VARIABLE TOLERANCE OF THE DEVELOPING FOLLICLE AND CORPUS-LUTEUM TO GONADOTROPIN-RELEASING-HORMONE ANTAGONIST-INDUCED GONADOTROPIN WITHDRAWAL IN THE HUMAN

To examine the differential sensitivity of the ovary to temporary withdrawal of gonadotropin support at different stages of folliculogenesis and corpus luteum function, GnRH antagonist blockade of gonadotropin secretion was examined in 17 studies using the Nal-Glu GnRH antagonist. A vehicle control, antagonist treatment, and follow-up cycle format was used in each study. A previously determined ED100 dose of the Nal-Glu GnRH antagonist (150-mu-g/kg) or vehicle was administered sc every 24 h for 3 consecutive days in the midfollicular phase (MFP), late follicular phase (LFP), and midluteal phase (MLP). In studies in the MFP (n = 7), the largest follicle was 11 +/- 2 mm (mean +/- SEM), and the mean estradiol (E2) level was 220 +/- 44 pmol/L on the first day of antagonist administration. Administration of the antagonist resulted in a 75 +/- 6% suppression of LH (P < 0.005), no significant change in FSH, and suppression of E2 to the assay detection limit (P < 0.05). Total cycle length was increased compared to that of the vehicle control cycle (37.3 +/- 1.3 vs. 26.3 +/- 1.1 days; P < 0.005) due to prolongation of follicular phase length (P < 0.005) and reinitiation of folliculogenesis. In the LFP (n = 5), the largest follicle was 16 +/- 1 mm (P < 0.05 vs. MFP), and the E2 level was 394 +/- 95 pmol/L (P < 0.05 vs. MFP) on the first day of antagonist administration. Antagonist administration resulted in a 65 +/- 6% suppression of LH (P < 0.05), a 47 +/- 11% decrease in FSH (P < 0.05), and no significant change in E2. Total cycle length was prolonged (32.4 +/- 2.2 vs. 25.6 +/- 0.4 days; P < 0.05) due to an increase in follicular phase length (P < 0.02); however, the prolongation of the follicular phase was significantly less than that of the MFP (8.0 +/- 1.5 vs. 15.1 +/- 0.1 days; P < 0.001), suggesting ovulation from the initial dominant follicle. In studies in the MLP (n = 5), LH, E2, and progesterone decreased to the assay detection limit after antagonist administration, while FSH decreased by 36 +/- 4% (P < 0.05). Menstrual bleeding occurred within 24-48 h of the final Nal-Glu antagonist injection. The total cycle length was decreased after antagonist administration (21.8 +/- 1 vs. 27.8 +/- 1.1 days; P < 0.001), due entirely to luteal phase shortening (7.2 +/- 0.2 vs. 14.0 +/- 0.7 days; P < 0.001) with demise of the corpus luteum. We conclude that 1) the use of an ED100 dose of the Nal-Glu GnRH antagonist for 3 days in normal women results in persistence of the relatively greater suppression of LH compared to FSH previously demonstrated in single dose studies; 2) this degree of gonadotropin deprivation produces different results depending upon the underlying maturation of the dominant follicle or corpus luteum; 3) in the follicular phase, the developing follicle becomes more tolerant to gonadotropin withdrawal as it becomes functionally more mature from the MFP to the LFP; and 4) in the MLP, this degree of gonadotropin withdrawal is not tolerated, and luteolysis occurs.