THE ANTIGONADOTROPIC ACTIVITY OF PROGESTINS (19-NORTESTOSTERONE AND 19-NORPROGESTERONE DERIVATIVES) IS NOT MEDIATED THROUGH THE ANDROGEN RECEPTOR

To further study the mechanism of the antigonadotropic activity of pro gestins, the effects of a 19-nortestosterone derivative, norethisteron e acetate (NETA), and a 19-norprogesterone derivative, no-megestrol ac etate (NOMA), were compared. The aim was to assess whether their actio n is exerted via the androgen receptor. Ten healthy postmenopausal wom en were treated for five monthly periods of 24 days separated by 10 da ys in a randomized cross-over design. Transdermal estradiol, Estraderm TTS (25 mu g; one patch every 3 days), was given from days 1-24 durin g the five periods. On the last 12 days, of each estradiol treatment, they all received a placebo, NOMA (5 mg/day), NOMA in association with the nonsteroidal antiandrogen, flutamide (FLU; 250 mg, twice a day), NETA (10 mg/day), or NETA plus FLU. On the other hand, three castrated patients with complete androgen insensitivity (CAI) received NOMA and NETA for two periods of 12 days separated by 3 weeks. In postmenopaus al women, the effects of NOMA and NETA on metabolic parameters were st udied. Only NETA decreased high density lipoprotein cholesterol. Plasm a LH, FSH, and estradiol were measured during each treatment period. A significant decrease in mean plasma LH and FSH levels and their respo nses to exogenous GnRH was observed with NOMA and NETA treatments comp ared to placebo (P <0.001). The pulsatile frequency, but not the ampli tude, of LH was significantly decreased during both treatments. Intere stingly, the effects of both progestins on gonadotropins were not anta gonized by FLU administration. In the patients with CAI, the pulsatile study of gonadotropins was performed before and on day 12 of NOMA and NETA treatments. As in postmenopausal women, both progestins induced similar decreases in LH and FSH. In conclusion, a 19-nortestosterone d erivative, NETA, and a 19-norprogesterone derivative, NOMA, have simil ar antigonadotropic activities. This effect, not antagonized by FLU an d observed in patients with CAI, is not mediated via the androgen rece ptor. The absence of deleterious effects of 19-norprogesterone derivat ives on metabolic parameters should favor the therapeutic use of these compounds.