Hypogonadism and testosterone treatment following stroke in men with type 2 diabetes
October 2018
STUDY: Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The Aging Male: the official journal of the International Society for the Study of the Aging Male. 2018:1-10
Low testosterone levels are associated with development of type 2 diabetes in men and could represent a biomarker that may be causally involved in type 2 diabetes development.1 In line with this, a recent meta-analysis concluded that higher testosterone levels can significantly decrease the risk of type 2 diabetes in men, and that testosterone is an important protective factor against type 2 diabetes development.2
Type 2 diabetes is a well-established risk factor for stroke.3,4 Other significant independent and modifiable risk factors for (ischemic) stroke include hypertension, hyperlipidemia, elevated waist circumference, and coronary artery disease5,6, all of which are worsened by hypogonadism.7 Not surprisingly, men with acute ischemic stroke have significantly lower testosterone levels than controls.8 The difference in testosterone levels between patients and control subjects could not be explained by risk factors for stroke, including age, blood pressure, diabetes, ischemic heart disease, smoking, and/or atrial fibrillation.8 This suggests that hypogonadism may be a common denominator in men with type 2 diabetes and stroke.
Here we summarise the results of a new study from Moscow that was recently published in The Aging Male which treated hypogonadal patients with type 2 diabetes who had recently suffered a stroke, with testosterone undecanoate for up to 5 years.9
KEY POINTS
- Men with hypogonadism and type 2 diabetes who have suffered a non-fatal ischemic stroke have a high risk for recurring stroke and mortality.
- Long-term testosterone therapy with injectable testosterone undecanoate for up to 5 years reduces risk of a second stroke and increases longevity in hypognadal men with type 2 diabetes.
- In hypogonadal men who do experience a second non-fatal stoke, testosterone undecanoate treatment reduces risk of death, speeds up recovery and increases likelihood of return to work.
- The increased survival seen after 5 years of testosterone undecanoate treatment is accompanied by:
- reduced body weight
- reduced HbA1c (although patients were well controlled at baseline)
- improved lipid profile (reduction in LDL and triglycerides)
- reduced blood pressure
- increased muscle strength
- reduced depressive symptoms and improved quality of life
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.
Figure 1: Recurrent stroke and return to work after treatment with testosterone undecanoate for 2 years.
Data from: Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The Aging Male the official journal of the International Society for the Study of the Aging Male. 2018:1-10
47 of 72 patients in the testosterone undecanoate group received testosterone undecanoate injections regularly. The remaining 25 patients stopped the regular treatment after the first 2 years. All 71 patients were alive at the end of the study.
After 5 years, repeated ischemic stroke occurred in 3 of the 47 patients (6.4%) in the testosterone undecanoate group, although none were fatal. In the group that had ceased testosterone undecanoate treatment, 1 patient had a fatal stroke (4%). In the control group, 11 (36.7%) patients had a repeated stroke and 6 deaths occurred (3 stroke, 1 myocardial infarction, 1 lung cancer). In the control group, 24 patients were alive, 3 had died from repeated stroke, 2 from myocardial infarction, and 1 from lung cancer (mortality 20%), figure 2.
Figure 2: Recurrent stroke, stroke fatality and mortality after treatment with testosterone undecanoate for 5&nsbp;years.
TU; testosterone undecanoate Data from: Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The Aging Male the official journal of the International Society for the Study of the Aging Male. 2018:1-10
The reduced incidence of repeated stroke and mortality was accompanied by reductions in blood pressure, LDL cholesterol, triglycerides, body weight, and improved glycemic control, all of which are known risk factors for cardiovascular disease. These improvements were especially pronounced during the first 2 years of testosterone undecanoate treatment. Furthermore, men who received testosterone undecanoate treatment reported increased muscle strength and improved ability to work, and enhanced quality of life. Among the untreated men, there was a progressive deterioration over time in all these parameters.
Commentary
The present study confirms the high prevalence of hypogonadism in men who have suffered an ischemic stroke, particularly in men with comorbid type 2 diabetes. For men with hypogonadism who had suffered an ischemic stroke, the correction of testosterone deficiency with testosterone undecanoate treatment, starting during the acute phase of the disease and lasting for at least 2 years, significantly reduces risk of recurrent stroke and mortality, compared to men who had a stroke but did not receive testosterone undecanoate treatment. The accompanying improvements in these cardiovascular risk factors have been observed in numerous other long-term studies of injectable testosterone undecanoate treatment for up to 10 years, which also documented the safety of long-term testosterone undecanoate treatment.22-25
Although this is a relatively small study with only 102 testosterone treated men, it is very encouraging in that it confirms the cardiovascular safety of long-term testosterone undecanoate treatment in patients at very high risk, and that it is even protective and reduces mortality. This is in agreement with results from other studies.25-27 A study published in the European Heart Journal showed that in 83000 men with low testosterone, adequately performed testosterone therapy - which elevates testosterone levels from low into the mid-normal range – results in a major and significant reduction in myocardial infarction, stroke and all-cause mortality by 24%, 36% and 56% respectively, during a long-term follow-up of up to 14 years.26 Another study published in the Journal of the American Medical Association (JAMA) showed that in a large group of 8800 men who received testosterone therapy in the past 3 years had a significant reduced risk of stroke and transient ischemic attack by 28% (HR 0.72) compared to non-treated men.27 The study with the longest follow-up to date treated 360 men with hypogonadism (testosterone levels of 12.1 nmol/L or less and symptoms) with testosterone undecanoate for up to 10 years.25 296 patients who opted against testosterone therapy served as controls. In the testosterone treatment group, there were 2 deaths, neither of which were related to cardiovascular events in the control there were 21 deaths, 19 of which were related to CVD events (5 fatal myocardial infarction, 4 fatal stroke, 7 fatal heart failure, 2 fatal thromboembolism, 1 fatal lung embolism, 1 fatal pneumonia and 1 fatal lung failure). There were also 30 nonfatal strokes and 26 nonfatal myocardial infarctions in the control group, but and none in the treatment group.25
The study presented here suggests that testosterone therapy may be effective for secondary prevention of stroke. This is consistent with results from another notable study showing that patients with a history of cardiovascular disease (n=40 with previous myocardial infarction and n=7 with previous stroke) did not have a second event while being treated with testosterone undecanoate for 8 years.28 There was a sustained improvement in all cardiometabolic risk factors, and it was concluded that testosterone therapy may be effective as an add-on treatment for the secondary prevention of cardiovascular events in hypogonadal men with a history of cardiovascular disease.28
The results from the present study and the studies commented on above suggest that low testosterone levels are associated with a significantly higher incidence of major adverse cardiovascular events (MACE) in aging men, and that preventing reductions in testosterone levels in older men may reduce their burden of MACE, including stroke, and increase longevity. The possibility that testosterone therapy could benefit men with type 2 diabetes who have suffered a stroke - even though their testosterone levels are higher than levels that are normally considered to indicate hypogonadism16 – warrants further investigation.
For more information about the other studies mentioned above, see our previous reports:
Recommendations
References
- Schipf S, Haring R, Friedrich N, et al. Low total testosterone is associated with increased risk of incident type 2 diabetes mellitus in men: results from the Study of Health in Pomerania (SHIP). The aging male : the official journal of the International Society for the Study of the Aging Male. 2011;14(3):168-175. 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
- Tuomilehto J, Rastenyte D, Jousilahti P, Sarti C, Vartiainen E. Diabetes mellitus as a risk factor for death from stroke. Prospective study of the middle-aged Finnish population. Stroke. 1996;27(2):210-215. Return to content
- Ottenbacher KJ, Ostir GV, Peek MK, Markides KS. Diabetes mellitus as a risk factor for stroke incidence and mortality in Mexican American older adults. J Gerontol A Biol Sci Med Sci. 2004;59(6):M640-645. Return to content
- Al-Rubeaan K, Al-Hussain F, Youssef AM, Subhani SN, Al-Sharqawi AH, Ibrahim HM. Ischemic Stroke and Its Risk Factors in a Registry-Based Large Cross-Sectional Diabetic Cohort in a Country Facing a Diabetes Epidemic. Journal of diabetes research. 2016;2016:4132589. Return to content
- Wang W, Zhang Y, Lee ET, et al. Risk Factors and Prediction of Stroke in a Population with High Prevalence of Diabetes: The Strong Heart Study. World Journal of Cardiovascular Diseases. 2017;7(5):145-162. Return to content
- Traish AM. Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev. 2018;6(1):86-105. Return to content
- Jeppesen LL, Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS, Winther K. Decreased serum testosterone in men with acute ischemic stroke. Arterioscler Thromb Vasc Biol. 1996;16(6):749-754. Return to content
- Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The aging male : the official journal of the International Society for the Study of the Aging Male. 2018:1-10. Return to content
- Stegmayr B, Asplund K. Diabetes as a risk factor for stroke. A population perspective. Diabetologia. 1995;38(9):1061-1068. Return to content
- Hu G, Sarti C, Jousilahti P, et al. The impact of history of hypertension and type 2 diabetes at baseline on the incidence of stroke and stroke mortality. Stroke. 2005;36(12):2538- 2543. Return to content
- Svartberg J, Midtby M, Bonaa KH, Sundsfjord J, Joakimsen RM, Jorde R. The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromso Study. Eur J Endocrinol. 2003;149(2):145-152. Return to content
- Abbasi A, Mattson DE, Cuisinier M, et al. Hyposomatomedinemia and hypogonadism in hemiplegic men who live in nursing homes. Arch Phys Med Rehabil. 1994;75(5):594-599. Return to content
- Yeap BB, Alfonso H, Chubb SA, et al. In older men, higher plasma testosterone or dihydrotestosterone is an independent predictor for reduced incidence of stroke but not myocardial infarction. J Clin Endocrinol Metab. 2014;99(12):4565- 4573. Return to content
- Holmegard HN, Nordestgaard BG, Jensen GB, Tybjaerg-Hansen A, Benn M. Sex Hormones and Ischemic Stroke: A Prospective Cohort Study and Meta-Analyses. J Clin Endocrinol Metab. 2016;101(1):69-78. Return to content
- Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis. 2010;210(1):232-236. Return to content
- Srinath R, Gottesman RF, Hill Golden S, Carson KA, Dobs A. Association Between Endogenous Testosterone and Cerebrovascular Disease in the ARIC Study (Atherosclerosis Risk in Communities). Stroke. 2016;47(11):2682- 2688. Return to content
- Zeller T, Schnabel RB, Appelbaum S, et al. Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men, but protective in women - results from the FINRISK study. European journal of preventive cardiology. 2018;25(11):1133-1139. Return to content
- Fanaei H, Karimian SM, Sadeghipour HR, et al. Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. Brain Res. 2014;1558:74-83. Return to content
- Pan Y, Zhang H, Acharya AB, Patrick PH, Oliver D, Morley JE. Effect of testosterone on functional recovery in a castrate male rat stroke model. Brain Res. 2005;1043(1-2):195-204. Return to content
- Momosaki R, Abo M, Watanabe S, Kakuda W, Yamada N, Mochio K. Effects of testosterone levels on functional recovery with rehabilitation in stroke patients. Neurol Med Chir (Tokyo). 2014;54(10):794-798. Return to content
- Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. Andrologia. 2016;48(7):793-799. Return to content
- Haider A, Yassin A, Doros G, Saad F. Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. International journal of endocrinology. 2014;2014:683515. Return to content
- Francomano D, Lenzi A, Aversa A. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in aging men with metabolic syndrome. International journal of endocrinology. 2014;2014:527470. Return to content
- Traish AM, Haider A, Haider KS, Doros G, Saad F. Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups. J Cardiovasc Pharmacol Ther. 2017;22(5):414-433. Return to content
- Sharma R, Oni OA, Gupta K, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36(40):2706- 2715. Return to content
- Cheetham TC, An J, Jacobsen SJ, et al. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA internal medicine. 2017;177(4):491-499. Return to content
- Haider A, Yassin A, Haider KS, Doros G, Saad F, Rosano GM. Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study. Vascular health and risk management. 2016;12:251-261. Return to content
