What is known about hypogonadism, type 2 diabetes and stroke
The risk of stroke is 4 times higher in men with type 2 diabetes compared to non-diabetic men.10 Type 2 diabetes and hypertension increase stroke risk independently, and their combination increases the risk drastically. A significant proportion of the risk of stroke assumed to be related to hypertension may be attributable to concomitant diabetes.11 Among men with type 2 diabetes and hypertension, the risk of stroke mortality is nearly 10 times higher than among subjects without either of the diseases.11 Additional adjustments for BMI, cholesterol, education, smoking, alcohol consumption, and physical activity did not appreciably change these risk estimates.11
Men who have suffered a stroke have significantly lower testosterone levels than men who never had a stroke.12 The prevalence of hypogonadism in male stroke patients can be as high as 88%.13
Most studies have shown an inverse association between testosterone levels and risk of stroke; men with low testosterone levels have a significantly higher stroke risk than men with higher testosterone levels.8,14-18 In one study the risk of stroke was approximately half for men with the highest testosterone levels (15.79–46.50 nmol/L) compared to those with lowest testosterone levels (<9.82 nmol/L), even after adjustment for age, conventional cardiovascular risk factors and the presence of concurrent comorbidities.14 In men with acute ischemic stroke, low testosterone levels are associated with worse stroke severity, larger infarct size and increased 6-month mortality.8
In a group of men 30-69 years old, (mean age 48 years) who were followed for 6.5 years, those with the lowest testosterone levels (<14.2 nmol/L) had a 4.6-fold increased risk for cardiovascular events (including stroke), even after adjustment for age, body mass index, current smoking, systolic blood pressure, HDL cholesterol, non-HDL cholesterol, HbA1c, % flow-mediated dilation (FMD), medications (antihypertensives, statins, hypoglycemic agents and antiplatelet agents), estradiol and DHEA-S.16 In another study of older men 76 - 81 years old (mean age 78 years) who were followed for 3.5 years, those with low to normal total testosterone levels (8 to 11.7 nmol/L) had a 2-fold increased risk of incident stroke and transient ischemic attack, compared with men with total testosterone levels higher than 11.7 nmol/L, even after adjusting for age, waist-hip ratio, waist circumference, medical comorbidity (Charlson index), smoking status, presence or absence of diabetes, exercise history, past alcohol intake, use of aspirin or clopidogrel, and the presence of hypertension and dyslipidemia.16
Notably, the higher risk of cerebrovascular events (stroke and transient ischemic attack) is not limited to men with unequivocally low total testosterone levels of 8 nmol/L and below, but is already present in men with low to normal testosterone levels (14.2 nmol/L or 410 ng/dL).16 This is above the commonly used diagnostic threshold of 12 nmol/L (350 ng/dL) for hypogonadism. These results suggest that testosterone possibly could affect the pathogenesis of ischemic stroke in men8, and that even modestly reduced testosterone levels – which by many physicians would not be considered low - could be harmful for men’s health. This underscores the importance of taking into consideration a patient’s complete medical history and avoid a myopic focus on testosterone levels alone.
Experimental data have shown that testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, brain-derived neurotrophic factor levels and neurogenesis.19,20 This has been confirmed in humans; in male stroke patients those with higher endogenous testosterone levels had a higher functional independence at discharge.21 Further studies are needed to determine whether testosterone therapy that effectively elevates testosterone levels could prevent development of stroke and/or positively impact post-stroke recovery and survival.
What this study adds
The aim of the present study was to find out the prevalence of hypogonadism in men who had suffered ischemic stroke, and to evaluate the efficacy of injectable testosterone undecanoate treatment in patients with hypogonadism and type 2 diabetes who had recently suffered a hemispheric ischemic stroke.
154 male patients aged from 52 to 69 years in whom hemispheric ischemic stroke had occurred for the first time were included in the first part of the study that sought to find the prevalence of hypogonadism in male stroke patients.
To evaluate the efficacy of testosterone treatment, 102 men with type 2 diabetes and hypogonadism who had suffered ischemic stroke took part in the second part of the study. They were divided into a group receiving testosterone undecanoate treatment (n=72) and a non-treated control group (n=30) group. Testosterone undecanoate (1000 mg) was given by intramuscular injection at 1 week and 6 weeks after the stroke, and subsequently every 12 weeks for 2 years. After 5 years, a follow-up study was undertaken; 47 patients remained on testosterone (testosterone non-stop group), and 25 patients had stopped testosterone treatment (testosterone discontinued group). All 30 patients in the control group were followed up to 5 years.
It was found that the prevalence of hypogonadism was 26.3% in men who had suffered a stroke but had not type 2 diabetes, but 66.3% in men who had comorbid type 2 diabetes.
At baseline, men in the testosterone group and control group did not differ significantly by age, clinical characteristics, and androgen status or biochemical blood analysis.
After 2 years, repeated ischemic stroke occurred in 3 (7.1%) patients in the testosterone undecanoate group and in 5 patients (16.7%) in the control group. 12 (28.6%) patients in the testosterone undecanoate group and 2 (6.6%) in the control group returned to work (Figure 1). At the 5 year time point, all patients had reached pensionable age (60 years in Russia) with 3 patients in the testosterone undecanoate group continuing work. No patients in the control group continued work.