Effect of testosterone therapy on insulin resistance, glycemic control, endothelial function and atherosclerosis

STUDY: Groti K, Zuran I, Antonic B, Forsnaric L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. The Aging Male: the official journal of the International Society for the Study of the Aging Male. 2018:1-12.

Hypogonadism, also known as testosterone deficiency or low testosterone, is common among men with type 2 diabetes, affecting 40-80%.1-4 There is a bidirectional relationship between low testosterone and insulin resistance; testosterone deficiency contributes to development of insulin resistance and its pathological manifestations - the metabolic syndrome and type 2 diabetes - and insulin resistance/metabolic syndrome/type 2 diabetes contribute to development of testosterone deficiency.5

Here we summarise the results of a randomised controlled trial that specifically investigated the effects of testosterone therapy on insulin resistance, visceral obesity, glycemic control, lipid abnormalities, endothelial function and atherosclerosis in obese hypogonadal men with type 2 diabetes.6

Key Points

  • There is a bidirectional relationship between testosterone deficiency and insulin resistance/ type 2 diabetes; testosterone deficiency contributes to development of insulin resistance/ type 2 diabetes, and insulin resistance/ type 2 diabetes contribute to development of testosterone deficiency.
  • This placebo-controlled clinical study shows that treatment with testosterone undecanoate injections for 1 year results in several beneficial health outcomes:
    • Reduced insulin resistance (HOMA-IR)
    • Reduced insulin, fasting blood glucose and HbA1c levels
    • Increased flow-mediated dilatation (a measure of endothelial function)
    • Reduced carotid intima media thickness (a measure of atherosclerosis)
  • No adverse side effects related to testosterone undecanoate treatment were observed. In the testosterone group, levels of hemoglobin, red blood cell count and hematocrit increased, but never exceeded their respective upper safety limits. PSA levels increased marginally by 0.22 µg/L, as expected.
  • One study participant in the testosterone group was enrolled with preexisting (diagnosed) benign prostate hyperplasia and was under permanent supervision of a urologist; his basal PSA level was 4.0 µg/L and did not change.

What is known about hypogonadism, insulin resistance, endothelial function and atherosclerosis

Testosterone deficiency is common in men with diabetes, regardless of diabetes type.1-4 Data suggest that insulin resistance may be a common denominator in both hypogonadism and type 2 diabetes5, and an important treatment target for intervention in these conditions.1

A meta-analysis of 12 prospective studies showed that high total testosterone levels are significantly associated with a 35% decreased risk of type 2 diabetes in men (RR = 0.65), suggesting that testosterone has a protective effect against development of type 2 diabetes.7 In addition to reducing symptoms of testosterone deficiency, testosterone treatment of hypogonadal type 2 diabetic men increases insulin sensitivity and improves glucose metabolism (as shown by reductions in blood glucose and HbA1c levels) as well as body composition (decreases in visceral and subcutaneous body fat and increases in lean body mass).8,9

Endothelial dysfunction is an early marker for atherosclerosis and can be detected before structural changes to the vessel wall are apparent on angiography or ultrasound.10 Many of the risk factors that predispose to atherosclerosis also cause endothelial dysfunction10-12 and endothelial dysfunction may be considered relevant for classifying subjects in terms of cardiovascular risk.13 Insulin resistance and its consequences, such as hyperglycemia, are key players in the development of endothelial dysfunction and atherosclerosis, which are well-established consequences of diabetes.14-16 Interestingly, even non-diabetic insulin resistance is associated with endothelial dysfunction.17

Forearm flow mediated dilatation (FMD) is the most common non-invasive test of endothelial (dys)function18, which significantly predicts cardiovascular events19 and all-cause mortality.20 Low testosterone levels in male outpatients are associated with endothelial dysfunction independent of age and other risk factors, suggesting a protective effect of endogenous testosterone on the endothelium.21 Not surprisingly, the harmful effect of endothelial dysfunction on cardiovascular risk is elevated in the presence of hypogonadism.22

Atherosclerosis is the underlying cause of heart disease.23 Carotid intima-media thickness (CIMT) is a validated noninvasive technique for measuring the atherosclerotic burden and represents a surrogate measure of atherosclerosis.24,25 Multiple studies have clearly shown that low testosterone is associated with increased CIMT.26-36 Interestingly, low free testosterone was reported to be associated with progression of CIMT independent of age and after adjustment for several cardiovascular risk factors (body mass index, waist-to-hip ratio, hypertension, diabetes, smoking, and serum cholesterol levels).31

What this study adds

The present study, published in the journal The Aging Male, was conducted to assess effects of testosterone therapy on parameters of the metabolic syndrome and vascular function in obese hypogonadal men with type 2 diabetes.6

Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Half were treated with testosterone undecanoate (1000 mg i.m. every 10 weeks) while the other half received placebo injections.

Measurements taken at the start of the study and after one year included body weight, waist circumference, FMD, CIMT, and biochemical and hormonal blood tests. Derived parameters (BMI, HOMA-IR, free testosterone and bioavailable testosterone) were calculated.

Results showed that testosterone therapy for 1 year elevated testosterone levels from 7.24 nmol/L (209 ng/dL) to 17.04 nmol/L (492 ng/dL) and significantly reduced HOMA-IR by 4.64, HbA1c by 0.94% points, and increased FMD by 2.4% points. While CIMT improved in both groups, the improvement was twice as large in the testosterone group. Fasting levels of insulin and blood glucose were also significantly reduced in the testosterone group.

No adverse side effects related to testosterone undecanoate treatment were observed. In the testosterone group, levels of hemoglobin, red blood cell count and hematocrit increased, but all elevations remained within the normal range. PSA levels increased by 0.22 µg/L. One study participant in the testosterone group was enrolled with preexisting (diagnosed) benign prostate hyperplasia and was under permanent supervision by a urologist; his basal PSA level was 4.0 µg/L and did not change after treatment with testosterone undecanoate.

It was concluded that treatment with testosterone undecanoate normalised serum testosterone levels, improved glycemic control and endothelial function and reduced the atherosclerotic burden in obese hypogonadal men with type 2 diabetes.

Commentary

There is general agreement that treatments that simultaneously improve insulin sensitivity, lipid metabolism and endothelial dysfunction are effective in preventing/delaying the development of atherosclerosis.37 A growing number of interventions known to reduce cardiovascular risk have been shown to improve endothelial function, and it has been suggested that endothelial function is valuable as a surrogate marker for the evaluation of new therapeutic strategies and in the care of patients.38

It is not known whether the effect of testosterone on FMD is mediated via the association of testosterone with cardiovascular risk factors or directly through effects on the vascular endothelium. Data suggest that the association of testosterone and FMD is independent of major cardiovascular risk factors.39 Further support for a direct effect of testosterone on endothelial function comes from experimental studies. Acute administration of testosterone in physiological doses increases FMD in men with coronary heart disease40 and induces coronary artery dilatation and accompanying increases in coronary blood flow in men with established coronary artery disease.41

Most previous studies have shown that testosterone therapy reduces CIMT.42-45 In one large trial, testosterone therapy did not affect markers of atherosclerosis (intima-media thickness and coronary artery calcium score).45 However, in men not taking statins, one marker of atherosclerosis (coronary artery calcium) was significantly lower in the testosterone group than in the placebo group. In the present study, most subjects were taking statins and hypertension medications, which may explain the reduction in CIMT in the placebo group. Nevertheless, the reduction in CIMT was twice as large among men treated with testosterone (from 0.89 to 0.79, -0.10) compared to those treated with placebo (from 0.83 to 0.78, -0.05). In another study, treatment with testosterone undecanoate for 1 year reduced CIMT by -0.22 mm (from a baseline value of 1.03).43 This suggests that the reduction in CIMT with testosterone therapy is greater in men with more severe atherosclerosis. To put this in perspective one can compare the reductions in CIMT after testosterone therapy with that seen in statin drug trials. For ex. in the ARBITER trial, atorvastatin reduced CIMT by only -0.034 after 1 year.46 Hence, testosterone therapy is a promising treatment in hypogonadal men, who are at increased risk of heart disease. Indeed, long-term treatment with testosterone undecanoate for 8 years has been shown to reduce mortality, as well as non-fatal heart attacks and strokes, compared to men not receiving testosterone therapy.47 The testosterone-group has a remarkable reduction in mortality between 66% and 92% compared to non-treated men.47

Interestingly, young men (age 24-39 years) with idiopathic hypogonadotropic hypogonadism have higher CIMT and lower FMD compared to age-matched peers, and both CIMT and FMD is improved in this patient population with testosterone therapy48 This confirms previous reports that low testosterone is associated with progression of CIMT independent of age.31

It has been suggested that the effects of testosterone on insulin resistance occur via changes in body composition.5 There is also evidence that testosterone regulates insulin sensitivity directly; acute sex steroid withdrawal induces insulin resistance in healthy men49, and both acute50,51 and chronic52 hyperglycemia can lower testosterone levels. This could explain the improvements in HOMA-IR, HbA1c, insulin and blood glucose levels with testosterone therapy seen in the present study, in which no changes were observed in BMI and waist circumference. However, it should be noted that most previous studies of testosterone therapy in obese hypogonadal diabetic men showed significant improvements in body composition8,9,53 and marked sustained weight loss paralleled with reduction in waist circumference54-56, along with improvements in glycemic control and symptoms.

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Last updated: 2018
G.MKT.GM.MH.01.2018.0500