
| secretion granules in epithelium strongly acid phosphatase-positive
| |
| | |
| nuclei strong acid phosphatase reaction
| |
| | |
| stroma slight PAS reaction; acid phosphatase-positive; strong alkaline
| |
| | |
| phosphatase reaction
| |
| | |
| Mouse
| |
| Histochemical observations :
| |
| | |
| secretion in lumen moderately PAS-positive and acidophilic
| |
| | |
| cytoplasm moderately basophilic at base and lateral margins of cells;. . .
| |
| | |
| apical granules acid phosphatase-positive
| |
| secretion granules in epithelium weakly PAS-positive and acidophilic...
| |
| Golgi region; granules PAS-positive and acidophilic
| |
| stroma intensely PAS- and alkaline phosphatase-positive
| |
| Electron microscopic observations:
| |
| cytoplasm complex pattern of basal and lateral ergastoplasmic membranes;
| |
| | |
| | |
| | |
| Phosphatase activity reduced
| |
| | |
| Slight basophilia
| |
| | |
| Activity lost
| |
| | |
| Remained weakly acid phosphatase-positive
| |
| | |
| Acid and alkaline phosphatase activity reduced
| |
| | |
| | |
| | |
| Secretory granules less acidopliiliWeakly basophilic
| |
| | |
| | |
| | |
| abundant RNA-rich granules
| |
| | |
| Golgi region; parallel arrays of smooth-surfaced membranes and vesicles
| |
| | |
| | |
| | |
| Reduced in number; less acidophilii
| |
| Phosphatase activity reduced
| |
| | |
| | |
| | |
| Ergastoplasmic channels less distended and contorted
| |
| Relative number reduced
| |
| | |
| | |
| | |
| by vesicular zones are present in the supranuclear region (Fig. 6.36) and resemble the
| |
| secretion in the lumen in staining reactions.
| |
| The Golgi complex appears in osmium preparations as irregular networks or a vesicular structure (Fig. 6.32); the basement
| |
| membrane is poorly defined or absent
| |
| (Moore, Hughes and Gallagher, 1930).
| |
| | |
| The extracellular secretion is only slightly
| |
| PAS-positive but varies in the intensity of
| |
| reaction; there is little reaction in the epithelial cells except in some cells with stained
| |
| granules; fibers of the lamina propria,
| |
| smooth muscles, and walls of arterioles are
| |
| weakly reactive (Leblond, 1950; ]\Ielampy
| |
| and Cavazos, 1953). Stroma and capillaries
| |
| are strongly alkaline phosphatase-positive
| |
| (Bern, 1949a; Dempsey, Greep and Deane,
| |
| 1949; :\lelarapy and Cavazos, 1953). The
| |
| cytoplasm, secretion granules, nuclei, and
| |
| stroma give an intense acid phosphatase
| |
| reaction; the cytojilasm is strongly baso
| |
| | |
| | |
| philic and the reaction is abolished by ribonuclease (]\lelampy and Cavazos, 1953).
| |
| | |
| The response to castration is rapid. In 2
| |
| days the cells are reduced in height mainly
| |
| by reduction in apical mass ; secretion granules are few, small, and indistinct. By 10
| |
| days, cells are small, secretion granules are
| |
| gone, nuclei are small with heavily staining
| |
| chromatin (Fig. 6.35), and Golgi bodies
| |
| have begun to fragment; at 20 days, these
| |
| changes are more advanced and the remnant of the Golgi bodies (Fig. 6.33) occupies almost the entire supranuclear region
| |
| (Moore, Hughes and Gallagher, 1930). In
| |
| a cytometric study, Cavazos and ]\Ielampy
| |
| (1954) found a statistically significant reduction in cell height by 6 hours after castration; by 48 hours many nucleoli are
| |
| smaller than normal and by 60 hours most
| |
| nucleoli are small; nuclear diameters are
| |
| reduced but change more slowly.
| |
| | |
| | |
| | |
| 410
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| '0 (?rCf
| |
| | |
| | |
| | |
| f-\
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| | |
| | |
| r-^
| |
| | |
| | |
| Q'
| |
| | |
| | |
| | |
| | |
| | |
| | |
| ''1
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ^
| |
| | |
| | |
| | |
| Figs. 6.32-6.36. Rat seminal vesicle; camera lucida drawing.s ,: 3000. Figs. 6.32-6.34. ManuKopsch preparations for Golgi apparatus. Fig. 6.32. Normal male. Fig. 6.33. 20-day castrate.
| |
| Fig. 6.34. 20-day castrate injected with testis extract. Fig. 6.35. 10-day castrate. Fig. 6.36. 20day castrate injected with testis extract. (From C. R. Moore, W. Hughes and T. F. Gallagher,
| |
| Am. J. Anat., 45, 71-107, 1930.)
| |
| | |
| | |
| | |
| Gonadectomy causes gradual reduction
| |
| and disappearance of alkaline phosphatase
| |
| activity (Dempsey, Greep and Deane, 1949;
| |
| Melampy and Cavazos, 1953) and hypophysectomy, with consequent diminution of
| |
| testicular hormones, gives similar results
| |
| (Dempsey, Greep and Deane, 1949). Bern
| |
| and Levy (1952) reported some retention of
| |
| alkaline phosphatase activity in the fibromuscular tissue of castrates. Acid phosphatase activity decreased within 10 days following castration (Melampy and Cavazos,
| |
| 1953).
| |
| | |
| In early experiments (Moore, Hughes
| |
| and Gallagher, 1930) , administration of bull
| |
| testis extracts to castrated rats maintained
| |
| normal histologic structure or repaired involutional changes (Figs. 6.34 and 6.36),
| |
| | |
| | |
| | |
| and androsterone, testosterone, and testosterone propionate gave similar resvdts
| |
| (Moore and Price, 1937, 1938). Androgen
| |
| treatment in castrates produced detectable
| |
| changes within 2 days. Burkhart (1942 1
| |
| observed cell hypertrophy ahd enlargement
| |
| of nuclei 23 hours after a single injection
| |
| of testosterone propionate into 40-day castrates; mitotic activity began at 35 hours
| |
| and reached a maximum at 43 hours. Cavazos and Melampy (1954) treated castrates
| |
| with testosterone propionate and found increases in nuclear diameter within 12 hours,
| |
| cell height within 24 hours, and nucleolar
| |
| size l)y 36 hours; mitotic activity was evident at 48 hours. The same hormone restoi'cd normal alkaline and acid phosphatase activity in castrates within 10 days
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 411
| |
| | |
| | |
| | |
| (Dempsey, Grecp and Deane, 1949; Melampy and Cavazos, 1953).
| |
| | |
| Mouse prostate and seminal vesicles.
| |
| Ventral prostate. The epithelial cells in the
| |
| adult gland are low to moderately tall
| |
| columnar; acini are surrounded by a thin
| |
| fibromuscular layer; lumina contain finely
| |
| granular, acidophilic secretion. The cytoplasm appears somewhat foamy with a
| |
| clear zone in the supranuclear Golgi region
| |
| and rather dense basophilia near the lumen
| |
| (Franks, 1959). In approj)riate histologic
| |
| preparations, the Golgi apparatus is visible
| |
| as a network in the apical cytoplasm close
| |
| to the nucleus and the twisted strands are
| |
| oriented parallel to the long axis of the cell
| |
| (Horning, 1947).
| |
| | |
| Brandes and Portela (1960c) observed by
| |
| electron microscopy an endoplasmic reticulum of cisternae or vesicles that are usually
| |
| flattened but have dilations. RNA-rich
| |
| granules are attached to the outer surface
| |
| of the thin membranes bounding the vesicles
| |
| and occur also in the cytoplasmic matrix;
| |
| the arrangement of cisternae may be parallel or in a random pattern. The luminal
| |
| margin of cells exhibits small cytoplasmic
| |
| projections covered by the cell membrane.
| |
| There are also extensions of the margin
| |
| which ai)pear similar to fragments of cytoplasm that seem to lie free in the lumen,
| |
| and are presumably detached from the apical tips of cells. The lumina also contain
| |
| structures that resemble profiles of the endoplasmic reticulum and mitochondria. The
| |
| supranuclear Golgi complex consists of
| |
| vacuoles of various sizes and flattened vesicles; endoplasmic reticulum and mitochondria are present in the Golgi zone.
| |
| | |
| Histochemical findings (Table 6.8) indicate alkaline phosphatase activity in the
| |
| stroma with a positive reaction in the basement membrane, endothelium of blood vessels, and sheaths of smooth muscle fibers
| |
| (Brandes and Bourne, 1954). With longer
| |
| incubation periods of the tissue (Bern,
| |
| 1949a), the epithelium and secretion in the
| |
| lumina are strongly reactive and the stroma
| |
| shows some activity. Brandes and Bourne
| |
| (1954) reported acid phosphatase activity
| |
| in the epithelium; the Golgi region gave
| |
| the strongest reaction and the nuclei were
| |
| moderately positive. Luminal secretion, ag
| |
| | |
| | |
| gregations of granules in the Golgi region
| |
| and apical cytoplasm, basement membranes, and capillary endothelium were
| |
| PA8-positive. Sulfhydryl and disulfide reactions were moderately strong in epithelial
| |
| cells and basement membranes.
| |
| | |
| Gonadectomy results in typical cell retrogression with reduction in cell height and
| |
| nuclear size. Brandes and Bourne (1954)
| |
| summarized their results as follows: after
| |
| gonad removal, the Golgi apparatus showed
| |
| some fragmentation and was not so dense
| |
| by 12 to 14 days; alkaline phosphatase activity was slightly less intense by 4 days;
| |
| changes in acid pliosphatase activity in the
| |
| Golgi region were evident by 4 days and
| |
| marked by 21 to 22 days; the PAS reaction
| |
| was reduced by 8 days and almost lost in
| |
| the epithelium by 21 to 22 days. Subcutaneous implantation of pellets of testosterone propionate 13 to 32 days after castration produced a rapid return to normal
| |
| of Golgi apparatus and phosphatase activity and a gradual recovery of normal
| |
| PAS reactions. Allen (1958) reported a significant increase in mitotic activity in the
| |
| epithelium of 30-day castrates within 30
| |
| to 36 hours following a single injection of
| |
| 16 /xg. of testosterone propionate; peak activity was reached in 42 to 48 hours.
| |
| | |
| Dorsal prostate. The epithelial cells resemble rather closely those of the coagulating gland but the cytoplasm is more granular, the centrally placed nuclei darker, and
| |
| the Golgi apparatus in the apical cytoplasm (in close contact with the nucleus) is
| |
| less dense than the Golgi networks in the
| |
| coagulating gland (Horning, 1947). Histochemically, the distribution of phosphatase
| |
| activities and PAS reaction in normal
| |
| males, castrates, and castrates treated with
| |
| testosterone propionate are similar to the
| |
| findings in the coagulating gland (Bern,
| |
| 1949a, 1951; Brandes and Bourne, 1954).
| |
| | |
| Coagulating gland {anterior prostate).
| |
| The secretory cells are columnar and the
| |
| nuclei are approximately midway between
| |
| basement membrane and lumen. The cytoplasm is granular and the condensed Golgi
| |
| apparatus is a flattened network oriented
| |
| transversely in the most apical region of
| |
| the cytoplasm (Horning, 1947).
| |
| | |
| Electron microscopic studies by Brandes
| |
| | |
| | |
| | |
| 412
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| TABLE 6.8
| |
| | |
| Summary of the effects of testicular androgen on the mouse prostate and coagulating glands
| |
| | |
| | |
| | |
| Normal Males
| |
| | |
| | |
| | |
| Castrated Males
| |
| | |
| | |
| | |
| General Characteristics
| |
| | |
| | |
| | |
| All lobes
| |
| alveoli with folded
| |
| | |
| | |
| | |
| lucosa; secretion in luniina.
| |
| | |
| | |
| | |
| columnar epithelial cells
| |
| | |
| cytoplasm of epithelial cells granular or foamy
| |
| | |
| nuclei basal .
| |
| | |
| stroma of connective tissue and smooth muscle
| |
| | |
| Histochemical observations:
| |
| | |
| secretion in lumina PAS-positive
| |
| | |
| cytoplasm acid phosphatase-positive; sulfhydryl reaction
| |
| | |
| intracytoplasmic granules PAS-positive; near luminal border
| |
| | |
| Golgi region PAS-positive granules; strong acid phosphatase activity.
| |
| | |
| basement membrane PAS- and alkaline phosphatase-positive
| |
| | |
| Stroma PAS- and alkaline phosphatase-positive
| |
| | |
| Electron microscopic observations:
| |
| | |
| epithelial cells with microvilli
| |
| | |
| Golgi complex smooth surfaced membranes and vesicles
| |
| | |
| | |
| | |
| Iveolar size; loss of villi and bulk of
| |
| | |
| | |
| | |
| Reduction i
| |
| | |
| secretion
| |
| | |
| Reduction in cell size; pseudostratification
| |
| .\ppears less dense
| |
| Shrunken and pyknotic
| |
| Fibromuscular increase
| |
| | |
| Almost completely negative
| |
| | |
| Phosphatase activity reduced
| |
| | |
| Almost completely negative
| |
| | |
| Almost completely negative
| |
| | |
| Activity retained; less intense
| |
| | |
| Activity retained in sheaths of smooth muscles
| |
| | |
| Cell size reduced
| |
| | |
| | |
| | |
| Specific Characteristics
| |
| | |
| | |
| | |
| Ventral lobes
| |
| | |
| Histochemical observations :
| |
| secretion in lumina strong alkaline phosphatase activity
| |
| cytoplasm alkaline pliosphatase-positive
| |
| | |
| Golgi loose networks in apical cytoplasm
| |
| | |
| Electron microscopic observations:
| |
| cytoplasm; ergastoplasm with generally flattened cisternae..
| |
| Dorsal lobes
| |
| Histochemical observations :
| |
| | |
| Golgi compact networks in apical cytoplasm
| |
| | |
| Coagulating glands (anterior prostate)
| |
| Histochemical observations :
| |
| Secretion in lumina intense protein reaction; PAS-positive;.
| |
| | |
| sulfhydryl reaction
| |
| | |
| cytoplasm high concentrations of RNA basally and apically
| |
| | |
| protein reactions, intense apically
| |
| | |
| sulfhydryl reaction, especially strong apically
| |
| | |
| Golgi condensed apical networks
| |
| | |
| Electron microscopic observations:
| |
| cytoplasm extremely dilated ergastoplasmic cisternae
| |
| | |
| | |
| | |
| Reduced in amount; fragmented
| |
| Cisternae collapsed; reduced granules
| |
| | |
| Retluced in amount; fragmented
| |
| | |
| | |
| | |
| Some PAS reaction retained
| |
| | |
| Sulfhydryl reaction lost
| |
| | |
| Markedly decreased
| |
| | |
| Greatly reduced
| |
| | |
| Reaction lost
| |
| | |
| Reduced in amount; fragmented
| |
| | |
| Cisternae collapsed; granules reduced
| |
| | |
| | |
| | |
| and Portela (1960b) show that these epithelial cells are characterized by an endoplasmic reticulum with greatly dilated cisternae. This dilation is more marked in
| |
| the middle of the cell and in the basal region (Fig. 6.37) where the dilated cisternae
| |
| appear as intercommunicating channels in
| |
| which the cytoplasmic matrix forms isolated profiles or strands containing mitochondria and other organelles. The matrix
| |
| is more abundant in the Golgi region and
| |
| protrudes from the luminal margin of the
| |
| cells as microprojections covered by tlu;
| |
| cell membrane.
| |
| | |
| Alkaline phosphatase activity is localized
| |
| in the stroma (Bern, 1949a, 1951 ; Brandes
| |
| | |
| | |
| | |
| and Bourne, 1954; Bern, Alfert and Blair,
| |
| 1957) ; acid phosphatase activity (Brandes
| |
| and Bourne, 1954) is found in the epithelium and is particularly strong in the Golgi
| |
| zone. Brandes and Bourne (1954) and Bern,
| |
| Alfert and Blair (1957) reported PAS-positive reactions in the epithelial cells in the
| |
| Golgi region and apical cytoplasm, and intense reactions in luminal secretion, basement membrane, and stroma. Sulfhydryl
| |
| and disulfide reactions are evident in luminal secretion, epithelium (especially in the
| |
| a]ucal region), basement membrane, and
| |
| fibromuscular tissue. The reactions are
| |
| stronger than in the ventral prostate. Bern,
| |
| Alfert and Blair (1957) found high con
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODTTCTIVE GLANDS
| |
| | |
| | |
| | |
| 4i;
| |
| | |
| | |
| | |
| cy
| |
| | |
| | |
| | |
| /Jf-!^
| |
| | |
| | |
| | |
| pc
| |
| | |
| | |
| | |
| N.pc
| |
| | |
| :y
| |
| | |
| | |
| | |
| | |
| . .... ^
| |
| | |
| | |
| | |
| cy
| |
| | |
| | |
| | |
| | |
| \
| |
| | |
| | |
| | |
| m
| |
| | |
| | |
| | |
| ..^cy
| |
| | |
| | |
| | |
| ^"^^
| |
| | |
| | |
| | |
| ^m
| |
| | |
| | |
| | |
| V*'
| |
| | |
| | |
| | |
| ^
| |
| | |
| | |
| | |
| cy
| |
| | |
| | |
| | |
| | |
| | |
| | |
| IS
| |
| | |
| | |
| | |
| Fig. 6.37. Mouse coagulating gland, normal male. Electronmicrograph X 39,000. Caulfield's
| |
| modification of Palade's osmic acid fixative. Basal portion of an epithelial cell; insert, details of basement membrane region: bm, basement membrane: ci, dilated cisternae: cm,
| |
| plasma or cell membrane; cy, cytoplasmic matrix; ?n, mitochondrion: /;, nucleus. (From D.
| |
| Brandes, unpublished.)
| |
| | |
| | |
| | |
| centrations of RNA basally and apically in
| |
| the epithelial cells. Strong protein reactions
| |
| are present in luminal secretion and apical
| |
| regions of the cells.
| |
| | |
| The response to gonadectomy (Brandes
| |
| and Bourne, 1954) includes reduction of alkaline and acid phosphatase activity within
| |
| 4 days, PAS reactions by 8 days, and slight
| |
| | |
| | |
| | |
| fragmentation and loss of density of the
| |
| Golgi apparatus by 12 to 14 days. Changes
| |
| are more marked after longer periods of
| |
| castration (Table 6.8), although Bern
| |
| (1951) observed retention of stromal alkaline phosphatase for long periods. RNA
| |
| concentrations in the cell (Bern, Alfert and
| |
| Blair, 1957) are greatly decreased but some
| |
| | |
| | |
| | |
| 414
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 6.38. Mouse seininul \esick\ norniMl male. Pliotomicrograpli
| |
| preparation. (From E. Howard, Am. J. Anat., 65, 105-149, 1939.)
| |
| | |
| | |
| | |
| 50. Houm-liematoxvlin
| |
| | |
| | |
| | |
| accunuilation remains in the apical region.
| |
| The sulfhydryl reaction is partially lost luit
| |
| the cells retain apical reactivity.
| |
| | |
| Testosterone propionate implanted subcutaneously 13 to 32 days after testis removal (Brandes and Bourne, 1954) rapidly
| |
| restored the Golgi apparatus and enzyme
| |
| activity to normal, and the PAS reaction
| |
| returned gradually. Allen (1958) showed
| |
| that the epithelium of 30-day castrates responds to a single injection of 16 fig. of
| |
| testosterone propionate by an increase in
| |
| mitotic activity within 30 to 36 hours.
| |
| | |
| Se7ninal vesicles. The epithelial cells in
| |
| adult glands are colunniai- with basal nuclei
| |
| and secretory granules surrounded by halos
| |
| in the supranuclear cytoplasm (Fig. 6.35) ;
| |
| the epithelium rests on a layer of smooth
| |
| muscle and connective tissue stroma (Howard, 1939).
| |
| | |
| In electron micrographs (Deane and
| |
| Porter, 1959), it can be seen that the surface membranes of secretory cells Ivdvv
| |
| microvilli which extend into the lumen. The
| |
| supranuclear region contains secretory
| |
| granules enclosed in vesicles or cisternae,
| |
| smaller membrane-bound vesicles, and parallel arrays of smooth Golgi membranes.
| |
| Moderately distended ergastoplasmic cliannels with membranes studded with pi'csumed libonucleoprotein ])articles lorm
| |
| comi)lex convolutions along the latci'al luai'gins and at the base of cells. The nucleus
| |
| possesses clumped chromatin along the
| |
| meml)rane (Figs. 6.39, 6.42, and 6.43). Fu
| |
| | |
| | |
| jita (1959) described essentially the same
| |
| type of endoplasmic reticulum and the
| |
| presence of microvilli and secretion granules. In addition, small granules in the
| |
| Golgi region were interpreted as precursors
| |
| of secretory granules.
| |
| | |
| Histochemical preparations (Table 6.7)
| |
| show strong alkaline phosphatase activity
| |
| in stromal elements (Atkinson, 1948; Bern.
| |
| 1951 ) ; acid phosphatase activity is present
| |
| in the apical or Golgi region of the epithelial cells (Deane and Dempsey, 1945). Secretory material and secretory granules in
| |
| the lumen and cytoplasm are acidophilic
| |
| and weakly PAS-positive, whereas the reticulum in the lamina propria is intensely
| |
| PAS reactive (Fig. 6.44). Lateral margins
| |
| and basal regions of the cells (Fig. 6.45)
| |
| are moderately basophilic (Deane and Porter, 1959).
| |
| | |
| Following castration of adult mice, the
| |
| secretory epithelium retrogresses with loss
| |
| of secretion granules and reduction in cell
| |
| heiglit and nuclear size. Effects of gonadectomy may be retarded and not uniform in
| |
| all cells (Howard, 1939), but changes
| |
| within 5 days have been rei:)orted for cell
| |
| and nucleai- size (Martins and Rocha,
| |
| 1 929 ) .
| |
| | |
| {electron mici'osco])ic and histochemical
| |
| studies (Table ().7l reveal marked changes
| |
| within a week aftei' gonad removal (Deane
| |
| and Porter, 1959). Cell size is reduced,
| |
| there are fewer secretory granules, ergastoplasmic channels are less distended and
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 415
| |
| | |
| | |
| | |
| | |
| Fig. 6.39. Mouse seminal vesicle, normal male. Electronmierograph X 4200; osmic acid
| |
| fixation with sucrose. Epithelial cells showing basal and lateral ergastoplasmic channels and
| |
| membranes, and supranuclear \-psicles containing .secretory granules. (From H. W. Deane
| |
| and K. R. Porter, unpubli.shed.)
| |
| | |
| | |
| | |
| coin-oliitcd (Fig. 6.40). The relative number
| |
| of riboniicleoprotein particles is somewhat
| |
| leduced, secretory granules are less acidophilic, and the cytoplasm is only weakly
| |
| basophilic (Fig. 6.45). Secretion granules
| |
| were still visible by electron microscopy 10
| |
| days after castration but they were not
| |
| visible at 25 days (Fujita, 1959) .
| |
| | |
| Atkinson (1948) found that alkaline phosphatase activity disappears almost completely from the stroma within 10 days, but
| |
| Bern, Alfert and Blair (1957) observed retention in the fibromuscular tissue.
| |
| | |
| Martins and Rocha (1929) reported complete prevention of castration effects by injection of extracts of bull or goat testes.
| |
| The epithelium of castrates responds readily to androgens. A single dose of 16 /x,g. of
| |
| testosterone propionate in 30-day castrates
| |
| resulted in increased mitotic activity beginning 30 to 36 hours after treatment and
| |
| | |
| | |
| | |
| reached a peak at 42 to 48 hours (Allen,
| |
| 1958). Administration of testosterone to
| |
| castrates completely restored the fine
| |
| structure to normal (Fujita, 1959). Alkaline phosphatase activity in the stroma
| |
| returned to normal within 10 days with testosterone propionate administration (Atkinson, 1948). The same hormone given to
| |
| normal males for one week resulted in increased cell height, more abundant and
| |
| acidophilic secretion and secretory granules, increased basophilia (Fig. 6.45), more
| |
| distended and convoluted ergastoplasmic
| |
| channels (Fig. 6.41), and a relative increase
| |
| in ribonucleoprotein particles (Deane and
| |
| Porter, 1959).
| |
| | |
| Discussion. The secretory cells in the
| |
| epithelia of rat and mouse prostatic lobes
| |
| and seminal vesicles have many histologic
| |
| characteristics in common and some marked
| |
| dissimilarities. In light microscopy with
| |
| | |
| | |
| | |
| 416
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| V\v, 6 40 Mouse seminal vesicle, 7-(lay castrate. Electronmicrograph X 4200; osmic acid
| |
| fixation wjtli sucrose. Note the reduction in cell height, number of secretory granules, and
| |
| contortion of the ergastoplasmic membranes. Arrow indicates microvilli. (From H. W. Deane
| |
| and K. R. Porter, unpublished.)
| |
| | |
| | |
| | |
| routine fixation and stains, the most obvious differences are in cell height, position
| |
| and staining intensity of the nuclei, presence or absence of secretory granules, and
| |
| in such cytoplasmic characteristics as the
| |
| supranuclear clear zone in the rat ventral
| |
| prostate and the basal vesicular region in
| |
| the coagulating gland. The Golgi apparatus
| |
| varies in density, structure, and position
| |
| in the apical cytoplasm. Studies on ultrastructure reveal striking differences in the
| |
| degree of dilation and the disposition of the
| |
| endoplasmic reticulum. In the rat ventral
| |
| prostate the most dilated cisternae are in
| |
| the supranuclear region; in the dorsal lobe,
| |
| generally distended vesicles are disposed
| |
| throughout the cytoplasm in both cell
| |
| types; in the coagulating gland, there is
| |
| extreme dilation of the sacs, particularly in
| |
| the basal region. The flattened vesicles of
| |
| the mouse ventral prostate are disposed at
| |
| random; the coagulating gland, like that of
| |
| the rat, shows greatly dilated cisternae,
| |
| especially basally. Moderately distended
| |
| ergastoplasmic channels in the basal and
| |
| lateral regions of cells are characteristic of
| |
| the mouse seminal vesicles.
| |
| | |
| Changes following castration are detect
| |
| | |
| | |
| able by light microscopy within 2 days in
| |
| the rat seminal vesicle; 4 days in the ventral prostate; 10 days in the coagulating
| |
| gland.
| |
| | |
| Harkin (1957a) suggested a correlation
| |
| between distention of the sacs and secretory
| |
| activity of the cells in the rat ventral prostate. Within 24 hours after gonadectomy,
| |
| he observed dilation of the sacs, but within
| |
| 2 days, collapse of the apical sacs was
| |
| marked and by 4 days, there was general
| |
| collapse of the vesicles in other regions of
| |
| the endoplasmic reticulum. At this stage
| |
| secretory activity of the cells was apparently reduced.
| |
| | |
| Brandes and Portela (1960a, b, c) discussed the relation of the cisternae to secretion in the mouse glands. They proposed
| |
| that the extremely dilated cisternae of the
| |
| coagulating glands contain secretory products which are released into the lumina of
| |
| acini by some undetermined mechanism.
| |
| They found no evidence that the Golgi complex is involved in the elaboration of secretory material in the cisternae, but histochemical findings suggest that it might take
| |
| part in formation of secretory products that
| |
| are not intracisternal. The ventral prostate
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 417
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 6.41. Mouse seminal vesicle, intact male treated with testosterone propionate for 7
| |
| days. Electron micrograph X 4200; osmic acid fixation with sucrose. Note increase in cell
| |
| height, abundance of secretory granules and contortion of the ergastoplasmic membranes.
| |
| (From H. W. Deane and K. R. Porter, unpublished.)
| |
| | |
| | |
| | |
| is characterized by flattened vesicles. Brandes and Portela doubted that there is transport of secretory material to these cisternae
| |
| and release from the intracisternal spaces
| |
| into the acinar Imnen. They suggested an
| |
| apocrine type of release involving extrusion
| |
| of portions of the apical cytoplasm from the
| |
| | |
| | |
| | |
| free margin of cells. The possibility of implication of the Golgi apparatus in the production of secretory material was considered.
| |
| | |
| From a study of the rat, Brandes and
| |
| Groth (1961) concluded that the dilated
| |
| cisternae of coagulating glands, dorsolat
| |
| | |
| | |
| 418
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 6.42. Moil. M - :,,:ii il , i -id, , nui n, il n, ,i , I i_ (,;(,) l-.l, ,ii,m
| |
| micrograpli X 36,000: omiik- ;ici(l tixation; section liiat((l with iii.myl cicclatc to enhance the
| |
| density of nucleoi)ro1(Mn.-^. Infianuclear region of an epithehal cell; nucleus at the top ; ergastopla.sniic channel.s with inomhianes studded with particles; arrow indicates a mitochondrion.
| |
| (From H. W. Deane and K. R. Porter, unpublished.)
| |
| | |
| | |
| | |
| eral and ventral prostates contain secretory
| |
| products, and that it is probable that the
| |
| membranes of the endoplasmic reticulum
| |
| (or the granules associated with them)
| |
| play an active role in the syntheses of the
| |
| proteins present in the glandular secretions.
| |
| Attemi)ts have been made to correlate
| |
| | |
| | |
| | |
| structure of cells as observed by light and
| |
| electron microscopy with histochemical localizations of mucoproteins (PAS reaction),
| |
| alkaline and acid phosphatase activity, and
| |
| basophilic material. Various interpretations
| |
| have been offered for the functional significance of these substances, all of which
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVK GLANDS
| |
| | |
| | |
| | |
| 419
| |
| | |
| | |
| | |
| are under control of andi'ogcnic hormones
| |
| of testicular origin. Leblond (1950) stated
| |
| that the presence of PAS-positive granules
| |
| in the Golgi region supjiorts the concept of
| |
| participation of the Golgi apparatus in the
| |
| secretory process. Brandes and Portela
| |
| (1960b) suggested that the vesicles and
| |
| vacuoles in the Golgi zone might represent
| |
| presecretory or secretory material. The possibility that collapse of ergastoplasmic sacs
| |
| after gonadectomy might be correlated with
| |
| reduction in PAS-positive secretory material was proposed by Harkin (1957a).
| |
| | |
| Alkaline and acid phosphatase activity is
| |
| also found in the Golgi region, but the significance of this localization is not clear.
| |
| Harkin (1957a) suggested that reduction in
| |
| acid phosphatase activity following castration might be correlated with the decrease
| |
| in numbers of mitochondria.
| |
| | |
| The histochemical pattern of enzyme activity has been discussed by Brandes and
| |
| Bourne (1954), and the functional significance of distribution of epithelial and stromal alkaline phosphatase activity has been
| |
| treated by Bern (1949a).
| |
| | |
| Cytoplasmic basophilia that was abolished by ribonuclease was demonstrated in
| |
| the epithelial cells of the rat seminal vesicle
| |
| (Melampy and Cavazos, 1953). In the
| |
| mouse seminal vesicle, Deane and Porter
| |
| (1959) found cytoplasmic basophilia (all
| |
| of which was attributable to ribonucleic
| |
| acid) localized in regions which corresponded to the distribution of ergastoplasmic membranes with their associated particles of presumed ribonucleoprotein. The
| |
| relative number of particles was apparentlj^
| |
| reduced after one week of castration, and
| |
| increased with testosterone propionate administration to normal males. These
| |
| changes were not considered marked enough
| |
| to account for the pronounced reduction in
| |
| basophilia following gonadectomy, and the
| |
| increase with androgenic hormone treatment of normal males.
| |
| | |
| Rixon and Whitfield (1959) found high
| |
| concentrations of zinc, lipid, and basophilic
| |
| material in a luminal border organelle in
| |
| the lateral prostate of rats. Silver staining
| |
| demonstrated fibrils, and it was suggested
| |
| that zinc may be involved in the ergastoplasmic reticulum, possibly with lipopro
| |
| | |
| | |
| tein, and would be associated with the
| |
| microsome fraction in homogenatcs.
| |
| | |
| In the discussion of changes in structure
| |
| and histochemical localizations of substances after gonadectomy and with hormone administration, no specific mention
| |
| was made of differences in response among
| |
| the glands. There arc, however, pronounced
| |
| differences in rate of regression following
| |
| withdrawal of testicular hormone, and in
| |
| rate and degree of response to administered
| |
| androgen. These differences in hormone
| |
| sensitivity or threshold have been established by such end points as changes in
| |
| histologic structure, weight (which includes
| |
| increase in mass of cells and accumulation
| |
| and storage of secretion), and secretion of
| |
| specific substances such as fructose and
| |
| citric acid (Mann, 1954a). In order of
| |
| sensitivity they are first, secretory function,
| |
| second, histologic structure, and finally,
| |
| weight, whichis frecjuently used as an end
| |
| point (Dorfman and Shipley, 1956).
| |
| | |
| Responsiveness of the epithelial cells depends on many factors and varies with specific glands, age of the animal, genetic
| |
| strain, and species. A few examples will
| |
| illustrate these points. Following castration
| |
| of adult rats the seminal vesicles retrogress
| |
| more rapidly than the ventral prostate and
| |
| recjuire higher doses of testosterone propionate to restore normal histological structure (Price, 1944a). The ability of the
| |
| seminal vesicles and the ventral ])rostate
| |
| in young rats to respond to testosterone
| |
| propionate increases with age to a peak
| |
| which is specific for the organ (Price and
| |
| Ortiz, 1944; Price, 1947). This is true also
| |
| for the female prostate (Price, 1944b) and
| |
| the accessory glands in young male hamsters (Ortiz,' 1947). The effect of age on
| |
| responsiveness in the mouse ventral prostate was studied by Lasnitzki ( 1955a ) who
| |
| cultured glands from mice 4 to 6 weeks of
| |
| age and 6 months old in normal control medium and in the presence of testosterone
| |
| propionate. Young prostates regressed on
| |
| the control medium but retained normal
| |
| histologic structure when the hormone was
| |
| added. In the control medium, older glands
| |
| maintained normal structure and became
| |
| hyperplastic with addition of the androgen.
| |
| Franks (1959) also found differences re
| |
| | |
| | |
| 420
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| . (i 1.; .Mnii-i -(iiiiiiit Ill III ill - iiiir ~|icciiiii'ii. Ill, muilii Ml Kill, and preparation as Fig. 6.39). Suprunuclcur icgiuu of au epilht'lial c-ell ; nucleus at the hottoui; numerous
| |
| membrane-bound vesicles with secretory granules in the larger vesicles; arrows indicate some
| |
| of the parallel arrays of smooth-surfaced Golgi membranes. (From H. W. Deane and K. R.
| |
| Porter, unjiuhlished.)
| |
| | |
| | |
| | |
| lated to age in the response of cultured
| |
| mouse ventral prostate to testosterone propionate. The Long-Evans and SpragueDawlcy strains of rats differ in responsiveness of the ventral prostate of adult
| |
| hypojihysectomized castrates to testosterone
| |
| | |
| | |
| | |
| propionate (Lostroh and Li, 1956). Species
| |
| differences in rate of retrogression of accessory glands in adult castrates are marked.
| |
| As reported above, changes in histologic
| |
| structure occur rapidly in rats, more slowly
| |
| and less uniformly in mice (Howard, 1939),
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 421
| |
| | |
| | |
| | |
| | |
| Fig. 6.44. Mouse seminal vesicle, normal male. Photomicrofirapli - 250. Carnoy's fixative,
| |
| stained by the periodic acid-Schiff method, counterstained with hematoxylin. Note the intense PAS-reaction in the reticulum in the lamina propria and surrounding the smooth muscle
| |
| fibers; secretory material in the lumen is moderately reactive. (From H. W. Deane and K. R.
| |
| Porter, unpublished.)
| |
| | |
| | |
| | |
| ctncl slowly and somewhat incompletely in
| |
| guinea pigs (Sayles, 1939, 1942) and hamsters (Ortiz, 1953). It should be noted that
| |
| in adult castrated guinea pigs the ability
| |
| to secrete fructose and citric acid is apparently lost in cells which show only partial
| |
| retrogression histologically (Ortiz, Price,
| |
| Williams-Ashman and Banks, 1956).
| |
| | |
| Another type of variation in responsiveness is demonstrated when weights of seminal vesicles and ventral prostrates in immature castrated rats are used as end
| |
| points for the potency of various C19 steroids (Dorfman and Shipley, 1956 L When
| |
| lower dosages of testosterone and 17aniethyl-A^-androstene-3^ , 17/?-diol are given
| |
| the ventral prostate is more responsive than
| |
| the seminal vesicles, but at high dosage levels the percentage increase in seminal vesi
| |
| | |
| | |
| cle weight equals or exceeds that of the prostate. Three other C19 steroids are far more
| |
| effective on the ventral prostate than on
| |
| seminal vesicles.
| |
| | |
| The female prostate in adult rats responds histologically and gravimetrically
| |
| to a number of C19 steroids (Korenchevsky,
| |
| 1937). These findings have been confirmed
| |
| and extended by Huggins and Jensen
| |
| | |
| (1954) and Huggins, Parsons and Jensen
| |
| | |
| (1955) in hypophysectomized female rats.
| |
| These workers examined the relation of molecular structure to the growth-promoting
| |
| ability of the steroids.
| |
| | |
| Atrophy in male accessory glands of rats
| |
| and mice has been reported under conditions of inanition and vitamin deficiency.
| |
| These results are not usually attributable
| |
| to reduction in responsiveness of the glands
| |
| | |
| | |
| | |
| 422
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 6.45. Moil-^c .^einiiial mmcIi- l'li(iiniiiicinmn|ilis x 7UU. C'ain(>\-'- ti\ati\ c-nictliylcnie
| |
| blue. Top, normal mali' ; in k Idle 7-ila\ ca-tiaN , iMJitoin, intact male ticatcil wil li ic.-tostcionp
| |
| proprionate for 7 days. Hasoi)lidic inatciial ( ciga-tDplasm) occurs at the hasc and along lateral margins of cells; the Golgi zone appears clear; secretory granules are unstained. Basophilic material and Golgi zone are less evident after castration and more highly developed
| |
| after testosterone treatment than normal. (From H. W. Deane and K. R. Porter, unjniblished.)
| |
| | |
| | |
| | |
| themselves Init to (liiuiniition in <2;onadotrophin titer by way of pituitary inhibition. Moore and Samuels (1931) showed
| |
| that gonadotrophin or androgen treatment
| |
| repaired the atrophied accessory glands in
| |
| vitamin B-deficient rats and in those on
| |
| limited food intake. Further, Lutwak-Mann
| |
| and Mann (1950) demonstrated reduction of
| |
| fructose and citric acid in accessory glands
| |
| of rats on a vitamin B-deficient diet, but
| |
| treatment with chorionic gonadotrophin not
| |
| only restored the levels of these substances
| |
| to normal but produced hypersecretion.
| |
| Grayhack and Scott ( 1952 ) reported that the
| |
| growth response to testosterone propionate
| |
| of the ventral and posterior prostate in castrated rats on reduced food intake, vitaminfree casein, or glucose was little different
| |
| from normally fed rats at lower dosages, but
| |
| at higher levels there was less resj^onse in
| |
| rats on limited dietarv intake. Testosterone
| |
| | |
| | |
| | |
| propionate did not produce normal stimulation of the accesisory glands in castrated
| |
| mice on limited food intake (Goldsmith and
| |
| Nigrelli, 1950) . In adult rats, a folic acid antagonist (Aminopterin) partially prevented
| |
| the reduction in jirostatic weight produced
| |
| by estradiol but did not interfere with
| |
| testosterone stimulation of the prostate in
| |
| castrated adults or intact immature animals
| |
| (Brendler, 1949).
| |
| | |
| The senile changes which occur in adx'anced age in the prostate glands of the
| |
| rat, mouse and of man have been describetl
| |
| by Moore (1936) and interjireted on tht.
| |
| basis of decrease in testicular androgen.
| |
| Presenile variations in histologic structui'e
| |
| are pr()l)al)ly ivhited to changes in responsiveness to andi'ogens. In a brief report on
| |
| electron microscopy (Harkin, 1957b), involutional changes in the rat ventral prostate were described. With increasing age.
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 423
| |
| | |
| | |
| | |
| eloctron-denye material is deposited in the
| |
| Golgi region of epithelial cells and these
| |
| bodies are said to resemble structures found
| |
| in hyperplastic prostates in man.
| |
| | |
| 2. Adrenal Androgens
| |
| | |
| A large Ixxly of evidence jioints to effects
| |
| of hormones from the adrenal cortex on the
| |
| accessory reproductive glands of male rats
| |
| and mice and on prostate glands of female
| |
| rats. The significance of this relationshi})
| |
| is unknown and the effects are slight in
| |
| many cases. Reviews by Parkes (1945),
| |
| Ponse (1950), Courrier, Baclesse and Marois (1953), Moore (1953) and Delost
| |
| (1956) deal extensively with the subject. In
| |
| man, a relationship between pathologies of
| |
| the adrenal cortex and virilism is well recognized (Dorfman and Shipley, 1956).
| |
| | |
| The marked development of the ventral
| |
| prostate in young castrated rats (Price,
| |
| 1936) was attributed by Howard (1938) to
| |
| the action of androgen from the adrenal
| |
| cortex. The same explanation was suggested for the extensive development of the
| |
| seminal vesicles and prostate in young castrated mice (Howard, 1939). The ventral
| |
| prostate does not develop in immature castrated-adrenalectoraized rats according to
| |
| Burrill and Greene (1939a) and Howard
| |
| (1941), but Gersh and Grollman (1939) did
| |
| not confirm these findings. The impairment
| |
| of prostate and seminal vesicle development in young castrated-adrenalectomized
| |
| mice (Howard, 1946) was considered to be
| |
| the result of poor physical condition rather
| |
| than loss of adrenal androgen. Gonadectomy in young male mice of an inbred
| |
| strain (Woolley and Little, 1945a. b) produced adrenal cortical carcinoma correlated
| |
| w^ith strong stimulation of the prostate and
| |
| seminal vesicles. Spiegel (1939) castrated
| |
| young guinea pigs and found the development of adrenal-cortical tumors and evidence of stimulation of prostates and seminal vesicles.
| |
| | |
| In the field vole {Microtus arvalis P.),
| |
| Delost (1956) observed extensive development of the ventral prostate in young castrated males. Gonadectomy of adult males
| |
| during the breeding season results in atrophy of seminal vesicles, and dorsal and lateral prostate, whereas the ventral prostate
| |
| | |
| | |
| | |
| shows an intense secretory activity by one
| |
| month after testis removal. Adrenalectomy
| |
| of castrates produces complete involution
| |
| of the ventral prostate. Outside the breeding period, there is atrophy of all accessory
| |
| glands except the ventral prostate which
| |
| exhibits strong activation that can be prevented by adrenalectomy.
| |
| | |
| The prostate gland of young female rats
| |
| undergoes development and differentiation,
| |
| and resembles the male ventral prostate
| |
| with which it is homologous (Price, 1939;
| |
| Mahoney, 1940). Development still occurs
| |
| following ovariectomy (Burrill and Greene,
| |
| 1939b; Price, 1942) or adrenalectomy (Burrill and Greene, 1941), but not in ovariectomized-adrenalectomized females. A comparison of the responsiveness of female and
| |
| male prostates indicated that the male gland
| |
| is more sensiti\'e to adrenal androgens
| |
| (Price, 1942).
| |
| | |
| Autotransplants of adrenals into one
| |
| seminal vesicle of adult castrated rats produced slight local stimulation of the gland
| |
| and also androgenic effects on the other
| |
| seminal vesicle and on the ventral prostate
| |
| (Katsh, Gordon and Charipper, 1948). But
| |
| androgenic action was local and barely
| |
| discernible in somewhat similar experiments (.lost and Geloso, 1954). Price and
| |
| Ingle (1957) autotransplanted adrenals into
| |
| seminal vesicles and ventral prostates of
| |
| adult castrates and observed definite but
| |
| local stimulation of seminal vesicles, coagulating glands, and ventral prostates. Negative results of adrenal transplants in seminal vesicles of nonadrenalectomized rats
| |
| were reported by Moore (1953). Takewaki
| |
| (1954) failed to detect any androgenic effect of autotransplants of adrenals placed
| |
| subcutaneously in contact with seminal vesicle grafts in castrated males.
| |
| | |
| The finding that treatment of young castrated male rats with adrenocorticotrophin
| |
| caused stimulation of the ventral prostate
| |
| (Davidson and Moon, 1936) has been confirmed by Deanesly (1960) who observed,
| |
| in addition, a slight stimulation of the seminal vesicles. Nelson (1941) also found androgenic effects on accessory glands following ACTH treatment but Moore (1953),
| |
| van der Laan (1953), and Takewaki (1954)
| |
| obtained negative results. In hypophysec
| |
| | |
| | |
| 424
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| tomized-castrated rats, ACTH was reported
| |
| ineffective in increasing ventral prostate
| |
| weight (van der Laan, 1953; Grayhack,
| |
| Bunce, Kearns and Scott, 1955) , but Lostroh
| |
| and Li (1957) obtained some growth of
| |
| ventral pi'ostates and seminal vesicles at
| |
| certain dosage levels. They emphasized that
| |
| dosage is a critical factor in demonstrating
| |
| the androgen-secreting ability of the adrenal cortex under ACTH stimulation. Administration of ACTH to hypophysectomized-castrated-adrenalectomized rats does
| |
| not affect the accessory glands.
| |
| | |
| There has been no general agreement on
| |
| the androgenicity of desoxycorticosterone
| |
| on the accessory glands (see reviews by
| |
| Parkes, 1945 and by Courrier, Baclesse and
| |
| Marois, 1953). Lostroh and Li (1957) reported that ll-desoxy-17-hydroxy-corticosterone and 11-dehydro-corticosterone displayed an androgenic activity equivalent to
| |
| 4 fxg. of testosterone propionate on the ventral prostates and seminal vesicles of hypophysectomized-castrated adult rats. Corticosterone, cortisone, and hydrocortisone
| |
| were ineffective. Grayhack, Bunce, Kearns
| |
| and Scott (1955) found cortisone ineffective
| |
| on the weight of ventral prostates in hypophysectomized castrates. In the field vole
| |
| (Microtus arvalis P.), Delost (1956) produced effects on the ventral prostate by
| |
| cortisone administration.
| |
| | |
| 3. Ovarian Androgens
| |
| | |
| It has long been known that mammalian
| |
| ovaries can secrete androgenic hormones
| |
| which have virilizing effects in females. Discussion of the evidence for androgenic activity of the ovary has been presented by
| |
| Ponse (1948) and Parkes (1950). More recently the subject has been extensively reviewed (Ponse, 19541), 1955). Much of the
| |
| interest in ovarian androgens in the rodent
| |
| has centered on the question of their site of
| |
| origin in the ovary and the effects of temperature and gonadotrophin administration
| |
| on androgen production (see reviews, and
| |
| Chapter 7 by Young) . However, the use of
| |
| male accessory glands as bio-indicators for
| |
| ovarian androgen has contributed to our
| |
| knowledge of the responsiveness of the
| |
| glands.
| |
| | |
| Methods for approaching this problem include transplantation of ovaries into vai'i
| |
| | |
| | |
| ous sites in castrated male rats and mice;
| |
| ])lacing ovarian autotransplants into the
| |
| ears of females ; transplantation of male accessory glands into females; and observations of prostate glands in females of the
| |
| so-called female prostate strains of rats.
| |
| The use of such females as hosts for grafts
| |
| of male prostatic tissue has permitted a direct comparison of responsiveness in these
| |
| homologous glands.
| |
| | |
| The first observations that ovarian grafts
| |
| maintain normal prostates and seminal vesicles in castrated males w^ere made in guinea
| |
| pigs (Lipschiitz, 1932) and mice (de Jongh
| |
| and Korteweg, 1935). Hill (1937) transplanted ovaries into the ears of castrated
| |
| male mice and obtained stimulation of the
| |
| prostate and seminal vesicles. Deanesly
| |
| ( 1938) reported similar findings in rats.
| |
| Local effects from ovaries grafted into seminal vesicles of castrated rats w^ere shown
| |
| by Katsh (1950). Takewaki (1953) also
| |
| found local stimulating effects on seminal
| |
| vesicles when rat ovaries and seminal vesicles were transplanted close together into
| |
| the spleens of gonadectomized males and
| |
| females.
| |
| | |
| In experiments in which ventral prostates
| |
| and seminal vesicles were transplanted subcutaneously into adult female rats (Price,
| |
| 1941, 1942) it was sliown that the ventral
| |
| prostate is well maintained in virgin females (Fig. 6.46) and highly stimulated
| |
| during jiregnancy and lactation in the host.
| |
| It is comi)letely retrogressed in spayed females. Seminal vesicle grafts, however, are
| |
| stimulated only rarely. This occurs only in
| |
| females that have littered repeatedly and
| |
| have been lactating for long periods. This
| |
| indicates that the threshold of response of
| |
| the ventral prostate to ovarian androgens
| |
| is lower than that of the seminal vesicles.
| |
| Evidence of functional stimulation with
| |
| production of fructose and/or citric acid
| |
| was obtained in coagulating glands, and
| |
| ventral, lateral, and dorsal prostates trans])lanted into female rats in which the ovaries were stimulated by gonadotrophin
| |
| treatment (Price, Mann and LutwakMann, 1955). It may be assumed that the
| |
| effects were attributable to ovarian androgens since ventral prostate grafts in spayed
| |
| females (Greene and Burrill, 1939) are not
| |
| stimulated histologicallv when gonado
| |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 425
| |
| | |
| | |
| | |
| | |
| Fig. 6.46. Rat male and female prostates. Photomicrographs X 650. Bouin-hematoxylin
| |
| preparation. Top, host prostate from an adult virgin female; middle, male prostate graft from
| |
| the above female host; bottom, prostate from a pregnant female. Note the semi-regressed
| |
| epithelium in the female prostate of the virgin female host compared with the columnar
| |
| epithelium and light areas in the male prostate graft and the prostate from a pregnant female. (From D. Price, Anat. Rec, 82, 93-113, 1942.)
| |
| | |
| | |
| | |
| trophin is administered. Great stimulation
| |
| of ventral prostate grafts in the ovarian
| |
| bursa of females was obtained by Ponse
| |
| (1954a).
| |
| | |
| The female prostate gland is normally
| |
| jiartially retrogressed in adult females except during pregnancy and lactation (Fig.
| |
| 6.46) when it appears stimulated (Burrill
| |
| and Greene, 1942; Price, 1942); in spayed
| |
| females it is atrophic (Price, 1942). The
| |
| striking development of the female prostate
| |
| in pregnancy and lactation in a number of
| |
| species of mammals is discussed in Section
| |
| I. Hernandez (1942) obtained stimulation
| |
| of female prostates by autotransplants of
| |
| oA-aries into ears, hind legs, or tails of rats.
| |
| | |
| Transplantation of rat ventral prostates
| |
| into virgin females shows that the male
| |
| | |
| | |
| | |
| prostate has a lower threshold to ovarian
| |
| androgens than the female gland and maintains high epithelium and cellular light
| |
| areas whereas the epithelium of the host
| |
| prostate (Fig. 6.46) is low and retrogressed
| |
| (Price, 1942).
| |
| | |
| 4- Progesterone
| |
| | |
| The administration of progesterone in
| |
| relatively enormous doses has stimulating
| |
| effects as determined by weight, histologic
| |
| structure, and function of some of the accessory glands in castrated male rats, mice,
| |
| and guinea pigs. The literature has been
| |
| reviewed by Greene, Burrill and Thomson
| |
| (1940), Parkes (1950), and Price, Mann
| |
| and Lutwak-Alann (1955).
| |
| | |
| Burkhart (1942) treated adult 40-day
| |
| | |
| | |
| 426
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| castrated rats with one or two 20-mg. doses
| |
| of progesterone and observed a slight stimulation of mitotic activity in the ventral
| |
| prostate and seminal vesicles after 55 hours
| |
| but a pronounced hypertrophy of epithelium and connective tissue in both glands.
| |
| The ventral prostate is more sensitive to
| |
| progesterone than the seminal vesicles.
| |
| | |
| In castrated rats (Price, IMann and Lutwak-Mann, 1955), treatment with 25 mg.
| |
| of progesterone daily stimulated the secretion of fructose or citric acid in seminal
| |
| vesicles, coagulating glands, and ventral,
| |
| lateral and dorsal prostates, and produced
| |
| histologic changes in the last three glands.
| |
| The effect, however, was only equivalent
| |
| to that of about 5 /xg. of testosterone propionate. The lowest threshold to the hormone is in the ventral prostate and the
| |
| highest in the seminal vesicles. Lostroh and
| |
| Li (1957) found no effects of 0.5 mg. of
| |
| progesterone daily on the ventral prostate
| |
| and seminal vesicles of hypophysectomizedcastrated adult rats, but the same dose of
| |
| 17a-hydroxy progesterone was the androgenic equivalent of 4 /xg. of testosterone propionate. It may be noted that the following
| |
| transformations are involved in the biosynthesis of testicular androgens: cholesterol —> pregnenolone — > progesterone — >
| |
| 17a-hyclroxy progesterone — > androst-4-ene3,17-dione -^ testosterone (Dorfman,
| |
| 1957). The slight androgenic actions of progesterone and 17a-hydroxy progesterone
| |
| may result from their conversion to androstane derivatives by extragonadal tissues. The findings of Katsh (1950) that
| |
| progesterone crystals implanted directly
| |
| into the seminal vesicles of castrated rats
| |
| have no stimulating influence may be significant in this regard.
| |
| | |
| C. EFFECTS OF ESTROGENS
| |
| | |
| Administration of estrogenic hormones to
| |
| normal males affects the accessory glands
| |
| both indirectly and directly. The effects fall
| |
| into three categories: inhibition as evidenced by weight changes, involution of the
| |
| epithelium, and loss of secretory activity
| |
| (attributable to inhibition of pituitary gonadotro])hin and reduction in endogenous
| |
| androgen) ; direct stimulation of fibromuscular tissue; and stimulation of hyi)erplasia
| |
| and stratified squamous metaplasia of the
| |
| | |
| | |
| | |
| ei)ithelium with possible keratinization. In
| |
| no case does estrogen induce secretory activity of epithelial cells. The reduction in
| |
| seci'etion as determined cjuantitatively (see
| |
| Section II) may result from castration atrophy of secretory cells, or from hyperplastic and metaplastic transformations of
| |
| the e])ithelium witli resultant loss of normal
| |
| secretory function.
| |
| | |
| The observed responses to estrogen treatment in glands of intact and castrated
| |
| males, and in organ cultures of prostatic tissue, represent the dual effects of androgen
| |
| withdrawal and estrogen addition. The extensive literature on the effects of estrogen
| |
| and the evidence for so-called antagonistic, cooperative and synergistic effects of
| |
| simultaneous administration of androgen
| |
| and estrogen have been discussed extensivelv (Zuckerman, 1940; Emmens and
| |
| Parkes, 1947; Ponse, 1948; Bern, 1949b;
| |
| Burrows, 1949).
| |
| | |
| The observation that administration of
| |
| estrogen to intact male rats causes atrophjof the accessory glands which is mediated
| |
| by way of reduction of pituitary gonadotrophin and failure of secretion of testicular
| |
| hormones was made by Moore and Price
| |
| (1932). Estrogen-induced atrophy was prevented by simultaneous treatment with
| |
| gonadotrophin or androgen. Direct stimulating effects were reported by Freud
| |
| | |
| (1933) and David, Freud and de Jongh
| |
| | |
| (1934) who observed fibromuscular growth
| |
| in seminal vesicles of estrogen-treated castrated rats and stratification in the duct
| |
| epithelium of the lateral prostate. Simultaneous treatment with androgen enhanced
| |
| the hypertrophic effect of estrogen on the
| |
| fibromuscular wall of the seminal vesicle
| |
| but prevented epithelial change in the lateral prostate ducts. Korenchevsky and Dennison (1935) found estrogen stimulation of
| |
| the muscular layer of the rat seminal vesicle with no effect on the epithelium, but in
| |
| coagulating glands (and to a lesser degree
| |
| in the dorsal prostate ) there was not only fibromuscular hypertrophy but also metaplastic transformation of the epithelium
| |
| with stratification; changes in the ventral
| |
| and lateral lobes were slight and the epitiieHum was unaffected. Androgen treatment
| |
| prevented the jxithologic changes induced
| |
| by estrogen. Harsh, Overholser and Wells
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 427
| |
| | |
| | |
| | |
| (1939) noted stratified, sqiuinious epithelium in the ducts of the seminal vesicles,
| |
| and ducts and acini of coagulating glands
| |
| following estrogen administration. But a
| |
| slight delay in castration atrophy and a
| |
| weak stimulating effect of estrogen on seminal vesicle epithelium were observed by
| |
| Overholser and Nelson ( 1935 ) and Lacassagne and Raynaud (1937).
| |
| | |
| Ovaries transplanted into castrated male
| |
| rats (Pfeiffer, 1936) induce fibromuscular
| |
| hyi^ertrophy in host seminal vesicles and
| |
| coagulating glands; stratified sciuamous
| |
| cornified epithelium appears also in coagulating glands, and hyperplasia and metal^lasia are present in lateral prostates. Estrogenic stimulation of fibromuscular tissue
| |
| occurs (Price, 1941) in seminal vesicle
| |
| grafts in normal female hosts but no such
| |
| effects are evident in ventral prostate
| |
| grafts.
| |
| | |
| Burkhart (1942) injected a single dose
| |
| of estradiol benzoate into 40-day-castrated
| |
| rats and observed no effect on the ventral
| |
| prostate. But in the seminal vesicles, hypertrophy of epithelial cells occurred by 27
| |
| liours after treatment and by 55 hours,
| |
| mitotic activity was evident in the epithelium and to some extent in the connective
| |
| tissue.
| |
| | |
| In histochemical studies (Bern and Levy,
| |
| 1952) , metaplastic changes were observed
| |
| in the seminal vesicle epithelium after estrogen treatment but no cornification occurred; the replacing epithelium was alkaline phosphatase-positive in contrast to the
| |
| negative reaction in the original epithelium
| |
| (Table 6.7). Fibromuscular hypertrophy
| |
| was found but no definite alteration in enzyme concentrations except an absence of
| |
| activity in edema of the subepithelial
| |
| stroma. No metaplastic changes appeared
| |
| in the coagulating gland epithelium, but
| |
| the ducts of the dorsal prostate underwent
| |
| metaplasia; alkaline phosphatase activity
| |
| of the stroma in both glands was retained
| |
| as in the castrate. The ventral prostate ejnthelium was atrophic but still enzyme-active after 120 days of treatment and the
| |
| stroma reacted positively.
| |
| | |
| The effects of estrogen on the accessory
| |
| glands of mice are far more marked than
| |
| in rats. Long continued and strong doses of
| |
| ■estrogen cause hyperplasia, metaplasia and
| |
| | |
| | |
| | |
| keratinization in the epithelium of mouse
| |
| coagulating glands (Lacassagne, 1933 ) . The
| |
| same effects, with fibromuscular hypertrophy, were described in coagulating glands
| |
| and prostates by Burrows and Kennaway
| |
| (1934), Burrows (1935a), and de Jongh
| |
| (1935) who prevented epithelial metaplasia
| |
| in prostates by simultaneous treatment with
| |
| androgen. Burrows (1935b) studied the localization of responses to estrogenic compounds and found that in order of time of
| |
| response, the coagulating gland is first,
| |
| seminal vesicles next, and finally the prostatic lobes. Changes begin in the urethral
| |
| ends of ducts and jirogress peripherally into
| |
| the acini. Li the degree of response, the coagulating glands and seminal vesicles show
| |
| the most drastic changes with the appearance of stratified, squamous, keratinizing
| |
| epithelium and ultimate loss of acini. The
| |
| effects on the lobes of the prostate include
| |
| stratified, cornifying epithelium but the
| |
| changes are not so i)ronounced. Some hypertroj^hy of fibromuscular stroma occurs
| |
| in all the glands and hyperplasia is marked
| |
| in the fibromuscular wall of the seminal
| |
| vesicles.
| |
| | |
| Tislowitz (1939) found stimulation of
| |
| mitotic activity in muscle and connective
| |
| tissue of seminal vesicles and ventral prostate glands of immature castrated mice
| |
| treated with estrogen. Stratification and
| |
| cornification appear in the ventral prostate
| |
| epithelium, with mitoses in the basal cell
| |
| layers and also in seminal vesicle epithelium. Allen (1956) compared the mitogenic
| |
| activity of a single dose of 16 /xg. of estradiol
| |
| benzoate on seminal vesicles, coagulating
| |
| glands, and ventral prostates of 30-daycastrated mice. Significant increases in mitotic activity occur in seminal vesicles and
| |
| coagulating glands about 24 hours after
| |
| treatment; the ventral prostate does not respond significantly until 72 hours and gives
| |
| a low absolute value of mitoses.
| |
| | |
| Horning (1947) studied some of the initial changes in prostatic epithelium of intact mice receiving estrogen. Slight hypertrophy of epithelial cells and extensive
| |
| fragmentation and dispersal of hypertrophied portions of the Golgi network occur
| |
| by 8 days in the coagulating gland. At the
| |
| same period, hypertrophic changes are less
| |
| pronounced in the ejuthelium of the dorsal
| |
| | |
| | |
| | |
| 428
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| prostate and there is only slight fragmentation of the Golgi apparatus. In the ventral
| |
| prostate no epithelial hypertrophy is found
| |
| but the Golgi network hypertrophies without fragmentation or dispersal. The ventral
| |
| prostate is definitely less sensitive to estrogen than the other two glands.
| |
| | |
| After longer periods of estrogen administration, Bern (1951) observed fibromuscular hypertrophy of the seminal vesicle and
| |
| intense alkaline phosphatase activity as in
| |
| untreated intact males (Table 6.7) ; the
| |
| epithelium, which is normally negative in
| |
| enzyme activity, becomes positive and the
| |
| beginning of metaplastic changes is occasionally visible. In the coagulating gland,
| |
| stratified scjuamous metaplasia with masses
| |
| of keratin is found and the metaplastic
| |
| epithelium is strongly alkaline phosphatasepositive; enzyme activity is retained in the
| |
| stroma but is variable. Bern, Alfert and
| |
| Blair (1957) reported that the metaplastic
| |
| coagulating gland epithelium is strongly
| |
| alkaline phosphatase reactive, virtually
| |
| PAS-negative, has dense homogeneous
| |
| RNA concentrations decreasing in amount
| |
| from base to lumen, and a dense homogeneous cytoplasmic protein reaction with a
| |
| gradient of increasing intensity from base
| |
| to lumen. The enlarged vesicular nuclei of
| |
| the metaplastic epithelium have lower concentrations of deoxyribonucleic acid (DNA)
| |
| than the nuclei of normal epithelial cells.
| |
| The cytoplasm of these cells is as reactive
| |
| as normal cells for sulfhydryl groups, and
| |
| the newly formed keratin is intensely reactive; the greatest concentrations of disulfide
| |
| groups are in superficial keratin.
| |
| | |
| In the dorsal prostate (Bern, 1951), estrogen causes fibromuscular hypertrophy
| |
| with variable retention of alkaline phosi)hatase activity. Metaplastic changes involving
| |
| basal cell proliferation and stratification begin and the metaplastic epithelium is intensely alkaline phosphatase active, a rvversal of the normal reaction.
| |
| | |
| Brandes and Bourne (1954), using diethylstilbestrol, observed an increase in
| |
| fibromuscular stroma in coagulating glands.
| |
| dorsal and ventral prostates, and epithelial
| |
| hyperplasia and stratification in varying
| |
| degrees. The most pronounced changes occurred in the coagulating gland. The effects
| |
| of estrogen on Golgi networks, and on PAS
| |
| | |
| | |
| | |
| and acid and alkaline phosphatase reactions
| |
| are in general similar to the results of castration (Table 6.8).
| |
| | |
| Ventral prostate glands have been grown
| |
| in culture by the watch glass method, with
| |
| estrogens added to the medium. Lasnitzki
| |
| (1954, 1958) reported hyperplasia and
| |
| squamous metaplasia of the epithelium in
| |
| young i^rostate tissue from C3H mice. In
| |
| older glands, stimulation of fibromuscular
| |
| tissue occurred. Franks (1959) using the
| |
| C57 strain and a different culture medium
| |
| observed no epithelial hyperplasia and
| |
| metaplasia, but obtained increases in stroma
| |
| and muscle. He attributed atrophic changes
| |
| in the epithelium, which appear more
| |
| marked in estrogen-treated than in control
| |
| cultures, to direct inhibition by the hormone. Ventral prostate tissue from young
| |
| mice is more sensitive to estrogen than tissue from adult or old males.
| |
| | |
| In the dog, Huggins and his collaborators
| |
| demonstrated the effects of estrogen and
| |
| combinations of estrogen and androgen on
| |
| histologic structure and secretion in the
| |
| prostate (see Section II). Estrogen causes
| |
| decrease or increase in prostatic size depending on the dosage and on the levels of
| |
| endogenous or exogenous androgen (Huggins and Clark, 1940) . Sciuamous metaplasia
| |
| of the epithelium of ducts and acini occurs
| |
| with estrogen treatment, but only in the
| |
| posterior lobe.
| |
| | |
| Discussion. The results of estrogen administration to rats and mice vary with
| |
| species, age of animal, specific gland under
| |
| consideration, dosage, duration of treatment, and presence or absence of endogenous or exogenous androgen. Interpretation
| |
| of the findings rests on the understanding
| |
| that androgen directly stimulates mitotic
| |
| and secretory activity in the epithelial cells.
| |
| Estrogen inhibits i)ituitary function and
| |
| thus i-eduees testicular androgen in intact
| |
| males. It directly increases mitotic activity
| |
| in th(> epithelium of the accessory glands,
| |
| and inckices (>pithelial liy|)erplasia and
| |
| iiietaphisia, and fibromuscular hyperplasia.
| |
| Whether the effects of simultaneous presence of androgen with exogenous estrogen
| |
| are classified as protective, competitive
| |
| (antagonistic), or cooperative (synergistic)
| |
| on the acce.ssoiy glands depends on the
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 429
| |
| | |
| | |
| | |
| relative levels of the two hormones. Both
| |
| affect mitotic activity directly.
| |
| | |
| In a comparison of the effectiveness of
| |
| androgen and estrogen on mitotic activity,
| |
| Allen (1956, 1958) showed that a dose of
| |
| 16 fjig. of testosterone propionate induces
| |
| statistically significant increases in mitotic
| |
| activity of the epithelium of seminal vesicles, coagulating glands and ventral prostates of castrated mice in 30 to 36 hours.
| |
| The same dose of estradiol benzoate increases mitotic activity in 24 hours in seminal vesicles and coagulating glands, but not
| |
| until 72 hours in ventral prostates.
| |
| | |
| Differences in responsiveness to estrogen
| |
| are evident between rats and mice but in
| |
| both species there is a gradient of reactivity
| |
| with coagulating glands showing the most
| |
| marked changes, seminal vesicles next, and
| |
| prostatic lobes least. In glands of both species, the duct epithelium is more sensitive
| |
| than acinar epithelium and the first observable effects are on urethral ends of
| |
| ducts. Hyperplastic and metaplastic responses to estrogen occur also to varying degrees in accessory glands of other mammals
| |
| — man, monkey, dog, cat, ground squirrel,
| |
| and guinea pig. Zuckerman (1940) reviewed
| |
| the effects of estrogen in male and female
| |
| rodents and other mammals and suggested
| |
| from the evidence that "stratified squamous
| |
| proliferation or metaplasia is usually a primary response of tissue in whose development oestrogen-sensitive entodermal sinus
| |
| epithelium has played a part."
| |
| | |
| On the basis of the pathologic effects of
| |
| estrogen on the mouse coagulating glands
| |
| and the protective action of androgen, several workers originally suggested that benign prostatic hypertrophy in man might
| |
| result from a primary imbalance in the normal ratio of estrogenic to androgenic hormones in the male organism (Zuckerman,
| |
| 1936). Further study has not supported this
| |
| concept.
| |
| | |
| D. HORMONAL CONTROL OF SPONTANEOUS
| |
| PROSTATIC NEOPLASMS
| |
| | |
| Spontaneous tumors of the prostate occur
| |
| in rodents rarely if at all, but benign
| |
| growths are extremely common in aging
| |
| dogs and men, and prostatic cancer is a
| |
| major prol^lem in man. It is noteworthy that
| |
| | |
| | |
| | |
| neoplasms of the seminal vesicles in man
| |
| are rare (Dixon and Moore, 1952).
| |
| | |
| 1. Benign Growths
| |
| | |
| In the dog, prostatic enlargement which
| |
| is essentially due to cystic hyperplasia of
| |
| the epithelium occurs in almost all senile
| |
| males with functioning testes, but is not
| |
| found in castrates (Huggins, 1947b). In
| |
| these prostatic growths, which characteristically involve the entire gland, tall columnar secretory epithelium is always present
| |
| in some acini. Canine prostatic hyperplasia
| |
| is under control of testicular androgens
| |
| (Huggins and Clark, 1940) and marked involution of these tumors as evidenced by
| |
| their size and secretory activity (see Section II) can be induced by gonadectomy or
| |
| treatment with suitable dosages of estrogen.
| |
| Estrogen overdosage, however, causes prostatic enlargement and a metaplasia of the
| |
| posterior lobe which does not resemble cystic hyperplasia. Huggins and Moulder
| |
| (1945) reported that dogs feminized by estrogen-secreting Sertoli cell tumors of the
| |
| testis do not have cystic hyperplasia. The
| |
| important factors in this pathologic growth
| |
| seem to be age and testicular androgens
| |
| (Huggins, 1947b), but prolonged administration of testosterone propionate to aged
| |
| castrate dogs results in normal-appearing
| |
| prostates and not cystic hyperplasia.
| |
| | |
| Benign prostatic hypertrophy in man is
| |
| rarely encountered before the age of 40
| |
| (Moore, 1943; Huggins, 1947b) but it is
| |
| extremely common in old men. It differs
| |
| markedly from prostatic hyperplasia in
| |
| dogs; the lesions are limited to the medullary region of the prostate and are spheroidal neoplastic nodules involving, usually,
| |
| both epithelium and fibromuscular tissue;
| |
| other nodular types occur but are less frequent (Huggins, 1947b; Franks, 1954). The
| |
| prostatic epithelium is composed of tall
| |
| secretory cells (Huggins and Stevens, 1940).
| |
| Despite the fact that castration may be
| |
| followed by some shrinkage of hypertrophied human prostate tissue (White, 1893;
| |
| Cabot, 1896; Huggins and Stevens, 1940),
| |
| it is generally admitted that this treatment
| |
| is of little value. Estrogen treatment results
| |
| in changes in the acini of the inner or medullary (periurethral) part of the prostate,
| |
| and stratification with squamous metaplasia
| |
| | |
| | |
| | |
| 430
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| of the duct epithelium, but there is little
| |
| effect on nodular stroma and acini (Huggins, 1947bj. Since benign prostatic hypertrophy has not been observed in men castrated early in life, testicular androgen is
| |
| presumably involved in its etiology (Huggins, 1947b). However, it is doubtful
| |
| whether androgens are causative agents for
| |
| this disease. Lesser, Vose and Dixey (1955)
| |
| found that in men over the age of 45 who
| |
| had received androgen treatment for noncancerous conditions, the incidence of benign enlargement of the prostate was no
| |
| greater than in untreated controls.
| |
| | |
| 2. Prostatic Cancer
| |
| | |
| Prostatic cancer is a common disease in
| |
| elderly men. This carcinoma, which characteristically arises in the posterior (outer)
| |
| region of the prostate, consists of an abnormal growth of cells resembling adult prostatic epithelium rather than undifferentiated
| |
| tissue (Huggins, Stevens and Hodges, 1941 ).
| |
| It was found that these neoplasms are hormone-dependent and usually are influenced
| |
| by anti-androgenic therapy; those which
| |
| fail to respond are not adenocarcinomas
| |
| with acini present in the tumor, but are undifferentiated carcinomas with solid masses
| |
| of malignant cells (Huggins, 1942). However, the two types intergrade and both
| |
| contain large amounts of acid phosphatase
| |
| and are considered cancers of adult prostatic epithelium. The beneficial effects of
| |
| castration or estrogenic treatment or both
| |
| simultaneously, on metastatic carcinoma of
| |
| the prostate in man were first demonstrated
| |
| by Huggins and his collaborators (Huggins
| |
| and Hodges, 1941 ; Huggins, Stevens and
| |
| Hodges, 1941 ; Huggins, Scott and Hodges,
| |
| 1941 ; Huggins, 1943, 1947a). This discovery
| |
| was facilitated by the availability of a
| |
| chemical index of the activity of the neoplasm, namely, the acid phosphatase activity of blood serum.
| |
| | |
| Although testosterone increases the level
| |
| of serum acid phosphatase in patients with
| |
| prostatic cancer (Huggins and Hodges,
| |
| 1941 ; Sullivan, Gutman and Gutman, 1942 1 ,
| |
| androgen treatment does not always exacerbate the growth of the tumor (Trunnel and
| |
| Duffy, 1950; Brendler, Chase and Scott,
| |
| 1950; Brendler, 1956; Franks, 1958) or may
| |
| even decrease it (Pearson, 1957). It is ciues
| |
| | |
| | |
| tionable if androgens induce prostatic cancer, inasmuch as their prolonged administration neither increases the incidence of
| |
| this disease in man (Lesser, Vose and Dixey,
| |
| 1955) nor induces it in dogs (Hertz, 1951).
| |
| | |
| The response of human metastasizing
| |
| prostate cancer to anti-androgenic therapy
| |
| is often very dramatic, but neither castration nor treatment with estrogens cures this
| |
| disease. The tumor may regress for considerable periods of time, but eventually it recurs
| |
| and begins to grow again. A small proportion of cases do not benefit at all (Huggins,
| |
| 1957; Franks, 1958). Nevertheless, castration and/or estrogen therapy remain the
| |
| best treatment for prostatic carcinoma in
| |
| man (Nesbit and Baum, 1950; Huggins,
| |
| 1956; O'Conor, Desautels, Pryor, Munson
| |
| and Harrison, 1959).
| |
| | |
| Huggins and Scott (1945) suggested that
| |
| the failure of some patients with prostatic
| |
| cancer to obtain long lasting improvement
| |
| from castration or estrogen treatment, or
| |
| the two combined, lay in the secretion of
| |
| androgenic substances by the adrenal
| |
| glands. Early attempts to study the effect
| |
| of bilateral adrenalectomy on human prostatic cancer were thwarted by the lack of
| |
| suitable adrenal cortical steroids for adequate substitution therapy. But with the
| |
| advent of cortisone, bilateral adrenalectomy
| |
| could be accomplished with ease (Huggins
| |
| and Bergenstal, 1951, 1952). It seems, however, that adrenalectomy is of limited value
| |
| to patients with prostatic cancer in relapse
| |
| after orchiectomy and/or treatment with
| |
| estrogens (Whitmore, Randall, Pearson and
| |
| West, 1954; Huggins, 1956; Fergusson,
| |
| 1958).
| |
| | |
| E. EFFECTS OF CERTAIN AROMATIC
| |
| HYDROCARBONS (CARCINOGENS)
| |
| | |
| Spontaneous tumors have not been found
| |
| in the prostate glands of rodents, but tumors
| |
| can be induced in rats and mice by treatment with carcinogenic chemicals such as
| |
| benzpyrene and metiiylcholanthrene. There
| |
| lias been considerable interest in inducing
| |
| such tvnnois and studying their inception
| |
| and growth, and the iH'lation of steroid hormones to their de^•elopment. Such investigations have contributed to an understanding of early neoi)lastic changes in the rodent
| |
| prostate, but have had limited applicability
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 431
| |
| | |
| | |
| | |
| to the })rol)lcm of hormonal control of prostatic cancer in man.
| |
| | |
| The first induction of prostatic cancer in
| |
| rodents was accomplished by Moore and
| |
| Melchionna (1937) who injected benzpyrene in lard directly into the rat anterior
| |
| prostate (it should be noted that Moore and
| |
| ]\Ielchionna used "anterior" in the sense of
| |
| ventral as indicated by their histologic descriptions of a characteristic clear zone in
| |
| the peripheral cytoplasm of the epithelial
| |
| cells; this is typical only of the ventral
| |
| lobe). The treatment was followed within
| |
| 210 days by the development of squamous
| |
| cell carcinomas in 72 per cent, and sarcomas
| |
| in 5 per cent, of intact rats. Essentially similar results were obtained in an equivalent
| |
| number of rats castrated at the time of carcinogen injection. Castration after tumors
| |
| had developed did not cause atrophy of tumor cells. No metastases were found but
| |
| there was anaplasia of cells and the tumors
| |
| were invasive. The squamous metaplasia
| |
| occurred in columnar secretory epithelium
| |
| which was close to, or in contact with, benzpyrene cysts. The sequence of changes was
| |
| reduction in cell height, loss of the clear
| |
| area in the peripheral cytoplasm, pseudostratification, true stratification, development of intercellular bridges, and formation
| |
| of keratohyaline. It was concluded that
| |
| testicular androgen is not an important factor in the development of these squamous
| |
| cell carcinomas, but on the basis of a small
| |
| series of experimental animals it was suggested that exogenous androgen treatment
| |
| in castrates may increase the incidence of
| |
| sarcomas.
| |
| | |
| In 1946, Dunning, Curtis and Segaloff implanted compressed methylcholanthrene
| |
| l)ellets into rat prostates (lobe not specified)
| |
| and induced metastasizing squamous cell
| |
| carcinomas. The tumors were transplantable and metastasized equally well in male
| |
| and female hosts. Bern and Levy (1952) injected methylcholanthrene in lard into ventral prostates of intact Long-Evans rats
| |
| and induced extensive neoplasms within 7
| |
| to 9 months. All but one were squamous cell
| |
| carcinomas; the exception was a sarcoma.
| |
| Quantitative determinations of enzyme activity showed a loss of alkaline phosphatase
| |
| in cancerous prostates but no significant
| |
| changes in acid phosphatase activity. Histo
| |
| | |
| | |
| chemically, the stroma and capillaries were
| |
| alkaline phosphatase reactive, but the carcinomas had virtually lost the strong alkaline phosphatase activity of the epithelium
| |
| of origin (Table 6.2). There was some pseudoreaction or reaction in sloughed keratin
| |
| and necrotic areas.
| |
| | |
| Allen (1953) injected a suspension of
| |
| methylcholanthrene in distilled water into
| |
| ventral prostates or coagulating glands of
| |
| intact and castrated rats. All were autopsied 180 days later. A high percentage of
| |
| squamous cell carcinomas and a few sarcomas developed; metastases occurred in a
| |
| few cases. There was no statistically significant difference between tumor incidence in
| |
| the ventral prostate and coagulating gland.
| |
| Tumors of the ventral prostate were found
| |
| in 70.6 per cent of the intact rats and in 100
| |
| per cent of the castrates; in castrates injected with testosterone propionate there
| |
| were tumors in 57.7 per cent of the animals,
| |
| and in castrates treated with estradiol benzoate, 77.8 per cent. It was concluded that
| |
| tumor incidence was highest in castrates
| |
| and lowest in intact males or castrates
| |
| treated with testosterone propionate, and
| |
| that estrogen did not affect tumor incidence.
| |
| ]\Iirand and Staubitz (1956) placed methylcholanthrene crystals in ventral prostates of
| |
| 99 intact Wistar rats and observed the effects for over 300 days. The resulting tumors were classified as 30 squamous cell
| |
| carcinomas, 3 leiomyosarcomas, and 2 adenocarcinomas; squamous cell carcinomas
| |
| and adenocarcinomas metastasized. Fragments of squamous cell carcinomas were
| |
| transplanted and survived and metastasized
| |
| more successfully in males than in females.
| |
| | |
| Horning (1946) imjiregnated strips of
| |
| tissue from mouse dorsal prostates and anterior prostates (coagulating glands) with
| |
| crystals of methylcholanthrene and inserted them as subcutaneous homografts
| |
| into intact males. By this method adenocarcinomas were induced in grafts of both
| |
| dorsal prostate and coagulating gland.
| |
| | |
| In mice of the RIII and Strong A strains
| |
| (Horning and Dmochowski, 1947) methylcholanthrene in lard was injected into dorsal and anterior prostates (coagulating
| |
| glands). Squamous cell carcinomas and sarcomas developed in Strong A mice, but only
| |
| sarcomas in RIII. Squamous metaplasia of
| |
| | |
| | |
| | |
| 431
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| the epithelium occurred in the RIII strain
| |
| but no malignant proliferation of metaplastic cells followed. It was noted that the
| |
| epithelial changes which occurred with
| |
| raethylcholanthrene treatment were "almost
| |
| identical" with the secjuence of changes following prolonged estrogen administration in
| |
| Strong A mice (Horning, 1947).
| |
| | |
| Horning (1949, 1952) studied the effects
| |
| of castration, diethylstilbestrol, and testosterone propionate on growth rates of prostatic tumors transplanted as grafts. Tumors
| |
| were induced in ventral prostate, dorsal
| |
| prostate, and coagulating gland tissue of
| |
| Strong A mice by wrapping pieces of epithelium around crystals of methylcholanthrene and transplanting the grafts su!)cutaneously into 75 intact males. Of the 54
| |
| tumors which developed, 42 were adenocarcinomas or secreting glandular carcinomas,
| |
| 10 were squamous cell carcinomas, and 2,
| |
| spindle cell sarcomas. Neoplastic development began, apparently, in epithelium in
| |
| a nonsecretory phase, and hyperplastic
| |
| changes followed the sequence of mitosis,
| |
| abnormal cell division, and pyknosis accompanied by an increase in fibromuscular
| |
| tissue. Three distinct types of epithelial proliferation then occurred; one, with tonguelike groups of early malignant cells, gave
| |
| rise to secretory glandular carcinomas; the
| |
| second, from acinar ejMthelium, and the
| |
| third, from duct epithelium, developed into
| |
| squamous cell carcinomas with keratinization and formation of keratin pearls. Some
| |
| grafts had foci of the first and third type
| |
| and the evidence suggested that the tumors
| |
| subsequently became squamous cell carcinomas. Both tumor types were transplantable and were cari'icd through many serial
| |
| transi)lantations without losing their histologic characteristics.
| |
| | |
| In an effort to study effects of testicular
| |
| androgen on growth, transplants of an adenocarcinoma were made into intact and castrated males. The tumors grew rapidly and
| |
| progressively in intact mice but regressed
| |
| in castrates. Testosterone propionate administration to castrated males bearing regressed tumors resulted in a resumption of
| |
| tumor growth in some cases. Gonadectomy
| |
| of the host had little effect on the growth of
| |
| transplanted s(|uamous cell carcinomas. An
| |
| | |
| | |
| drogen-dependence of secreting glandular
| |
| carcinomas was suggested.
| |
| | |
| When stilbestrol pellets were implanted
| |
| into one flank of intact males and a glandular carcinoma into the opposite flank, the
| |
| effects varied from slight to pronounced retardation of the tumor but complete regression did not occur. The squamous cell
| |
| carcinomas were insensitive to stilbestrol.
| |
| | |
| Additional experiments (Horning, 1952)
| |
| involved transplanting pieces of prostatic
| |
| epithelium impregnated with methylcholanthrene alone, or with the carcinogen combined with stilbestrol or testosterone propionate into intact males (groups of 35
| |
| for each treatment). The carcinogen alone
| |
| induced 8 adenocarcinomas and 5 squamous
| |
| cell carcinomas; carcinogen and stilbestrol,
| |
| 23 squamous cell carcinomas and 3 sarcomas; carcinogen and testosterone propionate, 2 squamous cell carcinomas and 1
| |
| sarcoma. The increased tumor incidence
| |
| with estradiol was interpreted as an inhibitory action of the estrogen on secretory
| |
| epithelial cells, making them more susceptible to methylcholanthrenc.
| |
| | |
| Brandes and Bourne (1954) made homografts of pieces of ventral and anterior prostate (coagulating gland) impregnated with
| |
| methylcholanthrenc into intact males of the
| |
| Strong A strain, and studied histochemical
| |
| changes. The grafts underwent squamous
| |
| metaplasia and the processes of epithelial
| |
| proliferation, stratification, and keratinization were completed within 10 days in some
| |
| cases. Histochemical changes from the normal i)attern (Table 6.8) occurred concurrently. Alkaline phosphatase activity disappeared early; acid phosphatase activity
| |
| became weak in nuclei and cytoplasm but
| |
| keratohyalin granules were strongly reactive; PAS-positive reactions were gradually
| |
| lost in luminal secretion and intracytoplasmic granules but retained in the basement membrane. In some grafts there was
| |
| transformation into squamous cell carcinomas and when this happened phosjihatase
| |
| activity was lost but the basement membranes were still PAS-positive.
| |
| | |
| Lasnitzki (1951, 1954, 1955a. b, 1958)
| |
| grew ventral jirostate glands from C3H and
| |
| Strong A mice in culture by the watch-glass
| |
| t('chnif|ue and added methylcholanthrenc to
| |
| the medium. Hyperplasia and squamous
| |
| metaplasia resulted in glands ex]ilanted
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 433
| |
| | |
| | |
| | |
| from both young and older mice. When
| |
| estrone and carcinogen were added simultaneously to cultures of young glands, squamous metaplasia was increased; with older
| |
| glands, hyperplasia was inhibited and stromal increase occurred. The relation of vitamin A to the response of prostates to methylcholanthrene was studied (Lasnitzki.
| |
| 1955b). Vitamin A added to the medium
| |
| caused an increase in secretion and deposition of PAS-positive material in the secretory cells but did not influence growth or
| |
| development; the vitamin added simultaneously with methylcholanthrene did not influence hyperplasia, but did prevent keratin
| |
| formation and degenerative changes in the
| |
| secretory epithelium; excess vitamin A following the carcinogen prevented formation
| |
| of keratin and decreased hyperplasia.
| |
| | |
| Summary. Treatment of rat and mouse accessory glands with benzpyrene or methylcholanthrene has induced precancerous and
| |
| cancerous changes which led to the development of adenocarcinomas, squamous cell
| |
| carcinomas, and sarcomas. The first type of
| |
| tumor has been induced in large numbers
| |
| only in mice and by the homograft method.
| |
| | |
| The evidence suggests that, in mice,
| |
| growth of adenocarcinomas is androgendependent, but squamous cell carcinomas
| |
| are little affected by androgen loss or estrogen treatment. The incidence of tumors has
| |
| been increased by simultaneous administration of estrogen and carcinogen but reduced
| |
| by the administration of androgen with carcinogen. In rats, it has been affirmed and
| |
| denied that incidence and growth of squamous cell carcinomas are reduced in intact
| |
| males ; estrogen has not affected tumor incidence. Species and strain differences in response are marked.
| |
| | |
| F. EFFECTS OF NONSTEROID HORMONES
| |
| | |
| There is e-\'idence that hormones from the
| |
| anterior pituitary may directly affect the
| |
| weight and histologic structure of accessory
| |
| glands, or act synergistically with androgen.
| |
| However, the findings have been somewhat
| |
| conflicting. Dosage level, age, and strain of
| |
| rats have varied, and questions have been
| |
| raised with respect to the purity of the hormone preparations.
| |
| | |
| Attention was focused on the pituitary in
| |
| relation to accessory glands when Huggins
| |
| and Russell (1946) observed that prostatic
| |
| | |
| | |
| | |
| atrophy is more marked in the hypophysectomized than in the castrated dog. Van der
| |
| Laan (1953) found the ventral prostates
| |
| of hypophysectomized-castrated immature
| |
| rats less responsive to testosterone propionate than the glands of castrates; a crude
| |
| extract of beef pituitaries restored responsiveness in hypophysectomized-castrates.
| |
| Prostates of young adult hypophysectomized-castrated Sprague-Dawley rats were
| |
| also less responsive (total weight of dorsal
| |
| and ventral prostates) to testosterone propionate than those of castrates (Grayhack,
| |
| Bunce, Kearns and Scott, 1955). Paesi, de
| |
| Jongh and Hoogstra (1956) administered
| |
| pituitary extracts simultaneously with a
| |
| low dose of testosterone propionate to hypophysectomized-castrated rats and reported a slightly greater ventral prostate
| |
| weight than with the androgen alone.
| |
| | |
| To identify the hormones of the anterior
| |
| pituitary that are capable of affecting the
| |
| accessory glands or influencing their responsiveness to androgen, the following hormone
| |
| preparations have been injected alone and
| |
| in various combinations into hypophysectomized-castrated rats: prolactin (luteotrophin; LTH), growth hormone (somatotrophin; STH), adrenocorticotrophin
| |
| ( ACTH ) , interstitial cell-stimulating hormone (luteinizing hormone; ICSH; LH),
| |
| follicle stimulating hormone (FSHl. In addition, chorionic gonadotrophin and thyroxine have been administered. Of these
| |
| hormones, only prolactin and growth hormone have been shown to act directly on
| |
| accessory glands (for comprehensive data
| |
| on negative and positive results of these
| |
| hormones see Grayhack, Bunce, Kearns and
| |
| Scott, 1955; Lostroh and Li, 1956, 1957 ».
| |
| The degree to which contamination with
| |
| prolactin or growth hormone might influence the assay of ICSH preparations by the
| |
| ventral prostate test has been examined by
| |
| Lostroh, Squire and Li (1958).
| |
| | |
| 1. Prolactin {LTH)
| |
| | |
| When Pasqualini (1953) treated castrated
| |
| adult rats with testosterone propionate followed by administration of a lower dose of
| |
| androgen plus LTH, the amount of secretion
| |
| in the seminal vesicles was greater than with
| |
| androgen alone. Prostate weights were increased slightly by LTH with androgen.
| |
| Van der Laan (1953) reported that in adult
| |
| | |
| | |
| | |
| 434
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| hypophysectomized-castrated rats LTH had
| |
| no effect on ventral prostate weiglit. Grayhack, Bunce, Kearns and Scott (1955) made
| |
| the same observation for prostate weights
| |
| in young adult Sprague-Dawley rats, but
| |
| found that LTH augmented the effect of
| |
| testosterone propionate on prostate weight.
| |
| | |
| A difference in response between LongEvans and Sprague-Dawley strains of rats
| |
| was observed by Lostroh and Li (1956).
| |
| In immature hypophysectomized-castrated
| |
| Long-Evans rats, LTH alone had no effect
| |
| on ventral prostate or seminal vesicle
| |
| weights, and no synergistic effect when administered with a low dose of testosterone
| |
| propionate; in Sprague-Dawleys, however,
| |
| the weights of ventral prostates and coagulating glands were increased by LTH but,
| |
| again, no synergism occurred with exogenous androgen. Chase, Geschwind and Bern
| |
| (1957) reported that in immature hypophysectomized-castrated Sprague-Dawleys,
| |
| LTH did not affect weights of ventral prostates or coagulating glands but it did increase seminal vesicle weight. When LTH
| |
| was administered with testosterone propionate, glandular tissue in the ventral prostate
| |
| was increased and weights of coagulating
| |
| glands (in some cases) and seminal vesicles
| |
| were significantly higher than with androgen alone.
| |
| | |
| In the immature hypophysectomized
| |
| Sprague-Dawley rats that were not castrated, LTH alone did not affect ventral
| |
| prostate weight but when given simultaneously with ICSH it acted synergistically
| |
| (Segaloff, Steelman and Flores, 1956). These
| |
| results were confirmed by Lostroh, Squire
| |
| and Li (1958) for the Sprague-Dawley
| |
| strain, but in Long-Evans rats, LTH neither
| |
| increased prostatic weight, nor augmented
| |
| prostatic response to ICSH.
| |
| | |
| Antliff, Prasad and Meyer (1960) have
| |
| shown that in the guinea pig, LTH had no
| |
| effect on seminal vesicles of castrated or hypophysectomized males, but when it was
| |
| administered with subminimal doses of testosterone propionate, seminal vesicle weight
| |
| and epithelial height were increased.
| |
| | |
| 2. Growth Hormone {STH)
| |
| | |
| Van der Laan (1953) found no effects of
| |
| STH on ventral prostate weights in young
| |
| hypophysectomized-castrated rats. Huggins,
| |
| | |
| | |
| | |
| Parsons and Jensen ( 1955) observed only
| |
| slight effects on weights of ventral prostates
| |
| and seminal vesicles with administration of
| |
| STH to young hypophysectomized-castrated Sprague-Dawley rats, but a synergistic effect on weight was evident with
| |
| simultaneous treatment with STH and testosterone propionate.
| |
| | |
| In hypophysectomized-castrated LongEvans rats (Lostroh and Li, 1956, 1957),
| |
| STH produced slight histologic changes and
| |
| significant weight increases in the ventral
| |
| jirostate; when administered with testosterone propionate, an additive effect on weight
| |
| was obtained. The changes in the seminal
| |
| vesicles were less evident. The effects on
| |
| Sprague-Dawley rats included weight increases in ventral prostates and seminal
| |
| vesicles and a greatly enhanced weight response when STH and testosterone propionate were administered simultaneously (hypophysectomized-castrates in this strain
| |
| gave a limited response to the androgen I .
| |
| Chase, Geschwind and Bern (19571 found
| |
| no consistent weight increases of ventral
| |
| prostates, coagulating glands or seminal
| |
| vesicles in young hypophysectomized-castrated Sprague-Dawleys treated with STH
| |
| or STH and testosterone propionate. Simultaneous administration of STH, LTH and
| |
| testosterone, however, induced significant
| |
| increases in all accessories above the weights
| |
| produced by the androgen alone.
| |
| | |
| Lostroh, Squire and Li (19581 determined that STH had no effect on the ventral
| |
| prostate response to ICSH in hypophysectomized Long-Evans rats, but })roduced an
| |
| enhanced response in Sprague-Dawleys. It
| |
| was concluded that the Long-Evans strain is
| |
| jjreferable for the testing of crude ICSH extracts, inasmuch as neither STH, LTH, nor
| |
| both simultaneously, affect the response of
| |
| the ventral prostate to ICSH.
| |
| | |
| With regard to the action of STH on histologic structure of the prostate in hypopiiysectomized-castrated rats, it should be noted
| |
| that the effects are slight; nuclei api)ear
| |
| vesicular, and the connective tissue stroma
| |
| is increased (Lostroh and Li, 1957). The
| |
| synergistic action of STH on prostate
| |
| growth in hypoi)hysectomized-castrated
| |
| rats when administered simultaneously with
| |
| testosterone is more striking. In a general
| |
| discussion of the many biologic effects of
| |
| | |
| | |
| | |
| ACCESSORY MAMMALIAN REPRODUCTIVE GLANDS
| |
| | |
| | |
| | |
| 435
| |
| | |
| | |
| | |
| growtli hormone, Li (1956) wrote, ''Does
| |
| this ability to act as a synergist mean that
| |
| growth hormone plays a permissive or supporting role in the biological action of a hormone or of a biological agent? It is not unreasonable to assume that growth hormone
| |
| creates the necessary and sufficient environment for other biological agents to exercise
| |
| the full scope of their functions."
| |
| | |
| Acknowledgments. We are greatly indebted to
| |
| Drs. Thaddeiis Mann, James Harkin, Helen Deane,
| |
| Keith Porter, and David Brandes for generously
| |
| supplying luipublished data and electronmicrographs. Mrs. Eva Brown provided invaluable assistance in the preparation of the manuscript. We
| |
| wish to thank our artist. Mr. Kenji Toda, for many
| |
| of the original figures. The researches of one of us
| |
| (D. P.) cited in the chapter were supported in part
| |
| by grants from the Dr. Wallace C. and Clara A.
| |
| Abbott Fund of the University of Chicago and by
| |
| Research Grants 2912 and 5335 from the National
| |
| Institutes of Health, Public Health Service.
| |
| | |
| IV. References
| |
| | |
| Abul-F.^dl,M. A.M., AND King, E.J. 1948. Properties of the acid phosphatases of erythrocytes
| |
| and of the human jn'ostate gland. Biochem. J.,
| |
| 45, 51-60.
| |
| | |
| Alex.\nder, D. p., Huggett, A. St. G., Nixon, D.
| |
| A., AND WiDDAS, W. F. 1955. The placental
| |
| transfer of sugars in the sheep : the influence of
| |
| concentration gradient upon the rates of hexose
| |
| formation as shown in umbilical perfusion of
| |
| the placenta. J. Physiol., 129, 367-383.
| |
| | |
| Allen, J. M. 1953. Responses of the rat prostate
| |
| gland to methylcholanthrene. J. Exper. Zool.,
| |
| 123, 289-313.
| |
| | |
| Allen, J. M. 1956. The influence of hormones on
| |
| cell division. I. Time-response of ear. seminal
| |
| vesicle, coagulating gland and \entral prostate
| |
| of castrate male mice to a single injection of
| |
| estradiol benzoate. Exper. Cell Res., 10, 523532.
| |
| | |
| Allen, J. M. 1958. The influence of hormones on
| |
| cell division. II. Time response of ear, seminal
| |
| vesicle, coagulating gland and ventral prostate
| |
| of castrate male mice to a single injection of
| |
| testosterone propionate. Exper. Cell Res., 14,
| |
| 142-148.
| |
| | |
| Andrewes, G. S., AND Taylor, K. B. 1955. Metabolic studies on surviving prostatic tissue. Brit.
| |
| J. Exper. Path., 36, 611-616.
| |
| | |
| AxTLiFF, H. A., Prasad, M. R. N., .and Meyer, R. K.
| |
| 1960. Action of prolactin on seminal vesicles
| |
| of guinea pig. Proc. Soc. Exper. Biol. & Med.,
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| 103, 77-80.
| |
| | |
| A.^^plund, J. 1947. Quantitative determination of
| |
| the content of contractive substances in human
| |
| sperm and their significance for the motility
| |
| and vitality of spermatozoa. Acta physiol.
| |
| scandinav., 13, 103-108.
| |
| | |
| Atkinson, W. B. 1948. Effect of androgen on al
| |
| | |
| | |
| kaline phosphatase in the seminal vesicle of the
| |
| mouse (abst.). Anat. Rec, 100, 731.
| |
| | |
| AwAPARA, J. 1952a. The action of sex hormones
| |
| on the metabolism of amino acids in the prostate. Texas Reports Biol. & Med., 10, 22-31.
| |
| | |
| AwAPARA, J. 1952b. The influence of sex hormones on the transaminases of the accessory sex
| |
| organs of the male rat. Endocrinology, 51, 7579.
| |
| | |
| B.\cox, J. S. D., AND Bell, D. J. 1948. Fructose
| |
| and glucose in the blood of the foetal sheep.
| |
| Biochem. J., 42, 397-405.
| |
| | |
| B.ARON, D. N., Gore, M. B. R., and Willi.\ms, D. C.
| |
| 1960. An androgen-activated pyridine nucleotide transhydrogenase in prostatic tissue. Biochem. J., 74, 20P.
| |
| | |
| B.\RRON, E. S. G., .\ND HuGGiNS, C. 1944. Metabolism of isolated prostatic tissue. J. Urol., 51,
| |
| 630-634.
| |
| | |
| Barrox, E. S. G., and Huggins, C. 1946a. The citric acid and aconitase content of the prostate.
| |
| Proc. Soc. Exper. Biol. & Med., 63, 85-87.
| |
| | |
| Barron, E. S. G., axd Huggixs, C. 1946b. The
| |
| metabolism of the pro.state: transamination
| |
| and citric acid. J. Urol., 55, 385-390.
| |
| | |
| Batelli, F. 1922. Une methode pour obtenir
| |
| remission complete du liciuide des vesicules
| |
| seminales chez le cobaye. Compt. rend. Soc.
| |
| physicjue et hist. nat. de Geneve, 39, 73-74.
| |
| | |
| Be.auvallet, M., and Brochart M. 1949. Presence
| |
| de nor-adrenaline dans le sperme du Taureau.
| |
| Compt. rend. Soc. biol., 143, 237-239.
| |
| | |
| Berg, 0. C, Huggins, C, .and Hodges, C. V. 1941.
| |
| Concentrations of ascorbic acid and phosphatases in secretions of the male genital tract. Am.
| |
| J. Physiol., 133, 82-87.
| |
| | |
| Bergstrom, S. 1949. Prostaglandinets kemi.
| |
| Nord. Med., 42, 1465-1466.
| |
| | |
| Bern, H. A. 1949a. The di.stribution of alkaline
| |
| phosphata.se in the genital tract of male mammals. Anat. Rec, 104, 361-377.
| |
| | |
| Bern, H. A. 1949b. The effects of sex steroids on
| |
| the sex accessories in the male Dutch rabbit.
| |
| Am. J. Anat., 84, 231-276.
| |
| | |
| Bern, H. A. 1951. Estrogen and alkaline phosphatase activity in the genital tract of the male
| |
| mouse. Endocrinology, 48, 25-33.
| |
| | |
| Bern, H. A. 1953. The effect of sex steroids on
| |
| the respiration of the rat ventral prostate in
| |
| vitro. J. Endocrinol., 9, 312-321.
| |
| | |
| Bern, H. A., and Krichesky, B. 1943. Anatomic
| |
| and histologic studies of the sex accessories of
| |
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| year of age. Cancer Res., 5, 506-509.
| |
| | |
| WoTiz, H. H., AND Lemon, H. M. 1954. Studies
| |
| in steroid metabolism. I. Metabolism of testosterone bv human prostatic tissue slices.
| |
| J. Biol. Chem., 206, 525-532.
| |
| | |
| WoTiz, H. H., Lemon, H. M., and Voulg.\ropoulos,
| |
| A. 1954. Studies in steroid metabolism. II.
| |
| Metabolism of testosterone by human tissue
| |
| slices. J. Biol. Chem., 209, 437^45.
| |
| | |
| WusT, H. 1957. Glykolytische Enzyme im menschlichen Seminalplasma bei Xormo-, Oligound Azoospermie. Arch. Klin. Exper. Dermat.,
| |
| 205, 351-356.
| |
| | |
| Yamada, K. 1933. fber den Zuckergehalt des
| |
| Samens. Japan. J. Med. Sc. (II. Biochem.), 2,
| |
| 245.
| |
| | |
| YiNG, S. H., Day, E., Whitmore, W. F., Jr., and
| |
| Tagnon, H. J. 1956. Fibrinolytic activity m
| |
| human prostatic fluid and semen. Fertil. &
| |
| Steril., 7, 80-87.
| |
| | |
| Young, D. 1949. Bilateral aplasia of the vas deferens. Brit. J. Surg., 36, 417-418.
| |
| | |
| Zeller, E. a. 1941. Uber das Vorkommen der
| |
| Diamin-oxydase in menschlichen Sperma. Helvet. Chim." Acta, 24, 117-120.
| |
| | |
| Zeller, E. A., and Joel, C. A. 1941. Beitriige zur
| |
| Fermentchemie des miinnlichen Gesehlechtsapparats. 2. Mitteilung. Uber das Vorkommen der
| |
| Cholinesterase, der Mono- und Diamin-oxydase in Sperma und Prostata, und iiber die
| |
| Beeinflussung der Spermien-Beweglichkeit
| |
| durcli Fermentinhibitoren. Helvet. Chim.
| |
| Acta, 24, 968-976.
| |
| | |
| ZiMMET, D. 1939. Vitamine C et liquide d'ejaculation du cobaye. Effets sur les caracteres generaux de lejaculat, les spermatozoides et la
| |
| reproduction. Compt. rend. Soc. l)iol., 130,
| |
| 1476-1479.
| |
| | |
| ZoRGNioTTi, A. W., AND Brendler, H. 1958. Studies in semen coagulation. Proc. Soc. Exper. Biol!
| |
| & Med., 96, 195-197.
| |
| | |
| ZucKERMAN, S. 1936. The endocrine control of the
| |
| prostate. Proc. Roy. Soc. Med., 29, 81-92.
| |
| | |
| ZucKERMAN, S. 1940. The histogenesis of tissues
| |
| sensitive to oestrogens. Biol. Rev., 15, 231-271.
| |
| | |
| | |
| | |
| THE MAMMALIAN OVARY
| |
| | |
| William C. Young, Ph.D.
| |
| | |
| PROFESSOR OF ANATOMY, UNIVERSITY OF KANSAS, LAWRENCE, KANSAS
| |
| | |
| | |
| | |
| I. Introduction 449
| |
| | |
| II. FOLLICULOGENESIS 451
| |
| | |
| A. Growth of Primary and Small Ve
| |
| sicular Follicles 451
| |
| | |
| B. Growth of Vesicular Follicles 455
| |
| | |
| C. Preovulatory Swelling 455
| |
| | |
| 1). Ovulation . ." 456
| |
| | |
| E. Folliculogenesis in Pregnancy and
| |
| | |
| Lactation 457
| |
| | |
| III. Corpus Luteum 459
| |
| | |
| IV. Follicular Atresia 4(11
| |
| | |
| V. Hormones of the Ovary 4(i4
| |
| | |
| A. Sites of Origin 466
| |
| | |
| B. Amounts of Hormone Produced. . . . 471
| |
| VI. Age of the Animal and Ovarian
| |
| | |
| Functioning 476
| |
| | |
| VII. Other Endocrine Glands and the
| |
| | |
| Ovaries 478
| |
| | |
| A. Thyroid 478
| |
| | |
| B. Adrenal Cortex 480
| |
| | |
| VIII. Concluding Remarks 483
| |
| | |
| IX. References 484
| |
| | |
| I. Introduction
| |
| | |
| Despite the impetus given to the study of
| |
| ovarian structure and physiology by the
| |
| work of Edgar Allen and Edward A. Doisy
| |
| in the 1920's, knowledge of the mammalian
| |
| ovary has hardly progressed beyond a descriptive phase. This cannot be attributed to
| |
| lack of effort, although it must be realized
| |
| that the ovary as an object of investigation
| |
| has not held its own with the hypophysis,
| |
| the thyroid, the adrenal, and the testis. Nor
| |
| lias there been any failure to apply new
| |
| techniques to the many problems of ovarian
| |
| structure and physiology. Histochemical and
| |
| cytochemical techniques were seized ujion
| |
| for what they might contribute to the prol)lem of the site of hormone production,^ and,
| |
| | |
| ' Demp.sey and Bassett, 1943; Dempsey. 1948;
| |
| Claesson, 1954; Claesson and Hillarp, 1947a-c ;
| |
| Claesson, Diczfalusy. Hillarp and Hogberg, 1948;
| |
| Claesson, Hillarp, Hogberg, and Hokfelt. 1949:
| |
| | |
| | |
| | |
| in at least one series of studies (Zachariae,
| |
| 1957, 1958; Zachariae and Jensen, 1958;
| |
| Jensen and Zachariae, 1958), to the mechanism of ovulation. Methods for obtaining
| |
| blood from the ovarian vein have been devised (Paschkis and Rakoff, 1950; Rakoff
| |
| and Cantarow, 1950; Xeher and Zarrow,
| |
| 1954; Edgar and Ronaldson, 1958) and refined techniques for the assay of secreted
| |
| estrogens and progesterone have been developed (Reynolds and Ginsburg, 1942;
| |
| Hooker and Forbes, 1947; Emmens, 1950a,
| |
| b; Haslewood, 1950; Wolstenholme, 1952;
| |
| Zander and Simmer, 1954; Brown, 1955;
| |
| Loraine, 1958; Sommerville and Deshpande,
| |
| 1958j . The collection of follicles and corpora
| |
| lutea timed more accurately with respect
| |
| to the moment of ovulation has become possible, and distinction between the normal
| |
| and the pathologic has become clearer
| |
| (Deane, 1952). Recently, the electron microscope has been found to have a place,
| |
| in an investigation of the finer structure
| |
| of the cells of the corpus luteum (Lever,
| |
| 1956), in the unraveling of the jirocesses
| |
| whereby the zona pellucida is formed
| |
| around the developing oocyte (Chiquoine,
| |
| 1959; Odor, 1959), and in studies of ovarian
| |
| oocytes and unfertilized tubal ova (Odor,
| |
| 1960; Odor and Renninger, 1960) (see Figs.
| |
| 14.6 to 14.8). As Villee has indicated in his
| |
| chapter, great strides have been taken toward an understanding of the metabolic
| |
| pathways in estrogen and progesterone synthesis and degradation.
| |
| | |
| Two factors may have contributed to the
| |
| | |
| McKay and Robinson, 1947; Meyer and McShan,
| |
| 1950; Barker, 1951; Rockenschaub, 1951; White,
| |
| Hertig, Rock and Adams, 1951 ; Deane, 1952; Nishizuka, 1954; Ford and Hirschman, 1955; Noach and
| |
| \an Rees, 1958.
| |
| | |
| | |
| | |
| 449
| |
| | |
| | |
| | |
| 450
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| disappointment that has been expressed.
| |
| First, the purification and synthesis of the
| |
| hormones in the 1930's (Allen, 1939; Doisy,
| |
| 1939) and the later successful development
| |
| of synthetic estrogens and gestagens ( Solmssen, 1945; Dodds, 1955; Rock, Garcia and
| |
| Pincus, 1956; St. Whitelock, 1958) provided
| |
| a means whereby much of ovarian physiology could be studied out of context with
| |
| the processes by which this organ functions.
| |
| Specifically, there are many effector actions
| |
| of ovarian hormones, many interrelationships with other hormones and with each
| |
| other, many problems of tissue responsiveness, and many questions bearing on processes of ovarian hormone metabolism, all of
| |
| which can be studied in ovariectomized animals.
| |
| | |
| Secondly, there were many practical reasons why chemists should have striven to
| |
| synthesize estrogenic substances and gestagens which are suitable for replacement
| |
| therapy. Once prepared, these synthetic substitutes are of interest, but their development and therapeutic application may well
| |
| have diverted attention from studies of the
| |
| ovary.
| |
| | |
| If there is disappointment with the progress that has been recorded, we would direct
| |
| attention to substantial accomplishments
| |
| which should stand us in good stead in the
| |
| future. Among these are the numerous careful descriptions of the growth and maturation of ovarian follicles and the meticulous
| |
| accounts of corpus luteum formation, structure, and involution. In a general way it has
| |
| become clear that in many species estrogen
| |
| and progesterone are produced while the
| |
| follicles are maturing, and that, during the
| |
| functional life of the corpus luteum, progesterone and estrogen are secreted. Estimates of the amounts produced have been
| |
| numerous and of more than ordinary interest. In addition, they probably represent
| |
| steps toward the determination of additional
| |
| important information : the day-to-day rate
| |
| of production correlated with the growth of
| |
| the follicles and the development of the
| |
| corpora lutea, and, in species in which
| |
| variable numbers of follicles and corpora
| |
| lutea develop, steps in an effort to ascertain
| |
| whether, for example, 10 follicles in an individual produce more hormone than 5.
| |
| This knowledge, if we possessed it, might
| |
| | |
| | |
| | |
| contribute significantly to current theories
| |
| of gonadal-pituitary relationships because
| |
| thresholds are involved in the regulatory
| |
| processes <see chapters by Everett and
| |
| Greep ) .
| |
| | |
| It could be disappointing that, on the
| |
| basis of evidence which is largely circumstantial and inferential, almost every tissue
| |
| component of the ovary, membrana granulosa, theca interna, and interstitial cells,
| |
| has been claimed to be the source of estrogen and progesterone. But it is encouraging
| |
| that information has been obtained which
| |
| prompts us to recognize that it may be futile
| |
| and unrealistic to attempt to identify specific cell types as the sources of hormones
| |
| in the ovary. Current thought, stimulated
| |
| by the discovery that testicular cells, placental tissue, and occasionally the adrenal
| |
| cortex are sources of estrogen and progesterone, and that ovarian tissue produces
| |
| androgens, is leaning toward the view that
| |
| the several tissues involved in steroid hormone biosynthesis may be subject to metabolic aberrations which change their hormone production either in rate or in kind.
| |
| The a])i)roach to the problem now seems to
| |
| be through enzymatic biochemistry rather
| |
| than through gross or finer morphology. Examples of this approach which are suggestive for further work on the ovaries are
| |
| jirovided by the numerous studies by Samuels and his associates (Samuels, Helmreich,
| |
| Lasater and Reich, 1951 ; Huseby, Samuels
| |
| and Helmreich, 1954; Beyer and Samuels,
| |
| 1956; Samuels and Helmreich, 1956; Slaunwhite and Samuels, 1956).
| |
| | |
| It is known in a general way that follicular maturation, ovulation, and corpus
| |
| luteum formation are controlled by gonadotroi)hic hormones from the pituitary. However, as Greep emphasizes in his chapter,
| |
| the specific gonadotrophic hormones have
| |
| not yet been isolated and identified, nor
| |
| have their specific roles in ovarian physiology b(»en demonstrated. To be sure, ovulation has been repoited following the
| |
| injection of allegedly purified pituitary
| |
| gonadotrophins into hypojihysectomized
| |
| rats (Velardo, 1900), but until stages normally seen ill the jn'ocess of folliculogenesis
| |
| and ()\-ulati()ii can he rejn'oduced consistently by the use of pituitary gonadotroI)hins, and until target organ responses simi
| |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 451
| |
| | |
| | |
| | |
| lar to those in intact cycling animals are
| |
| being evoked, no satisfactory conceptualization of ovarian functioning will be possible.
| |
| | |
| Chorionic gonadotrophins are not without practical value in the stimulation of
| |
| ovulation (Cole and Miller, 1933; Folley
| |
| and Malpress, 1944; Folley, Greenbaum
| |
| and Roy, 1949; Marden, 1951; Umbaugh,
| |
| 1951; Robinson, 1954; and others); nevertheless, their contribution to ovarian physiology may be limited. Bradbury has pointed
| |
| out in a personal communication that the
| |
| human placental hormone (HCG) is exotic
| |
| for laboratory animals. It has practically
| |
| no effect on the ovaries of guinea pigs or
| |
| field mice. In rats its biologic effects arc
| |
| finite different from those of pituitary luteinizing hormone (LH) or interstitial cellstimulating hormone (ICSH) (Selye, Collip
| |
| and Thomson, 1935; Evans, Simpson, Tolksdorf and Jensen, 19391. HCG is so ineffective in the hypophysectomized rat that it
| |
| has been assumed, in the case of the intact
| |
| animal, either that it acts through the pituitary or that it requires the presence of the
| |
| pituitary to be effective (Aschheim, Fortes
| |
| and Mayer, 1939; Noble, Rowlands, Warwick and Williams, 1939) . If HCG and other
| |
| chorionic gonadotrojihins are exotic, as such
| |
| results would indicate, the extrapolation of
| |
| effects which have followed their use to the
| |
| normal functioning of the ovary could be
| |
| seriously misleading.
| |
| | |
| What we have written is intended to set
| |
| the tone for what follows. Many of the solid
| |
| accomplishments of the past two decades
| |
| will be recounted, but the areas of uncertainty and the difficulties which slowed
| |
| down the progress of the twenties and thirties will be enumerated in the hope that
| |
| the curiosity of a new generation will be
| |
| aroused and guide us into a period of even
| |
| more productive eft'ort.
| |
| | |
| II. Folliculogenesis
| |
| | |
| A. GROWTH OF PRIMARY AND SM.\LL
| |
| VESICULAR FOLLICLES
| |
| | |
| In mammals, by the time of birth, oogonia
| |
| have completed their proliferative activity
| |
| and become primary oocytes. The serosal
| |
| surface of the ovary is covered by a layer
| |
| of cells known as the germinal epithelium.
| |
| There has been and still is considerable
| |
| | |
| | |
| | |
| speculation whether adult germinal epithelium contains, or gives rise to, any germ
| |
| cells (Sneider, 1940; Mandl and Zuckerman,
| |
| 1950, 1951a-d, 1952b; Zuckerman, 1951;
| |
| Green and Zuckerman, 1951). The subject
| |
| is reviewed extensively by Brambell ( 1956 )
| |
| and in the chapter by Blandau. Careful
| |
| studies of human ovaries have been made
| |
| by Block (1951a, b, 1952, 1953). From all
| |
| this material, it is clear that a satisfactory
| |
| answer has not been given. The latter may
| |
| be awaiting the development of a fresh approach and until then another review of the
| |
| many conflicting reports and opinions would
| |
| be repetitious.
| |
| | |
| ]\Iore relevant to the present review is
| |
| the relationship between ovarian estrogens,
| |
| on the one hand, and germ cell proliferation
| |
| and follicle development, on the other. It
| |
| has been claimed that exogenous estrogen
| |
| stimulates mitotic activity in the germinal
| |
| epithelium in mice, rats, and the minnow,
| |
| Phoximis laevis L. (Bullough, 1942a, 1943;
| |
| Stein and Allen, 1942; de Wit, 1953; von
| |
| Burkl, Kellner, Lindner and Springer, 1954) .
| |
| Bullough (1943) suggested that new cycles
| |
| of oogenesis are intiated by estrogen in the
| |
| follicular fluid of large and rupturing follicles. Mandl and Zuckerman (1950) and
| |
| Dornfeld and Berrian (1951) were less certain. The former expressed the belief that
| |
| the direct effect of estrogenic stimulation
| |
| cannot be measured by comparing the total
| |
| number of oocytes in the ovary. The latter,
| |
| after finding that isotonic saline, gelatine,
| |
| or agar injected into the perovarian capsules
| |
| of immature rats elicited mitoses in the
| |
| germinal epithelium, concluded that the reaction was in response to injury rather than
| |
| to the substance injected. Notwithstanding
| |
| the precautionary notes sounded by ]\Iandl
| |
| and Zuckerman and by Dornfeld and Berrian, the number of reports of increased
| |
| mitotic activity near the site of ovulation
| |
| or when estrogen is placed in contact with
| |
| the germinal epithelium remains impressive.
| |
| Particularly because of the analogy with
| |
| the androgenic control of spermatogenesis
| |
| pointed out by Bullough ( 1942b) and others,
| |
| the possibility should be tested further.
| |
| | |
| As the oocyte starts to grow, the flat investing cells proliferate and form the membrana granulosa. By the time the rat oocyte
| |
| has completed its growth it has acciuired
| |
| | |
| | |
| | |
| 452
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| :^l!:
| |
| | |
| | |
| | |
| I--|(..7.1. Munlry l,yi„,pliy>r,-ini,iiz<Ml 1 y,-uv | hvm, ,u^ly . I'., Hide- :nv ,n ) ,i n^i .—in . ' ~::,-i>s
| |
| (jl (le\f'lu]iiiieiil. C<nic('iitr;itiun ul' uorylcs m ihc corlcx n'S('inl)lfs llial in iVlal or jusciiilc
| |
| o\aiie8. No evidence of estrogen production in this animal. (Courtesy of Dr. Ernest Knobil.)
| |
| | |
| | |
| | |
| foiii' layers of granulosa cells (Mandl and
| |
| Zuokerman, 1952a). The increase in size of
| |
| the growing follicle is relatively constant
| |
| until the stage of antrum formation (Paesi,
| |
| 1949a ». Follicles grow and develop to this
| |
| stage in rats and guinea pigs even after
| |
| hypophysectomy (Dempsey, 1937; Paesi,
| |
| 1949b). It is thus apparent that the gonadotrophic hormones of the pituitary are not
| |
| essential for the early growth of ovarian
| |
| follicles (Fig. 7.1). The rate of this early
| |
| follicular growth may, however, be accelerated in the presence of certain, but perhaps
| |
| not all, gonadotrophic hormones (Pencharz,
| |
| 1940; Sim])son, Evans, Fraenkel-Conrat and
| |
| Li, 1941 ; Gaarenstroom and de Jongh, 1946;
| |
| Payne and Hellbaum, 1955).
| |
| | |
| As the granulosa of the growing follicle
| |
| ])roliferates, the surrounding tissue differentiates into theca interna. Dubreuil (1942,
| |
| 1948, 1950) postulated that the granulosa j)roduces an inductor substance which
| |
| causes the differentiation of the theca interna. Hisaw (1947), in a review of the
| |
| literature bearing on this point, also suggested that there must be organizers within
| |
| | |
| | |
| | |
| the developing gramdosa cells which stimulate tlifferentiation of the theca interna.
| |
| Furthermore, this autonomous process continues until the follicle reaches a stage of
| |
| development at which it becomes responsive
| |
| to gonadotrophic hormones. Hisaw called
| |
| this the stage of "comjietency."
| |
| | |
| Somewhere in this process estrogens seem
| |
| to have a role, or, if the ojjinions expressed
| |
| by Bullough (1943) and the other investigators whose work has just been cited can
| |
| be confirmed, perhaps there is a continued
| |
| stimulation by these substances. If large
| |
| doses of estrogen are administered to imnuitui'c or to liypopliyscctomi/ed immature
| |
| rats, many follicles (k'\x'lop to the early
| |
| antrum stage within 72 hours. The theca
| |
| interna differentiates ai'ound these estrogenstimulated follicles. When immature rats
| |
| ai'e giv(m large doses of estrogen there is
| |
| a <le(iiiil(' incicasc in ox'arian weight and
| |
| in the iiuiiihei' of medium-sized follicles
| |
| ( ]''ig. 7.2 1 ; small amounts, on the othei'
| |
| hand, ai'e iiihihitoiy (Paesi, 1952). Increased giowth of large follicles, or at least
| |
| a retai'dation of their degeneration, has
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 453
| |
| | |
| | |
| | |
| | |
| y^
| |
| | |
| | |
| | |
| Fig 7.2. Intact immature lat given estrogen for 3 days. Active proliferation of granulosa
| |
| in many follicles. Decreased incidence of atresia and hypertrophy of theca. (Courtesy of Dr.
| |
| J. T. Bradburv.)
| |
| | |
| | |
| | |
| Ijeen reported in hypuphyscctoiuizcd I'uts
| |
| given stilbc-^trol (Pencharz, 1940; Williams,
| |
| 1944; Desclin, 1949; Payne and Hellbaum,
| |
| 1955; Ingram, 1959 1. Histologically, when
| |
| estrogen is given, there is a marked increase
| |
| in mitotic activity of the granulosa cells and
| |
| a decrease in atresia (Williams, 1945a; de
| |
| Wit, 1953; Payne and Hellbaum, 1955;
| |
| Payne, Hellbaum and Owens, 1956; Williams, 1956). The fact that estrogen stimulates the follicle and protects it against atresia suggests that the granulosa is not a
| |
| significant source of estrogen. On the other
| |
| hand, if estrogen is jiroduced by the theca
| |
| interna, it could exert a localized stimulatory action on the membrana granulosa
| |
| (Corner, 1938; Bullough, 1942b, c, 1943).
| |
| The differentiation and development of the
| |
| theca interna is nicely timed for a localized
| |
| jiroduction of estrogen around each Graafian
| |
| follicle.
| |
| | |
| Estrogen not only stimulates the granulosa to proliferate, but also renders the
| |
| follicles more responsive to exogenous gonadotrophins. Williams (1945b) found that
| |
| the ovary in the stilbestrol-treated hypol^hysectomized rat was more responsive to
| |
| small doses of pregnant mare serum
| |
| (PMS) than was the ovarv in the intact
| |
| | |
| | |
| | |
| immatui'e rat. Payne and Runser (1958)
| |
| found that stilbestrol augmented the response of hypophysectomized immature rat
| |
| ovaries to exogenous pituitary extracts. In
| |
| Bradbury's experience at Iowa 48 hours of
| |
| stilbestrol pretreatment rendered the ovaries
| |
| of both intact immature and hypophysectomized rats more responsive to Armour's
| |
| LH (Lot No. R377242H), but not to Armour's follicle-stimulating hormone (FSH)
| |
| {Ah 1027) . Furthermore, increasing the dosage of stilbestrol from 0.02 mg. to 0.2 mg.
| |
| markedly increased the response of the
| |
| ovaries to a given dose of LH. He suggested
| |
| that the possibility should be exi)lored that
| |
| the local (})erifollicular) concentration of
| |
| estrogen determines the resjionsiveness of
| |
| the maturing follicles. Thoughtful discussions of the subject are given by Paesi
| |
| (1952) and by Bradbury (1961). The former suggested that 2 or 3 types of estrogen
| |
| action may be involved in the stimulation
| |
| of the ovary which is seen wdien estrogen is
| |
| administered. Bradbury applied estradiol
| |
| or stilbestrol to one ovary of the immature
| |
| rat, leaving the other ovary untreated. The
| |
| various unilateral responses — increase in
| |
| weight, formation of corpora lutea, greater ■
| |
| reactivity to gonadotrophins — demonstrated
| |
| | |
| | |
| | |
| 454
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| .Sj^cr^r
| |
| | |
| | |
| | |
| •■/>:
| |
| | |
| | |
| | |
| | |
| ikm
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 7.O. Imuiuturu li.ypophy.sectomized rat treated with Arniuui - i>il. (iiauulo.sa ha^
| |
| proliferated and follicles have developed antra. The theca is diffeientiated but the interstitium is deficient. (Couitesy of Dr. R. M. Melampy.)
| |
| | |
| | |
| | |
| clearly the local stimulating effect of estrogens with the ovary, as well as the systemic
| |
| effect by way of the pituitary.
| |
| | |
| If estrogen administration to immature or
| |
| to hypophysectomized immature rats is continued 7 to 10 days, the granulosa of the
| |
| stimulated follicles degenerates. This atretic
| |
| process differs from natural atresia in that
| |
| it seems to start peripherally rather than
| |
| centrally. The oocytes do not fragment or
| |
| give off polar bodies as frecjuently as do
| |
| oocytes in normally atretic follicles. It seems
| |
| that the stimulatory effect of estrogen on
| |
| the granulosa is very temporary. Its din-ation, however, is long enough to be coni])atible with the noi'inal pi'ocess of maturation and ovuhitiou.
| |
| | |
| Before concluding the subject, a certain
| |
| amount of back-tracking may be dcsii'able.
| |
| One of the first suggestions to be made by
| |
| Edgar Allen (1922; see also the biogi'aphic;il
| |
| sketch in this book) was tliat the ovum is
| |
| | |
| | |
| | |
| the dynamic center of the follicle. If the
| |
| suggestion is placed in the context that has
| |
| since been developed, the sequence of events
| |
| would l)e an inductive influence of the
| |
| oocyte on the membrana granulosa, a continued inductive influence (oocyte or membrana granulosa?) on the surrounding connective tissue cells until the theca interna
| |
| is formed,- and then the secretion of estro
| |
| 'Resuhs obtained by Genther (1931), Schmidt
| |
| (1936), Humphreys and Zuckerman (1954). and
| |
| Wcstman (1958) suggest that a similar functional
| |
| iclationship exists between the granulosa and interstitial cells. According to Genther, x-ray-iujured
| |
| o\aries composed of interstitial cells produced estrogen only if a growing follicle was present. The
| |
| in\oluted condition of the uteri in rabbits in wliich
| |
| all oocytes and f()llicl(>s iiad been destroyed by
| |
| x-rays led Humphreys and Zuckerman to conclude
| |
| that the ovaries of these animals were not producing estrogen. The results reported by Westman
| |
| suggested tliat interstitial cell function continues
| |
| only lor .1 limited jieriod after x-ray-induced degeneration of the granulosa cells. The results from
| |
| an ingenious investigation by Ingram (1957) ar(
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 455
| |
| | |
| | |
| | |
| gen wliich feeds back to stimulate further
| |
| growth of the meinbrana granulosa and follicle.
| |
| | |
| Attractive as such a hypothesis is, it has
| |
| at least one weakness. If gonadotrophic
| |
| extract rich in FSH is administered to immature rats for three days, there is a generalized stimulation of granulosa tissue
| |
| (Fig. 7.3). Small follicles increase in size,
| |
| medium sized follicles develop an antrum,
| |
| and Graafian follicles become large and
| |
| vesicular (Parkes, 1943), but ovulation is
| |
| uncommon. At autopsy the ovaries are pale
| |
| and edematous. The ovaries are markedly
| |
| increased in size from numerous follicles becoming vesicular. Histologically there is
| |
| little stimulation of the theca interna. Gaarenstroom and de Jongh (1946) recognized this ovarian response when they
| |
| suggested that FSH be designated as Ge
| |
| (gonadotrophin e])ithelial). This tissue response offers evidence that FSH is primarily
| |
| f'oncerned with growth and proliferation of
| |
| the granulosa cells, but there is no explanation to account for the failure of these
| |
| granulosa cells to stimulate the differentiation of the theca interna and the eventual
| |
| secretion of estrogens.
| |
| | |
| During all of follicular growth, the presence of estrogen has come to l^e assumed and
| |
| its production by the growing follicle is
| |
| thought to begin with the appearance of the
| |
| theca interna (see below). On the other
| |
| hand, the amount produced and the rate of
| |
| production are unknown. The amount must
| |
| increase with the growth of the follicles.
| |
| Gillman and Gilbert (1946) found during
| |
| their investigation of perineal turgescence
| |
| in the baboon that, once the perineum
| |
| reaches maximal turgescence, additional
| |
| estrogen is required to maintain it. They
| |
| concluded that in normal animals, during
| |
| the second part of the phase of turgescence,
| |
| there must be an increased output of ovarian
| |
| estrogen. Direct studies have yielded little
| |
| | |
| similarly suggestive. Autografts of ovarian medulla
| |
| without cortical tissue or oocytes, and autografts of
| |
| cortical tissue were transplanted to various sites in
| |
| .sexually mature rabbits. The grafts of cortical tissu(> p(>rsisti'(l after the medullary grafts had disappeared. Ingram concluded that medullary tissue
| |
| containing interstitial tissue but no follicles cannot survive.
| |
| | |
| | |
| | |
| information. Foi'd and Hirschman (1955)
| |
| estimated alkaline phosphatase activity in
| |
| the ovary of the rat, but the concentrations
| |
| in the theca interna and ovarian tissue as
| |
| a whole were relatively constant during the
| |
| phases of the cycle.
| |
| | |
| B. GROWTH OF VESICULAR FOLLICLES
| |
| | |
| The growth of the follicle which is dependent on stimulation by hypophyseal gonadotrophins has been described for a number
| |
| of animals and, for a few (cow, sow, ewe,
| |
| guinea pig, rat) plotted with respect to the
| |
| time of the preceding ovulation (McKenzie,
| |
| 1926; Hammond, 1927; Grant, 1934; Myers,
| |
| Young and Dempsey, 1936; Boling, Blandau, Soderwall and Young, 1941 ; von Burkl
| |
| and Kellner, 1956). Data of the latter sort
| |
| are especially valuable for the baselines
| |
| they provide for experimental studies of the
| |
| factors affecting the pituitary-gonadal relationships. Deviations in the shape of the
| |
| curve of follicular growth, and disparities
| |
| in the size of the growing follicles and in the
| |
| size and structure of the corpora lutea, are
| |
| clear indicators of abnormalities in function
| |
| which have been too little used.
| |
| | |
| C. PREOVULATORY SWELLING
| |
| | |
| Without exception in the animals listed
| |
| above, and probably in the horse, goat, and
| |
| bat, if we may judge from the data presented by Hammond and Wodzicki (1941),
| |
| Wimsatt (1944), and Harrison (1946,
| |
| 1948b), a linear period of growth during
| |
| most of the diestrum is followed by a positive acceleration (preovulatory swelling) ;
| |
| shortly before estrus and ovulation. The
| |
| point at which this acceleration occurs is
| |
| the point in the development of the follicle
| |
| where physiologic evidence for the production of progesterone by the unruptured follicle was first found (Dempsey, Hertz and
| |
| Young, 1936; Astwood, 1939). As we will
| |
| see later, however, the ^'moment" the preovulatory swelling begins is not necessarily
| |
| the point in time when the first progesterone
| |
| is produced.
| |
| | |
| In most sjiecies in which the course of
| |
| the preovulatory swelling has been followed,
| |
| it is a 10- to 12-hour process (Hammond,
| |
| 1927; Grant, 1934; Myers, Young and
| |
| | |
| | |
| | |
| 456
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Dempsey, 1936; Doling, Blandau, Soderwall and Young, 1941 ; Rowlands and Williams, 1943; Rowlands, 1944), although in
| |
| the cat and ferret the process is triggered
| |
| by mating and extends over 25 to 30 hours.
| |
| The preovulatory swelling can be initiated
| |
| by injecting gonadotrophins of the LH or
| |
| ICSH type, but they are effective only on
| |
| well matured follicles (Hisaw, 1947; Talbert, Meyer and McShan, 1951). The
| |
| younger follicles are not stimulated and, on
| |
| the contrary, they may show an accelerated
| |
| atresia. It could be postulated that the follicules with well developed theca interna
| |
| were "competent" and that stimulated theca
| |
| interna produced estrogen which favored
| |
| the development of these follicles. The
| |
| smaller follicles were "incompetent" in the
| |
| absence of a thecal investment and became
| |
| atretic. If HCG is injected into immature
| |
| rats, the theca interna around the vesicular
| |
| follicles hypertro])hies within 24 hours and
| |
| these follicles enlarge rapidly. The vasodilation of the theca blood vessels is grossly
| |
| evident within a few hours (Kupperman,
| |
| McShan and Meyer, 1948; Sturgis and
| |
| Politou, 1951; Odcblad, Nati, Selin and
| |
| Westin, 1956).
| |
| | |
| Explanation has been sought for the nature of the changes within the follicle which
| |
| lead to the accelerated enlargement culminating in ovulation. Studies of the staining
| |
| qualities of such follicles reveal that the
| |
| metachromatic polysaccharides of the granulosa (hyaluronic acid and chondroitin
| |
| sulfuric acid) become progressively depolymerized and orthochromatic. This hydrolysis of the mucopolysaccharides gives rise to
| |
| an increased osmolarity which may be the
| |
| major factor in the preovulatory swelling of
| |
| the follicle (Harter, 1948; Catchpole, Gersh
| |
| and Pan, 1950; Odeblad, 1954; Zachariae,
| |
| 1958; Zachariae and Jensen, 1958; Jensen
| |
| and Zachariae, 1958). Accompanying the
| |
| swelling is a dispersal of the cells of the
| |
| cumulus oophorus. This may be a cons(^quence of the breakdown of the intcrcclhihii'
| |
| substance in the stinudated niciubraiia gi'aiiulosa.
| |
| | |
| The time r('(|uirc(l for follicular growth
| |
| and maturation fi'oin the stage when its
| |
| further development is dependent on pituitary gonadotrophin stimulation to ovulation
| |
| is related to the length of the cycle and
| |
| | |
| | |
| | |
| therefore varies greatly from species to species. Somewhat less than 4 to 5 days are required in the rat (Boling, Blandau, Soderwall and Young, 1941 ) , somewhat less than
| |
| 16 days in the guinea pig (Myers, Young
| |
| and Dempsey, 1936), somewhat less than
| |
| 21 days in the cow (Hammond, 1927), and
| |
| ])resumably comparable intervals in other
| |
| species. Vermande-Van Eck (1956) estimated that in the rhesus monkey the average time required for the growth of a mature
| |
| follicle from the large follicle without an
| |
| antrum is 4 to 6 weeks; 11 days are estimated to lie necessary for the complete development of a follicle in the rabbit (Desaive, 1948) . Ovulation occurred earlier than
| |
| normal when the corpora lutea from the
| |
| ])receding cycle were removed, but the rate
| |
| of follicular development was not altered
| |
| (Dem])sey, 1937). Presumptive evidence exists, however, that the rate of growth may
| |
| be slower in pubescent chimpanzees (Young
| |
| and Yerkes, 1943), baboons (Gillman and
| |
| Gilbert, 1946), and guinea jngs (Ford and
| |
| Young, 1953).
| |
| | |
| D. OVULATION
| |
| | |
| Ovulation, under normal circumstances,
| |
| ))robably is explosive (Hill, Allen and
| |
| Kramer, 1935, in the rabbit; Blandau, 1955,
| |
| in the rat). In 1 of 2 human i)atients Doyle
| |
| (1951) saw a gush of follicular fluid at the
| |
| time of ovulation. In 163 ovulations timed
| |
| l)y Blandau the interval between the rupture
| |
| of the stigma and the escape of the ovum
| |
| was 72 seconds when most of the folliculai'
| |
| fluid escai)ed in advance of the ovum, and
| |
| 216 seconds when the cumulus oophorus preceded the follicular fluid. The slower, steady,
| |
| continuous flow of the liquor folliculi which
| |
| has been described by Walton and Hammond (1928) in the cow, Markee and Hinsey (1936) in the rabbit, and by Doyle
| |
| (1951) in one human sul)ject could be an
| |
| artifact of the procedures used in watching
| |
| the jM'Ocess.
| |
| | |
| The mechanisiu heading up to formation
| |
| of the stigma and rupture of the follicle is
| |
| unknown. Claesson (1947), using the submicroscoi)ical differences which can be ol)served in ])olarized light, distinguished
| |
| smooth muscle from connective tissue cells
| |
| and rep()rte(l that no bundles of smooth
| |
| muscle or isolated cells were found in the
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 457
| |
| | |
| | |
| | |
| theca externa in ovaries from the cow, pig,
| |
| rabbit, and guinea pig. The earlier contradictory results he reviewed were attributed to the nonspecificity of the older
| |
| staining methods. A possible clue to the
| |
| mechanism of ovulation wliich does not seem
| |
| to have been explored was given by the observations of Boling, Blandau, Soderwall
| |
| and Young ( 1941 ) when they were studying
| |
| follicular growth in the rat. Immediately
| |
| before ovulation, but at no other time, a
| |
| large pocket at the base of the cumulus,
| |
| and described as an invagination of the
| |
| granulosa, is a constant feature of follicular structure (Fig. 9 in their article). No
| |
| guess w^as made as to its significance.
| |
| | |
| In all the spontaneously ovulating infrahuman mammals that have been studied,
| |
| except the dog (Evans and Cole, 1931 ) ,
| |
| possibly other Canidae, and the mouse
| |
| (Snell, Fekete, Hummel and Law, 1940)
| |
| in which it takes place early in estrus, ovulation occurs toward the end of heat (see
| |
| reviews in Young, 1941; Dukes, 1943; and
| |
| more recent articles on the chimpanzee, rhesus monkey, baboon, cow, and mare by
| |
| Young and Ycrkes, 1943; van Wagenen,
| |
| 1945, 1947; Gillman and Gilbert, 1946;
| |
| Cordiez, 1949; and Trum, 1950; respectively ) . Only in the human female in which
| |
| cyclic waxing ^nd waning of sexual desire
| |
| is not easily detected does uncertainty exist.
| |
| | |
| Since an early period, when emphasis was
| |
| given to the opinion that ovulation occurs
| |
| about midway in the intermenstrual interval (Knaus, 1935; Hartman, 1936; Farris,
| |
| 1948), much evidence has been produced
| |
| indicating that it may occur at other times
| |
| as well, even during menstruation (Teacher,
| |
| 1935; Rubenstein, 1939; Sevitt, 1946; Bergman, 1949; Stieve, 1952; and many others).
| |
| If we may judge from what has been found
| |
| in the chimpanzee (Young and Yerkes,
| |
| 1943), baboon (Gillman and Gilbert, 1946),
| |
| ihcsus monkey (Rossman and Bartclmez,
| |
| 1946), and man (Bergman, 1949; Buxton,
| |
| 1950), irregularities in the length of the
| |
| preovulatory and postovulatory phases of
| |
| the cycle complicate the problem and could
| |
| account for some of the confusion. In the
| |
| chimjianzee, baboon, and human female, in
| |
| which the irregularities can be located wdth
| |
| respect to the time of ovulation, age influences the length of both phases, and fol
| |
| | |
| | |
| lowing pregnancies there are similar irregularities. In the baboon, environmental
| |
| stresses result in temporary or even prolonged inhibition of ovarian activity. There
| |
| is no reason for believing that the same factors have less effect on folliculogenesis in
| |
| the human female; irregularities in adolescence (Engle and Shelesnyak, 1934) and following pregnancy (Sharman, 1950, 1951)
| |
| are common and there are many reports of
| |
| psychic effects (see reviews by Kelley, 1942;
| |
| Kelley, Daniels, Poe, Easser and Monroe,
| |
| 1954; Kroger and Freed, 1950; Randall and
| |
| McElin, 1951; Bos and Cleghorn, 1958).
| |
| In all cases follicular growth is interrupted
| |
| and amenorrhea follows. But if the estimates are correct that the average fertile
| |
| woman ovulates normally about 85 per cent
| |
| of the time (Farris, 1952), or that perfectly
| |
| healthy women may have 3 or 4 anovulatory
| |
| cycles a year (de Allende, 1956; also see
| |
| table in Bergman, 1949), there must also
| |
| be cases in which much of follicular growth
| |
| is normal, or at least adequate to stimulate
| |
| growth changes in the uterus, but ovulation
| |
| does not occur. As if the complications noted
| |
| above are not enough, the reviews of the
| |
| methods used in determining the time of
| |
| ovulation (D'Amour, 1934; Cohen and
| |
| Hankin, 1960) and the critical study of
| |
| Buxton and Engle (1950) in which an attempt was made to correlate basal body
| |
| temperature, the condition of the endometrium, and the stage of folliculogenesis in
| |
| the ovary, suggest either that a really sensitive indicator of the time of ovulation has
| |
| not been found, or if one exists, that it has
| |
| not been used in a study sufficiently systematic to reveal the true situation in the
| |
| human female. The problem is one of the
| |
| many that is with us very much as it was
| |
| 20 years ago.
| |
| | |
| E. FOLLICULOCJENESIS IN PREGNANCY
| |
| AND LACTATION
| |
| | |
| Before leaving the subject of follicular
| |
| growth, its course in pregnancy and lactation should be reviewed. Information has
| |
| been obtained from many species, but in
| |
| most cases it is not complete and a considerable amount of conjecture is necessary.
| |
| What is certain is that pregnancy affects
| |
| the process of folliculogensis in many ways ;
| |
| each must be the reflection of a different in
| |
| | |
| | |
| 458
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| terrelationsliip betwen pituitary, gonads,
| |
| and placenta. In the mare, and presumably
| |
| other species in which multiple ovulations
| |
| occur early in pregnancy, the involvement
| |
| of chorionic gonadotrophins, pituitary gonadotrophins, and estrogen of placental origin
| |
| has been suggested (Rowlands, 1949). When
| |
| folliculogenesis is inhibited just before the
| |
| stage of the preovulatory swelling, as it is
| |
| in many pregnant animals (see below), the
| |
| nervous system may be involved. An unusually significant investigation in which
| |
| the threshold of stimulation to ovulation in
| |
| the rabbit was correlated with threshold
| |
| changes in cerebral activity has recently
| |
| been completed (Kawakami and Sawyer,
| |
| 1959). It was demonstrated that pregnancy
| |
| or prolonged treatment with progesterone
| |
| maintains the electroencephalogram (EEGj
| |
| after-reaction threshold to low frequency
| |
| stimulation of hypothalamic or rhinencephalic nuclei at an elevated level. At this
| |
| level, gonadotrophin release does not occur
| |
| in response to coitus or other ovulatory
| |
| stimuli. The discovery of this fact has provided a basis for understanding the various
| |
| ovarian conditions associated with pregnancy and lactation, or at least those in
| |
| which follicular development proceeds to
| |
| the point of preovulatory swelling and then
| |
| stops. It may be that some other mechanism
| |
| of inhibition accounts for the more severe
| |
| retardation of folliculogenesis in si)ecies in
| |
| which this occurs.
| |
| | |
| The European hares, Lepus tiniidus L.,
| |
| and L. ciiniculus L., are reported as mating
| |
| during pregnancy with the occurrence of
| |
| superfetation (Lienhart, 1940). Pregnancy,
| |
| therefore, has little or no effect on any
| |
| stage of folliculogenesis in these species.
| |
| The domestic rabbit appears to he somewhat
| |
| more affected and perhaps more variable.
| |
| Claesson, Hillarj), Hogberg and ll()kfeh
| |
| (1949) state that the ovaiics of pii'gnant
| |
| rab})its are composed almost entirely of
| |
| interstitial gland, except for the corpoi'a lutea, but, according to Hannnond and Marshall (1925) and Dawson (1946), mature
| |
| follicles ai'e present and pregnant animals
| |
| will occasionally mate. However, if we may
| |
| assume that the reaction of i)regnant animals is similar to that of ])seudopregnant
| |
| animals (Makepeace, Weinstein and Friedman, 1938), pituitary gonadoti'opliin is not
| |
| | |
| | |
| | |
| released and ovulation does not occur. From
| |
| examination of the ovaries and from the
| |
| fact that fertile matings can occur within a
| |
| very few hours after parturition (Dempsey,
| |
| 1937; Boling, Blandau, Wilson and Young,
| |
| 1939; Blandau and Soderwall, 1941), it is
| |
| clear that follicular development in the
| |
| pregnant guinea pig and rat proceeds to a
| |
| point just short of the preovulatory swelling. According to Nelson (1929) and Swezy
| |
| and Evans (1930), cycles of oogenesis occur
| |
| in laboratory rats, and, although the follicles may form small corpora lutea (Swezy
| |
| and Evans), ordinarily they do not rupture.
| |
| The musk-rat. Ondatra zibethica, and the
| |
| African bat, Xycteris luteola, must display
| |
| an advanced follicular development during
| |
| pregnancy because there is evidence of postl)artum estrus (Warwick, 1940; Matthews,
| |
| 1941, respectively). Brown and Luther
| |
| (1951) state that postpartum estrus occurs
| |
| within 3 days after farrowing in the sow, if
| |
| the young pigs are removed. We assume,
| |
| from this latter statement and from the rel^ort that estrus and service may occur during pregnancy in this species (Perry and
| |
| Pomeroy, 1956), that large follicles are
| |
| present in the ovaries of the pregnant sow.
| |
| | |
| Heat ])eriods in the jjregnant ewe are associated with follicular growth, but ovulation
| |
| does not occur, and late in pregnancy follicle size decreases significantly (Williams,
| |
| Garrigus, Norton and Nalbandov, 1956 ) .
| |
| The first heat after {parturition was an average of 23.9 days later, range 1 to 61 days.
| |
| According to Harrison (1948b), widespread
| |
| atretic changes can be seen in all the follicles in the goat, beginning the 40th day of
| |
| |)regnancy. By the (iOth day. no healthy follicles can be found.
| |
| | |
| Hammond (1927) was of the opinion that
| |
| during jircgnancy in the cow, follicles develop to the size at which the jireovulatory
| |
| swelling begins, but Dukes (1943), citing a
| |
| study by Weber, wrote that cows come into
| |
| heat 3 to 7 weeks after parturition. Support
| |
| for this \-iew comes from the report l)y Hafez
| |
| ( 1954) that the average interval to the postpartum esti'us in another bovine, the Egyptian buffalo, is 43.8 days, range 16 to 76
| |
| days. The iclatixcly long postpartum inter\al in these two species is presumptive evidence that follicles are relatively small at
| |
| the end of pregnancy in bovines.
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 459
| |
| | |
| | |
| | |
| Between the 40th and 150th day of pregnancy in the mare the ovaries contain numerous actively growing follicles and several
| |
| functional corpora lutea (Cole, Howell and
| |
| Hart, 1931; Rowlands, 1949). However,
| |
| from the 150th day until the late stages,
| |
| there is a regression of all the corpora lutea
| |
| and an absence of large follicles. In the late
| |
| stages only minute vestiges of corpora lutea
| |
| and small follicles remain. If the latter is
| |
| true, follicular growth must be rapid after
| |
| parturition, because the first heat following
| |
| foaling was between the 7th and 10th days
| |
| in 77 per cent of the many mares Trum
| |
| (1950) studied. In the African elephant,
| |
| Loxodonta africana, there is also a replacement of the corpora lutea (one plus several
| |
| accessory corpora lutea j about midway
| |
| through pregnancy (Perry, 1953). Some are
| |
| formed following ovulation and some not.
| |
| They persist until term when they involute
| |
| rapidly. During the late stages of pregnancy
| |
| no follicles with antra are founcl. Dawson
| |
| ( 1946) wrote that the domestic cat does not
| |
| possess mature follicles at the time of parturition. In nonlactating animals the proestrous level is reached the 4th week after
| |
| parturition.
| |
| | |
| Presumptive evidence exists that the follicles in the parturitive chimpanzee are small
| |
| (Young and Yerkes, 1943 ) . In the human female the appearance of the first ovulatory
| |
| cycle after pregnancy is irregular (Sharman,
| |
| 1950, 1951 ; AlcKeown, Gibson and Dougray,
| |
| 1954). According to Sharman, it may occur
| |
| about 6 weeks after delivery in nonlactating
| |
| women. This suggests that follicles are small
| |
| at the end of ju-egnancy in the human female.
| |
| | |
| Inhibitory effects of lactation on follicular
| |
| development are indicated by the substance
| |
| of many of the reports cited above (Dawson;
| |
| Dukes; Perry; Schwartz; Sharman; Williams, Garrigus, Norton and Nalbandov)
| |
| and by much other information. As would
| |
| be expected, the intra- and interspecies variations are great. Studies in progress at Iowa
| |
| (Bradbury, personal communication) are revealing that some women experience an
| |
| atrophy of the vaginal epithelium during the
| |
| second and third month of lactation. The
| |
| atrophy is indicative of a lack of ovarian estrogen and suggests that follicular development is not normal. Observations that are
| |
| | |
| | |
| | |
| similarly suggestive have been made in other
| |
| species. The absence of estrogen in significant ciuantities during lactation in the mouse
| |
| (Atkinson and Leathem, 1946) and guinea
| |
| pig (Rowlands, 1956) is believed to be the
| |
| reflection of a delay in the resumption of
| |
| follicular growth and ovulation. Mother rats
| |
| and mice may copulate and conceive within
| |
| 24 hours after delivering a litter of young.
| |
| AVhile the mother is nursing the newborn litter, the fertilized eggs of the new pregnancy
| |
| develop into blastocysts, but these blastocysts fail to implant in the uterus at the
| |
| usual time (Talmadge, Buchanan, Kraintz,
| |
| Lazo-Wasem and Zarrow, 1954; Whitten,
| |
| 1955; Cochrane and Meyer, 1957). This delay in implantation is apparently due to a
| |
| lack of estrogen, because an injection of estrogen will result in implantation of the
| |
| blastocysts. The suppression of estrous cycles during lactation in the mouse and rat is
| |
| influenced in part by the size of the litter. A
| |
| litter of 8 to 10 young will inhibit cycles,
| |
| whereas cycles are displayed if the litter is
| |
| reduced to 2 or 3 young (Parkes, 1926a;
| |
| Hain, 1935). The cottontail rabbit [Sijlvilagus floridamis) seems to be a species in
| |
| which ovarian follicular development is little if any affected by lactation, for Schwartz
| |
| ( 1942 ) stated that suckling does not prevent
| |
| ovulation after coitus, at least in the early
| |
| stages of lactation.
| |
| | |
| III. Corpus Liiteuni
| |
| | |
| The formation of the corpus luteum has
| |
| been described for many species ( see reviews
| |
| in Corner, 1945; Harrison, 1948a; Brambell,
| |
| 1956). In general, after rupture of the follicle and discharge of the ovum, the granulosa is invaded by blood vessels from the
| |
| theca interna (Bassett, 1943). They form a
| |
| rich network among the enlarging granulosa
| |
| lutein cells. The extent and nature of the
| |
| contribution from the theca interna varies
| |
| from species to species, but, as Corner states,
| |
| the origin of the major part of the epithelioid cells of the corpus luteum from the
| |
| granulosa may now be considered a fact.
| |
| | |
| Whereas there may be a fairly uniform
| |
| pattern of development and control of ovarian follicles in mammalian forms, there are
| |
| diverse mechanisms for the formation and
| |
| maintenance of corpoi'a lutea; consequently
| |
| | |
| | |
| | |
| 460
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| specific examples must be presented in order
| |
| to avoid the dangers of generalization.
| |
| | |
| In the rabbit copulation triggers a neurohumoral mechanism which releases gonadotrophin from the pituitary which subsequently induces ovulation in 10 to 12 hours.
| |
| The ruptured follicles form corpora lutea
| |
| which have a functional span of about 28
| |
| days if pregnancy ensues but only 14 days if
| |
| the mating is infertile. Crystals of estrogen
| |
| implanted into a corpus luteum of a rabbit
| |
| will cause its persistence while other corj^ora
| |
| lutea regress (Hammond and Robson, 1951 ).
| |
| This suggests that either estrogen makes the
| |
| corpus luteum more sensitive to pituitary
| |
| maintenance (Hammond, 1956) or estrogen
| |
| protects the corpus luteum from luteolytic
| |
| action. In the cat, copulation induces ovulation about 25 hours after mating; the corpora lutea function for 36 days after an infertile mating, but gestation lasts 62 to 64
| |
| days. The ferret ovulates about 30 hours
| |
| after copulation and the corpora lutea are
| |
| functional for 42 days, w^hether the mating
| |
| is fertile or infertile (Brambell, 1956 1.
| |
| | |
| In the unmated rat and mouse ovulation
| |
| is spontaneous, but the resulting corpora lutea are nonfunctional and begin to regress
| |
| within 2 days. After copulation the corpora
| |
| lutea persist for 18 days if impregnation has
| |
| occurred, but for only 12 days after an infertile mating. Copulation probably results
| |
| in the release of enough additional gonadotrophin (LH or LTH) to activate the corpora lutea. In rats and mice the pituitary
| |
| hormone, prolactin, is luteotrophic (LTH)
| |
| (Desclin, 1949; Everett, 1956). These species have functional corpora lutea throughout lactation— actually two sets, that of
| |
| pregnancy and that of the postpartum ovulation. Using the rat and taking weight and
| |
| levels of ovarian enzymes as measures of activity, these corpora lutea were studied by
| |
| Meyer and McShan and their associates and
| |
| the results summarized in a ic\'i('\v (]\Ieyer
| |
| and McShan, 1950). They found that "the
| |
| weight of the corpora lutea of pregnancy increased greatly during the latt(>r half and
| |
| that the amount of enzymes per corjius luteum was also greater. With some caution,
| |
| they concluded that these corpora lutea are
| |
| more highly functional during this phase of
| |
| pregnancy than during the first half.
| |
| | |
| Not only copulation, but also injection of
| |
| | |
| | |
| | |
| estrogen at estrus is followed by the formation of functional corpora lutea. The estrogen maintenance of corpora lutea in rabbits
| |
| and mice is offset by hypophysectomy
| |
| (Hohn and Robson, 1949); presumably,
| |
| therefore, maintenance is mediated through
| |
| the anterior })ituitary. Reece and Turner
| |
| (1937) showed that estrogen stimulates the
| |
| rat i^ituitary to produce prolactin so the latter may be the luteotrophic agent in this
| |
| s]:)ecies. Moore and Nalbandov (1955) found
| |
| that prolactin is luteotrophic in sheep. To
| |
| date this is the only species other than the
| |
| rat and mouse in which prolactin has been
| |
| shown to have luteotrophic activity.
| |
| | |
| In the guinea pig, monkey, man, and
| |
| many other species, ovulation and the formation of functional corpora lutea are spontaneous. Copulation is not known to have
| |
| any neurohumoral influence in these species.
| |
| The corjiora lutea of the human female function for 2 to 3 months in pregnancy and for
| |
| only 12 to 14 days in. an infertile cycle. Bergman ( 1949 ) states that the duration of the
| |
| luteal i^hase is limited to a maximum of 16
| |
| days. In the rhesus monkey the functional
| |
| life has been estimated to be about 13.5 days
| |
| in the normal cycle, and approximately 30
| |
| days when pregnancy intervenes (Hisaw,
| |
| 1944) . In the bitch, ovulation is spontaneous
| |
| and the corpora lutea remain functional for
| |
| 6 weeks irrespective of mating or pregnancy.
| |
| In the lactating African elephant the corpora lutea degenerate soon after parturition
| |
| (Perry, 1953) ; in the lactating domestic cat
| |
| they not only persist, l)ut they become ''rejuvenated" (Dawson, 1946).
| |
| | |
| As a general statement, it can be said that
| |
| the functional span of the corpora lutea is
| |
| cithei' adequate to permit implantation or
| |
| it is prolonged by copulation (as in rats and
| |
| mice) so that imjilantation can occur. But
| |
| inasmuch as imj:)lantation occurs in many
| |
| species, including man, about the sixth day
| |
| after ovulation and fertilization, the margin
| |
| of safety is not great and a delay in the secretion of chorionic gonadotrophin by the
| |
| tro])hoblast must reduce the chances of a
| |
| successful pregnancy.
| |
| | |
| Ill some species, e.f/., rats, mice, rabbits,
| |
| an ill felt ih' mating prolongs the life of the
| |
| corpora hitea. This prolonged interval of
| |
| functional luteal activity is known as pseudoj)regnancy. As Everett has noted in his
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 461
| |
| | |
| | |
| | |
| chapter, in pseudopregnancy the hormonal
| |
| aspects of pregnancy are duplicated, but no
| |
| fetal tissues are present. In the pseudopregnant bitch, for example, the hormonal aspects of pregnancy are so nearly duplicated
| |
| that lactation begins at the time a normal
| |
| gestation would have terminated.
| |
| | |
| The duration of pseudopregnancy in different species offers evidence of adaptive or
| |
| evolutionary mechanisms to control the duration of corpus luteum function, mechanisms that must be endogenous to the uterus.
| |
| Rats and mice have a pseudopregnancy of
| |
| 12 days duration after a sterile mating, cervical stimulation, or injection of estrogen at
| |
| estrus. There is no comparable condition in
| |
| guinea pigs, monkeys, or man. However, if
| |
| rabbits, rats, or guinea pigs are hysterectomized, any subsequent corpora lutea will
| |
| function for a time equivalent to the duration of gestation in each species (Chu, Lee
| |
| and You, 1946; Bradbury, Brown and Gray,
| |
| 1950), although Velardo, Olsen, Hisaw and
| |
| Dawson (1953) stated that, in the rat, hysterectomy has no effect on the length of
| |
| pseudopregnancy. Hysterectomy in the cow
| |
| and sow will prolong the life of the corpus
| |
| luteum (Melampy, personal communication). Experimental distention of the uterus
| |
| l)y beads has resulted in alteration of the
| |
| length of the estrous cycle in ewes (Nall)andov, Moore and Norton, 1955). The only
| |
| explanation which seems to account for
| |
| these results is that there is a luteolytic
| |
| agent in the uterus (probably in the endometrium) of some polyestrous species which
| |
| shortens the life of the corpora lutea in nonpregnant animals. In pregnancy, or when
| |
| massive deciduomas are present, if Velardo,
| |
| Olsen, Hisaw and Dawson are correct, the
| |
| conversion of endometrium to decidual tissue may cause it to lose its luteolytic ability.
| |
| In future studies on the duration of the
| |
| functional span of cor]5ora lutea, the possibility of luteotrophic and luteolytic mechanisms should be considered. On the other
| |
| hand, a fresh start may be advisable. Fewproblems in reproductive and clinical endocrinology (Marx, 1935) seem to have been
| |
| as resistant to clarification.
| |
| | |
| In unmated females of species not having
| |
| a spontaneous "pseudopregnancy," the corlius luteum involutes shortly after its formation. The rat, in which 4 to 8 corpora lutea
| |
| | |
| | |
| | |
| are formed in each ovary at intervals of 4
| |
| to 5 days, has recognizable involuting corpora lutea from the two preceding cycles,
| |
| but no remnants of older ones. The early
| |
| stages of involution of the corpus luteum
| |
| have been described (Brewer, 1942; Boling,
| |
| 1942; Dawson, 1946; Duke, 1949; Moss,
| |
| Wrenn and Sykes, 1954; Corner, Jr., 1956;
| |
| Rowlands, 1956; Dickie, Atkinson and Fekete, 1957). The timetables of cellular
| |
| changes given by Brewer and by Corner, Jr.
| |
| are of interest for the comparison they permit with physiologic estimates of the duration of secretory activity by the human corpus luteum. On day 7 the corpus luteum
| |
| seems to have reached its peak of activity,
| |
| as judged by the vacuolation of its cells in
| |
| Bouin's or Zenker's fluid-fixed and hematoxylin and eosin-stained preparations. Corpora
| |
| lutea of days 9 to 12 show evidence of i)rogressive secretory exhaustion.
| |
| | |
| The later stages of cori:)ora lutea degeneration have not received the same careful attention. In women the corpus luteum undergoes a slow hyaline degeneration and the
| |
| corpora albicantia persist as old scars for
| |
| months or years. They may be present in
| |
| ovaries 15 to 20 years after the menopause.
| |
| Whether the final stage of degeneration is a
| |
| process of lysis, phagocytosis, or transformation into connective tissue has not been
| |
| studied.
| |
| | |
| IV. Follicular Atresia
| |
| | |
| It was long ago estimated that the infantile liuman ovary contains about 400,000
| |
| oocytes (Fig. 7.4). In the 30 years of reproductive life about 400 ova may mature and
| |
| ovulate. On this basis about 1 oocyte in 1000
| |
| achieves ovulation; the other 999 are lost
| |
| through a degenerative process known as
| |
| atresia. The problem is not different in any
| |
| other species. Whether it is monotocous or
| |
| polytocous, there is always an enormous
| |
| wastage of oocytes in each cycle of folliculogenesis. Atresia may have its onset at any
| |
| stage of follicular growth or maturation and
| |
| oocytes may degenerate before they have
| |
| acquired a distinct membrana granulosa
| |
| (Mandl and Zuckerman. 1950; de Wit, 1953;
| |
| Payne, Hellbaum and Owens, 1956; Williams, 1956). In advanced stages of follicular development the granulosa cells may
| |
| show pycnotic changes before any degenera
| |
| | |
| | |
| 462
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 7.4. Ovary from 28-moiith-old child. Many primordial follicles just beneath the tunica
| |
| albuginea. (Courtesy of Dr. J. T. Bradbury.)
| |
| | |
| | |
| | |
| | |
| Fill. 7.5. Iimuaturc rat h
| |
| grow to medium size. Many become atretic and leave
| |
| stitial tissue. (Courtesy of Dr. R. M. Melampy.)
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 463
| |
| | |
| | |
| | |
| | |
| Fig. 7.6. Intact immature rat given progesterone for 3 days. The various-sized follicles in
| |
| this area are in early stages of atresia. The pycnotic granulosa cells are dispersing into the
| |
| follicular fluid and the oocyte in the small follicle at the upper left is denuded. (Courtesv of
| |
| Dr. J. T.Bradburv.)
| |
| | |
| | |
| | |
| tive clianges are evident in the oocyte. When
| |
| vesicular follicles become atretic the granulosa disintegrates and the cells disperse into
| |
| the liquor folliculi (Knigge and Leathern,
| |
| 19.56 ( . If the follicle has developed a distinct
| |
| theca interna, the theca regresses after the
| |
| granulosa has disintegrated. In rats the
| |
| atretic follicles leave no recognizable histologic remnants. In some species the theca regresses back to ovarian interstitial tissue
| |
| (Dawson and AlcCabe, 1951; Williams,
| |
| 1956). In the ovary of the human female
| |
| and rhesus monkey the atretic follicle leaves
| |
| a scar (corpus atreticum) in which the meml)rana propria persists for months as a
| |
| folded hyaline membrane within the loose
| |
| fibrous remnant of the theca.
| |
| | |
| The cause of follicular atresia is not
| |
| known. Immediately after hypophysectomy
| |
| there is a wave of atresia in the ovary of the
| |
| immature rat (Fig. 7.5) and rabbit (Foster,
| |
| Foster and Hisaw, 1937). In adult rats the
| |
| postovulatory wave of follicular atresia has
| |
| | |
| | |
| | |
| l)een attrilnited to an action of the corjiora
| |
| lutea (Atkinson and Leathem, 1946). Injections of androgen or of progesterone increase
| |
| the incidence of atr(>sia in rat ovaries (Fig.
| |
| 7.6) (Paesi, 1949b; Barraclough, 1955;
| |
| Payne, Hellbaum and Owens, 1956). Further study is necessary to determine whether
| |
| the atresia is due to a direct effect of androgen or progesterone on the follicles, or
| |
| whether the postovulatory decline in gonadotrophins, like hypophysectomy, withdraws a supi:)orting influence and permits
| |
| the follicles to degenerate. The supporting
| |
| influence may be estrogenic because injections of estrogen at the time of hypophysectomy will prevent, or at least delay,
| |
| the expected follicular atresia (Fig. 7.7).
| |
| Some months after hypophysectomy the
| |
| number of remaining oocytes is greater
| |
| than in the ovaries of normal litter-mate
| |
| sisters (Ingram, 1953). This suggests that
| |
| vegetating oocytes are less liable to undergo
| |
| | |
| | |
| | |
| 464
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| It:
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| '^l&^h
| |
| | |
| | |
| | |
| ■ ■;%.%,
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 7.7. iiniuaiKi. li.\ pupliy.sectomized rat treated with estrogen (dit'thylstilbe.Ntrol).
| |
| Many follicles have developed to a size appropriate for antrum formation. The interstitium
| |
| i.s atrophic but the theca is differentiated. One follicle is obviously atretic. (Courtesy of Dr.
| |
| J. T. Bnidburv.)
| |
| | |
| | |
| | |
| atresia than those which have entered the
| |
| growth phase.
| |
| | |
| Hisaw (1947) discussed the problem and
| |
| marshaled a number of facts in support of
| |
| the idea that atresia is due to a defective
| |
| differentiation of the theca interna, with a
| |
| ^resulting deficiency of estrogen which is
| |
| considered necessary for growth and differentiation of the granulosa. Ultimately the
| |
| ])ituitary is involved because the success
| |
| which has been achieved in the j^roduction
| |
| of sui)erovulation reveals that the number
| |
| of follicles maturing and ovulating is a
| |
| measure of the amount of gonadotrophic
| |
| hormone. But it is eciually true that there is
| |
| an optimal dosage and time beyond which
| |
| defects appear in the form of cystic follicles
| |
| and premature luteinization (see review by
| |
| Hisaw and more recently Zarrow, Caldw(>ll,
| |
| Hafez and Piiicus, 19581.
| |
| | |
| The disintegration of the discus proligerus
| |
| of the nuiture follicle and the dissolution of
| |
| the granulosa in an atretic follicle have
| |
| led several investigators to suggest that the
| |
| | |
| | |
| | |
| stimulus to ovulation and/or atresia is identical (Harman and Kirgis, 1938; Dawson
| |
| and McCabe, 1951 ; Moricard and Gothie,
| |
| 1953; Williams, 1956). Moricard and Gothic
| |
| found that intrafollicular injection of HCG
| |
| or P]\1S caused first polar body formation
| |
| within 4 liours. Control injections of estrogen or scrum were ineffective. Dempsey
| |
| (1939) noted that maturation spindles were
| |
| present in ne:iily all the oocytes in medium
| |
| and large follicles which had undergone
| |
| atresia shortly after ovulation had been induced by luteinizing hormone. Inasmuch as
| |
| the tubal egg ntay give off the second polar
| |
| body about the time the corona radiata is
| |
| lost, it is interesting to speculate on the significance of the fact that the eggs in atretic
| |
| follicles may also give off polar bodies just
| |
| as they are denuded of granulosa (Fig. 7.8).
| |
| | |
| V. Hormones of the Ovary
| |
| | |
| The hoi'mones of the ovary are the estrogens, pi-ogesterone. androgen, and relaxin.
| |
| The first three are the o\'ai"ian steroid hor
| |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 46.
| |
| | |
| | |
| | |
| Vu,. 7.S. Aticiic lolliric in immature rat gi\en progesterone for 3 day:
| |
| and second metaphase si>indle. (Courtesy of Dr. J. T. Biadbury.)
| |
| | |
| | |
| | |
| mones and are among the most important
| |
| hormones participating in the regulation of
| |
| reproductive physiology. In the present
| |
| hook, as in editions 1 and 2, the discussions
| |
| of their many actions consititute one of the
| |
| central themes.
| |
| | |
| Relaxin is a protein rather than a steroid
| |
| hormone and has always been considered
| |
| more or less apart from the latter. The steps
| |
| in proving its existence were reviewed by
| |
| Hisaw and Zarrow in 1950, and the present
| |
| status of the subject is discussed in the chapter by Zarrow. Unlike the other ovarian hormones, its clinical value is still uncertain
| |
| (Swann and Schumacher, 1958; Stone, 1959).
| |
| | |
| Ovarian androgens present a perplexing
| |
| problem. Evidence for their production is
| |
| abundant (Guyenot and Naville-Trolliet.
| |
| 1936; Hill, 1937a, b; Deanesly, 1938a; Bradbury and Gaensbauer, 1939; Greene and
| |
| Burrill, 1939; Chamorro, 1943; Price, 1944;
| |
| Katsh, 1950; Desclin, 1955; Johnson, 1958).
| |
| l)ut the extent to which they are produced
| |
| l)y the ovaries of normal females, and the
| |
| nature of their action in normal females are
| |
| | |
| | |
| | |
| uncertain (Parkes, 1950). It has been postulated that they are produced during the
| |
| normal cycle in the rat. Payne, Hellbaum
| |
| and Owens (1956) suggested that the interstitial androgens produced at estrus are responsible for the postovulatory atresia of
| |
| the partially developed follicles. The production of ovarian androgens has been demonstrated most effectively under abnormal
| |
| conditions of stimulation. The newborn rat
| |
| ovary will produce androgens when stimulated by human chorionic gonadotrophin
| |
| (Bradbury and Gaensbauer, 1939). The
| |
| treated infant rat shows a marked enlargement of the clitoris and may even develop
| |
| the cartilage anlage of the os penis. Female
| |
| guinea pigs are masculinized by injections
| |
| of HOG (Guyenot and Naville-Trolliet,
| |
| 1936). Ovaries transplanted to the ear of
| |
| the castrate male mouse will produce enough
| |
| androgen to maintain the prostate and seminal vesicle (Hill, 1937a, b). Ovarian transl^lants into the seminal vesicle may exhibit
| |
| a localized androgenic stimulation of that
| |
| tissue (Katsh, 1950). Ovaries of a rat in
| |
| | |
| | |
| | |
| 4(36
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| parabiosi;? with a castrate partner become
| |
| hypertrophied and produce enougli androgen to stimulate prostatic tissue (Jolmson,
| |
| 1958) ; associated with the condition is an
| |
| unusual thecal and interstitial tissue hypertrophy. The masculinizing features of the
| |
| Stein-Leventhal syndrome ( polycystic
| |
| ovary) have been attributed to the presence
| |
| of androgens, having their source perhaps
| |
| in the hilar cells of the ovaries (Lisser and
| |
| Traut, 1954) , but the action of other steroids
| |
| with masculinizing properties also has been
| |
| suggested (Fischer and Riley, 1952). The
| |
| latter possibility might well be checked in
| |
| any case when the production of androgens
| |
| by the ovary is suspected.
| |
| | |
| Estrogen and progesterone are the ovarian
| |
| hormones whose action in the female has
| |
| been studied the most extensively. The steps
| |
| which led to their extraction and chemical
| |
| identification were described by Doisy and
| |
| by Willard Allen in the 1932 and 1939 editions and will not be repeated here. Attention, however, will be directed to the isolation and identification of several naturally
| |
| occurring gestagens in addition to progesterone (Davis and Plotz, 1957; Zander, Forbes,
| |
| von Miinstermann and Neher, 1958). These
| |
| are metabolic degradation products which
| |
| still retain progestational activity.
| |
| | |
| Now as in the period 1932 to 1939, there
| |
| are many unsolved problems, but it is
| |
| equally true that much of interest and value
| |
| has been learned. Not the least of these contributions has been the clarification of the
| |
| l)athways of their biosynthesis (see chapter
| |
| by Villeej . In the sections which follow particular attention will be given to the problem of their origin, to the rate of production,
| |
| the manner of transport and storage, and to
| |
| their "half-life."
| |
| | |
| A. CELLULAR ORTOIX
| |
| | |
| As Villee points out in his chajiter, estrogen and progesterone are apparently derived from cholesterol by a series of chemical changes. Within the ovary and in the
| |
| corpora lutea of rats, there is a definite reduction in the concentration of ascorbic acid
| |
| and cholesterol after gonadotrophin administration. These changes have been considered (ividence for tiie activation of hormone
| |
| synthesis (Everett, 1947; Miller and Everett, 1948; Levin and Jailer, 1948; Aldman,
| |
| | |
| | |
| | |
| Claesson, Hillarp and Odeblad, 1949; Claesson, Hillarp, Hogberg and Hokfelt, 1949;
| |
| Noach and van Rees, 1958).
| |
| | |
| Efforts to identify the cell types in which
| |
| these processes take place have not been altogether successful. We have noted, for example, that several tissues such as testis,,
| |
| placenta, and occasionally the adrenal cortex can produce estrogen. These are tissues,,
| |
| then, which produce more than one hormone.
| |
| Gardner emphasized this during a discussion of Parkes' (1950) review of androgenic
| |
| activity of the ovary, when he called attention to Dr. Furth's observations that some
| |
| ovarian tumors possess potentialities for bisexual hormone production. About the same
| |
| time, Shippel (1950) postulated that thecal
| |
| cells may be a source of estrogen and androgen and that the type of hormone produced
| |
| may depend on particular stresses or stimuli. On the other hand, many investigators,,
| |
| and particularly those interested in the apjilication of histocheraical procedures,^ have
| |
| l^roceeded under the assumption that there
| |
| are tissues of the ovary in which one hormone is iH'oduced predominantly. They
| |
| found, for example, that the reactions of follicular granulosa and theca cells are strikingly different (Demi)sey and Bassett, 1943;
| |
| Dempsey, 1948; Shij^pel, 1950). To be sure,
| |
| the results w^iich have been obtained have
| |
| not led to agreement with respect to details,
| |
| but there is much evidence from the reactions which have been described, as well as
| |
| from the older morphologic studies, that
| |
| theca interna, interstitial, and luteal cells
| |
| and, perhaps to a lesser extent, granulosa
| |
| cells, are active in steroid hormone synthesis. What is less certain than the fact that
| |
| these cells, and consequently the ovaries,
| |
| produce estrogen, progesterone, and androgen is their relative role compared with that
| |
| of other tissues. Presumably it is major;
| |
| nevertheless, evidence for the extra-ovarian
| |
| origin of estrogenic substances is provided
| |
| by the occurrence of cyclic vaginal activity
| |
| in ovariectomized animals (Kostitch and
| |
| Telebakovitch, 1929; Mandl, 1951; Veziris,
| |
| | |
| "Dempsey and Bassett, 1943; Dempsey, 1948;
| |
| Claesson and Hillarp, 1947a-c ; Claesson, Diczfahisy, Hillarp and Hogl)erg, 1948; McKay and Robinson. 1947: Sliii)iH>l. 1950: Barker. 1951: Rockenscliauh. 1951: Wliite, Heitis, Rock and Adams.
| |
| 1951: Deane. 1«)52: Fuiulue-lm, 1954: Xisliizuka.
| |
| 1954.
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 467
| |
| | |
| | |
| | |
| 1951) and by the high titer of estrogens in
| |
| the urine from ovariectomized rats on a high
| |
| fat diet (Ferret, 1950).
| |
| | |
| Corner, as long ago as 1938, in a consideration of the subject, emphasized that there
| |
| is only circumstantial evidence that the
| |
| ovary is the major site of estrogen production. Attempts to extract estradiol or any
| |
| other estrogen from ovarian tissue had
| |
| yielded very small amounts. MacCorquodale, Thayer and Doisy (1936) processed 4
| |
| tons of hog ovaries and recovered about 6
| |
| mg. estradiol from each ton. They estimated
| |
| that the concentration in liquor folliculi was
| |
| of the order of 1 part in 15,000,000 and that
| |
| about 0.1 of this concentration is in the rest
| |
| of the ovarian tissue. There are much better
| |
| sources from which "ovarian hormone" can
| |
| be extracted than from the ovary, i.e., placentas, pregnancy urine, the urine of the
| |
| stallion or boar. The adrenal is also a source
| |
| and there may be other tissues as well, for
| |
| Bulbrook and Greenwood (1957) reported
| |
| that urinary estrogen continued to be excreted after oophorectomy and adrenalectomy of a breast-cancer patient.
| |
| | |
| Whatever the relationships are quantitatively between the follicles and the other
| |
| estrogen-secreting tissues, the evidence that
| |
| the follicles are a major source of estrogenic
| |
| substances remains impressive. This is also
| |
| true of the corpus luteum. The human corpus luteum produces as much, or more, estrogen than was produced during the follicular phase. In the rat and mouse, estrogen
| |
| production during the luteal phase must be
| |
| low because more than 1 part of estrogen
| |
| nullifies the action of 1000 parts of progesterone in these species ( Velardo and Hisaw,
| |
| 1951). By contrast, ratios as high as 100
| |
| parts of estrogen to 1000 parts of progesterone enhance the progestational reactions in
| |
| women (Long and Bradbury, 1951).
| |
| | |
| The different tissues of the ovary — membrana granulosa, theca interna, and interstitial cells — have been studied in efforts to
| |
| ascertain whether they are sites of the production of specific hormones. Inasmuch as
| |
| unruptured follicles and corpora lutea secrete both hormones, the two structures
| |
| must be considered. It has long been known
| |
| that corpora lutea secrete estrogen as well
| |
| as progesterone. Evidence supporting the
| |
| conclusion that jirogesterone is secreted by
| |
| | |
| | |
| | |
| the preovulatory follicle is more recent, but
| |
| it comes from many sources. The possibility
| |
| was first suggested following the discoveries
| |
| that the beginning of mating behavior
| |
| (Dempsey, Hertz and Young, 1936) and the
| |
| decrease in tissue uterine fluid (Astwood,
| |
| 1939) , which depend on the presence of small
| |
| amounts of progesterone, coincide with the
| |
| beginning of the preovulatory swelling.
| |
| More recently, progesterone has been found
| |
| in the follicular fluid from sows, cows, and
| |
| the human female, and, in small quantities
| |
| in blood plasma of the rabbit, human female,
| |
| and rhesus monkey during the follicular
| |
| phase of the cycle (Duy vene de Wit, 1942 ;
| |
| Forbes, 1950, 1953; Bryans, 1951; Kaufmann, 1952; Edgar, 1953b; Buchholz, Dibbelt and Schild, 1954; Zander, 1954).
| |
| | |
| Earlier in this section it was noted that
| |
| there is much evidence from both histochemical and the older morphologic studies
| |
| that theca interna, interstitial tissue, and
| |
| luteal cells, and to a lesser extent, granulosa
| |
| cells secrete the ovarian steroid hormones.
| |
| Many who have used histochemical methods
| |
| still feel that, even though these methods
| |
| demonstrate steroids and their precursors,
| |
| the reactions are not sufficiently specific for
| |
| identification of the individual hormones.
| |
| Others, however, have been more confident,
| |
| and when the evidence they have presented
| |
| is combined with that reported in some of
| |
| the more conventional morphologic studies
| |
| the following summarization of opinion
| |
| seems justified. Granulosa cells of the follicles and granulosa lutein cells of the corpora lutea contain progesterone or a precursor and secrete this hormone (Nishizuka,
| |
| 1954; Green, 1955). Cells of the theca interna, theca lutein cells, and interstitial cells
| |
| are believed to secrete estrogen and possibly
| |
| androgen (Corner, 1938; Deanesly, 1938a;
| |
| Pfeifter and Hooker, 1942; Hernandez, 1943;
| |
| Claesson and Hillarp, 1947a, b; Rockenschaub, 1951 ; Aron and Aron, 1952; Furuhjelm, 1954; Nishizuka, 1954; Fetzer, Hillebrecht, Muschke and Tonutti, 1955; Johnson, 1958). The interstitial cells have been
| |
| the object of much study and will be given
| |
| especial attention.
| |
| | |
| Interstitial tissue or cells in the ovary is
| |
| not as clear a concept as it is in the teste.-.
| |
| In the latter interstitial or Leydig cells are
| |
| derivatives of connective tissue elements
| |
| | |
| | |
| | |
| 468
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| irf^'t'H-'^
| |
| | |
| | |
| | |
| . 7.'.). Aii< ^lioii.-. ral)l)U. J^aigc lulliclf^ lUulcifioinK ati< Ma Iiilcr^l il luui i,> \i>ilil<- only
| |
| as the narrow wedge of granular tissue extending from the cortex into the intrafollit-ular septum. (Courtesy of Dr. J. T. Bradbiuy.)
| |
| | |
| | |
| | |
| and can (ledift'erentiate to form connective
| |
| tissue cells (Esaki, 1928; Williams, 1950).
| |
| The role of Leydig cells as secretors of
| |
| testicular androgen or a precursor is not
| |
| (juestioned. In the ovary it is also presumed
| |
| that undifferentiated connective tissue elements exist, indeed much of the stroma must
| |
| be composed of such cells. It is believed
| |
| rather generally, although unequivocal proof
| |
| has not been given, that the theca interna is
| |
| derived from connective tissue elements and
| |
| that, as a component of the Graafian follicle,
| |
| it secretes estrogen and possibly androgen
| |
| Hoc. cit.). After ovulation and corpus luteura formation, and after atresia in the case
| |
| of follicles not rui)turing, the cells of the
| |
| theca interna may pcrhajjs I'csuinc their
| |
| place as connective tissue cells or they may
| |
| become interstitial cells (Mossman, 1937;
| |
| Dawson and McCabe, 1955; Rennels, 1951 ;
| |
| Nishizuka, 1954; Williams, 1956). The
| |
| |)rominence of interstitial tissue varies from
| |
| species to species and also with stages of the
| |
| | |
| | |
| | |
| rei)roductive cycle. Whether it is functional
| |
| in i^roducing hormones has been controversial, but most contemporary investigators
| |
| seem to feel that internal secretory capacity
| |
| has been demonstrated. In all the work that
| |
| has been done, supporting evidence is varied; in some cases it is circumstantial, but in
| |
| others it is quite substantial.
| |
| | |
| Interstitial tissue is deficient in the anestrous rabbit, and even though there may be
| |
| considerable follicular development, there
| |
| seems to be little or no estrogen production
| |
| (Claesson and Hillarp, 1947a) (Fig. 7.9).^
| |
| The liypei'ti'opliied iiitei'stitium of the estroiis i;il)l)it (Fig. 7.10) undergoes further
| |
| de\-el()pnicnt (hii'ing prc'gnancy and seems
| |
| almost as luteinized as th(^ corpora lutea
| |
| | |
| ' Rogr('ssi\-e changes in tlic rciirodiictixe tract
| |
| and accessory structures following ovariectomy of
| |
| the anestrous opossimi were taken to indicate that
| |
| these parts receive estrogenic stimidation of ovarian origin during th(^ anestnun (Morgan, 1946;
| |
| Risman. 1946).
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 469
| |
| | |
| | |
| | |
| | |
| | |
| Kid, 7,10. l'(isto\nl.-,l,,iy
| |
| stigma is evident. Note tli
| |
| of Dr. J. T. Bradburv.)
| |
| | |
| | |
| | |
| epithelioid natiii
| |
| | |
| | |
| | |
| of the hypertiopliied mterstitiuin. (Courtesy
| |
| | |
| | |
| | |
| (Fig. 7.11). Grossly the ovary in the anestrous rabbit is translucent whereas the estrous ovaries and the ovaries during pregnancy have a chalky white opacity due to
| |
| the development of the interestitium. After
| |
| hypophysectomy the interstitial cells of the
| |
| rat ovary exhibit a deficiency condition and
| |
| the nuclear appearance has suggested the
| |
| name "wheel cells." If pituitary ICSH is
| |
| administered, the deficiency cells are restored to normal (Fig. 7.12). Hyperplastic
| |
| ovarian interstitium in older women has
| |
| been considered a probable source of estrogen in some cases and of androgen in others.
| |
| The stimulation of interstitium by injected gonadotrophins may be associated
| |
| with the formation of estrogens and/or androgens (Bradbury and Gaensbauer, 1939;
| |
| Marx and Bradbury, 1940). Some rats displayed a permanent estrus; others, during
| |
| a period of androgenic function, were masculinized. During this period, the theca and
| |
| interstitium were not luteinized in many
| |
| cases and it was concluded from the responses of accessory organs that these small
| |
| | |
| | |
| | |
| immature cells had secreted male hormone
| |
| and perhaps female hormone, too. In rats
| |
| with fully luteinized theca and interstitium
| |
| and the pronounced estrous symptoms, it
| |
| was considered that the androgenic effect
| |
| was no longer apparent. Information obtained recently, however, suggests that the
| |
| permanent estrus, when it was shown, may
| |
| have been a consequence of an androgenic
| |
| effect. Cystic follicles which might have
| |
| stimulated a permanent estrus had a vagina
| |
| been present, were found in many adult
| |
| guinea pigs which had received androgen
| |
| prenatally (Tedford and Young, 1960).
| |
| | |
| Without necessarily excluding the possibility that the heterotypical hormone is also
| |
| jiroduced, many articles contain suggestions
| |
| that interstitial tissue has specific estrogenic
| |
| or androgenic activity. There is the report
| |
| that an ovarian interstitial-cell tumor was
| |
| producing estrogens (Plate, 1957). The observation that estrogen continues to be secreted by ovaries in which the follicles have
| |
| been destroyed by x-rays was reported by
| |
| Parkes (1926b, i927a,^b), Brambell and
| |
| | |
| | |
| | |
| 470
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| V J ' *
| |
| | |
| | |
| | |
| k •'
| |
| | |
| | |
| | |
| 6^i;>ir/
| |
| | |
| | |
| | |
| | |
| | |
| | |
| ^ V
| |
| | |
| | |
| | |
| ^,
| |
| | |
| | |
| | |
| Fi(. 7 11 ()\,ii\ liMiii jir. ^uaiii i.ililni l.amc luu uiiz. d < . IK m liiu. ih.niiiii ( uipu- liiii iim.
| |
| Hvi)f'itioi)lue(l intPi-titium. Pninoidial t'olhcles in cortex. (Couitc^y of Di. J. T. Bra(U)iuy.)
| |
| | |
| | |
| | |
| Parkes (1927), Genther (1931), Schmidt
| |
| (1936), Mandl and Zuckerman (1956a, b),
| |
| and others. This conclusion w^ould seem to be
| |
| .strengthened by the recent report that there
| |
| is no intensification of the secretion of gonadotrophins by x-rayed rats in which there
| |
| was an apparent destruction of the ova and
| |
| folhcles (AVestman, 1958). Evidence of an
| |
| entirely different sort for the secretion of estrogen by interstitial tissue has been i)resented by Ingram (1957). Autografts of
| |
| medullary tissue containing interstitial tissue but no follicles were made in rabbits.
| |
| Five animals from which this tissue was recovered had uteri which were not as atroi)hic
| |
| as the uteri of spayed animals. He noted,
| |
| however, that in the absence of the follicular apparatus the capacity to secrete estrogen is soon lost. As we have seen,- Ingram is
| |
| one of several investigators who have related the functioning of interstitial tissue to
| |
| granulosa elements.
| |
| | |
| | |
| | |
| Histochemical staining procedures for
| |
| cholesterol indicated to Dempsey (1948)
| |
| that the theca interna is a possible source of
| |
| estrogen. The results obtained during a more
| |
| extensive utilization of histochemical reactions in studies of the ovaries of nonpregnant, psoudopregnant, and pregnant rabbits,
| |
| and in the ovaries of rats and guinea pigs
| |
| were consistent with the conclusion that a
| |
| li])i(l i)recursor of estrogenic substances is
| |
| ]:)resent in interstitial tissue (Claesson, 1954;
| |
| Claesson and Hillarji, 1947a, b; Claesson,
| |
| Diczfalusy, Hillarp and Hclgberg, 1948).
| |
| | |
| Rennels (19511, on the basis of histochemical reactions in the oxaries of innnature rats, advanced the liypothesis that interstitial tissue has a dual origin. There is
| |
| a primary type present between 10 and 18
| |
| (lays aftei- bii'th wliicli is dosc^ly associated
| |
| with gi'anulosa ()Ut<j;i()wtlis and ingrowing
| |
| cords of cells from the germinal epithelium.
| |
| A secondary type is formed later from the
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 471
| |
| | |
| | |
| | |
| -i:-* :^-"!r
| |
| | |
| | |
| | |
| | |
| | |
| | |
| t:^-^-!..
| |
| | |
| | |
| | |
| 4"
| |
| | |
| | |
| | |
| | |
| jP^-'-^i'
| |
| | |
| | |
| | |
| | |
| Fig. 7.12. Immature hypoi)liyspftomized rat alter 3 days treatment with Armour's IC8H.
| |
| The interstitium is restored and is mildly hyperplastic. Nearly all of the vesicular follicles
| |
| are atretic. The theca blends into the interstitimn. Two of the oocytes contain maturation
| |
| spindles. (Courtesy of Dr. R. M. Melampy.)
| |
| | |
| | |
| | |
| theca interna of atretic follicles. He presented no evidence for the production of estrogen by the latter tissue, but expressed the
| |
| opinion that Claesson and Hillarp (1947b)
| |
| had done so. Under the assumption that estrogen rather than androgen is produced by
| |
| o^'aries of untreated rats during the early
| |
| juvenile period (10th to 18th day), he interpreted the presence of histochemically reactive materials in the iirimary interstitial
| |
| tissue as an indicator of estrogenic activity.
| |
| To Huseby, Samuels and Helmreich (1954),
| |
| the steroid-3/?-ol dehydrogenase activity in
| |
| interstitial cell tumors having androgenic
| |
| activity, suggested a relationship between
| |
| the presence of this enzyme and the production of the androgen.
| |
| | |
| B. AMOUNTS OF HORMONE PRODUCED
| |
| | |
| Dependable estimates of the rate of estrogen and progesterone production would
| |
| provide investigators of reproductive physiology with interesting and valuable information. It must be recognized, however, that
| |
| there are many pitfalls and outright difficid
| |
| | |
| | |
| ties; consetiuently the estimates which have
| |
| been made must be regarded as tentative.
| |
| Furthermore, they are of limited value. The
| |
| amounts produced probably deviate greatly
| |
| from the quantities which are effective in
| |
| meeting the threshold requirements of the
| |
| tissues the ovarian hormones stimulate. This
| |
| latter information would make the greater
| |
| contribution to an understanding of the
| |
| functioning of these substances in the regulation of rei^roductive processes. Most efforts
| |
| to estimate the rate of secretion of estrogen
| |
| have involved measurements of the amount
| |
| of hormone given subcutaneously that will
| |
| restore normal structure or function in ovariectomized animals. As Corner (1940) emphasized, estimates obtained in this manner
| |
| are based on the assumption that a hormone
| |
| injected once daily in an oil solution is utilized by the body as efficiently as a hormone
| |
| produced by an animal's own ovaries. Gillman (1942), Barahona, Bruzzone and Lip.schutz (1950), and Zondek (1954) are
| |
| among the many who have directed attention to the fact that the amount of an esiro
| |
| | |
| | |
| 472
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| gen required to e^'okc one response often
| |
| is different from that required for a second
| |
| response. For example, the amount of estradiol necessary to produce perineal enlargement in the baboon is less than that
| |
| required to produce withdrawal bleeding. In
| |
| the human female, the order of sensitivity of
| |
| three tissues to estrogen is uterine cervix,
| |
| vaginal mucosa, endometrium (Zondek,
| |
| 1954). Theoretically, therefore, if the response of tissues is to be used in estimating
| |
| the amount of hormone produced, the investigator should follow the response having
| |
| the highest threshold value. Gillman also
| |
| called attention to another complication.
| |
| The minimal amount of estrogen necessary
| |
| to produce a response does not necessarily
| |
| approximate the amount being produced,
| |
| because, in the instance he cites, larger
| |
| amounts do not produce a larger perineum.
| |
| | |
| Another comi^licating circumstance is the
| |
| occurrence of ''inherent" cycles (in some
| |
| cases the length of a reproductive cycle) of
| |
| responsiveness which have been demonstrated in ovariectomized females receiving
| |
| constant amounts of estrogen from exogenous sources. Many such animals have displayed cyclic vaginal changes (del Castillo
| |
| and Calatroni, 1930; Bourne and Zuckerman, 1941a), uterine l)leeding (Zuckerman,
| |
| 1940-41 ), and running activity (Young and
| |
| Fish, 1945). This unknown factor must be
| |
| taken into consideration in any attempt to
| |
| estimate the rate of estrogen production.
| |
| Existence of this factor gives emphasis to
| |
| the importance of direct determinations,
| |
| wiien they can be made, either from follicular fluid or from freshly drawn blood. Corresponding considerations would hardly be
| |
| tliough of as applying to progesterone. Most,
| |
| if not all, of its actions are synergistic or
| |
| potentiating. Presumably, therefore, they
| |
| are directly dependent, not so much on any
| |
| changes in the inherent responsiveness of the
| |
| tissues as on the extent to which the tissues
| |
| have been conditioned or primed by the estrogen.
| |
| | |
| A part of the picture which must be
| |
| brought into context with the problem of estrogen secretion comes from a review of the
| |
| temporal factors in a normal cyclic animal.
| |
| In animals with short estrous cycles (4 or 5
| |
| days in the rat, mouse, and hamster) . and in
| |
| | |
| | |
| | |
| species in which the cycles are longer as in
| |
| the guinea pig it has generally been assumed
| |
| that estrogen is produced maximally at the
| |
| time of estrus. This is an assumption based
| |
| on the simultaneous occurrence of the cornified vaginal smear and the display of estrous behavior. When one considers that 48
| |
| to 72 hours are necessary for vaginal epithelium to proliferate and then degenerate into
| |
| cornified cells, it is obvious that the estrogen
| |
| which starts these changes must be elaborated 2 or 3 days before estrus and therefore before the size of the follicles is maximal. Zondek (1940) demonstrated that if an
| |
| immature rat was injected with HCG the
| |
| ovaries could be removed 27 hours later and
| |
| the rat would exhibit vaginal cornification in
| |
| 84 to 96 hours. This emphasizes that the estrogen which caused the cornified smear had
| |
| been elaborated 2 or 3 days before vaginal
| |
| estrus (Zondek and Sklow, 1942; Green,
| |
| 1956). The dilation of the uterus with fluid
| |
| late in the proestrum (Astwood, 1939) is
| |
| also evidence that the efi^ective estrogen had
| |
| been elaborated 24 to 30 hours earlier.
| |
| | |
| Problems of assay are involved in any
| |
| attempt to estimate secreted estrogen and
| |
| are discussed briefly by Emmens (1950a, b).
| |
| They are more serious in the case of the estrogens than in the case of progesterone. The
| |
| bioassay of estrogens is usually based on
| |
| vaginal cytology or change in uterine weight.
| |
| The vaginal cytology or smear method is essentially the original method of Allen and
| |
| Doisy(kahnt and Doisy, 1928; Allen, 1932).
| |
| Ovariectomized rats or mice are given subcutaneous injections of the substance being
| |
| tested for estrogenic i)otency. Smears are
| |
| made of the vaginal contents 24, 48, 60, and
| |
| 72 hours later. If the smear reveals the presence of cornified cells 60 to 72 hours after
| |
| the first injection, the tested substance is
| |
| judged to be estrogenic. By using groups of
| |
| animals at each of several dose levels, the
| |
| minimal eft'ectiA-e dose can be judged. The
| |
| smallest amount of substance which will
| |
| jiroduce cornified smears in 50 to 70 ]ier cent
| |
| of the test grouj) is usually designated as the
| |
| rat or mouse unit. Intravaginal tests, introduced by Berger (1935) and by Lyons and
| |
| Templeton (1936), and refined, especially
| |
| by Biggei's ( 1953) and by Biggers and Claringbold (1954, 1955), are 200 times more
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 473
| |
| | |
| | |
| | |
| sensitive than tliose in which the estrogen is
| |
| administered subcutaneously. When the
| |
| mean number of arrested mitoses was used
| |
| as the measure of estrogenic activity, the
| |
| sensitivity was increased another ten times
| |
| ( Martin and Claringbold, 1958).
| |
| | |
| Immature rats or mice can also be used
| |
| foi' the assay of estrogens. The establishment of vaginal patency and mucified or
| |
| cornificd vaginal smear denote estrogen effects. Vaginal patency per se, however, is
| |
| not specific for estrogen because androgen
| |
| will also induce precocious vaginal patency
| |
| (Rubinstein, Abarbanel and Nader, 1938;
| |
| Marx and Bradbury, 1940). Injection of estrogen into immature animals causes a rapid
| |
| increase in the weight of the uterus, due to
| |
| water imbibition. Astwood (1938) found
| |
| that the immature rat uterus increases in
| |
| weight as early as 6 hours after an injection
| |
| of estrogen; however, the optimal response
| |
| was at 30 hours. Just above threshold levels
| |
| graded doses produce graded increases in
| |
| uterine weight. This makes it possible to
| |
| plot a dose-response curve so that closer
| |
| approximations of potency can be achieved.
| |
| Some authors have used ovariectoraized animals for the uterine response method. This
| |
| requires a prior operation and subsequent
| |
| adhesions may make it difficult to strip out
| |
| the uterus cleanly at the end of the test.
| |
| | |
| Whatever the test, each estrogen derivative or synthetic estrogen has an optimal
| |
| assay interval for maximal effect depending
| |
| in part on its solubility, rate of absorption,
| |
| and utilization (Hisaw, 1959). For this reason a standard assay may not be an accurate
| |
| indicator of the estrogenic potency of several comijounds. This factor plus some
| |
| competitive antagonism make this method
| |
| impractical for the assay of mixtures of estrogens (Merrill, 1958). Whatever their
| |
| faults, the bioassay methods in general are
| |
| very sensitive and will detect estrogens in
| |
| 0.1 to 1.0 ixg. quantities.
| |
| | |
| The chemical assay methods for estrogen
| |
| are rather involved and have usually been
| |
| relial)le only in milligram quantities. Fluorometric methods were tried and generally
| |
| discarded because frequently small amounts
| |
| of contaminants were strongly fluorescent;
| |
| consequently fluorescence was being obtained in the absence of biologic activity
| |
| | |
| | |
| | |
| (Bitman, Wrenn and Sykes, 1958) . Recently
| |
| paper chromatographic methods have permitted sufficient purification and isolation
| |
| to make identification and quantification of
| |
| estrogens in microgram quantities (Brown,
| |
| 1955; Smith, 1960; Svendsen, 1960).
| |
| | |
| The most common bioassay methods for
| |
| progesterone are still the Corner-Allen and
| |
| the Clauberg tests which utilize the rabbit.
| |
| The animal is primed with estrogen and
| |
| then given progesterone after an appropriate
| |
| interval. A portion of the uterus is removed
| |
| and examined histologically for the degree
| |
| of glandular develojiment in the endometrium. The test is relatively insensitive since
| |
| it requires about 1 mg. progesterone per rabbit. McGinty, Anderson and McCullough
| |
| (1939) increased the sensitivity of the test
| |
| to 0.5 to 5.0 /xg. by injecting the progesterone
| |
| into the lumen of an isolated segment of the
| |
| rabbit uterus. The histologic response of the
| |
| endometrium in this isolated segment was
| |
| then judged.
| |
| | |
| Hooker and Forbes (1947) adapted the
| |
| McGinty intra-uterine technique to the
| |
| uterus of the ovariectomized mouse. The
| |
| end result is judged histologically by the
| |
| characteristics of the endometrial stromal
| |
| nuclei of the isolated uterine segment. The
| |
| sensitivity is of the order of 0.3 fxg. per ml.
| |
| and the method has been used widely. This
| |
| advantage of the Hooker-Forbes technique
| |
| is that it is sensitive enough to detect gestagens in l)lood plasma and liquor folliculi.
| |
| Disadvantages are that the test is not specific for progesterone, and that certain gestagens such as 17-a-hydroxyprogesterone
| |
| which is devoid of progestational activity
| |
| in some species (rabbit, guinea pig, man)
| |
| are very active in the mouse test (Zarrow,
| |
| Neher, Lazo-Wasem and Salhanick, 1957;
| |
| Short, 1960).
| |
| | |
| There are spectrophotometric techniques
| |
| for jn'ogesterone assay (Reynolds and Ginsburg, 1942; Zander and Simmer, 1954;
| |
| Short, 1958; Sommerville and Deshpande,
| |
| 1958 ) . These methods have the advantage of
| |
| instrumental precision, but require rather
| |
| tedious initial chemical purification. However, they have proved of especial value
| |
| in comparative studies of the blood levels
| |
| of progesterone in sheep with active and
| |
| inactive ovaries, in studies of the progester
| |
| | |
| | |
| 474
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| one content of unruptured follicles in the
| |
| ovaries of cows and sows, and in determinations of the cjuantities of progesterone secreted by 1 or 2 corpora lutea in sheep ( Edgar, 1953a, b; Edgar and Ronaldson, 19581.
| |
| | |
| After allowance was made for these considerations tentative estimates were given:
| |
| rhesus monkey, 200 I.U. or 20 y estrone
| |
| daily; human' female, 3000 I.U. or 300 y
| |
| estrone daily (Corner, 1940); baboon
| |
| {Papio porcarius) , somewhat more than 0.04
| |
| mg. estradiol benzoate daily (Gillman,
| |
| 1942) ; guinea pig, less than the equivalent
| |
| of 1.8 fjig. estradiol daily (Barahona, Bruzzone and Lipschutz, 1950). The variation in
| |
| the responsiveness of individual animals
| |
| was recognized by all the investigators. Two
| |
| important variables were not considered,
| |
| the cyclic growth of follicles, and the number of developing follicles. Presumptive evidence that the amount of secreted estrogen
| |
| increases as the follicle enlarges was provided by the demonstration that more and
| |
| more estrogen is required to maintain perineal turgescence (Gillman and Gilbert,
| |
| 1946). The number of developing follicles
| |
| may vary greatly within a species, in the
| |
| guinea pig, for example, from 1 to at least 6.
| |
| The fact that two corpora lutea in the ewe
| |
| do not produce more progesterone than one
| |
| (Edgar and Ronaldson, 1958) could prepare
| |
| us for a corresponding finding with respect
| |
| to estrogen.
| |
| | |
| The problem of estimating the rate of
| |
| progesterone secretion is l)eset by many
| |
| of the difficulties that confront an investigator attempting to estimate the rate of
| |
| estrogen production, but one circumstance
| |
| especially has facilitated progress by those
| |
| especially interested in progesterone. It is
| |
| that the amount of excreted free prcgnanediol or excreted sodium pregnanediol glucuronidate is about 1/7 the amount of injected progesterone (Trolle, 1955a, b) ; from
| |
| determinations of cither of tlic former,
| |
| therefore, the amount of the latter can be
| |
| estimated with what is believed to be a
| |
| reasonable degree of accuracy. The pioneer
| |
| attempt of Corner (1937) to calculate the
| |
| amount of progesterone secreted by the rabbit, sow, and human female resulted in
| |
| estimates (60 mg. during the luteal phase of
| |
| the cycle in the latter) wliicli are much
| |
| lower than those made more recentlv lObei
| |
| | |
| | |
| and Weber, 1951, 200 mg.; Kaufmann, 1952,
| |
| 200 mg.; Trolle, 1955a, b, 260 to 440 mg.).
| |
| It now seems that the lower estimate made
| |
| by Corner can be attributed to the uncontrolled loss of sodium pregnanediol glucuronidate during storage, owing to bacterial hydrolysis (Trolle, 1955a). The rise
| |
| in the 24-hour values after ovulation, the attainment of a peak the 7th and 8th days,
| |
| and the decline between then and menstruation, are shown nicely in Trolle's
| |
| (1955a) study. His data provide an excellent confirmation of the estimates based on
| |
| structural changes within the cell (Brewer,
| |
| 1942; Corner, .Jr., 1956). The amount of
| |
| free pregnanediol excreted during the cycle
| |
| and therefore the amount of secreted progesterone varied from woman to woman,
| |
| and in the same woman there was variation
| |
| from one cycle to another.
| |
| | |
| Data obtained by Duncan, Bowerman,
| |
| Hearn and Alelampy (1960) from their
| |
| chromatographic study have provided the
| |
| basis of an estimate that the following average amounts of jn-ogesterone are present in
| |
| the luteal tissue from swine: 23 /Ag. on day
| |
| 4 of the cycle; 213 /^g. on day 8; 335 yug. on
| |
| day 12; 311 [xg. on day 16; /xg. on day 18.
| |
| From day 16 to day 102 of pregnancy, the
| |
| amount rose from 477 [xg. on day 16 to 578
| |
| fxg. on day 48 and then decreased to a low
| |
| of 120 ixg. on day 102.
| |
| | |
| Edgar and Ronaldson (1958) made direct
| |
| measurements of the progesterone in lilood
| |
| collected from the ovarian vein in ewes. The
| |
| assay method consisted of extraction of 20
| |
| ml. of blood by, and partition between, organic solvents, final separation by chromotographic i)artition on filter paper, and
| |
| subsequent estimation of the hormone by
| |
| ultraviolet absorjjtion spectroscopy. They
| |
| reported that there is great variability from
| |
| animal to animal. The concentration in
| |
| yearling sheep was not lower than that in
| |
| older animals. Because of the liypothesis
| |
| advanced by Young and Yerkes ( 1943) that
| |
| the amount of secreted progesterone is low
| |
| in adolescent chimpanzees, an extension of
| |
| the Edgar and Ronaldson jirocedures to
| |
| |)iimates would be of interest. In this connection, Edgar and Ronaldson postulated
| |
| what has been brought out as a generalization in so many studies of the steroid hormones. The absolute amount of progesterone
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 475
| |
| | |
| | |
| | |
| circulating in the fluids of the body may be
| |
| less important than the minimal amount.
| |
| The ewes secreting less than the minimum
| |
| may be unable to maintain pregnancy,
| |
| whereas those secreting more may simply
| |
| have surpluses which are of little significance. The same principle may be extended
| |
| to the human female (Davis, Plotz, Lupu
| |
| and Ejarque, 1960 ».
| |
| | |
| An observation new to the reviewer could
| |
| l)e important. When two corpora lutea were
| |
| present in one ovary the concentration of
| |
| I)rogesterone was in the same range as that
| |
| for the ewes with one corpus luteum (Edgar
| |
| and Ronaldson, 1958). In another ewe there
| |
| were 2 corpora lutea in one ovary and 1 in
| |
| the other, but the concentrations in the
| |
| blood from the 2 ovarian veins were almost
| |
| the same.
| |
| | |
| A facet of the problem of the rate of production of ovarian estrogen and progesterone which has become apparent is that
| |
| endogenously and exogenously administered
| |
| estrogen (Rakoff, Cantarow, Paschkis, Hansen and Walkling, 1944; Pearlman, 1957)
| |
| and progesterone (Haskins, 1950; Zander,
| |
| 1954; Rappaport, Goldstein and Haskins,
| |
| 1957; Davis and Plotz, 1957; Plotz and
| |
| Davis, 1957; Pearlman, 1957; Cohen, 1959)
| |
| disai)i:)ear from the blood very cjuickly, in
| |
| the human female and in such laboratory
| |
| mammals as the dog, rabbit, and mouse.
| |
| Zander, for example, injected 200 mg. of
| |
| progesterone intravenously into menopausal
| |
| and ovariectomized women. The concentration of this hormone in the blood was 1.44
| |
| /xg. per ml. after 3.5 minutes and 0.116 yu,g.
| |
| per ml. after 2 hours; 24 hours after the
| |
| injection progesterone could not be found by
| |
| the method he employed. The data obtained
| |
| by the other investigators were similar.^
| |
| Using some of these data obtained from reports in the literature and from his own
| |
| studies, Pearlman (1957) divided the total
| |
| amount of circulating hormone (M) by the
| |
| | |
| ■'To a cpitain extent, and possibly to a considerable extent, the rapid disappearance of progesterone from the blood is explained by its storage in
| |
| the fat tissue of the body (Davis and Plotz, 1957;
| |
| Davis, Plotz, Lupu and Ejarque, 1960). Following
| |
| intramuscular injection of C"-4-progesterone, and
| |
| assuming an even distribution of radioactivity in
| |
| the fat of the body, about 17.7 per cent, 33.7 per
| |
| cent, and 19.6 per cent of the administered dose
| |
| was present 12, 24, and 48 hours, respectively, after
| |
| the administration of the labeled hormone.
| |
| | |
| | |
| | |
| endogenous production rate (r) as a means
| |
| of obtaining the turnover time iT), i.e., the
| |
| time refjuired for a complete replacement
| |
| of the circulating hormone by a fresh supply
| |
| from the endocrine gland. His method was
| |
| not free from criticism by discussants;
| |
| nevertheless, informative estimates were
| |
| made. The turnover time of the various
| |
| estrogens was calculated to be about 6 minutes or less, that of progesterone, about 3.3
| |
| minutes.
| |
| | |
| Not unrelated to the i)roblem of the
| |
| amounts of hormone produced is the sul)ject
| |
| of plasma (and erythrocyte) binding of the
| |
| ovarian hormones. Especial attention was
| |
| given the subject by Rakoff, Paschkis and
| |
| Cantarow ( 1943 ) who reported that as much
| |
| as 50 per cent of the total estrogen content
| |
| of the serum of women is present in a combined or conjugated (bound) form, and
| |
| that almost all of the estrogens of pregnancy are bound to the protein fractions of
| |
| the serum. Shortly thereafter, Szego and
| |
| Roberts (1946) reported that two-thirds of
| |
| the total estrogen in the blood in human
| |
| l)lasma is normally associated with jn-otein
| |
| constituents, and in a subsequent series
| |
| of publications (Roberts and Szego, 1946,
| |
| 1947; Szego, 1953, 1957; and others) that
| |
| the liver is the site of the formation of the
| |
| protein-estrogen complex or estroprotein.
| |
| The nature of the complex soon become controversial and has not yet been resolved
| |
| (Eik-Nes, Schellman, Lumry and Samuels,
| |
| 1954; Antoniades, McArthur, Pennell, Ingersoll, Ulfelder and Oncley, 1957; Sandberg, Slaunwhit(> and Antoniades, 1957;
| |
| Daughaday, 1959). In the jiresent context,
| |
| however, othei- considei'ations are more important.
| |
| | |
| Protein-liinding is not confined to the estrogens and their metabolites, but other
| |
| steroidal hormones, progesterone, testosterone, and corticosteroids, are also present
| |
| in the blood in a bound-state. In studies of
| |
| the binding relationships of serum albumin,
| |
| the link to the esti'ogens was found to be
| |
| strongest, that to the corticosteroids relatively weak, and that to ])rogesterone and
| |
| testosterone intermediate (Sandberg, Slaunwhite and Antoniades, 1957; Slaunwhite and
| |
| Sandberg, 1958; Daughaday, 1959). The i;lationships in the case of other components
| |
| of i^rotein mixtures have been sliown to be
| |
| | |
| | |
| | |
| 47()
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| different, but they are ai)parently eriually
| |
| specific (Daughaclay, 1959; Slaunwhite and
| |
| Sandberg, 1959). A considerable specificity
| |
| of the binding sites may be involved ( Sandberg, Slaunwhite and Antoniades, 19571.
| |
| Daughaday (1959) states that separate
| |
| binding sites may exist for each of the
| |
| steroid hormones studied, and Szego (1957)
| |
| suggested that a competition for these sites
| |
| may be the basis for antagonisms which are
| |
| known to exist in many steroid interactions
| |
| (Courrier, 1950; Hisaw and Velardo, 1951;
| |
| Roberts and Szego, 1953; Velardo, 1959;
| |
| Velardo and Hisaw, 1951 ; Zarrow and
| |
| Neher, 1953).
| |
| | |
| The most important consideration has
| |
| to do with the significance of protein binding for the steroid hormones, and, in the
| |
| present chapter, the significance for estrogen and progesterone. Roberts and Szego
| |
| (1946, 1947) and Szego (1957) proposed
| |
| that formation of the estrogen-protein complex is necessary for the transport and
| |
| activity of endogenous and exogenous estrogens. Riegel and Mueller (1954), on the
| |
| other hand, found that the protein-estrogen
| |
| complex they used had only a slight, if any,
| |
| estrogenic activity, and Daughaday (1958,
| |
| 1959) expressed the opinion that the unbound steroid hormones of the plasma are
| |
| probably the biologically significant moieties. He suggested that the degree of protein binding imposes a major restraint on
| |
| the passage of hydrocortisone (and presumably other steroids) through the cajiillary membranes, but pointed out that this
| |
| view has not yet been established. He then
| |
| asked, in the event that the steroid-protein
| |
| complex does not function in the transi)ort
| |
| of hormones from the vascular component
| |
| to the cell, is it likely that the presence of
| |
| a steroid-protein complex stabilizes the
| |
| pliysiologically significant concentration of
| |
| unbound steroid very much as buffer salts
| |
| stabilize the small concentration of hydrogen ion? In this way, he continued, the
| |
| organism would l)c protected against the
| |
| rapid changes in concentration which characterize an unbuffered system.
| |
| | |
| At tiic ]ir(>sent stage in this controversial
| |
| sul).iect, any hypothesis with res])ect to the
| |
| significance of the protein binding of steroid
| |
| hormones must be tentative. It would seem,
| |
| however, that whatever emerges will have
| |
| | |
| | |
| | |
| validity only if it is compatible with the
| |
| cyclic waxing and waning of reproductive
| |
| phenomena. If the unbound, rather than the
| |
| bound fractions, are the active fractions, the
| |
| functioning of the ovarian steroid hormones
| |
| must dei)end on the presence of unbound
| |
| fractions, in some way made available at
| |
| cyclic intervals to the tissues on which these
| |
| hormones act. It would seem, too, that the
| |
| significance of the increased capacity for
| |
| l)inding in i)rcgnancy (Rakoff, Paschkis and
| |
| Cantarow, 1943; Baylis, Browne, Round
| |
| and Steinbeck, 1955; Daughaday, 1959;
| |
| Slaunwhite and Sandberg, 1959) should be
| |
| a ])art of the picture. Tentatively, this
| |
| greater binding capacity on the part of
| |
| the ])regnant adult, coupled with an inability of the developing fetuses to bind
| |
| androgens, might account for the failure of
| |
| the adult to be affected by the presence of
| |
| androgen at a time when the genital tracts
| |
| and neural tissues of the female fetuses she
| |
| is carrying are undergoing profound modifications (Phoenix, Goy, Gerall and Young,
| |
| 1959; Diamond, 1960).
| |
| | |
| VI. Age of the Animal and Ovarian
| |
| Functioninij
| |
| | |
| The position of the ovary is such — at one
| |
| and the same time being dependent on the
| |
| pituitary, possessing its own varying capacity to function, and having an effectiveness which is limited by the responsiveness
| |
| of the tissues on which its hormones act —
| |
| that no simple consideration of the relationshii) between the age of the animal and
| |
| ovarian functioning can be given. An investigation, therefore, should be planned
| |
| accordingly and we find experiments in
| |
| which the amount of gonadotrophic stimulation was varied when age was constant,
| |
| and experiments in which age was the variable and the amount of gonadotrophin the
| |
| constant. If hypo- or hyper-responsiveness
| |
| of the tissues is suspected, the point can be
| |
| checked by the use of spayed animals given
| |
| variable amounts of ()\-arian hormones.
| |
| When information of these sorts is brought
| |
| together, a fairly accurate account of the
| |
| relationship between age of the animal and
| |
| ovarian activity can l)e ])repared.
| |
| | |
| The results fi'oni many studies have revealed that the ovaries in both inunature
| |
| and senescent females are potentially able
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 477
| |
| | |
| | |
| | |
| to secrete hormones, both estrogen and
| |
| progesterone, in amounts which are in excess of those secreted by untreated animals.
| |
| The secretion of these hormones was elevated in rats, mice, and hamsters by the
| |
| implantation of whole pituitaries (Smith
| |
| and Engle, 1927 » or by the administration
| |
| of chorionic gonadotrophin (Price and Ortiz,
| |
| 1944; Ortiz, 1947; Green, 1955). The reactivation of senile ovaries was first demonstrated by Zondek and Aschheim (1927)
| |
| following the insertion of hypophyseal imjilants, and later by numerous other investigators listed in the review of the subject
| |
| l)y Tlmng, Boot and Miihlbock (1956). In
| |
| more recent experiments an enhanced secretion of estrogen and progesterone followed
| |
| the injection of old hamsters with chorionic gonadotrojihin (Peczenik, 1942; Ortiz,
| |
| 1955).
| |
| | |
| In women fertility may be lost before
| |
| the menopause (Engle, 1955). Studies in
| |
| progress at Iowa (Bradbury, personal communication) show that urinary gonadotroi')hins may be elevated before the menopause and the last ovarian cycles are
| |
| achieved in the presence of excessive
| |
| amounts of pituitary gonadotrophin. As a
| |
| rule the human ovary is devoid of oocytes
| |
| and produces relatively little estrogen at
| |
| the time of the menopause. Frequently, however, there is enough residual ovarian activity (estrogen production) to maintain the
| |
| vaginal epithelium for 10 to 15 years after
| |
| the menopause. These observations on
| |
| women suggest that as the supply of oocytes
| |
| l)ecomes depleted, less estrogen is produced
| |
| and more gonadotrophin is released to
| |
| stimulate the aging ovary. This secjuence
| |
| is in harmony with the concepts of Dubreuil
| |
| (1942) and Hisaw (1947), because with
| |
| fewer areas of granulosa there would be
| |
| fewer centers of organizer to bring al)out
| |
| the differentiation of thecal tissue competent
| |
| to produce estrogen.
| |
| | |
| Ovarian stromal hyperplasia has been
| |
| found in association with endometrial hyperplasia after the menopause (Morris and
| |
| Scully, 1958). Sherman and Woolf (1959)
| |
| suggested that the postmenopausal ovary
| |
| may produce abnormal sexogens which
| |
| bring about an endometrial proliferation
| |
| and ultimately adenocarcinoma of the endomi'trium. Their urinarv l)ioassay studies
| |
| | |
| | |
| | |
| indicate that the patients were excreting
| |
| ICSH-type gonadotrophin. The observation has been made at Iowa that a few
| |
| postmenopausal women with endometrial
| |
| carcinoma were maintaining an estrogenic
| |
| vaginal epithelium when they were ovariectomized at ages varying from 65 to 70
| |
| years. Subsequently the gonadotrophin excretion increased to the ciuantities usually
| |
| seen after the menopause. In these unusual
| |
| cases the aging ovaries produce estrogen, or
| |
| possibly estrogen and androgen, in quantities sufficient to suppress the usual excess
| |
| production of gonadotrophins.
| |
| | |
| The responsiveness or sensitivity of the
| |
| ovary to gonadotrophic stimulation is not
| |
| constant throughout the life of an individual. If we may judge from the studies
| |
| of Corey (1928) and Selye, Collip and
| |
| Thomson (1935) on newborn and 10- to
| |
| 15-day-old rats, Moore and Morgan (19431
| |
| on young opossums, and Price and Ortiz
| |
| (1944) and Ortiz (1947) on rats and hamsters, the prepubertal period is characterized
| |
| by very rapid and great increases in responsiveness to gonadotrophic stimulation.
| |
| Species differences are great. The opossum
| |
| ovaries do not respond to gonadotrophic
| |
| stimulation until about 100 days of age
| |
| (Moore and Morgan), whereas responsiveness was first detected in the rat ovary at
| |
| 4 to 10 days (Price and Ortiz) and in the
| |
| hamster ovary by the 10th day (Ortiz).
| |
| Such data, coupled with the appearance of
| |
| the ovaries at birth, would seem to exclude
| |
| the possibility of gonadotrophic stimulation during the prenatal period, and perhaps the capacity for being stimulated as
| |
| well.
| |
| | |
| Certain other species are different and
| |
| present problems. There is an extensive follicular development and luteinization in
| |
| the fetal ovaries of the giraffe which is the
| |
| basis for the suggestion that the ovaries of
| |
| this species are responsive to gonadotrophin
| |
| before birth (Amoroso, 1955). Such a conclusion is predicated on the assumption either that serum gonadotrophin crosses the
| |
| placental membrane or that the fetal pituitary secretes gonadotrophin. Neither hypothesis has been proved. Evidence exists
| |
| that the ovaries of the horse and seal are
| |
| strongly stimulated before birth (Cole,
| |
| Hart, Lyons and Catchpole, 1933; Amoroso,
| |
| | |
| | |
| | |
| 47!
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Harrison, Harrison-Matthews and Rowlands, 1951; Amoroso and Rowlands, 1951),
| |
| but an unusual structural condition is found
| |
| in these ovaries. No vesicular follicles are
| |
| present and the ovaries, which are larger
| |
| than those of the adult, are composed mostly
| |
| of interstitial tissue which is enclosed by a
| |
| thin cortex containing short chains of germ
| |
| cells and a few oocytes surrounded by a single layer of epithelial cells. Comparable information does not exist for the seal, but in
| |
| the horse the development of this condition
| |
| is reached during the estrogenic phase and
| |
| after the gonad-stimulating hormone is no
| |
| longer detectable in the blood of the pregnant adult. As a result, and cjuite apart from
| |
| the belief that serum gonadotrophin does
| |
| not cross the placenta (Amoroso and Rowlands, 1955 j, the massive interstitial tissue
| |
| liyperplasia is thought to have been stimukited by estrogenic rather than by gonadotrophic action.
| |
| | |
| The immediate jiostpubertal jieriod and
| |
| middle age are periods of relative stability.
| |
| The period of old age has been too little
| |
| studied and is in need of attention. In old
| |
| mice the ovaries are reported to become
| |
| unresponsive to exogenous gonadotrophin
| |
| (Green, 1957). Ortiz (1955), on the other
| |
| hand, stated that although a certain degree
| |
| of ovarian sensitivity is lost in old hamsters, there is a surprising degree of responsiveness present until death, not only
| |
| after the animal is no longer fertile, but
| |
| even in animals with ovaries almost completely atrophic.
| |
| | |
| In young animals and in old animals there
| |
| are irregularities of ovarian function and
| |
| irregularities in the character of the cycles
| |
| which probably can be related to imbalances
| |
| in the pituitary-ovarian relationship. In
| |
| polytocous sjK'cies, fewer follicles ovulate
| |
| in young animals (Young, Dempsey, JMyei-s
| |
| and Hagquist, 1938; Ford and Young, 1953,
| |
| the guinea pig; Perry, 1954, the domestic
| |
| pig; Ingram, Mandl and Zuckerman, 1958.
| |
| the mouse and rat), and in old animals
| |
| (Perry; Ingram, Mandl and Zuckerman).
| |
| These statements of fact, iiowcx-cr. do not
| |
| reveal what is presumed to be more important. In young and old animals the nature of the irregularities, particularly those
| |
| of ovarian function, seem to differ. Evidence
| |
| collecte(l fi'om rhesus monkeys (Hartman,
| |
| | |
| | |
| | |
| 1932) and chimpanzees (Young and Yerkes,
| |
| 1943) suggests follicular growth without
| |
| ovulation and luteinization, or in the guinea
| |
| pig a sluggishness of follicular growth which
| |
| is followed by ovulation and the formation of functional corpora lutea (Ford and
| |
| Young, 1953) . In old animals there may also
| |
| be abnormalities of follicular growth, but
| |
| as the numerous reports are read, the impression is given that abnormalities of
| |
| luteinization are more prominent (Deanesly,
| |
| 1938b; Wolfe, 1943; Wolfe and Wright,
| |
| 1943; Loci), 1948; Thung, Boot and Miihlbock, 1956; Dickie, Atkinson and Fekete,
| |
| 1957; Green, 1957). Additional investigation
| |
| will be necessary before we can be sure
| |
| that the pituitary-gonadal imbalance in
| |
| young animals differs from that in old animals. On the whole, the possibility seems to
| |
| have received little attention, but its importance justifies more careful study.
| |
| | |
| VII. Other Endocrine Glands and
| |
| the Ovaries
| |
| | |
| A. THYROID
| |
| | |
| The relationship of the thyroid to the
| |
| functioning of the ovaries was one of the
| |
| first subjects of modern endocrinologic investigation. Notwithstanding, disappointment must be expressed that after more
| |
| than 50 years of effort, little more than
| |
| cautious generalization is possible. This
| |
| admission is not a confession of defeat; to
| |
| be sure, there is an unfortunate number of
| |
| uncertainties, but we have come to know
| |
| what is necessary in the way of experimental design and techniques to enable us
| |
| to proceed with the confidence that a gratifying clarification can be achieved. The
| |
| greatest obstacle could be, not the lack of
| |
| means, but rather the failure to use the
| |
| means which are alnmdantly at liand for
| |
| more coordinated eft'orts than many which
| |
| lia\e cliaracterized this field in the past.
| |
| | |
| The general l)elief that the thyroid is invoh-ed in reproductive function is grounded
| |
| in two categories of observations. The first
| |
| includes those demonstrating that ovarian
| |
| lioi'inones exert an action on the thyroid.
| |
| 'I'lieic lia\-e been many I't'ports that in the
| |
| human female the thyi'oid enlarges at puberty, at menstruation, and during pregnancy (Gamier, 1921; Marine, 1935; Neu
| |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 479
| |
| | |
| | |
| | |
| mann, 1937; and others). Modern
| |
| counterparts are the reports of the increase during pregnancy in the concentration of serum precipitable iodine
| |
| (Heinemann, Johnson and Man, 1948;
| |
| Dowling, Freinkel and Ingbar, 1956a;
| |
| Tanaka and Starr, 1959), in serum thyroxine (Danowski, Gow, Mateer, Everhart,
| |
| Johnson and Greenman, 1950), and in the
| |
| accumulation of radioiodine (Pochin, 1952).
| |
| Some conflicting reports should be noted.
| |
| There was said to be no consistent alteration in the concentration of serum precipitable iodine in oophorectomized women
| |
| (Stoddard, Engstrom, Hovis, Servis and
| |
| Watts, 1957), and Pochin (1952) found no
| |
| detectable variation in P^^ uptake during
| |
| the menstrual cycle in 5 women he studied.
| |
| Comparable observations have been made
| |
| on laboratory mammals (Greer, 1952; Soliman and Reineke, 1954; Soliman and Badawi, 1956; Feldman, 1956a) and the baboon,
| |
| Papio ursinus (Van Zyl, 1957), except that
| |
| Brown-Grant (1956) could not agree from
| |
| his findings in the rat and rabbit that the
| |
| level of gonadal function exerts any striking
| |
| influence on thyroid activity in the normal
| |
| experimental animal.
| |
| | |
| In man (Engstrom, Markardt and Liebman, 1952; Engstrom and Alarkardt, 1954;
| |
| Bowling, Freinkel and Ingbar, 1956b) and
| |
| in laboratory mammals (chiefly the rat)
| |
| (Money, Kraintz, Eager, Kirschner and
| |
| Rawson, 1951; Feldman, 1956a; Feldman
| |
| and Danowski, 1956) the enhancement of
| |
| thyroid activity is attributed to the level
| |
| of circulating estrogen, whether it be endogenous or exogenous in origin. On the other
| |
| hand, many who have worked with laboratory mammals have not found evidence
| |
| of augmented thyroid activity, and not infreciuently decreases were reported (see
| |
| Paschkis, Cantarow and Peacock, 1948;
| |
| and the numerous articles cited by Farbman, 1944; and Feldman, 1956a). The conflicting results may perhaps be accounted
| |
| for by the circumstance that the response of
| |
| the thyroid seems to be related to the duration of the estrogen treatment and to the
| |
| estrogen that was used. Decreases in thyroid activity have been reported when the
| |
| estrogen treatment was prolonged (Feldman, 1956a), and Money and his associates
| |
| showed clearly that estrone and some other
| |
| | |
| | |
| | |
| components increased the collection of P-^^
| |
| by the thyroid of rats whereas estradiol,
| |
| estriol, and diethylstilbestrol decreased the
| |
| collection. ]\Iany attempts have been made
| |
| to ascertain the nature of the mechanism
| |
| whereby the effective estrogenic substances
| |
| exert their action on the thyroid (Noach,
| |
| 1955a, b; Feldman, 1956b; Dowling, Freinkel and Ingbar, 1956a, b; Bogdanove and
| |
| Horn, 1958). but they are so varied and
| |
| speculative that they will not be reviewed
| |
| here.
| |
| | |
| The second category of observations related to the thyroid and ovarian functioning
| |
| includes those in which there is evidence of
| |
| action of thyroid hormone on the ovary.
| |
| Reviews of this work are contained in the
| |
| articles by Peterson, Webster, Rayner and
| |
| Young (1952), Hoar, Goy and Young
| |
| (1957), and Parrott, Johnston and Durbin
| |
| (1960) and most of their citations of work
| |
| done on the relationship of the thyroid
| |
| to the ovary will not be repeated here.
| |
| As they point out, many investigators
| |
| have reported that thyroidectomy is followed by ovarian degeneration, arrested
| |
| folliculogenesis, and failure of ovulation.
| |
| Irregularity of the reproductive cycles
| |
| was common and much of this in the
| |
| guinea pig could be attributed to retarded
| |
| and sporadic follicular development (Hoar,
| |
| Goy and Young, loc cit.) . The latter investigators gave especial attention to the
| |
| condition of the ovaries in their hypothyroid
| |
| guinea pigs. In 10 pairs from thyroidectomized animals (oxygen consumption and
| |
| heart rate were depressed) follicular development was good in the sense that the
| |
| follicles appeared healthy, but a generation
| |
| of corpora lutea was missing in four. This
| |
| absence of corpora lutea, which is not seen
| |
| in normal adult guinea pigs, was believed
| |
| to be a consequence of the involution of the
| |
| older generation during the longer than normal interval between ovulations. It is considered significant in terms of the functional
| |
| capacity of such ovaries, that although the
| |
| percentage of sterile matings was higher
| |
| than in the controls, that, in the course of
| |
| the two studies at Kansas, 29 of 38 matings
| |
| were fertile. This experience may perhaps
| |
| account for the many reports (cited in tlu
| |
| papers from the Kansas laboratory) that
| |
| thvroidectomv or treatment with antithv
| |
| | |
| | |
| 480
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| roid drugs have no, or at the most rehitively little, effect on the ovary. To these,
| |
| several additional reports should be mentioned. In thyroid-deficient female mice,
| |
| fertility and litter frequency were affected
| |
| only to the extent that the estrous cycles
| |
| were prolonged (Bruce and Sloviter, 1957).
| |
| In the rabbit, thyroidectomy did not interI'upt or alter the periodicity of follicular
| |
| development, but it did eliminate the final
| |
| stages (Desaive, 1948). Parrott, Johnston
| |
| and Durl)in (1960) express the opinion that
| |
| the long i)hysiologic life of thyroid hormone
| |
| may account for many of the contradictions
| |
| in the reports of the relationship between
| |
| thyroid deficiency and reproduction.
| |
| | |
| Except as it is speculative, an unexplained action of thyroidectomy or the administration of goitrogenic drugs is the
| |
| augmentation of the ovarian response to
| |
| gonadotrophins and to anterior pituitary
| |
| im])lants (citations in Peterson, Webster,
| |
| Rayner and Young, 1952; and see in addition Janes, 1954; Janes and Bradbury,
| |
| 1952; Kar and Sur, 1953). Thyroid substances, on the other hand, were inhibitory.
| |
| Of alternative hyjiotheses, Janes favored
| |
| the suggestion that during the period of
| |
| propylthiouracil treatment, provided it was
| |
| short rather than long, there was an accumulation of gonadotrophin in the blood
| |
| and the ovarian response varied for some
| |
| unknown reason according to the concentration of this latter substance in the body
| |
| fluids. To Kar and Sur (1953) direct involvement of the hypophysis could be eliminated; instead a direct role of the thyroid
| |
| seemed more plausible. They postulated
| |
| that the absence of thyroid hormone reduced the utilization of gonadotrophic hormones by the ovary.
| |
| | |
| The reported effects of the hyi)erthyroid
| |
| state or of administered thyroid hormone
| |
| on the ovary are equally conflicting. The
| |
| ovaries are described as being atrophic or
| |
| exhibiting incomplete folliculogenesis, or as
| |
| being essentially normal or even hypertrophied (citations in Peterson, Webster,
| |
| Rayner and Young, loc. cit., Hoar, Gov
| |
| and Young, loc. n't.). Irregular cycles are
| |
| said to have occuitcmI in the rat and mouse.
| |
| but no irregularity was detected in guinea
| |
| pigs given thyroxine.
| |
| | |
| A tentative explanation can be given for
| |
| | |
| | |
| | |
| the many divergent reports of the relationship between the thyroid and the ovary,
| |
| divergencies which are found in the clinical
| |
| literature as well as in laboratory studies.
| |
| In doing so, we will recall that there is
| |
| abundant evidence that the ovary is a locus
| |
| of action of thyroid hormone. The action
| |
| may not be directly trophic, as is that of
| |
| the pituitary, but it is assumed to be su])l)ortive, jiossil)ly directly so. or jiossiljly
| |
| indirectly through regulation of the general
| |
| metabolic level. Whatever its nature, there
| |
| must be great interspecies and even intraspecies variation in the need of the ovary
| |
| for such action. In addition, within a species
| |
| there appears to be a wide range of tolerance, for Peterson, Webster, Rayner and
| |
| Young (1952) found in their study, in
| |
| which the thyroid state was estimated from
| |
| measurements of oxygen consumption and
| |
| heart rate, that reproduction occurred in females in which oxygen consumption ranged
| |
| from an average of 50.0 to 93.5 cc. per 100
| |
| gr. i)er hr. (52.9 in the controls), and heait
| |
| rate from 238 to 316 beats per minute (272
| |
| in the controls). In females that failed to
| |
| rejiroduce, the lowest values were lower
| |
| than in the animals which did reproduce;
| |
| nevertheless, there was much overlai)i)ing,
| |
| for in this group oxygen consumption ranged
| |
| from an average of 46.7 to 94.1 cc. per 100 gr.
| |
| l)er hr., and heart rate from 202 to 330 beats
| |
| j)er minute. Within sucli a framework, there
| |
| are bound to be more divergent results
| |
| than when normal functioning depends on
| |
| nioi'e narrowly circumscribed conditions,
| |
| and the failure to replicate a result does
| |
| not have the same significance. As a part
| |
| of the investigation of sucli a problem, more
| |
| and better correlated infoi'niation is re(|uiicd, and this could be the most pressing
| |
| ne('(l in the field of oxarian (and icproducti\-cl functioning and the thAM'oid.
| |
| | |
| | |
| | |
| B. ADRENAL CORTEX
| |
| | |
| Tlu^ adrenal cortex elaborates its steroid
| |
| )nn()iu's in a biosyiU lictic scciuencc \H'ry
| |
| | |
| | |
| | |
| siiiiilai' to that in the o\aiy. In fact, i)rogcstci'onc is an intermediate substance in
| |
| the synthesis of glucocorticoids. Estrogen
| |
| has been found in extracts of adrenal cortical tissue, but whether it represents a degradation pi'oduct within the adrenal or an
| |
| artifact resulting from the chemical i)i'o
| |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 481
| |
| | |
| | |
| | |
| cedurcs is not clear. Occasionally adrenal
| |
| tumors produce physiologically significant
| |
| amounts of estrogen, but normally the adrenal production of estrogen, if any, is not
| |
| of physiologic significance. The atrophy of
| |
| the female genital tract after bilateral ovariectomy suggests strongly that this is so.
| |
| | |
| The major hormone of the adrenal cortex,
| |
| hydrocortisone or corticosterone, depending
| |
| on the species, has a profound effect on protein and carbohydrate metabolism. An overproduction, as manifested by Cushing's disease, results in a wasting of body protein
| |
| and other metabolic disturbances which by
| |
| nonspecific influences tend to reduce gonadal
| |
| function. Similarly a loss of adrenal function (Addison's disease) leads to anemia,
| |
| electrolyte imbalance, and hypoglycemia.
| |
| There is usually a decrease in ovarian function but some Addisonian patients have
| |
| conceived and carried their pregnancies
| |
| with only sodium and fluid supplements.
| |
| | |
| There is a hereditarv metabolic defect
| |
| | |
| | |
| | |
| of the human adrenal which renders it defective in i)roducing hydrocortisone. This
| |
| is the adrenogenital syndrome. In these
| |
| jiatients the adrenals produce excessive
| |
| amounts of intermediate products which are
| |
| excreted in the urine. Some of these compounds are androgenic 17-ketosteroids and
| |
| may cause virilization (Bradbury, 1958).
| |
| These androgens tend to inhibit the gonadotrophic activity of the pituitary and leave
| |
| the ovaries unstimulated and infantile (Fig.
| |
| 7.13). Replacement therapy with corticoids
| |
| reduces the adrenocorticotrophic hormone
| |
| ( ACTH) activity of the pituitary and then
| |
| the adrenal production of androgen ceases.
| |
| This then permits the pituitary to stimulate
| |
| normal cyclic activity in the ovaries (Fig.
| |
| 7.14). The adrenogenital syndrome thus
| |
| has a profound effect on ovarian function
| |
| which is specific through its production of
| |
| androgen. More complete descriptions of the
| |
| condition and of the rationale of treatment have been prepared by Wilkins ( 1949) ,
| |
| | |
| | |
| | |
| | |
| CHOLESTEROL
| |
| | |
| | |
| | |
| PREGNENOLONE
| |
| | |
| | |
| | |
| PROGESTERONE
| |
| | |
| | |
| | |
| HYDROXYPROGESTERONE
| |
| | |
| | |
| | |
| Fig. 7.13. Scliematic representation of the interaction of the adrenal and the ovary in the
| |
| adrenogenital syndrome. The process of hormone biosynthesis is defective in the adrenal
| |
| (BLOCK) and the degraded by-products (17-ketosteroids) being androgenic suppress the
| |
| formation of gonadotrophins (GTH). (Courtesy of Dr. J. T. Bradbury.)
| |
| | |
| | |
| | |
| 482
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| CHOLESTEROL
| |
| | |
| | |
| | |
| CORTISOL
| |
| | |
| | |
| | |
| CHOLESTEROL
| |
| | |
| GONAD
| |
| | |
| | |
| | |
| \
| |
| | |
| | |
| | |
| ANDROGEN
| |
| ESTROGEN
| |
| | |
| | |
| | |
| PREGNENOLONE
| |
| | |
| | |
| | |
| ;
| |
| | |
| | |
| | |
| PREGNENOLONE
| |
| | |
| | |
| | |
| ADHeNAL
| |
| | |
| | |
| | |
| ^
| |
| | |
| | |
| | |
| \
| |
| | |
| | |
| | |
| 17-HYDROXYPROGESTERONE
| |
| | |
| | |
| | |
| PROGESTERONE
| |
| | |
| | |
| | |
| PROGESTERONE
| |
| | |
| | |
| | |
| 17-HYDROXYPR06ESTER0NE
| |
| | |
| | |
| | |
| Fit. 7 14. Tieatnieiit witli (oiti>one (or other glucocorticoid) reduces ACTH production
| |
| and adrenal hormone .synthesis subside-^. This permits the normal pituitaiy-gonadal interactions to be established. (Courtesy of Dr. J. T. Bradbury.)
| |
| | |
| | |
| | |
| A\'ilkins, Crigler, Silverman, Gardner and
| |
| Migeon (1952), and Bradbury (1958).
| |
| Milder categories of what is believed to be
| |
| adrenal cortical hyperplasia have also been
| |
| described and are responsive to treatment
| |
| with cortisone. They are characterized by
| |
| amenorrhea or oligomenorrhea, hirsutism,
| |
| slightly elevated 17-ketosteroid excretion
| |
| values, and difficulty in becoming pregnant
| |
| (Jones, Howard and Langford, 1953; Jefferies, AYeir, Weir and Prouty, 1958; Jefferies, I960). Indications arc that these
| |
| abnormalities, like those typical of the
| |
| adrenogenital syndrome, affect the ovary,
| |
| not directly, but rather by the creation of
| |
| a pituitary gonadotrophic-ovarian imbalance.
| |
| | |
| Some evidence exists for more direct relationships between the adrenal cortex and
| |
| the ovary. These may involve actions of
| |
| ovai-iaii liormones on the adrenal, and ac
| |
| | |
| | |
| tions of adrenal cortical hormones on the
| |
| ovary. In general, however, the relationships are tenuous or at least not sharply
| |
| defined. It is evident from the review by
| |
| Parkes (1945) that sexual dimorphism in
| |
| adrenal cortical structure has been demonstrated in a number of species, notably the
| |
| mouse and rat and possibly the guinea pig,
| |
| but it has not been detected in a number
| |
| of other species. The effects of gonadcctomy
| |
| and the injection of hormones, particularly
| |
| estrogens, into gonadectomized animals are
| |
| less clear, but they are suggestive of an action on the adrenal, however ill defined and
| |
| variable it seems to be. A seasonal hypertrophy of the adrenal has been reported
| |
| as occurring in the mole, Talpa europaea,
| |
| (Kolmer, 1918) and the ground squirrel,
| |
| Citellus tridecemlineatus (Mitchill), (Foster, 1934), as has enlargement at the time
| |
| of estrus in the rat (Andersen and Kennedy,
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 483
| |
| | |
| | |
| | |
| 1932; Bourne and Ziickennan, 1941bj. More
| |
| recently, a significantly higher excretion of
| |
| 17-hydroxy corticosteroids has been found
| |
| during the second and third weeks, and
| |
| therefore during the luteal phase, of the
| |
| menstrual cycle (Maengwyn-Davies and
| |
| Weiner, 1955).
| |
| | |
| Whether a causal relationship exists between these indications of a fluctuating activity within the adrenal cortex, and seasonal and cyclic changes within the ovaries
| |
| remains to be determined. Little information exists. Bourne and Zuckerman {loc.
| |
| cit.) described the changes in the adrenals
| |
| of ovariectomized rats injected with estrone
| |
| and concluded that the changes are inde|)endent of the gonads. Foster's observation
| |
| that the active appearance of the adrenal
| |
| can be seen during pregnancy as well as
| |
| during estrus suggests, but does not prove,
| |
| that there is a hormonal regulation in the
| |
| ground squirrel which is dependent on reproductive processes.
| |
| | |
| Data with respect to possible direct effects
| |
| of adrenal cortical secretions on the ovary
| |
| ai'e ambiguous. Cortisone acetate administered to rabbits 5 to 33 days in daily doses
| |
| of 5 to 20 mg. did not inhibit the ovulation
| |
| which occurs after mating or after the injection of copper acetate (De Costa and
| |
| Abelman, 1953). The ability of the ovary
| |
| of the rat to respond after adrenalectomy
| |
| was tested by the administration of gonadotrophic extracts (Brolin and Lindl)ack,
| |
| 1951). They found that the ovaries could be
| |
| stimulated to increase the weight of the
| |
| uterus without the cooperation of the adrenals and considered that this result does not
| |
| support the view that there is a direct relationship between adrenal corticoids and
| |
| the biosynthesis of ovarian (also testicular)
| |
| hormones. In other experiments (Payne,
| |
| 1951; Smith. 1955), adrenalectomy abolished (Payne) or interfered significantly
| |
| (Smith) with the ovarian hyperemia response to injections of HCG and pituitary
| |
| extract (Antuitrin T) , the response utilized
| |
| by Farris (1946) as a test for early pregnancy. Cortisone and hydrocortisone were
| |
| partially effective in restoring the response
| |
| in adrenalectomized animals. According to
| |
| Payne, isocortisone acetate and compound
| |
| A acetate were also effective, but in larger
| |
| doses. No report of the use of corticosterone
| |
| | |
| | |
| | |
| (comi)ound B) is gi\'en; replacement therapy with this hormone would have been
| |
| more physiologic because it is the natural
| |
| corticoid of rats. It was concluded that the
| |
| hyperemia response is more nearly normal
| |
| in animals with normal adrenal function;
| |
| Payne believes that the response is mediated
| |
| through this gland. Despite what seem to
| |
| be clear-cut results which have been confirmed, it is felt that additional closely controlled exi^eriments must be done in order
| |
| to show whether these adrenal hormones
| |
| affect the ovary directly or whether most
| |
| of the effects are nonspecific metabolic alterations.
| |
| | |
| VIII. Concluding Remarks
| |
| | |
| The avenue followed by investigators interested in the functioning of the mammalian ovary has long carried a two-way
| |
| traffic. In addition, there has been movement into the out of many side streets. No
| |
| understanding of the pattern of the traffic
| |
| in such a situation is possible and no satisfactory regulation can be achieved unless
| |
| something is known about the nature, origin,
| |
| and destination of the vehicles composing
| |
| the traffic. Equally important, this information cannot l)e obtained by standing on one
| |
| spot. This analogy contains much that is
| |
| relevant for what has been attempted in
| |
| this book. The problem of the ovary has
| |
| been approached from the vantage point
| |
| of forces and substances originating in the
| |
| pituitary and the environment which act
| |
| centripetally on it (Creep, Everett), and
| |
| from the vantage j^oint of many of the
| |
| tissues and organs on which the hormones
| |
| we associate with it exert their action (the
| |
| Hisaws, Cowie and Folley, Zarrow, Young
| |
| in his chapter on mating behavior). In this
| |
| chapter and that prepared l)y Dr. Villce
| |
| positions have been taken near the ovary
| |
| and attemj^ts made to bring together much
| |
| of the information gathered by investigators
| |
| who were in a sense looking right at it.
| |
| | |
| Whether our perspective is developed
| |
| from a familiarity with all the material
| |
| which has been brought together or whether
| |
| it is restricted by the narrower treatment
| |
| given here, it is obvious that the unsolved
| |
| problems outnumber by far any that have
| |
| been solved, if indeed there are such. Wc
| |
| have learned much about the functioning
| |
| | |
| | |
| | |
| 484
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| of the o\'ary, but there is little we can explain. As we indicated earlier, a part of
| |
| this failure can be ascribed to the lack of
| |
| gonadotrophic preparations which either
| |
| singly or in combination will evoke changes
| |
| identical with those in untreated normal
| |
| animals, but this chapter alone contains an
| |
| enumeration of many other problems solution of which does not depend on this particular advance. The disappointment we express may be a reflection of what seems to
| |
| be the modus operandi in science. The extent of our application to unsolved problems is very unequal, but more often than
| |
| not it can be traced to an investigator's success in achieving a "breakthrough"*' as
| |
| Edgar Allen, Doisy, Smith and Englc, Willard Allen and Corner, Hisaw and other
| |
| colleagues did in the twenties. At such a
| |
| time, enthusiasm is intense and there follows
| |
| a period of gratifying accomplishment, but
| |
| obstacles are encountered and often interest
| |
| lags, until another breakthrougli occurs. In
| |
| the meantime, effort may have been diverted
| |
| by discoveries elsewhere and the area of
| |
| investigation which attracted so many is
| |
| neglected and suffers. Ovarian physiology
| |
| should not remain in this state for long.
| |
| There is no tissue of the body in which
| |
| the changes are as conspicuous and as dramatic as those in the ovary and there is no
| |
| tissue which presents more variable aspects.
| |
| Many of the stages in the cycle of ovarian
| |
| structure and functioning are related to
| |
| changes elsewhere in the body — changes in
| |
| growth, in motility, in secretion, and in beliavior. All these changes, including those
| |
| within the ovaries, offer excellent end points
| |
| for continued quantitative and qualitative
| |
| studies.
| |
| | |
| IX. References
| |
| | |
| Aldman, B., Claesson, L., Hillarp, N.-A., and OdeBLAD, E. 1949. Studies on the storage mechanism of oestrogen-precursors. Acta enclocrinol.,
| |
| 2, 24-32.
| |
| | |
| Allen, E. 1922. The oestrous cycle in the mouse.
| |
| Am. J. Anal., 30, 297-371.
| |
| | |
| Allen, E. 1932. The ovarian foUirulai- lioriiioiic.
| |
| theehn; animal reactions. In Sex and hih iinil
| |
| Secretions, 1st ed., E. Allen, Ed., pp. 392-t,S0.
| |
| Baltimore: The Williams & Wilkins Company.
| |
| | |
| Allen, W. M. 1939. Biochemistry of the corpus
| |
| | |
| " The word was not a part of the language of science at that time and prolial)ly was never used l)y
| |
| them
| |
| | |
| | |
| | |
| luteum hormone, progesterone. In Sex and Internal Secretions, 2nd ed., E. Allen, C. H. Danforth and E. A. Doisy, Eds., pp. 901-928. Baltimore: The Williams & Wilkins Company.
| |
| | |
| Amoroso. E. C. 1955. Endocrinologv of pregnancy. Brit. Med. Bull., 11, 117-125.
| |
| | |
| Amoroso, E. C, Harrlsox, R. J., Harrlsox-M.\tthews, L., and Rowlands, I. W. 1951. ReIjroductive organs of near-term and new-born
| |
| seals. Nature, London, 168, 771-772.
| |
| | |
| Amoro.so, E. C, and Rowlands, I. W. 1951. Hoimonal effects in the pregnant mare and foetal
| |
| foal. J. Endocrinol., 7, 1-liii.
| |
| | |
| Andersen, D. H., and Kennedy. H. S. 1932. Studies on the physiology of reproduction. IV.
| |
| Changes in the adrenal gland of the female
| |
| rat associated with the oestrous cycle. J. Physiol., 76, 247-260.
| |
| | |
| Antonl\des, H. N., McArthur, J. W., Pennell,
| |
| R. B., Ingersoll, F. M., Ulfelder, H., and
| |
| Oncley, J. L. 1957. Distribution of infused
| |
| estrone in human plasma. Am. J. Physiol.,
| |
| 189, 455-459.
| |
| | |
| Aron, M., and Aron, C. 1952. La glande thecale
| |
| de lovaire de cobaye. Arch. Anat. Histol. et
| |
| Embryol., 34, 27-41.
| |
| | |
| ASCHHEIM,, S., PORTES, L., AND M.\YER, M. 1939.
| |
| | |
| Les hormones gonadotropes. Etude critique de
| |
| quelques points relatifs a leur role dans la
| |
| physiologie et la pathologie des fonctions de
| |
| I'ovaire. Ann. endocrinoL, 1, 42-54.
| |
| | |
| AsTwooD, E. B. 1938. A six-hour assay for the
| |
| quantitative determination of estrogen. Endocrinology, 23, 25-31.
| |
| | |
| AsTW^ooD, E. B. 1939. Changes in the weight and
| |
| water content of the uterus of the normal adult
| |
| rat. Am. J. Physiol., 126, 162-170.
| |
| | |
| Atkinson, W. B., and Leathem, J. H. 1946. The
| |
| day to day level of estrogen and progestin
| |
| during lactation in the mouse. Anat. Rec, 95,
| |
| 147-155.
| |
| | |
| Barahona, M., Bruzzone, S., and Lipschutz, a.
| |
| 1950. On the control of follicular development in intrasplenic ovarian grafts by minute
| |
| (|uantities of oestrogen. Endocrinologv, 46,
| |
| 407-413.
| |
| | |
| Barker, W. L. 1951. A cytochemical study of
| |
| lipids in sows' ovaries during the estrous cycle.
| |
| Endocrinology, 48, 772-785.
| |
| | |
| Barr.aclough, C. a. 1955. Influence of age on
| |
| the response of prcweaning female mice to
| |
| testosterone i)ro])i()nate. Am. J. Anat., 95, 493521.
| |
| | |
| Bassett, D. L. 1943. The changes in the va.scular pattern of the ovary of the albino lat during the estrous cycle. Am. J. Anat., 73, 251291.
| |
| | |
| Bavlis, H. I., Browne, J. C, Round, B. P., .and
| |
| Steinbeck, A. W. 1955. Plasma 17-hydroxycorticosteroids in pregnancy. Lancet, 1, 62-67.
| |
| | |
| Beroer, M. 1935. Besonders hohe Wirk.'^amkeit
| |
| des Follikelhormons bei vaginaler Instillation.
| |
| Klin. Wchnschr., 14, 1601-1602.
| |
| | |
| Behcman, p. 1949. Sexual cycle, time of ovulation, and time of optimal fertility in women.
| |
| | |
| | |
| | |
| MAMMALIAN OVARY
| |
| | |
| | |
| | |
| 485
| |
| | |
| | |
| | |
| Acta obst. et gvnec. scandinav., Supi)l. 29,
| |
| 4, 1-139.
| |
| | |
| Beyer, K. F., AND Samuels, L. T. 1956. Distrilmtion of steroid-3^-ol-dehydrogenase in cellular
| |
| structures of the adrenal gland. J. Biol. Chem.,
| |
| 219, 69-76.
| |
| | |
| BiGGERS, J. D. 1953. The characteristics of the
| |
| dose-response line in Allen-Doisy tests obtained by the intravaginal administration of
| |
| oestrone in distilled water and in 50 i)cr cent
| |
| aciueous glycerol. J. Endocrinol., 9, 145-154.
| |
| | |
| BiGGERS, J. D., AND Clarinobold, P. J. 1954. Optimum conditions for the local (intravaginal)
| |
| action of oestrogens. Australian J. Biol., 7,
| |
| 118-139.
| |
| | |
| BiGGERS, J. D., AND Clakixgbold, P. J. 1955.
| |
| Mitotic activity in the vaginal epithelium
| |
| of the mouse following local oestrogenic stimulation. J. Anat., 89, 124-131.
| |
| | |
| BiTM.\N, J., Wrenn, T. R., and Sykes, J. F. 1958.
| |
| Estrogen determination in blood and body
| |
| fluids of cattle. In Reproduction and Infertility, III, Symposium, F. X. Gassner, Ed.,
| |
| pp. 141-156. New York: Pergamon Press.
| |
| | |
| Bl.\ndau, R. J. 1955. Ovulation in the living albino rat. Fertil. & Steril., 6, 391-404.
| |
| | |
| Blandau, R. J., AND Soderwall, A. L. 1941. Postparturitional heat and the time of ovulation in
| |
| the albino rat. Data on parturition. Anat. Rec,
| |
| 81, 419-430.
| |
| | |
| Block, E. 1951a. Quantitatixc morphological investigations of the follicular system in women.
| |
| Methods of (luantitative determinations. Acta
| |
| Anat., 12, 267-285.
| |
| | |
| Block, E. 1951b. Quantitative morphological investigations of the follicular system in women.
| |
| Variations in the different phases of the sexual
| |
| cycle. Acta endocrinol., 8, 33-54.
| |
| | |
| Block, E. 1952. Quantative morphological investigations of the follicular system in women.
| |
| Variations at different ages. Acta anat., 14,
| |
| 108-123.
| |
| | |
| Block, E. 1953. A cjuantitative morphological investigation of the follicular system in newborn female infants. Acta anat., 17, 201-206.
| |
| | |
| BoGDANOVE, E. M., and Horn, E. H. 1958. Thyroid iodide concentration in estradiol-treated
| |
| hvpophysectomized rats. Endocrinology, 62,
| |
| 97-99.
| |
| | |
| BoLiNG, J. L. 1942. Growth and regression of
| |
| corpora lutea during the normal estrous cycle
| |
| of the rat. Anat. Rec, 82, 131-145.
| |
| | |
| BoLiNG, J. L., Blandau, R. J., Wilson, J. G., and
| |
| Young, W. C. 1939. Post-parturitional heat
| |
| responses of newborn and adult guinea pigs.
| |
| Data on parturition. Proc. Soc. Exper. Biol. &
| |
| Med., 42, 128-132.
| |
| | |
| BoLiNG, J. L., Blandau, R. J., Soderwall, A. L., and
| |
| Young, W. C. 1941. Growth of the Graafian
| |
| follicle and the time of ovulation in the albino
| |
| rat. Anat. Rec, 79, 313-331.
| |
| | |
| Bos, C., AND Cleghorn, R. a. 1958. P.sychogenic .sterility. Fertil. & Steril., 9, 84-98.
| |
| | |
| Bourne, G., and Zuckerman, S. 1941a. The influence of the adrenals on cyclical changes
| |
| | |
| | |
| | |
| in the accessory reproductive organs of female rats. J. Endocrinol., 2, 268-282.
| |
| | |
| Bourne, G., and Zuckerman, S. 1941b. Changes
| |
| in the adrenals in relation to the normal and
| |
| artificial threshold oestrous cycle in the rat.
| |
| J. Endocrinol., 2, 283-310.
| |
| | |
| Bradbury, J. T. 1947. Ovarian influence on the
| |
| response of the anterior pituitary to estrogens.
| |
| Endocrinology, 41, 501-513.
| |
| | |
| Bradbury, J. T. 1958. Adrenogenital syndrome
| |
| and adrenal hyperplasia. Clin. Obst. & Gynec,
| |
| 1, 257-270.
| |
| | |
| Br.\dbury, J. T. 1961. Direct action of estrogen
| |
| on the ovary of the immature rat. Endocrinology, 68, 115-120.
| |
| | |
| Bradbury, J. T., and G.aensbauer, F. 1939. Masculinization of the female rat by gonadotrophic
| |
| extracts. Proc. Soc. Exper. Biol. & Med., 41,
| |
| 128-131.
| |
| | |
| Bradbury, J. T., Brown, W. E., and Gray, L. A.
| |
| 1950. Maintenance of the corpus luteum and
| |
| physiologic actions of progesterone. Recent
| |
| Progr. Hormone Res., 5, 151-194.
| |
| | |
| Brambell, F. W. R. 1956. Ovarian changes. In
| |
| Marshall's Physiology of Reproduction, 3rd
| |
| ed., A. S. Parkes, Ed., Vol. 1, Part 1, pp. 397542. London: Longmans, Green & Company.
| |
| | |
| Br.^mbell, F. W. R., .\nd Parkes, A. S. 1927.
| |
| Changes in the ovary of the mouse following
| |
| exposure to x-rays. III. Irradiation of the
| |
| non-parous adult. Proc. Roy. Soc. London,
| |
| Ser. B, 101, 316-328.
| |
| | |
| Brewer, J. I. 1942. Studies of the human corpus
| |
| luteum. Evidence for the early onset of regression of the corpus luteum of menstruation.
| |
| Am. J. Obst. & Gynec, 44, 1048-1062.
| |
| | |
| Brolin, S. E., and Lindback, M. 1951. The reacting capacit.v of the gonads after adrenalectomy as judged by the response to gonadotrophins in the rat. Acta endocrinol., 8, 55-71.
| |
| | |
| Brown, J. B. 1955. A chemical method for determination of oestriol, oestrone, and oestradiol
| |
| in human urine. Biochem. J., 60, 185-195.
| |
| | |
| Brown, J. H., and Luther, H. G. 1951. Results
| |
| of rebreeding sows three days after farrowing —
| |
| effect of gonadotrophic hormone on litter
| |
| size, boar acceptance, fertilitv, etc. J. Anim.
| |
| Sc, 10, 1022.
| |
| | |
| Brown-Grant, K. 1956. Gonadal function and
| |
| thyroid activity. J. PhvsioL, 131, 70-84.
| |
| | |
| Bruce, H. M., and Sloviter, H. A. 1957. Effect
| |
| of destruction of thyroid tissue by radioactive
| |
| iodine on reproduction in mice. J. Endocrinol.,
| |
| 15, 72-82.
| |
| | |
| Bryans, F. E. 1951. Progesterone of the blood
| |
| in the menstrual cycle of the monkey. Endocrinology, 48, 733-740.
| |
| | |
| Buchholz, R., Dibbelt, L., and Schild, W. 1954.
| |
| Uber die Bildung des Progesterons im mensuellen Zyklus. Geburtsh. u. Frauenh., 14, 620-636.
| |
| | |
| Bulbrook, R. D., and Greenwood, F. C. 1957.
| |
| Persistence of urinary oestrogen excretion after oophorectomy and adrenalectomv. Brir.
| |
| M. J., 1,662-666.
| |
| | |
| BuLLOUGH, W. S. 1942a. Gametogenesis and
| |
| | |
| | |
| | |
| 48()
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| some endocrine factors affecting it in the adult
| |
| minnow {Phoxinus laevis L.). J. Endocrinol.,
| |
| 3, 211-219.
| |
| | |
| BuLLOiTGH, W. S. 1942b. Oogenesis and its relation to the oestrous cycle in the adult mouse.
| |
| J. Endocrinol., 3, 141-149.
| |
| | |
| BuLLOtiGH, W. S. 1942c. The method of growth
| |
| of the follicle and corpus luteum in the mouse
| |
| ovary. J. Endocrinol., 3, 150-156.
| |
| | |
| BuLLOUGH, W. S. 1943. The effects of oestrone
| |
| on the ovary of the mouse. J. Endocrinol., 3,
| |
| 235-243.
| |
| | |
| BuRKL, W. v., Kellner, G., Lindner, A., .and
| |
| Springer, K. 1954. Uber die Neubildung von
| |
| FoUikeln im Ratteno\ar im Verlauf einer
| |
| chronischen Hexostrolbehandlung. Ztschr.
| |
| mikro-anat. Forsch., 61, 37-65.
| |
| | |
| BuRKL, W. v., AND IvELLNER, G. 1956. Das Wachstum der FoUikel und die Reifimg der Eizellen
| |
| in den verschiedenen Zyklusphasen bei der
| |
| Ratte. Acta Anat., 27, 309-323.
| |
| | |
| Buxton, C. L. 1950. The atypical secretory
| |
| phase. In Menstruation and Its Disorders.
| |
| E. T. Engle, Ed., pp. 270-288. Springfield, 111.:
| |
| Charles C Thomas.
| |
| | |
| Buxton, C. L., and Engle, E. T. 1950. Time of
| |
| ovulation. A correlation between basal temperature, the appearance of the endometrium,
| |
| and the appearance of the ovary. Am. J. Obst.
| |
| & Gynec, 60, 539-551.
| |
| | |
| Catchpole, H. R., Gersh, I., and Pan, S. C. 1950.
| |
| Some properties of ovarian connective tissue in
| |
| relation to parenchymatous changes. J. Endocrinol., 6, 277-281.
| |
| | |
| Chamorro, a. 1943. Secretion de substance androgene par I'ovaire de la souris normals,
| |
| sous Taction d'extrait gonadotrope ecjuine.
| |
| Compt. rend. Soc. biol., 137, 108-109.
| |
| | |
| Chiquoine, a. D. 1959. Electron microscopic
| |
| observations on the developmental cytology
| |
| of the mammalian ovum (Abstr.). Proc. Am.
| |
| A. Anat., Anat. Rec, 133, 258.
| |
| | |
| Chu, J. P., Lee, C. C., and You, S. S. 1946.
| |
| Fimctional relation between the uterus and
| |
| the corpus luteum. J. Endocrinol., 4, 392-398.
| |
| | |
| Claesson, L. 1947. Is there any smooth musculature in the wall of the Graafian follicle?
| |
| Acta Anat., 3, 295-311.
| |
| | |
| Claesson, L. 1954. Quantitative relationship between gonadotrophic stimulation and lipid
| |
| changes in the interstitial gland of the rabbit
| |
| ovary. Acta phvsiol. scandinav., Suppl. 113,
| |
| 31,23-51.
| |
| | |
| Claesson, L., Diczfalusy, E., Hillarp, N-A., and
| |
| HoGBERG, B. 1948. The formation mechanism of oestrogenic hormones. III. Lipids of
| |
| the pregnant rabbit ovary and their changes at
| |
| gonadotropic stimulation. Acta phvsiol. scandinav., 16, 183-200.
| |
| | |
| Claesson, L., and Hillarp, N-A. 1947a. The
| |
| formation mechanism of oestrogenic hormones.
| |
| I. The presence of an oestrogen-precursor in
| |
| the rabbit ovarv. Acta phj^siol. scandinav., 13,
| |
| 115-129.
| |
| | |
| Claesson, L., and Hillarp, N-A. 1947b. The
| |
| | |
| | |
| | |
| formation mechanism of oestrogenic hormones,
| |
| II. The presence of the oestrogen-precursor
| |
| m the ovaries of rats and guinea pigs. Acta
| |
| physiol. scandinav., 14, 102-119.
| |
| | |
| Cl.aesson, L., and Hill.\rp, N-A. 1947c. Critical
| |
| remarks on the histochemical reactions for
| |
| ketosteroids. Acta anat., 3, 109-114.
| |
| | |
| Claesson, L., Hillarp, N-A., Hogberg, B., and
| |
| Hokfelt, B. 1949. Changes in the ascorbic
| |
| acid content in the interstitial gland of the
| |
| rabbit ovary following gonadotrophic stimulation. Acta endocrinol., 2, 249-256.
| |
| | |
| Cochrane, R. L., and Meyer, R. K. 1957. Delayed nidation in the rat induced by progesterone. Proc. Soc. Exper. Biol. & " Med., 96,
| |
| 155-159.
| |
| | |
| Cohen, M. R., .and H.ankin, H. 1960. Detecting
| |
| ovulation. Fertil. & Steril., 11, 497-507.
| |
| | |
| Cohen, S. M. 1959. Fate of progesterone injected
| |
| subcutaneouslv in mice. Endocrinologv, 65,
| |
| 971-972.
| |
| | |
| Cole, H. H., Hart, G. H., Lyons, W. R., and
| |
| Catchpole, H. R. 1933. The development
| |
| and hormonal content of fetal horse gonads.
| |
| Anat. Rec, 56, 275-293.
| |
| | |
| Cole, H. H., Howell, C. E., and Hart, G. H.
| |
| 1931. The changes occurring in the ovary of
| |
| the mare chu'ing pregnancy. Anat. Rec, 49,
| |
| 199-209.
| |
| | |
| Cole, H. H., and Miller, R. F. 1933. Artificial
| |
| induction of ovulation and oestrum in the ewe
| |
| during anoestrum. Am. J. Phvsiol., 104, 165171.
| |
| | |
| CoRDiEZ, E. 1949. Le moment de I'ovulation
| |
| dans I'espece bovine. Ann. Med. Vet., 93, 6573.
| |
| | |
| Corey, E. L. 1928. Effect of prenatal and postnatal injections of the pituitary gland in the
| |
| white rat. Proc. Soc Exper. Biol. & Med.,
| |
| 25, 498-499.
| |
| | |
| Corner, G. W. 1937. The rate of secretion of
| |
| progestin by the corpus luteum. Cold Spring
| |
| Harbor Symposia Quant. Biol., 5, 62-65.
| |
| | |
| Corner, G. W. 1938. The sites of formation of
| |
| estrogenic substances in the animal body.
| |
| Physiol. Rev., 18, 154-172.
| |
| | |
| Corner, G. W. 1940. The rate of secretion of
| |
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| CoUoquia on Endocrinology, Vol. 2. Boston:
| |
| Little, Brown & Company.
| |
| | |
| Young, W. C. 1941. Observations and experiments on mating behavior in female mammals.
| |
| Quart. Rev. Biol., 16, 135-156, 311-335.
| |
| | |
| Young, W. C, Dempsey, E. W., Myers, H. I.,
| |
| AND Hagquist, C. W. 1938. The ovarian condition and sexual behavior in the female guinea
| |
| pig. Am. J. Anat., 63, 457-487.
| |
| | |
| Y'oung, W. C, and Fi.sh, W. R. 1945. The ovarian hormones and spontaneous running activity in the female rat. Endocrinology, 36, 181189.
| |
| | |
| Y'ouNG. W. C, AND Y'erkes, R. M. 1943. Factors
| |
| influencing the reproductive cycle in the chimpanzee; the period of adolescent sterility and
| |
| related problems. Endocrinology, 33, 121-154.
| |
| | |
| ZacharL'\e, F. 1957. Studies on the mechani.sm
| |
| of ovulation. Autoradiographic investigations
| |
| on the uptake of radioactive sulphate C°S)
| |
| into the ovarian follicular mucopolysaccharides. Acta endocrinol., 26, 215-223.
| |
| | |
| Zacharl\e, F. 1958. Studies on the mechanism
| |
| of ovulation. Permeability of the blood-li(|uor
| |
| barrier. Acta endocrinol., 27, 339-342.
| |
| | |
| Zachariae, F.. and Jensen, C. E. 1958. Studies
| |
| on the mechanism of ovulation. Histochemical
| |
| and physicochemical investigations on genuine
| |
| follicular fluids. Acta endocrinol., 27, 343-355.
| |
| | |
| | |
| | |
| Zander, J. 1954. Progesterone in human Ijlood
| |
| and tissues. Nature, London, 174, 406-407.
| |
| | |
| Zander, J., Forbes, T. R., vox Munstermann, A.
| |
| M., AND Neher, R. 1958. Two naturally occurring metabolites of progesterone — isolation,
| |
| identification, biologic activity, and concentration in human tissues. J. Clin. Endocrinol., 18,
| |
| 337-353.
| |
| | |
| Zander, J., and Simmer, H. 1954. Die chemische
| |
| Bestimmimg von Progesteron in organislien
| |
| Substraten. Klin. Wchnschr., 32, 529-540.
| |
| | |
| Zarrow, M. X., AND Neher, G. M. 1953. Studies
| |
| on the validity of the Hooker-Forbes test for
| |
| the determination of progesterone in untreated
| |
| blood. J. Clin. Endocrinol., 8, 203-209.
| |
| | |
| Zarrow, M. X., Neher, G. M.. Lazo-Wasem, E. A.,
| |
| AND Salhanick, H. A. 1957. Biological activity of certain progesterone-like compounds
| |
| as determined by the Hooker-Forbes bioassav.
| |
| J. Chn. Endocrinol., 17, 658-666.
| |
| | |
| Zarrow, M. X., Caldwell, A. L., H.\fez, E. S. E.,
| |
| AND PiNCus, G. 1958. Superovulation in the
| |
| immature rat as a possible assav for LH and
| |
| HCG. Endocrinology, 63, 748-758.
| |
| | |
| Zondek, B. 1940. On the mechanism of action of
| |
| gonadotrophin from pregnancy urine. J. Endocrinol., 2, 12-20.
| |
| | |
| Zondek, B. 1954. Some problems related to ovarian function and to pregnancy. Recent Progr.
| |
| Hormone Res., 10, 395-423.
| |
| | |
| Zondek, B., and Ascheim, S. 1927. Hypophysen^•OI•del•lappen und Ovarium. Beziehungen der
| |
| cndokrinen Driisen zur Ovarialfunktion. Arch.
| |
| Gynak., 130, 1-45.
| |
| | |
| Zondek, B., and Sklow, J. 1942. Further investigations on the mechanisms of oestrone production in the ovary. J. Endocrinol., 3, 1-4.
| |
| | |
| Zuckerman, S. 1940-41. Periodic uterine bleeding in spayed rhesus monkeys injected thiily
| |
| with a constant threshold dose of oestron(>. J.
| |
| Endocrinol., 2, 263-267.
| |
| | |
| Zuckerman, S. 1951. The number of oocytes in
| |
| the mature ovary. Recent Progr. Hormone
| |
| Res.. 6, 63-109.
| |
| | |
| | |
| | |
| 8
| |
| | |
| | |
| | |
| THE MAMMALIAN FEMALE REPRODUCTIVE
| |
| | |
| CYCLE AND ITS CONTROLLING
| |
| | |
| MECHANISMS
| |
| | |
| John W. Everett, Ph.D.
| |
| | |
| PROFESSOR OF ANATOMY, DUKE UNIVERSITY
| |
| DURHAM, NORTH CAROLINA
| |
| | |
| | |
| | |
| I. Introduction 497
| |
| | |
| II. Cycles Spontaneously Interrcpted. 498
| |
| | |
| III. PiTUITARY-OVARIAN DORMANCY 499
| |
| | |
| A. The Ovary in Anestrum 500
| |
| | |
| B. The Hypophysis 500
| |
| | |
| C. Relationship of the Anestrum to the
| |
| | |
| Seasons 501
| |
| | |
| IV. Attainment of Maturity. Emergence OF Full Ovarian Function. . 502
| |
| V. Follicular Cycles. Growth and
| |
| | |
| Atresia 504
| |
| | |
| A. Correlation of Ovarian Secretion
| |
| | |
| with the Follicular Cycle 507
| |
| | |
| B. Cyclic Manifestations after Ovari
| |
| ectomy or Hypophysectomy 509
| |
| | |
| C. Cyclic Manifestations in the Ab
| |
| sence of Ovarian Follicles 509
| |
| | |
| D. Hypothalamus and Gonadotrophin
| |
| | |
| Secretion. General Considerations 510
| |
| | |
| VI. Follicle Maturation and Ovulation 513
| |
| | |
| A. Time of Ovulation 513
| |
| | |
| B. Ovarian Steroids and Ovulation. . . 514
| |
| | |
| 1. Estrogens 514
| |
| | |
| 2. Gestagens 517
| |
| | |
| C. Role of the Nervous System in Ovu
| |
| lation " 520
| |
| | |
| 1. The hypophyseal portal veins and
| |
| | |
| the chemotransmitter hypothesis ' 523
| |
| | |
| 2. Central depressants and ovula
| |
| tion 526
| |
| | |
| 3. The central nervous system as a
| |
| | |
| timing mechanism for ovulation 520
| |
| | |
| D. Persistent Follicle 529
| |
| | |
| VII. The Luteal Phase 530
| |
| | |
| 1. Luteotrophic substances 530
| |
| | |
| 2. "Nonfunctional" corpora lutea. . 531
| |
| A. Pseudopregnancy 532
| |
| | |
| 1. Duration of pseudopregnancy. .. . 533
| |
| | |
| 2. Neural factors in pseudopreg
| |
| nancy 534
| |
| | |
| | |
| | |
| B. Luteolytic Mechanisms 537
| |
| | |
| C. Effect of the Uterus on Luteal Func
| |
| tion 538
| |
| | |
| VIII. Concluding Comments 540
| |
| | |
| IX. References 541
| |
| | |
| I. Introduction
| |
| | |
| The chain of events that constitutes the
| |
| female reproductive process is characteristically repeated from time to time with
| |
| considerable regularity during the adult life
| |
| of an individual, and is therefore a cycle.
| |
| In the broad sense, this sequence begins
| |
| with ovogenesis and terminates when the
| |
| progeny require no further shelter and
| |
| nurture. In mammals this has become a
| |
| highly complex process, involving profound
| |
| maternal adjustments synchronized with
| |
| successive stages in development of the
| |
| ovum, fetus, and offspring. The complete
| |
| mammalian cycle comprises a sequence of
| |
| stages which may be identified as follows:
| |
| (II follicle growth, including growth of the
| |
| ovocyte; (2) ovulation, a progressive process including preovulatory maturation of
| |
| follicles and ova, and the structural change
| |
| of ruptured follicles to corpora lutea; (3)
| |
| progravidity; (4) gravidity; (5) parturition; and (6) postpartum nurture, including
| |
| lactation, protection, and training. Although
| |
| it is obvious that this full sequence is often
| |
| realized, it may nevertheless be retarded or
| |
| frankly interrupted at almost any point.
| |
| | |
| In advanced human societies economic
| |
| and social factors have diminished the number of complete cycles to such degree that
| |
| they are rarities in the lifetime of an in
| |
| | |
| | |
| 497
| |
| | |
| | |
| | |
| 498
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| dividual and infertile ("menstmal") cycles
| |
| are the rule. Inasmuch as corresponding
| |
| factors operate among domesticated animals, the expression "female reproductive
| |
| cycle" commonly refers to those truly
| |
| abortive cycles that succeed one another in
| |
| the absence of insemination. The term is
| |
| used in that restricted sense in this chapter.
| |
| | |
| With even that restriction, the female cycle is actually a multiplicity of interlocking
| |
| cycles, in which the rhythmic interplay between hypophysis and ovary is fundamental. Attention must therefore be focused
| |
| on the physiology of the ovary and on the
| |
| hormonal and neural mechanisms that integrate hypophysis and ovary as a functional system. Cyclic alterations in sex accessories and other nongonadal tissues are
| |
| considered mainly as indicators. The
| |
| "menstrual cycle," being strictly a uterine
| |
| cycle, comes in this category, together with
| |
| changes in behavior.
| |
| | |
| No attempt is made to present an exhaustive description of the varied adaptive
| |
| modifications of the ovarian cycle among
| |
| the several mammalian orders. The reader
| |
| may consult works of the late F. H. A.
| |
| Marshall whose full bibliography is given
| |
| by Parkes (1949 1. Asdell's Patterns of
| |
| Mammalian Reproduction (1946» is anotlu'i' A-alual)lo source.
| |
| | |
| II. Cycles Spontaneously Interrupted
| |
| | |
| Cycles in the natural state are only imperfectly known, from random and often erratic sampling. One may safely assume that,
| |
| as a rule, under optimal conditions they
| |
| are complete, fertile cycles. There are, then,
| |
| relatively few subhuman species in wdiich
| |
| the characteristics of incomplete cycles have
| |
| been studied. These species are necessarily
| |
| the very ones that have been amenable to
| |
| some form of human restraint.
| |
| | |
| Segregation of the sexes or any other
| |
| interference with insemination should be regarded as a first experimental approach
| |
| to understanding the complete cycle. Such
| |
| factors unriuestionably operate in nature on
| |
| occasion. Controlled changes of environmental conditions afford another approach
| |
| in which natural factors are simulated.
| |
| | |
| The statement was made earlier that the
| |
| complete cycle may conceivably be interrupted at almost any point. It has been
| |
| | |
| | |
| | |
| learned that in different species segregated
| |
| females interrupt their cycles at different
| |
| stages and that usually the point of interruption is species-characteristic. These facts
| |
| have been of great service to the study of
| |
| reproduction, first, by arousing the curiosity of the investigator and, second, by
| |
| supplying a variety of ready made conditions individually appropriate for particular
| |
| experimental studies.
| |
| | |
| Examples of mammalian cycles are
| |
| schematically diagrammed in Figure 8.1.
| |
| It is customary to state that the usual, or
| |
| standard, infertile cycle is like that in primates or the guinea pig. The follicular
| |
| phase culminates in spontaneous ovulation,
| |
| after which corpora lutea are organized and
| |
| become spontaneously functional for a
| |
| period of time that is usually considerably
| |
| shorter than in pregnancy.
| |
| | |
| In a few animals (rat, mouse, hamster)
| |
| the cycle terminates shortly after ovulation
| |
| before the corpora lutea become fully functional. Such corpora lutea are said to be
| |
| inactive, in the sense that they cannot produce a decidual response to uterine trauma
| |
| (Long and Evans, 1922). Sterile mating or
| |
| analogous stimulation induces a luteal phase
| |
| which corresponds to that of the "standard"
| |
| mammal. This phenomenon is not entirely
| |
| limited to the small rodents, having been
| |
| described in the European hedgehog
| |
| (Deanesly, 1934).
| |
| | |
| To this writer's knowledge there have not
| |
| been described any mammalian species in
| |
| which it is the rule that in isolated females
| |
| the process of ovulation begins (follicle maturation, prelutein changes in granulosa,
| |
| secretion of secondary liquor folliculi, and
| |
| so on) without proceeding to eventual rupture of the follicles. Many cases could l3e
| |
| cited, however, in which this has occurred
| |
| "abnormally." Characteristically, some degree of luteinization occurs in the wall of
| |
| such a follicle and a lutein cyst is formed.
| |
| | |
| On the other hand, there are numerous
| |
| species (reflex ovulators) in which the preovulatory maturation of follicles and ovulation nearly always fail in the absence of
| |
| the male. The known species in which this
| |
| is true are widely distributed among the
| |
| mammalian orders and are often closely
| |
| iclated to other species in which spontaneous ovulation is usual. The domestic rabbit
| |
| | |
| | |
| | |
| MAMIMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 499
| |
| | |
| | |
| | |
| GUINEA
| |
| PIG
| |
| | |
| | |
| | |
| PRIMATE
| |
| | |
| | |
| | |
| | |
| Fig. 8.1. Diagrams of cycles of representative, familiar mammals. , the follicular phase,
| |
| | |
| highly schematized and inaccurate in detail ; , atresia ; i , ovulation ; • , fully active
| |
| | |
| corpora lutea; O, corpora lutea regressing or otherwise not fully active. When sterile mating
| |
| or equivalent stimulation (SM) is introduced, the cycles of the rat, rabbit and cat become
| |
| directly comparable with those of the other species.
| |
| | |
| | |
| | |
| furnishes the classic exaini)le of reflex ovulation. Other reflex ovulators are the domestic cat (Greulich, 1934), the ferret (Hammond and Walton, 1934), mink (Hansson,
| |
| 1947), marten (Pearson and Enders, 1944),
| |
| the 13-lined ground squirrel (Foster, 1934),
| |
| and the mole shrew (Pearson, 1944). To this
| |
| list have been added the muskrat (Miegel,
| |
| 1952) and a field mouse, Microtus californicus (Greenwald, 1956). Even among
| |
| the marsupials, the female Didelphijs azarae
| |
| is said not to form corpora lutea in the absence of the male (Martinez-Esteve, 1937).
| |
| A few of these species display nearly constant estrus (rabbit, ferret), competent
| |
| follicles being present most of the time in
| |
| the isolated female during the breeding season.
| |
| | |
| Among even the spontaneous ovulators
| |
| the cycle may sometimes not progress beyond the follicular phase. Thus, at the
| |
| approach of puberty, waves of advanced
| |
| follicle development and secretion of estrogen may take place without, however, leading to ovulation or corpus luteum forma
| |
| | |
| | |
| tion. The first cycles of primates are often
| |
| anovulatory ones. In the adult macacjue, at
| |
| least in some colonies, such cycles are characteristic during the summer months (Hartman, 1932) . A somewhat comparable seasonal effect has been reported in girls soon
| |
| after the menarche (Engle and Shelesnyak,
| |
| 1934). Menstrual cycles without ovulation
| |
| have frecjuently been recognized in adult
| |
| women in recent years, bearing no evident
| |
| relationship to seasonal factors (Lopez Colombo de Allende, 1956). Anovulatory cycles
| |
| were described in the mouse by Allen (1923)
| |
| and have been noted occasionally in other
| |
| species, but without clear measure of their
| |
| incidence.
| |
| | |
| III. Pituitary-Ovarian Doriiianey
| |
| | |
| Varying levels of pituitary-ovarian dormancy are expressed in different ways from
| |
| species to species or even from habitat to
| |
| habitat within a given species. A general
| |
| similarity exists between the anestrum of
| |
| seasonal breeders and the prepubertal state.
| |
| In fact, in animals that have a distinct sea
| |
| | |
| | |
| 500
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| son, puberty occurs at the very time when
| |
| older females are emerging from anestrum.
| |
| Whereas anestrum is often correlated with
| |
| season of the year, there are exceptions,
| |
| notably among dogs, in which the correlation is ill defined (Engle, 1946).
| |
| | |
| In its shortest form ovarian quiescence
| |
| lasts for only a few days, probably often
| |
| without being recognized, between the end
| |
| of one cycle and the active follicular phase
| |
| of the next. In the chimpanzee it is thought
| |
| to be the chief factor in the irregularity of
| |
| length of the cycle (Young and Yerkes,
| |
| 1943). Rossman and Bartelmez (1946) described a comparable occurrence in monkeys. At the other extreme, anestrum may
| |
| occupy the major part of the year in monestrous animals that have a very limited
| |
| breeding season.
| |
| | |
| A. THE OVARY IN ANESTRUM
| |
| | |
| Generally speaking, depression of ovarian
| |
| function is most extreme in greatly prolonged periods of quiescence. In the ferret,
| |
| Hammond and Marshall (1930) reported
| |
| that in the anestrous ovary follicles can
| |
| hardly be recognized with the naked eye,
| |
| because they remain small and deeply
| |
| placed. The largest follicles at the "end of
| |
| the season" averaged 460 /x in diameter
| |
| whereas a "long time after" the average
| |
| was only 240 jx, increasing again to 720 yu,
| |
| at the api^roach of a new season. By contrast, the largest follicles of animals in full
| |
| heat ranged between 1220 and 1440 /x. Follicle atresia abounds in the anestrous ovary
| |
| of the 13-lined ground squirrel (Johnson,
| |
| Foster and Coco, 1933). In sheep, however,
| |
| follicles of large size may be present at
| |
| any time during anestrum (Kammlade,
| |
| Welch, Nalbandov and Norton, 1952).
| |
| | |
| Some moderate degree of secretory activity of the ovary is indicated even at the
| |
| depth of i^rolonged seasonal anestrum (13lincd ground squirrel, Moore, Simmons,
| |
| Wells, Zalesky and Nelson, 1934; ferret,
| |
| Hill and Parkes, 1933; opossum, Risman,
| |
| 1946). Although at this time uterus, vagina,
| |
| and vulva are small, ovariectomy or hypol^hysectomy causes a further reduction. On
| |
| the other hand, these structures are readily
| |
| stimulated by injection of estrogens.
| |
| | |
| It may be said that low-grade follicular
| |
| cycles proceed throughout the anestrous
| |
| | |
| | |
| | |
| interval, but whether there is any synchronization of one follicle with another is
| |
| unknown. Some insight into this problem
| |
| is furnished by study of (1) the transition
| |
| from anestrum to the breeding season, and
| |
| (2) the closely analogous phenomena of
| |
| adolescence. In the report by Hammond and
| |
| Marshall, it was shown that in ferrets during anestrum and proestrum there is a progressive increase in size of the vulva which
| |
| directly parallels the diameter of the largest
| |
| follicles. The absence of overt cyclic change
| |
| is not surprising in view of the fact that
| |
| estrus is continuous in this species. In
| |
| polyestrous animals, on the other hand, it
| |
| might be expected that during anestrum follicle growth and accompanying estrogen secretion are cyclic, at least at the approach
| |
| of puberty or of "the season." Important information on this question has been obtained from some of the primates, notably
| |
| the macaque (Allen, 1927; Hartman, 1932)
| |
| and the chimpanzee (Zuckerman and Fulton, 1934; Schultz and Snyder, 1935).
| |
| | |
| Slight transitory reddening of the skin of
| |
| the perineum ("sex skin") of the monkey
| |
| may occur at intervals for several months
| |
| preceding the onset of menses, accompanied
| |
| by moderate desquamation of vaginal epithelium. During the long intervals of amenorrhea that some individuals exhibit during
| |
| the summer, there is a tendency toward
| |
| cyclic vaginal desciuamation (Fig. 8.2). The
| |
| sex skin of the chimpanzee may begin to
| |
| swell more than a year before the first
| |
| menstruation. During the ensuing months
| |
| the swelling may be irregularly cyclic or
| |
| continuous. Thus, one may judge that lowgrade follicular cycles, accompanied by periodic increases in estrogen secretion, may
| |
| succeed one another during seasonal or
| |
| ])repubertal anestrum, but that in certain
| |
| cases these cycles may overlap to such degree that rather continuous estrogen secretion takes place.
| |
| | |
| B. THE HYPOPHYSIS
| |
| | |
| The secretory activity of the anestrous
| |
| ovary is apparently adequate to prevent
| |
| "castration" changes in the adenohypophysis, for as shown by Moore, Simmons,
| |
| \^'ells, Zalesky and Nelson (1934) removal
| |
| of the ovary of anestrous ground squirrels
| |
| I'esults in hypertrophy of the hypophysis,
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 501
| |
| | |
| | |
| | |
| z
| |
| | |
| 28 days
| |
| | |
| | |
| 1
| |
| | |
| | |
| 28 days
| |
| A
| |
| | |
| | |
| 28 days
| |
| | |
| | |
| < "
| |
| | |
| 3
| |
| s
| |
| UJ .
| |
| Q
| |
| | |
| | |
| III Menses
| |
| | |
| | |
| "^ v-^^/^
| |
| | |
| | |
| A>
| |
| | |
| | |
| ^ Mensesllll
| |
| | |
| | |
| | |
| | |
| 21 ' 15
| |
| JUNE JULY
| |
| | |
| | |
| ' 15
| |
| AUGUST
| |
| | |
| | |
| 15
| |
| SEPTEMBER
| |
| | |
| | |
| 15
| |
| OCTOBER
| |
| | |
| | |
| | |
| Fig. 8.2. Vaginal cycles during seasonal amenorrhea in a monkey. (A portion of the record
| |
| of monkey ^38 from C. G. Hartman, Contr. EmbryoL, Carnegie Inst. Washington, 13,
| |
| Fig. 26, p. 121, 1932.)
| |
| | |
| | |
| | |
| increased gonadotrophin content thereof,
| |
| and increased numbers of basophile cells.
| |
| Warwick (1946) reported a highly significant increase of pituitary potency in
| |
| spayed anestrous ewes. This is closely analogous to the results of ovariectomy in immature animals (Hohlweg, 1934). As measured by ovarian activity, gonadotrophin
| |
| secretion (release) may be greatly diminished during profound anestrum. The actual
| |
| hypophyseal content of gonadotrophin
| |
| seems to be markedly reduced during anestrum in some species (Moore, Simmons,
| |
| Wells, Zalesky and Nelson, 1934), but
| |
| possibly not in others. Cole and Miller
| |
| (1935) and Warwick (1946) reported that
| |
| there is no seasonal variation in sheep. A
| |
| study by Kammlade, Welch, Nalbandov
| |
| and Norton (1952) indicates that the average content is somewhat higher during anestrum than it is in cycling ewes. The major
| |
| factor in this difference, however, seems
| |
| to be that during the cycle the potency of
| |
| the pituitary drops during estrus and the
| |
| early luteal phase.
| |
| | |
| Somewhat similarly the potency of the
| |
| immature rat hypophysis has been stated
| |
| to be as high as that of the sexually active
| |
| adult (Clark, 1935). The fact that the
| |
| ovaries of the immature female or of the
| |
| anestrous adult can be stimulated by injection of gonadotrophin indicates that gonadotrophin content of, the hypophysis in
| |
| these cases is not a fair measure of liberation of the hormone into the blood stream.
| |
| Therefore, it seems justifiable to assume, as
| |
| Robinson (1951) did in the interpretation
| |
| of anestrum in the ewe, that, in spite of the
| |
| possible absence of seasonal assay variation.
| |
| | |
| | |
| | |
| there is, nevertheless, a depression of hypophyseal gonadotrophin release during anestrum. We may further assume that it is not
| |
| completely depressed, for the ovary remains
| |
| slightly active. Ovary and hypophysis are
| |
| evidently in a state of equilibrium at a
| |
| relatively low level of function. It seems
| |
| likely that this state of affairs is brought
| |
| about by the central nervous system, inasmuch as the seasonal depression in some
| |
| species is closely dependent on the daily
| |
| ratio of light to darkness.
| |
| | |
| C. RELATIONSHIP OF THE ANESTRUM TO
| |
| THE SEASONS
| |
| | |
| This relationship is so varied among different species that many interesting questions are raised. In many cases the midpoint
| |
| of anestrum coincides approximately with
| |
| the shortest days of the year (Fig. 8.3).
| |
| There are other examples, however, largely
| |
| among the Artiodactyla, in which it coincides with the longest days. Sheep are notable examples (Robinson, 1951). Others,
| |
| like the European common hare, experience
| |
| a short anestrum during the time of rapidly
| |
| decreasing daylight (Asdell, 1946). The
| |
| Russian yak, on the other hand, is said
| |
| to experience anestrum from December to
| |
| May (i.e., while day length is increasing).
| |
| A general explanation of these varied adaptive manifestations is elusive. There is reason to believe that although illumination,
| |
| or the light/darkness ratio, (Kirkpatrick
| |
| and Leopold, 1952; Hammond, Jr., 1953)
| |
| has a rather direct and primary effect in
| |
| some cases, its role is more or less indirect
| |
| in others where such things as temperature,
| |
| humidity, availability of food and water
| |
| assume major importance (Marshall, 1942).
| |
| | |
| | |
| | |
| 502
| |
| | |
| | |
| | |
| PHYSIOLOriY OF GONADS
| |
| | |
| | |
| | |
| NDJFMAMJJASON
| |
| | |
| | |
| | |
| INSECTIVORA
| |
| | |
| MOLE SHREW
| |
| | |
| COMMON SHREW
| |
| CARNIVORA
| |
| | |
| BROWN BEAR (EUR.)
| |
| | |
| FERRET
| |
| | |
| COYOTE
| |
| | |
| WILD CAT (EUR.)
| |
| | |
| BAD3ER (AMER.)
| |
| LAGOMORPHA
| |
| | |
| HARE (ENG.)
| |
| | |
| COTTONTAIL (N . ENG.)
| |
| RODENTIA
| |
| | |
| 13-L. GROUND SQUIRREL
| |
| | |
| WOODCHUCK
| |
| | |
| GRAY SQUIRREL
| |
| | |
| DORMOUSE
| |
| | |
| FIELD MOUSE (EUR. )
| |
| | |
| MUSKRAT (MARYLAND)
| |
| (IOWA)
| |
| | |
| PORCUPINE
| |
| ARTIODACTYLA
| |
| | |
| LLAMA
| |
| | |
| ROE DEER
| |
| | |
| MULE DEER
| |
| | |
| GIRAFFE
| |
| | |
| SHEEP (HAMP )
| |
| | |
| BIGHORN
| |
| | |
| GOAT
| |
| | |
| YAK (RUSS. )
| |
| | |
| INDIAN ANTELOPE
| |
| PERISSODACT YLA
| |
| | |
| HORSE
| |
| | |
| | |
| | |
| | |
| Fig. 8.3. Some representative seasonal breeders. Solid bars indicate breeding seasons
| |
| (according to Asdell, 1946); blank intervals, periods of anestrum. Months of the year represented by letters at top of chart ; winter and summer solstaces marked by wavy lines. Southern hemisphere seasons converted to corresponding ones of the northern hemisphere. End
| |
| of season for the Bighorn is vmcertain.
| |
| | |
| | |
| | |
| The complexity of the i)rol)lem is well
| |
| illustrated by the 13-lined ground squirrel
| |
| whose breeding season, like that of a multitude of small rodents, comes in the spring.
| |
| Moore, Simmons, Wells, Zalesky and Nelson (1934) reported that increasing illumination, elevated temperature, and feeding
| |
| all failed to bring the females into estrus
| |
| out of season. If, however, hibernation was
| |
| first induced by low temperature and darkness, premature estrus would follow. The
| |
| conclusion was reached that hibernation itself is a necessary prerequisite. Ovarian development actually begins, under natural
| |
| conditions, in early January in the midst
| |
| of hibernation. Females exix'i-imentally
| |
| maintained "continually for several months
| |
| in cold and darkness, with more or less
| |
| normal hibernation, [exhibit] sexual development at any time of the year, and
| |
| periods of estrum have thus been . . . maintained for many months. ..." The impres
| |
| | |
| | |
| sion is given tliat the conditions favoring
| |
| hibernation also favor sexual development
| |
| to such extent that breeding potentiality
| |
| continues for a few months after emergence,
| |
| in spite of elevated temperatures and long
| |
| periods of illumination. In another rodent,
| |
| Peromyscus leucopus, however, the length
| |
| of daily illumination is of paramount importance. Temperature changes (4 to 25°C. )
| |
| have no effect on rejiroduction when lighting
| |
| is adequate (Whitaker, 1940). Whereas a
| |
| similar primaiy dependence on lighting
| |
| can be shown in a number of other species
| |
| from several orders, it is unwise to generalize that this is usually true.
| |
| | |
| IV. Attainment of Maturity. Emergence
| |
| of Full Ovarian Function
| |
| | |
| Ahhough ('merg(>nce of the ovary from
| |
| the state of quiescence is gradual, there is
| |
| usually some outward sign that allows the
| |
| observer to say that puberty has ari'ived
| |
| or the breeding season has begun. In ])ri
| |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 503
| |
| | |
| | |
| | |
| mates the accepted sign is the first menstruation ; in rats it is the opening of the vagina ;
| |
| in many animals it is the swelling and reddening of the genitalia heralding the initial
| |
| l^roestrum. In other eases, e.g., sheep, the
| |
| only clear indication may be the behavior
| |
| of the female toward the male. From these
| |
| facts it is readily apparent that any one
| |
| sign is employed simply because it happens
| |
| to be accessible to easy observation. Yet
| |
| the increasing output of estrogen, whether
| |
| steady or cyclic, affects many parts of the
| |
| organism at the same time. Furthermore, in
| |
| any one individual the threshold for exl)ression of a given sign may be relatively
| |
| liigh with respect to that of some other
| |
| manifestation. Thus, in Hartman's monkeys (1932), some were noted in which desquamation of vaginal epithelium occurred
| |
| in wave-like manner for a long time before
| |
| menstruation. In others "menstrual" bleeding occurred with regularity while the uterus
| |
| remained very small and A'aginal desquamation was negligible.
| |
| | |
| Hartman summarized the step-wise manner of maturation of ovary and accessory
| |
| organs of the monkey during adolescence
| |
| or following amenorrheic episodes somewhat as follows. The color of the sex skin
| |
| may be the first to appear. A slight menstrual flow usually takes place before desquamation of vaginal epithelium becomes
| |
| measurable. "More rarely there may be
| |
| one or more low desquamation cycles before
| |
| a bleeding is recorded. Whole cycles marked
| |
| liy jieriodic bleeding and some vaginal desquamation may occur before there is any
| |
| noticeable increase in size of the ovaries
| |
| and uterus. These organs increase also in a
| |
| saltatory manner, hence the term 'staircase'
| |
| phenomenon for the process. Finally, the
| |
| endocrines effect the acme of the reproductive process — ovulation."
| |
| | |
| Individual variation in the degree of abruptness with which the first ovulation is
| |
| achieved is well illustrated in a study of
| |
| puljertal guinea pigs by Ford and Young
| |
| (1953). In most cases the first period of
| |
| vaginal opening was much longer than in
| |
| subsequent cycles. Whatever the duration,
| |
| ovulation was more closely related to the
| |
| end than to the beginning of the period, as
| |
| indicated by histologic study of ovaries.
| |
| | |
| Even ovulation and corpus luteum for
| |
| | |
| | |
| mation do not signify that full power of
| |
| reproduction has arrived. For example, the
| |
| first cycle of the adolescent rat may culminate in ovulation without sexual receptivity
| |
| (Blandau and Money, 1943). In the ewe,
| |
| an ovulation without overt signs of heat
| |
| may at times take place during the anestrum, especially just before and just after
| |
| the breeding season (McKenzie and Terrill,
| |
| 1936). The phenomenon is occasional in
| |
| ewes during the season and has also been
| |
| described in cattle (Hammond, 1946). In
| |
| fact, the full manifestation of estrus in
| |
| sheep seems to require the presence of a
| |
| "waning" corpus luteum (Robinson, 1951).
| |
| In sheep the transition from seasonal or
| |
| prepubertal anestrum to the breeding season may involve relatively minor changes
| |
| in hypophyseal activity. Even in the immature rat both the hypophysis and the
| |
| ovary are capable of far greater secretory
| |
| function than they normally display. In the
| |
| equilibrium that prevails, the ovary appears to hold the upper hand by reason of
| |
| a low hypophyseal threshold at which estrogen suppresses gonadotrophin secretion in
| |
| the immature individual (Hohlweg and
| |
| Dohrn, 1932; Byrnes and Meyer, 1951b)
| |
| and a low ovarian threshold at which gonadotrophin stimulates estrogen secretion.
| |
| Byrnes and Meyer (1951a) reported that
| |
| suppression of hypophyseal gonadotrophin
| |
| content in immature rats can be accomplished with doses of estrogen much smaller
| |
| than those that affect uterine growth. It is
| |
| also known that the immature ovary can be
| |
| induced experimentally to secrete estrogen
| |
| by injection of amounts of gonadotrophin
| |
| that are too small to produce significant
| |
| increase of ovarian weight or follicle development (Levin and Tyndale, 1937; Moon
| |
| and Li, 1952). When a gonadectomized immature rat is united in parabiosis (Kallas,
| |
| 1929, 1930 » with a normal or hypophysectomized female littermate, precocious puberty is induced in the latter animal because
| |
| insufficient estrogen passes to the first partner to inhibit gonadotrophin secretion (see
| |
| Finerty, 1952). The somewhat analogous
| |
| experiment of transplanting ovaries to the
| |
| spleen produces ovarian hypertrophy in
| |
| much the same way. Here again, it is
| |
| thought that the hypophysis becomes hyperactive because the amount of estrogen
| |
| | |
| | |
| | |
| 504
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| reaching the ghmd is greatly diminished,
| |
| through inactivation bj^ the liver (Biskind,
| |
| 1941).
| |
| | |
| Although it is true that estrogens have
| |
| a suppressing action on gonadotrophin secretion, it has become increasingly evident
| |
| that they can also stimulate hypophyseal
| |
| function in certain ways, as Engle pro{)osed in 1931. Thus short-term injection of
| |
| estrogen into intact immature rats and mice
| |
| will invoke precocious puberty not only by
| |
| stimulating the sex accessories, but also by
| |
| increasing gonadotrophin secretion and thus
| |
| causing ovarian growth and even ovulation.
| |
| Frank, Kingery and Gustavson (1925j reported that after such treatment regular
| |
| cycles continued after treatment was withdrawn. Lane (1935) found that when 22day-old female rats were injected daily
| |
| with estrogen there was an early increase in
| |
| number of ovarian follicles, including vesicular stages. After the first 10 days the nonvesicular follicles became depressed although vesicular follicles were retained.
| |
| This was interpreted to mean that for a
| |
| short time estrogen actually stimulates the
| |
| follicle-stimulating hormone (FSH) l)ut
| |
| eventually suppresses it, although luteinizing hormone (LH) secretion remains
| |
| elevated. Hohlweg (1934) had already demonstrated that when somewhat older prepubertal rats are given single, rather large
| |
| injections of estrogen, ovulation and corpus
| |
| luteum formation are induced within a few
| |
| days (p. 514). Obviously LH secretion is
| |
| greatly increased.
| |
| | |
| Various bits of evidence implicate the
| |
| nervous system in the processes leading to
| |
| puberty and to the onset of estrus in seasonal breeders. This will be discussed in the
| |
| following section with respect to the general
| |
| (juestion of the relationship of the hypothalamus to gonadotrophin secretion.
| |
| | |
| V. Follicular Cycles. Growth
| |
| and Atresia
| |
| | |
| Attention will be focused here on the
| |
| dynamic pattern of follicle development
| |
| throughout the cycle, the extent to which
| |
| this i)attern depends on hyi)o[)hyseal conti'ol, and the functional changes in the
| |
| o\aiy associated with estrus in preparation
| |
| foi' the more specialized events that lead to
| |
| ovuhition and corpus luteum formation.
| |
| | |
| | |
| | |
| Production of primordial follicles and
| |
| the early growth stages have been said to
| |
| be independent of the hypophysis (Smith,
| |
| 1939; Hisaw, 1947). This view derives from
| |
| the fact that following hypophysectomy the
| |
| ovaries retain large numbers of healthy
| |
| proliferating follicles below the stage of
| |
| antrum formation. There are, however, several indications that these developmental
| |
| stages may be accelerated by gonadotrophic
| |
| stimulation. It was briefly reported by
| |
| Simpson and van Wagenen (1953) that administration of purified FSH to immature
| |
| monkeys caused not only a 10- to 20-fold
| |
| 'increase of ovarian weight, but also stimulation of granulosa in follicles of all sizes.
| |
| Indirect evidence comes from the fact that
| |
| follicle atresia generally becomes maximal
| |
| late in estrus or metestrum, when depressed
| |
| FSH might be expected on theoretical
| |
| grounds. Harrison (1948) reported tliat in
| |
| ovaries of goats killed on the third or fourth
| |
| days of estrus healthy primary ovocytes are
| |
| rare. Some few, however, presumably remain. Myers, Young and Dempsey (1936)
| |
| stated that in the estrous guinea pig there
| |
| are few nonatretic follicles aside from those
| |
| destined for ovulation. However, small
| |
| numbers of normal ai)pearing nonvesicular
| |
| follicles were found.
| |
| | |
| There seems to be general agreement that,
| |
| very quickly after this catastrophic elimination of follicles, renewed growth promptly
| |
| ensues. Whether or not the wave of atresia
| |
| represents a depression of FSH secretion, no
| |
| one would deny that the new growth reflects
| |
| this type of gonadotrophic stimulation.
| |
| Characteristically the population of small
| |
| and medium follicles is restored early in the
| |
| luteal phase of the polyestrous cycle. This
| |
| is clearly indicated for the guinea pig ovary
| |
| (Myers, Young and Dempsey, 1936) when
| |
| the data are converted from average volumes to average diameters (Fig. 8.4). Beginning on the fourth day after estrus, when
| |
| the largest follicles are approximately 300 fx
| |
| in diameter and when theca interna and
| |
| antra have formed, rapid growth of granulosa, theca, and antra continues for several
| |
| days. This is confirmed by counts of mitotic
| |
| figures obtained by the colchicine technique
| |
| (Schmidt, 1942), indicating greatest mitotic
| |
| activity in theca and granulosa of follicles
| |
| between 300 fi and 600 fx in diameter. By the
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 505
| |
| | |
| | |
| | |
| | |
| 4 8 12
| |
| | |
| DAYS AFTER BEGINNING OF ESTRUS
| |
| | |
| Fig. 8.4. A schematic repiesentation of the folhcuhir cycle in the guinea pig. The heavj^
| |
| sohd curve represents the diameters of the largest follicles, recalculated from the data of
| |
| Myers, Young and Dempsey (1936). The arrow point indicates ovulation. The other solid
| |
| curves and broken lines represent impressionistically the growth and atresia, respectivelj^
| |
| of other groups of follicles that are not ordinarily destined for ovulation.
| |
| | |
| | |
| | |
| 11th or 12th day the largest follicles (ca.
| |
| 800 /x) are "competent," i.e., capable of
| |
| being ovulated (Dempsey, Hertz and
| |
| Young, 1936; Dempsey, 1937). While the
| |
| largest follicles are developing to this stage,
| |
| multitudes of others begin to grow, being
| |
| carried on to various stages of development
| |
| before regression sets in.
| |
| | |
| This pattern of the follicular cycle seems
| |
| to be generally true among mammals that
| |
| have been carefully studied, when allowance
| |
| is made for the fact that from one species to
| |
| another the characteristic maxima of follicle
| |
| diameter are extremely variable (shrew, 350
| |
| fjL-, rat, 900 /*; cow, 19,000 /x; mare 70,000 /x;
| |
| Asdell, 1946). In ovulatory cycles of polyestrous animals the greater part of follicle
| |
| growth is accomplished while the luteal
| |
| phase of the preceding cycle is in progress.
| |
| In successive anovulatory cycles like those
| |
| of the cat the patterns of the follicular cycles are probably much the same (Evans
| |
| and Swezy, 1931 » . In the rabbit and ferret,
| |
| where more or less constant estrus char
| |
| | |
| | |
| acterizes the isolated females in season,
| |
| there is probably considerable telescoping
| |
| of successive waves of follicle growth such
| |
| that as one set of follicles begins to undergo
| |
| atresia another set is ready to take its place
| |
| (Hill and White, 1933). The difference between cat cycles and rabbit cycles seems to
| |
| be chiefly one of degree. The writer has seen
| |
| both types represented in persistent-estrous
| |
| rats, among litter mates of inbred strains
| |
| (Everett, 1939, and unpublished).
| |
| | |
| At the end of the luteal phase of the
| |
| cycle in polyestrous animals there are already present several competent follicles
| |
| among an extensive population of smaller
| |
| ones. For example, the guinea pig corpus
| |
| luteum usually shows signs of regression on
| |
| day 13 of the cycle. It has been proved that
| |
| ovulation can be induced as early as day
| |
| 12 by injection of LH (Dempsey, 1937),
| |
| several days earlier than it would normalh^
| |
| occur (Fig. 8.5). In the human and monkey
| |
| it is possible that the "preferred" follicles
| |
| are recognizable by their larger size during
| |
| | |
| | |
| | |
| 506
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 1000
| |
| | |
| | |
| | |
| 750
| |
| | |
| | |
| | |
| 500
| |
| | |
| | |
| | |
| Volume
| |
| (lO^cu.//)
| |
| | |
| 250
| |
| | |
| | |
| | |
| Normal Cycle
| |
| | |
| | |
| | |
| Cycle After Removal
| |
| of Corpora Luteo
| |
| | |
| | |
| | |
| | |
| Progesterone
| |
| Treated or Pregnant
| |
| | |
| | |
| | |
| 'Corpora Luteo
| |
| Removed and
| |
| Oestrin Injected
| |
| | |
| | |
| | |
| Fig. 8.5. The guinea pig follieular cycle and some of its experimental modifications. (After
| |
| E. W. Dempsey, Am. J. Physiol., 120, 126-132, 1937.)
| |
| | |
| | |
| | |
| or soon after menstruation (Allen, Pratt,
| |
| Newell and Bland, 1930; Hartman, 1932).
| |
| In many mammals competent follicles may
| |
| be present much earlier. Ablation of corpora
| |
| lutea soon after ovulation in sheep (McKenzie and Terrill, 1936) and cattle (Hammond, Jr., and Bhattacharya, 1944) is followed in 2 to 4 days by another ovulation,
| |
| much sooner than in the guinea pig (Fig.
| |
| 8.5). Removal of the primate corpus luteum,
| |
| at the other extreme, produces no such immediate response, judging from the details
| |
| of three cases among Hartman's (1932) protocols (#40, #41, and #99). Whereas the
| |
| next ovulations took place earlier than expectation, the intervals between unilateral
| |
| ovariectomy and ovulation were 16, 14, and
| |
| 22 days, respectively.
| |
| | |
| From detailed investigations in the rat,
| |
| only the earlier stages of follicle growth
| |
| may properly be regarded as pure FSH effects (Lane, 1935). Lane and Greep (1935)
| |
| found that addition of Lli to FSH causes a
| |
| marked increase in the proportion of vesicular follicles to follicles without antra. The
| |
| use of more highly purified materials
| |
| ((irecp, van Dyke and Chow, 1942; Fraenkel-Conrat, Li and Simpson, 1943) has
| |
| amply confirmed the necessity for combination of the two gonadotrophins to yield maximal follicle growth and estrogen secretion
| |
| ill rats. Morphologic evidence indicates that
| |
| | |
| | |
| | |
| LH acts selectively on thecal tissue and,
| |
| therefore, on the interstitial tissue derived
| |
| therefrom. Inasmuch as thecal tissue is the
| |
| presumptive major source of ovarian estrogen (see below), it follows, perhaps, as Hisaw (1947) suggested that "the theca interna through the action of LH acquires
| |
| competence to respond to FSH" (by secreting estrogen) .
| |
| | |
| Convincing evidence that thecal tissue
| |
| and its derivatives are the principal sources
| |
| of ovarian estrogen was assembled by Corner (1938). The status of this question remains essentially the same today. Few endocrinologists, however, would assume that no
| |
| other ovarian cells have this capacity (see
| |
| discussion in the chapter on the ovary).
| |
| Nevertheless, there is a direct correlation in
| |
| time between the marked rise in estrogen
| |
| secretion as the follicular jihase of the cycle
| |
| advances, on the one hand, and the organization of tlicca interna of the largest follicles into organs of obvious endocrine character, on the other. "When especially
| |
| ])rominent the theca interna is referred to
| |
| as the "thecal gland" (Mossman, 1937;
| |
| Stafford, Collins and ]\Iossman (1942).
| |
| | |
| Thecal tissue from the multitudes of
| |
| atretic follicles should not be neglected as
| |
| a possible additional source of estrogen.
| |
| From the standpoint of chronologic relations to the cycle tiiis (iiiestioii has hardly
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 507
| |
| | |
| | |
| | |
| been touched. Pointing up our ignorance,
| |
| Sturgis (1949) in a careful study of atresia
| |
| of large follicles in the monkey ovary, speculated that their hypertrophied thecal tissue
| |
| may serve the useful purpose of estrogen
| |
| secretion during the interim between follicle
| |
| rupture and organization of the corpus
| |
| luteum.
| |
| | |
| We are in need of ciuantitative appraisals
| |
| not only of the total numbers of healthy and
| |
| atretic follicles of all categories present in
| |
| representative species at progressive stages
| |
| of the cycle, as in the work on the rat by
| |
| Mandl and Zuckerman (1952), but also of
| |
| the respective volumes of theca, granulosa,
| |
| interstitial tissue, and corpora lutea. Lane
| |
| and Davis (1939) determined in rat ovaries
| |
| at four stages of the cycle the respective
| |
| total volumes of theca, granulosa, and antra
| |
| in all healthy follicles, as well as the separate mitotic indices of theca and granulosa.
| |
| Such differential information on multiplication of cells and increase of antral volume
| |
| is important. Although the latter accounts
| |
| for a major part of the increase in volume
| |
| of the larger follicles, it represents a function quite apart from protoplasmic growth
| |
| per se.
| |
| | |
| There is now considerable evidence that
| |
| estrogen itself exerts a growth -promoting
| |
| influence on the follicle and, furthermore,
| |
| sensitizes it to gonadotrophic stimulation.
| |
| Details may be found in papers by Pencharz
| |
| (1940), Williams (1940, 1944, 1945a, b),
| |
| Simpson, Evans, Fraenkel-Conrat and Li
| |
| (1941) , Gaarenstroom and de Jongh (1946) ,
| |
| and Desclin (1949a,) . Although it seems that
| |
| these effects have not been elicited by physiologic doses, the possibility remains that
| |
| estrogen operates within the confines of the
| |
| ovary as a mediator of some of the effects
| |
| of the gonadotrophins. In the neighborhood
| |
| of cells that produce it the estrogen concentration is probably far above that which
| |
| would be considered physiologic for the remainder of the body.
| |
| | |
| A. CORRELATION OF OVARIAN SECRETION
| |
| W^ITH THE FOLLICULAR CYCLE
| |
| | |
| Knowledge of the secretory output of
| |
| the ovary during the cycle is almost entirely
| |
| indirect and derives chiefly from (1) substitution experiments carried out in a vari
| |
| | |
| | |
| ety of si)ecies, and (2) assays of urine,
| |
| mainly human but occasionally from other
| |
| forms. Satisfactory assays of blood estrogen
| |
| have been very limited and chemical analysis of the steroid content of ovarian venous
| |
| blood is in only its preliminary stages.
| |
| | |
| The early substitution experiments are
| |
| chiefly of historic interest (Allen, Danforth
| |
| and Doisy, 1939). In great measure these
| |
| investigations constitute crucial steps in
| |
| proof that the ovary secretes steroid hormones which are fundamentally responsible
| |
| for the manifestations of estrus. Conversely, then, these manifestations might be
| |
| considered to reflect an increase of estrogen
| |
| secretion and their absence a relative decrease. It has been learned, however, that
| |
| the action of estrogen in certain instances
| |
| may be greatly modified by progesterone,
| |
| androgens, and certain adrenocortical steroids (notably desoxycorticosterone). Androgens are known to be secreted in the female
| |
| by the adrenal cortex (Dorfman and van
| |
| Wagenen, 1941 ; Gassner, 1952) and by the
| |
| ovaries (Hill, 1937a, b; Parkes, 1950;
| |
| Deanesly, 1938; Burrill and Greene, 1941;
| |
| Pfeiffer and Hooker, 1942; Alloiteau, 1952).
| |
| Progesterone secretion is probably not confined to the luteal phase of the cycle (see p.
| |
| 519j. Evidence for its secretion during follicle maturation is considerable and its possible production even earlier cannot be
| |
| excluded. These considerations make it unwise, therefore, to regard phenomena such
| |
| as vaginal cornification, turgescence of
| |
| vulva and sex skin, uterine growth, as direct
| |
| ciuantitative measures of estrogen output.
| |
| This point may be illustrated by certain observations made in chim])anzees by Fish,
| |
| Young and Dorfman (1941) and illustrated
| |
| in Figure 8.6. Assays of urinary estrogens
| |
| during the cycle exhibited two peaks, only
| |
| the first of which coincided with the swelling
| |
| of sex skin. The second peak of estrogen excretion was unaccompanied by swelling, presumably because of the coordinate increase
| |
| of progesterone secretion. Had swelling been
| |
| the only guide only the first peak would
| |
| have been apparent.
| |
| | |
| Assays of urinary estrogen in primates
| |
| have often shown double peaks such as illustrated for the chimpanzee. PedersenBjergaard and Pederson-Bjergaard (1948i.
| |
| | |
| | |
| | |
| 508
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| I.U. '00
| |
| | |
| | |
| | |
| | |
| I.U.
| |
| | |
| | |
| | |
| ( »ott
| |
| | |
| | |
| | |
| Androgens
| |
| Curve of genital swelling
| |
| | |
| | |
| | |
| | |
| 25 27 29
| |
| | |
| | |
| | |
| Day of cycle
| |
| | |
| | |
| | |
| Fig. 8.6. E.strogen and androgen excretion by a female chimpanzee, Mamo. , total
| |
| | |
| estrogens; , estradiol; -•-•, estrone; , estriol. Menstruation indicated by solid
| |
| | |
| areas on base line. (From W. R. Fish, W. C. Young and R. I. Dorfman, Endocrinology, 28,
| |
| 588,1941.)
| |
| | |
| | |
| | |
| studying one woman for 2 years, found
| |
| single peaks at midinterval in 8 cycles and
| |
| double peaks in 12 cycles. On the average
| |
| the first peak was reached on day 12 and the
| |
| second on day 21. Similar double peaks were
| |
| noted in blood estrogen assays in a large
| |
| group of normal young women (Markee
| |
| and Berg, 1944). An additional lesser rise
| |
| was observed during menstruation.
| |
| | |
| None of the available assays of urinary or
| |
| blood estrogen can be accepted as an absolute measure of the rate of hormone production. Urinary assays have certain advantages, in spite of the fact that probably only
| |
| a variable fraction of the ovarian product
| |
| is measured. Intrinsically they are measures
| |
| of rate, whereas assays of blood estrogen
| |
| measure concentration alone at the moment
| |
| of bleeding. Attempts have been made to
| |
| measure estrogens in ovarian venous blood,
| |
| but with little success because of the extreme dilution (Rakoff and Cantarow,
| |
| 1950). We may hope that development of
| |
| sufficiently sensitive methods of detection
| |
| will soon allow systematic evaluation of
| |
| ovarian output by such direct means. Tracer
| |
| techniciucs have shown (Werthessen,
| |
| Schwenk and Baker, 1953) in perfused ovaries of the sow that C^^-acetate enters into
| |
| the synthesis of estrone and /^-estradiol.
| |
| | |
| Several years ago Corner (1940) esti
| |
| | |
| | |
| mated, from the known amounts of injected
| |
| estrone required to maintain the normal
| |
| status of sex skin and endometrium in castrates that the ovaries of an adult rhesus
| |
| monkey secrete the equivalent of about 20
| |
| fig. estrone daily. On a weight basis the estrone equivalent secreted by the ovaries of
| |
| a woman would then be on the order of 300
| |
| /Ag. per day. Actual substitution data from
| |
| castrated women gave an estimate of the
| |
| same order of magnitude (420 ;u,g. per day).
| |
| Whatever the rate of secretion may be at
| |
| different times, it would seem a 'priori that
| |
| effects on extra-ovarian tissues should be
| |
| more directly related to amount of estrogen
| |
| in circulation. The assays of human bloodestrogen in normal women by Markee and
| |
| Berg (1944) and in gynecologic patients by
| |
| Fluhmann (1934), although differing in absolute values, agree in indicating that the
| |
| variation of blood estrogen concentration
| |
| from one stage of the cycle to another may
| |
| be relatively small. If this is true, then it
| |
| nuist be supposed that cyclic changes in the
| |
| accessory organs are brought about by relatively moderate changes in circulating estrogen. In support of this view Markee (1948)
| |
| demonstrated in the macaque that a mere 50
| |
| per cent reduction in the daily dose of estrogen can invoke menstruation if the
| |
| change is abrupt.
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 509
| |
| | |
| | |
| | |
| B. CYCLIC MANIFESTATIONS AFTER
| |
| OVARIECTOMY OR HYPOPHYSECTOMY
| |
| | |
| Residual cyclic changes in the vagina
| |
| liave been reported in ovariectomized mice
| |
| (Kostitch and Telebakovitch, 1929) and
| |
| rats (Mandl, 1951). The periodicity is very
| |
| nearly that of the normal cycles, at least in
| |
| the latter species. Vaginal cycles of similar
| |
| duration with more extreme estrous changes
| |
| are found in ovariectomized rats receiving
| |
| daily injection of threshold doses of estrogens (del Castillo and Calatroni, 1930;
| |
| Bourne and Zuckerman, 1941). The same
| |
| was remarked in mice by Emmens (1939)
| |
| and a report by Veziris (1951) indicates
| |
| that vaginal periodicity may obtain in castrated or menopausal women receiving estrogen. Although sucli events have been
| |
| called ''threshold cycles," the term may
| |
| simply express the fact that they are most
| |
| easily recognized when estrogen is given at
| |
| threshold level. Hartman (1944), employing
| |
| a modified Shorr stain for vaginal smears,
| |
| found that castrated rats given large
| |
| amounts of estrogen daily (5 to 100 fig. estradiol dipropionate) displayed complete
| |
| cornification at 4- to 5-day intervals. During the time intervening there was admixture of Shorr cells, smaller epithelial cells,
| |
| and leukocytes.
| |
| | |
| Analogous phenomena have been recognized in the endometrium of castrated monkeys (Zuckerman, 1937, 1941) injected daily
| |
| for as long as 1 year with threshold doses of
| |
| estrone (10 fig.). Larger doses prevent cyclic
| |
| bleeding (see Hisaw, 1942). From the report
| |
| of Veziris (1951) it may be judged that
| |
| threshold endometrial cycles also occur in
| |
| women and that the vaginal and endometrial cycles are synchronized in considerable extent.
| |
| | |
| Full explanation of these phenomena is
| |
| not at hand. From the standpoint of the
| |
| present discussion certain considerations are
| |
| especially noteworthy. (1) Vaginal "threshold cycles" have been obtained in castrated
| |
| rats in the absence of either hypophysis or
| |
| adrenals (Bourne and Zuckerman, 1941 ; del
| |
| Castillo and di Paola, 1942) . The former authors encountered the phenomenon in two
| |
| rats from which both the hypophysis and
| |
| adrenals had been removed. It is important
| |
| | |
| | |
| | |
| to remember, however, that the pars tuberalis remains in situ after the usual hypophysectomy procedure, that accessory
| |
| adrenocortical tissue is frequent in rats, and
| |
| that gonadal rests might remain unrecognized. (2) The reported lengths of vaginal
| |
| and endometrial cycles agree favorably with
| |
| the cycle lengths in intact individuals of the
| |
| respective species. The degree of conformity
| |
| between vaginal and uterine cycles indicated by Veziris {loc. cit.) suggests some
| |
| sort of integrating mechanism. Much more
| |
| information is required, however, before one
| |
| may reject the alternative view that rhythmic activity is an innate characteristic of
| |
| these organs.
| |
| | |
| C. CYCLIC MANIFESTATIONS IN THE ABSENCE
| |
| OF OVARIAN FOLLICLES
| |
| | |
| Many years ago Parkes (1926a, b) and
| |
| Brambell, Parkes and Fielding (1927a, b)
| |
| reported vaginal and uterine cycles in mice
| |
| in which the entire follicular apparatus had
| |
| been destroyed by x-radiation. Schmidt
| |
| (1936) described the phenomenon in the
| |
| guinea pig, noting that, although most of
| |
| her estrous animals had one or more large
| |
| atretic or cystic follicles, as she had earlier
| |
| reported (Genther, 1931), a few animals
| |
| exiiil)ited periodic vaginal opening of short
| |
| duration and correlated proestrous vaginal
| |
| smears, in the absence of follicles. Her assays of urinary estrogen were negative in
| |
| these animals, unlike the positive assays in
| |
| those in which one or more follicles were
| |
| demonstrable. Attempts by several workers
| |
| (Drips and Ford, 1932; Levine and Witschi,
| |
| 1933; Mandel, 1935) to reproduce in rats
| |
| the results that Parkes and Brambell had
| |
| found in mice, were unsuccessful, a fact indicating no estrogenic activity in ovaries
| |
| completely lacking follicles and ova. Parkes
| |
| (1952) more recently returned to this problem, reporting vaginal cycles and "fully
| |
| functional" uteri in castrated rats bearing
| |
| grafts of ovaries in which all organized follicles and ovocytes had been destroyed by
| |
| deep freezing. These were true estrous cycles, in the sense that the animals would
| |
| mate.
| |
| | |
| Many questions are posed by these observations. The fundamental one seems to
| |
| be whether these cycles express periodicity
| |
| of hypophyseal gonadotrophin secretion.
| |
| | |
| | |
| | |
| 510
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| The answer may be long in coming. Meanwhile, one would like to know whether castration changes are visible in the hypophysis
| |
| and whether constant estrus may be invoked
| |
| by exposure to continuous light or by postnatal treatment of the host with androgen
| |
| or other steroids (see p. 529 1 .
| |
| | |
| D. HYPOTHALAMUS AND GONADOTROPHIN
| |
| SECRETION. GENERAL CONSIDERATIONS
| |
| | |
| Experimental studies, ostensibly addressed to the general problem of neural
| |
| control of gonadotropin secretion, have in
| |
| fact often been concerned with the special
| |
| problems of reflex ovulation <p. 520) or
| |
| of provoked pseudopregnancy (p. 532).
| |
| Whereas substantial information is now
| |
| available w^ith respect to these special phenomena, particularly ovulation, information
| |
| is limited about control of the day-to-day
| |
| secretion of gonadotrophin that in the female is responsible for follicle stimulation
| |
| and estrogen secretion (Benoit and Assenmacher, 1955; Harris, 1955). However, evidence in regard to induction of precocious
| |
| puberty and early onset of estrus in seasonal
| |
| breeders leaves no doubt that the nervous
| |
| system is in some manner a regulator of
| |
| follicle-stimulating activitv of the i)ars distalis.
| |
| | |
| Numerous reports associate precocious
| |
| l)uberty with lesions in the hypothalamus
| |
| (Weinberger and Grant, 1941; Bauer, 1954;
| |
| Harris, 1955). Donovan and van der Werff
| |
| ten Bosch (1956) reported off-season estrus
| |
| in ferrets and precocious puberty in rats
| |
| following retrochiasmatic lesions in the hyjiotlialamus. Exposure of immature rats to
| |
| continuous light causes the vagina to open
| |
| prematurely (Fiske, 1941). When 22-dayold female rats were given electrical stimulation of the cervix uteri daily for 10 days
| |
| (Swingle, Seay, Perlmutt, Collins, Fedor
| |
| and Barlow, 1951), a large proportion exhibited significant increase in uterine weight
| |
| beyond that found in control animals, without change in ovarian weight. In fact, 7 of
| |
| 50 rats ovulated or at least formed "several
| |
| well-developed corpora lutca." Somewhat
| |
| similarly, according to Aron and AronBrunetierc (1953), mechanical stimulation
| |
| of the vagina or the adjacent segment of the
| |
| uterus in innnatur(> guinea pigs regularly
| |
| | |
| | |
| | |
| provoked follicle growth and estrogen secretion. In gregarious birds the development of
| |
| ovulable follicles requires that other individuals of the species be present. In the pigeon, even the mirror image of the female
| |
| constitutes a sufficient stimulus (Matthews,
| |
| 1939).
| |
| | |
| Studies by Flerko and his associates
| |
| (1954-1957) present consistent evidence
| |
| that restricted bilateral lesions in the region
| |
| of the paraventricular nuclei serve to liberate the hypophysis from inhibitory effects
| |
| of estrogen and androgen. This work is in
| |
| agreement with that of Donovan and van
| |
| der Werff ten Bosch in that somewhat similarly located lesions brought on precocious
| |
| puberty. As noted elsewhere, gonadectomy
| |
| in immature rats quickly results in hypersecretion of gonadotrophin.
| |
| | |
| Transplantation of the hypophysis to
| |
| sites remote from the hypothalamus has
| |
| produced divergent results. At the present
| |
| writing, the chief divergence seems to rest
| |
| between the sexes. In male guinea pigs and
| |
| rats several workers have reported maintenance of male reproductive tracts by intra-ocular transplants of hypophyses (May,
| |
| 1937; Schweizer, Charipper and Kleinberg,
| |
| 1940; Cutuly, 1941a; Courrier, 1956; Goldberg and Knobil, 1957). Quite to the contrary, however, there has at best been only
| |
| equivocal evidence of maintenance of female tracts, a matter of sex difference which
| |
| needs full investigation. JNIay's (1937) report of 2 fertile female rats is unacceptable
| |
| because of inadequate controls. Schweizer,
| |
| Charipper and Haterius (1937) found in
| |
| several hypophysectomized guinea pigs that
| |
| intra-ocular pituitary grafts produced constant estrus and significant follicle stimulation, accompanied by uterine and mammary
| |
| gland develoi)inent. Although the search for
| |
| pituitary remnants in the sella turcica was
| |
| reported negative, the histologic check was
| |
| limited to scrapings from the sella floor.
| |
| Other authors, notably Phelps, Ellison and
| |
| Burch (1939), Westman and Jacobsohn
| |
| (1940), Harris and Jacobsohn (1952), and
| |
| Elverett ( 1956a) obtained in female rats little or no evidence of gonadotrophin secretion from apparently healthy, well vascularized grafts. The respective sites were
| |
| intraniusculai', intra-ocular, in the sub
| |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 511
| |
| | |
| | |
| | |
| arachnoid space under the temporal lobe of
| |
| the brain, and beneath the renal capsule —
| |
| all distant from the hypothalamus.
| |
| | |
| Transplantation of the pars distalis into
| |
| sites close to the hypothalamus, on the other
| |
| hand, is characteristically followed by
| |
| maintenance of the female reproductive
| |
| tract and essentially normal sex functions.
| |
| Greep (1936) found that re-implantation
| |
| of hypophyses into the (presumably) emptied capsule was frequently followed in both
| |
| male and female rats by return of virtually
| |
| normal reproductive powers. Females exhibited cycles and even went through successful pregnancy and lactation. The result
| |
| observed in male rats was confirmed by
| |
| Cutuly (1941a). The obvious difficulty of
| |
| establishing completeness of hypophysectomy has been the only criticism of these
| |
| instructive experiments. This fault has been
| |
| eliminated by an improved procedure devised by Harris and Jacobsohn (1952). Hypophysectomy was performed by the parapharyngeal route, after which the tissue to
| |
| l)e grafted was introduced by a transtemporal approach to a site immediately beneath the median eminence. This permitted
| |
| later histologic search for remnants of the
| |
| original gland in its capsule. In many cases,
| |
| including all in which the graft comprised
| |
| several hypophyses from the animal's own
| |
| newborn young, entirely normal gonadotrophic function was recorded. This included
| |
| resumption of regular estrous cycles, typically during the 2nd or 3rd postoperative
| |
| week. Several of the rats became pregnant
| |
| and delivered viable litters. In marked contrast, none of the grafts that were placed
| |
| under the temporal lobe gave any indication
| |
| of gonadotrophin secretion, although they
| |
| were as well preserved and richly vascularized as the others. Explanation of the difference seems to be that grafts under the
| |
| median eminence acquire blood supply from
| |
| regenerated hypophyseal portal veins and
| |
| iience a neurovascular linkage with the hypothalamus. The importance of this relationship has been amply confirmed by Nikitovitch-Winer and Everett (1957, 1958d)
| |
| in studies described below.
| |
| | |
| In lieu of significant numbers of nerve fibers entering the pars distalis (see Rasmussen, 1938; Harris. 1948a I, the hypophyseal
| |
| | |
| | |
| | |
| portal veins afford the most likely means
| |
| by which the gland is brought under hypothalamic control. Recently it was demonstrated in rats and monkeys that these vessels have the power of rapid regeneration
| |
| after simple stalk-section (Harris, 1949,
| |
| 1950a, b). This fact at once gives a ready
| |
| explanation of many of the discordant results of stalk-section experiments reported
| |
| in the past. Harris (1950b) explored in rats
| |
| the efficacy of various materials as barriers
| |
| to regeneration, with the result that numerous examples of partial regeneration were
| |
| produced. Degree of recovery of gonadotropliic activity by the hypophysis was
| |
| strikingly correlated with degree of anatomic vascular recovery. Restoration of normal ovarian function after simple interruption of the stalk, as reported in the guinea
| |
| pig by Dempsey (1939), in rats by Dempsey and Uotila (1940) , and in the human by
| |
| Dandy (1940), is thus explained by the assumption that portal vein regeneration had
| |
| taken place. On the other hand, Westman
| |
| and Jacobsohn (1937-1938), who always
| |
| inserted a barrier of metal foil between the
| |
| median eminence and hypophyseal capsule,
| |
| consistently found ovarian atrophy, as did
| |
| Harris when portal vein regeneration was
| |
| completely obstructed. Attempting to prove
| |
| that the portal vessels are not essential in
| |
| regulating the hypophysis, Thompson and
| |
| Zuckerman (1954) stated that increased
| |
| illumination induced estrus in two ferrets
| |
| after stalk-section and in the absence of
| |
| demonstrable regeneration of portal vessels.
| |
| Donovan and Harris (1954), however, examining the histologic sections prepared
| |
| from 1 of the 2 animals, found many such
| |
| vessels that were uninfected. In their own
| |
| experimental series, an estrous response to
| |
| light was always associated with regeneration of the portal veins.
| |
| | |
| Greep and Barrnett (1951) rightly emphasized the prime importance of a good
| |
| vascular supply for recovery of function by
| |
| the pars distalis after either transplantation
| |
| or stalk-section. They pointed to the extensive central infarction and scarring that
| |
| characteristically followed stalk-section by
| |
| their technique, an obvious factor contributing to hypopituitarism. Harris (1950a I,
| |
| however, reported good function from sev
| |
| | |
| | |
| 512
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| eral hypophyses in which there was pronounced central necrosis in company with
| |
| well regenerated portal vessels. A study by
| |
| Nikitovitch-Winer and Everett (1957,
| |
| 1958b) established beyond doubt that qualitative functional losses after stalk-sectron
| |
| or transplantation of the pars distalis result,
| |
| not from impaired blood supply per se, but
| |
| from the loss of the intimate neurovascular
| |
| relationship with the hypothalamus. Hypo])hyseal autografts, after first being
| |
| placed under the kidney capsule for several weeks with the usual atrophy of the
| |
| ovarian follicular apparatus and interstitial
| |
| tissue, were later retransplanted to a site
| |
| immediately under the median eminence. In
| |
| the definitive series of 14 such experiments,
| |
| 13 rats resumed estrous cycles spontaneously 8 to 68 days after retransplantation ;
| |
| 7 were fertile and carried litters to term. A
| |
| correlated study (Nikitovitch-Winer and
| |
| Everett, 1959) demonstrated clearly that on
| |
| the occasion of each of these successive
| |
| transplantations there was massive necrosis
| |
| of the interior of the glandular mass, leaving but a thin shell from which the functional tissue of the graft was reconstituted.
| |
| In spite of this double insult some special
| |
| influence of the hypothalamus brought
| |
| about renewed function in a surprising number of cases. Together with the restoration
| |
| of gonadotrophic activity there was significant improvement in thyroid-stimulating
| |
| hormone (TSH) and adrenocorticotrophic
| |
| hormone (ACTH) secretion. The considerable net loss of hypophyseal parenchyma
| |
| resulting from the two operations was reflected only quantitatively in the effects on
| |
| the various target organs. Ovarian weights,
| |
| numbers of follicles and corpora lutea, adrenal weights and extent of adrenal hypertroi)liy after unilateral adrenalectomy, and
| |
| thyroid uptake of P^^ were all intermediate
| |
| between those of the normal female rat and
| |
| control animals in which the graft remained
| |
| on the kidney or was retransplanted under
| |
| the temporal lobe of the brain.
| |
| | |
| Regulation of pars distalis secretion by
| |
| means of the stalk vessels may conceivably
| |
| be carried out either by regulation of blood
| |
| How or by transmission of chemical mediatoi-s from the proximal capillary plexus in
| |
| the median eminence to the pars distalis. An
| |
| | |
| | |
| | |
| experiment describetl by Swingle, Seay,
| |
| Perlmutt, Collins, Fedor and Barlow (1951)
| |
| suggested that a mediator subject to Dibenamine blockade might be involved in precocious puberty. Although significant uterine enlargement was produced in immature
| |
| rats by daily stimulation of the cervix uteri
| |
| for 10 days, no such effects were observed
| |
| in similar rats given Dibenamine daily by
| |
| stomach tube. Unfortunately, there were no
| |
| controls for the possible effect of Dibenamine in nonstimulated or gonadotrophininjected animals.
| |
| | |
| Fluhmann (1952) invoked precocious
| |
| vaginal opening and ovarian stimulation in
| |
| immature rats by injection of neostigmine.
| |
| The locus of such cholinergic action is unknown. Parenthetically, Barbarossa and di
| |
| Ferrante (1950) reported follicle stimulation in immature rats after injection of
| |
| intermedin, an effect not found in hypophysectomized subjects. Benoit and Assenmacher (1955) proposed that, in the drake,
| |
| gonad-stimulating activity is governed by
| |
| an agent contained in neurosecretory substance, which is demonstrable in abundance
| |
| in the retrochiasmatic region of the median
| |
| eminence. Capillaries there drain selectively
| |
| into an anterior set of portal venules. Oxytocin has been suggested as a possible mediator for gonadotrophin secretion (Shibusawa, Saito, Fukuda, Kawai, Yamada
| |
| and Tomizawa, 1955; Armstrong and
| |
| Hansel, 1958). There is much interest
| |
| as this is being written (1958) in the
| |
| jiossibility that vasopressin, oxytocin, or
| |
| other agents associated with neurosecretory substances of the neui-ohyjioiihysis
| |
| are responsible for control of production and release of the various trophic
| |
| hormones of the pars distalis. As an
| |
| alternative or even a supplement to neurochemical regulation, a vasomotor mechanism cannot be denied (Green, 1951), for
| |
| conceivably only a slight shift in blood flow
| |
| through the jiars distalis might tip the balance of hormone production one way oi- anothei-. Thus the matter stands: whereas it
| |
| is apjiarent that the hypothalamus intervenes in follicle growth and estrogen secretion, how it does so is little more than speculati\'e.
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 51)5
| |
| | |
| | |
| | |
| VI. Follicle Maturation and Ovulation
| |
| | |
| A variety of evidence indicates discontinuity between growth of large follicles, on
| |
| the one hand, and their preovulatory maturation, on the other. Such is clearly the case
| |
| among "reflex ovulators." Evidence that the
| |
| same is true for spontaneous ovulators will
| |
| be outlined below. Follicle maturation, ovulation, and structural transformation of the
| |
| follicles to corpora lutea seem to represent
| |
| successive stages in a distinct physiologic
| |
| process, superimposed on the follicle growth
| |
| cycle and brought about by a relatively
| |
| abrupt increase in circulating gonadotrophin
| |
| (theoretically LH). Since there is evidence
| |
| (p. 519) that progesterone secretion may
| |
| become detectable as this process begins,
| |
| there might be justification for regarding it
| |
| as merely the first portion of the luteal
| |
| phase. However, the fact that luteinization
| |
| ( i.e., the organization per se of luteal tissue)
| |
| does not necessarily lead to functional cor|)ora lutea warrants treatment of the ovulation-luteinization phase as a distinct phenomenon.
| |
| | |
| Although it is customary to state that the
| |
| hypopliysis invokes ovulation by release of
| |
| LH, there is considerable question about
| |
| the auxiliary roles played by other gonadotrophic hormones (Hisaw, 1947). Inasmuch
| |
| as the time of release has been known in
| |
| only the reflex ovulators, one might look to
| |
| them for information. However, the available data (Hill, 1934) pertain only to the
| |
| ovulating i)otency of the total gonadotrophin content of the hypophysis at various
| |
| times after coitus. Substitution experiments
| |
| are unsatisfactory because the presence of
| |
| competent follicles implies the presence of
| |
| l)oth FSH and a small amount of LH. The
| |
| substitution of even the purest hormone
| |
| preparations immediately after hypophysectomy leads to equivocal results inasmuch
| |
| as it must be assumed that some FSH and
| |
| LH of intrinsic origin remain in circulation.
| |
| Talbert, Meyer and McShan (1951) determined that in rats, when hypophysectomy
| |
| is performed at the onset of proestrum, the
| |
| follicles remain capable of responding to injected LH for about 6 hours. Morphologic
| |
| signs of follicle deterioration do not appear
| |
| until nuich later. Adding to the uncertainty
| |
| | |
| | |
| | |
| is the fact that relatively pure preparations
| |
| of either FSH or LH will ovulate an estrous
| |
| rabbit (Greep, van Dyke and Chow, 1942).
| |
| On the other hand, until the recent use of
| |
| species-specific gonadotrophins (van Wagenen and Simpson, 1957), the primate ovary
| |
| was notoriously difficult to ovulate therapeutically. Until effluent blood from the hypophysis can be assayed, there is little
| |
| likelihood that the gonadotrophin complex
| |
| that is normally responsible for ovulation
| |
| can be known. Thus, whereas the expression,
| |
| LH-release, will be employed occasionally
| |
| to refer to the release of gonadotrophin that
| |
| in^•okes ovulation, the term is used purely
| |
| for convenience and brevity, and should be
| |
| ai^propriately qualified by the reader.
| |
| | |
| A. TIME OF OVUL.\TION
| |
| | |
| The time of ovulation with respect to
| |
| other events of the cycle is relatively easy
| |
| to determine in reflex ovulators, but in spontaneous ovulators has proven to be more
| |
| elusive. In the former, laparotomy at various intervals after the stimulus enables exact measure to be made of the time required
| |
| to accomplish ovulation. For most of the
| |
| spontaneous ovulators, save the few in
| |
| which the ripening follicles can be palpated
| |
| as in monkeys and cattle, it has been necessary to attempt to correlate ovulation with
| |
| some easily detectable external sign. Inasmuch as the ovulation stimulus to the hyj)oiihysis in these animals is probably invoked by ovarian hormones and these are
| |
| equally responsible for phenomena such as
| |
| vaginal cornification and behavioral estrus,
| |
| a considerable degree of correlation might
| |
| be expected between ovulation and a given
| |
| change in the vaginal smear or onset of estrous behavior. The predictability of the
| |
| relationship, however, must depend in great
| |
| measure on the degree of correlation among
| |
| thresholds of response in the various tissues
| |
| concerned. In the primates that have no
| |
| sharply limited period of sex desire the
| |
| i:)roblem is even more troublesome. When
| |
| reference is made to the date of the last
| |
| menstruation, prediction is erratic because
| |
| of the variable occurrence of postmenstrual
| |
| quiescence (Rossman and Bartelmez, 1943;
| |
| Young and Yerkes, 1943). Consequently,
| |
| attempts must be made to find indicato:
| |
| | |
| | |
| 514
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| such as basal body temperature fluctuations
| |
| which may bear some intrinsically closer
| |
| relationship to the event in question. (See
| |
| Hartman, 1936, and Buxton and Engle,
| |
| 1950, for discussion of this very practical
| |
| ]iroblera. )
| |
| | |
| Among mammals generally, si)ontaneous
| |
| ovulation takes place sometime during estrus (Asdell, 1946) . It is found during early
| |
| estrus in the opossum, red fox, dog, mouse
| |
| and hamster. In the rat some authors have
| |
| placed it early (Young, Boling and Blandau,
| |
| 1941) and others late (Long and Evans,
| |
| 19221 with respect to vaginal estrus. In the
| |
| writer's colony both relations hold, in 4-day
| |
| and 5-day cycles, respectively. Ovulation in
| |
| late estrus is reported for the cotton rat,
| |
| bank vole, guinea pig, pig, horse, and ass.
| |
| Sheep usually ovulate shortly before the
| |
| end of heat, sometimes a few hours afterward. As stated earlier, ovulation may even
| |
| occur in guinea pigs, rats, sheep, and cattle
| |
| without overt estrus. The cow usually ovulates several hours after the end of heat. The
| |
| marsupial cat is said to ovulate 5 days
| |
| afterward (Hill and O'Donoghue, 1913).
| |
| The extreme is represented by certain bats
| |
| (Asdell, 1946) which copulate in autumn
| |
| and ovulate in the spring after a prolonged
| |
| state of subestrus. These variations probably express several factors.
| |
| | |
| Among reflex ovulators there is considerable interspecies variation in the interval
| |
| between the stimulus that invokes release
| |
| of gonadotroj^hin from the hypophysis and
| |
| the eventual rupture of the Graafian follicles
| |
| (rabbit, ca. 10 hours; ferret, ca. 30 hours;
| |
| cat, 24 to 54 hours; 13-lined ground sciuirrcl,
| |
| 8 to 12 hours; mink, 36 to 50 hours) . Among
| |
| spontaneous ovulators the comparable interval is clearly defined for only the rat, 10
| |
| to 12 hours (Everett, Sawyer and Markce,
| |
| 1949) . In the cow the data obtained by Hansel and Trimberger (1951) and Hough,
| |
| Bearden and Hansel (1955) i)lace the outside limit at about 30 hours. Here again,
| |
| threshold differentials among tlic various tissues of the individual are piobably of gicat importance. 'I'hus in one
| |
| species the threshold foi' gonadoti'ophin
| |
| release may be lower than that foi' estrous behavior with the result tliat by
| |
| the time the latter makes its ai)pearance
| |
| the former has already transpired and
| |
| | |
| | |
| | |
| ovulation will shortly take place. The rat,
| |
| for example, releases LH during the afternoon, begins to show estrous behavior
| |
| around 8 p.m., and ovulates around 2 a.m.
| |
| (Everett, 1948, 1956b). In other species
| |
| these time relationships may be reversed.
| |
| In the cow, activation of the hypophysis apparently occurs several hours after the onset
| |
| of estrus (Hansel and Trimberger, 1951).
| |
| The cow remains in heat 10 to 18 hours and
| |
| ovulates 13!/2 to 151/2 hours after going out
| |
| of heat (Asdell, 1946). The early termination of estrus apparently reflects a refractory state which sets in after estrogen
| |
| activity has continued for a time, for castrates receiving continued estrogen therapy
| |
| remain in estrus for similarly brief periods.
| |
| In the mare, ovulation is delayed until a few
| |
| hours before the end of estrous periods that
| |
| may extend for 5 to 10 days or longer. This
| |
| suggests a relative refractoriness of the LHrelease mechanism in this animal. Such a
| |
| state of affairs approaches that in persistent
| |
| estrus or in the anovulatory cycle.
| |
| | |
| B. OVARIAN STEROmS AND OVULATION
| |
| | |
| 1. Estrogens
| |
| | |
| Chronic administration of estrogen to the
| |
| intact animal eventually produces ovarian
| |
| atrophy by suppression of gonadotrophin
| |
| secretion. However, some moderate basic
| |
| level of continuous estrogen secretion must
| |
| be compatible with normal function of the
| |
| hypophyseal-ovarian system; witness the
| |
| fact that blood estrogen assays in normal
| |
| women (]Markee and Berg, 1944) indicate
| |
| only a 2-fold increase at midinterval above
| |
| a base value of considerable magnitude.
| |
| | |
| Induction of corpus luteum formation by
| |
| injected estrogen was first demonstrated by
| |
| Hohlweg (1934) in prepubertal rats^ and
| |
| the phenomenon has been repeatedly observed by other woi'kers (Desclin, 1935;
| |
| Mazer, Israel and Aljjcrs, 1936; Westman
| |
| and Jacobsolm, 1938b; Herold and Effkemann, 1938; Price and Ortiz, 1944; Cole,
| |
| 1946). The fact that the effect was not obtained in rats younger than 30 to 36 days
| |
| l>y Piice and Ortiz, whereas Cole observed
| |
| it in the age-range of 21 to 28 days, demon
| |
| ' Tlic eH'cct was later ol)1aiii(^(l witli androgens
| |
| (Holilwpg, 1937; Salmon, 1938; Xathanson, Fianspen and Sweenev, 1938).
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCl.E
| |
| | |
| | |
| | |
| 515
| |
| | |
| | |
| | |
| B
| |
| | |
| | |
| | |
| | |
| ^,
| |
| | |
| | |
| ^ >
| |
| | |
| | |
| 1 2
| |
| | |
| | |
| 3 4 5
| |
| | |
| | |
| e
| |
| | |
| | |
| A
| |
| | |
| | |
| | |
| 12 3 4 5
| |
| | |
| | |
| | |
| 12 3 4 5
| |
| | |
| | |
| | |
| Fig. 8.7. Experimental modifications of the 5-day cycle in rats. Two units of the ordinate
| |
| represent full vaginal estrus. Time in days on abscissa, each unit 24 hours (midnight to midnight). X, ovulation time; -p, progesterone, usually 1 to 2 mg.; e, estradiol benzoate, standard
| |
| do.se 50 /xg. (From J. W. Everett, Endocrinology, 43, 393, 1948.)
| |
| | |
| | |
| | |
| strates the existence of strain differences in
| |
| the age factor. This probably explains the
| |
| absence of luteinization in the experience of
| |
| Lane (1935) and Merckel and Nelson
| |
| (1940). Hohlweg and Chamorro (1937)
| |
| demonstrated the importance of the hypophysis in the response. When hypophysectomy was performed 2 days after injection
| |
| of estrogen no corpora liitea developed, but
| |
| hypophysectomy on the 4th day did not interfere with corpus luteum formation. The
| |
| effect could be produced in 50-gm. rats with
| |
| as little as 4 |U,g. estradiol benzoate. Westman and Jacobsohn (1938b) reported that
| |
| transsection of the hypophyseal stalk less
| |
| than 2Vt days after injection prevented the
| |
| reaction, but after that time the operation
| |
| did not interfere. Bradbury (1947) assayed
| |
| the gonadotrophin content of hypophyses of
| |
| normal and castrated immature rats (30 to
| |
| 32 days old at autopsy) 2 to 5 days after
| |
| injection of estrogen or other steroids. These
| |
| rats were apparently too young to form
| |
| corpora lutea in response to the treatment,
| |
| l)ut marked interstitial-cell stimulation, indicative of LH (ICSH) activity, was observed as early as 96 hours. In the intact
| |
| animals significant loss of potency occurred
| |
| 72 to 96 hours after injection, in agreement
| |
| with the hypophysectomy data of Hohlweg
| |
| and Chamorro (1937). In castrated rats,
| |
| however, there was no loss of potency, thus
| |
| suggesting that some ovarian factor in addition to estrogen is essential for stimulation
| |
| of the hypophysis. It is unfortunate that the
| |
| study was confined to animals too young to
| |
| give the full response of luteinization.
| |
| | |
| | |
| | |
| Induction of ovulation in adult animals
| |
| by estrogen was first reported by Hammond,
| |
| Jr., Hammond and Parkes (1942) and by
| |
| Hammond, Jr. (1945) in the anestrous ewe.
| |
| Whereas the s])ontaneous occurrence of occult ovulation was approximately 5 per
| |
| cent, injection of stilbestrol was followed by
| |
| corpus luteum formation in 4 of 11 ewes,
| |
| with recovery of ova in 3. Injection of stilbestrol di-n-butyrate was followed by corpus luteum formation in 5 of 6 ewes and ova
| |
| were recovered in 3. The finding was confirmed by Casida (1946) who stated that in
| |
| cycling ewes ovulation can be invoked by
| |
| injection of diethylstilbestrol on the 4th day
| |
| of the cycle, but not at other times. In 1947
| |
| Everett reported the induction of ovulation
| |
| in pregnant rats within 40 hours after injection of estradiol benzoate (as little as 2 or
| |
| 3 /xg.) or implantation of estradiol crystals
| |
| or pellets. The response was not obtained in
| |
| animals autopsied 24 hours after treatment
| |
| nor in other animals hypophysectomized at
| |
| 24 hours and autopsied the following day. In
| |
| other studies with adult rats it was demonstrated (Everett, 1948) that in 5-day cyclic
| |
| rats the injection of estrogen at mid-diestrum will regularly induce ovulation 24
| |
| hours earlier than exi:)ected (Figs. 8.7D,
| |
| 8.8F|. Persistent-estrous rats were refractory to estrogen in this respect.- Nevertheless, when such animals were made pseudopregnant by daily injection of progesterone,
| |
| | |
| "The tendency toward refractoriness of similar
| |
| animals with respect to induction of estrous 1) ha\'ior had earlier been reported by Boling,
| |
| Blandau, Rundlett and Young (1941).
| |
| | |
| | |
| | |
| 516
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| B
| |
| | |
| | |
| | |
| | |
| 12 3 4
| |
| | |
| | |
| | |
| | |
| 12 3 4
| |
| | |
| | |
| | |
| | |
| | |
| | |
| T%
| |
| | |
| | |
| ^'
| |
| | |
| | |
| 2 3 4 5
| |
| | |
| | |
| 1
| |
| P
| |
| | |
| | |
| 2 3 4 5
| |
| e v^^
| |
| / y
| |
| | |
| r-U^'f*^ 1 tA 1
| |
| | |
| | |
| | |
| 12 3 4 5
| |
| | |
| Fig. 8.8. Experimental modification of the 4-day cycle in rats. Same key as in Figure 8.7.
| |
| Progesterone dosage 1.5 mg. per day. Artificial 5-day cycles in D, E, and F indicated by
| |
| dotted lines and numbering. (From J. W. Everett, Endocrinology, 43, 395, 1948.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| B
| |
| | |
| | |
| | |
| | |
| | |
| e NO OVULATION
| |
| | |
| | |
| | |
| | |
| j~~r~r~r
| |
| | |
| | |
| | |
| Fig. 8.9. Experiment with persistent-estrous rats. Units of ordinate and abscissa have same
| |
| meaning as in Figure 8.7. A. Secjuence of "progesterone cycles." Each dose of progesterone
| |
| (p) is 1.0 mg. Ovulation (x) in about 70 per cent of the cycles. B. Progesterone cycle followed
| |
| by unsuccessful attempt to induce ovulation by estrogen during the second c-ycle. C . Pseudopregnancy maintained by daily iiijoctinn of 1.5 mg. ]irogosteronr. Ovulation induced by
| |
| estrogen in several such cases. (From .1. \V. Everett, EiKhxTinolojiy. 43, ;5i»9, 194S.)
| |
| | |
| | |
| | |
| ovulation and corpus luteuni loiniatioii were
| |
| induced by estrogen (Fig. 8.9 1.
| |
| | |
| Early attempts to induce luteinization in
| |
| the guinea pig with estrogen were unsuccessful ( Dempsey, 1937; see Fig. 8.5), but iiioiv
| |
| recently Lipschutz, Iglesias, Bruzzone, 11 uniercz and Penaranda (1948) have shown by
| |
| the use of intrasplenic ovarian autografts
| |
| | |
| | |
| | |
| that luteinization is a reguhir feature in experiments in which estrogen is administered
| |
| systcniically. Interestingly enough the implantation of estrogen jiellets in or near the
| |
| ox'ariaii grafts had tlic coiitrai'y effect of
| |
| pi'cvcnliiig luteinization.
| |
| | |
| it was early I'cportcd that rabbits fail to
| |
| ovulate in response to estrogen injection
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 517
| |
| | |
| | |
| | |
| (Bachman, 1936; Mazer, Israel and Alpers,
| |
| 1936 ». Hisaw (1947j inferred that this is
| |
| generally true for reflex ovulators. Nevertheless, it was found by Klein and Mayer
| |
| ( 1946) and Klein (1947) that when pseudol^regnant or pregnant rabbits were treated
| |
| with estrogen and then mated, new ovulation resulted and new corpora lutea were
| |
| formed, events that do not otherwise occur.
| |
| The phenomenon was further explored by
| |
| Sawyer (1949). Whereas untreated rabbits,
| |
| unlike cats, do not ovulate in response to
| |
| mechanical stimulation of the vagina, treatment with estrogen on the preceding 2 days
| |
| results in a positive response to this stimulus. In fact, his later observations (1959)
| |
| indicate that estrogen priming for a longer
| |
| period (4 days) occasionally results in
| |
| "spontaneous" ovulation, especially during
| |
| the winter and spring.
| |
| | |
| In the anestrous cat, in the response to
| |
| mechanical stimulation of the vagina, estrogen facilitates the ovulation of follicles
| |
| primed with equine gonadotrophin (Sawyer
| |
| and Everett, 1953).
| |
| | |
| Induction of ovulation by estrogen in
| |
| primates remains to be demonstrated. It is
| |
| of interest in this connection that Funnell,
| |
| Keaty and Hellbaum (1951) observed in
| |
| menopausal women an increased excretion
| |
| of LH during estrogen therapy, in contrast
| |
| to FSH excretion at other times. The general
| |
| experience has been that injection of estrogen during the early part of the cycle significantly postpones the next expected ovulation and menstruation (monkey, Ball and
| |
| Hartman, 1939; baboon, Gillman, 1942; human, Sturgis and ^leigs, 1942; Brown, Bradbury and Jennings, 1948). Gillman reported
| |
| that a single injection of estrogen precipitates widespread atresia of vesicular follicles. Brown and Bradbury (1947) reported
| |
| IH-eliminary data that in 4 of 6 women
| |
| there was increased gonadotrophin excretion
| |
| during the 24 hours following estrogen administration. They proposed that delay of
| |
| ovulation by estrogen given early in the
| |
| primate cycle may be the result of premature discharge of gonadotrophin before the
| |
| Graafian follicle is competent. Sturgis and
| |
| Meigs had suggested, on the contrary, that
| |
| the estrogen suppresses hypophyseal function. D'Amour (1940), finding in urinary
| |
| assays that the initial peak of estrogen ex
| |
| | |
| | |
| cretion preceded the peak excretion of urinary gonadotrophin, postulated that the
| |
| increase of estrogen stimulates the gonadotrophin release that is responsible for ovulation. O. W. Smith (1944) proposed that
| |
| not estrogen itself, but some metabolite resulting from inactivation by the liver, is
| |
| responsible for LH release. This interesting
| |
| hypothesis has not been substantiated.
| |
| | |
| 3. Gestagens
| |
| | |
| Suppression of estrus and ovulation by
| |
| functional corpora lutea, suggested by
| |
| Beard (1898), was experimentally demonstrated in the guinea pig by Loeb (1911). It
| |
| is now well established in several species
| |
| that removal of the corpora lutea results in
| |
| early resumption of estrus and ovulation
| |
| (see p. 506), and that administration of
| |
| progesterone suppresses these events. There
| |
| is considerable evidence favoring the view
| |
| that the primary effect is to selectively suppress the secretion of LH. Dempsey (1937)
| |
| noted that in guinea pigs receiving daily injection of progesterone (50 /^g.) all stages of
| |
| follicle development proceeded except the
| |
| maturation enlargement that heralds LH
| |
| release (Fig. 8.5). Astwood and Fevold
| |
| (1939) and Cutuly (1941b) found similar
| |
| results in rats. Essentially the same phenomenon has been noted in sheep by Dutt
| |
| and Casida (1948). Bradbury (1947) reported that in immature rats the injection of
| |
| progesterone at the time of estrogen injection prevented the release of gonadotrophin
| |
| (LH?) which otherwise followed estrogen
| |
| injection by 72 to 96 hours. In ovariectomized guinea pigs containing intrasplenic
| |
| autografts, preparations in which luteinization can be induced by estrogen (see above) ,
| |
| the simultaneous administration of gestagens prevented this action (Lipschutz, Iglesias, Bruzzone, Humerez and Pefiaranda,
| |
| 1948; Iglesias, Lipschutz and Guillermo,
| |
| 1950; Mardones, Bruzzone, Iglesias and
| |
| Lipschutz, 1951). Mardones and co-w^orkers
| |
| also made the interesting observation that
| |
| among several steroids having progestational activity, "antiluteinizing activity is
| |
| not concomitant with, or subordinated to"
| |
| the former function. Proportionately very
| |
| large amounts of ethinyl testosterone and
| |
| ethinyl-A-'^-androstenediol exhibited very
| |
| little antiluteinizing activity. There is evi
| |
| | |
| | |
| 518
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| denceinmice (Solve,, 1939) that siippreijsion
| |
| of FSH secretion may occur when as much
| |
| as 1 mg. of progesterone is injected daily.
| |
| Alloiteau ( 1954 ) believes that this also occurs in the rat, although Cutuly (1941b)
| |
| found only slight evidence of FSH suppression when as much as 6 mg. progesterone
| |
| were given daily for several weeks.
| |
| | |
| So much emphasis has been placed on the
| |
| suppressing effect of progesterone that its
| |
| facilitating actions were recognized only in
| |
| recent years. The first indication that progesterone can promote ovulation and corpus
| |
| luteum formation in mammals was encountered in a study of persistent-estrous rats
| |
| (Everett, 1940a, b). Daily injection of 0.25
| |
| to 1.0 mg. caused the prompt interrujition
| |
| of the state of persistent follicle and the resumption of outwardly normal cycles. Corjiora lutea were formed in approximately
| |
| 70 per cent of these cycles.^ The effect was
| |
| obtained not only in older rats in which
| |
| persistent estrus had developed spontaneously, but also in young rats in which the
| |
| condition had been induced by continuous
| |
| illumination. The dose level employed is below that required to suppress cycles in normal rats (1.5 mg. daily; Phillips, 1937).
| |
| Subsequently, it was found (Everett, 1943)
| |
| that the daily injection could be avoided if
| |
| a single "interrupting" dose was given, followed by a single injection during proestrum
| |
| or early estrus of each recurrent cycle (Fig.
| |
| 8.9.4). The histologic appearance of the
| |
| ovaries reverted toward the normal after a
| |
| succession of "i)rogesterone cycles" and, significantly, the interstitial-cell nuclei were
| |
| "repaired." Attempts in normal rats to invoke o\'u]ati()n earliei' than the expected
| |
| time were sticcessful in the 5-day cycle
| |
| (Figs. S.7B, 8.8^). Injection of from 0.5 mg.
| |
| to 2 mg. on the "third day of diestrum" regularly (4 mg. occasionally) invoked ovulation (luring the coming night (Everett,
| |
| 1944a, 1948) unless the treatment was given
| |
| too late in the dai/ (EA'erett and Sawyer,
| |
| 1949; see discussion on ]). 526 I'egarding the
| |
| diurnal rhythm and ovulation). Attempts
| |
| to advance ovulation in the 4-day cycle
| |
| were unsuccessful, possibly because the follicles were not competent or the animals'
| |
| | |
| ''Marvin (1947) described a similar rosull willi
| |
| desoxycorticosterone acetate.
| |
| | |
| | |
| | |
| intrinsic estrogen levels were not elevated
| |
| sufficiently early.
| |
| | |
| Ovulation induced by progesterone has
| |
| been reported in several species. A direct
| |
| action on the excised ovary of the toad
| |
| Xeno-pns was early demonstrated by Zwarenstein (1937) but such action is apparently
| |
| not found in higher vertebrates. In the domestic hen injection of progesterone can
| |
| invoke ovulation several hours ahead of
| |
| schedule (Fraps and Dury, 1943; Rothchild
| |
| and Fraps, 1949). Pfeiffer (1950) observed
| |
| new corpora lutea in 10 rhesus monkeys
| |
| treated with progesterone during presumptive anovulatory cycles of the summer
| |
| months. Similar attempts have been made in
| |
| women (Rothchild and Koh, 1951); although there were said to be definite indications of induced ovulation, the evidence
| |
| is equivocal. On the other hand, a rei~)ort
| |
| (Hansel and Trimberger, 1952) states that
| |
| in heifers the injection of small doses of progesterone (5 to 10 mg. ) at the beginning of
| |
| estrus significantly advances ovulation time.
| |
| This is in contrast with the inhibitory effect
| |
| of larger doses (50 mg.) beginning before
| |
| the onset of estrus (Ulberg, Christian and
| |
| Casida, 1951). Even in the rabbit (Sawyer,
| |
| Everett and Markee, 1950), spontaneous
| |
| ovulation was noted in 4 of 10 animals after
| |
| combined estrogen and progesterone injection.
| |
| | |
| From certain of the foregoing statements
| |
| it may be inferred that whether suppression
| |
| or stimulation follows administration of
| |
| ju-ogestcrone depends critically on the time
| |
| of injection, on the amount given, on the
| |
| status of the ovary, and probal)ly on a
| |
| l)riming action of estrogen. A significant illustration of the critical nature of the time
| |
| factor in rats is given by the experiments
| |
| represented in Figure 8.8r and E. If after
| |
| the first injection of 1.5 mg. progesterone
| |
| on the first day of diesti'uni, a second injection follows in. about 24 lioui's. the imjiending estrus and o\-ulation are retarded an
| |
| additional 24 hours. However, if the second
| |
| injection is given 48 hours after the first,
| |
| the impending estrus and ovulation are advanced. Evidence^ of the synergistic action
| |
| of estrogen and progesterone in evoking
| |
| oA'ulation is given by the ex]ieriments represented in Figuiv 8.9/> and (\ Sawver (1952)
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 519
| |
| | |
| | |
| | |
| investigated the synergism in rabl^ts. Employing estrogen-primed animals, he found
| |
| that ovulation was facilitated when progesterone was injected less than 4 hours
| |
| before either mating, mechanical stimulation of the vagina, or intravenous injection of copper acetate. Inhibition was obtained when progesterone was injected 24
| |
| hours before such stimulation, thus confirming the often-cited observations of ]Makepeace, Weinstein and Friedman (1937 » and
| |
| Friedman (1941) that progesterone inhiijits
| |
| ovulation in rabbits.
| |
| | |
| Preovulatory secretion of gestagens now
| |
| seems likely. Morphologic luteal changes in
| |
| preovulatory follicles are considered in the
| |
| chapter on the ovary. A variety of evidence
| |
| in primates indicates that progestational
| |
| clianges in the endometrium begin before
| |
| ovulation (Bartelmez, Corner and Hartman, 1951). Several workers have reported
| |
| tiie excretion of small amounts of pregnanediol during the follicular phase of the
| |
| human cycle (Wilson, Randall and Osterberg, 1939; Smith, Smith and Schiller, 1943;
| |
| Davis and Fugo, 1948). Determination of
| |
| plasma progesterone in women by the
| |
| Hooker-Forbes test indicates the presence
| |
| of significant amounts a day or two before
| |
| a major rise in basal body temperature
| |
| (Forbes, 1950). In monkeys a small quantity (ca. 0.5 to 1.0 ixg. per ml.) was detected
| |
| l)etween the 4th and 9th days, rising in the
| |
| 10- to 15-day period to concentrations of 2
| |
| to 6 jxg. per ml. (Forbes, Hooker and Pfeiffer, 1950; Bryans, 1951). In both species a
| |
| transient decline seems to intervene before
| |
| the marked rise to still higher concentrations during the luteal phase. In the rat,
| |
| Constantinides (1947) studied the stromal
| |
| nuclei of the endometrium at different
| |
| stages of the cycle and found that by the
| |
| Hooker-Forbes criteria there is evidence of
| |
| progesterone secretion during proestrum.
| |
| Astwood (1939) on the basis of water content of rat uteri concluded that progesterone
| |
| secretion begins with proestrum. In the rabl)it, Forbes (1953) assayed peripheral blood
| |
| at various intervals after mating or gonadotrophin injection. Although no progesterone
| |
| was detectable in controls, significant
| |
| amounts appeared an average of 97 minutes
| |
| after mating and 66 minutes after gonado
| |
| | |
| | |
| trophin injection. As much as 2.5 /xg. ])er ml.
| |
| was found during the first 8 to 10 hours,
| |
| although marked fluctuations were noted
| |
| from time to time in the blood of individual
| |
| animals. Verly (1951) reported that soon
| |
| after mating the urine of rabbits contains
| |
| significant amounts of pregnanediol.
| |
| | |
| It has become customary to state that
| |
| the gestagen that appears during the follicular phase of the cycle is probably formed by
| |
| the maturing follicle itself. Indeed, assays
| |
| of fluid from Graafian follicles and cysts
| |
| have indicated the presence of the hormone
| |
| (Duyvene de Wit, 1942; Hooker and
| |
| Forbes, 1947; Edgar, 1952, 1953). However,
| |
| if it is to take part in the release of ovulating hormone gestagen must be secreted earlier than preovulatory maturation. For this
| |
| also there is some evidence. Two reports
| |
| cited above indicate that in monkeys, at
| |
| least, there is a detectable amount present
| |
| in the blood during the early follicular
| |
| phase. The known fact that a waning corpus luteum favors the experimental induction of estrus and/or ovulation in sheep and
| |
| cattle (Hammond, Jr., 1945; Robinson,
| |
| 1951 ; Alarden, 1952) is suggestive. Although
| |
| Hammond, Jr., Hammond and Parkes
| |
| (1942) tested this possibility by progesterone sul)stitution with negative results, the
| |
| amount given may have been too small, as
| |
| Robinson suggested. A waning corpus luteum in the rat favors ovulation, as disclosed in persistent-estrous animals in which
| |
| pseudopregnancy had been induced (Everett, 1939). Each of three pseudopregnancies
| |
| was followed b}' a short cycle before the
| |
| animals returned to persistent estrus.
| |
| | |
| In the course of studies growing out of
| |
| this observation evidence was advanced
| |
| (Everett, 1945) which indicated that corpora lutea of the normal rat are not wholly
| |
| inactive during the short cycle. Transient
| |
| depletion of cholesterol was observed in
| |
| such corpora lutea during the proestrum
| |
| that followed their formation. This implies
| |
| a transient increase of luteotrophin secretion. Significantly this occurs before the release of LH. It is this writer's opinion that
| |
| gestagen from such sources is not essential
| |
| for the induction of ovulation but that it
| |
| does facilitate the action of estrogen.
| |
| | |
| | |
| | |
| 520
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| C. ROLE OF THE NERVOUS SYSTEM
| |
| IN OVULATION
| |
| | |
| Historically, the fact of neural control of
| |
| reflex ovulation has been recognized in the
| |
| ral)bit for many years. The comparable role
| |
| of the nervous system in spontaneous ovulation, on the other hand, has more recently
| |
| become apparent. It now seems justifiable
| |
| and useful to postulate in the hypothalamus
| |
| of reflex ovulators and spontaneous ovulators alike the existence of a mechanism
| |
| that is peculiarly concerned with release
| |
| of ovulating hormone. Whether it consists
| |
| in a discrete anatomic entity is immaterial
| |
| for the present.
| |
| | |
| The suggestion has been made that the
| |
| outstanding difference between reflex and
| |
| sjiontaneous ovulation may be in the kinds
| |
| of afferent impulses that most readily excite the hypothalamus (Sawyer, Everett
| |
| and Markee, 1949). The difference is not
| |
| absolute, for spontaneous ovulation has been
| |
| induced in rabbits by estrogen-progesterone
| |
| injection (see p. 519) and reflex ovulation
| |
| has been demonstrated under special circumstances in rats (Dempsey and Searles,
| |
| 1943; Everett, 1952a) and cattle (Marion,
| |
| Smith, Wiley and Barrett, 1950). The random distribution of reflex ovulators and
| |
| spontaneous ovulators among mammalian
| |
| orders becomes more understandable if one
| |
| assumes that dual controls are widely represented and that special adaptations favor
| |
| one or the other in given species.
| |
| | |
| The ovulation reflex in rabbits is apparently initiated by afferent impulses of multiple origin, among them not only impulses
| |
| from the genitalia, but also propriocejUive
| |
| impulses from muscles that are utilized in
| |
| coitus. Brooks (1937, 1938) found that,
| |
| although the sacral segments of the spinal
| |
| cord and the abdominal sympathetic chains
| |
| could be eliminated without jM'eventing ovulation, the luml)ai' cord must remain. Only
| |
| by paralysis of the lower half of the body
| |
| so that the female could not take pai't in
| |
| coitus was ovulation pi'cvcntfMl. The neocortex could be removed, together with the
| |
| olfactory bulbs, labyrinths, auditory apparatus and eyes without impairing the
| |
| ovulation response. Even after complete decortication, ovulation followecl coitus in 1
| |
| out of 3 j'abbits. It must l)e admitted, how
| |
| | |
| | |
| ever, that, although various parts of the
| |
| nervous system may thus be eliminated
| |
| without changing the end result, some of
| |
| them may normally play a considerable
| |
| role. With little cjuestion, direct stimuli from
| |
| the genitalia play a part in the natural
| |
| reflex. Under certain experimental conditions detectable electrical activity in the
| |
| rabbit rhinencephalon is associated with the
| |
| induction of ovulation (Sawyer, 1955).
| |
| Electrical stimulation of the amygdala will
| |
| induce ovulation in rabbits and cats (Koikegami, Yamada and Usei, 1954; Shealy
| |
| and Peele, 1957 ) .
| |
| | |
| In rats, Davis (1939) found that removal of the neocortex had no effect on the
| |
| estrous cycle and ovulation. Removal of
| |
| portions or of the entire sympathetic chains
| |
| of rats likewise did not interfere with ovulation (Bacq, 1932). Bunn and Everett
| |
| (1957) reported ovulation in constantestrous rats after electrical stimulation of
| |
| the amygdala.
| |
| | |
| The importance of the dorsal thalamus is
| |
| unknown. The reticular activating system
| |
| has been implicated as a component of the
| |
| ovulation mechanism (Sawyer, 1958), but
| |
| the manner of its contribution is not clear.
| |
| There is little cjuestion, on the other hand,
| |
| of the indispensability of the hypothalamus
| |
| and its neurovascular connection to the
| |
| adenoliyi:)ophysis through the median eminence and the hypophyseal portal veins.
| |
| | |
| Although the observation by ]\Iarshall
| |
| and Verney (1936) that ovulation can be
| |
| induced by passing an electric current
| |
| through the heads of estrous rabbits hardl}^
| |
| limited the effect to the hypothalamus itself, it was later shown that more localized
| |
| electrical stimuli api)lied to certain hypothalamic regions are consistently effective
| |
| (preoptic area, Haterius, 1937; Christian.
| |
| 1956; posterior hypothalamus or tuber
| |
| cinereum, Harris, 1937, 19481); tuber cinereum or adjacent hypothalamic areas,
| |
| Markee, Sawyer anirHollinshead. 1946;
| |
| medial hypothalamus fi'om ])i-eo])tic area
| |
| to mammillai'V bodies. Kui'otsiu Kurachi
| |
| and Ban, 195o"; Kuiotsu, Kurachi, Tabaya>hi and Ban, 1952).
| |
| | |
| Ahliougli liypotliahimic lesions. l)oth
| |
| natural and expeiimental. hax'c frecjuently
| |
| been reported to interfere with normal
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| sex function (.see Harris. 1948a, 1955, for
| |
| references), the majority of these reports
| |
| do not api^ly to the question at issue — control of ovulation. When ovarian atrophy
| |
| occurs, as it frequently did in these cases,
| |
| it reflects a profound depression of gonadotroi)hin secretion and absence of competent
| |
| follicles. However, Dey, Fisher, Berry and
| |
| Ranson (1940) and Dey (1941, 1943) 'found
| |
| in guinea pigs that gross bilateral electrolytic lesions placed in the rostral hypothalamus resulted in persistent follicles with
| |
| continuous estrogen secretion. Similar results were obtained in rats by Hillarp
| |
| (1949) when small bilateral electrolytic lesions were placed in the anterior hypothalamic area near the paraventricular nuclei
| |
| or between this region and the median eminence. Greer (1953) reported continuous
| |
| estrus in rats after placing certain small
| |
| lesions in the ventromedial nucleus, provided they were bilateral. There was no
| |
| correlation with obesity. There are at least
| |
| four significant points in common among
| |
| these several ablation experiments. ( 1 ) The
| |
| effective lesions were rost rally placed and
| |
| either were limited to or included the
| |
| medial group of nuclei. (2) The tuber
| |
| cinereum, median eminence, and stalk
| |
| connection to the hypophysis were intact.
| |
| (3) Although development of competent
| |
| follicles was not evidently impaired, estrogen secretion became continuous instead of
| |
| cyclic. (4) The proper impetus for release
| |
| of ovulating hormone from the hypophysis
| |
| was absent. It would be most instructive to
| |
| learn whether ovulation can be invoked
| |
| in such animals by reflex stimulation or by
| |
| direct electrical stimulation of the tuber.
| |
| AUoiteau and Courvoisier (1953) reported
| |
| that rats in constant estrus as a result of
| |
| hypothalamic lesions did not undergo
| |
| pseudopregnancy after stimulation of the
| |
| cervix uteri. This observation, confirmed
| |
| by Greer (1953), could be construed as indirect evidence of failure of reflex ovulation,
| |
| for Greer regularly obtained pseudopregnancy by cervical stimulation, once corpora
| |
| lutea had been formed by other means.
| |
| | |
| Other findings by Greer are important
| |
| because of their bearing on the location and
| |
| character of a presumptive ovulation center.
| |
| Althougli the onset of persistent estrus after
| |
| | |
| | |
| | |
| making the lesions was sometimes almost
| |
| immediate (following a brief anestrous interval), in other cases it was preceded by
| |
| several apparently normal cycles. In any
| |
| event, once the condition had become established, the daily injection of small amounts
| |
| of progesterone brought about the recurrence of cycles and corpus luteum formation. In about half of the cases these cycles
| |
| continued for awhile after withdrawal of
| |
| treatment, whereas in the remainder there
| |
| was a prompt return to persistent estrus.
| |
| Essentially the same results were reported
| |
| by AUoiteau (1954), and the observations
| |
| suggest that the areas involved in such lesions may be of only secondary importance.
| |
| | |
| The use of radioactive phosphorus for
| |
| estimating energy exchange in tissues affords a different approach to the problem
| |
| of neural control of ovulation (Borell, Westman and Orstrom, 1947, 1948). This method
| |
| has the virtue that the experimental subject
| |
| remains undamaged until injection of P'*compounds 30 minutes before the end of
| |
| the experiment. In rabbits there is a marked
| |
| increase in phosphorus turn-over in the
| |
| tuber cinereum within 2 minutes post
| |
| coitum, and continuing for about an hour
| |
| thereafter (Table 8.1). The adenohypoi)hysis shows increasing activity during the
| |
| first 10 minutes which reaches a peak at
| |
| about 1 hour and then regresses somewhat,
| |
| although it remains relatively high for 24
| |
| hours. Response of the ovary to gonadotroi:)hin release is marked by a rapid rise
| |
| during the second half-hour and another
| |
| pronounced increase near the time of ovulation. In rats, at various stages of the
| |
| estrous cycle, phosphorus exchange in both
| |
| tuber cinereum and adenohypophysis is
| |
| maximal during proestrum. In the ovary
| |
| high values were reported during diestrum
| |
| and proestrum, somewhat lower values during estrus and metestrum.
| |
| | |
| Possibly correlated with the above information is the observation (Gitsch,
| |
| 1952b) that in rats the acetylcholine (ACh)
| |
| content of the tuberal region becomes elevated during proestrum and estrus. It is
| |
| said that ACh synthesis requires high
| |
| energy phosphate (see Bain, 1952). Further
| |
| investigation by Gitsch (1952a) and Gitscl:
| |
| and Reitinger (1953) revealed that ACh
| |
| | |
| | |
| | |
| TABLE 8.1
| |
| Sequence of events in rabbit ovulation
| |
| | |
| | |
| | |
| Time Post Coitum Central Nervous System
| |
| | |
| | |
| | |
| Hypophysis
| |
| | |
| | |
| | |
| Ovary
| |
| | |
| | |
| | |
| Circulating Blood
| |
| | |
| | |
| | |
| <30 sec.
| |
| | |
| <2 mill.
| |
| | |
| 10 mill.
| |
| 30 mill.
| |
| | |
| 60 mill.
| |
| | |
| 75-90 mill.
| |
| | |
| 13^-2 hrs.
| |
| 3-5 hrs.
| |
| | |
| 6-7 hrs.
| |
| | |
| 7-8 hrs.
| |
| 9-11 hrs.
| |
| | |
| | |
| | |
| Barbiturate-sensitive and atropinesensitive mechanisms^
| |
| | |
| t Phosphorylation
| |
| in tuber cinereum^
| |
| | |
| t Phosphorylation
| |
| | |
| in tuber ciner
| |
| reumt Phosphoryhition
| |
| | |
| in tuber cine
| |
| reum^
| |
| | |
| | |
| | |
| t Phosphorylation
| |
| in tuber cinereum
| |
| | |
| | |
| t Phosphoryhition^
| |
| | |
| | |
| | |
| Release of LH ca.
| |
| 20 per cent. 6 Hypophysectomy
| |
| prevents ovulation^' 12
| |
| | |
| Release of LH nowsufficient for ovulation."' 12 Phosphorylation at
| |
| peak^
| |
| | |
| | |
| | |
| I Phosphor\iatioii
| |
| | |
| | |
| | |
| i Animal may be bled
| |
| and transfused
| |
| without prevent
| |
| ! ing ovulationi2
| |
| | |
| | |
| | |
| folliculi.
| |
| in egg
| |
| | |
| | |
| | |
| f Liquor
| |
| Tetrad.'
| |
| nuclei*
| |
| | |
| Cholesterol depletion in interstitial
| |
| gland. ^ Egg nucleus migrates,
| |
| membrane dissolves.** • " Prominent corona*
| |
| | |
| Liquor folliculi increasingly viscous*
| |
| | |
| First polar hotly'*
| |
| | |
| Marked .swelling of
| |
| follicles. Thecal
| |
| hypertrophy,! ■ i°
| |
| hyperemia
| |
| | |
| OvuL.^Tion."
| |
| t Phosphorylation2
| |
| | |
| | |
| | |
| Bleeding and transfusion now prevent
| |
| ovulationi2
| |
| | |
| Progesterone detectable ^
| |
| | |
| | |
| | |
| Increased estrogen
| |
| (endometrial hj-peremia)'
| |
| | |
| | |
| | |
| ' Asdell, 1946.
| |
| | |
| 2 Borell, Westman and Orstrom, 1947.
| |
| | |
| 3 Claesson and Hillarp, 1947a.
| |
| " Fee and Parkes, 1929.
| |
| | |
| '^ Forbes, 1953.
| |
| | |
| « Hill, 1934.
| |
| | |
| ^ Sawyer, Markee and Hollinshcad, 1947.
| |
| | |
| * Pincus and Enzmann, 1935.
| |
| | |
| ^ Sawyer and associates, 1947, 1949, 1950.
| |
| | |
| 1" Walton and Hammond, 192S.
| |
| | |
| " Waterman, 1943.
| |
| | |
| '2 Weslmaii and .lacohsohn, 1936.
| |
| | |
| | |
| | |
| 522
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 523
| |
| | |
| | |
| | |
| in the rat hypothalamus is increased also
| |
| by administration of estrogen or by castration, conditions that similarly increase
| |
| lihosphorus exchange (Borell and Westman,
| |
| 1949). The ACh content is depressed during
| |
| pregnancy or when the rat has been injected with progesterone. It is also lowered
| |
| by Pentothal anesthesia, a matter of interest
| |
| in relation to the fact that the barbiturates
| |
| suppress ovulation (see p. 526).
| |
| | |
| The location and measurement of activity
| |
| in discrete nuclei and pathways are largely
| |
| in the future, although a beginning has been
| |
| made in the rabbit, cat, rat, and mouse.
| |
| Sawyer (1955) found in rabbits, after the
| |
| combined administration of pentobarbital
| |
| intravenously and histamine by way of the
| |
| 3rd ventricle, that there was associated
| |
| with induction of ovulation a characteristic
| |
| change in intrinsic electrical activity of the
| |
| rhinencephalon, extending into the preoptic
| |
| area. If the olfactory tracts were cut, however, this activity could not be elicited and
| |
| ovulation failed. According to Porter, Cavanaugh and Sawyer (1954), vaginal stimulation of estrous cats caused altered electrical activity in two hypothalamic regions:
| |
| | |
| (1 ) in the lateral hypothalamic area at
| |
| the anterior tuberal level during stimulation
| |
| and for 15 to 45 seconds afterward; and
| |
| | |
| (2) in the anterior hypothalamic area near
| |
| the medial forebrain bundle, where response
| |
| was delayed as much as 5 n:iinutes after
| |
| stimulation. According to a i)reliminary
| |
| account (Critchlow and Sawyer, 1955) in
| |
| curarized, proestrous rats, there were i)eriods lasting approximately 20 minutes in
| |
| the midafternoon, during which altered
| |
| electrical activity appeared differentially in
| |
| the preoptic area or anterior hypothalamus.
| |
| | |
| Another approach to localization has been
| |
| described by Hertl (1952, 1955). On the
| |
| pro])Osition that increased function of particular cells is reflected by increased volume
| |
| of their nuclei, cell nuclear volumes were
| |
| measured in hypothalamic nuclei of female
| |
| mice at different stages of the estrous cycle.
| |
| During proestrum and estrus there was
| |
| said to be a functional edema in hypothalamic nucleus 20 of Griinthal (possibly the
| |
| pars posterior of the ventromedial nucleus
| |
| of Krieg) and to lesser extent in nucleus 16
| |
| (Nucl. arcuatus).
| |
| | |
| | |
| | |
| 1. The Ilypophi/seal Portal Veins and the
| |
| Chemotransmitter Hypothesis
| |
| | |
| As noted elsewhere, hypothalamic control
| |
| of the jiars distalis is probably mediated by
| |
| the hypophyseal portal circulation. Evidence for this has been especially convincing with respect to control of ovulation,
| |
| although indications are that other phases
| |
| of the cycle are also regulated by this
| |
| means. Pertinent data from numerous transplantation and stalk-section experiments
| |
| may be summarized by the following statement. Aside from a questionable grafting
| |
| experiment (2 rats) reported by May
| |
| (1937), in no case has ovulation or luteinization been reported in the absence of vascular linkage of the pars distalis with the
| |
| median eminence; on the other hand, ovulatory cycles have often been cjuickly restored when the gland has been revascularized by the portal vessels (see especially,
| |
| Harris, 1950a; Harris and Jacobsohn, 1952;
| |
| Nikitovitch-Winer and Everett, 1957,
| |
| 1958b).
| |
| | |
| Although the importance of local vasomotor regulation in the stalk vessels remains
| |
| to be evaluated (Green, 1951), there is extensive support for the hypothesis that ovulatory release of gonadotrophin is invoked
| |
| by a chemotransmitter (Harris, 1948a,
| |
| 1955). If one accei)ts the prevailing opinion
| |
| that nerve fibers entering the pars distalis
| |
| are too few to account for its secretomotor
| |
| control and that the flow of blood in the
| |
| hyi^ophyseal portal vessels is toward the
| |
| gland (Wislocki and King, 1936; Green,
| |
| 1947; Green and Harris, 1947, 1949; Barrnett and Greep, 1951 ; Landsmeer, 1951 ;
| |
| ]McConnell, 1953; Xuereb, Prichard and
| |
| Daniel, 1954; Worthington, 1955), the
| |
| plausibility of the chemotransmitter hypothesis becomes inescapable.^
| |
| | |
| Evidence that the transmitter may l)e
| |
| | |
| ^ For a dissenting view, see Zuckerman (1952).
| |
| Reference should also be made to the hypothesis
| |
| formulated by Spatz (1951) and associates (see
| |
| Nowakowski, 1950, 1952). They postulated that
| |
| a descending pathway in the spinal cord is the
| |
| connecting link between hypothalamus and ovaries. With respect to ovulation, this is clearly
| |
| denied by the fact that local stimulation of the
| |
| hypotlialamus provokes ovulation in rabbits in
| |
| which the thoracic spinal cord has been transsected (Christian, Markee and Markee, 1955).
| |
| | |
| | |
| | |
| 524
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| adrenergic was presented by Markee, Sawyer and Hollinshead (1948), who provoked
| |
| ovulation in rabbits by instilling epinephrine directly into the pars distalis. Detailed
| |
| experiments supporting this w^ere fully reviewed by Markee, Everett and Sawyer
| |
| (1952). In discussion following that paper,
| |
| Sawyer reported the induction of ovulation
| |
| in rabbits by the injection into the third
| |
| ventricle of either epinephrine or norepinephrine, and suggested that the latter is
| |
| "more closely related to the natural mediator than is epinephrine." Donovan and
| |
| Harris (1956), from studies in which the
| |
| rabbit hypophysis was slowdy infused in
| |
| situ with solutions of epinephrine or norepinephrine, concluded that neither substance
| |
| is the agent in question, and that the positive results of Markee, Sawyer and Hollinshead (1948) were the effects of low pH and
| |
| not of the drugs per se. Proof of the negative
| |
| is elusive, however, and one must note that
| |
| Donovan and Harris did not meet the conditions of timing and drug concentration
| |
| that obtained in the earlier work.
| |
| | |
| Intravenous injection of Dibenamine or
| |
| its congener, SKF-501,-^ will usually prevent
| |
| ovulation in rabl)its when injection is completed within 1 minute after coitus (Sawyer
| |
| and associates, 1947-50). On the other
| |
| hand, when injection is delayed until 3 minutes or later, ovulation is unaffected. The
| |
| nonadrenergic hydrolysis product of Dibenamine, 2-dibenzylaminoethanol, does not
| |
| have the blocking action, although its central excitatory powers are much like those
| |
| of the parent substance. The failure of
| |
| blockade by Dibenamine, if injection is
| |
| withheld for 3 minutes, demonstrates that
| |
| the drug does not interfere with the actual
| |
| discharge of ovulating hormone into the
| |
| l)lood stream, for that process recjuires
| |
| about an hour (Fee and Parkes, 1929; Westman and Jacobsohn, 1936). The Dibenamine-sensitive mechanism thus serves as a
| |
| trigger, the gland being adequately stimulated within 1 01' 2 minutes post coitum.
| |
| This estin^ate is in remarkal)le agreement
| |
| with the earlier mentioned obscMA'ations on
| |
| | |
| •'■' Dibenamine is iV,iV-dibenzyl-/:i-cliloioetliy lamine. SKF-501 is A'-(9-fluorenyl)-.V-ethyl-/i-chlor()ethylamine hydrochlorifle. Banthine is /i-dictliylaminuc'tliyl-.\anthene-9-cai'l)Oxvlak' niclliohroiniilc
| |
| | |
| | |
| | |
| l)hosphorus exchange in the tuber cinereum
| |
| and hypoi)hysis (p. 521, and Table 8.1 1.
| |
| | |
| A mechanism that is subject to blockade by atropine or Banthine^ evidently precedes the Dibenamine-sensitive process
| |
| — temjDorally if not anatomically. To accomplish blockade in rabbits, these anticholinergic drugs must be injected intravenously within about 30 seconds after
| |
| coitus (Sawyer and associates, 1949-1951).
| |
| It should be recalled that Foster, Haney
| |
| and Hisaw (1934) reported failure of ovulation in several rabbits treated with small
| |
| amounts of atropine before mating. ]\Iakepeace (1938), however, was unable to confirm the effect with somewhat larger doses
| |
| and the former observation was forgotten.
| |
| | |
| A seemingly crucial experiment devised
| |
| by Sawyer gives conclusive evidence that
| |
| the atropine-sensitive process is antecedent
| |
| to the Dibenamine-sensitive one. It was
| |
| based on two facts: (1) intravenous injection of nearly lethal doses of epinephrine
| |
| does not induce ovulation in estrous rabbits,
| |
| and (2) atropine protects rabbits against
| |
| fatal pulmonary edema after injection of
| |
| large amounts of epinephrine. In rabbits
| |
| protected by atropine in dosage that was
| |
| also sufficient to block the ovulation reflex,
| |
| the injection of twice-lethal doses of epinephrine caused ovulation or significant degrees of follicle maturation in 5 of 7 cases.
| |
| These effects were not found in rabbits protected by Dibenamine. Supporting evidence
| |
| was adduced by Christian (1956i who
| |
| found that atropine would not prevent
| |
| ovulation in response to electi'ical stimulation of the medial preoptic area or adjacent
| |
| parts of the hypothalanuis, whereas in a significant number of such rabliits ovulation
| |
| was blocked by SKF-501.
| |
| | |
| Extension of the blocking experiments to
| |
| the rat, as an example of a spontaneous ovulator, disclosed that in this species also ovulation can be blocked by Dibenamine, SKF501, atropine, and Banthine, when the injections ai'c appropriately timed with respect to the stage- of the cycle and time of
| |
| day (Sawyer, Everett and Markee, 1949;
| |
| Everett, Sawyer and Markee, 1949; Everett
| |
| and Sawyer, 1949, 1950, 1953: see \). 526).
| |
| Furthermore, blockade of ])oth estrogenimhiccd and pi'ogcstci-oiic-induced ovuhition
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 525
| |
| | |
| | |
| | |
| was aceomi)lished with cither Dibonamine
| |
| or atropine. Neither agent, however, prevented ovulation after injection of sheep
| |
| liypophyseal LH. A report by Hansel and
| |
| Trimberger (1951) stated that in cattle a
| |
| significant delay of ovulation (as great as
| |
| 72 hours) followed atropine administration.
| |
| In control experiments the simultaneous
| |
| injection of atropine and human chorionic
| |
| gonadotrophin was followed by ovulation
| |
| slightly earlier than the normally expected
| |
| time. Treatments were begun 1 to 5 hours
| |
| after the onset of estrus. This work was confirmed and extended by Hough, Beardon
| |
| and Hansel (1955). In the hen, blockade of
| |
| ovulation, normal or induced by progesterone, has been reported after administration of Dibenamine, Dibenzyline, SKF-501
| |
| or atropine (Zarrow and Bastian, 1953;
| |
| van Tienhoven, 1955). According to van
| |
| Tienhoven, the drugs did not interfere with
| |
| the ovulating action of extrinsic gonadotrophin.
| |
| | |
| It is important that the same drugs will
| |
| block ovulation in lioth rabbits and rats
| |
| (Table 8.2) . Of ec^ual significance is the fact
| |
| that several agents that are ineffective in
| |
| rabbits are also ineffective in rats (notably
| |
| 2-dibenzylaminoethanol, the imidazoline
| |
| adrenolytic drugs, and the ganglion blocking
| |
| agents). These considerations are interjireted to mean that spontaneous ovulation
| |
| is invoked by neurohumoral mechanisms
| |
| that are very like those in the reflex ovulation of rabbits.
| |
| | |
| The suggestion that the l)locking effects
| |
| might result from nonspecific stress, causing
| |
| the hypophysis to be so actively secreting
| |
| ACTH that gonadotroiihin secretion is interfered with (Dordoni and Timiras, 1952),
| |
| is clearly denied by several facts. ( 1 ) In
| |
| the rabbit studies, none of the various
| |
| agents prevented ovulation when injected
| |
| more than a minute post coitum. (2) In one
| |
| study (Sawyer, Markee and Everett, 1950b)
| |
| ovulation was actually induced by the intravenous injection of "lethal" doses of epinephrine when the animals WTre protected
| |
| by atropine. (3) In rats ovulation is unaffected by massive intravenous doses of
| |
| either the imidazoline drugs or 2-dibenzylamionethanol in amounts known to be
| |
| stressing (Sawyer and Parkerson, 1953).
| |
| | |
| | |
| | |
| TABLE 8.2
| |
| Pharmacologic Agents and Blockade of Ovulation
| |
| | |
| | |
| | |
| Antiadrenergics
| |
| | |
| /3-Haloalkylamines
| |
| | |
| Dibenamine
| |
| | |
| SKF-501
| |
| | |
| Dibenzyline
| |
| | |
| ImidazoHnes
| |
| | |
| Priscoline
| |
| | |
| Regitine
| |
| | |
| Yohimbine
| |
| | |
| Anticholinergics
| |
| | |
| Atropine
| |
| | |
| Banthine
| |
| | |
| Antihistaminics
| |
| | |
| Neo-antergan
| |
| | |
| Ganglion blockers
| |
| | |
| Tetraethvlammonium. .
| |
| | |
| SC-1950/
| |
| | |
| Barbiturates
| |
| | |
| Nembutal
| |
| | |
| Dial
| |
| | |
| Ipral
| |
| | |
| Amvtal
| |
| | |
| Barbital
| |
| | |
| Phenobarl)ital
| |
| | |
| Prominal
| |
| | |
| Others
| |
| | |
| Morphine
| |
| | |
| Procaine, locally near
| |
| tuber
| |
| | |
| Procaine, systemically .
| |
| | |
| Chlorpromazine
| |
| | |
| Reserpine
| |
| | |
| Ether
| |
| | |
| 2,4-Dimtrophenol
| |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Rat
| |
| | |
| | |
| Cow
| |
| | |
| | |
| Bi
| |
| | |
| | |
| Bi
| |
| | |
| | |
| | |
| | |
| Bi
| |
| | |
| | |
| Bi
| |
| | |
| | |
| | |
| | |
| 01
| |
| | |
| | |
| 01
| |
| | |
| | |
| | |
| | |
| 0^
| |
| | |
| | |
| 01
| |
| | |
| ■?4. 5
| |
| | |
| | |
| | |
| | |
| Bi
| |
| | |
| | |
| BI
| |
| | |
| | |
| B6
| |
| | |
| | |
| Bi
| |
| | |
| | |
| Bi
| |
| | |
| | |
| | |
| | |
| 01
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 01
| |
| | |
| | |
| 01
| |
| | |
| | |
| | |
| | |
| 01
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Bi
| |
| | |
| | |
| Bi
| |
| Bi
| |
| Bi
| |
| Bi
| |
| B'
| |
| Bi 8
| |
| | |
| B9
| |
| | |
| BIO
| |
| | |
| | |
| | |
| | |
| Bii
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 01
| |
| | |
| | |
| B12
| |
| B13
| |
| B14
| |
| B16
| |
| | |
| | |
| | |
| | |
| | |
| B3
| |
| | |
| | |
| | |
| I Sawyer and associates, 1947-1951; Everett
| |
| and associates, 1949-1950; Christian, 1956; and see
| |
| present text.
| |
| | |
| ^ van Tienhoven, 1955; van Tienhoven, Nalbandov and Norton, 1954.
| |
| | |
| 3 Zarrow and Bastian, 1953.
| |
| | |
| •• Fugo and Gross, 1942.
| |
| | |
| 5 Sulman and Black, 1945.
| |
| | |
| ^Hansel and Triml)erger, 1951; Hough, Beardon and Hansel, 1955.
| |
| | |
| ' Fraps and Case, 1953.
| |
| | |
| * Doring and Goz, 1952.
| |
| | |
| » Westman, 1947.
| |
| | |
| 1" Barraclough and Sawyer, 1955.
| |
| | |
| II Westman and Jacol)8ohn, 1942.
| |
| 1- Barraclough, 1956.
| |
| | |
| 13 Barraclough, 1955.
| |
| | |
| " Unpublished. Temporary, during deep anesthesia.
| |
| | |
| 1^ Unpublished. EDso : 25 mg. per kg. subcutaneously.
| |
| | |
| Key: B = Blockade.
| |
| | |
| = No blockade.
| |
| | |
| 1 = Ovulation induced by the drug.
| |
| | |
| | |
| | |
| 526
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Nor is it influenced by severe trauma, heat,
| |
| cold, or formalin injection coincident with
| |
| the known "critical period" (Everett, unpublished).
| |
| | |
| 2. Central Depressants and Ovulation
| |
| | |
| Reported evidence of a blocking action
| |
| of barbiturates on ovulation traces back
| |
| to experiments by Westman (1947) who injected female rats with Prominal twice
| |
| daily for 3 weeks. Approximately 30 per
| |
| cent of these rats experienced prolonged
| |
| vaginal estrus and had ovaries containing
| |
| only follicles at the end of the experiment.
| |
| Almost identical results were reported by
| |
| Doring and Goz (1952) when rats were
| |
| treated daily with phenobarbital. The agreement is not unexpected in view of the fact
| |
| that in the body Prominal is quickly demethylated to phenobarbital. It was shown
| |
| by Everett and Sawyer (1950) that when
| |
| administration of barbiturates to rats is
| |
| critically timed with respect to stage of the
| |
| cycle and the time of day, blockade of ovulation can be accomplished at will in shortterm experiments (Fig. 8.10). Chronic
| |
| administration introduces considerable uncertainty for reasons that are not yet clear
| |
| (Everett, 1952b). In the rabbit, the rapid
| |
| intravenous injection of pentobarbital or
| |
| Pentothal, within as short a time as 12
| |
| seconds after coitus, generally failed to
| |
| block ovulation (Sawyer, Everett and
| |
| Markee, 1950) . However, it was later shown
| |
| that barbiturate anesthesia will prevent the
| |
| ovulation that is otherwise caused in the
| |
| estrogen-primed rabbit by mechanical
| |
| stimulation of the vagina, the anesthesia
| |
| t)eing induced in advance of the stimulation
| |
| (unjuiblished i.
| |
| | |
| Other central dcpi-es^ants reported to
| |
| block ovulation in the rat are morj^hine,
| |
| reserj^ine, chlorpromazine (Barraclough and
| |
| Sawyer, 1955; Barraclough, 1955, 1956),
| |
| and even meprobamate acting synergistically with an anticholinergic drug (Gitscli,
| |
| 1958). Special interest attaches to the
| |
| mori)hine work, in that anicnoi'i lica and
| |
| sterility often a('C()in|)any moiphinc addiction in the human female. Related studies
| |
| (Sawyer, Critchlow and Barraclough, 1955),
| |
| in which recordings were made of electi'ical
| |
| acti\ity in various regions in the bi-ain.
| |
| | |
| | |
| | |
| demonstrated in rats that morphine acts
| |
| nmch like the barbiturates in depressing
| |
| activity in the reticular activating system.
| |
| The effect was also shown by atropine, in
| |
| doses that would block ovulation. The inference is that all three agents block by
| |
| striking at the same central elements of
| |
| the LH-release apparatus.
| |
| | |
| An interesting peculiarity of domestic
| |
| hens with respect to barbiturates was encountered by Fraps and Case (1953), who
| |
| noted that pentobarbital induces ovulation
| |
| jirematurely, and that pentobarbital and
| |
| progesterone supplement each other in this
| |
| capacity. Although these developments may
| |
| represent pharmacologic curiosities limited
| |
| to the bird, the possibility should be seriously considered that similar effects may
| |
| occur in other animals. In fact, pentobarbital in rabbits facilitates the release of
| |
| hypophyseal gonadotrophin in response to
| |
| intraventricular injection of histamine,
| |
| seemingly by an effect in the rhinencephalon
| |
| (Sawyer^ 1955).
| |
| | |
| 3. The Central Xervous System as a Timing
| |
| Mechanism for Oi'ulation
| |
| | |
| In the rat and the hen and probably many
| |
| other species the pro-ovulatory excitation of
| |
| the hypophysis is dejiendent in large measure on time of day.
| |
| | |
| In the rat, the blocking agents have
| |
| served to delimit a critical period on the day
| |
| of proestrum, before which ovulation can be
| |
| blocked and after which it will occur in
| |
| sjiite of injection of the blocking agent.
| |
| Under controlled illumination for 14 hours
| |
| daily, this critical period extends from
| |
| about 2 P.M. to 4 P.M. Administration of
| |
| either atroi^ine or i^entobarbital at 2 p.m.
| |
| consistently blocks ovulation (Fig. 8.10),
| |
| whereas injections later in the period are
| |
| progressively less eff"ecti\-e ( l']\-erett and
| |
| Sawyer, 1950, 1953; Everett, 1956b). Such
| |
| l)redictability of the hour of pituitary activation is, in itself, evidence of a relationship
| |
| between this event and diunial physiologic
| |
| I'liythnis.
| |
| | |
| Furthei' e\-i(lence is seen in the seciuelae
| |
| of pentobarbital injection (Fig. 8.11). Repetition at 2 P.M. on successive days results in a follicular cycle and prolonged
| |
| vaginal estrus with eventual atresia of all
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| <- — 24hr.— >
| |
| | |
| | |
| | |
| 527
| |
| | |
| | |
| | |
| DAY NIGHT
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 8.10. Deinoni^lration of 24-lioiir penodu-ity in the luteinizing hormone-release apparatus of female rats (Vanderbilt strain, 4-day cycle, controlled lighting: 14 hours per day).
| |
| Schematic representations of the normal cycle (A) and of characteristic results of different
| |
| regimes of Nembutal treatment (B to F). Vaginal stages indicated by Roman numerals over
| |
| each time scale; symbols above these show the corresponding follicle and corpus luteum
| |
| stages. The device marked <S defines the "critical period," the time limits of pituitary activation as experimentally determined (Fig. 8.11). OV indicates normal ovulation iinic in .1 and
| |
| estimated ovulation time elsewhere. NBTL indicates intraperitoneal injection of Nembutal.
| |
| (From J. W. Everett and C. H. Saw.yer, Endocrinology, 47, 200, 1950.)
| |
| | |
| | |
| | |
| large follicles, providing that on the second
| |
| and third days the dose is increased or
| |
| supplemented by a second injection. Omission of any of these injections results in
| |
| | |
| | |
| | |
| ovulation during the ensuing night. Thus,
| |
| there is a clearly defined 24-hour rhythm
| |
| in the LH-release mechanism. The results
| |
| confirm a similar conclusion based on the
| |
| | |
| | |
| | |
| i28
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| 2:00
| |
| | |
| | |
| | |
| 2.30
| |
| | |
| | |
| | |
| 3:00
| |
| | |
| | |
| | |
| 3:30
| |
| | |
| | |
| | |
| 4:00
| |
| | |
| | |
| | |
| TIME
| |
| | |
| | |
| | |
| Fig. 8.11. The "critical period" in certain rats on the afternoon of proestrum (Vanderbilt
| |
| strain, 4-day cycle, controlled lighting: 14 hours per day). Complete blockade of ovulation
| |
| (solid bars) is regularly found if either atropine or Nembutal is administered at 2:00 p.m.
| |
| Failure of blockade is usual when injections are made at 4:00 p.m. or later. Injection of
| |
| atropine at different times during the critical period results in jarogressive decline of percentage blocked and often accomplishes only partial blockade (cross-hatching). (From J. W.
| |
| Everett, Ciba Foundation Colloquia Endocrinol., 4, 172, 1952.)
| |
| | |
| | |
| | |
| 24-hour advancement of ovulation l)y i)rogcsterone. Approximately 24 hours before
| |
| pituitary stimulation would occur spontaneously there is a period limited to a
| |
| few hours during which progesterone can
| |
| he effective (Everett and Sawyer, 1949).
| |
| Although these time relationships were first
| |
| recognized in a colony of inbred rats in
| |
| North Carolina, they have since been confirmed in commercial rats (Sprague-Dawley ) kept under controlled lighting for only
| |
| a few weeks in southern California (Barraclough and Sawyer, 1955; Barraclough,
| |
| 1955, 1956). In these studies morphine,
| |
| reserpine, and chlorj^romazine wcic consistently effective when injected during pioestrus at 2 p.m., and ineffective at 4 p..m.
| |
| | |
| Not only is the critical period pictlictablc
| |
| under controlled lighting, but it may be
| |
| readily changed by sliiftiiig the ligliting
| |
| schedule. For example, after an abrupt 3
| |
| | |
| | |
| liour advance of the time switch controlling
| |
| the lights, the animals slowly readjusted
| |
| over a 2- to 3-week period (Everett, 1952b ) ;
| |
| when the switch was later returned to the
| |
| original setting, they required again about
| |
| 2 weeks to readjust. After a full 12-hour
| |
| change of lighting schedule, full reversal of
| |
| diurnal rhythms of activity and estrous
| |
| behavior similarly requires about 2 weeks
| |
| (Hemmingsen and Krarup, 1937).
| |
| | |
| The duration of the process of ])ituitai'y
| |
| activation in rabbits and its time relationship to release of LH and the subsequent
| |
| o\-uhiti()ii ha\'e l)een well defined (Table
| |
| 8.1 I. In no other species is the available
| |
| iufoi'uiation so complete, but some advance
| |
| has been luadt' in the rat (also the hen; see
| |
| chapter l)y van Tienhoven).
| |
| | |
| Diu'ation of the activating stimulus in the
| |
| rat has been estimated from the frequency
| |
| of partial blockade of ovulation after atro
| |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 529
| |
| | |
| | |
| | |
| piiU' injections in the midst of the critical
| |
| period (Everett and Sawyer, 1953; Everett,
| |
| 1956b L Unlike the trigger-like stimulus in
| |
| rabbits, that in rats is prolonged to about a
| |
| half-hour. In different individuals the stimulus begins at different times, (Fig. 8.11 L
| |
| Release of LH is probably coextensive with
| |
| the stimulus. In parallel experiments carried
| |
| out at various times during the critical
| |
| period, groups of proestrous rats w^ere hypophysectomized and other similar groups
| |
| were injected with atropine. The two procedures gave essentially the same results,
| |
| as measured on the following morning by
| |
| the proportionate numbers of rats in which
| |
| ovulation w^as found blocked or partially
| |
| blocked (Everett, 1956b). The time interval
| |
| from stimulation of the hypophysis to ovulation is 10 to 12 hours in rats (Everett,
| |
| Sawyer and INIarkee, 19491. thus ai)out
| |
| the same as in rabbits.
| |
| | |
| D. PERSISTENT FOLLICLE
| |
| | |
| The state of persistent follicle may be
| |
| considered as one in which for some reason
| |
| there is a physiologic blockade of the hypothalamic ovulating stimulus. In the rabbit
| |
| one may attribute failure of ovulation to
| |
| absence of reflex stimulation, on the one
| |
| hand, and a relatively high threshold of the
| |
| hypothalamo-pituitary apparatus for estrogen and progesterone, on the other. In the
| |
| rat certain conditions {e.g., continuous illumination) elevate the threshold of the
| |
| hypothalamo-pituitary system, with the
| |
| result that persistent estrus and jicrsistent
| |
| follicle occur (Hemmingsen and Krarup,
| |
| 1937; Browman, 1937; Everett, 1940a;
| |
| Dempsey and Searles, 1943). Additional
| |
| stimulation, furnished by either progesterone or coitus, is necessary to overcome this
| |
| blockade.
| |
| | |
| An age factor is operative in the spontaneous onset of persistent follicle in old
| |
| female rats. This condition is well recognized as an occasional occurrence (Evans
| |
| and Long, 1921 ; Doling, Blandau, Rundlett
| |
| and Young, 1941 ; Marvin and Meyer, 1941 ;
| |
| Hartman, 1944). In the DA strain (Everett,
| |
| 1939-1944) the age of onset was unusually
| |
| early in segregated females under normal
| |
| lighting conditions, i.e., about 150 days of
| |
| age which was more than 200 davs earlier
| |
| | |
| | |
| | |
| than in a normal strain. In Fi hyljrids the
| |
| age of onset was intermediate. This factor,
| |
| ill defined though it is, is also expressed in
| |
| sensitivity to continuous illumination. Postpubertal rats of the normal strain in continuous light continued to experience regular
| |
| cycles for as long as 40 days, whereas older
| |
| animals (200 to 250 days) began to show
| |
| persistent estrus within 10 days. Postpubertal DA rats, on the other hand, responded
| |
| as promptly as 250-day-old normal rats.
| |
| Hybrids again were intermediate. It was
| |
| also found in older DA rats that had spontaneously developed persistent estrus under
| |
| a lighting schedule of 14 hours per day, that
| |
| reduction of the light ration to 9 hours usually restored cyclic function. It seems, then,
| |
| that the age factor in cjuestion intensifies
| |
| the effect of a given amount of daily illumination.
| |
| | |
| Interference with ovarian cii'culation in
| |
| rats causes persistent follicle and failure
| |
| of luteinization. This effect has been reported after ligation of the pedicle (Fels,
| |
| 1952) , ligation of the oviduct with resultant
| |
| increase of pressure within the ovarian capsule (Haterius, 1936; Navori, Fugo and
| |
| Davis, 1952), hysterectomy with increased
| |
| pressure (Bradbury, Brown and Gray,
| |
| 1950), and transplantation of the ovary to
| |
| the tip of the tail (Hernandez, 1943; Bielschowsky and Hall, 1953). A possible explanation of this result is that the diminished
| |
| blood flow releases insufficient estrogen
| |
| to reach the threshold of the LH-release
| |
| mechanism. An alternative explanation may
| |
| l)e a change in the character of the secretory
| |
| product of the ovary. "Cystic" changes
| |
| of the ovaries are not uncommon after pelvic surgery in women.
| |
| | |
| The occurrence of persistent follicle in
| |
| rats following partial nephrectomy (Diaz,
| |
| 1940) has never been explained. It seemed
| |
| to be correlated with the development of
| |
| high blood pressure. Hence it may be allied
| |
| with the experiments just described.
| |
| | |
| Pfeiffer (1936, 1937) reported that when
| |
| testes are temporarily grafted into female
| |
| rats during early infancy and removed before puberty the host animals exhibit constant estrus after reaching maturity. The
| |
| same phenomenon has been observed after
| |
| postnatal treatment with testosterone or
| |
| | |
| | |
| | |
| 530
| |
| | |
| | |
| | |
| physioloc;y of gonads
| |
| | |
| | |
| | |
| chorionic gonadotroi)hin (Selye, 1940;
| |
| Bradbury, 1940, 1941), estrogen, progesterone, or desoxycorticosterone (Hale, 1944;
| |
| Takasugi, 1954). The adult ovaries develop
| |
| ])rominent follicles which never luteinize.
| |
| Pfeiffer reported that his constant-estrous
| |
| animals would not copulate. The conclusion
| |
| was reached that the hypophyses of these
| |
| rats had been masculinized by the early action of androgen. Subsequently (1941), he
| |
| attempted unsuccessfully to invoke ovulation in similar animals by daily injection of
| |
| small amounts of progesterone. Kempf
| |
| (1950) later accomplished this with 2 injections, more widely spaced (interval, 1
| |
| week ) . Takasugi was unable to produce
| |
| corpora lutea in postnatally estrogenized
| |
| rats by chronic progesterone treatment after
| |
| puberty, although vaginal cycles were observed. The further addition of androgen,
| |
| interestingly enough, brought about luteinization. It would seem that a prime effect of
| |
| the hormones during infancy is to produce
| |
| a permanently high threshold in the hypothalamic ovulating mechanism without destroying it.
| |
| | |
| VII. The Luteal Phase
| |
| | |
| The luteal phase presents more enigmas
| |
| than the phases that precede it. What initiates it? What keeps it going? What brings it
| |
| to an end? How is its duration determined?
| |
| | |
| Its beginning may arbitrarily be defined
| |
| as the moment of ovulation, yet gestagen secretion may start during the follicular
| |
| phase, and structural changes in the follicle
| |
| wall during pre-ovulatory maturation may
| |
| be considered as first steps in luteinization.
| |
| Fi'om the time of follicle rupture onward the
| |
| ac(iuisition of full secretory activity by the
| |
| cori)ora lutea roughly parallels their morphologic differentiation. It is even then a
| |
| gi'adual process.
| |
| | |
| Luteinization as a structural change does
| |
| not insure the attainment of secretory activity. The former is the ultimate effect of
| |
| the preovulatory discharge of hypojihyseal
| |
| luteinizing hormone; some other (lutcotrol)hic) factor must come into play to bring
| |
| about and maintain gestagen secretion. We
| |
| must, then, hv concerned with the special
| |
| character of luteotrophins, with nieclianisnis tliat favor their secretion by the hypo])hysis, with mechanisms that shortcMi or
| |
| | |
| | |
| | |
| lengthen the Hfc of the corpus luteum and,
| |
| therefore, witli the mechanisms that normally bring the corpus luteum phase to an
| |
| end. In the final analysis this last has an
| |
| im])oi-tance equal to the ovulation mechanism in the timing of recurrent cycles.
| |
| | |
| 1. Lutcotrophic Snbst(niccs
| |
| | |
| The term luteotropliin was proposed by
| |
| Astwood ( 1941 j to I'efer to a substance that
| |
| maintains function of corpora lutea, in distinction to substances that cause them to
| |
| form. It is now conceded that the substance
| |
| desci'ibed in that paper was probably the
| |
| lactogenic hormone. Evans, Simpson, Lyons
| |
| and Turpeincn (1941) demonstrated that
| |
| purified lactogen is luteotrophic in hypophysectomized rats. This has been confirmed by
| |
| several later investigations (Tobin, 1942;
| |
| Nelson and Pichette, 1943; Everett, 1944b;
| |
| Desclin, 1948; Gaarenstroom and de Jongh,
| |
| 1946 ) . Although lactogen seems to be the
| |
| hypophyseal luteotrophin in rats, such is not
| |
| necessarily true for all species (Bradbury,
| |
| Brown and Gray, 1950). Nevertheless, the
| |
| expression luteotrophin in the generic sense
| |
| continues to be desirable.
| |
| | |
| In the rabbit, lactogen is said to have little, if any, luteotrophic effect (Klein and
| |
| Mayer, 1943; Mayer, 1951). Yet rabbits
| |
| have never been tested with rabbit lactogen.
| |
| Several workers have failed to demonstrate
| |
| a luteotrophic function of lactogen preparations in monkeys (Hisaw, 1944; Bryans,
| |
| 1951) and women (Holmstrom and Jones,
| |
| 1949; Bradbury, Brown and Gray, 1950).
| |
| Positi^•e evidence of such activity in primates furnished by Fried and Rakoff ( 1952)
| |
| and more recently by Lyon (1956) lias not
| |
| gained wide acceptance. The former authors
| |
| re])orted that amounts of chorionic gonadoti'ophin which were tluMUseh-es inadequate,
| |
| wlicii siipplciiicnrcd by lacrogcii ( Luteoti-()pliiii, S(|uil)l>l prolonged the functional
| |
| life of the coi'pus luteuni in nonpregnant
| |
| women. Lyon rejjorted such prolongation
| |
| using lactogen alone. The Squibl) lactogen
| |
| was also used by Moore and Nalbandov
| |
| (1955) in prolonging the luteal phase of the
| |
| cycle in the ewe. As in the human experiments, howe\-er. one would like to know
| |
| whether lactogen is capable of initial stimul.'iiioii of secretory activity of corpora lutea
| |
| and of maintaining their function in the ab
| |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 531
| |
| | |
| | |
| | |
| sence of the hypophysis. There is no evidence for or against the lactogenic liormone
| |
| in this capacity, except in rats.
| |
| | |
| Estrogens have direct hiteotrophic action
| |
| in the rabbit (Robson, 1937, 1938, 1947).
| |
| The effect does not depend on the hypophysis and has been produced by impLantation
| |
| of estrogen crystals within corpora liitea
| |
| (Hammond, Jr., and Robson, 1951; Hammond, Jr., 1952). Westman (1934) had earlier shown that operative reduction of
| |
| ovarian stroma in pseudopregnant rabbits
| |
| results in corpus luteum regression and that
| |
| this can be prevented by administration of
| |
| estrogen. Corpora lutea induced by gonadotrophin injection or by mating, as the case
| |
| may be, require the presence of the hypophysis for their continued function ( Smith and
| |
| White, 1931; Westman and Jacobsohn,
| |
| 1936). Theoretically, then, in rabbits the
| |
| hypophysis liberates FSH and LH which act
| |
| on the interstitial tissue to cause estrogen
| |
| secretion. This in turn stimulates the corpora lutea to secrete progesterone.
| |
| | |
| The effect of estrogen on the corpora lutea
| |
| of rats is largely indirect and requires the
| |
| presence of the hypophysis. Massive dosage
| |
| with estrogen beginning soon after ovulation results in the enlargement of the corpora lutea and the production of sufficient
| |
| amounts of progesterone to mucify the vaginal mucosa (Selye, Collip and Thomson,
| |
| 1935; Wolfe, 1935; Desclin, 1935; Merckel
| |
| and Nelson, 1940). In fact, a single injection of 50 /Ag. estradiol bcnzoate on the day
| |
| after ovulation is sufficient to cause pseudopregnancy. These effects are now judged to
| |
| be the result of induced liberation of hypophyseal luteotrophin. vSimilar effects have
| |
| been reported after administration of androgens (McKeown and Zuckerman, 1937;
| |
| Wolfe and Hamilton, 1937; Freed, Greenhill
| |
| and Soskin, 1938; Laqueur and Fluhmann,
| |
| 1942).
| |
| | |
| Desclin (1949b) stated that in hypophysectomized rats the administration of estrogen augments the hiteotrophic action of
| |
| lactogen, producing functional corpora lutea in the presence of subthreshold doses of
| |
| the latter hormone. A physiologic synergism
| |
| of the two substances has thus been indicated. Mayer (1951) suggested that this
| |
| may explain the stimulation of corpora lutea
| |
| of lactation which follows estrogen treat
| |
| | |
| | |
| ment in this species. Greep and Chester
| |
| Jones (1950) postulated that estrogen favors corpus luteum function in the rat by
| |
| causing the luteal cells to produce cholesterol as a precursor of progesterone. Their
| |
| actual data, however, indicate that the increase of visible cholesterol after estrogen
| |
| treatment was confined to the interstitial
| |
| tissue.
| |
| | |
| Factors responsible for cholesterol storage
| |
| and mobilization in corpora lutea of the rat
| |
| were analyzed by Everett (1947). In hypophysectomized rats in which corpora lutea
| |
| were maintained by lactogen the injection
| |
| of pituitary LH induced the storage of
| |
| cholesterol, but this effect did not occur in
| |
| hypophysectomized rats in the absence of
| |
| lactogen. It could be induced during pregnancy or pseudopregnancy by estrogen if
| |
| the hypophysis remained in place. Addition
| |
| of an excess of lactogen prevented cholesterol storage. Lactogen thus tends to deplete
| |
| cholesterol content of rat luteal tissue as
| |
| ACTH tends to deplete adrenocortical cholesterol.
| |
| | |
| 2. ''XonfunctionaV' Corpora Lutea
| |
| | |
| In the short cycles of the rat, mouse,
| |
| hamster, and so on, the corpora lutea are
| |
| commonly said to be nonfunctional. The
| |
| meaning of this statement, of course, is that
| |
| they are incapable of supporting a decidual
| |
| reaction (Long and Evans, 1922), or of lireventing ovulation. They need not be totally
| |
| inactive, however, to fail to cause these
| |
| manifestations. Whereas daily injection of
| |
| 1.5 mg. or more of progesterone into intact
| |
| female rats will simulate pseudopregnancy
| |
| and indefinitely delay ovulation (Selye,
| |
| Browne and Collii^, 1936; Phillips, 1937),
| |
| smaller amounts of 1.0 rag. or less are compatible with the short cycle (Lahr and
| |
| Riddle, 1936; Phillips, 1937; Everett, 1940a,
| |
| b; and unpublished). In the absence of estrogen in castrated females, daily injection
| |
| of as little as 0.25 rag. progesterone will support deciduomata (Velardo and Hisaw,
| |
| 1951). Very small amounts of estrogen augment this action of progesterone (Rothchild,
| |
| Meyer and Spielman, 1940) but somewhat
| |
| larger amounts are inhibitory unless the
| |
| progesterone dose is proportionately increased (Velardo and Hisaw, 1951). In the
| |
| intact animal the progestational effects of
| |
| | |
| | |
| | |
| 53^
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| less than 1.0 mg. progesterone would be inhibited by the periodic rise in estrogen secretion.
| |
| | |
| Evidence that some rats, but not all, actually experience low-grade corpus luteum
| |
| activity during the short cycle was furnished
| |
| by Everett (1945). In the comparison of
| |
| ovaries from females of two strains of rats,
| |
| it was noted in the supposedly normal Vanderbilt strain that on the two days immediately following ovulation the corpora
| |
| lutea of the next youngest generation contained a great quantity of cholesterol, giving a strong Schultz reaction. By contrast,
| |
| comparable corpora lutea of the DA strain
| |
| were usually free of visible lipid in Sudan
| |
| preparations or the Schultz test. Administration of small amounts of lactogen (luteotrophin I during the cycle preceding the
| |
| current one, amounts inadequate to cause
| |
| l)seudopregnancy, resulted in the rich deposition of cholesterol in these otherwise lipidfree corpora lutea. The conclusion was
| |
| reached that the corpora lutea of the Vanderbilt rat must be slightly active during the
| |
| short cycle and those of the DA rat less so, if
| |
| at all. This would easily explain the relative
| |
| indifference of the Vanderbilt rat to continuous light and the ease with which persistent
| |
| cstrus could be induced in the DA rat by
| |
| such treatment (Everett, 1942a, b). In fact,
| |
| the low dosages of lactogen mentioned substituted for progesterone treatment in maintaining regular cycles in persistent-estrous
| |
| rats of the DA strain (Everett, 1944b). Significantly, the treatment was effective in
| |
| only those animals in which a set of corpora
| |
| lutea had been induced by other means at
| |
| the beginning of the experiment.
| |
| | |
| To be correlated with the above indications of low-grade function during the short
| |
| cycle, is the finding that corpora lutea of
| |
| the Vanderl)ilt rat retain full responsiveness
| |
| to luteotrophin throughout most of the diestrous interval (Nikitovitch-Winer and
| |
| Everett, 1958a). Responsiveness diminishes
| |
| near the onset of i:)roestrum. Once the rat
| |
| has entered proestrum these older corpora
| |
| lutea are not capable of sustained function.
| |
| The loss is not a function of time per se, but
| |
| of stage of the cycle.
| |
| | |
| .\. I'.^KTI)OPRE(;\.\XrY
| |
| | |
| The terms coi-pu,^ hitcuni of ()^•ulation and
| |
| corpus luteum of pscudojji'cgnancy are com
| |
| | |
| | |
| monly u.sed to differentiate the luteal bodies
| |
| occurring during the normal cycles from
| |
| those found during some unusually long
| |
| period of luteal activity. However, the
| |
| terms deny the fundamental similarity of
| |
| the luteal phase in the cycles of such animals as the guinea pig and the luteal phase
| |
| induced by sterile mating or its equivalent
| |
| in animals like the rat. In the unmated bitch
| |
| the spontaneous luteal phase of the cycle is
| |
| commonly called pseudopregnancy, yet it
| |
| is equally common to say that the guinea
| |
| pig does not experience pseudopregnancy.
| |
| The truth is that the luteal phase of the
| |
| canine cycle is simply longer than the luteal
| |
| phase in the guinea pig and may be marked
| |
| by a period of lactation near its close. In
| |
| the present discussion, the expression pseudopregnancy will be equivalent to saying
| |
| the luteal phase of the infertile cycle. Under
| |
| experimental conditions it will refer to any
| |
| period of sustained luteal function similar
| |
| to that of the normal progestational state.
| |
| Wherever appropriate, the distinction will
| |
| be made between a pseudopregnancy that is
| |
| spontaneous and one that is induced.
| |
| | |
| In most of the familiar animals that ovulate spontanously corpus luteum function
| |
| also begins spontaneously and continues for
| |
| at least several days after ovulation. With
| |
| respect to the rabbit, cat, and ferret, it is
| |
| often said that pseudopregnancy is invoked
| |
| by sterile copulation, whereas strictly speaking it is only ovulation and corpus luteum
| |
| formation which are invoked. The pseudopregnancy then follows automatically. This
| |
| interpretation seems appropriate, inasmuch
| |
| as in all three species the formation of
| |
| corpora lutea by l)rief treatment with hypophyseal or chorionic gonadotrophin is followed by long periods of progesterone secretion which can hardly be the direct effect
| |
| of the injected substances (Hill and Parkes,
| |
| 1930a, b; Foster and Hisaw, 1935; van
| |
| Dyke and Li, 1938). Quite different is the
| |
| pseudopregnancy of the rat, mouse, and
| |
| hauistei', in \\liich progestational activity is
| |
| invoked by stinudation of the cervix uteri,
| |
| l^verett (1952a) described the ex])eriiuental
| |
| dissociation in rats of the o^•^llati()n and
| |
| luteotr()])hic mechanisms. respectively.
| |
| When o\-uhition is blocked (by pentobarbital) in the cycle dui'ing which controlled
| |
| uiatinu occurs, pseudopi-egnancy begins
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 533
| |
| | |
| | |
| | |
| A
| |
| | |
| A.
| |
| | |
| | |
| A
| |
| | |
| | |
| A,
| |
| | |
| | |
| A
| |
| | |
| | |
| /
| |
| | |
| | |
| | |
| | |
| NB Np X
| |
| | |
| | |
| X
| |
| | |
| | |
| X
| |
| | |
| | |
| A
| |
| | |
| | |
| | |
| | |
| Q
| |
| | |
| / \
| |
| | |
| | |
| A
| |
| | |
| | |
| s A
| |
| | |
| | |
| A
| |
| | |
| | |
| s /
| |
| | |
| | |
| | |
| | |
| NB NB (X)
| |
| | |
| | |
| X
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| C
| |
| | |
| | |
| /^
| |
| | |
| | |
| A
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 8.12. Experimental dissociation in rats of the ovulation mechanism and that causing
| |
| pseudopregnancy. A. Control cycles for comparison with B and C . Points on base line
| |
| represent diestrum, on ascending lines proestrum, on highest level full vaginal estrum. X,
| |
| ovulation. B. Blockade with Nembutal {'NB) on day of proestrum and following day (see
| |
| Fig. 8.11E'). Ovulation during third night. C. Same basic procedure as B, but with copulation
| |
| during first night (M). Ovulation usually failing in this cycle (contrast with B) . Corpora
| |
| lutea formed after spontaneous ovulation in second cycle regularly become functional without further stimulation : the wavy line represents pseudopregnancy. The early copulation has
| |
| introduced some change in the animal such that this pseudopregnancy "spontaneously"
| |
| follows ovulation as in the standard mammalian cycle. (From J. W. Everett, Ciba Foundation Collofiuia Endocrinol.. 4, 172. 1952.)
| |
| | |
| | |
| | |
| "spontaneously" a]ter the next cyclic estrus
| |
| (Fig. 8.12). Dissociation of the two mechanisms is expressed in another way by certain Mustelidae, e.g., the mink and marten.
| |
| Ovulation in these forms is invoked by
| |
| mating, whereas corpus luteum activation
| |
| awaits appropriate environmental conditions, i.e., temperature and length of daily
| |
| illumination (Pearson and Enders, 1944;
| |
| Hansson, 1947). In the mink, during the period of relative luteal inactivity that follows mating early in the season, recurrent
| |
| estrus continues. If reraating takes place at
| |
| an interval of 6 days or more, new ovulations are induced (Hansson, 1947). Matings
| |
| late in the season are immediately followed
| |
| by luteal activity. The pseudopregnant cycles of a representative series of mammals
| |
| are much alike when conditions appropriate to the respective species are applied
| |
| (Fig. 8.1).
| |
| | |
| 1. Duration of Psciidopregndncn
| |
| | |
| The length of time that corpora lutea remain functional in the pseudopregnant cycle is thought to be relatively uniform in
| |
| the great majority of mammals, usually
| |
| about 10 to 15 days. Rarely it is shorter,
| |
| | |
| | |
| | |
| e.g., the hamster, 7 days, although usually
| |
| 9 to 10 days (Asdell, 1946). At the other
| |
| extreme, the corpora lutea remain functional
| |
| for periods corresponding to the duration of
| |
| pregnancy, as in the ferret, 5 to 6 weeks. In
| |
| fact, corpus luteum function lasting over a
| |
| month is usual in the other two carnivores
| |
| for which information is at hand: cat, 30 to
| |
| 44 days (Foster and Hisaw, 1935) ; and dog,
| |
| 30 days or more (Evans and Cole, 1931).
| |
| | |
| These figures are only approximations,
| |
| however, as the criteria on which they are
| |
| based differ. In the rat, in which pseudopregnancy is said to last 12 to 14 days, its
| |
| termination is taken to be the onset of the
| |
| next estrus, whereas the corpora lutea must
| |
| have undergone a decline of activity 2 or 3
| |
| days earlier (Everett, 1948). The decline is
| |
| probably not abrupt, inasmuch as the vaginal smear during the next estrus is very
| |
| strongly mucified and, as mentioned earlier
| |
| (p. 519), enough progesterone seems to be
| |
| secreted by the waning corpora lutea to facilitate ovulation. Morphologic criteria are
| |
| often employed as indicators of corpus luteum regression: characteristically, fatty
| |
| vacuolation of luteal cells, decrease in size
| |
| of the individual cells or of the entire corpus
| |
| | |
| | |
| | |
| 534
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| luteuni. and changes in the smusoidal pattern suggesting reduced circulation. Such
| |
| changes are first observed in the guinea pig
| |
| corpora lutea on about the 13th day of the
| |
| cycle. One has the choice of taking this date
| |
| as the end of the pseudopregnant phase or,
| |
| alternatively, the date on which the first
| |
| indications of estrus are noted. Either choice
| |
| is arbitrary, but the former seems preferable
| |
| as it suggests that progesterone secretion is
| |
| diminishing and probably is no longer sufficient to maintain progestational changes
| |
| in the uterus. In fact, regression of the endometrium sets in about a day earlier than
| |
| frank degenerative changes in the corpora
| |
| lutea. In the cat, according to van Dyke and
| |
| l.i (1938) the corpora lutea 20 days after
| |
| ovulation no longer secrete enough progesterone to cause motor effects of epinephrine in the myometrium, the so-called "epinephrine-reversal" effect, yet by histologic
| |
| criteria corpus luteum regression is not apparent until 28 days or later (Liche, 1939;
| |
| Foster and Hisaw, 1935). In the bitch the
| |
| uterus begins regression 20 to 30 days after
| |
| heat, l)ut the corpora lutea are said to remain in good condition for a longer time
| |
| (see Asdell, 1946, for references). Regression is so gradual that anestrum is not
| |
| reached until about 85 days. In the primates
| |
| the beginning of menstruation offers a means
| |
| of delimiting the luteal phase, inasmuch as
| |
| menstruation in the ovulatory cycle reflects
| |
| a marked reduction in corpus luteum function. Nevertheless, this reduction probably
| |
| occurs a few days before bleeding begins.
| |
| The i^eak of pregnanediol excretion in
| |
| women (Venning and Browne, 1937) and of
| |
| plasma progesterone concentration in
| |
| women and monkeys (Forbes, 1950; Bryans.
| |
| 1951 ) is passed about midway between ovuhition and menstruation.
| |
| | |
| 2. Xciivdl Factors in Pseudoprciindiicji
| |
| | |
| The importance of the nervous system
| |
| in control of pseudopregnancy is well recognized in only the few species re])resented
| |
| by the rat. .\ neural effect in the mink and
| |
| similar Mustelidae is implied by the relation of hiteal function to daily illumination,
| |
| as mentioned earlier. Beyond that fact, however, no information is available. Att(>ntion
| |
| will therefore be directed largely to the rat.
| |
| | |
| Not only sterile mating, but se\'eral other
| |
| | |
| | |
| | |
| procedures involving neural stimulation will
| |
| cause rats to become pseudopregnant. Stimulation of the cervix by mechanical means
| |
| (Long and Evans, 1922) or electric shock
| |
| (Shelesnyak, 1931) have become standard
| |
| methods. In fact, Greep and Hisaw (1938)
| |
| obtained pseudopregnancies after electrical
| |
| stimulation during early diestrum, several
| |
| days before ovulation. Pseudopregnancy is
| |
| also invoked by continuous stimulation of
| |
| the nipples for several days (Selye and McKeown, 1934). According to Harris (1936)
| |
| electric shock through the head is effective.
| |
| His negative results with "spinal shock"
| |
| are difficult to explain. From the description
| |
| of position of the electrode it seems doubtful that the current passed through the cord
| |
| itself, yet the sacral plexus must have been
| |
| stimulated.
| |
| | |
| Al)dominal sympathectomy or superior
| |
| cervical ganglionectomy are said to diminish
| |
| the numbers of animals responding to electrical or mechanical stimulation of the cervix (Vogt, 1931; Haterius, 1933; Friedgood
| |
| and Bevin, 1941). On the other hand, there
| |
| is no diminution of response to sterile copulation, which shows that the sympathetic
| |
| chains are not essential. Ball (1934) emphasized the quantitative aspects of the
| |
| problem, noting that partial resection of the
| |
| uterus or excision of the cervix diminished
| |
| the response to sterile copulation, but only
| |
| when "single-plug" matings were allowed.
| |
| Multiple plugs gave pseudopregnancy in 100
| |
| per cent of the animals. It may be assumed
| |
| that Vogt's (1933) negative results after
| |
| hysterectomy resulted from single-jilug copulations. Kollar (1953) re-opened the cjuestion and found that pelvic nerve resection
| |
| usually pi-evented the response to mating. It
| |
| is not clear, howevei', whether multiple copulations wnv the rule, although it seems that
| |
| the I'outiiie procedure was to leave the male
| |
| with the female overnight. His contention
| |
| was that cervicectomy fails to abolish the
| |
| resjionse completely because the vagina remains sensitive.
| |
| | |
| Anesthesia with ether, nitrous oxide, or
| |
| ethylene ( Mcyei', Leonard and Hisaw, 1929)
| |
| diniiiiished the ficciuency of response to
| |
| inecliaiiical stimulation of tlu> (•er\-ix. The
| |
| statement was made, although without v\\(len(c, that spinal anesthesia |)re\-ents pseudopreiinanev. Aeeoi'ding to A'ogt (1933),
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVP] CYCLE
| |
| | |
| | |
| | |
| 535
| |
| | |
| | |
| | |
| local anesthesia of the vagina and cervix by
| |
| cocaine or procaine prevented the response
| |
| to sterile copulation in 23 of 35 rats.
| |
| | |
| Removal of neocortex (Davis, 1939) did
| |
| not interfere with the pseudopregnancy response to electrical stimulation of the cervix, although there was slight impairment of
| |
| the response to mechanical stimulation or
| |
| sterile mating (single-plug?).
| |
| | |
| These results taken together have been
| |
| construed to mean that induction of pseudopregnancy in rats involves a reflex similar to
| |
| the ovulation reflex in rabbits. Certain considerations, however, raise the possibility
| |
| that it may not be a "trigger" stimulus to
| |
| the hypophysis as long believed (Everett,
| |
| 1952a). In the first place, it seems doubtful
| |
| that a trigger stimulus would result in continuation of a new pattern of secretion
| |
| (luteotrophin) for as long as 10 to 12 days.
| |
| Furthermore, as noted above, cervical stimulation during the diestrum preceding ovulation may induce pseudopregnancy (Greep
| |
| and Hisaw, 1938). Similarly, copulation
| |
| during a cycle in which ovulation is blocked
| |
| by pentobarbital results in a pseudoi)regnancv that begins after the next estrus (Fig.
| |
| 8.12)^.
| |
| | |
| We turn now to experiments concerned
| |
| directly with the hypothalamo-pituitary
| |
| system and pseudopregnancy. Westman and
| |
| Jacobsohn (1938c) cut the pituitary stalks
| |
| of estrous female rats. Barriers of metal foil
| |
| were inserted to prevent regeneration of
| |
| nerve fibers assumed to innervate the adenohypophysis. Regeneration of blood vessels
| |
| must have been equally impossible. Controls
| |
| were simply hypophysectomized. Two to 5
| |
| hours after the operations electrical stimulation of the cervix was administered to all
| |
| animals. Pseudopregnancies were demonstrated by deciduomas in traumatized uteri
| |
| of all the stalk-sectioned animals but not in
| |
| the completely hypophysectomized rats.
| |
| Desclin (1950) reported the maintenance of
| |
| pseudopregnancy in estrogen-treated rats
| |
| in which the only remaining hypophyseal
| |
| tissue was in the form of grafts in the kidney. Whereas in hypophysectomized controls the estrogen treatment (stilbestrol pellets) produced cornification of the vagina
| |
| and no enlargement of corpora lutea, the engrafted-estrogenized rats developed mucified vaginas and enlarged corpora lutea as
| |
| | |
| | |
| | |
| in intact rats similarly treated with estrogen. Desclin concluded that the grafted hypophysis is able to respond to estrogen by
| |
| liberating luteotrophin.
| |
| | |
| It is now apparent, however, that neither
| |
| cervical stimulation nor estrogen treatment
| |
| is needed to invoke pseudopregnancy when
| |
| the gland is isolated from the hypothalamus
| |
| (Everett, 1954, 1956a; Nikitovitch-Winer
| |
| and Everett, 1958a; Sanders and Rennels,
| |
| 1957; Desclin, 1956a, b). When autografts
| |
| of anterior hypophysis were made to the renal capsule or near the common carotid
| |
| artery on the day after ovulation in adult
| |
| cyclic rats, corpus luteum function was invoked and maintained without any stimulus other than the operative procedures
| |
| themselves. In short-term experiments in
| |
| which the uteri were traumatized 4 days
| |
| after the transplantation large deciduomas
| |
| were regularly found at 8 days in the proven
| |
| absence of residual hypophyseal tissue at
| |
| the original site (Everett, 1954). Hypophysectomized controls were negative. In longterm experiments, continuing luteal function
| |
| was demonstrated for as long as 3 months.
| |
| Here the test for luteal function was vaginal
| |
| mucification in the presence of massive
| |
| amounts of estrogen administered during
| |
| the final week of the experiment (Everett,
| |
| 1956a). Controls in which the grafts or the
| |
| ovaries were removed at the beginning of
| |
| such estrogen treatment responded with full
| |
| vaginal cornification. Follicular apparatus
| |
| and interstitial tissue of the ovaries atrophied promptly after the grafting operations, whereas corpora lutea forming at that
| |
| time were maintained for the long periods
| |
| without histologic sign of deterioration. In
| |
| later work, the decidual reaction was used
| |
| as the test for luteal function, positive reactions being elicited as late as 2 months
| |
| after the transplantation. It was discovered
| |
| that function of the graft is not influenced
| |
| by stage of the cycle at which transplantation is carried out and that grafts in the
| |
| anterior chamber of the eye secrete luteotrophin like those on the kidney (Nikitovitch-Winer and Everett, 1958a). Transsection of the pituitary stalk is sufficient
| |
| in itself to provoke pseudopregnancy. If an
| |
| effective barrier to vascular regeneration is
| |
| inserted, the pseudopregnancy will heorve
| |
| permanent, but otherwise it will l:i •■ i;!*'
| |
| | |
| | |
| | |
| 536
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| usual length of time (Xikitovitch-Winer,
| |
| 1957 j. In fact, there is reason to suspect
| |
| that even a transient impairment of circulation in the median eminence-hypophj'seal
| |
| linkage can be a sufficient impetus to pseudopregnancy. The experiments of Taubenhaus and Soskin ( 1941 ) in which application of an acetylcholine-prostigmine mixture
| |
| to the exposed hypophysis was followed by
| |
| pseudopregnancy, may well be explained
| |
| in some such way.
| |
| | |
| It thus seems that in the rat the deprivation of, or interference with, the normal connection of the pars distalis with the median
| |
| eminence facilitates secretion of luteotrophin and at the same time eliminates luteolytic mechanisms. It is significant that
| |
| transplants of pars distalis into the pituitary
| |
| capsule or to the immediate vicinity of the
| |
| median eminence resume cyclic function
| |
| (see page 512). The hypothalamus may
| |
| have an inhibitory effect on luteotrophic activity of the pars distalis during the short
| |
| cycle in this species. Greep and Chester
| |
| Jones (1950) made the pertinent suggestion
| |
| in attempting to explain the induction of
| |
| pseudopregnancy by estrogen treatment,
| |
| that the fundamental action of estrogen
| |
| here is the suppression of FSH and LH,
| |
| after which luteotrophic secretion may
| |
| "proceed apace."
| |
| | |
| There is necessarily some uncertainty
| |
| concerning the amount of luteotrophin secreted by the pars distalis when dissociated
| |
| from the brain. Three sets of facts indicate
| |
| that the output is larger than that in the
| |
| cycling animal. (1) Sufficient gestagen is
| |
| secreted by the engrafted animal to maintain a ])regnancy (Everett, 1956c; Meyer,
| |
| I'rasad and Cochrane, 1958) when the pituitary is trans])lanted on the day after
| |
| mating. (2) After stalk-transsection, in
| |
| which there is less initial destruction of
| |
| glandular parenchyma than in transplantation experiments, the corpora lutea enlarge
| |
| to a diameter like that usually found in late
| |
| pregnancy rather than remaining like those
| |
| of pseudopregnancy (Nikitovitch-Winer,
| |
| 1957). (3) A single homotransplant of pars
| |
| distalis placed subcutaneously in an otherwise normal female mouse will maintain a
| |
| se(iueiicc of pseudopregnancies that override
| |
| the short cycles expected of the animal's
| |
| own hypophysis (Miihlbock and Boot,
| |
| 19591. This is also true of rats (Nikitovitch
| |
| | |
| | |
| Winer, uni)ublislie(l). To avoid the conclusion that in such preparations the grafted
| |
| gland is secreting luteotrophin at an increased rate, one must assume that the outl)ut of this hormone from the intact gland
| |
| is only slightly below threshold and that the
| |
| graft adds just enough to make the total
| |
| output effective. To explain the maintenance
| |
| of pregnancy one might assume that the
| |
| luteotrophin output and the resulting gestagen secretion are no greater than during the
| |
| normal short cycle and that the formation
| |
| of deciduomas takes place because of the
| |
| deficiency of estrogen. The results of stalksection, however, cannot easily be explained
| |
| away. The weight of evidence, then, is in
| |
| favor of increased luteotrophin secretion by
| |
| hypophyses isolated from the brain by
| |
| severance of the stalk or transplantation.
| |
| | |
| Under certain experimental conditions it
| |
| has seemed that to establish pseudopregnancy all that is necessary is to block out
| |
| the forthcoming estrus and ovulation. Thus,
| |
| in cycling rats, when the hypophysis is
| |
| transplanted to the kidney as late as 60
| |
| hours after ovulation, the current diestrum
| |
| transforms into a permanent pseudopregnancy supported by the existing set of corpora lutea (Nikitovitch-Winer and Everett,
| |
| 1958a ». Similarly, injections of chlorpromazine (Barraclough, 1957) or Pathilon
| |
| (ditsch and Everett, 1958) begun during
| |
| diestrum, may transform it into a pseudopregnancy by blocking out the expected
| |
| estrus.
| |
| | |
| The Miihlhock-Boot experiment mentioned above furnishes an instructive model
| |
| of the standard mammalian cycle, in which
| |
| both ovulation and pseudopregnancy are
| |
| spontaneous events. Given the extra pituitary tissue producing luteotrophin at a presumably constant rate, with the output of
| |
| the normal ghmd fluctuating (juantitatively
| |
| and (jualitatively, the mouse or rat undergoes one ])seudopregnancy after another.
| |
| Possibly, in animals that normally liave a
| |
| spontaneou.- hiteal phase, thei'c is a considei'ahle poUion ot' the pars distalis which
| |
| I'unctions somewhat indepeiidentl}- of the
| |
| hyputhalaiiius. with a continuous output of
| |
| luteotrophin as from the grafted gland in
| |
| the Mvihlb()ck-P)Oot pi-epaiation. The portion nioic (Hrectly under control of the
| |
| me(lian eminence I zona tuberaHs'.'l would
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 537
| |
| | |
| | |
| | |
| then act like the intact hypoiihysis of the
| |
| Miihlbock-Boot mouse. Such a view, unfortunately, continues to set apart species
| |
| in which the luteal phase is not spontaneous,
| |
| by suggesting that only in them are special
| |
| neui'al nieclianisnis involved.
| |
| | |
| B. LUTEOLYTIC MECHANISMS
| |
| | |
| By luteolysis we shall refer to corpus luteum regression in any of its manifestations.
| |
| Supposedly the initial change is functional,
| |
| after which overt cytologic and histologic
| |
| changes appear, leading eventually to the
| |
| total loss of glandular tissue. Very likely
| |
| the initial stages are occult and only gradually reach recognizable proportions. Mention was made earlier of the fact that in
| |
| women and monkeys the peak of gestagen
| |
| secretion is about midway between ovulation and menstruation. In rats indirect evidence from progesterone injection experiments leads to the deduction that toward
| |
| the close of a pseudoi)regnancy gestagen
| |
| secretion must drop below the estrus-suppressing level several days before estrous
| |
| changes appear in the vaginal smear (see
| |
| Fig. 8.8). A more al)rupt drop is reported
| |
| for the ewe l)etween the 16th and 17th
| |
| (last) days of the cycle (Edgar and Ronaldson, 1958).
| |
| | |
| Long-term experiments with pituitary
| |
| autotransplants indicate that at least in the
| |
| rat the life span of the corpus luteum is not
| |
| limited by intrinsic factors. Some agent (s)
| |
| of extra-ovarian origin must, therefore, be
| |
| res]5onsible for at least the initial luteolytic changes. Various bits of information
| |
| suggest that the agent is associated with, if
| |
| not identical with, FSH and/or LH. Greep
| |
| (1938) noted that after hypophysectomy
| |
| in rats the daily injection of LH over a period of 10 days caused the corpora lutea to
| |
| regress more rapidly than otherwise. Greep,
| |
| van Dyke and Chow (1942) later were unable to repeat this with a more highly purified LH C'metakentrin") , a fact suggesting
| |
| that the earlier material was effective because of impurity. During the short cycle
| |
| of the rat, luteolysis is interrupted by translilantation of the pars distalis (Everett,
| |
| 1954; Nikitovitch-Winer and Everett,
| |
| 1958a). Whatever regressive changes are
| |
| in progress at that moment are evidently
| |
| suspended forthwith. They are first appar
| |
| | |
| | |
| ent during the third day of diestrum and become increasingly pronounced during proestrum and estrus. In this connection, it
| |
| should be recalled that during late diestrum
| |
| and proestrum patches of cells undergoing
| |
| fatty necrosis are first recognizable histologically (Boling, 1942; Everett, 1945).
| |
| | |
| Why is it that, in the face of a continuing
| |
| supply of luteotrophin in the MiihlbockBoot preparation, or in intact animals injected daily with lactogen (Lahr and Riddle,
| |
| 1936; Aschheim, 1954), luteolysis sets in
| |
| during the 2nd week? The question obviously cannot be answered from present
| |
| knowledge. Nevertheless, it is clear that the
| |
| pseudopregnancy that transpires when a
| |
| significant i)ortion of hypophyseal tissue
| |
| remains in normal relation to the hypothalamus is far from the steady state of that
| |
| which becomes established by total removal of the pars distalis to an extracranial
| |
| site. It is also apparent that the onset of
| |
| luteolysis may be postponed by such means
| |
| as hysterectomy or production of artificial
| |
| deciduomas (see p. 538). Furthermore,
| |
| during lactation-pseudoi)regnancies in rats,
| |
| Canivenc and Mayer (1953) prolonged luteal function to 34 days by substituting successive new litters of suckling young. This
| |
| technique should prove especially valuable
| |
| in experimental analysis of both luteotrophic and luteolytic mechanisms.
| |
| | |
| Benson and Folley (1956) suggested that
| |
| lactogen secretion is activated by oxytocin,
| |
| inasmuch as its injection prevented the normal inv'olution of the mammary glands after
| |
| withdrawal of the litters from lactating rats.
| |
| This observation has been confirmed by
| |
| McCann, Mack and Gale (1958), who also
| |
| noted the interruption of lactation by lesions of the sui)raoi)tico-hyiiophyseal tract.
| |
| Selye and ]\lcKeown (1934) long ago found
| |
| that pseudopregnancy could be induced in
| |
| cycling rats by the introduction of a suckling litter. Although all this is consistent
| |
| with the above-mentioned observation by
| |
| Canivenc and Alayer, other workers have
| |
| observed luteolytic effects of gonadotrophinfree oxytocin administered to cycling dairy
| |
| heifers (Armstrong and Hansel, 1958). Furthermore, Grosvenor and Turner (1958),
| |
| after first noting that the administration of
| |
| Dibenamine, atropine, or pentobarbital to
| |
| rats prevented the expected drop in assay
| |
| | |
| | |
| 588
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| able pituitary lactogen at nursing, found no
| |
| decrease when pentobarbitalized mothers
| |
| were injected with physiologic doses of oxytocin intravenously. When the dosage was
| |
| increased 30 to 60 times there was apparently some moderate discharge, but the authors regard it as insignificant.
| |
| | |
| C. EFFECT OF THE UTERUS ON
| |
| LUTEAL FUNCTION
| |
| | |
| This subject has been reviewed by Bradbury, Brown and Gray (1950). In three
| |
| species (Fig. 8.13) hysterectomy results in
| |
| significant prolongation of the functional
| |
| life-span of corpora lutea (guinea pig, Loeb,
| |
| 1927; rabbit, Asdell and Hammond, 1933;
| |
| rat, Bradbury, 1937). In each case the period of luteal function approximates that of
| |
| normal pregnancy. The fact that corpora lutea in the pseudopregnant ferret normally
| |
| function as long as in the pregnant animal
| |
| may be a clue to the noncffect of hysterectomy in that species (Deanesly and Parkes,
| |
| | |
| | |
| | |
| 19331. Ahhough Burford and Diddle (1936)
| |
| rej^orted that in monkeys total hysterectomy was followed by vaginal cycles of normal length, examination of their protocols
| |
| shows that during the several postoperative
| |
| months just 1 corpus luteum was produced
| |
| among all 5 animals. The experiment thus
| |
| seems inconclusive. Impairment of pelvic
| |
| circulation seems to be a common factor
| |
| complicating the results of hysterectomy in
| |
| women and may have been one cause of the
| |
| failure of luteinization in these monkeys.
| |
| | |
| An interpretation given by Loeb (1927)
| |
| and Bradbury, Brown and Gray (1950) for
| |
| the prolongation of luteal function by hysterectomy is that in species in which the effect is demonstrable the uterus secretes a
| |
| specific substance which abbreviates the life
| |
| of the corpus luteum. Hechter, Fraenkel,
| |
| Lev and Soskin (1940) found in rats that
| |
| grafts of estrous uteri shortened the pseudopregnancies of hysterectomized animals to
| |
| normal length. Implantation of similar tis
| |
| | |
| | |
| | |
| | |
| M 1
| |
| | |
| | |
| | |
| | |
| | |
| | |
| I I T
| |
| GUINFA
| |
| | |
| | |
| pin
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Actual duration
| |
| | |
| | |
| 2
| |
| | |
| | |
| none
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 1
| |
| | |
| | |
| | |
| | |
| | |
| | |
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| | |
| " 90± days (Loeb)(Brouha)
| |
| 70± days
| |
| | |
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| ?
| |
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| 5
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| RARRIT
| |
| | |
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| mil
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| mill
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| lilll
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| mill
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| mill
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| iiiii;*'
| |
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| 1
| |
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| 14-16 days
| |
| | |
| 24-29 days (Asdell S Hammond)
| |
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| n
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| ==
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| —
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| — '
| |
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| —
| |
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| 30 days
| |
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| RAT
| |
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| M\
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| Mil
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| nnn
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| nmn
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| 12 days
| |
| I8±days
| |
| 22 days
| |
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| ^H
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| FERRET
| |
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| | |
| 6 weeks (Parkes)
| |
| | |
| | |
| nil
| |
| | |
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| Hill
| |
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| lilll
| |
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| Hill
| |
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| Hill
| |
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| Mlllllillillllllllliilllllllliiiilll
| |
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| 1 1
| |
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| | |
| 6 weeks
| |
| 6 weeks
| |
| | |
| | |
| =
| |
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| =
| |
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| =1
| |
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| ^
| |
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| =
| |
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| | |
| | |
| | |
| | |
| ~
| |
| | |
| | |
| ~
| |
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| | |
| | |
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| | |
| | |
| | |
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| | |
| | |
| | |
| | |
| | |
| L Pseudopregnancy
| |
| | |
| | |
| iiiiiiiiiiii iiiiiiiiiiiii
| |
| | |
| | |
| | |
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| | |
| | |
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| | |
| | |
| Pseudopregnancy hysterectomized
| |
| | |
| | |
| m^^^g^^
| |
| | |
| | |
| | |
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| | |
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| | |
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| | |
| Mil
| |
| | |
| . Prpnnnnrv
| |
| | |
| | |
| | |
| Fi(i. 8.13. Reliilive duiation.s of p.seiulopicgnaiicy in normal and hysterectomizeil animals
| |
| of four species in relation to the duration of j^ostation characteristic of each. Gestation
| |
| plotted as a common unit of time. (After J. T. Bradbury, W. E. Brown and L. A. Gray,
| |
| Recent Proj,n-. Hormone Res., 5, 151-194, 1950.)
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTn'E CYCLE
| |
| | |
| | |
| | |
| 539
| |
| | |
| | |
| | |
| SIR' which had been killed by freezing had
| |
| no such effect, nor did successful grafts of
| |
| uteri from diestrous donors. Bradbury,
| |
| Brown and Gray (1950) found that partially hysterectomized rats in which the remaining uterine tissue was continuous with
| |
| the cervix, hence properly drained, experienced pseudopregnancies of normal length.
| |
| However, when the continuity was interrupted the uterine remnants became greatly
| |
| distended, the endometrium was destroyed,
| |
| and the animals had prolonged pseudopregnancies. Possibly the endometrium is the
| |
| source of the hypothetical "luteolytic" substance.*'
| |
| | |
| Under other circumstances the endometrium of rats has a luteotrophic rather than
| |
| luteolytic effect, for when deciduomas are
| |
| induced by trauma the pseudopregnancies of
| |
| otherwise normal animals are lengthened to
| |
| 22 days or more (Ershoff and Duell, 1943;
| |
| Velardo, Dawson, Olsen and Hisaw, 1953).
| |
| This is not true in mice, however, and Kamell and Atkinson (1948) suggest that the
| |
| I'eason may lie in the shorter life-span of the
| |
| decidual tissue in that species. Loeb (1927)
| |
| reported that deciduomas in cyclic guinea
| |
| pigs ])rolonged the luteal phase, i.e., delayed
| |
| the next ovulation from 3 to 7 days, which
| |
| is far less than the prolongation after hysterectomy.
| |
| | |
| As an alternative to the concept of conI rol of the corpus luteum by humoral agents
| |
| | |
| " The denial by Velardo, Olsen, Hisaw and
| |
| Dawson (1953) that hysterectomy in rats prolongs
| |
| l)seiidopregnancy is based on operations performed
| |
| later in the luteal phase than those of Bradbury,
| |
| Brown and Gray and of Hechter, Fraenkel, Lev
| |
| and Soskin. Whereas the latter workers had operated in the range from the 4th to the 7th day.^^
| |
| of p.seudopregnancy and many of Bradbury's
| |
| cases lacked uteri when they entered pseudopregnancy, Velardo and associates excised the uteri
| |
| on the 9th day. It seems possible that this difference in time may be crucial, for by the 9th
| |
| day of a 12-day pseudopregnancy the corpora
| |
| lutea must be on the verge of regression, if that
| |
| in'ocess has not already been initiated. After
| |
| maintaining pseudopregnancy in estrogenized,
| |
| liypophysectomized rats b}^ means of lactogen,
| |
| its withdrawal is followed about 3 days later by
| |
| estrous smears (Nelson and Bichette, 1943; Nelson, 1946). A slightly longer delay occurs in nonestrogenized, intact rats at the end of a lactogeninduced pseudopregnancy (Everett, unpublished)
| |
| or after withdrawal of progesterone treatment
| |
| (Fig. 8C).
| |
| | |
| | |
| | |
| formed in the uterus, Loeb considered the
| |
| jjossibility that neural mechanisms are involved. The idea was not acceptable, he felt,
| |
| because in partial hysterectomies the result
| |
| was not detennined by the locus of the part
| |
| removed. The finding by Hechter, Fraenkel,
| |
| Lev and Soskin (1940) that grafts of uterine
| |
| tissue in hysterectomized rats return the
| |
| duration of pseudopregnancy to normal, is
| |
| significant evidence pointing in the same direction.
| |
| | |
| A third hypothesis was advanced by
| |
| Heckel (1942) who found in rabbits that
| |
| the extent of prolongation of luteal function by subtotal hysterectomy is roughly
| |
| proportional to the amount of uterine tissue removed. The suggestion was offered
| |
| that removal of the uterus has an estrogensparing effect. The greater amount of estrogen thus available to the corpora lutea prolongs their life, according to this view.
| |
| | |
| Later investigations by Moore and Nalbandov (1953) revive the possibility that
| |
| the uterus influences the ovary by way of
| |
| the nervous system. In sheep the implantation of a plastic bead in utero during the
| |
| early luteal phase shortened the cycle by
| |
| several days. Successive cycles tended to be
| |
| unusually short. When the uterine segments
| |
| containing the beads were denervated, however, the cycles were essentially normal.
| |
| Other work from the same laboratory (Huston and Nalbandov, 1953) which indirectly
| |
| may bear on this problem, indicates that
| |
| the presence of a mechanical irritant (a
| |
| thread) in the oviduct of the domestic fowl
| |
| tends to block ovulation. The blockade may
| |
| extend for as long as 20 days if the thread
| |
| is placed in the isthmus (van Tienhoven,
| |
| 1953). The ovaries remain functional, producing large follicles which may be ovulated
| |
| at will by injection of LH. The authors feel
| |
| that this phenomenon, like the effect of the
| |
| bead in the sheep uterus, involves a neural
| |
| mechanism, Init crucial information is lacking. It may be significant that stimulation
| |
| of the ovaries was found in some hens, in
| |
| place of blockade.
| |
| | |
| We may hope that as more information
| |
| becomes available the assortment of facts
| |
| given in these paragraphs will fit into a
| |
| rational system. Not until this is realized
| |
| can we hope to understand the regulation of
| |
| the luteal phase.
| |
| | |
| | |
| | |
| 540
| |
| | |
| | |
| | |
| PHYSIOLOGY OF COXADS
| |
| | |
| | |
| | |
| VIII. Concluding Comments
| |
| | |
| From what has been written here it is
| |
| readily apparent that present knowledge of
| |
| the mechanisms controlling the reproductive
| |
| cycle is extremely spotty. The number of
| |
| assumptions necessary to knit the various
| |
| items of factual information into an orderly
| |
| pattern is disturbing. In spite of a voluminous literature which has grown during the
| |
| last 60 years, we are really only a few steps
| |
| ahead of our predecessors at the turn of
| |
| the century in terms of fundamental understanding. A brief recounting of some of
| |
| these steps may be desirable.
| |
| | |
| The first three decades saw the gradual
| |
| development of proof that the ovary is a
| |
| gland of internal secretion as well as the
| |
| producer of eggs, governing the uterus and
| |
| other accessory organs by secretion of hormones into the blood stream. For a while it
| |
| seemed that the events of the reproductive
| |
| cycle could be neatly explained, with the
| |
| ovary in the capacity of controlling agent.
| |
| Yet there were indications that the ovary
| |
| itself is not independent. As early as 19091910 (Aschner; Crowe, Gushing and Honuins) it was noted that destruction of the
| |
| hypophysis is accompanied by atrophy of
| |
| the gonads and reproductive tract. In 1927
| |
| the separate investigations of Smith and
| |
| Engle and of Zondek and Aschheim demonstrated conclusively that function of the
| |
| ovary depends vitally on the anterior hyjiophysis. Promptly it was learned that the
| |
| hypophyseal secretion of gonadotrophic
| |
| hormone is in turn modified by estrogens. In
| |
| the early 1930's the "push-pull" hypothesis
| |
| of pituitary-ovarian interaction was separately stated by Brouha and Simonnet and
| |
| by Moore (see Moore and Price, 1932).
| |
| Modified in detail as new facts appeared,
| |
| this hypothesis is held to the present day in
| |
| some quarters as a simple exi)lanation of
| |
| how the cycle comes about in polyestrous,
| |
| continuous breeders in which ovulation takes
| |
| l)lacc spontaneously. Much of the investigation of pituitary-ovarian i)hysiology during
| |
| the 1930's was performed within the framework of this hypothesis.
| |
| | |
| For seasonal breeders and reflex ovulators,
| |
| however, the assumption was necessary that
| |
| special controlling mechanisms are superimjiosed. It bccaiiie iccognizcd also that in
| |
| | |
| | |
| | |
| some vaguely defined manner even the human cycle is subject to intervention of the
| |
| nervous system. The possible importance of
| |
| the hypothalamus was debated at some
| |
| length in the twenties. In 1932 the existence
| |
| of a sex center there was proposed by Hohlweg and Junkmann. In an attempt to explain the coital excitation of the rabbit hypophysis which causes the liberation of
| |
| gonadotrophin, Hinsey and Markee (1933)
| |
| suggested diffusion of a chemical substance
| |
| from the posterior lobe to the anterior lobe.
| |
| Hinsey (1937) later elaborated on this possibility and mentioned the hypophyseal portal vessels as a plausible route by which the
| |
| substance might travel. We have seen the
| |
| later history of these ideas.
| |
| | |
| The "Sexualcentrum" of Hohlweg and
| |
| Junkmann was proposed as a mediator of
| |
| the effects of estrogen on the anterior hypophysis of rats. Westman and Jacobsohn
| |
| (1936-1940), on the other hand, believed
| |
| that through its stalk connection with the
| |
| hypophysis the rat hypothalamus governs
| |
| gonadotrophin synthesis, not release. The
| |
| latter they regarded as a direct effect of estrogen on the gland. These views did not
| |
| afford a common basis for spontaneous and
| |
| refiex ovulation.
| |
| | |
| Schweizer, Chari])i)er and Haterius
| |
| ( 1937) offered the first surmise of similarity,
| |
| after finding that guinea pigs bearing intraocular pituitary grafts developed persistent
| |
| estrus and large follicles that failed to go
| |
| through maturation changes. Their feeling
| |
| was that the normal connection of hypophysis with hypothalamus may be necessary for
| |
| cyclic liberation of LH. Almost concurrently, Dempsey (1937) expressed a similar
| |
| view as one alternative explanation of his
| |
| experimental results with the guinea i)ig cycle. Suggesting cautiously that release of
| |
| luteinizer may be brought about l)y a
| |
| "rhythmic discharge" from the central nervous system, he went on to mention the "possibility that a high level of oestrin is necessary but not directly responsible for the
| |
| release of luteinizer" (italics added). From
| |
| this it is only a short transition to certain
| |
| concepts set forth in the present exposition.
| |
| | |
| Accoi'ding to current views: (1) Reflex
| |
| ovulation and spontaneous ovulation alike
| |
| are go\-enicd by a liypothalamo-pituitary
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 541
| |
| | |
| | |
| | |
| apparatus whose final link to the pituitaiy
| |
| is neurohumoral by way of the hypophyseal
| |
| portal veins and whose activity precipitates
| |
| release of LH. (2) The apparatus includes
| |
| a hypothalamic center or centers whose excitation depends on estrogen-progesterone
| |
| levels and afferent impulses of various
| |
| kinds. (3) The sensitivity of the center (s)
| |
| is influenced not only by the sex steroids, but
| |
| by other poorly understood factors that
| |
| vary from species to species and from time
| |
| to time in individuals, e.g., the diurnal
| |
| rhythm in rats. Here in bare outline is a
| |
| plausible hypothesis that may be generally
| |
| applied to the events immediately relating
| |
| to ovulation.
| |
| | |
| Satisfactory hypotheses respecting other
| |
| phases of the cycle must await future developments. The extent and manner of intervention of the nervous system in the follicular and luteal phases remain unsettled.
| |
| Although the hypophyseal hormones concerned in ovarian follicle development have
| |
| been characterized, their exact chemical descrijition has not been accomplished. The
| |
| rate of their output at different stages of the
| |
| cycle is largely a matter of conjecture.
| |
| Structural changes that they jiroduce in the
| |
| ovary are well known, but in chemical terms
| |
| only the end products of ovarian activity are
| |
| well recognized, and these probably incompletely. The fact that the estrogens, in turn,
| |
| have a regulating effect on follicle-stimulating activity of the hypophysis is known, but
| |
| the mechanisms by which this effect is accomplished are uncertain. The hypophyseal
| |
| hormones that maintain the luteal phase
| |
| are recognized with any certainty in only
| |
| three species and there is a wide difference
| |
| between rabbits, on the one hand, and rats
| |
| and mice, on the other. For mammals generally, the luteotrophic factors have not been
| |
| identified. Whether the hypothalamus is
| |
| actively concerned in maintenance of the
| |
| luteal i)hase in the majority of mammals is
| |
| unknown. The morphologic effects of luteotrojihic stimulation on corpora lutea are well
| |
| recognized, but here again the chemical
| |
| mechanisms leading to the end products are
| |
| obscure. The action of the corpus luteum
| |
| hormone in regulation of the cycle is partially known, including the well established
| |
| fact that its continual jiresence in large
| |
| amount will suiijiress the estrogenic and
| |
| | |
| | |
| | |
| ovulatory phases. Yet, one cannot say
| |
| whether this effect is accomplished by direct
| |
| action on the hypophysis or by indirect action through the central nervous system.
| |
| Nor can one state how the hypophysisgonad equilibrium of the luteal phase is interrupted in the absence of a conceptus.
| |
| With respect to the ovulation mechanism
| |
| itself, the hypothesis outlined above requires
| |
| verification in additional species. Assuming
| |
| its validity, many details remain to be studied, e.g., the neural pathways and nuclei
| |
| involved, identification of neurochemical
| |
| activators of the pars distalis and their
| |
| sources and loci of action, the precise nature
| |
| of mechanisms whereby the gonadal steroids
| |
| excite or suppress, the cellular mechanisms
| |
| by which ovulating hormone is released into
| |
| circulation by the hypoi^hysis, and the cytochemical effects within the ovary. All too
| |
| evidently an encompassing theory of the
| |
| female reproductive cycle is far from realization.
| |
| | |
| IX. References
| |
| | |
| Allex. E., Daxforth, C. H., .and Doisy, E. A.,
| |
| Eds. 1939. Sex and Internal Secretions, 2nd
| |
| ed. Baltimore: The Williams & Wilkins Company.
| |
| | |
| Allen, E. 1923. Racial and familial cyclic inheritance and other evidence from the mouse
| |
| concerning the cause of estrous phenomena.
| |
| Am. J. Anat., 32, 293-304.
| |
| | |
| Allen, E. 1927. The menstrual cycle of the monkey, Macacus rhesus: observations on normal
| |
| animals, the effects of removal of the ovaries
| |
| and the effects of injection of ovarian and placental extracts into the spayed animals. Contr.
| |
| Embrvol., Carnegie Inst. Washington. 19,
| |
| 1-14.
| |
| | |
| Allen, E., Pratt, J. P., Newell, Q. U.. and Bland,
| |
| L. J. 1930. Human ova from large follicles:
| |
| including a search for maturation divisions and
| |
| observations of atresia. Am. J. Anat., 46, 1-53.
| |
| | |
| Alloiteau, J. J. 1952. La lordose reflexe par excitation du col uterin chez la rate. Son controle endocrinien. Compt. rend. Soc. biol., 146,
| |
| 237-238.
| |
| | |
| Alloiteau, J. J. 1954. Effets de doses minimes de
| |
| progesterone sur les fonctions gonadotropes de
| |
| la Ratte en oestrus permanent hypothalamique. Compt. rend. Soc. biol., 148, 875-877.
| |
| | |
| Alloiteau, J. J., .\nd Courvoisier, B. 1953. Effets
| |
| de I'excitation du col uterin chez la rate apres
| |
| lesions hypothalamique. Compt. rend. Soc.
| |
| biol., 147, 1040-1042.
| |
| | |
| Arm.strong, D. T., and Hansel, W. 1958. Alteration of the bovine estrous cvcle with oxvtocin.
| |
| Fed. Proc, 17, 6.
| |
| | |
| Arox, C, and Aron-Brunetiere, R. 1953, Effets
| |
| | |
| | |
| | |
| 542
| |
| | |
| | |
| | |
| PHYSIOLOGY OF (UJXADS
| |
| | |
| | |
| | |
| de la stimulation mecani(|ue du vagin et du
| |
| segment supracervical de Tutorus sur I'ovaire
| |
| du Cobaye. Compt. rend. Acad. Sc, 237, 846848.
| |
| | |
| AscHHEiM, p. 1954. Influence du tissue decidual
| |
| sur la pseudogestation provociuee par I'administration de prolactine chez le rat. Compt. rend.
| |
| Soc. biol., 148, 185-187.
| |
| | |
| Aschner, B. 1909. Demonstration von Hiinden
| |
| nach Extirpation der Hypophysis. Wien. klin.
| |
| Wchnschr., 22, 1730-1732.
| |
| | |
| AsDELL, S. A. 1946. Patterns of Mammalian Reproduction. Ithaca, X. Y.: Comstock Publishing Company.
| |
| | |
| AsDELL, S. A., .^ND Hammond, J. 1933. The effects
| |
| of prolonging the life of the corpus luteum in
| |
| the rabbit by hysterectomy. Am. J. Physiol.,
| |
| 103, 600-605".
| |
| | |
| AsTwooD, E. B. 1939. Changes in weight and
| |
| water content of the uterus of the normal
| |
| adult rat. Am. J. Physiol., 126, 162-170.
| |
| | |
| AsTWOOD, E. B. 1941. The regulation of corpus
| |
| luteum function by hypophyseal luteotrophin.
| |
| Endociinology, 28, 309-320.
| |
| | |
| AsTwooD, E. B., AND Fevold, H. L. 1939. Action
| |
| of progesterone on the gonadotropic activity
| |
| of the pituitary. Am. J. Physiol., 127, 192-198.
| |
| | |
| B.ACHMAN, C. 1936. Oestrogenic hormone and the
| |
| mechanism of corpus luteum formation in the
| |
| rabbit. Proc. Soc. Exper. Biol. & Med., 33,
| |
| 551-554.
| |
| | |
| Bacq, Z. M. 1932. Effect of sympathectomy on
| |
| sexual functions, lactation and maternal behavior in the albino rat, with a description of
| |
| the technique of svmpathectomy in the rat.
| |
| Am. J. Physiol., 99, 444-453.
| |
| | |
| B.'MN, J. A. 1952. Enzymatic aspects of barbiturate action. Fed. Proc, 11, 653-658.
| |
| | |
| B.ALL, J. 1934. Demonstration of quantitative relation between stimulus and response in pseudopregnancy in the rat. Am. J. Physiol., 107,
| |
| 698-703.
| |
| | |
| Ball, J., and Hartman, C. G. 1939. A case of delayed ovulation after estrin administration in
| |
| the intact monkev. Proc. Soc. Exper. Biol. &
| |
| Med., 40, 629-631.
| |
| | |
| B.^RBARo.ssA, C, AND Di Ferrante, H. 1950. Sugli
| |
| effetti dell'ipofisectomie nel correlazione intermedina-ovaio. Arch. "E. Maragliano" pat. e
| |
| clin., 5, 887-890.
| |
| | |
| Barraclouoh, C. A. 1955. Blockad(< of the release
| |
| of i)itui1arv gonadotrophin b\- ic.^^erijine. Fed.
| |
| Proc, 14, 9-10.
| |
| | |
| Bahracloucii, C. a. 1956. Blockade of the release of i)ituitary gonadotrophin by chlorpromazine. Anat. Rec, 124, 255.
| |
| | |
| Barraclough, C. a. 1957. Indiiction of i^seudopregnancy in the rat by reseri)ine and chlorpiomazine. Anat. Rec, 127, 262-263.
| |
| | |
| Barraclough, C. A., and Sawyer, C. H. 1955. Inhibition of the release of pituitaiy oxuhiloiy
| |
| hormone in th(> rat bv morphine. iMidociinology, 57, 329-337.
| |
| | |
| B.\rrnp:tt, R. J., AND Grlei', R. O. 1951. The d\rection of flow in the blood vessels of the infundibular stalk. Science, 113, 185.
| |
| | |
| | |
| | |
| Bahtelmez, G. W., Corner, G. W., and Hartman, C.
| |
| G. 1951. Cyclic changes in the endometrium
| |
| of the rhesus monkey {Macaca mulatta).
| |
| Contr. EmbryoL, Carnegie Inst. Washington,
| |
| 34, 99-144.
| |
| | |
| Bauer, H. G. 1954. Endocrine and other clinical raanife.stations of hypothalamic di.-;ease. J.
| |
| Clin. Endocrmol., 14, i3-31.
| |
| | |
| Beard, J. 1898. The rhythm of reproduction in
| |
| animals. Anat. Anz., 14, 97-102.
| |
| | |
| Benoit, J., and Assenmacher, I. 1955. Le controle hypothalamique de I'activite prehypophysaire gonadotrope. J. Phvsiol., Paris, 47, 427567.
| |
| | |
| Benson, G. K., .\nd Folley, S. J. 1956. Oxytocin
| |
| as stimulator for the release of prolactin from
| |
| the anterior pituitarv. Nature, London, 177,
| |
| 700.
| |
| | |
| Bielschowsky, F., and Hall. W. H. 1953. The
| |
| endocrine imbalance induced in female rats by
| |
| autotransplantation of the ovary into the tail.
| |
| Australian J. Exper. Biol. & Med. Sc, 31, 8598.
| |
| | |
| Blskind, G. R. 1941. Tiie inactivation of estradiol and estradiol benzoate in castrate female
| |
| lats. Endocrinology, 28, 894-896.
| |
| | |
| Blandau, R. J., AND Money, W. L. 1943. The attainment of sexual maturity in the female albino rat as determined by the copulatory respon.se. Anat. Rec, 86, 197-215.
| |
| | |
| Block, K. 1945. Biological conversion of cholesterol to pregnanediol. J. Biol. Chem., 157, 661666.
| |
| | |
| BoLiNG, J. L. 1942. Growtii and regression of
| |
| corpora lutea during the normal estrous cvcle
| |
| of the rat. Anat. Rec, 82, 131-145.
| |
| | |
| BoLiNG, J. L., Bl.>\ndau, R. J., Rundlett. B., and
| |
| Young, W. C. 1941. Factors underlying the
| |
| failure of cyclic mating behavior in the albino
| |
| rat. Anat. Rec, 80, 155-171.
| |
| | |
| Borell, U., Westman, A., and Orstrom, A. 1947.
| |
| Studies on the functions of the hypophysealdiencephalic system and of the ovaries by
| |
| means of radioactive phosphorus. Gvnaecologia, 123, 186-200.
| |
| | |
| Borell, U., Westman, \., a.nd Orstrom, A. 1948.
| |
| The jtliosj^hate metabolism in the hypophyseal(ii(>nc{'i)lialic system and ovaries of rats determined by means of P''-. Acta phvsiol. scandinav., 15, 245-253.
| |
| | |
| Borell, U., and WEST.^L\N, A. 1949. The effect of
| |
| oi'strogen on th(> i)hosiiliate turnover in th(>
| |
| hyiio])hy.'^eal-dienceplialic .system. Acta endocrmol., 3, 111-118.
| |
| | |
| Bourne, G., and Zucker.m.\n, S. 1941. Changes
| |
| in the adrenals in relation to the normal and
| |
| artificial threshokl oestrous cycle in {he ra(. J.
| |
| Endocrinol., 2, 283-310.
| |
| | |
| Bkadkury, J. T. 1937. Piolongation of the life
| |
| of the corpus luleum li\' hvsterectomv in the
| |
| rat. .\nat. Kec, 70, Sup].!. 1, 51.
| |
| | |
| linADiiiin, .1. T. 1940. Ob.^^ervations following the
| |
| cc>.-,iiion of treatment of the infantile female
| |
| lai witli an(h-og(>ns and gonadotropic extracts. Am. J. Pliysiol., 129, P315.
| |
| | |
| Bradiurv, J. T. 1941. Permanent after-effects
| |
| | |
| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
| |
| | |
| | |
| | |
| 543
| |
| | |
| | |
| | |
| followinji nia^^cvilinization of the infantile female lat. Endocrinology, 28, 101-106.
| |
| | |
| Bradbury, J. T. 1947. Ovarian influence on the
| |
| response of the anterior pituitary to estrogens.
| |
| Endocrinology, 41, 501-513.
| |
| | |
| Br.adbury, J. T., Brown, W. E.. .and Gr.\y, L. A.
| |
| 1950. Maintenance of the corpus luteum and
| |
| Ithysiologic actions of progesterone. Recent
| |
| Progr. Hormone Res., 5, 151-194.
| |
| | |
| Br.\mbell, F. W. R., P.arkes, A. S., .^^nd Fielding, U.
| |
| 1927a. Changes in the ovary of the mouse
| |
| following exposure to X-rays. I. Irradiation at
| |
| three weeks old. Proc. Roy. Soc. London, ser.
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| B, 101, 29-56.
| |
| | |
| Br.\.mbell, F. W. R., P.\rkes, A. S., .and Fielding, U.
| |
| 1927b. Changes in the ovary of the mouse
| |
| following exposure to X-rays. II. Irradiation
| |
| at or before birth. Proc. Roy. Soc, London,
| |
| ser. B, 101, 95-114.
| |
| | |
| Brooks, C. McC. 1937. The role of the ceroliral
| |
| cortex and of various sense organs in the excitation and execution of mating acti\itv m
| |
| the rabbit. Am. J. Physiol., 120, 544-553.
| |
| | |
| Brooks, C. McC. 1938. A study of the mechanism whereby coitus excites the ovulation producing activitv of the rabbit's pituitary. Am.
| |
| J. Physiol., 121, 157-177.
| |
| | |
| Brouha, L.. and Simonnet, H. 1930. Considerations sur le determinisme du cycle ovarien chez
| |
| les Mammiferes. In Proceedings 2nd International Congress Sex Research, pp. 339-344.
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| Edinburgh: Oliver & Boyd.
| |
| | |
| Browman, L. G. 1937. Light in its relation to
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| activity and e.strus rhythms ui the alljino rat,
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| J. Exper. Zool., 75, 375-388.
| |
| | |
| Brown, W. E., and Bradbury, J. T. 1947. Estrogen release of pituitary gonadotropin in
| |
| women. Tr. Conference Sterility & Infertility.
| |
| Am. Soc. Stud. Steril.. 3, 117-124.
| |
| | |
| Brown, W. E., Br.adbury, J. T., and Jennings, A. F.
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| 1948. Experimental alteration of the human
| |
| ovarian cycle bv estrogen. J. Clin. Endocrinol.,
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| 8, 453-460.
| |
| | |
| Bryans, F. E. 1951. Progesterone of the blood
| |
| in the menstrual cycle of the monkey. Endocrinology, 48, 733-740.
| |
| | |
| BuNN, J. P., .AND Everett, J. W. 1957. Ovulation
| |
| in persistent-estrous rats after electrical stimulation of the brain. Proc. Soc. Exper. Biol. &
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| Med., 96, 369-371.
| |
| | |
| BURFORD. T. H., AND DiDDLE, A. W. 1936. Effect of
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| total hysterectomy upon the o\ary of Macacus
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| rhesus. Surg. Gynec. & Obst., 62," 701-707.
| |
| | |
| BuRRiLL, M. W., AND Greene, R. R. 1941. Androgen jiroduction in the female rat. Endocrinology, 28, 871-873.
| |
| | |
| Buxton, C. L., .and Engle, E. T. 1950. Time of
| |
| ovulation: a correlation between basal temperature, the appearance of the endometrium
| |
| and the appearance of the ovary. Am. J. Obst.
| |
| & Gynec. 60, 539-551.
| |
| | |
| Byrnes, W. W., and Meyer, R. K. 1951a. The
| |
| inhibition of gonadotrophic hormone secretion
| |
| by physiological doses of estrogen. Endocrinology, 48, 133-136.
| |
| | |
| | |
| | |
| Byrnes, W. W., and Meyer. R. K. 1951b. Effect
| |
| of physiological amounts of estrogen on the secretion of follicle-stimulating and luteinizing
| |
| hormones. Endocrinology, 49, 449-460.
| |
| | |
| C.ANivENc, R., AND M.AYER, G. 1953. Les corps
| |
| gestatifs de la rate sont-ils prolonges par la
| |
| prolactine? Etude de I'aecouchement et de
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| I'ablation des cornes gray ides au cours de la
| |
| lactation prolongee. Compt. rend. Soc. bioL,
| |
| 147, 2025-2027.
| |
| | |
| Casida, L. E. 1946. Induction of ovulation and
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| | |
| Christian, C. D. 1956. Studies on the neuroendocrine control of ovulation in the rabbit.
| |
| Dissertation, Duke L^niversity.
| |
| | |
| Christian, C. D., M.arkee, S. J., and M.arkee, J. E.
| |
| 1955. Failure of spinal cord transection to
| |
| prevent ovulation following hypothalamic
| |
| stimulation in the rabbit. Anat. Rec. 121, 275.
| |
| | |
| Cl.aesson, L., and Hillarp, N.-A. 1947a. The
| |
| formation mechanism of oestrogenic hormones.
| |
| | |
| I. The presence of an oestrogen-precursor in
| |
| the labbit ovary. Acta physiol. scandinav., 13,
| |
| 115-129.
| |
| | |
| Claesson, L., and Hillarp, N.-A. 1947b. The
| |
| formation mechanism of oestrogenic hormones.
| |
| | |
| II. The presence of oestrogen precursor in the
| |
| OA'aries of rats and guinea-pigs. Acta physiol.
| |
| scandinav., 14, 102-119.
| |
| | |
| Cl.ark. H.M. 1935. A prepubertal reversal of the
| |
| sex difference in the gonadotropic hormone
| |
| content of the pituitary gland of the rat. Anat.
| |
| Rec. 61, 175-192.
| |
| | |
| Cole, H. H. 1946. Estrogen in late pregnancy
| |
| mare serum and ovarian inhibition. Endocrinology, 39, 177-182.
| |
| | |
| Cole, H. H., and Miller, R. F. 1935. Changes
| |
| of the reproducti\e organs of the ewe with
| |
| some data bearing on their control. Am. J.
| |
| Anat., 57, 39-97.
| |
| | |
| Constantinides, p. 1947. Progesterone secretion
| |
| during the oestrous cycle of the unmated rat.
| |
| J. Endocrinol., 5, Ixiv.
| |
| | |
| CoppEDGE, R. L., .AND Segalof^, A. 1951. Urinary
| |
| prolactin excretion in man. J. Clin. Endocrinol., 11,465-476.
| |
| | |
| Corner, G. W. 1937. The rate of .secretion of
| |
| progestin by the corpus luteum. Cold Spring
| |
| Harbor Symposia Quant. Biol., 5, 62-65.
| |
| | |
| Corner, G. W. 1938. The sites of formation of
| |
| estrogenic substances in the animal body.
| |
| Physiol. Rev., 18, 154-172.
| |
| | |
| Corner, G. W. 1940. Rate of secretion of estrogenic hormones by the ovaries of the monkey,
| |
| Macacus rhesus. Bull. Johns Hopkins Hosp.,
| |
| 67, 407-413.
| |
| | |
| Corner, G. W. 1942. The Hormones in Human
| |
| Reproduction. Princeton, X. J.: Princeton
| |
| LTniversity Press.
| |
| | |
| CouRRiER, R. 1956. Remarque sur la greffe d'hypophyse. Arch. Biol., Paris, 67, 461-469.
| |
| | |
| Critchlow, B. v., AND Sawyer, C. H. 1955. Electrical activity of the rat brain correlated with
| |
| | |
| | |
| | |
| 544
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| neurogenic rstinuilation of the adenohypophysis. Fed. Pioc, 14, 32-33.
| |
| Crowe, S. J., Gushing, H., and Homans, J. 1910.
| |
| Experimental hvpophysectomy. Bull. Johns
| |
| Hopkins Hosp., 21, 127-169.
| |
| CrTULY, E. 1941a. Autoplastic grafting of the
| |
| anterior pituitary in male rats. Anat. Rec, 80,
| |
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| Smith, P. E., and Engle, E. T. 1927. Experimental evidence regarding the role of the anterior pituitary in the development and regulation of the genital sy.stem. Am. J. Anat., 40,
| |
| 159-217.
| |
| | |
| SiHTH, P. E., and White, W. E. 1931. The effect
| |
| of hypophy.sectomy on ovulation and corpus
| |
| luteum formation in the rabbit. J. A. M. A.,
| |
| 97, 1861-1863.
| |
| | |
| Spatz, H. 1951. Neues liber die Verkniipfung von
| |
| Hyjjophyse und Hypothalamus. Mit besonderer Beriicksichtigung der Regulation sexueller Leistungen. Acta neuroveg., 3, 5-49.
| |
| | |
| Stafford, W. T., Collins, R. F., and Mossman,
| |
| H. W. 1942. The thecal gland in the guinea
| |
| pig ovary. Anat. Rec, 83, 193-203.
| |
| | |
| Sturgis, S. H. 1949. Rate and significance of
| |
| atresia of the ovarian follicle of the rhesus
| |
| monkey. Contr. Embryol., Carnegie Inst.
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| Washington, 33, 67-80.
| |
| | |
| Sturgis, S. H., ami Mi;i<;s. J. V. 1942. The use of
| |
| estradiol dii'iupionair in the treatment of essential dvsniriKirrliL'a. Surg. Gvnec & Obst.,
| |
| 75, 87-92.
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| | |
| Sulman, F., and Black, R. 1945. The alleged
| |
| endocrine effect of Yohimbine. Endocrinologv,
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| 36,70-71.
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| Swingle, W. W., Seay, P., Perlmutt, J., Collins,
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| |
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| Takasugi, N. 1954. Einfliisse von Androgen und
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| |
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| |
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| Taubenhaus, M., and Soskin, S. 1941. Relea.se
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| Ulberg, L. C. Christian, R. E., and Casida, L. E.
| |
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| 554
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
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| VAN TiENHOVEN, A., NaLBANDOV, A. V., AND NORTON,
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| | |
| | |
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| |
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| |
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| Werthessen, N. T., Schwenk, E., and Baker, C.
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| |
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| |
| | |
| Westman, A. 1934. Untersuchung iiber die Abhangigkeit der P^unktion des Corpus luteum
| |
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| |
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| |
| | |
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| |
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| |
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| | |
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| W^estman, a., and Jacobsohn, D. 1937c. Experimentelle Untersuchungen iiber die Bedeutung
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| |
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| |
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| Westman, A., and Jacobsohn, D. 1938a. Endokrinologische Untersuchungen an Ratten mit
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| durchtrenntem Hypophysenstiel. I. Hypophysenveranderungen nach Kastration untl
| |
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| |
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| |
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| |
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| | |
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| |
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| |
| | |
| Westman, A., and Jacobsohn, D. 1940. Endokrinologische Unteisucliungen an Kaninchen
| |
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| |
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| |
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| |
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| |
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| Williams. P. C. 1940. Effect of stilboestrol on
| |
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| | |
| | |
| MAMMALIAN REPRODUCTIVE CYCLE
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| 555
| |
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| | |
| | |
| the ovaries of hyi>ophyseftomized rats. Nature, London, 145, 388-389.
| |
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| Williams, P. C. 1945a. Ovarian stimulation by
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| WiLLi.AMS, P. C. 1945b. Studies of the biological
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| WiLsox, R. B., R.AXD.ALL, L. M., and Osterberg,
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| J. Obst. & Gynec, 37, 59-74.
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| |
| to vital dyes, with a study of the hypophyseal
| |
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| Wolfe, J. M. 1935. Reaction of ovaries of mature female rats to injection of oestrin. Proc.
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| Wolfe, J. M., and H.a.milton, J. B. 1937. Action
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| of male sex hormone with and without estrin
| |
| in the female rat. Proc. Soc. Exper. Biol. &
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| WoRTHiNGTON, W. C, Jr. 1955. Some observations on the hypophyseal portal system in the
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| XuEREB, G. P., Prichard, M. M. L., and Daniel,
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| P. M. 1954. The hypophysial portal \essels
| |
| in man. Quart. J. Exper. Physiol., 39, 219-230.
| |
| | |
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| Young, W. C, Boling, J. L., and Blandau, R. J.
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| 1941. The vaginal smear picture, sexual receptivity, and time of ovulation in the albino
| |
| rat. Anat. Rec, 80, 37-45.
| |
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| Young, W. C, and Yerkes, R. M. 1943. Factors
| |
| influencing the reproductive cycle in the chimpanzee; the period of adolescent sterility and
| |
| related problems. Endocrinology, 33, 121-154.
| |
| | |
| Z.ARRow, M. X., and Bastian, J. W. 1953. Blockade of ovulation in the hen with adrenolytic
| |
| and parasympatholytic drugs. Proc. Soc. Exper. Biol. & Med., 84, 457-459.
| |
| | |
| Zondek, B., and Aschheim, S. 1927. Hypophysenvorderlappen und Ovarium. Beziehungen der
| |
| endokrinen Driisen zur Ovarialfunktion. Arch.
| |
| Gynak., 130, 1^5.
| |
| | |
| ZucKERMAN, S. 1937. The menstrual cycle of
| |
| primates. X. The oestrone threshold of the
| |
| uterus of the rhesus monkey. Proc. Rov. Soc.
| |
| London, ser. B, 123, 441-471.
| |
| | |
| ZucKERMAN, S. 1941. Periodic uterine bleeding in
| |
| spayed rhesus monkeys injected daily with a
| |
| constant threshold dose of oestrone. J. Endocrinol., 2, 263-267.
| |
| | |
| ZucKERMAN, S. 1952. The influence of environmental changes on the anterior pituitary.
| |
| Ciba Foundation CoUociuia Endocrinol., 4,
| |
| 213-228.
| |
| | |
| ZucKERMAN, S., AND FuLTON, J. F. 1934. The
| |
| | |
| menstrual cycle of the primates. VII. The
| |
| sexual skin of the chimpanzee. J. Anat., 69,
| |
| 38-46.
| |
| ZwARENSTEiN, H. 1937. Experimental induction
| |
| of ovulation with progesterone. Nature, London, 139, 112-113.
| |
| | |
| | |
| | |
| 9
| |
| | |
| | |
| | |
| ACTION OF ESTROGEN AND PROGESTERONE
| |
| | |
| ON THE REPRODUCTIVE TRACT OF
| |
| | |
| LOWER PRIMATES
| |
| | |
| Frederick L. Hisaw, Ph.D.
| |
| | |
| THE BIOLOGICAL LAB0RAT0RIF:S, HARVARD TNIVERSITY, CAMBRIDGE,
| |
| MASSACHUSETTS
| |
| | |
| and ^
| |
| | |
| Frederick L. Hisaw, Jr., Ph.D.
| |
| | |
| DEPARTMENT OF ZOOLOGY, OREGON STATE COLLEGE, CORVALLIS,
| |
| OREGON
| |
| | |
| | |
| | |
| I. Introduction 556
| |
| | |
| II. Ovarian Hormones and Growth of
| |
| | |
| THE Genital Tract 558
| |
| | |
| III. Effects of Progesterone on the
| |
| | |
| Uterus 565
| |
| | |
| IV. Synergism between Estrogen and
| |
| | |
| Progesterone 567
| |
| | |
| V. Experimentally Produced Implantation Reactions 571
| |
| | |
| VI. The Cervix Uteri 572
| |
| | |
| VII. The Vagina 575
| |
| | |
| VIII. Sexual Skin 576
| |
| | |
| IX. Menstruation 578
| |
| | |
| X. The Mechanism of Menstru.^tion. . 583
| |
| XI. References 586
| |
| | |
| I. Introduction
| |
| | |
| Cyclic menstruation is the most characteristic feature of primate reproduction, and
| |
| distinguishes it from the estrous cycle of
| |
| lower mammals. This cardinal primate
| |
| event is heralded by the bloody uterine
| |
| effluent emanating from the vagina, whereas
| |
| in estrus the dominant characteristic is a
| |
| sudden modification in behavior featuring
| |
| an intense mating drive. However, the internal secretions that regulate the various
| |
| events in the menstrual and estrous cycles
| |
| are the same, and this similarity is fundamentally more significant than the key descriptive differences just mentioned. Estrus
| |
| comes at the peak of the growth phase of the
| |
| cycle and is associated with ovulation. In
| |
| | |
| | |
| | |
| contrast, menstruation occurs in the cycle
| |
| midway between times of ovulation and is
| |
| not accompanied by an increase in sexual
| |
| activity. From earliest times menstruation
| |
| has been recognized as degenerative: the
| |
| characteristic odor, and the necrotic changes
| |
| in the lining of the uterus, part of which is
| |
| cast off at this time, sustain this interpretation. Therefore, menstruation is at the
| |
| opposite phase of the cycle from estrus. It
| |
| is such an obvious event that menstrual
| |
| cycles are dated from the onset of bleeding.
| |
| Menstruation is not analogous to the proestrous bleeding in the dog or cow nor to the
| |
| slight bleeding of primates at midpoint between menstrual periods (Hartman, 1929).
| |
| The study of menstruation was at first almost entirely the province of the clinician
| |
| and the material for investigation limited to
| |
| w^omen. Hitschmann and Adler (1907),
| |
| Meyer (1911), Schroder (1914). Novak and
| |
| Te Linde (1924), and Bartelmez (1933) are
| |
| among many of the earlier investigators who
| |
| contributed descriptions of the cyclic
| |
| changes in the human endometrium. The
| |
| physiology of the menstrual cycle and attendant morphologic changes have continued to be an area of active research interest
| |
| in science and medicine. Among the many
| |
| more recent contributors are Bartelmez
| |
| | |
| | |
| | |
| 556
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 557
| |
| | |
| | |
| | |
| (1937), Latz and Reiner (1942), Haman
| |
| (1942), Knaus (1950), Mazer and Israel
| |
| (1951), and Crossen (1953).
| |
| | |
| The earlier concepts regarding the menstrual cycle were based primarily on the
| |
| changes occurring in the human endometrium and for convenience of description the
| |
| cycle was divided into four stages or periods. The first of these was the period of
| |
| active menstruation, and the length of the
| |
| cycle was dated from its onset. Most authors agreed that menses began by leaking
| |
| of blood from superficial vessels to form
| |
| lakes under the surface epithelium and that
| |
| there was some sloughing of tissue after the
| |
| beginning of bleeding. There was considerable disagreement as to the amount of destruction and loss of tissue; estimates of
| |
| various authors ranged from very little to
| |
| almost complete denudation of the surface.
| |
| Bartelmez (1933) emphasized both the wide
| |
| individual variability of the amount of tissue lost and differences in the stage of development of the endometria at the time of
| |
| menstruation.
| |
| | |
| The second period immediately following
| |
| menstruation began with regeneration of the
| |
| surface epithelium, which started sometimes
| |
| before menstrual bleeding had ceased and
| |
| was completed in a very short time. This
| |
| lieriod included the 5 to 7 days after cessation of menses, during which the endometrium grew in thickness. Frequent mitoses
| |
| were recognized, especially in the glands
| |
| which lengthened but remained straight and
| |
| tubular.
| |
| | |
| The third ("interval") period, lasting 6
| |
| to 10 days, was characterized by a somewhat thickened endometrium, still with
| |
| straight glands and showing little evidence
| |
| of secretory activity. At first this was considered a quiescent period as indicated by
| |
| the term "interval." However, as will be
| |
| shown later, such a characterization was not
| |
| justified from the physiologic viewpoint.
| |
| | |
| The fourth period, called the premenstrual period, included the 10 days or 2
| |
| weeks before menstruation. During this
| |
| phase the glands continued to increase in
| |
| size and became distended, coiled, or even
| |
| sacculated. The glandular cells increased
| |
| in height, and there was evidence of glycogen mobilization and secretion. Next, the
| |
| epithelium became "frayed out" along the
| |
| | |
| | |
| | |
| outer borders, then decreased in height, indicating secretory depletion. Decidual cells
| |
| appeared in the stroma at this time. The
| |
| endometrium was much thickened and extremely hyperemic. At the height of this
| |
| period the endometrium was approximately
| |
| 5 mm. in thickness, as compared with V2
| |
| mm. toward the end of menses. The term
| |
| premenstrual was usually applied to this
| |
| phase but today the term progestational
| |
| would seem preferable.
| |
| | |
| During and after these descriptions of the
| |
| changes in the human endometrium, many
| |
| attempts were made to locate the time of
| |
| ovulation in the menstrual cycle. When it
| |
| was found, as will be discussed later, that
| |
| ovulation occurred approximately midway
| |
| between two menses, and was preceded by
| |
| follicular growth and followed by development of a corpus luteum, it became customary to refer to the two halves of the menstrual cycle as the follicular phase and the
| |
| luteal phase. One advantage of this descriptive terminology was the emphasis it placed
| |
| on the homology of the two phases of the
| |
| menstrual cycle in primates with the follicular and luteal phases of the estrous cycles of lower mammals.
| |
| | |
| A theory to explain menstruation, widely
| |
| adopted in 1920, was formulated from this
| |
| morphologic evidence. The essentials were
| |
| that menstruation occurs because the lining
| |
| of the uterus, prepared for implantation of
| |
| the ovum, degenerates if fertilization of the
| |
| egg does not occur. This required that ovulation and corpus luteum formation precede
| |
| the i^remenstrual changes in the endometrium. Subsequent research disclosed that
| |
| menstrual cycles frequently occur in which
| |
| ovulation does not take place and bleeding
| |
| results from the breakdown of an "interval"
| |
| rather than a progestational endometrium.
| |
| | |
| The discovery of anovulatory cycles not
| |
| only brought about a revision of ideas regarding an explanation for menstruation
| |
| but also raised questions as to what constituted a normal menstrual cycle. The length
| |
| of the cycle and the amount and duration of
| |
| bleeding are approximately the same regardless of whether or not ovulation has
| |
| taken place. The gross features of menstruation under these two conditions are indistinguishable one from the other. However,
| |
| the biologic purpose of the menstrual cycle
| |
| | |
| | |
| | |
| 558
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| is reproduction wliicli obviously cannot l)0
| |
| fulfilled unless an ovum is made available
| |
| for fertilization. Therefore, in this sense it
| |
| seems quite clear that anovulatory cycles
| |
| should be considered incomplete and abnormal.
| |
| | |
| The investigation of changes taking place
| |
| in the uterine endometrium at various periods of the menstrual cycle in women was
| |
| confronted with many difficulties, the chief
| |
| one being that of obtaining normal tissue
| |
| representative of specific times of the cycle.
| |
| The entire uterus and both ovaries are essential for proper evaluations and it was
| |
| rarely possible to meet these requirements.
| |
| The material for such studies came from
| |
| autopsies and surgery and tissues usually
| |
| had suffered postmortem changes or the
| |
| surgical condition was one involving serious
| |
| pelvic disease. There have been, however,
| |
| a goodly number of instances in which
| |
| these difficulties were adequately overcome
| |
| (Stieve, 1926, 1942, 1943, 1944; Allen, Pratt,
| |
| Newell and Bland, 1930) and the clinic will
| |
| continue to make important contributions
| |
| (Rock and Hertig, 1942; Hertig and Rock,
| |
| 1944), but quite early the need became obvious for a suitable primate that could be
| |
| used as an experimental animal for research
| |
| on the different aspects of the physiology
| |
| of reproduction.
| |
| | |
| Since the initial observations by Corner
| |
| (1923) on the menstrual cycles of captive
| |
| rhesus monkeys iMacaca mulatta) , more
| |
| has been learned about the physiology of
| |
| reproduction of this animal than any other
| |
| primate. Monkeys of this species thrive under laboratory conditions, which has made
| |
| it possible to devise accurately controlled
| |
| experiments on normal healthy animals and
| |
| obtain reliable information on the menstrual cycle, gestation, fetal development,
| |
| and the interaction of hormones concerned
| |
| with regulating reproductive processes.
| |
| | |
| Other features that make the rhesus monkey such an attractive animal for these purposes are the many morphologic and physiologic attributes that are strikingly like
| |
| those of the human being. Tiic modal length
| |
| of their menstrual cycles is 28 days but
| |
| there is wide variation (Corner, 1923; Hartman, 1932; Zuckcrman, 1937a). From an
| |
| analysis of 1000 cycles recorded for some
| |
| 80 females of different ages, Zuckerman
| |
| | |
| | |
| | |
| (1937a) found an average cycle length of
| |
| 33.5 ± 0.6 days, and the mode 28 days with
| |
| an over-all range of 9 to 200 days. Ovulation
| |
| occtu's api:)roximately midway between two
| |
| menstrual periods, most between the 11th
| |
| and 14th days (Hartman, 1932, 1944; van
| |
| Wagenen, 1945, 1947), and although these
| |
| animals breed at all seasons of the year
| |
| many cycles are anovulatory, especially
| |
| during the hot summer months (Eckstein
| |
| and Zuckerman, 1956). A method developed
| |
| by Hartman for detecting the exact time of
| |
| ovulation by palpation of the ovaries in the
| |
| unanesthetized animal greatly facilitated
| |
| the timing of events of the menstrual cycle.
| |
| This procedure also made it possible to determine the age of corpora lutea with great
| |
| accuracy (Corner, 1942, 1945) and correlate their develojiment and involution with
| |
| corresponding changes in the endometrium
| |
| (Bartelmez, 1951 ) and, in ju-egnancy, with
| |
| the exact age of developing embryos ( Wislocki and Streeter, 1938; Heuser and
| |
| Streeter, 1941).
| |
| | |
| The primary purpose of the present discussion is to review the results of experimental investigations of physiologic processes occurring in the female reproductive
| |
| tract of lower primates during the menstrual
| |
| cycle, and particularly those processes that
| |
| are under hormonal control. The brief introductory presentation of basic observations could be greatly extended and we take
| |
| up the discussion of endocrine problems
| |
| knowing that we must return often to the
| |
| work of these authors and that of others to
| |
| be cited, as conclusions based on experimental data take on meaning only in terms
| |
| of normal function.
| |
| | |
| II. Ovarian Hormones and Growth
| |
| of the Genital Tract
| |
| | |
| The changes that are repeated in different parts of the reproductive tract with each
| |
| menstrual cycle are produced by ovarian
| |
| hormones, estrogens, and progesterone. The
| |
| dominant hormone of the follicular phase is
| |
| estradiol-17/y, which is secreted by the
| |
| Graafian follicle, and in the tissues is readily transformed in i)art to estrone, an estrogenic metabolite. Progesterone, secreted by
| |
| the corinis luteum, is jirimarily a hormone
| |
| of the luteal phase of the cycle. However,
| |
| small amounts of progesterone may appear
| |
| | |
| | |
| | |
| ESTROGEX AND PROGESTERONE
| |
| | |
| | |
| | |
| 559
| |
| | |
| | |
| | |
| ill the blood of monkeys as early as the 7th
| |
| (lay and attain a concentration of 1 fxg. per
| |
| ml. of serum at ovulation, whereas a maximal concentration of 10 /xg. per ml. is
| |
| reached at approximately the middle of the
| |
| luteal phase (Forbes, Hooker and Pfeiffer,
| |
| 1950; Bryans, 1951). Also, some estrogen is
| |
| present during the luteal phase, probably
| |
| secreted by the corpus luteum (estrogens
| |
| can be obtained from luteal tissue) or it
| |
| may be partially derived from developing
| |
| follicles. It is unlikely that estrogen is ever
| |
| entirely absent during a normal menstrual
| |
| cycle or that the presence of progesterone is
| |
| completely restricted to the luteal phase.
| |
| | |
| The dependence of the reproductive tract
| |
| on ovarian hormones is strikingly demonstrated by the profound atrophy that follows surgical removal of the ovaries. A progressive decrease in size of the Fallopian
| |
| tubes, uterus, cervix, and vagina takes place,
| |
| and usually, the involution of the uterine
| |
| endometrium involves tissue loss and bleeding, commonly referred to as post castrational bleeding. Dramatic as these effects
| |
| may seem, it is equally dramatic to find
| |
| that these atrophic structures can be restored entirely to their original condition by
| |
| the administration of ovarian hormones.
| |
| Therefore, it is seen at the beginning that
| |
| investigations dealing with the physiology
| |
| of the female reproductive tract of primates
| |
| in large measure involve a study of the independent and combined actions of estrogens and progesterone on the activities of
| |
| the various structures concerned.
| |
| | |
| Much can be learned about the action of
| |
| ovarian hormones by observing the changes
| |
| they produce in the gross appearance of the
| |
| atrophied reproductive tract of castrated
| |
| animals. Daily injections of an estrogen in
| |
| doses equivalent to 1000 I.U. or more for
| |
| 10 days or a fortnight will restore the uterus,
| |
| cervix, and vagina to a condition comparal)le with that found in a normal monkey at
| |
| the close of the follicular phase of a menstrual cycle (Fig. 9.1A). If a similar castrated monkey is given 1 or 2 mg. of progesterone daily for the same length of time,
| |
| very little if any change in size of the reproductive organs results. However, if first
| |
| the normal condition is restored by giving
| |
| estrogen and then is followed by the progesterone treatment, the size of the uterus
| |
| | |
| | |
| | |
| is maintained but that of the cervix and
| |
| vagina decreases to an extent approaching
| |
| that in a castrated animal (Fig. 9.1B). Such
| |
| experiments show that an estrogen promotes
| |
| growth of the reproductive tract whereas
| |
| progesterone is comparatively ineffective
| |
| when given alone. Yet progesterone can
| |
| maintain the size of the uterus when administered following an estrogen treatment but
| |
| it does not prevent involution of the cervix
| |
| and vagina.
| |
| | |
| An additional feature of the growth-stimulating action of the ovarian hormones is
| |
| brought out when estrogen and progesterone
| |
| are administered concurrently. If, after repair of the reproductive tract of a castrated
| |
| animal has been accomplished by a series of
| |
| injections of estrogen, both estrogen (1000
| |
| I.U.) and progesterone (1 or 2 mg.) are
| |
| given daily for 20 days, it will be found that
| |
| the uterus is larger than when either hormone is given alone for a similar length of
| |
| time, whereas the cervix and vagina have
| |
| involuted and are approximately the size
| |
| found in animals given only progesterone.
| |
| Thus it can be demonstrated that a synergistic effect on growth of the uterus occurs
| |
| when the two hormones are given simultane
| |
| | |
| | |
| | |
| FiG. 9.1. Reproductive tracts of three adolescent
| |
| monkeys which were castrated and given estrogen
| |
| daily for approximately 3 weeks. A shows the condition at the conclusion of the estrogen treatment,
| |
| B the condition following the injection of progesterone for an additional three weeks, and C the
| |
| effects of continuing the treatment with both estrogen and progesterone for a like period.
| |
| | |
| | |
| | |
| 560
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| ously whereas in the cervix and vagina the
| |
| growth -stimulating action of estrogen is
| |
| inhibited by progesterone (Fig. 9.1C). This
| |
| presents a most interesting situation in
| |
| which the combined actions of two hormones on three closely associated structures
| |
| of the reproductive tract join in a synergistic effort in promoting the growth of the
| |
| uterus although progesterone prevents estrogen from affecting growth of the cervix
| |
| and vagina.
| |
| | |
| These changes in gross morphology in
| |
| response to the ovarian hormones are reflected in the histology of the responding
| |
| tissues. Also, the character of the response
| |
| differs depending upon the physiologic nature of the tissue concerned; therefore, for
| |
| the sake of clarity each will be discussed
| |
| separately. The first of these to be considered is the uterus and particularly growth
| |
| of the endometrium.
| |
| | |
| | |
| | |
| It has been reported (Hisaw, 1935, 1950)
| |
| that growth of the endometrium, as induced
| |
| by estrogen, is limited. That is, a dosage of
| |
| estrogen capable of maintaining the endometrium of a castrated animal for an indefinite period without the occurrence of
| |
| bleeding, stimulates rapid growth for approximately the first 2 weeks. Within this
| |
| time a maximal thickness of the endometrium is attained which remains constant or
| |
| may become less during the course of treatment (Fig. 9.2). Engle and Smith (1935)
| |
| made similar observations. They found that
| |
| the endometria of castrated monkeys receiving estrogen for 100 days or longer were
| |
| thinner than endometria of animals on estrogen for a much shorter time. Also, on
| |
| prolonged treatment, the stroma of the endometrium becomes dense and the lumen
| |
| small whereas the size of the uterus remains
| |
| about the same. In fact, they state that in
| |
| | |
| | |
| | |
| | |
| I'll,. (1.2. I'll n Ml lour i-a.-^tra(c>d monkeys wliicli were givi^i 10 /ug. estradiol daily for 10
| |
| to 78 days. A was given estrogen for 10 days, B for 30 days, C for 60 days, and D for 78
| |
| days. Depression in the endometrium of anterior wall of D is the result of a biopsy taken
| |
| a year previously. (From F. L. Hisaw, in A Si/niposium on Steroid Hormones, University
| |
| of Wisconsin Press, 1950.)
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 561
| |
| | |
| | |
| | |
| four experimental animals the only well developed fundus was found in the animal on
| |
| the shortest treatment, i.e., 60 days.
| |
| | |
| The mitotic activity in the epithelium of
| |
| the glands and surface mucosa also indicates
| |
| a limited effect of estrogen. This can be
| |
| demonstrated to best advantage in the endometria of castrated monkeys that have been
| |
| on estrogen for different lengths of time and
| |
| have received an injection of colchicine 8
| |
| hours before their uteri were removed. A
| |
| comparison of the number of cells in mitosis
| |
| per square centimeter of surface mucosa at
| |
| 10, 30, 45, and 60 days is shown in Figure
| |
| 9.3. From this it can be seen that mitotic
| |
| activity approaches that in a castrated animal. Although the five points used in drawing the curve are quite inadequate for an
| |
| accurate analysis of the mitotic response in
| |
| the epithelial components of the endometrium, they do show that cell division is
| |
| most rapid soon after the beginning of an
| |
| estrogen treatment and subseciuently declines.
| |
| | |
| The loss of responsiveness of the endometrium to estrogen seems related more to the
| |
| length of treatment than to dosage of hormone. An endometrium of normal thickness
| |
| can be produced in 2 or 3 weeks at a dosage
| |
| level of estrogen that will not maintain the
| |
| growth induced for longer than about 40
| |
| days without bleeding (Hisaw, 1935; Engle
| |
| and Smith, 1935; Zuckerman, 1937b). The
| |
| response to a low dosage of estrogen that
| |
| will prevent bleeding during the course of
| |
| treatment (about 10 /xg. estradiol-17/8 daily)
| |
| is one of rapid endometrial growth at first,
| |
| as has been described, followed by a thinning of the endometrium. The refractoriness
| |
| of the endometrium to estrogen becomes so
| |
| pronounced after about 100 days of treatment that very few cell divisions are seen in
| |
| the epithelium of the glands and surface
| |
| mucosa. The general morphology of the endometrium retains the characteristic appearance of the follicular phase of the menstrual cycle except that the stroma is
| |
| usually more dense and the cells of the
| |
| glandular epithelium have large deposits of
| |
| glycogen between the nucleus and the basement membrane. However, metabolically
| |
| such endometria are surprisingly inactive.
| |
| Although they are dependent on the presence of estrogen and may bleed within about
| |
| | |
| | |
| | |
| Mitotic Response of
| |
| Uterine Lpithelium
| |
| TO looo I. u. Estrogen
| |
| PER D«y.
| |
| | |
| | |
| | |
| | |
| Fig. 9.3. The number of mitoses per square centimeter of surface epithelium of the endometrium in
| |
| a castrated monkey and in four castrated animals
| |
| given 10 /xg. estradiol daily for 10, 30, 45, and 60
| |
| days, respectively. One-tenth of actual number of
| |
| mitoses is shown on the ordinate. (From F. L.
| |
| Hisaw, in A Symposium on Steroid Hormones, University of Wisconsin Press, 1950.)
| |
| | |
| 48 hours if the treatment is stopped, the
| |
| activity of their oxidative enzymes and the
| |
| ratio of nucleoproteins (RNA:DNA) are
| |
| about the same as in the involuted endometria of castrated animals.
| |
| | |
| The effects that accompany moderate estrogenic stimulation become exaggerated in
| |
| several respects when large doses of estrogen
| |
| are given for an extended period. The disparity between the area of myometrium and
| |
| endometrium becomes greater as the treatment progresses (Fig. 9.4). Kaiser (1947)
| |
| described the destruction of the spiraled
| |
| arterioles of the endometrium in monkeys
| |
| given large doses of estrogen and Hartman,
| |
| Geschickter and Speert (1941) reported the
| |
| reduction of the reproductive tract to the
| |
| size of that of a juvenile animal by the end
| |
| of 18 months during which injections of
| |
| large doses of estrogen were supplemented
| |
| by subcutaneous implantation of estrogen
| |
| pellets. These observations not only show
| |
| that the endometrium becomes unresponsive
| |
| to estrogen when the treatment is prolonged
| |
| but that large doses produce injurious effects.
| |
| | |
| | |
| | |
| 562
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 9.4. .4. i'v'< — ' ri:,,ii of the uterus of a castrated monkey which had received 1.0 mg. estradiol
| |
| daily for 35 days. Compare with B which shows the
| |
| effects of 1/10 this dosage (100 fig. daily) when
| |
| gi\en for 185 days.
| |
| | |
| The limited response of the endometrium
| |
| to estrogen is in some respects surprising in
| |
| view of its remarkable growth potentialities and regenerative capacity. These qualities were dramatically demonstrated by
| |
| Hartman (1944) who dissected out as carefully as possible all of the endometrium
| |
| from the uterus of a monkey and wiped the
| |
| uterine cavity with a rough swab and yet
| |
| the undetected endometrial fragments that
| |
| remained were capable of restoring the entire structure. Also, considering the enormous increase in size of the uterus during
| |
| gestation, it is even more difficult to account for the rather sharp limitation of
| |
| growtli under the influence of estrogen.
| |
| | |
| The increase in tonus of the uterine musculature, a known effect of estrogen, has
| |
| been considered as possibly exercising a restrictive influence on growth of the endo
| |
| | |
| | |
| metrium. An attempt has been made to remove this containing influence the muscle
| |
| may have by making an incision through
| |
| the anterior wall of the uterus (Hisaw,
| |
| 1950) . A castrated monkey was given 10 ixg.
| |
| estradiol daily for 21 days at which time the
| |
| operation was performed and the treatment
| |
| continued with 30 ^g. estradiol daily for 40
| |
| days. The uterus was laid open by a sagittal incision from fundus to cervix and most
| |
| of the endometrium was removed from the
| |
| anterior wall. This caused gaping of the incised uterus and exposure of the endometrium on the posterior wall. The incision
| |
| was not closed and after hemorrhage was
| |
| completely controlled the uterus was returned to the abdomen.
| |
| | |
| Examination of the uterus at the conclusion of the experiment showed no indications
| |
| that endometrial growth had been enhanced.
| |
| The muscularis had reunited and only a few
| |
| small bits of endometrium were found in the
| |
| incision (Fig. 9.5). It seemed probable that
| |
| the purpose of the experiment had been defeated by rapid repair of the uterus. Therefore, a similar experiment was done in which
| |
| the musculature of the incised uterus was
| |
| held open by suturing a wire loop into the
| |
| incision. Yet the incision closed and no unusual growth of the endometrium was detected (Fig. 9.6).
| |
| | |
| Observations under these conditions are
| |
| necessarily limited to those made on the
| |
| uterus when it is removed at the conclusion
| |
| of an experiment and comparisons must be
| |
| made between uteri of different animals.
| |
| Obviously, it would be more desirable if the
| |
| response of an individual endometrium
| |
| could be followed during the course of treatment. It is possible to meet most of these
| |
| requirements under conditions afforded by
| |
| utero-abdominal fistulae, exteriorized uteri,
| |
| and endometrial implants in the anterior
| |
| chamber of the eye. In continuing our discussion we first shall present information
| |
| obtained by such techni(iues that have a
| |
| bearing on the response of the endometrium
| |
| to estrogen.
| |
| | |
| The surgical procedure used by Hisaw
| |
| ( 19501 for preparing utero-abdominal fistulae foi' studies of the exj^erimental induction
| |
| of endometrial growth by estrogen and progesterone was a modification of that used
| |
| by van Wagenen and Morse (1940) for ob
| |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 563
| |
| | |
| | |
| | |
| | |
| Figs. 9.5 and 9.6
| |
| | |
| The uteri of these two castrated monkeys were opened from fundus to cer\'ix by an incision
| |
| through the anterior wall while the animals were receiving estrogen. Part of the endometrium
| |
| of the anterior wall was removed and the incision in the myometrium was not closed.
| |
| | |
| Fig. 9.5. Estradiol, 10 fig., was given daily for 7 days; the uterus was opened and the animal
| |
| continued on 30 /xg. estradiol daily for 40 days. (From F. L. Hisaw, in A Sy7nposiii7n on Steroid
| |
| Hormones, University of Wisconsin Press, 1950.)
| |
| | |
| Fig. 9.6. Estradiol, 10 ^g., was given daily for 7 days; the uterus was opened and the treatment continued at a dosage of 30 /ig. estradiol daily for 20 days. (From F. L. Hisaw, in A
| |
| Symposium on Steroid Hormones, University of Wisconsin Press, 1950.)
| |
| | |
| | |
| | |
| serving changes in the endometrium (luring
| |
| the normal menstrual cycle. This procedure
| |
| makes frequent inspections possible either
| |
| by hand lens or dissecting microscope, of
| |
| most of the upper part of the endometrium
| |
| on the anterior and posterior walls of the
| |
| uterus. The elliptic slit formed by the endometrium of the two opposing walls can be
| |
| located easily, the two sides pressed apart
| |
| by any small smooth instrument, and the
| |
| surface of the endometrium examined.
| |
| Changes in thickness of the endometrium
| |
| cannot be ascertained without resorting to
| |
| biopsies but it is free to grow out of the
| |
| opened uterus if it is so inclined. However,
| |
| in such preparations the growth produced in
| |
| the endometrium by daily injections of 10
| |
| fjig. estradiol for periods of 2 or 3 weeks is
| |
| not sufficient to show any tendency whatever to grow out through the fistular opening or obstruct examination of the walls of
| |
| the uterus. The limited growth observed in
| |
| these experiments is in agreement with that
| |
| obtained with estrogen on intact and incised
| |
| uteri.
| |
| | |
| The cervix uteri of the rhesus monkey is
| |
| sufficiently long to make it possible to bring
| |
| the entire fundus to the exterior through a
| |
| midal)dominal incision. Advantage of this
| |
| | |
| | |
| | |
| was taken in an attempt to exteriorize the
| |
| uterus and maintain it outside the body for
| |
| long enough periods to make it possible to
| |
| study the growth responses of the endometrium (Hisaw, 1950). These preparations
| |
| did not i)rove satisfactory in all respects but
| |
| they did contribute a number of interesting
| |
| observations.
| |
| | |
| The operational i^rocedure used in these
| |
| experiments involved dividing the uterus
| |
| transversely from fundus to cervix so that
| |
| the anterior wall was deflected downward
| |
| and the posterior wall upward (Fig. 9.7).
| |
| The endometrium of the exteriorized uterus
| |
| is difficult to maintain but with proper care
| |
| it seems to retain its normal condition for
| |
| at least the first few days after the uterus
| |
| is opened. Small localized areas of ischemia
| |
| can be seen to come and go, probably action
| |
| of the coiled arteries, and there is a periodic
| |
| general blanching of the endometrium associated with rhythmic contractions of the
| |
| muscularis. This, however, does not seem
| |
| true of the whole endometrium. A zone surrounding the internal os of the cervix tends
| |
| to retain its blood-red color even during
| |
| strong contractions of the uterus and the
| |
| growth reactions of the endometrium in this
| |
| area are of particular interest.
| |
| | |
| | |
| | |
| 564
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 9.7. Exteriorized uteii. The uteri were divided transversely from fundus to cervix.
| |
| The anterior half is seen deflected to the right and the posterior half to the left. A and B
| |
| are of the same uterus taken 13 days after exteriorization showing the "blush" and "blanch"
| |
| reaction of uterine contractions. It can be seen that during blanching the endometrium
| |
| of the cervix does not become ischemic. C. Uterus 18 days after exteriorization, showing
| |
| response to estrogen. Ridges formed by growth of the endometrium surrounding the internal OS of the cervix can be seen at the upper edge of the photograph. D, taken 83 days
| |
| after exteriorization, shows response produced by a series of injections of 10 ^ig. estradiol
| |
| and 1 mg. progesterone daily. The transverse ridge is formed by the two opposed lips of
| |
| endometrium derived from the area surrounding the internal os of the cervix. Growth when
| |
| the two hormones are given is greater than when only estrogen is injected. (From F. L.
| |
| Hisaw, in A Symposium on Steroid Hormones, University of Wisconsin Press, 1950.)
| |
| | |
| | |
| | |
| The endometrium on the exposed anterior
| |
| and posterior halves of the uterus underwent
| |
| deterioration despite the best of care that
| |
| could be given, but that surrounding the internal OS of the cervix survived and retained
| |
| its capacity to grow, in one animal, for as
| |
| long as 9 months. When estrogen was given
| |
| this endometrium grew rapidly and within
| |
| a few days stood out as large elliptic lips
| |
| surrounding the internal os (Fig. 9.7).
| |
| Within 2 to 3 weeks the lips appeared to
| |
| reach their full size and further growth was
| |
| slow or absent. When estrogen treatments
| |
| were discontinued the endometrial lips underwent bleeding within a few days and
| |
| were entirely lost. At no time were activities
| |
| observed that could be ascribed to coiled
| |
| arterioles, nor did ischemia occur during involution previous to bleeding. It seems that
| |
| the response of this tissue to estrogen is like
| |
| that found in other experiments but the absence of ischemia preceding bleeding is ex
| |
| | |
| | |
| ceptional. The endometrium on the anterior
| |
| and posterior walls of uterine fistulae invariably showed ischemia for several hours
| |
| before active bleeding following the withdrawal of estrogen.
| |
| | |
| Markee (1940) approached the problem
| |
| of endometrial growth in monkeys by studying the changes that occur in bits of endometrial tissue transplanted to the anterior
| |
| chamber of the eye. Such transplants retain
| |
| in large measure the normal morphology of
| |
| endometrial tissue and changes in their cyclic growth parallel those going on simultaneously in the uterus. So much so that if
| |
| the animal has an ovulatory cycle, the ocular implants show conditions characteristic
| |
| of both the follicular and luteal phases, but
| |
| if ovulation fails to occur then the luteal
| |
| phase is omitted. Also, the morphologic
| |
| events taking place at menstruation can be
| |
| seen and recorded, since the transplants regress and bleed at each menstrual period.
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 565
| |
| | |
| | |
| | |
| These ingenious experiments will be referred
| |
| to often in the course of our discussion but
| |
| at present the response of endometrial
| |
| transplants in the eye to estrogen is of primary interest.
| |
| | |
| Monkeys having ocular transplants were
| |
| given 200 to 300 R.U. of estrone daily for
| |
| about 1 to 3 months. The transplants did
| |
| not grow to a certain size and then remain
| |
| stationary, but instead periods of rapid
| |
| growth were interrupted by periods of regression which usually involved a marked
| |
| decrease in size, and if regression was extensive and rapid, bleeding ensued. It also
| |
| was found that these episodes of regression
| |
| in the transplants were usually accompanied
| |
| by a decrease in the size of the uterus.
| |
| | |
| Comparisons between the results of these
| |
| experiments and those we have discussed
| |
| previously may be misleading since it seems
| |
| that only 1 of the 5 animals (no. 295) used
| |
| was castrated. Also, the dosage of estrogen
| |
| was not sufficient to maintain the endometrium of the uterus for an indefinite period
| |
| without bleeding and this also was reflected
| |
| in the transplants. It seems questionable
| |
| that the growth capacity of endometrial
| |
| transplants in the eye can be determined unless sufficient estrogen is given to prevent
| |
| bleeding in the uterus. Therefore, it would
| |
| seem that these experiments contribute less
| |
| to an analysis of the effects of estrogen on
| |
| endometrial growth than they do to an understanding of the events that precede and
| |
| accompany menstruation.
| |
| | |
| In summary, it seems clear that the outstanding effect of estrogen on the uterus of
| |
| the monkey is one of growth (Allen, 1927,
| |
| 1928). The involuted uterus of a castrated
| |
| animal can be restored to its normal size in
| |
| 2 or 3 weeks by daily injections of adequate
| |
| amounts of estrogen. At this time there is an
| |
| increase in vascularity, a clear-cut hyperemia as seen in rodents. There also is secretion of luminal fluid (Sturgis, 1942) but this
| |
| does not distend the uterus as in the mouse
| |
| and rat. This is accompanied by an increase
| |
| in tissue fluid, especially in epithelial tissues
| |
| (surface epithelium and glands) , and in the
| |
| connective tissue of the stroma. Glycogen
| |
| may be present at the basal ends of epithelial cells beneath the nuclei (Overholser and
| |
| Nelson, 1936) but it apparently is not readily released under the action of estrogen
| |
| | |
| | |
| | |
| alone (Lendrum and Hisaw, 1936; Engle
| |
| and Smith, 1938) . The glands of the endometrium maintain a straight tubular structure with some branching near the muscle
| |
| layers. The condition produced experimentally in the monkey's uterus by short term
| |
| treatments with estrogen is equivalent to
| |
| that present in the normal animal at midcycle, or even a few days later if ovulation
| |
| does not occur.
| |
| | |
| If, however, an estrogen treatment is continued for several months conditions develop in the uterus that are not found
| |
| during the follicular phase of a normal menstrual cycle. When the daily dose of estrogen
| |
| is small menstruation occurs at intervals
| |
| during the treatment (Zuckerman, 1937b)
| |
| and probably marks periods of endometrial
| |
| regression as observed by Markee (1940) in
| |
| eye transplants, but if the dosage is increased by a sufficient amount (about 10
| |
| /xg. estradiol- 17/3 daily) injections may be
| |
| continued for a year or longer without
| |
| bleeding. Although the size of the uterus remains within the range of normal variation
| |
| as the injections are continued, the myometrium tends to increase in thickness and the
| |
| endometrium becomes thinner, a condition
| |
| not corrected by further increases in dosage
| |
| or by prolonging the treatment. The cause
| |
| responsible for the limited response of the
| |
| endometrium under these conditions is not
| |
| known but apparently is not a restrictive influence of the myometrium as similar responses are given when the endometrium is
| |
| exposed by incising the uterus, in abdominal
| |
| fistulae, and in exteriorized uteri.
| |
| | |
| III. Effects of Progesterone
| |
| on the Uterus
| |
| | |
| It has been mentioned that a menstrual
| |
| cycle, in which ovulation occurs, can be conveniently divided into a follicular and a
| |
| luteal phase. The follicular phase extends
| |
| from menstruation to ovulation and the
| |
| luteal phase from ovulation to the following
| |
| menstruation. It has been shown in the
| |
| previous discussion that the endometrial
| |
| modifications characteristic of the follicular
| |
| phase of the cycle can be duplicated in a
| |
| castrated monkey by the injection of estrogen. Likewise, the progestational condition
| |
| characteristic of the luteal phase can be developed by giving progesterone. In fact, all
| |
| | |
| | |
| | |
| 566
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| the morphologic and physiologic features
| |
| that are known for anovulatory and ovulatory cycles can be reproduced in castrated
| |
| monkeys by estrogen and progesterone.
| |
| | |
| If one designs an experiment to simulate
| |
| the normal cycle in a castrated monkey
| |
| then estrogen should be given first to develop the conditions of the follicular phase
| |
| followed by progesterone for the progestational development of the luteal phase. Experience has shown that this is the most effective procedure for the production of a
| |
| progestational endometrium. Progesterone,
| |
| as compared with estrogen, is a weak growth
| |
| jH'omoter and although it can produce progestational changes in the atrophic endometrium of a castrated monkey when given in
| |
| large doses, its action is greatly facilitated
| |
| when preceded by estrogen. The first experiments in which progesterone was used
| |
| for this purpose were planned on this principle (Hisaw, Meyer and Fevold, 1930; Hisaw, 1935; Engle, Smith and Shelesnyak,
| |
| 1935).
| |
| | |
| The first noticeable effect of progesterone
| |
| is an elongation of the epithelial cells of the
| |
| surface membrane and necks of the glands.
| |
| When the treatment is continued, this effect progresses down the gland towards the
| |
| base. This change is followed closely by a
| |
| rearrangement of the nuclei which is more
| |
| pronounced in the glands than in the surface
| |
| epithelium. The nuclei under the influence
| |
| of estrogen in doses which reproduce the
| |
| conditions of the follicular phase of a normal cvcle, are situated niostlv in the basal
| |
| | |
| | |
| | |
| | |
| Fig. 9.8. Uterus of a castratefl monkey which
| |
| was given 2 mg. progesterone daily tor 113 days.
| |
| The endometrium is thin but bleeding occiu\s when
| |
| such treatment is stopped. The myometrimn is
| |
| soft and pliable and ilir l)lood vessels are cnlarsed
| |
| and have thick wails.
| |
| | |
| | |
| | |
| half of the cells, some of them touching the
| |
| basement membrane. The nuclei retreat
| |
| from the basement membrane when progesterone is given leaving a conspicuous clear
| |
| zone. This zone is produced by intracellular
| |
| deposits of glycogen. These early changes
| |
| usually appear before pronounced spiraling
| |
| and dilation of the glands.
| |
| | |
| Secretion begins in response to estrogenic
| |
| stimulation and increases greatly as progestational changes are established. It appears first in the necks of the glands and
| |
| progresses basalward. The surface epithelium takes a less conspicuous part in secretion and is usually reduced to a thin membrane when injections of progesterone are
| |
| continued until a fully developed progestational endometrium is established. This progressive action of progesterone is such that
| |
| it is possible to find all conditions in a single
| |
| gland from active secretion and fraying in
| |
| the neck region through primary swelling to
| |
| an unmodified condition at the base.
| |
| | |
| When treatment is continued for 25 to 30
| |
| days at doses of about 2.0 mg. daily, the
| |
| glands enter a state that has been called
| |
| "secretory exhaustion" (Hisaw, 1935). This
| |
| condition also is seen first in the necks of
| |
| the glands and progresses toward the base.
| |
| The glandular epithelium decreases in
| |
| thickness, and active secretion, as judged
| |
| by fraying of the cells, is absent. The glands
| |
| may become narrow and straight and the
| |
| endometrium may resemble that in castration atrophy. These involutionary changes
| |
| become even more pronounced if the treatment is continued for several months or a
| |
| year (Fig. 9.8). The endometrium by this
| |
| time is extremely thin. The glands are
| |
| straight, short, and narrow, and the stroma
| |
| very dense. The myometrium is thick in proportion to the endometrium and the uterine
| |
| blood vessels are large and have greatly
| |
| thickened walls. Such uteri tend to be somewhat smaller than normal and are soft and
| |
| pHable.
| |
| | |
| Thus, it is seen that when growth is produced in the endonietiiuni of a castrated
| |
| monkey by giving estrogen and then continued on injections of progesterone, there
| |
| follows a sequential development of all
| |
| stages of the luteal phase of a normal menstiual cycle terminating in secretory exhaustion. However, this condition cannot
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 567
| |
| | |
| | |
| | |
| be maintained by continuing the progesterone treatment, and involutionary processes
| |
| set in and the endometrium is reduced to a
| |
| thin structure. Yet, such degenerate endometria are dependent upon progesterone
| |
| and will bleed within about 48 hours if the
| |
| injections are stopped. It also was found
| |
| that after discontinuence of progesterone
| |
| daily injections of 10 /i.g. estradiol may not
| |
| prevent bleeding.
| |
| | |
| IV. Synergism between Estrogen
| |
| and Progesterone
| |
| | |
| There is considerable evidence that in
| |
| primates progesterone under normal conditions rarely if ever produces its effects in the
| |
| absence of estrogen. Large quantities of estrogen are present in human corpora lutea
| |
| (Allen, Pratt, Newell and Bland, 1930) and
| |
| during pregnancy the placenta secretes estrogens as well as progesterone (Diczfalusy,
| |
| 1953) . This apparently is a common feature
| |
| of primates, as indicated by the excretion of
| |
| estrogens in the urine of pregnant chimpanzees and rhesus monkeys (Allen, Diddle,
| |
| Burford and Elder, 1936; Fish, Young and
| |
| Dorfman, 1941 ; Dorfman and van Wagenen, 1941). Also, correlated with this is
| |
| the observation that estrogen and progesterone when given concurrently produce a
| |
| greater effect on the uterus of castrated
| |
| monkeys than either alone (Hisaw, Greep
| |
| and Fevold, 1937; Engle, 1937; Hisaw and
| |
| Greep, 1938; Engle and Smith, 1938) and
| |
| that an ineffective dose of progesterone is
| |
| greatly potentiated by estrogen. This synergistic effect of the two hormones on the
| |
| uterus of monkeys is quite different from
| |
| their action on the uteri of laboratory rodents and rabbits. In these animals the effects of progesterone can be inhibited quite
| |
| easily by a surprisingly small dose of estrogen (see chapter 7).
| |
| | |
| The synergism between estrogen and progesterone in the promotion of endometrial
| |
| growth can be demonstrated to best advantage under the conditions of some of the
| |
| physiologic preparations that have been discussed. For instance, it was shown (Fig.
| |
| 9.5) that growth of the endometrium under
| |
| the influence of estrogen was not enhanced
| |
| by relieving muscle tension by a midline incision through the anterior wall of the
| |
| uterus. Now, if a similar operation is per
| |
| | |
| | |
| | |
| FiG. 9.9. Uterus of a castrated monkey that received 10 fig. estradiol and 1 mg. progesterone
| |
| daily for 18 days, at which time the uterus was
| |
| opened from fundus to cervix and most of the
| |
| endometrium of the anterior wall removed. The
| |
| incision was not closed and the treatment was
| |
| continued for an additional 20 days. (From F. L.
| |
| Hisaw, in A Symposium on Steroid Hormones,
| |
| University of Wisconsin Press, 1950.)
| |
| | |
| formed on the uterus of a monkey that is
| |
| receiving 10 /tg. estradiol daily and the
| |
| treatment continued with the addition of a
| |
| daily dose of 1 mg. progesterone, there usually follows a rapid growth of endometrial
| |
| tissue out through the incision until by
| |
| about 3 weeks a mass is formed which approximates the size of the entire uterus (Fig.
| |
| 9.9). If this experiment is repeated and the
| |
| same dosage of progesterone is given without estrogen, there is no outgrowth of the
| |
| endometrium (Fig. 9.10).
| |
| | |
| A similar synergistic action can be seen in
| |
| utero-abdominal fistulae. We have mentioned that estrogen does not cause excessive
| |
| growth of the endometrium under these conditions. However, endometria that have
| |
| reached their maximal response to estrogen
| |
| will show a resumption of growth if 1 or 2
| |
| mg. progesterone are added daily to the
| |
| treatment. By the 4th or 5th day lobes of
| |
| blood-red endometrium begin to protrude
| |
| | |
| | |
| | |
| 568
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 9.10. Uteru.s of a castrated monkey which
| |
| was given 1 mg. progesteione (lail>' for 18 days
| |
| following an estrogen treatment. The uterus was
| |
| opened as described for Figure 9.9, and the injections of progesterone continued for 20 days. (From
| |
| F. L. Hisaw, in A Syiyiposium on Steroid Hormones, University of Wisconsin Press, 1950.)
| |
| | |
| through the opening of the fistula. Within a
| |
| few days tongue-like processes of endometrial tissue are thrust out of the opening
| |
| with each uterine contraction and are entirely or i^artially withdrawn at each relaxation.
| |
| | |
| Such outgrowths are difficult to protect
| |
| from mechanical injury and consequent tissue loss so it is not possible to determine accurately how much endometrium is produced in a given time. In one experiment an
| |
| animal was kept on 10 fxg. estradiol and 2
| |
| mg. progesterone daily for 98 days and it
| |
| was found that the endometrium continued
| |
| to grow, but the rate seemed considerably
| |
| slow^er toward the conclusion of the treatment than at the beginning. How long an
| |
| endometrium would continue to grow under
| |
| these conditions was not determined, but it
| |
| is obvious that much more endometrial tissue was produced by the treatment than is
| |
| ever found at one time in the uterus of a
| |
| monkey during a normal menstrual cycle.
| |
| This takes on added significance when it is
| |
| compared with the endometrial response in
| |
| the intact uterus of an animal given the
| |
| same dosage of estrogen and progesterone
| |
| for a similar length of time.
| |
| | |
| The progestational development of the
| |
| endometrium, when both hormones are
| |
| given, passes through the same stages as
| |
| those following the injection of only progesterone; i.e., presecretory swelling of the
| |
| glandular epithelium, active secretion, and
| |
| | |
| | |
| | |
| secretory exhaustion. The endometrium,
| |
| however, is considerably thicker than when
| |
| a comparable dose of progesterone is given
| |
| alone, and secretory exhaustion may not be
| |
| so pronounced by the 30th day (Fig. 9.11).
| |
| The glandular epithelium in the necks of
| |
| the glands may be reduced to a thin membrane scarcely thicker than the nuclei
| |
| whereas some secretion is usually present in
| |
| the dilated basal parts of the glands. Also
| |
| dilation of the glands in the basalis is
| |
| more pronounced following a 30-day estrogen-])rogesterone treatment than when the
| |
| same amount of progesterone is given separately.
| |
| | |
| Secretory exhaustion appears to be the
| |
| initial indication of an involutionary process that ensues when an estrogen-progesterone treatment is continued for a long time
| |
| (Hisaw, 1950). When a combination of the
| |
| two hormones, known to be capable of producing a large uterus with a thick, fully develojied, progestational endometrium within
| |
| al)out 20 days, is given for 100 days, an
| |
| astonishingly different endometrium results
| |
| (Fig. 9.12). It is thin, the stroma is dense
| |
| and the narrow straight glands are reduced
| |
| to cords of cells in the basal area. The condition is one suggesting inactivity and atrophy.
| |
| | |
| When such dosages of estrogen and i)rogesterone are given to castrated monkeys
| |
| for 200 days or a year further changes in
| |
| the endometrium occur. By 200 days the
| |
| epithelium of the surface mucosa and glands
| |
| | |
| | |
| | |
| | |
| Fk;. 9.11, .\ late i)r()ges1ati()iial condition produced in the endometrium of a castrated monkey
| |
| by giving 10 (ig. estradiol daily for 18 days followed
| |
| by 10 /xg. estradiol and 2 mg. progesterone daily
| |
| for 31 davs.
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 569
| |
| | |
| | |
| | |
| | |
| Fig. 9.12. The endometnuin of a castrated monkey that had received 10 /xg. estradiol
| |
| and 1 mg. progesterone daily for 99 days.
| |
| | |
| | |
| | |
| is lost except for small glandular vestiges
| |
| along the musciilaris at the base of the endometrium. There are no glands, coiled arteries, or large blood vessels in what one
| |
| might yet call the functionalis. All that remains is a modified stroma that resembles
| |
| decidual tissue (Fig. 9.13.4 and B). It is also
| |
| of interest that these endometria will menstruate if the treatment is discontinued and
| |
| in most if the injections of progesterone are
| |
| stopped and estrogen continued, but not if
| |
| estrogen is stopped and progesterone continued.
| |
| | |
| Even though in such experiments the endometrium has been under the influence of
| |
| both estrogen and progesterone for a year
| |
| and has undergone extremely abnormal
| |
| modification, it yet is capable of responding
| |
| to estrogen in a more or less characteristic
| |
| way when progesterone is stopped and in
| |
| | |
| | |
| jections of estrogen continued. Apparently
| |
| within about three weeks the modified endometrium is replaced, under the influence of
| |
| estrogen, by one that has few glands which
| |
| tend to be cystic, a mesenchymatous stroma,
| |
| and no coiled arteries (Fig. 9.14).
| |
| | |
| Under similar circumstances, if estrogen
| |
| is stopped and jjrogesterone is continued, the
| |
| modified endometrium is lost without bleeding and there is almost no repair of the endometrium even after a period of 3 weeks.
| |
| There seems to be an incompatability between the epithelial outgrowths from the
| |
| mouths of the glands and the underlying
| |
| stroma of the denuded surface. Consequently the epithelium crumbles away and
| |
| epithelization of the raw surface is not accomplished (Fig. 9.15j. How long this condition could continue has not been determined.
| |
| | |
| | |
| | |
| 570
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| Fk;. 9.13. The endometrium shown m .4 is (h;i( from a castraled mdiik.N wlml, l,a,l
| |
| received 10 /xg- estradiol and 2 mg. progesterone daily for 200 days. In B, jiart of ilie endometrium of a snndai animal given the same treatment for 312 days is shown at a higher
| |
| magnification. The endometrium is almost entirely a modified stroma in which glandular
| |
| epithelium and coiled arteries are absent. Only vestiges of glands are present in the basal
| |
| area next to the myometrium.
| |
| | |
| One of the most interesting aspects of
| |
| these observations is that these effects were
| |
| jiroduced by dosages of estrogen and progesterone that are very probably within the
| |
| range of normal physiology. From this it
| |
| appears that although growth of the endometrium is greater when the two hormones
| |
| are given together, due to their synergistic
| |
| interaction, this does not prevent involutionary changes from setting in when the
| |
| treatment is continued for a period of weeks
| |
| or months. In fact, greater damage to the
| |
| endometrium occurs under the simultaneous
| |
| action of the two hormones than when either
| |
| is given alone. Also, increasing the dose intensifies the damaging action of both estrogen and progesterone, so much so that very
| |
| large doses will almost completely destroy
| |
| the endometrium.
| |
| | |
| The myometrium, however, shows a different response to these treatments. Estrogen stimulates myometrial growth, which is
| |
| | |
| | |
| | |
| | |
| Fir;. 9.14. Uterus of a castrated monkey which
| |
| was given 10 ixg. of estradiol and 2 mg. progesterone daily for 307 days at which time the
| |
| injections of progesterone were stopped and estrogen continued for 20 days. Bleeding occurred the
| |
| second day following discontinuance of progesterone. The absence of coiled arteries and the presence of cystic glands and a mesenchymetous stroma
| |
| characterize the endometrium.
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 571
| |
| | |
| | |
| | |
| | |
| Fig. 9.15. Uterus of a castrated monkey which was given 10 yug. estradiol and 2 mg. progesterone daily for 275 days at which time estrogen was stopped and progesterone was continued for 21 days. A shows the thin endometrium and dense stroma whereas B shows failure
| |
| of formation of a surface epithelium following the loss of the modified functionalis presumably present at the conclusion of treatment with both hormono.^^ (see Fig. 9.13).
| |
| | |
| | |
| | |
| intensified both by cln-onic treatment and
| |
| high dosage, and seems to be equally effective when it is given alone or in combination with progesterone. Progesterone also
| |
| promotes growth of the muscularis but
| |
| seems less effective than estrogen and differs from it by causing pronounced thickening of the walls of the arcuate blood vessels.
| |
| These vascular changes extend to the coiled
| |
| arteries of the endometrium, which are also
| |
| affected by high dosages of estrogen. It
| |
| seems remarkable that estrogen is capable of
| |
| preventing the action of progesterone on the
| |
| myometrial blood vessels and correcting
| |
| such effects after they are produced and yet
| |
| at the same time it assists in the destruction of the coiled arteries in the endometrium.
| |
| | |
| V. Experimentally Produced
| |
| Implantation Reactions
| |
| | |
| Progestational endometria of the normal
| |
| menstrual cycle or those produced in castrated monkeys by progesterone, if mechanically traumatized, will develop endometrial
| |
| proliferations which seem identical with
| |
| those found at normal implantation sites of
| |
| fertilized ova (Figs. 9.16 and 9.171 (Hisaw,
| |
| | |
| | |
| | |
| 1935; Hisaw, Creep and Fevold, 1937; Wislocki and Streeter, 1938; Rossman, 1940).
| |
| The proliferated cells originate from the
| |
| surface and glandular epithelium and grow
| |
| into the surrounding stroma. The reaction
| |
| spreads from the point of injury and within
| |
| a few days may involve the entire inner
| |
| l)ortion of the endometrium bordering the
| |
| lumen. The implantation plaques on the 3rd
| |
| or 4th day present a fairly homogeneous appearance but soon thereafter certain cells
| |
| attain the proportions of giant cells and
| |
| many are multinucleated.
| |
| | |
| The development of the plaques is most
| |
| rapid during the first week, by the end of
| |
| which cell division is found only in the basal
| |
| half of the proliferation and evidence of regression is seen in the superficial portion
| |
| adjoining the uterine lumen. After 10 days
| |
| degenerative and phagocytic processes are
| |
| the dominant features and by 24 days the
| |
| ut'prus contains few or no ]iroliferation cells.
| |
| Wislocki and Streeter ( 1938,1 found that implantation plaques during pregnancy and
| |
| those experimentally induced underwent ajjl^roximately the same development arid
| |
| subsequent degeneration except for modifications produced by the invading troplio
| |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| :^a.
| |
| | |
| | |
| :^^--.^
| |
| | |
| | |
| | |
| tx: ^ .
| |
| | |
| | |
| | |
| Fig. 9.16. An area of the normal implantation
| |
| site of a developing ovum. (From Carnegie Institution, No. C467.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 9.17. An experimentally induced implantation reaction in a castrated monkey showing condition 6 days after mechanical traumatization of the
| |
| endometrium.
| |
| | |
| | |
| | |
| blast. Rossman (1940j made an extensive
| |
| morphologic study of these epithelial proliferations and concluded that they should
| |
| be regarded as typical metaplasias \vith an
| |
| embryotrophic function.
| |
| | |
| VI. The Cervix Uteri
| |
| | |
| The cervix uteri of the rhesus monkey is
| |
| remarkable for its size and complexity. It
| |
| forms a large segment that is set off from
| |
| the fundus by a conspicuous constriction at
| |
| the level of the internal os (Fig. 9.1). A
| |
| sagittal section (Fig. 9.18) shows the cervical canal not straight but thrown into several sharp turns by colliculi that extend
| |
| from its walls into the lumen. The largest
| |
| of these projects from the midventral wall.
| |
| The functional advantage of such tortuosity
| |
| of the cervical canal is not obvious but
| |
| since the cervix probably serves as a barrier
| |
| between the bacterial flora of the vagina and
| |
| the corpus uteri, this may be a useful adaptation.
| |
| | |
| The physiology of the cervix has received
| |
| much less attention than has been given the
| |
| uterus. This is regrettable in view of the
| |
| consideration it must receive in practical
| |
| obstetrics and gynecology, as well as the
| |
| possibility that physiologically the monkey
| |
| cervix may be homologous with that of the
| |
| human regardless of morphologic difTerences. Recent observations indicate that
| |
| this is indeed quite probable.
| |
| | |
| | |
| | |
| | |
| Fig. 9.18. Sagittal section of the cervix from a
| |
| normal monkey. The vagina and the external os of
| |
| the cervix are shown at the left and the entrance
| |
| to the fundus is at the right.
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 573
| |
| | |
| | |
| | |
| | |
| Fig. 9.19. Sagittal section of the cervix of a pregnant monkey showing conditions present
| |
| just previous to parturition on the 154th day of gestation. The dominant features are
| |
| dilation of the cervical canal and reduction of the cervical lips (shown at the left) and the
| |
| coUiculi. (From Carnegie Institution, No. C713.)
| |
| | |
| | |
| | |
| Hamilton (1949) made a detailed study
| |
| of the changes in the cervix of rhesus monkeys during the menstrual cycle, paying
| |
| particular attention to alterations that took
| |
| place in the cells of the surface epithelium
| |
| of the endocervical canal and the cervical
| |
| glands. It was found that heights of the
| |
| cells showed consistent increases and decreases during the cycle. The peaks came on
| |
| the 3rd, 13th to 15th, and 22nd days, the
| |
| greatest of these being the 14th day which
| |
| is approximately the time of ovulation. It
| |
| also was observed that, following a peak,
| |
| secretion was associated with the decline.
| |
| | |
| Attention was called b3^ Hamilton to the
| |
| rather close correlation between the fluctuations in height of the cervical epithelium in
| |
| monkeys and the fluctuations observed by
| |
| Markee and Berg (1944) in the blood estrogens of the human menstrual cycle. It was
| |
| concluded that, if similar changes in estrogen levels also occur in monkeys, one would
| |
| be justified in concluding that the increase
| |
| in cell height in the cervical mucosa was due
| |
| to the action of estrogen and the sudden periodic drops in blood estrogen caused secretion and consequent regression. However, it
| |
| is not clear how this could account for the
| |
| abundant secretion of the cervical glands in
| |
| | |
| | |
| | |
| the presence of high levels of estrogen during
| |
| late pregnancy (Fig. 9.19).
| |
| | |
| Much has been learned regarding the
| |
| physiology of the primate cervix from experiments on castrated monkeys. The cervical mucosa is very responsive to estrogen
| |
| and castration atrophy can be repaired and
| |
| a normal condition maintained by daily injections of small doses. Cervical secretion
| |
| may become abundant when an estrogen
| |
| treatment is prolonged and especially if
| |
| large doses are injected. However, the
| |
| amount of secretion induced by estrogen
| |
| never equals that of the last half of pregnancy, and it usually subsides if the injections are continued for several months.
| |
| | |
| Under conditions of chronic treatments
| |
| with estrogen metaplastic aberrations invariably appear in the epithelium of the
| |
| endocervix. This reaction was first reported
| |
| in monkeys by Overholser and Allen ( 1933,
| |
| 1935) and has been confirmed by many investigators (Engle and Smith, 1935; Hisaw
| |
| and Lendrum, 1936; Zuckerman, 1937c (.
| |
| Similar lesions may be found in the cervix
| |
| uteri of women (Fluhmann, 1954). They
| |
| seem especially prone to occur under conditions characterized by excessive production of estrogen, such as hyperplasia of the
| |
| | |
| | |
| | |
| 574
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| endometrium (Hellman, Rosenthal, Kistner
| |
| and Gordon, 1954) and granulosa-cell tumors of the ovary. Various degrees of metaplasia may occur in the cervix during pregnancy both in the mother and newborn but
| |
| Fluhmann (1954) did not find it as frequently as in nonpregnant women.
| |
| | |
| This reaction to estrogen as seen in the
| |
| cervix of castrated monkeys is initiated by
| |
| growth of small undifferentiated cells below
| |
| the columnar mucous cells of the secretory
| |
| epithelium. Fluhmann (1954) suggests that
| |
| these cells are really undifferentiated cells
| |
| of the cervical mucosa which have the potentiality of becoming columnar or squamous or simply undergoing multiplication
| |
| and remaining as indifferent or reserve cells.
| |
| These cells accumulate, in response to estrogen, to form aggregates of several cells
| |
| in thickness and, although this may occur in
| |
| any area of the endocervix, it is generally
| |
| more pronounced below the base of the
| |
| glands. As this process proceeds the columnar mucous cells are pushed outward and
| |
| are finally desquamated thus exposing the
| |
| underlying metaplastic cells to the lumen of
| |
| the gland (Fig. 9.20).
| |
| | |
| | |
| | |
| | |
| Fig. 9.20. Al.iaph
| |
| | |
| | |
| | |
| in a castrated monkey that li.-id rci-civcd 1 nig.
| |
| estriol daily for 48 days.
| |
| | |
| | |
| | |
| The cells of these lesions undergo a characteristic differentiation. When first formed
| |
| they are small, cuboidal, and have spherical nuclei with dense chromatin. As they increase in number those in the center of the
| |
| cellular mass become larger and acquire an
| |
| eosinophilic cytoplasm. Such collections, as
| |
| seen at the base of the cervical glands, may
| |
| grow in height and form cone-shaped masses
| |
| with the apexes protruding through the mucous epithelium into the lumen or they may
| |
| remain as more or less compact structures.
| |
| This difference in growth seems to have a
| |
| general relation to the dosage of estrogen.
| |
| Large doses cause more rapid growth and
| |
| cone formation with the loss of cells from
| |
| the apex either singly or in groups, whereas
| |
| small doses produce slower growth and desquamated cells are seldom seen in the lumen. However, regardless of the rate of
| |
| growth, the cells at the base of the lesion
| |
| remain undifferentiated and continue as the
| |
| principal area of cell proliferation.
| |
| | |
| Pearl formation is occasionally seen and
| |
| may be quite common in animals on low
| |
| dosages of estrogen. Under strong estrogenic
| |
| stimulation and consequently rapid growth,
| |
| these structures apparently are desquamated before they are completely formed.
| |
| However, very early stages are frequently
| |
| seen and may even be present in small
| |
| clumps of metaplastic cells, but they are
| |
| more commonly found in the larger collections at the base of the glands. Their appearance is initiated by swelling and disintegration of one or more adjacent cells
| |
| that form a center around which epidermidization takes place. Further development
| |
| does not proceed under the influence of esti'ogen, beyond the formation of a small central cavity.
| |
| | |
| The most conspicuous difference between
| |
| the metaplastic growths produced by estrogen and true cancer of the cervix in the
| |
| monkey (Hisaw and Hisaw, Jr., 1958) is
| |
| that the former remain noninvasive even
| |
| when the treatment is continued well over
| |
| a year. They also involute when the treatiiiciit is discontinued and they do not appeal' when progesterone is given simultaneously with estrogen. When the injections of
| |
| progesterone are started after metaplastic
| |
| growths have been formed in response to
| |
| estrogen, further growth is inhibited and
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| the keratinized cells of the lesion become
| |
| vacuolated and are lost.
| |
| | |
| In contrast with the effects of estrogen
| |
| on the cervix, the modifications that occur
| |
| as pregnancy advances are remarkable. The
| |
| cervix becomes a soft thin-walled structure,
| |
| the glands increase in number, and their
| |
| lumina become greatly enlarged, pressing
| |
| the stroma into thin partitions between
| |
| them, and the amount of mucus secreted is
| |
| enormous (Fig. 9.19). Attempts at duplicating these changes in castrated animals by
| |
| hormone therapy have been only partially
| |
| successful. Estrogen produces a solid thickwalled cervix that tends to be larger than
| |
| normal, an effect that is especially noticeable in young animals. Progesterone does
| |
| not promote cervical growth and repair of
| |
| the glands unless large doses are given and
| |
| even then there is little if any secretion. The
| |
| best results were obtained when both estrogen and progesterone were given and especially so when relaxin was added to the
| |
| treatment (see chapter by Zarrow).
| |
| | |
| VII. The Vagina
| |
| | |
| The general features of the vaginal smear
| |
| of rhesus monkeys have been described by
| |
| several investigators (Allen, 1927; Hartman, 1932; Westman, 1932) and a detailed
| |
| study of the cellular components at different times of the menstrual cycle has been
| |
| made by Lopez Columbo de Allende, Shorr
| |
| and Hartman (1945). The changes in the
| |
| vagina of a monkey are in most respects like
| |
| those found for the human being (Papanicolaou, Traut and Marchetti, 1948; Lopez
| |
| Columbo de Allende and Orias, 1950). Epithelial growth and desquamation of cornified cells continue at all stages of the cycle
| |
| but at various rates. The epithelium is
| |
| thinnest at menstruation and gradually increases in thickness during the follicular
| |
| phase, reaching a maximum at ovulation.
| |
| At this time there is a well developed basal
| |
| area in which numerous mitoses can be seen
| |
| and from which many papillae or ''bulbs"
| |
| extend into the underlying stroma. Above
| |
| this is an intermediate zone, an interepithelial zone of cornification (so called Dierk's
| |
| layer), and a heavily cornified outer zone
| |
| (Fig. 9.21).
| |
| | |
| Cellular proliferation is less rapid during
| |
| the luteal phase and apparently cells are
| |
| | |
| | |
| | |
| desquamated more rapidly than they are replaced. Consequently there is a decrease in
| |
| the thickness of the epithelium in the luteal
| |
| phase which may include an almost complete loss of the cornified zone (Davis and
| |
| Hartman, 1935). The effects are probably
| |
| due to progesterone because similar changes
| |
| are seen following the introduction of progesterone into a treatment in which estrogen
| |
| is being given.
| |
| | |
| The vaginal epithelium of a castrated
| |
| monkey is remarkably sensitive to estrogen.
| |
| A small daily dose of 5 to 10 /xg. estradiol
| |
| will stimulate growth of an atrophic epithelium of 4 to 8 cells in thickness to one of
| |
| 60 or even 80 layers thick within 3 weeks.
| |
| One of the first things that is noticed as the
| |
| vaginal epithelium thickens is the numerous
| |
| mitotic figures in the stratum germinativum
| |
| followed by a marked increase in the number of epithelial papillae along the basement membrane. This condition of rapid
| |
| growth, cornification, and loss of cells into
| |
| the vaginal lumen is typical of the follicular
| |
| phase of the menstrual cycle and can be
| |
| maintained indefinitely.
| |
| | |
| | |
| | |
| | |
| l''i(.. U.21. the vaginal epithelium of a castuUMJ
| |
| monkej' showing growth antl cornification induced
| |
| by estrogen.
| |
| | |
| | |
| | |
| 576
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Progesterone, in contrast with estrogen,
| |
| does not produce rapid growth of the vaginal epithelium but at the same time it is
| |
| not without an effect. The vaginal epithelium, weeks or months after castration, has
| |
| relatively few papillae projecting from its
| |
| basal border into the underlying stroma.
| |
| When progesterone is given, this condition
| |
| is changed but not in a spectacular way.
| |
| There is very slow growth without cornification. The epithelium remains thin but the
| |
| papillae become more numerous. These are
| |
| mostly small epithelial buds which tend to
| |
| remain solid but may show enlargement of
| |
| the cells in their centers.
| |
| | |
| When estrogen and progesterone are given
| |
| concurrently, the effects of estrogen on the
| |
| vaginal mucosa are modified. If an estrogen
| |
| treatment has continued for a sufficient time
| |
| to produce full cornification and then progesterone is added, the first indication of an
| |
| inhibition of estrogen is a decrease in mitotic activity. This is followed by a continuation of cornification and loss of cells
| |
| faster than they are replaced ; consequently,
| |
| most of the functionalis is lost and the epithelium becomes thinner. There is also a
| |
| noticeable decrease in the intensity of cornification, which in the monkey is never as
| |
| pronounced as in rodents, and under these
| |
| conditions is quite incomplete, each cell retaining a conspicuous nucleus. Partly cornified cells may be present for several weeks
| |
| | |
| | |
| | |
| .-•^ss;^
| |
| | |
| | |
| | |
| 4* ' V ^ §
| |
| | |
| | |
| | |
| | |
| | |
| Fig. 9.22. ^^•tgi^al epithelium of a pregnant monkey showing condition on the 154th day of gestation. (From Carnegie Institution, No. C713.)
| |
| | |
| | |
| | |
| when both estrogen and progesterone are
| |
| given, but eventually they almost entirely
| |
| disappear and the epithelium attains a condition resembling that of late pregnancy.
| |
| | |
| The inhibitory effect of progesterone on
| |
| the action of estrogen is shown perhaps even
| |
| better when a castrated monkey having a
| |
| fully involuted reproductive tract is first
| |
| given progesterone for a few days and then
| |
| (>strogen is added to the treatment, or when
| |
| injections of the two hormones are started
| |
| at the same time. In such experiments estrogen has little effect on the vaginal mucosa
| |
| even in doses that would produce marked
| |
| cornification if given alone. These observations show that a fully cornified vaginal
| |
| epithelium cannot be produced or maintained by estrogen when an effective dosage
| |
| of progesterone is included in the treatment
| |
| (Hisaw, Greep and Fevold, 1937).
| |
| | |
| Estrogens and progesterone are the dominant hormones of gestation and their simultaneous action is reflected by the changes
| |
| in the vaginal epithelium. The fully cornified vagina, present at the time of ovulation,
| |
| is gradually modified as pregnancy progresses into a condition strikingly like that
| |
| seen in experiments when estrogen and progesterone are given concurrently. In late
| |
| pregnancy the most striking feature of the
| |
| thin, uncornified epithelium is the presence
| |
| of numerous epithelial buds extending
| |
| deeply into the underlying stroma. They
| |
| may branch and rebranch and along their
| |
| course there is conspicuous enlargement of
| |
| the more centrally situated cells among
| |
| which cavities ai^pear, enlarge, and join
| |
| each other (Fig. 9.22). It seems quite probable that this process may be of considerable
| |
| importance in increasing the diameter of
| |
| the vagina.
| |
| | |
| VIII. Sexual Skin
| |
| | |
| A so-called sexual skin is jiresent in most
| |
| catarrhine monkeys, is not found in platyriliine monkeys, and among the anthropoids
| |
| occurs regularly only in the chimpanzee
| |
| I l^]ckstein and Zuckcrman, 1956). Changes
| |
| in the sexual skin during the menstrual cycle have been observed most extensively in
| |
| the monkey (Macaca), the baboon (Papio),
| |
| and the chimpanzee (Pan). The sexual skin
| |
| of t!ie baboon and chimpanzee undergo jiro
| |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 577
| |
| | |
| | |
| | |
| nounced swelling during the follicular phase
| |
| of the cycle. A maximal size is attained by
| |
| the middle of the cycle followed by a rapid
| |
| regression and loss of edema which at least
| |
| in the baboon is associated with a marked
| |
| increase in the output of urine (Gillman,
| |
| 1937a; Krohn and Zuckerman, 1937). The
| |
| subsidence of the sexual skin begins approximately at the time of ovulation and remains
| |
| in the reduced condition throughout the
| |
| luteal phase, followed by a subsequent initiation of swelling during or soon after
| |
| menstruation (Zuckerman, 1930, 1937e;
| |
| Zuckerman and Parkes, 1932; Gillman and
| |
| Gilbert, 1946; Young and Yerkes, 1943;
| |
| Nissen and Yerkes, 1943).
| |
| | |
| A w^ell developed sexual skin is present
| |
| in the monkey {Macaca mulatta) only during adolescence. With the appearance of
| |
| the menstrual cycles the sexual skin undergoes a process of maturation into the adult
| |
| condition in which cyclic changes in edema
| |
| are absent and the most noticeable feature
| |
| is a vivid red color. Such coloration is due
| |
| to vascular engorgement rather than pigment (Collings, 1926) and involves the
| |
| perineum, the buttocks, and may extend for
| |
| various distances down the legs and over
| |
| the symphysis pubis. The development and
| |
| maturation of the sexual skin have been described in considerable detail by several investigators (Hartman, 1932; Zuckerman,
| |
| van Wagenen and Gardiner, 1938) .
| |
| | |
| The sexual skin has been of considerable
| |
| interest both as to the nature of its responsiveness to ovarian hormones and the
| |
| manner in which its grossly visible changes
| |
| during the menstrual cycle parallel events
| |
| occurring in the reproductive tract. The
| |
| sudden loss of edema at the conclusion of
| |
| the follicular phase not only signals ovulation but also raises the question as to
| |
| whether the loss of tissue fluid is due to a
| |
| decrease in estrogen or is the direct effect
| |
| of progesterone. The importance of this
| |
| becomes obvious when it is considered that
| |
| a similar process also goes on simultaneously
| |
| in the endometrium and raises the question
| |
| again as to the respective roles played by
| |
| estrogen and progesterone in endometrial
| |
| growth and menstruation.
| |
| | |
| That the development and edema of the
| |
| sexual skin of adolescent rhesus monkeys
| |
| depend on the ovaries was first demon
| |
| | |
| | |
| strated by Allen ( 1927 ) . Involution and loss
| |
| of color follow castration, and the normal
| |
| condition can be restored by the injection
| |
| of estrogen. Also, when estrogen treatment
| |
| is continued for several weeks maturation of
| |
| the sexual skin occurs and a condition characteristic of that in the adult is established
| |
| (Zuckerman, van Wagenen and Gardiner,
| |
| 1938). The genital area loses its edema and
| |
| develops a brilliant red color which is retained as long as estrogen is administered.
| |
| Once this mature condition is established
| |
| the response of the sexual skin to subsequent estrogen treatments is limited to a
| |
| change in color.
| |
| | |
| Similar experiments have been performed
| |
| on the chacma baboon, Papio porcarius
| |
| (Parkes and Zuckerman, 1931; Gillman,
| |
| 1937b, 1938, 1940a). The large sexual skin
| |
| of these animals is very responsive to estrogen and development equal to that of the
| |
| follicular phase of the menstrual cycle can
| |
| be readily induced by daily injections for
| |
| about 2 weeks. However, the perineal swelling of the baboon differs from the sexual
| |
| skin of the genital area of the rhesus monkey in that it does not "mature" under the
| |
| influence of estrogen.
| |
| | |
| When large doses of estrogen are given to
| |
| a rhesus monkey a generalized edema of
| |
| the skin occurs beyond the genital area.
| |
| This first appears as deeply indented swellings along the sartorii from groin to knee,
| |
| and next appears at the base of the tail and
| |
| spreads gradually upward until it involves
| |
| the entire dorsal portion of the trunk. At the
| |
| same time, the skin of the face, scalp, and
| |
| supraorbital ridges becomes swollen and
| |
| finally the edema may extend out on the
| |
| arms and down the legs to the ankles (Bachman, Collip and Selye, 1935; Hartman,
| |
| Geschickter and Speert, 1941). A daily
| |
| dose of 500 /xg. or more of estriol or estradiol
| |
| w^ll produce this condition within 2 to 3
| |
| weeks and, when the treatment is continued for an extended period the effect
| |
| tends to subside.
| |
| | |
| Progesterone has a strong inhibitory action on the effects produced by estrogen on
| |
| both the genital and extragenital sexual
| |
| skin of the monkey. If daily injections of
| |
| progesterone are added to the treatmeiu
| |
| after full development of the sexual skin
| |
| has been induced by estrogen, there is a
| |
| | |
| | |
| | |
| 578
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| noticeable loss of edema by the 4th or 5th
| |
| day followed by rapid involution and reduction of the turgid folds of skin to loose,
| |
| flabby wrinkles within about 10 days. When
| |
| estrogen and progesterone are given concurrently to a castrated monkey from the
| |
| beginning of treatment edema does not appear but the sexual skin regains its normal
| |
| color. In fact, progesterone alone, like estrogen, can restore the color to the sexual
| |
| skin of castrated adult monkeys (Hisaw,
| |
| Greep and Fevold, 1937; Hisaw, 1942).
| |
| | |
| The interaction of estrogen and i)rogesterone on the sexual skin of rhesus monkeys can best be demonstrated by the reaction of the skin of the sexual area in
| |
| adolescent animals. The most striking effect
| |
| and probably the most important is the
| |
| sequence of events initiated by a single
| |
| dose of progesterone when given to an animal on continuous estrogen treatment. Under such treatment a full response of the
| |
| sexual skin is obtained by the end of 20
| |
| days. If at this time 1 mg. progesterone is
| |
| given in a single dose and the estrogen
| |
| treatment continued uninterruptedly, the
| |
| first indication of an effect of the luteal hormone is a slight loss of edema and color of
| |
| the sexual skin on the 4th or 5th day thereafter. The sexual skin is markedly reduced
| |
| by the 8th day, almost gone by the 9th, and
| |
| at the end of about a fortnight regains its
| |
| ability to respond to estrogen as shown by
| |
| a return of color and swelling. However, the
| |
| most remarkable eventuation of such treatment is menstruation which usually begins
| |
| on about the 10th day (Hisaw, 1942).
| |
| | |
| Involution of the sexual skin and menstruation following a single injection of
| |
| progesterone also have been produced in the
| |
| baboon by Gillman (1940a). He found that
| |
| 5 mg. progesterone, when given on the 8th
| |
| day of a normal menstrual cycle, would
| |
| cause an appreciable loss of edema of the
| |
| swollen perineal sexual skin by the day after
| |
| injection. This was followed by a progressive involution of the perineum until the
| |
| 13th day and swelling was re-initiated by
| |
| the end of the 15th day. Reduction of the
| |
| sexual skin at this dosage of progesterone
| |
| was not associated with menstruation. However, when the dose was increased to 20 mg.
| |
| both deturgescence of the sexual skin and
| |
| menstruation occurred. These effects pro
| |
| | |
| | |
| duced by progesterone in the presence of
| |
| endogenous estrogen have much in common
| |
| with those described above as occurring in
| |
| castrated monkeys on continuous estrogen
| |
| treatments.
| |
| | |
| IX. Menstruation
| |
| | |
| An experimental ai^proach to the physiology of menstruation dates from the observations of Allen (1927) that uterine
| |
| bleeding would occur in castrated monkeys
| |
| following the discontinuance of an estrogen
| |
| treatment. He suggested that normal menstruation is due to a fluctuation in estrogen
| |
| secretion and proposed the "estrogen-withdrawal" theory to account for the observed
| |
| facts. This concept led to an extensive investigation of the effects of estrogens on the
| |
| endometrium and of conditions that modify
| |
| their action. It was soon found that in both
| |
| castrated monkeys and human beings there
| |
| was a quantitative relationship between the
| |
| dosage of estrogen given and the maintenance of the endometrium. Bleeding occurred during treatment when the daily dose
| |
| of estrogen was small, but with larger doses
| |
| a point was reached at which the injections
| |
| could be continued for months or even years
| |
| without bleeding (Werner and Collier, 1933;
| |
| Zuckerman, 1937b, d).
| |
| | |
| Estrogen also will inliihit i)ostop('rative
| |
| bleeding which usually follows total castration, provided the ovaries are removed before or soon after ovulation (Hartman.
| |
| 1934). With the advent of a corpus luteum
| |
| and development of a progestational endometrium it becomes progressively more difficult, following castration, to prevent menstruation by injecting estrogen. Similar
| |
| results are obtained when estrogen is given
| |
| during a normal menstrual cycle. Small
| |
| doses may not prevent the onset of menstruation, but if continued, subsequent menstrual periods are delayed (Corner, 1935).
| |
| Large doses when given during the luteal
| |
| phase of the cycle do not disturb the normal
| |
| menstrual rhythm, but may do so if the
| |
| treatment is started during the follicular
| |
| phase (Zuckerman, 1935. 1936a).
| |
| | |
| Progesterone, in contrast with estrogen,
| |
| will prevent menstruation from an endometrium representative of any stage of the normal cycle. It will delay onset of the next menses even when the treatment is started only
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 579
| |
| | |
| | |
| | |
| a few days before the expected menstruation (Corner, 1935; Corner and Allen, 1936) .
| |
| Also, the bleeding that invariably follows
| |
| the discontinuance of a long treatment with
| |
| estrogen can be inhibited indefinitely by
| |
| giving progesterone (Hisaw, 1935; Engle,
| |
| Smith and Shelesnvak, 1935; Zuckerman,
| |
| 1936b).
| |
| | |
| An impression held by many of the earlier investigators was that progesterone
| |
| could not produce its effects on the primate
| |
| endometrium unless it w^as preceded by the
| |
| action of estrogen. It is true, of course, that
| |
| progesterone is a comparatively weak
| |
| growth promoter and its effects can be demonstrated to best advantage on an endometrium that has been developed by estrogen. However, Hisaw, Greep and Fevold
| |
| (1937) produced a progestational endometrium in a monkey that had been castrated
| |
| 242 days previously by giving synthetic
| |
| progesterone. Also, the endometrium of this
| |
| animal was found capable of forming a
| |
| decidual plaque upon traumatization. Soon
| |
| afterwards Hartman and Speert (1941) observed menstruation following the withdrawal of progesterone in castrated monkeys
| |
| that had not been given estrogen and more
| |
| recently similar results have been reported
| |
| by Eckstein ( 1950) . At the same time it has
| |
| l)een found that progesterone will induce
| |
| menstruation in women suffering from
| |
| amenorrhea and also that uterine bleeding
| |
| can l)e jirecipitated l)y similar treatment
| |
| (hiring the follicular j^hase of the cycle
| |
| (Zondek and Rozin, 1938; Rakoff, 1946).
| |
| | |
| These observations have been confirmed
| |
| and extended by Krohn (1951; 1955) who
| |
| finds that menstrual bleeding can be induced in monkeys wdth secondary amenorrhea by the injection of 5 daily doses of
| |
| progesterone. Progesterone (5 mg. daily for
| |
| 5 days) also precipitates uterine bleeding
| |
| in castrated monkeys at intervals of about
| |
| 8 days provided the treatment is started
| |
| innnediately a menstrual bleeding has been
| |
| induced either by removel of the ovaries
| |
| or withdrawal of estrogen. The most interesting aspect of these observations is
| |
| that the number of short 8-day cycles that
| |
| can be obtained in this way in a castrated
| |
| animal seems to be related to the size of the
| |
| initial dose of estrogen used to induce withdrawal bleeding. This also applies to pro
| |
| | |
| | |
| gesterone-withdrawal bleeding, so the effect does not depend upon the particular
| |
| hormone used to obtain the bleeding. It also
| |
| is of interest that such conditioning of the
| |
| endometrium to subsequent responses to the
| |
| 5-day treatments with progesterone may
| |
| last for several months on a continuous regime. It is surprising that such a series of
| |
| responses cannot be initiated unless the
| |
| first injection of progesterone is given within
| |
| 6 days following the initial withdrawal
| |
| bleeding. These observations have much in
| |
| common with those of Phelps (1947) who
| |
| also studied the influence of previous treatment on experimental menstruation in monkeys.
| |
| | |
| There seems to be a quantitative relationship between the dosage of progesterone
| |
| given in combination with estrogen and the
| |
| ability of estrogen to prevent bleeding after
| |
| the injections of progesterone are stopped. It
| |
| has been mentioned that once a fully
| |
| developed i^rogestational reaction has been
| |
| produc(Hl l)y progesterone, it is extremely
| |
| difficult, if not impossible, to inhibit menstruation by giving estrogen following the
| |
| withdrawal of progesterone. However, Hisaw and Greep (1938) found that progestational endometria produced ijy small
| |
| doses of estrogen plus api^roximately 0.5
| |
| mg. progesterone daily for 18 to 21 days
| |
| did not bleed following progesterone withdrawal when continued on 10 to 20 times the
| |
| original dosage of estrogen. In fact, such
| |
| endometria were brought back to a condition typical for the action of estrogen and
| |
| again transformed into a presecretory progestational state without the intervention of
| |
| bleeding. Similar observations were made
| |
| previously by Zuckerman (1936a, 1937d).
| |
| | |
| These experimental results give grounds
| |
| for some doubt as to the adequacy of the
| |
| estrogen-withdrawal theory to account fully
| |
| for menstruation. Not only can progesterone
| |
| bring about menstruation without the intervention of estrogen but other steroid hormones are capable of pi'oducing similar effects. Desoxycorticosterone in large doses
| |
| can inhibit estrogen-withdrawal bleeding in
| |
| castrated monkeys (Zuckerman, 1939, 1951 )
| |
| and induce phases of uterine bleeding in
| |
| rapid succession in normal monkeys
| |
| (Krohn, 1951). So too can testosterone prevent estrogen-withdrawal bleeding (Hart
| |
| | |
| | |
| 580
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| man, 1937; Engle and Smith, 1939; Duncan,
| |
| Allen and Hamilton, 1941) and inhibit progesterone-withdrawal bleeding as well (Engle and Smith, 1939). Testosterone also will
| |
| precipitate bleeding during an estrogen
| |
| treatment (Hisaw, 1943) and in normal
| |
| monkeys if given early in the cycle (Krohn,
| |
| 1951). Just what specific action these compounds have in common that enables them
| |
| to produce these effects or whether there are
| |
| different modes of action that lead to the
| |
| same results is not known, but, before mentioning certain possibilities, it may be helpful to consider information regarding the
| |
| influence of estrogen-progesterone interactions on menstruation.
| |
| | |
| Among the most significant observations
| |
| regarding primary causes of menstruation
| |
| are a few indications that there may be an
| |
| intrinsic difference in the ways in which estrogen and progesterone produce their effects on the endometrium. One of the first
| |
| indications of this was the discovery that a
| |
| short series of injections of progesterone
| |
| during treatment with estrogen will precipitate menstruation (Corner, 1937; Zuckerman, 1937d; Hisaw and Greep, 1938). This
| |
| can be demonstrated by giving a castrated
| |
| monkey a maintenance dose of estrogen
| |
| daily for 2 or 3 weeks, then adding a daily
| |
| injection of progesterone for 5 to 10 days
| |
| and continuing the estrogen treatment. As
| |
| a rule bleeding appears within 2 or 3 days
| |
| after stopping progesterone. The most interesting point brought out by such experiments is that bleeding can occur under these
| |
| conditions in the presence of an otherwise
| |
| maintenance dosage of estrogen.
| |
| | |
| Perhaps the most surprising as well as
| |
| most important fact brought out by subsequent experiments was the small amount of
| |
| progesterone required to bring about bleeding under these conditions. It was found that
| |
| only a single injection of 1 mg. was required
| |
| for animals on chronic treatment with a
| |
| maintenance dose of estradiol (1000 LIT.)
| |
| and some bled when 0.5 mg. progesterone
| |
| was given (Hisaw, 1942). The sequence of
| |
| events following the injection of progesterone can be seen to best advantage in an
| |
| adolescent monkey whose sexual skin also
| |
| respond" to the estrogen treatment. When
| |
| the 1 mg. ]irogesterone is given on the 20th
| |
| day of estrogen treatment the edema of th(^
| |
| | |
| | |
| | |
| sexual skin will have attained its maximal
| |
| development. The first indication of an effect of progesterone is a slight loss of edema
| |
| and color of the sexual skin which appears
| |
| on the 4th or 5th day and by the 9th or 10th
| |
| day the edema is almost gone and the sexual
| |
| skin is pale. Blood apjiears in the vaginal
| |
| lavage between the 7th and 10th days, of
| |
| about 70 per cent of the animals on this dosage. The sexual skin may remain markedly
| |
| reduced and pale until about the 15th day
| |
| after which both color and edema rapidly
| |
| return. These effects can also be seen when
| |
| 1 mg. progesterone is given for a series of
| |
| days. However, neither the time of appearance nor loss of edema of the sexual skin is
| |
| significantly hastened, and if the injections
| |
| extend over no more than 5 days the time
| |
| between the first injection and bleeding remains approximately the same.
| |
| | |
| Similar observations have been made by
| |
| Gillman and Smyth (1939) on the South
| |
| African baboon iPapio porcarius). They
| |
| found that 3 mg. or more of progesterone
| |
| when given in a single injection during the
| |
| follicular phase of the cycle would cause
| |
| the relatively enormous perineal swellings
| |
| to pass rapidly through deturgescence and
| |
| reach a flabby resting condition within 5 to
| |
| 7 days, and after a delay of about 24 hours
| |
| once again begin to swell. As much as 10 or
| |
| 15 mg. in a single dose caused perineal deturgescence without bleeding, whereas 20
| |
| mg. in a single dose or a total of 15 mg. if
| |
| divided into 2 or 3 injections and given at
| |
| 3 or 4 day intervals, produced both deturgescence and bleeding (Gillman, 1940b).
| |
| The l)aboon diff"ers from the monkey in that
| |
| larger doses of progesterone are required to
| |
| produce the effects and the sexual skin does
| |
| not ''mature" on repeated treatments and
| |
| lose its responsiveness; otherwise the basic
| |
| physiology of the reaction in both animals
| |
| seems to be the same.
| |
| | |
| The most important fact l)rought out by
| |
| these experiments is that the effects of a
| |
| single injection of progesterone can continue
| |
| in the presence of estrogen for as long as 10
| |
| to 15 days. It is highly imi^robable that progesterone lingers in the body for so long a
| |
| time (Zarrow, Shoger and Lazo-Wasem,
| |
| 1954). In general it is considered the most
| |
| ephemeral of the sex steroids and is probablv inactivated within at least a few hours
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 581
| |
| | |
| | |
| | |
| after it is administered. It seems more lilvely
| |
| that progesterone modifies the sexual skin
| |
| in a way that renders it unresponsive to estrogen and that about a fortnight is required
| |
| to recover the original condition.
| |
| | |
| This takes on added significance when the
| |
| possibility is considered that effects similar
| |
| to those seen in the sexual skin might also
| |
| be going on simultaneously in the uterine
| |
| endometrium. An appreciable dehydration
| |
| of the endometrium occurs just previous to
| |
| menstruation (van Dyke and Ch'en, 1936)
| |
| and a loss of interstitial fluid before bleeding has been observed in endometrial implants in the eyes of monkeys and described
| |
| in detail by Markee (1940) . This was shown
| |
| by periodic regression in size and compactness of the grafts which resulted in a decrease in area of 25 to more than 75 per
| |
| cent. Because cyclic changes in endometrial
| |
| grafts in the eye are correlated with events
| |
| of the menstrual cycle there is reason to believe that similar reactions were going on
| |
| in the endometrium of the uterus.
| |
| | |
| Endometrial regression, as described by
| |
| Markee, did not always lead to menstruation although it invariably preceded, accompanied, and followed menstrual bleeding.
| |
| Menstruation occurred only when regression
| |
| was rapid and extensive. This was seen in
| |
| the endometrial grafts in the eye during a
| |
| normal menstrual cycle at the time of involution of a corpus luteum and during an
| |
| anovulatory cycle soon after the involution
| |
| of a large follicle. It also begins soon after
| |
| the last of a series of injections of estrogen
| |
| or i^'ogesterone. A slow decrease in size of
| |
| the ocular grafts, without concomitant
| |
| bleeding, can be induced in castrated monkeys by gradual withdrawal of estrogen,
| |
| and when estrogen is given in amounts that
| |
| are inadequate for maintaining the endometrium for an extended period the "break
| |
| through" bleeding that eventually ensues is
| |
| preceded by a rapid and extensive endometrial regression. Because this reaction also
| |
| occurs w^hen menstruation is induced by such
| |
| an unusual procedure as spinal transection
| |
| (Markee, Davis and Hinsey, 1936), it probably is a phenomenon that always precedes
| |
| menstruation.
| |
| | |
| It seems from these observations that the
| |
| changes in the endometrium preceding menstruation are initiated by a sudden with
| |
| | |
| | |
| drawal of a stimulus on which the endometrium at the time relies for the maintenance
| |
| of a particular physiologic condition, and
| |
| bleeding and tissue loss are incidents that
| |
| occur during the readjustment necessary for
| |
| the return to an inactive state. What this involves is only partly known, but an understanding of the initial changes in the endometrium that usher in menstruation most
| |
| certainly holds the explanation of the real
| |
| cause. This has been a perennial subject for
| |
| discussion and many suggestions and theories have been set forth in an extensive
| |
| literature to account for various aspects of
| |
| menstruation. Among the more recent general discussions are those by Zuckerman
| |
| (1949, 1951), Corner (19511, and Zondek
| |
| ( 1954 ) .
| |
| | |
| The estrogen- withdrawal or estrogen-deprivation theory proposed by Edgar Allen
| |
| has received more attention than any other.
| |
| From what has been mentioned earlier it is
| |
| clear that this theory can account for uterine bleeding subsequent to the discontinuance of a series of estrogen injections and
| |
| also perhaps menstruation at the conclusion
| |
| of an anovulatory cycle. However, it is not
| |
| so obvious as to how this theory can explain
| |
| the occurrence of menstruation at the close
| |
| of the luteal phase of a normal cycle. Estrogen in large doses will not inhibit such
| |
| bleeding, but it is postponed if progesterone
| |
| is given. It is equally difficult to see how this
| |
| theory is helpful in accounting for the fact
| |
| that a small dose of progesterone will precipitate bleeding in the presence of a maintenance dosage of estrogen. As little as 2
| |
| /xg. progesterone will induce bleeding when
| |
| applied topically to the endometrial lips of
| |
| an exteriorized uterus (Fig. 9.7) in a monkey that is receiving 10 fig. estradiol daily
| |
| (Hisaw, 1950).
| |
| | |
| Uterine bleeding precipitated by administering progesterone during an estrogen
| |
| treatment has been explained on the grounds
| |
| that progesterone in some way interferes
| |
| with the action of estrogen on the endometrium. Therefore, it is assumed that an animal receiving both estrogen and progesterone is in a sense "deprived" of estrogen.
| |
| That is, when the two hormones are given
| |
| simultaneously, progesterone itself is capable of maintaining the endometrium without bleeding; but when it is stopped, the
| |
| | |
| | |
| | |
| 582
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| suggestion is that the animal is physiologically deprived of estrogen and literally deprived of progesterone (Corner, 1951). Although this view is in descriptive agreement
| |
| with the observed facts the idea of the inhibitory effect of progesterone does not take
| |
| into consideration the synergistic interaction of the two hormones on the endometrium.
| |
| | |
| The physiologic function of progesterone
| |
| is the conversion of an estrogen-endometrium into a progestational endometrium
| |
| suitable for receiving and nourishing a developing blastocyst. Such an endometrium
| |
| is adapted for this specific reproductive
| |
| function and accordingly its physiologic nature must be quite different from that of the
| |
| follicular phase of the cycle. Indeed, it is
| |
| known that these two structures (follicular
| |
| and luteal phase endometrial are morphologically and biochemically unlike in a number of respects. This gradual transformation,
| |
| following ovulation, occurs as progesterone
| |
| becomes the dominant hormone, and consequently, as this proceeds, the endometrium
| |
| progressively loses competence to respond
| |
| to estrogen. However, this does not imply
| |
| that estrogen is without effect in the general
| |
| economy of the progestational endometrium.
| |
| It has been shown in a number of ways that
| |
| the action of progesterone on the primate
| |
| endometrium is greatly facilitated by the
| |
| presence of estrogen. In fact, it seems probable that rarely if ever does progesterone
| |
| perform its function in the absence of estrogen (Hisaw, 1959; chapter by Zarrow).
| |
| | |
| After consideration of the endometrial
| |
| specializations brought about by ]irogesterone, it seems rather jwintless to hark back
| |
| to the follicular phase and inject the past
| |
| recoi'd of accomjilishments and prerogatives
| |
| that estrogen had at that time into the explanation of an entirely different hormonal
| |
| situation. It seems more in keeping with the
| |
| facts to state outright that menstruation
| |
| following the involution of a corpus luteum
| |
| or the discontinuance of progesterone, even
| |
| though estrogen is present, is due to a decrease or absence of progesterone.
| |
| | |
| It also has become less certain that menstruation at the conclusion of an anovulatory cycle is really an estrogen-withdrawal
| |
| bleeding. This is possible, of couisc, but at
| |
| | |
| | |
| | |
| the same time the exceedingly small amount
| |
| of progesterone required to induce bleeding
| |
| in the presence of estrogen makes it difficult
| |
| to be sure what the situation might be. Even
| |
| a negative test for progesterone in the blood,
| |
| by our present methods, does not necessarily
| |
| indicate the absence of a physiologically effective amount of progesterone. Zarrow,
| |
| Shoger and Lazo-Wasem (1954) found that
| |
| in rabbits an intramuscular injection of 40
| |
| mg. progesterone was required to produce
| |
| an appreciable concentration of the hormone in the blood as determined by the
| |
| Hooker-Forbes method. Yet, 0.2 mg. progesterone daily for 5 days will produce a
| |
| progestational reaction in the uterus equivalent to that of the 5th day of normal pseudopregnancy. In monkeys 0.5 mg. daily when
| |
| given with 10 fxg. estradiol is an adequate
| |
| dosage of progesterone to induce unquestionable progestational changes in the endometrium and much less will cause bleeding. These observations indicate that the
| |
| minimal effective concentration of progesterone in the blood may be less than is possible to detect by our present methods.
| |
| | |
| This also seems to hold for the human being. Estimates of secretion and metabolism
| |
| of progesterone in the human being have
| |
| been based primarily on the recovery of its
| |
| excretory product sodium pregnanediol glucuronidate in the urine. It seems obvious
| |
| that such determinations must be only general approximations because only about 20
| |
| per cent of the progesterone secreted or injected can be accounted for by the pregnanediol in the urine. Also, it is generally known
| |
| that a physiologically effective dosage of
| |
| progesterone does not necessarily lead to the
| |
| excretion of pregnanediol (Hamblen, Cuylcr,
| |
| Powell, Ashley and Baptist, 1939; Seegar,
| |
| 1940). In other words, the threshold dose of
| |
| progesterone for endometrial stimulation is
| |
| l)elow that at which the hormone is excreted
| |
| as pregnanediol. In fact, it has been suggested by some investigators that there is
| |
| no quantitative relationship between the
| |
| l)rogesterone present in the blood and the
| |
| pregnanediol excreted in the urine (Buxton,
| |
| 1940; Sommerville and Marrian, 1950;
| |
| Kaufmann, Westphal and Zander, 1951).
| |
| | |
| These findings and the wide variation in
| |
| the amount of prc'gnancdiol excreted during
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 58.3
| |
| | |
| | |
| | |
| a menstrual cycle (Venning and Browne,
| |
| 1937) suggest that, even in the absence of
| |
| ovulation, sufficient progesterone may be
| |
| present to influence menstruation. There
| |
| also is the possibility of progestational hormone from some extra-ovarian source, such
| |
| as the suprarenal cortex. This was suggested
| |
| by Zuckerman (1937b, 1941 j as a possible
| |
| explanation for periodic bleeding in monkeys on a constant submaintenance dose of
| |
| estrogen. This thought becomes more plausible in view of the fact that progesterone is
| |
| one of the precursors in the metabolic synthesis of androgens, estrogens, and adrenal
| |
| cortical steroids (Dorfman, 1956). Also, it
| |
| has been shown that desoxycorticosterone
| |
| acetate is converted to progesterone in vivo
| |
| (Zarrow, Hisaw and Bryans, 1950). Therefore, progesterone is not restricted to ovarian luteal function but instead is of rather
| |
| general occurrence in the body and the
| |
| likelihood is that small amounts are a constant constituent of the blood.
| |
| | |
| Also, the amount of progesterone from
| |
| extra-ovarian sources may fluctuate, as suggested by Zuckerman (1949), and consequently disturb the normal menstrual
| |
| rhythm and probably cause bleeding in
| |
| monkeys on a continuous submaintenance
| |
| dose of estrogen. However, as to the latter,
| |
| there is an alternative explanation. Castrated monkeys on a continuous treatment
| |
| of 10 fxg. of estradiol daily do not show
| |
| "break-through" bleeding, and a synergistic
| |
| effect on growth of the uterus is seen when
| |
| 0.5 mg. or more of progesterone daily is introduced into the treatment. However, the
| |
| simultaneous administration of 0.25 mg. or
| |
| even 0.125 mg. progesterone daily in similar
| |
| exj^eriments results in bleeding between
| |
| a!)out the 10th to 16th day of the combination treatment. Thus, a dosage of progesterone less than that required for synergism or
| |
| prevention of bleeding when given alone,
| |
| modifies the endometrium so that it can no
| |
| longer be maintained by 10 fxg. estradiol
| |
| daily (Hisaw, Jr., unpublished). When it is
| |
| considered that the endometrium becomes
| |
| increasingly dependent on estrogen during
| |
| a chronic treatment, even after maximal
| |
| growth is attained (Hisaw, 1942), it seems
| |
| plausible that the effectiveness of a dosage
| |
| of estrogen only slightly alcove the thresh
| |
| | |
| | |
| old for bleeding may be decreased sufficiently by the endogenous progesterone from
| |
| extra-ovarian sources to precipitate bleeding.
| |
| | |
| Although it is obvious that the normal
| |
| menstrual cycle is primarily under the control of the ovarian estrogens and progesterone, it is also equally clear that menstruation is not due to a specific hormonal action.
| |
| Experimental evidence indicates that any
| |
| natural or synthetic compound having the
| |
| capacity for promoting growth or sustaining
| |
| an existing metabolic state in the endometrium is also capable of inducing withdrawal bleeding. However, this does not imply that all compounds capable of inducing
| |
| menstruation do so by the same biochemical
| |
| action; in fact, there is considerable evidence that this is not so (see chapter by
| |
| Villee). Yet in each instance a series of
| |
| events is set in motion that leads up to active bleeding.
| |
| | |
| X. The Mechanism of Menstruation
| |
| | |
| The immediate cause and mechanism of
| |
| menstruation has continued to be a topic of
| |
| special interest for many years and the subject of frequent general discussions. A generalization in keeping with our present
| |
| knowledge is that no gross morphologic feature of the endometrium is distinctive of
| |
| menstruation. A menstruating endometrium
| |
| may be representative of any stage of the
| |
| follicular or luteal phase of the cycle. The
| |
| most frequently discussed hypothesis regarding the mechanism of menstruation is
| |
| that proposed by Markee (1940, 1946)
| |
| which is based on direct observations of
| |
| vascular changes in endometrial grafts in
| |
| the anterior chamber of the eye of monkeys
| |
| (see p. 564). The changes observed in the
| |
| endometrium shortly before bleeding are,
| |
| briefly, as follows. (1) There is extensive
| |
| and rapid regression of the endometrium due
| |
| to loss of ground substance from the stroma
| |
| (Fig. 9.23). (2) The rapid regression brings
| |
| about a disproportion between the length of
| |
| the coiled arteries and thickness of the endometrium with the formation of additional
| |
| coils. (3) The increased coiling of the arteries retards the circulation of blood
| |
| through them and their branches. This stasis
| |
| begins 1 to 3 davs before the onset of the
| |
| | |
| | |
| | |
| 584
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Repair
| |
| | |
| | |
| | |
| Fig. 9.23. A diagram indicating correlated changes in ovary and endometrium during
| |
| an ovulatory cycle of rhesus monkey. Thickness of endometrium, density of stroma, gland
| |
| form, and three types of arteries are indicated. There is a gradual rise in thickness up to the
| |
| time of ovulation, and a brief decline followed by development of the luteal or progestational phase with accumulation of secretion in the glands due to relaxation of the
| |
| myometrium. This is followed by loss of ground substance from the stroma, which is the
| |
| primary factor in the premenstrual regression of the ischemic phase. This is a prelude to
| |
| extravasation and shedding of tissue. Incidentally, secretion is extruded and glands collapse. There is further regression throughout the phase of menstruation. More than the
| |
| basal zone (coarse stipple) survives menstruation. During repair, thickening of the endometrium is associated with increase in ground substance in the stroma and growth in the
| |
| glands. (From G. W. Bartelmez, 1957, Am. J. Obst. & Gynec, 74, 931-955, 1957, with
| |
| some modification of description.)
| |
| | |
| | |
| | |
| flow, and is associated with leukocytosis in
| |
| the endometrium. (4) The portion of the
| |
| coiled arteries located adjacent to the muscularis constricts 4 to 24 hours before the
| |
| onset of the flow. This vasoconstriction persists throughout the menstrual period except when individual coiled arteries relax
| |
| and blood circulates through them for a few
| |
| minutes. Markee postulated that the immediate cause of menstruation under these
| |
| conditions was the injurious effect of anoxemia upon the tissues of the endometrium
| |
| l)rought about by mechanical compression
| |
| and constriction of the coiled arteries.
| |
| Therefore, the coiled arteries and their modifications become the central feature upon
| |
| which the theory is based.
| |
| | |
| Although this offers an explanation for
| |
| many of the facts, it falls short in that now
| |
| it is known that menstruation can occur in
| |
| the absence of coiled arteries. Kaiser (1947)
| |
| showed that no spiral arteries are present in
| |
| | |
| | |
| | |
| the endometrium of three species of South
| |
| American monkeys known to menstruate.
| |
| He also found that the coiled vessels of the
| |
| endometrium could be destroyed almost
| |
| completely by giving large doses of estrogen
| |
| and yet bleeding followed estrogen withdrawal.
| |
| | |
| Several experimental conditions under
| |
| which the coiled vessels of the endometrium
| |
| are destroyed have been mentioned in the
| |
| present discussion and in each instance
| |
| bleeding invariably followed withdrawal of
| |
| the supporting stimulus. The extremely
| |
| atrophic endometrium present at the conclusion of a prolonged treatment with progesterone (Fig. 9.8) will bleed when the
| |
| injections are stopped, and if estrogen injections are started immediately thereafter
| |
| the endometrium that develops is normal
| |
| with the exception of the absence of coiled
| |
| arteries; even so, it also will bleed when
| |
| the treatment is stopped. Even a more
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 58c
| |
| | |
| | |
| | |
| drastic destruction of endometrial structures occurs when both estrogen and progesterone are given for several months. Not
| |
| only are the coiled arteries destroyed but
| |
| also the glands and the luminal epithelium.
| |
| All that remains is a modified stroma penetrated by a few small blood and lymph vessels and scattered glandular rudiments along
| |
| the myometrium (Fig. 9.13). Yet, in spite
| |
| of this, bleeding follows discontinuance of
| |
| the treatment.
| |
| | |
| These observations prove conclusively
| |
| that the spiral arteries of the endometrium
| |
| do not hold the solution to the menstrual
| |
| process. However, the descriptive account
| |
| by Markee of the events that take place in
| |
| the endometrium during the cycle remains
| |
| one of the major contributions to our knowledge of the primate endometrium. Phelps
| |
| (1946) also made a very careful study of the
| |
| vascular changes in intraocular endometrial
| |
| transplants in ovariectomized monkeys receiving estrogen and progesterone, and concluded that the primary function of the
| |
| coiled arteries is concerned with vascularization of the implantation site of a developing embryo.
| |
| | |
| There also is reason for doul^ting that
| |
| ischemia is a determining factor in the
| |
| menstrual process. That constriction of the
| |
| endometrial vessels does occur is well established, but that tissue destruction and bleeding are consequences of prolonged anoxemia
| |
| may be questioned. The endometrium
| |
| around the internal cervical os as seen in
| |
| incised exteriorized uteri (Fig. 9.7) contains
| |
| very few coiled arteries and does not take
| |
| part in the periodic blushing and blanching
| |
| of the fundus, but instead remains blood-red
| |
| even during menstruation. Also, certain
| |
| tongues of endometrium in a uterine fistula
| |
| may become crowded by their neighbors to
| |
| an extent of being partly or completely deprived of blood, yet they do not bleed even
| |
| though their unfavorable situation leads to
| |
| deterioration within a few days.
| |
| | |
| Emmel, Worthington and Allen (1941)
| |
| attempted to induce menstruation in monkeys by operative ischemia. Circulation to
| |
| the fundus of the uterus was interrupted by
| |
| means of a tourniquet for periods of 1 to 8V4
| |
| hours, and in two instances for 19 hours.
| |
| This procedure did not precijiitate uterine
| |
| | |
| | |
| | |
| bleeding nor did it hasten the onset of an
| |
| expected bleeding following estrogen withdrawal. In fact, when the uterus was deprived of blood for periods longer than 3
| |
| hours impairment of the bleeding response
| |
| to estrogen withdrawal was observed, and
| |
| 19 hours of ischemia caused atrophy of the
| |
| uterus without bleeding.
| |
| | |
| It also has been reported that a toxic substance formed in the endometrium is responsible for menstruation. This menstrual
| |
| toxin is supposed to be present in the endometrium just previous to and during menstruation, and to be a substance resembling
| |
| or identical with necrosin, a material found
| |
| in pleural exudate following an inflammatory reaction (Smith and Smith, 1951).
| |
| Zondek (1953) reports that menstrual blood,
| |
| when obtained under relatively sterile conditions, is no more toxic to experimental
| |
| animals than sterile tissue extracts. He also
| |
| found that death of animals given injections
| |
| of menstrual blood was due to bacteremia,
| |
| an effect that could be prevented by giving
| |
| antibiotics. Nor was he able to demonstrate
| |
| a toxic substance in the premenstrual or
| |
| menstrual endometrium. It might be mentioned in this connection that endometrial
| |
| tissue destroyed by experimental ischemia
| |
| in the experiments by Emmel, Worthington
| |
| and Allen (1941), obviously did not influence menstruation nor did involuting endometrial tissue in uterine fistulae (p. 564).
| |
| Therefore, the presence of a specific toxin
| |
| that may induce menstruation has not been
| |
| conclusively demonstrated.
| |
| | |
| Regardless of the specific cause of menstruation, the evidence shows that it can
| |
| occur in the absence of coiled arteries, endometrial glands, or surface mucosa, and is
| |
| unrelated to the thickness of the endometrium. This statement is based on conditions that have been experimentally induced
| |
| in the monkey and they strongly indicate
| |
| that menstruation, whatever the cause, is a
| |
| stromal phenomenon. This view seems to be
| |
| in agreement with the observations reported
| |
| by Bartelmez in his elegant studies of the
| |
| morphology of the endometrium of both
| |
| monkeys and the human being. He emphasizes changes taking place in the connective
| |
| tissue elements of the stroma and points out
| |
| that much less tissue is lost at menstruation
| |
| | |
| | |
| | |
| 586
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| than i.< commonly thought (Bartehnez,
| |
| 1957). The reduction in thickness is clue primariiy to loss of ground substance from the
| |
| stroma, and conversely, the outstanding
| |
| feature of repair is the increase in stromal
| |
| ground substance (Fig. 9.23). ^Mitoses are
| |
| rarely seen in the stroma during repair and
| |
| arc not abundant enough in any phase according to Bartelmez to account for the observed increase in thickness of the endometrium. Our present knowledge indicates that
| |
| an explanation of menstruation may be
| |
| found in the metabolic effects induced in the
| |
| stromal connective tissue of the endometrium by a sudden withdrawal of a supporting hormonal stimulus.
| |
| | |
| XI. References
| |
| | |
| Allen, E. 1927. The menstrual CA'cle in the monkey, Macacus rhesus: observations on normal
| |
| animals, the effects of removal of the ovaries
| |
| and the effects of injections of ovarian and
| |
| placental extracts into the .spayed animals.
| |
| Contr. Embrvol., Carnegie Inst. Washington,
| |
| 19, 1-44.
| |
| | |
| Allen. E. 1928. Further experiments with an
| |
| ovarian hormone in the ovariectomized adult
| |
| monkey, Macacus rhesus, especially the degenerative phase of the experimental menstrual cycle. Am. J. Anat., 42, 467^87.
| |
| | |
| Allen, E., Diddle, A. W., Burford, T. H., .and Elder, J. H. 1936. Analyses of urine of the
| |
| chimpanzee for estrogenic content during various stages of the menstrual cycle. Endocrinology, 20, 546-549.
| |
| | |
| Allen, E., Pr.\tt, J. P., Xewell, Q. U., .and Bl.and,
| |
| L. J. 1930. Human tubal ova ; related early
| |
| corpora lutea and uterine tubes. Contr. Embryol., Carnegie Inst. Washington, 22, 45-76.
| |
| | |
| B.ACHMAN, C, CoLLip, J. B., .\ND Selye, H. 1935.
| |
| The effects of prolonged estriol administration
| |
| upon the sex skin of Macaca mulatta. Proc.
| |
| Roy. Soc, London, .■^er. B., 117, 16-21.
| |
| | |
| B.artel.mez, G. W. 1933. Histologic studies on
| |
| the menstruating mucous membrane of the human uterus. Contr. Embryol.. Carnegie Inst.
| |
| Washington, 24, 141-186.
| |
| | |
| B.artel.mez, G. W. 1937. ^Menstruation. Plnsiol.
| |
| Rev.. 17, 28-72.
| |
| | |
| B.ARTELMEZ, G. W. 1951. Cyclic changes in the
| |
| endometrium of the rhesus monkey {Macacus
| |
| mulaltn). Contr. Embryol., Carnegie Inst.
| |
| Washington. 34, 101-144.
| |
| | |
| B.ARTELMEz, G. W. 1957. The pha.scs of the menstrual cycle and their interpretation in terms
| |
| of the pregnancv cycle. Am. J. Obst. & Gvnec,
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| 74, 931-955.
| |
| | |
| BRY.AN.S, F. E. 1951. Progesterone of the lilood
| |
| in the menstrual cycle of the monkey. Endocrinology, 48, 733-740.
| |
| | |
| BrxTo.N, C. L. 1940. Pregnanediol determina
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| | |
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| tions as an aid in clinical diagnosis. Am. J.
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| Obst. & Gynec, 40, 202-211.
| |
| | |
| CoLLiNGS, M. R. 1926. A study of the cutaneous
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| reddening and swelling about the genitalia of
| |
| the monkev, Macacus rhesus. Anat. Rec, 33,
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| 271-287.
| |
| | |
| Corner, G. W. 1923. Ovulation and menstruation in Macacus rhesus. Contr. Embrj^oL, Carnegie Inst. Washington, 15, 73-101.
| |
| | |
| Corner, G. W. 1935. Influence of the ovarian
| |
| hormones, estrin and progestin, upon the menstrual cvcle of the monkev. Am. J. Phj'siol.,
| |
| 113,238-250.
| |
| | |
| Corner, G. W. 1937. Experimental menstruation. Science, 85, 437-438.
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| | |
| Corner, G. W. 1942. The fate of the corpora
| |
| lutea and the nature of the corpora aberrantia
| |
| in the rhesus monkey. Contr. Embryol., Carnegie Inst. Washington, 30, 87-96.
| |
| | |
| Corner, G. W. 1945. Development, organization
| |
| and breakdown of the corpus luteum in the
| |
| rhesus monkey. Contr. Embrj'ol., Carnegie Inst.
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| Washington, 31, 119-146.
| |
| | |
| Corner, G. W. 1951. Our knowledge of the menstrual cycle, 1910-1950. Lancet, 1, 919-923.
| |
| | |
| Corner, G. W., and Allen, W. M. 1936. Inhibition of menstruation by crj-stalline progesterone. Proc. Soc. Exper. Biol. & Med.. 34, 723724.
| |
| | |
| Crossex, R. J. 1953. Diseases of Women. St.
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| Louis: C. V. Mosby Company.
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| | |
| Davls, M. E., and H.art^lan, C. G" 1935. Changes
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| in vaginal epithelium during pregnancy in relation to the vaginal cvcle. J. A. M. A., 104,
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| 279-285.
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| | |
| Diczfall'.sy, E. 1953. Chorionic gonadotrophin
| |
| and estrogens in the human placenta. Acta
| |
| endocrinol., Suppl. 12, 87-167.
| |
| | |
| DoRFMAN, R. I. 1956. Metabolism of androgens,
| |
| estrogens and corticoids. Am. J. Med., 21, 679687.
| |
| | |
| DoRFMAN, R. I., AND VAN W.AGENEN, G. 1941. The
| |
| | |
| sex hormone excretion of adult female and
| |
| pregnant monkevs. Surg. Gvnec. & Obst., 73,
| |
| 545-548.
| |
| | |
| Duncan, P. A., Allen. E., and Ha.milton. J. B.
| |
| 1941. The action of testosterone proprionate
| |
| on experimental men.struation in the monkev.
| |
| Endocrinology. 28, 107-111.
| |
| | |
| Eckstein, P. 1950. The induction of progesterone withdrawal bleeding in spayed monkeys. J.
| |
| Endocrinol., 6, 405-411.
| |
| | |
| EcK.STEiN, P., AND ZucKERMAN, S. 1956. In Marshall's Physiology of Reproducliori. A. S.
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| Parkes, Ed. Vol. 1, ]\ 334. London: Longmans
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| Green & Company.
| |
| | |
| EmMEL, V. M., WORTHINGTON, R. V., AND AlLEN. E.
| |
| | |
| 1941. Attempts to induce menstruation by
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| operative ischemia in monkey's. Endocrinologv,
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| 29, 330-335.
| |
| | |
| Engle. E. T. 1937. Problems of experimental
| |
| menstruation. Cold Spring Harbor Svmposia
| |
| Quant. Biol., 5, 111-114.
| |
| | |
| Engle, E. T., .and S.mith, P. E. 1935. Some uterine effects obtained in female monkeys during
| |
| continued estrin administration, with especial
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 587
| |
| | |
| | |
| | |
| reference to tlio r('i\ ix uteri. Auat. Rec, 6,
| |
| 471-483.
| |
| | |
| Encle, E. T., Smith, P. E., and Shelesnyak, M. C.
| |
| 1935. The role of estrin and progestin in experimental menstruation. Am. J. Obst. & Gynec. 29, 787-797.
| |
| | |
| Engle, E. T., and Smith, P. E. 1938. The endometrium of the monkey and est rone-progesterone balance. Am. J. Anat., 63, 349-365.
| |
| | |
| Engle, E. T., and Smith, P. E. 1939. Certain actions of testosterone on the endometrium of
| |
| the monkey and on uterine bleeding. Endocrinology, 25^ 1-6.
| |
| | |
| Fish, W. R., Young, W. C, and Dorfman, R. I.
| |
| 1941. Excretion of estrogenic and androgenic
| |
| substances by female and male chimpanzees
| |
| with known mating behavior records. Endocrinology, 28, 585-592.
| |
| | |
| Fluhmann, C. F. 1954. Comparative studies of
| |
| squamous metaplasia of the cer\ix uteri and
| |
| endometrium. Am. J. Obst. ct Gynec, 68,
| |
| 1447-1462.
| |
| | |
| Forbes, T. R., Hooker, C. W., and Pfeiffer, C. A.
| |
| 1950. Plasma progesterone levels and the
| |
| menstrual cycle of the monkey. Proc. Soc. Exper. Biol. & Med., 73, 177-179.
| |
| | |
| GiLLMAN, J. 1937a. The cyclical changes in the
| |
| vaginal smear in the baboon and its relationship to the perineal swelling. South African J.
| |
| M. Sc, 2, 44-56.
| |
| | |
| GiLLMAN, J. 1937b. Experimental studies on the
| |
| menstrual cycle of the baboon (Papio porcarhis). South African J. M. Sc, 2, 156-166.
| |
| | |
| GiLLMAN, J. 1938. Experimental studies on the
| |
| menstrual cycle of the baboon (Papio porcarius). South African J. M. Sc, 3, 6&-71.
| |
| | |
| GiLLMAN, J. 1940a. Experimental studies on the
| |
| menstrual cycle of the baboon (Papio porcarius). VI. The effect of progesterone upon
| |
| the first part of the cycle in normal female
| |
| baboons. Endocrinology, 26, 80-87.
| |
| | |
| GiLLMAN, J. 1940b. The effect of multiple injections of progesterone on the turgescent perineum of the baboon (Papio porcarius). Endocrinology, 26, 1072-1077.
| |
| | |
| GiLLMAN, J., AND GILBERT, C. 1946. The reproductive cycle of the chacma baboon (Papio
| |
| itrsiDiis) with special reference to the problems
| |
| of menstrual iriegularities as assessed by the
| |
| behaviour of the sex skin. South African J. M
| |
| Sc, Biol. Suppl., 11, 1-54.
| |
| | |
| GiLLMAN, J., .AND Smyth, G. S. 1939. The hormonal content of the human luteal follicle of
| |
| pregnancy as determined by its effect on the
| |
| perineum of the baboon. South African J. M.
| |
| Sc, 4, 3&-45.
| |
| | |
| Haman, J. O. 1942. The length of the menstrual
| |
| cvcle. A study of 150 normal women. Am. J.
| |
| Obst. & Gynec, 43, 870-873.
| |
| | |
| Hamblen, E. C., Cuyler, W. K., Powell, N. B.,
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| Ashley, C, and B.aptist, M. 1939. Some
| |
| clinical observations upon the metabolism and
| |
| utilization of crystalline progesterone. Endocrinology, 25, 13-16.
| |
| | |
| Hamilton, C. E. 1949. Observations on the cervi
| |
| | |
| | |
| cal mucosa of the Rhesus monkey. Contr. EnibryoL, Carnegie Inst. Washington, 33, 81-101.
| |
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| H.artman, C. G. 1929. Three types of uterine
| |
| bleeding in the monkey and the homology of
| |
| menstruation (Abstr.). Anat. Rec, 42, 19.
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| | |
| Hartman, C. G. 1932. Studies in the reproduction of the monkey, Macacus (Pithecus) rhe.S-//.S, with special reference to menstruation and
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| piegnancy. Contr. Embryol., Carnegie Inst.
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| Washington, 23, 1-16.
| |
| | |
| H.ARTMAN, C. G. 1934. Some attempts to influence the menstrual cvcle in the monkev.
| |
| Am. J. Obst. & Gynec, 27, 564-570.
| |
| | |
| Hartman, C. G. 1937. Menstruation inhibiting
| |
| action of testosterone. Proc Soc. Exper. Biol.
| |
| & Med., 37, 87-89.
| |
| | |
| H.ARTMAN, C. G. 1944. Regeneration of the monkey uterus after surgical removal of the endometrium and accidental endometriosis. Western J. Surg. Obst. & Gynec, 52, 87-102.
| |
| | |
| Hartman, C. G., .and Speert, H. 1941. Action of
| |
| progesterone on the genital organs of the unjirimed Rhesus monkev. Endocrinology, 29,
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| 639-648.
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| H.ARTMAN, C. G., GeSCHICKTER, G. F., AND SpEERT, H.
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| 1941. Effects of continuous estrogen administration in verv large doses. Anat. Rec, Suppl.
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| 2, 79, 31.
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| Hellman, L. M., Rosenthal, A. H., Kistner, R.
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| W., AND Gordon, R. 1954. Some factors influencing the proliferation of the leserve cells
| |
| in the human cervix. Am. J. Obst. & Gvnec.
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| 67, 899-915.
| |
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| Hertig, a. T., and Rock, J. 1944. On the development of the early human ovum, with special
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| reference to the trophoblast of the previllous
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| stage ; a description of 7 normal and 5 pathologic human ova. Am. J. Obst. & Gvnec, 47,
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| 149-184.
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| | |
| Heuser, C. H., and Streeter, G. L. 1941. Development of the macaque embryo. Contr. Embryol., Carnegie Inst. Washington, 29, 17-55.
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| Hisaw, F. L. 1935. The physiology of menstruation in Macacus rhesus monkevs. Am. J. Obst.
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| & Gynec, 29, 638-659.
| |
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| HiSAW% F. L. 1942. The interaction of the ovarian hormones in experimental menstruation.
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| Endocrinology, 30, 301-308.
| |
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| HiSAW, F. L. 1943. Androgens and experimental
| |
| menstruation in the monkey (Macaca viulatta). Endocrinology, 33, 39-47.
| |
| | |
| HisAW, F. L. 1950. Factors influencing endometrial growth in monkeys (Macaca mulatta). In
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| A Symposium on Steroid Hormones, E. S.
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| Gordon, Ed., pp. 259-276. Madison: University of Wisconsin Press.
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| Hisaw, F. L. 1959. Endocrine adaptations of the
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| mammalian estrous cycle and gestation. In Columbia University Symposium on Comparative
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| Endocrinology, pp. 533-552.
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| Hisaw, F. L., Creep, R. O., and Fevold, H. L.
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| 1937. Effects of progesterone on the female
| |
| genital tract after castration atrophy. Proc
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| Soc. Exper. Biol. & Med., 36, 840-842."
| |
| | |
| His.\w, F. L.. AND Creep, R. O. 1938. The inhibition of uterine bleeding with estradiol and
| |
| | |
| | |
| | |
| 588
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| progesterone and associated endometrial modifications. Endocrinology, 23, 1-14.
| |
| His.\w, F. L., .^ND His.wv, F. L., Jr. 1958. Spontaneous carcinoma of the cervix uteii in a
| |
| monkey (Macaca mulatto). Cancer, 11, 810816.
| |
| HiSAW, F. L., .4ND Lendrum, F. C. 1936. Squamous metaplasia in the cervical glands of the
| |
| monkey following oestrin administration. Endocrinology, 20, 228-229.
| |
| HiSAW, F. L., Meyer, R. K., axd Fevold, H. L.
| |
| 1930. Production of a premenstrual endometrium in castrated monkeys by ovarian hormones. Proc. Soc. Exper. Biol. & Med., 27,
| |
| 400-403.
| |
| HiTSCHMANN, F., AND Adler, L. 1907. Die Lehre
| |
| von der Endometritus. Ztschr. Geburtsh. u.
| |
| GynJik., 60, 63-86.
| |
| Kaiser, I. H. 1947. Absence of coiled arterioles
| |
| in the endometrium of menstruating New
| |
| World monkeys. Anat. Rec, 99, 353-363.
| |
| Kaufmann, C, Westphal, U., and Zander, J. 1951.
| |
| Untersuchungen liber die biologische Bedeutang der Ausscheidungsprodukte des Gelbkcirperhormons. Arch. Gynak., 179, 247-299.
| |
| Knaus, H. 1950. Die Physiologie der Zeugung
| |
| | |
| des Menschen. Wien: Wilhelm Maudrich.
| |
| Krohn, p. L. 1951. The induction of menstrual
| |
| bleeding in amenorrhoeic and normal monkeys
| |
| by progesterone. J. Endocrinol., 7, 310-317.
| |
| Krohn, P. L. 1955. The induction of cyclic uterine bleeding in normal and spayed rhesus monkeys by progesterone. J. Endocrinol., 12, 6985.
| |
| Krohn, P. L., and Zuckerman, S. 1937. Water
| |
| metabolism in relation to the menstrual cycle.
| |
| J. Physiol., 88, 369-387.
| |
| Latz, L. J., and Reiner, E. 1942. Further studies
| |
| on the sterile and fertile periods in women.
| |
| Am. J. Obst. & Gynec, 43, 74-79.
| |
| Lendrum, F. C., .and Hisavv^ F. L. 1936. Cytology
| |
| of the monkey endometrium under influence of
| |
| follicidar and corpus luteum hormones. Proc.
| |
| Soc. Exper. Biol. & Med., 34, 394-396.
| |
| Lopez Columbo de Allende, I., and Orias, O. 1950.
| |
| Cytology of the Human Vagina. New York:
| |
| Paul B. Hoeber, Inc.
| |
| Lopez Colu.mbo de Allende, I., Shorr, E., and Hartman, C. G. 1945. A comparative study of the
| |
| vaginal smear cycle of the rhesus monkey and
| |
| the human. Contr. Embryol., Carnegie Inst.
| |
| Washington, 31, 1-26.
| |
| M.arkee, J. E. 1940. Menstruation in intraocular endometi'ial tr;msplants in the I'hesus monkey. Contr. Embrvol., Carnegie Inst. Washington, 28, 219-308.
| |
| Markee, J. E. 1946. Morphologic and endocrine
| |
| basis foi' menstrual bleeding. In Progress in
| |
| Gynecology, Meigs and Sturgis, Eds. Vol. II,
| |
| pp. 37-47. New York: (hune and Stiattdii.
| |
| Markee, J. E., and Berg, B. 1944. Cyclic fluctuations in blood estrogen as a possible cause of
| |
| menstruation. Stanford Med. Bull., 2, 55-60.
| |
| Markee, J. E., D.wis, J. H., and Hinsf.y, J. C.
| |
| 1936. Uterine bleeding in spinal iii()nk(>vs.
| |
| Anat. Rec, 64, 231-245.
| |
| | |
| | |
| | |
| Mazer, C, and Israel, S. L. 1951. Diagnosis and
| |
| Treatment of Menstrual Disorders and Sterility. New York: Paul B. Hoeber, Inc.
| |
| | |
| Meyer, R. 1911. Uber Corpus luteum-Bildung
| |
| beim Menschen. Arch. Gynak., 93, 354-404.
| |
| | |
| Nissen, H. W., and Yerkes, R. M. 1943. Reproduction in the chimpanzee: report on 49
| |
| births. Anat. Rec, 86, 567-578.
| |
| | |
| Novak, E., and Te Linde, R. W. 1924. Endometrium of menstruating uterus. J. A. M. A., 83,
| |
| 900-906.
| |
| | |
| OvERHOLSER, M. D., AND Allen, E. 1933. Ovaiiau
| |
| hormone and traumatic stimulation of monkey's cervix to a condition resembling early
| |
| cancer. Proc Soc. Exper. Biol. & Med., 30,
| |
| 1322-1326.
| |
| | |
| OvERHOLSER, M. D., AND Allen, E. 1935. Atypical growth induced in cervical epithelium of
| |
| monkey by prolonged injections of ovarian
| |
| hormone combined with chronic trauma. Surg.
| |
| Gynec. & Obst., 60, 129-136.
| |
| | |
| OvERHOLSER, M.D.,. AND Nelson, W. 0. 1936. Migration of nuclei in uterine epithelium. A
| |
| monkey following prolonged estrin injections.
| |
| Proc Soc Exper. Biol. & Med., 34, 839-841.
| |
| | |
| P.APANicoL.Aou, G. N., Traut, H. F., and M.archetti,
| |
| A. A. 1948. The Epithelia of Woman/s Reproductive Organs. New York: Commonwealth Fund.
| |
| | |
| Parkes, a. S., and Zuckerm.an, S. 1931. The
| |
| menstrual cycle of the Primates. II. Some
| |
| effects of oestrin on baboons and macaques.
| |
| J. Anat., 65, 272-276.
| |
| | |
| Phelps, D. 1946. Endometrial vascular reactions and the mechanism of nidation. Am. J.
| |
| Anat., 79, 167-197.
| |
| | |
| Phelps, D. H. 1947. The factor of previous
| |
| treatment in experimental menstruation. J.
| |
| Clin. Endocrinol., 7, 611-623.
| |
| | |
| Rakoff, a. E. 1946. Studies on high dosage progesterone therapy of amenorrhea. Am. J. Obst.
| |
| & Gynec, 51, 480-491.
| |
| | |
| Rock, J., and Hertig, A. 1942. Some aspects of
| |
| early human development. Am. J. Obst. &
| |
| Gynec, 44, 973-983.
| |
| RossM.AN, I. 1940. The decidual reaction in the
| |
| rhesus monkey {Macaca mulatta). I. The
| |
| epithelial proliferation. Am. J. Anat., 66, 277365.
| |
| Schroder, R. 1914. Uber das Verhalten der Uterusschleimhaut um die Zeit der Menstruation.
| |
| Monatsschr. Geburtsh. u. Gynak., 39, 3-21.
| |
| Seeg.ar, E. G. 1940. The histologic effect of progesterone on hyperplastic endometria. Am. J.
| |
| Obst. & Gynec, 39, 469-476.
| |
| S.mith, O. W., and S.mith, G. V. 1951. Endocrinology and related phenomena of the human
| |
| menstrual cvcle. Recent Progr. Hormone Res.,
| |
| 7, 209-253.
| |
| | |
| So.MMKKVILLK, I. V ., AND MaRRIAN, G. F. 1950.
| |
| | |
| I'rinary excretion of prcgnanediol in human
| |
| subjects following the administration of progesterone and of pregnane-3a:20a-diol. I3iochem. J., 46, 285-289.
| |
| Stieve, H. 1926. Di(> regelmassigen Verliinderungen der Muskulatur und des Bindegewebs in
| |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 589
| |
| | |
| | |
| | |
| der meuschlichen Gebarmutter in ihier Abhangigkeit von der Follikelreife und der Aiisbildung eines gelben Korpers, nebst Beschreibung eines menschlichen Eies im Zustand der
| |
| ersten Reifteilung. Ztschr. mikroskop.-anat.
| |
| Forsch, 6, 351-397.
| |
| | |
| Stieve, H. 1942. Der Einfluss von Angst und
| |
| psychischer Erregung auf Bau und Funktion
| |
| der weiblit'hen Geschlechtsorgane. Zeutralbl.
| |
| Gynak., 66, 1698-1708.
| |
| | |
| Stieve, H. 1943. Weitere Tatsachen zur Kliirung
| |
| der Frage: Wann wird das Ei aus dem Eierstock ausgestossen? Zentralbl. Gvnak., 67, 5877.
| |
| | |
| Stieve, H. 1944. Paracyclische Ovulationen. Zentralbl. Gynak., 68, 257-272.
| |
| | |
| Sturgis, S. H. 1942. Method for obtaining uterine fluid from the monkey : effect of pilocarpine, atropine, physiologic salt solution and
| |
| adrenalin. Endocrinology, 31, 664-672.
| |
| | |
| VAN Dyke, H. B., and Ch'en, G. 1936. Observations on biochemistry of genital tract of female
| |
| macacjue particularly during menstrual cycle.
| |
| Am. J. Anat., 58, 473-499.
| |
| | |
| VAN Wagenen, G. 1945. Mating in relation to
| |
| pregnancy in the monkey. Yale J. Biol. &
| |
| Med., 17, 745-760.
| |
| | |
| VAN Wagenen, G. 1947. Early mating and pregnancy in the monkev. Endocrinologv, 40, 3743.
| |
| | |
| VAN W.^genen, G., and Morse, A. H. 1940. Cyclic
| |
| changes in the exteriorized uterus. Endocrinology, 27, 268-273.
| |
| | |
| Venning, E. H., and Browne, J. S. L. 1937. Studies on corpus luteum function. I. The vn-inary
| |
| excretion of sodium pregnandiol glucuronidate
| |
| in the human men.^trual cvcle. Endocrinologv,
| |
| 21,711-721.
| |
| | |
| Werner, A. A., and Collier, W. D. 1933. The
| |
| effect of theelin injections on the castrated
| |
| woman. J. A. M. A., 100, 633-640.
| |
| | |
| Westman, a. 1932. Studien iiber den Sexualzyklus bei Makakus-Rhesus-Affen, nebst einigen Bemerkungen liber den menstruellen
| |
| Blutungs-mechanismus. Acta obst. et gynec.
| |
| scandinav., 12, 282-328.
| |
| | |
| WiSLOCKi, G. B., and Streeter. G. L. 1938. On
| |
| the placentation of the macaque {Macaca
| |
| mulatta), from the time of implantation until
| |
| the formation of the definitive placenta. Contr.
| |
| Embryol., Carnegie Inst. Washington, 27, 166.
| |
| | |
| Young, W. C, and Yerkes, R. M. 1943. Factors
| |
| influencing the reproductive cycle in the chimpanzee; the period of adolescent sterility and
| |
| related problems. Endocrinology, 33, 121-154.
| |
| | |
| Z.ARRow, M. X., Hisaw, F. L., and Bryans, F. 1950.
| |
| Conversion of desoxycosterone acetate to progesterone in vivo. Endocrinology, 46, 403-404.
| |
| | |
| Zarrow, M. X., Shoger, R. L., and Lazo-Wasem, E.
| |
| A. 1954. The rate of disappearance of exogenous progesterone from the blood. J. Clin.
| |
| Endocrinol., 14, 645-652.
| |
| | |
| | |
| | |
| Zondek, B. 1953. Does menstrual blood contain
| |
| a specific toxin? Am. J. Obst. & Gvnec, 65,
| |
| 1065-1068.
| |
| | |
| -Zondek, B. 1954. On the mechanism of uterine
| |
| bleeding. Am. J. Obst. & Gynec, 68, 310-314.
| |
| | |
| Zondek. B., and Rozin, S. 1938. Production of
| |
| uterine haemorrhage in the normal cycle and
| |
| hi amenorrhoea through progesterone. J. Obst.
| |
| & Gynaec. Brit. Emp., 45, 918-931.
| |
| | |
| Zuckerman, S. 1930. The menstrual cycle of the
| |
| Primates. I. General nature and homology.
| |
| Proc. Zool. Soc, London, 1930, 691-754.
| |
| | |
| Zuckerman, S. 1935. The menstrual cycles in the
| |
| Primates. VIII. The estrin-vvithdrawal theory
| |
| of menstruation. IX. The effect of estrin on
| |
| the denervated sexual skin. Proc. Rov. Soc,
| |
| London, ser. B., 118, 13-33.
| |
| | |
| Zuckerman, S. 1936a. Inhibition and induction of
| |
| uterine bleeding bv means of estrone. Lancet,
| |
| 2, 9-13.
| |
| | |
| Zuckerman, S. 1936b. The interrelation of estrone
| |
| and progestin in the menstrual cvcle. J. PhvsioL, 86, 31-33.
| |
| | |
| Zuckerman, S. 1937a. The duration and phases
| |
| of the menstrual cycle in Primates. Proc. Zool.
| |
| Soc, London, ser. A., 1937, 315-329.
| |
| | |
| Zuckerman, S. 1937b. The menstrual cycle of
| |
| the Primates. X. The oestrone threshold of
| |
| the uterus of the rhesus monkey. XL The part
| |
| played by oestrogenic hormone in the menstrual cycle. Proc. Roy. Soc, London, ser. B.,
| |
| 123,441-471.
| |
| | |
| ZucKER.MAN, S. 1937c Effects of prolonged oestrin-stimulation on the cervix uteri. Lancet, 1,
| |
| 435-437.
| |
| | |
| Zuckerman, S. 1937d. Further observations on
| |
| endocrine interaction in the menstrual cvcle. J.
| |
| Physiol., 89, 49-51.
| |
| | |
| Zuckerman, S. 1937e. The duration and phases
| |
| of the menstrual cycle in Primates. Proc. Zool.
| |
| Soc London, ser. A., 1937, 315-329.
| |
| | |
| Zuckerman, S. 1939. The effect of sex hormones,
| |
| cortin, and vasopressin on water-retention in
| |
| the reproductive organs of monkeys. J. Endocrinol., 1, 147-155.
| |
| | |
| Zuckerman, S. 1941. Periodic uterine bleeding
| |
| in spayed rhesus monkeys injected daily with
| |
| constant threshold dose of oestrone. J. Endocrinol., 2, 263-267.
| |
| | |
| Zuckerman, S. 1949. The menstrual cvcle. Lancet, 2, 176.
| |
| | |
| Zuckerman, S. 1951. The hormonal basis of uterine bleeding. Acta endocrinol., 7, 378-388.
| |
| | |
| Zuckerman, S., and P.arkes, A. S. 1932. The
| |
| menstrual cycle of the primates. V. The cycle
| |
| of the baboon. Proc Zool. Soc. London, 1932,
| |
| 139-191.
| |
| | |
| Zuckerman, S., van W.agenen, G., and Gardiner, R.
| |
| H. 1938. The sexual skin of the rhesus monkey. Proc Zool. Soc, London, ser. A., 108,
| |
| 385-401.
| |
| | |
| | |
| | |
| 10
| |
| | |
| | |
| | |
| THE MAMMARY GLAND
| |
| AND LACTATION
| |
| | |
| A. T. Cowie and S. J. FoUeij
| |
| | |
| NATIONAL INSTITUTE FOR RESEARCH IN DAIRYING, SHINFIELD,
| |
| READING, ENGLAND
| |
| | |
| | |
| | |
| I. Introduction
| |
| | |
| I. Introduction 590
| |
| | |
| II. Development of the Mammary
| |
| | |
| Gland 591
| |
| | |
| A. Histogenesis 591
| |
| | |
| B. Normal Postnatal Development . 593
| |
| | |
| 1. Methods of assessing mammary
| |
| | |
| development 593
| |
| | |
| 2. Mammary development in the
| |
| | |
| nonpregnant female 594
| |
| | |
| 3. Mammary growth in the male . . 595
| |
| | |
| 4. Mammary development during
| |
| | |
| pregnancy 596
| |
| | |
| 5. Mammary involution 598
| |
| | |
| C. Experimental Analysis of Hormonal
| |
| | |
| Influences 598
| |
| | |
| 1. Ovarian hormones in the animal
| |
| | |
| with intact pituitary 598
| |
| | |
| 2. Anterior pituitary hormones. . . 601
| |
| | |
| 3. Metabolic hormones (corticoids,
| |
| | |
| insulin, and thyroid hormones) 604
| |
| III. Endocrine Influences in Milk Secretion 606
| |
| | |
| A. Anterior Pituitary Hormones 606
| |
| | |
| 1. Initiation of secretion (laeto
| |
| genesis) 606
| |
| | |
| 2. Maintenance of milk secretion —
| |
| | |
| galactopoiesis 609
| |
| | |
| 3. Suckling stimulus and the main
| |
| tenance of lactation 611
| |
| | |
| B. Hormones of the Adrenal Corte.x . . 612
| |
| | |
| C. Ovarian Hormones 613
| |
| | |
| D. Thyroid Hormones 617
| |
| | |
| E. Parathyroid Hormone 618
| |
| | |
| F. Insulin 619
| |
| | |
| IV. Removal of Milk from the Mammary
| |
| | |
| Glands: Physiology of Suckling
| |
| AND Milking 619
| |
| | |
| A. Milk-Ejection Reflex 619
| |
| | |
| B. Role of the Neurohypophysis 621
| |
| | |
| C. Milk-Ejection Hormone 622
| |
| | |
| D. Effector Contractile Mechanism of
| |
| | |
| the Mammary Gland 623
| |
| | |
| E. Inhibition of Milk Ejection 624
| |
| | |
| | |
| | |
| F. Neural Pathways of the Milk-Ejec
| |
| tion Reflex 625
| |
| | |
| G. Mechanism of Suckling 626
| |
| | |
| V. Relation between the Reflexes
| |
| | |
| Concerned in the Maintenance of
| |
| Milk Secretion and Milk Ejection 627
| |
| VI. Pharmacologic Blockade of the Reflexes Concerned in the Maintenance OF Milk Secretion and
| |
| | |
| Milk E.tection 630
| |
| | |
| VII. Conclusion 632
| |
| | |
| VIII. References 632
| |
| | |
| This account of the hormonal control of
| |
| the mammary gland is in no way intended
| |
| as an exhaustive treatment of mammary
| |
| gland physiology, but rather an attempted
| |
| synthesis of current knowledge which it is
| |
| hoped will be of interest as an exposition of
| |
| the authors' conception of the present status
| |
| of the subject. Since the publication of the
| |
| second edition of this book, the emphasis
| |
| in the field under review has tended to shift
| |
| towards the development of quantitative
| |
| techniques for assessing the degree of mammary development, towards attempts at a
| |
| ])enetration into the interactions of hormones with the biochemical mechanisms of
| |
| the mammary epithelial cells, and towards
| |
| an increasing preoccupation with the interplay of nervous and endocrine influences
| |
| in certain phases of lactation. The reader's
| |
| acquaintance with the classical foundations
| |
| of the subject as described in the second
| |
| edition of this book (Turner, 1939) and in
| |
| other subsequent reviews (Follcy, 1940;
| |
| Petersen, 1944, 1948; Folley and Malpress,
| |
| 1948a, b; Mayer and Klein. 1948, 1949;
| |
| Follev, 1952a, ]9r)6; Dabelow. 1957) will
| |
| | |
| | |
| | |
| 590
| |
| | |
| | |
| | |
| MAMMARY GLAXD AND LACTATION
| |
| | |
| | |
| | |
| 591
| |
| | |
| | |
| | |
| therefore be assumed and used as a point
| |
| of departure for the present account which
| |
| can most profitably be concerned mainly
| |
| with developments which have occurred
| |
| since the last edition was published. Reference will freciuently be made to these reviews in which authority will be found
| |
| for the many ex cathedra statements that
| |
| will be made, but original sources will be
| |
| cited wherever appropriate.^
| |
| | |
| As an aid to logical treatment of the subject the scheme of classification proposed
| |
| by Cowie, Folley, Cross, Harris, Jacobsohn
| |
| and Richardson (1951) will be followed in
| |
| this chapter. Besides introducing a system of
| |
| terminology in respect of the physiology
| |
| of suckling or milking, these writers have
| |
| put forward a classification scheme which
| |
| is an extension of one previously proposed
| |
| by one of the present authors (Folley,
| |
| 1947). This scheme considers the phenomenon of lactation as divisible into a number
| |
| of phases as follows:
| |
| | |
| [ [Milk synthesis
| |
| | |
| I Milk secretion ■! Passage of milk from
| |
| I I the alveolar cells
| |
| | |
| Lactation<J [Passive withdrawal of
| |
| | |
| ij milk
| |
| | |
| JThe milk-ejection re[ Hex
| |
| | |
| | |
| | |
| Milk removal
| |
| | |
| | |
| | |
| I
| |
| | |
| As is logical and customary, discussion of
| |
| lactation itself will be preceded by consideration of mammary development.
| |
| | |
| II. Development of the Mammary
| |
| Gland
| |
| | |
| A. HISTOGENESIS
| |
| | |
| References to the earlier work on the
| |
| histogenesis of the mammary gland in various species will be found in Turner ( 1939,
| |
| | |
| ^ Within the last 10 years there have been
| |
| several symposia devoted to the problems of the
| |
| physiology of lactation. The proceedings of these
| |
| symposia have been published: Mecanisme physiologie de la secretion lactee. Strasbourg, 1950,
| |
| Colloqvies Internationaux du Centre National de
| |
| la Recherche Scientificiue. XXXII, 1951, Paris;
| |
| Svmposium sur la physiologie de la lactation,
| |
| Montreal, 1953, Rev. Canad. Biol., 13, No. 4. 1954;
| |
| .Symposium sur la physiologie de la lactation,
| |
| Brussels, 1956, Ann. endocrinol. 17, 519; A Discussion on the Physiology and Biochemistry of Lactation. London. 1958, Proc. Roy. Soc, .ser. B, 149,
| |
| 301.
| |
| | |
| | |
| | |
| 1952,) and Folley (1952a). There have also
| |
| been studies on the opossum (Plagge, 1942) ,
| |
| the mouse and certain wild rodents (Raynaud, 1949b), the rhesus monkey (Speert,
| |
| 1948), and man (Williams and Stewart,
| |
| 1945; Tholen, 1949; Hughes, 1950).
| |
| | |
| A question which in the last decade has
| |
| been receiving attention is whether the prenatal differentiation and development of the
| |
| mammary primordium is hormonally controlled. According to Balinsky (1950a, b),
| |
| the mitotic index of the mammary bud in
| |
| the embryo of the mouse and rabbit is lower
| |
| than that of the surrounding epidermis and
| |
| he concludes that differentiation of the bud
| |
| is due not to cellular proliferation (growth)
| |
| but to a process of aggregation ("morphogenetic movement") of epidermal cells. This
| |
| author also reports that for some time after
| |
| its formation, the mammary bud is cjuiescent as regards growth, thus exhibiting
| |
| negative allometry compared with the whole
| |
| embryo, until the sprouting of the primary
| |
| duct initiates a phase of positive allometry.
| |
| The cjuestion is, what is the stimulus responsible for the onset of this allometric
| |
| phase? Is the growth and ramification of the
| |
| duct primordium, like that of the adult duct
| |
| system, due to the action of estrogen emanating from the fetal gonad or from the
| |
| mother?
| |
| | |
| Hardy (1950) has shown that dift'erentiation and growth of the mammary bud of
| |
| the mouse could proceed in explants from
| |
| the ventral body wall of the embryo, cultured in vitro, even when no primordia
| |
| were present at the time of explantation
| |
| (10-day embryo). Primary and then secondary mammary ducts and a streak canal
| |
| differentiated and a developmental stage
| |
| similar to that in the 7-day-old mouse could
| |
| be reached. Balinsky (1950b) was also able
| |
| to observe the formation and growth of
| |
| mammary buds in approximately their normal locations in a minority of cases in which
| |
| body-wall explants of 10-day mouse embryos were cultivated in vitro. Discounting
| |
| the rather remote possibility that the effects
| |
| were due to minute amounts of sex hormones
| |
| present in the culture media, these observations indicate that hormonal influences are
| |
| not necessary for the prenatal stages of
| |
| mammary develo]iment, and in accord with
| |
| | |
| | |
| | |
| 592
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| this Balinsky ( 1950b j found that addition
| |
| of estrogens or mouse pituitary extract to
| |
| the culture medium had no effect on the
| |
| growth of the mammary rudiment in vitro.
| |
| | |
| On the other hand, extensive studies by
| |
| Raynaud (1947c, 1949b) of the sex difference in the histogenesis of the mammary
| |
| gland in the mouse, first described by Turner and Gomez (1933), indicate that the
| |
| mammary rudiment is sensitive to the influence of exogenous gonadal steroids during
| |
| the prenatal stages. The mammary bud in
| |
| the strain of mouse studied by Raynaud
| |
| shows no sex differences in development until the 15th to 16th day at which time the
| |
| genital tract, hitherto indifferent, begins to
| |
| differentiate. Coincident with this the mammary bud in the male becomes surrounded
| |
| by a condensation of special mesenchymal
| |
| cells the action of which constricts the bud
| |
| at its junction with the epidermis from
| |
| which it ultimately becomes completely
| |
| detached (Fig. 10.1). The inguinal glands
| |
| seem particularly susceptible to this influence because they exhibit this effect
| |
| earlier than the thoracic glands and in some
| |
| strains the second inguinal bud in the male
| |
| tends to disappear completely. Sex differences in the prenatal development of the
| |
| mammary rudiment in certain species of
| |
| wild mouse were also described by Raynaud
| |
| (1949b).
| |
| | |
| The fact that, after x-ray desti'uction of
| |
| the gonad in the 13-day male mouse embryo,
| |
| the mammary bud remains attached to the
| |
| epidermis and the duct primordia ramify
| |
| in a manner similar to the primordia in the
| |
| female shows that this phenomenon of detachment of the mammary bud is due to the
| |
| action of the fetal testis (Raynaud and
| |
| Frilley, 1947, 1949). That the masculinizing action of the fetal testis seems to be
| |
| due to the hormonal secretion of a substance having the same effect as testosterone
| |
| is suggested by the fact that injection of testosterone into the pregnant mother causes
| |
| the mammary buds in the female embryo to
| |
| undergo the male type of development (Fig.
| |
| 10.1). Here again the inguinal glands seem
| |
| most sensitive because sufficiently high
| |
| doses in many cases cause complete disappearance of the primordia of the second
| |
| inguinal glands (Raynaud, 1947a. 1949a).
| |
| | |
| | |
| | |
| On the other hand, destruction of the fetal
| |
| gonad in the female has no effect on the
| |
| development of the mammary bud (Raynaud and Frilley, 1947, 1949), yet the lattW
| |
| is not completely indifferent to the action
| |
| of estrogen because high doses of estrogen
| |
| administered to the mother, or lower doses
| |
| injected early into the embryo itself inhibit
| |
| the growth of the mammary bud (Raynaud.
| |
| 1947b, 1952; Raynaud and Raynaud, 1956,
| |
| 1957), an effect reminiscent of the well
| |
| known action of excessive doses of estrogen
| |
| on the adult mammary duct system (for
| |
| reference see Folley, 1952a) . In pouch young
| |
| of the opossum, on the other hand, Plagge
| |
| (1942) found that estrogen treatment stimulated growth of the mammary duct primordia. Similarly in the fetal male mouse
| |
| low doses of estrogen stimulate growth
| |
| of the mammary bud (Raynaud, 1947d),
| |
| but this may be an indirect effect ascribable to estrogen's antagonizing the inhibitory action of the fetal testis.
| |
| | |
| The problem of the histogenesis of the
| |
| teat has also come under experimental attack. Raynaud and Frilley (1949) showed
| |
| that the formation of the ''epithelial hood,"
| |
| the circular invagination of the epidermis
| |
| surrounding the mammary bud which constitutes the teat anlage in the mouse, is not
| |
| hormonally determined since its appearance
| |
| was not prevented by the irradiation of the
| |
| fetal ovary at the 13th day of life. In the
| |
| male mouse the epithelial hood does not
| |
| normally appear and the male is born without teats. This is undoubtedly due to the
| |
| action of the fetal testis inasmuch as the
| |
| teat anlagen develop in the male embryos
| |
| whose testes are irradiated at 13 days (Raynaud and Frilley, 1949).
| |
| | |
| The foregoing observations jioint to an
| |
| ahormonal type of development for the teat
| |
| and mammary bud in the female fetus, at
| |
| least in the mouse, although the mammary
| |
| bud is specifically susceptible to the action
| |
| of excess exogenous estrogen which can inliibit its development without affecting that
| |
| of other skin gland ])rimordia. The mammary hud is a'so sus('ei)tible to the action
| |
| of anch'ogen which in the normal male fetus
| |
| not only dii-ects its development along charact(M-istic lines, but also suppresses the formation of the teat.
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 593
| |
| | |
| | |
| | |
| | |
| | |
| PwokcTiL del
| |
| | |
| | |
| | |
| Fig. 101. Sex difference in the development of the mammaiy bud of the fetal mouse and
| |
| effect of androgen on the histogenesis of the female mammary bud. A. First inguinal gland
| |
| of female fetus (15 days, 17 hours). B. First inguinal gland of male fetus (15 days, 17 hours).
| |
| C. Second inguinal gland of female fetus (15 days, 16 hours) from a mother receiving testosterone propionate. D. First inguinal gland of female fetus from the same litter as that in C.
| |
| (From A. Ravnaud, Ann. endocrinol., 8, 248-253, 1947.)
| |
| | |
| | |
| | |
| For further information on the morphogenesis of the mammary ghmd, the reader
| |
| is referred to the recent detailed accounts
| |
| by Dabelow (1957) and Raynaud (1960).
| |
| | |
| B. NORM.\L POSTNATAL DEVELOPMENT
| |
| | |
| 1. Methods of Assessing Mammary Development
| |
| | |
| In the last two decades the increasing
| |
| availability of the ovarian hormones in pure
| |
| form and the prospect of the large scale
| |
| practical application of fundamental knowledge of the hormonal control of the mammary gland to the artificial stimulation of
| |
| udder growth and lactation in the cow, have
| |
| together effected a demand for greater accuracy in studying and assessing the degree
| |
| of mammary development. Various quantitative and objective procedures have now
| |
| been evolved which allow results of developmental studies to be subjected to statistical
| |
| investigation. These methods have been re
| |
| | |
| | |
| viewed recently (Folley, 1956) and we need
| |
| but mention them briefly.
| |
| | |
| In those species in which, save in late
| |
| pregnancy, the mammae are more or less
| |
| flat sheets of tissue, the classical wholemount preparations have been the basis for
| |
| several quantitative studies. From such
| |
| preparations the area covered by the duct
| |
| systems can be measured by suitable means
| |
| (e.g., as in our studies on the rat mammary
| |
| gland; Cowie and Folley, 1947d), thus providing an accurate measure of duct extension. Such measurements, however, give no
| |
| information on the morphologic changes
| |
| within this area and so a semiquantitative
| |
| scoring system to assess the degree of duct
| |
| complexity has been used in conjunction
| |
| with the measurements of area (see Cowie
| |
| and Folley, 1947d) . More reliable and objective techniciues for measuring duct complexity were later developed in our laboratory by
| |
| Silver (1953a) and Flux (1954a). Species
| |
| such as the guinea pig in which the gland,
| |
| | |
| | |
| | |
| 594
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| even when immature, is three-dimensional
| |
| demand other methods. For such cases a precise but rather tedious method has been
| |
| described by Benson, Cowie, Cox and Goldzveig (1957) which involves the determination of the volume of glandular tissue from
| |
| area measurements of serial sections of the
| |
| gland in conjunction with semiquantitative
| |
| scoring procedures for assessing the morphologic characteristics of the tissue.
| |
| | |
| Particularly applicable to the lactating
| |
| gland is the procedure developed by Richardson (see Cowie, Folley, Malpress and
| |
| Richardson, 1952; Richardson, 1953) for assessing the total internal surface area of the
| |
| mammary alveoli. It is of interest to note
| |
| in passing that this technique is based on
| |
| that developed by Short (1950) for measuring the surface area of the alveoli in the
| |
| lung, the similarity in the geometry of the
| |
| two organs allowing ready transference of
| |
| the method from one to the other.
| |
| | |
| At present these quantitative procedures
| |
| have the disadvantage of being slow and
| |
| time consuming, and it seems likely that
| |
| their further development will involve the
| |
| use of electronic scanning methods to speed
| |
| up the examination of the tissues. Of recent
| |
| introduction are some biochemical procedures for assessing changes in mammary
| |
| development. The desoxyribonucleic acid
| |
| (DNA) content of any particular type of
| |
| cell is said to be remarkably constant (see
| |
| Vendrely, 1955, for review) and the amount
| |
| of DNA in a tissue has been used as a reference standard directly related to the number
| |
| of cells present in a tissue and to provide an
| |
| estimate of the number of cells formed during the developmental phases of a gland or
| |
| tissue (see Leslie, 1955, for review). Studies
| |
| on DNA changes which occur in the mammary gland during pregnancy and lactation
| |
| have been made in the rat by Kirkham and
| |
| Turner (1953), Grecnbaum and Slater
| |
| (1957a), Griffith and Turner (1957), and
| |
| Shimizu (1957). It should be noted, however, that some authorities have doubts as
| |
| to the constancy under all conditions of the
| |
| DNA content of a cell (see Brachet, 1957)
| |
| and results obtained by this technique
| |
| should be interpreted with some caution
| |
| (see also Griffith and Turner, 1957). Other
| |
| chemical methods for assessing mammary
| |
| development include (a) the determination
| |
| | |
| | |
| | |
| of the iron content of the gland, based on
| |
| the observation that iron retention occurs in
| |
| the epithelium of the mammary glands of
| |
| mice (Rawlinson and Pierce, 1950) ; (b)
| |
| whole-mount autoradiographs using P^(Lundahl, Meites and Wolterink, 1950) ;
| |
| and (c) determination of the total content
| |
| of alkaline phosphatase in the mammary
| |
| gland (Huggins and Mainzer, 1957, 1958).
| |
| | |
| In view of the relative rapidity of the biochemical methods it seems likely that they
| |
| will be used increasingly in the future.
| |
| | |
| A technique of clinical interest allowing
| |
| the qualitative assessment of changes in
| |
| mammary structure in the breast of pregnant and lactating women is the radiographic method described by Ingleby, Moore
| |
| and Gershon-Cohen (1957).
| |
| | |
| To those seeking information of the microscopic anatomy of the human mammary
| |
| gland we would recommend the excellent
| |
| and beautifully illustrated review by Dabelow (1957), and new facts on the cytologic changes occurring during milk secretion will be found in the electron microscopic
| |
| study of the rat mammary gland by Bargmann and Knoop (1959), and of the mouse
| |
| mammary gland by Hollmann (1959).
| |
| | |
| Having briefly outlined the various quantitative methods of assessing mammary development we will now consider recent
| |
| studies on normal mammary growth.
| |
| | |
| 2. Mammary Development in the X on pregnant Female
| |
| | |
| It has been the general belief that until
| |
| puberty the mammary ducts show little
| |
| growth, but more precise studies in which
| |
| the rate of increase in mammary gland area
| |
| has been related to the increase in body size
| |
| have now shown that in the monkey, rat,
| |
| and mouse a phase of ra])id duct growth is
| |
| initiated before puberty.
| |
| | |
| The first use of this procrdure, relative
| |
| gi'owth analysis (for terminology see Huxley and Teissier, 1936), for the quantitative
| |
| investigation of mammary duct growth was
| |
| made by Folley, Guthkelch and Zuckerman
| |
| (1939), who showed that over a wide range
| |
| of body weights, the breast in the nonpregnant female rhesus monkey grows faster
| |
| than the body as a whole. Subsequently,
| |
| more detailed studies of the dynamics of
| |
| mammary growth using relative growth
| |
| | |
| | |
| | |
| MAMMARY GLAXD AND LACTATION
| |
| | |
| | |
| | |
| 595
| |
| | |
| | |
| | |
| olO.
| |
| | |
| | |
| | |
| rCMALC RATS
| |
| | |
| ACt$ : i - lOO DAYS
| |
| | |
| | |
| | |
| C 22 NO DAY
| |
| | |
| | |
| | |
| | |
| LOC„ CBOOY WtlCHT C>
| |
| | |
| | |
| | |
| Fig. 10.2. Relative mammary gland growth in the female hooded Norway
| |
| Cowie. J. Endocrinol.. 6, 145-157, 1949.)
| |
| | |
| | |
| | |
| (From A.T.
| |
| | |
| | |
| | |
| analysis were made in the rat by Cowie
| |
| (1949) and Silver (1953a, b) and in the
| |
| mouse by Flux (1954a, b), and their results
| |
| will now be summarized. In the rat the
| |
| total mammary area increased isometrically
| |
| with the body surface (a = 1.1 as compared
| |
| with the theoretic value of 1.0) until the
| |
| 21st to 23rd day when a phase of allometry
| |
| (a = 3.0) set in. The onset of the allometric
| |
| phase could be prevented by ovariectomy on
| |
| the 22nd day (see Fig. 10.2). Since estrous
| |
| cycles do not begin until the 35th to 42nd
| |
| day in this strain of rat, it is clear that the
| |
| rapid extension of the mammary ducts began well before puberty. In the immature
| |
| male rat the increase of mammary area on
| |
| body surface was slightly but significantly
| |
| allometric; this was not altered by castration at the 22nd day. Earlier ovariectomy,
| |
| i.e., when the pups were 10 days old, was
| |
| followed by a phase of slightly allometric
| |
| growth of the mammary glands in the fe
| |
| | |
| | |
| males (a = 1.5). With regard to the female
| |
| mouse (CHI strain) a i)hase of marked allometry in mammary duct growth set in
| |
| about the 24th day (a = 5.2) which could
| |
| also be prevented by prior ovariectomy.
| |
| | |
| It is clear that the presence of the ovary
| |
| is essential for the change from isometry to
| |
| allometry, but the nature of the mechanisms
| |
| governing the change is still uncertain (for
| |
| further discussion, see Folley, 1956).
| |
| | |
| 3. Mammary Growth in the Male
| |
| | |
| The testes have apparently little effect on
| |
| mammary duct extension in the rat inasmuch as the gland in the male grows isometrically or nearly so and its specific
| |
| growth rate is unaffected by castration. Castration at 21 days, however, does prevent
| |
| for a time development of the lobules of alveoli, first described by Turner and Schultze
| |
| (1931 ) , which are characteristic of the mammary gland in the male rat. Eventually.
| |
| | |
| | |
| | |
| 596
| |
| | |
| | |
| | |
| PHY,SI(3L0GY OF GONADS
| |
| | |
| | |
| | |
| however, some alveoli do develop in the
| |
| mammae of immaturely castrated male rats
| |
| (Cowie and Folley, 1947d; Cowie, 1949;
| |
| Ahren and Etienne, 1957) and it has been
| |
| ])Ostulated that these arise from the enhanced production by the adrenal cortex of
| |
| mammogenic steroids (androgens or progesterone) due to the hormone imbalance
| |
| brought about by gonadectomy (see Folley,
| |
| 1956 L
| |
| | |
| In a recent study, Ahren and Etienne
| |
| (1957) have shown that the ducts and alveoli in the mammary gland of the male rat
| |
| are remarkable in that their epithelial lining
| |
| is unusually thick, being composed of several layers of cells. It had been previously
| |
| noted by van Wagenen and Folley (1939)
| |
| and Folley, Guthkelch and Zuckerman
| |
| (1939) that testosterone caused a thickening
| |
| of the mammary duct epithelium in the
| |
| monkey and sometimes papillomatous outgrowths of epithelium into the lumen of the
| |
| duct. It would thus seem that, although the
| |
| hormone of the testis is capable of eliciting
| |
| alveolar development, these alveoli and
| |
| ducts differ from those occurring in the female in the nature of their epithelium. It
| |
| w^as further observed by Ahren and Etienne
| |
| (1957) that in the castrated male rat the
| |
| alveoli, which eventually developed, had a
| |
| simple epithelial lining somewhat similar to
| |
| that seen in the normal female rat, suggesting that, if the adrenals are responsible, the
| |
| mammogenic steroid is more likely to be
| |
| progesterone than an androgen.
| |
| | |
| A study of considerable clinical interest is
| |
| that of Pfaltz (1949) on the developmental
| |
| changes in the mammary gland in the
| |
| human male. The greatest development
| |
| reached was at the 20th year; by the 40th
| |
| year there occurred an atrophy first of the
| |
| l)arenchyma and later of the connective
| |
| tissue. In the second half of the fifth decade
| |
| there was renewed growth of the parenchyma and connective tissues. The hormonal background of these changes and the
| |
| possible relationship with prostatic hyjiertrophy are discussed by Pfaltz. (Further
| |
| details of the microscopic anatomy of the
| |
| mammary gland of the human male may be
| |
| found in the studies by Graumann, 1952,
| |
| 1953, and Dabclow, 1957.)
| |
| | |
| | |
| | |
| 4- Mammary Development during Pregnancy
| |
| | |
| It has been customary to divide mammary changes during pregnancy into two
| |
| phases, a phase of growth and a secretory
| |
| phase. In the former there occurs hyperplasia of the mammary parenchyma
| |
| whereas, in the latter, the continued increase
| |
| in gland size is due to cell hypertrophy and
| |
| the distension of the alveoli with secretion
| |
| (see Folley, 1952a j . Although it was realized
| |
| that these two phases merged gradually, recent studies have confirmed earh^ reports
| |
| {e.g., those of Cole, 1933; Jeffers, 1935) that
| |
| a wave of cell division occurs in the mammary gland towards the end of parturition
| |
| or at the beginning of lactation. Al'tman
| |
| (1945) described a doubling in number of
| |
| cells per alveolus, in the mammary gland
| |
| of the cow at parturition, but the statistical
| |
| significance of his findings is difficult to
| |
| assess. More recently, how^ever, Greenbaum
| |
| and Slater (1957a) found that the DNA
| |
| content of the rat mammary gland doubled
| |
| between the end of pregnancy and the 3rd
| |
| day of lactation, a finding which they interpret as resulting in the main from hyperplasia of the gland cells. Likewise in the
| |
| mouse mammary gland, Lewin (1957) observed between parturition and the 4th day
| |
| of lactation a great increase both in the
| |
| DNA content of the mammary gland and
| |
| in the total cell count. Studies on the factors
| |
| controlling this wave of cell division are
| |
| awaited with interest. Also associated with
| |
| the onset of copious milk secretion is a considerable increase in cell volume and coincident ally the mitochondria elongate and may
| |
| increase in diameter (Howe, Richardson and
| |
| Birbeck, 1956). Cross, Goodwin and Silver
| |
| (1958) have followed the histologic changes
| |
| in the mammary glands of the sow, by
| |
| means of a biopsy technique, at the end of
| |
| pregnancy, during parturition, and at weaning. At the end of pregnancy there was a
| |
| ])i'()gr('ssi\-c' distension of the alveoli, the
| |
| existing hyaline eosinoi)hilic secretion within
| |
| the alveoli was gradually replaced by a basophilic material, and fat globules appeared.
| |
| At i)arturition the alveoli were contracted
| |
| and their walls appeared folded (Fig. 10.3).
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 597
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 10.3. Sections of biopsy specimens from the mammary gland of a sow before and
| |
| din-ing parturition. A. Six days before parturition: the mammary alveoh are small and contain a nongranular eosinophilic secretion. B. Two days before parturition: alveoli have increased in size and fat globules are conspicuous. C. Fifteen hours before parturition: alveoli
| |
| are now distended with secretion which consists of an outer zone of eosinophilic material
| |
| and fat globules, and a central zone of basophilic granular secretion. D. During parturition:
| |
| alveoli contracted with folded epithelium and sparse secretion. (From B. A. Cross, R. F. W.
| |
| Goodwm and L A. Silver, J. Endocrinol., 17, 63-74, 1958.)
| |
| | |
| | |
| | |
| 598
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 5. Mam /nary Involution
| |
| | |
| The involutionary changes which occur in
| |
| the mammary gland after weaning in various species were described in the previous
| |
| edition of this book (Turner, 1939) and in a
| |
| later review by Folley (1952a). Since that
| |
| time, a few further studies have appeared.
| |
| | |
| There is evidence that the course of the
| |
| histologic changes in the regressing mammary gland may differ according to whether
| |
| the young are weaned after lactation has
| |
| reached its peak and is declining, or whether
| |
| they are removed soon after parturition,
| |
| when the effects of engorgement with milk
| |
| seem to be more marked (see, for example,
| |
| Williams, 1942, for the mouse). In rats
| |
| whose young were weaned soon after parturition Silver (1956) was able to re-establish lactation provided suckling was resumed
| |
| within 4 or 5 days; after that time irreversible changes in the capillary blood supply to the alveoli had set in. A further point
| |
| arises from a study on the cow by Mosimann
| |
| (1949) which indicates that the course of
| |
| the regressive changes in a gland which has
| |
| undergone one lactation only may differ
| |
| from those seen in glands from muciparous
| |
| animals. Oshima and Goto (1955) have used
| |
| quantitative histometric methods in a study
| |
| of the involuting rat mammary gland ; the
| |
| values which they obtained for the percentage parenchyma 7 to 10 days after removal of the young agree quite well with
| |
| tiiose reported by Benson and Folley
| |
| ( 1957b) for rats weaned at the 4th day and
| |
| killed 9 days later.
| |
| | |
| The biochemical changes occurring in
| |
| mammary tissue during involution arc of
| |
| some interest and have been studied in our
| |
| laboratory by McNaught (1956, 1957). She
| |
| studied mammary slices taken from rats
| |
| whose young were removed at the 10th day
| |
| and also slices from suckled glands, the escajie of milk from which was prevented by
| |
| ligation of the galactophores, the other
| |
| glands in the same animals remaining intact
| |
| and serving as controls. Her results, some of
| |
| whichare summarized in Figure 10.4, suggest that functional changes which may be
| |
| taken as indicative of involution (decrease
| |
| in oxygen up-take, respiratory quotient
| |
| (R.Q.), and glucose up-take; increase in
| |
| lactic acid prcxUiction ) are seen as early as
| |
| | |
| | |
| | |
| 8 to 12 hours after weaning. Continued
| |
| suckling without removal of milk retards
| |
| the onset of these changes, but only for some
| |
| hours. Injections of oxytocin into the rats
| |
| after weaning (see page 607) did not retard
| |
| these biochemical changes. Essentially simihii' results were independently reported by
| |
| Ota and Yokoyama (1958) and Mizuno and
| |
| Chikamune (i958).
| |
| | |
| C. EXPERIMENTAL ANALYSIS OF HORMONAL
| |
| INFLUENCES
| |
| | |
| 1. Ovarian Hortnones in the Animal with
| |
| Intact Pituitary
| |
| | |
| We shall see later (page 602) that the
| |
| mammogenic effects of the ovarian hormones are largely dependent on the integrity
| |
| of the a'nterior pituitary and thus to analyze accurately the role of hormones in mammary development it is necessary to use hypophysectomized animals. Information of
| |
| considerable academic and practical importance has been obtained, however, from
| |
| studies in the animal with intact pituitary
| |
| and these we shall now consider.
| |
| | |
| Early studies involving hormone administration pointed to the conclusion that estrogens were in general resi)onsible for the
| |
| growth of the mammary (hicts, whereas progesterone was necessary for complete lobulealveolar growth (see reviews, l)y Turner,
| |
| 1939; Folley and Malpress, 1948a; Folley,
| |
| 1952a). The foundation for i^liis general
| |
| statement is now more sure, for as a result
| |
| of experimental studies over the last 10
| |
| years, what seemed to be exceptions to this
| |
| generalization have been shown to be otherwise. In some species (mouse, rat, guinea
| |
| \)ig, and monkey) it is true that progesterone alone, if given in sufficiently large doses,
| |
| will evoke duct and alveolar development in
| |
| the ovariectomized animal, but this is probably a pharmacologic rather than a physiologic effect. There are great differences in
| |
| the response of the mammary ducts to estrogen and on this basis it has become usual to
| |
| divide species into three broad categories
| |
| (see FoUey, 1956). It is, however, necessary
| |
| to add the warning that in the estrogentre.'ited spayed animal progesterone from the
| |
| a(h'eiial eoiiex may synergize with the exogenous estrogen (see Folley, 1940; Trentin
| |
| and 1'ui'iier, 1947; Hohn, 1957) and it mav
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 599
| |
| | |
| | |
| | |
| O2 Uptake
| |
| | |
| | |
| | |
| G\
| |
| | |
| | |
| | |
| ucose
| |
| | |
| | |
| | |
| uptake
| |
| | |
| | |
| | |
| | |
| Lactic acid
| |
| production.
| |
| | |
| | |
| | |
| s 12
| |
| ■Hours
| |
| | |
| Fig. 10.4. Oxygen uptake, respiratory quotient, glucose uptake, and lactic acid production
| |
| of mammary gland slices from lactating rats killed at various times after weaning (A — A)
| |
| and from rats in which svickling was maintained, but in which the galactophores of certain
| |
| | |
| glands were ligatured (• •) to prevent the escape of milk, the nonligatured glands
| |
| | |
| (O O) acting as controls. (Courtesy of Dr. M. L. McNaught.)
| |
| | |
| | |
| | |
| be that the I'eal basis for the categories is
| |
| to be found largely in differences in endogenous progesterone production by the adrenal
| |
| cortex.
| |
| | |
| The first category comprises those in
| |
| which estrogens, in what are believed to be
| |
| physiologic doses, evoke primarily and
| |
| mainly duct growth; alveoli may appear,
| |
| but only if high doses are given and the
| |
| administration is prolonged. Examples of
| |
| this class are the mouse, rat, rabbit, and cat.
| |
| Silver (1953a), using the relative-growth
| |
| technique, has obtained information on the
| |
| | |
| | |
| | |
| levels of estrogen necessary for normal
| |
| mammary duct growth in the nonpregnant
| |
| rat. In the young ovariectomized rat, the
| |
| normal mammary growth rate was best imitated by injecting 0.1 ;u,g. estradiol dipropionate every second day (from 21 days of
| |
| age) and increasing the dose step- wise with
| |
| body weight. In the ovariectomized mouse,
| |
| Flux (1954a) found it necessary to give
| |
| 0.055 /jLg. estrone daily to attain mammarv
| |
| duct growth comparable with that obser\-( . i
| |
| in intact mice.
| |
| | |
| In the second category are those s]:»ecies
| |
| | |
| | |
| | |
| (JOO
| |
| | |
| | |
| | |
| PHYSIOLOGY OI-' GONADS
| |
| | |
| | |
| | |
| in which estrogen in physiologic doses causes
| |
| growth of the ducts and the lobule-alveoL^r
| |
| system, the classical example being the
| |
| guinea pig in which functional mammae can
| |
| be developed after gonadectomy in either
| |
| sex by estrogen alone. A recent study by
| |
| Hohn (1957), however, strongly suggests
| |
| that progesterone from the adrenal cortex
| |
| participates in the effect. The earlier view,
| |
| moreover, that complete mammary growth
| |
| can be evoked in the gonadectomized guinea
| |
| l)ig by estrogen alone (Turner and Gomez.
| |
| 1934; Nelson, 1937.) does not find support
| |
| in the recent study of Benson, Cowie, Cox
| |
| and Goldzveig (1957), who, using both subjective and objective methods of assessing
| |
| the degree of mammary development, found
| |
| that over a wide dose range of estrone, further development of the mammary gland
| |
| was obtained when jirogesterone was also
| |
| administered; essentially similar conclusions have been reached by Smith and Richterich (1958).
| |
| | |
| Also in this second category are cattle
| |
| and goats in which, however, the male
| |
| mammary gland is not equipotential with
| |
| that of the female. The early studies on
| |
| these species have been reviewed at length
| |
| by FoUey and Malpress (1948a) and Folley (1952a, 1956). Briefly it may be said
| |
| that these studies clearly showed that estrogen alone induced extensive growth of lobule-alveolar tissue of which the functional
| |
| capacity was considerable although the milk
| |
| yields in general were less than those expected from similar animals after parturition. The response to estrogen treatment
| |
| was, moreover, very erratic. It was generally
| |
| believed that the deficiencies of this treatment could be made good if progesterone
| |
| were also administered, a view supported by
| |
| the observations of Mixner and Turner
| |
| (1943) that the mammary gland of goats
| |
| treated with estrogens, when examined histologically, showed the i)resence of cystic
| |
| alv(>oli, an abnormality which tended to
| |
| disappear when jirogestcrone was also administered.
| |
| | |
| When progesterone became more readily
| |
| available, an extensive study of the role of
| |
| estrogen and progesterone in mammary development in the goat was carried out
| |
| (Cowie, Folley, ^lalpress and Richai'dson.
| |
| | |
| | |
| | |
| 1952; Benson, Cowie, Cox, Flux and Folley,
| |
| 1955). The mammary tissue was examined
| |
| histologically and the procedure devised by
| |
| Richardson (see page 594) used to estimate
| |
| the area and "porosity" of the alveolar epithelium. The udders grown in immaturely
| |
| ovariectomized virgin goats by combined
| |
| treatment with estrogens and progesterone
| |
| in various proportions and at different absolute dose levels were compared with udders resulting from treatment with estrogen
| |
| alone. As in the earlier observations of Mixner and Turner (1943) , histologic abnormalities were noted, the more widespread being
| |
| a marked deficiency of total epithelial surface, associated with the presence of cystic
| |
| alveoli, in the udders of the estrogen-treated
| |
| animals. The addition of progesterone prevented the appearance of many of these abnormalities and increased the surface area
| |
| of the secretory epithelium. JMoreover, when
| |
| estrogen and progesterone were given in a
| |
| suitable ratio and absolute level the milk
| |
| yields obtained were remarkably uniform
| |
| as between different animals and the glandular tissue was virtually free from abnormalities.
| |
| | |
| Studies in the cow have been less extensive, but there is evidence that both estrogen
| |
| and progesterone are necessary for complete
| |
| normal mammary development (Sykes and
| |
| Wrenn, 1950, 1951; Reineke, INIeites, Cairy
| |
| and Huffman, 1952; Flux and Folley, cited
| |
| by Folley, 1956; Meites, 1960).
| |
| | |
| The case for the inclusion of the monkey
| |
| in the present category has been strengthened by the excellent monograph of Speert
| |
| ( 1948) who has had access to more extensive
| |
| material than many of the earlier workers
| |
| whose results are reviewed by him (see also
| |
| Folley, 1952a). The sum total of available
| |
| evidence now justifies the conclusion that
| |
| estrogen alone will cause virtually complete
| |
| growth of the duct and lobule-alveolar systems of the monkey breast. Extensive lobulealveolar development in the monkey breast
| |
| in response to estrogen is shown in Figure
| |
| 10.5. The synergistic effect of estrogen and
| |
| jirogesterone on the monkey breast has not
| |
| yet been adequately studied, but from available evidence it does not seem to be very
| |
| dramatic. If it is permissible to argue from
| |
| pi'iinates to man. it seems jiossible that coidd
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 601
| |
| | |
| | |
| | |
| | |
| Fig. 10.5. Wliole mounts of breast of an ovariectomized immature female rhesus monkey
| |
| before (left) and after (right) e.strogen treatment. (From H. Speert, Contr. Embrvol.,
| |
| Carnegie Inst. Washington, 32, 9-65, 1948.)
| |
| | |
| | |
| | |
| the necessary experiments be done the
| |
| human breast would show a considerable
| |
| growth response to estrogen alone.
| |
| | |
| Finally, in the third category are those
| |
| species in which estrogen in physiologic
| |
| doses causes little or no mammary growth.
| |
| The bitch and probably the ferret seem to
| |
| belong to this class (see Folley, 1956).
| |
| | |
| There has been considerable discussion
| |
| in the past regarding the ratio of progesterone to estrogen optimal for mammary
| |
| growth. Only recently, however, has this
| |
| question been fully investigated in any species. Benson, Cowie, Cox and Goldzveig
| |
| (1957) have shown that in the guinea pig
| |
| the absolute quantities of progesterone and
| |
| estrogen are the crucial factors in controlling
| |
| mammary growth; altering the dose levels
| |
| but maintaining the ratio gave entirely different growth responses. In view of the
| |
| varying ability of the different estrogens to
| |
| stimulate mammary duct growth (Reece,
| |
| 1950) it is essential in discussing ratios to
| |
| take into consideration the nature of the
| |
| estrogen used, a fact not always recognized
| |
| in the past.
| |
| | |
| 2. Anterior Pituitary Hormones
| |
| | |
| Soon after the discovery by Strieker and
| |
| Grueter (1928, 1929) of the lactogenic effects of anterior iiituitarv extracts, it was
| |
| | |
| | |
| | |
| shown that anterior i)ituitary extracts had a
| |
| mammogenic effect in the ovariectomized
| |
| animal and that the ovarian steroids had
| |
| little or no mammogenic effect in hypophysectomized animals. C. W. Turner and his
| |
| colleagues postulated that mammogenic activity of the anterior pituitary was due to
| |
| specific factors which they termed "mammogens"; other workers, in particular
| |
| W. R. Lyons, believed the mammogenic effect was due to prolactin. The theory of specific mammogens has been fully reviewed in
| |
| the past (Trentin and Turner, 1948; Folley
| |
| and Malpress, 1948a) and we do not propose
| |
| to discuss it further for there is now little
| |
| evidence to support it. Damm and Turner
| |
| ( 1958) , while recently seeking new evidence
| |
| for the existence of a specific pituitary mammogen, concur in the view expressed by
| |
| Folley and Malpress (1948a) that final
| |
| proof of the existence of a specific mammogen will depend on the development of
| |
| l)etter assay techniques and the characterization or isolation of the active principle.
| |
| | |
| The mammogenic effects of prolactin were
| |
| observed in the rabbit by Lyons (1942)
| |
| who injected small quantities of prolactin
| |
| directly into the galactophores of the suitably prepared mammary gland. IV'Iilk secretion occurred but Lyons also noted that the
| |
| l)rolactin caused active growth of the alveo
| |
| | |
| | |
| 602
| |
| | |
| | |
| | |
| PHYSIOLOGY OF CIOXADS
| |
| | |
| | |
| | |
| lar epithelium. Recently, Mizuno, lida and
| |
| Naito (1955) and Mizuno and Naito (19561
| |
| have confirmed Lyons' observations on the
| |
| mammogenic effect of intracluct injections
| |
| of prolactin in the rabbit both by histologic
| |
| and biochemical means (DNA estimations)
| |
| and there seems little doubt that the prolactin is capable of exerting a direct effect
| |
| on the growth of the mammary parenchyma,
| |
| at least in the rabbit whose pituitary is intact.
| |
| | |
| In the last 18 years much information on
| |
| the role of the anterior pituitary in mammary growth has been obtained by Lyons
| |
| and his colleagues in studies on hypophysectomized, hypophysectomized-ovariectomized, and hypophysectomized-ovariectomized-adrenalectomized (triply operated)
| |
| rats of the Long-Evans strain. In 1943
| |
| Lyons showed that in the hypophysectomized-ovariectomized rat, estrogen + progesterone + prolactin induced lobulealveolar development, but the degree of
| |
| development was less than that obtained
| |
| in the ovariectomized rat with intact pituitary receiving estrogen and progesterone.
| |
| When supplies of purified anterior-pituitary hormones became available the experiments were extended (Lyons, Li and
| |
| Johnson, 1952) and it was shown that if
| |
| somatotrophin (STH) was added to the
| |
| hormone combination of estrogen -f progesterone + prolactin, the degree of lobulealveolar development obtained in the hypophysectomized-ovariectomized rat was
| |
| much enhanced. The omission of prolactin
| |
| from the hormonal tetrad prevented lobulealveolar development from occurring. In
| |
| the hypophysectomized-ovariectomized-adrenalectomized rat the above hormonal tetrad could also evoke lobule-alveolar development, provided the animals were given
| |
| saline to drink (Lyons, Li, Cole and Johnson, 1953). In yet more recent experiments
| |
| Lyons, Li and Johnson (1958) observed that
| |
| somatotrophin has a direct stimulatory effect on duct growth, but in the hypophysectomized-ovariectomized rat, the presence of
| |
| estrogen is also necessary to evoke normal
| |
| duct development (Fig. 10.6a, b, c) ; Likewise, in the triply operated rat, STH plus
| |
| estrogen is mammogenic, but the presence of
| |
| a corticoid is r('([ui]'ed to o])tain full duct de
| |
| | |
| | |
| velopment (Fig. 10.6r/). Lyons and his colleagues were able to build up the mammary
| |
| glands of triply operated rats from the state
| |
| of bare regressed ducts to full prolactational
| |
| lobule-alveolar development by giving estrogen + STH + corticoids for a period of
| |
| 10 days to obtain duct proliferation followed by a further treatment (for 10 to 20
| |
| days) with estrone + progesterone -I- STH
| |
| -I- prolactin + corticoid to induce lobulealveolar development. Alilk secretion could
| |
| then be induced by a third course of treatment lasting about 6 days in which only
| |
| prolactin and corticoids were given (Fig.
| |
| 10. 6e, /). Essentially similar results have
| |
| been obtained in studies with the hooded
| |
| Norway rat (Cowie and Lyons, 1959).
| |
| | |
| Studies on mammogenesis in the hypophysectomized mouse have revealed some
| |
| differences in the response of the mammary
| |
| gland of this species in comparison with
| |
| that of the rat and indications of strain
| |
| differences within the species. The mammary gland of the hypophysectomized male
| |
| weanling mouse of the Strong A2G strain
| |
| shows no response to the ovarian steroids
| |
| alone, to prolactin, or to STH alone, but it
| |
| responds with vigorous duct proliferation
| |
| to combinations of estrogen + progesterone
| |
| + prolactin, or of estrogen 4- progesterone
| |
| + STH (Hadfield, 1957; Hadfield and
| |
| Young, 1958). In the hypophysectomized
| |
| male mouse of the CHI strain slight duct
| |
| growth occurs in response to estrogen +
| |
| jirogesterone and this is much enhanced
| |
| when STH is also given; the further addition of prolactin then results in alveolar
| |
| development (Flux, 1958). Extensive studies
| |
| in triply operated mice of the C3H 'HeCrgl
| |
| strain have been reported by Nandi (1958a,
| |
| b). In this strain some duct growth was observed in triply operated animals in response to steroids alone (estrogen -I- progesterone + corticoids), but normal duct
| |
| develojmient was believed to be due to the
| |
| action of estrogen + STH + corticoids, a
| |
| conclusion in agreement with Lyons' observations in the rat. Extensive lobuleahcohii' development could be induced by
| |
| a number of hormone coml)inations, one
| |
| of the most effective being estrogen + progesterone + corticoids + prolactin + STH,
| |
| milk secretion occurring when the ovarian
| |
| | |
| | |
| | |
| MAMMARY C5LAND AND LACTATION
| |
| | |
| | |
| | |
| 603
| |
| | |
| | |
| | |
| | |
| Fig. 10.6. Typical areas of whole mounts of the abdominal mammary gland of rat.s after
| |
| the following treatments: A. Untreated rat on day 31, 14 days after hypophysectomy. The
| |
| gland has regressed to a bare duct system. B. Rat hypophysectomized and ovariectomized on
| |
| day 30 and injected daily with 2 mg. somatotrophin (STH) for 7 days. Note the presence
| |
| of end clubs, r. Rat treated as in B but which received, in addition to the STH, 1 ^g. estrone.
| |
| Note profuse eiid-rhil' ] iroliferatiou. D. Rat li.\|M)]ili\s(>ctomized on day 30. ovariectomized
| |
| and adri'nali^ctoinized on day 60, and injected daily from days 60 to 69 with 1 mg. STH +
| |
| 0.1 mg. DCA + 1 fig. estrone. Note again the profuse number of end buds indicative of
| |
| duct proliferation. E. Same treatment as in D followed by 10 days treatment with 5 mg.
| |
| prolactin + 2 mg. STH + 1 /xg. estrone + 2 mg. progesterone + 0.1 mg. DCA + 0.05 mg.
| |
| prednisolone acetate. Note excellent lobule-alveolar growth. F. Same treatment as in D
| |
| followed by 20 days treatment with 5 mg. prolactin + 2 mg. STH + 1 fig. estrone + 2 mg.
| |
| progesterone + 0.1 mg. DCA + 0.05 mg. prednisolone acetate; thereafter given 0.1 mg. prolactin locally over this gland and 0.1 mg. DCA + 0.1 mg. prednisolone acetate systemically for
| |
| 6 days. Note fully developed lobules with ah'eoli filled with milk. (All glands at the same
| |
| magnification.) (From W. R. Lyons. C. H. Li and R. E. Johnson, Recent Progr. Hormone
| |
| Res., 14, 219-254, 1958.)
| |
| | |
| | |
| | |
| 604
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| steroids were withdrawn, while the })rohictin, STH, and Cortisol were continued. A
| |
| further interesting observation made by
| |
| Nandi is that in the C3H/HeCrgl mouse
| |
| STH can replace prolactin in the stimulation of all phases of mammary development
| |
| and in the induction of milk secretion; enhanced effects were obtained, however, when
| |
| prolactin and STH were given together.
| |
| Nandi also considers that progesterone
| |
| plays a greater role in duct development in
| |
| the mouse than in the rat.
| |
| | |
| The above experiments clearly indicate
| |
| that both in the triply operated rat and
| |
| mouse, it is possible to build up the mammary gland to the full prolactational state
| |
| by injecting the known ovarian, adrenal
| |
| cortical, and anterior pituitary hormones.
| |
| There would thus seem to be no necessity
| |
| to postulate the existence of other unidentified pituitary mammogens. It must be
| |
| recognized, however, that in normal pregnancy the placenta may be an important
| |
| source of mammogenic hormones. The placenta of the rat contains a substance or substances possessing luteotrophic, mammogenic, lactogenic, and crop-sac stimulating
| |
| properties, but it is uncertain whether this
| |
| material is identical with pituitary prolactin
| |
| (Averill, Ray and Lyons, 1950; Canivenc,
| |
| 1952; Canivenc and Mayer, 1953; Ray,
| |
| Averill, Lyons and Johnson, 1955). There
| |
| is also some evidence of the presence of a
| |
| somatotrophin-like principle in rat placenta
| |
| (Ray, Averill, Lyons and Johnson, 19551.
| |
| | |
| 3. Metabolic Hormones {Corticoids, Insulin,
| |
| and Thyroid Hormones)
| |
| | |
| We have already noted that Lyons and
| |
| his colleagues were able to obtain full duct
| |
| development in the triply operated rat only
| |
| when corticoids were given. Early studies
| |
| of the role of the adrenals in mammary development have given conflicting and uncertain results (see review by Folley,
| |
| 1952a). Recent studies have not entirely
| |
| clarified the position. Flux (1954b) tested
| |
| a number of 11 -oxygenated corticoids, and
| |
| found that not only were they devoid of
| |
| mammogenic activity in the ovariectomized
| |
| virgin mouse, but that they inhibited the
| |
| gi'owth-promoting effects of estrogen on the
| |
| mammary ducts, whereas 11-desoxycorticosterone acted synergistically with estro
| |
| | |
| | |
| gen in promoting duct growth. In subsequent
| |
| studies it was shown that injections of adrenocorticotrophin (ACTH) into intact
| |
| female mice did not influence mammary
| |
| growth (Flux and ]\lunford, 1957), but
| |
| that Cortisol acetate in low doses (12.5 /^g.
| |
| l)er day) stimulated mammary development in ovariectomized and in ovariectomized estrone-treated mice, whereas at
| |
| higher levels (25 and 50 ftg. per day) it was
| |
| without effect (Munford, 1957). In the virgin rat, on the other hand, glucocorticoids
| |
| are said to stimulate mammary growth and
| |
| to induce milk secretion (Selye, 1954; Johnson and Meites, 1955). Some light on these
| |
| conflicting results has been shed by the
| |
| studies of Ahren and Jacobsohn (1957)
| |
| who investigated the effects of cortisone on
| |
| the mammary glands of ovariectomized
| |
| and of ovariectomized-hypophysectomized
| |
| rats, both in the presence and absence of
| |
| exogenous ovarian hormones. In the hypophysectomized animals, cortisone promoted
| |
| enlargement and proliferation of the epithelial cells lining the duct walls, but normal growth and differentiation did not occur, nor did the addition of estrogen and
| |
| progesterone appreciably alter these effects ;
| |
| in rats with intact pituitaries, however,
| |
| cortisone stimulated secretion but not
| |
| mammary growth, whereas the addition of
| |
| estrogen and progesterone promoted both
| |
| growth and al)undant secretion. Ahren and
| |
| Jacobsohn concluded that "the effect elicited by cortisone in the mammary gland
| |
| should be analysed with due regard to the
| |
| endocrine state of the animal both as to its
| |
| effects on the structures of the mammary
| |
| gland and to the consequences resulting
| |
| from an eventual upset of the general metabolic equilibrium." They consider that in
| |
| circumstances optimal for mammary gland
| |
| growth and maintenance of homeostasis
| |
| the predominant actions of cortisone are enhancement of alveolar growth and stimulation of secretion, whereas under conditions
| |
| ill which the metabolic actions of cortisone
| |
| are not efficiently counteracted, gland
| |
| growth is either inhibited or an abnormal
| |
| development of certain iiianimaiy cells
| |
| may be e^■()ked.
| |
| | |
| That the general metabolic milieu may
| |
| indeed profoundly influence the response
| |
| of the iiuuiimarv gland to hormones has
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 605
| |
| | |
| | |
| | |
| been emiiha.-^ized by the recent experiments
| |
| of Jacobsohn and her colleagues. Following
| |
| on the work of Salter and Best (1953) who
| |
| showed that hypophysectomized rats could
| |
| be made to resume body growth by the injections of long-acting insulin, Jacobsohn
| |
| and her colleagues (Ahren and Jacobsohn,
| |
| 1956; Ahren and Etienne, 1958; Ahren,
| |
| 1959) found that treatment with estrogen
| |
| and progesterone would stimulate considerable mammary duct growth in hypophysectomized-gonadectomized rats when given
| |
| with suitable doses of long-acting insulin
| |
| (Fig. 10.7). This growth-supporting effect
| |
| of insulin could be nullified if cortisone was
| |
| also administered (Ahren and Jacobsohn,
| |
| 1957) but could be enhanced by giving thyroxine (Jacobsohn, 1959).
| |
| | |
| The thyroid would thus appear to be another endocrine gland whose hormones affect
| |
| | |
| | |
| | |
| mammary growth intlirectly by altering the
| |
| metabolic environment. Studies in this field,
| |
| reviewed by Folley (1952a, 1956), indicate
| |
| that in the rat some degree of hypothyroidism enhances alveolar development wdiereas
| |
| in the mouse, hypothyroidism seems to
| |
| inhibit mammary development. Chen, Johnson, Lyons, Li and Cole (1955) have shown
| |
| that mammary growth can be induced in
| |
| hypophysectomized - adrenalectomized-thyroidectomized rats by giving estrone, progesterone, prolactin, STH, and Cortisol, no
| |
| replacement of the thyroid hormones being
| |
| necessary.
| |
| | |
| These investigations on the effect of the
| |
| metabolic environment on mammary development seem to ])e opening up new avenues
| |
| of approach to the advancement of our
| |
| understanding of the mechanisms of mammary growth and we would recommend.
| |
| | |
| | |
| | |
| | |
| | |
| 0-5 cm.
| |
| | |
| | |
| | |
| | |
| | |
| Fig. 10.7. Whole mount preparation of .second thoracic mammary gland of : ^. Ovariectomized rats injected with estrone and progesterone. B. Hypophysectomized-ovariectomized
| |
| rat injected with estrone and progesterone. C. Hypophysectomizcd-o\ariectomized rat. D.
| |
| Hypophysectomized-ovariectomized rat injected with estrone, progesterone, and insulin.
| |
| (From K. Ahren and D. Jacobsohn, Acta physiol. scandinav., 37, 190-203, 1956.)
| |
| | |
| | |
| | |
| GOG
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| to those seeking further information about
| |
| this important new fiekl, the recent review
| |
| by Jacobsohn (19581.
| |
| | |
| III. Endocrine Influences in Milk
| |
| Secretion
| |
| | |
| A. ANTERIOR PITUITARY HORMONES
| |
| | |
| 1. Initiation of Secretion iLactogenesis)
| |
| | |
| The early experiments leading to the
| |
| view that the anterior pituitary was not
| |
| only necessary for the initiation of milk
| |
| secretion, but in fact i)rovided a positive
| |
| lactogenic stimulus, are now well known
| |
| and the reader is referred to the reviews by
| |
| Folley (1952a, 1956) and Lyons (1958) for
| |
| further particulars. That pituitary prolactin
| |
| can evoke milk secretion in the suitably
| |
| de\-eloped mammary gland of the rabbit
| |
| with intact pituitary has been amply confirmed, and the original experiments of
| |
| Lyons (1942) involving the intraduct injection of prolactin have been successfully
| |
| repeated by Meites and Turner (1947) and
| |
| | |
| | |
| | |
| | |
| Fk;. 10.8. Liictation.'il lespon.scs in pseudoincgnant rabbit to different doses of prolactin injeclcd
| |
| intraductallv. (Fiom T. R. Bradley and P. M.
| |
| Clarke, J. Endo.ninol., 14, 28-36, 1956.)
| |
| | |
| | |
| | |
| Bradley and Clarke (1956) (Fig. 10.8).
| |
| However, endogenous pituitary hormones
| |
| may have participated in the response in
| |
| such experiments and in the last 20 years
| |
| there has been considerable discussion as to
| |
| whether prolactin should be regarded as
| |
| the lactogenic hormone or as a component
| |
| of a lactogenic complex. This whole question
| |
| has been fully discussed in recent years (see
| |
| Folley, 1952a, 1956) and it now seems
| |
| reasonably certain that lactogenesis is a
| |
| response to the co-operative action of more
| |
| than one anterior pituitary hormone, that
| |
| is, to a lactogenic hormone complex of which
| |
| prolactin is an important component, as
| |
| first suggested by Folley and Young (1941 ) .
| |
| The recent reports by Nandi (1958a, b)
| |
| that STH -I- Cortisol can induce milk secretion in triply operated mice with suitably
| |
| developed glands is further strong evidence
| |
| against regarding prolactin as the lactogenic
| |
| hormone.
| |
| | |
| Secretory activity is evident in the mammary gland during the second half of pregnancy, but abundant milk secretion does
| |
| not set in until parturition or shortly thereafter. The nature of the mechanism controlling the initiation of abundant secretion has
| |
| been the subject of speculation for many
| |
| years. The earlier theories w^ere discussed
| |
| l)y Turner ( 1939 ) in the second edition of
| |
| this book, and included the theory put
| |
| forward by Nelson with reference to the
| |
| guinea pig, that the high levels of blood
| |
| estrogen in late pregnancy suppressed the
| |
| secretion or release of prolactin from the
| |
| pituitary and had also a direct inhibitory
| |
| cttcct on the mammary parenchyma, the
| |
| fall in the levels of estrogen occurring at
| |
| parturition then allowing the anterior pituitary to exert its full lactogenic effect. This
| |
| concept proved inadequate to exjilain observations in other species and it was later
| |
| extended by Folley and Malpress (1948b)
| |
| to embrace the concept of two thresholds
| |
| for oi:)posing influences of estrogen upon
| |
| jiituitary lactogenic function, a lower
| |
| threshold for stimulation and a higher one
| |
| for inhibition. Subsequent observations on
| |
| the inhibitory role of progesterone, in the
| |
| pix'sence of estrogen, on milk secretion, however, necessitated further modification of
| |
| the theorv. Before discussing these modifica
| |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 607
| |
| | |
| | |
| | |
| tions it is convenient to refer to the ingenious theory put forward by Meites and
| |
| Turner (1942a, b; 1948) which was based on
| |
| their extensive investigation of the prolactin content of the pituitary in various
| |
| physiologic and experimental states. According to Meites and Turner, estrogen
| |
| elicits the secretion of prolactin from the
| |
| anterior pituitary thereby causing lactogenesis, whereas progesterone is an inhibitory agent, operative in pregnancy, inhibiting or over-riding the lactogenic action of
| |
| estrogen. The induction of lactation was
| |
| thus ascribed to a fall in the body level
| |
| of progesterone relative to that of estrogen
| |
| heheved to occur at the time of parturition.
| |
| Subsequent studies in the rabbit by jVIeites
| |
| and Sgouris (1953, 1954) revealed that
| |
| combinations of estrogen and progesterone
| |
| could inhibit, at the mammary gland level,
| |
| the lactogenic effects of exogenous prolactin.
| |
| This effect was, however, relative and by increasing the prolactin or decreasing the steroids, lactogenesis ensued. Inasmuch as the
| |
| theory of Meites and Turner did not take
| |
| into account the eventuality that estrogen
| |
| and progesterone act at the level of the mammary gland, Meites ( 1954) modified the con('ei)t, postulating that milk secretion was
| |
| held in check during pregnancy first by the
| |
| combined effect of estrogen and progesterone which make the mammary gland refractory to prolactin and, secondly, by a
| |
| low rate of prolactin secretion. The role of
| |
| progesterone in over-riding the stimulatory
| |
| effect of estrogen on the pituitary he now
| |
| considered to be of only minor importance.
| |
| Meites also explained the continuance of
| |
| lactation in pregnant animals by postulating that the initial level of prolactin was
| |
| sufficiently high as a result of the suckling
| |
| stimulus to overcome the inhibitory action
| |
| of the ovarian hormones on the mammary
| |
| gland. One of us (Folley, 1954, 1956) put
| |
| forward a tentative theory, combining various features of previous hypotheses, which
| |
| seemed capable of harmonizing most of
| |
| the known facts regarding the initiation of
| |
| milk secretion. In this it was emphasized
| |
| that measurements of the prolactin content
| |
| of the pituitary were not necessarily indicative of the rate of prolactin release (a recent
| |
| study bv Grosvenor and Turner (1958c)
| |
| | |
| | |
| | |
| lends further support to this contention)
| |
| and were best considered as largely irrelevant; low circulating levels of estrogen
| |
| activate the lactogenic function of the anterior pituitary whereas higher levels tend
| |
| to inhibit lactation even in the absence of
| |
| the ovary; lactogenic doses of estrogen
| |
| may be deprived of their lactogenic action
| |
| by suitable doses of progesterone, the combination then acting as a potent inhibitor
| |
| of lactation, this being the influence operating in pregnancy; at parturition the relative fall in the progesterone to estrogen ratio
| |
| removes the inhibition which is replaced by
| |
| the positive lactogenic effect of estrogen
| |
| acting unopposed.
| |
| | |
| It was observed by Gaines in 1915 that
| |
| although a colostral secretion accumulated
| |
| in the mammary gland during pregnancy,
| |
| the initiation of copious secretion was associated with functioning of the contractile
| |
| mechanisms in the udder responsible for
| |
| milk ejection; later Petersen (1944) also
| |
| suggested that the suckling or milking stimulus might be partly responsible for the
| |
| onset of lactation. Recent studies have provided evidence that this may well be so,
| |
| and these will be considered later when discussing the role of the suckling and milking
| |
| stimulus in the maintenance of milk secretion (see page 611).
| |
| | |
| During the past decade a fair amount of
| |
| information has been obtained about the
| |
| biochemical changes which occur in mammary tissue near the time of parturition,
| |
| and which are almost certainly related to
| |
| lactogenesis. The earlier work has been reviewed in some detail by one of us (Folley,
| |
| 1956) and need only be referred to briefly
| |
| here.
| |
| | |
| Folley and French (1949), studying rat
| |
| mammary gland slices incubated in media
| |
| containing glucose, showed that — QOo increased from a value of about 1.3 in late
| |
| pregnancy to a value of about 4.4 at day
| |
| 1 of lactation, and thereafter increased
| |
| still further. At the same time the R.Q.
| |
| which was below unity (approximately
| |
| 0.83) at the end of pregnancy, increased to
| |
| unity soon after parturition, and by day
| |
| 8 had reached a value of 1.62 at approximately which level it remained for the rest
| |
| of the lactation period. In accord with the
| |
| | |
| | |
| | |
| G08
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| increased respiratory activity of the tissue
| |
| about the time of parturition in the rat
| |
| mammary gland, Moore and Nelson (1952)
| |
| reported increases in the content of certain
| |
| respiratory enzymes, succinic oxidase and
| |
| cytochrome oxidase, in the guinea pig mammary gland at about this time. Greenbaum
| |
| and Slater (1957b) made similar observations about mammary gland succinic oxidase in the rat. Recent work is beginning to
| |
| throw light on the metabolic pathways involved in this increase in respiratory activity. Thus McLean (1958a) has adduced
| |
| evidence indicating an increase in the activity of the pentose phosphate pathway
| |
| in the rat mammary gland at about the time
| |
| of parturition. Mammary gland slices taken
| |
| from rats at various stages of the lactation
| |
| cycle were incubated in media containing
| |
| either glucose 1-C^^ or glucose 6-C^-^, and
| |
| the amount of radioactivity appearing in
| |
| the respiratory CO2 was determined. The
| |
| results given in Figure 10.9 show that although the recovery of C^^'Oo from C-6 was
| |
| relatively unaffected by the initiation of lactation, the C^^Oo originating from C-1 began a striking increase at the time of
| |
| parturition (see also Glock, McLean and
| |
| Whitehead, 1956, and Glock and McLean,
| |
| 1958, from which Figure 10.9 was taken).
| |
| | |
| | |
| | |
| pregnancy
| |
| | |
| | |
| | |
| in\'oliition
| |
| | |
| | |
| | |
| | |
| Imc;. 1().<», The relative amounts of C'Oi; formed
| |
| fioin iiiilucosc 1-C'^ and glucose 6-C" by rat niani
| |
| maiy gland slices. O O, C'^Oi formed from
| |
| | |
| glucose 1-C^'. • • . C^'Oi! formed from glucose
| |
| | |
| 6-C". (From G. E. Glock and P. McLean, Proc.
| |
| Roy. Soc, London, ser. B, 149, 354-362, 1958.)
| |
| | |
| | |
| | |
| Despite the well known pitfalls which surround the interpretation of C-1: C-6 quotients in experiments such as these, it seems
| |
| clear that lactation is associated with an
| |
| increase in the metabolism of glucose by
| |
| the pentose phosphate cycle, whereas the
| |
| proportion going by the Embden-Meyerhof
| |
| jmthway would appear to be relatively unaffected. These conclusions are supported by
| |
| the fact that the levels in rat mammary
| |
| tissue of two enzymes concerned in this
| |
| pathway of glucose breakdown, glucose
| |
| 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, show very striking increases at the time of parturition
| |
| (Glock and McLean, 1954; McLean, 1958a).
| |
| Other enzymes concerned in glucose breakdown whose activities in mammary tissue
| |
| begin to increase at parturition are hexokinase and phosphoglucose isomerase (]\IcLean, 1958a). In connection with the glucose metabolism of rat mammary tissue it
| |
| may be noted that addition of insulin to
| |
| the incubation medium markedly increases
| |
| the — QOo and R.Q. of rat mammary slices
| |
| metabolizing glucose or glucose plus acetate
| |
| (see page 619), and that this tissue only
| |
| becomes sensitive to insulin just after parturition (Balmain and Folley, 1951). It
| |
| is interesting to speculate which of the two
| |
| above-mentioned pathways of glucose
| |
| breakdown in mammary tissue resjjonds to
| |
| the action of insulin. According to Abraham,
| |
| Cady and Chaikoff (1957) addition of insulin in vitro increased the production by
| |
| lactating rat mammary slices of C^'^Oo from
| |
| glucose l-C^'*, but not from glucose 6-C^'*,
| |
| which might indicate that insulin stimulates
| |
| preferentially the pentose phosphate pathway. Against this, insulin increased the incorporation of both these carbon atoms
| |
| (and also the 3:4 carbon atoms of glucose)
| |
| into fatty acids of the slices to about the
| |
| same extent. McLean (1959) believes that
| |
| the stimulatory effect of insulin on the
| |
| pentose jihosphate pathway in the lactating
| |
| rat mammary gland is secondary to its
| |
| stimulating effect on lipogenesis. The latter
| |
| l)rocess generates the oxidized form of tril)hosphopyridine nucleotide (TPN) which is
| |
| needed for the first two steps of the pentose
| |
| phosphate cycle.
| |
| | |
| The inci-casc in the R.Q. of mammary
| |
| | |
| | |
| | |
| MAMMARY GLAXD AND LACTATION
| |
| | |
| | |
| | |
| 009
| |
| | |
| | |
| | |
| tissue beginning at parturition observed
| |
| by Folley and French (1949) was interi:)reted as indicating that this tissue assumes
| |
| the power of effecting net fatty acid synthesis from ghicose at this time. Much subsequent evidence confirming this idea has
| |
| been reviewed by Folley (1956). It only
| |
| rt'mains to add that Ringler, Becker and
| |
| Nelson (1954), Lauryssens, Peelers and
| |
| Donck (1956), and Read and Moore (1958)
| |
| ha^-e shown that the amount of coenzyme
| |
| A in mammary tissue undergoes an increase
| |
| at parturition. Moreover, the recent findings
| |
| of McLean (1958b), who showed that the
| |
| levels of pyridine nucleotides in the mammary gland of the rat begin to increase
| |
| at parturition, reaching a high level by the
| |
| end of lactation, may be significant in this
| |
| connection. McLean found that although
| |
| the increase in the tissue levels of diphosl^hopyridine nucleotide was almost entirely
| |
| due to an increase in the oxidized form
| |
| (DPN), in the case of TPN it was the reduced form (TPNH) which increased. The
| |
| latter might well be used for reductive syntheses such as lipogenesis.
| |
| | |
| The rate of synthesis of milk constituents
| |
| other than fat must also begin to increase at
| |
| parturition, and Greenbaum and Greenwood
| |
| (1954) showed that an increase in the levels
| |
| of glutamic aspartic transaminase and of
| |
| glutamic dehydrogenase in rat mammary
| |
| tissue occurs at this time. The authors believe these enzymes are concerned in the
| |
| provision of substrates for the synthesis of
| |
| milk protein. It is significant in connection
| |
| with milk protein synthesis that the mammary gland ribonucleic acid (RNA) in the
| |
| rat undergoes a marked rise at parturition
| |
| (Greenbaum and Slater, 1957a).
| |
| | |
| The above - mentioned biochemical
| |
| changes in mammary tissue which occur at
| |
| al)out the time of parturition are almost
| |
| certainly closely related to the effect on this
| |
| tissue of members of the anterior pituitary
| |
| lactogenic complex, and particularly prolactin. Attempts have been made to elicit
| |
| the characteristic respiratory changes, described above, in mammary slices in vitro
| |
| by addition of prolactin and adrenal glucocorticoids to the incubation medium (see
| |
| Folley, 1956). So far, however, definitive results luive not been obtained and it is doubt
| |
| | |
| | |
| ful whether any biochemical changes in
| |
| lactating mammary gland slices in vitro
| |
| have been demonstrated which could with
| |
| certainty be ascribed to the action of prolactin (in this connection see also Bradley
| |
| and Mitchell. 1957).
| |
| | |
| 2. Maintenance of Milk Secretion — Galactopoiesis
| |
| | |
| It is well known that the removal of the
| |
| pituitary of a lactating animal will end
| |
| milk secretion (for references see Folley,
| |
| 1952a). The cessation of milk secretion has
| |
| been generally ascribed to the loss of the
| |
| anterior lobe, but when the importance of
| |
| the neurohypophysis in milk ejection became established (see page 621), it was
| |
| clear that in the hypophysectomized animal
| |
| it was necessary to distinguish between a
| |
| failure in milk secretion and a failure in
| |
| milk ejection, since either would lead to
| |
| failure of lactation. It has now been shown
| |
| in the rat that adequate oxytocin therapy
| |
| ensuring the occurrence of milk ejection
| |
| after hypophysectomy will not restore lactation (Cowie, 1957) and it may thus be
| |
| concluded that the integrity of the anterior
| |
| lobe is essential for the maintenance of
| |
| milk secretion. The effect of hypophysectomy on milk secretion is dramatic, because in the rat, milk secretion virtually
| |
| ceases within a day of the operation and
| |
| biochemical changes in the metabolic activity of the mammary tissue can be detected within 4 to 8 hours (Bradley and
| |
| Cowie, 1956). It is of interest to note that
| |
| these metabolic changes are similar to those
| |
| observed during mammary involution (see
| |
| page 598).
| |
| | |
| Since the second edition of this book,
| |
| there have been surprisingly few studies on
| |
| replacement therapy in hypophysectomized
| |
| lactating animals. In such studies we would
| |
| stress the need for rigorous methods of
| |
| assessing the efficacy of treatment. In the
| |
| past the presence of milk in the gland as
| |
| revealed by macroscopic or microscopic
| |
| examination has been regarded as an indication of successful replacement. This,
| |
| however, gives no measure of the degree of
| |
| maintenance of lactation and some measure
| |
| of the daily milk yield of such animals
| |
| should be obtained (see also Cowie, 1957).
| |
| | |
| | |
| | |
| GIO
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| It is abo now obvious that oxytocin may
| |
| have to be injected to ensure milk ejection;
| |
| under certain circumstances, however, the
| |
| neurohypophyseal tissue remaining after
| |
| the removal of the posterior lol^e may be
| |
| capable of releasing oxytocin and permitting milk ejection (see Benson and Cowie,
| |
| 1956; Bintarningsih, Lyons, Johnson and Li.
| |
| 1957, 1958).
| |
| | |
| The earliest report on the maintenance
| |
| of lactation after hypophysectomy is that of
| |
| Gomez (1939, 1940), who found that hypophysectomized lactating rats could rear
| |
| their litters if given anterior-pituitary extract, adrenal cortical extracts, glucose, and
| |
| posterior pituitary extract. These experiments are difficult to assess because they are
| |
| reported only in abstract, but the use of posterior pituitary extract at a time when the
| |
| role of oxytocin in milk ejection was not
| |
| generally recognized is worthy of note. Recently, slight maintenance of milk secretion
| |
| in hypophysectomized rats has been obtained with prolactin alone, and greater
| |
| maintenance when adrenocorticotrophic
| |
| hormone ( ACTH I or STH was administered
| |
| with prolactin (Cowie, 1957). Similar
| |
| studies were reported by Bintarningsih,
| |
| Lyons, Johnson and Li (1957, 1958) (see
| |
| also Lvons, Li and Johnson, 1958) in which
| |
| | |
| | |
| | |
| I «
| |
| | |
| c
| |
| | |
| -^ 4
| |
| | |
| -0
| |
| | |
| I 1
| |
| | |
| | |
| | |
| £
| |
| | |
| | |
| | |
| Z -6
| |
| | |
| | |
| | |
| z
| |
| | |
| | |
| | |
| J
| |
| | |
| | |
| | |
| E
| |
| | |
| | |
| | |
| :^ 2 ^^,
| |
| | |
| | |
| | |
| TV
| |
| | |
| 2 ^
| |
| | |
| | |
| | |
| Fig. 10.10. Effect on the luilk yield of the cow
| |
| of injected hormones of the anterior pituitary.
| |
| (From the results of P. M. Cotes, J. A. Crichton,
| |
| S. J. Folley and F. G. Young, Nature, London.
| |
| 164, 992-993, 1919.)
| |
| | |
| | |
| | |
| considerable maintenance of milk secretion
| |
| was obtained in hypophysectomized rats
| |
| with prolactin and certain corticoids. Of
| |
| related interest is the observation by Elias
| |
| (1957) that Cortisol and prolactin can induce secretory activity in explants of mouse
| |
| mammary gland growing on a synthetic
| |
| medium. (Tissue culture techniques have
| |
| been little exploited in mammary studies
| |
| and further developments in this field may
| |
| be expected.)
| |
| | |
| The evidence to date suggests that, in the
| |
| rat, prolactin is an essential component of
| |
| the hormone complex involved in the maintenance of lactation with ACTH and STH
| |
| also participating, but further studies are
| |
| recjuired to determine the most favorable
| |
| balance of these factors.
| |
| | |
| Preliminary studies on the maintenance of
| |
| lactation in the goat after hypophysectomy
| |
| suggest that both prolactin and STH are important in the initiation and maintenance of
| |
| milk secretioii (Cowie and Tindal, 1960).
| |
| Our knowledge of the process in other species is derived from studies on the effect
| |
| of exogenous anterior pituitary hormones
| |
| on established lactation in intact animals—
| |
| galactopoietic effects (for reference see
| |
| Folley, 1952a, 1956). In the cow, considerable increase in milk yield can be obtained
| |
| by injecting STH (Cotes, Crichton, Folley
| |
| and Young, 1949), whereas prolactin has
| |
| a negligible galactopoietic effect (Fig. 10.10;
| |
| for discussion see also Folley, 1955). Recently the precise relationship between the
| |
| dose of STH (ox) and the lactational response in the cow was established in our laboratory by Hutton (1957) who observed a
| |
| highly significant linear relationship between log doses of STH (single injection)
| |
| and the increase in milk yield obtained (Fig.
| |
| 10.11 ) ; increases in fat yield relative to the
| |
| yield of nonfatty solids also occurred. In the
| |
| lactating rat, on the other hand, STH has
| |
| no galactopoietic effect (Meites, 1957b;
| |
| Cowie, Cox and Naito, 1957), whereas prolactin has (Johnson and Meites, 1958). Such
| |
| studies must be interpreted with caution as
| |
| endogenous pituitary hormones were present ; nevertheless, it seems reasonable to
| |
| conclude that STH is likely to be an impoi'tant factor in the maintenance of lactation in the row.
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 611
| |
| | |
| | |
| | |
| mq qro\Om hormone (onthmeTTc scale)
| |
| | |
| | |
| | |
| fa-25 12-5 25-0 50-0
| |
| | |
| | |
| | |
| 100-0
| |
| | |
| | |
| | |
| 200-0
| |
| | |
| | |
| | |
| S-«^0
| |
| | |
| | |
| | |
| | |
| 'Zoo-o
| |
| | |
| | |
| | |
| Fig. 10. IL Effect of graded doses of growth hormone on milk yield of row. Upper curve,
| |
| doses plotted on arithmetic scale. Lower curve, doses plotted on logarithmic scale. (From
| |
| J. B. Hutton, J. Endocrinol., 16, 115-125, 1957.)
| |
| | |
| | |
| | |
| C)ther hormones of the anterior pituitary
| |
| in all probability influence milk secretion
| |
| through their target glands and these will
| |
| be dealt with later.
| |
| | |
| 3. Suckling Stimulus and the Maintenance
| |
| of Lactation
| |
| | |
| It has been long believed that regular
| |
| milking is an important factor in maintaining lactation and that if milk is allowed
| |
| to accumulate in the gland, as occurs at
| |
| weaning, atrophy of the alveolar epithelium
| |
| and glandular involution occur. Evidence
| |
| in support of this concept was obtained in
| |
| studies showing that ligature or occlusion of
| |
| | |
| | |
| | |
| the main ducts of some of the mammae of a
| |
| lactating animal resulted in atrophy of the
| |
| glands concerned although the other glands
| |
| were suckled normally (Kuramitsu and
| |
| Loeb, 1921; Hammond and Marshall, 1925;
| |
| Fauvet, 1941a). Studies by Selye and his
| |
| colleagues, however, revealed that such
| |
| occluded glands did not atrophy as quickly
| |
| as did glands of animals in which the suckling stimulus was no longer maintained
| |
| (Selye, 1934; Selye, Collip and Thomson,
| |
| 1934) and it was postulated that the suckling stimulus evoked from the anterior
| |
| pituitary the secretion of prolactin which
| |
| maintained the secretory activity of the
| |
| gland. This theory has been widely accepted
| |
| | |
| | |
| | |
| 012
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| although it has been suggested that a complex of hormones rather than prolactin alone
| |
| is released (Folley, 1947). Williams (1945)
| |
| showed that prolactin could in fact maintain the integrity of the mammary gland in
| |
| the unsuckled mouse thus mimicking the
| |
| effects of the suckhng stimulus; other supporting evidence has been reviewed by
| |
| Folley (1952a). Recent studies in goats,
| |
| however, have shown that milk secretion
| |
| may continue more or less at the normal
| |
| level after complete denervation of the udder (Tverskoi, 1958; Denamur and Martinet, 1959a, b, 1960) and it may be that in
| |
| some species the suckling or milking stimulus is loss important in the maintenance of
| |
| milk secretion.
| |
| | |
| Milk secretion is essentially a continuous
| |
| process whereas the suckling or milking
| |
| stimulus is intermittent ; indeed the milking
| |
| stimulus may be of remarkably brief duration (in the cow about 10 minutes in all per
| |
| 24 hours) and it is therefore likely that the
| |
| stimulus triggers off the release of sufficient
| |
| galactopoietic complex to maintain mammary function for some hours. Grosvenor
| |
| and Turner (1957b) reported that suckling
| |
| causes a rapid drop in the prolactin content
| |
| of the pituitary in the rat, and that the
| |
| prenursing level of prolactin in the pituitary
| |
| is not fully regained some 9 hours later.
| |
| It is difficult, however, to relate pituitary
| |
| levels of prolactin to the rate of its secretion into the circulation and, although these
| |
| observations are interesting, further advances are unlikely until a method of assay
| |
| for blood prolactin becomes available and
| |
| the "half-life" of prolactin in circulation is
| |
| known.
| |
| | |
| The experiments of Gregoire (1947) on
| |
| the maintenance of involution of the thymus
| |
| during nursing suggests that the suckling
| |
| stimulus releases ACTH which, as we have
| |
| seen, is galactopoietic in the rat; thus, so far
| |
| as the rat is concerned, there would appear
| |
| to be good evidence that the suckling stimulus releases at least two known important
| |
| components of the galactopoietic complex.
| |
| | |
| The milking and suckling stimulus is also
| |
| responsible for eliciting the milk-ejection
| |
| reflex and the relation between the two reflexes will be discussed later in this chapter
| |
| (sec ])age 619 1.
| |
| | |
| | |
| | |
| B. HORMONES OF THE ADRENAL CORTEX
| |
| | |
| Adrenalectomy results in a marked inhibition of milk secretion and the early experiments in this field were reviewed by
| |
| Turner in 1939. Since then, however, purified adrenal steroids have become available
| |
| enabling further analysis to be made of the
| |
| role of the adrenal cortex in lactation.
| |
| | |
| Gaunt, Eversole and Kendall (1942) considered that in the rat the defect in milk
| |
| secretion after adrenalectomy could be repaired by the administration of the adrenal
| |
| steroids most closely concerned with carbohydrate metabolism, whereas we came to
| |
| the somewhat opposing view that the defect
| |
| was best remedied by those hormones
| |
| primarily concerned with electrolyte metabolism (Folley and Cowie, 1944; Cowie and
| |
| Folley, 1947b, c). The reasons for these
| |
| differing observations are not yet entirely
| |
| clear. Virtually complete restoration of
| |
| milk secretion was subsequently obtained
| |
| in our strain of rat by the combined administration of desoxycorticosterone acetate
| |
| (DCA) and cortisone, or with the halogenated steroids, 9a-chlorocortisol and 9afluorocortisol (Cowie, 1952; Cowie and
| |
| Tindal, 1955; Cowie and Tindal, unpublished; see also Table 10.1). It would therefore seem that both glucocorticoid and
| |
| mineralocorticoid activity was necessary to
| |
| maintain the intensity of milk secretion at
| |
| its normal level. The interesting observation
| |
| was made by Flux (1955» and later confirmed by Cowie and Tindal (unpublished)
| |
| that the ovaries contribute to the maintenance of lactation after adrenalectomy, a
| |
| contribution which could be simulated in the
| |
| adrenalectomized-ovariectomized rat by the
| |
| administration of 3 mg. progesterone daily.
| |
| The differences in the size of the ovarian
| |
| contribution may partly accoimt for the apparent differences in various strains of rat of
| |
| the relative importance of mineralo- and
| |
| glucocorticoids in sustaining milk secretion
| |
| after adrenalectomy. The only other species
| |
| in which the maintenance of lactation after
| |
| adrenalectomy has been studied is the goat
| |
| in which, as in the rat, lactation can be
| |
| maintained with cortisone and desoxycorticosterone, the latter being apparently the
| |
| more critical steroid (Cowie and Tindal.
| |
| 1958; Figs. 10.12a, b).
| |
| | |
| | |
| | |
| MAMM.\RY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 613
| |
| | |
| | |
| | |
| There have been several studies on the
| |
| effects of corticoids and adrenocortieotrophin on lactation in the intact animal.
| |
| ACTH and the corticoids depress lactation
| |
| in the intact cow (Fig. 10.10) (Cotes, Crichton, Folley and Young, 1949; Flux, Folley
| |
| and Rowland, 1954; Shaw, Chung and
| |
| Bunding, 1955; Shaw, 1955), whereas in the
| |
| rat ACTH and cortisone have been reported
| |
| as exhibiting galactopoietic effects (Meites,
| |
| private communication; Johnson and
| |
| Meites, 1958). With larger doses of cortisone, however, an inhibition of milk secretion in the rat has been reported (MercierParot, 1955).
| |
| | |
| The main function of the cortical steroids
| |
| in lactation is still uncertain. They may act
| |
| in a "supporting" or "permissive" manner
| |
| (see Ingle, 1954), maintaining the alveolar
| |
| cells in a state responsive to the galacto])oictic complex, or they may act by maintaining the necessary levels of milk precursors in the blood.
| |
| | |
| Biochemical studies are, however, Ix'ginning to add to our information on the role
| |
| of the corticoids in lactation. In the rat,
| |
| adrenalectomy prevents the increase in liver
| |
| and mammary gland arginase which occurs
| |
| during normal lactation and it has been
| |
| suggested that this depression of arginase
| |
| activity interferes with deamination of
| |
| amino acids, and thereby inhibits any increase in gluconeogenesis from protein and
| |
| thus starves the mammary gland of nonnitrogenous milk precursors (Folley and
| |
| Greenbaum, 1947, 1948). As there is little
| |
| arginase in the mammary gland of other
| |
| species {e.g., rabbit, cow, goat, sheep), this
| |
| mechanism may not have general validity
| |
| (for further discussion see Folley, 1956).
| |
| Other biochemical studies have suggested
| |
| that the steroids of the adrenal cortex may
| |
| be concerned in mammary lipogenesis, but
| |
| the results so far have been conflicting and
| |
| no firm conclusions can as yet be drawn
| |
| (see Folley, 1956).
| |
| | |
| C. OVARIAN HORMONES
| |
| | |
| There is no evidence that ovariectomy has
| |
| any deleterious effect on lactation (Kuramitsu and Loeb, 1921; de Jongh, 1932; Folley and Kon, 1938; Flux, 1955); neither
| |
| is there evidence for the belief, once
| |
| | |
| | |
| | |
| TABLE 10.1
| |
| | |
| Replacement therapy in lactating rats
| |
| | |
| adrenalectomized on the fourth
| |
| | |
| day of lactation
| |
| | |
| (From A. T. Cowie and S. J. Folley,
| |
| | |
| J. Endocrinol., 5, 9-13, 1947.)
| |
| | |
| | |
| | |
| Treatment
| |
| | |
| | |
| Number of
| |
| Litters
| |
| | |
| | |
| Number
| |
| | |
| of Pups
| |
| | |
| per
| |
| | |
| Litter
| |
| | |
| | |
| Litter-growth
| |
| | |
| Index*
| |
| gm. + S.E.
| |
| | |
| | |
| Control
| |
| | |
| Adrenalectomy
| |
| | |
| Adrenalectomy + cortisone + DC A (tablet
| |
| implantsf)
| |
| | |
| | |
| 8
| |
| | |
| 9
| |
| | |
| 7
| |
| | |
| | |
| 8
| |
| 8
| |
| 8
| |
| | |
| | |
| 15.6 + 0.5
| |
| | |
| 7.5 ± 0.6
| |
| 14.9 ± 0.6
| |
| | |
| | |
| | |
| (Above results from Cowie, 1952)
| |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| 6
| |
| | |
| | |
| 8
| |
| | |
| | |
| 14.5 ± 0.8
| |
| | |
| | |
| Adrenalectomy
| |
| | |
| | |
| 6
| |
| | |
| | |
| 8
| |
| | |
| | |
| 6.2 ± 0.4
| |
| | |
| | |
| Adrenalectomy + chloro
| |
| | |
| 5
| |
| | |
| | |
| 8
| |
| | |
| | |
| 13.1 ± 0.5
| |
| | |
| | |
| cortisol (100 Mg per
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| day)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| (Above results from Cowie and Tindal, 1955)
| |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| 8
| |
| | |
| | |
| 12
| |
| | |
| | |
| 17.7 ± 0.8
| |
| | |
| | |
| Adrenalectomy
| |
| | |
| | |
| 8
| |
| | |
| | |
| 12
| |
| | |
| | |
| 7.5 ± 0.5
| |
| | |
| | |
| Adrenalectomy + ovari
| |
| | |
| 5
| |
| | |
| | |
| 12
| |
| | |
| | |
| 3.6 ± 0.5
| |
| | |
| | |
| ectomy
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Adrenalectomy + ovari
| |
| | |
| 7
| |
| | |
| | |
| 12
| |
| | |
| | |
| 14.5 ± 0.7
| |
| | |
| | |
| ectomy + fiuorocorti
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| sol (200 Mg per day)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| (Above results from Cowie and Tindal,
| |
| unpublished)
| |
| | |
| * The litter-growth index is defined as the mean
| |
| daily gain in weight per litter over the 5-day period from the 6th to the 11th days.
| |
| | |
| t 2 X 11 mg. tablets cortisone giving mean daily
| |
| absorption of 850 ^ig., and 1 X 50 mg. tablet DCA
| |
| giving mean daily absorption of 360 ng.
| |
| | |
| widely held, that ovariectomy increases
| |
| and prolongs lactation in the nonpregnant
| |
| cow (see Richter, 1936).
| |
| | |
| Although the integrity of the ovary is
| |
| not essential for the maintenance of lactation, there can be no doubt that ovarian
| |
| hormones, in certain circumstances, profoundly influence milk secretion. Estrogens
| |
| have long been regarded as possessing the
| |
| power to inhibit lactation, a concept on
| |
| which Nelson based his theory of the mechanism of lactation initiation (see page 606 1 .
| |
| Some workers, however, have expressed
| |
| doubts that the effect is primarily on milk
| |
| secretion, and have suggested that in ex
| |
| | |
| | |
| 614
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| periments on laboratory animals the apparent failure in milk secretion could be a
| |
| secondary effect due to either a toxic action
| |
| of the estrogen causing an anorexia in the
| |
| mother, interference with milk ejection, or
| |
| disturbance of maternal behavior or to toxic
| |
| effects on the young, whose growth rate
| |
| serves as a measure of lactational performance, through estrogens being excreted in
| |
| milk. The evidence to date shows that in
| |
| | |
| | |
| | |
| the intact rat estrogens even in very low
| |
| doses inhibit milk secretion, their action
| |
| depending on the presence of the ovary ; the
| |
| ovarian factor concerned appears to be progesterone, estrogen and progesterone acting
| |
| locally on the mammary gland and rendering it refractory to the lactogenic complex. In the ovariectomized rat much larger
| |
| doses of estrogen are necessary to inhibit
| |
| lactation, and the evidence is not entirely
| |
| | |
| | |
| | |
| Body
| |
| | |
| | |
| | |
| Goat 478
| |
| | |
| | |
| | |
| weight ^^L
| |
| :.) 45 L
| |
| | |
| Plasma Na
| |
| (m-equiv./l.) ^^^^
| |
| | |
| Plasma K
| |
| (m-equiv./l
| |
| | |
| Milk K 40 (m-equiv./l.) 30
| |
| | |
| | |
| | |
| Milk Na ,
| |
| | |
| (m-equiv./l.)
| |
| | |
| | |
| | |
| Solids-notfat (%)
| |
| | |
| Yield of
| |
| solids-notfat (g)
| |
| Fat (%)
| |
| | |
| | |
| | |
| Milk yield
| |
| (kg)
| |
| | |
| | |
| | |
| Goat died-*
| |
| | |
| 5 15 25 4 14 24
| |
| Mgr. Apr.
| |
| | |
| | |
| | |
| Fig. 10.12i4. Effect of replaconi(>nt therapy with (losoxycoiticostcM-oiu
| |
| c-ortisone aoetate (CA) on milk yield, milk composition, and concent
| |
| | |
| | |
| | |
| (DCA) and
| |
| tion of Na and K
| |
| in milk and blood plasma of the goat after adrenalectomy. Duration of replacement therapy
| |
| (pellet implantation) indicated by horizontal lines; the names of steroids and their mean
| |
| daily absorption rates are given adjacent to the lines. Note in Figure 12.4 the considerable
| |
| maintenance of milk vield with DCA alone. See also Figure 12/?. (From A. T. Cowic and
| |
| J. S. Tindal. J. Endocrinol., 16, 403-414, 1958.)
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 6L
| |
| | |
| | |
| | |
| Goat 515
| |
| | |
| | |
| | |
| Body 5Q _
| |
| weight —
| |
| | |
| (kg) 40
| |
| 150
| |
| Plasma Na ^ ^.
| |
| / /I \ ^40 —
| |
| | |
| (m-equiv./l) —
| |
| | |
| 130
| |
| | |
| | |
| | |
| Plasma K
| |
| (m-equiv./l)
| |
| | |
| | |
| | |
| Milk K
| |
| (m-equiv./l.)
| |
| | |
| | |
| | |
| Milk Na
| |
| (m-equiv./l.)
| |
| | |
| Solids-not- ^ H
| |
| | |
| fat {%) 7 U
| |
| | |
| Yield of 200
| |
| solids-not- —
| |
| | |
| fat (g) 100
| |
| Fat (- ^
| |
| | |
| | |
| | |
| Fat yield
| |
| | |
| | |
| | |
| Milk yield
| |
| (kg)
| |
| | |
| | |
| | |
| | |
| 13 23 2 12 22 2 12 22
| |
| Oct. Nov Dec.
| |
| | |
| Fig. 12B.
| |
| | |
| | |
| | |
| 11 21 31 10 20
| |
| | |
| Jan. Feb
| |
| | |
| | |
| | |
| conclusive that there is a true inhibition of
| |
| milk secretion (see Cowie, 1960). In the
| |
| cow estrogen in sufficient doses depresses
| |
| milk yield, but its mode of action has not
| |
| been fully elucidated. In women, estrogens
| |
| are used clinically to suppress unwanted
| |
| lactation, but as the suckling stimulus is
| |
| also removed about the same time, the role
| |
| of the estrogen is difficult to assess (see
| |
| Meites and Turner, 1942a).
| |
| | |
| | |
| | |
| It has been well established that progesterone by itself has no effect on milk secretion (see Folley, 1952a), save in the adrenalectomized animal (see page 612), and
| |
| so it would appear that the physiologic
| |
| inhibition of lactation is effected Ijy estrogen
| |
| and progesterone acting synergistically as
| |
| first demonstrated by Fauvet (1941b) and
| |
| confirmed by others including Masson
| |
| (1948), Walker and Matthews (1949),
| |
| | |
| | |
| | |
| GIG
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Cowie, FoUey, Malpress and Richarcl.son
| |
| (1952J,, and Meites and Sgouris (1954).
| |
| There is clear evidence that the estrogenprogesterone combination acts at least
| |
| partly on the mammary parenchyma (Desclin, 1952; Meites and Sgouris, 1953) but
| |
| the mechanism of the action is unknown.
| |
| The hormonal interplay and complex endocrine interactions in the process of lactation
| |
| inhibition with estrogen has recently been
| |
| discussed at length by von Berswordt-Wallrabe (1958).
| |
| | |
| Lactogenic effects of estrogens have already been mentioned; these have been
| |
| demonstrated most strikingly in cows and
| |
| goats, in which milk secretion has been induced in udders being developed by exogenous estrogen. These experiments have
| |
| been reviewed in some detail by Folley and
| |
| Malpress (1948b) and Folley (1956).^ It is
| |
| generally assumed that estrogens act by
| |
| | |
| | |
| | |
| stimulating the production of lactogenic and
| |
| galactopoietic factors by the anterior
| |
| pituitary. In experiments on the ovariectomized goat we have shown (Cowie,
| |
| Folley, Malpress and Richardson, 1952;
| |
| Benson, Cowie, Cox, Flux and Folley, 1955)
| |
| that it is possible to select a daily dose of
| |
| estrogen which will induce mammary
| |
| growth but relatively little secretion in the
| |
| sense that the udder does not become tense
| |
| and distended as will happen when a lower
| |
| dose of estrogen is given — an observation we
| |
| may quote in support of the "double-threshold" theory of estrogen action. The lactogenic effect of the lower dose of estrogen
| |
| could be abolished, however, by administering progesterone simultaneously with the
| |
| estrogen (Fig. 10.13), an observation in
| |
| accord with those of other workers on the
| |
| rabbit and rat (see above).
| |
| | |
| In 1936 one of us (Folley, 1936) reported
| |
| | |
| | |
| | |
| | |
| Fig. 10.13. Photographs of goat uddois dovelopcd by daily injections of hoxoostiol (HX)
| |
| with and without progesterone (PG). The hibels indicate the daily dose in mg. of each
| |
| substance. (Results from A. T. Cowie, S. J. Folley, F. H. Malpre.ss and K. C. Ricliardson,
| |
| J. Endocrinol., 8, 64-88, 1952.)
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| GK
| |
| | |
| | |
| | |
| that certain dose levels of estrogen in the
| |
| lactating cow produced long-lasting changes
| |
| in milk composition characterized by increases in the percentages of fat and nonfatty solids. This was regarded as an example of galactopoiesis and was termed the
| |
| "enrichment" effect. The effect, however, w^as
| |
| somewhat erratic and it has recently been
| |
| re-investigated by Hiitton (1958) who confirmed and extended the earlier observations.
| |
| Hutton found that galactopoietic responses
| |
| (Figs. 10.14 and 10.15) were obtained only
| |
| within a restricted dose range, the limits
| |
| of which were affected by the stage of pregnancy and the breed of the cow. Hutton
| |
| further concluded that in the normal cow
| |
| changes in milk composition and yield associated with advancing pregnancy were
| |
| probably determined by the progressive rise
| |
| of blood estrogen levels.
| |
| | |
| D. THYROID HORMONES
| |
| | |
| Studies on the effect of removal of the
| |
| thyroids on milk secretion have been reviewed by one of us (Folley, 1952a) ; the
| |
| evidence strongly suggests that the thyroid
| |
| glands are not essential for milk secretion,
| |
| but in their absence the intensity and duration of lactation is reduced. Histologic and
| |
| cytologic studies of the thyroid of the lactating cat suggest that there is a considerable outpouring of the thyroid secretion in
| |
| the early stages of lactation (Racadot,
| |
| 1957), and Grosvenor and Turner (1958b)
| |
| have reported that the thyroid secretion
| |
| rate is higher in lactating than in nonlactating rats.
| |
| | |
| Since the last edition of this l)ook, a great
| |
| volume of experimental results has been
| |
| published on the use of thyroid-active materials for increasing the milk yield of cows.
| |
| These experiments have been extensively
| |
| reviewed by Blaxter (1952) and Meites
| |
| (1960) and we need here only touch on the
| |
| salient points.
| |
| | |
| In the early studies i^reparations of dried
| |
| thyroid gland were fed to cows or injections
| |
| of DL-thyroxine were given, but the use on
| |
| a large scale of thyroid-active materials
| |
| for increasing the milk yield of cows only
| |
| became feasible when it was shown that
| |
| certain iodinated proteins exhibited thyroidlike activitv when given in the feed. Al
| |
| | |
| | |
| 9-9
| |
| 97
| |
| | |
| o 9-3
| |
| ^ 9-1
| |
| | |
| | |
| | |
| 8-9
| |
| | |
| | |
| | |
| •'' Guernsey
| |
| | |
| | |
| | |
| Shorthorn
| |
| | |
| | |
| | |
| 8-5
| |
| | |
| | |
| | |
| •^U^ri
| |
| | |
| I L
| |
| | |
| | |
| | |
| 20 40 60 80 100
| |
| | |
| Oestradiol monobenzoite (mg)
| |
| | |
| Fig. 10.14. Effect of graded doses of estradiol
| |
| benzoate on percentage of nonfatty solids in milk
| |
| from cows of three breeds. (From J. B. Hutton,
| |
| J. Endocrinol., 17, 121-133, 1958.)
| |
| | |
| Oestradiol monobenzoate (mg) (arith. scale)
| |
| | |
| 10 20 30 40 50
| |
| | |
| | |
| | |
| | |
| 6-25 12-5 250 500
| |
| | |
| Oestradiol monobenzoate (mg) (log scale)
| |
| | |
| Fig. 10.15. Effect of graded doses of estradiol
| |
| benzoate on fat content of cows' milk. Upper curve,
| |
| doses plotted on arithmetic scale. Lower curve,
| |
| doses plotted on logarithmic scale. (From J. B.
| |
| Hutton, J. Endocrinol., 17, 121-133, 1958.)
| |
| | |
| though these materials were readily made
| |
| and were economical for large-scale use, they
| |
| possessed several disadvantages. Their activity was difficult to assay and standardize,
| |
| they were frequently unpalatable, and their
| |
| administration entailed a considerable intake of iodine which could be undesirable.
| |
| Nevertheless, a large number of experiments
| |
| were carried out all over the world with
| |
| this type of material. In 1949, however, a
| |
| new and improved method for the synthesis
| |
| of L-thyroxine was developed (Chalmers,
| |
| Dickson, Elks and Hems, 1949) and thyroxine became available in large quantities.
| |
| It was then shown jjy Bailey, Bartlett and
| |
| Folley (1949) that this material was ealac
| |
| | |
| | |
| 618
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ,
| |
| | |
| | |
| | |
| | |
| | |
| | |
| /" \^
| |
| | |
| | |
| Cont-rol.
| |
| | |
| | |
| | |
| | |
| A<' / " "^ - ^*
| |
| | |
| | |
| — • DO m§.
| |
| | |
| | |
| | |
| | |
| .^''\ / V- -' v;.
| |
| | |
| | |
| 100 m|.
| |
| | |
| | |
| | |
| | |
| ^..^-Av / V
| |
| | |
| | |
| 150mg.
| |
| | |
| | |
| | |
| | |
| ^^^4?^^/ . V
| |
| | |
| | |
| | |
| | |
| | |
| | |
| ,.-•*.. \ vv / .^-r \ \
| |
| | |
| | |
| • — •• tva --^-^ y \ \ \
| |
| | |
| | |
| •••\-'^\ \ x- ^ .. \ ^
| |
| | |
| | |
| \. *-^ '• •■*— . \ \
| |
| | |
| | |
| *■*•—., \ \ \ \
| |
| | |
| | |
| | |
| | |
| .... -.... "•N-:w<r:Viy: y^
| |
| | |
| | |
| Sl-art of hrcAhnc.ih \\ y' i'
| |
| | |
| | |
| hrc iXhuciil' \\ //
| |
| | |
| | |
| \v/y
| |
| | |
| | |
| \ V /
| |
| | |
| | |
| \ /
| |
| | |
| | |
| \ /
| |
| | |
| | |
| \/
| |
| | |
| | |
| V
| |
| | |
| | |
| | |
| 10
| |
| | |
| | |
| | |
| 50
| |
| | |
| | |
| | |
| 50
| |
| | |
| | |
| | |
| Dau5
| |
| | |
| | |
| | |
| Fig. 10.16. Effect of L-thyroxine given in the feed on the milk yield of groups of cows
| |
| (the indicated dose levels were fed daily). (From G. L. Bailey, S. Bartlett and S. J. Folley,
| |
| Nature, London, 163, 800. 1949.)
| |
| | |
| | |
| | |
| topoietic when ]ed to lactating cows in daily
| |
| doses of about 100 mg. (Fig. 10.16). It had,
| |
| moreover, none of the drawbacks of the
| |
| iodinated proteins, its purity could be
| |
| checked chemically, it was odorless and
| |
| tasteless. AVith the introduction of synthetic thyroxine, iodinated proteins have
| |
| become obsolete as galactopoietic agents.
| |
| | |
| The more recently isolated 3:5:3-triiodo-L-thyronine, reported to be 5 to 7
| |
| times more active than thyroxine in various
| |
| biologic tests in small animals and also in
| |
| man, has little or no effect on the milk yield
| |
| when fed to cows, but is somewhat more
| |
| active than thyroxine in promoting galactopoiesis when administered subcutaneously,
| |
| which suggests that the material is inactivated in the gut, probably in the rumen
| |
| f Bartlett, Burt, Folley and Rowland, 1954).
| |
| | |
| The extensive experiments on galactopoiesis in dairy cattle with thyroxine and
| |
| thyroid-active substances have made it
| |
| possible to reach reasonably firm conclusions as to the practical value of the procedure. There is great variability in the
| |
| response to treatment; in general a better
| |
| response is ol)taincd during the decline of
| |
| lactation than at the peak and end of lactation. The use of thyroid-active substances
| |
| | |
| | |
| | |
| in animals undergoing their first, second,
| |
| or third lactation is of doubtful benefit because the boost in yield is largely cancelled
| |
| out by a shortening of the lactation period. Short-term administration at suitable
| |
| times can result in considerable galactopoiesis, but this is frequently followed by marked
| |
| falls in yield when the administration of
| |
| thyroid-active material ends. The administration of thyroid-active materials to
| |
| dairy cows, if carried out with due care,
| |
| has no ill effects on the health and reproductive abilities of the cows (see Leech
| |
| and Bailey, 1953) , but because of the rather
| |
| small net gain in yield (about 3 per cent)
| |
| the practical application of the procedure
| |
| seems to be limited.
| |
| | |
| The mode of action of thyroxine and
| |
| thyroid-active substances on milk secretion
| |
| is uncertain. It is tmlikely that it is a
| |
| specific effect on the alveolar cells; rather
| |
| is it probably related to the effects of
| |
| the thyroid hormone on the general metabolic rate.
| |
| | |
| E. PARATHYROm HORMONE
| |
| | |
| The early studies on the influence of the
| |
| parathyroid glands on milk secretion indicated, as might be expected from their
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| ()19
| |
| | |
| | |
| | |
| role in calcium metabolism, that the parathyroids were important in the maintenance
| |
| of secretion (see review by Folley, 1952a).
| |
| Indeed in the rat, we demonstrated that
| |
| the severe impairment of milk secretion previously observed in "thyroidectomized" rats
| |
| was due not to the removal of the thyroids,
| |
| but to the simultaneous ablation of the
| |
| l)arathyroids (Cowie and Folley, 1945).
| |
| This observation has since been confirmed
| |
| and extended by Munson and his colleagues
| |
| (Munson, 1955) who demonstrated an influence on the calcium-concentrating mechanism of the mammary glands. Within 24
| |
| hours of parathyroidectomy the concentration of calcium in the milk of the lactating
| |
| rat was increased markedly despite a
| |
| greatly depressed level of calcium in the
| |
| serum; there was also a decrease in water
| |
| content of the milk, but this did not entirely
| |
| account for the increase in calcium content
| |
| since the calcium content expressed as mg.
| |
| per gm. milk solids was significantly higher
| |
| after parathyroidectomy (Toverud and
| |
| Munson, 1956). Further studies in this field
| |
| are awaited with interest.
| |
| | |
| F. INSULIN
| |
| | |
| Early experiments (see review by Folley,
| |
| 1952a) indicated that the endocrine pancreas might influence mammary function in
| |
| two ways; indirectly by way of the general
| |
| intermediary metabolism by which the supply of milk precursors may be regulated,
| |
| and directly through its role in the carbohydrate metabolism of the mammary gland
| |
| itself.
| |
| | |
| Most recent studies have been concerned
| |
| with the effect of insulin on mammary tissue in vitro. Mammary gland slices from
| |
| lactating rats actively synthesize fat from
| |
| small molecules, glucose, and glucose plus
| |
| acetate, but not from acetate alone (Folley
| |
| and French, 1950). The addition of insulin
| |
| to the incubation medium very markedly
| |
| increases the R.Q. (see Table 10.2) and
| |
| glucose uptake of the tissue slices and experiments with isotopes show that the rate
| |
| of fat synthesis is increased (Balmain, Folley and Glascock, 1952). Mammary gland
| |
| slices from lactating sheep, on the other
| |
| hand, can utilize acetate alone but not glucose alone for fat synthesis (Folley and
| |
| French, 1950) and sheep tissue is not re
| |
| | |
| | |
| TABLE 10.2
| |
| | |
| Effect of different substrates and of insulin on the
| |
| | |
| respiratory quotient (R.Q.) of lactating mammary
| |
| | |
| gland slices from various species
| |
| | |
| (From S. J. Follev and M. L. McNaught, Brit.
| |
| | |
| M. BulL, 14, 207-211, 1958.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Respiratory
| |
| Quotients
| |
| | |
| | |
| Anlrml
| |
| | |
| | |
| Substrate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Without
| |
| insulin
| |
| | |
| | |
| With
| |
| insulin
| |
| | |
| | |
| Mouse
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.90
| |
| | |
| | |
| 2.14
| |
| | |
| | |
| | |
| | |
| Glucose + acetate
| |
| | |
| | |
| 1.46
| |
| | |
| | |
| 2.14
| |
| | |
| | |
| Rat
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.57
| |
| | |
| | |
| 1.80
| |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 0.82
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Glucose + acetate
| |
| | |
| | |
| 1.53
| |
| | |
| | |
| 2.03
| |
| | |
| | |
| Guinea pig
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.17
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.30
| |
| | |
| | |
| _
| |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 0.92
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Glucose -t- acetate
| |
| | |
| | |
| 1.24
| |
| | |
| | |
| 1.67
| |
| | |
| | |
| Sheep
| |
| | |
| | |
| Glucose
| |
| Acetate
| |
| | |
| | |
| 0.88
| |
| 1.09
| |
| | |
| | |
| 1.09
| |
| | |
| | |
| | |
| | |
| Glucose + acetate
| |
| | |
| | |
| 1.52
| |
| | |
| | |
| 1.50
| |
| | |
| | |
| Goat
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 0.86
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 1.17
| |
| | |
| | |
| —
| |
| | |
| | |
| Cow
| |
| | |
| Glucose
| |
| | |
| | |
| 0.84
| |
| | |
| | |
| _
| |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 1.12
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| sponsive to insulin in vitro. This clear-cut
| |
| species difference is interesting and underlines the need for further study. It is of
| |
| passing interest to note that the response
| |
| in vitro of rat mammary tissue to insulin
| |
| has been made the basis of a highly specific
| |
| in vitro bio-assay for insulin (Fig. 10.17)
| |
| (Balmain, Cox, Folley and McNaught,
| |
| 1954; McNaught, 1958)!
| |
| | |
| Further references and discussion on the
| |
| role of insulin in mammary function and
| |
| lipogenesis will be found in the reviews by
| |
| Folley (1956), and Folley and McNaught
| |
| (1958, 1960).
| |
| | |
| IV. Removal of Milk from the
| |
| | |
| Mammary Glands: Physiology
| |
| | |
| of Suckling and Milking
| |
| | |
| A. MILK-EJECTION REFLEX
| |
| | |
| Since the second edition of this book,
| |
| there have been major advances in our
| |
| knowledge of the physiology of milk removal. In the mammary gland the greater
| |
| | |
| | |
| | |
| 620
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 22
| |
| | |
| | |
| rs 2-5//g/ml.
| |
| | |
| | |
| 20
| |
| | |
| | |
| yT
| |
| | |
| | |
| ■~^
| |
| | |
| | |
| yO
| |
| | |
| | |
| i 18
| |
| | |
| | |
| - Cf
| |
| | |
| | |
| >
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| -o
| |
| | |
| | |
| | |
| | |
| ■;;16
| |
| | |
| | |
| - i:/^
| |
| | |
| | |
| c
| |
| | |
| | |
| | |
| | |
| u=
| |
| | |
| | |
| | |
| | |
| «14
| |
| | |
| | |
| / J3 as^g/mi.
| |
| | |
| | |
| 8 12
| |
| | |
| | |
| Z' j^p^ £) 0-Vg/ml.
| |
| | |
| | |
| — 10
| |
| | |
| | |
| y rf^ ,-fP
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 1
| |
| 3 8
| |
| | |
| | |
| si r^^ r-f^ y^ Control
| |
| | |
| | |
| o °
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| M J
| |
| | |
| | |
| A y^ ^cr ,^y^
| |
| | |
| | |
| 4J
| |
| | |
| | |
| | |
| | |
| z
| |
| | |
| | |
| Pr( .iif^ jy''^^
| |
| | |
| | |
| 4
| |
| | |
| | |
| ^ M^ ^r^
| |
| | |
| | |
| 2
| |
| | |
| | |
| L_l 1 1 1 1 \ 1 \ 1 1 \ 1
| |
| | |
| | |
| | |
| 15 30
| |
| | |
| | |
| | |
| 60 90 120
| |
| | |
| Time (min)
| |
| | |
| | |
| | |
| 150
| |
| | |
| | |
| | |
| Fig. 10.17. Effect of various concentrations of
| |
| insulin on the respiratory metabolism of slices
| |
| of rat mammarj' glands. (From J. H. Balmain, C. P.
| |
| Cox, S J. Folley and M. L. McNaught, J. Endocrinol., 11, 269-276, 1954.)
| |
| | |
| portion of the milk secreted by the alveohir
| |
| cells in the intervals between suckling or
| |
| milking remains within the alveoli and the
| |
| fine ducts. Only a small portion passes into
| |
| the larger ducts and cisterns or sinuses from
| |
| which it can be immediately removed by
| |
| suckling, milking, or cannulation; its removal requires no maternal participation
| |
| and has been termed passive withdrawal
| |
| (see Cowie, Folley, Cross, Harris, Jacobsohn and Richardson, 1951, and page 612).
| |
| The larger portion of the milk in the alveoli
| |
| and fine ducts becomes available only with
| |
| the active participation of the mother and
| |
| requires the reflex contraction of special cells
| |
| (see page 623) surrounding the alveoli in response to the milking or suckling stimulus
| |
| to eject the milk from the alveoli and fine
| |
| ducts into the cistern and sinuses of the
| |
| gland. The occurrence of this reflex has long
| |
| been known, although its true nature has
| |
| only recently been generally recognized.^
| |
| | |
| -H. K. Waller {Clinical Slujlits un Lnrfallon,
| |
| London: Heinemann, 1938), and later one of us
| |
| (S. J. Folley, Physiology and Biochemistry of Lactation, London and Edinburgh: Oliver & Boyd,
| |
| 1956) have drawn attention to the fact that the
| |
| theme of the "milk-ejection reflex" was the inspiration of a paiming by II Tintoretto entitled "The
| |
| Origin of the Milky Way" which hangs in the
| |
| | |
| | |
| | |
| 111 the past it has been termed the "draught"
| |
| in lactating women (see Isbister, 1954) and
| |
| the "let-down" of milk in the cow. The
| |
| latter term is particularly misleading since
| |
| it implies the release of some restraint,
| |
| whereas there is, in fact, an active and
| |
| forceful expulsion of milk from the alveoli
| |
| and we have, therefore, urged that this term
| |
| be no longer used in scientific literature and
| |
| that it be replaced by the term "milk ejection" (Folley, 1947; Cowie, Folley, Cross,
| |
| Harris, Jacobsohn and Richardson, 1951),
| |
| a term, incidentally, which was used by
| |
| Gaines in 1915 in his classical researches
| |
| on the phenomenon (see below j.
| |
| | |
| The true nature of the milk removal process was for many years not recognized,
| |
| probably because it was assumed that the
| |
| mammary gland could not contain all the
| |
| milk obtainable at a milking, and this assumption made it necessary to postulate a
| |
| very active secretion of milk during suckling
| |
| or milking. Even as late as 1926 two phases
| |
| of milk secretion were described in the cow ;
| |
| the first phase was one of slow secretion
| |
| occurring between milkings, the second
| |
| phase was one of very active secretion occurring in response to the milking stimulus
| |
| when a volume of milk about equal to that
| |
| produced in the first phase was secreted in
| |
| a matter of a few minutes (Zietzschmann,
| |
| 1926). That some physiologic mechanism
| |
| | |
| National Gallery, London. Both authors point out
| |
| tliat the picture shows evidence of a considerable
| |
| intuiti^■e understanding of the physiologic nature
| |
| of the milk-ejection reflex. Thus, it illustrates, first,
| |
| that the application of the suckling stimulus causes
| |
| a considerable increase in intranianiinai >• jiressure
| |
| resulting, in this instance, in a sjnni cii' milk from
| |
| the nipples, and second, that ihv Muklmg stimulus
| |
| applied to one nipple gives rise to a systemic rather
| |
| than a localized effect, for the milk is forcibly
| |
| ejected from the suckled and unsuckled breasts
| |
| ahke. The same theme was also treatetl by Rubens
| |
| in a picture called "The Birth of the Milky Way"
| |
| which can be seen in the Prado Museum, Madrid.
| |
| This picture differs from Tintoretto's in one important detail, the stream of milk coming only from
| |
| one breast.
| |
| | |
| The forcible ejection of milk from the nipple has
| |
| doubtless been the subject of many statues. An example known to the authors is the fountain in the
| |
| Sfiuare at Palos Verdes, near Los Angeles, California. The center piece of this fountain has a nude
| |
| female torso at each of its four corners from whose
| |
| nipples spurt streams of water.
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 621
| |
| | |
| | |
| | |
| was involved in the discharge of preformed
| |
| milk from the mammary gland had, however, been recognized. Schafer (1898) considered that milk discharge was aided by
| |
| contraction of plain muscle w^ithin the
| |
| gland and pressure on the alveoli produced
| |
| by vasodilation.
| |
| | |
| The first full investigation of the physiology of milk removal was that by Gaines
| |
| in 1915. Unfortunately, his remarkably accurate observations and perspicacious
| |
| conclusions aroused little general interest
| |
| and were almost wholly overlooked for
| |
| more than quarter of a century. It is now
| |
| of interest to recall the more important of
| |
| Gaines' observations. First, he made a clear
| |
| distinction between milk ejection and milk
| |
| secretion — "Milk secretion, in the sense
| |
| of the formation of the milk constituents,
| |
| is one thing; the ejection of the milk from
| |
| the gland after it is formed is quite another
| |
| thing. The one is probably continuous; the
| |
| other, certainly discontinuous." Secondly,
| |
| he concluded that "Nursing, milking and the
| |
| insertion of a cannula in the teat, excite a
| |
| reflex contraction of the gland musculature
| |
| and expression of milk. There is a latent
| |
| period of 35 to 65 seconds. . . . Removal of
| |
| milk from the gland is dependent on this
| |
| reflex, and it may be completely inhibited
| |
| l)y anaesthesia. The conduction in the reflex
| |
| arc is dependent upon the psychic condition
| |
| of the mother." He also observed that the
| |
| increased flow of milk following the latent
| |
| period after stimulation was associated wath
| |
| a steep rise in pressure within the gland
| |
| cistern and that the reflex could be conditioned. Thirdly, with reference to the gland
| |
| capacity, he reported that "the indication
| |
| is that practically the entire quantity of
| |
| milk obtained at any one time is present
| |
| as such in the udder at the beginning of
| |
| milking." Lastl3^ he confirmed earlier observations that injections of posterior pituitary extract caused a flow of milk in the
| |
| lactating animal and he postulated that
| |
| "pituitrin has a muscular action on the active mammary gland causing a constriction
| |
| of the milk ducts and alveoli with a consequent expression of milk. This action
| |
| holds, also, on the excised gland in the
| |
| absence of any true secretory action." Gaines
| |
| regarded the milk-ejection reflex as a
| |
| | |
| | |
| | |
| l)urely neural arc although he emphasized
| |
| that the effect was "very similar to that
| |
| produced by pituitrin." All that is required
| |
| to bring these views of milk ejection in line
| |
| with present day concepts is to recognize
| |
| that the reflex arc is neurohormonal in character, the efferent component of which is
| |
| a hormone released from the neurohypophysis. When Gaines was carrying out these
| |
| experiments hardly anything was known of
| |
| neuro-endocrine relationships and there was
| |
| no background of knowledge to lead anyone
| |
| to conceive that the effects of the posterior
| |
| pituitary extract might represent a physiologic rather than a pharmacologic effect.
| |
| In 1930 Turner and Slaughter hinted at
| |
| a possible physiologic role of the posterior
| |
| pituitary in milk ejection and, as we have
| |
| noted (page 610), Gomez (1939) used posterior pituitary extract in replacement therapy given to hypophysectomized lactating
| |
| rats. It was not until 1941, however, that
| |
| the role of the posterior pituitary in milk
| |
| ejection was seriously postulated by Ely
| |
| and Petersen (1941) who, having shown in
| |
| the cow that milk ejection occurred in the
| |
| mammary gland to which all efferent nerve
| |
| fibers had been cut, suggested that the reflex
| |
| was neurohormonal, the hormonal component being derived from the posterior pituitary, and being, in all likelihood, oxytocin.
| |
| The neurohormonal theory of Ely and Petersen and the subsequent work of Petersen and
| |
| his colleagues (see reviews by Petersen,
| |
| 1948; and Harris, 1958), unlike the earlier
| |
| work of Gaines, aroused wide interest and its
| |
| practical applications permitted rationalization of milking techniques in the cowshed
| |
| thereby improving milk yields. Despite the
| |
| attractiveness of the concept, however, a
| |
| further 10 years were to elapse before unequivocal evidence of the correctness of the
| |
| theory was forthcoming and this evidence
| |
| we shall now briefly review.
| |
| | |
| B. ROLE OF THE NEUROHYPOPHYSIS
| |
| | |
| The first reliable indication that the
| |
| suckling or milking stimulus does in fact
| |
| cause an outpouring of neurohypophyseal
| |
| hormones were the observations that inhibition of diuresis occurred following the
| |
| application of the milking or suckling
| |
| stimulus (Cross, 1950; Peeters and Cous
| |
| | |
| | |
| 622
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| sens, 1950; Kalliala and Karvoncn, 1951;
| |
| Kalliala, Karvonen and Leppanen, 1952).
| |
| It was also shown that electrical stimulation
| |
| of the nerve paths to the posterior pituitary
| |
| resulted in milk ejection (Cross and Harris,
| |
| 1950, 1952; Andersson, 1951a, b, c; Popovich, 1958 », and that when lesions were
| |
| placed in these tracts the milk-ejection reflex was abolished (Cross and Harris, 1952) .
| |
| | |
| Further evidence was adduced when it
| |
| was found that removal of the posterior
| |
| pituitary immediately abolished the milkejection reflex in the lactating rat, and that
| |
| it was necessary to inject such animals several times a day with oxytocin if their litters
| |
| were to be reared (Cowie, quoted by Folley,
| |
| 1952b). Earlier workers had claimed that
| |
| the posterior lolie was not essential for lactation (Smith, 1932; Houssay, 1935), but an
| |
| explanation of these discordant conclusions
| |
| was provided when it was shown that the
| |
| impairment of the reflex after removal of
| |
| the posterior lobe is not permanent and that
| |
| the reflex re-establishes itself after some
| |
| weeks, presumably because the remaining
| |
| portions of the neurohypophysis take over
| |
| the functions of the posterior lobe (Benson
| |
| and Cowie, 1956). That the neurohypophysis participates in milk ejection would now
| |
| appear to be beyond question.
| |
| | |
| The discovery of the role of the neurohypophyseal hormones in milk ejection has
| |
| provided an explanation of some longstanding clinical observations on what has been
| |
| termed the natural "sympathy" between
| |
| the uterus and the breasts. Thus the beneficial effects of the suckling stimulus and the
| |
| occurrence of the "draught" {i.e., milk ejection) in causing uterine contraction after
| |
| parturition were emphasized over a century
| |
| ago by both Smith (1844) and Patcrson
| |
| (1844). 0})servations have also been made
| |
| on the I'cciprocal process of stimuli arising
| |
| from the reproductive organs apparently
| |
| causing milk ejection. In domestic animals
| |
| two such examples were mentioned by Martiny (1871). According to Herodotus, the
| |
| Scythians milk their mares thus: "They
| |
| take l)lowpipes of bone, very like flutes, and
| |
| put them into the genitals of the mares and
| |
| blow with their mouths, others milk. And
| |
| they say that the I'cason why thoy do so is
| |
| this, that when the marc's \-cins ai'c filled
| |
| | |
| | |
| | |
| with air, the udder cometh down" (translation by Powell, 1949). Kolbe (1727) described a similar procedure of blowing air
| |
| into the vagina used by the Hottentots when
| |
| milking cows which were normally suckled
| |
| by calves and in which, presumably, milk
| |
| ejection did not occur in response to hand
| |
| nnlking. A drawing depicting this procedure
| |
| from Kolbe's book was recently published in
| |
| the Ciba Zeitschrift (No. 84^ 1957) along
| |
| with a photograph of African natives still
| |
| using the method!-^
| |
| | |
| In 1839, Busch described the occurrence
| |
| of milk ejection, the milk actually spurting
| |
| from the nipple, in a lactating woman during coitus. A satisfactory explanation of
| |
| these curious observations is now forthcoming. Harris (1947) suggested that coitus
| |
| might cause the liberation of oxytocin from
| |
| the neurohypophysis and, within the next
| |
| few years it was demonstrated that stimulation of the reproductive organs evoked milk
| |
| ejection in the cow (Hays and VanDemark.
| |
| 1953) and reports confirmatory of Busch's
| |
| long forgotten observations also appeared
| |
| (Harris and Pickles, 1953; Campliell and
| |
| Petersen, 1953).^
| |
| | |
| C. MILK-EJECTIOX HORMONE
| |
| | |
| There is much circumstantial evidence
| |
| to confirm the belief that the milk-ejection
| |
| hormone is oxytocin (see Cowie and Policy.
| |
| 1957). Attemi)ts, however, to demonstrate
| |
| oxytocin in the blood after application of
| |
| the milking stimulus have given rather inconclusive results. Early claims that the
| |
| hormone could be demonstrated in blood are
| |
| | |
| ^ A similar drawing, also apparently from Kolbe '.•<
| |
| book, has been used in the campaign for clean milk
| |
| production! Heineman (1919) discussing sanitary
| |
| l^recautions in the cowshed says of the picture
| |
| "another picture shows a nude Hottentot milking
| |
| a cow while another one is liolding the tail of the
| |
| cow to prevent its dropping into the open pail.
| |
| This ])icture might well serve as a model to some
| |
| modern producers who do not take such precautions
| |
| and calmly lift the tail out of the milk with their
| |
| hands wlicn it hnjipens to switch into the pail."
| |
| | |
| ' W(- h;i\(' hi'cii able to find only one painting
| |
| illustrating this plienomenon. It is a picture by a
| |
| contemporary French painter, Andre Masson, entitled "Le Viol" and painted in 1939. It illustrates
| |
| in Masson 's personal idiom the act of rape and it is
| |
| interesting to note that a stream of milk is depicted
| |
| as being I'orcibly (\iected from one breast of the
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 623
| |
| | |
| | |
| | |
| of doiil)tful validity, because the milk-ejection effect observed may have been due to
| |
| 5-hydroxytryptamine (see Linzell, 1955),
| |
| and more recent attempts to assay the level
| |
| of oxytocin in the blood have not been
| |
| entirely satisfactory or conclusive. There
| |
| seem to be other polypeptide substances in
| |
| blood which possess oxytocic activity, although the thiogly collate inactivation test
| |
| indicates that these are different from oxytocin (Robertson and Hawker, 1957), and
| |
| no marked changes in the blood oxytocic
| |
| activity associated with suckling or milking
| |
| have been detected (Hawker and Roberts,
| |
| 1957; Hawker, 1958). However, it would
| |
| seem doubtful whether the present assay
| |
| techniques are sufficiently sensitive and specific to detect changes in blood oxytocin of
| |
| the magnitude likely to be associated with
| |
| milking or suckling. In the lactating cow
| |
| the intravenous injection of 0.05 to 2.0 I.U.
| |
| oxytocin will cause milk ejection (Bilek and
| |
| .Tanovsk>% 1956; Donker, 1958), in the goat
| |
| 0.01 to 1 I.U. (Cowie, cited by Folley,
| |
| 1952b; Denamur and Martinet, 1953), in
| |
| the sow 0.2 to 1.0 I.U. (Braude, 1954; Whittlestone, 1954; Cross, Goodwin and Silver,
| |
| 1958) in the rabbit 0.05 I.U. (Cross, 1955b) ,
| |
| and in the lactating woman 0.01 I.U. (Beller, Krumholz and Zeininger, 1958) . If these
| |
| (loses give any indication of the quantity
| |
| of endogenous oxytocin released, then the
| |
| concentration in the peripheral blood is
| |
| likely to be very small ; indeed Cross, Goodwin and Silver (1958) calculated that a
| |
| threshold dose (10 mU.) of oxytocin in
| |
| the sow w^ould give a plasma concentration
| |
| of about 1 (U,U. per ml, and until it can be
| |
| shown that the assay techniques are sufficiently sensitive to detect the changes
| |
| in oxytocin concentration produced by intravenous injections of "physiologic" doses
| |
| of oxytocin, no great reliance can be placed
| |
| on the results of assays.
| |
| | |
| Attempts have been made to demonstrate
| |
| alterations in the hormone content of the
| |
| neural lobe following the suckling or milking stimulus. In the goat and cow no detectable changes have been reported, but in
| |
| the smaller species (dog, cat, rat, guinea
| |
| pig) decreases have been described (see
| |
| Cowie and Folley, 1957). It is likely that in
| |
| many species the amount released is small
| |
| | |
| | |
| | |
| relative to the total hormone content of the
| |
| gland and within the limits of error of the
| |
| | |
| assay.
| |
| | |
| D. EFFECTOR CONTRACTILE MECHANISM OF
| |
| THE MAMMARY GLAND
| |
| | |
| In the last 10 years considerable research
| |
| has been devoted to a study of the effector
| |
| contractile tissue in the mammary gland;
| |
| this work has recently been reviewed in
| |
| some detail (see Folley, 1956) and only the
| |
| salient features need be mentioned here.
| |
| | |
| Although earlier histologists had from
| |
| time to time figured myoepithelial or "basket" cells in close association with the mammary alveoli, the morphology and distribution of the cells remained vague until
| |
| Richardson (1949) published a detailed and
| |
| illuminating description (Fig. 10.18). His
| |
| beautiful observations have since been confirmed and supplemented by Linzell (1952)
| |
| and Silver (1954). Richardson also disposed
| |
| of the oft repeated view that smooth-muscle fibers around the alveoli played an iml)ortant role in milk ejection. From a study
| |
| of the general orientation of the myoepithelial cells and the precise relationship between
| |
| these cells and the folds in the secretory epithelium from contracted glands, Richardson
| |
| considered it reasonable to regard the myoepithelium as the contractile tissue in the
| |
| mammary gland which responds to oxytocin
| |
| causing contraction of the alveoli and widening of the ducts. The evidence adduced by
| |
| Richardson, although good, was nevertheless circumstantial, and it was desirable that
| |
| attempts be made to visualize the contraction of the myoepithelial cells in response to
| |
| oxj^tocin. In this connection it is of interest
| |
| to recall that Gaines (1915) reported that
| |
| when a drop of pituitrin was placed on the
| |
| cut surface of the mammary gland from a
| |
| lactating guinea pig, minute white dots appeared within a few seconds beneath the
| |
| pituitrin and slowly swelled to tiny milky
| |
| rivulets streaming beautifully through the
| |
| clear liquid. Much later the local effects of
| |
| posterior pituitary extract on the mammary
| |
| gland were studied by Zaks (1951) in the
| |
| living mouse, when it was reported that it
| |
| caused contraction of the alveoli and expansion of the ducts. These observations
| |
| were considerablv extended bv Linzell
| |
| | |
| | |
| | |
| 624
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 10.18. Surface view of contracted alveoli (of goat) showing myoepithelial cells.
| |
| (Courtesy of K. C. Richardson.)
| |
| | |
| | |
| | |
| | |
| Fig. 10.19. Recording of pressure changes witliin
| |
| a galactophore of a forcibly restrained lactating
| |
| rabbit. The litter was allowed to suckle the noncannulated mammary glands but obtained only
| |
| 8 gm. milk, there being only a slight rise in the
| |
| milk pressure probably associated with a slight
| |
| contraction of the myoepithelium in response to
| |
| mechanical stimulation. When 5 mU. oxytocin were
| |
| injected (5P) there was a rapid milk ejection
| |
| response which could be inhibited by injecting 1
| |
| yug. adrenaline (lA) just before the oxytocin. After
| |
| a few minutes 5 mU. oxytocin were again effective
| |
| and the litter obtained 44 gm. milk when they were
| |
| allowed to suckle. A more complete milk ejection
| |
| respon.so was obtained with 50 mU. oxytocin (50P)
| |
| and the young obtained a further 59 gm. milk.
| |
| Anesthesia did not enhance the milk-ejection response to 50 mU. oxytocin. During emotional inhibition of milk ejection the mammary gland thus
| |
| remains responsive to oxytocin. (From B. A. Cross,
| |
| J. Endocrinol., 12, 29-37, 1955.)
| |
| | |
| | |
| | |
| (19ooi who studied the local effects of
| |
| liighly purified oxytocin and vasopressin
| |
| and a number of other drugs on the mammnry gland, and confirmed that oxytocin
| |
| and vasopressin produced alveolar contraction and widening of the ducts. Although in
| |
| these experiments the myoepithelial cells
| |
| themselves could not be visualized, nevertheless the effects observed leave little
| |
| doubt that the effector mechanism was the
| |
| niyoei)ithelium.
| |
| | |
| The myoepithelium is responsive to stimuli other than those arising from the presence of neurohypophyseal hormones in the
| |
| blood inasmuch as partial milk ejection
| |
| may occur in response to local mechanical
| |
| stimulation of the mammary gland (Cross,
| |
| 1954; Yokoyama, 1956; see also Fig. 10.191.
| |
| These observations may explain the recent
| |
| reports by Tverskoi (1958) and Denamuiand Martinet (1959a, b) that milk yields
| |
| can be maintained in goats in the absence of
| |
| the milk-ejection reflex.
| |
| | |
| E. INHIBITION OF MILK EJECTION
| |
| | |
| (laines (1915) stressed that the conduction in the milk-ejection reflex pathway was
| |
| dei)endent on the psychic condition of the
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 625
| |
| | |
| | |
| | |
| mother. Many years later Ely and Petersen
| |
| (1941) confirmed this and, having shown
| |
| that injections of adrenaline blocked the
| |
| milk-ejection reflex, postulated that the increased blood level of adrenaline in emotionally disturbed cows interfered with the
| |
| action of oxytocin. In the last few years, the
| |
| nature of the inhibitory mechanisms has
| |
| been more fully investigated. Braude and
| |
| Mitchell (1952) showed in the sow that
| |
| adrenaline exerts at least part of its inhibitory effect at the level of the mammary
| |
| gland and that, whereas the injection of
| |
| adrenaline before the injection of oxytocin
| |
| blocked milk ejection, less inhibition occurred if both were given together. Cross
| |
| (1953, 1955a) confirmed these observations
| |
| in the rabbit and demonstrated that electrical stimulation of the posterior hypothalamus (sympathetic centers) inhibited the
| |
| milk-ejection response to injected oxytocin,
| |
| an effect which was abolished after adrenalectomy. Cross concluded from his experiments that any central stimulation causing
| |
| sympathetico-adrenal activity inhibits the
| |
| milk-ejection response and that the effect
| |
| appears to depend on a constriction of the
| |
| mammary blood vessels resulting from the
| |
| release of adrenaline and excitation of the
| |
| sympathetic fibers to the mammary glands.
| |
| Whereas such a mechanism could account
| |
| for the emotional disturbance of the reflex.
| |
| Cross was careful to point out that there
| |
| was no direct proof that this was so and he
| |
| later demonstrated (Cross, 1955b) that in
| |
| rabbits in which emotional inhibition of
| |
| milk ejection was present, milk ejection
| |
| could be effected by the injection of oxytocin (Fig. 10.19). In such cases there was
| |
| clearly no peripheral inhibitory effect of
| |
| milk ejection. Cross concluded that the main
| |
| factor in emotional disturbance of the milkejection reflex is a partial or complete inhibition of oxytocin release from the posterior pituitary gland. At present nothing is
| |
| known of the nature of this central inhibitory mechanism.^
| |
| | |
| ^ A curious form of the suckling stimulus is illustrated in carvings which siumount the main door
| |
| of the church of Sainte Croix in Bordeaux. The
| |
| carvings illustrate penances prescribed for wrong
| |
| doers who have committed one of the seven deadly
| |
| sins. The penance for indulgence in the sin of luxiu y
| |
| is the application to the breasts of serpents or toads.
| |
| | |
| | |
| | |
| Inhibition of the milk ejection reflex may
| |
| also occur when the mammary gland becomes engorged with secretion to such an
| |
| extent that the capillary circulation is so reduced that oxytocin can no longer reach the
| |
| myoepithelium (Cross and Silver, 1956;
| |
| Cross, Goodwin and Silver, 1958).
| |
| | |
| F. NEURAL PATHWAYS OF THE
| |
| MILK-EJECTION REFLEX
| |
| | |
| Interpretation of some of the earlier
| |
| studies on neural pathways is difficult because investigators did not realize that, although the milk ejection reflex normally
| |
| occurs in response to the suckling stimulus,
| |
| it can become conditioned and can then occur in response to visual or auditory stimuli
| |
| associated with the act of nursing. In such
| |
| cases an apparent lack of effect on milk
| |
| ejection of section of nerves or nerve tracts
| |
| would not necessarily imply that the nerves
| |
| normally carrying the stimuli arising from
| |
| the suckling had not been cut. Studies on
| |
| the effects of hemisection of the spinal cord
| |
| in a few goats led Tsakhaev (1953) to the
| |
| conclusion that the apparent pathway used
| |
| by the milk-ejection stimulus was uncrossed. More recently pathways within the
| |
| spinal cord have been investigated by Eayrs
| |
| and Baddeley (1956) who found inter alia
| |
| that lactation in the rat was inhibited by
| |
| lesions to the lateral funiculi, and by section
| |
| of the dorsal roots of nerves supplying the
| |
| segments in which the suckled nipples were
| |
| situated. With few exceptions hemisection
| |
| of the spinal cord abolished lactation when
| |
| the only nipples available for suckling
| |
| were on the same side as the lesion, but not
| |
| when the contralateral nipples were available. It was concluded that the pathway
| |
| used by the suckling stimulus enters the
| |
| central nervous system by the dorsal routes
| |
| and ascends the cord deep in the lateral
| |
| funiculus of the same side. Inasmuch as in
| |
| these experiments lactation was assessed
| |
| from the growth curve of the pups, it is not
| |
| always clear whether the failure of lactation
| |
| was due to a cessation of milk secretion or to
| |
| loss of the milk-ejection reflex. It was noted,
| |
| however, that injections of oxytocin in some
| |
| | |
| It may be questioned whether this unusual form of
| |
| the suckling stimulus would not inhibit rather than
| |
| evoke the milk-ejection reflex.
| |
| | |
| | |
| | |
| 626
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| cases restored lactation for up to 2 days
| |
| after it had ceased as a result of lesions of
| |
| the cord which would suggest a primary
| |
| interference with milk ejection. In the goat,
| |
| Andersson (1951b) considered that stimuli may reach the hypothalamus by way of
| |
| the medial lemniscus in the medulla, but
| |
| little definite information is available concerning the pathways used by the stimuli
| |
| to reach the hypothalamus and there is here
| |
| scope for further investigations. (For further discussion see review by Cross, 1960.)
| |
| From the hyopthalamus there is little doubt
| |
| that the route to the posterior lobe is by
| |
| way of the hypothalamo-hypophyseal tract
| |
| which receives nerve fibers from the cells in
| |
| the hypothalamic nuclei, and in the main
| |
| from the paraventricular and supra-optic
| |
| nuclei. It was generally assumed that the
| |
| posterior lobe hormones were secreted in
| |
| the posterior lobe from the pituicytes in response to stimuli passing down the hypothalamo-hypophyseal tract. In the last decade, however, much evidence has come to
| |
| light which suggests that the so-called posterior lobe hormones are in fact elaborated
| |
| in the cells of the hypothalamic nuclei and
| |
| are then transported down the axones as a
| |
| neurosecretion and stored in the posterior
| |
| lobe (see Scharrer and Scharrer, 1954).
| |
| | |
| Before leaving the neural pathways of the
| |
| milk-ejection reflex, brief reference must be
| |
| made to the recent discovery by Soviet physiologists that there is also a purely nervous
| |
| reflex (segmental in nature) involved in the
| |
| ejection of milk. It is said that within a few
| |
| seconds of the application of the milking
| |
| stimulus, reflex contraction of the smooth
| |
| muscle in the mammary ducts occurs, causing a flow of milk from the ducts into the
| |
| cistern. This reflex contraction of the smooth
| |
| muscle is also believed to occur in response
| |
| to stimuli arising within the gland between
| |
| milkings thus aiding the redistribution of
| |
| milk in the udder. This purely nervous reflex
| |
| is stated to occur some 30 to 60 seconds before the reflex ejection of milk from the alveoli by oxytocin (for further details sec
| |
| review by Baryshnikov, 1957). The conditioned reflexes associated with suckling and
| |
| milking have been the subject of numerous
| |
| investigations l)y Grachev (see Grachev,
| |
| | |
| | |
| | |
| 1953, 1958) ; these and other Russian researches into the motor apparatus of the udder have been fully reviewed by Zaks
| |
| (1958).
| |
| | |
| G. MECHANISM OF SUCKLING
| |
| | |
| In the past, various theories have been
| |
| put forward as to how the suckling obtains
| |
| milk from its mother's mammary gland. In
| |
| the human infant some considered that the
| |
| lips formed an airtight seal around the nipple and areola thus allowing the child to
| |
| suck, whereas others believed that compression of the lacteal sinuses between the gums
| |
| aided the expulsion of the milk (see Ardran,
| |
| Kemp and Lind, 1958a, b for review) . In the
| |
| calf the act of suckling was studied by
| |
| Krzywanek and Briiggemann (1930) who
| |
| described how the base of the teat was
| |
| pinched off between upper and lower jaws
| |
| and the teat compressed from its base towards its tip by a stripping action of the
| |
| tongue. Smith and Petersen (1945) on the
| |
| other hand, concluded that the calf wrapped
| |
| its tongue round the teat and obtained milk
| |
| by suction.
| |
| | |
| Much misunderstanding about the nature
| |
| of the act of suckling has arisen because the
| |
| occurrence of milk ejection was overlooked
| |
| or its significance was not appreciated. As a
| |
| result, the idea became prevalent that success or failure in obtaining milk could be
| |
| reckoned solely in terms of the power behind
| |
| the baby's suction. This erroneous concept
| |
| was vigorously attacked by Waller (1938),
| |
| who pointed out that once the "draught"
| |
| had occurred the milk at times flowed so
| |
| freely from the breast that the baby had to
| |
| break off and turn its head to avoid choking.
| |
| A similar observation had been made by Sir
| |
| Astley Cooper in 1840 who in describing the
| |
| "draught" in nursing women wrote, "If the
| |
| nipple be not immediately caught by the
| |
| child, the milk escapes from it, and the child
| |
| when it receives the nipple is almost choked
| |
| l)y the rapid and abundant flow of the fluid;
| |
| if it lets go its hold, the milk spurts into the
| |
| infant's eyes." An even earlier comment was
| |
| made by Soranus, a writer on paediatrics in
| |
| the cai'ly half of the second century A.D.,
| |
| that it was unwise to allow the infant to fall
| |
| asleep at the breast since the milk some
| |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 627
| |
| | |
| | |
| | |
| times flowed without suckling and the infant
| |
| choked. It must thus be emphasized that
| |
| once milk ejection has occurred the milk in
| |
| the gland cisterns or sinuses is under considerable pressure and the suckling has
| |
| merely to overcome the resistance of the
| |
| sphincters in the nipple or teat to obtain the
| |
| milk.
| |
| | |
| Recently the use of cineradiograjihy has
| |
| allowed a more accurate analysis of the
| |
| mechanism of suckling. Studies by Ardran,
| |
| Kemp and Lind (1958b) have shown that
| |
| the human infant sucks the nipple to the
| |
| back of the mouth and forms a "teat" from
| |
| the mother's breast; when the jaw is raised
| |
| this teat is compressed between the upper
| |
| gum and the tip of the tongue resting on
| |
| the lower gum, the tongue is then applied
| |
| to the lower surface of the "teat" from before backwards pressing it against the hard
| |
| palate. Suction may assist the flow of milk
| |
| so expressed from the nipple, but is only of
| |
| secondary importance. Studies by Ardran,
| |
| Cowie and Kemp (1957, 1958) in the goat
| |
| have extended these observations, because
| |
| it was possible in this species to follow the
| |
| withdrawal, from the udder, of milk made
| |
| radiopaque with barium sulfate. As with
| |
| the infant, the neck of the teat was obliterated between the tongue and the palate of
| |
| the kid and the contents of the teat sinus
| |
| were displaced into the mouth cavity by a
| |
| suitable movement of the tongue; while
| |
| the first mouthful w^as being displaced into
| |
| the pharynx, the jaw and tongue were lowered to allow the refilling of the teat sinus.
| |
| The normal method of obtaining milk is,
| |
| therefore, for the suckling to occlude the
| |
| neck of the teat and then to expel the contents of the teat sinus by exerting positive
| |
| pressure on the teat (120 mm. Hg in the
| |
| goat), so forcing the contents through the
| |
| teat canal or nipple orifices into the mouth
| |
| cavity, a process which may be aided by
| |
| negative pressure created at the tip of the
| |
| teat. Human infants, goat kids, and calves
| |
| can obtain milk through rubber teats by
| |
| suction alone provided the orifice is large
| |
| enough (see Krzywanek and Briiggemann,
| |
| 1930; Martyugin, 1944; Ardran, Kemp and
| |
| Lind, 1958a) , but this procedure occurs only
| |
| w^hen the structure of the rubber teat is such
| |
| that the suckling is unable to ol)literate the
| |
| | |
| | |
| | |
| neck of the teat and cannot, therefore, strip
| |
| the contents of the teat by positive pressure.
| |
| | |
| V. Relation between the Reflexes Concerned in the Maintenance of Milk
| |
| Secretion and Milk Ejection
| |
| | |
| We have seen that the suckling or milking stimulus is responsible for initiating the
| |
| reflex concerned wath the maintenance of
| |
| milk secretion and also the milk-ejection reflex; the question now arises as to what extent their arcs share common paths. It
| |
| would seem logical to assume that a common
| |
| path to the hypothalamus exists and parts
| |
| of this, as we have seen, have been partially
| |
| elucidated. Although the hypothalamo-hypophyseal nerve tracts provide an obvious
| |
| link between hypothalamus and the posterior lobe, the connections between the hypothalamus and anterior pituitary are still
| |
| a matter of some controversy. The possible
| |
| avenues of communication to the anterior
| |
| lobe are neural and vascular and these may
| |
| be subdivided into central and peripheral
| |
| neural connections and into portal and systemic vascular connections. The various experimental findings relating to these routes
| |
| have recently been critically discussed by
| |
| Sayers, Redgate and Royce (1958), and by
| |
| Greep and Everett in their chapters in this
| |
| book, and it is clear that at present no definite conclusions can be reached concerning
| |
| their relative importance. So far as the specific question of maintenance of milk secretion is concerned, the experiments of Harris
| |
| and Jacobsohn (1952), which showed that
| |
| pituitary grafts maintained lactation when
| |
| implanted adjacent to the median eminence
| |
| in hypophysectomized rats, were consistent
| |
| with the existence of a hormonal transmitter, passing by w^ay of the hypophyseal portal system. On the other hand, transplantation studies by Desclin (1950, 1956) and
| |
| Everett ( 1954, 1956) have revealed that in
| |
| the rat the anterior lobe can spontaneously
| |
| secrete prolactin in situations remote from
| |
| the median eminence, and Donovan and van
| |
| der Werff ten Bosch (1957) have reported
| |
| that milk secretion continued in rabbits in
| |
| wiiich the pituitary portal vessels had been
| |
| completely destroyed, although there was,
| |
| however, an inferred change in milk composition. Evidence has recentlv been obtained
| |
| | |
| | |
| | |
| 628
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| which has confirmed that pituitary tissue
| |
| grafted under the kidney capsule in rats apparently secretes prolactin and will give
| |
| slight maintenance of milk secretion in hypophysectomized animals, this maintenance
| |
| being considerably enhanced if ACTH or
| |
| STH is also administered (Cowie, Tindal
| |
| and Benson, 1960). It would thus seem
| |
| that the cells of the anterior lobe have
| |
| the ability when isolated from the hypophyseal portal system to secrete prolactin,
| |
| but the experiments cited above allow no
| |
| conclusions to be drawn regarding the route
| |
| by which the galactopoietic function of the
| |
| pituitary is normally controlled.
| |
| | |
| Recent reports that bilateral cervical
| |
| sympathectomy in the lactating goat causes
| |
| a fall in the milk yield suggest that the galactopoietic functions of the anterior lobe
| |
| may be influenced by the sympathetic nervous system (Tsakhaev, 1959; Tverskoy,
| |
| 1960) . Declines in milk yield also occur after
| |
| section of the pituitary stalk in the goat, but
| |
| it is not clear in such cases whether the effects are due to the interruption of nervous
| |
| or vascular pathways within the stalk
| |
| (Tsakhaev, 1959; Tverskoy, 1960). In these
| |
| studies on stalk section the cut ends of the
| |
| pituitary stalk were not separated by a plastic plate, so some restoration of the hyl^ophyseal portal system may have occurred.
| |
| Further experiments on the effects of section of the pituitary stalk on lactation in
| |
| which restoration of the hypophyseal portal
| |
| is prevented by the insertion of a plate are
| |
| being conducted in our laboratory and also
| |
| in the Soviet Union. Another possible mode
| |
| of communication between hypothalamus
| |
| and anterior pituitary has been investigated
| |
| by Benson and Folley (1956, 1957a, b) who
| |
| have suggested that the oxytocin released
| |
| from the neurohypophysis in response to the
| |
| suckling stimulus may directly act on the
| |
| cells of the anterior lobe and stimulate the
| |
| release of the galactopoietic complex. The
| |
| careful anatomic researches of Landsmeer
| |
| (1951), Daniel and Prichard (1956, 1957,
| |
| 1958) and Jewell (1956) have demonstrated
| |
| in several species the existence of direct
| |
| vascular connections from the neurohylK)physis to the anterior lobe so that the
| |
| neurohypophyseal hormones liberated into
| |
| the blood stream would in fact be carried
| |
| | |
| | |
| | |
| direct to the anterior pituitary cells in very
| |
| high concentrations. Clearly such a concept
| |
| would provide a simple explanation of how
| |
| the hormonal integration, coordination, and
| |
| maintenance of mammary function is
| |
| achieved. It has already been noted (see
| |
| page 607) that a connection between milk
| |
| ejection and the onset of copious lactation
| |
| has been suggested. There is considerable
| |
| evidence that oxytocin is liberated during
| |
| parturition in sufficient quantities to cause
| |
| contraction of the alveoli and milk ejection
| |
| (see Harris, 1955; Cross, 1958; Cross, Goodwin and Silver, 1958) ; if, therefore, oxytocin
| |
| can release the lactogenic and galatopoietic
| |
| complexes from the anterior pituitary, a
| |
| simple explanation of the mechanism triggering off the onset of copious milk secretion, before the application of the milking
| |
| stimulus, is available.
| |
| | |
| We must now consider what experimental
| |
| evidence there is to support this rather attractive theory. First, Benson and Folley
| |
| (1956, 1957a, b) demonstrated that regular
| |
| injections of oxytocin can retard mammary
| |
| regression after weaning in a similar fashion to injections of prolactin (see page
| |
| 610), and they have shown that the presence of the pituitary is essential for oxytocin
| |
| to elicit this effect. Synthetic oxytocin
| |
| proved equally effective, thus discounting
| |
| the possibility of a contaminant in natural
| |
| oxytocin being concerned (Fig. 10.20) . These
| |
| experiments have so far only been carried
| |
| out in rats, but they strongly suggest that
| |
| oxytocin can elicit the secretion of prolactin.
| |
| In agreement with this concept are several
| |
| observations that regular injections of oxytocin have galactopoietic effects in lactating
| |
| cows and that oxytocin has luteotrophic effects in rats (see review by Benson, Cowie
| |
| and Tindal, 1958) . There is, moreover, some
| |
| evidence that the suckling stimulus may
| |
| cause the release of vasopressin or the antidiuretic hormone (ADH) from the neurohypoi)hysis (see page 621), and it has been
| |
| shown that ADH or some material closely
| |
| associated with it may cause the secretion of
| |
| ACTH from the anterior lobe (see review
| |
| by Benson, Cowie and Tindal, 1958) ; so
| |
| there are some grounds for supposing that
| |
| the hormones of the posterior lobe evoke
| |
| the secretion of several components of the
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 10.20. Sections from abdominal mammary gland of rats from wliuli Ur- pups were
| |
| removed on the fourth day of lactation and which received thereafter for 9 daj^s: A. LO
| |
| I.U. synthetic oxytocin three times daily. B. Saline daily. Note the maintenance of gland
| |
| structure in A. (Courtesy of Dr. G. K. Benson.)
| |
| | |
| | |
| | |
| galactopoietic complex from the anterior
| |
| lobe. It was hoped to gain further evidence
| |
| on this point by studies on hypophysectomized rats bearing pituitary homografts
| |
| under the kidney capsule (see Benson,
| |
| Cowie, Folley and Tindal, 1959) . As already
| |
| noted, such grafts secrete prolactin and will
| |
| give a slight maintenance of milk secretion,
| |
| but these grafts will not maintain normal
| |
| milk secretion even when such animals are
| |
| injected with oxytocin and ADH (Cowie,
| |
| Tindal and Benson, 1960). It must, therefore, be assumed that if these posterior
| |
| pituitary hormones are responsible for the
| |
| release of the galactopoietic complex, some
| |
| other hypothalamic factor is also necessary
| |
| to maintain the anterior lobe in a responsive
| |
| condition. Everett (1956) suggested that
| |
| the hypothalamus by way of its neurovascular connections with the anterior lobe,
| |
| normally exerts a partial inhibitory effect on
| |
| prolactin secretion. It may thus be that
| |
| when the anterior lobe is removed from
| |
| hypothalamic influence, the synthetic activities of its cells are centered on prolactin
| |
| | |
| | |
| | |
| production to the detriment of the other
| |
| components of the galactopoietic complex,
| |
| so that these are no longer available for release in response to neurohypophyseal hormones. There is need, however, for experimentation in other species.
| |
| | |
| The theory that the release of the galactopoietic complex is effected by the hormones of the posterior lobe secreted in response to the suckling stimulus is attractive
| |
| in that it appears to afford a simple explanation of the hormonal integration of mammary function, but it must be pointed out
| |
| that the observations on the maintenance of
| |
| mammary structure after weaning by injections of oxytocin do not prove that prolactin
| |
| or the galactopoietic complex is released in
| |
| response to oxytocin under normal conditions of milking or suckling, and more research, particularly in species other than the
| |
| rat, is necessary. Grosvenor and Turner
| |
| (1958a) injected oxytocin into anesthetized
| |
| lactating rats and, on the basis of assays of
| |
| the pituitary content of prolactin, considered
| |
| that oxytocin caused no significant release of
| |
| | |
| | |
| | |
| 630
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| prolactin. They had previously shown that
| |
| there was an immediate fall in the pituitary
| |
| content of prolactin after nursing (Grosvcnor and Turner, 1957b) and therefore
| |
| concluded that their findings were contrary
| |
| to the hypothesis that oxytocin is a hormonal link in the discharge of prolactin.
| |
| This, however, cannot be regarded as conclusive because of the difficulties of relating
| |
| pituitary content of a hormone to blood
| |
| levels of the hormone and also the difficulty
| |
| of determining the physiologic dose of oxytocin, for if the oxytocin is carried directly
| |
| from the neurohypophysis into the anterior
| |
| lobe, then the concentration in the blood
| |
| reaching the anterior lobe may be relatively
| |
| great (see also Cowie and Folley, 1957).
| |
| | |
| Other theories of the reflex maintenance
| |
| of milk secretion have been put forward. In
| |
| 1953 Tverskoi, observing that repeated injections of oxytocin were galactopoietic in
| |
| the goat, suggested that alveolar contraction
| |
| stimulated sensory nerve endings in the
| |
| alveolar walls which reflcxly caused the release of prolactin. It is obvious that his
| |
| observations could be explained on the basis
| |
| of the Benson-Folley theory of direct pituitary stimulation by oxytocin. This possibility was indeed considered by Tverskoi.
| |
| but rejected on the grounds that oxytocin
| |
| did not affect the prolactin content of the
| |
| pituitary (Meites and Turner, 1948). In
| |
| 1957 Tverskoi found it necessary to revise
| |
| his theory, having found that full lactation
| |
| could be maintained in the goat after complete and repeated denervation of the udder
| |
| provided oxytocin was regularly given to
| |
| evoke milk ejection. He then suggested that
| |
| alveolar contraction stimulates the synthetic activities of the mammary epithelium
| |
| causing an uptake of prolactin from the
| |
| blood, the fall in the blood prolactin level
| |
| then stimulating the further production of
| |
| prolactin by the anterior lobe. Although
| |
| these latter observations of Tverskoi might
| |
| again be explained on the basis of direct
| |
| pituitary stimulation by exogenous oxytocin, more recent studies on goats have
| |
| cast doubts on the validity of such an explanation. Tverskoi (1958) and Denannir
| |
| and Martinet (1959a, b, 1960) have shown
| |
| that lactating goats will continue to lactate,
| |
| giving nonnal or onlv niodcratelv reduced
| |
| | |
| | |
| | |
| milk yields after section of all nervous connections between the udder and brain (cord
| |
| section, radicotomy, bilateral sympathectomy) and without their receiving oxytocin
| |
| and in the absence of conditioned milkejection reflexes. It has already been noted
| |
| that milk ejection in such animals may result from mechanical stimulation of the
| |
| myoepithelial cells by udder massage (see
| |
| page 624) , but the release of the galactopoietic complex from the anterior pituitary
| |
| would seem in these goats to have been independent of neurohormonal reflex activities. AVhether in such animals the release is
| |
| spontaneous or dependent on the level of
| |
| hormones in the blood as suggested by
| |
| Tverskoi (1957) is a matter for further research.
| |
| | |
| VI. Pharmacologic Blockade of the Reflexes Concerned in the Maintenance
| |
| of Milk Secretion and Milk Ejection
| |
| | |
| Various attempts have been made to
| |
| investigate the mechanism controlling release of anterior pituitary hormones by the
| |
| use of dibenamine, atropine, and other
| |
| drugs. In reviewing such experiments, Harris
| |
| (1955) concluded that there was no convincing evidence of the participation of
| |
| adrenergic, cholinergic, or histaminergic
| |
| agents in the control of gonadotrophic and
| |
| adrenocorticotrophic hormone release. Recently Grosvenor and Turner (1957a) reported that various ergot alkaloids, dibenamine, and atropine blocked milk ejection
| |
| in the rat; the ergot alkaloids doing so
| |
| within 10 minutes of administration, the
| |
| atropine and dibenamine within 2 to 4 hours.
| |
| Inasmuch as milk ejection occurred in response to exogenous oxytocin, it was concluded that these drugs acted centrally, and
| |
| the presence of adrenergic and cholinergic
| |
| links in the neurohormone arc was postulated to be responsible for the discharge of
| |
| oxytocin. Later, on the basis of assays of
| |
| jntuitary prolactin after nursing in druginjected lactating rats, it was suggested
| |
| that cholinergic and adrenergic links are
| |
| iinohcd in the reflex resi)onsible for prolactin release (Grosvenor and Turner,
| |
| 1958a). Ergot alkaloids, however, administered in our laboratory to lactating rats had
| |
| no significant effect on the lactational per
| |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 631
| |
| | |
| | |
| | |
| fonnance as judged by the growth of the
| |
| litters in comparison with the growth of
| |
| litters of pair-fed control rats, showing that
| |
| apparent inhibitory effects of the alkaloids
| |
| on lactation were due to depressed food intake of the mothers (Tindal, 1956a). Inasmuch as growth of the litter depends on
| |
| efficient milk secretion and milk ejection,
| |
| Tindal's observations seem to throw doubt
| |
| on the importance of the adrenergic link in
| |
| these reflexes. On the other hand, IVIeites
| |
| (1959) has reported that adrenaline and
| |
| acetylcholine can induce or maintain mammary development and milk secretion in
| |
| suitably prepared rats, observations which
| |
| could be interpreted as supporting the presence of adrenergic and cholinergic links as
| |
| postulated by Grosvenor and Turner
| |
| (1958a).
| |
| | |
| There have been clinical reports of women developing galactorrhoea after treatment with trancjuilizing drugs {e.g., Sulman
| |
| and Winnik, 1956; Marshall and Leiberman, 1956; Piatt and Sears, 19561 and interesting observations have recently ap
| |
| | |
| | |
| peared on the lactogenic effects of reserpine
| |
| in animals. Milk secretion has been initiated
| |
| both in virgin rabbits after suitable estrogen
| |
| priming and in the pseudopregnant rabbit
| |
| by reserpine (Sawyer, 1957; Meites, 1957a).
| |
| On the other hand, in our laboratory Tindal
| |
| (1956b, 1958) had been unable to detect
| |
| any mammogenic or lactogenic effects with
| |
| chlorpromazine or reserpine in rabbits
| |
| (Dutch breed), rats, or goats, nor did reserpine stimulate the crop-sac when injected
| |
| into pigeons. Recently, using New Zealand
| |
| White rabbits, Tindal (1960) has induced
| |
| milk secretion with reserpine. The reason
| |
| for these contradictory results is not entirely
| |
| clear, although breed differences in the response would appear to exist in the rabbit.
| |
| In our laboratory, Benson (1958) has shown
| |
| that reserpine is strikingly active in retarding mammary involution in the lactating rat after weaning, the effect being of
| |
| such a magnitude as has so far only been
| |
| equalled by a combination of prolactin and
| |
| STH (Fig. 10.21). It has been tentatively
| |
| suggested that the tranquilizing drugs may
| |
| | |
| | |
| | |
| ^^:f/
| |
| | |
| | |
| | |
| mm\"^>m.-Wi
| |
| | |
| | |
| | |
| | |
| | |
| | |
| ■w^
| |
| | |
| | |
| .•^^:j^-^ f4kr 1"
| |
| | |
| | |
| | |
| | |
| Fig. 10.2L Sections from the abdominal mammary gland of rats from whichthe pujis were
| |
| removed on the fourth day of lactation and which received thereafter for 9 days: A 100 fj.g.
| |
| reserpine daily. B. Sahne dailJ^ Note the retardation of involution effected by reserpine.
| |
| (Courtesy of Dr. G. K. Benson.)
| |
| | |
| | |
| | |
| 632
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| remove .some hypothalamic restraining
| |
| mechanism on the release of jn'olactin and
| |
| probably of other anterior-pituitary hormones (Sulman and Winnik, 1956; Benson,
| |
| Cowie and Tindal, 1958), an effect which,
| |
| if confirmed, may throw light on the behavior of pituitary transplants in sites remote from the median eminence.
| |
| | |
| VII. Conclusion
| |
| | |
| Any reader familiar with the chajiter on
| |
| the mammary gland in the previous edition
| |
| of this book cannot fail to note the main
| |
| directions in which the subject has advanced
| |
| in the intervening two decades. These reflect, as they are bound to do, the road taken
| |
| by the science of endocrinology itself, a road
| |
| leading to greater biochemical understanding on the one hand and to ever closer rapprochement with neurophysiology on the
| |
| other.
| |
| | |
| The mammary gland offers unique opportunities of studying the biochemical mechanisms of hormone action because it is an
| |
| organ with quite exceptional synthetic capabilities, an organ which is perhaps the most
| |
| comprehensive hormone target in the mammalian body. Biochemists are entering this
| |
| promising field in increasing numbers and
| |
| we may expect to reap the fruits of their
| |
| labors in the future.
| |
| | |
| VIII. References
| |
| | |
| Abraham, S., Cady, P., and Chaikoff, I. L. 1957.
| |
| Effect of insulin in vitro on pathways of glucose utilization, other than Embden-Meyerhof,
| |
| in rat mammarv gland. J. Biol. Cliem., 224,
| |
| 955-962.
| |
| | |
| Ahren, K. 1959. The effect of various do.^es of
| |
| estrone and progesterone on the mammary
| |
| glands of castrated hypophysectomized rats
| |
| injected with insulin. Acta endocrinol., 30, 435458.
| |
| | |
| Ahren, K., and Etienne, M. 1957. The development of the mammary gland in normal and
| |
| castrated male rats after the age of 21 days.
| |
| Acta physiol. scandinav., 41, 283-300.
| |
| | |
| Ahren, K., .\nd Etienne, M. 1958. Stimulation
| |
| of mammary glands in hypophysectomized
| |
| male rats treated with ovarian hormones and
| |
| insulin. Acta endocrinol., 28, 89-102.
| |
| | |
| Ahren, K., and Jacoksoun, D. 1956. Mammary
| |
| gland growth in hypophy-sectomized rats injected with ovarian hormones and insulin. Ada
| |
| physiol. scandinav., 37, 190-203.
| |
| | |
| Ahren, K., and Jacobsohn, D. 1957. The action
| |
| of cortisone on tlip mammary glands of rats
| |
| | |
| | |
| | |
| imder various states of hormonal imbalance.
| |
| | |
| Acta phy.siol. scandinav., 40, 254-274.
| |
| [Al'tman, a. D.] A.abTMaH, A. JX. 1945. Hsm
| |
| eneHHH b BbiMenn KopoB b nporiecce pasAOH.
| |
| | |
| Vestnik Zhivotn., 1, 85-96.
| |
| Andersson, B. 1951a. Some observations on the
| |
| | |
| neurohormonal regulations of milk ejection.
| |
| | |
| Acta physiol. scandinav., 23, 1-7.
| |
| Andersson, B. 1951b. The effect and localization
| |
| | |
| of electrical stimulation of certain parts of the
| |
| | |
| brain stem in sheep and goats. Acta physiol.
| |
| | |
| scandinav., 23, 8-23.
| |
| Andersson, B. 1951c. Further studies on the milk
| |
| | |
| ejection mechanism in sheep and goats. Acta
| |
| | |
| physiol. scandinav., 23, 24-30.
| |
| Ardran, G. M., Cowie, A. T., .-^nd Kemp, F. H.
| |
| | |
| 1957. A cineradiographic study of the teat
| |
| sinus during suckling in the goat. Vet. Rec, 69,
| |
| 1100-1101.
| |
| | |
| Ardrax, G. M., Cowie. A. T., and Kemp, F. H.
| |
| | |
| 1958. Further obser\ations on the teat sinus
| |
| of the goat during suckling. Vet. Rec, 70, 808809.
| |
| | |
| Ardran, G. M., Kemp, F. H., and Lind. J. 1958a.
| |
| A cineradiographic studv of bottle feeding.
| |
| Brit. J. Radiol., 31, 11-22.
| |
| | |
| Ardr.\n, G. M., Kemp, F. H., .\nd Lind, J. 1958b.
| |
| A cineradiographic studv of breast feeding.
| |
| Brit. J. Radiol., 31, 156-162.
| |
| | |
| Ardran, G. M., and Kemp. F. H. 1959. A correlation between suckling pres-sures and the movements of the tongue. Acta pediat., 48, 261-272.
| |
| | |
| AvERiLL, S. C, R.\Y, E. W., .\ND Lyons, W. R.
| |
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| |
| | |
| WiLLi.-VMS, W. L. 1945. The effects of lactogenic
| |
| hormone on the postparturient unsuckled
| |
| mammary glands of the mouse. Anat. Rec.
| |
| 93, 171-183.
| |
| | |
| | |
| | |
| 642
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Williams, W. L., and Stewart, C. A. 1945. Mammarv development in the newborn human.
| |
| Anat. Rec, 91, 307-308.
| |
| | |
| YoKOYAMA, A. 1956. Milk-ejection responses following administration of "tap" stimuli and
| |
| posterior-pituitary extracts. Endocrinol. Japon.,
| |
| 3, 32-38.
| |
| | |
| [Zaks,M. G.] 3aKC, M. r. 1951. HoBbie aaHHbie
| |
| o (i)yHKUHH MOTopHoro auoapaTa BbiMenu. Ix
| |
| CSopHHK Ji;oKJiajiOB BTopott Bcecoio3Hofi
| |
| | |
| | |
| | |
| KoHcbepeHunii no MonoHHOMy Jlejiy, R. B.
| |
| Davidov, 2d. p. 150-163. Moscow: Sel'khozgiz.
| |
| | |
| [Zaks, :\I. G.] 3aKc, M. T. 1958. <Dn.3iiononiH
| |
| ABiiraTejibHoro annapara mojiomhoh a;ejie.3M
| |
| cejibCKOxosHitcTBeHHbix xnBOTHbix. Moscow,
| |
| Leningrad: Akademiya Nauk, S.S.S.R.
| |
| | |
| ZiETZSCHMANN, 0. 1926. Bau und Funktion der
| |
| Milchdriise. In "Lehrbuch der Chemie und
| |
| Physiologie der Milch, 2nd ed., W. Grimmer,
| |
| Ed., p. 1-35. Berlin: Paul Parey.
| |
| | |
| | |
| | |
| 11
| |
| | |
| | |
| | |
| SOME PROBLEMS OF THE METABOLISM AND
| |
| | |
| MECHANISM OF ACTION OF STEROID
| |
| | |
| SEX HORMONES
| |
| | |
| Claude A. Villee, Ph.D.
| |
| | |
| ASSOCIATE PROFESSOR OF BIOLOGICAL CHEMISTRY,
| |
| HARVARD UNIVERSITY
| |
| | |
| | |
| | |
| I. Introduction 643
| |
| | |
| II. The Biosynthesis op Steroids 643
| |
| | |
| A. Cholesterol 644
| |
| | |
| B. Progesterone 644
| |
| | |
| C. Androgens 645
| |
| | |
| D. Estrogens 647
| |
| | |
| E. Biosynthesis of Other Steroids 647
| |
| | |
| F. Interconversions of Steroids 647
| |
| | |
| G. Catabolism of Steroids (548
| |
| | |
| H. Transport, Conjugation, and Excretion 650
| |
| | |
| III. Effects of Sex Hormones on Inter
| |
| mediary Metabolism 650
| |
| | |
| A. Estrogens 652
| |
| | |
| B. Androgens 659
| |
| | |
| C. Progesterone 660
| |
| | |
| IV. References 661
| |
| | |
| I. Intro<luction
| |
| | |
| The chemical structure of the sex hormones, their isohition from biologic materials, and many of their chemical properties were fully described in the previous
| |
| edition of Sex and Internal Secretions (W.
| |
| M. Allen, 1939; Doisy, 1939; Koch, 1939).
| |
| The major steroid sex hormones were isolated and identified 20 to 30 years ago.
| |
| Estrone, in fact, was crystallized from pregnancy urine by Doisy, Veler and Thayer
| |
| (1929) before the true structure of the steroid nucleus was known. The isolation, identification, and chemical synthesis of estradiol, progesterone, and testosterone were
| |
| accomplished during the 1930's. Additional
| |
| substances with androgenic, estrogenic, or
| |
| progestational activity have subsequently
| |
| been isolated from urine or from tissues but
| |
| these are probably metabolites of the major
| |
| | |
| | |
| | |
| sex steroids. The steroids are now routinely
| |
| synthesized from cholesterol or from plant
| |
| sterols. It would be possible to carry out
| |
| the total synthesis of steroids from simple
| |
| precursors but this is not commercially
| |
| practicable.
| |
| | |
| The two decades since the previous edition have been marked by major advances
| |
| in our understanding of the intermediary
| |
| metabolism of steroids — the synthesis of
| |
| cholesterol from two-carbon units, the conversion of cholesterol to pregnenolone and
| |
| progesterone, and the derivation of corticoids, androgens, and estrogens from progesterone. These advances were made possible
| |
| by the development of vastly improved
| |
| methods for the isolation and identification
| |
| of steroids: chromatography on paper or
| |
| columns, counter-current distribution, labeling with radioactive or heavy isotopes,
| |
| infrared spectroscopy, and so on. There have
| |
| been concomitant increases in the information regarding the sites and mechanisms of
| |
| action of these biologically important substances and the means by which they stimulate or inhibit the growth and activity of
| |
| particular tissues of the body. The following
| |
| discussion will attempt to present a general
| |
| picture of these two fields and not an exhaustive citation of the tremendous body of
| |
| relevant literature.
| |
| | |
| II. The Biosynthesis of Steroids
| |
| | |
| When the steroid hormones were first discovered it was generally believed that each
| |
| | |
| | |
| | |
| 643
| |
| | |
| | |
| | |
| 644
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| endocrine gland made its characteristic
| |
| steroid by some unique biosynthetic mechanism, one that was independent of those in
| |
| other glands. However, there is now abundant evidence that the biosynthetic paths
| |
| in the several steroid-secreting glands have
| |
| many features which are similar or identical.
| |
| | |
| It is now well established that progesterone is not simply a female sex hormone
| |
| produced by the corpus luteum, but a common precursor of adrenal glucocorticoids
| |
| such as Cortisol and adrenal mineralocorticoids such as aldosterone, androgens, and
| |
| estrogens. The adrenal cortex, ovary, testis,
| |
| and placenta have in common many enzymes for the biosynthesis of steroids. Androgenic tumors of the human ovary, for example, have been shown to produce
| |
| testosterone and its metabolites. The transplantation of an ovary into a castrate male
| |
| mouse will result in the maintenance of the
| |
| male secondary sex characters, which suggests that the normal ovary can also synthesize androgens.
| |
| | |
| A. CHOLESTEROL
| |
| | |
| The early work of Bloch (1951), Rilling,
| |
| Tchen and Bloch (1958), and of Popjak
| |
| (1950) showed that labeled acetate is converted to labeled cholesterol. The pattern of
| |
| the labeling present in the cholesterol synthesized from acetate-1-C^^ or acetate-2-C^''
| |
| as precursor led to speculations as to how
| |
| the steroid nucleus is assembled. Further
| |
| work (Langdon and Bloch, 1953) revealed
| |
| that squalene and certain branched-chain,
| |
| unsaturated fatty acids are intermediates
| |
| in this synthesis. The current hypothesis,
| |
| which is supported by a wealth of experimental evidence, states that two moles of
| |
| acetyl coenzyme A condense to form acetoacetyl coenzyme A, which condenses with a
| |
| third molecule of acetyl coenzyme A to form
| |
| yS-hydroxy-^-methyl glutaric acyl coenzyme
| |
| A (Fig. 11.1). The coenzyme A group is
| |
| removed and the hydroxymethyl glutaric
| |
| acid is reduced to mevalonic acid. Mevalonic
| |
| acid, 3-hydroxy-3-methylpentano-5-lactone,
| |
| is metabolized to a 5-carbon isoprenoid
| |
| compound and three moles of these condense
| |
| to form a 1 5-carbon hydrocarbon. The headto-head condensation of two molecules of
| |
| this 15-carbon compound yields the 30
| |
| | |
| | |
| carbon equalene. This is metabolized, by
| |
| way of lanosterol and the loss of three
| |
| methyl groups, to cholesterol, which seems
| |
| to be the common precursor of all of the
| |
| steroid hormones (Tchen and Bloch, 1955;
| |
| Clayton and Bloch, 1956).
| |
| | |
| The question of whether cholesterol is
| |
| an obligate intermediate in the synthesis of
| |
| steroid hormones has not been definitely
| |
| answered. There is clear evidence that cholesterol is converted to steroids without first
| |
| being degraded to small units and subsequently reassembled. Werbin and LeRoy
| |
| (1954) administered cholesterol labeled
| |
| with both carbon-14 and tritium (H^) to
| |
| human subjects and isolated from their
| |
| urine tetrahydrocortisone, tetrahydrocortisol, androsterone, etiocholanolone and 11ketoetiocholanolone. These substances,
| |
| known to be metabolites of steroid hormones, were labeled with both C^^ and H^
| |
| and the labeled atoms were present in the
| |
| ratio expected if they were derived directly
| |
| from cholesterol. Experiments by Dorfman
| |
| and his colleagues (Caspi, Rosenfeld and
| |
| Dorfman, 1956) also provide evidence for
| |
| the synthesis of steroids via cholesterol.
| |
| Cortisol and 11-desoxycortisol were isolated
| |
| from calf adrenals perfused with acetate-1C^^ and from a patient with an adrenal tumor to whom acetate- 1-C^^ had been administered. It is known that cholesterol
| |
| synthesized from acetate-l-C^'* is labeled in
| |
| carbon 20 but not in carbon 21. The Cortisol
| |
| and 11-desoxycortisol also proved to be labeled in carbon 20 but not in carbon 21.
| |
| This evidence does not, of course, exclude
| |
| biosynthetic paths for the steroids other
| |
| than one by way of cholesterol, but it does
| |
| suggest that cholesterol is at least an important precursor of them. Direct evidence
| |
| that cholesterol is synthesized from squalene
| |
| in man is provided by the experiments of
| |
| Eidinoff, Knoll, Marano, Kvamme, Rosenfeld and Hcllman (1958), who prepared tritiated squalene and administered it orally
| |
| to human subjects. They found that the
| |
| cholesterol of the blood achieved maximal
| |
| specific aeti\'ity in 7 to 21 liours.
| |
| | |
| B. PROCiE.STERONE
| |
| | |
| Cholesterol undergoes an oxidative cleavage of its side chain to yield isocaproic
| |
| acid and pregnenolone (Fig. 11.2). The lat
| |
| | |
| | |
| CH3C0-SC0A
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| SCoA
| |
| | |
| | |
| | |
| 645
| |
| | |
| | |
| | |
| CH^CO-SCoA
| |
| | |
| | |
| | |
| Acetyl CoA
| |
| | |
| | |
| | |
| CH3COCH2CO~SCoA
| |
| | |
| | |
| | |
| Acetoacetyl CoA
| |
| | |
| | |
| | |
| Sesquiterpene
| |
| (15C)
| |
| | |
| | |
| | |
| COOH
| |
| | |
| ► HO— C— CHI ^
| |
| | |
| CO-' SCO A
| |
| | |
| pOH-p methylglutaric acyl Co A
| |
| | |
| | |
| | |
| CHg
| |
| | |
| C-CHI
| |
| | |
| CH
| |
| II
| |
| CHo
| |
| | |
| | |
| | |
| Isoprene unit
| |
| (5C)
| |
| | |
| | |
| | |
| CHO
| |
| | |
| I
| |
| | |
| CHo
| |
| I ^
| |
| | |
| HO-C-CH^
| |
| 1 3
| |
| | |
| CHo
| |
| I 2
| |
| COOH
| |
| | |
| Mevalonic acid
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Squalene Lanosterol Cholesterol
| |
| | |
| (30C) (30C) (27C)
| |
| | |
| Fig. 11.1. Biogenesis of cholesterol.
| |
| | |
| | |
| | |
| ter is dehydrogenated in ring A by the
| |
| enzyme 3-^-ol dehydrogenase and a spontaneous shift of the double bond from the
| |
| A5 , 6 to the A4 , 5 position results in progesterone. Progesterone undergoes successive
| |
| hydroxylation reactions, which require molecular oxygen and reduced triphosphopyridine nucleotide (TPNH), at carbons 17,
| |
| 21, and 11. These hydroxylations yield,
| |
| in succession, 17-a-hydroxy progesterone,
| |
| Reichstein's compound S (ll-desoxy-17-hydroxycorticosterone), and Cortisol (17-a-hydroxvcorticosterone) .
| |
| | |
| | |
| | |
| C. ANDROGENS
| |
| | |
| 17-a-Hydroxy progesterone is also the immediate precursor of androgens and estrogens. Oxidative cleavage of its side chain
| |
| yields A-4-androstenedione, which undergoes reduction to testosterone (Fig. 11.2).
| |
| A-4-Androstenedione may be hydroxylated
| |
| at carbon 11 to yield ll-/3-hydroxy-A-4androstenedione, which is an androgen isolated from human urine. It has also been
| |
| found as a metabolite of certain androgenic
| |
| tumors of the adrenal cortex.
| |
| | |
| | |
| | |
| 04 G
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| CH
| |
| | |
| | |
| Y^ .
| |
| | |
| | |
| socaproic C
| |
| | |
| | |
| =0
| |
| | |
| | |
| | |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| r^
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 0^-OH
| |
| | |
| | |
| ^r^
| |
| | |
| | |
| | |
| | |
| | |
| HO
| |
| | |
| | |
| HO
| |
| | |
| | |
| J
| |
| | |
| | |
| HO
| |
| | |
| | |
| Cholesterol
| |
| | |
| | |
| Pregnenolone
| |
| | |
| | |
| 17-Hydr
| |
| | |
| | |
| oxy
| |
| | |
| Dehydroepi
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| preg
| |
| | |
| | |
| nenolone
| |
| | |
| | |
| androsterone
| |
| | |
| | |
| CH3
| |
| | |
| | |
| | |
| | |
| | |
| | |
| CH3
| |
| | |
| | |
| | |
| | |
| f3
| |
| | |
| | |
| H-C-OH
| |
| 1
| |
| | |
| | |
| , f
| |
| | |
| | |
| c=o
| |
| | |
| 1
| |
| | |
| | |
| | |
| | |
| 1
| |
| | |
| c=o
| |
| | |
| 1
| |
| | |
| | |
| ^ ■
| |
| | |
| | |
| | |
| | |
| -x^V
| |
| | |
| | |
| t^
| |
| | |
| | |
| | |
| | |
| ^XP""°"
| |
| | |
| | |
| r^^
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ^^<Y
| |
| | |
| | |
| „ijj
| |
| | |
| | |
| - \^Xaj
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| JJ
| |
| | |
| | |
| A -3- Ketopregnene
| |
| | |
| | |
| Progest
| |
| | |
| | |
| erone
| |
| | |
| | |
| 17
| |
| | |
| | |
| -Hydroxy
| |
| | |
| 20-oc-ol
| |
| | |
| | |
| y
| |
| | |
| | |
| | |
| | |
| y
| |
| | |
| | |
| progesterone
| |
| | |
| | |
| CH^OH
| |
| | |
| | |
| X
| |
| | |
| | |
| CH OH
| |
| | |
| | |
| /
| |
| | |
| | |
| | |
| | |
| | |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 1
| |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| "
| |
| | |
| | |
| | |
| | |
| Desoxy—
| |
| corticosterone
| |
| | |
| | |
| | |
| CH2OH
| |
| c=o
| |
| | |
| | |
| | |
| 1 7- Hydroxy desoxycorticosterone
| |
| (Reichstein's "S")
| |
| | |
| | |
| | |
| | |
| | |
| CH^OH
| |
| HCO C=0
| |
| | |
| | |
| | |
| .JOJ
| |
| | |
| | |
| | |
| CH^OH
| |
| | |
| c=o
| |
| | |
| | |
| | |
| A -androstenedione
| |
| | |
| | |
| | |
| OH
| |
| | |
| | |
| | |
| | |
| | |
| o ' -- o
| |
| | |
| Corticosterone 18-aldo- 11- desoxy- Cortisol Testosterone
| |
| | |
| corticosterone (Kendall's
| |
| | |
| Cmpd. "F")
| |
| | |
| | |
| | |
| HCO C=0
| |
| | |
| | |
| | |
| | |
| 19 -Hydroxy- ^■^■
| |
| androstenedione
| |
| | |
| | |
| | |
| .;^
| |
| | |
| | |
| | |
| | |
| Aldosterone
| |
| | |
| | |
| | |
| HO
| |
| | |
| Estradiol
| |
| Fig. 11.2. Biosynthetic paths from cholesterol.
| |
| | |
| | |
| | |
| | |
| Estrone
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 647
| |
| | |
| | |
| | |
| D. ESTROGENS
| |
| | |
| A-4-Androstenedione and testosterone are
| |
| precursors of the estrogens. Baggett, Engel,
| |
| Savard and Dorfman (1956) demonstrated
| |
| the conversion of testosterone to estradiol17/? by slices of human ovary. Ryan (1958)
| |
| found that the enzymes to carry out this
| |
| conversion are also present in the human
| |
| placenta, located in the microsomal fraction
| |
| of placental homogenates. Homogenates of
| |
| stallion testis convert labeled testosterone
| |
| to labeled estradiol and estrone. Slices of
| |
| human adrenal cortical carcinoma also have
| |
| been shown to convert testosterone to estradiol and estrone, and Nathanson, Engel
| |
| and Kelley (1951) found an increased urinary excretion of estradiol, estrone, and estriol following the administration of adrenocorticotrophic hormone to castrate women.
| |
| Thus it seems that ovary, testis, placenta,
| |
| and adrenal cortex have a similar biosynthetic mechanism for the production of estrogens and androgens. The first step in
| |
| the conversion of testosterone or A-4-androstenedione to estrogens is the hydroxylation
| |
| at carbon 19, again by an enzymatic process
| |
| which requires molecular oxygen and
| |
| TPNH. Meyer (1955) first isolated and
| |
| characterized 19-hydroxy-A-4-androstene3,17-dione from a perfused calf adrenal.
| |
| When this was incubated with dog placenta
| |
| it was converted to estrone. The steps in the
| |
| conversion of the 19-hydroxy-A-4-androstenedione to estrone appear to be the introduction of a second double bond into ring
| |
| A, the elimination of carbon 19 as formaldehyde, and rearrangement to yield a
| |
| phenolic ring A. The requirements for the
| |
| aromatization of ring A by a microsomal
| |
| fraction of human placenta were studied by
| |
| Ryan (1958). West, Damast, Sarro and
| |
| Pearson (1956) found that the administration of testosterone to castrated, adrenalectomized women resulted in an increased
| |
| excretion of estrogen. This suggests that
| |
| tissues other than adrenals and gonads, presumably the liver, can carry out this same
| |
| series of reactions.
| |
| | |
| E. BIOSYNTHESIS OF OTHER STEROIDS
| |
| | |
| To complete the picture of the interrelations of the biosyntheses of steroids, it
| |
| should be noted that other evidence shows
| |
| | |
| | |
| | |
| that progesterone is hydroxylated at carbon
| |
| 21 to yield desoxycorticosterone and this is
| |
| subsequently hydroxylated at carbon 11 to
| |
| yield corticosterone. Desoxycorticosterone
| |
| may undergo hydroxylation at carbon 18
| |
| and at carbon 11 to yield aldosterone, the
| |
| most potent salt-retaining hormone known
| |
| (Fig. 11.2).
| |
| | |
| Dehydroepiandrosterone is an androgen
| |
| found in the urine of both men and women.
| |
| Its rate of excretion is not decreased on
| |
| castration and it seems to be synthesized
| |
| only by the adrenal cortex. It has been
| |
| postulated that pregnenolone is converted
| |
| to 17-hydroxy pregnenolone and that this,
| |
| by cleavage of the side chain between carbon 17 and carbon 20, would yield dehydroepiandrosterone.
| |
| | |
| F. INTERCONVERSIONS OF STEROIDS
| |
| | |
| The interconversion of estrone and estradiol has been shown to occur in a number
| |
| of human tissues. A diphosphopyridine nucleotide-linked enzyme, estradiol- 17/3 dehydrogenase, which carries out this reaction
| |
| has been prepared from human placenta
| |
| and its properties have been described by
| |
| Langer ancl Engel (1956). The mode of
| |
| formation of estriol and its isomer, 16-epiestriol, is as yet unknown.
| |
| | |
| There are three major types of reactions
| |
| which occur in the interconversions of the
| |
| steroids: dehydrogenation, "hydroxylation,"
| |
| and the oxidative cleavage of the side chain.
| |
| An example of a dehydrogenation reaction
| |
| is the conversion of pregnenolone to progesterone by the enzyme 3-/3-ol dehydrogenase,
| |
| which requires diphosphopyridine nucleotide (DPN) as hydrogen acceptor. This important enzyme, which is involved in the
| |
| synthesis of progesterone and hence in the
| |
| synthesis of all of the steroid hormones, is
| |
| found in the adrenal cortex, ovary, testis,
| |
| and placenta. Other dehydrogenation reactions in which DPN is the usual hydrogen
| |
| acceptor are the readily reversible conversions of A-4-androstenedione ^ testosterone, estrone ^ estradiol, and progesterone
| |
| :;^ A-4-3-ketopregnene-20-a-ol. This latter
| |
| substance, and the enzymes producing it
| |
| from progesterone, have been found by Zander (1958) in the human corpus luteum and
| |
| placenta.
| |
| | |
| The oxidative reactions leading to the
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| introduction of an OH group on the steroid
| |
| nucleus are usually called "hydroxylations."
| |
| Specific hydroxylases for the introduction
| |
| of an OH group at carbons 11, 16, 17, 21, 18,
| |
| and 19 have been demonstrated. All of these
| |
| require molecular oxygen and a reduced
| |
| pyridine nucleotide, usually TPNH. The
| |
| ll-/3-hydroxylase of the adrenal cortex has
| |
| been shown to be located in the mitochondria (Hayano and Dorfman, 1953) . Experiments with this enzyme system, utilizing
| |
| oxygen 18, showed that the oxygen atoms
| |
| are derived from gaseous oxygen and not
| |
| from the oxygen in the water molecules
| |
| (Hayano, Lindberg, Dorfman, Hancock and
| |
| Doering, 1955). Thus this hydroxylation reaction also involves the reduction of molecular oxygen.
| |
| | |
| The oxidative cleavage of the side chains
| |
| of the steroid molecule appears to involve
| |
| similar hydroxylation reactions. The experiments of Solomon, Levitan and Lieberman
| |
| (1956) indicate that the conversion of cholesterol to pregnenolone involves one and
| |
| possibly two of these hydroxylation reactions, with the introduction of OH groups
| |
| at carbons 20 and 22 before the splitting off
| |
| of the isocaproic acid.
| |
| | |
| In summary, this newer knowledge of the
| |
| biosynthetic paths of steroids has revealed
| |
| that the differences between the several
| |
| steroid-secreting glands are largely quantitative rather than qualitative. The testis,
| |
| for example, produces progesterone and
| |
| estrogens in addition to testosterone. The
| |
| change from the secretion of estradiol by
| |
| the follicle to the secretion of progesterone
| |
| by the corpus luteum can be understood as
| |
| a relative loss of activity of an enzyme in
| |
| the path between progesterone and estradiol.
| |
| If, for example, the enzyme for the 17-hydroxylation of progesterone became inactive
| |
| as the follicle cells are changed into the
| |
| corpus luteum, progesterone rather than
| |
| estradiol would subsequently be produced.
| |
| | |
| Knowledge of these pathways also provides an explanation for certain abnormal
| |
| changes in the functioning of the glands.
| |
| Bongiovnnni (1953) and Jailer (1953)
| |
| showed that the adrenogenital syndrome
| |
| results from a loss of an enzyme or enzymes
| |
| for the hydroxylation reactions at carbons
| |
| 21 and 11 of progesterone, which results in
| |
| an impairment in the production of Cortisol.
| |
| | |
| | |
| | |
| The pituitary, with little or no Cortisol to
| |
| inhibit the secretion of adrenocorticotrophic
| |
| hormone (ACTH), produces an excess of
| |
| this hormone which stimulates the adrenal
| |
| to produce more steroids. There is an excretion of the metabolites of progesterone
| |
| and 17-hydroxy progesterone, pregnanediol
| |
| and pregnanetriol respectively, but some of
| |
| the 17-hydroxy progesterone is converted to
| |
| androgens and is secreted in increased
| |
| amount.
| |
| | |
| G. CATABOLISM OF STEROmS
| |
| | |
| Many of the steroid hormones are known
| |
| to act on the pituitary to suppress its secretion of the appropriate trophic hormone,
| |
| ACTH, the follicle-stimulating hormone
| |
| (FSH), or luteinizing hormone (LH). It
| |
| would seem that the maintenance of the
| |
| proper feedback mechanism between steroid-secreting gland and pituitary requires
| |
| that the steroids be continuously inactivated
| |
| and catabolized. The catabolic reactions of
| |
| the steroids are in general reductive in nature and involve the reduction of ketonic
| |
| groups and the hydrogenation of double
| |
| bonds. The reduction of a ketonic group to
| |
| an OH group can lead to the production of
| |
| two different stereoisomers. If the OH group
| |
| projects from the steroid nucleus on the
| |
| same side as the angular methyl groups
| |
| at carbon 18 and carbon 19, i.e., above the
| |
| plane of the four rings, it is said to have
| |
| the yS-configuration and is represented by a
| |
| heavy line. If the OH projects on the opposite side of the steroid nucleus, below
| |
| the plane of the four rings, it is said to
| |
| have the a-configuration and is represented
| |
| by a dotted line. Although both isomers are
| |
| possible, usually one is formed to a much
| |
| greater extent than the other.
| |
| | |
| The first catabolic step is usually the
| |
| reduction of the A4-3-ketone group of ring
| |
| A, usually to 3aOH compounds with the
| |
| hydrogen at carbon 5 attached in the /3configuration. The 5/3-configuration represents the CIS configuration of rings A and B.
| |
| The elimination of the A4-3-ketone group
| |
| greatly decreases the biologic activity of
| |
| the steroid and increases somewhat its solubility in water. This reductive process occurs largely in the liver. Progesterone is
| |
| converted by reduction of its A4-3-ketone
| |
| group to pregnane-3a:20a-diol, and 17-hy
| |
| | |
| | |
| STEROID SEX HORMONES 649
| |
| | |
| EXCRETORY PRODUCTS
| |
| | |
| | |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| Progesterone
| |
| | |
| | |
| | |
| 1 3
| |
| | |
| HCOH
| |
| | |
| | |
| | |
| | |
| HO H
| |
| | |
| Pregnanediol
| |
| | |
| | |
| | |
| CH,
| |
| | |
| | |
| | |
| | |
| -OH
| |
| | |
| | |
| | |
| 17 Hydroxy progesterone
| |
| | |
| | |
| | |
| CH,
| |
| | |
| | |
| | |
| ^ H-C-OH
| |
| | |
| ■OH
| |
| | |
| | |
| | |
| | |
| HO H
| |
| | |
| Pregnanetriol
| |
| | |
| | |
| | |
| OH
| |
| | |
| | |
| | |
| | |
| | |
| Testosterone
| |
| | |
| | |
| | |
| | |
| Androsterone
| |
| | |
| | |
| | |
| HO
| |
| | |
| | |
| | |
| | |
| /
| |
| | |
| | |
| | |
| androstenedione
| |
| | |
| | |
| | |
| | |
| HO H
| |
| | |
| Etiocholanolone
| |
| | |
| | |
| | |
| Dehydroepiandrosterone
| |
| | |
| Fk;. 11.3. Excretory products of progesterone and androgen
| |
| | |
| | |
| | |
| (Iroxy progesterone is converted to pregnane3a:17a:20a-triol (Fig. 11.3). Testosterone
| |
| and dehydrocpiandroesterone are both converted to A4-androstenedione and the reduction of its A4-3-ketone group results in a
| |
| mixture of androsterone (3a,5a-configuration) and ctiochohmolone (3a,5/?-configuration ) .
| |
| | |
| | |
| | |
| The catabohsm of estradiol is not completely known. Estradiol, estrone, and estriol are found in the urine but they account
| |
| for less than half of an administered dose of
| |
| labeled estradiol. The /3-isomer, 16-epiestriol, and two other phenolic steroids, 16-ahydroxy estrone and 2-methoxyestrone,
| |
| have recently been isolated from normal
| |
| | |
| | |
| | |
| 650
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| urine and are known to be estrogen metabolites (Marrian and Bauld, 1955).
| |
| | |
| H. TRANSPORT, CONJUGATION, AND EXCRETION
| |
| | |
| Steroids circulate in the blood in part as
| |
| free steroids and in part conjugated with
| |
| sulfate or glucuronic acid (c/. review by
| |
| Roberts and Szego, 1953b j . The steroids are
| |
| generally conjugated by the hydroxy 1 group
| |
| at carbon 3 with inorganic sulfate or with
| |
| glucuronic acid. In addition, either the conjugated or nonconjugated forms may be
| |
| bound to certain of the plasma proteins such
| |
| as the ^-globulins (Levedahl and Bernstein,
| |
| 1954) . There is evidence of specific binding
| |
| of certain steroids with particular proteins,
| |
| e.g., the binding of Cortisol to "transcortin"
| |
| (Daughaday, 1956). Between 50 and 80 per
| |
| cent of the estrogens in the blood are present closely bound to plasma proteins. A
| |
| similar large fraction of the other steroid
| |
| hormones is bound to plasma proteins ; presumably this prevents the hormone from being filtered out of the blood as it passes
| |
| through the glomerulus of the kidney. The
| |
| steroids excreted in the urine are largely in
| |
| the conjugated form, as sulfates or glucuronides.
| |
| | |
| The liver plays a prime role in the catabolism of the steroids. It is the major site
| |
| of the reductive inactivation of the steroids
| |
| and their conjugation with sulfate or glucuronic acid. These conjugated forms are more
| |
| water-soluble and the conjugation probably
| |
| promotes their excretion in the urine. Rather
| |
| large amounts of certain steroids, notably
| |
| estrogens, are found in the bile of certain
| |
| species. These estrogens are free, not conjugated; the amount of estrogens present
| |
| in the bile suggests that this is an important pathway by which they are excreted. It has been suggested that the bacteria of the gastrointestinal tract may
| |
| degrade the steroids excreted in the bile and
| |
| further that there is an "enterohepatic circulation" of steroids with reabsorption
| |
| from the gut, transport in the portal system
| |
| to the liver, and further degradation within
| |
| the liver cells.
| |
| | |
| III. Effects of Sex Hormones on
| |
| Intermediary Metabolism
| |
| | |
| The literature concerning the effects of
| |
| hormones on intermediary metabolism is
| |
| | |
| | |
| | |
| voluminous and contains a number of contradictions, some of which are real and
| |
| some, perhaps, are only apparent contradictions. Evidence that a hormone acts at one
| |
| site does not necessarily contradict other
| |
| evidence that that hormone may act on a
| |
| different metabolic reaction. From the following discussion it should become evident
| |
| that there may be more than one site of
| |
| action, and more than one mechanism of
| |
| action, of any given hormone.
| |
| | |
| The hormones are so different in their
| |
| chemical structure, proteins, peptides,
| |
| amino acids, and steroids, that it would
| |
| seem unlikely, a priori, that they could all
| |
| influence the cellular machinery by comparable means. The basic elements of an
| |
| enzyme system are the protein enzyme, its
| |
| cofactors and activators, and the substrates
| |
| and products. A hormone might alter the
| |
| over-all rate of an enzyme system by altering the amount or activity of the protein
| |
| enzyme, or by altering the availability to
| |
| the enzyme system of some cofactor or substrate molecule. Some of the mechanisms
| |
| of hormone action which have been proposed are these. (1) The hormone may alter
| |
| the rate at which enzyme molecules are
| |
| produced de novo by the cell. (2) The hormone may alter the activity of a preformed
| |
| enzyme molecule, i.e., it may convert an
| |
| inactive form of the enzyme to an active
| |
| form. (3) The hormone may alter the permeability of the cell membrane or the
| |
| membrane around one of the subcellular
| |
| structures within the cell and thus make
| |
| substrate or cofactor more readily available
| |
| to the enzyme. Or, (4) the hormone may
| |
| serve as a coenzyme in the system, that is,
| |
| it may be involved in some direct fashion
| |
| as a partner in the reaction mediated by the
| |
| enzyme. Each of these theories has been
| |
| advanced to explain the mode of action of
| |
| the sex hormones.
| |
| | |
| The problem of the hormonal control of
| |
| metabolism has been investigated at a variety of biologic levels. The earliest experiments were done by injecting a hormone
| |
| into an intact animal and subsequently
| |
| measuring the amount of certain constituents of the blood, urine, or of some tissue.
| |
| There are several difficulties with such experiments. All of the homeostatic mechanisms of the animal operate to keep condi
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 651
| |
| | |
| | |
| | |
| tions constant and to minimize the effects
| |
| of the injected hormone. In addition, there
| |
| is a maze of interactions, some synergistic
| |
| and some antagonistic, between the different
| |
| hormones both in the endocrine gland and
| |
| in the target organs, so that the true effect
| |
| of the substance injected may be veiled. Our
| |
| growing understanding of the interconversions of the steroid hormones warns us that
| |
| an androgen, for example, may be rapidly
| |
| converted into an estrogen, and the metabolic effects observed on the administration
| |
| of an androgen may, at least in part, result
| |
| from the estrogens produced from the injected androgen.
| |
| | |
| To eliminate some of the confusing effects
| |
| of these homeostatic mechanisms some investigators remove the liver, kidneys, and
| |
| other viscera before injecting the hormone
| |
| under investigation. Such eviscerated preparations have been used by Levine and his
| |
| colleagues in their investigations of the
| |
| mode of action of insulin (c/. Levine and
| |
| Goldstein, 1955).
| |
| | |
| Other investigators have incubated slices
| |
| of liver, kidney, muscle, endocrine glands,
| |
| or other tissues in glass vessels in a chemically defined medium and at constant temperature. Such experiments have the advantage that metabolism can be studied
| |
| more directly, oxygen consumption and carbon dioxide production can be measured
| |
| manonietrically, and aliquots of the incubation medium can be withdrawn for chemical
| |
| and radiochemical analyses. The amounts of
| |
| substrate, cofactors, and hormone present
| |
| can be regulated and the interfering effects
| |
| of other hormones and of other tissues are
| |
| eliminated. Theoretically, working with a
| |
| simpler system such as this should lead to
| |
| greater insight into the physiologic and
| |
| chemical events that occur when a hormone
| |
| is added or deleted. The chief disadvantage
| |
| of this experimental system is that it is
| |
| difficult to prove that the conditions of the
| |
| experiment are "physiologic." With tissue
| |
| slices there is the possibility that the cut
| |
| edges of the cells may introduce a sizeable
| |
| artifact. Kipnis and Cori (1957) found that
| |
| the rat diaphragm, as it is usually prepared
| |
| for experiments in vitro, has an abnormally
| |
| large extracellular space and is more permeable to certain pentoses than is the intact
| |
| diaphragm.
| |
| | |
| | |
| | |
| It has been postulated that a hormone
| |
| may influence the metabolism of a particular cell by altering the permeability of the
| |
| cell membrane or of the membrane around
| |
| one of the subcellular particles. Experiments
| |
| with tissue homogenates, in which the cell
| |
| membrane has been ruptured and removed,
| |
| provide evidence bearing on such theories.
| |
| If an identical hormone effect can be obtained in a cell-free system, and if suitable
| |
| microscopic controls show that the system is indeed cell-free, the permeability
| |
| theory may be ruled out.
| |
| | |
| Ideally the hormone effect should be
| |
| studied in a completely defined system,
| |
| with a single crystalline enzyme, known
| |
| concentration of substrates and cofactors,
| |
| and with known concentration of the pure
| |
| hormone. Colowick, Cori and Slein (1947)
| |
| reported that hexokinase extracted from
| |
| diabetic muscle has a lower rate of activity
| |
| than hexokinase from normal muscle and
| |
| that it could be raised to the normal rate
| |
| by the addition of insulin in vitro. The
| |
| reality of this effect has been confirmed by
| |
| some investigators and denied by others
| |
| who were unable to repeat the observations.
| |
| Cori has suggested that the decreased rate
| |
| of hexokinase activity in the diabetic results from a labile inhibitor substance produced by the pituitary. Krahl and Bornstein
| |
| (1954) have evidence that this inhibitor is
| |
| a lipoprotein which is readily inactivated
| |
| by oxidation.
| |
| | |
| The two hormones whose effects can be
| |
| demonstrated reproducibly in an in vitro
| |
| system at concentrations in the range which
| |
| obtains in the tissues are epinephrine (or
| |
| glucagon) and estradiol (and other estrogens) . Epinephrine or glucagon stimulates
| |
| the reactivation of liver phosphorylase by
| |
| increasing the concentration of adenosine3'-5'-monophosphate (Haynes, Sutherland
| |
| and Rail, 1960), and estrogens stimulate an
| |
| enzyme system found in endometrium,
| |
| placenta, ventral i)rostate of the rat, and
| |
| mammary gland. The estrogen-stimulable
| |
| enzyme was originally described as a DPNlinked isocitric dehydrogenase, but the estrogen-sensitive enzyme now appears to be
| |
| a transhydrogenase which transfers hydrogens from TPN to DPN (Talalay and Williams-x\shman, 1958; Yillee and Hngerman,
| |
| 1958).
| |
| | |
| | |
| | |
| 052
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| The various tissues of the body respond in
| |
| quite different degrees to the several hormones. This difference in response is especially marked with the sex hormones.
| |
| Those tissues which respond dramatically
| |
| to the administration of a hormone are
| |
| termed the "target organs" of that hormone. Just what, at the cellular level, differentiates a target organ from the other
| |
| tissues of the body is not known exactly
| |
| but there is evidence that each kind of tissue is characterized by a certain pattern of
| |
| enzymes. The pattern of enzymes is established, by means as yet unknown, in the
| |
| course of embryonic differentiation. The
| |
| enzyme glucose 6-phosphatase, which hydrolyzes glucose 6-phosphate and releases
| |
| free glucose and inorganic phosphate, is
| |
| present in liver but absent from skeletal
| |
| muscle. Even though a given reaction in
| |
| two different tissues may be mediated by
| |
| what appears to be the same enzyme, the
| |
| enzymes may be different and subject to
| |
| different degrees of hormonal control. Henion and Sutherland (1957) showed that the
| |
| phosphorylase of liver responds to glucagon
| |
| but the phosphorylase of heart muscle does
| |
| not. Further, the two enzymes are immunologically distinct. An antiserum to purified
| |
| liver phosphorylase will not react with heart
| |
| phosphorylase to form an inactive antigenantibody precipitate, but it does react in
| |
| this manner with liver phosphorylase. Further, perhaps more subtle, differences between comparable enzymes from different
| |
| tissues have appeared when lactic dehydrogenases from liver, heart, skeletal muscle,
| |
| and other sources were tested for their rates
| |
| of reaction with the several analogues of the
| |
| pyridine nucleotides now available (Kaplan. Ciotti, Hamolsky and Bicbcr, 1960).
| |
| p]xtension of this technique may reveal differences in response to added hormones.
| |
| | |
| In addition to these differences in the response to a hormone of the tissues of a
| |
| single animal, there may be differences in
| |
| the response of the comparable tissues of
| |
| different species to a given dose of hormone.
| |
| Estrone, estriol, and other estrogens have
| |
| different potencies relative to estradiol in
| |
| different species of mammals. There are
| |
| slight differences in the amino acid sequences of the insulins and vasopressins
| |
| from flifferent species and quite marked
| |
| | |
| | |
| | |
| differences in the chemical structure (Li and
| |
| Papkoff, 1956) and physiologic activity
| |
| (Knobil, Morse, Wolf and Greep, 1958)
| |
| of the pituitar}^ growth hormones of cattle
| |
| and swine, on the one hand, and of primates, on the other.
| |
| | |
| A. ESTROGENS
| |
| | |
| The amount or activity of certain enzymes in the target organs of estrogens
| |
| has been found to vary with the amount of
| |
| estrogen present. Examples of this phenomenon are /^-glucuronidase (Odell and
| |
| Fishman, 1950) , fibrinolysin (Page, Glendening and Parkinson, 1951), and alkaline
| |
| glycerophosphatase (Jones, Wade, and
| |
| Goldberg, 1953). Kochakian (1947) reported that the amount of arginase in the
| |
| rat kidney increased after the injection of
| |
| estrogens. Enzyme activity is increased by
| |
| other hormones as well; for example, progesterone has been found to increase the
| |
| activity of phosphorylase (Zondek and
| |
| Hestrin, 1947) and of adenosine triphosphatase (Jones, Wade, and Goldberg, 1952).
| |
| | |
| In most experiments the amount of enzyme present has been inferred from its
| |
| activity, measured chemically or histochemically under conditions in which the
| |
| amount of enzyme is rate-limiting. This
| |
| does not enable one to distinguish between
| |
| an actual increase in the number of molecules of enzyme present in the cell and an
| |
| increase in the activity of the enzyme molecules without change in their number. A
| |
| few enzymes can be measured by some
| |
| other property, such as absorption at a
| |
| specific wavelength, by which the actual
| |
| amount of enzyme can be estimated (see
| |
| review by Knox, Auerbach, and Lin, 1956).
| |
| Knox and Auerbach (1955) found that the
| |
| activity of the enzyme tryptophan peroxidase-oxidase (TPO) of the liver was
| |
| decreased in adrenalectomized animals and
| |
| increased by the administration of cortisone. Knox had shown previously that
| |
| th(> administration of the substrate of
| |
| the enzyme, tryptophan, would lead
| |
| to an increase in the activity of the enzyme which was maximal in 6 to 10
| |
| hours. Evidence that the increased activity
| |
| of enzyme following the administration of
| |
| cortisone represents the synthesis of new
| |
| protein molecules is supplied by experi
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 653
| |
| | |
| | |
| | |
| ments in which it was found that the increase in enzyme activity is inhibited by
| |
| ethionine and this inhibition is reversed
| |
| by methionine. The amino acid analogue
| |
| ethionine is known to inhibit protein synthesis and this inhibition of protein synthesis is overcome by methionine.
| |
| | |
| The injection of estrogen into the immature or castrate rodent produces a striking uptake of water by the uterus followed
| |
| by a marked increase in its dry weight
| |
| (Astwood, 1938). Holden (1939) postulated that the imbibition of water results
| |
| from vasodilatation and from changes in the
| |
| permeability of the blood vessels of the
| |
| uterus. There is clear evidence (Mueller,
| |
| 1957) that the subsequent increase in dry
| |
| weight is due to an increased rate of synthesis of proteins and nucleic acids. The
| |
| sex hormones and other steroids could be
| |
| pictured as reacting with the protein or
| |
| lipoprotein membrane around the cell or
| |
| around some subcellular structure like a
| |
| surface-wetting agent and in this way inducing a change in the permeability of the
| |
| membrane. This might then increase the
| |
| rate of entry of substances and thus alter
| |
| the rate of metabolism within the cell.
| |
| This theory could hardly account for the
| |
| many notable specific relationships between
| |
| steroid structure and biologic activity.
| |
| Spaziani and Szego (1958) postulated that
| |
| estrogens induce the release of histamine in
| |
| the uterus and the histamine then alters the
| |
| permeability of the blood vessels and produces the imbibition of water secondarily.
| |
| | |
| The uterus of the ovariectomized rat is
| |
| remarkably responsive to estrogens and
| |
| has been widely used as a test system.
| |
| After ovariectomy, the content of ribonucleic acid of the uterus decreases to a
| |
| low level and then is rapidly restored after
| |
| injection of estradiol (Telfer, 1953). A
| |
| single injection of 5 to 10 yu,g. of estradiol
| |
| brings about (1) the hyperemia and water
| |
| imbibition described previously; (2) an
| |
| increased rate of over-all metabolism as
| |
| reflected in increased utilization of oxygen
| |
| (David, 1931; Khayyal and Scott, 1931;
| |
| Kerly, 1937; MacLeod and Reynolds, 1938;
| |
| Walaas, Walaas and Loken, 1952a; Roberts
| |
| and Szego, 1953a) ; (3) an increased rate
| |
| of glycolysis (Kerly, 1937; Carroll, 1942;
| |
| Stuermer and Stein, 1952; Walaas, Walaas
| |
| | |
| | |
| | |
| and Loken, 1952b; Roberts and Szego,
| |
| 1953a) ; (4) an increased rate of utilization
| |
| of phosphorus (Grauer, Strickler, Wolken
| |
| and Cutuly, 1950; Walaas and Walaas,
| |
| 1950) ; and (5) tissue hypertrophy as reflected in increased dry weight (Astwood,
| |
| 1938), increased content of ribonucleic acid
| |
| and protein (Astwood, 1938; Telfer, 1953;
| |
| Mueller, 1957), and finally, after about
| |
| 72 hours, an increased content of desoxyribonucleic acid (Mueller, 1957).
| |
| | |
| An important series of experiments by
| |
| Mueller and his colleagues revealed that
| |
| estrogens injected in vivo affect the metabolism of the uterus which can be detected
| |
| by subsequent incubation of the uterus in
| |
| vitro with labeled substrate molecules.
| |
| Mueller (1953) first showed that pretreatment with estradiol increases the rate
| |
| of incorporation of glycine-2-C^'* into uterine protein. He then found that estrogen
| |
| stimulation increases that rate of incorporation into protein of all other amino acids
| |
| tested: alanine, serine, lysine, and tryptophan. The peak of stimulation occurred
| |
| about 20 hours after the injection of estradiol. In further studies (Mueller and Herranen, 1956) it was found that estrogen
| |
| increases the rate of incorporation of glycine-2-C^^ and formate-2-C^'* into protein,
| |
| lipid, and the purine bases, adenine and
| |
| guanine, of nucleic acids. A stimulation of
| |
| cholesterol synthesis in the mouse uterus
| |
| 20 hours after administration of estradiol
| |
| was shown by Emmelot and Bos (1954).
| |
| | |
| In more detailed studies of the effects of
| |
| estrogens on the metabolism of "one-carbon
| |
| units" Herranen and Mueller (1956) found
| |
| that the incorporation of serine-3-C^'* into
| |
| adenine and guanine was stimulated by
| |
| pretreatment with estradiol. The incorporation was greatly decreased when unlabeled
| |
| formate was added to the reaction mixture
| |
| to trap the one-carbon intermediate. In
| |
| contrast, the incorporation of C^^02 into
| |
| uridine and thymine by the surviving uterine segment was not increased by pretreatment with estradiol in vivo (Mueller,
| |
| 1957).
| |
| | |
| To delineate further the site of estrogen
| |
| effect on one-carbon metabohsm, Herranen
| |
| and Mueller (1957) studied the effect of
| |
| estrogen pretreatment on serine aldolase,
| |
| the enzyme which catalyzes the equilibrium
| |
| | |
| | |
| | |
| 654
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| between serine and glycine plus an active
| |
| one-carbon unit. They found that serine
| |
| aldolase activity, measured in homogenates of rat uteri, increased 18 hours after
| |
| pretreatment in vivo with estradiol. It
| |
| seemed that the estrogen-induced increase
| |
| in the activity of this enzyme might explain
| |
| at least part of the increased rate of onecarbon metabolism following estrogen injection. They found, however, that incubation of uterine segments in tissue culture
| |
| medium (Eagle, 1955) for 18 hours produced a marked increase in both the activity
| |
| of serine aldolase and the incorporation of
| |
| glycine-2-C^'* into protein. The addition of
| |
| estradiol to Eagle's medium did not produce
| |
| a greater increase than the control to
| |
| which no estradiol was added. Uterine segments taken from rats pretreated with estradiol for 18 hours, with their glycine-incorporating system activated by hormonal
| |
| stimulation, showed very little further
| |
| stimulation on being incubated in Eagle's
| |
| medium for 18 hours. With a shorter period
| |
| of i^retreatment with estradiol, greater stimulation occurred on subsequent incubation
| |
| in tissue culture fluid. These experiments
| |
| suggest that the hormone and the incubation in tissue culture medium are affecting
| |
| the same process, one which has a limited
| |
| capacity to respond. When comparable experiments were performed with other
| |
| labeled amino acids as substrates, similar
| |
| results were obtained.
| |
| | |
| Mueller's work gave evidence that a considerable number of enzyme systems in the
| |
| uterus are accelerated by the administration
| |
| of estradiol — not only the enzymes for the
| |
| incorporation of serine, glycine, and formate
| |
| into adenine and guanine, but also the enzymes involved in the synthesis of fatty
| |
| acids and cholesterol and indejX'ndent enzymes for the activation of amino acids by
| |
| the formation of adenosine monoiihosphate
| |
| (AMP) derivatives. The initial step in
| |
| protein synthesis has been shown to be the
| |
| activation of the carboxyl grou]) of the
| |
| amino acid with transfer of energy from
| |
| ATP, the formation of AMP -"amino
| |
| acid, and the release of jiyrophosphate
| |
| (Hoagland, Keller and Zamecnick, 1956).
| |
| This reversible step was studied with homogenates of uterine tissue, P^--labeled
| |
| ]n'rni)liosi)liate, and a variety of amino
| |
| | |
| | |
| | |
| acids (Mueller, Herranen and Jervell,
| |
| 1958). Seven of the amino acids tested,
| |
| leucine, tryptophan, valine, tryosine, methionine, glycine, and isoleucine, stimulated the
| |
| exchange of P^^ between pyrophosphate and
| |
| ATP. Pretreatment of the uteri by estradiol
| |
| injected in vivo increased the activity
| |
| of these three enzymes. The activating
| |
| effect of mixtures of these amino acids
| |
| was the sum of their individual effects,
| |
| from which it was inferred that a specific
| |
| enzyme is involved in the activation of
| |
| each amino acid. Since estrogen stimulated the exchange reaction with each of
| |
| these seven amino acids, Mueller concluded that the hormone must affect the
| |
| amount of each of the amino acid-activating enzvmes in the soluble fraction of the
| |
| cell.
| |
| | |
| Mueller (1957) postulated that estrogens
| |
| increase the rate of many enzyme systems
| |
| both by activating preformed enzyme molecules and by increasing the rate of de novo
| |
| synthesis of enzyme molecules, possibly by
| |
| removing membranous barriers covering the
| |
| templates for enzyme synthesis. To explain
| |
| why estrogens affect these enzymes in the
| |
| target organs, but not comparable enzymes
| |
| in other tissues, one would have to assume
| |
| that embryonic differentiation results in
| |
| the formation of enzymes in different tissues
| |
| which, although catalyzing the same reaction, have different properties such as
| |
| their responsiveness to hormonal stimulation.
| |
| | |
| As an alternative hypothesis, estrogen
| |
| might affect some reaction which provides
| |
| a substance required for all of these enzyme reactions. The carboxyl group of
| |
| amino acids must be activated by ATP before the amino acid can be incorporated
| |
| into proteins; the synthesis of both purines
| |
| and pyrimidines requires ATP for the
| |
| activation of the carboxyl group of certain
| |
| precursors and for several other steps; the
| |
| synthesis of cholesterol requires ATP for
| |
| the conversion of mevalonic acid to
| |
| squalene; and the synthesis of fatty acids
| |
| is also an energy-requiring process. Thus if
| |
| (>strogens acted in some way to increase the
| |
| amount of biologically useful energy, in
| |
| the form of ATP or of energy-rich thioesters
| |
| such as acetyl coenzyme A, it would increase
| |
| the rate of synthesis of all of these compo
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 655
| |
| | |
| | |
| | |
| nents of the cell. This would occur, of course,
| |
| only if the supply of ATP, rather than the
| |
| amount of enzyme, substrate, or some other
| |
| cofactor, were the rate-limiting factor in the
| |
| synthetic processes.
| |
| | |
| When purified estrogens became available, they were tested for their effects on
| |
| tissues in vitro. Estrogens added in vitro increased the utilization of oxygen by the rat
| |
| uterus (Khayyal and Scott, 1931) and the
| |
| rat pituitary (Victor and Andersen, 1937).
| |
| The addition of estradiol- 17^ at a level of
| |
| 1 fxg. per ml. of incubation medium increased
| |
| the rate of utilization of oxygen and of
| |
| pyruvic acid by slices of human endometrium and increased the rate at which labeled glucose and pyruvate were oxidized to
| |
| C^-^Os (Hagerman and Villee, 1952, 1953a,
| |
| 1953b) . In experiments with slices of human
| |
| placenta similar results were obtained and
| |
| it was found that estradiol increased the
| |
| rate of conversion of both pyruvate-2-C^'*
| |
| and acetate-l-Ci4 to C^^Os (Villee and
| |
| Hagerman, 1953) . From this and other evidence it was inferred that the estrogen acted
| |
| at some point in the oxidative pathway
| |
| common to pyruvate and acetate, i.e., in the
| |
| tricarboxylic acid cycle.
| |
| | |
| Homogenates of placenta also respond to
| |
| estradiol added in vitro. With citric acid as
| |
| substrate, the utilization of citric acid and
| |
| oxygen and the production of a-ketoglutaric
| |
| acid were increased 50 per cent by the
| |
| addition of estradiol to a final concentralion of 1 fjig. per ml. (Villee and Hagerman,
| |
| 1953). The homogenates were separated by
| |
| differential ultracentrifugation into nuclear,
| |
| mitochondrial, microsomal, and nonparticulate fractions. The estrogen-stimulable system was shown to be in the nonparticulate
| |
| fraction, the material which is not sedimented by centrifugating at 57,000 X g
| |
| for 60 minutes (Villee, 1955). Experiments
| |
| with citric, as-aconitic, isocitric, oxalosuccinic, and a-ketoglutaric acids as substrates and with fluorocitric and transaconitic acids as inhibitors localized the
| |
| estrogen-sensitive system at the oxidation
| |
| of isocitric to oxalosuccinic acid, which then
| |
| undergoes spontaneous decarboxylation to
| |
| a-ketoglutaric acid (Villee and Gordon,
| |
| 1955). Further investigations using the enzymes of the nonparticulate fraction of
| |
| the human placenta revealed that, in ad
| |
| | |
| | |
| dition to isocitric acid as substrate, only
| |
| DPN and a divalent cation such as Mg+ +
| |
| or Mn++ were required (Villee, 1955; Gordon and Villee, 1955; Villee and Gordon,
| |
| 1956). The estrogen-sensitive reaction was
| |
| formulated as a DPN-linked isocitric dehydrogenase:
| |
| | |
| Isocitrate + DPN* -^ a-ketoglutarate
| |
| | |
| + CO2 + DPXH + H*
| |
| | |
| It was found that the effect of the hormone on the enzyme can be measured by
| |
| the increased rate of disappearance of citric
| |
| acid, the increased rate of appearance of
| |
| a-ketoglutaric acid, or by the increased
| |
| rate of reduction of DPN, measured spectrophotometrically by the optical density at
| |
| 340 m/x. As little as 0.001 /xg. estradiol per
| |
| ml. (4 X 10~^ m) produced a measurable
| |
| increase in the rate of the reaction, and
| |
| there was a graded response to increasing
| |
| concentrations of estrogen. The dose-response curve is typically sigmoid. This system has been used to assay the estrogen
| |
| content of extracts of urine (Gordon and
| |
| Villee, 1956) and of tissues (Hagerman,
| |
| Wellington and Villee, 1957; Loring and
| |
| Villee, 1957).
| |
| | |
| Attempts to isolate and purify the estrogen-sensitive enzyme were not very successful. By a combination of low temperature
| |
| alcohol fractionation and elution from calcium phosphate gel a 20-fold purification
| |
| was obtained (Hagerman and Villee, 1957).
| |
| However, as the enzyme was purified it was
| |
| found that an additional cofactor was required. Either uridine triphosphate (UTP)
| |
| or ATP added to the system greatly
| |
| increased the magnitude of the estrogen effect and, subsequently, adenosine diphosphate (ADP) was recovered from the incubation medium and identified by paper
| |
| chromatography (Villee and Hagerman,
| |
| 1957). Talalay and Williams-Ashman
| |
| (1958) confirmed our observations and
| |
| showed that the additional cofactor was
| |
| triphosphopyridine nucleotide (TPN) which
| |
| was required in minute amounts. This finding was confirmed by Villee and Hagerman
| |
| (1958) and the estrogen-sensitive enzyme
| |
| system of the placenta is now believed to be
| |
| a transhydrogenase which catalyzes the
| |
| transfer of hydrogen ions and electrons
| |
| | |
| | |
| | |
| 656
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| fromTPNHtoDPN:
| |
| | |
| TPXH + DPN^ -> DPNH + TPN^
| |
| | |
| The transhydrogenation system can be
| |
| coupled to glucose 6-phosphate dehydrogenase as well as to isocitric dehydrogenase
| |
| (Talalay and Williams-Ashman, 1958; Villee and Hagerman, 1958) and presumably
| |
| can be coupled to any TPNH-generating
| |
| system.
| |
| | |
| If the estrogen-stimulable transhydrogenation reaction were readily reversible, an
| |
| enzyme such as lactic dehydrogenase which
| |
| requires DPN should be stimulated by
| |
| estrogen if supplied with substrate amounts
| |
| of TPN, catalytic amounts of DPN, and
| |
| a preparation from the placenta containing
| |
| the transhydrogenase. Experiments to test
| |
| this prediction were made using lactic dehydrogenase and alcohol dehydrogenase of
| |
| both yeast and liver (Villee, 1958a). It was
| |
| not possible to demonstrate an estrogen
| |
| stimulation of either enzyme system in
| |
| either the forward or the reverse direction.
| |
| The stimulation of the lactic dehydrogenase-DPN oxidase system of the rat uterus
| |
| by estrogens administered in vivo reported
| |
| by Bever, Velardo and Hisaw (1956)
| |
| might be explained by the stimulation of
| |
| a transhydrogenase, but it has not yet been
| |
| possible to demonstrate a coupling of this
| |
| transhydrogenase and lactic dehydrogenase.
| |
| | |
| The stimulating effect of a number of
| |
| steroids has been tested with a system in
| |
| which the transhydrogenation reaction is
| |
| coupled to isocitric dehydrogenase (Villee
| |
| and Gordon, 1956; Hollander, Nolan and
| |
| Hollander, 1958). Estrone, equilin, equilenin, and 6-ketoestradiol have activities
| |
| essentially the same as that of estradiol17 j3. Samples of 1 -methyl estrone and 2methoxy-estrone had one-half the activitj''
| |
| of estradiol. Estriol is only weakly estrogenic in this system; 33 fig. estriol are less
| |
| active than 0.1 fig. estradiol- 17/3 (Villee,
| |
| 1957a). The activities of estriol and 16epiestriol are similar, whereas 16-oxoestradiol is more active than either, with about
| |
| 10 per cent as much activitv as csti'adiol17/3.
| |
| | |
| Certain analogues of stilbestrol have been
| |
| shown to be anti-estrogens in vivo. When
| |
| applied topically to the vagina of the rat,
| |
| they prevent the cornification normally in
| |
| | |
| | |
| duced by the administration of estrogen
| |
| (Barany, Morsing, Muller, Stallberg, and
| |
| Stenhagen, 1955). One of these, 1,3-di-phydroxyphenylpropane, was found to be
| |
| strongly anti-estrogenic in the placental
| |
| system in vitro: it prevented the acceleration of the transhydrogenase-isocitric dehydrogenase system normally produced by
| |
| estradiol- 17/3 (Villee and Hagerman, 1957).
| |
| The inhibitory power declines as the length
| |
| of the carbon chain connecting the two
| |
| phenolic rings is increased and 1 , 10-di-phydroxyphenyldecane had no inhibitory action. Similar inhibitions of the estradiolsensitive system were observed with stilbestrol, estradiol-17a, and a smaller antiestrogenic effect was found with estriol
| |
| (Villee, 1957a). The inhibition induced
| |
| by these compounds can be overcome by
| |
| adding increased amounts of estradiol-17^.
| |
| When stilbestrol is added alone at low concentration, 10~' M, it has a stimulatory effect equal to that of estradiol-17^ (Glass,
| |
| Loring, Spencer and Villee, 1961).
| |
| | |
| The quantitative relations between the
| |
| amounts of stimulator and inhibitor suggest
| |
| that this inhibition is a competitive one. It
| |
| was postulated that this phenomenon involves a competition between the steroids
| |
| for specific binding sites on the estrogensensitive enzyme (Villee, 1957b; Hagerman
| |
| and Villee, 1957). When added alone, estriol
| |
| and stilbestrol are estrogenic and increase
| |
| the rate of the estrogen-sensitive enzyme.
| |
| In the presence of both estradiol and estriol,
| |
| the total enzyme activity observed is the
| |
| sum of that due to the enzyme combined
| |
| with a potent activator, estradiol- 17^, and
| |
| that due to the enzyme combined with a
| |
| weak activator, estriol. When the concentration of estriol is increased, some of the
| |
| estradiol is displaced from the enzyme and
| |
| the total activity of the enzyme system is
| |
| decreased.
| |
| | |
| Two hypotheses have been proposed for
| |
| the mechanism of action of estrogens on the
| |
| enzyme system of the placenta. One states
| |
| that the estrogen combines with an inactive
| |
| form of the enzyme and converts it to an
| |
| active form (Hagerman and Villee, 1957).
| |
| When this theory was formulated the evidence indicated that the estrogen acted on
| |
| a specific DPN-linked isocitric dehydrogenase. The theory is equally applicable if the
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 657
| |
| | |
| | |
| | |
| estrogen-sensitive enzyme is a transhydrogenase, as the evidence now indicates. The
| |
| results of kinetic studies with the coupled
| |
| isocitric dehydrogenase-transhydrogenase
| |
| system are consistent with this theory
| |
| (Gordon and Villee, 1955; Villee, 1957b;
| |
| Hagerman and Villee, 1957). Apparent
| |
| binding constants for the enzyme-hormone
| |
| complex (Gordon and Villee, 1955j and for
| |
| enzyme-inhibitor complexes have been calculated (Hagerman and Villee, 1957).
| |
| | |
| The observation that estradiol and estrone, which differ in structure only by a
| |
| pair of hydrogen atoms, are equally effective in stimulating the reaction suggested
| |
| that the steroid might be acting in some way
| |
| as a hydrogen carrier from substrate to
| |
| pyridine nucleotide (Gordon and Villee,
| |
| 1956). Talalay and Williams-Ashman
| |
| (1958) suggested that the estrogens act as
| |
| coenzymes in the transhydrogenation reaction and postulated that the reactions were:
| |
| | |
| Estrone + TPNH + H*
| |
| | |
| — Estradiol + TPN^
| |
| | |
| Estradiol + DPN+
| |
| | |
| — Estrone + DPNH + H*
| |
| | |
| | |
| | |
| Sum : TPNH
| |
| | |
| | |
| | |
| H*
| |
| | |
| | |
| | |
| - DPN^
| |
| — TPN^ + H^
| |
| | |
| | |
| | |
| DPNH
| |
| | |
| This formulation implies that the estrogen-sensitive transhydrogenation reaction
| |
| is catalyzed by the estradiol-17y3 dehydrogenase characterized by Langer and Engel
| |
| (1956). This enzyme was shown by Langer
| |
| (1957) to use either DPN or TPN as hydrogen acceptor but it reacts more rapidly
| |
| with DPN. Ryan and Engel (1953) showed
| |
| that this enzyme is present in rat liver, and
| |
| in human adrenal, ileum, and liver. However, no estrogen-stimulable enzyme is
| |
| demonstrable in rat or human liver (Villee,
| |
| 1955). The nonparticulate fraction obtained
| |
| by high speed centrifugation of homogenized rabbit liver rapidly converts estradiol
| |
| to estrone if DPN is present as hydrogen
| |
| acceptor, but does not contain any estrogenstimulable transhydrogenation system.
| |
| | |
| It will not be possible to choose between
| |
| these two hypotheses until either the estrogen-sensitive transhydrogenase and the
| |
| estradiol dehydrogenase have been separated or there is conclusive proof of their
| |
| | |
| | |
| | |
| identity. Talalay, Williams-Ashman and
| |
| Hurlock (1958) reported a 100-fold purification of the dehydrogenase without separation of the transhydrogenase activity
| |
| and found that both activities were inhibited identically by sulfhydryl inhibitors.
| |
| In contrast, Hagerman and Villee (1958)
| |
| obtained partial separation of the two activities by the usual techniques of protein
| |
| fractionation, and reported that a 50 per
| |
| cent inhibition of transhydrogenase is obtained with p-chloromercurisulfonic acid at
| |
| a concentration of 10~^ m whereas 10"^ m
| |
| p-chloromercurisulfonic acid is required for
| |
| a 50 per cent inhibition of the dehydrogenase. The evidence that these two activities are mediated by separate and distinct proteins has been summarized by
| |
| Villee, Hagerman and Joel (1960).
| |
| | |
| The transhydrogenase present in the
| |
| mitochondrial membranes of heart muscle
| |
| was shown by Ball and Cooper (1957) to be
| |
| inhibited by 4 X 10"^ m thyroxine. The
| |
| estrogen-sensitive transhydrogenase of the
| |
| placenta is also inhibited by thyroxine (Villee, 1958b). The degree of inhibition is a
| |
| function of the concentration of the thyroxine and the inhibition can be overcome by
| |
| increased amounts of estrogen. Suitable control experiments show that thyroxine at
| |
| this concentration does not inhibit the glucose 6-phosphate dehydrogenase or isocitric
| |
| dehydrogenase used as TPNH-generating
| |
| systems to couple with the transhydrogenase. Triiodothyronine also inhibits the
| |
| estrogen-sensitive transhydrogenase but
| |
| tyrosine, diiodotyrosine and thyronine do
| |
| not. The thyroxine does not seem to be
| |
| inhibiting by binding the divalent cation,
| |
| Mn + + or ]Mg+ + , required for activity, for
| |
| the inhibition is not overcome by increasing
| |
| the concentration of the cation 10-fold.
| |
| | |
| In the intact animal estrogens stimulate
| |
| the growth of the tissues of certain target
| |
| organs. The estrogen-sensitive enzyme has
| |
| been shown to be present in many of the
| |
| target organs of estrogens: in human endometrium, myometrium, placenta, mammary
| |
| gland, and mammary carcinoma, in rat ventral prostate gland and uterus, and in mammotrophic-dependent transplantable tumors
| |
| of the rat and mouse pituitary. In contrast,
| |
| it is not demonstrable in comparable preparations from liver, heart, lung, brain, or
| |
| | |
| | |
| | |
| 658
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| kidney. The growth of any tissue involves
| |
| the utilization of energy, derived in large
| |
| part from the oxidation of substrates, for
| |
| the synthesis of new chemical bonds and for
| |
| the reduction of substances involved in the
| |
| synthesis of compounds such as fatty acids,
| |
| cholesterol, purines, and pyrimidines.
| |
| | |
| The physiologic responses to estrogen
| |
| action, such as water imbibition and protein
| |
| and nucleic acid synthesis, are processes not
| |
| directly dependent on the activity of transhydrogenase. However, all of these processes
| |
| are endergonic, and one way of increasing
| |
| their rate would be to increase the supply of
| |
| biologically available energy by speeding
| |
| up the Krebs tricarboxylic acid cycle and
| |
| the flow of electrons through the electron
| |
| transmitter system. Much of the oxidation
| |
| of substrates by the cell produces TPNH,
| |
| whereas the major fraction of the biologically useful energy of the cell comes from the
| |
| oxidation of DPNH in the electron transmitter system of the cytochromes. Hormonal
| |
| control of the rat of transfer of hydrogens
| |
| from TPN to DPN could, at least in theory,
| |
| influence the over-all rate of metabolism in
| |
| the cell and secondarily influence the
| |
| amount of energy available for synthetic
| |
| processes. Direct evidence of this was shown
| |
| in our early experiments in which the oxygen consumption of tissue slices of target
| |
| organs was increased by the addition of
| |
| estradiol (Hagerman and Villee, 1952; Villee and Hagerman, 1953).
| |
| | |
| This theory assumes that the supply of
| |
| energy is rate-limiting for synthetic processes in these target tissues and that the
| |
| activation of the estrogen-sensitive enzyme
| |
| does produce a significant increase in the
| |
| supply of energy. The addition of estradiol
| |
| in vitro produces a significant increase in
| |
| the total amount of isocitric acid dehydrogenated by the placenta (Villee, Loring
| |
| and Sarner, 1958) . Slices of endometrium to
| |
| which no estradiol was added in vitro
| |
| utilized oxygen and metabolized substrates
| |
| to carbon dioxide at rates which paralleled
| |
| the levels of estradiol in the blood and urine
| |
| of the patient from whom the endometrium
| |
| was obtained (Hagerman and Villee,
| |
| esses in these target tissues and that the
| |
| 1953b). Estradiol increases the rate of synthesis of ATP by liomogenates of human
| |
| | |
| | |
| | |
| placenta (Villee, Joel, Loring and Spencer,
| |
| 1960).
| |
| | |
| The reductive steps in the biosynthesis of
| |
| steroids, fatty acids, purines, serine, and
| |
| other substances generally require TPNH
| |
| rather than DPNH as hydrogen donor. The
| |
| cell ordinarily contains most of its TPN
| |
| in the reduced state and most its DPN in
| |
| the oxidized state (Glock and McLean,
| |
| 1955). If the amount of TPN+ is ratelimiting, a transhydrogenase, by oxidizing
| |
| TPN and reducing DPN, would permit
| |
| further oxidation of substrates such as isocitric acid and glucose 6-phosphate, which
| |
| require TPN+ as hydrogen acceptor and
| |
| which are key reactions in the Krebs tricarboxylic acid cycle and the hexose monophosphate shunt, respectively. Furthermore,
| |
| the experiments of Kaplan, Schwartz, Freeh
| |
| and Ciotti (1956) indicate that less biologically useful energy, as ATP, is obtained
| |
| when TPNH is oxidized by TPNH cytochrome c reductase than when DPNH is
| |
| oxidized by DPNH cytochrome c reductase.
| |
| Thus, a transhydrogenase, by transferring
| |
| hydrogens from TPNH to DPN before
| |
| oxidation in the cytochrome system, could
| |
| increase the energy yield from a given
| |
| amount of TPNH produced by isocitrate or
| |
| glucose 6-phosphate oxidation. The increased amount of biologically useful energy
| |
| could be used for growth, for protein and
| |
| nucleic acid synthesis, for the imbibition of
| |
| water, and for the other physiologic effects
| |
| of estrogens.
| |
| | |
| Estrogen stimulation of the transhydrogenation reaction would tend to decrease
| |
| rather than increase the amount of TPNH
| |
| in the cell. Thus the estrogen-induced stimulation of the synthesis of steroids, fatty
| |
| acids, proteins, and purines in the uterus
| |
| can be explained more reasonably as due to
| |
| an increased supply of energy rather than
| |
| to an increased supply of TPNH.
| |
| | |
| The theory that estrogens stimulate transhydrogenation by acting as coenzymes
| |
| which are rapidly and reversibly oxidized
| |
| and reduced does not explain the pronounced estrogenic activity in vivo of stilbestrol, 17a-ethinyl estradiol, or bfsdehydrodoisynolic acid, for these substances do
| |
| not contain groups that could be readily
| |
| oxidized or reduced. The exact mechanism
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| (359
| |
| | |
| | |
| | |
| of action of estrogens at the biochemical
| |
| level remains to be elucidated, but the
| |
| data available permit the formulation of a
| |
| detailed working hypothesis. The notable
| |
| effects of estrogens and androgens on behavior (see chapter by Young) are presumably due to some direct or indirect effect of the hormone on the central nervous
| |
| system. The explanation of these phenomena
| |
| in physiologic and biochemical terms remains for future investigations to provide.
| |
| | |
| B. ANDROGENS
| |
| | |
| Although there is a considerable body of
| |
| literature regarding the responses at the biologic level to administered androgens and
| |
| progesterone, much less is known about the
| |
| site and mechanism of action of these hormones than is known about the estrogens.
| |
| The review by Roberts and Szego (1953b)
| |
| deals especially with the synergistic and
| |
| antagonistic interactions of the several
| |
| steroidal sex hormones.
| |
| | |
| The rapid growth of the capon comb following the administration of testosterone
| |
| has been shown to involve a pronounced
| |
| increase in the amount of mucopolysaccharide present, as measured by the content
| |
| of glucosamine (Ludwig and Boas, 1950;
| |
| Schiller, Benditt and Dorfman, 1952). It
| |
| is not known whether the androgen acts by
| |
| increasing the amount or activity of one of
| |
| the enzymes involved in the synthesis of
| |
| polysaccharides or whether it increases the
| |
| amount or availability of some requisite
| |
| cofactor. Many of the other biologic effects
| |
| of androgens do not seem to involve
| |
| mucopolysaccharide synthesis and the
| |
| relation of these observations to the
| |
| other roles of androgens remains to he determined.
| |
| | |
| Mann and Parsons (1947) found that
| |
| castration of rabbits resulted in a decreased
| |
| concentration of fructose in the semen.
| |
| Within 2 to 3 weeks after castration the
| |
| amount of fructose in the semen dropped
| |
| to zero, but rapidly returned to normal following the subcutaneous implantation of a
| |
| pellet of testosterone. Fructose reappeared
| |
| in the semen of the castrate rat 10 hours
| |
| after the injection of 10 mg. of testosterone
| |
| (Rudolph and Samuels, 1949). The coagulating gland of the rat, even when trans
| |
| | |
| | |
| planted to a new site in the body, also responds by producing fructose when the host
| |
| is injected with testosterone. The amount
| |
| of citric acid and ergothioneine in the semen
| |
| is also decreased by castration and increased by the implantation of testosterone
| |
| pellets (Mann, 1955). The experiments of
| |
| Hers (1956) demonstrate that fructose
| |
| is produced in the seminal vesicle by
| |
| the reduction of glucose to sorbitol and
| |
| the subsequent oxidation of sorbitol to
| |
| fructose. The reduction of glucose requires TPNH as hydrogen donor and the
| |
| oxidation of sorbitol requires DPN as
| |
| hydrogen acceptor. The sum of these two
| |
| reactions provides for the transfer of hydrogens from TPNH to DPN. If androgens
| |
| act as cofactors which are reversibly oxidized and reduced, and thus transfer hydrogens from TPNH to DPN as postulated
| |
| by Talalay and Williams-Ashman (1958),
| |
| one would expect that an increased amount
| |
| of androgen, by providing a competing system for hydrogen transfer, would decrease
| |
| rather than increase the production of fructose. The marked increases in the citric
| |
| acid and ergothioneine content of semen
| |
| are not readily explained by this postulated
| |
| site of action of androgens.
| |
| | |
| An increase in the activity of /3-glucuronidase in the kidney has been reported
| |
| following the administration of androgens
| |
| (Fishman, 1951). This might be interpreted
| |
| as an arlaptive increase in enzyme induced
| |
| by the increased concentration of substrate,
| |
| or by a direct effect of the steroid on the
| |
| synthesis of the enzyme.
| |
| | |
| The respiration of slices of prostate gland
| |
| of the dog is decreased by castration or by
| |
| the administration of stilbestrol (Barron
| |
| and Huggins, 1944). The decrease in respiration occurs with either glucose or pyruvate
| |
| as substrate. The seminal vesicle of the rat
| |
| responds similarly to castration. Rudolph
| |
| and Samuels (1949) found that respiration
| |
| of slices of seminal vesicle is decreased by
| |
| castration and restored to normal values
| |
| within 10 hours after the injection of testosterone. Experiments by Dr. Phillip Corfman in our laboratory with slices of prostate
| |
| gland from patients with benign prostatic
| |
| hypertrophy showed that oxygen utilization
| |
| was reduced 50 per cent by estradiol added
| |
| | |
| | |
| | |
| 660
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| in vitro at a level of 1 /xg. per ml. Respiration of slices of the ventral prostate gland
| |
| of the rat is decreased by castration and increased by administered testosterone (Nyden and Williams-Ashman, 1953). These
| |
| workers showed that lipogenesis from acetate-l-C^* in the prostate is also significantly diminished by castration and
| |
| restored to normal by administered testosterone.
| |
| | |
| The succinic dehydrogenase of the liver
| |
| has been found to be increased by castration
| |
| and decreased by the administration of testosterone (Kalman, 1952; Rindani, 1958),
| |
| the enzyme is also inhibited by testosterone
| |
| added in vitro (Kalman, 1952). In contrast,
| |
| Davis, Meyer and McShan (1949) found
| |
| that the succinic dehydrogenase of the
| |
| prostate and seminal vesicles is decreased
| |
| by castration and increased by the administration of testosterone.
| |
| | |
| An interesting example of an androgen
| |
| effect on a specific target organ is the decreased size of the levator ani and
| |
| other perineal muscles of the rat following castration. The administration of
| |
| androgen stimulates the growth of these
| |
| muscles and increases their glycogen content
| |
| (Leonard, 1952). However, their succinoxidase activity is unaffected by castration
| |
| or by the administration of testosterone.
| |
| Courrier and Marois (1952) reported that
| |
| the growth of these muscles stimulated by
| |
| androgen is inhibited by cortisone. The
| |
| remarkable responsiveness of these muscles
| |
| to androgens in vivo gave promise that
| |
| slices or homogenates of this tissue incubated with androgens might yield clues as to
| |
| the mode of action of the male sex hormones. Homogenates of perineal and masseter muscles of the rat responded to androgens administered in vivo with increased
| |
| oxygen consumption and ATP production
| |
| iLoring, Spencer and Villee, 1961). The experiments suggested that the activity of
| |
| DPNH-cytochromo r reductase in these
| |
| tissues is controlled by aiKh'ogeiis.
| |
| | |
| C. PROGESTERONE
| |
| | |
| Attempts to clarify the biochemical basis
| |
| of the role of progesterone have been hampered by the requirement, in most instances,
| |
| for a previous stimulation of the tissue by
| |
| estrogen. The work of Wade and Jones
| |
| | |
| | |
| | |
| (1956a, b) demonstrated an interesting effect of progesterone added in vitro on several aspects of metabolism in rat liver mitochondria. Progesterone, but not estradiol,
| |
| testosterone, 17a-hydroxyprogesterone, or
| |
| any of several other steroids tested, stimulated the adenosine triphosphatase activity
| |
| of rat liver mitochondria. This stimulation
| |
| is not the result of an increased permeability
| |
| of the mitochondrial membrane induced by
| |
| progesterone, for the stimulatory effect is
| |
| also demonstrable with mitochondria that
| |
| have been repeatedly frozen and thawed to
| |
| break the membranes. Other experiments
| |
| showed that ATP was the only substrate
| |
| effective in this system ; progesterone did not
| |
| activate the release of inorganic phosphate
| |
| from AMP, ADP, or glycerophosphate.
| |
| | |
| In other experiments with rat liver mitochondria (Wade and Jones, 1956b), progesterone at a higher concentration (6 X lO"'*
| |
| m) was found to inhibit the utilization of
| |
| oxygen with one of the tricarboxylic acids
| |
| or with DPNH as substrate. This inhibition
| |
| is less specific and occurred with estradiol,
| |
| testosterone, pregnanediol, and 17a-hydroxy progesterone, as well as with progesterone. The inhibition of respiration by high
| |
| concentrations of steroids in vitro has been
| |
| reported many times and with several different tissues; it seems to be relatively unspecific. Wade and Jones were able to show
| |
| that progesterone inhibits the reduction of
| |
| cytochrome c but accelerates the oxidation
| |
| of ascorbic acid. They concluded that progesterone may perhaps uncouple oxidation
| |
| from phosphorylation in a manner similar
| |
| to that postulated for dinitrophenol. The
| |
| site of action of this uncoupling appears to
| |
| be in the oxidation-reduction path between
| |
| DPNH and cytochrome c. Mueller (1953)
| |
| found that progesterone added in vitro decreases the incorporation of glycine-2-C^'*
| |
| into the protein of strips of rat uterus, thus
| |
| counteracting the stimulatory effect of estradiol administered in vivo.
| |
| | |
| Zander (1958) reported that A4-3-ketopregnene-20-a-ol and A4-3-ketopregnene20-^-ol arc effective gestational hormones
| |
| in the mouse, rabbit, and man, although
| |
| somewhat less active in general than is
| |
| progesterone. An enzyme in rat ovary which
| |
| converts progesterone to pregnene-20-a-ol,
| |
| and also catalyzes the reverse reaction, was
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 661
| |
| | |
| | |
| | |
| described by Wiest (1956). The conversion
| |
| occurred when slices of ovary were incubated with DPN. Wiest postulated that
| |
| the progesterone-pregnene-20-a-ol system
| |
| might play a role in hydrogen transfer, in
| |
| a manner analogous to that postulated by
| |
| Talalay and Williams-Ashman (1958) for
| |
| estrone-estradiol- 17^, but his subsequent
| |
| experiments ruled out this possibility, for
| |
| he was unable to demonstrate any progesterone-stimulable transhydrogenation reaction.
| |
| | |
| The nature of the effect of progesterone
| |
| and of estrogens on myometrium has been
| |
| investigated extensively by Csapo. Csapo
| |
| and Corner (1952, 1953) found that ovariectomy decreased the maximal tension of
| |
| the myometrium and decreased its content
| |
| of actomyosin. The administration of estradiol to the ovariectomized rabbit over a
| |
| period of 7 days restored both the actomyosin content and the maximal tension of the
| |
| myometrium to normal. The concentration
| |
| of ATP and of creatine phosphate in the
| |
| myometrium is decreased by ovariectomy
| |
| but is restored by only 2 days of estrogen
| |
| treatment. This suggests that the effect on
| |
| intermediary metabolism occurs before the
| |
| effect on protein {i.e., actomyosin) synthesis. Csapo (1956a) concluded that estrogen
| |
| is a limiting substance in the synthesis of
| |
| the contractile proteins of myometrium, but
| |
| he could not differentiate between an effect
| |
| of estrogen on some particular biosynthetic
| |
| reaction and an effect of estrogen on some
| |
| fundamental reaction which favors synthesis in general. He was unable to demonstrate
| |
| any comparable effect of progesterone on
| |
| the contractile actomyosin-ATP system of
| |
| the myometrium.
| |
| | |
| Other observations provide an explanation for the well known effect of progesterone in decreasing the contractile activity of
| |
| myometrium, not by any effect on the contractile system itself, but in some previous
| |
| step in the excitation process. Under the
| |
| domination of progesterone the myometrial
| |
| cells have a decreased intracellular concentration of potassium ions and an increased
| |
| concentration of sodium ions (Horvath,
| |
| 1954). The change in ionic gradient across
| |
| the cell membrane is believed to be responsible for the altered resting potential and
| |
| the partial depolarization of the cell mem
| |
| | |
| | |
| brane which results in decreased conductivity and decreased pharmacologic reactivity
| |
| of the myometrial cell. The means by which
| |
| progesterone produces the changes in ionic
| |
| gradients is as yet unknown. Csapo postulates that the hormone might decrease the
| |
| rate of metabolism which in turn would
| |
| lessen the rate of the "sodium pump" of the
| |
| cell membrane. The contractile elements,
| |
| the actomyosin-ATP system, are capable of
| |
| full contraction but, because of the partial
| |
| block in the mechanism of excitation and of
| |
| propagation of impulses (Csapo, 1956b),
| |
| the muscle cells cannot operate effectively;
| |
| the contractile activity remains localized.
| |
| Csapo (1956a) showed that the progesterone
| |
| block is quickly reversible and disappears if
| |
| progesterone is withdrawn for 24 hours. He
| |
| concluded that the progesterone block is
| |
| necessary for the continuation of pregnancy
| |
| and that its withdrawal is responsible for
| |
| the onset of labor.
| |
| | |
| ]\Iost investigators who have speculated
| |
| about the mode of action of steroids —
| |
| whether they believe the effect is by activating an enzyme, by altering the permeability of a membrane, or by serving as a
| |
| coenzyme in a given reaction— have emphasized the physical binding of the steroid to
| |
| a protein as an essential part of the mechanism of action or a preliminary step to
| |
| that action. They have in this way explained
| |
| the specificities, synergisms, and antagonisms of the several steroids in terms of the
| |
| formation of specific steroid-protein complexes. The differences between different
| |
| target organs, e.g., those that respond to
| |
| androgens and those that respond to estrogens, can be attributed to differences in the
| |
| distribution of the specific proteins involved
| |
| in these binding reactions. Viewed in this
| |
| light, the problem of the mode of action of
| |
| sex hormones becomes one aspect of the
| |
| larger problem of the biochemical basis of
| |
| embryonic differentiation of tissues.
| |
| | |
| IV. References
| |
| | |
| Allen, W. M. 1939. Biochemistry of the corpus
| |
| luteum hormone, progesterone. In Sex and
| |
| Internal Secretions. 2nd ed., E. Allen, C. H.
| |
| Danforth and E. A. Doisy, Eds., pp. 901-928.
| |
| Baltimore : The Wilhams & Wilkins Company.
| |
| | |
| AsTWOOD, E. B. 1938. A six-hour assay for the
| |
| quantitative determination of estrogen. Endocrinology, 23, 25-31.
| |
| | |
| B.-vcGETT, B., Engel, L. L., Savard, K., .and Dorfman,
| |
| | |
| | |
| | |
| 062
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| R. I. 1956. The conversion of testosterone3C" to C"-estradiol-17/3 by human ovarian
| |
| tissue. J. Biol. Chem., 221, 931-941.
| |
| Ball, E. G., .4nd Cooper, O. 1957. Oxidation of
| |
| reduced triphosphopyridine nucleotide as mediated by the transliydrogenase reaction and
| |
| its inhibition by thvroxine. Proc. Nat. Acad.
| |
| Sc, 43, 357-364.
| |
| | |
| B.AU\NY, E., MORSING, P., MxJLLER, W., StALLBERG,
| |
| | |
| G., AND Stenhagen, E. 1955. Inhibition of
| |
| estrogen-induced proliferation of the vaginal
| |
| epithelium of the rat by topical application of
| |
| certain 4, 4'-hydroxy-diphenyl-alkanes and related compounds. Acta Soc. Med. Uppsala, 60,
| |
| 68-74.
| |
| | |
| B.\RR0N, E. S. G., .\ND HUGGIN.S, C. 1944. The
| |
| metabolism of isolated prostatic tissue. J.
| |
| Urol., 51, 630-634.
| |
| | |
| Bever, a. T., Velardo, J. T., and His.w, F. L.
| |
| 1956. Action of estrogens on lactic dehydrogena.se-DPNH oxidase system of rat uterus.
| |
| Endocrinology, 58, 512-522.
| |
| | |
| Bloch, K. 1951. II. Use of isotopes in liormone
| |
| problems: the biologic synthesis of cholesterol.
| |
| Recent Progr. Hormone Res., 6, 111-129.
| |
| | |
| BoNGiovANNi, A. M. 1953. The detection of pregnanediol and pregnanetriol in the urine of patients with adrenal hyperplasia. Suppression
| |
| with cortisone. Bull. John Hopkins Hosp., 92,
| |
| 244-251.
| |
| | |
| Carroll, W. R. 1942. Influence of estrogen on
| |
| respiration of rat uterine tissue. Proc. Soc.
| |
| Exper. Biol. & Med., 49, 50-52.
| |
| | |
| Caspi, E., Rosenfeld, G., and Dorfman, R. T.
| |
| 1956. Degradation of cortisol-C" and corticosterone-C" biosynthesized from acetate1-C". J. Organ. Chem., 21, 814-815.
| |
| | |
| Cl.ayton, R. B., and Bloch, K. 1956. The biologic
| |
| conversion of lanosterol to cholesterol. J. Biol.
| |
| Chem.. 218, 319-325.
| |
| | |
| CoLOWicK, S. P., CoRi, G. T., .AND Slein, M. W.
| |
| 1947. The effect of adrenal cortex and anterior pituitary extracts and insulin on the hexokina.se reaction. J. Biol. Chem., 168, 583-596.
| |
| | |
| CouRRiER, R., AND Marois, M. 1952. Endocrinologie: relations entre la testosterone et le
| |
| cortisone dans leur effets sur certains organes
| |
| recepteiM's. Compt. rend. Acad. Sc, 234, 271273.
| |
| | |
| Cs.APO, A. 1956a. Progesterone Ijlock. Am. J.
| |
| Anat., 98, 273.
| |
| | |
| CsAPO, A. 1956b. The mechanism of effect of the
| |
| ovarian steroids. Recent Progr. Hormone Res.,
| |
| 12,405-431.
| |
| | |
| CsAPO, A., AND Corner, G. W. 1952. The antagonistic effects of estrogen and progesterone on
| |
| the staiicase phenomenon in uterine muscle.
| |
| Endocrinology, 51, 378-385.
| |
| | |
| CsAPO, A., AND Corner, G. W. 1953. The effect of
| |
| estrogen on the isometric tension of rabbit
| |
| uterine strips. Science, 117, 162-164.
| |
| | |
| Daughaday, W. H. 1956. E\idence for iwo corticosteroid binding systems in human plasma.
| |
| J. Lab. & Clin. Med., 48, 799-800.
| |
| | |
| David, J. C. 1931. The action of estrin on the
| |
| | |
| | |
| | |
| ox.ygen consumption of the uteri of mice. J.
| |
| Pharmacol. & Exper. Therap., 43, 1-11.
| |
| | |
| Davis, J. S., Meyer, R. C, and McShan, W. H.
| |
| 1949. Effect of androgen and estrogen on succinic dehydrogenase and cytochrome oxidase
| |
| of rat prostate and seminal vesicle. Endocrinology, 44, 1-7.
| |
| | |
| DoiSY, E. A. 1939. Biochemistry of estrogenic
| |
| compounds. In Sex and Internal Secretions,
| |
| 2nd ed., E. Allen, C. H. Danforth and E. A.
| |
| Doisy, Eds., pp. 846-876. Baltimore: The Williams & Wilkins Companv.
| |
| | |
| DoiSY, E. A., Veler, CD., .\nd Th.ayer, S. A.
| |
| 1929. Folliculin from urine of pregnant
| |
| women. Am. J. Physiol., 90, 329-330.
| |
| | |
| E.AGLE, H. 1955. The specific amino acid requirements of a human carcinoma cell (strain
| |
| HeLa) in tissue culture. J. Exper. Med., 102,
| |
| 37-48.
| |
| | |
| Eidinoff, M. L., Knoll, J. E., Marano, B. J.,
| |
| KvAM.ME, E., Rosenfeld, R. S., and Hellman, L.
| |
| 1958. Cholesterol biosynthesis: studies related to the metabolic role of squalene. J. Clin.
| |
| Invest., 37, 655-659.
| |
| | |
| E.MMELOT, P., AND Bos, L. 1954. Thc influence
| |
| of estrogens on the protein and lipid metabolism of the mouse uterus studied with acetate1-C". Rec. Trav. Chim., 73, 874-877.
| |
| | |
| FiSHMAN, W. H. 1951. Relationship between estrogens and enzvme activitj'. Vitamins & Hormones, 9, 213-236.
| |
| | |
| Glass, R. B., Loring. J. M., Spencer, J. M., and
| |
| ViLLEE, C. A. 1961. The estrogenic properties in vitro of diethylstilbestrol and substances related to estradiol. Endocrinologv,
| |
| 68, 327-333.
| |
| | |
| Glock, G. E., and McLean, P. 1955. Levels of
| |
| oxidized and reduced diphosphopyridine and
| |
| triphosphopyridine nucleotide in animal tissues. Biochem. J., 61, 388-390.
| |
| | |
| Gordon, E. E., .and Villee, C. A. 1955. Spectrophotometric studies of the stimulation of human placental preparations bv estradiol. J.
| |
| Biol. Chem., 216, 215-224.
| |
| | |
| Gordon, E. E., and Villee, C. A. 1956. An in
| |
| vitro assaj' for estradiol-17|3 and estrone. Endocrinology, 58, 150-157.
| |
| | |
| Grauer, R. C, Strickler, H. S., Wolken, J. J., and
| |
| CuTULY, E. 1950. Influence of estradiol on
| |
| P''" uptake bv the uterus. Proc. Soc. Exper.
| |
| Biol. & Med.,75, 651-654.
| |
| | |
| H.\germ.an, D. D., and Villee, C. A. 1952. Effects
| |
| of estradiol on the metal)olism of human endometrium in vitro. Arch. Biocliem., 40, 481483.
| |
| | |
| Hagerman, D. D., .AND Villee, C. A. 1953a. Effects
| |
| of estradiol on the metabolism of human endometrium in vitro. J. Biol. Clunn., 203, 425431.
| |
| | |
| Hagerman, D. D., AND Villee, C. A. 1953b. Effects of the menstrual cycle on the metabolism of human endometrium. Endocrinology,
| |
| 53, 667-673.
| |
| | |
| HAGER.^L\x, D. D., AND ViLLEE, C. A. 1957. Estro
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 663
| |
| | |
| | |
| | |
| gen sensitive isocitric dehydrogenase. J. Biol.
| |
| Chem., 229, 589-597.
| |
| | |
| Hagerman, D. D., and Villee, C. A. 1958. Metabolic studies of the mechanism of action of
| |
| estrogens. In Symposium on the Endocrinology of Pregnancy, Charles Lloyd, Ed., pp. 317328. New York: Academic Press, Inc.
| |
| | |
| Hagerman, D. D., Wellington, F. M., and Villee,
| |
| C. A. 1957. Estrogens in marine invertebrates. Biol. Bull., 112, 180-183.
| |
| | |
| Hayano, M., and Dorf>l\n, R. I. 1953. The enzymatic C-lli3-hvdroxylation of steroids. J.
| |
| Biol. Chem., 201,^175-188.
| |
| | |
| Hayano, M., Lindberg, M. C, Dorfman, R. I.,
| |
| Hancock, J. E. H., and Doering, W. von E.
| |
| 1955. On the mechanism of the C-ll/3-hydroxylation of steroids; a study with H20^*
| |
| and 02'^ Arch. Biochem., 59, 529-532.
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| Haynes, R. C, Sutherland, E. W., and Rall, T.
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| W. 1960. The role of cyclic adenylic acid in
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| 16, 121-132.
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| Henion, W. F., and Sutherland, E. W. 1957. Immunologic differences of phosphorylases. J.
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| Herranen, A. M., and Mueller, G. C. 1957. The
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| Hers, H. G. 1956. La mecanisme de la transformation de glucose ou fructose par les
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| vesicles seminales. Biochim. et Biophys. Acta,
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| properties of growth hormone from human
| |
| | |
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| 664
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| PHYSIOLOGY OF GONADS
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| human endometrium. Am. J. Obst. it Gvn(H'.,
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| |
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| STEROID SEX HORMONES
| |
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| 665
| |
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| ViLLEE, C. A. 1957b. Role of estrogens in regulating the metabolism of the placenta and
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| In Proceedings Conference on Endocrinology
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| |
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| ct Gvnec, 54, 173-175.
| |
| | |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS ON ENDOCRINE SECRETIONS
| |
| | |
| James H. Leathern, Ph.D.
| |
| | |
| PROFESSOR OF ZOOLOGY, RUTGERS, THE STATE UNIVERSITY,
| |
| NEW BRUNSWICK, NEW JERSEY
| |
| | |
| | |
| | |
| I. Introduction' 666 I, Introduction
| |
| | |
| II. Nature of Problems in Nutritional -j-. -, .^ ^ ,• ,• t ,
| |
| | |
| Studies 668 Despite the accumulation of many data
| |
| | |
| A. Thyroid Cxland, Nutrition, and Re- in the field of reproductive endocrinology
| |
| | |
| production ()68 during the past 20 years and the long es
| |
| B. Adreiial Gland, Nutrition, and Re- ^ _^ tablished awareness of a nutritional in
| |
| C. Diabetef^Mellitus, Nutrition, and '' ^f^f on fertility and fecundity, knowl
| |
| Reproduction ()72 edge bearing on nutrition and the endocrine
| |
| | |
| D. Sterile-Obese Syndrome 673 glands subserving reproduction has ad
| |
| E. Diet and the Liver 673 vanced comparatively slowly. However, re
| |
| III. Hypophysis and Diet 674 markable advances have been made in each
| |
| | |
| A. Inanition 674 speciality SO that nutritional-endocrine
| |
| | |
| ^roein. .. w problems should continue to be a fruitful
| |
| | |
| C. Carbohvdrate and Fat ()7() ^ „ ^i-r^x i-ii
| |
| | |
| D Vitamins 676 ^^^^^ ^^^' ^tudy. Data which have yet to
| |
| | |
| IV. Male Reproductive System (i77 be obtained eventually w'ill contribute to
| |
| | |
| A. Testis 677 the coherence one would prefer to present
| |
| | |
| 1. Inanition 677 now.
| |
| | |
| 2. Protein 678 'y\^q endocrinologist appreciates the deli
| |
| 4 Vitamins (i8() ^^^^ balance which exists between the hy
| |
| B. Influence of Nutrition on the Respon- ' pophysis and the gonads. In a sense, a simi
| |
| siveness of Male Reproductive Tis- lar interdependence exists between nutrition
| |
| | |
| sues to Hormones 681 and the endocrine glands, including those
| |
| | |
| 1. Testis ■ . . 681 ^j^|-^ reproductive functions. Not only does
| |
| | |
| 2. feeminal vesicles and i)rostate 682 x •<• • n xi • j i -•
| |
| | |
| V. Female Reproductive System 683 nutrition influence synthesis and release of
| |
| | |
| A. Ovaries 683 hormones, but hormones in turn, through
| |
| | |
| 1. Inanition 683 their regulation of the metabolism of pro
| |
| 2. Protein 684 teins, carbohydrates, and fats, influence nu
| |
| 3. Carbohydrate 685 trition. Thus, dietary deficiencies may create
| |
| | |
| 5 Vitamins 685 endocrine imbalance, and endocrine imbal
| |
| B. Influence of Nutrition on the ResiK)n- '^^ce may create demands for dietary fac
| |
| siveness of Female Pe])ro<luct ive tors. It follows, therefore, that, in any conTissues to Hormones 687 sideration of this interrelationship, one must
| |
| | |
| 1 . Ovary ... 687 consider not only undernutrition and lack of
| |
| | |
| 2. uterus and vagina 688 -n c j \ l ^ i ^ cc i. r
| |
| | |
| 3. Mammary gland 689 specific foods, but also possible effects of
| |
| | |
| C. Pregnancy. . 689 antithyroid substanccs in foods, antimetab
| |
| VI. Concluding Remarks 693 olites, and overnutrition, especially for the
| |
| | |
| VII.Pkferencks (;!)4 child (Forbes, 1957).
| |
| | |
| 666
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 667
| |
| | |
| | |
| | |
| Our understanding of the means by which
| |
| hormones exert their effects is relatively
| |
| slight, as is our knowledge of the biochemical mechanisms by w^hich supplements and
| |
| deficiencies of vitamins and amino acids
| |
| influence hormone action. Nevertheless,
| |
| support for the statement that modifications
| |
| of nutrition influence endocrine gland secretions or hormone action on distant target organs or tissues is provided by an
| |
| enumeration of a few basic cell components
| |
| requiring proteins, lipids, and vitamins.
| |
| (1) Proteins combine with lipids to form
| |
| lipoproteins which are essential features
| |
| of the internal and external cellular membranes and interfaces. Hormones, as well as
| |
| nutrition, influence cell membranes and
| |
| therefore cell transport is affected. It is well
| |
| known that hormones influence electrolyte
| |
| and carbohydrate transfer and recently an
| |
| endocrine control of amino acid transport
| |
| was demonstrated (Noall, Riggs, Walker
| |
| and Christensen, 1957). The effect of modifications of nutrition on the capacity of hormones to influence cell transport must await
| |
| study. (2) Enzymes are proteins with chemically active surfaces and often include nonprotein groups such as vitamins. Nutritional
| |
| and hormonal changes cause alterations in
| |
| enzyme concentrations (Knox, Auerbach
| |
| and Lin, 1956). Vitamin, mineral, and fat
| |
| deficiencies favor a decrease in enzymes,
| |
| whereas protein deficiencies have varied effects (Van Pilsum, Speyer and Samuels,
| |
| 1957). Enzyme changes caused by hormones
| |
| appear to be a consequence of metabolic
| |
| adaptations. The importance of a nutritional base on which a hormone can express
| |
| an effect on the enzymes of the reproductive
| |
| organs can only be determined after further
| |
| data have been obtained. (3) Proteins combined with nucleic acids become nucleoproteins, some of which are organized in the
| |
| cytoplasm and may be templates for cellular protein synthesis. Other nucleoproteins
| |
| are contained in the nucleus. Nutrition and
| |
| hormones influence tissue nucleoproteins
| |
| but studies involving the reproductive organs are few. How^ever, one possible cause
| |
| of human infertility is low desoxyribose
| |
| nucleic acid in the sperm ("Weir and Leuchtenberger, 1957).
| |
| | |
| Proteins are characteristic components of
| |
| | |
| | |
| | |
| tissues and hypophyseal hormones are protein in nature; also the major portion of
| |
| gonadal dry weight is protein. Such being
| |
| the case, it is important to appreciate that
| |
| the protein composition of the body is in
| |
| a dynamic state and that proteins from the
| |
| tissues and from the diet contribute to a
| |
| common metabolic pool of nitrogen. This
| |
| metabolic pool contains amino acids which
| |
| may be withdrawn for rebuilding tissue
| |
| protein and for the formation of new protein
| |
| for growth. Obviously, the character of the
| |
| metabolic pool of nitrogen reflects dietary
| |
| protein level and quality. A food protein
| |
| which is deficient in one or more amino
| |
| acids will restrict tissue protein synthesis.
| |
| Hormones also influence the metabolic pool
| |
| by affecting appetite as well as absorption,
| |
| utilization, and excretion of foods, and thus
| |
| hormones could accentuate the effect of a
| |
| poor diet, or create demands beyond those
| |
| normally met by an adequate diet. In addition a study of the tissues and organs of
| |
| the body reveals that contributions to the
| |
| metabolic pool are not uniform, thus one
| |
| tissue or organ may be maintained at the
| |
| expense of another. In protein deprivation
| |
| in adults the liver quickly contributes increased amounts of nitrogen to the metabolic
| |
| pool whereas the testis does not. On the
| |
| other hand, protein contributions to the
| |
| nitrogen pool by the hypophysis, and the
| |
| amino acid withdrawals needed for hormone
| |
| synthesis, are unknown. Data suggesting
| |
| that the addition of specific nutrients to
| |
| diets improves hypophyseal hormone synthesis have been presented (Leathem,
| |
| 1958a).
| |
| | |
| In 1939 jNIason rightfully emphasized the
| |
| need for vitamins in reproduction. Since
| |
| then, much additional knowledge has been
| |
| obtained. Vitamins of the B complex have
| |
| been more clearly identified and a better
| |
| understanding of their function has been
| |
| gained. Thiamine is important for carbohydrate metabolism, pyridoxine for fat metabolism, and the conversion of tryptophan
| |
| to nicotinic acid, and vitamin B12 may be
| |
| involved in protein synthesis. In addition,
| |
| vitamins have been found to serve as coenzymes, and folic acid to be important for
| |
| estrogen action on the uterus. Tliosr. and
| |
| | |
| | |
| | |
| 668
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| many other findings prompt a survey of the
| |
| relationships of vitamins to reproduction.
| |
| | |
| It is the intention of the author to review
| |
| enough of the evidence which interrelates
| |
| nutrition and reproduction to create an
| |
| awareness of the problems in the area.
| |
| Reviews dealing with the general subject
| |
| of hormonal-nutritional interrelationships
| |
| have been presented (Hertz, 1948; Samuels,
| |
| 1948; Ershoff, 1952; Zubiran and GomezMont, 1953; Meites, Feng and Wilwerth,
| |
| 1957; Leathem, 1958a,). Other reviews have
| |
| related reproduction to nutrition with emphasis on laboratory (Mason, 1939; Guilbert, 1942; Lutwak-Mann, 1958) and farm
| |
| animals (Reid, 1949; Asdell, 1949), and on
| |
| protein nutrition (Leathem, 1959b, c). An
| |
| encyclopedic survey of the biology of human nutrition has been made by Keys,
| |
| Brozec, Hernschel, Michelsen and Taylor
| |
| (1950).
| |
| | |
| II. Nature of Problems in Nutritional
| |
| Studies
| |
| | |
| A. THYEOID GLAND, NUTRITION, AND
| |
| REPRODUCTION
| |
| | |
| Normal development of the reproductive
| |
| organs and their proper functioning in
| |
| | |
| TABLE 12.1
| |
| Ovarian response to chorionic gonadrotrophin,
| |
| | |
| as modified by thiouracil and diet
| |
| | |
| (From J. H. Leathem, in Recent Progress in
| |
| | |
| the Endocrinology of Reproduction, Academic
| |
| | |
| Press, Inc., New York, 1959.)
| |
| | |
| | |
| | |
| Diet
| |
| | |
| | |
| Ovarian Weight
| |
| | |
| | |
| Cholesterol
| |
| | |
| | |
| Total
| |
| | |
| | |
| Free
| |
| | |
| | |
| 18 per cent casein .
| |
| | |
| 18 tier cent +
| |
| | |
| I'hiouracil
| |
| | |
| per cent casein . .
| |
| per cent + thiouracil
| |
| | |
| 18 per cent gelatin . . .
| |
| | |
| | |
| mg.
| |
| | |
| 87
| |
| 342
| |
| | |
| 59
| |
| 133
| |
| | |
| 59
| |
| 186
| |
| 27.5
| |
| | |
| | |
| %
| |
| 0.41
| |
| | |
| 0.20
| |
| | |
| 0.47
| |
| | |
| 0.22
| |
| | |
| 0.66
| |
| 0.26
| |
| 1.56
| |
| | |
| | |
| 0.18
| |
| 0.12
| |
| 0.23
| |
| 0.15
| |
| | |
| 0.22
| |
| | |
| | |
| 18 per cent -f
| |
| thio uracil
| |
| | |
| | |
| 0.18
| |
| 18
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Chorionic gonadotrophin = 10 I. U. X 20 days.
| |
| | |
| | |
| | |
| adults are dependent not only on the endocrine glands composing the hypophysealgonadal axis, but on others as well. The
| |
| importance of the thyroid, although not
| |
| the same for all species, is readily apparent
| |
| from the effects of prolonged hypo- and
| |
| hyperthyroid states on reproduction. Many
| |
| of these effects have been enumerated elsewhere (chapters by Albert, by Young on the
| |
| ovary, and by Zarrow) , but others also are
| |
| important. Thus steroid production may be
| |
| altered in hypothyroid animals; certainly
| |
| its metabolism is influenced. Myxedema is
| |
| associated with a profound change in androgen metabolism. Endogenous production of
| |
| androsterone is very low and subnormal
| |
| amounts of administered testosterone are
| |
| converted to androsterone. Triiodothyronine
| |
| corrects this defect (Hellman, Bradlow,
| |
| Zumoff, Fukushima and Gallagher, 1959).
| |
| The gonads of male and female offspring of
| |
| cretin rats are subnormal. The testes may
| |
| contain a few spermatocytes but no spermatozoa, and Leydig cells seem to secrete
| |
| little or no androgen. The ovaries may contain a few small follicles with antra, but
| |
| corpora lutea are absent and ovarian lipid
| |
| and cholesterol concentrations are very
| |
| low. Nevertheless, the gonads are competent to respond to administered gonadotrophin with a marked increase in weight.
| |
| However, administration of chorionic gonadotrophin to the hypothyroid rat stimulated follicular cyst formation rather than
| |
| folliculogenesis and corpora lutea formation
| |
| (Leathem, 1958b), but, for even this aberrant development, dietary protein was required (Leathem, 1959b) (Table 12.1). The
| |
| relationship between hypothyroidism and
| |
| ovarian function may provide a clue to a
| |
| possible origin of ovarian cysts, long known
| |
| to be a common cause of infertility and associated reproductive disorders. Clinical
| |
| cases of untreated myxedema exhibit ovarian cysts, and rats made hypothyroid for
| |
| eight months, had a higher percentage of
| |
| cystic ovaries than did euthyroid rats
| |
| (Janes, 1944).
| |
| | |
| The reproductive system of the adult
| |
| male is less affected than that of the immature male by a decrease in thyroid function, just as the testis of the adult is less
| |
| likely to reflect a change in protein nutrition
| |
| which is sufficient to alter the immature rat
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 669
| |
| | |
| | |
| | |
| testis. On the other hand, the lack of
| |
| demonstrable thyroid dysfunction in the
| |
| adult male does not exclude the possibility
| |
| of an effect of thyroid hormone on reproduction. The conversion of thyroxine to triiodothyronine may be hindered (Morton,
| |
| 1958) . Thyroxine was found to decrease the
| |
| number of active cells in the semen and to
| |
| reduce motility, whereas triiodothyronine
| |
| increased the number of active spermatozoa
| |
| (Farris and Colton, 1958; Reed, Browning
| |
| and O'Donnell, 1958j. Small dosages of thyroxine stimulated spermatogenesis in the
| |
| mouse, rabbit, and ram (Maqsood, 1952)
| |
| and were beneficial in normal guinea pigs
| |
| and rats (Richter and Winter, 1947; Young,
| |
| Rayner, Peterson and Brown, 1952).
| |
| | |
| In many species reproduction occurs despite hypothyroidism, but fecundity may
| |
| be subnormal (Peterson, Webster, Rayner
| |
| and Young, 1952). Feeding an antithyroid
| |
| drug, thiouracil, to female rats may or may
| |
| not prevent pregnancy, but it reduces the
| |
| number of young per litter. Thiouracil feeding continued through lactation will decrease litter size (Leathem, 1959b). Hypothyroid guinea pigs gave birth to some live
| |
| young, but the percentage approached normal only when thyroxine was administered
| |
| (Hoar, Goy and Young, 1957). Pregnant
| |
| euthyroid animals responded to thyroxine
| |
| by delivering more living young than normal control pigs (Peterson, Webster, Ravner and Young, 1952) . The extent to which
| |
| such effects are consequences of the reduction in appetite, metabolism, and absorption of food from the gut which are associated with hypothyroidism has not been
| |
| determined.
| |
| | |
| Hyperthyroidism, on the other hand, will
| |
| increase the appetite and enhance absorption of food from the gut, as the increased
| |
| metabolism requires more calories, minerals,
| |
| vitamins, choline, and methionine. In adult
| |
| rats hyperthyroidism induces a marked loss
| |
| in body fat and accelerates protein catabolism. The two effects, if unchecked, result
| |
| in loss of body weight and death. In immature males hyperthyroidism slows gain
| |
| in body weight, retards testis growth and
| |
| maturation, and abolishes androgen secretion (Table 12.2). Altering dietary protein
| |
| in adult animals failed to modify the thyroid hormone effects, thereby suggesting
| |
| | |
| | |
| | |
| TABLE 12.2
| |
| | |
| Effects of diet and thyroid {0.2 'per
| |
| | |
| cent) on immature rats
| |
| | |
| (From J. H. Leathem, in Recent Progress in
| |
| | |
| the Endocrinology of Reproduction, Academic
| |
| | |
| Press, Inc., New York, 1959.)
| |
| | |
| | |
| | |
| Diet
| |
| | |
| | |
| Testis Weight
| |
| | |
| | |
| Seminal
| |
| | |
| | |
| (Casein) X 30 Days
| |
| | |
| | |
| Actual
| |
| | |
| | |
| Relative
| |
| | |
| | |
| Vesicles
| |
| | |
| | |
| 20 per cent
| |
| | |
| 20 per cent +
| |
| thyroid
| |
| | |
| 6 per cent
| |
| | |
| 6 per cent +
| |
| thyroid
| |
| | |
| per cent
| |
| | |
| per cent -|thyroid
| |
| | |
| | |
| mg.
| |
| 1G94
| |
| | |
| 1090
| |
| | |
| 825
| |
| | |
| 245
| |
| | |
| 140
| |
| | |
| 95
| |
| | |
| | |
| mg./lOOgm.
| |
| | |
| 1035
| |
| | |
| 881
| |
| 1232
| |
| | |
| 650
| |
| | |
| 346
| |
| | |
| 261
| |
| | |
| | |
| mg.
| |
| 88
| |
| | |
| 9
| |
| 16
| |
| | |
| 7
| |
| 7
| |
| 6
| |
| | |
| | |
| | |
| that the metabolic demands of other tissues
| |
| were making increased withdrawals from
| |
| the metabolic pool of nitrogen and thus
| |
| hindering testis growth. In euthyroid rats, a
| |
| 6 per cent protein diet will permit testis
| |
| growth in the absence of a gain in body
| |
| weight, but hyperthyroidism prevents this
| |
| preferential effect. Although Moore (1939)
| |
| considered the effect of thyroid hormone on
| |
| reproduction as possibly due to general body
| |
| emaciation, the testis seems to be less responsive than the body as a whole. Adult
| |
| rats fed 0.2 per cent desiccated thyroid
| |
| exhibited no correlation between loss of
| |
| body weight, change in testis weight, or
| |
| protein composition of testis at two levels
| |
| of casein and lactalbumin (Leathem,
| |
| 1959b) . The testes were seemingly not influenced by the metabolic nitrogen changes
| |
| which caused a loss in carcass nitrogen
| |
| and an associated increase in kidney and
| |
| heart nitrogen.
| |
| | |
| The mechanism of thyroid hormone action on reproduction is far from clear. As
| |
| we have noted, a part of its action may be
| |
| through the regulation of nutritional processes. Thyroid function is influenced by
| |
| the biologic value of the dietary protein
| |
| (Leathem, 1958a) and the specifie amino
| |
| acids fed (Samuels, 1953). In turn, an
| |
| altered thyroid function will influence the
| |
| nitrogen contributions to the metabolic pool
| |
| by reducing appetite and absorption from
| |
| | |
| | |
| | |
| 670
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| the gut, and by changing the contributions
| |
| of nitrogen to the metabolic pool made by
| |
| the body tissues. Hypothyroidism interferes
| |
| with the refilling of body protein stores;
| |
| consequently, protein needs of the reproductive organs may not be fully met (Leathern, 1953). It is consistent with this
| |
| opinion that testis recovery from protein
| |
| deprivation in hypothyroid rats was aided
| |
| by thyroxine treatment (Horn, 1955).
| |
| | |
| Conversion of carotene to vitamin A may
| |
| be prevented by hypothyroidism, suggesting
| |
| that a subnormal amount of this vitamin
| |
| may contribute to fetal loss. An increased
| |
| intake of B vitamins might be required as
| |
| hypothyroidism aggravates a vitamin B12
| |
| deficiency, and increased intake of B vitamins enhances the capacity of young rats to
| |
| withstand large doses of thiouracil (Meites,
| |
| 1953). Although a reduced metabolic rate
| |
| might seemingly reduce vitamin requirements, more efficient metabolic activities,
| |
| in the absence of hormonal stimuli, seem to
| |
| occur when vitamin intake is increased
| |
| (Meites, Feng and Wilwerth, 1957).
| |
| | |
| Reproduction is influenced by effects
| |
| which are the opposite of a number of
| |
| those just cited, i.e., effects of malnutrition
| |
| on thyroid function. The need for iodine in
| |
| the prevention of goiter is well known.
| |
| However, certain foods prevent the utilization of iodine in the synthesis of thyroid
| |
| hormone. The foods containing an antithyroid or goitrogenic agent, as tested in
| |
| man, include rutabaga, cabbage, brussels
| |
| sprouts, cauliflower, turnip, rape, kale, and
| |
| to a lesser extent peach, pear, strawberry,
| |
| spinach, and carrot (Greer and Astwood,
| |
| 1948). A potent goitrogen isolated from
| |
| rutabaga is L-5-vinyl-2-thiooxazolidine
| |
| ((ireer, 1950, 1956). Reduced food intake
| |
| will decrease the thyroid gland response to
| |
| goitrogens (Gomez-Mont, Paschkis and
| |
| Cantarow, 1947; Meites and Agrawala,
| |
| 1949), the uptake of I^^^ (Meites, 1953),
| |
| and the level of thyrotrophic hormone in
| |
| laboratory animals (D'Angelo, 1951). The
| |
| thyroid changes associated with malnutrition in man arc uncertain (Zubiran and
| |
| Gomez-Mont, 1953). However, a decreased
| |
| functioning of the gland in anorexia nervosa, followed by an increased functioning
| |
| on refeeding (Poiioff, Lasche, Nodine,
| |
| | |
| | |
| | |
| Schneeberg and \'ieillard, 1954), is suggestive of a direct nutritional need.
| |
| | |
| Changes in the thyrotrophic potency of
| |
| the rat hypophysis have been observed in
| |
| various vitamin deficiencies. Thiamine deficiency may increase thyroid function, but
| |
| vitamin A deficiency may have the opposite
| |
| effect (Ershoff, 1952). The difficulties inherent in the assay of thyroid-stimulating
| |
| hormone (TSH) , even by current methods,
| |
| prevent one from drawing definite conclusions from the available data.
| |
| | |
| Immature animals given thyroxine are
| |
| retarded in growth and do not survive. However, increasing dietary thiamine, pyridoxine, or vitamin B12 improves the ability of
| |
| the young rat to withstand large dosages
| |
| of thyroid substances (Meites, 1952), as
| |
| does methionine (Boldt, Harper and Elvehjem, 1958). Consideration must also be
| |
| given to the need for nutritional factors
| |
| which play a minor role in normal metabolic
| |
| states but increase in importance in stress.
| |
| Thus yeast and whole liver contain antithyrotoxic substances (Drill, 1943; Ershoff,
| |
| 1952; Overby, Frost and Fredrickson,
| |
| 1959).
| |
| | |
| Excessive thyroid hormone will prevent
| |
| maturation of the ovary and in adult rats
| |
| will cause ovarian atrophy with a cessation
| |
| of estrous cycles. Addition of yeast to the
| |
| diet permitted estrous cycles to continue
| |
| (Drill, 1943), but gonadal inhibition in the
| |
| immature animal was not ]3revented. However, whole liver or its w^ater-insoluble fraction counteracted the gonadal inhibition induced by hyperthyrodism in immature
| |
| rats (Ershoff, 1952). Biochemical mechanisms by which these dietary supplements
| |
| can benefit rats given excessive quantities
| |
| of hormone are unknown.
| |
| | |
| B. .\DREXAL GLAND, NUTRITION, AND
| |
| REPRODUCTION
| |
| | |
| The problem of the relationship between
| |
| adrenal steroid secretions and the reproductive system is one that still requires
| |
| clarification. Furthermore, the possible influences of nutrition can only be inferred
| |
| from the effects of adrenal steroids on the
| |
| major metabolic systems of the body.
| |
| | |
| In the female there is a close relationshiji
| |
| between the adrenal and the estrous and
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| iul
| |
| | |
| | |
| | |
| menstrual cycles (Zuckerman, 1953; chapter by Young on the ovary). The ovary
| |
| would seem to require cortical steroids for
| |
| the normal functioning of its own metabolic
| |
| processes and for those which it influences
| |
| peripherally. The Addisonian patient may
| |
| show ovarian follicular atresia and a loss of
| |
| secondary sex characteristics, and the untreated adrenalectomized rat exhibits a
| |
| decrease in ovarian size and has irregular
| |
| cycles (Chester Jones, 1957). The decline
| |
| in size of the ovary after adrenalectomy
| |
| is due to impaired sensitivity to folliclestimulating hormone (FSH) rather than to
| |
| a decreased production of FSH, and the
| |
| ovarian response is corrected by cortisone
| |
| (Mandl, 1954).
| |
| | |
| Reproductive potential is not necessarily
| |
| lost when there is adrenal insufficiency, but
| |
| pregnancy is not well tolerated by women
| |
| with Addison's disease. Furthermore, adrenalectomy in rats at the time of mating or
| |
| 4 to 6 days after mating resulted in abortion. Improved pregnancy maintenance was
| |
| obtained in adrenalectomized rats given
| |
| saline or cortisone acetate (Davis and Plotz,
| |
| 1954) , whereas desoxycorticosterone acetate
| |
| alone extended the pregnancy period beyond
| |
| normal time (Houssay, 1945). Essentially
| |
| normal pregnancies were obtained in adrenalectomized rats given both cortisone
| |
| acetate and desoxycorticosterone acetate
| |
| (Cupps, 1955). Substitution of cortisone
| |
| acetate for adrenal secretions may be incomplete because the adrenal hormone in
| |
| the normal rat is primarily corticosterone
| |
| and because cortisone enhances the excretion of certain amino acids and vitamins. It
| |
| would be interesting to test a diet with a
| |
| high vitamin content on the capacity of an
| |
| adrenalectomized rat to maintain pregnancy, because improved survival of operated rats is obtained by giving vitamin Bio
| |
| (Meites, 1953) or large doses of pantothenic acid, biotin, ascorbic acid, or folic
| |
| acid (Ralli and Dumm, 1952; Dumm and
| |
| Ralli, 1953).
| |
| | |
| An adrenal influence over protein metabolism is well known, but protein nutrition,
| |
| in turn, can influence cortical steroid effectiveness. In fact, an extension of the life
| |
| span of adrenalectomized rats is not obtained with adrenal steroids if the diet
| |
| | |
| | |
| | |
| lacks protein (Leathern, 1958a). A low
| |
| protein diet alone will not improve survival after adrenalectomy, but better survival is obtained when the rats are given
| |
| saline. When the low protein diet was supplemented with methionine, a definite improvement in life span was observed and the
| |
| possibility that cortisone exerts its effect by
| |
| drawing on the carcass for methionine was
| |
| suggested (Aschkenasy, 1955a, b).
| |
| | |
| Reducing dietary casein to 2 per cent
| |
| seriously endangers pregnancy in the rat,
| |
| but the addition of progesterone permits
| |
| 80 per cent of the pregnancies to be maintained. However, removal of the adrenal
| |
| glands counteracts the protective action of
| |
| the progesterone, only 10 per cent of the
| |
| pregnancies continuing to term. Addition
| |
| of methionine to the low casein diet improved pregnancy maintenance, but 1 mg.
| |
| cortisone acetate plus progesterone provided the best results (Aschkenasy-Lelu
| |
| and Aschkenasy, 1957; Aschkenasy and
| |
| Aschkenasy-Lelu, 1957). These data emphasize the importance of nutrition in obtaining an anticipated hormone action. Further investigation might be directed toward
| |
| the study of whole proteins other than casein, for the biologic value of proteins differs from normal when tested in adrenalectomized rats (Leathem, 1958a) .
| |
| | |
| As Albert has noted in his chapter, adrenalectomy has little or no effect on the
| |
| testis. Gaunt and Parkins (1933) found no
| |
| degenerative changes in the testes of adult
| |
| rats dying of adrenal insufficiency, although
| |
| an increase in the testis : body-weight ratios
| |
| was noted in rats fed 18 per cent and 4 per
| |
| cent protein (Aschkenasy, 1955c). If adrenalectomized rats are kept on a maintenance dosage of cortisone acetate for 20
| |
| days and fed dietary proteins of different
| |
| biologic values, one finds that testis-composition of protein, lipid, and glycogen varies in the same manner as in the normal
| |
| rat (Wolf and Leathem, 1955) (Table 12.3).
| |
| | |
| When the adrenal glands are intact, the
| |
| influence of diet on their functional capacity and indeed on the hypophyseal- adrenal
| |
| axis must be considered. Zubiran and Gomez-]\Iont (1953) showed that patients exhibiting gonadal changes associated with
| |
| chronic malnutrition also exhibit adrenal
| |
| | |
| | |
| | |
| 672
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GOXADS
| |
| | |
| | |
| | |
| TABLE 12.3
| |
| | |
| Nutritional effects on the testes of cortisonemaintained adrenalectomized rats
| |
| (From R. C. Wolf and J. H. Leathern,
| |
| Endocrinology, 57, 286, 1955.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Testes Composition
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| (per cent)
| |
| | |
| | |
| Treatment
| |
| | |
| | |
| Diet
| |
| | |
| | |
| Testes
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Protein
| |
| | |
| | |
| Lipid
| |
| | |
| | |
| Glycogen
| |
| | |
| | |
| | |
| | |
| | |
| | |
| mg.
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Corti
| |
| | |
| 20 per cent
| |
| | |
| | |
| 703
| |
| | |
| | |
| 68.5
| |
| | |
| | |
| 30.4
| |
| | |
| | |
| 0.13
| |
| | |
| | |
| sone
| |
| | |
| | |
| casein
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ace
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| tate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| | |
| | |
| 1211
| |
| | |
| | |
| 70.5
| |
| | |
| | |
| 29.4
| |
| | |
| | |
| 0.15
| |
| | |
| | |
| Corti
| |
| | |
| 20 per cent
| |
| | |
| | |
| 808
| |
| | |
| | |
| 61.0
| |
| | |
| | |
| 31.8
| |
| | |
| | |
| 0.17
| |
| | |
| | |
| sone
| |
| | |
| | |
| wheat
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ace
| |
| | |
| ghiten
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| tate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| | |
| | |
| 816
| |
| | |
| | |
| 62.3
| |
| | |
| | |
| 32.2
| |
| | |
| | |
| 0.17
| |
| | |
| | |
| Corti
| |
| | |
| 20 per cent
| |
| | |
| | |
| 1014
| |
| | |
| | |
| 64.3
| |
| | |
| | |
| 31.3
| |
| | |
| | |
| 0.17
| |
| | |
| | |
| sone
| |
| | |
| | |
| peanut
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ace
| |
| | |
| flour
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| tate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| | |
| | |
| 699
| |
| | |
| | |
| 68.5
| |
| | |
| | |
| 31.3
| |
| | |
| | |
| 0.12
| |
| | |
| | |
| | |
| hypofimction. Several clinical tests permitted the evaluation of subnormal adrenal
| |
| function which, however, did not reach
| |
| Addisonian levels. Malnutrition not onlyreduced hypophyseal adrenocorticotrophic
| |
| hormone (ACTH), but also prevented an
| |
| incomplete response by the adrenal glands
| |
| to injected ACTH. In laboratory rodents,
| |
| anterior hypophyseal function is also influenced by dietary protein and vitamin
| |
| levels (Ershoff, 1952). The importance of
| |
| dietary protein in the hypophyseal-adrenal
| |
| system has recently been re-emphasized
| |
| (Leathem, 1957; Goth, Nadashi and Slader,
| |
| 1958). Furtiiermore, adrenal cortical function is affected by vitamin deficiencies
| |
| (Morgan, 1951), from which it appears
| |
| that pantothenic acid is essential for cortical hormone elaboration (Eisenstcin, 1957).
| |
| Administration of excessive amounts of
| |
| cortical steroids can induce morphologic
| |
| changes which have been compared to inanition (Baker, 1952). Not only is nitrogen
| |
| loss enhanced, but hyperglycemia can also
| |
| be induced which, therefore, increases the
| |
| need for thiamine. Cortical steroids influence the metabolism of various vitamins
| |
| | |
| | |
| | |
| (Draper and Johnson, 1953; Dhyse, Fisher,
| |
| Tullner and Hertz, 1953; Aceto, Li Moli
| |
| and Panebianco, 1956; Ginoulhiac and
| |
| Nani, 1956). H a vitamin deficiency already
| |
| exists, administration of cortisone will aggravate the condition (Meites, Feng and
| |
| Wilwerth, 1957). Nevertheless, drastic effects of therapeutic doses of cortisone on
| |
| reproductive function do not occur. In rare
| |
| cases loss of libido has been reported in
| |
| the male, but mori)hologic changes in the
| |
| testis were not observed (JVladdock, Chase
| |
| and Nelson, 1953). Cortisone has little if
| |
| any effect on the weight of the rat testis
| |
| (Moore, 1953; Aschkenasy, 1957) and does
| |
| not influence testis cholesterol (Migeon,
| |
| 1952). In the female, menstrual disturbances have been noted in association with
| |
| cortisone therapy, with the occurrence of
| |
| hot flashes (Ward, Slocumb, Policy, Lowman and Hench, 1951). However, cortisone
| |
| corrected disturbances during the follicular
| |
| phase, possibly by increasing FSH release
| |
| (Jones, Howard and Langford, 1953). Cortisone also increased the number of follicles
| |
| in the ovary of the rat (Moore, 1953), but
| |
| not in the rabbit. Cortisone administration
| |
| did not prevent the enhanced ovarian response to chorionic gonadotrophin seen in
| |
| hypothyroid rats (Leathem, 1958b) and
| |
| had little effect on mice in parabiosis ( Noumura, 1956).
| |
| | |
| In pregnant female rabbits resorption and
| |
| stunting of fetuses occurred during treatment with large doses of cortisone (Courrier
| |
| and Collonge, 1951). Similar effects were
| |
| noted in mice (LcRoy and Domm, 1951 ;
| |
| Robson and Sharaf, 1951).
| |
| | |
| Some of the metabolic derangements of
| |
| human toxemia of pregnancy have been
| |
| correlated with accelerated secretion of
| |
| adrenal steroids creating a steroid imbalance (see chapter by Zarrow). Cortisone is
| |
| reported to have a beneficial effect on some
| |
| cases (Moore, Jessop, 'Donovan, Barry,
| |
| Quinn and Drury, 1951). Protein inade({uacies may also be etiologic in toxemia and
| |
| further (>xamination of the possibility
| |
| sliould he made.
| |
| | |
| C. DIABETES MELLITUS, NUTRITION, AND
| |
| REPRODUCTION
| |
| | |
| (llycosuria can be induced experimentally
| |
| by starvation, overfeeding, and shifting
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 673
| |
| | |
| | |
| | |
| diet^ from one of high fat content to one
| |
| i; which is isocaloric but high in carbohydrate
| |
| (Ingle, 1948). Force feeding a high carbohydrate diet will eventually kill a rat despite insulin administration aimed at controlling glycosuria (Ingle and Nezamis,
| |
| 1947). In man excessive eating leading to
| |
| obesity increases insulin demand and, in
| |
| many diabetics of middle age, obesity precedes the onset of diabetes. With our present
| |
| knowledge we must conclude that overfeeding is wrong when glycosuria exists and that
| |
| vitamin B supplements may be of value
| |
| in diabetes (Meites, Feng and Wilwerth,
| |
| 1957; Salvesen, 1957).
| |
| | |
| In man urinary 17-ketosteroids and androgen levels are subnormal in diabetes
| |
| (Horstmann, 1950), and in the diabetic rat
| |
| pituitary gonadotrophins are reduced
| |
| (Shipley and Danley, 1947), but testis hyaluronidase does not change (Moore, 1948) .
| |
| When hyperglycemia exists in rats, semen
| |
| ■] carbohydrates increase (Mann and Lutwak-Mann, 1951).
| |
| | |
| Hypoglycemia influences the male reproductive organs. In rats tolbutamide or
| |
| insulin produce lesions of the germinal
| |
| epithelium which can be prevented by
| |
| \' simultaneous administration of glucose.
| |
| When 2 to 5 hypoglycemic comas are induced, such testis injuries increase progressively in number and frequency, and
| |
| only a partial return to normal is observed
| |
| a month later (Mancini, Izquierdo, Heinrich, Penhos and Gerschenfeld, 1959).
| |
| | |
| It is well known that the incidence of
| |
| infertility in the pre-insulin era was high
| |
| in young diabetic women. Fertility is also
| |
| reduced in diabetic experimental animals,
| |
| and rat estrous cycles are prolonged (Davis,
| |
| Fugo and Lawrence, 1947) . Insulin is corrective (Sinden and Longwell, 1949; Ferret,
| |
| Lindan and Morgans, 1950). Pregnancy in
| |
| women with uncontrolled diabetes may
| |
| terminate in abortion or stillbirth, possibly
| |
| l)ecause toxemia of pregnancy is high (Pedersen. 1952). In rats pancreatectomy performed the 8th to 12th day of pregnancy
| |
| increased the incidence of stillbirths (Hultciuist, 1950). In another experiment almost
| |
| one- fourth of 163 animals with diabetes
| |
| induced by alloxan on the 10th to 12th day
| |
| of pregnancy died before parturition and
| |
| | |
| | |
| | |
| about 25 ])er cent of the survivors aborted
| |
| (Angcrvall, 1959).
| |
| | |
| D. STERILE-OBESE SYNDROME
| |
| | |
| A sterile-obese syndrome in one colony of
| |
| mice has been shown to be a recessive monogenic trait (Ingalls, Dickie and Snell, 1950).
| |
| Obesity was transmitted to subsequent generations by way of ovaries that were transplanted from obese donors to nonobese recipients (Hummel, 1957). Obesity was
| |
| transmitted by obese females receiving hormonal therapy and mated to obese males
| |
| kept on restricted food intake (Smithberg
| |
| and Runner, 1957). In addition to the investigations of the hereditary nature of the
| |
| sterile-obese syndrome, the physiologic
| |
| basis for the sterility has been studied in
| |
| reference to the presence of germ cells, viability of ova and sperm, integrity of the
| |
| ovary, and response of the uterus to estrogen (Drasher, Dickie and Lane, 1955). The
| |
| data indicate that sterility in some obese
| |
| males can be prevented by food restriction
| |
| and that sterility in certain obese females
| |
| can be corrected.
| |
| | |
| E. DIET AND THE LIVER
| |
| | |
| The concentration of hormones which
| |
| reaches the target organs in the blood is the
| |
| result of the rate of their production, metabolism, and excretion. How hypophyseal
| |
| hormones are destroyed is not clear, but
| |
| current data make it apparent that pituitary hormones have a short half-life in the
| |
| circulatory system. Exerting a major control over circulating estrogen levels is the
| |
| liver, with its steroid-inactivating systems.
| |
| Zondek (1934) initially demonstrated that
| |
| the liver could inactivate estrogens and this
| |
| finding has had repeated confirmation
| |
| (Cantarow, Paschkis, Rakoff and Hansen,
| |
| 1943; De:\Ieio, Rakoff, Cantarow and
| |
| Paschkis, 1948; Vanderlinde and Westerfield, 1950). Other steroids are also inactivated by the liver with several enzyme
| |
| systems being involved; the relative concentration of these enzymes varies among
| |
| species of vertebrates (Samuels, 1949).
| |
| | |
| The liver is a labile organ which readib.'
| |
| responds to nutritional modifications; the
| |
| induced liver changes alter the steroid-inactivating systems of this organ. Thus, inanition (Drill and Pfeiffer, 1946; Jailer,
| |
| | |
| | |
| | |
| G74
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 1948) , vitamin B complex deficiency (Segaloff and Segaloff, 1944; Biskind, 1946), and
| |
| protein restriction (Jailer and Seaman,
| |
| 1950) all influence the capacity of the liver
| |
| to detoxify steroids. Reduced protein intake
| |
| is a primary factor in decreasing the effectiveness of the steroid-inactivating system
| |
| (Jailer and Seaman, 1950; Vanderlinde and
| |
| Westerfield, 1950). Rats fed an 8 per cent
| |
| casein diet lose their capacity to inactivate
| |
| estrone within 10 days. However, ascorbic
| |
| acid alone or in combination with glutathione restored the estrone-inactivating system (Vasington, Parker, Headley and Vanderlinde, 1958).
| |
| | |
| Failure of steroids to be inactivated will
| |
| influence the hypophyseal-gonadal axis. In
| |
| turn the excess of estrogen will decrease
| |
| gonadotrophin production by the hypophysis and thus reduce steroid production by
| |
| the gonad. In addition nutritional modifications influence hypophyseal and possibly
| |
| gonadal secretory capacity directly. Conceivably, nutritional alterations could
| |
| modify the amount of steroid secreted or
| |
| interfere with complete steroid synthesis
| |
| by a gland.
| |
| | |
| Fatty infiltration of the liver and a
| |
| general increase in fat deposition occur in
| |
| fed and fasted rats after the injection of
| |
| certain pituitary extracts and adrenal steroids and after the feeding of specific diets.
| |
| Impaired estrogen inactivation has been
| |
| associated with a fatty liver, but Szego and
| |
| Barnes (1943) believe that the major influence is inanition. In fact, estrogens, especially ethinyl estradiol, interfere with
| |
| fatty infiltration of the liver induced by a
| |
| low protein diet (Gyorgy, Rose and Shipley, 1947) or by a choline-deficient diet
| |
| (Emerson, Zamecnik and Nathanson, 1951).
| |
| Stilbestrol, however, did not prevent the increase in liver fat induced by a protein-free
| |
| diet (Glasser, 1957). Estrogens that are
| |
| effective in preventing fatty infiltration may
| |
| act by sparing methionine or choline or by
| |
| inhibiting growth hormone (Flagge, Marasso and Zimmerman, 1958).
| |
| | |
| Ethionino, the antimetabolite of nu'thioniiK', Avill induce a fatty liver and inhibit hepatic protein synthesis in female,
| |
| but not in male rats (Farber and Segaloff,
| |
| 1955; Farber and Corban, 1958). Pretreatment of females with testosterone prevents
| |
| | |
| | |
| | |
| the ethionine effect, but this blockage of
| |
| ethionine action need not be related to
| |
| androgenic or progestational properties of
| |
| steroids (Ranney and Drill, 1957).
| |
| | |
| III. Hypophysis and Diet
| |
| | |
| Studies involving acute and chronic starvation have shown that gonadal hypofunction during inanition is primarily due to
| |
| diminished levels of circulating gonadotrophins. Because of the similarity to
| |
| changes following hypophysectomy, the
| |
| endocrine response to inanition has been
| |
| referred to as "pseudohypophysectomy."
| |
| | |
| A. INANITION
| |
| | |
| The hypophysis has been implicated in
| |
| human reproduction disturbances associated with undernutrition. Hypophyseal
| |
| atrophy and a decrease in urinary gonadotrophins have been observed in chronic
| |
| malnutrition (Klinefelter, Albright and
| |
| Griswold, 1943; Zubiran and Gomez-]\Iont,
| |
| 1953) and anorexia nervosa (Perloff,
| |
| Lasche, Nodine, Schneeberg and Vieillard,
| |
| 1954). Refeeding has restored urinary
| |
| gonadotrophin levels in some cases, but
| |
| hypoj^hyseal damage may result from severe
| |
| food restriction at puberty (VoUmer, 1943;
| |
| Samuels, 1948).
| |
| | |
| The influence of inanition on the reproductive organs of lal)oratory rodents
| |
| is well recognized but the cft'ects on the
| |
| hypophysis cannot be presented conclusively. In support of prior investigations,
| |
| Mulinos and Pomerantz (1941a, b) in rats
| |
| and Giroud and Desclaux (1945) in guinea
| |
| pigs observed a hypophyseal atrophy following chronic underfeeding as well as a
| |
| decrease in cell numbers and mitoses. In
| |
| fact, refeeding after chronic starvation
| |
| resulted in only a partial recovery of hypophyseal weight (Quimby, 1948). Nevertheless, complete starvation did not influence relative gland weight in female rats
| |
| (Meites and Reed, 1949), and cytologic
| |
| evidence (periodic acid-Schiff (PAS) test)
| |
| of an estimated 3- fold increase in gonadoti'ophin content was claimed following
| |
| chronic starvation (Pearse and Rinaldini,
| |
| 1950). Assays of hypophyseal gonadotrophin content in chronically starved rats
| |
| of both sexes have l)een reported as decreased (Mason and Wolfe, 1930; Werner,
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 675
| |
| | |
| | |
| | |
| 1939), unchanged (,]\Iarrian and Parkes,
| |
| 1929; Pomerantz and Mulinos, 1939; Maddock and Heller, 1947; Meites and Reed,
| |
| 1949; Blivaiss, Hanson, Rosenzweig and
| |
| McNeil, 1954), or increased (Rinaldini,
| |
| 1949; Vanderlinde and Westerfield, 1950).
| |
| An increase in pituitary gonadotrophin was
| |
| evident when hormone content was related
| |
| to milligrams of tissue (Meites and Reed,
| |
| 1949). Thus, the hormone release mechanism may fail in starvation, and eventually
| |
| gonadotrophin production will be reduced
| |
| to a minimum (]\laddock and Heller, 1947).
| |
| | |
| Gonadectomy of fully fed rats is followed
| |
| by an increase in hypophyseal gonadotrophin content. Chronic starvation, however, prevented the anticipated changes in
| |
| the pituitary gland following gonadectomy
| |
| in 8 of 12 female rats (Werner, 1939). On
| |
| the other hand, if adult female rats were
| |
| subjected to 14 days of reduced feeding
| |
| 1 month after ovariectomy, no change in
| |
| the elevated gonadotrophin levels was noted
| |
| (Meites and Reed, 1949). In contrast,
| |
| Gomez-Mont (1959) observed above normal
| |
| urinary gonadotrophins in many menopausal and postmenopausal women despite
| |
| undernutrition.
| |
| | |
| It is apparent that uniformity of opinion
| |
| as to how starvation influences hypophyseal
| |
| gonadotrophin content has not been attained. Several explanations can be given for
| |
| the discrepancies. (1) There have been unfortunate variations in experimental design.
| |
| IVIaddock and Heller (1947) starved rats
| |
| for 12 days, whereas Rinaldini (1949) used
| |
| a low calorie diet of bread and milk for
| |
| 30 days. Other variations in feeding have
| |
| included feeding one-half the intake required for growth (Mulinos and Pomerantz,
| |
| 1941b I, regimens of full, one-half, oneciuarter, and no feeding for 7 and 14 days
| |
| (Meites and Reed, 1949), and feeding inadequate amounts of a standard rat diet
| |
| for 1 to 4 months (Werner, 1939). (2)
| |
| Hypophyseal implants and anterior pituitary extracts should not be compared, for
| |
| variable gonadotrophin production may follow implantation procedures, depending on
| |
| whether necrosis or growth occurs (Maddock and Heller, 1947). (3) There has been
| |
| an insufficient standardization of experimental materials. The assay animal has
| |
| usually been the immature female rat, but
| |
| | |
| | |
| | |
| occasionally the immature mouse has been
| |
| used, and Rinaldini (1949) used the hypophysectomized rat.
| |
| | |
| B. PROTEIN
| |
| | |
| The need for specific food elements by
| |
| the hypophysis warrants consideration,
| |
| for the hormones secreted by this gland
| |
| are protein in nature and the amino acids
| |
| for protein synthesis must be drawn from
| |
| body sources. However, dietary protein
| |
| levels can vary from 15 per cent to 30 per
| |
| cent without influencing hypophyseal gonadotrophin content in rats (Weatherby and
| |
| Reece, 1941), but diets containing 80 per
| |
| cent to 90 per cent of casein increased
| |
| hypophyseal gonadotrophin (TuchmannDuplessis and Aschkenasy-Lelu, 1948). Removal of protein from the diet will decrease
| |
| hypophyseal gonadotrophin content in
| |
| adult male rats in comparison with pair-fed
| |
| and ad libitum-ied controls, but the decrease may or may not be significant in a
| |
| 30-day period; luteinizing hormone (LH)
| |
| seemed to be initially reduced. Extension of
| |
| the period of protein depletion another 2
| |
| months resulted in a significant lowering of
| |
| hy]iophyseal gonadotrophin levels (Table
| |
| 12.4) (Leathern, 1958a). On the other
| |
| hand, an increased FSH with no decrease
| |
| in LH activity was observed in the hypophyses of adult female rats following
| |
| 30 to 35 days of protein depletion (Srebnik
| |
| and Nelson, 1957). The available data indicate that not only may a sex difference
| |
| exist, but also that species may differ; restitution of gonadotrophin in the discharged
| |
| rabbit pituitary was not influenced by in
| |
| TABLE 12.4
| |
| | |
| Influence of a protein-free diet on hypophyseal
| |
| | |
| gonadotrophin content
| |
| | |
| (From J. H. Leathern, Recent Progr. Hormone
| |
| | |
| Res., 14, 141, 1958.)
| |
| | |
| | |
| | |
| Days on PFD*
| |
| | |
| | |
| Xo. of Rats
| |
| | |
| | |
| Anterior
| |
| Pituitary
| |
| Weight
| |
| | |
| | |
| Recipient
| |
| Ovarv
| |
| Weight
| |
| | |
| | |
| | |
| | |
| | |
| | |
| nig.
| |
| | |
| | |
| mg.
| |
| | |
| | |
| | |
| | |
| | |
| 9
| |
| | |
| | |
| 8.3
| |
| | |
| | |
| 74
| |
| | |
| | |
| 30
| |
| | |
| | |
| 9
| |
| | |
| | |
| 7.3
| |
| | |
| | |
| 54
| |
| | |
| | |
| 50
| |
| | |
| | |
| 7
| |
| | |
| | |
| 7.0
| |
| | |
| | |
| 33
| |
| | |
| | |
| 90
| |
| | |
| | |
| 17
| |
| | |
| | |
| 6.0
| |
| | |
| | |
| 23
| |
| | |
| | |
| | |
| L^ntreated recipient ovarian weight = 15.4 mg.
| |
| * PFD = Protein-free diet.
| |
| | |
| | |
| | |
| 67G
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| adequate dietary protein (Friedman and
| |
| Friedman, 1940).
| |
| | |
| When anterior pituitar}^ glands of 60gm. male rats were extracted and administered to immature female recipients, ovarian
| |
| weight increased from 13.0 to 37.3 mg.
| |
| After feeding 20 per cent casein or fox chow
| |
| ad libitum for 14 days, the hypophyses of
| |
| male rats contained almost twice as much
| |
| gonadotrophin per milligram of tissue as
| |
| did the hypophyses of the initial controls.
| |
| Removal of protein from the diet for 14
| |
| days, however, reduced hypophyseal gonadotrophin concentration below the level
| |
| of the initial controls (Leathem and Fisher,
| |
| 1959).
| |
| | |
| Data on the hypophyseal hormone content as influenced by specific amino acid
| |
| deficiencies have not come to the author's
| |
| attention. Cytologically, however, Scott
| |
| (1956) noted that an isoleucine-deficient
| |
| diet depleted the pituitary gonadotrophic
| |
| cells of their PAS-positive material and reduced the size of acidophilic cells. Omission
| |
| of threonine, histidine, or tryptophan invoked similar effects. The changes probably represent the interference of a single
| |
| amino acid deficiency with protein metabolism rather than specific effects attributable to the lack of amino acid itself. Excessive amino acid provided by injecting
| |
| leucine, methionine, valine, tyrosine, or
| |
| glycine caused release of gonadotrophin
| |
| (Goth, Lengyel, Bencze, Saveley and Majsay, 1955).
| |
| | |
| Administration of 0.1 mg. stilbestrol for
| |
| 20 days to adult male rats eliminated detectable hypophyseal gonadotrophins. Hormone levels returned during the postinjection period provided the diet contained
| |
| adequate protein, whereas a protein-free diet
| |
| markedly hindered the recovery of hypophyseal gonadotrophins. The gonadotrophin
| |
| content of the pituitary gland correlated
| |
| well with the recovery of the reproductive
| |
| system, indicating that gonadotrophin production was subnormal on ]irotein-free feeding (Leathem, 1958a).
| |
| | |
| C. CAHBOHYDR.\TE .\ND FAT
| |
| | |
| Reproduction does not appear to be influenced by carbohydrates per se and hypophyseal alterations have not been noted.
| |
| | |
| | |
| | |
| Fat-deficient diets, however, do influence
| |
| reproduction and the hypophysis exhibits
| |
| cellular changes. Pituitary glands of female rats fed a fat-free diet contain a subnormal number of acidophiles and an increased number of basophiles (Panos and
| |
| Finerty, 1953) . In male rats the feeding oi
| |
| a fat-free diet increased hypophyseal basophiles, followed progessively by more castration changes (Finerty, Klein and Panos,
| |
| 1957; Panos, Klein and Finerty, 1959).
| |
| | |
| D. VITAMINS
| |
| | |
| Despite the many investigations relating
| |
| reproduction to vitamin requirements, relatively few have involved hypophyseal hormone estimations. Thus in 1955, Wooten,
| |
| Nelson, Simpson and Evans reported the
| |
| first definitive study which related pyridoxine deficiency to hypophyseal gonadotrophin content. Using the hypophysectomized rat for assay, pituitary glands
| |
| from Bo-deficient rats were shown to have
| |
| a 10-fold increase in FSH per milligram of
| |
| tissue and a slightly increased LH content.
| |
| Earlier studies had revealed that vitamin
| |
| Bi-free diets decreased pituitary gonadotrophins in male rats (Evans and Simpson,
| |
| 1930) and a similar effect of the folic acid
| |
| antagonist, aminopterin, in the monkey was
| |
| found later (Salhanick, Hisaw and Zarrow, 1952).
| |
| | |
| Male rats deficient in vitamin A exhibited
| |
| a 43 per cent increase, and castrated vitamin
| |
| A-deficient rats a 100 per cent increase in
| |
| hypophyseal gonadotrophin potency over
| |
| the normal controls (Mason and Wolfe,
| |
| 1930). The increase of gonadotrophin was
| |
| more marked in vitamin A-deficient male
| |
| than in vitamin A-deficient female rats.
| |
| Associated with the increase in hormone
| |
| level was a significant increase in basophile
| |
| cells (Sutton and Brief, 1939; Hodgson,
| |
| Hall, Sweetman, Wiseman and Converse,
| |
| 1946; Erb, Andrews, Hauge and King,
| |
| 1947).
| |
| | |
| A re\-iew of the literature up to 1944 permitted Mason to suggest that the anterior
| |
| hypophysis was not the instigator of reproductive disturbances in vitamin E deficiency. Nevertheless, Griesbach, Bell and
| |
| Livingston (1957), in an analysis of the
| |
| pituitary gland during progessive stages of
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 677
| |
| | |
| | |
| | |
| tocopherol deprivation, observed cytologic
| |
| changes in the hypophysis which preceded
| |
| testis changes. The "peripheral or FSH
| |
| gonadotrophes" increased in number, size,
| |
| and activity. The LH cells exhibited a
| |
| hyperplasia of lesser extent, but possibly
| |
| sufficient to increase LH in circulation and
| |
| to cause hypertrophy of the male accessory
| |
| glands. Gonadotrophic hormone content of
| |
| pituitary glands from vitamin E-deficient
| |
| rats may be decreased (Rowlands and
| |
| Singer, 1936), unchanged (Biddulph and
| |
| Meyer, 1941), or increased to a level between normal and that of the castrate, when
| |
| the adult male rats were examined after 22
| |
| weeks on a deficient diet (Nelson, 1933;
| |
| Drummond, Noble and Wright, 1939).
| |
| Using hypophysectomized male rats as assay animals, evidence was obtained that
| |
| FSH was increased in the pituitary glands
| |
| of vitamin E-deficient male and female rats
| |
| (P'an, Van Dyke, Kaunitz and Slanetz,
| |
| 1949).
| |
| | |
| IV. Male Reproductive System
| |
| | |
| A. TESTIS
| |
| | |
| The two basic functions of the male
| |
| gonads are to produce gametes and secrete
| |
| steroids. Spermatogenic activity can be
| |
| estimated from testis morphology and examination of semen samples. Androgen secretion can be estimated from urinary steroid levels, accessorj^ gland weight, and
| |
| from analyses of accessory sex gland secretions, i.e., fructose and citric acid. In normal maturation in the rabbit, rat, boar,
| |
| and bull, androgen secretion precedes spermatogenesis (Lutwak-Mann, 1958). On this
| |
| basis it would appear that well fed young
| |
| bulls may come into semen production 2 to
| |
| 3 months sooner than poorly fed animals
| |
| (Brat ton, 1957).
| |
| | |
| 1. Inanition
| |
| | |
| Complete starvation will pre^•ent maturation of immature animals. Furthermore,
| |
| marked undernutrition in 700 boys, 7 to 16
| |
| years of age, was associated with genital
| |
| infantilism in 37 per cent and cryptorchidism in 27 per cent (Stephens, 1941).
| |
| Restriction of food intake to one-half of the
| |
| normal in maturing bull calves had a
| |
| | |
| | |
| | |
| marked delaying effect on the onset of
| |
| seminal vesicle secretion, but a lesser delaying effect on spermatogenesis (Davies,
| |
| Mann and Rowson, 1957) . Limiting the food
| |
| intake to one-third of the normal did not
| |
| prevent the immature rat testis from forming spermatozoa at the same time as their
| |
| controls (Talbert and Hamilton, 1955).
| |
| When testis maturation was prevented by
| |
| inanition, a rapid growth and maturation
| |
| occurred on refeeding (Ball, Barnes and
| |
| Visscher, 1947; Quimby, 1948) but Schultze
| |
| (1955) observed that full body size was not
| |
| attained.
| |
| | |
| The reproductive organs of the adult are
| |
| more resistant to changes imposed by diet
| |
| than are those of the immature animal.
| |
| Thus, Mann and Walton (1953) found that
| |
| 23 weeks of underfeeding produced little
| |
| change in sperm density and motility in mature animals although seminal vesicle function was reduced. Li the male rat testis
| |
| hypofunction follows partial or complete
| |
| starvation (]\Iason and Wolfe, 1930; Mulinos and Pomerantz, 1941a; Escudero, Herraiz and Mussmano, 1948), but there is no
| |
| reduction in testicular nitrogen (Addis, Poo
| |
| and Lew, 1936). Loss of Leydig cell function precedes cessation of spermatogenesis
| |
| (Moore and Samuels, 1931) and is evident
| |
| by the atrophy of the accessory sexual organs (^lulinos and Pomerantz, 1941a) and
| |
| by an alteration in accessory gland secretion
| |
| (Pazos and Huggins, 1945; Lutwak-]\Iann
| |
| and Mann, 1950). Evidence of a tubular
| |
| effect is provided by the lack of motile
| |
| sperm (Reid, 1949). Severe dietary restriction is associated with the absence of
| |
| spermatozoa in the seminiferous tubules and
| |
| epididymis (Mason, 1933; Menze, 1941).
| |
| | |
| The human male suffering from chronic
| |
| malnutrition exhibits hypogonadism. The
| |
| testes atrophy and exhibit a decrease in size
| |
| of the seminiferous tubules; basement membrane thickening and small Leydig cells
| |
| are seen. These individuals excrete significantly subnormal amounts of 17-ketosteroids (Zubiran and Gomez-Mont, 19531.
| |
| Acute starvation may also decrease urinary
| |
| 17-ketosteroid and androgen levels as much
| |
| as 50 per cent, with recovery evident on refeeding (Perloff, Lasche, Nodine, Schneeberg and Vieillard. 1954).
| |
| | |
| | |
| | |
| 6/
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| TABLE 12.5
| |
| | |
| Effect of diet on the testes of immature rats
| |
| | |
| (From J. H. Leathern, in Re-productive Phijsiology
| |
| | |
| and Protein Nutrition, Rutgers University
| |
| | |
| Press, New Brunswick, N. J., 1959.)
| |
| | |
| | |
| | |
| Sperm
| |
| | |
| | |
| | |
| Initial control . . .
| |
| 20 per cent X 30
| |
| | |
| days
| |
| | |
| 6 per cent X 30
| |
| | |
| days
| |
| | |
| 3 per cent X 30
| |
| | |
| days
| |
| | |
| per cent X 30
| |
| | |
| days
| |
| | |
| per cent + 5
| |
| per cent liver. ,
| |
| | |
| per cent + 5
| |
| per cent yeast
| |
| | |
| G5 per cent X 30
| |
| davs
| |
| | |
| | |
| | |
| No. of
| |
| Rats
| |
| | |
| | |
| Testis
| |
| | |
| | |
| Weight
| |
| | |
| | |
| | |
| | |
| mg.
| |
| | |
| | |
| mg./lOOgm.
| |
| | |
| | |
| 10
| |
| | |
| | |
| 329
| |
| | |
| | |
| 825
| |
| | |
| | |
| 10
| |
| | |
| | |
| 1694
| |
| | |
| | |
| 1035
| |
| | |
| | |
| 16
| |
| | |
| | |
| 824
| |
| | |
| | |
| 890
| |
| | |
| | |
| 12
| |
| | |
| | |
| 380
| |
| | |
| | |
| 930
| |
| | |
| | |
| 10
| |
| | |
| | |
| 140
| |
| | |
| | |
| 346
| |
| | |
| | |
| 10
| |
| | |
| | |
| 112
| |
| | |
| | |
| 291
| |
| | |
| | |
| 10
| |
| | |
| | |
| 119
| |
| | |
| | |
| 296
| |
| | |
| | |
| 10
| |
| | |
| | |
| 1747
| |
| | |
| | |
| 1040
| |
| | |
| | |
| | |
| | |
| | |
| 100
| |
| | |
| 50
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 100
| |
| | |
| | |
| | |
| 2. Protein
| |
| | |
| The minimal amount of dietary protein
| |
| which will support reproduction, lactation,
| |
| and growth is 16.7 per cent (Goettsch, 1949) .
| |
| Thus, it is not surprising that maturation
| |
| of testes and accessory sex organs was prevented in immature rats (Horn, 1955) and
| |
| mice (Leathern and DeFeo, 1952) when
| |
| they were fed a protein-free diet for 15 to
| |
| 30 days after weaning. Furthermore, supplements of 5 per cent liver to the casein-free
| |
| diet had no effect. After a month, the testes,
| |
| averaging 329 mg., decreased to 140 mg. in
| |
| rats fed per cent casein, but the weight
| |
| increased to an average of 1694 mg. and
| |
| 1747 mg. in rats fed 20 per cent and 65 per
| |
| cent casein, respectively (Table 12.5). Following protein depletion, there was a decrease in tubular ribonucleic acid and an increase in lipid. Accumulation of gonadal
| |
| lipid in the inactive testis may be an abnormal assimilation of a degenerative nature or simply nonutilization. A diet containing 6 per cent casein permitted the
| |
| formation of spermatozoa in some animals
| |
| (Guilbert and Goss, 1932). When the 6 per
| |
| cent casein diet was fed to immature animals for 30 days 50 per cent of the rats
| |
| exhibited some spermatozoa; in addition,
| |
| testis weight increased slightly and seminal
| |
| | |
| | |
| | |
| vesicle weight doubled, but body weight was
| |
| not improved (Horn, 1955). Thus, as we
| |
| noted earlier, the reproductive system may
| |
| gain special consideration for protein allotments when supplies are limited.
| |
| | |
| Gain in testis weight in immature male
| |
| rats and the biochemical composition of the
| |
| immature testis are influenced by the nutritive value of the protein fed. The testes of
| |
| normal immature rats contain 85 per cent
| |
| water, 10.5 per cent protein, 4.5 per cent
| |
| lipid, and detectable glycogen (Wolf and
| |
| Leathern, 1955). Proteins of lower nutritive
| |
| value (wheat gluten, peanut flour, gelatin ) may permit some increase in testis
| |
| weight, but testis protein concentration decreased, percentage of water increased, and
| |
| lipid and glycogen remained unchanged
| |
| (Table 12.6). The enzyme ^fi-glucuronidase,
| |
| which has frequently been associated with
| |
| growth processes, exhibited no change in
| |
| concentration as the testis matured or was
| |
| jirevented from maturing by a protein-free
| |
| diet (Leathem and Fisher, 1959). Not only
| |
| are the weight and composition of the testis
| |
| influenced by feeding proteins of varied biologic value, but the release of androgen is
| |
| more markedly altered. When a 22-day-old
| |
| male rat was fed a 20 per cent casein diet
| |
| for 30 days, the seminal vesicle and ventral
| |
| prostate weights increased 9- to 10-fold in
| |
| comparison with initial control weight. Sub
| |
| TABLE 12.6
| |
| | |
| Niiiritioiial effects on testis-coin position
| |
| | |
| in immature rats
| |
| | |
| (From R. C. Wolf and J. H. Leathem,
| |
| | |
| Endocrinology, 57, 286, 1955.)
| |
| | |
| | |
| | |
| 20 pel' cent casein
| |
| | |
| 20 per cent wheat
| |
| gluten
| |
| | |
| 20 per cent i)eanut flour
| |
| | |
| 20 i)er cent gelatin
| |
| | |
| 5 per cent casein
| |
| | |
| Fox chow
| |
| | |
| Initial control . .
| |
| | |
| | |
| | |
| No. of
| |
| Rats
| |
| | |
| | |
| Final
| |
| Body
| |
| Weight
| |
| | |
| | |
| | |
| | |
| gm.
| |
| | |
| | |
| 7
| |
| | |
| | |
| 128
| |
| | |
| | |
| 8
| |
| | |
| | |
| 82
| |
| | |
| | |
| 8
| |
| | |
| | |
| 81
| |
| | |
| | |
| 5
| |
| | |
| | |
| 53
| |
| | |
| | |
| 5
| |
| | |
| | |
| 61
| |
| | |
| | |
| 8
| |
| | |
| | |
| 115
| |
| | |
| | |
| 7
| |
| | |
| | |
| 61
| |
| | |
| | |
| | |
| 72.3j30.4
| |
| 04.634.0
| |
| | |
| | |
| | |
| 1468
| |
| 1017
| |
| | |
| 1257 66.1
| |
| 2101
| |
| | |
| | |
| | |
| 28.8
| |
| | |
| | |
| | |
| 0.11
| |
| 0.18
| |
| 0.11
| |
| 0.10
| |
| | |
| | |
| | |
| 684,62.4 29.2 0.26
| |
| 1515'70.3 30.3 0.15
| |
| 273 72. 7:30. 10.19
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 679
| |
| | |
| | |
| | |
| stitution of wheat gluten and peanut flour
| |
| for casein, limited the increase in the weight
| |
| of the seminal vesicles to less than 100 per
| |
| cent. In fact, seminal vesicle weight as related to body weight did not increase in
| |
| animals fed 20 per cent wheat gluten.
| |
| | |
| The withholding of dietary protein from
| |
| an immature rat for 30 days, during which
| |
| time maturation occurs in the fully fed animal, did not impose a permanent damage.
| |
| Refeeding of protein permitted the rapid recovery of testis weight and the appearance
| |
| of spermatoza, 70 per cent of all animals
| |
| having recovered in 30 days when fully fed,
| |
| whereas only 25 per cent recovered when
| |
| 6 per cent casein was fed. Recovery of
| |
| androgen secretion was somewhat slower
| |
| than that of the tubules as estimated by
| |
| seminal vesicle weight.
| |
| | |
| Variations in protein quality are a reflection of amino acid patterns, and amino
| |
| acid deficiencies interfere with testis maturation (Scott, 1956; Pomeranze, Piliero,
| |
| Medeci and Plachta, 1959). Alterations in
| |
| food intake which follow amino acid deficiencies have required forced feeding or
| |
| pair-fed controls, but it is clear from what
| |
| w^as found in the controls that the gonadal
| |
| changes were not entirely due to inanition
| |
| (Ershoff, 1952).
| |
| | |
| If the diet is varied so that caloric intake
| |
| per gram is reduced to half while retaining
| |
| the dietary casein level at 20 per cent, immature rat testis growth is prevented. The
| |
| effect is unlike that obtained with this level
| |
| of protein in the presence of adequate calories. Furthermore, the caloric restriction
| |
| may increase testis glycogen (Leathem,
| |
| 1959c).
| |
| | |
| Protein anabolic levels are higher in the
| |
| tissues of young growing animals and the
| |
| body is more dependent on dietary protein
| |
| level and quality for maintenance of the
| |
| metabolic nitrogen pool than in adult animals. On the other hand, body protein reserves in adult animals permit internal
| |
| shifts of nitrogen to the metabolic pool and
| |
| to tissues when dietary sources are reduced
| |
| or endocrine imbalances are imposed. Thus,
| |
| Cole, Guilbert and Goss (1932) fed a low
| |
| protein diet to adult male rats for 60 to 90
| |
| days before the sperm disappeared, but the
| |
| animals would not mate. Amount of semen
| |
| and sperm produced by sheep have been re
| |
| | |
| | |
| TABLE 12.7
| |
| | |
| Arlult rat testes and seminal vesicles
| |
| | |
| after protein depletion
| |
| | |
| (From J. H. Leatliem, Recent Progr. Hormone
| |
| | |
| Res., 14, 141, 1958.)
| |
| | |
| | |
| | |
| Days on
| |
| | |
| | |
| No. of
| |
| | |
| | |
| Testis
| |
| | |
| | |
| H2O
| |
| | |
| | |
| Protein
| |
| | |
| | |
| Total
| |
| | |
| | |
| Seminal
| |
| | |
| | |
| PFD*
| |
| | |
| | |
| Rats
| |
| | |
| | |
| Weight
| |
| | |
| | |
| Protein
| |
| | |
| | |
| Vesical
| |
| | |
| | |
| | |
| | |
| | |
| | |
| nig.
| |
| | |
| | |
| %
| |
| | |
| | |
| %dry
| |
| | |
| | |
| gm.
| |
| | |
| | |
| mg.
| |
| | |
| | |
| Control
| |
| | |
| | |
| 9
| |
| | |
| | |
| 2852
| |
| | |
| | |
| 85.9
| |
| | |
| | |
| 66.7
| |
| | |
| | |
| 0.28
| |
| | |
| | |
| 1276
| |
| | |
| | |
| 30
| |
| | |
| | |
| 9
| |
| | |
| | |
| 2600
| |
| | |
| | |
| 86.0
| |
| | |
| | |
| 66.1
| |
| | |
| | |
| 0.24
| |
| | |
| | |
| 689
| |
| | |
| | |
| 50
| |
| | |
| | |
| 7
| |
| | |
| | |
| 2398
| |
| | |
| | |
| 85.4
| |
| | |
| | |
| 64.1
| |
| | |
| | |
| 0.22
| |
| | |
| | |
| 320
| |
| | |
| | |
| 90
| |
| | |
| | |
| 25
| |
| | |
| | |
| 1429
| |
| | |
| | |
| 85.7
| |
| | |
| | |
| 69.6
| |
| | |
| | |
| 0.13
| |
| | |
| | |
| 168
| |
| | |
| | |
| | |
| * PFD = Protein-free diet.
| |
| | |
| lated to the dietary protein level (Popoff
| |
| and Okultilschew, 1936). Removal of protein from the diet for 30 days had little
| |
| effect on the adult rat testis weight, spermatogenesis, or nitrogen content (Leathem,
| |
| 1954). However, seminal vesicle w^eight was
| |
| reduced 50 per cent (Aschkenasy, 1954).
| |
| Prolonged protein depletion was required
| |
| before the testis exhibited a loss in protein
| |
| and a reduction in size. A loss of spermatozoa was not observed consistently, although some testes were completely atrophic
| |
| (Table 12.7). Accessory organ weight decrease reflected the disappearance of androgen (Leathem, 1958a). Interstitial cell atrophy has also been noted in rats fed a low
| |
| vegetable protein (cassava) diet (Adams,
| |
| Fernand and Schnieden, 1958).
| |
| | |
| Sterility may or may not be induced with
| |
| diets containing 65 per cent protein (Reid.
| |
| 1949; Leathem, 1959c) but a 15 to 18 per
| |
| cent dietary level of a poor protein such
| |
| as maize or gelatin will decrease sperm motility and increase the number of abnormal
| |
| sperm. The influence of proteins having different nutritional values in support of the
| |
| growth of testes from the level to which
| |
| they were depressed by stilbestrol indicated
| |
| that casein, lactalbumin, and wheat gluten
| |
| are equally competent to support testis
| |
| growth whereas gelatin is deficient. Whole
| |
| proteins may have several amino acid deficiencies, but the administration of amino
| |
| acid antagonists may help to identify important individual amino acids. As an example, ethionine causes severe seminiferous
| |
| tubule atrophy and Leydig cell hypoplasia
| |
| (Kaufman, Klavins and Kinney, 1956;
| |
| Goldberg, Pfau and Ungar, 1959). Studies
| |
| in man have indicated a sharp reduction in
| |
| | |
| | |
| | |
| 680
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| spermatozoa after 9 days on an argininedeficient diet (Holt, Albanese, Shettles,
| |
| Kajdi and Wangerin, 1942).
| |
| | |
| Adequate dietary protein cannot maintain reproductive function if the diet is
| |
| calorie deficient. Thus, a decrease in seminal
| |
| vesicle weight could be related to a decrease
| |
| in dietary calories while protein levels were
| |
| constant (Rosenthal and Allison, 1956).
| |
| However, the accessory gland weight loss
| |
| imposed by caloric restriction could be
| |
| slowed by increasing the dietary protein
| |
| (Rivero-Fontan, Paschkis, West and Cantarow, 1952).
| |
| | |
| Alterations in testis function imposed by
| |
| inadequate protein are corrected when protein is returned to the diet at normal levels
| |
| (Aschkenasy and Dray, 1953). Nevertheless, the nutritional state of the animal as
| |
| a factor influencing recovery has been demonstrated with stilbestrol-treated adult male
| |
| rats. While being fed an 18 per cent casein
| |
| diet, adult male rats were injected with 0.1
| |
| mg. stilbestrol daily for 20 days. Testis
| |
| weight decreased from 2848 to 842 mg.,
| |
| spermatogenesis was abolished, and testis
| |
| water and protein content were significantly
| |
| reduced. Despite a reduction in food intake,
| |
| pair-fed controls exhibited no effect on reproductive organs. When a protein-free diet
| |
| was substituted for the normal diet during
| |
| the administration of stilbestrol, atrophy of
| |
| the reproductive system was observed. Cessation of hormone administration was followed by a rapid return of testicular function toward normal when 18 per cent casein
| |
| was fed both during the injection period
| |
| and the recovery period. Within 30 days
| |
| spermatogenesis and testicular composition
| |
| were fully recovered. However, when 18
| |
| per cent casein was fed in the postinjection
| |
| period to rats that had received a proteinfree diet while being given stilbestrol, recovery was clearly slow. After a month,
| |
| spermatozoa were observed in only 30 per
| |
| cent of the testes and testis weight was subnormal. Despite the seeming similarity of
| |
| response by the two nutritional groups during the injection period, the postinjection recovery on identical dietary intake revealed
| |
| marked differences in rate of recoverv (Leathem, 1958a).
| |
| | |
| | |
| | |
| 3. Fat
| |
| | |
| Linoleic, linolenic, and arachidonic acids
| |
| are designated as essentially fatty acids, but
| |
| the physiologic role of these substances is
| |
| not clearly understood. Nevertheless, the
| |
| male reproductive organs are influenced by
| |
| dietary essential fatty acid levels. High
| |
| fat diets may enhance testicular weight
| |
| (Kaunitz, Slanetz, Johnson and Guilmain,
| |
| 1956) whereas removal of fat from the diet
| |
| resulted in a degeneration of the seminiferous tubules as evidenced by intracellular
| |
| vacuolation and a reduction in spermatids
| |
| and spermatozoa (Panos and Finerty,
| |
| 1954). After 5 months of feeding a fatfree diet, the rat testis may be devoid of
| |
| sperm (Evans, Lepkovsky and Murphy,
| |
| 1934). Testis degeneration occurred despite
| |
| dietary supplements of vitamins A and E
| |
| and in animals whose health appeared quite
| |
| normal (Ferrando, Jacques, Mabboux and
| |
| Prieur, 1955; Ferrando, Jacques, Mabboux
| |
| and SoUogoub, 1955).
| |
| | |
| Weanling rats fed 14 per cent arachis (peanut) oil for 15 weeks exhibited a marked
| |
| impairment of spermatogenesis (Aaes-Jorgensen, Funch and Dam, 1956) and 28
| |
| per cent arachis oil induced testicular damage of such an order that 15 weeks of feeding
| |
| ethyl linoleate did not restore fertility
| |
| (Aaes-Jorgensen, Funch and Dam, 1957).
| |
| | |
| 4. Vitamins
| |
| | |
| Testicular dysfunction as judged by failure of sperm formation or atrophy of the
| |
| secondary sex organs has been observed in
| |
| deprivations of thiamine, riboflavin, pyridoxine, calcium pantothenate, biotin, and
| |
| vitamins A and E. One must distinguish,
| |
| however, between effects of inanition associated w^ith a vitamin deficiency and a
| |
| specific vitamin effect (Skelton, 1950) ; one
| |
| must also consider species differences (Biskind, 1946).
| |
| | |
| There is no question but that vitamin E
| |
| deficiency in the rat results in a specific
| |
| and irreversible damage to the testis. Tubular damage may proceed to the point where
| |
| only Sertoli cells remain and yet the interstitial cells are not influenced (Mason,
| |
| 1939). Similar changes followed vitamin E
| |
| deficiency in the guinea pig (Pappenheimer
| |
| and SchogolefT, 1944; Curto, 1954; Ingel
| |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 681
| |
| | |
| | |
| | |
| man-Siindberg, 1954) , hamster (Mason and
| |
| Mauer, 1957), and bird (Herrick, Eide and
| |
| Snow, 1952; Lowe, Morton, Cunningham
| |
| and Vernon, 1957). However, little or no
| |
| effect of an absence of vitamin E was noted
| |
| in the rabbit (Mackenzie, 1942) and mouse
| |
| (Bryan and Mason, 1941), or in live stock
| |
| (Blaxter and Brown, 1952), or man (Lutwak-Mann, 1958), although vitamin E is
| |
| present in human testes (Dju, Mason and
| |
| Filer, 1958). Treatment of low-fertility
| |
| farm animals with wheat germ oil or tocopherol or the use of this vitamin clinically
| |
| have provided only inconclusive results
| |
| (Beckmann, 1955) . Although some positive
| |
| effects have been reported in man, the results may be due in part at least to the sparing action of tocopherol toward vitamin A.
| |
| | |
| Vitamin A deficiency influences the testis
| |
| but changes are closely associated with the
| |
| degree of inanition. In the rat, a vitamin deficiency sufficient to cause ocular lesions
| |
| did not prevent sperm formation, but a deficiency of such proportions as to cause a
| |
| body weight loss did cause atrophy of the
| |
| germinal epithelium (Reid, 1949). Vitamin
| |
| A deficiency will induce sterility in mice
| |
| (McCarthy and Cerecedo, 1952). A gross
| |
| vitamin deficiency in bulls before expected
| |
| breeding age prevented breeding ; adult bulls
| |
| may exhibit a lower quality semen but they
| |
| remain fertile (Reid, 1949). Vitamin A deficiency induces metaplastic keratinization
| |
| of the epithelium lining the male accessory
| |
| sex organs (Follis, 1948) and thus may influence semen.
| |
| | |
| Testis damage induced by vitamin A deficiency can be reversed, but vitamin A
| |
| therapy in man for oligospermia not due to
| |
| vitamin lack was without effect (Home
| |
| and Maddock, 1952) .
| |
| | |
| Age of the animal and dosage are factors
| |
| which influence the results obtained in male
| |
| rats with administered vitamin A. Immature
| |
| male rats given 250 I.U. of vitamin A per
| |
| gram of body weight daily exhibited a loss
| |
| of spermatocytes, an effect which was accentuated by tocopherol (Maddock, Cohen
| |
| and Wolbach, 1953). Little or no effect of
| |
| similar treatment was observed in adult
| |
| rats. The liver is the major storage depot
| |
| for vitamin A and the fact that the male rat
| |
| liver is more quickly depleted and less capa
| |
| | |
| | |
| ble of storage than is the liver of the female
| |
| should be considered in any attempted correlation of the vitamin and hormone levels
| |
| (Booth, 1952).
| |
| | |
| Other vitamin deficiencies have been
| |
| shown to influence the testis. A lack of
| |
| thiamine had little effect on testis weight,
| |
| but did influence the Leydig cells and prevented growth of the accessory sex organs
| |
| (Pecora and Highman, 1953). A chronic
| |
| lack of ascorbic acid will cause a degeneration of both Leydig cells and seminiferous
| |
| tubules. The effects of vitamin deficiency on
| |
| the testis has been distinguished from those
| |
| due to inanition and have been related to
| |
| changes in carbohydrate metabolism (Mukherjee and Banerjee, 1954; Kocen and
| |
| Cavazos, 1958) . The importance of ascorbic
| |
| acid in the testis as related to function is
| |
| not evident, but concentrations of this vitamin are maximal at 1 week of age (Coste,
| |
| Delbarre and Lacronique, 1953).
| |
| | |
| Serious anatomic and functional impairments of testes were noted in pantothenic
| |
| acid deficiency (Barboriak, Krehl, Cowgill
| |
| and Whedon, 1957), and development of
| |
| the rat testis and seminal vesicles was retarded by a biotin deficiency (Bishop and
| |
| Kosarick, 1951; Katsh, Kosarick and Alpern, 1955), but the animals did not exhibit
| |
| marked alterations in other endocrine organs (Delost and Terroine, 1954). Testosterone hastened the development of vitamin
| |
| deficiency and enhanced the severity of biotin deficiency in both sexes, thereby suggesting a hormone-vitamin relationship
| |
| (Okey, Pencharz and Lepkovsky, 1950). On
| |
| the other hand, testosterone had no effect on
| |
| the tolerance of mice for aminopterin, but
| |
| castration increased the tolerance (Goldin,
| |
| Greenspan, Goldberg and Schoenberg 1950).
| |
| | |
| B. INFLUENCE OF NUTRITION ON THE EE
| |
| SPONSIVENESS OF MALE REPRODUCTIVE
| |
| | |
| TISSUES TO HORMONES
| |
| | |
| 1. Testis
| |
| | |
| a. Inanition. The testes of birds on limited
| |
| food intake were more responsive to hypophyseal gonadotrophin than fully fed birds
| |
| (Byerly and Burrows, 1938; Breneman,
| |
| 1940). In the rat several investigators have
| |
| shown that the testis will respond to gonadotrophin despite inanition (Moore and Sara
| |
| | |
| | |
| 682
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| TABLE 12.8
| |
| | |
| Influence of diet and pregnant mare serum (PMS)
| |
| | |
| on testes and seminal vesicles of
| |
| | |
| immature male mice
| |
| | |
| (From V. J. DeFeo and J. H. Leathern,
| |
| | |
| unpublished.)
| |
| | |
| | |
| | |
| Diet (Per cent
| |
| Protein X Days Fed)
| |
| | |
| | |
| | |
| per cent X 10
| |
| per cent X 10
| |
| per cent X 20
| |
| per cent X 20
| |
| | |
| | |
| | |
| l.u.
| |
| | |
| 3
| |
| | |
| 3
| |
| | |
| | |
| | |
| stage of
| |
| Spermatogenesis
| |
| | |
| | |
| | |
| 4
| |
| 1
| |
| | |
| 1 5
| |
| 5
| |
| | |
| | |
| | |
| Spermatids
| |
| | |
| | |
| | |
| Seminal
| |
| Vesicles
| |
| | |
| | |
| | |
| mg.
| |
| | |
| 2.7
| |
| 4.5
| |
| | |
| 2.7
| |
| 3.5
| |
| | |
| | |
| | |
| uels, 1931; Funk and Funk, 1939; Meites,
| |
| 1953), with a stimulation of Leydig cells,
| |
| an increase in testis size, and, in 40 days,
| |
| a return of spermatozoa. Underfed males injected with gonadotrophin sired litters (Mulinos and Pomerantz, 1941a, b). Improved
| |
| nutrition aided by unknown liver factors
| |
| enhanced the response to androgen in severe human oligospermia (Glass and Russell, 1952).
| |
| | |
| b. Protein. Feeding a protein-deficient
| |
| diet to adult male rats for 60 to 90 days
| |
| did not prevent stimulation of the testes and
| |
| seminal vesicles after pregnant mare's serum
| |
| (PMS) administration (Cole, Guilbert and
| |
| Goss, 1932). As we have noted, immature
| |
| animals are prevented from maturing when
| |
| diets lack protein. Nevertheless, a gonadal
| |
| response to injected gonadotrophin was obtained in immature mice fed a protein-free
| |
| diet for 13 days; tubules and Leydig cells
| |
| were stimulated and androgen was secreted
| |
| (Table 12.8). Refeeding alone permitted a
| |
| recovery of spermatogenesis which was not
| |
| hastened by concomitant PMS (Leathem,
| |
| 1959c).
| |
| | |
| The maintenance of testis weight and
| |
| spermatogenic activity with testosterone
| |
| propionate in hypophysectomized adult
| |
| male rats is well known, but these studies
| |
| have involved adequate nutrition. If hypophysectomized rats were fed a protein-free
| |
| diet and injected with 0.25 mg. testosterone
| |
| propionate daily, testis weight and spermatogenesis were less well maintained than
| |
| in rats fed protein. Testis protein concentra
| |
| | |
| | |
| tion was also reduced. These data suggest
| |
| that influences of nutrition on the testis can
| |
| be direct and are not entirely mediated
| |
| through hypophyeal gonadotrophin changes
| |
| (Leathem, 1959b).
| |
| | |
| c. Fat. The rat fed for 20 weeks on a fatfree diet exhibits a degeneration of the
| |
| seminiferous epithelium within the first
| |
| weeks which progresses rapidly thereafter.
| |
| Chorionic gonadotrophin or rat pituitary extract started during the 20th week failed to
| |
| counteract the tubular degeneration, but
| |
| testosterone propionate proved effective
| |
| (Finerty, Klein and Panos, 1957). The result shows that the ineffectiveness of the
| |
| gonadotrophins could not be due to the failure of androgen release (Greenberg and Ershoff, 1951).
| |
| | |
| d. Vitamins. Gonadotrophins failed to
| |
| promote spermatogenesis in vitamin A(Mason, 1939) or vitamin E- (]Mason,
| |
| 1933; Geller, 1933; Drummond, Noble and
| |
| Wright, 1939) deficient rats, but in another
| |
| experiment the atrophic accessory sex organs of vitamin A-depleted rats were stimulated (Mayer and Goodard, 1951). Lack
| |
| of vitamin A favored an enhanced response
| |
| to PMS when the ratios of seminal vesicle
| |
| weight to body weight were computed
| |
| (Meites, 1953). The failure of gonadotrophins to stimulate testis tubules suggests a
| |
| specific effect of avitaminosis A and E
| |
| (Mason, 1933) on the responsiveness of the
| |
| germinal epithelium.
| |
| | |
| Subnormal responses of rats to PMS, as
| |
| measured by relative seminal vesicle weight,
| |
| were obtained when there were individual
| |
| vitamin B deficiencies, but the influence was
| |
| due largely to inanition (Drill and Burrill,
| |
| 1944; Meites, 1953). Nevertheless, sufficient
| |
| response to chorionic gonadotrophin was obtained so that fructose and citric acid levels
| |
| were restored to normal. Such an effect was
| |
| not observed to follow dietary correction unless an unlimited food intake was allowed
| |
| (Lutwak-Mann. 1958).
| |
| | |
| | |
| | |
| 2. Sc
| |
| | |
| | |
| | |
| il W.siclfx and Prosfate
| |
| | |
| | |
| | |
| a. Inanition. Although the accessory reproductive organs resppnd to direct stimulation despite an inadequate food intake
| |
| (Mooi'c and Samuels. 19311, tlio increase
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 683
| |
| | |
| | |
| | |
| in weight may be subnormal in mice and
| |
| rats (Goldsmith, Nigrelli and Ross, 1950;
| |
| Kline and Dorfman, 1951a, Grayhack and
| |
| Scott, 1952), or above normal in chickens
| |
| (Breneman, 1940). Complete deprivation
| |
| of food reduced the quantity of prostatic
| |
| fluid in the dog, but exogenous androgen restored the volume, increased acid phosphatase, and induced tissue growth (Pazos and
| |
| Huggins, 1945) .
| |
| | |
| 6. Protein. The response of the seminal
| |
| vesicles to androgen was investigated in immature rats, using weight and /5-glucuronidase as end points. Castration and 10 days
| |
| on a protein-free diet preceded the 72-hour
| |
| response to 0.25 mg. testosterone propionate.
| |
| The lack of protein did not prevent a normal weight increase, and enzyme concentration was unchanged. If an 18 per cent diet
| |
| was fed during the 3-day period that the
| |
| androgen was acting, no improvement in
| |
| weight response was noted, but enzyme concentration increased 100 per cent. Thus,
| |
| when protein stores are depleted, the androgen response may be incomplete in the absence of dietary protein (Leathern, 1959c).
| |
| Nevertheless, varied protein levels do not
| |
| influence seminal vesicle weight-response
| |
| when caloric intake is reduced (RiveroFontan, Paschkis, West and Cantarow,
| |
| 1952).
| |
| | |
| c. Vitamins. Vitamin deficiencies do not
| |
| prevent the seminal vesicles from responding to androgen. In fact, in vitamin B deficiency, testosterone restored fructose and
| |
| citric acid levels to normal despite the need
| |
| for thiamine in carbohydrate metabolism
| |
| (Lutwak-Mann and Mann, 1950). In the
| |
| male, unlike the female, the effects of folic
| |
| acid deficiency in reducing responsiveness
| |
| to administered androgen were largely due
| |
| to inanition in both mice and rats (Goldsmith, Nigrelli and Ross, 1950; Kline and
| |
| Dorfman, 1951a) , and vitamin A deficiency
| |
| which leads to virtual castration does not
| |
| prevent an essentially normal response of
| |
| the accessory glands to testosterone propionate (Mayer and Truant, 1949). Restricting the caloric intake of vitamin Adeficient rats retarded the curative effects
| |
| of vitamin A in restoring the accessory sex
| |
| glands of the A-deficient animals (Mason,
| |
| 1939).
| |
| | |
| | |
| | |
| V. Female Reproductive System
| |
| | |
| A. OVARIES
| |
| | |
| 1. Inanition
| |
| | |
| Mammalian species generally exhibit a
| |
| delay in sexual maturation when food intake is subnormal before puberty, and
| |
| ovarian atrophy with associated changes
| |
| in cycles if inanition is imposed on adults.
| |
| In human beings a decrease in fertility and
| |
| a greater incidence of menstrual irregularities were induced by war famine (Zimmer,
| |
| Weill and Dubois, 1944). Ovarian atrophy
| |
| with associated amenorrhea and sterility
| |
| were invoked by chronic undernutrition
| |
| (Stephens, 1941). The ovarian morpliologic
| |
| changes were similar to those of aging.
| |
| Urinary estrogens were subnormal in 22 of
| |
| 25 patients exhibiting amenorrhea associated with limited food intake (Zubiran and
| |
| (_lomcz-Mont, 1953).
| |
| | |
| The nutritional requirements of jM'imates
| |
| other than man have been studied in female
| |
| baboons. The intake of vitamins and other
| |
| essential nutrients was found to be of the
| |
| same order as that recommended for man.
| |
| Caloric intake varied with the menstrual
| |
| cycle, being least during the follicular phase
| |
| and maximal during the 2 to 7 days preceding menstruation (Gilbert and Gillman,
| |
| 1956). Various diets were also studied to
| |
| assess their importance in maintaining the
| |
| normal menstrual rhythm. The feeding of
| |
| (a) maize alone, (b) assorted vegetables
| |
| and fruit, or (c) maize, skimmed milk, and
| |
| fat led to menstrual irregularities or to
| |
| amenorrhea. The mechanism regulating ovulation was the first to be deranged. The
| |
| addition of various vitamins or of animal
| |
| protein did not correct the menstrual disorders. However, inclusion of ox liver in
| |
| the diet did maintain the menstrual rhythmicity, but the beneficial effect could not
| |
| be attributed to its protein content (Gillman and Gilbert, 1956 ) .
| |
| | |
| In lower mammals that have been studied,
| |
| inanition will hinder vaginal opening, and
| |
| delay puberty and ovarian maturation and
| |
| functioning. In adult rats and mice ostrous
| |
| cycles are interrupted and the reprorUictive
| |
| system becomes atrophic when body weight
| |
| loss exceeds 15 per cent. The ovaries be
| |
| | |
| | |
| 684
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| come smaller, ovulation fails, and large
| |
| vesicular follicles decrease in number with
| |
| an increase in atresia, but primary follicles
| |
| show a compensatory increase (Marrian
| |
| and Parkes, 1929; Mulinos and Pomerantz,
| |
| 1940; Stephens and Allen, 1941; Guilbert,
| |
| 1942; Bratton, 1957). The ovarian interstitial cells mav be markedly altered or absent
| |
| (Huseby and Ball, 1945; Rinaldini, 1949)
| |
| and the ovary may exhibit excessive luteinization (Arvy, Aschkenasy, AschkenasyLelu and Gabe, 1946) or regressing corpora
| |
| lutea (Rinaldini, 1949) . However, the ovarian changes induced by inanition may be
| |
| reversed by refeeding, with a return to reproductive capacity (Ball, Barnes and Visscher, 1947; Schultze, 1955). The effect of
| |
| feed-level on the reproductive capacity of
| |
| the ewe has been reported (El-Skukh, Nulet,
| |
| Pope and Casida, 1955), but one must realize that high planes of nutrition may adversely influence fertility (Asdell, 1949).
| |
| Nevertheless, additional protein and calcium added to an adequate diet extended
| |
| the reproductive life span (Sherman, Pearson, Bal, McCarthy and Lanford, 1956).
| |
| | |
| 2. Protein
| |
| | |
| The availability of just protein has an
| |
| important influence on the female reproductive system. In immature rats ovarian
| |
| maturation was prevented by feeding diets
| |
| containing per cent to 1.5 per cent protein
| |
| (Ryabinina, 1952) and low protein diets decreased the number of ova but without altering their ribonucleic acid (RNA) or glycogen content (Ishida, 1957). Refeeding 18
| |
| per cent protein for only 3 days was marked
| |
| by the appearance of vesicular follicles and
| |
| the release of estrogen in mice previously fed
| |
| a protein-free diet (Leathem, 1958a). In
| |
| experiments involving the opposite extreme,
| |
| in which 90 per cent protein diets were used,
| |
| a retardation of ovarian growth, and a delay in follicular maturation, in vaginal
| |
| opening, and in the initiation of estrous
| |
| cycles were noted (Aschkenasy-Lelu and
| |
| Tuchmann-Duplessis, 1947; TuchniannDuplcssis and Aschkenasy-Lelu, 1948).
| |
| | |
| Adult female rats fed a protein-free diet
| |
| for 30 days exhibited ovaries weighing 22
| |
| mg. compared with ovaries weighing 56 mg.
| |
| from i)air-fed controls fed 18 per cent casein.
| |
| Ovarian glycogen, ascorbic acid, and cho
| |
| | |
| | |
| lesterol were all influenced by protein
| |
| deprivation and anestrum accompanied
| |
| the ovarian changes. Furthermore, uterine
| |
| weight and gl3^cogen decreased in rats fed
| |
| protein-free diets (Leathem, 1959b).
| |
| | |
| In adult rats the feeding of 3.5 per cent
| |
| to 5 per cent levels of protein (GuillDert and
| |
| Gross, 1932) was followed by irregularity
| |
| of the cycles or by their cessation. The
| |
| cycles became normal when 20 to 30 per cent
| |
| protein was fed (Aschkenasy-Lelu and
| |
| Aschkenasy, 1947). However, abnormally
| |
| high levels of casein (90 per cent) induced prolonged periods of constant estrus
| |
| (Tuchmann-Duplessis and AschkenasyLelu, 1947). Nevertheless, not all species
| |
| responded to protein depletion in the same
| |
| manner. For example, the rabbit exhibited
| |
| estrus and ovulation despite a 25 per cent
| |
| body weight loss imposed by to 2 per cent
| |
| protein diets (Friedman and Friedman,
| |
| 1940).
| |
| | |
| Despite a normal level of protein in the
| |
| diet, inadequate calories will interfere with
| |
| reproductive function and induce ovarian
| |
| atrophy (Escudero, Herraiz and Mussmano,
| |
| 1948; Rivero-Fontan, Paschkis, West and
| |
| Cantarow, 1952). Furthermore, the effects
| |
| of 15 per cent and 56 per cent protein levels
| |
| on estrous cycles could not be distinguished
| |
| when calories were reduced 50 per cent (Lee,
| |
| King and Visscher, 1952). Returning mice
| |
| to full feeding after months of caloric deficiency resulted in a sharp increase in reproductive performance well above that expected for the age of the animal (Visscher,
| |
| King and Lee, 1952). This type of rebound
| |
| phenomenon has not been explained.
| |
| | |
| Reproductive failure assigned to dietary
| |
| protein may be a reflection of protein
| |
| quality as well as level. Specific amino acid
| |
| deficiencies lead to cessation of estrus
| |
| (White and AVhite, 1942; Berg and Rohse,
| |
| 1947) and thus feeding gelatin or wheat
| |
| as the protein source and at an 18 per cent
| |
| level was quickly followed by an anestrum
| |
| (Leathem, 1959b). Supplementation of the
| |
| wheat diet with lysine corrected the reproductive abnormalities (Courrier and
| |
| Raynaud, 1932), but neither lysine (Pearson, Hart and Bohstedt, 1937) nor cystine
| |
| (Pearson, 1936) added to a low casein diet
| |
| was beneficial. Control of food intake must
| |
| be considered in studies involving amino
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 685
| |
| | |
| | |
| | |
| acids, for a deficiency or an excess can create an imbalance and alter appetite. Opportunity to study the amino acids in reproduction is now possible because of the work of
| |
| Greenstein, Birnbaum, Winitz and Otey
| |
| (1957) and Schultze (1956) , who maintained
| |
| rats for two or more generations on synthetic diets containing amino acids as the
| |
| only source of protein. Similarly, the amino
| |
| acid needs for egg-laying in hens has been
| |
| reported (Fisher, 1957). Tissue culture
| |
| methods also permit the study of the nutritional requirements of embryonic gonadal
| |
| tissue, the success of avian gonadal tissue in
| |
| culture being judged by survival, growth,
| |
| and differentiation. In experiments in which
| |
| this technique was used it was found that a
| |
| medium made up of amino acids as the basic
| |
| nitrogen source can maintain gonadal explants very successfully, even though the
| |
| choice of amino acids does not exactly correspond to the 10 essential amino acids recommended for postnatal growth (StengerHaffen and Wolff, 1957).
| |
| | |
| 3. Carbohydrate
| |
| | |
| The absence of dietary carbohydrate does
| |
| not appreciably affect the regularity of
| |
| estrous cycles in rats provided the caloric
| |
| need is met. However, the substitution of
| |
| 20 per cent sucrose for corn starch induced
| |
| precocious sexual maturity which was followed by sterility (Whitnah and Bogart,
| |
| 1956). The ovaries contained corpora lutea,
| |
| but the excessive luteinization of unruptured
| |
| follicles suggested a hypophyseal disturbance. Substitution of 20 per cent lactose for
| |
| corn starch had no effect. Increased amounts
| |
| of lactose retarded the gain in body weight
| |
| and blocked ovarian maturation, possibly
| |
| because the animal could not hydrolyze adequate amounts of the disaccharide. Addition of whole liver powder to the diet
| |
| counteracted the depressing action of 45 per
| |
| cent lactose on the ovary (Ershoff, 1949).
| |
| | |
| 4. Fat
| |
| | |
| There seems to be little doubt that dietary
| |
| fat is reciuired for normal cyclic activity,
| |
| successful pregnancy, and lactation, and
| |
| that the requirements for essential fatty
| |
| acids are lower in females than in males
| |
| (Deuel, 1956).
| |
| | |
| Conception, fetal development, and par
| |
| | |
| | |
| turition can take place in animals fed a
| |
| diet deficient in fatty acids (Deuel, Martin
| |
| and Alfin-Slater, 1954) , despite a reduction
| |
| in total carcass arachidonic acid (Kummerow. Pan and Hickman, 1952). Earlier
| |
| reports indicated that a deficiency of essential fatty acids caused irregular ovulation and impaired reproduction (Burr and
| |
| Burr, 1930; Maeder, 1937). The large pale
| |
| ovaries lead Sherman (1941) to relate essential fatty acid deficiency to carotene
| |
| metabolism. In this regard the removal of
| |
| essential fatty acids from an adequate diet
| |
| supplemented with vitamin A and E lead
| |
| to anestrum and sterility while maintaining
| |
| good health (Ferrando, Jacques, Mabboux
| |
| and Prieur, 1955). Perhaps the differences
| |
| in opinion regarding the effects of fatty acid
| |
| deficiency can be related to the duration of
| |
| the experimental period. Panos and Finerty
| |
| (1953) found that growing rats placed on
| |
| a fat-free diet exhibited a normal time for
| |
| vaginal opening, normal ovarian weight,
| |
| follicles, and corpora lutea, although interstitial cells were atrophic. However, regular estrous cycles were noted for only 20
| |
| weeks, thereafter 60 per cent of the animals
| |
| exhibited irregular cycles.
| |
| | |
| A decrease in reproductive function may
| |
| be invoked by adding 14 per cent arachis
| |
| oil to the diet (Aaes-Jorgensen, Funch and
| |
| Dam, 1956) . Increasing dietary fat by adding rape oil did not influence ovarian function but did cause the accumulation of
| |
| ovarian and adrenal cholesterol (Carroll
| |
| and Noble, 1952).
| |
| | |
| Essential fatty acid deficiency is associated with underdevelopment and
| |
| atrophic changes of the uterine mucosa.
| |
| Adding fat to a stock diet enhanced uterine
| |
| weight in young animals at a more rapid
| |
| pace than body weight (Umberger and
| |
| Gass, 1958) .
| |
| | |
| 5. Vitamins
| |
| | |
| Carotenoid pigments are present in the
| |
| gonads of many vertebrates and marine invertebrates, and, in mammals, are particularly prominent in the corpus luteum.
| |
| However, no progress has been made in
| |
| determining either the importance of the
| |
| carotenoids in the ovary or of the factors
| |
| controlling their concentrations. It is well
| |
| known that vitamin A deficiency induces
| |
| | |
| | |
| | |
| 686
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| a characteristic keratinizing metaplasia of
| |
| the uterus and vagina, but estrous cycles
| |
| continue despite the vaginal mucosal
| |
| changes. Furthermore, ovulation occurs
| |
| regularly until advanced stages of deficiency appear. The estrous cycle becomes
| |
| irregular in cattle fed for a long period
| |
| of time on fodder deficient in carotene. The
| |
| corpora lutea fail to regress at the normal
| |
| rate and ovarian follicles become atretic and
| |
| cystic ( Jaskowski, Watkowski, Dobrowolska and Domanski, cited by Lutwak-Mann,
| |
| 1958). The alterations in reproductive organs associated with a lack of vitamin A
| |
| may be due in part to a vitamin E deficiency
| |
| since the latter enhances the rate at which
| |
| liver stores of vitamin A are depleted.
| |
| | |
| Definite effects of hypervitaminosis A
| |
| have been observed on reproduction. Masin
| |
| (1950) noted that estrus in female rats
| |
| could be prolonged by administration of
| |
| 37,000 I.U. of vitamin A daily. The implications, however, have not been studied.
| |
| The effect of hypervitaminosis A may actually induce secondary hypovitaminoses.
| |
| The displacement of vitamin K by excess
| |
| A is almost certain and similar relationships
| |
| appear to exist with vitamin D (Nieman
| |
| and Klein Obbink, 1954).
| |
| | |
| The failure of vitamin E-deficient female rats to become pregnant is apparently
| |
| due to disturbances of the implantation
| |
| process rather than to the failure of ovulation. There is no direct proof of ovarian
| |
| dysfunction (Blandau, Kaunitz and Slanetz,
| |
| 1949). However, the ovary of the rat deficient in vitamin E may have more connective tissue and pigment, and Kaunitz
| |
| (1955) showed by ovarian transplantation
| |
| that some nonspecific ovarian dysfunction
| |
| appears to exist (cited by Cheng, 1959 (.
| |
| Vitamin E is essential for birds, but there
| |
| is little evidence for a dependency in most
| |
| mammals; sheep, cows, goats, and pigs have
| |
| been studied. Treatment of low-fertility
| |
| farm animals with tocopherol has not provided conclusive data favoring its use (Lutwak-Mann, 1958), nor has the treatment
| |
| of human females been rewarded with any
| |
| indication that vitamin E might be helpful
| |
| in cases of abnormal cycles and habitual
| |
| abortion (Beckmann, 1955).
| |
| | |
| No specific reproductive disturbances in
| |
| man, the rhesus monkey, or the guinea pig
| |
| | |
| | |
| | |
| have been associated with vitamin C deficiency (Mason, 1939). Nevertheless, the
| |
| high ascorbic acid content of ovarian and
| |
| luteal tissue and of the adrenal cortex suggests a physiologic role in association with
| |
| steroid synthesis. (3varian ascorbic acid
| |
| varies with the estrous cycle, dropping
| |
| sharply in the proestrum (Coste, Delbarre
| |
| and Lacronique, 1953), and decreasing in
| |
| resjionse to gonadotrophin (Hokfelt, 1950;
| |
| Parlow, 1958). Virtually no ascorbic acid is
| |
| present in bovine follicular fluid (LutwakMann, 1954) or in rat ovarian cyst fluid
| |
| (Blye and Leathem, 1959). Uterine ascorbic
| |
| acid decreased in immature mice treated
| |
| with estrogen, but remained unchanged
| |
| in rats following thiouracil administration
| |
| (Leathem, 1959a). Its role in the uterus
| |
| awaits elucidation.
| |
| | |
| Delayed sexual maturation and ovarian
| |
| atrophy have been described when there
| |
| are deficiencies of thiamine, riboflavin, pyridoxine, pantothenic acid, biotin, and B12
| |
| (Ershoff, 1952; Ullrey, Becker, Terrill and
| |
| Notzold, 1955). However, as we noted when
| |
| deficiencies of the vitamins were being considered, much of the impairment of reproductive function can be related to inanition
| |
| rather than to a vitamin deficiency (Drill
| |
| and Burrill, 1944). Pyridoxine deficiency,
| |
| although not affecting structure (Morris,
| |
| Dunn and Wagner, 1953) , markedly reduces
| |
| the sensitivity of the ovary to administered
| |
| gonadotrophin (Wooten, Nelson, Simpson
| |
| and Evans, 1958) .
| |
| | |
| Bird, frog, and fish eggs contain considerable quantities of vitamins. In fact, the
| |
| daily human requirements for vitamins may
| |
| be contained in a hen's egg and thus it is
| |
| not surprising that hatchability is decreased
| |
| l)y virtually any vitamin deficiency. Lutwak-Mann (1958) has provided an excellent
| |
| survey of these data with numerous references to studies of frogs and fishes. Nearly
| |
| all the B vitamins are present in fish roe
| |
| and the pantothenic acid concentration in
| |
| cod ovaries {Gadus morrhua) exceeds most
| |
| otlicr natural sources. The amount of the
| |
| latter varies with the reproductive cycle,
| |
| d(>creasing to its lowest level before spawning. Riboflavin and vitamin B12 , on the
| |
| other h;ui(l, do not change (Braekkan,
| |
| 1955).
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 687
| |
| | |
| | |
| | |
| B. INFLUENCE OF NUTRITION ON THE RESPONSIVENESS OF FEMALE REPRODUCTIVE TISSUES
| |
| TO HORMONES
| |
| | |
| 1. Ovary
| |
| | |
| a. Inanition. Marrian and Parkes (1929)
| |
| were the first to show that the quiescent
| |
| ovary of the underfed rat can respond to
| |
| injections of anterior pituitary as evidenced
| |
| by ovulation and estrous smears. Subsequently the ovaries of underfed birds, rats,
| |
| and guinea pigs were found to be responsive
| |
| to serum gonadotrophin (Werner, 1939;
| |
| Stephens and Allen, 1941; Mulinos and
| |
| Pomerantz, 1941b; Hosoda, Kaneko, Mogi
| |
| and Abe, 1956). A low calorie bread-andmilk diet for 30 days did not prevent ovarian response to rat anterior pituitary or to
| |
| chorionic gonadotrophin. In these animals
| |
| an increase in ovarian weight with repair
| |
| of interstitial tissue, as well as folhcle
| |
| stimulation and corpus luteum formation,
| |
| were observed (Rinaldini, 1949). Rats from
| |
| which food had been withdrawn for 12
| |
| days could respond to castrated rat pituitary extract with an increase in ovarian
| |
| and uterine weight (Maddock and Heller,
| |
| 1947). Nevertheless, differences in the time
| |
| and degree of responsiveness to administered gonadotrophin were noted in rabbits.
| |
| Animals on a high plane of nutrition responded to gonadotrophin at 12 weeks,
| |
| whereas rabbits on a low plane of nutrition
| |
| responded at 20 weeks and fewer eggs were
| |
| shed (Adams, 1953).
| |
| | |
| b. Protein. Protein or amino acid deficiencies in the rat do not prevent a response
| |
| to administered gonadotrophin (Cole, Guilbert and Goss, 1932; Courrier and Raynaud,
| |
| 1932) . However, the degree and type of
| |
| gonadal response is influenced by the diet.
| |
| Thus, immature female mice fed to 6 per
| |
| cent casein for 13 days exhibited only follicular growth in response to pregnant mare
| |
| serum, whereas the ovarian response in
| |
| mice fed 18 per cent casein was suggestive
| |
| of follicle-stimulating and strongly luteinizing actions (Table 12.9). Furthermore,
| |
| the ovarian response was significantly less
| |
| after 20 days of nonprotein feeding than
| |
| after 10 days of depletion (Leathem,
| |
| 1958a). Ovarian stimulation by a gonadotrophin involves tissue protein synthesis
| |
| and thus the type of whole protein fed
| |
| | |
| | |
| | |
| could influence the responses. Yamamoto
| |
| and Chow (1950) fed casein, lactalbumin,
| |
| soybean, and wheat gluten at 20 per cent
| |
| levels and noted that the response to gonadotrophin as estimated by tissue nitrogen
| |
| was related to the nutritive value of the
| |
| protein. The ovarian weight response to
| |
| chorionic gonadotrophin was less in rats
| |
| fed 20 per cent gelatin than those fed 20
| |
| per cent casein (Leathem, 1959b). Inasmuch
| |
| as the hypophysis may influence the gonadal response to injected hormone despite
| |
| the diet, hypophysectomized rats fed a protein-free diet for 5 weeks and hyophysectomized rats on a complete diet were tested
| |
| for response to gonadotrophins. The response to FSH was not influenced by diet,
| |
| but the protein-depleted rats were twice
| |
| as sensitive to interstitial cell-stimulating
| |
| hormone (ICSH), human chorionic gonadotrophin (HCG), and PMS as the normal
| |
| rats (Srebnik, Nelson and Simpson, 1958).
| |
| Protein-depleted, normal mice were twice as
| |
| sensitive to PMS as fully fed mice (Leathem and Defeo, 1952 1 .
| |
| | |
| c. Vitamins. In the female vitamin B
| |
| deficiencies do not prevent ovarian responses to gonadotrophin (Figge and Allen,
| |
| 1942), but the number of studies is limited.
| |
| Be deficiency in DBA mice was associated
| |
| with an increased sensitivity of the ovary
| |
| to gonadotrophins (Morris, Dunn and Wagner, 1953), whereas pyridoxine deficiency
| |
| in the rat decreased ovarian sensitivity,
| |
| especially to FSH (Wooten, Nelson, Simp
| |
| TABLE 12.9
| |
| | |
| Influence of dietary protein and pregnant mare
| |
| | |
| serum {PMS) on the mouse ovary
| |
| | |
| (From J. H. Leathem, Recent Progr. Hormone
| |
| | |
| Res., 14, 141, 1958.)
| |
| | |
| | |
| | |
| Diet fPer cent
| |
| Protein X Days Fed)
| |
| | |
| | |
| | |
| | |
| c-5,
| |
| | |
| •g-s
| |
| | |
| 1*
| |
| | |
| | |
| k
| |
| | |
| r
| |
| | |
| | |
| 1
| |
| 11
| |
| | |
| | |
| c
| |
| 1
| |
| | |
| | |
| | |
| | |
| I.U.
| |
| | |
| | |
| mg.
| |
| | |
| | |
| | |
| | |
| | |
| | |
| mg.
| |
| | |
| | |
| per cent X 23
| |
| | |
| | |
| | |
| | |
| | |
| 1.2
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 4.8
| |
| | |
| | |
| per cent X 2.3
| |
| | |
| | |
| 3
| |
| | |
| | |
| 2.8
| |
| | |
| | |
| 13
| |
| | |
| | |
| | |
| | |
| | |
| 10.8
| |
| | |
| | |
| per cent X 13
| |
| | |
| | |
| | |
| | |
| | |
| 1.4
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 4.9
| |
| | |
| | |
| per cent X 13
| |
| | |
| | |
| 3
| |
| | |
| | |
| 4.4
| |
| | |
| | |
| 16
| |
| | |
| | |
| 1
| |
| | |
| | |
| 15.1
| |
| | |
| | |
| 6 per cent X 13
| |
| | |
| | |
| | |
| | |
| | |
| 3.2
| |
| | |
| | |
| 6
| |
| | |
| | |
| | |
| | |
| | |
| 7.7
| |
| | |
| | |
| 6 per cent X 13
| |
| | |
| | |
| 3
| |
| | |
| | |
| 5.6
| |
| | |
| | |
| 12
| |
| | |
| | |
| 1
| |
| | |
| | |
| 31.9
| |
| | |
| | |
| 18 per cent X 13
| |
| | |
| | |
| | |
| | |
| | |
| 5.0
| |
| | |
| | |
| 10
| |
| | |
| | |
| 2
| |
| | |
| | |
| 51.6
| |
| | |
| | |
| 18 per cent X 13
| |
| | |
| | |
| 3
| |
| | |
| | |
| 8.0
| |
| | |
| | |
| 7
| |
| | |
| | |
| 4
| |
| | |
| | |
| 51.3
| |
| | |
| | |
| | |
| 088
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| son and Evans, 1958 j. Administration of
| |
| vitamin C concomitant witli gonadotropliin
| |
| has been claimed to enhance ovarian response (DiCio and Schteingart, 1942), but
| |
| in another study the addition of ascorbic
| |
| acid inhibited the hiteinizing and ovulating
| |
| action of the gonadotrophin (Desaive,
| |
| 1956).
| |
| | |
| Whether induced by vitamin deficiency
| |
| or by inanition, the anestrum in rats which
| |
| follows 2 to 3 weeks' feeding of a vitamin
| |
| B-deficient diet has been explored as a
| |
| method for the assay of gonadotrophin.
| |
| Pugsley (1957) has shown that there is
| |
| considerable convenience of method and a
| |
| satisfactory precision of response for the
| |
| assay of HCG and pregnant mare serum.
| |
| | |
| 2. Uterus and Vagina
| |
| | |
| a. Inanition. Limited food intake does
| |
| not prevent an increase in uterine weight
| |
| after estrogen. Testosterone propionate will
| |
| markedly increase uterine growth despite
| |
| a 50 per cent reduction in food intake
| |
| (Leathem, Nocenti and Granitsas, 1956).
| |
| Furthermore, dietary manipulations involving caloric and protein levels did not prevent the uteri of spayed rats from responding to estrogen (Vanderlinde and
| |
| Westerfield, 1950). More specific biochemical and physiologic responses must be
| |
| measured because starvation for 4-day periods clearly interferes with deciduoma formation (DeFeo and Rothchild, 1953). A
| |
| start in the direction of studying tissuecomposition changes has been made by
| |
| measuring glycogen. However, no changes
| |
| were noted in uterine glycogen in fasting
| |
| rats (Walaas, 1952), and estrogen promoted
| |
| glycogen deposition in the uteri of starved
| |
| rats as well as in the uteri of fully fed rats
| |
| (Bo and Atkinson, 1953).
| |
| | |
| b. Fat. Interest in the hormone content of
| |
| fat from the tissues of animals treated with
| |
| estrogen for the purpose of increasing body
| |
| weight has raised the question of tissue hormone content. If estrogen was to be detected in tissues, an increase in dietary fat
| |
| was necessary. However, the increase in
| |
| dietary fat decreased the uterine response to
| |
| stilbcstrol (I'mberger and Gass, 1958), thus
| |
| complicating the assay.
| |
| | |
| c. Vitainins. Stimulation of the uterus
| |
| by estrogen does not require tliianiinc, ribo
| |
| | |
| | |
| flavin, pyridoxine, or pantothenic acid. On
| |
| the other hand, a deficiency of nicotinic acid
| |
| appears to enhance the response to low
| |
| doses of estrogen (Kline and Dorfman,
| |
| 1951a, b). However, Bio appears to be
| |
| needed for optimal oviduct response (Kline,
| |
| 1955) and is required for methyl group synthesis from various one-carbon precursors
| |
| including serine and glycine (Johnson,
| |
| 1958).
| |
| | |
| Response of the bird oviduct to stilbestrol
| |
| requires folic acid (Hertz, 1945, 1948). It
| |
| was shown subsequently that stilbestrol and
| |
| estrone effects in frogs, rats, and the rhesus
| |
| monkey also require folic acid. A folic acid
| |
| deficiency can be induced by feeding aminopterin. In this way the estrogen effects
| |
| can be prevented. Aminopterin also prevents
| |
| the action of progesterone in deciduoma
| |
| formation, from which it may be inferred
| |
| that folic acid is necessary for deciduoma
| |
| formation in the rat. Increased steroid or
| |
| folic acid levels can reverse the antagonist's
| |
| effect (Velardo and Hisaw, 1953).
| |
| | |
| The mechanism of folic acid action is not
| |
| clear. It may function in fundamental metabolic reactions linked with nucleic acid
| |
| synthesis. Brown (1953) showed that
| |
| desoxyribonucleic acid could be substituted
| |
| for folic acid in the bird. In the rat aminopterin interferes with the increase in
| |
| uterine nucleic acids, and with nitrogen
| |
| and P-^- uptake by nucleic acids following
| |
| estrogen. Folic acid has been implicated in
| |
| the metabolism of several amino acids
| |
| (Davis, Meyer and McShan, 1956).
| |
| | |
| Rats ovariectomized at weaning and
| |
| maintained on a vitamin E-free diet for
| |
| 6 weeks to 10 months responded to estradiol
| |
| in the same manner as rats supplemented
| |
| with tocopherol. This finding suggests that
| |
| an intimate physiologic relationship between estradiol and vitamin E is not very
| |
| probable (Kaunitz, Slanetz and Atkinson,
| |
| 1949). Nevertheless, vitamin E has been
| |
| re]:»orted to act synergistically with ovarian
| |
| hormones in dc^ciduoma formation (Kehl,
| |
| Douard and Lanfranchi. 1951 ) and to influence nucleic acid turnover (Dinning.
| |
| Simc and Day, 1956).
| |
| | |
| A vitamin-hormone interrelationship is
| |
| apparent when estrogen and vitamin A are
| |
| considered. Vitamin A-deficient female rats
| |
| present evidence of a metaplastic uterine
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 689
| |
| | |
| | |
| | |
| epithelium in 11 to 13 weeks, but similar
| |
| changes failed to develop in ovariectomized
| |
| rats. Vitamin A-deficient castrated rats
| |
| quickly developed symptoms of metaplasia
| |
| when estrogen alone was administered, but
| |
| no adverse effect followed the administration of estrogen combined with vitamin A
| |
| (Bo, 1955, 1956). The vagina is different.
| |
| Its epithelium becomes cornified in vitamin
| |
| A-deficient normal and castrated rats. The
| |
| cornification is histologically indistinguishable from that occurring in the estrous
| |
| rat and can be prevented by vitamin A.
| |
| In fact, vitamin A will quantitatively inhibit the effect of estrogen on the vaginal
| |
| mucosa when both are applied locally
| |
| (Kahn, 1954). Conversion of ^-carotene to
| |
| vitamin A is influenced by tocopherol, vitamin Bi2 , insulin, and thyroid, with evidence
| |
| for and against a similar action by cortisone
| |
| (Lowe and Morton, 1956; Rice and Bo,
| |
| 1958). An additional vitamin-hormone relationship is suggested by the augmentation
| |
| of progesterone action in rabbits given vitamin Do .
| |
| | |
| 3. Mammary Gland
| |
| | |
| Inanition prevents mammary growth, but
| |
| feeding above recommended requirements
| |
| for maintenance and growth from birth
| |
| to the first parturition also seems to interfere with mammary growth. Furthermore,
| |
| steroid stimulation of the mammary gland
| |
| is influenced by nutritional factors. Using
| |
| the male mouse, Trentin and Turner (1941)
| |
| showed that as food intake decreased, the
| |
| amount of estradiol required to produce a
| |
| minimal duct growth w^as proportionately
| |
| increased. In the immature male rat a
| |
| limited food intake prevented the growth of
| |
| the mammary gland exhibited by fully fed
| |
| controls. Nevertheless, the gland was competent to respond to estrogen (Reece, 1950) .
| |
| Inasmuch as the glands of force-fed hypophysectomized rats did not respond to estrogen (Samuels, Reinecke and Peterson,
| |
| 1941; Ahren, 1959), one can assume that,
| |
| despite inanition, a hypophyseal factor was
| |
| present to permit the response of the mammary gland to estrogen. However, inanition
| |
| (IMeites and Reed, 1949) , but not vitamin
| |
| deficiencies (Reece, Turner, Hathaway and
| |
| Davis, 1937), did reduce the content of
| |
| hypophyseal lactogen in the rat.
| |
| | |
| | |
| | |
| Growth of the mammary gland duct in
| |
| the male rat in response to estradiol requires a minimum of 6 per cent casein. Protein levels of 3 per cent and per cent failed
| |
| to support growth of the duct (Reece, 1959) .
| |
| | |
| C. PREGNANCY
| |
| | |
| The human male after attaining adulthood is confronted with the problem of
| |
| maintaining the body tissues built up during
| |
| the growth period. However, in the human
| |
| female it has been estimated that the replacement of menstrual losses may require
| |
| the synthesis of tissue equivalent to 100
| |
| per cent of her body weight (Flodin, 19531.
| |
| In the event of pregnancy and in all viviparous species, the female is presented with
| |
| even more formidable demands and a limitation of nutritional needs can lead to loss
| |
| of the embryo or fetus. The role of nutrition
| |
| at this point in reproduction has always received considerable attention and is complicated by the circumstance that many food
| |
| substances influence pregnancy (Jackson,
| |
| 1959). However, in many instances there is
| |
| no evidence that fetal loss or malformation
| |
| induced by nutritional modifications has
| |
| been the consequence of an endocrine imbalance and thus limitation of the immense
| |
| literature is permissible.
| |
| | |
| During the first 15 days of pregnancy, a
| |
| rat may gain 50 gm. Since the fetuses and
| |
| placentas are small, most of the gain is maternal and is associated with an' increase
| |
| in food intake of as much as 100 calories
| |
| per kilogram of body weight (Morrison,
| |
| 1956). During the first 2 weeks of pregnancy, marked storage of fat and water occurs in the maternal body and the animal's
| |
| positive nitrogen balance is above normal.
| |
| Liver fat also increases (Shipley, Chudzik,
| |
| Curtiss and Price, 1953). The increased food
| |
| intake in early pregnancy may therefore
| |
| provide a reserve for late fetal growth, as
| |
| food intake may decline to 65 per cent of
| |
| the general pregnancy level during the last
| |
| 7 days (Morrison, 1956). During this last
| |
| week, fetal growth is rapid. The rapid
| |
| growth has been related to (1) greater demands of the fetus, (2) greater amounts of
| |
| food in the maternal blood, and (31 greater
| |
| permeability of the placenta. Certainly the
| |
| anabolic potential of fetal tissues is high
| |
| and the mother can lose weight while the
| |
| | |
| | |
| | |
| 690
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| fetuses gain. But it is also important to
| |
| recall that there is a shift in protein, because
| |
| its distribution in organs of pregnant rats
| |
| differs from that in nonpregnant animals
| |
| (Poo, Lew and Addis, 1939). Other changes
| |
| in the maternal organism were enumerated
| |
| b}^ Newton (1952) and by Souders and
| |
| Morgan (1957).
| |
| | |
| A measure of nitrogen balance during
| |
| pregnancy, rather than weight of young at
| |
| birth, has been suggested as a means of
| |
| determining a diet adequate for reproduction (Pike, Suder and Ross, 1954). After
| |
| the 15th day, a retention of body protein
| |
| increases, blood amino nitrogen and amino
| |
| acids decrease, and urea formation decreases. These metabolic activities suggest
| |
| an increase in growth hormone although the
| |
| levels of this hormone have not been estimated (Beaton, Ryu and McHenry, 1955).
| |
| Placental secretions have also been associated with the active anabolic state of the
| |
| second half of pregnancy, because removal
| |
| of the fetuses in the rat did not change the
| |
| anabolic activity, whereas removal of the
| |
| placentas was followed by a return to normal (Bourdel, 1957). A sharp increase in
| |
| liver ribose nucleic acid has been observed
| |
| during late pregnancy in mice and rats and
| |
| the effect attributed to a placental secretion
| |
| or to estrogen. Species differences also influence the results because only a modest
| |
| change in liver RNA was observed in guinea
| |
| pigs and no change occurred in cats (Campbell and Kostcrlitz, 1953; Campbell, Innes
| |
| and Kosterlitz, 1953a, b).
| |
| | |
| Clinical observations have related both
| |
| | |
| TABLE 12.10
| |
| | |
| Nutrition and pregnancy in rats
| |
| | |
| (From J. H. Leathern, in Recent Progress in
| |
| | |
| the Endocrinology of Reproduction, Academic
| |
| | |
| Press, Inc., New York, 1959.)
| |
| | |
| | |
| | |
| | |
| | |
| Calories/kg.
| |
| Body Weight
| |
| | |
| | |
| Fetuses, Day 20
| |
| | |
| | |
| | |
| | |
| No.
| |
| | |
| | |
| Average
| |
| weight
| |
| | |
| | |
| 18 per cent casein
| |
| | |
| 18 per cent casein
| |
| | |
| 6 per cent casein
| |
| | |
| per cent casein
| |
| | |
| 18 per cent gelatin
| |
| | |
| 18 per cent gelatin
| |
| | |
| | |
| 200
| |
| 100
| |
| | |
| 250
| |
| 200
| |
| 200
| |
| 100
| |
| | |
| | |
| 8
| |
| 6
| |
| | |
| | |
| | |
| | |
| | |
| | |
| gm.
| |
| 6.1
| |
| | |
| 3.5
| |
| | |
| | |
| | |
| toxemia of pregnancy (Pequignot, 1956)
| |
| and prematurity to inadequate nutrition
| |
| (Jeans, Smith and Stearns, 1955). The potential role of protein deprivation in the
| |
| pathogenesis of the toxemia of pregnancy
| |
| prompted studies in sheep and rats. In sheep
| |
| nutritionally induced toxemia simulates the
| |
| spontaneous toxemia (Parry and Taylor,
| |
| 1956), but only certain aspects of toxemia
| |
| were observed in the pregnant rat subjected
| |
| to low protein diets. When rats were fed 5
| |
| per cent casein and mated, fluid retention
| |
| was observed (Shipley, Chudzik, Curtiss
| |
| and Price, 1953) and pregnancy was completed in only 48 per cent of the animals
| |
| Curtiss, 1953). Gain in body weight in the
| |
| adult rat and gain in fetal weight were subnormal as the result of a low protein feeding
| |
| during pregnancy.
| |
| | |
| Complete removal of protein from the
| |
| diet beginning at the time of mating did not
| |
| prevent implantation but did induce an 86
| |
| to 100 per cent embryonic loss. The effect
| |
| was not related solely to food intake (Nelson and Evans, 1953) , as we will see in what
| |
| follows when the relationship between protein deficiency and the supply of estrogen
| |
| and progesterone is described. Limiting protein deprivation to the first 9 to 10 days of
| |
| pregnancy will also terminate a pregnancy,
| |
| but when the protein was removed from the
| |
| diet during only the last week of pregnancy,
| |
| the maternal weight decreased without an
| |
| effect on fetal or placental weight (Campbell and Kosterlitz, 1953). As would be anticipated, a successful pregnancy requires
| |
| protein of good nutritional quality and the
| |
| caloric intake must be adequate. Thus, an
| |
| 18 per cent gelatin diet failed to maintain
| |
| pregnancy when 200 calories per kilogram
| |
| were fed, whereas a similar level of casein
| |
| was adequate (Table 12.10). However, reducing caloric intake to 100 calories despite
| |
| an otherwise adequate protein ration influenced the number and size of fetuses
| |
| (Leathern, 1959b). Additional proteins
| |
| should be studied and related to biochemical changes in pregnancy and to the need for
| |
| specific amino acids; for example, elimination of methionine or tryptophan from the
| |
| diet may or may not be followed by resorption (Sims, 1951; Kemeny, Handel, Kertesz
| |
| and Sos, 1953; Albanese, Randall and Holt,
| |
| 1943). Excretion of 10 amino acids was in
| |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 691
| |
| | |
| | |
| | |
| creased during normal human pregnancy
| |
| (Miller, Ruttinger and Macey, 1954).
| |
| | |
| That a relationship exists, between the
| |
| dietary requirements just described to the
| |
| endocrine substances which participate in
| |
| the control of pregnancy, is suggested by the
| |
| fact that the deleterious effects of a proteinfree diet on pregnancy in rats have been
| |
| counteracted by the administration of estrone and progesterone. Pregnancy was
| |
| maintained in 30 per cent, 60 to 80 per cent,
| |
| and per cent of protein-deficient animals
| |
| by daily dosages of 0.5 /xg., 1 to 3 fig., and 6
| |
| jug. estrone, respectively. On the other hand,
| |
| injection of 4 to 8 mg. progesterone alone
| |
| maintained pregnancy in 70 per cent of the
| |
| animals (Nelson and Evans, 1955) , and an
| |
| injection of 4 mg. progesterone with 0.5 //.g.
| |
| estrone provided complete replacement
| |
| therapy (Nelson and Evans, 1954). Food
| |
| intake did not increase. The results suggest
| |
| that reproductive failure in the absence of
| |
| dietary protein was due initially to lack of
| |
| progesterone and secondarily to estrogen,
| |
| the estrogen possibly serving as an indirect
| |
| stimulation for luteotrophin secretion and
| |
| release. It is well known that hypophysectomy or ovariectomy shortly after breeding
| |
| will terminate a pregnancy and that replacement therapy requires both ovarian
| |
| hormones. Thus, the protein-deficient state
| |
| differs somewhat from the state following
| |
| hypophysectomy or ovariectomy, but the
| |
| factors involved are not known.
| |
| | |
| Pregnancy alters nutritional and metabolic conditions in such a way that labile
| |
| protein stores of the liver and other parts of
| |
| the body are influenced, but similar effects
| |
| are imposed by a transplanted tumor, especially when it reaches 10 per cent of the
| |
| body weight. ' Thus, transplantation of a
| |
| tumor into a pregnant animal would place
| |
| the fetuses in competition with the tumor for
| |
| the amino acids of the metabolic pool. Under
| |
| these circumstances will the pregnancy be
| |
| maintained? An answer to the question may
| |
| not yet be given. Nevertheless, Bly, Drevets
| |
| and Migliarese (1955) observed various degrees of fetal damage in pregnant rats bearing the Walker 256 tumor, and 43 per cent
| |
| fetal loss was obtained with a small hepatoma (Paschkis and Cantarow, 1958).
| |
| | |
| Essential fatty acid deficiency, at least
| |
| in the initial stages, does not interfere with
| |
| | |
| | |
| | |
| development of the fetuses or parturition in
| |
| the rat, but the pups may be born dead or
| |
| they do not survive more than a few days
| |
| (Kummerow, Pan and Hickman, 1952). A
| |
| more pronounced deficiency has induced
| |
| atrophic changes in the decidua, resorption
| |
| of fetuses, and prolonged gestation. Death
| |
| of the fetuses appears to be secondary to
| |
| placental injury. Hormonal involvement, if
| |
| any, when there is fatty acid deficiency and
| |
| pregnancy seems not to have been investigated.
| |
| | |
| Pregnancy and lactation are major factors influencing vitamin requirements. It is
| |
| not surprising, therefore, that vitamin deficiencies influence the course of a pregnancy. The subject has recently been reviewed by Lutwak-jMann (1958).
| |
| | |
| A deficiency of vitamin A does not noticeably affect early fetal development, but
| |
| later in gestation placental degeneration occurs with hemorrhage and abortion. When
| |
| the deficiency is moderate the pregnancy is
| |
| not interrupted, but the fetuses are damaged
| |
| (Warkany and Schraffenberger, 1944; Wilson, Roth and Warkany, 1953; Giroud and
| |
| Martinet, 1959). In calves and pigs the
| |
| abnormalities are associated with the eyes
| |
| and palate (Guilbert, 1942) ; in birds skeletal abnormalities are seen (Asmundson and
| |
| Kratzer, 1952). The use of hormones in an
| |
| effort to counteract the effects seems to have
| |
| been attempted only in the rabbit where
| |
| 12.5 mg. progesterone improved reproduction impaired by vitamin A lack (Hays and
| |
| Kendall, 1956). Vitamin A excess also
| |
| proves highly detrimental to pregnancy, as
| |
| resorption and malformations occur. Administration of excessive vitamin A on days
| |
| 11 to 13 of pregnancy induced cleft palate in
| |
| 90 per cent of the embryos (Giroud and
| |
| Martinet, 1955) . In another experiment the
| |
| effect of excessive vitamin A was augmented
| |
| by cortisone (Woollam and Millen, 1957).
| |
| | |
| Vitamin E deficiency has long been known
| |
| to influence pregnancy in rodents and fetal
| |
| death appears to precede placental damage
| |
| and involution of the corpora lutea. Gross
| |
| observations of the abnormal embryos have
| |
| been reported (Cheng, Chang and Bairnson, 1957). Estrogen, progesterone, and lactogen were not effective in attempts at corrective therapy (Ershoff, 1943), but estrone
| |
| and progesterone markedly reduced the in
| |
| | |
| | |
| 692
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| cidence of congenital malformations associated with vitamin E lack (Cheng, 1959).
| |
| In the test of a possible converse relationship, estradiol-induced abortion in guinea
| |
| pigs was not prevented by vitamin E (Ingelman-Sundberg, 1958) .
| |
| | |
| Fat-soluble vitamins incorporated in the
| |
| diet may be destroyed by oxidation of the
| |
| unsaturated fatty acids. To stabilize the
| |
| vitamins, the addition of diphenyl-p-phenylenediamine (DPPD) to the diet has
| |
| proven successful, but recent studies show
| |
| that DPPD has an adverse effect on reproduction and thus its use in rat rations
| |
| is contraindicated (Draper, Goodyear, Barbee and Johnson, 1956).
| |
| | |
| Vitamin-hormone relationships in pregnancy have been studied with regard to
| |
| thiamine, pyridoxine, pantothenic acid, and
| |
| folic acid. Thiamine deficiency induced stillbirths, subnormal birth weights, resorption
| |
| of fetuses, and loss of weight in the mother.
| |
| However, as in the case of protein deficiency, pregnancy could be maintained with
| |
| 0.5 fjLg. estrone and 4 mg. progesterone (Nelson and Evans, 1955). Estrone alone had
| |
| some favorable effect on the maintenance
| |
| of pregnancy in thiamine-deficient animals,
| |
| but it was less effective in protein-deficient
| |
| animals.
| |
| | |
| Fetal death and resorptions as well as
| |
| serum protein and nonprotein nitrogen
| |
| (NPN) changes similar to those reported
| |
| for toxemia of pregnancy (Ross and Pike,
| |
| 1956; Pike and Kirksey, 1959) were induced
| |
| by a diet deficient in vitamin Be . Administration of 1 fxg. estrone and 4 mg. progesterone maintained pregnancy in 90 per cent of
| |
| vitamin Be-deficient rats (Nelson, Lyons
| |
| and Evans, 1951). However, the pyridoxinedeficient rat required both steroids to remain pregnant and in this regard resembled
| |
| the hypophysectomized animal (Nelson,
| |
| Lyoas and Evans, 1953). Nevertheless, a
| |
| hypophyseal hormone combination which
| |
| was adequate for the maintenance of pregnancy in the fully fed hypophysectomized
| |
| rat (Lyons, 1951) was only partially successful when there was a deficiency of pyridoxine. An ovarian defect is suggested.
| |
| | |
| The folic acid antagonist, 4-aminopteroylglutamic acid, will rapidly induce the
| |
| death of early implanted embryos in mice.
| |
| | |
| | |
| | |
| rats, and man (Thiersch, 1954j . Removal
| |
| of folic acid from the diet or the addition
| |
| of x-methyl folic acid will induce malformations when low doses are given and resorptions when high doses are given. Furthermore, this effect is obtained even when
| |
| the folic acid deficiency is delayed until
| |
| day 9 of a rat pregnancy or maintained for
| |
| only a 36-hour period. A deficiency of
| |
| pantothenic acid will also induce fetal resorption. The vitamin is required for hatching eggs (Gillis, Heuser and Norris, 1942).
| |
| In animals deficient in folic acid or in
| |
| pantothenic acid, estrone and progesterone
| |
| replacement therapy did not prevent fetal
| |
| loss, suggesting that the hormones cannot
| |
| act (Nelson and Evans, 1956). In the above
| |
| mentioned deficiencies replacement of the
| |
| vitamin is effective. However, vitamins
| |
| other than those specifically deleted may
| |
| provide replacement, thus ascorbic acid
| |
| seems to have a sparing action on calcium
| |
| pantothenate (Everson, Northrop, Chung
| |
| and Getty, 1954) .
| |
| | |
| Pregnancy can be interrupted by altering
| |
| vitamins other than those discussed above,
| |
| but the hormonal aspects have not been
| |
| explored. Thus, the lack of choline, riboflavin, and Bi2 will induce fetal abnormalities and interrupt gestation (Giroud, Levy,
| |
| Lefebvres and Dupuis, 1952; Dryden, Hartman and Gary, 1952; Jones, Brown, Richardson and Sinclair, 1955; Newberne and
| |
| O'Dell, 1958) . Choline lack is detrimental to
| |
| the placenta (Dubnov, 1958), riboflavin
| |
| deficiency may impair carbohydrate use
| |
| (Nelson, Arnrich and Morgan, 1957) and/or
| |
| induce electrolyte disturbances (Diamant
| |
| and Guggenheim, 1957) , and Bjo spares choline and may be concerned with nucleic
| |
| acid synthesis (Johnson, 1958). Excessive
| |
| amounts of Bio are not harmful. It is interesting to note that uterine secretions and
| |
| rabbit blastocyst fluid are rich in vitamin
| |
| B]2 (Lutwak-Mann, 1956), but its presence
| |
| in such large amounts has not been explained.
| |
| | |
| An additional substance, lithospermin, extracted from the plant, Lathijrus odoratus,
| |
| is related to hormone functioning; it is antigonadotrophic when eaten by nonpregnant
| |
| animals and man. The feeding of this substance to prciiiiant rats terminated the pregnancies about the 17th day. Treatment with
| |
| estrogen and progesterone was preventive
| |
| (Walker and Wirtschafter, 1956). It is assumed, therefore, that lithospermin interfered with the production of these hormones.
| |
| A repetition of the experiment on a species
| |
| in which the hypophysis and ovaries are
| |
| dispensable during much of pregnancy
| |
| would be of interest.
| |
| | |
| In retrospect it has been found that a
| |
| deficiency in protein and the vitamins
| |
| thiamine, pyridoxine, pantothenic acid, and
| |
| folic acid individually can interrupt a pregnancy. Furthermore, a combination of estrone and progesterone which is adequate to
| |
| maintain pregnancy after hypophysectomy
| |
| and ovariectomy, is equally effective in protein or thiamine deficiency. This suggests
| |
| that the basic physiologic alteration is a
| |
| deprivation of ovarian hormones. However,
| |
| protein- and thiamine-deficiency states differ from each other as shown by the response to estrogen alone (thiamine deficiency is less responsive), and these states
| |
| differ from hypophysectomy in which estrone alone has no effect. A pyridoxine deficiency seems to involve both ovary and
| |
| hypophysis, for neither steroids nor pituitary hormones were more than partially
| |
| successful in maintaining pregnancy in rats.
| |
| Lastly, pantothenic acid and folic acid
| |
| deficiencies may not create a steroid deficiency. What is involved is not known;
| |
| many possibilities exist. Pantothenic acid,
| |
| for example, participates in many chemical
| |
| reactions. Furthermore, it is known that
| |
| thiamine is essential for carbohydrate metabolism but not for fat metabolism whereas
| |
| pyridoxine is involved in fat metabolism
| |
| and in the conversion of tryptophan to nicotinic acid. It is clear, though, that much
| |
| ground must be covered before the formulation of fruitful hypotheses may be anticipated.
| |
| | |
| VI. Concluding Remarks
| |
| | |
| The development, composition, and normal functioning of the reproductive system
| |
| is dependent on adequate nutrition. However, the requirements are many and only
| |
| gradually are data being acquired which are
| |
| pertinent to the elucidation of the nutritional-gonadal relationship.
| |
| | |
| | |
| | |
| The demands for nutrient substances is
| |
| not always the same. During pregnancy and
| |
| lactation there is a need for supplemental
| |
| feeding. A similar need exists in birds and
| |
| in the many cold-blooded vertebrates in
| |
| which reproduction is seasonal. Atypical endocrine states create imbalances and a need
| |
| for nutrient materials which vary, unpredictably, we must acknowledge, until the
| |
| numerous interrelationships have been clarified.
| |
| | |
| At many points where determination of
| |
| cause and effect are possible, an indirect
| |
| action of dietary factors on reproduction is
| |
| indicated. No other conclusion seems possible in view of the many instances in which
| |
| the effect of dietary deficiencies can be
| |
| counteracted by the administration of a
| |
| hormone or combination of hormones. The
| |
| direct action is not immediately apparent;
| |
| it probably is on the processes by which
| |
| metabolic homeostasis is maintained, and is
| |
| in the nature of a lowering of the responsiveness to the stimuli which normally trigger these processes into action. The processes
| |
| may be those by which pituitary and gonadal hormones are produced or they may be
| |
| the mechanisms by which these hormones
| |
| produce their effects on the genital tracts
| |
| and on the numerous other tissues on which
| |
| they are known to act.
| |
| | |
| Because of the many interrelationships,
| |
| some of which are antagonistic and some
| |
| supportive, determination of the role of specific dietary substances is not easy. For
| |
| those who work with laboratory species,
| |
| the problem is further complicated by the
| |
| many strain differences. For everyone, the
| |
| problem is complicated by the many species
| |
| differences which are the result of an evolution toward carnivorous, herbivorous, or
| |
| omnivorous diets, to say nothing of the
| |
| countless specific preferences within each
| |
| group.
| |
| | |
| Finally, it is something of a paradox in our
| |
| culture that much of our effort has been devoted to investigations of the effects of deficiencies and undernutrition rather than
| |
| to the effects of excesses and overnutrition.
| |
| Much evidence supports the view that in
| |
| the aggregate the latter are fully as deleterious as the former, but the means by which this result is achieved are largely unknown.
| |
| | |
| | |
| | |
| VII. References
| |
| | |
| Aak.s-Jorgensen, E., Funch, J. P., and Dam, H.
| |
| | |
| 1956. Role of fat in diet of rats; influence
| |
| on reproduction of hydrogenated arachis oil
| |
| as sole dietary fat. Brit. J. Nutrition, 10, 317.
| |
| | |
| Aaes-Jorgensen, E., Funch, J. P., and Dam, H.
| |
| | |
| 1957. Role of fat in diet of rats; influence of
| |
| small amount of ethyl linoleate on degeneration of spermatogenic tissue caused by hydrogenated arachis oil as sole dietary fat. Brit. J.
| |
| Nutrition, 11, 298.
| |
| | |
| AcETO, G., Li Moli, S., and Panebianco, N. 1956.
| |
| Influence of adrenocorticotrophin (ACTH) on
| |
| the urinary excretion of thiamine. Acta vitaminol., 10, 175.
| |
| | |
| Adams, C. E. 1953. Mammalian germ cells. Ciba
| |
| Foundation Symposium, 198.
| |
| | |
| Adams, C. W. M., Fernand, V. S. V., and Schnieden,
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