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THE HISTORY OF STEROIDAL CONTRACEPTIVE DEVELOPMENT: THE ESTROGENS JOSEPH W. GOLDZIEHER* While one group of veterinarians and biologists was exploring the endocrinology of the corpus luteum, others were looking at the biological activity of ovarian tissue itself. As early as 1912, Adler [1] and Fellner [2] in Vienna, and Iscovesco [3] in Paris, obtained ovarian extracts that gave evidence of estrogenic activity. By 1921, Fellner [2] reported that lipid extracts of pregnant cows' ovaries had potent estrogenic effects. Haberlandt [3], aware of these findings, concluded that ovarian interstitial tissue also functions in pregnancy to inhibit ovulation. He was, of course, unaware that he was dealing with a hormone different from that found in his extracts of corpus luteum tissue. Some years later, Fellner published additional experiments [4] in which injectable extracts and an orally active material (he named it "Feminin") produced sterility in rabbits [5] and mice. By 1927 [4] he concluded that these extracts had different effects at different doses (now a known property of estrogens ) and that they prevented pregnancy by destruction of ova and by inhibition of corpus luteum formation. The breakthrough in the study of estrogenic substances came when Aschheim and Zondek [6] discovered the assay based on an estrus reaction in the immature mouse or rat. With this assay it became apparent that urine was a better starting material than tissue extract. Both Butenandt [7] and the Allen/Doisy team [8] started work in late 1927 and strove neck-and-neck for nearly two years. Then, in the fall of 1929 the latter team announced the isolation of crystalline estrone. By 1933 estrone had been converted to estradiol, and two years later Doisy showed that this, too, was a physiological substance; experiments with defined materials became possible. By 1930, Reiprich [9] in Breslau suggested that the antifertility action of the estrogens might be brought about by pituitary inhibition. Thus, by this early date, the concept of contracep- *Address: 1303 McCullough, #626, San Antonio, Texas 78212.© 1993 by The University of Chicago. All rights reserved. 0031-5982/93/3603-0825101.00 Perspectives in Biology and Medicine, 36, 3 ¦ Spring 1993 363 tion with sex steroids had not only been explicitly enunciated, but a mechanism of action had been correctly inferred. As soon as estrogenic materials became clinically available, they were tested in a wide variety of gynecological disorders. None of these clinicians gave any evidence of being aware of the work of Adler or Fellner, whose estrogenic extracts inhibited ovulation in rodents. However, at the Conference on Contraceptive Research and Clinical Practice, held in New York in December 1936, Kurzrok [10] presented a paper entitled "The Prospects for Hormonal Sterilization." He was apparently unaware of Haberlandt's work and of information on the antiovulatory activity of the corpus luteum and its hormone. He did mention that estrone, by inhibiting ovulation, was a possible modality for hormonal sterilization, and concluded with the opinion that "the potentialities of hormonal sterilization are tremendous." Like Haberlandt, he was ignored . In 1938 Wilson and Kurzrok [11] observed that the complaint of (functional) dysmenorrhea signified ovulation, for it occurred only in patients with a functioning corpus luteum. This led other gynecologists to explore ovulation inhibition as a treatment for dysmenorrhea, and in 1940 Sturgis and Albright [12] in Boston reported that frequent injections of estradiol benzoate prevented dysmenorrhea when ovulation was successfully inhibited. Of 65 patients treated for this complaint, 63 were relieved. In the same year, Karnaky [13] in Houston "produced a physiologic sterility" with a continuous regimen of 10 to 25 mg stilbestrol daily. In 1941 Gillman [14] in Johannesburg was also making observations on the inhibition of ovulation with estradiol in baboons. Although many possible applications of these findings were considered , contraception was not among them. Nor was this possibility mentioned in two subsequent communications by Sturgis in 1942. He did, however, confirm Hartman's original observations of the importance of initiating estrogen therapy early in the cycle if ovulation were to be inhibited. Other reports on estrogen treatment for dysmenorrhea—by Hamblen, Goldzieher, and associates in 1943 [15] and 1947 [16], and by Lyon [17] (who used ethinyl estradiol) in 1943, also made no mention of contraception, a...