To further study the mechanism of the antigonadotropic activity of
progestins, the effects of a
19-nortestosterone derivative,
norethisterone acetate (NETA), and a
19-norprogesterone derivative,
nomegestrol acetate (
NOMA), were compared. The aim was to assess whether their action is exerted via the
androgen receptor. Ten healthy postmenopausal women were treated for five monthly periods of 24 days separated by 10 days in a randomized cross-over design. Transdermal
estradiol,
Estraderm TTS (25 micrograms; one patch every 3 days), was given from days 1-24 during 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 postmenopausal women, the effects of
NOMA and NETA on metabolic parameters were studied. Only NETA decreased
high density lipoprotein cholesterol. Plasma LH, FSH, and
estradiol were measured during each treatment period. A significant decrease in mean plasma LH and FSH levels and their responses to exogenous
GnRH was observed with
NOMA and NETA treatments compared to placebo (P < 0.001). The pulsatile frequency, but not the amplitude, of LH was significantly decreased during both treatments. Interestingly, the effects of both
progestins on
gonadotropins were not antagonized 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 derivative, NETA, and a
19-norprogesterone derivative,
NOMA, have similar antigonadotropic activities. This effect, not antagonized by FLU and observed in patients with CAI, is not mediated via the
androgen receptor. The absence of deleterious effects of
19-norprogesterone derivatives on metabolic parameters should favor the
therapeutic use of these compounds.