What is hypogonadism?
(also known as testosterone deficiency or low testosterone)
Hypogonadism is a well-established medical condition that negatively affects male sexuality, reproduction, quality of life, general health and longevity.3,4 Hypogonadism is characterized by low testosterone levels or insufficient testosterone action, with accompanying symptoms and signs,3,4 particularly low sexual desire, erectile dysfunction, poor morning erections, inability to perform vigorous activity, depressed mood and fatigue.5 Hypogonadism results from reduced testicular synthesis of testosterone due to:3
Hypogonadism can occur in men of any age; therefore the terms ’late-onset hypogonadism’ and ’age-related hypogonadism’ are misleading and should be discarded.8-10 The term ‘andropause’ has been used as a synonym for hypogonadism, with claims that it is the “male version of menopause”. While some symptoms of andropause are similar to menopause, drawing this parallel is erroneous because not all men develop hypogonadism, and in those who do, testosterone levels have declined progressively over an extended period of time.11 In contrast, menopause affects all women universally and occurs quite abruptly.
Fundamental concepts regarding hypogonadism and testosterone therapy: International Expert Consensus Resolutions
In 2015, an international expert consensus conference about hypogonadism (testosterone deficiency) and its treatment was held in Prague, sponsored by King’s College London and the International Society for the Study of the Aging Male (ISSAM).4 The impetus for this meeting was to address the widespread misinformation and confusion about hypogonadism and testosterone therapy.12 The ultimate goal of this consensus conference was to document what is true or untrue about hypogonadism and testosterone therapy, to the best degree possible based on existing scientific and clinical evidence, as summarized in table.3,4
1. TD is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.
TD (low levels of testosterone):
2. The symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying cause.
3. TD is a global public health concern.
4. T therapy for men with TD is effective, rational, and evidence based.
High-level evidence shows T therapy effectively:
Strongly suggestive evidence for improvement in mood,energy
5. There is no T level threshold that reliably distinguishes those who will respond to treatment from those who will not.
No study has revealed a single testosterone threshold that reliably separates those who experience signs and symptoms of TD from those who do not, nor who will likely respond to treatment.
Interpretation of total T levels is confounded by:
Free T can be a useful indicator of androgen status.
6. There is no scientific basis for any age-specific recommendations against the use of T therapy in men.
7. The evidence does not support increased risks of CV events with T therapy.
8. The evidence does not support increased risk of PCa with T therapy
9. Evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes.
CV; cardiovascular; PCa; prostate cancer; RCT; randomized controlled trial; SHBG; sex hormone
binding globulin; T; testosterone; TD; testosterone deficiency; VTE; venothrombotic events.
How common is hypogonadism?
How are men affected by hypogonadism?
Why is it important to treat hypogonadism?
Low testosterone can be diagnosed by an assessment of symptoms and a blood test to measure testosterone levels. If tests confirm hypogonadism, a range of different testosterone replacement therapies and formulations are available to normalize testosterone levels.
- Dohle et al. EAU Guidelines. 2018: Arnhern, the Netherlands. Return to content
- Kumar et al. J Adv Pharm Technol Res. 2010 Jul-Sep: 1(3): 297-301) Return to content
- Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686. Return to content
- Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. 2016;91(7):881-896. Return to content
- Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-135. Return to content
- Carruthers M. The paradox dividing testosterone deficiency symptoms and androgen assays: a closer look at the cellular and molecular mechanisms of androgen action. The journal of sexual medicine. 2008;5(4):998-1012. Return to content
- Morgentaler A, Khera M, Maggi M, Zitzmann M. Commentary: Who is a candidate for testosterone therapy? A synthesis of international expert opinions. The journal of sexual medicine. 2014;11(7):1636-1645. Return to content
- Juang PS, Peng S, Allehmazedeh K, Shah A, Coviello AD, Herbst KL. Testosterone with dutasteride, but not anastrazole, improves insulin sensitivity in young obese men: a randomized controlled trial. The journal of sexual medicine. 2014;11(2):563-573. Return to content
- Chandel A, Dhindsa S, Topiwala S, Chaudhuri A, Dandona P. Testosterone concentration in young patients with diabetes. Diabetes Care. 2008;31(10):2013-2017. Return to content
- Haring R, Baumeister SE, Volzke H, et al. Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. 2011;18(1):86-96. Return to content
- Saad F, Gooren LJ. Late onset hypogonadism of men is not equivalent to the menopause. Maturitas. 2014;79(1):52-57. Return to content
- Morgentaler A, Zitzmann M, Traish AM, Fox A. International expert consensus conference on testosterone deficiency and its treatment held in Prague, Czech Republic. The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;18(4):205-206. Return to content
- Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769. Return to content
- Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, de Boer H. High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Neth J Me. 2008;66(3):103-109. Return to content
- Pellitero S, Olaizola I, Alastrue A, et al. Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg. 2012;22(12):1835-1842. Return to content
- Kapoor D, Aldred H, Clark S, Channer KS, Jones TH. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care. 2007;30(4):911-917. Return to content
- Hackett GI, Cole NS, Deshpande AA, Popple MD, Kennedy D, Wilkinson P. Biochemical hypogonadism in men with type 2 diabetes in primary care practice. The British Journal of Diabetes & Vascular Disease. 2009;9(5):226-231. Return to content
- Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clin Endocrinol (Oxf). 2012;76(5):665-673. Return to content
- Kohler TS, Kim J, Feia K, et al. Prevalence of androgen deficiency in men with erectile dysfunction. Urology. 2008;71(4):693-697. Return to content
- Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015–2016. Available at https://www.cdc.gov/nchs/data/databriefs/db288.pdf (accessed October 12, 2019). Return to content
- NCD Risk Factor Collaboration. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 2016;387(10027):1513-1530. Return to content
- Stokes A, Preston SH. The contribution of rising adiposity to the increasing prevalence of diabetes in the United States. Prev Med. 2017;101:91-95. Return to content
- Astrup A, Finer N. Redefining type 2 diabetes: 'diabesity' or 'obesity dependent diabetes mellitus'? Obesity reviews : an official journal of the International Association for the Study of Obesity. 2000;1(2):57-59. Return to content
- Yip WCY, Sequeira IR, Plank LD, Poppitt SD. Prevalence of Pre-Diabetes across Ethnicities: A Review of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) for Classification of Dysglycaemia. Nutrients. 2017;9(11). Return to content
- Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151(1):54-61. Return to content
- Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. A prospective study of risk factors for erectile dysfunction. J Urol. 2006;176(1):217-221. Return to content
- Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Available at https://www.endocrinepractice.org/article/S1530-891X(20)44630-0/fulltext (accessed 4 July, 2020) Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016;22 Suppl 3:1-203. Return to content
- American Diabetes Association. Summary of Revisions: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S4-S6. Return to content
- Derby CA, Zilber S, Brambilla D, Morales KH, McKinlay JB. Body mass index, waist circumference and waist to hip ratio and change in sex steroid hormones: the Massachusetts Male Aging Study. Clin Endocrinol (Oxf). 2006;65(1):125-131. Return to content
- Travison TG, Araujo AB, Kupelian V, O'Donnell AB, McKinlay JB. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab. 2007;92(2):549-555. Return to content
- Camacho EM, Huhtaniemi IT, O'Neill TW, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Aging Study. Eur J Endocrinol. 2013;168(3):445-455. Return to content
- Haring R, Ittermann T, Volzke H, et al. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. The aging male : the official journal of the International Society for the Study of the Aging Male. 2010;13(4):247-257. Return to content
- Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J Endocrinol. 2013;217(3):R47-71. Return to content
- Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217(3):R25-45. Return to content
- Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes Metab Res Rev. 2012;28 Suppl 2:52-59. Return to content
- Saad F, Gooren L. The role of testosterone in the metabolic syndrome: a review. J Steroid Biochem Mol Biol. 2009;114(1-2):40-43. Return to content
- Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl. 2009;30(1):10-22. Return to content
- Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009;30(1):23-32. Return to content
- Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl. 2009;30(5):477-494. Return to content
- Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. 2015;90(2):224-251. Return to content
- Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis. 2009;207(2):318-327. Return to content
- Firtser S, Juonala M, Magnussen CG, et al. Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years. The Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2012;222(1):257-262. Return to content
- Makinen JI, Perheentupa A, Irjala K, et al. Endogenous testosterone and serum lipids in middle-aged men. Atherosclerosis. 2008;197(2):688-693. Return to content
- Hotta Y, Kataoka T, Kimura K. Testosterone Deficiency and Endothelial Dysfunction: Nitric Oxide, Asymmetric Dimethylarginine, and Endothelial Progenitor Cells. Sex Med Rev. 2019;7(4):661-668. Return to content
- Traish A, Bolanos J, Nair S, Saad F, Morgentaler A. Do Androgens Modulate the Pathophysiological Pathways of Inflammation? Appraising the Contemporary Evidence. J Clin Med. 2018;7(12). Return to content
- Makinen J, Jarvisalo MJ, Pollanen P, et al. Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol. 2005;45(10):1603-1608. Return to content
- Svartberg J, von Muhlen D, Mathiesen E, Joakimsen O, Bonaa KH, Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. 2006;259(6):576-582. Return to content
- Srinath R, Hill Golden S, Carson KA, Dobs A. Endogenous testosterone and its relationship to preclinical and clinical measures of cardiovascular disease in the atherosclerosis risk in communities study. J Clin Endocrinol Metab. 2015;100(4):1602-1608. Return to content
- Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Endogenous Testosterone Levels and Cardiovascular Risk: Meta-Analysis of Observational Studies. The journal of sexual medicine. 2018;15(9):1260-1271. Return to content
- Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends in endocrinology and metabolism: TEM. 2010;21(8):496-503. Return to content
- Yeap BB, Knuiman MW, Divitini ML, et al. Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men. J Clin Endocrinol Metab. 2016;101(3):1299-1306. Return to content
- Huang Y, Dai W, Li Y. Potential associations of testosterone/estradiol ratio, leukocyte hTERT expression and PBMC telomerase activity with aging and the presence of coronary artery disease in men. Exp Gerontol. 2019;117:38-44. Return to content
- Chen YQ, Zhao J, Jin CW, et al. Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway. Age (Dordr). 2016;38(3):60. Return to content
- Zhang L, Lei D, Zhu GP, Hong L, Wu SZ. Physiological testosterone retards cardiomyocyte aging in Tfm mice via androgen receptor-independent pathway. Chin Med Sci J. 2013;28(2):88-94. Return to content
- McHenry J, Carrier N, Hull E, Kabbaj M. Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol. 2014;35(1):42-57. Return to content
- Celec P, Ostatnikova D, Hodosy J. On the effects of testosterone on brain behavioral functions. Frontiers in neuroscience. 2015;9:12. Return to content
- Shores MM, Sloan KL, Matsumoto AM, Moceri VM, Felker B, Kivlahan DR. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry. 2004;61(2):162-167. Return to content
- Joshi D, van Schoor NM, de Ronde W, et al. Low free testosterone levels are associated with prevalence and incidence of depressive symptoms in older men. Clin Endocrinol (Oxf). 2010;72(2):232-240. Return to content
- Kische H, Gross S, Wallaschofski H, et al. Associations of androgens with depressive symptoms and cognitive status in the general population. PloS one. 2017;12(5):e0177272. Return to content
- Almeida OP, Yeap BB, Hankey GJ, Jamrozik K, Flicker L. Low Free Testosterone Concentration as a Potentially Treatable Cause of Depressive Symptoms in Older Men. JAMA psychiatry. 2008;65(3):283-289. Return to content
- Korenman SG, Grotts JF, Bell DS, Elashoff DA. Depression in Nonclassical Hypogonadism in Young Men. J Endocr Soc. 2018;2(11):1306-1313. Return to content
- Ford AH, Yeap BB, Flicker L, et al. Prospective longitudinal study of testosterone and incident depression in older men: The Health In Men Study. Psychoneuroendocrinology. 2016;64:57-65. Return to content
- Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab. 1999;84(10):3681-3685. Return to content
- 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):2482-2488. Return to content
- Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur J Endocrinol. 2009;161(3):435-442. Return to content
- Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(10):3007-3019. Return to content
- Holmboe SA, Skakkebaek NE, Juul A, et al. Individual testosterone decline and future mortality risk in men. Eur J Endocrinol. 2018;178(1):123-130. Return to content
- Haring R, Volzke H, 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(12):1494-1501. Return to content
- Adelborg K, Rasmussen TB, Norrelund H, Layton JB, Sorensen HT, Christiansen CF. Cardiovascular Outcomes and All-cause Mortality Following Measurement of Endogenous Testosterone Levels. Am J Cardiol. 2019;123(11):1757-1764. Return to content
- Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058. Return to content
- 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):725-733. Return to content
- Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706-2715. Return to content
- Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Serum testosterone, testosterone therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract. 2016;70(3):244-253. Return to content
- Hackett G, Jones PW, Strange RC, Ramachandran S. Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes. World journal of diabetes. 2017;8(3):104-111. Return to content
- Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. 2020;23(1):81-92. Return to content
- Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. 2019;6(42):1104-1111. Return to content
- Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433. Return to content
- Oni OA, Dehkordi SHH, Jazayeri MA, et al. Relation of Testosterone Normalization to Mortality and Myocardial Infarction in Men With Previous Myocardial Infarction. Am J Cardiol. 2019;124(8):1171-1178. Return to content
- Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes. 2020;44(6):1264-1278. Return to content
- Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiencyand a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular health and risk management. 2016;12:251-261. Return to content