The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index.
Effect of Estrogen versus Testosterone on Circulating Osteoprotegerin and Other Cytokine Levels in Normal Elderly Men
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 Serum TNF-alpha, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF-alpha and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements,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 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]
In the citing paper
“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]
Citations
Cites
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M.-S., Lüthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80209-3 · Cited by 5,130
Self-citationEstrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man
Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R. M., Specker, B., Williams, T. C., Lubahn, D. B., & Korach, K. S. (1994) · New England Journal of Medicine · doi:10.1056/nejm199410203311604 · Cited by 2,471
Increased Osteoclast Development After Estrogen Loss: Mediation by Interleukin-6
Jilka, R. L., Hangoc, G., Girasole, G., Passeri, G., Williams, D. C., Abrams, J. S., Boyce, B. F., Broxmeyer, H. E., & Manolagas, S. C. (1992) · Science · doi:10.1126/science.1621100 · Cited by 1,440
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Yasuda, H., Shima, N., Nakagawa, N., Mochizuki, S.-I., Yano, K., Fujise, N., Sato, Y., Goto, M., Yamaguchi, K., Kuriyama, M., et al. (1998) · Endocrinology · doi:10.1210/endo.139.3.5837 · Cited by 1,201
Nongenotropic, Sex-Nonspecific Signaling through the Estrogen or Androgen Receptors
Kousteni, S., Bellido, T., Plotkin, L. I., O’Brien, C. A., Bodenner, D., Li, H., Han, K., Gregorio, G. B. D., Katzenellenbogen, J. A., Katzenellenbogen, B. S., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00268-9 · Cited by 1,163
Effect of testosterone and estradiol in a man with aromatase deficiency
Carani, C., Qin, K., Simoni, M., Faustini-Fustini, M., Serpente, S., Boyd, J., Korach, K. S., & Simpson, E. R. (1997) · New England Journal of Medicine · doi:10.1056/nejm199707103370204 · Cited by 1,151
Estrogen promotes apoptosis of murine osteoclasts mediated by TGF–β
Hughes, D. E., Dai, A., Tiffee, J. C., Li, H. H., Mundy, G. R., & Boyce, B. F. (1996) · Nature Medicine · doi:10.1038/nm1096-1132 · Cited by 813
Falahati-Nini, A., Riggs, B. L., Atkinson, E. J., O’Fallon, W. M., Eastell, R., & Khosla, S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10942 · Cited by 757
Self-citationKousteni, S. (2001) · Cell · doi:10.1016/s0092-8674(02)08100-x · Cited by 757
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1 of the 32 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
- Chen, 2001, Gender-independent induction of murine osteoclast apoptosis in vitro by either estrogen or non-aromatizable androgens, J Bone Miner Res, 16, S159
- Chen, 2000, Effects of 17β-estradiol (E2), genistein (GEN) and daidzein (DIZ) on osteoclastogenesis inhibitory factor (OCIF) and osteoclast differentiation factor (ODF) mRNA expressed during MC3T3–E1 cell differentiation, J Bone Miner Res, 15, S495
- Sarikaya, 2001, Serum osteoprotegerin levels in humans, J Bone Miner Res, 16, S215
- Riggs, 2001, Evidence that postmenopausal women with vertebral fractures due to type I osteoporosis have enhanced responsiveness of bone to estrogen deficiency, J Bone Miner Res, 16, S281
Cited by
Sorted by citations
Sex Steroids and the Construction and Conservation of the Adult Skeleton
Riggs, B. L., Khosla, S., & Melton, L. J. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.3.0465 · Cited by 1,846
“Both in osteoblastic cells in vitro and in elderly men in vivo, androgen decreases (88, 89) and E increases (78, 89) OPG production, which may partly explain why the antiresorptive action of T is weaker than the antiresorptive action of E.”
BackgroundSelf-citationKearns, A. E., Khosla, S., & Kostenuik, P. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0014 · Cited by 824
Self-citationMalkin, C. J., Pugh, P. J., Jones, R. D., Kapoor, D., Channer, K. S., & Jones, T. H. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031069 · Cited by 731
Interleukin-6 in Aging and Chronic Disease: A Magnificent Pathway
Maggio, M. G., Guralnik, J. M., Longo, D. L., & Ferrucci, L. (2006) · The Journals of Gerontology Series A · doi:10.1093/gerona/61.6.575 · Cited by 696
“Similarly, Khosla and coauthors found that antiandrogen treatment in men increased IL-6 and sIL-6r levels, and testosterone partially reverses this effect (86).”
BackgroundRole of RANK ligand in mediating increased bone resorption in early postmenopausal women
Eghbali-Fatourechi, G., Khosla, S., Sanyal, A., Boyle, W. J., Lacey, D. L., & Riggs, B. L. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17215 · Cited by 825
“Moreover, although we and others have demonstrated previously that estrogen stimulates OPG production both in vitro (15, 16) and in vivo (17), circulating OPG levels did not differ between the three groups.”
BackgroundResultSelf-citation
Metadata
- 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
- 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
- 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 › Endocrinology › 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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