Pulsatile intravenous infusion of recombinant human luteinizing hormone under acute gonadotropin-releasing hormone receptor blockade reconstitutes testosterone secretion in young men

Johannes D Veldhuis, Ali Iranmanesh

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20 Citations (Scopus)

Abstract

The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean ± SEM) from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter (P < 0.01) and Te concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10-25 h after ganirelix administration) at mean values of 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 ± 0.3, LH peak maxima to 7.1 ± 0.6, incremental LH peak amplitudes to 3.7 ± 0.4, and interpeak nadir LH concentrations to 3.3 ± 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 ± 52, Te peak maxima to 552 ± 64, incremental Te amplitudes to 188 ± 23, and interpeak nadir Te concentrations to 366 ± 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 ± 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40-70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 ± 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 ± 12 min; P = 0.012). We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.

Original languageEnglish (US)
Pages (from-to)4474-4479
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number9
DOIs
StatePublished - Sep 2004

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LHRH Receptors
Luteinizing Hormone
Intravenous Infusions
Testosterone
Gonadotropin-Releasing Hormone
Young Adult
Injections
Leydig Cells
Half-Life
Time delay
Reference Values

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{d413b23bad5043b28747bca2328500ce,
title = "Pulsatile intravenous infusion of recombinant human luteinizing hormone under acute gonadotropin-releasing hormone receptor blockade reconstitutes testosterone secretion in young men",
abstract = "The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean ± SEM) from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter (P < 0.01) and Te concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10-25 h after ganirelix administration) at mean values of 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 ± 0.3, LH peak maxima to 7.1 ± 0.6, incremental LH peak amplitudes to 3.7 ± 0.4, and interpeak nadir LH concentrations to 3.3 ± 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95{\%} range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 ± 52, Te peak maxima to 552 ± 64, incremental Te amplitudes to 188 ± 23, and interpeak nadir Te concentrations to 366 ± 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 ± 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40-70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 ± 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 ± 12 min; P = 0.012). We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.",
author = "Veldhuis, {Johannes D} and Ali Iranmanesh",
year = "2004",
month = "9",
doi = "10.1210/jc.2004-0203",
language = "English (US)",
volume = "89",
pages = "4474--4479",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "9",

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T1 - Pulsatile intravenous infusion of recombinant human luteinizing hormone under acute gonadotropin-releasing hormone receptor blockade reconstitutes testosterone secretion in young men

AU - Veldhuis, Johannes D

AU - Iranmanesh, Ali

PY - 2004/9

Y1 - 2004/9

N2 - The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean ± SEM) from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter (P < 0.01) and Te concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10-25 h after ganirelix administration) at mean values of 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 ± 0.3, LH peak maxima to 7.1 ± 0.6, incremental LH peak amplitudes to 3.7 ± 0.4, and interpeak nadir LH concentrations to 3.3 ± 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 ± 52, Te peak maxima to 552 ± 64, incremental Te amplitudes to 188 ± 23, and interpeak nadir Te concentrations to 366 ± 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 ± 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40-70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 ± 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 ± 12 min; P = 0.012). We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.

AB - The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean ± SEM) from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter (P < 0.01) and Te concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10-25 h after ganirelix administration) at mean values of 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 ± 0.3, LH peak maxima to 7.1 ± 0.6, incremental LH peak amplitudes to 3.7 ± 0.4, and interpeak nadir LH concentrations to 3.3 ± 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 ± 52, Te peak maxima to 552 ± 64, incremental Te amplitudes to 188 ± 23, and interpeak nadir Te concentrations to 366 ± 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 ± 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40-70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 ± 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 ± 12 min; P = 0.012). We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.

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