Abstract
Bone metabolism is influenced by sex steroids during growth and adulthood in both men and women. Although this influence is well described in women, the relative importance of androgens and estrogens in the regulation of the male skeleton remains uncertain. Even though estradiol has been considered the 'female hormone', levels of serum estradiol in elderly men are higher than those in postmenopausal women. Estradiol levels are more strongly associated with BMD, bone turnover and bone loss than testosterone levels are in adult men. Case reports of young men with estrogen resistance or aromatase deficiency also suggest a crucial role for estradiol in regulation of skeletal growth in men. Moreover, serum levels of both estrogens and androgens are inversely associated with the risk of fracture in aging men. A large, prospective, population-based study showed that levels of serum estradiol predict the risk of fracture, independently of serum testosterone. Evidence suggests that a threshold level of estradiol exists below which the male skeleton is impaired; rates of bone loss and fracture seem to be increased and bone maturation delayed in men with estradiol levels below this threshold. On the basis of these findings, we propose that not only androgens, but also estrogens, are important regulators of bone health in men.
Key Points
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Sex steroids influence growth and maintenance of the skeleton in both men and women
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Serum levels of estradiol are higher in aging men than in postmenopausal women
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Studies of men with estrogen resistance or aromatase deficiency demonstrated the importance of estrogens in skeletal maturation and growth-plate closure in men, which led to a paradigm shift
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Cross-sectional and longitudinal studies showed that serum levels of estrogens are more strongly associated with BMD and bone loss than levels of androgens are in adult and aging men
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Serum levels of both androgens and estrogens are inversely associated with incident fractures in elderly men
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Recent evidence suggests that a threshold level exists for estradiol in adult men; subthreshold levels are associated with increased fracture risk, bone loss and delayed bone maturation
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References
Riggs, B. L., Khosla, S. & Melton, L. J. 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 23, 279–302 (2002).
Vanderschueren, D. et al. Androgens and bone. Endocr. Rev. 25, 389–425 (2004).
Windahl, S. H., Vidal, O., Andersson, G., Gustafsson, J. A. & Ohlsson C. Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERβ(−/−) mice. J. Clin. Invest. 104, 895–901 (1999).
Vidal, O. et al. Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc. Natl Acad. Sci. USA 97, 5474–5479 (2000).
Moverare, S. et al. Differential effects on bone of estrogen receptor α and androgen receptor activation in orchidectomized adult male mice. Proc. Natl Acad. Sci. USA 100, 13573–13578 (2003).
Sims, N. A. et al. A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice. J. Clin. Invest. 111, 1319–1327 (2003).
Venken, K. et al. Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J. Bone Miner. Res. 21, 576–585 (2006).
Labrie, F. et al. Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer. J. Steroid Biochem. Mol. Biol. 113, 52–56 (2009).
Khosla, S. Melton, L. J. 3rd, Atkinson, E. J. & O'Fallon, W. M. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J. Clin. Endocrinol. Metab. 86, 3555–3561 (2001).
Riggs, B. L., Khosla, S. & Melton, L. J. 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J. Bone Miner. Res. 13, 763–773 (1998).
Stepan, J. J., Lachman, M., Zverina, J., Pacovský, V. & Baylink, D. J. Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J. Clin. Endocrinol. Metab. 69, 523–527 (1989).
Smith, E. P. et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N. Engl. J. Med. 331, 1056–1061 (1994).
Smith, E. P. et al. Impact on bone of an estrogen receptor-α gene loss of function mutation. J. Clin. Endocrinol. Metab. 93, 3088–3096 (2008).
Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C. & Qin, K. 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 (1995).
Carani, C. et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med. 337, 91–95 (1997).
Bilezikian, J. P., Morishima, A., Bell, J. & Grumbach, M. M. Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N. Engl. J. Med. 339, 599–603 (1998).
Rochira, V., Faustini-Fustini, M., Balestrieri, A. & Carani, C. Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters. J. Clin. Endocrinol. Metab. 85, 1841–1845 (2000).
Herrmann, B. L. et al. Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J. Clin. Endocrinol. Metab. 87, 5476–5484 (2002).
Bouillon, R., Bex, M., Vanderschueren, D. & Boonen, S. Estrogens are essential for male pubertal periosteal bone expansion. J. Clin. Endocrinol. Metab. 89, 6025–6029 (2004).
Lanfranco, F. et al. A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment. Bone 43, 628–635 (2008).
Bertelloni, S., Baroncelli, G. I., Battini, R., Perri, G. & Saggese, G. Short-term effects of testosterone treatment on reduced bone density in boys with constitutional delay of puberty. J. Bone Miner. Res. 10, 1488–1495 (1995).
Finkelstein, J. S., Klibanski, A. & Neer, R. M. A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. J. Clin. Endocrinol. Metab. 81, 1152–1155 (1996).
Seeman, E. Sexual dimorphism in skeletal size, density, and strength. J. Clin. Endocrinol. Metab. 86, 4576–4584 (2001).
Turner, R. T., Wakley, G. K. & Hannon, K. S. Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J. Orthop. Res. 8, 612–617 (1990).
Lorentzon, M., Swanson, C., Andersson, N., Mellström, D. & Ohlsson, C. Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study. J. Bone Miner. Res. 20, 1334–1341 (2005).
Greendale, G. A., Edelstein, S. & Barrett-Connor, E. Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo study. J. Bone Miner. Res. 12, 1833–1843 (1997).
Khosla, S. et al. 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 (1998).
Orwoll, E. et al. Testosterone and estradiol among older men. J. Clin. Endocrinol. Metab. 91, 1336–1344 (2006).
Slemenda, C. W. et al. Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. J. Clin. Invest. 100, 1755–1759 (1997).
Ongphiphadhanakul, B., Rajatanavin, R., Chanprasertyothin, S., Piaseu, N. & Chailurkit, L. Serum oestradiol and oestrogen-receptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males. Clin. Endocrinol. (Oxf.) 49, 803–809 (1998).
Center, J. R., Nguyen, T. V., Sambrook, P. N. & Eisman, J. A. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J. Clin. Endocrinol. Metab. 84, 3626–3635 (1999).
Amin, S. et al. Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study. Ann. Intern. Med. 133, 951–963 (2000).
van den Beld, A. W., de Jong, F. H., Grobbee, D. E., Pols, H. A. & Lamberts, S. W. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J. Clin. Endocrinol. Metab. 85, 3276–3282 (2000).
Szulc, P. et al. Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study. J. Clin. Endocrinol. Metab. 86, 192–199 (2001).
Mellström, D. et al. Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J. Bone Miner. Res. 21, 529–535 (2006).
Araujo, A. B., Travison, T. G., Leder, B. Z. & McKinlay, J. B. Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men. J. Clin. Endocrinol. Metab. 93, 2135–2141 (2008).
Van Pottelbergh, I., Goemaere, S. & Kaufman, J. M. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J. Clin. Endocrinol. Metab. 88, 3075–3081 (2003).
Gennari, L. et al. Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J. Clin. Endocrinol. Metab. 88, 5327–5333 (2003).
Khosla, S. et al. Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men. J. Bone Miner. Res. 20, 730–740 (2005).
Falahati-Nini, A. et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J. Clin. Invest. 106, 1553–1560 (2000).
Leder, B. Z., LeBlanc, K. M., Schoenfeld, D. A., Eastell, R. & Finkelstein, J. S. Differential effects of androgens and estrogens on bone turnover in normal men. J. Clin. Endocrinol. Metab. 88, 204–210 (2003).
Smith, M. R., Fallon, M. A., Lee, H. & Finkelstein, J. S. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J. Clin. Endocrinol. Metab. 89, 3841–3846 (2004).
Doran, P. M., Riggs, B. L., Atkinson, E. J. & Khosla, S. Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J. Bone Miner. Res. 16, 2118–2125 (2001).
Taxel, P. et al. The effect of aromatase inhibition on sex steroids, gonadotropins, and markers of bone turnover in older men. J. Clin. Endocrinol. Metab. 86, 2869–2874 (2001).
Kaufman, J. M. & Vermeulen, A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr. Rev. 26, 833–876 (2005).
Gennari, L. et al. A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism. J. Clin. Endocrinol. Metab. 89, 2803–2810 (2004).
Eriksson, A. L. et al. Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men. J. Clin. Endocrinol. Metab. 94, 1033–1041 (2009).
Clarke, B. L. & Khosla, S. Androgens and bone. Steroids 74, 296–305 (2009).
Smith, M. R. Osteoporosis during androgen deprivation therapy for prostate cancer. Urology 60, 79–85 (2002).
Shahinian, V. B., Kuo, Y. F., Freeman, J. L. & Goodwin, J. S. Risk of fracture after androgen deprivation for prostate cancer. N. Engl. J. Med. 352, 154–164 (2005).
Behre, H. M., Kliesch, S., Leifke, E., Link, T. M. & Nieschlag, E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J. Clin. Endocrinol. Metab. 82, 2386–2390 (1997).
Snyder, P. J. et al. Effects of testosterone replacement in hypogonadal men. J. Clin. Endocrinol. Metab. 85, 2670–2677 (2000).
Wang, C. et al. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin. Endocrinol. 54, 739–750 (2001).
Barrett-Connor, E. et al. 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 (2000).
Goderie-Plomp, H. W. et al. Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study. J. Clin. Endocrinol. Metab. 89, 3261–3269 (2004).
Bjornerem, A. et al. A prospective study of sex steroids, sex hormone-binding globulin, and non-vertebral fractures in women and men: the Tromso Study. Eur. J. Endocrinol. 157, 119–125 (2007).
Amin, S. et al. Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am. J. Med. 119, 426–433 (2006).
Meier, C. et al. Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch. Intern. Med. 168, 47–54 (2008).
Mellström, D. et al. Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J. Bone Miner. Res. 23, 1552–1560 (2008).
Khosla, S., Melton, L. J. 3rd & Riggs, B. L. Clinical review 144: estrogen and the male skeleton. J. Clin. Endocrinol. Metab. 87, 1443–1450 (2002).
Ly, L. P. & Handelsman, D. J. Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays. Eur. J. Endocrinol. 152, 471–478 (2005).
Sartorius, G., Ly, L. P., Sikaris, K., McLachlan, R. & Handelsman, D. J. Predictive accuracy and sources of variability in calculated free testosterone estimates. Ann. Clin. Biochem. 46, 137–143 (2009).
Cummings, S. R. et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N. Engl. J. Med. 339, 733–738 (1998).
Center, J. R. Nguyen, T. V., Sambrook, P. N. & Eisman, J. A. Hormonal and biochemical parameters and osteoporotic fractures in elderly men. J. Bone Miner. Res. 15, 1405–1411 (2000).
Legrand, E. et al. Osteoporosis in men: a potential role for the sex hormone binding globulin. Bone 29, 90–95 (2001).
Acknowledgements
The authors' own work cited in this Review was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF–LUA research grant in Gothenburg, the Lundberg Foundation, and the Torsten and Ragnar Söderberg's Foundation.
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Vandenput, L., Ohlsson, C. Estrogens as regulators of bone health in men. Nat Rev Endocrinol 5, 437–443 (2009). https://doi.org/10.1038/nrendo.2009.112
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DOI: https://doi.org/10.1038/nrendo.2009.112
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