[Analogs of gonadoliberin. Value in physiology and therapeutics]

Abstract

Since the chemical structure of gonadotrophin releasing hormone (GnRH) was discovered in 1971, several antagonist and agonist analogues have been synthesized. Via different mechanisms, these 2 classes of analogues inhibit luteinizing hormone (LH) and to a lesser degree follicle stimulating hormone (FSH) and induce reversible reduction in sexual hormone levels. GnRH is a decapeptide synthesized by the hypothalamus and released by pulses into the portal system of the hypothalamo-hypophysis. In all agonist analogues, a hydrophobic d-amino acid is substituted for glycine at position 6. Some agonists also have a second substitution at position 10. All have a characteristic longer, though variable, half-life and are more effective at lower doses than native GnRH. After initial stimulation to reach flare-up, desensitization occurs resulting in a sharp reduction in the levels of LH and FSH. When the agonist is withdrawn, recovery of initial levels is rather slow, lasting several days. GnRH agonist analogues have been used in precocious puberty, endometriosis, uterine fibromas, certain functional disorders and as a mean of inducing ovulation. Hormone-dependent cancer is also an indication. Antagonist analogues have many amino acid substitutions. They act by competitive inhibition of endogenous GnRH leading to an immediate drop in LH and FSH levels. They have been used in an attempt at male contraception and are effective inhibitors of the normal cycle in females, opening new perspectives in contraception. GnRH antagonists also have a role to play in the treatment of polycystic ovaries and in ovary stimulation during in vitro fecundation.