MAMMALIAN REPRODUCTIVE CYCl.E 



515 



B 



12 3 4 5 



12 3 4 5 



Fig. 8.7. Experimental modifications of the 5-day cycle in rats. Two units of the ordinate 

 represent full vaginal estrus. Time in days on abscissa, each unit 24 hours (midnight to mid- 

 night). X, ovulation time; -p, progesterone, usually 1 to 2 mg.; e, estradiol benzoate, standard 

 do.se 50 /xg. (From J. W. Everett, Endocrinology, 43, 393, 1948.) 



strates the existence of strain differences in 

 the age factor. This probably explains the 

 absence of luteinization in the experience of 

 Lane (1935) and Merckel and Nelson 

 (1940). Hohlweg and Chamorro (1937) 

 demonstrated the importance of the hy- 

 pophysis in the response. When hypophysec- 

 tomy was performed 2 days after injection 

 of estrogen no corpora liitea developed, but 

 hypophysectomy on the 4th day did not in- 

 terfere with corpus luteum formation. The 

 effect could be produced in 50-gm. rats with 

 as little as 4 |U,g. estradiol benzoate. West- 

 man and Jacobsohn (1938b) reported that 

 transsection of the hypophyseal stalk less 

 than 2Vt days after injection prevented the 

 reaction, but after that time the operation 

 did not interfere. Bradbury (1947) assayed 

 the gonadotrophin content of hypophyses of 

 normal and castrated immature rats (30 to 

 32 days old at autopsy) 2 to 5 days after 

 injection of estrogen or other steroids. These 

 rats were apparently too young to form 

 corpora lutea in response to the treatment, 

 l)ut marked interstitial-cell stimulation, in- 

 dicative of LH (ICSH) activity, was ob- 

 served as early as 96 hours. In the intact 

 animals significant loss of potency occurred 

 72 to 96 hours after injection, in agreement 

 with the hypophysectomy data of Hohlweg 

 and Chamorro (1937). In castrated rats, 

 however, there was no loss of potency, thus 

 suggesting that some ovarian factor in addi- 

 tion to estrogen is essential for stimulation 

 of the hypophysis. It is unfortunate that the 

 study was confined to animals too young to 

 give the full response of luteinization. 



Induction of ovulation in adult animals 

 by estrogen was first reported by Hammond, 

 Jr., Hammond and Parkes (1942) and by 

 Hammond, Jr. (1945) in the anestrous ewe. 

 Whereas the s])ontaneous occurrence of oc- 

 cult ovulation was approximately 5 per 

 cent, injection of stilbestrol was followed by 

 corpus luteum formation in 4 of 11 ewes, 

 with recovery of ova in 3. Injection of stil- 

 bestrol di-n-butyrate was followed by cor- 

 pus luteum formation in 5 of 6 ewes and ova 

 were recovered in 3. The finding was con- 

 firmed by Casida (1946) who stated that in 

 cycling ewes ovulation can be invoked by 

 injection of diethylstilbestrol on the 4th day 

 of the cycle, but not at other times. In 1947 

 Everett reported the induction of ovulation 

 in pregnant rats within 40 hours after injec- 

 tion of estradiol benzoate (as little as 2 or 

 3 /xg.) or implantation of estradiol crystals 

 or pellets. The response was not obtained in 

 animals autopsied 24 hours after treatment 

 nor in other animals hypophysectomized at 

 24 hours and autopsied the following day. In 

 other studies with adult rats it was demon- 

 strated (Everett, 1948) that in 5-day cyclic 

 rats the injection of estrogen at mid-dies- 

 trum will regularly induce ovulation 24 

 hours earlier than exi:)ected (Figs. 8.7D, 

 8.8F|. Persistent-estrous rats were refrac- 

 tory to estrogen in this respect.- Neverthe- 

 less, when such animals were made pseudo- 

 pregnant by daily injection of progesterone, 



"The tendency toward refractoriness of similar 

 animals with respect to induction of estrous 1) - 

 ha\'ior had earlier been reported by Boling, 

 Blandau, Rundlett and Young (1941). 



