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 micrograms/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 less than 0.005), no significant change in FSH, and suppression of E2 to the assay detection limit (P less than 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 less than 0.005) due to prolongation of follicular phase length (P less than 0.005) and reinitiation of folliculogenesis. In the LFP (n = 5), the largest follicle was 16 +/- 1 mm (P less than 0.05 vs. MFP), and the E2 level was 394 +/- 95 pmol/L (P less than 0.05 vs. MFP) on the first day of antagonist administration. Antagonist administration resulted in a 65 +/- 6% suppression of LH (P less than 0.05), a 47 +/- 11% decrease in FSH (P less than 0.05), and no significant change in E2. Total cycle length was prolonged (32.4 +/- 2.2 vs. 25.6 +/- 0.4 days; P less than 0.05) due to an increase in follicular phase length (P less than 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 less than 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 less than 0.05). Menstrual bleeding occurred within 24-48 h of the final Nal-Glu antagonist injection.(ABSTRACT TRUNCATED AT 400 WORDS)
Hall
J E
JE
Department of Medicine, Massachusetts General Hospital, Boston 02114.
Bhatta
N
N
Adams
J M
JM
Rivier
J E
JE
Vale
W W
WW
Crowley
W F
WF
D000328:Adult; D003338:Corpus Luteum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004967:Estrogens / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005498:Follicular Phase / Q000187:drug effects / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D006062:Gonadotropins / Q000502:physiology*; D006801:Humans; D007267:Injections; D008183:Luteal Phase / Q000187:drug effects / Q000502:physiology; D007986:Luteinizing Hormone / Q000097:blood; D006080:Ovarian Follicle / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011374:Progesterone / Q000097:blood
D004967:Estrogens; D006062:Gonadotropins; C057805:LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone