The history of steroidal contraceptive development: the estrogens.

Abstract

Our understanding of estrogenic activity began in 1912, when Adler and Fellner in Vienna and Iscovesco in Paris obtained the first ovarian extracts and Haberlandt concluded that ovarian interstitial tissue inhibits ovulation during pregnancy, through the 1920s when Fellner produced sterility in rabbits and mice and Allen and Doisy isolated crystalline estrone. By 1930, Reiprich correctly assigned the antifertility action of the estrogens to pituitary inhibition. The testing of estrogenic materials for a variety of gynecological disorders continued in the 1930s, with researchers seemingly unaware of the earlier ovulation inhibition work. In 1936, Kurzrok predicted the prospects for hormonal sterilization in a paper that was largely ignored. Research continued on the use of estrogen to treat dysmenorrhea by inhibiting ovulation. At this point, contraception was not one of the many possible applications of this procedure under consideration. In 1945, Albright identified the potential of ovulation-inhibiting doses of estrogen as a contraceptive. His suggestion was also doomed to oblivion. Since none of the estrogens at that time were consistent in their ovulation-inhibiting effect, clinical trials would have been disastrous. In 1960, clinical trials with the 19-norprogestins took place in Mexico City. The oral contraceptives (OCs) were "contaminated" with mestranol, and research revealed that the ethinyl group has a special role in potentiating gonadotropin-suppressing action. This led to the development of "sequential" OCs, which in turn were replaced by monophasic formulations of lower dosage. By 1975, the dosages were reduced even further. Debates over proper dosage were confounded by the fact that mestranol must be demethylated to become biologically active. It is now known that plasma ethinyl estradiol levels are comparable from a single oral dose of 50 mcg mestranol and from 35 mcg ethinyl estradiol. Current research continues with the 11 beta-methoxy ethinyl estradiol, which is 10 times as potent as ethinyl estradiol and has some unusual metabolic features because it does not form oxidative metabolites.