title: Neuroendocrine mechanisms by which selective Leydig cell castration unleashes increased pulsatile LH release.
abstract: 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analysis) rhythmicity of serum LH concentrations is not disturbed when androgenic negative-feedback signaling is withdrawn abruptly, but the apparent process randomness of LH release increases, as quantified by higher approximate entropy values.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.
authors.affiliation: Department of Internal Medicine, University of Virginia Health Sciences Center, National Science Foundation Center for Biological Timing, Charlottesville 22908, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: A D
authors.initials: AD
authors.lastname: Zwart
authors.forename: A
authors.initials: A
authors.lastname: Iranmanesh
mesh_terms: D000293:Adolescent; D000328:Adult; D000728:Androgens / Q000172:deficiency; D019277:Entropy; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007985:Leydig Cells / Q000187:drug effects / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood*; D008297:Male; D009490:Neurosecretory Systems / Q000502:physiology*; D009919:Orchiectomy; D011673:Pulsatile Flow
chemical_list: D000728:Androgens; D007986:Luteinizing Hormone; D007654:Ketoconazole