Effects of a superactive luteinizing hormone-releasing factor agonist on gonadotropin and ovarian function during the menstrual cycle

Abstract

The effect of a potent luteinizing hormone-releasing factor (LRF) agonist (D-Trp6, Pro9 NEt)-LRF on pituitary gonadotropin release and its concomitant ovarian response was examined in normal women during the early follicular (EFP), late follicular (LFP), and midluteal (MLP) phases. A single subcutaneous injection of 50 micrograms of LRF agonist in subjects during the EFP caused prompt release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to levels comparable to those found during spontaneous midcycle gonadotropin surges, while in LFP subjects gonadotropin levels rose 1 1/2 to 2 times above the levels of midcycle surges. The LH/FSH release in the MLP was almost identical to that found in the EFP. The ovarian response as measured by increasing estradiol levels followed a similar pattern during the 48 hours after injection in all three phases of the cycle. The inappropriate gonadotropin surge induced by LRF agonist in EFP subjects resulted in prolonged follicular phases and anovulation. Three of four subjects in the LFP showed evidence of ovulation in response to the same dose of LRF agonist. The pharmacodynamics of gonadotropin-ovarian responses to this potent LRF agonist reported here should provide an important reference for systemic investigation and rational clinical application.

PIP: A potent luteinizing hormone-releasing factor (LRF) agonist (D-Trp6-Pro9 NEt)-LRF was studied to determine its effect on pituitary gonadotropin release, and its concomitant ovarian response was examined in normal women during the early follicular (EFP), late follicular (LFP), and midluteal phases (MLP). 16 normal, healthy women volunteered for this study where a single subcutaneous dose of 50 mcg of LRF agonist was injected during the EFP, LFP, and MLP. During the EFP, an injection caused prompt release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to levels comparable to those of the spontaneous midcycle gonadotropin surge. In LFP subjects, gonadotropin levels rose 1.5-2 times above the midcycle surge level. The LH/FSH release in MLP was almost identical to that found in the EFP. Ovarian response, as measured by increasing estradiol levels, followed a similar pattern during the 48 hours after injection in all 3 phases of the cycle. Prolonged follicular phases and anovulation were the result of the gonadotropin surge induced by LRF agonist in EFP. 3/4 subjects in the LFP showed evidence of ovulation in response to the same dose of agonist. This study demonstrates that this LRF agonist is a potent agonist of LRF in human subjects, and is approximately 144 times more potent than the decapeptide LRF.