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OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition
Context. Investigations of testosterone (T)-mediated feedback on LH secretion are few and contradictory. Discrepancies may reflect the choice of androgen, as well as dose, route and/or pattern (continuous vspulsatile) of administration. Moreover, for controlled T feedback studies, endogenous T secre...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554825/ http://dx.doi.org/10.1210/js.2019-OR16-5 |
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author | Roelfsema, Ferdinand Yang, Rebecca Liu, Peter Takahashi, Paul Veldhuis, Johannes |
author_facet | Roelfsema, Ferdinand Yang, Rebecca Liu, Peter Takahashi, Paul Veldhuis, Johannes |
author_sort | Roelfsema, Ferdinand |
collection | PubMed |
description | Context. Investigations of testosterone (T)-mediated feedback on LH secretion are few and contradictory. Discrepancies may reflect the choice of androgen, as well as dose, route and/or pattern (continuous vspulsatile) of administration. Moreover, for controlled T feedback studies, endogenous T secretion must be shut down and replaced by iv T infusion. Objective. The goal of this study was to quantify feedback in relation to the infused T pattern (pulsatile vs nonpulsatile) with the hypotheses that: 1) feedback by T pulses is less inhibitory, 2) T feedback operates partly at the pituitary level, 3) T feedback is controlled in part by body composition. Design. This was a placebo-controlled, blinded, and prospectively randomized crossover study comprising 16 men (age range 23-54 yr and BMI between 22.3-34.2 kg/m(2)). Subjects received ketoconazole (1600 mg over 22 h to block endogenous T secretion: serum T below 85 ng/dL) followed by pulsatile or continuous iv T addback (total T dose 5 mg/22 h). Cortisol inhibition was treated with low-dose dexamethasone. Setting. The study was performed in a Clinical Translational Research Unit. Interventions. Subjects underwent 14 h of blood sampling at 10-min intervals, starting at 0600 h. T was given continuously starting at 0900 h or as 45-min squarewave pulses every 90 min. To test pituitary feedback, a bolus iv injection of 33 ng/kg GnRH was given at 1630 h. Outcome measures. Log-transformed LH and T concentration ratios before and after GnRH administration. In addition, a four-parameter logistic regression between serum T concentration and LH secretion rate (calculated by deconvolution analysis) was used to independently estimate feedback of T on LH. Results. Despite higher T (total, bioavailable and free T) concentrations during pulsatile feedback, LH concentrations and secretion rates, whether driven by endogenous or exogenous GnRH, were similar to those during continuous infusion, indicating diminished pulsatile T feedback. This interpretation was corroborated by the right-shift (i.e. towards higher T concentrations) of the T-LH inhibitory dose-response curve. During continuous and pulsatile T infusion, LH concentrations and LH:T ratios depended positively on BMI to a similar extent before and after GnRH administration. Under both feedback regimens, basal but not pulsatile LH secretion correlated negatively with CT-estimated abdominal visceral fat mass. Age was not a significant covariate over the limited range explored. Conclusion. In summary, pulsatile T is less effective as a negative feedback signal on LH secretion than continuous T administration, as demonstrated by two independent methods. This difference in feedback strength was evident for exogenous GnRH-stimulated LH release as well, and thus occurs probably in part at the pituitary level, while not excluding additional hypothalamic involvement. |
format | Online Article Text |
id | pubmed-6554825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-65548252019-06-13 OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition Roelfsema, Ferdinand Yang, Rebecca Liu, Peter Takahashi, Paul Veldhuis, Johannes J Endocr Soc Neuroendocrinology and Pituitary Context. Investigations of testosterone (T)-mediated feedback on LH secretion are few and contradictory. Discrepancies may reflect the choice of androgen, as well as dose, route and/or pattern (continuous vspulsatile) of administration. Moreover, for controlled T feedback studies, endogenous T secretion must be shut down and replaced by iv T infusion. Objective. The goal of this study was to quantify feedback in relation to the infused T pattern (pulsatile vs nonpulsatile) with the hypotheses that: 1) feedback by T pulses is less inhibitory, 2) T feedback operates partly at the pituitary level, 3) T feedback is controlled in part by body composition. Design. This was a placebo-controlled, blinded, and prospectively randomized crossover study comprising 16 men (age range 23-54 yr and BMI between 22.3-34.2 kg/m(2)). Subjects received ketoconazole (1600 mg over 22 h to block endogenous T secretion: serum T below 85 ng/dL) followed by pulsatile or continuous iv T addback (total T dose 5 mg/22 h). Cortisol inhibition was treated with low-dose dexamethasone. Setting. The study was performed in a Clinical Translational Research Unit. Interventions. Subjects underwent 14 h of blood sampling at 10-min intervals, starting at 0600 h. T was given continuously starting at 0900 h or as 45-min squarewave pulses every 90 min. To test pituitary feedback, a bolus iv injection of 33 ng/kg GnRH was given at 1630 h. Outcome measures. Log-transformed LH and T concentration ratios before and after GnRH administration. In addition, a four-parameter logistic regression between serum T concentration and LH secretion rate (calculated by deconvolution analysis) was used to independently estimate feedback of T on LH. Results. Despite higher T (total, bioavailable and free T) concentrations during pulsatile feedback, LH concentrations and secretion rates, whether driven by endogenous or exogenous GnRH, were similar to those during continuous infusion, indicating diminished pulsatile T feedback. This interpretation was corroborated by the right-shift (i.e. towards higher T concentrations) of the T-LH inhibitory dose-response curve. During continuous and pulsatile T infusion, LH concentrations and LH:T ratios depended positively on BMI to a similar extent before and after GnRH administration. Under both feedback regimens, basal but not pulsatile LH secretion correlated negatively with CT-estimated abdominal visceral fat mass. Age was not a significant covariate over the limited range explored. Conclusion. In summary, pulsatile T is less effective as a negative feedback signal on LH secretion than continuous T administration, as demonstrated by two independent methods. This difference in feedback strength was evident for exogenous GnRH-stimulated LH release as well, and thus occurs probably in part at the pituitary level, while not excluding additional hypothalamic involvement. Endocrine Society 2019-04-30 /pmc/articles/PMC6554825/ http://dx.doi.org/10.1210/js.2019-OR16-5 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Neuroendocrinology and Pituitary Roelfsema, Ferdinand Yang, Rebecca Liu, Peter Takahashi, Paul Veldhuis, Johannes OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition |
title | OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition |
title_full | OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition |
title_fullStr | OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition |
title_full_unstemmed | OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition |
title_short | OR16-5 Feedback on LH in Testosterone-Clamped Men Depends on the Mode of Testosterone Administration and Body Composition |
title_sort | or16-5 feedback on lh in testosterone-clamped men depends on the mode of testosterone administration and body composition |
topic | Neuroendocrinology and Pituitary |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554825/ http://dx.doi.org/10.1210/js.2019-OR16-5 |
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