Luteinizing Hormone - Releasing Hormone Analogs: Female Contraception

Abstract

Exploration of the potential uses of luteinizing hormone-releasing hormone (LHRH) analogs in contraception has involved inhibition of ovulation of implantation and luteolysis. LHRH analogs when given chronically have the paradoxical effect of down-regulating or desensitizing LHRH receptors in the pituitary raising LH and FSH levels and producing a hypogonadal state. Studies in rhesus monkeys have documented that LHRH given in the early follicular phase block follicular growth and delay ovulation. In women the LHRH analog 4f-Antag given sc also prolonged follicular phase but had no effect on luteal phase. Several LHRH analogs have effectively inhibited ovulation in women: Buserelin Naferelin Leuprolide ad D-TRP. While ovulation is consistently blocked some women experience amenorrhea some oligomenorrhea and some menstruation-like bleeding. Estrogen levels resemble follicular phase levels but the degree of gonadotropin suppression varied from hypoestrogenic conditions of vasomotor symptoms and atrophic vagina to a potential for endometrial hyperplasia. Combined treatments with LHRH analogs and progestins norethisterone or medroxyprogesterone acetate have been tested to induce withdrawal bleeding and prevent endometrial build-up. Another problem with these experimental ovulation-inhibiting treatments is that the intranasal spray route produced variable absorption but the daily injections are not practical. Long-acting implants or injections are being formulated. Conflicting results have appeared in studies on the possible luteolytic effect of LHRH analogs. Work in rhesus monkeys and in women suggests that a narrow window of time is required to get a luteolytic effect. Multiple doses or chronic administration of LHRH analogs will terminate early pregnancy in small animals and nonhuman primates. No effect on implantation has been reported in the few small trials in women to date.