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 Serum TNF-alpha, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF-alpha and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements,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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C., & Qin, K. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.12.8530621 · Cited by 1,416
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
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-citationKelly, D. M., & Jones, T. H. (2015) · Obesity Reviews · doi:10.1111/obr.12282 · Cited by 487
Regulation of Vascular Calcification by Osteoclast Regulatory Factors RANKL and Osteoprotegerin
Collin‐Osdoby, P. (2004) · Circulation Research · doi:10.1161/01.res.0000149165.99974.12 · Cited by 474
Tumor necrosis factor-α: molecular and cellular mechanisms in skeletal pathology
Nanes, M. S. (2003) · Gene · doi:10.1016/s0378-1119(03)00841-2 · Cited by 440
Sex Steroids and the Construction and Conservation of the Adult Skeleton
Riggs, B. L. (2002) · Endocrine Reviews · doi:10.1210/er.23.3.279 · Cited by 434
The role of androgens and estrogens on healthy aging and longevity
Horstman, A. M., Dillon, E. L., Urban, R. J., & Sheffield-Moore, M. (2012) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/gls068 · Cited by 396
Pathophysiology of Age-Related Bone Loss and Osteoporosis
Khosla, S., & Riggs, B. L. (2005) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2005.07.009 · Cited by 376
“Combined in vitro and in vivo studies have demonstrated that estrogen suppresses RANKL production by osteoblastic, T cells, and B cells [15] and also increases OPG production [18,19].”
BackgroundSelf-citationThe role of the immune system in the pathophysiology of osteoporosis
Clowes, J. A., Riggs, B. L., & Khosla, S. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00334.x · Cited by 366
“This finding suggested that the differential effects of estrogen compared with testosterone on OPG production may explain, at least in part, why testosterone is a weaker inhibitor of bone resorption in humans (79).”
BackgroundSelf-citationTanaka, S., Nakamura, K., Takahasi, N., & Suda, T. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00327.x · Cited by 325
“Estrogen has been demonstrated to upregulate the gene expression and protein synthesis of OPG both in vitro in human (111) and in rodent (112) osteoblastic cells and in vivo in elderly men (113).”
BackgroundResultTestosterone: a vascular hormone in health and disease
Kelly, D. M., & Jones, T. H. (2013) · Journal of Endocrinology · doi:10.1530/joe-12-0582 · Cited by 301
“Khosla et al. (2002) reported that TNFa, IL6 and IL6 soluble receptor were elevated in elderly men where hypogonadism was induced by GNRH antagonists.”
BackgroundThe effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review
Xu, J., Yu, L., Liu, F., Wan, L., & Deng, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1222129 · Cited by 292
“Studies have indicated that IL-6 has been implicated in a number of age-related diseases, including osteoporosis, and its levels rise with age (145, 146), possibly through the P3IK/AKT, MAPK, and JAK/STAT pathways (147–149).”
BackgroundClarke, B. L., & Khosla, S. (2010) · Radiologic Clinics of North America · doi:10.1016/j.rcl.2010.02.014 · Cited by 221
“Combined in vitro and in vivo studies have shown that estrogen normally suppresses RANKL production by osteoblastic cells and T- and B-lymphocytes [20,21], and increases OPG production by osteoblastic cells [24,25], so that estrogen deficiency leads to an alteration in the RANKL/OPG ratio that favors bone resorption.”
BackgroundSelf-citationMalkin, C. J., Pugh, P. J., Morris, P. D., Kerry, K. E., Jones, R. D., Jones, T. H., & Channer, K. S. (2004) · Heart · doi:10.1136/hrt.2003.021121 · Cited by 250
The Anti-Inflammatory Effects of Testosterone
Bianchi, V. E. (2018) · Journal of the Endocrine Society · doi:10.1210/js.2018-00186 · Cited by 261
“The different action T vs estradiol on OPG secretionmay explain why T is less efficient than estradiol on inhibiting bone resorption in humans [114].”
BackgroundKapoor, D., Clarke, S., Stanworth, R. D., Channer, K. S., & Jones, T. H. (2007) · European Journal of Endocrinology · doi:10.1530/eje-06-0737 · Cited by 234
“In another study, elderly men with hypogonadism induced with gonadotrophin-releasing agonists developed significant increases in serum TNF-a and IL-6 ( 31 ).”
BackgroundYialamas, M. A., Dwyer, A. A., Hanley, E., Lee, H., Pitteloud, N., & Hayes, F. J. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0454 · Cited by 220
“TNF- levels in one study of elderly men (28), T replacement”
BackgroundRogers, A., & Eastell, R. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0794 · Cited by 215
“In studies where a change in OPG has been observed, these measurements have often been made within a few days of starting treatment before changes in bone turnover have become established (97).”
BackgroundInfluentialInteraction between osteoblast and osteoclast: impact in bone disease.
Phan, T. C. A., Xu, J., & Zheng, M. (2004) · PubMed · doi:10.14670/hh-19.1325 · Cited by 213
Correlates of osteoprotegerin levels in women and men.
Khosla, S., Arrighi, H. M., Melton, III, Atkinson, E. J., O'Fallon, W. M., Dunstan, C., & Riggs, B. L. (2002) · Osteoporosis International · doi:10.1007/s001980200045 · Cited by 205
Self-citationMaggio, M., Basaria, S., Ble, A., Lauretani, F., Bandinelli, S., Ceda, G. P., Valenti, G., Ling, S. M., & Ferrucci, L. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1097 · Cited by 200
Misra, M., Miller, K. K., Cord, J., Prabhakaran, R., Herzog, D. B., Goldstein, M. A., Katzman, D. K., & Klibanski, A. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2855 · Cited by 186
Goëb, V., & Trouvin, A. (2010) · Clinical Interventions in Aging · doi:10.2147/cia.s10153 · Cited by 194
“12 Furthermore, a negative association between OPG and PTH was found in men.”
Bobjer, J., Katrinaki, M., Tsatsanis, C., Giwercman, Y. L., & Giwercman, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061466 · Cited by 173
“Other studies have suggested an immuno modulatory action of testosterone [24,25].”
Page, S. T., Plymate, S. R., Bremner, W. J., Matsumoto, A. M., Hess, D. L., Lin, D. W., Amory, J. K., Nelson, P. S., & Wu, J. D. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00484.2005 · Cited by 177
“Other interventional trials of T replacement in hypogonadal or elderly men have suggested that the T decreases production of proinflammatory cytokines such as TNF- and IL-6 (17, 23) and increases immunosuppressive IL-10 (23).”
BackgroundFemale reproductive system and bone
Clarke, B. L., & Khosla, S. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.07.006 · Cited by 158
Self-citationMohamad, N.-V., Soelaiman, I. N., & Chin, K. (2020) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530320666200604160614 · Cited by 142
Role of endocrine-immune dysregulation in osteoporosis, sarcopenia, frailty and fracture risk
Joseph, C., Kenny, R. A., Taxel, P., Lorenzo, J., Duque, G., & Kuchel, G. A. (2005) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2005.01.004 · Cited by 137
Ominsky, M. S., Li, X., Asuncion, F., Barrero, M., Warmington, K. S., Dwyer, D., Stolina, M., Geng, Z., Grisanti, M. S., Tan, H., et al. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080109 · Cited by 132
Morabito, N., Gaudio, A., Lasco, A., Atteritano, M., Pizzoleo, M. A., Cincotta, M., La Rosa, M., Guarino, R., Meo, A., & Frisina, N. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040113 · Cited by 127
“Whereas for the former, data are few and contrasting both in vitro((33)) and in vivo,((34,35)) the evidence for the latter is clearer.”
ResultHeparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity.
Irie, A., Takami, M., Kubo, H., Sekino-Suzuki, N., Kasahara, K., & Sanai, Y. (2007) · Bone · doi:10.1016/j.bone.2007.04.190 · Cited by 116
“1 ng/ ml [44,45], while 0.”
Delmas, P. D. (2008) · Journal of Clinical Densitometry · doi:10.1016/j.jocd.2008.02.002 · Cited by 117
The effects of hyperprolactinemia on bone and fat
Shibli-Rahhal, A. A., & Schlechte, J. (2008) · Pituitary · doi:10.1007/s11102-008-0097-3 · Cited by 114
“demonstrated an increase in TNF-a, IL-6 and IL-6 soluble receptor levels in men who were rendered hypogonadal by administration of a GnRH agonist and an aromatase inhibitor, and these effects were reversed by administration of estrogen or testosterone [82].”
BackgroundTestosterone and Atherosclerosis in Aging Men
Jones, R. D., Nettleship, J. E., Kapoor, D., Jones, H. T., & Channer, K. S. (2005) · American Journal of Cardiovascular Drugs · doi:10.2165/00129784-200505030-00001 · Cited by 112
Corrales, J. J., Almeida, M., Burgo, R., Mories, M. T., Miralles, J. M., & Orfao, A. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06779 · Cited by 110
“The partial androgen deficiency detected in aging men has been related to the development of multiple symptoms and signs, and it has been shown that androgen-replacement therapy may induce improvements of lean body mass (Tenover 1992, Snyder et al. 1999, Kenny et al. 2001 ), bone mineral density (Kenny et al. 2001), l…”
BackgroundInfluentialInflammatory burden and amino acid metabolism in cancer cachexia
Durham, W. J., Dillon, E. L., & Sheffield‐Moore, M. (2008) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32831cef61 · Cited by 110
Sex Hormone-Binding Globulin as an Independent Predictor of Incident Type 2 Diabetes Mellitus in Men
Lakshman, K. M., Bhasin, S., & Araujo, A. B. (2010) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glq002 · Cited by 100
“It is possible that the observed inverse correlation between T and inflammatory cytokines (34,35) may be mediated primarily by ShBG levels.”
BackgroundDifferential Effects of Estradiol, Progesterone, and Testosterone on Vaginal Structural Integrity
Pessina, M. A., Hoyt, R. F., Goldstein, I., & Traish, A. M. (2005) · Endocrinology · doi:10.1210/en.2005-0870 · Cited by 99
“Progesterone and estradiol are known to have opposing effects in the uterus (23, 24), and a similar antagonistic effect between estradiol and testosterone has been reported in other systems, such as bone resorption in men (25) and aromatase gene expression in rat testes (26).”
BackgroundAssociation of sex hormones and C‐reactive protein levels in men
Kupelian, V. A., Chiu, G. R., de Araújo, A. B., Williams, R. E., Clark, R. V., & McKinlay, J. B. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03713.x · Cited by 98
Sex differences in vascular aging in response to testosterone
Moreau, K. L., Babcock, M. C., & Hildreth, K. L. (2020) · Biology of Sex Differences · doi:10.1186/s13293-020-00294-8 · Cited by 98
Serum Osteoprotegerin in Adolescent Girls with Anorexia Nervosa
Misra, M., Soyka, L. A., Miller, K. K., Herzog, D. B., Grinspoon, S. K., de Chen, D., Neubauer, G., & Klibanski, A. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030088 · Cited by 91
“levels (3), whereas PTH, testosterone, IGF-I, and cortisol”
BackgroundLi, X., Zhou, Z.-Y., Zhang, Y.-Y., & Yang, H.-L. (2016) · PLOS ONE · doi:10.1371/journal.pone.0154677 · Cited by 89
Direct transcriptional targets of sex steroid hormones in bone
Krum, S. A. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22970 · Cited by 90
“For example, men treated with a GNRH antagonist and an aromatase inhibitor (to prevent the enzyme aromatase from converting testosterone to estrogen) had more of the osteoclastogenic cytokine TNFa in the serum than men treated with replacement testosterone [Khosla et al., 2002].”
BackgroundAssociation between endogenous sex steroid hormones and inflammatory biomarkers in US men
Tsilidis, K. K., Rohrmann, S., McGlynn, K. A., Nyante, S. J., López, D. S., Bradwin, G., Feinleib, M., Joshu, C. E., Kanarek, N., Nelson, W. G., et al. (2013) · Andrology · doi:10.1111/j.2047-2927.2013.00129.x · Cited by 88
“Studies have shown that the induction of hypogonadism in older men is followed by a significant increase in IL-6 concentrations (Khosla et al., 2002), a potent stimulator of inflammation, and that activation of the androgen receptor exerts a direct anti-inflammatory effect (Vignozzi et al.”
BackgroundMaı̈moun, L., Couret, I., Mariano‐Goulart, D., Dupuy, A., Micallef, J., Péruchon, E., Ohanna, F., Cristol, J., Rossi, M., & Leroux, J. L. (2005) · Calcified Tissue International · doi:10.1007/s00223-004-0048-6 · Cited by 83
“tion [35].”
Testosterone and Coronary Artery Disease
Nettleship, J. E., Jones, R. D., Channer, K. S., & Jones, T. H. (2008) · Frontiers of hormone research · doi:10.1159/000176047 · Cited by 90
Turner, A., Chen, T. C., Barber, T. W., Malabanan, A. O., Holick, M. F., & Tangpricha, V. (2004) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2004.02125.x · Cited by 86
“When the same elderly men rendered hypogonadal with GnRH agonists were treated with oestrogen, there were increases in OPG (Khosla et al., 2002).”
BackgroundCheung, J., Mak, Y. T., Papaioannou, S., Evans, B. A., Fogelman, I., & Hampson, G. (2003) · Journal of Endocrinology · doi:10.1677/joe.0.1770423 · Cited by 83
Wiren, K. M., Zhang, X.-W., Toombs, A. R., Kasparcova, V., Gentile, M. A., Harada, S.-I., & Jepsen, K. J. (2004) · Endocrinology · doi:10.1210/en.2003-1016 · Cited by 80
Gannagé‐Yared, M., Fares, F., Semaan, M., Khalife, S., & Jambart, S. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02522.x · Cited by 76
Oh, K. W., Rhee, E. J., Lee, W. Y., Kim, S. W., Baek, K. H., Kang, M. I., Yun, E. J., Park, C. Y., Ihm, S. H., Choi, M. G., et al. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2004.02179.x · Cited by 73
“…a positive correlation between serum OPG levels and total body, total hip and femoral neck BMD, although these correlations disappeared after adjusting for age and BMI and in a study by Khosla et al. (2002), mid-lateral spine BMD was inversely correlated with BMD in males under the age of 50.”
BackgroundResultMartini, G., Gennari, L., Merlotti, D., Salvadori, S., Franci, M. B., Campagna, S., Avanzati, A., De Paola, V., Valleggi, F., & Nuti, R. (2007) · Bone · doi:10.1016/j.bone.2006.08.003 · Cited by 72
“003 testosterone decreases while estrogen increases OPG levels [4–6].”
BackgroundHofbauer, L., Hicok, K., Chen, D., & Khosla, S. (2002) · European Journal of Endocrinology · doi:10.1530/eje.0.1470269 · Cited by 72
Self-citationDIAMOND, T. H., Bucci, J. A., Kersley, J. H., Aslan, P., LYNCH, W. B., & Bryant, C. (2004) · The Journal of Urology · doi:10.1097/01.ju.0000130508.61020.66 · Cited by 69
Sode, M., Burghardt, A. J., Kazakia, G. J., Link, T. M., & Majumdar, S. (2010) · Bone · doi:10.1016/j.bone.2010.02.021 · Cited by 67
“These discrepancies may be attributed to the complex hormonal interplay involving estrogen [56–58], serum bioavailable estradiol [51], and IGF-I levels [50].”
BackgroundScherr, D. S., & Pitts, W. R. (2003) · The Journal of Urology · doi:10.1097/01.ju.0000077558.48257.3d · Cited by 65
Aromatase in bone: roles of Vitamin D3 and androgens
Yanase, T., Suzuki, S., Goto, K., Nomura, M., Okabe, T., Takayanagi, R., & Nawata, H. (2003) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(03)00349-2 · Cited by 66
Pantsulaia, I., Trofimov, S., Kobyliansky, E. D., & Livshits, G. (2002) · Cytokine · doi:10.1006/cyto.2002.1959 · Cited by 64
Kamel, H. K. (2005) · Drugs & Aging · doi:10.2165/00002512-200522090-00003 · Cited by 64
Babcock, M. C., DuBose, L. E., Witten, T. L., Stauffer, B. L., Hildreth, K. L., Schwartz, R. S., Kohrt, W. M., & Moreau, K. L. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab715 · Cited by 64
Hampson, G., Martin, F. C., Moffat, K., Vaja, S., Sankaralingam, S., Cheung, J., Blake, G. M., & Fogelman, I. (2003) · Osteoporosis International · doi:10.1007/s00198-003-1440-1 · Cited by 60
“This is likely to be physiologically and clinically relevant, as this degree of increase in OPG has been demonstrated in vivo with estrogen [29].”
BackgroundThe Effects of α-Tocopherol on Bone: A Double-Edged Sword?
Chin, K., & Ima-Nirwana, S. (2014) · Nutrients · doi:10.3390/nu6041424 · Cited by 58
“showed that withdrawal of estrogen or testosterone caused elevation in interleukin-1 (IL1), interleukin-6 (IL6) and tumor necrosis factor-α (TNFα) levels in elderly men and treatment with either testosterone or estrogen alone was able to suppress this increase [22].”
BackgroundSaylor, P. J., Kozak, K. R., Smith, M. R., Ancukiewicz, M., Efstathiou, J. A., Zietman, A. L., Jain, R. K., & Duda, D. G. (2012) · The Oncologist · doi:10.1634/theoncologist.2011-0321 · Cited by 57
Sex differences in the pulmonary circulation: implications for pulmonary hypertension
Martin, Y. N., & Pabelick, C. M. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00857.2013 · Cited by 56
Maggio, M. G., Blackford, A. L., Taub, D. D., Carducci, M. A., Blè, A., Metter, E. J., Braga‐Basaria, M., Dobs, A. S., & Basaria, S. S. (2006) · Journal of Andrology · doi:10.2164/jandrol.106.000141 · Cited by 55
“current findings are in contrast to those of Khosla et al ( 7 ).”
ResultHaring, R., Baumeister, S. E., Völzke, H., Dörr, M., Kocher, T., Nauck, M. A., & Wallaschofski, H. (2012) · Journal of Andrology · doi:10.2164/jandrol.111.015065 · Cited by 54
Karsdal, M. A., Bay‐Jensen, A., Henriksen, K., & Christiansen, C. (2012) · Menopause international · doi:10.1258/mi.2012.012025 · Cited by 56
Men, bone and estrogen: unresolved issues
ORWOLL, E. S. (2003) · Osteoporosis International · doi:10.1007/s00198-002-1332-9 · Cited by 51
“influence of estrogen on osteoprotegerin levels [27, 28].”
Stilgren, L. S., Rettmer, E., Eriksen, E. F., Hegedűs, L. D., Beck‐Nielsen, H., & Abrahamsen, B. (2004) · Bone · doi:10.1016/j.bone.2004.03.012 · Cited by 52
“First, OPG is also influenced by other hormones, for example, estradiol, testosterone, and growth hormone [14,30–33].”
BackgroundPark, J. H., Park, K. H., Cho, S., Choi, Y. S., Seo, S. K., Lee, B. S., & Park, H. S. (2013) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e31827cabca · Cited by 53
Trofimov, S., Pantsulaia, I., Kobyliansky, E., & Livshits, G. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500305 · Cited by 51
“Given the important changes in sex hormone levels that occur at about age 50 in both men and women, it has been suggested that OPG production in a healthy population may be influenced by these hormones ( 9 , 12).”
Crisafulli, A., Altavilla, D., Squadrito, G., Romeo, A., Adamo, E. B., Marini, R., Inferrera, M. A., Marini, H. R., Bitto, A., D’Anna, R., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030891 · Cited by 50
Zitzmann, M., Erren, M., Kamischke, A., Simoni, M., & Nieschlag, E. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0847 · Cited by 49
Ganesan, K., Balachandran, C., Manohar, B. M., & Puvanakrishnan, R. (2008) · Bone · doi:10.1016/j.bone.2008.05.025 · Cited by 49
Hofbauer, L. C., Schoppet, M., Schüller, P., Viereck, V., & Christ, M. (2003) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2003.01969.x · Cited by 49
“Furthermore, oestrogen administration to elderly men rendered hypogonadal increased OPG levels, whereas testosterone administration had the opposite effect (Khosla et al., 2002a), suggesting that OPG production is enhanced by oestrogens both in vitro and in vivo.”
BackgroundRzewuska-Lech, E., Jayachandran, M., Fitzpatrick, L. A., & Miller, V. M. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00366.2004 · Cited by 47
“In addition, whether or not 17 -estradiol promotes OPG synthesis in bone is dependent on hormonal status and coexisting diseases (33).”
The role of estrogens in men and androgens in women
Khosla, S., & Bilezikian, J. P. (2003) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(02)00087-7 · Cited by 43
“Recently, Khosla et al [57] have reported that this may, indeed, be the case for estrogen versus testosterone regulation of osteoprotegerin (OPG), which blocks the final effector molecule for osteoclast development, receptor activator of NF-jB ligand (RANKL) [58].”
BackgroundSelf-citationTestosterone for secondary prevention in men with ischaemic heart disease?
Malkin, C. J., Pugh, P. J., Jones, T. H., & Channer, K. S. (2003) · QJM · doi:10.1093/qjmed/hcg086 · Cited by 45
Buckley, K. A., & Fraser, W. D. (2002) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456320203900602 · Cited by 45
Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men
Leder, B. Z., & Finkelstein, J. S. (2005) · Osteoporosis International · doi:10.1007/s00198-005-1890-8 · Cited by 44
“flicting results [75,76].”
Buendía-González, F. O., & Legorreta‐Herrera, M. (2022) · Biomolecules · doi:10.3390/biom12121768 · Cited by 43
The Pathogenesis, Treatment and Prevention of Osteoporosis in Men
Mosekilde, L., Vestergaard, P., & Rejnmark, L. (2012) · Drugs · doi:10.1007/s40265-012-0003-1 · Cited by 43
“This has been explained by the finding that estrogen in vivo increases osteoblastic OPG production, whereas testosterone decreases the production [36].”
IL-6, cancer and cachexia: metabolic dysfunction creates the perfect storm
White, J. P. (2017) · Translational Cancer Research · doi:10.21037/tcr.2017.03.52 · Cited by 45
“In relation to IL-6, hypogonadism in healthy older men was associated with increased levels of circulating IL-6 while testosterone replacement returned IL-6 levels back to baseline (55).”
BackgroundGrinspoon, S. K., Friedman, A. J., Miller, K. K., Lippman, J. S., Olson, W. H., & Warren, M. P. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030033 · Cited by 43
“cells, and to increase OPG in men (35, 36).”
BackgroundTestosterone Regulates Bone Response to Inflammation
Steffens, J. P., Herrera, B. S., Coimbra, L. S., Stephens, D., Rossa, C., Spolidório, L. C., Kantarcı, A., & Dyke, T. E. V. (2014) · Hormone and Metabolic Research · doi:10.1055/s-0034-1367031 · Cited by 44
Association of endogenous sex hormone with C‐reactive protein levels in middle‐aged and elderly men
Nakhai-Pour, H. R., Grobbee, D. E., Muller, M., & van der Schouw, Y. T. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.02745.x · Cited by 42
Jim, H., Park, J. Y., Permuth‐Wey, J., Rincon, M., Phillips, K. M., Small, B. J., & Jacobsen, P. B. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.03.001 · Cited by 43
“The directionality of our findings is consistent with the majority of studies indicating that the A allele at rs1800629 is associated with increased gene expression and higher circulating levels of TNF-a (Abraham and Kroeger, 1999; Kroeger et al., 1997, 2000; Wilson et al., 1997).”
InfluentialThe Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions
Vasconcelos, A. R., Cabral‐Costa, J. V., Mazucanti, C. H., Scavone, C., & Kawamoto, E. M. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00009 · Cited by 41
“This effect was partially rescued by treatment with estrogen or testosterone, with a complete rescue being achieved by a combined therapy of both hormones (63).”
BackgroundSmith, A., Jones, R. D., & Channer, K. S. (2005) · Current Vascular Pharmacology · doi:10.2174/157016106775203090 · Cited by 40
“Testosterone has been demonstrated to suppress the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in vitro, while increasing expression of the anti-inflammatory cytokine IL-10 [67-69].”
BackgroundBashir, A. A., Mak, Y. T., Sankaralingam, S., Cheung, J., Nwa., M., Grigoriadis, A. E., Fogelman, I., & Hampson, G. (2005) · Steroids · doi:10.1016/j.steroids.2005.04.011 · Cited by 40
Do androgens play any role in the physical frailty of ageing men?
O’Connell, M. D. L., Tajar, A., Roberts, S. A., & Wu, F. C. W. (2010) · International Journal of Andrology · doi:10.1111/j.1365-2605.2010.01093.x · Cited by 39
Kallio, A., Guo, T., Lamminen, E., Seppänen, J., Kangas, L., Väänänen, H. K., & Härkönen, P. L. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.03.005 · Cited by 37
“The ability of estrogen to decrease the expression of these cytokines in osteoblastic cells has previously been shown by several researchers (Spelsberg et al., 1999; Brady et al., 2002 Khosla et al., 2002).”
BackgroundAndrogen deprivation therapy for prostate cancer and the risk of autoimmune diseases
Liu, J., Yu, C., Chuang, H.-C., Wu, C., & Hsu, R. (2019) · Prostate Cancer and Prostatic Diseases · doi:10.1038/s41391-019-0130-9 · Cited by 37
Doumouchtsis, K., Kostakis, A., Doumouchtsis, S. K., Grapsa, E., Passalidou, I., Tziamalis, M. P., Poulakou, M. V., Vlachos, I. S., & Perrea, D. N. (2008) · Hemodialysis International · doi:10.1111/j.1542-4758.2008.00249.x · Cited by 37
RANKL inhibition for the management of patients with benign metabolic bone disorders
Anastasilakis, A. D., Toulis, K. A., Pοlyzos, S. A., & Terpos, E. (2009) · Expert Opinion on Investigational Drugs · doi:10.1517/13543780903048929 · Cited by 37
“Hormone replacement therapy decreased sOPG [38,126] and sRANKL [126] in early postmenopausal women, while sOPG has been reported to increase in hypogonadal elderly men receiving estradiol [127] and in women receiving a GnRH agonist for endometriosis [128].”
BackgroundCancer cachexia and anabolic interventions: a case report
Dillon, E. L., Basra, G., Horstman, A. M. H., Casperson, S. L., Randolph, K. M., Durham, W. J., Urban, R. J., Diaz‐Arrastia, C., Levine, L., Hatch, S. S., et al. (2012) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-012-0066-6 · Cited by 37
“Testosterone has been shown to reduce inflammatory cytokines such as TNF-α, IL-6, and IL-1B in humans [18–20].”
BackgroundNakhai-Pour, H. R., Grobbee, D. E., Emmelot‐Vonk, M. H., Bots, M. L., Verhaar, H. J. J., & van der Schouw, Y. T. (2007) · American Heart Journal · doi:10.1016/j.ahj.2007.09.001 · Cited by 34
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
