HealtH Screening Update
Can Serum Testosterone Be Used as a Marker of Overall Health? Michael A. Mederos,1 Aaron M. Bernie, MD,2 Jason M. Scovell,1 Ranjith Ramasamy, MD1 1Department of Urology, Baylor College of Medicine, Houston, TX; 2Department of Urology, New YorkPresbyterian Hospital and Weill Cornell Medical College, New York, NY
Low serum testosterone has been associated with obesity, type 2 diabetes, metabolic syndrome, and atherosclerosis. Individuals with these comorbidities are at increased risk of premature death and other adverse health effects. Clinical data portend low testosterone as a risk factor for developing these conditions which are supported by the hypogonadal-obesity-adipocytokine hypothesis. The authors support comprehensive evaluation for these comorbid conditions in men found to have low serum testosterone. [Rev Urol. 2015;17(4):226-230 doi: 10.3909/riu0674]
®
© 2016 MedReviews , LLC
Key words Androgen deficiency • Aging male • Comorbidities • Diabetes • Cardiovascular disease
T
estosterone 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
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Can Serum Testosterone Be Used as a Marker of Overall Health? 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
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
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.
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 crosssectional 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
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,
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 cardio-
… 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.
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
vascular 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)
Vol. 17 No. 4 • 2015 • Reviews in Urology • 227
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Can Serum Testosterone Be Used as a Marker of Overall Health? continued
↓ HPG axis
Estradiol
Testosterone aromatase
↓ Testosterone
↑ Inflammatory adipocytokines (TNF, IL-6, IL-1) and leptin
Increased lipogenesis/ obesity
Figure 1. Association of obesity and low serum testosterone. HPG, hypothalamic-pituitary-gonadal; IL, interleukin; TNF, tumor necrosis factor.
when compared with an agematched group. With these same data, they found that the magni-
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, and increased incidence of MetS is well established.
tude 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-obesityadipocytokine hypothesis as proposed by Kapoor and colleagues.27 This bidirectional model demonstrates that inflammatory cytokines from adipose (adipokines)
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 testos-
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
The elevated level of estradiol reduces testosterone levels further by suppressing the secretion of luteinizing hormone and testosterone via kisspeptin, causing secondary hypogonadism.
terone 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
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.
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Can Serum Testosterone Be Used as a Marker of Overall Health?
Testosterone deficiency
Adipose hypertrophy & hyperplasia Diabetes
Insulin resistance
↑ Mortality
Obesity
Dyslipidemia Metabolic Syndrome
Atherosclerosis
Figure 2. Hypogonadal-obesity-adipocytokine hypothesis depicting the interrelationship between low serum testosterone and obesity, insulin resistance, atherosclerosis, and mortality.
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.
References 1.
Fahed AC, Gholmieh JM, Azar ST. Connecting the lines between hypogonadism and atherosclerosis [published online February 16, 2012]. Int J Endocrinol. doi: 10.1155/2012/793953.
2.
3.
4.
5.
Brand JS, Rovers MM, Yeap BB, et al. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies. PLoS One. 2014;9:e100409. 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;102:39-46. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660-1665. 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 (EPICNorfolk) Prospective Population Study. Circulation. 2007;116:2694-2701.
6.
7.
8.
9.
10.
Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71-82. Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol. 2014;63:250-259. Ungefroren H, Gieseler F, Fliedner S, Lehnert H. Obesity and cancer. Horm Mol Biol Clin Investig. 2015;21:5-15. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16:223-231. Cao J, Chen TM, Hao WJ, et al. Correlation between sex hormone levels and obesity in the elderly male. Aging Male. 2012;15:85-89.
Main Points • Low serum testosterone has been associated with obesity, type 2 diabetes (T2D), metabolic syndrome (MetS), and atherosclerosis. In addition, low serum testosterone is inversely associated with increased mortality. • The association between low testosterone, as well as low sex hormone-binding globulin, and increased incidence of MetS is well established. • 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. • Current literature supports the independent association between low testosterone levels and MetS; several randomized controlled trials also suggest that increasing serum testosterone improves MetS parameters. • We advocate evaluating a patient with low serum testosterone comprehensively for coexisting comorbidities rather than simply supplementing with exogenous testosterone. Vol. 17 No. 4 • 2015 • Reviews in Urology • 229
4004170006_RiU0674.indd 229
20/01/16 2:23 pm
Can Serum Testosterone Be Used as a Marker of Overall Health? continued 11.
12.
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16.
17.
18.
Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33:1186-1192. Travison TG, Araujo AB, Kupelian V, et al. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab. 2007;92:549-555. Allan CA, McLachlan RI. Androgens and obesity. Curr Opin Endocrinol Diabetes Obes. 2010;17: 224-232. Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med. 2014;11: 1567-1576. Al Hayek AA, Khader YS, Jafal S, et al. Prevalence of low testosterone levels in men with type 2 diabetes mellitus: a cross-sectional study. J Family Community Med. 2013;20:179-186. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27:1036-1041. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93:1834-1840. Pitteloud N, Mootha VK, Dwyer AA, et al. Relationship between testosterone levels, insulin sensitivity,
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and mitochondrial function in men. Diabetes Care. 2005;28:1636-1642. Yeap BB, Chubb SA, Hyde Z, et al. Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study. Eur J Endocrinol. 2009;161:591-598. Rubinow KB, Snyder CN, Amory JK, et al. Acute testosterone deprivation reduces insulin sensitivity in men. Clin Endocrinol (Oxf). 2012;76:281-288. Cunningham GR. Testosterone and metabolic syndrome. Asian J Androl. 2015;17:192-196. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011;8:272-283. Haring R, Völzke H, Felix SB, et al. Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes. 2009;58:2027-2031. Kupelian V, Page ST, Araujo AB, et al. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91:843-850. Malkin CJ, Pugh PJ, Jones RD, et al. Testosterone as a protective factor against atherosclerosis— immunomodulation and influence upon plaque development and stability. J Endocrinol. 2003;178: 373-380. Alkamel A, Shafiee A, Jalali A, et al. The association between premature coronary artery disease and level
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32. 33.
of testosterone in young adult males. Arch Iran Med. 2014;17:545-550. Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol (Oxf). 2005;63:239-250. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149:601-608. Zhang J, Huang X, Liao M, et al. Both total testosterone and sex hormone-binding globulin are independent risk factors for metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China. Diabetes Metab Res Rev. 2013;29:391-397. Hautanen A, Mänttäri M, Manninen V, et al. Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study. Atherosclerosis. 1994;105:191-200. Bornstein J, Heifetz S, Kellner Y, et al. Clobetasol dipropionate 0.05% versus testosterone propionate 2% topical application for severe vulvar lichen sclerosus. Am J Obstet Gynecol. 1998;178(1 Pt 1):80-84. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111-1119. Mårin P, Odén B, Björntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab. 1995;80: 239-243.
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Can Serum Testosterone Be Used as a Marker of Overall Health? Michael A. Mederos,1 Aaron M. Bernie, MD,2 Jason M. Scovell,1 Ranjith Ramasamy, MD1 1Department of Urology, Baylor College of Medicine, Houston, TX; 2Department of Urology, New YorkPresbyterian Hospital and Weill Cornell Medical College, New York, NY
Low serum testosterone has been associated with obesity, type 2 diabetes, metabolic syndrome, and atherosclerosis. Individuals with these comorbidities are at increased risk of premature death and other adverse health effects. Clinical data portend low testosterone as a risk factor for developing these conditions which are supported by the hypogonadal-obesity-adipocytokine hypothesis. The authors support comprehensive evaluation for these comorbid conditions in men found to have low serum testosterone. [Rev Urol. 2015;17(4):226-230 doi: 10.3909/riu0674]
®
© 2016 MedReviews , LLC
Key words Androgen deficiency • Aging male • Comorbidities • Diabetes • Cardiovascular disease
T
estosterone 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
226 • Vol. 17 No. 4 • 2015 • Reviews in Urology
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Can Serum Testosterone Be Used as a Marker of Overall Health? 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
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
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.
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 crosssectional 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
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,
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 cardio-
… 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.
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
vascular 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)
Vol. 17 No. 4 • 2015 • Reviews in Urology • 227
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20/01/16 2:23 pm
Can Serum Testosterone Be Used as a Marker of Overall Health? continued
↓ HPG axis
Estradiol
Testosterone aromatase
↓ Testosterone
↑ Inflammatory adipocytokines (TNF, IL-6, IL-1) and leptin
Increased lipogenesis/ obesity
Figure 1. Association of obesity and low serum testosterone. HPG, hypothalamic-pituitary-gonadal; IL, interleukin; TNF, tumor necrosis factor.
when compared with an agematched group. With these same data, they found that the magni-
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, and increased incidence of MetS is well established.
tude 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-obesityadipocytokine hypothesis as proposed by Kapoor and colleagues.27 This bidirectional model demonstrates that inflammatory cytokines from adipose (adipokines)
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 testos-
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
The elevated level of estradiol reduces testosterone levels further by suppressing the secretion of luteinizing hormone and testosterone via kisspeptin, causing secondary hypogonadism.
terone 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
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.
228 • Vol. 17 No. 4 • 2015 • Reviews in Urology
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Can Serum Testosterone Be Used as a Marker of Overall Health?
Testosterone deficiency
Adipose hypertrophy & hyperplasia Diabetes
Insulin resistance
↑ Mortality
Obesity
Dyslipidemia Metabolic Syndrome
Atherosclerosis
Figure 2. Hypogonadal-obesity-adipocytokine hypothesis depicting the interrelationship between low serum testosterone and obesity, insulin resistance, atherosclerosis, and mortality.
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.
References 1.
Fahed AC, Gholmieh JM, Azar ST. Connecting the lines between hypogonadism and atherosclerosis [published online February 16, 2012]. Int J Endocrinol. doi: 10.1155/2012/793953.
2.
3.
4.
5.
Brand JS, Rovers MM, Yeap BB, et al. Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies. PLoS One. 2014;9:e100409. 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;102:39-46. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660-1665. 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 (EPICNorfolk) Prospective Population Study. Circulation. 2007;116:2694-2701.
6.
7.
8.
9.
10.
Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71-82. Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol. 2014;63:250-259. Ungefroren H, Gieseler F, Fliedner S, Lehnert H. Obesity and cancer. Horm Mol Biol Clin Investig. 2015;21:5-15. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014;16:223-231. Cao J, Chen TM, Hao WJ, et al. Correlation between sex hormone levels and obesity in the elderly male. Aging Male. 2012;15:85-89.
Main Points • Low serum testosterone has been associated with obesity, type 2 diabetes (T2D), metabolic syndrome (MetS), and atherosclerosis. In addition, low serum testosterone is inversely associated with increased mortality. • The association between low testosterone, as well as low sex hormone-binding globulin, and increased incidence of MetS is well established. • 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. • Current literature supports the independent association between low testosterone levels and MetS; several randomized controlled trials also suggest that increasing serum testosterone improves MetS parameters. • We advocate evaluating a patient with low serum testosterone comprehensively for coexisting comorbidities rather than simply supplementing with exogenous testosterone. Vol. 17 No. 4 • 2015 • Reviews in Urology • 229
4004170006_RiU0674.indd 229
20/01/16 2:23 pm
Can Serum Testosterone Be Used as a Marker of Overall Health? continued 11.
12.
13.
14.
15.
16.
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