ESTROGEN AND PROGESTERONE 



58.3 



a menstrual cycle (Venning and Browne, 

 1937) suggest that, even in the absence of 

 ovulation, sufficient progesterone may be 

 present to influence menstruation. There 

 also is the possibility of progestational hor- 

 mone from some extra-ovarian source, such 

 as the suprarenal cortex. This was suggested 

 by Zuckerman (1937b, 1941 j as a possible 

 explanation for periodic bleeding in mon- 

 keys on a constant submaintenance dose of 

 estrogen. This thought becomes more plausi- 

 ble in view of the fact that progesterone is 

 one of the precursors in the metabolic syn- 

 thesis of androgens, estrogens, and adrenal 

 cortical steroids (Dorfman, 1956). Also, it 

 has been shown that desoxycorticosterone 

 acetate is converted to progesterone in vivo 

 (Zarrow, Hisaw and Bryans, 1950). There- 

 fore, progesterone is not restricted to ovar- 

 ian luteal function but instead is of rather 

 general occurrence in the body and the 

 likelihood is that small amounts are a con- 

 stant constituent of the blood. 



Also, the amount of progesterone from 

 extra-ovarian sources may fluctuate, as sug- 

 gested by Zuckerman (1949), and conse- 

 quently disturb the normal menstrual 

 rhythm and probably cause bleeding in 

 monkeys on a continuous submaintenance 

 dose of estrogen. However, as to the latter, 

 there is an alternative explanation. Cas- 

 trated monkeys on a continuous treatment 

 of 10 fxg. of estradiol daily do not show 

 "break-through" bleeding, and a synergistic 

 effect on growth of the uterus is seen when 

 0.5 mg. or more of progesterone daily is in- 

 troduced into the treatment. However, the 

 simultaneous administration of 0.25 mg. or 

 even 0.125 mg. progesterone daily in similar 

 exj^eriments results in bleeding between 

 a!)out the 10th to 16th day of the combina- 

 tion treatment. Thus, a dosage of progester- 

 one less than that required for synergism or 

 prevention of bleeding when given alone, 

 modifies the endometrium so that it can no 

 longer be maintained by 10 fxg. estradiol 

 daily (Hisaw, Jr., unpublished). When it is 

 considered that the endometrium becomes 

 increasingly dependent on estrogen during 

 a chronic treatment, even after maximal 

 growth is attained (Hisaw, 1942), it seems 

 plausible that the effectiveness of a dosage 

 of estrogen only slightly alcove the thresh- 



old for bleeding may be decreased suffi- 

 ciently by the endogenous progesterone from 

 extra-ovarian sources to precipitate bleed- 

 ing. 



Although it is obvious that the normal 

 menstrual cycle is primarily under the con- 

 trol of the ovarian estrogens and progester- 

 one, it is also equally clear that menstrua- 

 tion is not due to a specific hormonal action. 

 Experimental evidence indicates that any 

 natural or synthetic compound having the 

 capacity for promoting growth or sustaining 

 an existing metabolic state in the endome- 

 trium is also capable of inducing with- 

 drawal bleeding. However, this does not im- 

 ply that all compounds capable of inducing 

 menstruation do so by the same biochemical 

 action; in fact, there is considerable evi- 

 dence that this is not so (see chapter by 

 Villee). Yet in each instance a series of 

 events is set in motion that leads up to ac- 

 tive bleeding. 



X. The Mechanism of Menstruation 



The immediate cause and mechanism of 

 menstruation has continued to be a topic of 

 special interest for many years and the sub- 

 ject of frequent general discussions. A gen- 

 eralization in keeping with our present 

 knowledge is that no gross morphologic fea- 

 ture of the endometrium is distinctive of 

 menstruation. A menstruating endometrium 

 may be representative of any stage of the 

 follicular or luteal phase of the cycle. The 

 most frequently discussed hypothesis re- 

 garding the mechanism of menstruation is 

 that proposed by Markee (1940, 1946) 

 which is based on direct observations of 

 vascular changes in endometrial grafts in 

 the anterior chamber of the eye of monkeys 

 (see p. 564). The changes observed in the 

 endometrium shortly before bleeding are, 

 briefly, as follows. (1) There is extensive 

 and rapid regression of the endometrium due 

 to loss of ground substance from the stroma 

 (Fig. 9.23). (2) The rapid regression brings 

 about a disproportion between the length of 

 the coiled arteries and thickness of the en- 

 dometrium with the formation of additional 

 coils. (3) The increased coiling of the ar- 

 teries retards the circulation of blood 

 through them and their branches. This stasis 

 begins 1 to 3 davs before the onset of the 



