LHRH antagonists for male contraception

The potential of antagonistic analogs of LHRH as contraceptive agents was recognized shortly after the discovery and sequencing of LHRH (Schally et al., 1971). LHRH agonists with prolonged duration of action compared to authentic LHRH were thought to be useful for the treatment of infertility due to LHRH deficiency. However, extensive studies in animals and humans with potent agonists revealed paradoxical inhibitory effects on male reproductive function (Pelletier et al., 1978; Rivier et al., 1980; Heber and Swerdloff, 1981; Linde et al., 1981). While detailed and extensive clinical studies with potent LHRH agonists are well underway, preliminary human studies published to date have used much less potent antagonists (Gonzalez-Barcena et al., 1977; Canales et al., 1978). Since clinical studies using LHRH agonists are already initiated, why then propose studies of LHRH antagonists as potential male contraceptive agents? First, the efficacy of agonists in predictably suppressing spermatogenesis completely has not been demonstrated to date in man. Second, agonists have the potential disadvantage of a delay in the onset of their inhibitory effects caused by the initial stimulatory effects of agonist administration on gonadotropin and testosterone secretion (Sandow et al., 1978; Happ et al., 1978; Crowley et al., 1980). Third, although the primary site of action of LHRH agonists in the human male is the pituitary gland (Heber et al., 1983) irreversible effects of agonist treatment on testicular histology have been observed in rats (Vickery, 1981).