582 



PHYSIOLOGY OF GONADS 



suggestion is that the animal is physiologi- 

 cally deprived of estrogen and literally de- 

 prived of progesterone (Corner, 1951). Al- 

 though this view is in descriptive agreement 

 with the observed facts the idea of the in- 

 hibitory effect of progesterone does not take 

 into consideration the synergistic interac- 

 tion of the two hormones on the endome- 

 trium. 



The physiologic function of progesterone 

 is the conversion of an estrogen-endome- 

 trium into a progestational endometrium 

 suitable for receiving and nourishing a de- 

 veloping blastocyst. Such an endometrium 

 is adapted for this specific reproductive 

 function and accordingly its physiologic na- 

 ture must be quite different from that of the 

 follicular phase of the cycle. Indeed, it is 

 known that these two structures (follicular 

 and luteal phase endometrial are morpho- 

 logically and biochemically unlike in a num- 

 ber of respects. This gradual transformation, 

 following ovulation, occurs as progesterone 

 becomes the dominant hormone, and conse- 

 quently, as this proceeds, the endometrium 

 progressively loses competence to respond 

 to estrogen. However, this does not imply 

 that estrogen is without effect in the general 

 economy of the progestational endometrium. 

 It has been shown in a number of ways that 

 the action of progesterone on the primate 

 endometrium is greatly facilitated by the 

 presence of estrogen. In fact, it seems prob- 

 able that rarely if ever does progesterone 

 perform its function in the absence of estro- 

 gen (Hisaw, 1959; chapter by Zarrow). 



After consideration of the endometrial 

 specializations brought about by ]irogester- 

 one, it seems rather jwintless to hark back 

 to the follicular phase and inject the past 

 recoi'd of accomjilishments and prerogatives 

 that estrogen had at that time into tlie ex- 

 planation of an entirely different hormonal 

 situation. It seems more in keeping with the 

 facts to state outright that menstruation 

 following the involution of a corpus luteum 

 or the discontinuance of progesterone, even 

 though estrogen is present, is due to a de- 

 crease or absence of progesterone. 



It also has become less certain that men- 

 struation at the conclusion of an anovula- 

 tory cycle is really an estrogen-withdrawal 

 bleeding. This is possible, of couisc, but at 



the same time the exceedingly small amount 

 of progesterone required to induce bleeding 

 in the presence of estrogen makes it difficult 

 to be sure what the situation might be. Even 

 a negative test for progesterone in the blood, 

 by our present methods, does not necessarily 

 indicate the absence of a physiologically ef- 

 fective amount of progesterone. Zarrow, 

 Shoger and Lazo-Wasem (1954) found that 

 in rabbits an intramuscular injection of 40 

 mg. progesterone was required to produce 

 an appreciable concentration of the hor- 

 mone in the blood as determined by the 

 Hooker-Forbes method. Yet, 0.2 mg. pro- 

 gesterone daily for 5 days will produce a 

 progestational reaction in the uterus equiva- 

 lent to that of the 5th day of normal pseudo- 

 pregnancy. In monkeys 0.5 mg. daily when 

 given with 10 fxg. estradiol is an adequate 

 dosage of progesterone to induce unques- 

 tionable progestational changes in the en- 

 dometrium and much less will cause bleed- 

 ing. These observations indicate that the 

 minimal effective concentration of proges- 

 terone in the blood may be less than is pos- 

 sible to detect by our present methods. 



This also seems to hold for the human be- 

 ing. Estimates of secretion and metabolism 

 of progesterone in the human being have 

 been based primarily on the recovery of its 

 excretory product sodium pregnanediol glu- 

 curonidate in the urine. It seems obvious 

 that such determinations must be only gen- 

 eral approximations because only about 20 

 per cent of the progesterone secreted or in- 

 jected can be accounted for by the pregnane- 

 diol in the urine. Also, it is generally known 

 that a physiologically effective dosage of 

 progesterone does not necessarily lead to the 

 excretion of pregnanediol (Hamblen, Cuylcr, 

 Powell, Ashley and Baptist, 1939; Seegar, 

 1940). In other words, the threshold dose of 

 progesterone for endometrial stimulation is 

 l)elow that at which the hormone is excreted 

 as pregnanediol. In fact, it has been sug- 

 gested by some investigators that there is 

 no quantitative relationship between the 

 l)rogesterone present in the blood and the 

 pregnanediol excreted in the urine (Buxton, 

 1940; Sommerville and Marrian, 1950; 

 Kaufmann, Westphal and Zander, 1951). 



These findings and the wide variation in 

 the amount of prc'gnancdiol excreted during 



