Testosterone is a male sex hormone that affects sexual development and function and enhances muscle strength and bone density.¹ Low testosterone levels have been associated with a variety of comorbid conditions, such as metabolic syndrome (MetS), obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD).^1-3 Each of these comorbid conditions is a strong risk factor that contributes to an increased risk of major adverse cardiovascular events.¹ In addition, low serum testosterone is inversely associated with increased mortality.^4,5

This review explores the association between low serum testosterone and diseases that portend poor health, such as MetS, obesity, T2D, and CVD, and reviews current clinical studies and proposed mechanisms by which low testosterone is associated with these diseases.

Clinical Studies

Obesity

More than one-third of the population is obese, with a body mass index (BMI) > 30 kg/m², according to the National Health and Nutrition Examination Survey.⁶ Obesity has been linked to various health issues, such as CVD and cancer.^7,8 Although data vary, an association has been made between morbid obesity (BMI > 35 kg/m²) and increased overall mortality.^6,9

The link between obesity and low testosterone has been established for several decades, and a number of population-based studies have demonstrated an increased incidence of low testosterone in obese men.^10,11 The Massachusetts Male Aging Study showed that obesity has a greater effect on lowering serum testosterone than normal aging.¹² As obese men lose weight, testosterone levels typically rise back toward normal levels.¹³ Similarly, treatment with exogenous testosterone in obese men can often lead to reduction in BMI.¹⁴

Type 2 Diabetes

T2D is a major cause of morbidity in the United States. An estimated 29 million Americans have T2D, and nearly 86 million Americans over age 20 have insulin resistance. Additionally, the International Diabetes Federation suggests that over 400 million cases of T2D worldwide can be expected by 2030.¹⁵

Clinical studies suggest a relationship between T2D, insulin resistance, and decreased serum testosterone. Multiple cross- sectional studies have shown that men with T2D have lower levels of testosterone compared with men without diabetes, and prospective studies have shown that individuals with low testosterone were more likely to develop T2D.^15,16 Similarly, decreased testosterone levels have been independently associated with increased insulin resistance in men with T2D.^17,18 Furthermore, insulin resistance has been associated with low testosterone in men who do not have obesity or T2D, suggesting that this association can exist despite presence of other comorbidities.¹⁹ A physiologic relationship was shown in a placebo-controlled randomized trial of men aged 18 to 55 years (n = 22). In this study, acyline, a gonadotrophin-releasing hormone (GnRH) antagonist, resulted in an acute reduction in serum testosterone and an increase in fasting insulin levels with no significant change in fasting glucose levels at 4 weeks. Subsequent discontinuation of acyline resulted in a restoration of baseline insulin levels. After GnRH antagonist therapy was stopped, fasting insulin levels returned to baseline levels, suggesting a causative effect of decreasing testosterone’s role on insulin resistance.²⁰ These data suggest that low testosterone may play a role in the development of T2D and increased insulin resistance.

Metabolic Syndrome

Insulin resistance and central obesity are key components of MetS. Historically, MetS has been defined by multiple factors related to insulin resistance, including hypertension, elevated BMI, and elevated triglyceride levels. An individual with MetS must currently meet three or more of the following criteria: (1) waist circumference > 40 inches in men, (2) triglycerides ≥ 150 mg/dL, (3) high-density lipoprotein cholesterol < 40 mg/dL, (4) blood pressure ≥ 135/85 mm Hg, and (5) fasting blood sugar ≥ 100 mg/dL.²¹ Studies suggest that up to 25% of adults have MetS.²¹

A meta-analysis performed by Corona and colleagues²² showed that the current literature supports the independent association between low testosterone levels and MetS, and the few randomized controlled trials available also suggest that increasing serum testosterone improves MetS parameters. In a 5-year prospective study of men aged 20 to 79 years, the risk of developing MetS was greatest in men with testosterone levels in the bottom quartile. Low baseline testosterone level was a stronger predictor for MetS in young men (20-39 y) than in elderly men.²³ Furthermore, data suggest that low testosterone may be a predictor of future MetS development.²⁴

Atherosclerosis

CVD is the most common cause of death in the United States. Risk factors for atherosclerotic cardiac disease can be attributed to age, dyslipidemia, hypertension, obesity, and diabetes. The relationship between atherosclerosis and serum testosterone has been established independent of concurrent T2D and MetS. Men with low serum testosterone appear to have a higher risk of developing atherosclerosis than eugonadal men.^1,5 It has been suggested that testosterone may act as a cytokine mediator, limiting vascular inflammation; as a result, it may play a protective role against the development of atherosclerosis.²⁵

A prospective analysis illustrated that men with lower testosterone levels are at greater risk for cardiovascular and all-cause mortality compared with men with greater serum testosterone levels.⁵ The authors suggest that testosterone may serve as a predictive marker for men at high risk for CVD and atherosclerosis. Similarly, it has been shown that low levels of free testosterone and total testosterone are decreased in young adults with coronary artery disease (CAD) when compared with an age-matched group. With these same data, they found that the magnitude of CAD (1-vessel, 2-vessel, and 3-vessel disease) was inversely related to the levels of free and total testosterone. Finally, these authors concluded that low testosterone (defined as < 250 ng/dL) is a stronger risk factor for premature CAD than age, T2D, or smoking.²⁶ This suggests that low testosterone may serve as a strong marker of the disease.

Pathophysiology

The physiologic association between testosterone and the comorbidities is multifactorial. This relationship is best explained by the hypogonadal-obesity- adipocytokine hypothesis as proposed by Kapoor and colleagues.²⁷ This bidirectional model demonstrates that inflammatory cytokines from adipose (adipokines) and insulin resistance plays a central role in lowering serum testosterone levels.²⁷

The association between low testosterone, as well as low sex hormone-binding globulin (SHBG), and increased incidence of MetS is well established.^23,28,29 Hyperinsulinemia, as seen in diabetic and obese men, results in a decrease in SHBG, leading to an overall decrease in total testosterone.^9,30 As a result, many of these men may have normal free testosterone levels and low total testosterone levels. A secondary method of decreased testosterone occurs as men gain more adipose tissue, as seen in those who are morbidly obese. In these men, adipose tissue decreases testosterone directly by converting it to estradiol via aromatization. The elevated level of estradiol reduces testosterone levels further by suppressing the secretion of luteinizing hormone (LH) and testosterone via kisspeptin, causing secondary hypogonadism. Finally, an increase in adipose tissue also results in increased levels of inflammatory cytokines (tumor necrosis factor-a, interleukin [IL]-6, and IL-1b) that also have a negative effect on LH and testosterone secretion (Figure 1).³¹ Interestingly, these inflammatory molecules also contribute to insulin resistance and the development of T2D.³² Leptin, another cytokine that is elevated with obesity, decreases LH activity on the testis itself. Furthermore, lipoprotein lipase, the enzyme responsible for triglyceride uptake, is normally inhibited by testosterone. In a bidirectional fashion, a decrease in testosterone may increase adipogenesis, exacerbating the reduction of testosterone via the mechanisms just described (Figure 2).³³

Conclusions

Low serum testosterone is associated with MetS, obesity, T2D, and atherosclerosis. Although the pathophysiology between low testosterone and these diseases share some common mechanisms, low serum testosterone is independently associated with each of these comorbidities. Clearly, hypogonadal men are at an increased risk of developing comorbidities and premature death. Therefore, we advocate evaluating a patient with low serum testosterone comprehensively for coexisting comorbidities rather than simply supplementing with exogenous testosterone. 

The authors report no real or apparent conflicts of interest. Dr. Ramasamy is a National Institutes of Health K12 Scholar supported by a Male Reproductive Health Research Career Development Physician-Scientist Award (HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Program.

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