518 



PHYSIOLOGY OF GONADS 



denceinmice (Solve,, 1939) that siippreijsion 

 of FSH secretion may occur when as much 

 as 1 mg. of progesterone is injected daily. 

 Alloiteau ( 1954 ) believes that this also oc- 

 curs in the rat, although Cutuly (1941b) 

 found only slight evidence of FSH suppres- 

 sion when as much as 6 mg. progesterone 

 were given daily for several weeks. 



So much emphasis has been placed on the 

 suppressing effect of progesterone that its 

 facilitating actions were recognized only in 

 recent years. The first indication that pro- 

 gesterone can promote ovulation and corpus 

 luteum formation in mammals was encoun- 

 tered in a study of persistent-estrous rats 

 (Everett, 1940a, b). Daily injection of 0.25 

 to 1.0 mg. caused the prompt interrujition 

 of the state of persistent follicle and the re- 

 sumption of outwardly normal cycles. Cor- 

 jiora lutea were formed in approximately 

 70 per cent of these cycles.^ The effect was 

 obtained not only in older rats in which 

 persistent estrus had developed spontane- 

 ously, but also in young rats in which the 

 condition had been induced by continuous 

 illumination. The dose level employed is be- 

 low that required to suppress cycles in nor- 

 mal rats (1.5 mg. daily; Phillips, 1937). 

 Subsequently, it was found (Everett, 1943) 

 that the daily injection could be avoided if 

 a single "interrupting" dose was given, fol- 

 lowed by a single injection during proestrum 

 or early estrus of each recurrent cycle (Fig. 

 8.9.4). The histologic appearance of the 

 ovaries reverted toward the normal after a 

 succession of "i)rogesterone cycles" and, sig- 

 nificantly, the interstitial-cell nuclei were 

 "repaired." Attempts in normal rats to in- 

 voke o\'u]ati()n earliei' than the expected 

 time were sticcessful in the 5-day cycle 

 (Figs. S.7B, 8.8^). Injection of from 0.5 mg. 

 to 2 mg. on the "third day of diestrum" reg- 

 ularly (4 mg. occasionally) invoked ovula- 

 tion (luring the coming night (Everett, 

 1944a, 1948) unless the treatment was given 

 too late in the dai/ (EA'erett and Sawyer, 

 1949; see discussion on ]). 526 I'egarding the 

 diurnal rhythm and ovulation). Attempts 

 to advance ovulation in the 4-day cycle 

 were unsuccessful, possibly because the fol- 

 licles were not competent or the animals' 



''Marvin (1947) described a similar rosull willi 

 desoxycorticosterone acetate. 



intrinsic estrogen levels were not elevated 

 sufficiently early. 



Ovulation induced by progesterone has 

 been reported in several species. A direct 

 action on the excised ovary of the toad 

 Xeno-pns was early demonstrated by Zwar- 

 enstein (1937) but such action is apparently 

 not found in higher vertebrates. In the do- 

 mestic hen injection of progesterone can 

 invoke ovulation several hours ahead of 

 schedule (Fraps and Dury, 1943; Rothchild 

 and Fraps, 1949). Pfeiffer (1950) observed 

 new corpora lutea in 10 rhesus monkeys 

 treated with progesterone during presump- 

 tive anovulatory cycles of the summer 

 months. Similar attempts have been made in 

 women (Rothchild and Koh, 1951); al- 

 though there were said to be definite indi- 

 cations of induced ovulation, the evidence 

 is equivocal. On the other hand, a rei~)ort 

 (Hansel and Trimberger, 1952) states that 

 in heifers the injection of small doses of pro- 

 gesterone (5 to 10 mg. ) at the beginning of 

 estrus significantly advances ovulation time. 

 This is in contrast with the inhibitory effect 

 of larger doses (50 mg.) beginning before 

 the onset of estrus (Ulberg, Christian and 

 Casida, 1951). Even in the rabbit (Sawyer, 

 Everett and Markee, 1950), spontaneous 

 ovulation was noted in 4 of 10 animals after 

 combined estrogen and progesterone injec- 

 tion. 



From certain of the foregoing statements 

 it may be inferred that whether suppression 

 or stimulation follows administration of 

 ju-ogestcrone depends critically on the time 

 of injection, on the amount given, on tlie 

 status of the ovary, and probal)ly on a 

 l)riming action of estrogen. A significant il- 

 lustration of the critical nature of the time 

 factor in rats is given by the experiments 

 represented in Figure 8.8r and E. If after 

 the first injection of 1.5 mg. progesterone 

 on the first day of diesti'uni, a second injec- 

 tion follows in. about 24 lioui's. the imjiend- 

 ing estrus and o\-ulation are retarded an 

 additional 24 hours. However, if the second 

 injection is given 48 hours after the first, 

 tlie impending estrus and ovulation are ad- 

 vanced. Evidence^ of the synergistic action 

 of estrogen and progesterone in evoking 

 oA'ulation is given by tlie ex]ieriments repre- 

 sented in Figuiv 8.9/> and (\ Sawver (1952) 



