Abstract
Estrogen is a critical hormone for bone homeostasis in men, but no information is available on the role of estrogen metabolism among men. The aim of this study was to evaluate the effect of estrogen hydroxylation on male bone mineral density (BMD). Participants consisted of 61 healthy Caucasian males (mean age 66.6 ± 1.0 years). Urinary estrogen metabolites were measured by enzyme-linked immunosorbent assay, serum estradiol by ultrasensitive radioimmunoassay, sex hormone binding globulin by radioimmunoassay, and BMD of the lumbar spine and the proximal femur by dual-energy X-ray absorptiometry. Active estrogen metabolites, 16α-hydroxyestrone (16αOHE1) and estriol (E3), positively correlated with adjusted BMD in all regions of the proximal femur (all P < 0.05) but not at the lumbar spine, and those in the highest tertile of urinary 16αOHE1 had the highest BMD. Free estradiol index (FEI) also positively correlated with BMD of the total hip, femoral neck, and intertrochanter (all P < 0.05), while there was no correlation between BMD with inactive metabolites (2−hydroxyestrone and 2-methoxyestrone) and serum testosterone. Multiple regression analysis showed 16αOHE1, FEI, and body mass index are important independent predictors of BMD in all regions of the proximal femur. Estrogen metabolism may modulate BMD in men. Increased urinary 16αOHE1 and E3 levels are associated with high BMD at the proximal femur, and 16αOHE1 appears to be a major determinant of BMD among the metabolites evaluated.
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Falahati-Nini A, Riggs BL, Atkinson EJ, O’Fallon WM, Eastell R, Khosla S (2000) Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106:1553–1560
Barrett-Connor E, Mueller JE, von Muhlen DG, Laughlin GA, Schneider DL, Sartoris DJ (2000) Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study. J Clin Endocrinol Metab 85:219–223
Grodin JM, Siiteri PK, MacDonald PC (1973) Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 36:207–214
Fishman J, Bradlow HL, Gallagher TF (1960) Oxidative metabolism of estradiol. J Biol Chem 235:3104–3107
Martucci C, Fishman J (1977) Direction of estradiol metabolism as a control of its hormonal action - uterotropic activity of estradiol metabolites. Endocrinology 101:1709–1715
Fishman J, Martucci C (1980) Biological properties of 16a-hydroxyestrone: implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab 51:611–615
Leelawattana R, Ziambaras K, Roodman-Weiss J, et al. (2000) The oxidative metabolism of estradiol conditions postmenopausal bone density and bone loss. J Bone Miner Res 15:2513–2520
Michnovicz JJ, Adlercreutz H, Bradlow HL (1997) Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst 89:718–723
Armamento-Villareal R, Villareal DT, Avioli LV, Civitelli R (1992) Estrogen status and heredity are major determinants of premenopausal bone mass. J Clin Invest 90:2464–2471
Klug TL, Bradlow HL, Sepkovic DW (1994) Monoclonal antibody-based enzyme immunoassay for simultaneous quantitation of 2- and 16 alpha-hydroxyestrone in urine. Steroids 59:648–655
Szulc P, Hofbauer LC, Heufelder AE, Roth S, Delmas PD (2001) Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J Clin Endocrinol Metab 86:3162–3165
Napoli N, Villareal DT, Mumm S, et al. (2005) Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. J Bone Miner Res 20:232–239
Smith EP, Boyd J, Frank GR, et al. (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061
Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689–3698
Carani C, Qin K, Simoni M, et al. (1997) Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337:91–95
Bilezikian JP, Morishima A, Bell J, Grumbach MM (1998) Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603
Khosla S, Melton LJ III, Atkinson EJ, O’Fallon WM, Klee GG, Riggs BL (1998) Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 83:2266–2274
Riggs BL, Khosla S, Melton LJ III (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302
Khosla S, Melton LJ III, Atkinson EJ, O’Fallon WM (2001) Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 86:3555–3561
Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC (1997) Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. J Clin Invest 100:1755–1759
Greendale GA, Edelstein S, Barrett-Connor E (1997) Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J Bone Miner Res 12:1833–1843
Murphy S, Khaw KT, Cassidy A, Compston JE (1993) Sex hormones and bone-mineral density in elderly men. Bone Miner 20:133–140
Barrett-Connor E, Mueller JE, von Muhlen DG, Laughlin GA, Schneider DL, Sartoris DJ (2000) Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study. J Clin Endocrinol Metab 85:219–223
Westerlind KC, Gibson KJ, Malone P, Evans GL, Turner RT (1998) Differential effects of estrogen metabolites on bone and reproductive tissues of ovariectomized rats. J Bone Miner Res 13:1023–1031
Muti P, Bradlow HL, Micheli A, et al. (2000) Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 11:635–640
Osborne MP, Bradlow HL, Wong GY, Telang NT (1993) Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk. J Natl Cancer Inst 85:1917–1920
Swaneck GE, Fishman J (1988) Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proc Natl Acad Sci USA 85:7831–7835
Michnovicz JJ, Bradlow HL (1990) Dietary and pharmacological control of estradiol metabolism in humans. Ann N Y Acad Sci 595:291–299
Michnovicz JJ, Hershcopf RJ, Naganuma H, Bradlow HL, Fishman J (1986) Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med 315:1305–1309
Michnovicz JJ, Galbraith RA (1991) Cimetidine inhibits catechol estrogen metabolism in women. Metabolism 40:170–174
Michnovicz JJ, Galbraith RA (1990) Effects of exogenous thyroxine on C-2 and C-16 alpha hydroxylations of estradiol in humans. Steroids 55:22–26
Schneider J, Bradlow HL, Strain G, Levin J, Anderson K, Fishman J (1983) Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites. J Clin Endocrinol Metab 56:973–978
Napoli N, Donepudi S, Sheikh S, Rini GB, Armamento-Villareal R (2005) Increased 2-hydroxylation of estrogen in women with family history of osteoporosis. J Clin Endocrinol Metab 90(4):2035—2041
Liu G, Peacock M, Eilam O, Dorulla G, Braunstein E, Johnston CC (1997) Effect of osteoarthritis in the lumbar spine and hip on bone mineral density and diagnosis of osteoporosis in elderly men and women. Osteoporos Int 7:564–569
Lim SK, Won YJ, Lee JH, et al. (1997) Altered hydroxylation of estrogen in patients with postmenopausal osteopenia. J Clin Endocrinol Metab 82:1001–1006
Muti P (2004) The role of endogenous hormones in the etiology and prevention of breast cancer: the epidemiological evidence. Ann N Y Acad Sci 1028:273–282
Acknowledgment
This work was supported by National Institutes of Health grants R03 AR049401 (to R. A.-V.) and K12 HD01459 (Building Interdisciplinary Research Careers in Women’s Health) and the General Clinical Research Center at Washington University.
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Napoli, N., Faccio, R., Shrestha, V. et al. Estrogen Metabolism Modulates Bone Density in Men. Calcif Tissue Int 80, 227–232 (2007). https://doi.org/10.1007/s00223-007-9014-4
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DOI: https://doi.org/10.1007/s00223-007-9014-4