# Book - Human Embryology (1945) 3

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Hamilton WJ. Boyd JD. and Mossman HW. Human Embryology. (1945) Cambridge: Heffers.

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# Chapter III Cyclic Changes in the Female Genital Tract

Female mammals of all species are normally capable of repeated pregnancies during then mature sexual life span Each of these pregnancies is the result of, and the cause of, a complex sequence of cyclic changes in the female which is manifest in her anatomy, her physiology and her behaviour.

In most mature female mammals breeding and non-breeding seasons can be recognized. The duration and frequency of these seasons varies from species to species and can be coi related with periodic changes in the reproductive system. The chief characteristic of the breeding season is the phenomenon of oestrus, or heat, when the female is receptive to the male Oestrus IS essentially a phenomenon of behaviour but it is the culmination of a series of morphological and functional changes in the ovaries and the reproductive tract which are known as the oestrous cycle The changes occui ring at the time of oestrus itself normally include ovulation, an increase in the vascularity of the whole reproductive tract accompanied by an increase in the height of the uterine mucosa and of its epithelial cells, growth of the uterine muscle and a rapid proliferation, followed by marked cornification, of the vaginal epithelium.

Some mammals exhibit oestrus only once m a breeding season and are consequently said to be monoestrous Other mammals are polyoestrous, that is, they show oestrous behaviour at regular intervals throughout the year or on several occasions during a longer or shorter breeding season In certain mammals domesticity tends to convert a primarily monoestrous condition into an irregularly polyoestrous one.

Since oestrus and ovulation occur at approximately the same time, insemination is assured at the most favourable period for fertilization of the eggs. Normally, then, pregnancy follows oestrus and the cycle is not complete until the young have been born and the mother has entered another oestrous period. If for some reason pregnancy does not occur, an oestrous cycle instead of a pregnancy cycle takes place In this case, after a certain period usually shorter than the pregnancy cycle, the female again comes into “heat ” In a sense then these oestrous cycles are abnormal, for the purpose of oestrus is to produce a pregnancy In many laboratory and domestic animals, however, insemination is artificially prevented, and oestrous cycles recur in long sequences.

The phenomenon of oestrus is controlled by the oestrogenic hormone (oestradiol). This IS a steroid, derived from phenanthrene, and is closely allied chemically to the luteal hormone and the hormones of the adrenal cortex, some of which possess similar physiological effects. ' Oestradiol is excreted in the urine as a series of degradation substances (e g. oestrone and oestriol) which have weaker oestrogenic properties. All of these substances together with certain synthetic products (e g , stilboestrol) are known as oestrogens as they can produce oestrous phenomena in spayed (ovariectomized) ammals The origin of oestradiol is not yet definitely known. Some investigators consider that it is produced by the granulosa cells of the follicles but the follicular fluid and granulosa cells contain little if any more oestradiol than the other ovarian tissues Corner (1938) is inclined to the view that the thecal gland produces muc of the oestrogemc hormone This gland consists of specialized theca interna cells of ripCj nearly ripe or recently ovulated follicles (Mossman, 1937) Dempsey and Bassett (i 943 l showed by histo-chemical tests, that sex hormone steroids are absent from the granulosa cells and the follicular fluid but are present m the cells of the thecal, interstitial and mtea glands.

The rhythmical chan{,es m the o\ar> constitute the o anan (oogenetic) cyU and those in the uterus ^\hich chiefly m\oKe its lining the endomefmm, constitute the utmn< cycle In the human female though there is no commcing evidence for a breeding season and no uell defined oestrous periods, striking c\chc changes arc also shown b> the ovary and uterus The ovarian cycle is similar to that of rcgularlv poly oestrous mammals The ulenne cvcle includes morphological changes such as arc shown bv other mammals but, m the absence of fertilization terminates in a phase of haemorrhagic destruction of the endometrium known as menslruation For this reason the human utenne cycle is often called the mcns\'nial nde The loss of blood at menstruation is the outward manifestation of one of the phases of the menstrual cycle Menstruation which also occurs in some other primates, is not to be confused with oestrus (see page 33 for di cussion) as is demorntrated by the fact that ovulation does not occur at this time It ism fact known that ovailationm woman normallv occurs about half way between mentrual periods (see page 31) ahhough no obviously greater sexual desire occurs at this time However if pregnancy results from this ovulation then menstrual periods normally do not recur until some time after delivery of the child W ilh rcgularlv repeated pregnancies menstruation might nev er occur again as it is a sequel to the non fertilization of an ovaim The menstrual period and cvcle can then be regarded as basically abnormal, the biologically normal condition being a senes of pregnancy cycles following one another throughout the fertile years of life The human ovanan cycle is probably of the same length as the menstrual cycle (page ah) During the ovarian cycle hormones are produced by the ovary which influence and control the difTercnt phases of the menstrual cycle.

## Ovarian Cycle

The proliferation of oocy tes and the shedding of an ovaim or ov a, as described on page 14 arepcnodic and together with the recurrent formation of the corpus lutcum (after each ovulation) and the accompanying changes in the interstitial tissue and theca! gUnd constitute the ovarian cycle This cycle is repeated throughout the reproductive life of the individual With the exception of the ovum or ova which will be shed at the next ovulation and some ova in primordial and primary follicles all the maturing ova developed m a single ovanan cycle will degenerate and, with their follicles become ctreUc In the succeeding cycle these arc replaced by the growth of persisting primordial ovanan follicles and by the proliferation of new primordial oocytes The number of ova present m the ovary increases towards the end of the menstrual cycle probably as the result of the removal of the inhibition due to the corpus lutcum of the previous ovarian cycle (sec later, and Evans and Swczv 1931)

The growth of the follicles is gradual up to the pre ovulation stage when a rapid increase vn size occurs In the human subject muaWy only a sin^Ie/olhclr grows to maturilv and ruptures in each cycle the oth«r follicles undergo atresia, which may occur when they are small or at later stages even when they irc almost fully developed IMien a follicle becomes atretic, its ovum undergoes hyaline swelling and fatty degeneration the folhciilar cavity collapses the granule a cells degenerate and disappear and arc ultimately replaced by connective tissue and the theca interna cells may become transformed into a group of intentitial gland cells.

There w a cy die production of hormones by the ov iry during the grow th of the follicle As the npcning follicle nears maturity its theca interna cells take on the character of an endocrine gland both cy tologically and m their relation to their v ascular supply This is the thecal gland Its cells probably produce the oestrogenic hormone which is taken up by its blood vessels This hormone causes changes m the accessory sex organs i c the uterus the vagina and utenne tubes and also influences the production by the pituitary of the gonadotrophic hormones The oestrogenic hormone is responsible for the phenomena of oestrus m lower mammal.

After the rupture of the follicle and the formation of the corpus lutcum the cells of the latter produce a second hormone called progesUroiu This hormone also exerts its influence upon the accessory sex organs bringing about the progestational changes in the uterus which are discussed on page 27.

## Corpus Luteum

As stated earlier, after ovulation the ruptured follicle collapses and its wall becomes folded, the granulosa cells hypertrophy to almost three times their original diameters, become polyhedral in shape, develop a yellowish pigment (the carotinoid, lutein) and become vascularized by ingrowth of vessels from the thecal gland to form a corpus luteum (Figs 14, 15 and 16) ; their nuclei, however, except immediately after ovulation, show few mitoses. The modified granulosa cells are called luteal cells. In some mammals there is an increase in the number of luteal cells m the early stages of formation of the gland due in part at least to mitotic division of young luteal cells According to some investigators (Solomons and Gatenby, 1924, and Shaw, 1925) the glandular cells of the theca interna also increase in size to become “paraluteal” cells These may be persistent thecal gland cells which in most mammals persist for a few days as a zone round the recently ruptured follicle, but which have usually completely disappeared by the time the embryo begins to implant in the uterus In some species true luteal cells are added to the

Fig 14 — A schematic drawing of the corpus luteum The blood vessels and fibrin are in red, the fibrous trabeculae blue

periphery of the corpus luteum by continuous dilTerentiation from the immediately surrounding stroma cells (Mossman and Judas, 1949). For a review of the literature on the corpus luteum see Harrison (1948).

The fate of the corpus luteum in women, but not in all mammals, depends on whether or not pregnancy follows ovulation. In the absence of pregnancy a corpus luteum (spurium) of menstruation, with a functional life of approximately fourteen days, is formed. In the event of pregnancy, the corpus luteum becomes a corpus luteum (verum) of pregnancy The granulosa derived cells of the corpus luteum produce the hormone, progesterone, which in the human is necessary for successful maintenance of the earlier stages of pregnancy Removal of the corpus luteum from the human female during these early stages of pregnancy results in abortion, and m some mammals (e.g , rabbit, rat and goat) removal, even m late stages of gestation, terminates the pregnancy. Hartman and Corner (1947) have shown that the corpus luteum of pregnancy m monkey may be removed as early ty-fifth day without disturbing t y* In the human species and in the chimpanzee progesterone is excreted as the urine

THE CORPUS LUTEU

The functional life of such a corpus luteu

1. Stage of Hyperaemia. There with the rupture of the follicle The granu colour During this period the glandular ce easily distinguished. Between the theca an many blood vessels but the granulosa cells

2. Stage of Vascularization.

the ingrowth of blood vessels from the vascu is observed and may be so abundant as to fill th

The cells of the membrana granulosa become lutcahzcd, \acuohtcd and polyliedral m shape The stroma cells of the theca imade the area of luteahzed cells and form a \ascularized connectise tissue (Figs 15 and 16)

3 Stage of Maturity The luteal cells enlarge and become dislinctl> sacuolated and am blood present in the ca\it\ is absorbed The inner or luminal margin of the corpus luteum often shous a delicate la>er of flattened cells uhich are modified luteal cells (Solomons and Gatenb), 1924) The blood sesseU increase in size and become more numerous and lhrou<'h them’ the hormone enters the blood stream The stage of maturit> is reached tuo or three days before the onset of the next menstrual period The mature structure may be easily recognized on the surface of the o\ary as a yellowish projection surrounded by a hypencmic aret and it may constitute one third or even one half of the \oliimc of the ovary The mature stage of the corpus luteum corresponds to the premenstrual or luteal phase of the endometrium 4 Stage of Regression Before the onset of menstruation the corpus luteum diminishes in size loses its vascularity becomes fibrotic and the Juteil cells show fatty de generation Baily degenerative changes are always to be seen in the corpus luteum during menstruation Later hyalimzation of the luteal cells occurs and cicatrization of the fibrous tissue eventually obliterates the lumen This fibrouc remnant of the corpus luteum is called

Fig. 15 — Photomicrograph of a section of a human corpus luicum approximately 48 hours after ovulation X 130

Fig. iC — A high power schematic view of the rec tangular area of Fig 14 sho\ mg the detailed histolofiy of the corpus luteum Blood vessels are earned amongsl the luteal cells and thecal gland cells b> the fibrous trabeculae x c 200

a “corpus albicans ” The rate of regression varies considerably but eventually any given corpus albicans disappears.

## The Corpus Luteum of Pregnancy

If pregnancy occurs the corpus luteum increases in size, but remains essentially similar in appearance to the corpus luteum of menstruation up to the end of twelve weeks of pregnancy. The luteal zone, however, is broader and there is usually a greater amount of fibrous tissue along Its inner border. The cavity may become filled with a straw-coloured fluid Further, the visible cellular changes m the distribution of lipides are prolonged and intensified during early pregnancy (Papanicolaou et al , 1948). In the human subject the corpus luteum of pregnancy is considered to remain active until the end of the fourth month, when regressive changes begin It can usually be distinguished until after parturition.

The persistence of the corpus luteum of pregnancy beyond fourteen days is believed to be due to the production by the foetal tissues (e g., the developing placenta) of substances, possibly oestrogenic hormones, which prolong its life. The functional replacement of the corpus luteum m those species in which the organ degenerates relatively early m pregnancy IS also believed to be due to the vicarious activity of hormones from the placental tissue replacing that of the corpus luteum.

## Uterine Or Menstrual Cycle

This cycle of changes in the human female and closely related primates has as its most stiiking character the periodic flow of blood from the uterus As this flow has a monthly (28 day) periodicity in most women it has traditionally been called the “menses ” The length of the menstrual cycle of different individuals is, however, subj'ect to wide variations The most common length is 28 days, less frequent are cycles of 25, 26, 27, 29 or 30 days or longer, but a 21 day cycle is not uncommon Variability in the length of different cycles may be shown in the same individual. The first day of haemorrhage, 1 e , menstruation, is taken as the lirst day of the cycle The duration of the menstrual flow is subject to wide variations in different women, and, from time to time, in the same woman Fluhman (1939) gives the average duration as 3 to 6 days.

## Changes in the Endometrium

The menstiual cycle is characterized especially by phases of growth and degeneration in the endometrial tissues, but there are also less marked cyclic changes in the uteime tubes, uterine muscles and vaginal epithelium If pregnancy occurs, the cyclic function is interrupted by a long gestation period Following parturition, other adjustments are established, associated with lactation, which if it is continued, usually inhibits for a variable time the resumption of the cyclic changes.

It is customary to subdivide the endometrial cyclic changes into four phases — {a) menstrual, {b) post-menstrual , {c) interval or prolifer ative', and (rf) pre-menstrual, pre' decidual or secretory If the menstrual cycle IS considered in its relations to the ovarian cycle, there are only two phases, afolh' cular phase and a luteal or progestational phase which terminates with menstruation (Fig. 24).

1 r

l5f,|

» v-s l' ^


ENDOMETRIAL

"“stroma

UTERINE

"muscle

^ view of the endometrium on the 5th

menstrual cycle Menstruation had just ceased (The magnifications of Figs 17 to 21 are all approximately X 20 ) 1

® power view of the endometrium on the 6th day of the menstrual cycle (after Schroder in von Mollendorff (1930))

## Cyclic Changes in the Female Genital Tract

The first or Follicular Phase This includes the post phases It js characterized b> a period of growth which begins s metnum following the previous menstruation The growth phase to the action of the oestrogenic (follicular) hormone which in a 28 da> menstrual c^cle produces lU ma-cimal effect during the first 14. da\s During the first few dd>s of this phase the regeneration of the surface epithelium which began to take place before the menstrual flow had ceased is completed Frequent mitoses ma\ be rt cognized stK*ru especnli> m the epithelium of the glands which lengthen com c hut remain straight and tubular The endometrium at this period is thin (Figs i7A and B), with an average thick ness of o 5 mm to i mm the stroma is compact and the ncvvlv regenerated epithelium becomes cuboidal Dating the later part of the follicular phase, which continues until ovulation or in the non occurrence of ovoilation for a st» tu comparable period there is eontmued growth of all parts of the endometrium (Fig 18A) The surface epithelium becomes columnar as does to a lesser cMcnt, that of the urcK > glands (Fig aaA) there is usually some serous secretion “ " 1 he endometrial stroma now siiows a division into a denser menstrual and proliferative vith the repair of the endo of the endometrium is due superficial layer stratum (ompaclum an intermediate more loosely arranged layer stratum spongtosum and a deep layer, stratum basalt (Figs 18A and B)

The Second or Progestational Phase This includes the second half of the menstrual <ycle le the secretory and menstrual phases The accompanying changes in the endometrium follow one of two possible courses ^^hen ovulation occurs a corpus luteum develops and the endometrium is changed gradually into a true progestational state due to the action of progesterone probably associated with a synergic decrease in the amount of oestrogenic hormone As a result the endometrium increases m thickness up to 5 or even 7 mm , it shows active secretory changes and persists m this state until mcmtru ation If ovulation does not occur no progesterone is pro duced as a corpus luteum is not formed the folJich s undergo atre la and the secretion of the oestrogenic hormone diminishes the result is a gradual but mcrcasinj, degenera tion of the endometrium without an intervening secretory phase

The progestational endometrium following noimal ovulation is soft velvety and oedematous (ic water logged owing to the distension of the intercellular spaces by fluid) and usuallv pale in colour because of the oedema It can now be more readily div idcd into the stratum com pactum with densely packed swollen stroma cells the oedematous stratum spongiosum which surraunds the dilated glands and the sirilum basalc which shows no hvpmrophy or oedema (Figs 18B and l9^

The superficial parts of the glands tend to be straight and narrow, whereas the deeper parts arc tortuous and markedly dilated (Figs, 19 and 23), The convolutions of the glands are often so marked that in longitudinal section they present a serrated appearance (Fig. ig) with the gland cells often collected into tufts During the early part of the luteal phase the epithelium of the dands IS columnar with the nuclei in the peripheral part of the cells, leaving a clear basal zone which IS filled vith glycogen (Fig. 22B) In the later part of this phase the epithelium becomes cuboidal with irregular, frayed outline, the cytoplasm apparently melting away as a secretion into the lumma of the glands (Fig 2 qC). The secretion is rich in mucin and glycogen The

Fig 18 — A lower power new of the endomelrium on j jib day of the men strualcycJc The endometrium shows a separation into stratum compactum and straium spongiosum After O I ear> and Culbertson (1928) By thecouriesv ofSurg G}nee and Obilet B A lot er po\ er view of the endometrium on the 16th day 01 the menstrual cycle The glands are here slightly dilated (after Schroder in ton MollendorfT 1930)

Fig 19— a lower power view of the endo.

menstrua

® dilated and shov

>pical hacksaw” appearance (aftei Schroder m von Mollendorff, ,930)

Fig 20 — A lower power view of the endometrium on the 28th day of the menstrual cycle The endometrium shows oedema and blood has been extravasated under the epithelium (modified after Bartelmez, 1933)

the amount of r i resemble those of the decidua (page 67), with an increase m

arteries leadino- ^ eucocytes and large mononuclear cells are numerous The small

become verv tr> from the basal zone through the spongy to the compact zone

case is from^an^e^d”^ known as the spiral arteries (Fig, 23) Menstruation in this

n ometrium which has undergone progestational hypertrophy.

,, menstruation

of the ovaries and^ be considered as the outward and visible sign of the periodic activity

of the tvnp , ^^^®t™ntion which occurs from the progestational endometrium

the t)pe just described is that which is characteristic of mature sex life.

CYCLIC CHANGES IN THE FEMALE GENITAL 1IG\CT aq

Some authontito difTercntiate between the Upe of bleeding which occurs from an endo metnum which has not been subjected to the influence of the luteal hormone, i e from a uterus m a woman in which o\ulation has not occurred m the c>clc concerned (inos-ular c\cle) and menstruation following normal o\ulation Shas\ (i934) Schroeder (19*3) emphasize that the two t>pes of bleeding should be regarded as separate and distinct, and the\ would restrict the term menstruation to bleeding from a progestational endometrium \ccording to them bleeding in the absence of o\uhtion should be considered as pathological No\ak (1921) Bartelmez (1937) and others regard menstruation as a periodic physiological bleeding from the uterine mucosa and hold the opinion that it ma> occur in the absence of ovailation The bleeding m both o\ular and ano\ailar cycles occurs following a growth phase and is degenerative in character being preceded b\ oedema and accompanied by necrosis of the endometnum Apparently there is no good reason for not calling both these types of uterine bleeding men struation regardless of whether a follicular or progesta lional endometrium is imolNcd Menstruation without ovailation is the exception in mature sexual life, but it is however common in girls at puberty and at the commencement of menopausal changes and in the former it may be the explanation of their rcimve infertility *

## Histology of Menstruation

During menstruation the superficial layers of the endometrium are shed The basal layer remains essen tially the same throughout the menstrual cycle and from It the regeneration of tile endometrium after menstruation occurs.

Preceding the onset of menstruation there is some shrinkage of the endometrium due to the diminishing oedema Bartelmez (1933) regards the oedema as a manifestation of the pre^ravid sta^e produced by the progesterone.

Immediately before the actual bleeding period there 18 superficial congestion of the endometnum accom panicd by dilatation of the veins and some necrosis of the superficial cells This is followed b\ a leaking of blood from the superficial \ cssels to form lakes under the surface epithelium (Fi 20) some of this blood escapes into the uterine cavity The endometnum may show liulc or no loss during the first day while on the second day inmanyr cases the endometrium is shed down to the basal layer (Fig 21) There is considerable variation m the amount of tissue lost Normally n is not shed en masse but rather crumbles away m small pieces This tissue loss may be ascribed to destruc tion of the capillary bed The circulation m the endometnum appears to be controlled during menstruation to prev ent excessiv c blood loss There is ev idence that some parts of the stratum spongiosum persist throughout the menstrual period and are reorganized during the repair following menstruation (Bartelmez J931)

o a I — \ lovi pov.fr view of the endo itieirmm on the first day of the m nsttiia\ cvctc The superficial lasers of the endometnum have been shed (modifierl after Batielmer 1911'

• It IS V ell known that adolescent pre mariial intercourse though frequently praciised in onmitur only rarely rwults m pregnancy although €>vert menstrual rhenomena are well wiabhshcd fsee M F Ashlev Montagu adolescent Sterility —Qvari Rn B,ol jom VoJ 14 t>o t

Towards the end of menstruation the endometrium may be reduced to o 5 mm, in thickness, 1 e , to approximately one-tenth of its maximum thickness. The denuded endometrial stroma is completely and rapidly re-epithelialized from the epithelium of the stumps of the glands which lie retained in the basal layer. The loosely arranged cells of the basal layer multiply to form the stroma of the endometrium after the circulation has been re-established The regenerative processes begin as early as the third day of menstruation, and proceed very rapidly. Papanicolaou (ipSjii) states that the restoration of the epithelium is brought about by the transformation

of the endometrial stroma cells into an epithelial layer. Markee (1940) has been able to observe the changes

Fig 22 —A A high power view of the epithelium of an uterine gland on the loth dav of the menstrual cycle The

celS’ epithelial

B A high power view of the epithelium on the 1 6th day of the menstrual cvclc.

C A high power view of the uterine gland on the 25th day of the menstrual cvclc The secretion from the cells has p.^sed into the lumen of the glands w Inch IS now distended The epithelium IS columnar with irregular edges

Schroder m von

Mollcndorfl 1930 )

which occur in the endometrium during the menstrual cycle in the macaque monkey by transplanting small pieces of It into the anterior chamber of the eye

Sources of Menstrual Flow. The menstrual discharge is derived from the endometrium above the level of the internal os. The cervical mucosa takes no part in the menstrual bleeding, nor does the mucosa of the uterine tube. The discharge itself consists of blood, epithelial cells and detritus resulting from degeneration of the stroma and normally does not clot. There is great variation in the amount of blood lost during the menstrual period ; the average amount in the healthy woman is 50 to 60 c c It may, however, be double or treble that amount without being considered abnormal (Frank, 1929).

Cause of Menstruation. The cause of menstruation has received considerable attention but so far has not been fully explained. - In a general sense it is brought about apparently by the withdrawal or decrease of a complex hormonal influence, probably both ostrogemc and progestational hormones, which is necessary if the conditions existing in the endometrium at the end of the cycle are to be maintained.

There can be little doubt that the changes occurring m the uterus as the result of the action of the oestradiol and progesterone are a preparation of the endometrium for the reception of a fertilized ovum In the absence of fertilization and implantation the corpus luteum degenerates and menstruation occurs The persistence of a functional corpus luteum and therefore the presence of progesterone after the 28th day of the menstrual cycle prevents the degenerative changes from occurring in the endometrium There is evidence, however, that oestradiol continues to be produced during the luteal phase of the menstrual cycle and that it acts synergically with progesterone (Hisaw et al., 1937). It may be that, at this period, oestradiol helps to maintain the activity of the corpus luteum. In the normal non-pregnant cycle the amount of oestradiol present is minimal just before menstruation and there is an accompanying cessation of progesterone production It is probably the simultaneous withdrawal of both of these hormones that brings about normal menstruation There is evidence, however, that the rcmo\al of either ocstradiol or proi>estcronc alone maj precipitate bleeding (Corner, 1P38, Hisa\% and Creep 1938, and Phelps, 1916) M has been stated carhrr, uterine bleeding may occur in the absence of o\ulation Phis phenomenon can be explained b\ the decrease m the amount of oestrogenic hormone towards the end of the cycle

The actual menstrual haemorrhage is probably due to changes m the arteries winch supply the superficial two thirds of the endometrium (Bartclmez, 1933 and Markec 1940 and 1948) There is a period before mcnstniation during which the arteries increase m length and become much coiled (Fig 23) This is followed by stasis of the blood and later b\ \asoconstnction of the arteries which leads to anaemia and csentually necrosis of the superficial parts of the endometrium, which arc sloughed off Tlic vessels

for a short time dilate allowing haemorrhage into the endometrium to occur the blood loss being controlled by a mechanism which is not yet fully understood (Schlegcl 10^5 and Rcvnolds 1947) It must also be pointed out that a phenomenon closely rescmblin^ menstruation occurs in certain New ^\orld monkeys m which coiled endometrial arteries arc completeK absent or very poorly developed (kaiser, 1948 and sec Ramsev 1949 and Okkels for discussion)

TIME OF OVULATION Ovulation m the human female as in most mammals is spontaneous that is rupture of the follicle (or follicles) occurs indepcndcnil) of copulation In certain mammals (e g the cat the rabbit the ferret) however ovulation only occurs if mating takes place In most mammals whether ovulation is spontaneous or induced follicular rupture occurs in close relation to oestrus In woman and mam of the primates there is no distinct oestrus and there has long been confusion on the time in the uterine cycle at whtcli ovulation occurs particularly in us temporal relationship to menstruation Recent research lvowe\er has greatly clarified ideas both on this problem and on the intimately related one of tlic penod of fertility in the human female

It is now generally licld that ovulation occurs not more than once in a single ovanan cycle though occasionally more than one ovum is shed

This view IS not accepted by all investigators Flius

Samuels (1937) and St, esc (.9,4) hue adduced eMdence that osulal.on mi) ocrur scleral times m a single c)cle (supplementac) or paracvdrc oiulltion) Man) other imestigators base faded to substantiate these uorkers claum for as Siegler {1944) has summarized the general attitude their data arc too meagre to uariant practical consideration In vieu of the vast amount of evidence m us support the view that ovulation normalK occurs once in a cycle Will be accepted m this book

The determination of the precise time in n fejvcn cycle at which ovuhtion will occur or has occurred is a problem of the greatest importance Unfortunately aviilablc methods do not permit of complete assurance but it has been shown that ov ulation precedes menstruation y a penod of time usually 14 days which vanes withm narrow limits m most women That is, in a 28-day menstrual cycle ovulation occurs at about the imd-pomt. The more or less fixed relationship between a given ovulation and the next menstruation is determined by the lunct.onal length of life of the corpus luteum resulting from that ovulation In general, regression of the corpus luteum, and the associated decline in the production of progesterone, commences about 10 days after ovulation and menstruation itself begins 4 days later. While the time leiationship between ovulation and the immediately succeeding menstruation is ‘‘impressively regular” (Papanicolaou et al , 1948), the time relationship between any given O /ulation and the preceding menstruation is much more variable This variability is the result of an inconstancy in the degree of development of the ovarian follicles at the time of the preceding mensti nation and of differences in their rates of growth and the effects of competition amongst them General hormonic and psychological factors may also be involved.

In view of the considerable importance of the problem the methods that have been used to determine the time relationship between ovulation and menstruation have been summarized

1 Allen et al (1930), who have recovered living ova m washings from the uterine tube, and who have studied the young corpora lutea, believe that ovulation takes place on or about the 14th day of the menstrual cycle The recovery of ova is the most convincing method of demonstrating that ovulation has occurred

2 Knaus (1929) has evolved a method for determining the time of ovulation which depends on the non-reactivity of the uterine muscle to pituitrin in the presence of a functional corpus luteum This change occurs apparently 12 days before the expected succeeding menstrual period, 01 15 to 17 days after the first day of the preceding period Assuming that it takes about Uso days to establish the activity of the corpus luteum, and for the uterus to become lefiactoiy, Knaus concludes that ovulation occurs at about the 14th day if the cycle is of 28 days, or in any case about 14 days before the beginning of the succeeding menstrual cycle. The phenomenon of non-reactivity of the uterus to pituitrin does not occur in anovular cycles.

3. The inspection of the ovaries of women has given results which point to the period of the middle of the cycle as being the most likely time of ovulation.

4 Venning and Brown (1937), who have been able to recover the luteal hormone from uiine, have shown that there is an increase in the amount after ovulation, 1 e , about the 15th or 16th day of the cycle This increase is maintained until just before menstruation.

5. Changes in the histological appearances of the endometrium at different times in the menstrual cycle The histological appearances of the progestational phase of the endometrium are specific, and if they are present it is assumed that ovulation has previously occurred. This method is used clinically m the investigation of sterility when portions of the mucosa are removed by cuiettage during the pre-menstrual period

6 Bun et al (1937) have shown that there is a relatively enormous rise in the electncal potentials across the pelvis just before the time of rupture of the ovarian follicle

7. Papanicolaou (i933®) found that in one-third of women examined there is a definite cyclic change in the vaginal smear He is of the opinion that there is a stage in the cycle in these cases where red cells are present, and other changes are found that are indicative of ovulation Unfortunately, the method is not as decisive m women as it is m other mammals

8 Farris (1946 and 1948) has shown that the urine of sexually mature women, during a period of about four days before ovulation, contains a gonadotrophic substance which produces ovarian hyperaemia m immature rats following subcutaneous administration This substance is presumably of pituitary origin Investigations by Corner et al (1950) indicate that the urinary’’ rat test of Farris gives the time of ovulation in a high proportion of cases with sufficient accuracy to be of clinical value.

g.^ It has been shown by many investigators that the normal body temperature has a cyclic variation throughout the menstrual cycle

At about the mid point in i cycle «f20d\y< therein \ Ifmcrim of the nciiii d l( iii|trinhMi

follo^^cd by a rise which pcnisls until luotliysl)crorrincmtruition«lirnlliriri-«m iin n lowi lidi

until menstruation ceases Hus is followed 1 >> a second rise svlutli persists to llir mid pultil of the cycle Such cyclic varntion in temperature does not mciir in <i\ iiie( loniirrd woiiirii or in women after the menopause Ihc evidence siipi>orls the (Oiitriition tint tin mid lyilr nse in the basal temperature coincides approximately with oviilitioii (lot dist iissjoii sri Martin 1943 Tarns 19^8 )

The evidence accumulated from the almc sources {khiiM to the time of oviil ilioii us hrmj the 14th (ii) day previous to the cxpccicil date of onset of the next inrnstni ilu n It most Ik stressed however that there is much variation from vvoman to worn m, due m p irt to difli irmrs in the length of the menstrual cycle, cspeciiHyin die diir ilion of the folio ill ir pli tse in womni with a regular 2&-day cycle the evidence however, seems tlrirly to lodu ilr lliil oviditloii occurs at aI>out the middle of the cycle lor a discussion on vinilioiis in rrlihon lo the o-called safepenod secFlcckr/a/ (tyjo), I apanicolaoii r/a/ i-otnrr fl al

## Oestrus And Menstituation

Oestrus IS that special penod in the sck cycle <if nuny fern dr mimmd ilotmy whldi ihe female is vsalling to receive the male It is ass^Kivtcd with 1 ntirnher of < ft tni rs in the prnif il svaicfn eg rapid npeninj, of the ovarian follicles, f^rowth irid fK-dem 1 f<f the menu ind comification of the vaginal mucr/sa This last chance c in l>e flemonstr ifed in the hvini' unim tl b\ talung vaginal smean In women, however there is no well defined iK-slroiit f>f millin' penod In the pait much confusion was caused h/ atternpls lo rorrelite the rhirn'es fhil occur at oestrus in lower ferms with the chan es th it r<eiif in women it men ini iiir n

In raanv unjulates carnivores and rwlenfs the t>^Ufxi cycle e m l^e snlKlivided mfo more or les.1 dutmet phases —

«( \n erviTj-i phase during which the generative or; ms ire rjiiiesrenl md rfien atrophic \h, a /rs-siet r u.f phase dufin^ whieb there it grr miIi md prolifer »lion fif (ifi< yfes in l^e o -an and eroAth of the insues of the repTwluetive rr/an , m'lre esjK-ri dly the end' meirmm et t-e irenis ard the ntcosa cf the va«ona thi 1 f'lf' ^ed hy ft} an fKl/f n (heii)

phase* dL-ir2 er soen after which cvailation veurs, and at which there rrn/ le* (e g , m ihe bi ch sTcht haer'errha^'e /Vfri the en-o-r ed endemetfium Oe-rnis i f' IfoA'ed hy j re; riirey if luccesa^J nat.rg takes place er h a perjrxl ef / m'nptfinnr/j, m seme ^inirn^l , jf ihe rrMlmg has fcern sterile If rating net crnirrrf! anether peneiej nrir^tirut frll'\/s In ammal whe-e tfia 1- cr^I ls short it is i: lall/ calVd <i 7 -< rj. f.ur if ler?* r^t r^itru , althnj/h ihi Ut.r' t— r is rj- V icf equent' ii ed

I wxj f rmc-l thcT -ri-t {i^t fy-irr,u e-penap/ in the fueh wa cemyrtrrtHeff mer IT wer-r- srer r h>eth cerditer there 1 Heed.r'e ffrm the uterus In seme wrnir- t e— ra/ fee leue- ah,e'er>rsl pam ( iri/^Wrere’ j ^ sli'»ht feijee rrhey^,

and-ar-iij a fclord-,^-eJ s'. e'-a-je at aVn* t‘-e r-ide'V ef the rer trual eyrie s her. e /ul^nen a kre s-u to eren- Tr s w'* Jes efhley,dh« he'en re-emded h/ serre ^utferiftei

s- c-rca-a'-Ie w d- re hae-er-^i-r- at ey-fn in t‘-e htreh The eerpns lufeum herrnere

er-ser-re ^ ser-r m s' <31 err'er-e-rlf g-e ^tr ry rn, rer p.r.ne with

tha u-i^ I- f^e >■ i-nar Ir-'a e j- fi-e ser>-rr* h ' el the ner tru d r,r(r- ff p-r r see; I'ee* ‘i-acrre' en et po- e'rer-*- ,r /i e-tiH her' 1 hieh e enf.i dl/ • r rt rsterr d h errevh e

-eci-rniha r-e- r-ant en in mar are* tre h

•C a-r* t'*r de-’— e— i rj j-e^ fererne/ if re

■‘•irhcernr-ir h. no' reeurrerr e. ^ ir

e‘'i re* ifee* pee je* p'-e r•e** mersf- 1 .t r e ,n ef** err'rrre e u

## Relationship of the Hypophysis (Pituitary) to the Female Sex Cycle

It IS now know^n that the cyclic changes occurring in the ovary are under the control of hormones produced by the anterior lobe of the pituitary. These hormones exert little or no direct action on the uterus or vagina, but act mainly through intermediation of the ovaries. 1 hei e are, apparently, at least ttvo gonadotrophic hormones produced by the pituitary which act on the ovary (Evans et al , 1933, Fevold, 1937, Creep el al., 1940); a follicle stimulating hormone (FSH) and a luteahzing hormone (LH) (Fig. 24), The FSH is responsible for the control of the development of the follicle and for oestradiol secretion. The early growth of the follicles can hn\\e\. ■ occur independently of the anterior pituitary hormones (Smith and Engle, 1927) LU c^'i nols ;Ke luteahzation of the follicle after ovulation and possibly also the production of ' il liujii' 'p Theie is, however, evidence for the activity of a third gonadotrophic e d p lb *' opine hoimone (LTH, and probably identical with prolactin), which he sti ohif for progesterone secretion by the corpus luteum. Either FSH or

Fig 24 A graphic presentation of the relationships of the anterior pitmtaiy, the otarian follicle, the corpus luteum and the endometrium

Menstruation is represented as occuriing fiom days one to four during which most of the endometrium IS desquamated This is followed by the follicular phase of growth which is brought about y ne action ot the follicular stimulating hormone, FSH, of the pituitary on the growing follicle IS IS o lowed by the luteal phase during which the luteahzing hormone of the pituitary acts on shown (Afler^'s”\i ^ degeneration of the corpus luteum of the previous cycle are

LH may separately produce ovulation, the optimum condition for ovulation is probably prepuce of a synergic balance between the concentrations of the tw'o hormones in the blood (Hisavv et al., 1937) If the anterior lobe of the pituitary is removed the ovarian cycle ceases. Injection of extracts of the pituitary or the implantation of grafts into immature animals causes ovulation (Zondek and Ascheim, 1927).

T e factors responsible for the cyclic production of the gonadotrophic hormones are numerous and are not yet fully understood The ovarian hormones themselves appear to have a reciprocal effect on the hypophysis, thus an increased production of oestradiol by the ovaries may inhibit production of FSH which will lead to a diminished secretion of oestradiol, wnth, in turn, t le diminution of the inhibitory action. That the gonads have an action on the hypophysis IS also shown by the histological changes occurring m the latter as the result of spaying and castration when charactenstic involuted cells (“castrate cells”) appear in its pars anterior A nerv'oi^ mechanisrn appears also to be a factor in control of the sex cycle This mechanism involves the hypothalamic nuclei and the hypothalamic-hypophyseal pathways There may be an mhercnt rhythmic control b> the hvpolhalimus but in man> \crtcbrnc. (bird, ferrets, etc see Bissonnettc 1932 nnd 1935 Marslnll 1936) cm ironmental conditions, for cxamp e h«ht ma% act reBcxI) b% \\a> of the optic ncrxc and tract and the Ii>pothahmic centres The nervous mechanism of control ofthccjcle however tssubsidiarv in importance to the hormonal for the pituitarv can still exert its controlhnt, action when its nerves have been sectioned or even when the gland itself has been transplanted {Creep t93G).

arl\ c< rpora lutea I Jour Obsl Cm 1 rtit/ranr t( the luiman ulrriis Coni ib

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Hamilton WJ. Boyd JD. and Mossman HW. Human Embryology. (1945) Cambridge: Heffers.