ESTROGEN AND PROGESTERONE 



581 



after it is administered. It seems more lilvely 

 that progesterone modifies the sexual skin 

 in a way that renders it unresponsive to es- 

 trogen and that about a fortnight is required 

 to recover the original condition. 



This takes on added significance when the 

 possibility is considered that effects similar 

 to those seen in the sexual skin might also 

 be going on simultaneously in the uterine 

 endometrium. An appreciable dehydration 

 of the endometrium occurs just previous to 

 menstruation (van Dyke and Ch'en, 1936) 

 and a loss of interstitial fluid before bleed- 

 ing has been observed in endometrial im- 

 plants in the eyes of monkeys and described 

 in detail by Markee (1940) . This was shown 

 by periodic regression in size and compact- 

 ness of the grafts which resulted in a de- 

 crease in area of 25 to more than 75 per 

 cent. Because cyclic changes in endometrial 

 grafts in the eye are correlated with events 

 of the menstrual cycle there is reason to be- 

 lieve that similar reactions were going on 

 in the endometrium of the uterus. 



Endometrial regression, as described by 

 Markee, did not always lead to menstrua- 

 tion although it invariably preceded, accom- 

 panied, and followed menstrual bleeding. 

 Menstruation occurred only when regression 

 was rapid and extensive. This was seen in 

 the endometrial grafts in the eye during a 

 normal menstrual cycle at the time of in- 

 volution of a corpus luteum and during an 

 anovulatory cycle soon after the involution 

 of a large follicle. It also begins soon after 

 the last of a series of injections of estrogen 

 or i^'ogesterone. A slow decrease in size of 

 the ocular grafts, without concomitant 

 bleeding, can be induced in castrated mon- 

 keys by gradual withdrawal of estrogen, 

 and when estrogen is given in amounts that 

 are inadequate for maintaining the endome- 

 trium for an extended period the "break 

 through" bleeding that eventually ensues is 

 preceded by a rapid and extensive endome- 

 trial regression. Because this reaction also 

 occurs w^hen menstruation is induced by such 

 an unusual procedure as spinal transection 

 (Markee, Davis and Hinsey, 1936), it prob- 

 ably is a phenomenon that always precedes 

 menstruation. 



It seems from these observations that the 

 changes in the endometrium preceding men- 

 struation are initiated by a sudden with- 



drawal of a stimulus on which the endome- 

 trium at the time relies for the maintenance 

 of a particular physiologic condition, and 

 bleeding and tissue loss are incidents that 

 occur during the readjustment necessary for 

 the return to an inactive state. What this in- 

 volves is only partly known, but an under- 

 standing of the initial changes in the endo- 

 metrium that usher in menstruation most 

 certainly holds the explanation of the real 

 cause. This has been a perennial subject for 

 discussion and many suggestions and the- 

 ories have been set forth in an extensive 

 literature to account for various aspects of 

 menstruation. Among the more recent gen- 

 eral discussions are those by Zuckerman 

 (1949, 1951), Corner (19511, and Zondek 

 ( 1954 ) . 



The estrogen- withdrawal or estrogen-de- 

 privation theory proposed by Edgar Allen 

 has received more attention than any other. 

 From what has been mentioned earlier it is 

 clear that this theory can account for uter- 

 ine bleeding subsequent to the discontinu- 

 ance of a series of estrogen injections and 

 also perhaps menstruation at the conclusion 

 of an anovulatory cycle. However, it is not 

 so obvious as to how this theory can explain 

 the occurrence of menstruation at the close 

 of the luteal phase of a normal cycle. Estro- 

 gen in large doses will not inhibit such 

 bleeding, but it is postponed if progesterone 

 is given. It is equally difficult to see how this 

 theory is helpful in accounting for the fact 

 that a small dose of progesterone will pre- 

 cipitate bleeding in the presence of a main- 

 tenance dosage of estrogen. As little as 2 

 /xg. progesterone will induce bleeding when 

 applied topically to the endometrial lips of 

 an exteriorized uterus (Fig. 9.7) in a mon- 

 key that is receiving 10 fig. estradiol daily 

 (Hisaw, 1950). 



Uterine bleeding precipitated by admin- 

 istering progesterone during an estrogen 

 treatment has been explained on the grounds 

 that progesterone in some way interferes 

 with the action of estrogen on the endome- 

 trium. Therefore, it is assumed that an ani- 

 mal receiving both estrogen and progester- 

 one is in a sense "deprived" of estrogen. 

 That is, when the two hormones are given 

 simultaneously, progesterone itself is capa- 

 ble of maintaining the endometrium with- 

 out bleeding; but when it is stopped, the 



