Neuroendocrine mechanisms by which selective leydig-cell castration unleashes increased pulsatile lh release in the human

A model of ketoconazole-induced hypoandrogenemia and deconvolution-estimated LH secretory enhancement

A. P. Zwart, A. Iranmanesh, Johannes D Veldhuis

Research output: Contribution to journalArticle

Abstract

As a novel experimental paradigm for reversible Leydig-cell castration in the human, we administered a potent steroidogenic enzyme inhibitor, ketoconazole (KTCZ), with physiological amounts of glucocorticoid to counteract concurrent inhibition of Cortisol biosynthesis. Six young men received 1000 mg KTCZ at midnight, followed by 400 mg q 6 h orally for 48 h with 0.5 mg dexamethasone BID replacement. Serum testosterone concentrations fell to 32 + 6 ng/dL (versus baseline 524 ±24) during the second 24 h of study, when blood samples were withdrawn at 10-min intervals. Sera were submitted to LH IRMA and multiparameter deconvolution analysis to quantitate the number, duration, amplitude, and mass of underlying LH secretory bursts and the half-life of endogenous LH (Meth Enzymol 210:539,1992). In response to KTCZ, mean (24-h) serum LH concentrations rose from 3.8 ±0.25 to 10.5 + 1.1 IU/L (P<0.01), with a smaller increase in FSH from 3.8 + 0.81 to 6.6 + 1.4 IU/L. Deconvolution analysis under an assumption of purely pulsatile LH release revealed a significant acceleration of LH secretory burst frequency, viz., from (median) 12 to 23 bursts/24 h (P<0.01) with corresponding decline in the interpulse interval from 118 (basal) to 62 min (KTCZ). LH secretory burst amplitude, mass, and duration were unaffected by androgen withdrawal, but the estimated endogenous half-life of LH increased from 95 min to 227 min (P<0.05). A new waveform-independent deconvolution technique (Meth Neurosci 28:1-24,1995) assuming a known LH half-life (J Clin Invest 77:1122, 1986) corroborated increased LH secretory burst frequency after KTCZ (namely 21 vs 12 pulses/day), but with a rise in putative basal LH secretion from 0.041 to 0.20 lU/L/min (P<0.05) Both deconvolution models predicted the increases in serum LH concentration peak maxima and interpeak valleys, as appraised by a model-independent discrete peak-detection algorithm, Cluster analysis (AJP 2SO:E486, 1986). In conclusion, a novel human model of reversible Leydig-cell castration unleashes pulsatile LH release via a nearly 2-fold acceleration in LH secretory burst frequency with either a concomitant prolongation of endogenous LH half-life and/or the emergence of basal LH secretion.

Original languageEnglish (US)
JournalJournal of Investigative Medicine
Volume44
Issue number3
StatePublished - 1996
Externally publishedYes

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Ketoconazole
Leydig Cells
Castration
Deconvolution
Half-Life
Serum
Biosynthesis
Cluster analysis
Enzyme Inhibitors
Dexamethasone
Glucocorticoids
Androgens
Cluster Analysis
Hydrocortisone
Testosterone
Blood

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{9e6794a4a58b4ac79ca0bdcd60893f18,
title = "Neuroendocrine mechanisms by which selective leydig-cell castration unleashes increased pulsatile lh release in the human: A model of ketoconazole-induced hypoandrogenemia and deconvolution-estimated LH secretory enhancement",
abstract = "As a novel experimental paradigm for reversible Leydig-cell castration in the human, we administered a potent steroidogenic enzyme inhibitor, ketoconazole (KTCZ), with physiological amounts of glucocorticoid to counteract concurrent inhibition of Cortisol biosynthesis. Six young men received 1000 mg KTCZ at midnight, followed by 400 mg q 6 h orally for 48 h with 0.5 mg dexamethasone BID replacement. Serum testosterone concentrations fell to 32 + 6 ng/dL (versus baseline 524 ±24) during the second 24 h of study, when blood samples were withdrawn at 10-min intervals. Sera were submitted to LH IRMA and multiparameter deconvolution analysis to quantitate the number, duration, amplitude, and mass of underlying LH secretory bursts and the half-life of endogenous LH (Meth Enzymol 210:539,1992). In response to KTCZ, mean (24-h) serum LH concentrations rose from 3.8 ±0.25 to 10.5 + 1.1 IU/L (P<0.01), with a smaller increase in FSH from 3.8 + 0.81 to 6.6 + 1.4 IU/L. Deconvolution analysis under an assumption of purely pulsatile LH release revealed a significant acceleration of LH secretory burst frequency, viz., from (median) 12 to 23 bursts/24 h (P<0.01) with corresponding decline in the interpulse interval from 118 (basal) to 62 min (KTCZ). LH secretory burst amplitude, mass, and duration were unaffected by androgen withdrawal, but the estimated endogenous half-life of LH increased from 95 min to 227 min (P<0.05). A new waveform-independent deconvolution technique (Meth Neurosci 28:1-24,1995) assuming a known LH half-life (J Clin Invest 77:1122, 1986) corroborated increased LH secretory burst frequency after KTCZ (namely 21 vs 12 pulses/day), but with a rise in putative basal LH secretion from 0.041 to 0.20 lU/L/min (P<0.05) Both deconvolution models predicted the increases in serum LH concentration peak maxima and interpeak valleys, as appraised by a model-independent discrete peak-detection algorithm, Cluster analysis (AJP 2SO:E486, 1986). In conclusion, a novel human model of reversible Leydig-cell castration unleashes pulsatile LH release via a nearly 2-fold acceleration in LH secretory burst frequency with either a concomitant prolongation of endogenous LH half-life and/or the emergence of basal LH secretion.",
author = "Zwart, {A. P.} and A. Iranmanesh and Veldhuis, {Johannes D}",
year = "1996",
language = "English (US)",
volume = "44",
journal = "Journal of Investigative Medicine",
issn = "1081-5589",
publisher = "Lippincott Williams and Wilkins",
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TY - JOUR

T1 - Neuroendocrine mechanisms by which selective leydig-cell castration unleashes increased pulsatile lh release in the human

T2 - A model of ketoconazole-induced hypoandrogenemia and deconvolution-estimated LH secretory enhancement

AU - Zwart, A. P.

AU - Iranmanesh, A.

AU - Veldhuis, Johannes D

PY - 1996

Y1 - 1996

N2 - As a novel experimental paradigm for reversible Leydig-cell castration in the human, we administered a potent steroidogenic enzyme inhibitor, ketoconazole (KTCZ), with physiological amounts of glucocorticoid to counteract concurrent inhibition of Cortisol biosynthesis. Six young men received 1000 mg KTCZ at midnight, followed by 400 mg q 6 h orally for 48 h with 0.5 mg dexamethasone BID replacement. Serum testosterone concentrations fell to 32 + 6 ng/dL (versus baseline 524 ±24) during the second 24 h of study, when blood samples were withdrawn at 10-min intervals. Sera were submitted to LH IRMA and multiparameter deconvolution analysis to quantitate the number, duration, amplitude, and mass of underlying LH secretory bursts and the half-life of endogenous LH (Meth Enzymol 210:539,1992). In response to KTCZ, mean (24-h) serum LH concentrations rose from 3.8 ±0.25 to 10.5 + 1.1 IU/L (P<0.01), with a smaller increase in FSH from 3.8 + 0.81 to 6.6 + 1.4 IU/L. Deconvolution analysis under an assumption of purely pulsatile LH release revealed a significant acceleration of LH secretory burst frequency, viz., from (median) 12 to 23 bursts/24 h (P<0.01) with corresponding decline in the interpulse interval from 118 (basal) to 62 min (KTCZ). LH secretory burst amplitude, mass, and duration were unaffected by androgen withdrawal, but the estimated endogenous half-life of LH increased from 95 min to 227 min (P<0.05). A new waveform-independent deconvolution technique (Meth Neurosci 28:1-24,1995) assuming a known LH half-life (J Clin Invest 77:1122, 1986) corroborated increased LH secretory burst frequency after KTCZ (namely 21 vs 12 pulses/day), but with a rise in putative basal LH secretion from 0.041 to 0.20 lU/L/min (P<0.05) Both deconvolution models predicted the increases in serum LH concentration peak maxima and interpeak valleys, as appraised by a model-independent discrete peak-detection algorithm, Cluster analysis (AJP 2SO:E486, 1986). In conclusion, a novel human model of reversible Leydig-cell castration unleashes pulsatile LH release via a nearly 2-fold acceleration in LH secretory burst frequency with either a concomitant prolongation of endogenous LH half-life and/or the emergence of basal LH secretion.

AB - As a novel experimental paradigm for reversible Leydig-cell castration in the human, we administered a potent steroidogenic enzyme inhibitor, ketoconazole (KTCZ), with physiological amounts of glucocorticoid to counteract concurrent inhibition of Cortisol biosynthesis. Six young men received 1000 mg KTCZ at midnight, followed by 400 mg q 6 h orally for 48 h with 0.5 mg dexamethasone BID replacement. Serum testosterone concentrations fell to 32 + 6 ng/dL (versus baseline 524 ±24) during the second 24 h of study, when blood samples were withdrawn at 10-min intervals. Sera were submitted to LH IRMA and multiparameter deconvolution analysis to quantitate the number, duration, amplitude, and mass of underlying LH secretory bursts and the half-life of endogenous LH (Meth Enzymol 210:539,1992). In response to KTCZ, mean (24-h) serum LH concentrations rose from 3.8 ±0.25 to 10.5 + 1.1 IU/L (P<0.01), with a smaller increase in FSH from 3.8 + 0.81 to 6.6 + 1.4 IU/L. Deconvolution analysis under an assumption of purely pulsatile LH release revealed a significant acceleration of LH secretory burst frequency, viz., from (median) 12 to 23 bursts/24 h (P<0.01) with corresponding decline in the interpulse interval from 118 (basal) to 62 min (KTCZ). LH secretory burst amplitude, mass, and duration were unaffected by androgen withdrawal, but the estimated endogenous half-life of LH increased from 95 min to 227 min (P<0.05). A new waveform-independent deconvolution technique (Meth Neurosci 28:1-24,1995) assuming a known LH half-life (J Clin Invest 77:1122, 1986) corroborated increased LH secretory burst frequency after KTCZ (namely 21 vs 12 pulses/day), but with a rise in putative basal LH secretion from 0.041 to 0.20 lU/L/min (P<0.05) Both deconvolution models predicted the increases in serum LH concentration peak maxima and interpeak valleys, as appraised by a model-independent discrete peak-detection algorithm, Cluster analysis (AJP 2SO:E486, 1986). In conclusion, a novel human model of reversible Leydig-cell castration unleashes pulsatile LH release via a nearly 2-fold acceleration in LH secretory burst frequency with either a concomitant prolongation of endogenous LH half-life and/or the emergence of basal LH secretion.

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