580 



PHYSIOLOGY OF GONADS 



man, 1937; Engle and Smith, 1939; Duncan, 

 Allen and Hamilton, 1941) and inhibit pro- 

 gesterone-withdrawal bleeding as well (En- 

 gle and Smith, 1939). Testosterone also will 

 precipitate bleeding during an estrogen 

 treatment (Hisaw, 1943) and in normal 

 monkeys if given early in the cycle (Krohn, 

 1951). Just what specific action these com- 

 pounds have in common that enables them 

 to produce these effects or whether there are 

 different modes of action that lead to the 

 same results is not known, but, before men- 

 tioning certain possibilities, it may be help- 

 ful to consider information regarding the 

 influence of estrogen-progesterone interac- 

 tions on menstruation. 



Among the most significant observations 

 regarding primary causes of menstruation 

 are a few indications that there may be an 

 intrinsic difference in the ways in which es- 

 trogen and progesterone produce their ef- 

 fects on the endometrium. One of the first 

 indications of this was the discovery that a 

 short series of injections of progesterone 

 during treatment with estrogen will precipi- 

 tate menstruation (Corner, 1937; Zucker- 

 man, 1937d; Hisaw and Greep, 1938). This 

 can be demonstrated by giving a castrated 

 monkey a maintenance dose of estrogen 

 daily for 2 or 3 weeks, then adding a daily 

 injection of progesterone for 5 to 10 days 

 and continuing the estrogen treatment. As 

 a rule bleeding appears within 2 or 3 days 

 after stopping progesterone. The most in- 

 teresting point brought out by such experi- 

 ments is that bleeding can occur under these 

 conditions in the presence of an otherwise 

 maintenance dosage of estrogen. 



Perhaps the most surprising as well as 

 most important fact brought out by subse- 

 quent experiments was the small amount of 

 progesterone required to bring about bleed- 

 ing under these conditions. It was found that 

 only a single injection of 1 mg. was required 

 for animals on chronic treatment with a 

 maintenance dose of estradiol (1000 LIT.) 

 and some bled when 0.5 mg. progesterone 

 was given (Hisaw, 1942). The sequence of 

 events following the injection of progester- 

 one can be seen to best advantage in an 

 adolescent monkey whose sexual skin also 

 respond" to the estrogen treatment. When 

 the 1 mg. ]irogesterone is given on the 20th 

 day of estrogen treatment the edema of th(^ 



sexual skin will have attained its maximal 

 development. The first indication of an ef- 

 fect of progesterone is a slight loss of edema 

 and color of the sexual skin which appears 

 on the 4th or 5th day and by the 9th or 10th 

 day the edema is almost gone and the sexual 

 skin is pale. Blood apjiears in the vaginal 

 lavage between the 7th and 10th days, of 

 about 70 per cent of the animals on this dos- 

 age. The sexual skin may remain markedly 

 reduced and pale until about the 15th day 

 after which both color and edema rapidly 

 return. These effects can also be seen when 

 1 mg. progesterone is given for a series of 

 days. However, neither the time of appear- 

 ance nor loss of edema of the sexual skin is 

 significantly hastened, and if the injections 

 extend over no more than 5 days the time 

 between the first injection and bleeding re- 

 mains approximately the same. 



Similar observations have been made by 

 Gillman and Smyth (1939) on the South 

 African baboon iPapio porcarius). They 

 found that 3 mg. or more of progesterone 

 when given in a single injection during the 

 follicular phase of the cycle would cause 

 the relatively enormous perineal swellings 

 to pass rapidly through deturgescence and 

 reach a flabby resting condition within 5 to 

 7 days, and after a delay of about 24 hours 

 once again begin to swell. As much as 10 or 

 15 mg. in a single dose caused perineal de- 

 turgescence without bleeding, whereas 20 

 mg. in a single dose or a total of 15 mg. if 

 divided into 2 or 3 injections and given at 

 3 or 4 day intervals, produced both detur- 

 gescence and bleeding (Gillman, 1940b). 

 The l)aboon diff"ers from the monkey in that 

 larger doses of progesterone are required to 

 produce the effects and the sexual skin does 

 not ''mature" on repeated treatments and 

 lose its responsiveness; otherwise the basic 

 physiology of the reaction in both animals 

 seems to be the same. 



The most important fact l)rought out by 

 these experiments is that the effects of a 

 single injection of progesterone can continue 

 in the presence of estrogen for as long as 10 

 to 15 days. It is highly imi^robable that pro- 

 gesterone lingers in the body for so long a 

 time (Zarrow, Shoger and Lazo-Wasem, 

 1954). In general it is considered the most 

 ephemeral of the sex steroids and is prob- 

 ablv inactivated within at least a few hours 



