Effect of Estrogen versus Testosterone on Circulating Osteoprotegerin and Other Cytokine Levels in Normal Elderly Men

Khosla, Sundeep; Atkinson, Elizabeth J.; Dunstan, Colin R.; O’Fallon, W. M.

doi:10.1210/jcem.87.4.8397

Cited by 191Bone Metabolism and DiseasesBone health and osteoporosis researchEstrogen and related hormone effects

Effect of Estrogen versus Testosterone on Circulating Osteoprotegerin and Other Cytokine Levels in Normal Elderly Men

Khosla, Sundeep, Atkinson, Elizabeth J., Dunstan, Colin R., O’Fallon, W. M.·2002·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jcem.87.4.8397

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Abstract

Recent studies have shown that estrogen (E) likely plays a dominant role in inhibiting bone resorption in normal elderly men. Because both E and T inhibit osteoclast development and activity, stimulate osteoclast apoptosis, and inhibit osteoblast production of IL-6, it is unclear why T is less potent than E in inhibiting bone resorption in vivo. Osteoprotegerin (OPG) binds to and inactivates RANKL, the final mediator of osteoclastogenesis. In vitro, OPG production is stimulated by E, and preliminary data suggest that T has the opposite effect. Thus, we analyzed serum for OPG levels from a study in which 59 elderly men (mean age, 68 yr) were made acutely hypogonadal using a GnRH agonist and were also placed on an aromatase inhibitor to block conversion of androgens to estrogens. They were studied first under conditions of physiologic E and T replacement, and then randomized to no replacement, replacement with E alone, T alone, or both E and T. E alone resulted in an 18.6 +/- 7.9% (mean +/- SEM) increase in serum OPG levels (P < 0.05), whereas T alone tended to decrease OPG levels (by 10.0 +/- 8.5%; P < 0.05 compared with E alone). Using a two-factor ANOVA model, there was a highly significant T effect (P = 0.006) on decreasing serum OPG levels. Serum TNF-alpha, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF-alpha and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements, the ANOVA models were not significant for E or T effects. Taken together, these data suggest that in vivo, T decreases OPG levels, whereas E tends to have the opposite effect. These differential effects of E vs. T on OPG production may explain, at least in part, why T has weaker effects than E on inhibiting bone resorption in vivo in humans.

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Testosterone replacement appeared to lower OPG levels in men made acutely hypogonadal by GnRH agonist and aromatase inhibitor blockade of estrogen production.
“Testosterone replacement appeared to lower OPG levels in men made acutely hypogonadal by GnRH agonist and who also received aromatase inhibitor blockade of estrogen production (106).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [106]
Elderly men with hypogonadism induced by gonadotrophin releasing hormone agonists developed a significant increase in serum TNFa and interleukin 6 compared with baseline.
“elderly men with hypogonadism induced by gonadotrophin releasing hormone agonists developed a significant increase in serum TNFa and interleukin 6 compared with baseline.42”
From Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life (2004) · cites this paper as [42]

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Authors: Khosla, S., Atkinson, E. J., Dunstan, C. R., & O’Fallon, W. M.
Affiliations: Mayo Clinic (US)
Amgen (United States) (US)
Corresponding author: Khosla, Sundeep
ORCID: Khosla, Sundeep
Atkinson, Elizabeth J.
Dunstan, Colin R.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2002-04-01
Volume: 87
Issue: 4
Pages: 1550-1554
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jcem.87.4.8397
OpenAlex: W2124998345
Cited by: 191
References: 32
Citations by year: 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 7 · 2013: 8 · 2012: 13
FWCI: 7.30
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG 04875, P01AG004875)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: estrogen, testosterone, osteoprotegerin, bone resorption, older men, aromatase inhibitors, hormone replacement therapy, cytokines, TNF-α, interleukin-6, soluble IL-6 receptor, RANKL, osteoclastogenesis, bone metabolism
MeSH terms: Aged, Aged, 80 and over, Bone Resorption, Estrogens, Glycoproteins, Humans, Male, Reference Values, Gonadal Steroid Hormones, Testosterone, Biomarkers, Cytokines, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Osteoprotegerin

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Effect of Estrogen versus Testosterone on Circulating Osteoprotegerin and Other Cytokine Levels in Normal Elderly Men

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