Comparative activities of compounds of the androsterone-testosterone series.

THE first isolation of a crystalline substance with male hormone properties was carried out by Butenandt [1931], who obtained from male urine a small amount of the substance to which he subsequently gave the name androsterone. Later, he was able to prepare larger quantities and to suggest that the substance was a fully hydrogenated cyclopentenophenanthrene derivative with a hydroxyl group in position 3 and a keto-group in position 17 [Butenandt, 1932; 1933]. Ruzicka et al. [1934] were able to confirm this hypothesis by the chemical preparation of androsterone from epicholestanol, thus determining the configurations of carbon atoms 3 and 5. In the meantime evidence had been accumulating that the male hormone activity of male urine differed quantitatively from that of testicular extracts, notably in its smaller activity per capon unit on the seminal vesicles of castrated rats (see Dingemanse et al. [1935] for refs.), and it was soon evident that androsterone was not the chief active principle of testicular extracts [David and Freud, 1935; Callow and Deanesly, 1935, 1]. The search for other male hormone substances therefore continued. Butenandt and Dannenbaum [1934] had previously isolated from male urine an unsaturated substance closely related to androsterone and having about one-third of its activity, transdehydroandrosterone. Ruzicka was led to believe that the testicular hormone itself, by analogy with progesterone, might be an unsaturated compound related to androsterone [Ruzicka and Wettstein, 1935, 1]; having produced transdehydroandrosterone (A5, 6-trans-3-hydroxy-17-keto-androstene) by degradation of cholesterol, he set about the systematic production of other compounds of the series. While these developments were taking place, David et al. [1935] had obtained from testis a crystalline substance having high activity on both capons and rats, and apparently of sterol type, to which they gave the name testosterone. On the basis of his biological tests of the substances prepared by Ruzicka, Tschopp [1935, 1] was able to suggest that the testosterone of Laqueur and his co-workers might be the androstenedione already prepared by Ruzicka, or possibly the corresponding 17-hydroxy-3-keto-compound. David [1935] then showed that oxidation of testosterone yielded the unsaturated diketo-compound and it seemed certain that testosterone must be A4-17-hydroxy-3-keto-androstene. The next step in this remarkable story was the report by Butenandt and Hanisch [1935, 1, 2] of the artificial production of this compound from dehydroandrosterone and its identification with Laqueur's testosterone. Simultaneously, Wettstein [1935], and soon afterwards Ruzicka and Wettstein [1935, 2], published details of the completion of their projected synthesis of A4-17-hydroxy-3-keto-androstene.