GnRH analogues for contraception

Abstract

The production of chemical analogues of GnRH permits direct suppression of the pituitary-gonadal axis at the level of the gonadotroph. Continuous administration of GnRH agonists desensitizes the gonadotroph and ovulation is uniformly prevented, forming the practical basis for use in contraception. However, long-term treatment is constrained by variable effects on oestrogen secretion, which cause irregular bleeding patterns on the one hand and risks of hypo-oestrogenism on the other. Their use as a post-partum contraceptive has attractions because any analogue in milk should be without biological activity in the infant. GnRH antagonists have the advantage of immediate inhibitory action. They have potential application in circumstances in which agonists have been employed and, in addition, can interrupt any stage of the menstrual cycle. Clinical trials to utilise their potential antifertility action have not been performed. Use of GnRH analogues for contraception in women may require combination with low dose oestrogen and progestin and it has been proposed that such development may yield important benefits in health. When combined with testosterone, GnRH antagonists may form the basis for a male contraceptive.

PIP: Use of gonadotropin releasing hormone (GnRH) analogues for contraception in women may require combination with low-dose estrogen and progestin. When combined with testosterone, GnRH antagonists may form the basis for a male contraceptive. Once-daily administration of GnRH agonist throughout the menstrual cycle prevents ovulation, even at low doses. Administration of buserelin intranasally at a dose of 300 mcg daily, starting at 6 weeks postpartum for the duration of breast feeding, prevented ovulation in a group of 9 women. During the study period, 7 of 9 control mothers ovulated. The use of GnRH agonists in treatment of sex-hormone-dependent tumors of the breast and uterus has become established by suppression of estrogen secretion by increasing the dose of agonist or, more effectively, by using a depot preparation. The development of GnRH antagonists involved a stepwise introduction of hydrophobic residues which block proteolysis, increase GnRH receptor affinity, and prolong the pharmacokinetics of the molecule. The GnRH antagonists have to be administered by injection every 24-48 hours, and high doses (3-5 mg per day) are required to obtain adequate suppression of the GnRH receptor. Longterm trials with GnRH antagonists in men are currently being conducted in a number of centers. In a recent report, 8 subjects received daily subcutaneous injections of 10 mg Nal-Glu antagonist for 20 weeks. Supplemental androgen therapy with testosterone enanthate was commenced at 2 weeks to provide low-normal replacement levels. Azoospermia was reached with 6-12 weeks in 6 of the 8 subjects, and doubling the dose of antagonist resulted in azoospermia in the remaining men. No significant changes in libido occurred. These preliminary clinical trials together with findings from longer-term studies in macaques, suggest that the GnRH/androgen combination may prove to be an effective and reversible system of male contraception.