5-ALPHA-REDUCTION OF NORETHISTERONE ENHANCES ITS BINDING-AFFINITY FORANDROGEN RECEPTORS BUT DIMINISHES ITS ANDROGENIC POTENCY

Norethisterone (NET), a 19-nor synthetic progestin, undergoes enzyme-m ediated Sec-reduction and exerts potent androgenic effects in target o rgans. To investigate its mode of androgenic action we examined, in a comparative manner, the in vitro metabolism of NET and testosterone (T ), as well as the binding affinities to androgen receptors (AR) and th e androgenic potency of NET, T, and their Sec-reduced derivatives. Bio conversion of [H-3]-NET and [H-3]-T was studied in rat prostate homoge nates, AR binding affinity was assessed in rat ventral prostates using [H-3]-mibolerone as the radioligand, and the androgenic potency was e valuated by the increase of beta-glucuronidase activity in the mouse k idney, and by the growth of accessory sex organs in castrated male rat s. The results demonstrated that Sec-NET displayed a higher AR binding affinity but a significantly lower androgenic potency than unchanged NET. The bioconversion studies indicated that the metabolism of NET wa s similar to that of T, although to a lesser extent, thus ruling out t he possibility that the synthetic progestin metabolizes rapidly into l ess active derivatives. To investigate the nature of the paradoxical e ffect of 5 alpha-reduction upon the NET molecule, the interaction with AR and the androgenic potency of T, 19-nortestosterone (19norT), 17 a lpha-ethynyl testosterone (ET) and their 5 alpha-reduced derivatives w ere examined. The results of AR binding studies revealed that 5 alpha- reduction of T and ET significantly enhanced their affinities, and tha t the Sec-derivative of 19norT displayed a similar binding affinity to that exhibited by 19norT. In terms of biological activity, the result s showed that Set-reduction of T and 19norT significantly increased th eir androgenic potency, whereas 5 alpha-reduction of ET resulted in a significant diminution of its androgenicity in a manner similar to tha t observed with the Sec-reduction of NET. When NET and 19norT were sim ultaneously administered with 5 alpha-dihydrotestosterone they exhibit ed a potent synandrogenic activity, an effect that was cancelled by th eir 5 alpha-reduction. Interestingly, ET displayed an antiandrogenic a ctivity, an effect that was also suppressed by its 5 alpha-reduction. The overall results demonstrated a distinctive, paradoxical effect of Sec-reduction upon the NET molecule, which was different from that see n in naturally occurring androgens, and which suggests that the presen ce of the 17 alpha-ethynyl group plays a key role in this phenomenon. The data provided further evidence that the metabolism of synthetic co ntraceptive progestins modulates the expression of their hormone-like actions. (C) 1997 Elsevier Science Ltd.