Correlation of aromatic hydroxylation of 11 beta-substituted estrogens with morphological transformation in vitro but not with in vivo tumor induction by these hormones.

In estrogen-induced cancer, catechol formation from administered steroids has been postulated to be a necessary event for estrogen activation and subsequent damage to cellular macromolecules. In the present study, this hypothesis has been tested using two homologous series of structurally related estrogens: estradiol, 11 beta-methylestradiol, 11 beta-ethylestradiol, 11 beta-methyl-17 alpha-ethinylestradiol, 11 beta-ethyl-17 alpha-ethinylestradiol, 11 beta-methoxy-17 alpha-ethinylestradiol, and 17 alpha-ethinylestradiol. In the Syrian hamster renal carcinoma model, only 11 beta-methylestradiol and 17 alpha-ethinylestradiol were weak carcinogens (2 of 20 and 2 of 24 hamsters with tumors, respectively). The other estrogens tested induced renal carcinoma within 6 to 9 months with an incidence in the 80-100% range. The tumor incidence in vivo did not correlate with the rates of catechol formation by hamster kidney microsomes in vitro. Compared to estradiol (relative rate, 100), catechol formation by the substituted estrogens was significantly lower, ranging from 48 (11 beta-methylestradiol) to 2 (11 beta-methoxy-17 alpha-ethinylestradiol). Kidney DNA of hamsters treated with the four 17 alpha-ethinyl estrogens, when analyzed by 32P postlabeling assay, contained the same set of covalently modified nucleotides the formation of which had previously been found to precede estrogen-induced renal carcinogenesis in vivo. In contrast, relative rates of catechol estrogen formation by BALB/c 3T3 microsomes correlated with induction of morphological transformation of BALB/c 3T3 cells and decreased in the following order: 11 beta-methylestradiol greater than 17 alpha-ethinylestradiol greater than or equal to estradiol greater than 11 beta-ethylestradiol greater than 11 beta-methoxy-17 alpha-ethinylestradiol. The hormonal potencies of several estrogen derivatives studied by various assays did not correlate with in vivo carcinogenic or in vitro cell-transforming activities. It is concluded from these experiments that in cell culture catechol formation and morphological transformation are directly related. In vivo, aromatic hydroxylation of administered estrogens did not correlate with the incidence of estrogen-induced renal carcinoma in Syrian hamsters.

Steroids and "the pill": early steroid research at Searle.

The announcement from the Mayo Clinic in 1949 of the dramatic effectiveness of cortisone in the treatment of rheumatoid arthritis stimulated tremendous interest in steroid chemistry, endocrinology, and related areas of medicine. Shortly thereafter, G. D. Searle & Co. initiated a major effort in steroid research, the objective of which was to discover better steroid drugs than those available at that time or steroids that could be used for conditions for which no compounds were previously available. This effort was remarkably successful and resulted in the introduction of several important pioneering drugs. These included norethandrolone, marketed in 1956 as Nilevar, the first anabolic agent with a favorable separation between protein building and virilization, and spironolactone, introduced in 1959 as Aldactone, the first steroid antialdosterone antihypertensive agent. Of special importance was the research that culminated in the discovery of Enovid. This substance, a combination of the progestin norethynodrel and the estrogen mestranol was first approved in 1957 for the treatment of a variety of disorders associated with the menstrual cycle. The era of oral contraception began in May 1960, when Enovid was approved by the Food and Drug Administration for ovulation inhibition, and was immediately thereafter introduced for such use.