Inhibition of ovulation: comparison between the mechanism of action of steroids and GnRH analogues

Abstract

The pulsatile secretion of GnRH is achieved by the fine regulation of oestrogens and progesterone. Progesterone is mainly responsible for a negative feedback effect at the hypothalamic level which decreases GnRH pulse frequency. Oestradiol exerts both a positive and a negative feedback effect, mostly at the pituitary level, and the use of steroids to prevent ovulation combines both effects. Recent developments in steroid research suggest a potential interest in the use of non-androgenic progestins which reproduce the negative feedback effect of progesterone with fewer metabolic side effects. GnRH agonists, although responsible for low plasma levels of oestradiol, may be useful in women at risk for steroid contraception. GnRH antagonists suppress transient gonadotrophin-dependent events in the menstrual cycle. Studies with the second generation GnRH antagonist, Nal--Glu, suggest a potential use of these compounds in suppressing ovulation.

PIP: Recent developments in steroid research suggest the potential of steroids and gonadotropin-releasing hormone (GnRH) analogues and antagonists in blocking selective events in the menstrual cycle. GnRH analogues suppress gonadotropin secretion by inhibiting GnRH action at the pituitary level, while gonadal steroids regulate gonadotropin secretion both at the pituitary and hypothalamic levels. The pulsatile secretion of GnRH is achieved by the fine regulation of estrogens and progesterone. Progesterone is chiefly responsible for a negative feedback effect at the hypothalamic level, which decreases GnRH pulse frequency. Estradiol exerts both a positive and negative feedback effect, mostly at the pituitary level, and the use of steroids to prevent ovulation combines both effects. GnRH agonists suppress bioactive luteinizing hormone (LH) secretion and, to a lesser extent, that of follicle-stimulating hormone (FSH). The repeated administration of GnRH agonists blocks ovulation and prevents normal follicular development. Agonists such as Buserelin nasal spray and nafarelin have resulted in significant levels of amenorrhea, and GnRH agonists may provide an alternative for women over 35 years of age or those who are at risk from the use of steroids. GnRH antagonists are still in a developmental phase, but are able to suppress bioactive gonadotropin production by competing with endogenous GnRH for its receptors. Preliminary human data suggest that the administration of a GnRH antagonist during the follicular phase will inhibit ovulation. Unfortunately, the longterm administration of these compounds is contraindicated by their side-effect of a decrease in bone mass.