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Cited by 121Hypothalamic control of reproductive hormonesHormonal and reproductive studiesGrowth Hormone and Insulin-like Growth Factors

Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis

Mulligan, T, Iranmanesh, A, Kerzner, R, Demers, LW, Veldhuis, JD·1999·European Journal of Endocrinology
DOI 10.1530/eje.0.1410257
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Abstract

OBJECTIVE: To examine the possibility that lower serum bioavailable testosterone concentrations, without increased LH release, in healthy older men, reflects hypothalamic GnRH deficiency. DESIGN: We used a randomized, double-blind, placebo-controlled design. METHODS: We treated each of five young (ages 20-34 years) and five older (ages 60-78 years) men with 2 weeks of randomized infusions of saline or pulsatile GnRH (100 ng/kg i.v. every 90 min). RESULTS: At baseline (saline infusion), older men had more LH pulses (young compared with old, 10 +/- 0.6 compared with 15 +/- 1, P = 0.0026) per 24h, reduced fractional LH pulse amplitude (219 +/- 17% compared with 167 +/- 40%, P = 0.0376), and more disorderly hormone release as judged by approximate entropy (ApEn) (LH, P < or = 0.0001; testosterone, P < or = 0.0047). In response to pulsatile i.v. GnRH infusions, serum 24-h LH concentrations (measured by immunoradiometric assay (IRMA)), increased equivalently in young and older men (to 7.3 +/- 1.2 and 7.2 +/- 1.8 IU/l respectively). GnRH treatment also normalized LH pulse frequency and amplitude, ApEn, and plasma biologically active LH (pooled) concentrations. In contrast, 24-h testosterone concentrations failed to increase equivalently in older men (young compared with old, 869 +/- 88 compared with 517 +/- 38 ng/dl, P = 0.0061), reflecting lower testosterone peak maxima (995 +/- 108 compared with 583 +/- 48 ng/dl, P = 0.0083) and interpeak nadirs (750 +/- 87 compared with 427 +/- 26 ng/dl, P = 0.0073). CONCLUSIONS: We have demonstrated that, in older men, successful reconstitution of 24-h pituitary (bioactive) LH output and pulsatile (IRMA) LH release patterns could be achieved by a fixed exogenous GnRH pulse signal, thereby implicating altered endogenous hypothalamic GnRH release in the relative hypogonadotropism of aging. The failure of testosterone concentrations to increase concomitantly points to a simultaneous Leydig cell defect. We conclude that aging in men is marked by a dual defect in the central nervous system-pituitary-Leydig cell axis.

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  • In men, the age-related decline in testosterone has been suggested to result from defective gonadotropin-releasing hormone secretion combined with reduced Leydig cell responsiveness.

    “In men, this decline in T has been suggested to be due to a combination of both defective gonadotropin-releasing hormone secretion and Leydig cell responsiveness.36”

    From Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications (2021) · cites this paper as [36]

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Authors
Mulligan, T., Iranmanesh, A., Kerzner, R., Demers, L., & Veldhuis, J.
Affiliations
  • Hunter Holmes McGuire VA Medical Center (US)
  • Salem VA Medical Center (US)
  • Pennsylvania State University (US)
  • U.S. National Science Foundation (US)
Corresponding author
Mulligan, T
ORCID
Venue
European Journal of Endocrinology
Publisher
Oxford University Press (OUP)
Published
1999-09-01
Volume
141
Issue
3
Pages
257-266
ISSN
  • 0804-4643 (ISSN-L)
  • 1479-683X
DOI
10.1530/eje.0.1410257
OpenAlex
W2118434339
Cited by
121
References
42
Citations by year
2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 4 · 2012: 4
FWCI
6.53
Type
journal article
Language
en
Open access
closed
Locations
  • European Journal of Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • U.S. Public Health Service
  • National Center for Research Resources (M01RR000847, MO1-RR00847)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30 HD28934)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
Leydig cell dysfunction, luteinizing hormone pulsatility, testosterone secretion, approximate entropy, GnRH agonist therapy, male hypogonadism, gonadotropic axis, LH bioactivity
MeSH terms
Adult, Aged, Aging, Dehydroepiandrosterone, Double-Blind Method, Follicle Stimulating Hormone, Humans, Hypothalamo-Hypophyseal System, Hypothalamus, Infusion Pumps, Infusions, Intravenous, Inhibins, Insulin-Like Growth Factor I, Leydig Cells, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Male, Middle Aged, Pituitary-Adrenal System, Prolactin, Testosterone, Cross-Over Studies

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