The metabolism of 19-nor contraceptive progestins modulates their biological activity at the neuroendocrine level.

In this communication, a series of studies from our laboratory dealing with the mechanism of action of 17 alpha-ethinyl derivatives of 19-nor testosterone are reviewed. The administration of norethisterone (NET) to long-term castrated female rats induces the nuclear translocation of pituitary estradiol receptors and is followed by some estrogenic-like effects at the hypothalamic-pituitary unit. It is established that an A-ring reduced metabolite of NET, the 3 beta,5 alpha-tetrahydro NET derivative, is responsible for the observed in vivo estrogenic effects of the parent compound. 3 beta,5 alpha-NET binds to the estrogen receptor and is efficient in inducing the pituitary estrogen-dependent progesterone receptor and in increasing the uterine weight in long-term castrated rats. Furthermore, administration of 3 beta,5 alpha-NET and the 5 alpha-reduced metabolite of NET (5 alpha-NET) are able to inhibit the release of gonadotropins in the castrated animal to a greater extent than NET. Moreover, pretreatment with tamoxifen, an estrogen binding site competitor, results in a significant diminution of the antigonadotropic potency of 3 beta,5 alpha-NET but not of the 5 alpha-NET, which is only inhibited by the administration of cyproterone acetate. These findings underline the importance of the metabolic rate of NET for the expression of its biological effects at the hypothalamic-pituitary unit.