VARIABLE OVARIAN RESPONSE TO GONADOTROPIN-RELEASING-HORMONE ANTAGONIST-INDUCED GONADOTROPIN DEPRIVATION DURING DIFFERENT PHASES OF THE MENSTRUAL-CYCLE

The gonadotropin dependence of ovarian follicular maturation and corpus luteum function can now be examined in women using antagonistic analogs of GnRH. We studied the responses of three groups of women throughout a control cycle and during the administration of a potent GnRH antagonist, detirelix ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10]GnRH, Syntex Research). Detirelix (10 mg, sc) was administered for 3 consecutive days during the midfollicular phase (n = 4), preovulatory phase (n = 4), and eariy luteal phase (n = 4). The pituitary response to detirelix was similar throughout the three phases of the menstrual cycle. Immunoreactive LH concentrations decreased to 35% (mean +/- SEM) of pretreatment values within 8 h after the initial injection and remained suppressed for 72 h after discontinuance of treatment. Immunoreactive FSH concentrations decreased to 73 +/- 3% of pretreatment levels within 8 h and returned to baseline within 24 h after the third injection. In contrast, the ovarian response to detirelix varied markedly during different phases of the cycle. Midfollicular phase treatment was associated with a decline in estradiol (E2) levels from pretreatment values of 246 +/- 48 to 81 +/- 15 pmol/L within 24 h of the last injection. Vaginal bleeding ensued in three of four women. Follicular recruitment was then reinitiated, and an ovulatory LH surge occurred 18.2 +/- 2.9 days after the last injection. Similarly, treatment during the eariy luteal phase produced a decline in E2 concentrations from 286 +/- 29 to 70 +/- 7 pmol/L and a decline in progesterone concentrations from 20 +/- 1.6 to 1.9 +/- 0.3 nmol/L within 24 h after the last injection. Luteolysis was associated with menstrual bleeding in all four women. The subsequent ovulatory LH surge occurred 16.5 +/- 1.0 days after discontinuance of treatment. In contrast, treatment during the preovulatory phase resulted in a decline in E2 concentrations from 844 +/- 66 to 429 +/- 132 pmol/L during the first 48 h of treatment. Gonadotropin and E2 concentrations subsequently recovered from suppression, growth of the dominant follicle resumed, and a LH surge occurred 5.8 +/- 1.4 days after the last injection. These data indicate that the GnRH antagonist detirelix produces rapid and consistent suppression of pituitary gonadotropin secretion. The magnitude of suppression and preferential suppression of LH vs. FSH are similar throughout the cycle. In contrast, the ovarian response to gonadotropin deprivation varies during the menstrual cycle. The emerging dominant follicle and the emerging corpus luteum respond to acute gonadotropin deprivation with functional and structural demise, followed by reinitiation of follicular recruitment. The mature preovulatory dominant follicle, however, is less susceptible to acute gonadotropin withdrawal and is capable of rapidly resuming growth and steroid secretion, followed by ovulation, once gonadotropin support is reinstituted.