Human menopausal gonadotropin stimulation in monkeys: blockade of the luteinizing hormone surge by a highly transient ovarian factor.

Women and monkeys treated with human menopausal gonadotropin (hMG) often fail to demonstrate timely luteinizing hormone (LH) or follicle-stimulating hormone (FSH) surges despite serum estradiol (E2) levels sufficient to elicit positive feedback of LH and FSH secretion. Here we explored the mechanism of this blockade of estrogen-mediated positive feedback by hMG and the duration of this effect in acutely ovariectomized monkeys. Cycling cynomolgus monkeys (n = 14) were administered hMG (22.5 IU, intramuscularly) daily beginning on cycle day 3. Three monkeys received an E2-benzoate challenge on day 10, resulting in peak E2 levels of 892 +/- 313 pg/ml, without subsequent LH or FSH surges. Four monkeys underwent bilateral ovariectomy on day 12, followed within 60 to 90 minutes by gonadotropin-releasing hormone (GnRH) administration (15 micrograms, intravenously). Five intact monkeys underwent a similar GnRH challenge. LH response to GnRH in the intact monkeys was significantly suppressed in comparison with the ovariectomized group. None of the animals manifested an FSH response to GnRH administration. Two additional monkeys did have a spontaneous LH surge during hMG administration. We conclude that hMG stimulates the production of an ovarian factor(s) which blocks the pituitary LH response to GnRH. This blockade of GnRH action on the pituitary may be the mechanism by which hMG stimulation prevents estrogen-mediated positive feedback of LH secretion. The putative ovarian factor(s) has a relatively short circulatory half-life and/or binding time, resulting in loss of its blocking activity within 90 minutes after bilateral ovariectomy. Evidence is presented to suggest that this factor(s), designated gonadotropin surge-inhibiting factor, belongs to an amorphous group of nonsteroidal ovarian hormones that remain to be further characterized.