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A testicular site of action for LHRH was first indicated by observations that LHRH agonists bound to high-affinity receptors in the interstitial tissue of the adult rat testis[1–5] and inhibited Leydig cell function in hypophysectomized rats in vivo [6–8]. Although there have been several reports since of proteins or peptides in testicular tissue and seminal plasma that have “LHRH-like” properties [9–24], the biochemical characteristics of most of these molecules, their relationships to the mammalian hypothalamic LHRH decapeptide and to one another, and their physiological significance remain poorly understood.

Discovery of LHRH1,2 and the availability of its potent agonistic analogues has led to a rapid increase in our knowledge of the pituitary-gonadal axis and has offered new and exciting therapeutic approaches in reproductive endocrinology as well as in sex steroid-dependent diseases.

Stimulated by the unexplained lack of success of LHRH and its agonists in the treatment of infertility in men1, we investigated in detail the effect of acute and chronic administration of these peptides on testicular functions in experimental animals. We then made the observation that short-term administration of an LHRH agonist to adult male rats leads to a loss of testicular LH and prolactin receptors, as well as to decreased serum testosterone levels accompanied by inhibition of ventral prostate, seminal vesicle and testis weight2–5. It is of great interest that, among the species so far studied, man is the most sensitive to the inhibitory effect of treatment with LHRH agonists on testicular steroidogenesis5,6. In fact, while, in the rat, treatment with LHRH agonists increases 5α-reductase activity and formation of 3α-androstanediol as well as 5α-dihydrotestosterone, which can partially counteract the inhibitory effect on testosterone production5,7, no such effect is seen in man, where androgen biosynthesis can be completely inhibited and medical castration is thus achieved relatively easily with no secondary effect other than those related to low circulating androgen levels5,8,9.

The isolation, identification, synthesis, and biologic evaluation of the hypothalamic peptide, luteinizing hormone (LH) releasing hormone (LHRH), have provided a framework for the potential use of this natural substance in the treatment of infertility (Schally et al., 1976, 1978; Vale et al., 1977; Corbin and Beattie, 1976). With the further extensive syn-thetic development of agonistic derivatives of LHRH (super analogues), and the pharmacologic elucidation of their highly potent LH-releasing and ovulation-inducing properties in laboratory animals, it was envisioned that such peptidic agents would be most useful in treating female and male fertility disorders. Further testing revealed that such compounds, in spite of their putative profertility classification, were paradoxically antifertility in nature. This is evidenced by the ability of such agonists to terminate pregnancy postcoitally, reduce fecundity precoitally, and retard female puberty in laboratory animals; in humans and farm animals, they generally result in luteal incompetence despite their intended use for ovulation induction and establishment of a viable pregnancy (Corbin et al., 1978).