Comparison of the Potential for Therapeutic Utilities with Gonadotropin-Releasing Hormone Agonists and Antagonists

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Abstract
Introduction THE SUCCESS in synthesis of very potent agonistic analogs of GnRH was at first expected to lead to a low cost profertility therapy. Early findings of gonadal suppressive effects with these agents, however, led to the discovery of pituitary receptor desensitization and downregulation caused by continuous presence of GnRH and its analogs. It was then established that GnRH must be secreted in a pulsatile manner to exert its physiological effect of activating the reproductive cascade from gonadotropin release to gonadal steroidogenesis and gametogenesis. Only after application of this knowledge has GnRH become a valuable therapeutic agent in hypogonadotropic hypogonadism (1). A number of highly potent agonistic analogs have now been described and are in various stages of clinical evaluation (see Table 1). The increases in potency over the native hormone are related to increased binding affinity and consequent retardation in dissociation rate from the receptors (3). In addition, some of the analogs have a prolonged circulatory half-life in vivo (4, 5). As these changes would be expected to favor down-regulation and desensitization of receptors, it has been widely concluded that the high potency agonist analogs will be of no use as profertility agents. This conclusion may have been premature because the use of very low doses of such agents has not been fully explored. In specific instances where this approach has been taken, such as therapy for cryptorchidism (6) and some veterinary indications (7), success has been achieved with agonist analogs of GnRH (also see below). In addition, although such an analog has not been reported, a highly potent but short lived analog of GnRH would have direct application to therapy in hypogonadism of hypothalamic origin.

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