https://orcid.org/0000-0002-8706-7464
Abstract
Introduction
We aimed to evaluate the predictive value of sex hormone levels on 3-month functional outcomes after acute ischemic stroke (AIS) in males.
Materials and methods
A total of 110 male AIS patients were included in this prospective study. Serum levels of testosterone and estradiol were measured at admission. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) were measured at admission and after 3 months. A mRS score ≥3 was considered as a poor functional outcome.
Results
The median age of the 110 subjects was 62.0 [23.3] years (range 35–93 years). Univariate logistic regression revealed that bioavailable testosterone, free testosterone, age, NIHSS at admission, mRS at admission, and prior ischemic stroke were associated with a poor functional outcome (mRS score ≥3) at 3 months. In multivariate analysis, only age, NIHSS at admission, and mRS at admission were independent predictors.
Conclusions
After controlling the covariates, bioavailable and free testosterone levels are not associated with the 3-month mRS in male patients with AIS. Age, NIHSS at admission, and mRS at admission are robust predictors for the functional outcomes.
Introduction
Stroke is a leading cause of death and long-term disability globally. While mortality rates have decreased worldwide over the past two decades, the absolute number of stroke events and stroke survivors are still high and continue to increase [Citation1]. Stroke causes a substantial burden to patients, family members, and the health care system. In order to optimize rehabilitation programs and to more efficiently allocate healthcare resources, it is necessary to identify the prognostic factors of disease development and patient functional outcomes [Citation2]. In addition, some of these factors may be involved in the mechanism of recovery from acute stroke, and may serve as potential therapeutic targets if they are adjustable. To date, several clinical parameters, such as age, baseline stroke severity, infarct volume and location, and pre-stroke physical function have been shown to predict the functional outcome after acute ischemic stroke (AIS) [Citation3–8]. Despite this, there has been persistent enthusiasm in finding new prognostic factors of such a prevalent and devastating disorder.
Low testosterone is associated with several cardiovascular risk factors, such as diabetes [Citation9], dyslipidemia [Citation10], and obesity [Citation11]. Testosterone deficiency is associated with an increase in pro-inflammatory cytokines and some biomarkers for atherosclerosis [Citation12–14]. Epidemiological studies have demonstrated that low testosterone increases the incidence of AIS [Citation15–18]. Low testosterone has also been reported in patients who have suffered from stroke [Citation19,Citation20]. Testosterone deficiency is associated with some neuropsychiatric diseases, such as depression [Citation21]. Testosterone was shown to protect neurons against ischemia in animal studies [Citation22], and it was also shown that testosterone enhances functional recovery after brain ischemia in male rats, which was probably mediated via the promotion of antioxidant defenses, brain-derived neurotrophic factor, and neurogenesis [Citation23]. Moreover, it was recently demonstrated that testosterone replacement therapy improves glycemic control and endothelial function in men with type 2 diabetes [Citation24,Citation25], and reduces obesity in hypogonadal men with erectile dysfunction [Citation26]. Yassin et al. [Citation27] suggest a lifelong treatment to continuously control these cardiometabolic parameters. While the true effect of testosterone supplement on the prevention of cardiovascular events is still to be determined, current evidence and expert opinions support a beneficial effect [Citation28]. On the other hand, estrogen has also been shown to be neuroprotective in animal models [Citation29]. These findings suggest that testosterone and/or estrogen may affect patient functional outcomes after AIS.
Compared with the high number of studies investigating the association between testosterone and coronary heart disease, its association with cerebrovascular diseases in humans has been less studied. Moreover, human studies regarding the effect of testosterone on stroke outcomes are scarce. The current study aimed to investigate whether the level of endogenous testosterone at the onset of AIS affected the disease severity and the functional outcomes after 3 months in male patients.
Materials and methods
Study subjects
The present prospective study enrolled 110 male patients with AIS who presented to a tertiary medical center between June 2015 and August 2017. All patients were admitted within 24 h of experiencing a new focal or global neurological event. The diagnosis of AIS was performed by the treating neurologist, with the assistance of appropriate diagnostic modules (e.g. MRI or CT scan). All patients diagnosed of acute ischemic stroke were enrolled in the current study. Patients were excluded from the study if any of the following applied: (1) patients who underwent either intravenous or intra-arterial thrombolysis; (2) those who died within 3 months of the event; (3) those who were not willing to participate the study. The study protocol was approved by the institutional review board (approval no. CGH-P103074). Written informed consent was obtained from all participants.
Initial evaluation and follow-up
Baseline demographics and biochemical data were obtained from the patient on their admission for AIS. The demographic data included age, body mass index (BMI), hypertension, diabetes mellitus, atrial fibrillation, hyperlipidemia, coronary arterial disease, previous stroke, and smoking habit. The baseline biochemical data included routine blood chemistry and hormone levels, including testosterone, estradiol, and sex hormone binding globulin. The levels of bioavailable and free testosterone were calculated using Vermeulen’s formula [Citation30]. The initial stroke severity and the functional status were assessed using the National Institute of Health Stroke Scale (NIHSS) and the Modified Rankin Scale (mRS).
All patients received standard medical care according to the current guidelines [Citation31] and the physicians’ expertise. Patients were discharged when their clinical condition was considered appropriate and they then underwent regular follow-ups at the outpatient clinic. At 3 months after the stroke, a second evaluation using the NIHSS and mRS was performed.
Statistics
The continuous variables are expressed as the median [interquartile range], and the categorical variables are expressed as a count (percentage). The serum levels of each sex hormone were categorized into three groups by tertile. The Kruskal–Wallis test was used to detect differences among the tertiles of each sex hormone. A mRS score ≥3 was considered to represent a poor functional outcome. Logistic regression was performed to assess the association of each sex hormone and other factors (age, comorbidities, NIHSS at admission, and mRS at admission) with the poor outcome (mRS ≥3). The procedure also yielded the odds ratio (OR) and 95% confidence interval (CI) for mRS ≥3. Multivariate analyses were performed with models listed as below: Model 1 adjusted for age; Model 2 adjusted for age and NIHSS at admission; Model 3 adjusted for age and mRS at admission; Model 4 adjusted for age, NIHSS at admission, and mRS at admission. A p value of <0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using SPSS 22.0 (IBM Corp., Armonk, NY).
Results
The median age of the 110 subjects was 62.0 [23.3] years (range 35–93 years). At admission, the median total testosterone, bioavailable testosterone, free testosterone, and estradiol were 438 [203] ng/dL, 139 [72.1] ng/dL, 6.6 [3.0] ng/dL, and 39.4 [20.0] pg/mL. The median NIHSS and mRS at admission were 4.0 [4.0] and 2.0 [1.8], respectively, and they were 1.0 [2.0] and 1.0 [2.3] at 3 months. The comorbidities and baseline NIHSS and mRS of the whole cohort and the comparisons among the tertiles of each sex hormones are listed in .
Table 1. Characteristics and initial neurological status of the 110 male patients with acute ischemic stroke.
compares the NIHSS and mRS at 3 months among the tertiles of each sex hormone. The median mRS at 3 months of first (<121 ng/dL), second (121–163 ng/dL), and third (>163 ng/dL) tertile of bioavailable testosterone of bioavailable testosterone were 1.5 [2.0], 1.0 [2.5], and 1.0 [2.0], respectively (p = 0.05).
Table 2. The association of male sex hormone levels with the 3-month functional outcomes.
Univariate logistic regression revealed that the lower and middle tertiles of bioavailable testosterone predicted a poor functional outcome (mRS score ≥3), with odds ratios of 5.91 (95%CI 1.50–23.30, p = 0.01) and 4.80 (95%CI 1.21–18.96, p = 0.03), respectively. The lower two tertiles of free testosterone also predicted a poor functional outcome, with odds ratios of 3.78 (95%CI 1.07–13.32, p = 0.04) and 3.49 (95%CI 1.00–12.24, p = 0.05), respectively. Neither total testosterone nor estradiol were associated with the mRS score ().
Table 3. Univariate logistic regression analysis determining the odds ratio of sex hormones for poor functional outcome (mRS ≥3) at 3 months.
Univariate logistic regression also revealed that age (odds ratio 1.07, 95%CI 1.03–1.10, p = 0.001), NIHSS at admission (odds ratio 1.38, 95%CI 1.16–1.64, p < 0.001), mRS at admission (odds ratio 11.6, 95%CI 4.26–31.6, p < 0.001), and prior ischemic stroke (odds ratio 2.85, 95%CI 1.05–7.76, p = 0.04) were significantly associated with a mRS ≥3 at 3 months. The association of other comorbidities with the functional outcomes was not significant.
In multivariate analysis, both bioavailable and free testosterone were not associated with the mRS at 3 months in all the Models. On the other hand, age, NIHSS at admission, mRS at admission remained significantly associated with mRS in multivariate analysis ().
Table 4. Multivariate logistic regression analysis determining the odds ratio of sex hormones for poor functional outcome (mRS ≥3) at 3 months.
Discussion
The current study investigated the association between serum levels of male sex hormones and the disease severity and functional outcomes at 3 months after AIS in male patients. While univariate analysis revealed an association of low bioavailable testosterone or low free testosterone at admission with poor functional outcome at 3 months, the association did not remain significant in multivariate analysis. On the other hand, age, NIHSS at admission, and mRS at admission remained robust predictors for the functional outcomes.
In the literature, there have been very few human studies regarding the effect of testosterone on functional outcomes after stroke. A study consisting of 29 cerebral hemorrhages and 82 infarctions demonstrated that the free testosterone concentration at admission was positively correlated with the Functional Independence Measure at discharge [Citation32]. Another recent study showed that long-term testosterone supplements significantly improved muscle strength, hypogonadal symptoms, and mental health 2–5 years after AIS [Citation20]. To the best of our knowledge, the current study was the first to investigate the effect of endogenous testosterone on the functional outcome in a cohort exclusively consisting of AIS patients, and it contained the largest case number to date. Our findings suggested that the relationship between testosterone and functional outcomes at 3 months can be explained by other clinical factors, such as age, pre-stroke physical conditions, and at-admission stroke severity and physical morbidities. It has been demonstrated that the endogenous testosterone level does not improves to the predictive value of Framingham Risk Score for cardiovascular diseases (including stroke) in men [Citation33]. Our findings also confirmed a recent study of Phan et al. [Citation3], which intended to evaluate the impact of Charlson comorbidity index on prediction of functional outcomes after AIS. The authors found that a model incorporating age, gender, comorbidity, and NIHSS at 24 h had a high AUC of 0.9. In this model, NIHSS at 24 h is the most important factors, explaining 87.3% of the variance, follow by age (8.5%), comorbidity (3.7%), and male sex (0.5%). A more recent study also confirmed that both baseline NIHSS and the change in stroke severity after 24 h are important prognostic factors for the functional outcome [Citation4]. On the other hand, it was also reported that pre-stroke physical conditions, as measured by pre-stroke mRS, predicts the functional outcome at the 90 d of AIS [Citation8]. As previous studies have observed an inverse relationship between testosterone and baseline comorbidities or frailty [Citation34,Citation35], testosterone can be viewed as an approximate of the comorbidity index or the general physical condition. From this perspective, our results were generally in line with the previous studies [Citation3], suggesting that testosterone level, comorbidities, and pre-stroke physical condition were relatively minor predictors, while age, initial NIHSS, and initial mRS robustly predicted the functional outcomes.
The strength of the current study was that this was the first to investigate the association of testosterone with the functional outcomes after AIS in males. However, there were still some limitations. First, the sample size was relative small, which limited the power to detect a difference. Second, the current study did not include those receiving intravenous and intra-arterial interventions because these interventions significantly change the clinical course and should be discussed separately. This limits the generalization of the results.
Conclusion
Bioavailable and free testosterone are associated with the 3-month mRS after AIS in male patients only in univariate analysis but not in multivariate analysis. Age, NIHSS at admission, and mRS at admission are robust predictors for the functional outcomes.
Ethics statement
The study protocol was approved by the institutional review board of Cathay General Hospital (CGH-P103074) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Written informed consent was obtained from the participants of this study.
Disclosure statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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