AJP - Regulatory, Integrative and Comparative Physiology, Vol 272, Issue 2 464-R474, Copyright © 1997 by American Physiological Society

ARTICLES

Neuroendocrine mechanisms by which selective Leydig cell castration unleashes increased pulsatile LH release

J. D. Veldhuis, A. D. Zwart and A. Iranmanesh
Department of Internal Medicine, University of Virginia Health Sciences Center, National Science Foundation Center for Biological Timing, Charlottesville 22908, USA.

A novel pharmacological model of acute reversible Leydig cell "castration" induced by a steroidogenic enzyme inhibitor, ketoconazole, achieves marked hypoandrogenemia in healthy men with an attendant 2.5-fold increase in 24-h mean serum luteinizing hormone (LH) concentrations. Mechanistically, the unleashing of amplified pulsatile LH release can be accounted for by any of three distinct models of deconvolution-estimated gonadotropin secretion, all of which are marked by a nearly twofold acceleration in LH secretory burst frequency. In addition, the models variously also predict concomitant prolongation of the endogenous LH half-life, an augmented LH secretory burst mass and duration, and/or the emergence of significant basal LH secretion. The nyctohemeral (cosinor analysis) rhythmicity of serum LH concentrations is not disturbed when androgenic negative-feedback signaling is withdrawn abruptly, but the apparent process randomness of LH release increases, as quantified by higher approximate entropy values. Thus we conclude that an intact (closed loop) androgen-mediated negative-feedback network in the adult human male is required to sustain low-frequency pulsatile LH release in a quantifiably orderly manner.

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