Endogenous sex hormones have been found to have a contributory role in the pathophysiology of diabetes. In this column I will be focusing on testosterone. In addition to its effect on the reproductive system, testosterone plays an important role in the metabolism of fat, protein and carbohydrates. Deficiency in testosterone is associated with reduced insulin sensitivity, abnormalities in cholesterol levels, and increased fat mass, as well as impaired glucose tolerance¹. In older individuals, studies have shown that low testosterone levels in men, and high levels in women, predicted insulin resistance and incident type 2 diabetes². Genome-wide association studies support these findings, with men exposed to higher levels of testosterone having lower type 2 diabetes risk and lower fasting blood sugar levels³. In population-based studies the inverse relationship between testosterone level and diabetes was stronger with total testosterone (measurement of free and bound testosterone) compared to free testosterone level, suggesting a potential role of sex hormone binding globulin (SHBG)⁴.

 Testosterone levels in males are affected by several factors and tend to be low in the elderly, the obese, and during periods of acute illnesses as well as with diurnal variation⁵. The prevalence of low testosterone levels in patients with type 2 diabetes mellitus is also common, ranging from 25-40% of patients⁶. There is a complex interplay between low testosterone level, adipose tissue and insulin resistance in the pathophysiology of low testosterone level in patients with diabetes. Luteinizing hormone is low despite low testosterone levels indicating dysregulation of the hypothalamus-pituitary-gonadal axis⁷. The relationship between low testosterone and development of diabetes appears to be bidirectional.

The impact of testosterone therapy in patients with type 2 diabetes and low testosterone levels has been explored in several randomized control trials (RCT). Testosterone therapy has been shown to improve insulin resistance but does not consistently improve glycemic outcome. However, most studies involved a limited number of patients and there was heterogeneity in terms of age, duration of diabetes and methods used to measure insulin resistance⁸. In one of the larger RCTs, involving 220 patients, investigators found that over a six-month period, testosterone replacement therapy administered via transdermal testosterone gel improved insulin resistance by 15.2% and reduced glycated hemoglobin (HbA1c) by 0.446%⁹.

In a recent real-world registry study, long-term testosterone therapy in men with type 2 diabetes and hypogonadism was reported to improve insulin resistance as well as glycemic control¹⁰. In addition, investigators found that a third of patients achieved diabetes remission. This was a prospective registry, examining patients in a single urology center over a period of 11 years. A total of 356 patients with type 2 diabetes and hypogonadal symptoms with total testosterone levels ≤ 12.1 nmol/L were included in the study. One hundred and seventy eight patients received parenteral testosterone undecanoate 1000 every 12 weeks following an initial six-week interval. This cohort was compared to a control group of 178 patients who declined testosterone replacement therapy. Both groups received standard diabetes treatment. The mean age of patients in the testosterone replacement group was 61.5 ± 5.4 years and patients were followed for a mean duration of 7.7 ± 3.0 years. Compared to the control group, at 11 years the estimated adjusted difference of fasting blood glucose was 64.9 mg/dL (3.6 mmol/L). Diabetes remission, defined as HbA1c of less than 6.5%, and discontinuation of all anti-diabetic medication was achieved by 34.3% of patients in the testosterone replacement group after a mean of 8.6 ± 2.9 years. Insulin resistance, as calculated by the homeostatic model assessment of insulin resistance (HOMA‐IR), also demonstrated a gradual and sustained decrease in the treatment group. During the study period, long term adverse outcomes of testosterone replacement were not observed; mortality rate, myocardial infarct and strokes were lower in the treatment group when compared to the control group. Because this was a registry study, at baseline the treatment and control groups were not balanced in terms of age, disease duration and glycemic variables. However, these differences were taken into account and adjusted for accordingly. This was the first study to show that diabetes remission was achievable in hypogonadal type 2 diabetes patients with testosterone replacement therapy¹⁰.

During the recent American Diabetes Association virtual sessions, results from the largest multi-center randomized control trial on testosterone therapy, the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, were discussed. In this study, testosterone treatment using intramuscular testosterone undecanoate combined with lifestyle intervention was compared to lifestyle intervention alone in terms of reduction of type 2 diabetes incidence and improvement in glucose tolerance. Overweight or obese men aged between 50-74 years with a serum testosterone of ≤ 14 nmol/L and impaired glucose tolerance or men with newly diagnosed type 2 diabetes were recruited. More than 1,000 patients participated in the study. Testosterone replacement therapy was found to reduce relative risk of type 2 diabetes by about 40% compared to lifestyle intervention alone. There was also improvement in body composition with increment in muscle mass and grip strength. One common adverse event of note in the treatment group was elevation in hematocrit (> 54%); therefore, it is important to consider other risk factors for elevated hematocrit such as obstructive sleep apnea before initiating treatment. As the population studied was a relatively low risk population with concurrent lifestyle interventions and frequent monitoring, the findings cannot be generalized to all patients. Testosterone replacement in hypogonadal type 2 diabetes patients has shown promising results. Patients in whom this therapy is being considered require an individualized assessment and approach to determine the best management strategy. 

References:

1. Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol. 2013;217(3):R25-45.
2. Rohwer RD, Liu S, You NC, et al. Interrelationship between alcohol intake and endogenous sex-steroid hormones on diabetes risk in postmenopausal women. J Am Coll Nutr. 2015;34(4):273-280.
3. Ruth KS, Day FR, Tyrrell J, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine. 2020;26(2):252-8.
4. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011;96(8):2341-53.
5. Trost LW, Mulhall JP. Challenges in testosterone measurement, data interpretation, and methodological appraisal of interventional trials. J Sex Med. 2016;13(7):1029-1046.
6. Dandona P, Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96(9):2643-51.
7. Cheung KK, Luk AO, So WY, et al. Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence. J Diabetes Investig. 2015;6(2):112-123.
8. Gianatti EJ, Grossmann M. Testosterone deficiency in men with type 2 diabetes: Pathophysiology and treatment. Diabet Med. 2020;37(2):174-86.
9. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(4):828-837.
10. Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long‐term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11‐year data from a real‐world registry study. Diab Obes and Metab. 2020 (Online ahead of print).