Hypogonadism markedly increases risk of type 2 diabetes and death
August 2019
STUDIES: Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. 2018;7(1):220-231.
Malipatil NS, Yadegarfar G, Lunt M, et al. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinology, Diabetes & Metabolism.0(0):e00064.
Type 2 diabetes is an increasingly common metabolic disorder in men,1,2 mirroring the increasing prevalence of obesity and reduced testosterone levels.3 Type 2 diabetes increases the risk of developing a number of serious health problems, resulting in higher medical care costs, reduced quality of life and increased mortality.4
Men with hypogonadism, also known as testosterone deficiency, are at increased risk for developing insulin resistance and type 2 diabetes.5,6 In men with existing type 2 diabetes, low testosterone levels are associated with a significantly increased mortality risk compared to men without testosterone deficiency.7,8 Here we summarise the results of recent studies that aimed to quantify the relationship between testosterone, diabetes and mortality.9,10
KEY POINTS
- Low testosterone levels increase risk for developing type 2 diabetes by nearly 40%.
- Low testosterone levels are associated with higher all-cause mortality in men with type 2 diabetes over a 14‐year follow‐up period.
- Men with type 2 diabetes who also have hypogonadism should be considered at very high risk for cardiovascular death.
- Screening for hypogonadism by laboratory measurement of testosterone levels should be part of routine clinical management of men with type 2 diabetes.
What is known about testosterone and type 2 diabetes
The global prevalence of type 2 diabetes and impaired glucose tolerance in adults has been increasing over past decades,11-14 and emerged as the fourth leading cause of disability globally.15 Type 2 diabetes confers a two-fold excess risk for a wide range of vascular diseases and cardiovascular mortality, independently from other conventional risk factors such as age, sex, and other traditional cardiovascular risk factors.16,17 Persistently high blood glucose levels cause generalized vascular damage affecting the heart, eyes, kidneys and nerves, resulting in various complications.18 Nevertheless, while hyperglycemia is the major risk factor for microvascular complications, cardiovascular disease is the principal cause of death in patients with type 2 diabetes.19
Men with type 2 diabetes have lower testosterone levels 18 and higher prevalence of hypogonadism than men without type 2 diabetes; up to 81% of men with type 2 diabetes have hypogonadism.20-24 Importantly, low testosterone levels may be a reversible risk factor for type 2 diabetes.25,26 For instance, a 2006 meta-analysis showed that men with testosterone levels >15.6 nmol/L (450 ng/dL) have a 42% reduced risk of developing type 2 diabetes compared to men with testosterone levels ≤15.6 nmol/L.25
It is notable that >15.6 nmol/L (450 ng/dL) is higher than the thresholds recommended by clinical guidelines to make the diagnosis of hypogonadism.
What new studies show
A large meta-analysis of 13 prospective population studies with 16,709 participants showed that higher total and free testosterone levels significantly decrease the risk of type 2 diabetes in men by 38% and 23%, respectively.10 This is the first meta-analysis of prospective population studies to investigate the association between testosterone levels and type 2 diabetes risk in men. The large sample size allowed for a reliable assessment of the causal relationship between testosterone and risk of type 2 diabetes, and provides strong epidemiological evidence for a causal role of low testosterone in the development of type 2 diabetes.
A 14‐year follow‐up study collected health record data of 550 men with type 2 diabetes to evaluate the influence of baseline testosterone levels on type 2 diabetes outcomes.9 Mean baseline total testosterone for the entire cohort was 13.7 nmol/L (395 ng/dL). Lower baseline total testosterone levels were significantly associated with a higher BMI and increased risk of stroke at follow‐up. Mortality rate was nearly twice as high in patients with lower total testosterone compared to normal baseline total testosterone (5.0% vs 2.8% per year). During the 14-year follow‐up period, 36.1% of men with normal baseline testosterone died vs 55.8% of men with hypogonadism at baseline (figure). The age‐adjusted hazard ratio for higher mortality associated with low total testosterone corresponded to 3.2 years reduced life expectancy for men who have both hypogonadism and type 2 diabetes, compared to men who only have type 2 diabetes.
Figure: Mortality in men with type 2 diabetes who have hypogonadism compared to men with type 2 diabetes who have normal testosterone levels.
Data from: Malipatil NS, Yadegarfar G, Lunt M, et al. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinology, Diabetes & Metabolism.0(0):e00064.
This study also found a significant association between total testosterone and BMI, HDL‐cholesterol and triglycerides; men with higher testosterone levels had higher HDL and lower BMI and triglyceride levels. It was concluded that low testosterone levels are associated with higher all‐cause mortality in men with type 2 diabetes.9 Men who have both hypogonadism and type 2 diabetes should be considered to be at a very high risk for cardiovascular events/death.
Commentary
The average life expectancy of a 50-year-old individual with diabetes is 6 years shorter than it would be without the disease.27 This, combined with the data presented above, suggests that men with both hypogonadism and type 2 diabetes have a life expectancy that is 10 years shorter compared to men who are free of hypogonadism and type 2 diabetes.
While the meta-analysis presented above shows that hypogonadism is a strong risk factor for development of type 2 diabetes,10 it has also been suggested that type 2 diabetes may be a risk factor for the development of hypogonadism.28 For instance, one prospective study showed that the
development of type 2 diabetes is a major driver of the age-related testosterone decline.29 Hence, it appears that the link between low testosterone and type 2 diabetes is bidirectional. A notable prospective cohort study including 1,400 men aimed to investigate the possible bidirectional relationship between testosterone and insulin resistance by analyzing if a low level of testosterone could predict the development of insulin resistance and vice versa.30 Results showed a significant longitudinal association between lower testosterone levels and the development of insulin resistance, which remained significant even after adjustment for confounding factors, including waist-hip ratio. However, degree of insulin resistance at baseline did not predict low testosterone levels at follow-up. This suggests that testosterone itself might have an important and independent effect on the development of insulin resistance over time. However, this was not the case for baseline insulin resistance. Hence, this study did not confirm the suggested bidirectional link between testosterone and insulin resistance/type 2 diabetes.30 The study authors acknowledged that the lack of association between baseline insulin resistance and testosterone levels at follow-up may be due to methodological differences. However, even though there may be a bidirectional association, the direction where insulin resistance decreases testosterone levels appears to be much weaker than the other direction where low testosterone increases insulin resistance.30
Effective prevention of type 2 diabetes requires early identification of high-risk individuals who might benefit from intervention. A notable study, the MAILES (Men Androgen Inflammation Lifestyle Environment and Stress) prospective study, aimed to determine whether low testosterone levels add clinically meaningful information beyond current type 2 diabetes risk prediction models.31 It was found that testosterone levels predict risk of developing type 2 diabetes over the next 5 years, independent of all risk factors included in type 2 diabetes risk assessment tools available for use in routine clinical practice, including the AUSDRISK (Australian Type 2 Diabetes Risk Assessment) tool. Testosterone levels below <16 nmol/L (461 ng/dL), which was prevalent in nearly half of the MAILES population of 2563 community-dwelling men aged 35-80 years in Adelaide, Australia, was best for predicting incident type 2 diabetes.31
The threshold of 16 nmol/L for defining low testosterone that is predictive of type 2 diabetes is higher than that reported in a previous systematic review of prospective cohort studies on type 2 diabetes risk in men (15.5 nmol/L or 447 ng/dL).25 It is also higher than the threshold of 12 nmol/L (350 ng/dL) for making the diagnosis of hypogonadism, as suggested by clinical guidelines.32-36 Another recent study found that the risk for diabetes already starts below 20 nmol/L (577 ng/dL), which is the mid-normal testosterone range.37 This suggests that men with symptoms of hypogonadism who have testosterone levels that are higher than the diagnostic threshold of 12 nmol/L (350 ng/dL) may derive health benefits from testosterone therapy. Support for a causal role of low testosterone in the development of type 2 diabetes comes from a notable study published in Diabetes Care, showing that testosterone therapy in men with hypogonadism and prediabetes completely prevents progression to frank type 2 diabetes, and even restores normoglycemia.38
The finding that testosterone remains a significant predictor for development of type 2 diabetes even after correction for all other diabetes risk factors suggests that screening for low serum testosterone would identify a large group of men at-risk who would otherwise not been detected by current risk assessment tools.31 This could have important implications for clinical decision making and prognosis for a large and growing population of men with low testosterone levels. Accordingly, in 2018 the American Diabetes Association added the recommendation to measure testosterone in men with diabetes who have symptoms or signs of hypogonadism, such as decreased sexual desire (libido) or sexual activity and/or erectile dysfunction.39
The second study summarised above confirms that men with type 2 diabetes who are also hypogonadal have worse health outcomes, including increased risk of stroke and a mortality rate that is nearly twice as high compared to men with type 2 diabetes without hypogonadism.9 A growing number of studies suggests that testosterone therapy may increase longevity in men with hypogonadism and type 2 diabetes, with increasing benefit with age.7,8,40 This is an area of active research in the field of men’s health.
Recommendations
References
- Nordstrom A, Hadrevi J, Olsson T, Franks PW, Nordstrom P. Higher Prevalence of Type 2 Diabetes in Men Than in Women Is Associated With Differences in Visceral Fat Mass. J Clin Endocrinol Metab. 2016;101(10):3740- 3746. Return to content
- Wandell PE, Carlsson AC. Gender differences and time trends in incidence and prevalence of type 2 diabetes in Sweden--a model explaining the diabetes epidemic worldwide today? Diabetes Res Clin Pract. 2014;106(3):e90-92. Return to content
- Andersson AM, Jensen TK, Juul A, Petersen JH, Jorgensen T, Skakkebaek NE. Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys. J Clin Endocrinol Metab. 2007;92(12):4696- 4705. Return to content
- Baena-Diez JM, Penafiel J, Subirana I, et al. Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis. Diabetes Care. 2016;39(11):1987-1995. Return to content
- Gyawali P, Martin SA, Heilbronn LK, et al. The role of sex hormone-binding globulin (SHBG), testosterone, and other sex steroids, on the development of type 2 diabetes in a cohort of community-dwelling middle-aged to elderly men. Acta Diabetol. 2018;55(8):861-872. Return to content
- Buysschaert M, Medina JL, Bergman M, Shah A, Lonier J. Prediabetes and associated disorders. Endocrine. 2015;48(2):371-393. 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
- 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
- Malipatil NS, Yadegarfar G, Lunt M, et al. Male hypogonadism: 14-year prospective outcome in 550 men with type 2 diabetes. Endocrinology, Diabetes & Metabolism.0(0):e00064. Return to content
- Yao QM, Wang B, An XF, Zhang JA, Ding L. Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. 2018;7(1):220-231. Return to content
- Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4-14. Return to content
- Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94(3):311-321. Return to content
- Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137-149. Return to content
- Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271-281. Return to content
- James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392(10159):1789-1858. Return to content
- Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215- 2222. Return to content
- Tancredi M, Rosengren A, Svensson AM, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med. 2015;373(18):1720-1732. Return to content
- Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian journal of endocrinology and metabolism. 2016;20(4):546−551. Return to content
- Abdul-Ghani M, DeFronzo RA, Del Prato S, Chilton R, Singh R, Ryder REJ. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care. 2017;40(7):813−820. 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
- 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
- Rezvani MR, Saadatjou SA, Sorouri S, Hassanpour Fard M. Comparison of serum free testosterone, luteinizing hormone and follicle stimulating hormone levels in diabetics and non-diabetics men- a case-control study. J Res Health Sci. 2012;12(2):98-100. 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
- Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(11):5462- 5468. Return to content
- Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295(11):1288-1299. 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;42(6):1104-1111. Return to content
- Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829-841. Return to content
- Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011;96(8):2341- 2353. 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
- Ottarsdottir K, Nilsson AG, Hellgren M, Lindblad U, Daka B. The association between serum testosterone and insulin resistance: a longitudinal study. Endocr Connect. 2018;7(12):1491- 1500. Return to content
- Atlantis E, Fahey P, Martin S, et al. Predictive value of serum testosterone for type 2 diabetes risk assessment in men. BMC endocrine disorders. 2016;16(1):26. Return to content
- Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. 2017;14(12):1504-1523. Return to content
- Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S. 2017 EAU Guidelines on Male Hypogonadism. Available at http://uroweb.org/wp-content/uploads/18-Male-Hypogonadism_2017_web.pdf (accessed April 8th, 2018). European Association of Urology Accessed. Return to content
- Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicines 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
- Khera M, Adaikan G, Buvat J, et al. Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). The journal of sexual medicine. 2016;13(12):1787-1804. Return to content
- Morgentaler A, Traish A, Hackett G, Jones TH, Ramasamy R. Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine. Sex Med Rev. 2019. Return to content
- O'Reilly MW, Glisic M, Kumarendran B, et al. Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort. Clin Endocrinol (Oxf). 2019;90(1):145-154. 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. Return to content
- American Diabetes Association (ADA). Updates to the Standards of Medical Care in Diabetes 2018. Diabetes Care. 2018;41(9):2045-2047. Return to content
- Hackett G. Metabolic Effects of Testosterone Therapy in Men with Type 2 Diabetes and Metabolic Syndrome. Sex Med Rev. 2019. Return to content
