Differential responses of biologically active luteinizing hormone secretion in older versus young men to interruption of androgen negative feedback

Johannes D. Veldhuis, Randall Urban, Maria L. Dufau

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

To investigate the responsiveness of the healthy aging male hypothalamo- pituitary-gonadal axis to short term interruption of androgen negative feedback, we administered a selective nonsteroidal competitive antagonist of the androgen receptor, flutamide hydrochloride (250 mg, orally, three times daily for 3.5 days), to five older (aged 63-72 yr) and eight young (aged 21-30 yr) men. Pulsatile bioactive LH release was assessed by the rat interstitial cell testosterone bioassay in plasma sampled at 10-min intervals for 8 h overnight at baseline and after flutamide administration. Pituitary responsiveness was evaluated after two successive iv injections of 10 μg GnRH. Deconvolution analysis was used to estimate the number, amplitude, duration, and mass of bioactive LH secretory bursts and the half- life of biologically active hormone. At baseline, older men exhibited a significantly lower spontaneous bioactive LH secretory burst frequency than young men, with a median of 5 events/8 h (older) vs. 7.5 bursts/8 h (younger, P < 0.05). In older men, mean 8-h plasma bioactive LH concentrations increased significantly in response to flutamide (P = 0.006), and the 8-h calculated secretion rate of bioactive LH rose concomitantly. These increases were similar to responses in young men. However, during antiandrogen administration, the frequency of bioactive LH secretory bursts failed to rise in older men to the baseline value seen in young men. Moreover, older (but not young) men showed a significant prolongation of the LH secretory burst duration in response to flutamide treatment. On the other hand, the estimated half-life of endogenous bioactive LH increased significantly after flutamide ingestion in young compared to older individuals. After GnRH injections, older and young men secreted similar amounts of LH before flutamide administration, but during flutamide treatment, older men released more biologically active LH after the first GnRH stimulus [older men, 104 ± 11 IU/L (median, 110); younger men, 44 ± 8.4 IU/L (median, 40); P < 0.05]. Serum free testosterone concentrations rose significantly during flutamide exposure in both young and older men, but estradiol concentrations increased significantly only in young men. In summary, healthy older men exhibit a reduced (overnight) spontaneous bioactive LH secretory burst frequency. Pharmacological attenuation of androgen-mediated negative feedback increases mean serum free testosterone concentrations and plasma bioactive LH concentrations to a similar degree in older and young individuals, but different mechanisms operate in the two age groups. In older men, flutamide treatment amplifies the mass of bioactive LH secreted per burst by prolonging the LH secretory burst duration, whereas in young men, flutamide administration increases the apparent half-life of biologically active LH significantly relative to values in older men. We conclude that competitive nonsteroidal blockade of the androgen receptor unmasks qualitatively altered mechanisms of increased bioactive LH release in healthy older men.

Original languageEnglish (US)
Pages (from-to)1763-1770
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume79
Issue number6
DOIs
StatePublished - Dec 1994

Fingerprint

Flutamide
Luteinizing Hormone
Androgens
Feedback
Gonadotropin-Releasing Hormone
Testosterone
Plasmas
Androgen Receptor Antagonists
Half-Life
Androgen Antagonists
Bioassay
Androgen Receptors
Deconvolution
Rats
Estradiol
Aging of materials
Hormones

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{77efdd7399584592906bd9cbd9684a1d,
title = "Differential responses of biologically active luteinizing hormone secretion in older versus young men to interruption of androgen negative feedback",
abstract = "To investigate the responsiveness of the healthy aging male hypothalamo- pituitary-gonadal axis to short term interruption of androgen negative feedback, we administered a selective nonsteroidal competitive antagonist of the androgen receptor, flutamide hydrochloride (250 mg, orally, three times daily for 3.5 days), to five older (aged 63-72 yr) and eight young (aged 21-30 yr) men. Pulsatile bioactive LH release was assessed by the rat interstitial cell testosterone bioassay in plasma sampled at 10-min intervals for 8 h overnight at baseline and after flutamide administration. Pituitary responsiveness was evaluated after two successive iv injections of 10 μg GnRH. Deconvolution analysis was used to estimate the number, amplitude, duration, and mass of bioactive LH secretory bursts and the half- life of biologically active hormone. At baseline, older men exhibited a significantly lower spontaneous bioactive LH secretory burst frequency than young men, with a median of 5 events/8 h (older) vs. 7.5 bursts/8 h (younger, P < 0.05). In older men, mean 8-h plasma bioactive LH concentrations increased significantly in response to flutamide (P = 0.006), and the 8-h calculated secretion rate of bioactive LH rose concomitantly. These increases were similar to responses in young men. However, during antiandrogen administration, the frequency of bioactive LH secretory bursts failed to rise in older men to the baseline value seen in young men. Moreover, older (but not young) men showed a significant prolongation of the LH secretory burst duration in response to flutamide treatment. On the other hand, the estimated half-life of endogenous bioactive LH increased significantly after flutamide ingestion in young compared to older individuals. After GnRH injections, older and young men secreted similar amounts of LH before flutamide administration, but during flutamide treatment, older men released more biologically active LH after the first GnRH stimulus [older men, 104 ± 11 IU/L (median, 110); younger men, 44 ± 8.4 IU/L (median, 40); P < 0.05]. Serum free testosterone concentrations rose significantly during flutamide exposure in both young and older men, but estradiol concentrations increased significantly only in young men. In summary, healthy older men exhibit a reduced (overnight) spontaneous bioactive LH secretory burst frequency. Pharmacological attenuation of androgen-mediated negative feedback increases mean serum free testosterone concentrations and plasma bioactive LH concentrations to a similar degree in older and young individuals, but different mechanisms operate in the two age groups. In older men, flutamide treatment amplifies the mass of bioactive LH secreted per burst by prolonging the LH secretory burst duration, whereas in young men, flutamide administration increases the apparent half-life of biologically active LH significantly relative to values in older men. We conclude that competitive nonsteroidal blockade of the androgen receptor unmasks qualitatively altered mechanisms of increased bioactive LH release in healthy older men.",
author = "Veldhuis, {Johannes D.} and Randall Urban and Dufau, {Maria L.}",
year = "1994",
month = "12",
doi = "10.1210/jc.79.6.1763",
language = "English (US)",
volume = "79",
pages = "1763--1770",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "6",

}

TY - JOUR

T1 - Differential responses of biologically active luteinizing hormone secretion in older versus young men to interruption of androgen negative feedback

AU - Veldhuis, Johannes D.

AU - Urban, Randall

AU - Dufau, Maria L.

PY - 1994/12

Y1 - 1994/12

N2 - To investigate the responsiveness of the healthy aging male hypothalamo- pituitary-gonadal axis to short term interruption of androgen negative feedback, we administered a selective nonsteroidal competitive antagonist of the androgen receptor, flutamide hydrochloride (250 mg, orally, three times daily for 3.5 days), to five older (aged 63-72 yr) and eight young (aged 21-30 yr) men. Pulsatile bioactive LH release was assessed by the rat interstitial cell testosterone bioassay in plasma sampled at 10-min intervals for 8 h overnight at baseline and after flutamide administration. Pituitary responsiveness was evaluated after two successive iv injections of 10 μg GnRH. Deconvolution analysis was used to estimate the number, amplitude, duration, and mass of bioactive LH secretory bursts and the half- life of biologically active hormone. At baseline, older men exhibited a significantly lower spontaneous bioactive LH secretory burst frequency than young men, with a median of 5 events/8 h (older) vs. 7.5 bursts/8 h (younger, P < 0.05). In older men, mean 8-h plasma bioactive LH concentrations increased significantly in response to flutamide (P = 0.006), and the 8-h calculated secretion rate of bioactive LH rose concomitantly. These increases were similar to responses in young men. However, during antiandrogen administration, the frequency of bioactive LH secretory bursts failed to rise in older men to the baseline value seen in young men. Moreover, older (but not young) men showed a significant prolongation of the LH secretory burst duration in response to flutamide treatment. On the other hand, the estimated half-life of endogenous bioactive LH increased significantly after flutamide ingestion in young compared to older individuals. After GnRH injections, older and young men secreted similar amounts of LH before flutamide administration, but during flutamide treatment, older men released more biologically active LH after the first GnRH stimulus [older men, 104 ± 11 IU/L (median, 110); younger men, 44 ± 8.4 IU/L (median, 40); P < 0.05]. Serum free testosterone concentrations rose significantly during flutamide exposure in both young and older men, but estradiol concentrations increased significantly only in young men. In summary, healthy older men exhibit a reduced (overnight) spontaneous bioactive LH secretory burst frequency. Pharmacological attenuation of androgen-mediated negative feedback increases mean serum free testosterone concentrations and plasma bioactive LH concentrations to a similar degree in older and young individuals, but different mechanisms operate in the two age groups. In older men, flutamide treatment amplifies the mass of bioactive LH secreted per burst by prolonging the LH secretory burst duration, whereas in young men, flutamide administration increases the apparent half-life of biologically active LH significantly relative to values in older men. We conclude that competitive nonsteroidal blockade of the androgen receptor unmasks qualitatively altered mechanisms of increased bioactive LH release in healthy older men.

AB - To investigate the responsiveness of the healthy aging male hypothalamo- pituitary-gonadal axis to short term interruption of androgen negative feedback, we administered a selective nonsteroidal competitive antagonist of the androgen receptor, flutamide hydrochloride (250 mg, orally, three times daily for 3.5 days), to five older (aged 63-72 yr) and eight young (aged 21-30 yr) men. Pulsatile bioactive LH release was assessed by the rat interstitial cell testosterone bioassay in plasma sampled at 10-min intervals for 8 h overnight at baseline and after flutamide administration. Pituitary responsiveness was evaluated after two successive iv injections of 10 μg GnRH. Deconvolution analysis was used to estimate the number, amplitude, duration, and mass of bioactive LH secretory bursts and the half- life of biologically active hormone. At baseline, older men exhibited a significantly lower spontaneous bioactive LH secretory burst frequency than young men, with a median of 5 events/8 h (older) vs. 7.5 bursts/8 h (younger, P < 0.05). In older men, mean 8-h plasma bioactive LH concentrations increased significantly in response to flutamide (P = 0.006), and the 8-h calculated secretion rate of bioactive LH rose concomitantly. These increases were similar to responses in young men. However, during antiandrogen administration, the frequency of bioactive LH secretory bursts failed to rise in older men to the baseline value seen in young men. Moreover, older (but not young) men showed a significant prolongation of the LH secretory burst duration in response to flutamide treatment. On the other hand, the estimated half-life of endogenous bioactive LH increased significantly after flutamide ingestion in young compared to older individuals. After GnRH injections, older and young men secreted similar amounts of LH before flutamide administration, but during flutamide treatment, older men released more biologically active LH after the first GnRH stimulus [older men, 104 ± 11 IU/L (median, 110); younger men, 44 ± 8.4 IU/L (median, 40); P < 0.05]. Serum free testosterone concentrations rose significantly during flutamide exposure in both young and older men, but estradiol concentrations increased significantly only in young men. In summary, healthy older men exhibit a reduced (overnight) spontaneous bioactive LH secretory burst frequency. Pharmacological attenuation of androgen-mediated negative feedback increases mean serum free testosterone concentrations and plasma bioactive LH concentrations to a similar degree in older and young individuals, but different mechanisms operate in the two age groups. In older men, flutamide treatment amplifies the mass of bioactive LH secreted per burst by prolonging the LH secretory burst duration, whereas in young men, flutamide administration increases the apparent half-life of biologically active LH significantly relative to values in older men. We conclude that competitive nonsteroidal blockade of the androgen receptor unmasks qualitatively altered mechanisms of increased bioactive LH release in healthy older men.

UR - http://www.scopus.com/inward/record.url?scp=0028557257&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028557257&partnerID=8YFLogxK

U2 - 10.1210/jc.79.6.1763

DO - 10.1210/jc.79.6.1763

M3 - Article

VL - 79

SP - 1763

EP - 1770

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 6

ER -