Inhibition of Testicular Androgen Biosynthesis by Chronic Administration of a Potent LHRH Agonist in Adult Men

Abstract

The antireproductive properties of LHRH and its agonists have now been clearly established. Using various dosing regimens and routes of administration in animal experiments and in clinical trials, these peptides invariably produce paradoxical inhibitory effects on reproductive function. This ability led to the concept that gonadal steroid-dependent (responsive) tumors might also be affected in a manner analogous to that produced by gonadectomy or by anti-androgenic or antiestrogenic drugs. Numerous data have now appeared in the medical literature on the potential efficacy of the LHRH agonists as a tumor therapy. Using different agonists (D-Ser⁶, D-Leu⁶and D-Trp⁶-LHRH) and various dosages, the investigators were successful in inducing a “medical castration” with androgen levels comparable to castrate control subjects. Objective tumor regression and significant clinical improvement paralleled the hormonal suppression shown in our studies and by other groups. Another interesting potential clinical application of the ability of LHRH agonist to inhibit testicular function is its development as a male contraceptive. This approach is being tested by a few groups. In order to preserve potency, exogenous androgens must be administered with the agonist. Long-term pituitary suppression in boys with idiopathic precocious puberty has now been achieved and premature sexual development suppressed. In man the main mechanism responsible for testicular inhibition seems to be the achievement of a temporary and reversible state of hypogonadotropic hypogonadism. Recent data show that LHRH agonist alters the ratio of bioactive and immunoreactive LH and suggest a direct effect on LH biosynthesis as a mechanism of action of LHRH agonist analogs. Other findings support the lack of direct effect of LHRH agonist on Leydig cells in humans. In view of the main potential clinical applications-as therapy for chronic hormone-dependent disease or as a male contraception-major new developments are being undertaken in the way of administration of these substances by slow delivery systems.

Key Words:

• LHRH agonist
• Testicular Androgens
• Medical castration