LH-RH analogues as contraceptives

Abstract

The chemical identification and synthesis of the hypothalamic hormone LHRH has led to the generation of over 1000 analogues during this past decade. As a result numerous highly potent peptidic derivatives have become available either as LHRH antagonists or agonists which have received considerable pharmacologic evaluation as potential fertility-regulating agents. The antagonists by virtue of their ability to inhibit LH and FSH have also received attention as ovulation inhibitors. In contrast the super agonists possess a more complex reproductive pharmacologic profile and have been studied for their profertility (conceptive) potential in hyporeproductive states and more extensively for their paradoxical contraceptive promise. In the latter case a plethora of animal and clinical studies have demonstrated that these agonists can inhibit reproductive processes in both the female and the male as is evidenced by gonadotropin hypersecretion pituitary desensitization ovulation inhibition gonadal down regulation steroid ogenic inhibition luteolysis interference with estrous and menstrual cycles early onset of menses pregnancy termination retardation of puberty and spermatogenic inhibition. In the animal and clinical safety studies the agonists have been observed to be well-tolerated and free of untoward side effects at efficacious doses. Any undesirable side effects observed during toxicologic pathologic and secondary (nonreproductive) pharmacologic testing in a variety of animal models associated with varied dosing regimens and routes of administration have occurred at doses in excess of those required for practical and utilitarian application. Thus these compounds provide excellent therapeutic margins. Recent clinical studies employing chronic nasal delivery of the agonists to females reinforce continued support of this novel approach to contraception. In human males the agonists can severely retard or halt entirely spermatogenesis associated with the unacceptable aide effects of testosterone decline and libidinal loss; studies are in progress to determine if testosterone replacement in association with the agonist will eliminate these inherent troublesome properties of the agonists. Collectively trials are currently in progress to establish practical routes of administration and dosing strategies to optimize contraceptive efficacy reliability predictability and patient compliance. (authors)