The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women

We have previously shown in postmenopausal women that a 19-nor-progesterone derivative, nomegestrol acetate (NOMA) had a strong antigonadotropic activ ity and that this effect was not mediated via the androgen receptor. The ai m of the present study was to further assess the action of this progestin o n gonadotropin secretion in women. To demonstrate at which level of the hyp othalamo-pituitary-ovarian axis the gonadotropin inhibition was exerted, 10 normally cycling (NC) women, 3 women with a gonadotropin-independent ovari an function [McCune-Albright (MCA) syndrome], and 5 women with functional h ypothalamic amenorrhea (FHA) participated in the study. NC women were treated orally with 5 mg NOMA for 21 days, after one control cycle. Plasma estradiol (E-2) and progesterone, LH, and FSH levels were mea sured during each cycle. A frequent sampling study (every 10 min for 4 h), followed by a classic GnRH test (100 mu g, iv), was performed on day II. Wo men with MCA were studied before, during NOMA, and after long-acting GnRH a gonist administration. In women with FHA, pulsatile GnRH (20 mu g sc, every 90 min) was given for two cycles with or without NOMA (5 mg for 21 days). In all NC women, ovulation was suppressed by NOMA. Mean plasma LH levels, L H pulse frequency, and the LH response to exogenous GnRH were significantly decreased. In MCA, neither NOMA nor GnRH agonist modified multiple ovarian cysts on ultrasound or plasma E-2, levels which remained elevated, ruling out a direct ovarian effect. In FHA, pulsatile GnRH administration recreate d a normal ovulatory menstrual cycle. Addition of NOMA prevented the increa se of plasma E-2, decreased the amplitude of LH pulses, and prevented ovula tion. In view of this unexpected action of NOMA at the pituitary level, sev en samples of normal human female pituitaries were tested for the presence of progesterone receptor (PR) using a double labeling immunocytochemical te chnique. The presence of PR was detected in the seven human pituitary tissu es. In addition, PR was found to be expressed only in gonadatroph cells. In conclusion, NOMA, a 19-nor-P derivative, has a potent antigonadotropic a ctivity exerted at the hypothalamic level, inhibiting ovulation in NC women . In women with FHA, NOMA decreased the gonadotropin stimulation induced by pulsatile GnRH administration. According to the presence of PR in gonadotr oph cells of normal human pituitaries, 19-nor-progesterone derivatives may also act on the gonadotropin secretion at the pituitary level.