The importance of luteinizing hormone in the control of inhibin and progesteron secretion by the human corpus luteum

Serum inhibin levels rise markedly during the luteal phase of the human menstrual cycle and are closely correlated with serum progesterone (P) levels, suggesting that the corpus luteum (CL) secretes inhibin. While FSH is the major regulator of inhibin secretion by the granulosa cells, the control of CL inhibin secretion is unclear. We hypothesized that, like P, CL inhibin secretion would be LH dependent. To examine this possibility, normal women were given the GnRH antagonist [Ac-D₂-Nal¹, D₄CL Phe², D₃Pal³, Arg⁵, DGlu⁶ (AA) DAla¹⁰]GnRH (Nal-Glu antagonist) for 3 consecutive days commencing on day 6-8 of the luteal phase. The daily doses were 2.5 (n = 3), 10 (n = 4), and 25 μg/kg (n = 5), sc. Serum LH levels fell 2 h after injection, and the fall was maximal (70-74%) at 6 h; the degree of suppression was not dose dependent. The duration of suppression was dose related, being less than 12 h, between 12, and 24 h, and more than 24 h for the 2.5, 10, and 25 μg/kg doses, respectively. Serum FSH levels declined by 22-43%, but the effect was not dose related. Serum P levels fell by 42-45% 8 h after each dose of antagonist. They returned to baseline 24 h after the 2.5 μg/kg dose, but after both the 10 and 25 μg/kg doses serum P levels continued to fall, and menstrual bleeding commenced within 48-72 h after the first antagonist injection. Serum inhibin levels were not altered relative to normal cycles by the 2.5 μg/kg dose, but fell by 48% and 58%, and 62% and 73% respectively, 48 and 72 h after the 10 and 25 μg/kg doses, respectively. Serum P and inhibin levels correlated closely in all women. To examine the relative roles of FSH and LH in the control of CL function, Nal-Glu antagonist (25 μg/kg, sc) was administered at 0 and 24 h commencing on day 6-8 of the luteal phase, in combination with either human menopausal gonadotropin (hMG; 150 IU, im, every 12 h) or hCG (1500 IU, im, once), both commencing at 0 h. hMG administration led to a rapid (by 2 h) and marked (3- to 9-fold) rise in serum FSH levels, whereas serum LH remained low, similar to antagonist alone treatment cycles. Serum P levels fell similarly after antagonist with or without hMG administration, as did serum inhibin and estradiol (E₂), except at 48 h when serum E₂ was significantly higher than during antagonist treatment alone. hCG administration led to 2- to 8-fold elevation in serum LH-like immunoactivity along with modest increases in serum P (+75%), E₂ (+37%), and inhibin (+60%) levels. We conclude that 1) the Nal-Glu antagonist is a potent inhibitor of gonadotropin secretion, and the duration of its effect is dose related; 2) under the regimen employed, a threshold dose for the induction of luteolysis exists between 2.5-10 μg/kg; 3) the duration of gonadotropin suppression required to induce luteolysis is between 12-24 h on 3 consecutive days; 4) inhibin and P secretion by the CL are coupled during alterations in gonadotropin levels; 5) coadministration of the Nal-Glu antagonist with hMG failed to maintain Cl function; and 6) hCG administration maintained CL P and inhibin secretion after antagonist injection, indicating that these hormones are predominantly under LH control.