STEROID SEX HORMONES 



661 



described by Wiest (1956). The conversion 

 occurred when slices of ovary were incu- 

 bated with DPN. Wiest postulated that 

 the progesterone-pregnene-20-a-ol system 

 might play a role in hydrogen transfer, in 

 a manner analogous to that postulated by 

 Talalay and Williams-Ashman (1958) for 

 estrone-estradiol- 17^, but his subsequent 

 experiments ruled out this possibility, for 

 he was unable to demonstrate any pro- 

 gesterone-stimulable transhydrogenation re- 

 action. 



The nature of the effect of progesterone 

 and of estrogens on myometrium has been 

 investigated extensively by Csapo. Csapo 

 and Corner (1952, 1953) found that ovari- 

 ectomy decreased the maximal tension of 

 the myometrium and decreased its content 

 of actomyosin. The administration of estra- 

 diol to the ovariectomized rabbit over a 

 period of 7 days restored both the actomyo- 

 sin content and the maximal tension of the 

 myometrium to normal. The concentration 

 of ATP and of creatine phosphate in the 

 myometrium is decreased by ovariectomy 

 but is restored by only 2 days of estrogen 

 treatment. This suggests that the effect on 

 intermediary metabolism occurs before the 

 effect on protein {i.e., actomyosin) synthe- 

 sis. Csapo (1956a) concluded that estrogen 

 is a limiting substance in the synthesis of 

 the contractile proteins of myometrium, but 

 he could not differentiate between an effect 

 of estrogen on some particular biosynthetic 

 reaction and an effect of estrogen on some 

 fundamental reaction which favors synthe- 

 sis in general. He was unable to demonstrate 

 any comparable effect of progesterone on 

 the contractile actomyosin-ATP system of 

 the myometrium. 



Other observations provide an explana- 

 tion for the well known effect of progester- 

 one in decreasing the contractile activity of 

 myometrium, not by any effect on the con- 

 tractile system itself, but in some previous 

 step in the excitation process. Under the 

 domination of progesterone the myometrial 

 cells have a decreased intracellular concen- 

 tration of potassium ions and an increased 

 concentration of sodium ions (Horvath, 

 1954). The change in ionic gradient across 

 the cell membrane is believed to be respon- 

 sible for the altered resting potential and 

 the partial depolarization of the cell mem- 



brane which results in decreased conductiv- 

 ity and decreased pharmacologic reactivity 

 of the myometrial cell. The means by which 

 progesterone produces the changes in ionic 

 gradients is as yet unknown. Csapo postu- 

 lates that the hormone might decrease the 

 rate of metabolism which in turn would 

 lessen the rate of the "sodium pump" of the 

 cell membrane. The contractile elements, 

 the actomyosin-ATP system, are capable of 

 full contraction but, because of the partial 

 block in the mechanism of excitation and of 

 propagation of impulses (Csapo, 1956b), 

 the muscle cells cannot operate effectively; 

 the contractile activity remains localized. 

 Csapo (1956a) showed that the progesterone 

 block is quickly reversible and disappears if 

 progesterone is withdrawn for 24 hours. He 

 concluded that the progesterone block is 

 necessary for the continuation of pregnancy 

 and that its withdrawal is responsible for 

 the onset of labor. 



]\Iost investigators who have speculated 

 about the mode of action of steroids — 

 whether they believe the effect is by acti- 

 vating an enzyme, by altering the permea- 

 bility of a membrane, or by serving as a 

 coenzyme in a given reaction— have empha- 

 sized the physical binding of the steroid to 

 a protein as an essential part of the mecha- 

 nism of action or a preliminary step to 

 that action. They have in this way explained 

 the specificities, synergisms, and antago- 

 nisms of the several steroids in terms of the 

 formation of specific steroid-protein com- 

 plexes. The differences between different 

 target organs, e.g., those that respond to 

 androgens and those that respond to estro- 

 gens, can be attributed to differences in the 

 distribution of the specific proteins involved 

 in these binding reactions. Viewed in this 

 light, the problem of the mode of action of 

 sex hormones becomes one aspect of the 

 larger problem of the biochemical basis of 

 embryonic differentiation of tissues. 



IV. References 



Allen, W. M. 1939. Biochemistry of the corpus 

 luteum hormone, progesterone. In Sex and 

 Internal Secretions. 2nd ed., E. Allen, C. H. 

 Danforth and E. A. Doisy, Eds., pp. 901-928. 

 Baltimore : The Wilhams & Wilkins Company. 



AsTWOOD, E. B. 1938. A six-hour assay for the 

 quantitative determination of estrogen. En- 

 docrinology, 23, 25-31. 



B.-vcGETT, B., Engel, L. L., Savard, K., .and Dorfman, 



