GnRH antagonists: Mechanism of action studies and clinical uses in women

Abstract

Endocrinologists at Hospital Bicetre in France studied the mechanisms of action of the 2nd generation gonadotropin releasing hormone (GnRH) antagonist Nal-Glu by administering it to castrated rams to those whose testes had not descended and to intact rams. It caused a significant and precipitous reduction in luteinizing hormone (LH) plasma levels within 2 hours in castrated rams. Yet it caused a rise in portal blood GnRH levels and in GnRH pulse frequency in intact rams and rams with undescended testes. Thus Nal-Glu did not influence the hypothalamus except to undo the negative feedback of testosterone. The researchers also injected 10 mg Nal-Glu on the 10th day of the follicular phase in normal women which lengthened the follicular phase from 16-22.8 days. Nal-Glu administration on day 10 also reduced plasma LH for 24 hours and estradiol levels for 72 hours; yet the reduction in plasma follicle stimulating hormone levels was not significant. The researchers administered 10 mg Nal-Glu to 5 other women on day 1 7 14 and 21 of their cycle which delayed ovulation and reduced mean estradiol levels. Further when researchers injected 10 20 or 30 mg Nal-Glu before ovulation and if estradiol levels were at least 150 pg/ml on the day of injection the preovulatory follicle was more or less independent and ovulation was not always delayed. Still ovulation did not occur in the original women during treatment. When the endocrinologists injected Nal-Glu during the luteal phase the corpus luteum function declined as the Nal-Glu dose size increased. They learned also that administration of low dose human chorionic gonadotropin (hCG) can restore corpus luteum function only if hCG is not blocked from the corpus luteum for more than 48 hours. These results indicated that clinicians can probably use GnRH antagonists in women to prevent LH surges in controlled ovarian hyperstimulation.