Sex Steroid Hormones and Osteosarcopenia

  • Christian M. GirgisEmail author


Sex steroids exert diverse, divergent and dynamic effects on muscle and bone. Beyond their essential role in sexual dimorphism, sex steroids contribute to the accrual, maintenance and age-related involution of the musculoskeletal system. Falls and fractures occur, dire consequences of musculoskeletal attrition and functional decline, in association with a critical reduction in sex steroids in older individuals. Conversely, the reversal of sex steroid deficiency and therapies that specifically target sex steroid receptor signalling (e.g. SARMs) mitigate aspects of musculoskeletal aging. This chapter will discuss key principles in sex steroid biology, evidence from preclinical and clinical studies on their anabolic and anti-catabolic effects on muscle and bone, and therapeutic possibilities for osteosarcopenia.


Osteosarcopenia Osteoporosis Sarcopenia Androgen Estrogen Bone Muscle Testosterone Estradiol Aging 


  1. Almeida M, Han L, Martin-Millan M, O'Brien CA, Manolagas SC (2007) Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem 282(37):27298–27305PubMedCrossRefPubMedCentralGoogle Scholar
  2. Almeida M, Laurent MR, Dubois V, Claessens F, O'Brien CA, Bouillon R et al (2017) Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 97(1):135–187PubMedCrossRefPubMedCentralGoogle Scholar
  3. Balagopal P, Nair KS, Stirewalt WS (1994) Isolation of myosin heavy chain from small skeletal muscle samples by preparative continuous elution gel electrophoresis: application to measurement of synthesis rate in human and animal tissue. Anal Biochem 221(1):72–77PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bandari J, Ayyash OM, Emery SL, Wessel CB, Davies BJ (2017) Marketing and testosterone treatment in the USA: a systematic review. Eur Urol Focus 3(4–5):395–402PubMedCrossRefPubMedCentralGoogle Scholar
  5. Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM et al (1999) A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 44(12):1012–1020PubMedPubMedCentralGoogle Scholar
  6. Bartell SM, Han L, Kim HN, Kim SH, Katzenellenbogen JA, Katzenellenbogen BS et al (2013) Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. Mol Endocrinol 27(4):649–656PubMedPubMedCentralCrossRefGoogle Scholar
  7. Basaria S, Lieb J 2nd, Tang AM, DeWeese T, Carducci M, Eisenberger M et al (2002) Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol 56(6):779–786CrossRefGoogle Scholar
  8. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM et al (2010) Adverse events associated with testosterone administration. N Engl J Med 363(2):109–122PubMedPubMedCentralCrossRefGoogle Scholar
  9. Basaria S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R et al (2013) The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci 68(1):87–95PubMedCrossRefPubMedCentralGoogle Scholar
  10. Basualto-Alarcon C, Jorquera G, Altamirano F, Jaimovich E, Estrada M (2013) Testosterone signals through mTOR and androgen receptor to induce muscle hypertrophy. Med Sci Sports Exerc 45(9):1712–1720PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R et al (2006) Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2(3):146–159PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bhat M, Kalam R, Qadri SS, Madabushi S, Ismail A (2013) Vitamin D deficiency induced muscle wasting occurs through the ubiquitin proteasome pathway and is partially corrected by calcium in male rats. Endocrinology 154(11):4018–4029PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bonaldo P, Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6(1):25–39PubMedPubMedCentralCrossRefGoogle Scholar
  14. Borrie AE, Kim RB (2017) Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers. Expert Opin Drug Metab Toxicol 13(2):149–156PubMedCrossRefPubMedCentralGoogle Scholar
  15. Bristow SM, Gamble GD, Stewart A, Horne L, House ME, Aati O et al (2014) Acute and 3-month effects of microcrystalline hydroxyapatite, calcium citrate and calcium carbonate on serum calcium and markers of bone turnover: a randomised controlled trial in postmenopausal women. Br J Nutr 112(10):1611–1620PubMedCrossRefPubMedCentralGoogle Scholar
  16. Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH et al (2009) Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha. FASEB J 23(1):232–240PubMedCrossRefPubMedCentralGoogle Scholar
  17. Calvani R, Martone AM, Marzetti E, Onder G, Savera G, Lorenzi M et al (2014) Pre-hospital dietary intake correlates with muscle mass at the time of fracture in older hip-fractured patients. Front Aging Neurosci 6:269PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cao JJ, Wronski TJ, Iwaniec U, Phleger L, Kurimoto P, Boudignon B et al (2005) Aging increases stromal/osteoblastic cell-induced osteoclastogenesis and alters the osteoclast precursor pool in the mouse. J Bone Miner Res 20(9):1659–1668PubMedCrossRefPubMedCentralGoogle Scholar
  19. Cawthon PM, Ensrud KE, Laughlin GA, Cauley JA, Dam TT, Barrett-Connor E et al (2009) Sex hormones and frailty in older men: the osteoporotic fractures in men (MrOS) study. J Clin Endocrinol Metab 94(10):3806–3815PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cheung AS, Zajac JD, Grossmann M (2014) Muscle and bone effects of androgen deprivation therapy: current and emerging therapies. Endocr Relat Cancer 21(5):R371–R394PubMedCrossRefPubMedCentralGoogle Scholar
  21. Cheung AS, Gray H, Schache AG, Hoermann R, Lim Joon D, Zajac JD et al (2017) Androgen deprivation causes selective deficits in the biomechanical leg muscle function of men during walking: a prospective case-control study. J Cachexia Sarcopenia Muscle 8(1):102–112PubMedCrossRefPubMedCentralGoogle Scholar
  22. Cheung AS, Cunningham C, Ko DD, Ly V, Gray H, Hoermann R et al (2018) Selective loss of levator ani and leg muscle volumes in men undergoing androgen deprivation therapy. J Clin Endocrinol Metab 104(6):2229–2238CrossRefGoogle Scholar
  23. Chiang C, Chiu M, Moore AJ, Anderson PH, Ghasem-Zadeh A, McManus JF et al (2009) Mineralization and bone resorption are regulated by the androgen receptor in male mice. J Bone Miner Res 24(4):621–631PubMedCrossRefPubMedCentralGoogle Scholar
  24. Ciciliot S, Rossi AC, Dyar KA, Blaauw B, Schiaffino S (2013) Muscle type and fiber type specificity in muscle wasting. Int J Biochem Cell Biol 45(10):2191–2199PubMedCrossRefPubMedCentralGoogle Scholar
  25. Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST et al (2011) The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle 2(3):153–161PubMedPubMedCentralCrossRefGoogle Scholar
  26. Davey RA, Grossmann M (2016) Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev 37(1):3–15PubMedPubMedCentralGoogle Scholar
  27. Davis SR, Wahlin-Jacobsen S (2015) Testosterone in women – the clinical significance. Lancet Diabetes Endocrinol 3(12):980–992PubMedCrossRefPubMedCentralGoogle Scholar
  28. Davis SR, McCloud P, Strauss BJ, Burger H (1995) Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 21(3):227–236PubMedCrossRefPubMedCentralGoogle Scholar
  29. de Rooy C, Grossmann M, Zajac JD, Cheung AS (2016) Targeting muscle signaling pathways to minimize adverse effects of androgen deprivation. Endocr Relat Cancer 23(1):R15–R26PubMedCrossRefPubMedCentralGoogle Scholar
  30. Dobs AS, Nguyen T, Pace C, Roberts CP (2002) Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 87(4):1509–1516PubMedCrossRefGoogle Scholar
  31. Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML et al (2013) Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol 14(4):335–345PubMedPubMedCentralCrossRefGoogle Scholar
  32. Dubois V, Laurent M, Boonen S, Vanderschueren D, Claessens F (2012) Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions. Cell Mol Life Sci 69(10):1651–1667PubMedCrossRefGoogle Scholar
  33. Dubois V, Laurent MR, Sinnesael M, Cielen N, Helsen C, Clinckemalie L et al (2014) A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle. FASEB J 28(7):2979–2994PubMedCrossRefGoogle Scholar
  34. Estrada M, Liberona JL, Miranda M, Jaimovich E (2000) Aldosterone- and testosterone-mediated intracellular calcium response in skeletal muscle cell cultures. Am J Physiol Endocrinol Metab 279(1):E132–E139PubMedCrossRefGoogle Scholar
  35. Estrada M, Espinosa A, Muller M, Jaimovich E (2003) Testosterone stimulates intracellular calcium release and mitogen-activated protein kinases via a G protein-coupled receptor in skeletal muscle cells. Endocrinology 144(8):3586–3597PubMedCrossRefGoogle Scholar
  36. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. JAMA 282(7):637–645PubMedCrossRefGoogle Scholar
  37. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD et al (2002) Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87(2):589–598PubMedCrossRefGoogle Scholar
  38. Ferrington DA, Krainev AG, Bigelow DJ (1998) Altered turnover of calcium regulatory proteins of the sarcoplasmic reticulum in aged skeletal muscle. J Biol Chem 273(10):5885–5891PubMedCrossRefGoogle Scholar
  39. Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA et al (2006) Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab 91(10):3908–3915PubMedCrossRefGoogle Scholar
  40. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB et al (2014) Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9(1):e85805PubMedPubMedCentralCrossRefGoogle Scholar
  41. Fitts RH, Peters JR, Dillon EL, Durham WJ, Sheffield-Moore M, Urban RJ (2014) Weekly versus monthly testosterone administration on fast and slow skeletal muscle fibers in older adult males. J Clin Endocrinol Metab 100(2):E223–E231. jc20142759PubMedPubMedCentralCrossRefGoogle Scholar
  42. 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(11):1833–1843PubMedCrossRefPubMedCentralGoogle Scholar
  43. Grossmann M, Zajac JD (2011) Androgen deprivation therapy in men with prostate cancer: how should the side effects be monitored and treated? Clin Endocrinol 74(3):289–293CrossRefGoogle Scholar
  44. Grossmann M, Cheung AS, Zajac JD (2013) Androgens and prostate cancer; pathogenesis and deprivation therapy. Best Pract Res Clin Endocrinol Metab 27(4):603–616PubMedCrossRefPubMedCentralGoogle Scholar
  45. Guo R, Yamashita M, Zhang Q, Zhou Q, Chen D, Reynolds DG et al (2008) Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins. J Biol Chem 283(34):23084–23092PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hamilton EJ, Ghasem-Zadeh A, Gianatti E, Lim-Joon D, Bolton D, Zebaze R et al (2010) Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy. J Clin Endocrinol Metab 95(12):E456–E463PubMedCrossRefPubMedCentralGoogle Scholar
  47. Hammes SR, Levin ER (2007) Extranuclear steroid receptors: nature and actions. Endocr Rev 28(7):726–741PubMedCrossRefPubMedCentralGoogle Scholar
  48. Hoffmann DB, Komrakova M, Pflug S, von Oertzen M, Saul D, Weiser L et al (2018) Evaluation of ostarine as a selective androgen receptor modulator in a rat model of postmenopausal osteoporosis. J Bone Miner Metab 37(2):243–255PubMedCrossRefGoogle Scholar
  49. Hsu B, Seibel MJ, Cumming RG, Blyth FM, Naganathan V, Bleicher K et al (2016) Progressive temporal change in serum SHBG, but not in serum testosterone or estradiol, is associated with bone loss and incident fractures in older men: the Concord health and ageing in men project. J Bone Miner Res 31(12):2115–2122PubMedCrossRefGoogle Scholar
  50. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A et al (2005) Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol 63(3):280–293CrossRefGoogle Scholar
  51. Jardi F, Laurent MR, Kim N, Khalil R, De Bundel D, Van Eeckhaut A et al (2018a) Testosterone boosts physical activity in male mice via dopaminergic pathways. Sci Rep 8(1):957PubMedPubMedCentralCrossRefGoogle Scholar
  52. Jardi F, Laurent MR, Dubois V, Kim N, Khalil R, Decallonne B et al (2018b) Androgen and estrogen actions on male physical activity: a story beyond muscle. J Endocrinol 238(1):R31–R52PubMedCrossRefPubMedCentralGoogle Scholar
  53. Kameda T, Mano H, Yuasa T, Mori Y, Miyazawa K, Shiokawa M et al (1997) Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J Exp Med 186(4):489–495PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T et al (2003) Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci U S A 100(16):9416–9421PubMedPubMedCentralCrossRefGoogle Scholar
  55. Khosla S (2010) Update on estrogens and the skeleton. J Clin Endocrinol Metab 95(8):3569–3577PubMedPubMedCentralCrossRefGoogle Scholar
  56. Kim SH, Katzenellenbogen JA (2006) Hormone-PAMAM dendrimer conjugates: polymer dynamics and tether structure affect ligand access to receptors. Angew Chem Int Ed Eng 45(43):7243–7248CrossRefGoogle Scholar
  57. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L et al (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104(5):719–730PubMedPubMedCentralGoogle Scholar
  58. Kousteni S, Chen JR, Bellido T, Han L, Ali AA, O'Brien CA et al (2002) Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298(5594):843–846PubMedCrossRefPubMedCentralGoogle Scholar
  59. Kovacheva EL, Hikim AP, Shen R, Sinha I, Sinha-Hikim I (2010) Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, notch, and Akt signaling pathways. Endocrinology 151(2):628–638PubMedCrossRefPubMedCentralGoogle Scholar
  60. Krasnoff JB, Basaria S, Pencina MJ, Jasuja GK, Vasan RS, Ulloor J et al (2010) Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study. J Clin Endocrinol Metab 95(6):2790–2799PubMedPubMedCentralCrossRefGoogle Scholar
  61. Laakkonen EK, Soliymani R, Karvinen S, Kaprio J, Kujala UM, Baumann M et al (2017) Estrogenic regulation of skeletal muscle proteome: a study of premenopausal women and postmenopausal MZ cotwins discordant for hormonal therapy. Aging Cell 16(6):1276–1287PubMedPubMedCentralCrossRefGoogle Scholar
  62. Laurent MR, Jardi F, Dubois V, Schollaert D, Khalil R, Gielen E et al (2016) Androgens have antiresorptive effects on trabecular disuse osteopenia independent from muscle atrophy. Bone 93:33–42PubMedCrossRefPubMedCentralGoogle Scholar
  63. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307–318PubMedCrossRefPubMedCentralGoogle Scholar
  64. Maatta JA, Buki KG, Ivaska KK, Nieminen-Pihala V, Elo TD, Kahkonen T et al (2013a) Inactivation of the androgen receptor in bone-forming cells leads to trabecular bone loss in adult female mice. Bonekey Rep 2:440PubMedPubMedCentralCrossRefGoogle Scholar
  65. Maatta JA, Buki KG, Gu G, Alanne MH, Vaaraniemi J, Liljenback H et al (2013b) Inactivation of estrogen receptor alpha in bone-forming cells induces bone loss in female mice. FASEB J 27(2):478–488PubMedCrossRefPubMedCentralGoogle Scholar
  66. Magnussen LV, Hvid LG, Hermann AP, Hougaard DM, Gram B, Caserotti P et al (2017) Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial. Andrology 5(5):946–953PubMedCrossRefPubMedCentralGoogle Scholar
  67. Malmstrom TK, Miller DK, Herning MM, Morley JE (2013) Low appendicular skeletal muscle mass (ASM) with limited mobility and poor health outcomes in middle-aged African Americans. J Cachexia Sarcopenia Muscle 4(3):179–186PubMedPubMedCentralCrossRefGoogle Scholar
  68. Manolagas SC (2010) From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 31(3):266–300PubMedPubMedCentralCrossRefGoogle Scholar
  69. Manolagas SC, Kousteni S, Jilka RL (2002) Sex steroids and bone. Recent Prog Horm Res 57:385–409PubMedCrossRefPubMedCentralGoogle Scholar
  70. Martin-Millan M, Almeida M, Ambrogini E, Han L, Zhao H, Weinstein RS et al (2010) The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol 24(2):323–334PubMedPubMedCentralCrossRefGoogle Scholar
  71. McGinnis MY, Lumia AR, Tetel MJ, Molenda-Figueira HA, Possidente B (2007) Effects of anabolic androgenic steroids on the development and expression of running wheel activity and circadian rhythms in male rats. Physiol Behav 92(5):1010–1018PubMedPubMedCentralCrossRefGoogle Scholar
  72. Metzger SO, Burnett AL (2016) Impact of recent FDA ruling on testosterone replacement therapy (TRT). Transl Androl Urol 5(6):921–926PubMedPubMedCentralCrossRefGoogle Scholar
  73. Miedlich SU, Karamooz N, Hammes SR (2016) Aromatase deficiency in a male patient – case report and review of the literature. Bone 93:181–186PubMedCrossRefPubMedCentralGoogle Scholar
  74. Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y et al (2009) Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem 52(12):3597–3617PubMedCrossRefPubMedCentralGoogle Scholar
  75. Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K et al (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130(5):811–823PubMedCrossRefPubMedCentralGoogle Scholar
  76. Oner J, Oner H, Sahin Z, Demir R, Ustunel I (2008) Melatonin is as effective as testosterone in the prevention of soleus muscle atrophy induced by castration in rats. Anat Rec (Hoboken) 291(4):448–455CrossRefGoogle Scholar
  77. Rana K, Lee NK, Zajac JD, MacLean HE (2014) Expression of androgen receptor target genes in skeletal muscle. Asian J Androl 16(5):675–683PubMedPubMedCentralCrossRefGoogle Scholar
  78. Rana K, Chiu MW, Russell PK, Skinner JP, Lee NK, Fam BC et al (2016) Muscle-specific androgen receptor deletion shows limited actions in myoblasts but not in myofibers in different muscles in vivo. J Mol Endocrinol 57(2):125–138PubMedCrossRefPubMedCentralGoogle Scholar
  79. Rariy CM, Ratcliffe SJ, Weinstein R, Bhasin S, Blackman MR, Cauley JA et al (2011) Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study. J Clin Endocrinol Metab 96(4):989–996PubMedPubMedCentralCrossRefGoogle Scholar
  80. Ristic BHV, Sirbu PD, Irizarry-Roman M, Bucs G, Sztanyi I, Binkley N, Orwig D, Neutel J, Homer K, Mancini M, Masamune H, Barker G, Lian B (2018) VK5211, a Novel Selective Androgen Receptor Modulator (SARM), Significantly Improves Lean Body Mass in Hip Fracture Patients: Results of a 12 Week Phase 2 Trial American Society of Bone and Mineral Reserach (ASBMR) annual meeting (Abstract 1072); Montreal, CanadaGoogle Scholar
  81. Robling AG, Castillo AB, Turner CH (2006) Biomechanical and molecular regulation of bone remodeling. Annu Rev Biomed Eng 8:455–498PubMedCrossRefPubMedCentralGoogle Scholar
  82. Schellinger D, Lin CS, Hatipoglu HG, Fertikh D (2001) Potential value of vertebral proton MR spectroscopy in determining bone weakness. AJNR Am J Neuroradiol 22(8):1620–1627PubMedPubMedCentralGoogle Scholar
  83. Serra C, Bhasin S, Tangherlini F, Barton ER, Ganno M, Zhang A et al (2011) The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle. Endocrinology 152(1):193–206PubMedCrossRefPubMedCentralGoogle Scholar
  84. Sestak I, Singh S, Cuzick J, Blake GM, Patel R, Gossiel F et al (2014) Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial. Lancet Oncol 15(13):1460–1468PubMedCrossRefPubMedCentralGoogle Scholar
  85. Silverman SL, Chines AA, Kendler DL, Kung AW, Teglbjaerg CS, Felsenberg D et al (2012) Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. Osteoporos Int 23(1):351–363PubMedCrossRefPubMedCentralGoogle Scholar
  86. Sims NA, Dupont S, Krust A, Clement-Lacroix P, Minet D, Resche-Rigon M et al (2002) Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-beta in bone remodeling in females but not in males. Bone 30(1):18–25PubMedCrossRefPubMedCentralGoogle Scholar
  87. 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(7):1755–1759PubMedPubMedCentralCrossRefGoogle Scholar
  88. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA et al (2016) Effects of testosterone treatment in older men. N Engl J Med 374(7):611–624PubMedPubMedCentralCrossRefGoogle Scholar
  89. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, Ellenberg SS, Cauley JA, Ensrud KE et al (2017) Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial. JAMA Intern Med 177(4):471–479PubMedPubMedCentralCrossRefGoogle Scholar
  90. Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA et al (2010) Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 95(2):639–650PubMedCrossRefPubMedCentralGoogle Scholar
  91. Sunters A, Armstrong VJ, Zaman G, Kypta RM, Kawano Y, Lanyon LE et al (2010) Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor alpha-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to ambient IGF, leading to phosphatidylinositol 3-kinase/AKT-dependent Wnt/LRP5 receptor-independent activation of beta-catenin signaling. J Biol Chem 285(12):8743–8758PubMedCrossRefPubMedCentralGoogle Scholar
  92. Surampudi PN, Wang C, Swerdloff R (2012) Hypogonadism in the aging male diagnosis, potential benefits, and risks of testosterone replacement therapy. Int J Endocrinol 2012:625434PubMedPubMedCentralCrossRefGoogle Scholar
  93. Swift-Gallant A, Monks DA (2013) Androgen receptor expression in satellite cells of the neonatal levator ani of the rat. Dev Neurobiol 73(6):448–454PubMedCrossRefPubMedCentralGoogle Scholar
  94. Thakur MK (1988) Molecular mechanism of steroid hormone action during aging. A review Mech Ageing Dev 45(2):93–110PubMedCrossRefPubMedCentralGoogle Scholar
  95. Ucer S, Iyer S, Bartell SM, Martin-Millan M, Han L, Kim HN et al (2015) The effects of androgens on murine cortical bone do not require AR or ERalpha signaling in osteoblasts and osteoclasts. J Bone Miner Res 30(7):1138–1149PubMedPubMedCentralCrossRefGoogle Scholar
  96. Uebelhart B, Herrmann F, Pavo I, Draper MW, Rizzoli R (2004) Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middle-aged men with low sex hormone levels. J Bone Miner Res 19(9):1518–1524PubMedCrossRefPubMedCentralGoogle Scholar
  97. Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C (2004) Androgens and bone. Endocr Rev 25(3):389–425PubMedCrossRefPubMedCentralGoogle Scholar
  98. Venken K, Schuit F, Van Lommel L, Tsukamoto K, Kopchick JJ, Coschigano K et al (2005) Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis. J Bone Miner Res 20(12):2138–2149PubMedCrossRefPubMedCentralGoogle Scholar
  99. Visser M, Goodpaster BH, Kritchevsky SB, Newman AB, Nevitt M, Rubin SM et al (2005) Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci 60(3):324–333PubMedCrossRefPubMedCentralGoogle Scholar
  100. Weissberger AJ, Ho KK, Lazarus L (1991) Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 72(2):374–381PubMedCrossRefPubMedCentralGoogle Scholar
  101. Weitzmann MN, Pacifici R (2006) Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 116(5):1186–1194PubMedPubMedCentralCrossRefGoogle Scholar
  102. White JP, Gao S, Puppa MJ, Sato S, Welle SL, Carson JA (2013) Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol 365(2):174–186PubMedCrossRefPubMedCentralGoogle Scholar
  103. Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J, Honda S et al (2009) Estrogen masculinizes neural pathways and sex-specific behaviors. Cell 139(1):61–72PubMedPubMedCentralCrossRefGoogle Scholar
  104. Wu Y, Bauman WA, Blitzer RD, Cardozo C (2010) Testosterone-induced hypertrophy of L6 myoblasts is dependent upon Erk and mTOR. Biochem Biophys Res Commun 400(4):679–683PubMedCrossRefPubMedCentralGoogle Scholar
  105. Xu L, Freeman G, Cowling BJ, Schooling CM (2013) Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 11:108PubMedPubMedCentralCrossRefGoogle Scholar
  106. Zhang X, Sui Z (2013) Deciphering the selective androgen receptor modulators paradigm. Expert Opin Drug Discovery 8(2):191–218CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of EndocrinologyRoyal North Shore HospitalSydneyAustralia
  2. 2.Department of EndocrinologyWestmead HospitalSydneyAustralia
  3. 3.University of SydneySydneyAustralia

Personalised recommendations