Testosterone, commonly considered the male hormone, plays a critical role in the development and maintenance of male reproductive and sexual health, bone health and behaviour. While decreases in testosterone levels are a natural consequence of aging, neither the extent of the decrease nor the subsequent impact on male health are well defined.1 Chronic illnesses may also contribute to low testosterone levels.2,3 Men who suffer from low testosterone levels may experience a wide range of symptoms and may benefit from treatment with testosterone supplementation or replacement therapy. This article provides an overview of low testosterone in men, called hypogonadism, and testosterone replacement as a treatment.

What is Hypogonadism?

Hypogonadism is a syndrome defined as low testosterone levels and its associated symptoms. Testosterone levels naturally fluctuate widely over the course of the day and are typically highest in the morning.4 As a result, testosterone levels, which are measured in the blood, should ideally be measured in the morning. If a low testosterone level is recorded in the morning, it should be confirmed at least a second time to ensure accuracy. Testosterone levels are often measured in conjunction with a panel of related markers (such as estradiol, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, and prolactin) in order to help determine the cause of the low testosterone levels.

Clinical symptoms associated with hypogonadism vary widely but can include sexual symptoms such as decreased sexual desire, reduced nocturnal and morning erections and impaired erectile function, cognitive symptoms such as mood changes, depressive thoughts and irritability and general symptoms such as fatigue, hot flushes, low bone mass, decreased muscle mass and strength and obesity.5 Importantly, while these symptoms suggest the presence of hypogonadism, they are not specific and can also be found in men with normal testosterone levels. Such symptoms may also be caused by other disease processes.

Prevalence and Causes

The prevalence of male hypogonadism increases with age. Low testosterone levels can appear in two to 13 percent of middle-aged men; a diagnosis of hypogonadism is made in about two to six percent of men aged 40-79.1,6

The primary source of testosterone production is the testes. Hormones produced by the hypothalamus in the brain and the pituitary gland — a pea-sized gland located at the base of the brain — are critical in regulating testosterone production in the testes. While hypogonadism can result from a disturbance anywhere along the hypothalamus/pituitary, gland-testes axis, the most common cause of age-related hypogonadism is the combined dysfunction of the hypothalamus/pituitary gland and the testes.7

Risk Factors

Hypogonadism is more prevalent in men with chronic diseases as well as those who are older. In particular, men with elements of metabolic syndrome, which describes a cluster of conditions that includes abdominal obesity, high blood pressure, elevated fasting blood glucose levels, high serum triglycerides and low levels of the good HDL cholesterol are at a higher risk of hypogonadism.2,3,8Studies show that the risk of hypogonadism increases the more medical problems a man has.9,10

Disease Course and Outcomes

Since testosterone has such wide-ranging effects on male health, the potential impact of hypogonadism is broad, as evidenced by the wide range of clinical symptoms associated with hypogonadism. In addition to quality of life issues associated with sexual dysfunction, cognitive impairment and fatigue, disease processes such as infertility, osteoporosis, Type 2 diabetes and cardiovascular disease may be exacerbated by hypogonadism. Furthermore, studies have linked low testosterone levels with increased mortality from cardiovascular and respiratory diseases.11

Treatment Options

Since many men with hypogonadism also suffer from chronic diseases related to metabolic syndrome, lifestyle modifications to reduce obesity, improve blood pressure and improve blood glucose levels have all been shown to improve testosterone levels in men.12-14

Beyond lifestyle modifications, hypogonadism can be managed with testosterone replacement therapy (TRT), which is available in numerous preparations. TRT has been shown to have multiple beneficial effects in hypogonadal men. Notably, TRT has been shown to result in improvements in muscle mass and strength, bone mineral density, lean body mass, blood sugar control and lipid profiles.15-17 Studies also show TRT improves sexual function, mood and depressive symptoms in hypogonadal men.18-20

Despite these well-demonstrated benefits, TRT is not indicated for all patients with hypogonadism. Men with prostate or breast cancer, severe chronic heart failure, increased prostrate size (called uncontrolled benign prostatic hyperplasia) and those desiring to have children should be cautious about TRT. Adverse effects can include acne, increased red blood cell count, infertility, breast swelling or tenderness and swelling of the feet or ankles.

The potential link between TRT and cardiovascular disease has generated significant controversy and discussion in the media. Unfortunately, there have not yet been any definitive studies that answer this important question. Current evidence reports mixed results, with some studies finding no risks associated with TRT and others finding adverse risks.

Ultimately, the management of hypogonadism should only be exercised in close consultation with a physician, who can help answer questions surrounding the risks and benefits of TRT and advise on the ideal management strategy as well as provide the required medical monitoring and follow up.


  1. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: The european male aging study. J Clin Endocrinol Metab. 2008;93(7):2737-2745. doi: 10.1210/jc.2007-1972 [doi].
  2. Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: A systematic review and meta-analysis of observational studies. Int J Epidemiol. 2011;40(1):189-207. doi: 10.1093/ije/dyq158 [doi].
  3. Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care. 2011;34(7):1669-1675. doi: 10.2337/dc10-2339 [doi].
  4. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56(6):1278-1281. doi: 10.1210/jcem-56-6-1278 [doi].
  5. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev. 2005;26(6):833-876. doi: er.2004-0013 [pii].
  6. Hall SA, Esche GR, Araujo AB, et al. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab. 2008;93(10):3870-3877. doi: 10.1210/jc.2008-0021 [doi].
  7. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol. 2009;55(1):121-130. doi: 10.1016/j.eururo.2008.08.033 [doi].
  8. Blaya R, Thomaz LD, Guilhermano F, et al. Total testosterone levels are correlated to metabolic syndrome components. Aging Male. 2016;19(2):85-89. doi: 10.3109/13685538.2016.1154523 [doi].
  9. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: Evidence from the european male ageing study. J Clin Endocrinol Metab. 2010;95(4):1810-1818. doi: 10.1210/jc.2009-1796 [doi].
  10. Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: A pathological link supporting cardiovascular diseases. Int J Androl. 2009;32(6):587-598. doi: 10.1111/j.1365-2605.2008.00951.x [doi].
  11. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75. doi: jc.2007-1792 [pii].
  12. 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 ageing study. Eur J Endocrinol. 2013;168(3):445-455. doi: 10.1530/EJE-12-0890 [doi].
  13. Casulari LA, Caldas AD, Domingues Casulari Motta L, Lofrano-Porto A. Effects of metformin and short-term lifestyle modification on the improvement of male hypogonadism associated with metabolic syndrome. Minerva Endocrinol. 2010;35(3):145-151. doi: R07101755 [pii].
  14. 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. doi: jc.2006-1859 [pii].
  15. Caminiti G, Volterrani M, Iellamo F, 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):919-927. doi: 10.1016/j.jacc.2009.04.078 [doi].
  16. Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: A meta-analysis. Clin Endocrinol (Oxf). 2005;63(3):280-293. doi: CEN2339 [pii].
  17. 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. doi: 154/6/899 [pii].
  18. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624. doi: 10.1056/NEJMoa1506119 [doi].
  19. Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: A meta-analysis study. J Sex Med. 2014;11(6):1577-1592. doi: 10.1111/jsm.12536 [doi].
  20. Amanatkar HR, Chibnall JT, Seo BW, Manepalli JN, Grossberg GT. Impact of exogenous testosterone on mood: A systematic review and meta-analysis of randomized placebo-controlled trials. Ann Clin Psychiatry. 2014;26(1):19-32. doi: acp_2601b [pii].