GnRH antagonists in men: Development of a male contraceptive

Abstract

Antagonist analogs of GnRH inhibit pituitary and gonadal function by competing with endogenous GnRH for binding to gonadotropin receptors. Administration of GnRH antagonists to humans induces rapid and sustained pituitary and gonadal suppression. Induction of suppression is potentiated by a decrease in the biological potency of the follicle stimulating hormone (FSH) and luteinizing hormone (LH) molecules. Development of GnRH antagonists however has been slow because of low potency of early prototype analogs and histamine-like side effects caused by more potent analogs. A GnRH antagonist synthesized at the Salk Institute by Drs. J. Rivier and W. Vale. has permitted short and longterm clinical studies because of its high potency and its relative lack of side effects in animal studies. We 1st gave this Nal-Glu antagonist as single doses to normal men and immunoreactive FSH LH and bioactive LH decreased significantly after all doses of the antagonist. Testosterone (T) levels decreased with the same rate after all doses of Nal-Glu by up to 90 9 +or- 2.8%. The duration of T suppression rather than the nadir reached was dose dependent. Then 5 mg Nal-Glu was given daily to normal men for 3 weeks. FSH LH and T progressively decreased and were totally suppressed from day 18 until the end of the study. A higher daily dose of 10 mg in 5 men could inhibit the brief escape seen during the 1st week of Nal-Glu administration; LH and T decreased promptly and remained suppressed throughout the study. In contrast serum free alpha-subunit decreased slowly to a nadir of only 50%. Estradiol also decreased whereas 17-OH-P levels did not change. In order to study the effects of the GnRH antagonist on the pulsatile secretion of LH we gave 5 mg of Nal-Glu to 5 normal men and collected blood samples every 10 min for 24 hours. LH pulse frequency expressed as the interval between pulses remained the same at 119 +or- 16 minutes during baseline and at 134 +or- 11 minutes following antagonist administration. However LH pulse amplitude decreased from 1.8 +or- 0.5 to 0.16 +or- 0.01 U/L. We then studied the effects of combined Nal-Glu antagonist and T administration in men in a protocol simulating a likely male contraceptive regimen. The antagonist 10 mg daily for 20 weeks was given to 8 normal men; T enanthate 25 mg every week was added to this regimen starting at 2 weeks. Sperm counts started declining on week 4 and complete azoospermia was reached in 7 of the 8 subjects. In the 8th man total sperm count was decreased at week 20 to a nadir of 1.4 million and residual sperm showed no motility and viability during the last 6 weeks of treatment. No systemic or significant local side effects were observed other than a small reaction at the injection site. These results indicate that prolonged administration of the Nal-Glu antagonist can effectively suppress pituitary and gonadal function. Furthermore combined administration of a GnRH antagonist and T can result in complete sustained and reversible azoospermia in men without loss of libido. (full text)