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Testosterone Replacement Therapy and Mortality in Older Men

Abstract

While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Several authors blame advertising and the availability of more convenient formulations, whilst others have pointed out that the routine testing of men with erectile dysfunction (ED) (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous under-diagnosis and under-treatment in line with evidence based guidelines. It is unlikely that persuasive advertising or convenient formulations could grow a market over such a sustained period if the treatment was not effective. Urologists and primary care physicians are the most frequent initiators of TRT usually for ED. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with a possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing that therapy associated with clear increases in serum testosterone levels to the normal range is associated with reduced all-cause mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively, they have compared non-treated patients with under-treated or non-compliant subjects involving a range of different therapy regimes. Recent evidence suggests long-acting injections may be associated with decreased cardiovascular risk, but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5-alpha reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. In a response to concerns about the possible risks associated with inappropriate prescribing expressed by Public Citizen, the Food and Drug Administration (FDA) published a complete refutation of all the concerns, only to issue a subsequent bulletin of concern over inappropriate use, whilst confirming the benefits in treating men with established testosterone deficiency. No additional evidence was provided for this apparent change of opinion, but longer term safety data on testosterone products were strongly suggested. In contrast, the European Medicines Agency (EMA), in November 2014, concluded that “there is no consistent evidence of increased cardiovascular risk with testosterone products”. This paper explores the most recent evidence surrounding the benefits and risks associated with TRT.

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References

  1. 1.

    Tajar A, Forti G, O’Neill T, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. JCEM. 2010;95(4):1810–8.

  2. 2.

    Hackett GI, Cole NS, Deshpande AA, Popple MD, Kennedy D, Wilkinson P. Biochemical hypogonadism in men with type 2 diabetes in primary care practice. Br J Diabetes Vasc Dis. 2009;9(5):226–31.

  3. 3.

    Pye SR, Huhtaniemi IT, Finn JD, et al. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014;99(4):1357–66.

  4. 4.

    Rastrelli G, Carter E, Ahern T. Development of and recovery from secondary hypogonadism in ageing men: prospective results from the EMAS. J Clin Endocrinol Metab. 2015;100:3172–82. doi:10.1210/jc.2015-1571. http://press.endocrine.org/journal/jcem.

  5. 5.

    Hauser R, Skakkebaek N, Torrari L, et al. Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union. J Clin Endocrinol Metab. 2015;100(4):1267–77.

  6. 6.

    Shores M, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone. J Clin Endocrinol Metab. 2012;97(6):1660–5.

  7. 7.

    Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725–33.

  8. 8.

    Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109–22.

  9. 9.

    Vigen R, O’Donnell I, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. J Am Med Assoc. 2013;310(17):1829–36.

  10. 10.

    Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805. doi:10.1371/journal.pone.008580.

  11. 11.

    Lunenfeld B, Mskhalaya G, Zitzmann M, Arver S, Kalinchenko S, Tishova Y, Morgentaler A. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male. 2015;18(1):5–15. doi:10.3109/13685538.2015.1004049.

  12. 12.

    Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M. EAU guidelines on male hypogonadism March 2015. http://www.eau.org. Accessed 29 May 2015.

  13. 13.

    Wylie K, Rees M, Hackett G, et al. Androgens, health and sexuality in women and men. Maturitas. 2010;67(3):275–89.

  14. 14.

    Dean J, McMahon C, Guay A, et al. The International Society for Sexual Medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J Sex Med. 2015;12(8):1660–86.

  15. 15.

    Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–59.

  16. 16.

    Hackett G, Cole N, Bhartia M, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014;68(2):203–15.

  17. 17.

    Home P, Mant J, Diaz J, Turner C, on behalf of the Guideline Development Group. Management of type 2 diabetes: summary of updated NICE guidance. BMJ. 2008;336:1306–8.

  18. 18.

    Hackett G, Kell P, Ralph D, et al. British Society for Sexual Medicine guidelines on the management of erectile dysfunction. J Sex Med. 2008;5(8):1841–6.

  19. 19.

    Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation. 2007;116(23):2694–701.

  20. 20.

    Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. 2002;25(1):55–60.

  21. 21.

    Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166(15):1660–5.

  22. 22.

    Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94(7):2482–8.

  23. 23.

    Vikan T, Schirmer H, Njølstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø study. Eur J Endocrinol. 2009;161(3):435–42.

  24. 24.

    Corona G, Monami M, Boddi V, et al. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med. 2010;7(4):1557–64.

  25. 25.

    Maggio M, Lauretani F, Ceda GP, et al. Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti area (InCHIANTI) study. Arch Intern Med. 2007;167(20):2249–54.

  26. 26.

    Yeap BB, Alfonso H, Chubb SAP et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014;99(1):E9–18.

  27. 27.

    Daka P, Langer RD, Larsson CA. Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus. BMC Endocr Disord. 2015;15:1–12. doi:10.1186/s12902-015-0034-1.

  28. 28.

    Araujo AB, Dixon JM, Suarez EA, et al. Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):3007–19.

  29. 29.

    Haring R, Völzke HV, Steveling A, et al. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J. 2010;31:1494–501.

  30. 30.

    Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, Maggi M. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13(10):1327–51.

  31. 31.

    Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011;97(11):870–5.

  32. 32.

    Corona G, Rastrelli G, Maseroli E, et al. Low testosterone syndrome protects subjects with high cardiovascular risk burden from major adverse cardiovascular events. Andrology. 2014;2(5):741–7.

  33. 33.

    Muraleedharan V, Jones TH. Testosterone and mortality. Clin Endocrinol. 2014;81(4):477–87.

  34. 34.

    Mesbah Oskui P, French WJ, et al. Testosterone and the cardiovascular system. A comprehensive review of the literature. Am Heart Assoc Contemp Rev. 2013;2:e000272 (Article ID).

  35. 35.

    Li L, Guo CY, Jia EZ, et al. Testosterone is negatively associated with the severity of coronary artery disease in men. Asian J Androl. 2012;14:875–8.

  36. 36.

    Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart. 2010;96(22):1821–5.

  37. 37.

    Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33(6):1186–92.

  38. 38.

    Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675–85.

  39. 39.

    Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L. Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;143(9):889–97.

  40. 40.

    Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2014;68(3):314–29.

  41. 41.

    Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJG, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol. 2010;73(5):602–12.

  42. 42.

    Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154(6):899–906.

  43. 43.

    Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl. 2009;30(6):726–33.

  44. 44.

    Hackett G, Cole N, Bhartia M, Wilkinson P, Raju J. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med. 2014;11:840–856. doi:10.1111/jsm.12404.

  45. 45.

    Jones TH, Arver S, Behre H. A placebo controlled study on the effects of transdermal testosterone gel in hypogonadal men with type ii diabetes or metabolic syndrome in diabetic control and insulin sensitivity: the TIMES 2 study. Diabetes Care. 2011;34:828–37.

  46. 46.

    Saad F, Yassin A, Haider A, Doros G, Gooren L. Elderly men over 65 years of age with late-onset hypogonadism benefit as much from testosterone treatment as do younger men Korean. J Urol. 2015;56:310–7.

  47. 47.

    Wu F, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123–35.

  48. 48.

    Corona G, Rastrelli G, Monami M, Saad F, Luconi M, Lucchese M, Facchiano E, Sforza A, Forti G, Mannucci E, Maggi M. Body weight loss reverses obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 2013;168(6):829–43.

  49. 49.

    Wing RR, Rosen RC, Fava JL, Bahnson J, Brancati F, Gendrano IN III, Kitabchi A, Schneider SH, Wadden TA. Effects of weight loss intervention on erectile function in older men with type 2 diabetes in the Look AHEAD trial. J Sex Med. 2010;7:156–65.

  50. 50.

    Esposito K, Giugliano F, Maiorino MI, Giugliano D. Dietary factors, Mediterranean diet and erectile dysfunction. J Sex Med. 2010;7(7):2338–45.

  51. 51.

    Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. 2005;82(Suppl):222S–5S.

  52. 52.

    English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur Heart J. 2000;21(11):890–4.

  53. 53.

    English KM, Jones RD, Jones TH, Morice AH, Channer KS. Testosterone acts as a coronary vasodilator by a calcium antagonistic action. J Endocrinol Investig. 2002;25(5):455–8.

  54. 54.

    English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chromic stable angina: a randomized, double-blind, placebo-controlled study. Circulation. 2000;102(16):1906–11.

  55. 55.

    Bai C-X, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation. 2005;112(12):1701–10.

  56. 56.

    Mathur A, Malkin C, Saleem B, Muthusammy R, Jones CH, Channer K. The long term benefits of testosterone on angina threshold and atheroma in men. Eur J Endocrinol. 2009;161(3):443–9.

  57. 57.

    Pugh PJ, Jones RD, West JN, et al. Testosterone treatment for men with chronic heart failure. Heart. 2004;90:446–7.

  58. 58.

    Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006;27:57–64.

  59. 59.

    Caminiti G, Volterrani, Iellamo MF, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure. A double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009;54(10):919–27.

  60. 60.

    Rodrigues dos Santos M, Sayegh ALC, Groehs RVC, et al. Testosterone deficiency increases hospital readmission and mortality rates in male patients with heart failure. doi:10.5935/abc.20150078.

  61. 61.

    Svartberg J, von MühlenD, Mathiesen E, Joakimsen O, Bønaa KH, and Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med 2006;259(6):5.

  62. 62.

    Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: systematic review and meta-analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab. 2013;27:557–79.

  63. 63.

    Grossmann M. Hoermann E, Wittert G. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clinical Endocrinology 12/2014. doi:10.1111/cen.12664.

  64. 64.

    Stellato RK, Feldman HA, Hamdy O, Horton ES, Mckinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts Male Aging Study. Diabetes Care. 2000;23(4):490–4.

  65. 65.

    Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the third National Health and Nutrition Survey (NHANES-III). Diabetes Care. 2007;30:234–8.

  66. 66.

    Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Bolona ER, Sideras K, Uraga MV, Erwin PJ, Montori VM. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82:29–39.

  67. 67.

    Xu L, Freeman G, Cowling B, and Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013;11 (article 108).

  68. 68.

    Gloud C. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 1986;6:807–813.

  69. 69.

    Schoenfeld MJ, Shortridge E, Cui Z, Muram DJ. Medication adherence and treatment patterns for hypogonadal patients treated with topical testosterone therapy: a retrospective medical claims analysis. J Sex Med. 2013;10(5):1401–9.

  70. 70.

    Layton B, Meier C, Sharpless J, et al. Comparative safety of testosterone dosage forms. JAMA Intern Med. doi:10.1001/jamainternmed.2015.1573.

  71. 71.

    Wu FC. Caveat emptor: does testosterone treatment reduce mortality in men? J Clin Endocrinol Metab. 2012;97(6):1884–6. doi:10.1210/jc.2012-1977.

  72. 72.

    Hackett G, Ramachandran S, Strange R, et al. Testosterone replacement therapy and PDE5 inhibitor use in type 2 diabetes are independently associated with a reduction in all-cause mortality. Poster 9-LB. Am Diabetes Assoc. 2015.

  73. 73.

    Spitzer M, Bhasin S, Travison TG, Davda MN, Stroh H, Basaria S. Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 2013;1(6):913–8.

  74. 74.

    Santi S, Guidi A, Granata A, et al. Chronic long term administration of vardenafil improves endothelial function and corrects hypogonadism in men with type 2 diabetes mellitus. A longitudinal, prospective, randomized, placebo-controlled double blind clinical trial. 380 Congresso Nazionale, Societa Italiana di Endocrinologia. Endocr Abstr 2015;37:C4.3. http://www.societaitalianadiendocrinologia.it/images/PDF_abstract/Abstract_PDF_SIE2015.pdf.

  75. 75.

    Anderson SG, Heald A, Hackett GI. Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all cause mortality. Poster 7-LB. Am Diabetes Assoc. 2015.

  76. 76.

    Morganuv L, Denisola I, Rohzkova T, et al. Androgen deficit and its treatment in stroke male patients with type II diabetes. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova 2011;111(8, part 2):21–24.

  77. 77.

    Baillargeon J, Urban RJ, Kuo Y-F, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother. 2014;48(9):1138–44.

  78. 78.

    Anderson J, May H, Lappe D. Abstract 13220: Cardiovascular impact of testosterone therapy in men with low testosterone levels. http://circ.ahajournals.org/content/130/Suppl_2/A13220.abstract?sid=de950f72-261c-46b7-b6e0-068078441b90[24.11.201411:39:14].

  79. 79.

    Sharma R, Oni OA, Gupta K. Normalisation of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;. doi:10.1093/eurheartj/ehv34.

  80. 80.

    Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol. 2014;2014:683515.

  81. 81.

    Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol 2014;527470.

  82. 82.

    Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39–46.

  83. 83.

    Borst S, Yarrow J. Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men. Am J Physiol Endocrinol Metab. 2015. doi:10.1152/ajpendo.00111.2015.

  84. 84.

    The Testosterone Trial. http://rt5.cceb.upenn.edu/portal/page/portal/T-Trial%20Portal/T-TrialPublicPageMain. Accessed 13 Sept 2015.

  85. 85.

    Wolf S. Increased heart attacks in men using testosterone therapy. 2014; 348.doi:10.1136/bmj.g1789 (Published 27 February 2014) Cite this as: 2014;348:g1789.

  86. 86.

    FDA Testosterone Products: Drug Safety Communication—FDA investigating risk of cardiovascular events. http://www.fda.gov/safety/medwatch/safetyinfomation/safetyalertsforhumanmedicalproducts/ucm384225.htm.

  87. 87.

    No consistent evidence of heart attacks with testosterone medications. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Testosterone_31/Position_provided_by_CMDh/WC500177617.pdf. Accessed 25 June 2015.

  88. 88.

    Traish A, Morgentaler A, Guay A. Death by testosterone—we think not. JSM. 2014;11(3):624–9.

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Correspondence to G. I. Hackett.

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No sources of funding were used to assist in the preparation of this review.

Conflicts of interest

Professor Geoffrey Ian Hackett is an occasional speaker for Bayer, Lilly and Menarini and has occasionally worked on the advisory board for Lilly and Pfizer.

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Hackett, G.I. Testosterone Replacement Therapy and Mortality in Older Men. Drug Saf 39, 117–130 (2016). https://doi.org/10.1007/s40264-015-0348-y

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Keywords

  • Testosterone
  • Erectile Dysfunction
  • Testosterone Level
  • Free Testosterone
  • Total Testosterone