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Annu. Rev. Physiol. 1949.11:21-44. REPRODUCTION?

By HusBert R. CATCHPOLE

Department of Pathology, University of Illinois College of Medicine Chicago, Illinois

THE OVARY AND OVULATION

Human ova.—An eighty-year quest for early human embryos, dating from the discovery of the Reichart ovum of 1868, reached a climax in the work of Rock, Hertig & Menkin (132, 171). The youngest embryos, two of two cells éach and two of three cells, were obtained by exposure of ova from unruptured follicles to human sperm in watch glasses. The naturally fertilized ovum is believed to reach the uterus on the third day, and on the sixth day it is a blastocyst of three tissues and begins the erosion of the maternal endometrium. On the ninth day, the trophoblast has been seen entering a maternal sinusoid. Development has been followed in this series till the fourteenth day, when the primitive streak appears. Robertson e¢ a}. (170) well illustrated and described a normal human embryo of seventeen days.

Histochemistry of the ovary.—In a critical examination of histochemical reactions of the ketosteroids, Claesson & Hillarp (34) concluded, in agreement with Gomori (75), that the substance reacting with phenylhydrazine was, in all probability, plasmal, and that at the present time it is not possible to demonstrate histochemically any carbonyl group of a ketosteroid. These authors have shown a substance in the ovary, having the polarization characteristics of cholesterol, which they believe to be the precursor of estrogenic hormone. In preovulatory follicles, the precursor is stored in the theca interna in the rat and rabbit, and in the interstitial gland of rat, rabbit, and guinea pig; it is lowest in amount in estrus and diestrus (32, 33). Analyses of total cholesterol in the ovaries of cyclic, pregnant, and lactating rats led Perlman & Leonard (149) to conclude that a close relationship existed between cholesterol and progesterone. In a study of glycogen and carbohydrate-protein complexes in the ovary of the rat during the estrus cycle, Harter (94) found the normally developing ovum to be the only cell with appreciable amounts of glycogen, while ovum, zona

1 This review covers the period from April 1, 1947 to June 1, 1948. 21 Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

22 CATCHPOLE

pellucida, granulosa cells of the follicle, luteal cells, macrophages, follicular fluid, intercellular substance, and basement membranes contained stainable glycoprotein. Increased cytoplasmic glycoprotein of the granulosa cells was related to antrum formation and follicular growth. The glycoproteins of normal and atretic ova differed in their solubility properties. The zona pellucida reacted to extractives in such a way as to suggest that its penetration by sperm cells could be due to a local increase in hydrogen ion concentration. An elegant method was used by Claesson (35) to show rather conclusively the absence of smooth muscle in the wall of the graffian follicle of cow, swine, rabbit, and guinea pig, when the application of classical staining methods failed to distinguish between smooth muscle and connective tissue. This demonstration depends on a decisive difference between the intrinsic molecular birefringence of muscle and the form birefringence of connective tissue. In studies of rabbit ovaries from sex differentiation to maturity, Duke (50) concluded that the connective tissue of the ovary is in a dynamic state and that the maturation of a follicle involves the thinning out and disappearance of the overlying tunica albuginea.

The outlines of a concept of follicular growth and ovulation “hay be drawn from some of the work reviewed above. It is suggested that the activity of enzymes acting on connective tissue is involved. Such enzymes (mucinases, spreading factors) have become known in recent years, and their action is, briefly, to depolymerize mucopolysaccharides of the type present in the ground substance of connective tissue. Presumably this action is reversible.

The follicle would then be accommodated by growth into a region.

of depolymerized (less viscous, less resistant) connective tissue stroma. At ovulation, a dissolution of the connective tissue of the follicular wall and the tunica albuginea would occur by a similar process. The nature and direction of these actions are predicated on the secretion of hormones which control the several stages and which have local effects on the cells of the ovarian stroma. Pluripotentialities of the ovary.—Hill (99) showed that mouse ovaries grafted into the ears of the donors themselves, or into the ears or testes of male recipients, permitted their adrenalectomized hosts to survive for a longer (if variable) time; cutting the mesovarium and with it the ovarian artery, vein, and nerves similarly induced an ovarian secretion of hormones with corticoid activity Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 23

(100). Moore & Wang (136) produced chemical destruction of the ovarian cortex prepuberally in rats, guinea pigs, cats, and opossums; study up to a year later revealed active follicular development, with little tendency for medullary cords to develop in a testicular direction.

Ovarian transplants.—Butcher (28) showed that transplanted ovaries of rats developed better if the capsule was retained, and that even in situ decapsulation of the ovary retarded its growth. Harris & Eakin (92) found that grafts of rat ovaries into paired normal and ovariectomized rats were larger and better vascularized in the latter. Estrus occurred generally in autogenous, sister to sister, and intrastrain grafts, less often in interstrain grafts, and was absent in heterologous grafts. ;

Corpus luteum and fertilization.—As is well known from the work of Cole et al. (39) the pregnant mare shows the remarkable phenomenon of ovulation and corpus luteum formation in the second month of pregnancy. Whether these animals come into heat at this time seems not to be definitely known [Cole (37)], nor has a case of superfetation been seen or reported, to the knowledge of the reviewer. Preliminary attempts by Amoroso et al. (5) to effect fertilization of ova recovered from pregnant mares were stated to have failed. In studies of the Wisconsin group (18) rabbits were artificially ovulated with gonadotrophin given intravenously and artificially inseminated; liberated ova were recovered and examined forty-five hours later. Prior administration of progesterone for . ten days suppressed the fertilizability of these ova, an effect partially nullified by estrogen. Jn acomparable experiment, the fertilizability of eggs from superovulated rabbits was around 80 per cent in juvenile, estrus, and anestrus does, but was zero at five days post partum (137). From the work of Harter (94) already quoted, it may be suggested that a likely locus of the barrier to fertilization is the zona pellucida whose specific glycoprotein may change under the influence of the luteal hormone.

Corpus luteum, progesterone, progestational proliferation.—In the corpus luteum of the pregnant rat, Bassett (11), on the basis of mitosis counts, distinguished an early proliferative phase and a late phase of cell hypertrophy. Forbes (66) showed that plasma levels of progesterone in the pregnant mouse were high till the seventh day and low in late pregnancy. These two studies would appear to relate progesterone secretion to the proliferative phase Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

24 CATCHPOLE

‘of the corpus luteum. Peckham & Greene (146) reported production

of deciduomata in the unilaterally pregnant rat till the seventh day of pregnancy, but not on the ninth day, and this failure was not corrected by removal of the pregnant cornu on the seventh day. Other experiments on the physiology of deciduomata were: failure of established deciduomata to inhibit the development of a new crop in the rat (147); inefficacy of a-tocopherol and prolactin, and a slight action of desoxycorticosterone in their production (165); failure of deciduomata to prolong pseudopregnancy in the mouse (112).

FEMALE REPRODUCTIVE TRACT

The menstrual cycle, human and primate——cCoiled arterioles similar to those in rhesus were described by Kaiser (109) in the uterine mucosae of the baboon, chimpanzee, and gibbon. The significance of coiling for menstruation seems to have been reduced by this author’s studies in platyrrhine monkeys, where no coiled arterioles were found (110). Since menstruation is microscopic in the latter forms and gross in those primates whose endometria contained coiled arterioles, it was considered possible that these vessels may regulate the amount of bleeding once the menstrual process has been established. From the work of Bensley (14), mitotic counts in the endometrium of the macaque showed peaks in the presence of a large follicle, as well as just before and after ovulation, and low values in the late luteal phase. Studies of Atkinson & Engle (9) and Arzac & Blanchet (6) essentially agreed that the alkaline phosphatase of the uterine epithelium of man paral ‘leled the mitotic rate in being high during the proliferative phase,

reduced in the secretory phase, and absent several days premenstrually and during menstruation. Glycogen showed an inverse relationship with the enzyme (6). In ovariectomized monkeys, the enzyme was present in glands and surface epithelium after estrogen treatment and was reduced following the addition of progesterone (9).

Abarbanel (1) produced cyclical changes in human cervical mucus by the use of estradiol and stiJbestrol in castrates. Progester one, testosterone propionate, and methyltestosterone failed to

stimulate the flow of cervical mucin. Atkinson e¢ al. (10) demonstrated relatively constant amounts of mucus throughout the cycle in the apical cytoplasm of cervical glandular epithelial cells, Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 25

although active secretion was rhythmic. It would thus seem to be a promising approach to study the physicochemical properties of mucus in cervical cells, since a change in state (e.g., depolymerization) under the influence of estrogens may be one condition, at least, of its release.

The question of threshold bleeding was reopened by Clark (36). In a female chimpanzee castrated for several years and receiving constant doses of estrogen and progesterone the sex skin waxed and waned and menstruation occurred periodically. These two indicators were dissociated in time, however, creating a situation difficult to reconcile with the theory of fluctuation in steroid output of the adrenal as originally suggested by Long & Zuckerman. The author’s proposal of a threshold alteration in the responding organs redefines the problem. Continuing their studies on the baboon, Gilbert & Gillman (72) found that administration of testosterone propionate to castrated males or females gave a turgescence response within the first week similar to that following estradiol; then new properties emerged and there occurred an active deturgescence at which point estrogens were relatively ineffective in restoring turgescence. Males were more refractory than females in this respect (73). Methods employed several years ago by Ogston e¢ al. (143) might contribute to the elucidation of hormonal effects on turgescence in primates. It was then shown that estrogens evoked a connective tissue reaction and that mucoproteins appeared in the exudates of swollen tissues. The effect of androgens on these reactions should prove instructive.

Some earlier experiments of Engle were recalled by a study of Ferin (60) in which ovariectomized women with implants of crystalline stilbestrol were given 40 mg. testosterone per day for six or seven days. There occurred in several cases a withdrawal hemorrhage, with a latency of eighteen to one hundred and fifteen hours. Since no progesterone changes were seen in the mucosa this treatment was claimed to be clinically advantageous as a way of avoiding cystic endometrial hyperplasia in the bearers of estrogen implants. Comparable findings by Marvin (127) in the rodent may conveniently be cited here.

Histochemistry of the uterus (see also previous section).—An intensive study by Pritchard (158) of alkaline phosphatase in the uterus of the pregnant rat showed general agreement with earlier reports, although the interpretation was modified. In the phase Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

26 CATCHPOLE

of proliferation and differentiation the enzyme was detected within the nucleus; during specific functional activity it: was exclusively cytoplasmic. In contradiction with the Harvard group, least activity was found in regions of the decidua, trophoblast, and metrial gland which are engaged in glycogen storage [cf. also Arzac (6)].

Physiology of the reproductive tract—It was shown by Kaiser (111) that the well-known actions of estrogens on endometrial vascular responses in intraocular endometrial homotransplants of rabbit uterus were unaffected by the powerful acetylcholine inhibitor, atropine. The author concluded that the estrogen effect was not cholinergic and that such changes in total acetylcholine as had been observed previously were of myometrial origin. Strong peristaltic waves were observed by Odor & Blandau (142) in the tubal sac of the rat oviduct, indicating an additional mechanism for transport of ova. Hamilton (85) found the cervix uteri of the rat to show a gradient from vagina to uterus in structure and in response to estrogens.

Miscellaneous.—F actors influencing the ‘growth and development of the mammalian reproductive tract were reviewed by Price (157). Castration of mice at birth permitted normal development, till at least three and a half months of age, of the external genitalia and of the os clitoris (161). In hamsters, male accessories regressed following castration at birth, but female accessories progressed normally until twenty-five days of age (117). Studies off the beaten path referred to phases of the sex cycle in the mole (74), tree kangaroo (128), and hedgehog (179). Harrison (93) contributed a considerable study of the ovary of the goat.

PREGNANCY AND PARTURITION

Van Wagenen (197) observed in the pregnant macaque three instances of spontaneous death of the fetus (diagnosed by x-ray) with viable placenta, paralleling earlier work in which the fetus was removed without disturbing the placenta. All animals continued in the physiological state of pregnancy, and the pyeloureteral dilatation which arose or persisted was shown to be independent of the presence of the fetus, but contingent on the functioning placenta. Zondek et al. (206) premised that with the death of the fetus, the first organ to die would be the placenta, and that this

would be reflected in failure to give a pregnancy test. This thesis Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 27

should be appraised in the light of Zondek’s own finding of a case of fetal death with viable placenta and persistence of urinary estrogens and gonadotrophins (203), as well as of the numerous demonstrations in primates and other mammals of placental retention and function following removal or destruction of the fetus. Studies such as these, nevertheless, will be expected to reveal the incidence of intrauterine death, with or without placental survival, at various stages of pregnancy in man. Of the correlates of pregnancy, the excretion of pregnanediol received considerable attention from the standpoints of assay techniques and clinical interpretation (13, 17, 43, 82, 104, 123, 153, 159, 183). Davis & Fugo (42) found that administration of large doses of testosterone propionate or stilbestrol to normal pregnant women did not modify the excretion of pregnanediol, contradicting reports of others on the efficacy of stilbestrol in-this respect (164).

Pregnancy as a variable complicating hypertension was studied by Grollman (79) in the rat, rabbit, and dog. The primary consideration was shown to be the relative increase in the vascular bed due to the presence of the placenta. The fall in blood pressure was thus greater in small than in large animals, and greater with large than with small litters. Pseudopregnancy and the presence of deciduomata were ineffective. Smith & Smith (182) reviewed the toxemias of pregnancy. Measurements of uterine pressures at various stages of labor by Torpin (195) showed high maximal pressures (up to 100 mm. mercury) and maintenance of positive pressures between contractions.

Risman (167) described a remarkable sequence of events occuring at parturition in the opossum, the outstanding feature of which was the breaking of connective tissue barriers by the fetuses. This process calls to mind the dissolution of structures in the pubic symphyses of some rodents.

Placenta and placental barrier—Two notes dealt with the source of fetal iron in the guinea pig and rat, using radioiron as a tracer. In the guinea pig it was computed by Flexner ef al. (62) that iron available from maternal plasma at the fortieth and fiftieth day, and near term, comfortably exceeded the fetal demand. Maternal red cells were regarded as an unlikely source since at the fortieth day they yielded at most one third of the fetal iron requirement. In rats rendered anemic by periodic bleeding evidence was derived by Everett & Henderson (58) that red cells Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

28 CATCHPOLE

crossed the placental barrier. In further studies of the Carnegie group, permeability of the human placenta to sodium was shown to increase seventy times between the ninth and thirty-sixth week, then to decrease rapidly till term, with a high safety factor at all times. Sodium passage in the middle of the ninth decile of pregnancy for sow, goat, cat, guinea pig, rabbit, rat, and man corresponds closely with the type of placentation according to Grosser’s scheme (63). From studies of cholesterol distribution in maternal, umbilical, and fetal blood, Sadowsky e# al. (172) found little evidence of special fetal involvement in cholesterol metabolism. The partition of injected phosphorus-labelled disodium phosphate between the phospholipids of maternal and fetal tissues in experiments of Popjak (155) with rats, guinea pigs, and rabbits indicated fetal liver and placenta to be sites of synthesis. Since very little radiophosphorus injected into fetuses appeared in the mother, it was considered highly probable that the fetus synthesizes all its phospholipids. Human trophoblast was cultivated by Gurchot et al. (81) in the anterior chamber of the rabbit eye and was stated to secrete chorionic gonadotrophin and steroid hormones. Evidence was given by Stewart e¢ al. (186) supplementing the earlier findings of Gey, that human placenta grown in tissue culture secreted gonadotrophin, in amounts according with the degree of proliferation of Langhans cells in the explants; estrogen was not detected.

Relaxin.—Work on relaxin represented largely extensions of activities reported last year (164). Hall & Newton (84) consider relaxin an undisputed hormonal entity whose action is essentially that of a potentiator of the action of estrogens on the symphysis. In the pubic symphysis of the young female guinea pig Talmage (193) described the gradual replacement of cartilage by connective tissue, a process that was completed in the first pregnancy. Castration reversed this sequence in the direction of chondrification.

. Estrogen ‘caused cartilage replacement while relaxin caused a

dissolution of the connective tissue formed in this site. Events in the pubic symphysis of the mouse described by Hall (83) also involved a reversible transformation of cartilage and connective tissue. The effect of relaxin on cartilage and connective tissue was stated to occur 7” vitro (192). An analysis of events so far described in the pubic symphysis would seem to point to a role of an enzyme of the mucinase class. The rapid softening of the connective tissue Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

° REPRODUCTION 29

of the symphysis by relaxin suggests a process of depolymerization of connective tissue elements, with attendant loss of rigidity. Whether relaxin induces secretion of the enzyme, or itself posesses this property, is speculative at this stage, as also is the nature of estrogen action in the preparatory process.

THE MAMMARY GLANDS AND LACTATION

The topic ‘Lactation, Function and Product” was reviewed by some score of British authorities (22), bringing a knowledge of all phases of this subject practically to date. Developmental and structural features of the mammary gland were also covered. Technical aspects of this review refer to British practice. A review by Petersen (151) emphasized lactation in bovines.

Mammary glands.—It has become accepted that the anterior pituitary gland secretes factors which affect mammary ducts and alveoli directly, without the mediation of steroid hormones from either the gonads or adrenals (65). The latter hormones find their principal expression in stages preparatory to, and during, secretion. It may be pointed out that proliferation of the mammary gland may involve not merely the “growth” of ducts and lobules which insinuate themselves by brute force into the surrounding connective tissue, but also preparation of the connective tissue stroma as well as of the mammary tree. Analysis of this interaction may assist in defining the prerequisites for growth of the mammary gland in different species. It is perhaps possible to see as one aspect of this the increased hydration of the mammary gland of the rat shown by Folley & Greenbaum (65) to occur under the influence of desoxycorticosterone.

The passage of substances into the milk appears to have gone relatively unexplored, although its importance has been emphasized by Burn (25) in relation to drug excretion by this route. Since the mammary gland is an organ of highly specialized syntheses, as well as excretion, such studies hold promise of considerable theoretical significance. Thus McConnell (129) found that radioselenium injected as an inorganic salt appeared as organoselenium in the milk.

Lactation.—Considerable interest has been shown in the several constituents of colostrum. In cattle, the nonfatty portion of colostrum supported life in calves better than the crude or clarified fatty portion (7). The Tiselius pattern for cow colostrum was quite Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

30 CATCHPOLE

different from that of milk or whey, showing that the difference in protein composition between milk and colostrum was not due simply to an increased percentage of whey components in the former (80). Colostrum feeding led to an increase in blood serum gamma globulins in lambs (31) and calves (89). The wheys of horse, goat, sheep, pig, and cow, but not of human, showed, in electrophoretic studies, a high component associated with antibody proteins (45). The role of immune proteins of bovine milk and colostrum was reviewed by Smith (181).

Lactation was the function most affected in attempts to maintain rats on purified diets (59, 139). Pteroylglutamic acid was one of the factors implicated, and evidently this, together with other unidentified factors, is normally supplied by the colostrum or milk to the young of the pig (27), mouse (135), and rat (64, 140).

EsTROGENS, NATURAL AND SYNTHETIC

Biology of estrogens.—In in vitro studies by Bischoff & Katherman (16) the distribution of estradiol in blood was found to be determined solely by forces governing its solubility in plasma and red cells, to which it is permeable. Nevertheless, Szego & Roberts (190) have postulated estroprotein combinations, based on the coprecipitation of part of the blood estrogens with protein. Bird et al. (15) found that estrogens accumulated in the oil of adipose, and in fat infiltrated tissues of birds, a phenomegpn that does not appear to have received any attention in mamma. Stilbestrol, dienestrol diacetate, and other synthetic estrogens were used in this study. Hooker e¢ al. (102) showed that the liver of the monkey failed to inactivate estrone and estradiol im vivo, but this was viewed in terms of a relative inefficiency as compared with the rat.

The mechanism of a-estradiol inactivation in the rat liver in vitro appeared to involve a dehydrogenation, but other details were disputed, in a system that is receiving close study (44, 121). In addition to a- and B-estradiol, Westerfield’s lactone acetate and estrolactone acetate were inactivated in rat liver 77 vivo while two doisynolic compounds were potentiated (177). Dimethyl-ethyl allenolic acid, which has an estrogenic action in the pregnant and parturient guinea pig, was not destroyed by the liver (41). In the rat, the mode of administration determined the fate of some estrogens, since stilbestrol and dienestrol per os were not inactiAnnu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 31

vated, while estrone, estradiol, and hexestrol per os were inactivated and estriol was inactivated whether given orally or parenterally (141).

Metabolic pathways.—Stimmel (187) found that single therapeutic doses of natural estrogens in man were metabolized, qualitatively at least, like massive doses. Interconversions of estradiol, estrone, and estriol proceeded much the same in absence of the ovary and uterus, and only a fraction of the injected material was recovered. Dodgson eé al. (47) found in the rabbit that the synthetic estrogens, stilbestrol and hexestrol, appeared as urinary glucuronides, while dienestrol given orally was excreted largely unchanged in the feces. According to Wilder Smith (199), stilbestrol and hexestrol administered to man were excreted 50 per cent as monoglucuronide and up to 6 per cent as sulfate, while less than 1 per cent was excreted unbound. The major estrogen of pregnant cow bile was shown to be estrone (145). Concerning the site of glucuronic acid conjugation, an ingenious experiment of Schmid (176) indicated that the liver was not essential.

REPRODUCTION IN THE MALE

Male germ cells and hyaluronidase.—With intensive studies continuing, not all the evidence points to the necessity of hyaluronidase as a disperser of the cumulus oophorus preparatory to fertilization. Leonard et al. (119) showed that fertilization in the rat occurred before mass displacement of the surrounding follicular cells; these tubal-masses were untouched by hyaluronidase introduced into the uterus, but were rapidly denuded by uterine fluid in vitro. Swyer (189) found that rabbit eggs were freed from the cumulus, but not from the corona radiata cells, by hyaluronidase, tn vitro, but introduction of such previously exposed eggs into the tubes of living animals completed the denudation. Since both cumulus and corona resisted the action of tubal extracts a mechanical explanation was advanced. Chang (30), working with rabbits and using minimal effective sperm densities, showed that the addition of hyaluronidase alone did not affect the fertilizing capacity, that normal semen supernatants with added hyaluronidase caused a nonsignificant increase, and that vasectomized buck semen, devoid of hyaluronidase, increased the fertilizing capacity significantly. While authors agree that hyaluronidase is definitely attached to sperm, the conditions of its release are debated. Swyer Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

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(188) found three quarters of the total semen activity to be associated with sperm cells, which were believed to liberate the enzyme progressively to surrounding fluids, but not actively to produce it. Perlman ef al. (150) kept rat sperm recovered from the uterus under various adverse conditions, incubated at 37°C., frozen, and toluene treated, and found an increase with time in the enzyme level, while the sperm themselves became less motile. Hechter & Hadidian (95) by successive washings in saline of rabbit sperm found hyaluronidase to be constantly renewed until the seventh washing when activity fell sharply. This experiment was interpreted as indicating synthesis of the enzyme by sperm. The potentialities of sperm exhausted of hyaluronidase are not known, but it was evident that when human semen was mixed with five volumes of Ringer solution, centrifuged, and resuspended in its original volume of saline the sperm lost none of their ability to penetrate mucus, in experiments of Pommerenke & Viergiver (154). Leonard e al. (120) found that the hyaluronidase levels of rat testis decreased to about the same extent thirty days after hypophysectomy or cryptorchidectomy and were correlated di“rectly-with the state of the germinal epithelium both in these animals and in a series of normal animals studied between twenty and ninety days. Sherber e¢ al. (178), from the same laboratory, showed that aspermic preparations diffused in skin, although they were inactive viscosimetrically on hyaluronic acid. The authors suggested the presence either of other spreading factors, or of amounts of hyaluronidase too small to be recognized by this technique. Effect of environmental conditions on sperm.—Rabbit semen had a pH of 7.0 to8.2 (mean 7.6) andsperm were more sensitive to acid (pH 5.8) than alkali (pH 9.5 to 10). With increasing pH, sperm became more sensitive to hypertonic solutions and around the optimal pH of 7.0 to 8.7, both hyper- and hypotonic solutions were equally deleterious. Complex variations arose from changing either the salt or the glucose concentration of the medium (53, 54). Human sperm were somewhat resistant to arbitrary changes in the tonicity of the medium (124). No very favorable results followed the addition to semen of sulfanilamide (46, 173) or sulfathiazole (46). Amounts of two hundred and fifty to one thousand Oxford Units of penicillin and up to 1,000 yg. of streptomycin per ml. of diluted semen retarded bacterial growth without reducing Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 33

livability of sperm. Higher levels were definitely deleterious to motility, while effects on fertility are not yet reported (3, 4). Reed & Reed (163) and Sanders (174) described structural details of human spermatozoa, from electron microscopic observations.

Seminal vesicles and prostate gland.mEmmens & Parkes (55) reviewed the effects of exogénous estrogens on the accessories of male mammals, Krichesky & Benjamin (116) found that estrogens caused reversible atrophy of intraocular prostatic implants in intact rabbits. After atrophy had occurred in castrated |hosts, fibrous and muscular tissues were stimulated to hypertrophy, a finding that agrees essentially with results on the gland im ‘sétu. Horning (103) considers the Golgi apparatus of the mouse prostatic epithelium to bea precise indicator of estrogenic stimulation.

THE HypopuHysis

Hypophysectomy.—Jost (106) used rabbit embryos decapitated at nineteen, twenty-one, and twenty-two days and surviving till term (twenty-eight days), and Wells (198) fetal rats similarly operated and surviving twenty-eight to one hundred and two hours before severance of the cords near term. In the former, certain anomalies of the genital tract were noted, but growth was not interfered with. In the latter, the volume of the male reproductive glands equalled that of controls.

Histochemistry of pituitary gland—Abolins (2) found that alkaline phosphatase in the anterior pituitary of the guinea pig was rather closely restricted to acidophil cells, where it was present in the nucleus and at the cell surface; when present in the cytoplasm it seemed to be concentrated in the region of the nucleus and of the Golgi apparatus.

Pituitary hormones.—Hitherto unpublished physicochemical and chemical data on pituitary interstitial cell stimulating hormone and prolactin were given in a review by Evans (56). This author condemned the use of the term pituitary luteotrophin and explicitly stated that maintenance of corpora lutea was a function of the purest lactogenic hormone preparations [see (126)].

The pituttary-gonad relationship—The concept that the seminiferous tubules are normally supported by androgen seems to be well established. Several years back, studies by Pencharz (148) and by Williams (200) showed that estrogens prevented ovarian atrophy and potentiated the action of gonadotrophins in hypophyAnnu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

34 CATCHPOLE

sectomized rats. Results bearing on these relationships have now been obtained using the intrasplenic ovarian graft preparation. In the rat, Heller & Jungck (96) found that estrogens suppressed the expected weight increase in ovaries so transplanted, and this was adduced in support of a thesis that in the presence of adequate amounts of pituitary secretion, ovarian activity is controlled largely by the level of circulating estrogens. However, in the guinea pig, Lipschutz e¢ al. (122) were able to control the heavy lutein and blood follicle formations only by estrogen in combination with progesterone, and the locus of action was placed in the pituitary gland. The question seems to arise how far the splenic transplant system may be regarded as a simple model of estrogen release of either the pituitary or the ovary. Since ovaries so transplanted go on to develop luteomata, caution seems desirable in the application of these results to normal reproductive physiology. Some further evidence was given by Junck e¢ al. (108) that pituitary hormones suffer inactivation in the gonads. From the work of Bradbury (19), physiological amounts of estrogen do not suppress the pituitary but, on thecontrary, release pituitary hormone to the blood stream. It was indicated, however, that the ovary may be a more potent regulator of pituitary function than are the crystalline estrogens. '

The hypothesis was advanced by Tepperman & Tepperman (194) that gonadotrophins affect androgen production in the male rat by a direct involvement in the metabolism of esterified cholesterol. In the work of Claesson & Hillarp (33) already referred to, administration of gonadotrophin to the rat mobilized in the ovary an estrogen precursor believed to be cholesterol.

Gonadotrophins, pregnancy tests.—With the introduction of the ovarian hypermeia test for pregnancy, the vascular aspect of pituitary action on the ovary is receiving some attention. Bradbury (20) described the formation of a rich perifollicular vascular network in the rat ovary forty-eight to seventy-two hours after administering pregnancy gonadotrophin. Rakoff & Fried (160) obtained a strong synergistic effect on ovarian hyperemia in the rat when chorionic gonadotrophin was given in conjunction with quite small amounts of a ‘‘pituitary synergist”’ said to be mostly follicle stimulating hormone. This agrees with the findings of Zondek & Sulman (204). It is possible that investigation of the hyperemia reaction as a phenomenon per se, and the related study Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 35

of how hormones affect the ovarian connective tissue, may help to resolve outstanding’ problems concerning (a) steroid effects on the ovary and (b) multiple gonadotrophic effects.

Meanwhile the clinical use of the hyperemia test appears to have established its value as an ancillary to the slower but more accurate Aschheim-Zondek and Friedman tests (23, 68, 166). It has also been used in equid pregnancy diagnosis (196, 205). The literature on effects of the gonadotrophic hormones on ovulation and spermatogenesis in amphibians in relation to pregnancy diagnosis was surveyed by Mello (131). The diagnostic reaction of GalliMainini (71), employing the appearance in the urine of sperm after injection of pregnancy urine into the male toad, has been extensively studied in South America and elsewhere. The original reaction called for the use of Bufo arenarum, indigenous to Uruguay and the Argentine (71, 156), amphibia react similarly: Xenopus laevis (70, 168), Brazilian frogs and toads (131), and the common Rana temporaria and R. esculenta (101), and R. pipiens (169) of North America

Antigonadotrophins——By administering chorionic gonadotrophin mixed with colloidal alumina to rabbits, antigonadotrophic sera that produced specific precipitates with the antigen were obtained by Bussard & Grabar (26); these precipitates may contain excess antibody or excess antigen and no essential difference was seen between these phenomena and the classical neutralization reactions. Some studies of Freud & Uyldert (67) and of Katzman et al. (113) confirm the older observations of Thompson on augmenting sera.

Hypothalamo-hypophyseal nervous and vascular link.—Harris (91) described the innervation of the neurohypophysis in the rabbit. He concluded that in the rabbit, rat, guinea pig, cat, dog, monkey, and man it is the function of the pars tuberalis to transmit an anatomic vascular pathway from the neurohypophysis to the pars distalis (90). Similar relations were obtained in amphibia by Green (76). These authors (77) suggested that nerve fibers from the hypothalamico-hypophyseal tract end at capillary loops in the pars tuberalis, whence a humoral link, the hypophysial-portal system, takes origin to subserve the pars distalis. The adrenergic nature of such a link was shown by Markee ef al. (125, 126). Confirmatory evidence was ,the inhibition of ovulation in the rabbit when the adrenergic-blocking drug, dibenamine, was given intra = Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

36 CATCHPOLE } |

venously within a minute after copulation. Time relations were such that a three minute delay permitted ovulation to occur (175). Following estrogen administration ‘to pregnant rats, an adrenergic stimulus, which can be blocked by dibenamine, passes to the adenohypophysis after a delay of at least eighteen hours (57).

ANIMAL BREEDING AND ECOLOGY

The limitations imposed by the environment on possibilities of genic selection were emphasized by Hammond (88) in a review which forms a valuable background for the consideration of a variety of situations. It was shown that most commercially valuable characters were quantitative in nature, and that removal of certain environmental limitations might be necessary to permit further selection to be made. Asdell (8) discussed the future of animal breeding in a popular article.

In Maryland, Phillips (152) found the average service per pregnancy to be 1.4 for the Karakul sheep, and 2.5 or more for other breeds, and the superiority of the first was attributed to adaptation to the hot environmental temperature that precedes the breeding season. The seasonal variation in day length is the chief controlling factor in the breeding season of sheep in England, according to Yeates (202), and in the fertility level of cattle in New York State, according to Mercier & Salisbury (133). Burkhardt (24) hastened the onset of estrus in mares by general irradiawith strong artificial light.

Cole & Casady (38) studied prolificacy in two strains of rats bearing, respectively, 8.9 and 6.5 young per birth and found that the gonadotrophin and thyrotrophin content of the pituitaries of these strains were not demonstrably different. Recently the concept of reproductive wastage has come to the fore. In wild rabbit populations, Brambell & Mills (21) showed that not more than 3.6 per cent of litters were totally lost, but that 36.5 per cent of litters surviving implantation suffered some loss of ova. Greenhill (78) stated that in man the fetal and neonatal death rate was high all over the world for fetuses that had reached a stage of viability. In women known to be fertile, the fetal survival index was placed by Rock & Hertig (171) at 25 per cent at the stage of fertilization. In a study by Drillien (49) of eight thousand births in Edinburgh, 1943-1945, the outcome of a pregnancy (death, stillbirth, or survival) was found to be closely related to the weight at birth. Annu. Rev. Physiol. 1949.11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

REPRODUCTION 37

SECONDARY SEX ATTRIBUTES

In this section will be considered a group of organs and some phenomena, either falling into the secondary sexual category or related to sex more remotely. Hamilton (87) mentions the hair as subject to androgenic control and has described the normal appearance of terminal (coarse) hairs in the external ear of males only. Also affected by androgens are: sebaceous glands, skin melanoblasts, muscle fibers of the panniculus, fibrils of dermal collagenous tissue, and mast cells of the dermis (86). From the work of Coujard (40) the anal scent glands of rabbits are ambosexual, and equally sensitive to follicular and androgenic hormones, while the inguinal glands react differentially. Ebling (52) found that testosterone propionate increased the activity of sebaceous glands of the female rat, while ostradiol-benzoate caused atrophy. The inguinal sebaceous glands of the guinea pig were greatly enlarged with anterior pituitary extract (180). Olfactory sensitivity to the lactone of the acid oxy-14-tetradecam-carboxylic-1, a synthetic macrocyclic compound with the odor of musk, prepared by Ruzicka, was shown to be linked to the presence of estrogen, in a remarkable report by Le Magnen (118). Boys, girls, men, and women at menstruation were relatively anosmic to the compound. In the course of the menstrual cycle, many women reacted to it with increasing intensity so that seven to nine days before the next menses it was appreciated violently. MussioFournier e¢ al. (138) found that pigmentation of the mammary areolae was increased by the local action of estrogen. Even the submaxillary gland responded to castration and showed sexual dimorphism, according to Raynaud (162). Antler growth in the male Virginia deer is under the complex control of an extra gonadal system, probably the anterior pituitary gland, from the studies of Wislocki ef al. (201). Male hormone was responsible for the initial priming of the mechanism and for the secondary hardening (calcification) and shedding of the velvet. Ovariectomized female deer grew antlers under androgen stimulation.

ENZYMES AND REPRODUCTIVE CONTROL

While it has become a truism that hormonal actions will eventually find their proximate explanation in appropriate enzyme systems, the outlines of such control are still dim and studies are largely of an ad hoe character. Enzyme studies in uterus and piAnnu. Rev. Physiol. 1949,11:21-44. Downloaded from www.annualreviews.org Access provided by University of New South Wales on 08/07/19. For personal use only.

38 CATCHPOLE

tuitary gland have already been dealt with. Acid and alkaline phosphatase were studied by Stafford et al. (185) in ovarian tissues of the rat in pregnancy and lactation using tissue homogenates, and concurrently alkaline phosphatase was followed histochemically by Talbert e¢ al. (191). Succinic dehydrogenase appeared to

. follow a similar time course, marked by a sharp midpregnancy

rise in the corpora lutea, and by a rise to even higher levels in the corpora of lactation (134). Steroid hormones in relation to the hydrolytic enzymes were reviewed by Kochakian (115). A new concept of the metabolic conjugation of estrogens with glucuronic acid as a prerequisite for their utilization was suggested by Fishman (61).

A group of enzymes that includes the spreading factors and hyaluronidases has been considered to play a role in certain phases of reproduction; such a function of the mammalian spreading factors was mentioned by Duran-Reynals (51) and the ‘possible function of hyaluronidase in fertilization has been actively investigated. The substrates of these enzymes are: intra- or extracellular mucopolysaccharides, ground substance, basement membranes, glycoprotein membranes, and connective tissue, including cartilage. Other possible roles of such enzyme systems have been indicated at appropriate places in this review.

REVIEWS AND Books

Certain topics not touched on in this reviewhave received ample treatment elsewhere. Such are: androgen metabolism, by Dorfman (48); the use of androgens in males, by Heller & Maddock (97); and in women by Carter e¢ al. (29); local actions of sex hormones, by Speert (184); spectrophotometric methods for estrogens, by Friedgood & Garst (69); and for sterol hormones, by Jones (105); reproductive epithelia, by Papanicolaou et al. (144); sex hormone deficiencies, by McCullagh (130); sexual behavior, by Kinsey et al. (114), and by Beach (12); B-vitamins in relation to estrogens, by Hertz (98); hormonal control of sexual differentiation, by Jost (107). .

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