MAMMALIAN REPRODUCTIVE CYCLE 



517 



(Bachman, 1936; Mazer, Israel and Alpers, 

 1936 ». Hisaw (1947j inferred that this is 

 generally true for reflex ovulators. Never- 

 theless, it was found by Klein and Mayer 

 ( 1946) and Klein (1947) that when pseudo- 

 l^regnant or pregnant rabbits were treated 

 with estrogen and then mated, new ovula- 

 tion 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, treat- 

 ment with estrogen on the preceding 2 days 

 results in a positive response to this stimu- 

 lus. 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, estro- 

 gen 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 estro- 

 gen during the early part of the cycle sig- 

 nificantly postpones the next expected ovu- 

 lation and menstruation (monkey, Ball and 

 Hartman, 1939; baboon, Gillman, 1942; hu- 

 man, Sturgis and ^leigs, 1942; Brown, Brad- 

 bury and Jennings, 1948). Gillman reported 

 that a single injection of estrogen precipi- 

 tates widespread atresia of vesicular fol- 

 licles. 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 ad- 

 ministration. They proposed that delay of 

 ovulation by estrogen given early in the 

 primate cycle may be the result of prema- 

 ture discharge of gonadotrophin before the 

 Graafian follicle is competent. Sturgis and 

 Meigs had suggested, on the contrary, that 

 the estrogen suppresses hypophyseal func- 

 tion. D'Amour (1940), finding in urinary 

 assays that tlie initial peak of estrogen ex- 



cretion preceded the peak excretion of uri- 

 nary gonadotrophin, postulated that the 

 increase of estrogen stimulates the gonado- 

 trophin release that is responsible for ovu- 

 lation. O. W. Smith (1944) proposed that 

 not estrogen itself, but some metabolite re- 

 sulting 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 demon- 

 strated 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 sup- 

 press the secretion of LH. Dempsey (1937) 

 noted that in guinea pigs receiving daily in- 

 jection 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 phe- 

 nomenon has been noted in sheep by Dutt 

 and Casida (1948). Bradbury (1947) re- 

 ported that in immature rats the injection of 

 progesterone at the time of estrogen injec- 

 tion prevented the release of gonadotrophin 

 (LH?) which otherwise followed estrogen 

 injection by 72 to 96 hours. In ovariecto- 

 mized guinea pigs containing intrasplenic 

 autografts, preparations in which luteiniza- 

 tion can be induced by estrogen (see above) , 

 the simultaneous administration of gesta- 

 gens prevented this action (Lipschutz, Ig- 

 lesias, 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 progesta- 

 tional 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- 



