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Mechanisms of Gonadotropin-Releasing Hormone Agonist Action in the Human Male^*

S. BHASIN and R. S. SWERDLOFF

Department of Medicine, Harbor-University of California at Los Angeles Medical Center Torrance, California 90509

Correspondence: Address requests for reprints to: S. Bhasin, M.D., Department Medicine, Harbor-University of California at Los Angeles Medical Center, 1000 West Carson Street, Carson, California 90509.

Abstract

AGONIST analogs of GnRH are being increasingly utilized to induce medical castration for treatment of a variety of hormonally responsive clinical disorders. However, the mechanism/s of their paradoxical antigonadal action in the human male remain poorly understood. Basal and integrated concentrations of immunoreactive LH after intermediate term (4–16 weeks) GnRH agonist treatment are only modestly decreased and cannot fully account for the far greater decline in serum testosterone (T) concentrations. Bioassayable LH concentrations, however, decrease markedly and parallel the fall in serum T suggesting secretion of qualitatively different LH species with diminished biological activity while the circulating concentrations of β-subunit parallel the measured bioassayable LH concentrations, free -subunit secretion remains persistently and disproportionately elevated during chronic GnRH agonist treatment. Cross-reactivity of free -subunits in the human LH RIA contributes to this disparity between the LH immuno and bioactivity. Chromatography of serum LH during GnRH agonist treatment suggests secretion of a qualitatively different LH species. Unlike the rat, in which the antifertility effects of the agonist are mediated predominantly by direct inhibition of testicular steroidogenesis, significant direct gonadal effects have not been demonstrated in man. Thus the bulk of evidence points to a predominant pituitary site of action in the human male. The molecular basis of the heterogeneity of LH during GnRH agonist, however, remains to be elucidated. The hypothesis that co- or posttranslational modification by the agonist may attenuate biologic activity of LH has not yet been directly tested.

Footnotes

^* This work was supported in part by NIH/NICHD Contract N01-HD-3-2838, General Clinical Research Center Grants RR00425, and Training Grant 2-T32-AM-07214-06.

Dr. Bhasin is the recipient of the Clinical Associate Physician Award of the General Clinical Research Center branch of the National Institutes of Health.

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