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Low Testosterone Level as a Predictor of Poststroke Emotional Disturbances: Anger Proneness and Emotional Incontinence
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Low Testosterone Level as a Predictor of Poststroke Emotional Disturbances: Anger Proneness and Emotional Incontinence Mun Hee Choi, MD,* Tae Sung Lim, MD, PhD,* Bok Seon Yoon, MS,† Keoung Sun Son, † Ji Man Hong, MD, PhD,*,† and Jin Soo Lee, MD, PhD*,† Background: The role of sex hormones in poststroke mood and emotional disturbances is unclear. We aimed to evaluate the impact of sex hormones on poststroke emotional disturbance, especially anger proneness (AP) and emotional incontinence (EI). We also investigated whether statins, which are widely used for stroke prevention, affect sex hormone levels or the presence of poststroke AP/EI based on the hypothesis that intensive treatment with statins would inhibit the synthesis of cholesterol, the preferred substrate of testosterone. Methods: We prospectively enrolled 40 patients who experienced ischemic stroke at least 3 months prior to study enrollment. We performed clinical and laboratory evaluations, including hormone-level measurements and neuropsychological tests. Poststroke AP and EI were assessed using interviews, then patients were divided into 2 groups: AP/EI-present or absent. Results: Of the 40 patients (30 men, mean age 58.8 years), 16 (40.0%) were classified as AP/EI-present group. AP/EI were not related to stroke severity or location; however, the testosterone level was significantly lower in patients with AP/EI than in those without AP/EI (2.1 § 1.7 vs. 3.9 § 2.5 ng/mL, P = .023). After adjusting for potential confounding variables, low testosterone levels were a significant independent predictor of AP/EI (odds ratio .68, 95% confidence interval .49.96, P = .027). In contrast, sex hormone levels and AP/EI prevalence did not differ between statin users and nonusers. Conclusions: AP/EI were associated with low testosterone levels in patients with previous ischemic stroke, but statin use did not affect AP/EI prevalence. Key Words: Stroke—anger proneness—emotional incontinence—testosterone— hydroxymethylglutaryl-CoA reductase inhibitors. © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction
From the *Department of Neurology, Ajou University Medical Center, Suwon, Republic of Korea; and †Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea. Received May 29, 2018; revision received July 28, 2018; accepted August 8, 2018. Funding: This work was partly supported by the CJ CheilJedang Corporation. They had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Address correspondence to Jin Soo Lee, MD, PhD, Department of Neurology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, Suwon, Gyeonggi 16499, Republic of Korea. E-mail: [email protected] 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.08.014
Although the prevalence of poststroke mood and emotional disturbances varies widely across different studies, they have a substantial negative impact on the recovery and prognosis of stroke patients.1-3 Patients with stroke may show impulsive behaviors and verbal aggression or become more irritable and hostile. These symptoms can be termed as poststroke anger proneness (AP).4 Emotional incontinence (EI) has been described using various terminologies; patients experience excessive, inappropriate, and uncontrollable emotions without apparent stimuli.5 Both AP and EI, which are poststroke emotional problems, have garnered relatively little attention compared to depression in patients with a history of stroke, these symptoms also degrade the quality of life of both patients and their relatives.6 AP/EI are known to share similar lesion distribution and pathogenic mechanisms, including serotonergic dysfunction.7
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Neurotransmitters have increasingly been implicated in poststroke AP/EI; however, in previous clinical trials, selective serotonin reuptake inhibitors have been shown to provide only partial benefits in patients with poststroke emotional problems.4,8 These inadequate results might be associated with diverse factors affecting poststroke AP/EI, including neurologic, socioenvironmental, and genetic factors.9 In the general population, gonadal hormones are considered major factors in mood disorders, showing pervasive sex differences, with women being more than twice as likely as men to experience emotional problems.10,11 Testosterone, which can freely pass through the blood-brain barrier, is known to alter neurotransmitters, the hypothalamus-pituitary axis, and cellular and molecular pathways; consequently, it can influence mood and emotion.12,13 Clinical evidence suggests that testosterone has beneficial effects on anxiety and depression, and hormone replacement therapy in hypogonadal men is known to relieve anxiety and attenuate depressive symptoms.14,15 In addition, testosterone has protective effect against anxiety and depression in both men and women.16 However, the relationship between sex hormones and other mood disorders such as AP or EI has not been elucidated, especially in patients with a history of stroke. Therefore, in the current study, we aimed to elucidate the relationship between sex hormones and poststroke emotional disturbance in patients with a history of stroke, especially AP and EI. In addition, a previous meta-analysis revealed that statins lowered testosterone levels, especially in women, in a middle-aged population.17 Therefore, we also investigated whether statins, the most frequently used drug for secondary prevention of ischemic stroke, affect sex hormone levels or the presence of poststroke AP/EI.
Patients and Methods Study Design and Participants This was a single-center, prospective, observational pilot study. Between December 2016 and March 2017, we enrolled 40 patients with ischemic stroke at the outpatient clinic of Ajou University Medical Center. Eligible patients were screened according to the following inclusion criteria: age greater than 19 years, greater than or equal to 3 months after acute ischemic stroke or transient ischemic attack, modified Rankin Scale score of 0-2 at screening, and agreement to participate with informed consent. We excluded patients who had already been treated with antidepressant or dementia medications, those with aphasia or dysarthria severe enough to exclude a reliable interview, and those with medical conditions that could affect emotion and mood, such as renal dysfunction or liver disease. Baseline demographics, stroke risk factors, lesion location, and current medications were investigated.
Study Procedures Blood was obtained in the morning at approximately 8 am after midnight fasting. Venous blood samples were collected for measuring complete blood count, routine chemistry, electrolytes, the lipid panel, and sex hormones. The lipid panel included total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels. Analysis of sex hormones comprised serum total testosterone, luteinizing hormone, follicle stimulating hormone, prostaglandin, and estradiol levels. Total testosterone was measured by radioimmunoassay. The recommendations of the Korean Society of Aging Male Research define hypogonadism as a serum total testosterone level less than 3.46 ng/mL,18 and the normal range of testosterone in our institute is 2.5-10.63 ng/mL for men and 0.0-.95 ng/mL for women. Poststroke mood and emotional disturbances were evaluated through interviews with patients and caregivers by the same researcher after sufficient training sessions. Most interviews were conducted in the presence of the relatives or caregivers. Neuropsychological and mood assessments included Beck Depression Inventory,19 Beck Anxiety Inventory,20 and the Korea-Mini Mental State Examination. AP was defined as the inability of patients to control anger or aggression,4 and EI was defined as excessive or inappropriate emotional outbursts, such as laughing or crying, per the reports of patients or their relatives.5 Patients who had either AP, EI, or both were included in the AP/EI-present group, whereas those without AP or EI were included in the AP/EI-absent group. Poststroke depression was defined as a Beck Depression Inventory score greater than 13,19 and poststroke anxiety was defined as a Beck Anxiety Inventory score greater than 7.20 The present study was approved by the institutional review board of Ajou University Medical Center (AJIRBBMR-SMP-16-340). All participants provided written informed consent.
Statistical Analysis For continuous variables, including laboratory findings, we report values as means § standard deviation, and differences between the 2 groups were compared using Student's t test. Neuropsychological scores are presented as median (range), and the 2 groups were compared with the Mann-Whitney test. Categorical variables were compared using the chi-square test. Binary logistic regression analysis was performed to identify independent predictors of AP/EI. For this analysis, age, male sex, baseline National Institutes of Health Stroke Scale (NIHSS) score, statin use, and testosterone levels were used as variables. We conducted all statistical analyses using SPSS software (ver. 20.0; IBM Corp., Armonk, NY).
Results A total of 40 patients (30 men, mean age of 58.8 years) with a median poststroke duration of 6.2 months (range,
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3.0-64.6 months) were included in this study. Sixteen patients (40.0%) had AP or EI at screening: 5 (12.5%) only had AP, 5 (12.5%) only had EI, and 6 (15.0%) had both. The clinical parameters, laboratory findings, and neuropsychological scale scores associated with the presence of AP/EI are shown in Table 1. General demographics and clinical variables were similar between the patients with and without AP/EI. Lesion location, stroke subtype, and stroke severity were not different between the AP/EIpresent and AP/EI-absent groups. However, serum total
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testosterone levels were significantly lower in the AP/EIpresent group than in the AP/EI-absent group (2.1 § 1.7 vs. 3.9 § 2.5 ng/mL, P = .023). The prevalence of poststroke depression was significantly higher in the AP/EIpresent group than in the AP/EI-absent group (50.0% vs. 8.3%, P = .007). There was no difference in poststroke anxiety, fatigability, and subjective happiness scales between the 2 groups. After adjusting for major confounding factors associated with AP/EI (age, male sex, baseline NIHSS score, statin use, and testosterone level), testosterone was
Table 1. Clinical and demographic patient characteristics according to the presence or absence of AP/EI
Age, years, mean (SD) Sex, male, n (%) Follow-up after stroke onset in months, median (range) Stroke risk factor, n (%) Hypertension Atrial fibrillation Coronary artery disease Current smoker Stroke subtype, n (%) Atherosclerosis Cardioembolism Small artery disease Others Stroke lesion, n (%) Cortical lesion Subcortical lesion Infratentorial lesion Transient ischemic attack NIHSS at stroke onset, median (range) mRS, median (range) Current medication, n (%) Antiplatelet Anticoagulation Statin Statin type, n (%) Rosuvastatin 20 mg Rosuvastatin 10 mg Atorvastatin 10 mg Pitavastatin Laboratory findings, mean (SD) LH, mIU/mL FSH, mIU/mL Testosterone, ng/mL Prostaglandin, ng/mL Estrogen, pg/mL Glucose, mg/dL CK, U/L K-Mini Mental State Examination score, median (range) Poststroke depression, n (%) Poststroke anxiety, n (%) Fatigue severity scale score, median (range) Subjective happiness scale score, median (range)
Overall (n = 40)
AP/EI (+) (n = 16)
AP/EI (¡) (n = 24)
P
58.8 (12.8) 30 (75.0) 6.2 (3.0-64.6)
61.6 (11.3) 10 (62.5) 6.8 (3.0-64.6)
57.5 (13.6) 20 (83.3) 5.8 (3.0-30.5)
.311 .159 .754
21 (52.5) 6 (15.0) 1 (2.5) 12 (30.0)
7 (43.8) 1 (6.2) 1 (6.2) 5 (31.2)
14 (58.3) 5 (20.8) 0 (0.0) 7 (29.2)
.366 .373 .400 1.000 .105
11 (27.5) 7 (17.5) 10 (25.0) 12 (30.0)
2 (12.5) 2 (12.5) 7 (43.8) 5 (31.2)
9 (37.5) 5 (20.8) 3 (12.5) 7 (29.2)
10 (25.0) 18 (45.0) 11 (27.5) 1 (2.5) 1 (0-16) 1 (0-2)
3 (18.8) 7 (43.8) 6 (37.5) 0 (0.0) 1 (0-12) 1 (0-2)
7 (29.2) 11 (45.8) 5 (20.8) 1 (4.2) 1 (0-16) .5 (0-1)
35 (87.5) 8 (20.0) 23 (57.5)
14 (87.5) 3 (18.8) 9 (56.2)
21 (87.5) 5 (20.8) 14 (58.3)
6 (15.0) 13 (32.5) 3 (7.5) 1 (2.5)
1 (6.2) 5 (31.2) 2 (12.5) 1 (6.2)
5 (20.8) 8 (33.3) 1 (4.2) 0 (0.0)
8.4 (10.6) 11.2 (16.5) 3.3 (2.3) 1.3 (.4) 97.1 (68.1) 94.0 (6.2) 121.7 (64.3) 28 (23-30) 10 (25.0) 12 (30.0) 24 (9-48) 18 (9-28)
11.4 (14.7) 16.7 (20.7) 2.1 (1.7) 1.3 (.2) 112.6 (98.4) 92.5 (3.8) 112.1 (57.6) 28.5 (23-30) 8 (50.0) 5 (31.2) 25 (9-45) 16 (9-25)
7.5 (8.1) 9.7 (16.2) 3.9 (2.5) 1.3 (.4) 86.8 (32.7) 94.9 (7.3) 125.5 (69.0) 28.5 (23-30) 2 (8.3) 7 (29.2) 22 (9-48) 20.5 (13-28)
.636
.734 .331 1.000 1.000 .896 .461
.300 .045 .023 .487 .956 .177 .553 .422 .007 1.000 .313 .052
Abbreviations: AP, anger proneness; CK, creatinine kinase; EI, emotional incontinence; FSH, follicle stimulating hormone; LH, luteinizing hormone; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.
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Table 2. Multiple logistic regression analyses for predicting AP/EI Variables
Univariate Analysis Odds Ratio (95% CI)
P Value
Multivariate Analysis Odds Ratio (95% CI)
P Value
Age Male sex Baseline NIHSS Statin use Testosterone
1.03 (.98-1.09) .33 (.08-1.46) 1.04 (.87-1.23) .77 (.21-2.80) .68 (.49-.96)
.305 .144 .671 .078 .027
.68 (.49-.96)
.027
Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale.
Table 3. Laboratory findings and neuropsychological scales according to the use of statin
Age, years, mean (SD) Sex, male, n (%) Follow up after stroke onset, months, mean (SD) NIHSS at stroke onset, median (range) Laboratory findings, mean (SD) LH, mIU/m FSH, mIU/m Testosterone, ng/mL Prostaglandin, ng/mL Estrogen, pg/mL Total cholesterol, mg/dL Triglyceride, mg/dL HDL, mg/dL LDL, mg/dL Poststroke AP/EI, n (%) Poststroke AP, n (%) Poststroke EI, n (%) Poststroke depression, n (%) Poststroke anxiety, n (%)
Statin Use (n = 23)
Statin Nonuse (n = 17)
P
59.1 (12.1) 19 (82.6) 9.9 (12.6) 1 (0-12)
58.9 (14.0) 11 (64.7) 7.5 (6.4) 1 (0-16)
.972 .274 .516 .448
10.1 (13.8) 12.3 (20.7) 3.3 (2.1) 1.3 (.3) 88.8 (65.3) 136.4 (24.3) 110.0 (59.4) 57.0 (14.8) 57.4 (20.4) 9 (39.1) 6 (26.1) 6 (26.1) 6 (26.1) 6 (26.1)
7.6 (6.5) 12.8 (14.8) 3.1 (2.7) 1.3 (.4) 108.4 (70.3) 166.4 (35.0) 122.2 (78.6) 55.7 (13.8) 88.1 (25.0) 7 (41.2) 5 (29.4) 5 (29.4) 4 (23.5) 6 (35.3)
.978 .342 .825 .841 .107 .003 .725 .773 <.001 .896 1.000 1.000 1.000 .530
Abbreviations: AP, anger proneness; EI, emotional incontinence; FSH, follicle stimulating hormone; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; LH, luteinizing hormone; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.
independently associated with the presence of AP/EI (Table 2; odds ratio .68, 95% confidence interval .49-.96, P = .027). The effect of statins on hormones and neuropsychological scale scores is shown in Table 3. Twenty-three patients (57.5%) were treated with statins at baseline. Most patients received rosuvastatin (10 mg in 13 patients and 20 mg in 6 patients), followed by atorvastatin (10 mg in 3 patients) and pitavastatin (2 mg in 1 patient). Sex hormone levels and neuropsychological scale scores did not differ between statin users and nonusers.
Discussion In the current study, poststroke AP/EI were associated with low testosterone levels in patients with a history of ischemic stroke. Moreover, the testosterone level was independently associated with the presence of AP/EI.
The statins used or the cholesterol levels, however, did not affect the AP/EI in our study population. Traditionally, studies on poststroke emotional lability have focused on pseudobulbar affect. Pseudobulbar affect is a broad term that refers to a variety of neurological symptoms caused by repetitive damage to the bilateral corticobulbar tract.21 Stroke-associated pseudobulbar effect primarily manifests in older patients with a history of stroke and of recurrent strokes involving the subcortical area.22 In the present study, all patients had experienced their first stroke or transient ischemic attack, and not all patients had experienced subcortical strokes involving the internal capsules and basal ganglia. Moreover, the ability to live independently was an inclusion criterion in the present study, which may have excluded patients with damage to the bilateral corticobulbar tract. The patients in our study were relatively younger than patients with pseudobulbar affect, who are usually in
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their 60s.23 Thus, poststroke AP/EI in our patients can be differentiated from pseudobulbar affect. Various factors affect poststroke AP/EI. Lesion location has consistently been reported to be associated with poststroke AP/EI.1 In addition, poststroke AP/EI is affected by multidimensional factors such as severity of stroke, history of stroke, history of depression, low social support, and genetic factors.9 In the current study, low testosterone levels were independently associated with poststroke AP/EI. Decreased testosterone levels have a negative effect on the mood of men with hypogonadism.24,25 Therefore, when clinicians encounter patients with stroke with AP/EI, measurement of testosterone levels could enable a better understanding of the patients’ condition and aid the development of a novel therapeutic approach for managing AP/EI. Testosterone and cholesterol molecules have similar chemical structures. We hypothesized that intensive treatment with statins, which have been widely used for preventing ischemic stroke, would inhibit the synthesis of cholesterol, the preferred substrate of testosterone; this, in turn, would affect AP/EI via a decline in testosterone levels.26,27 However, we found that statin use did not affect AP/EI in patients with chronic stroke. Nonetheless, this finding should be interpreted with caution because our study population was small and this was a pilot study. On the other hand, lowering of androgen levels can also be linked to the pleiotropic effects of statins, such as impaired glucose metabolism, reduced inflammation, and improved immune function.28,29 Thus, more detailed investigation is required in the future to elucidate the relationship between statins and androgens in a larger population of patients with stroke. This study has several limitations. First, the small sample size and single hospital-based study design limit the interpretation of the frequency of AP/EI; thus, the AP/EI proportion in our population cannot be generalized to the entire population of patients with chronic stroke. In the current study, we focused on the prevalence of AP/EI in patients with relatively mild sequelae rather than on the incidence. Incidence evaluation may introduce recall bias because, after a median of 6.2 months, patients and their family members could not accurately remember whether AP/EI symptoms developed after stroke or if they were present before stroke. Second, sex hormone levels can be affected by various factors such as age, sex, or proteinbinding capacities. These factors can be adjusted for in a future large population study. Nevertheless, the results of this pilot study can provide novel insights into a possible relationship between AP/EI and sex hormone imbalance, and these insights can inform and improve the design of future studies. In conclusion, the current study revealed that AP/EI was associated with low testosterone levels in patients with a history of ischemic stroke and relatively mild sequelae. When physicians encounter patients with
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poststroke emotional and mood disturbances, they should consider various factors, including sex hormone levels, in addition to the history of stroke. Statin use did not affect the level of sex hormones, and poststroke mood and emotional disturbances in the current study, but these findings need to be confirmed in a further large-scale study. Declarations of Interest None.
Supplementary Material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.08.014.
References 1. Kim JS. Post-stroke mood and emotional disturbances: pharmacological therapy based on mechanisms. J Stroke 2016;18:244-255. 2. Kotila M, Numminen H, Waltimo O, et al. Post-stroke depression and functional recovery in a population-based stroke register. The Finnstroke study. Eur J Neurol 1999;6:309-312. 3. van de Weg FB, Kuik DJ, Lankhorst GJ. Post-stroke depression and functional outcome: a cohort study investigating the influence of depression on functional recovery from stroke. Clin Rehabil 1999;13:268-272. 4. Kim JS, Choi S, Kwon SU, et al. Inability to control anger or aggression after stroke. Neurology 2002;58:1106-1108. 5. Kim JS, Choi-Kwon S. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000;54:1805-1810. 6. Noh SM, Chung SJ, Kim KK, et al. Emotional disturbance in CADASIL: its impact on quality of life and caregiver burden. Cerebrovasc Dis 2014;37:188-194. 7. Choi-Kwon S, Han SW, Kwon SU, et al. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke 2006;37:156-161. 8. Murai T, Barthel H, Berrouschot J, et al. Neuroimaging of serotonin transporters in post-stroke pathological crying. Psychiatry Res 2003;123:207-211. 9. Choi-Kwon S, Han K, Choi S, et al. Poststroke depression and emotional incontinence: factors related to acute and subacute stages. Neurology 2012;78:1130-1137. 10. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593-602. 11. Leach LS, Christensen H, Mackinnon AJ, et al. Gender differences in depression and anxiety across the adult lifespan: the role of psychosocial mediators. Soc Psychiatry Psychiatr Epidemiol 2008;43:983-998. 12. Dubrovsky BO. Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:169-192. 13. Eser D, Sch€ ule C, Romeo E, et al. Neuropsychopharmacological properties of neuroactive steroids in depression and anxiety disorders. Psychopharmacology 2006;186: 373-387. 14. Pope HGJr, GH Cohane, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression:
ARTICLE IN PRESS M.H. CHOI ET AL.
6
15.
16.
17.
18.
19.
20.
21.
22.
a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105-111. Zarrouf FA, Artz S, Griffith J, et al. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract 2009;15:289-305. McHenry J, Carrier N, Hull E, et al. Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol 2014;35:42-57. Schooling CM, Au Yeung SL, Freeman G, et al. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 2013;11:57. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006;27:135-137. Beck AT, Steer RA, Carbin MG. Psychometric properties of the beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev 1988;8:77-100. Beck AT, Epstein N, Brown G, et al. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893-897. Colamonico J, Formella A, Bradley W. Pseudobulbar affect: burden of illness in the USA. Adv Ther 2012;29:775-798. Schiffer R, Pope LE. Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci 2005;17:447-454.
23. Brooks BR, Crumpacker D, Fellus J, et al. PRISM: a novel research tool to assess the prevalence of pseudobulbar affect symptoms across neurological conditions. PLoS One 2013;8:e72232. 24. Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study. J Clin Endocrinol Metab 1999;84:573-577. 25. Shores MM, Sloan KL, Matsumoto AM, et al. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry 2004;61:162-167. 26. Smals AG, Weusten JJ, Benraad TJ, et al. The HMGCoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity. J Steroid Biochem Mol Biol 1991;38:465-468. 27. Raval AD, Hunter T, Stuckey B, et al. Statins for women with polycystic ovary syndrome not actively trying to conceive. Cochrane Database Syst Rev 2011;10: CD008565. 28. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-742. 29. Deng J, Wu Q, Liao Y, et al. Effect of statins on chronic inflammation and nutrition status in renal dialysis patients: a systematic review and meta-analysis. Nephrology 2012;17:545-551.
Low Testosterone Level as a Predictor of Poststroke Emotional Disturbances: Anger Proneness and Emotional Incontinence Mun Hee Choi, MD,* Tae Sung Lim, MD, PhD,* Bok Seon Yoon, MS,† Keoung Sun Son, † Ji Man Hong, MD, PhD,*,† and Jin Soo Lee, MD, PhD*,† Background: The role of sex hormones in poststroke mood and emotional disturbances is unclear. We aimed to evaluate the impact of sex hormones on poststroke emotional disturbance, especially anger proneness (AP) and emotional incontinence (EI). We also investigated whether statins, which are widely used for stroke prevention, affect sex hormone levels or the presence of poststroke AP/EI based on the hypothesis that intensive treatment with statins would inhibit the synthesis of cholesterol, the preferred substrate of testosterone. Methods: We prospectively enrolled 40 patients who experienced ischemic stroke at least 3 months prior to study enrollment. We performed clinical and laboratory evaluations, including hormone-level measurements and neuropsychological tests. Poststroke AP and EI were assessed using interviews, then patients were divided into 2 groups: AP/EI-present or absent. Results: Of the 40 patients (30 men, mean age 58.8 years), 16 (40.0%) were classified as AP/EI-present group. AP/EI were not related to stroke severity or location; however, the testosterone level was significantly lower in patients with AP/EI than in those without AP/EI (2.1 § 1.7 vs. 3.9 § 2.5 ng/mL, P = .023). After adjusting for potential confounding variables, low testosterone levels were a significant independent predictor of AP/EI (odds ratio .68, 95% confidence interval .49.96, P = .027). In contrast, sex hormone levels and AP/EI prevalence did not differ between statin users and nonusers. Conclusions: AP/EI were associated with low testosterone levels in patients with previous ischemic stroke, but statin use did not affect AP/EI prevalence. Key Words: Stroke—anger proneness—emotional incontinence—testosterone— hydroxymethylglutaryl-CoA reductase inhibitors. © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction
From the *Department of Neurology, Ajou University Medical Center, Suwon, Republic of Korea; and †Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea. Received May 29, 2018; revision received July 28, 2018; accepted August 8, 2018. Funding: This work was partly supported by the CJ CheilJedang Corporation. They had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Address correspondence to Jin Soo Lee, MD, PhD, Department of Neurology, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do, Suwon, Gyeonggi 16499, Republic of Korea. E-mail: [email protected] 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.08.014
Although the prevalence of poststroke mood and emotional disturbances varies widely across different studies, they have a substantial negative impact on the recovery and prognosis of stroke patients.1-3 Patients with stroke may show impulsive behaviors and verbal aggression or become more irritable and hostile. These symptoms can be termed as poststroke anger proneness (AP).4 Emotional incontinence (EI) has been described using various terminologies; patients experience excessive, inappropriate, and uncontrollable emotions without apparent stimuli.5 Both AP and EI, which are poststroke emotional problems, have garnered relatively little attention compared to depression in patients with a history of stroke, these symptoms also degrade the quality of life of both patients and their relatives.6 AP/EI are known to share similar lesion distribution and pathogenic mechanisms, including serotonergic dysfunction.7
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2018: pp 1 6
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Neurotransmitters have increasingly been implicated in poststroke AP/EI; however, in previous clinical trials, selective serotonin reuptake inhibitors have been shown to provide only partial benefits in patients with poststroke emotional problems.4,8 These inadequate results might be associated with diverse factors affecting poststroke AP/EI, including neurologic, socioenvironmental, and genetic factors.9 In the general population, gonadal hormones are considered major factors in mood disorders, showing pervasive sex differences, with women being more than twice as likely as men to experience emotional problems.10,11 Testosterone, which can freely pass through the blood-brain barrier, is known to alter neurotransmitters, the hypothalamus-pituitary axis, and cellular and molecular pathways; consequently, it can influence mood and emotion.12,13 Clinical evidence suggests that testosterone has beneficial effects on anxiety and depression, and hormone replacement therapy in hypogonadal men is known to relieve anxiety and attenuate depressive symptoms.14,15 In addition, testosterone has protective effect against anxiety and depression in both men and women.16 However, the relationship between sex hormones and other mood disorders such as AP or EI has not been elucidated, especially in patients with a history of stroke. Therefore, in the current study, we aimed to elucidate the relationship between sex hormones and poststroke emotional disturbance in patients with a history of stroke, especially AP and EI. In addition, a previous meta-analysis revealed that statins lowered testosterone levels, especially in women, in a middle-aged population.17 Therefore, we also investigated whether statins, the most frequently used drug for secondary prevention of ischemic stroke, affect sex hormone levels or the presence of poststroke AP/EI.
Patients and Methods Study Design and Participants This was a single-center, prospective, observational pilot study. Between December 2016 and March 2017, we enrolled 40 patients with ischemic stroke at the outpatient clinic of Ajou University Medical Center. Eligible patients were screened according to the following inclusion criteria: age greater than 19 years, greater than or equal to 3 months after acute ischemic stroke or transient ischemic attack, modified Rankin Scale score of 0-2 at screening, and agreement to participate with informed consent. We excluded patients who had already been treated with antidepressant or dementia medications, those with aphasia or dysarthria severe enough to exclude a reliable interview, and those with medical conditions that could affect emotion and mood, such as renal dysfunction or liver disease. Baseline demographics, stroke risk factors, lesion location, and current medications were investigated.
Study Procedures Blood was obtained in the morning at approximately 8 am after midnight fasting. Venous blood samples were collected for measuring complete blood count, routine chemistry, electrolytes, the lipid panel, and sex hormones. The lipid panel included total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels. Analysis of sex hormones comprised serum total testosterone, luteinizing hormone, follicle stimulating hormone, prostaglandin, and estradiol levels. Total testosterone was measured by radioimmunoassay. The recommendations of the Korean Society of Aging Male Research define hypogonadism as a serum total testosterone level less than 3.46 ng/mL,18 and the normal range of testosterone in our institute is 2.5-10.63 ng/mL for men and 0.0-.95 ng/mL for women. Poststroke mood and emotional disturbances were evaluated through interviews with patients and caregivers by the same researcher after sufficient training sessions. Most interviews were conducted in the presence of the relatives or caregivers. Neuropsychological and mood assessments included Beck Depression Inventory,19 Beck Anxiety Inventory,20 and the Korea-Mini Mental State Examination. AP was defined as the inability of patients to control anger or aggression,4 and EI was defined as excessive or inappropriate emotional outbursts, such as laughing or crying, per the reports of patients or their relatives.5 Patients who had either AP, EI, or both were included in the AP/EI-present group, whereas those without AP or EI were included in the AP/EI-absent group. Poststroke depression was defined as a Beck Depression Inventory score greater than 13,19 and poststroke anxiety was defined as a Beck Anxiety Inventory score greater than 7.20 The present study was approved by the institutional review board of Ajou University Medical Center (AJIRBBMR-SMP-16-340). All participants provided written informed consent.
Statistical Analysis For continuous variables, including laboratory findings, we report values as means § standard deviation, and differences between the 2 groups were compared using Student's t test. Neuropsychological scores are presented as median (range), and the 2 groups were compared with the Mann-Whitney test. Categorical variables were compared using the chi-square test. Binary logistic regression analysis was performed to identify independent predictors of AP/EI. For this analysis, age, male sex, baseline National Institutes of Health Stroke Scale (NIHSS) score, statin use, and testosterone levels were used as variables. We conducted all statistical analyses using SPSS software (ver. 20.0; IBM Corp., Armonk, NY).
Results A total of 40 patients (30 men, mean age of 58.8 years) with a median poststroke duration of 6.2 months (range,
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3.0-64.6 months) were included in this study. Sixteen patients (40.0%) had AP or EI at screening: 5 (12.5%) only had AP, 5 (12.5%) only had EI, and 6 (15.0%) had both. The clinical parameters, laboratory findings, and neuropsychological scale scores associated with the presence of AP/EI are shown in Table 1. General demographics and clinical variables were similar between the patients with and without AP/EI. Lesion location, stroke subtype, and stroke severity were not different between the AP/EIpresent and AP/EI-absent groups. However, serum total
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testosterone levels were significantly lower in the AP/EIpresent group than in the AP/EI-absent group (2.1 § 1.7 vs. 3.9 § 2.5 ng/mL, P = .023). The prevalence of poststroke depression was significantly higher in the AP/EIpresent group than in the AP/EI-absent group (50.0% vs. 8.3%, P = .007). There was no difference in poststroke anxiety, fatigability, and subjective happiness scales between the 2 groups. After adjusting for major confounding factors associated with AP/EI (age, male sex, baseline NIHSS score, statin use, and testosterone level), testosterone was
Table 1. Clinical and demographic patient characteristics according to the presence or absence of AP/EI
Age, years, mean (SD) Sex, male, n (%) Follow-up after stroke onset in months, median (range) Stroke risk factor, n (%) Hypertension Atrial fibrillation Coronary artery disease Current smoker Stroke subtype, n (%) Atherosclerosis Cardioembolism Small artery disease Others Stroke lesion, n (%) Cortical lesion Subcortical lesion Infratentorial lesion Transient ischemic attack NIHSS at stroke onset, median (range) mRS, median (range) Current medication, n (%) Antiplatelet Anticoagulation Statin Statin type, n (%) Rosuvastatin 20 mg Rosuvastatin 10 mg Atorvastatin 10 mg Pitavastatin Laboratory findings, mean (SD) LH, mIU/mL FSH, mIU/mL Testosterone, ng/mL Prostaglandin, ng/mL Estrogen, pg/mL Glucose, mg/dL CK, U/L K-Mini Mental State Examination score, median (range) Poststroke depression, n (%) Poststroke anxiety, n (%) Fatigue severity scale score, median (range) Subjective happiness scale score, median (range)
Overall (n = 40)
AP/EI (+) (n = 16)
AP/EI (¡) (n = 24)
P
58.8 (12.8) 30 (75.0) 6.2 (3.0-64.6)
61.6 (11.3) 10 (62.5) 6.8 (3.0-64.6)
57.5 (13.6) 20 (83.3) 5.8 (3.0-30.5)
.311 .159 .754
21 (52.5) 6 (15.0) 1 (2.5) 12 (30.0)
7 (43.8) 1 (6.2) 1 (6.2) 5 (31.2)
14 (58.3) 5 (20.8) 0 (0.0) 7 (29.2)
.366 .373 .400 1.000 .105
11 (27.5) 7 (17.5) 10 (25.0) 12 (30.0)
2 (12.5) 2 (12.5) 7 (43.8) 5 (31.2)
9 (37.5) 5 (20.8) 3 (12.5) 7 (29.2)
10 (25.0) 18 (45.0) 11 (27.5) 1 (2.5) 1 (0-16) 1 (0-2)
3 (18.8) 7 (43.8) 6 (37.5) 0 (0.0) 1 (0-12) 1 (0-2)
7 (29.2) 11 (45.8) 5 (20.8) 1 (4.2) 1 (0-16) .5 (0-1)
35 (87.5) 8 (20.0) 23 (57.5)
14 (87.5) 3 (18.8) 9 (56.2)
21 (87.5) 5 (20.8) 14 (58.3)
6 (15.0) 13 (32.5) 3 (7.5) 1 (2.5)
1 (6.2) 5 (31.2) 2 (12.5) 1 (6.2)
5 (20.8) 8 (33.3) 1 (4.2) 0 (0.0)
8.4 (10.6) 11.2 (16.5) 3.3 (2.3) 1.3 (.4) 97.1 (68.1) 94.0 (6.2) 121.7 (64.3) 28 (23-30) 10 (25.0) 12 (30.0) 24 (9-48) 18 (9-28)
11.4 (14.7) 16.7 (20.7) 2.1 (1.7) 1.3 (.2) 112.6 (98.4) 92.5 (3.8) 112.1 (57.6) 28.5 (23-30) 8 (50.0) 5 (31.2) 25 (9-45) 16 (9-25)
7.5 (8.1) 9.7 (16.2) 3.9 (2.5) 1.3 (.4) 86.8 (32.7) 94.9 (7.3) 125.5 (69.0) 28.5 (23-30) 2 (8.3) 7 (29.2) 22 (9-48) 20.5 (13-28)
.636
.734 .331 1.000 1.000 .896 .461
.300 .045 .023 .487 .956 .177 .553 .422 .007 1.000 .313 .052
Abbreviations: AP, anger proneness; CK, creatinine kinase; EI, emotional incontinence; FSH, follicle stimulating hormone; LH, luteinizing hormone; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.
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Table 2. Multiple logistic regression analyses for predicting AP/EI Variables
Univariate Analysis Odds Ratio (95% CI)
P Value
Multivariate Analysis Odds Ratio (95% CI)
P Value
Age Male sex Baseline NIHSS Statin use Testosterone
1.03 (.98-1.09) .33 (.08-1.46) 1.04 (.87-1.23) .77 (.21-2.80) .68 (.49-.96)
.305 .144 .671 .078 .027
.68 (.49-.96)
.027
Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale.
Table 3. Laboratory findings and neuropsychological scales according to the use of statin
Age, years, mean (SD) Sex, male, n (%) Follow up after stroke onset, months, mean (SD) NIHSS at stroke onset, median (range) Laboratory findings, mean (SD) LH, mIU/m FSH, mIU/m Testosterone, ng/mL Prostaglandin, ng/mL Estrogen, pg/mL Total cholesterol, mg/dL Triglyceride, mg/dL HDL, mg/dL LDL, mg/dL Poststroke AP/EI, n (%) Poststroke AP, n (%) Poststroke EI, n (%) Poststroke depression, n (%) Poststroke anxiety, n (%)
Statin Use (n = 23)
Statin Nonuse (n = 17)
P
59.1 (12.1) 19 (82.6) 9.9 (12.6) 1 (0-12)
58.9 (14.0) 11 (64.7) 7.5 (6.4) 1 (0-16)
.972 .274 .516 .448
10.1 (13.8) 12.3 (20.7) 3.3 (2.1) 1.3 (.3) 88.8 (65.3) 136.4 (24.3) 110.0 (59.4) 57.0 (14.8) 57.4 (20.4) 9 (39.1) 6 (26.1) 6 (26.1) 6 (26.1) 6 (26.1)
7.6 (6.5) 12.8 (14.8) 3.1 (2.7) 1.3 (.4) 108.4 (70.3) 166.4 (35.0) 122.2 (78.6) 55.7 (13.8) 88.1 (25.0) 7 (41.2) 5 (29.4) 5 (29.4) 4 (23.5) 6 (35.3)
.978 .342 .825 .841 .107 .003 .725 .773 <.001 .896 1.000 1.000 1.000 .530
Abbreviations: AP, anger proneness; EI, emotional incontinence; FSH, follicle stimulating hormone; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; LH, luteinizing hormone; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.
independently associated with the presence of AP/EI (Table 2; odds ratio .68, 95% confidence interval .49-.96, P = .027). The effect of statins on hormones and neuropsychological scale scores is shown in Table 3. Twenty-three patients (57.5%) were treated with statins at baseline. Most patients received rosuvastatin (10 mg in 13 patients and 20 mg in 6 patients), followed by atorvastatin (10 mg in 3 patients) and pitavastatin (2 mg in 1 patient). Sex hormone levels and neuropsychological scale scores did not differ between statin users and nonusers.
Discussion In the current study, poststroke AP/EI were associated with low testosterone levels in patients with a history of ischemic stroke. Moreover, the testosterone level was independently associated with the presence of AP/EI.
The statins used or the cholesterol levels, however, did not affect the AP/EI in our study population. Traditionally, studies on poststroke emotional lability have focused on pseudobulbar affect. Pseudobulbar affect is a broad term that refers to a variety of neurological symptoms caused by repetitive damage to the bilateral corticobulbar tract.21 Stroke-associated pseudobulbar effect primarily manifests in older patients with a history of stroke and of recurrent strokes involving the subcortical area.22 In the present study, all patients had experienced their first stroke or transient ischemic attack, and not all patients had experienced subcortical strokes involving the internal capsules and basal ganglia. Moreover, the ability to live independently was an inclusion criterion in the present study, which may have excluded patients with damage to the bilateral corticobulbar tract. The patients in our study were relatively younger than patients with pseudobulbar affect, who are usually in
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their 60s.23 Thus, poststroke AP/EI in our patients can be differentiated from pseudobulbar affect. Various factors affect poststroke AP/EI. Lesion location has consistently been reported to be associated with poststroke AP/EI.1 In addition, poststroke AP/EI is affected by multidimensional factors such as severity of stroke, history of stroke, history of depression, low social support, and genetic factors.9 In the current study, low testosterone levels were independently associated with poststroke AP/EI. Decreased testosterone levels have a negative effect on the mood of men with hypogonadism.24,25 Therefore, when clinicians encounter patients with stroke with AP/EI, measurement of testosterone levels could enable a better understanding of the patients’ condition and aid the development of a novel therapeutic approach for managing AP/EI. Testosterone and cholesterol molecules have similar chemical structures. We hypothesized that intensive treatment with statins, which have been widely used for preventing ischemic stroke, would inhibit the synthesis of cholesterol, the preferred substrate of testosterone; this, in turn, would affect AP/EI via a decline in testosterone levels.26,27 However, we found that statin use did not affect AP/EI in patients with chronic stroke. Nonetheless, this finding should be interpreted with caution because our study population was small and this was a pilot study. On the other hand, lowering of androgen levels can also be linked to the pleiotropic effects of statins, such as impaired glucose metabolism, reduced inflammation, and improved immune function.28,29 Thus, more detailed investigation is required in the future to elucidate the relationship between statins and androgens in a larger population of patients with stroke. This study has several limitations. First, the small sample size and single hospital-based study design limit the interpretation of the frequency of AP/EI; thus, the AP/EI proportion in our population cannot be generalized to the entire population of patients with chronic stroke. In the current study, we focused on the prevalence of AP/EI in patients with relatively mild sequelae rather than on the incidence. Incidence evaluation may introduce recall bias because, after a median of 6.2 months, patients and their family members could not accurately remember whether AP/EI symptoms developed after stroke or if they were present before stroke. Second, sex hormone levels can be affected by various factors such as age, sex, or proteinbinding capacities. These factors can be adjusted for in a future large population study. Nevertheless, the results of this pilot study can provide novel insights into a possible relationship between AP/EI and sex hormone imbalance, and these insights can inform and improve the design of future studies. In conclusion, the current study revealed that AP/EI was associated with low testosterone levels in patients with a history of ischemic stroke and relatively mild sequelae. When physicians encounter patients with
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poststroke emotional and mood disturbances, they should consider various factors, including sex hormone levels, in addition to the history of stroke. Statin use did not affect the level of sex hormones, and poststroke mood and emotional disturbances in the current study, but these findings need to be confirmed in a further large-scale study. Declarations of Interest None.
Supplementary Material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.08.014.
References 1. Kim JS. Post-stroke mood and emotional disturbances: pharmacological therapy based on mechanisms. J Stroke 2016;18:244-255. 2. Kotila M, Numminen H, Waltimo O, et al. Post-stroke depression and functional recovery in a population-based stroke register. The Finnstroke study. Eur J Neurol 1999;6:309-312. 3. van de Weg FB, Kuik DJ, Lankhorst GJ. Post-stroke depression and functional outcome: a cohort study investigating the influence of depression on functional recovery from stroke. Clin Rehabil 1999;13:268-272. 4. Kim JS, Choi S, Kwon SU, et al. Inability to control anger or aggression after stroke. Neurology 2002;58:1106-1108. 5. Kim JS, Choi-Kwon S. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000;54:1805-1810. 6. Noh SM, Chung SJ, Kim KK, et al. Emotional disturbance in CADASIL: its impact on quality of life and caregiver burden. Cerebrovasc Dis 2014;37:188-194. 7. Choi-Kwon S, Han SW, Kwon SU, et al. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke 2006;37:156-161. 8. Murai T, Barthel H, Berrouschot J, et al. Neuroimaging of serotonin transporters in post-stroke pathological crying. Psychiatry Res 2003;123:207-211. 9. Choi-Kwon S, Han K, Choi S, et al. Poststroke depression and emotional incontinence: factors related to acute and subacute stages. Neurology 2012;78:1130-1137. 10. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593-602. 11. Leach LS, Christensen H, Mackinnon AJ, et al. Gender differences in depression and anxiety across the adult lifespan: the role of psychosocial mediators. Soc Psychiatry Psychiatr Epidemiol 2008;43:983-998. 12. Dubrovsky BO. Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:169-192. 13. Eser D, Sch€ ule C, Romeo E, et al. Neuropsychopharmacological properties of neuroactive steroids in depression and anxiety disorders. Psychopharmacology 2006;186: 373-387. 14. Pope HGJr, GH Cohane, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression:
ARTICLE IN PRESS M.H. CHOI ET AL.
6
15.
16.
17.
18.
19.
20.
21.
22.
a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105-111. Zarrouf FA, Artz S, Griffith J, et al. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract 2009;15:289-305. McHenry J, Carrier N, Hull E, et al. Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol 2014;35:42-57. Schooling CM, Au Yeung SL, Freeman G, et al. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 2013;11:57. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006;27:135-137. Beck AT, Steer RA, Carbin MG. Psychometric properties of the beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev 1988;8:77-100. Beck AT, Epstein N, Brown G, et al. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893-897. Colamonico J, Formella A, Bradley W. Pseudobulbar affect: burden of illness in the USA. Adv Ther 2012;29:775-798. Schiffer R, Pope LE. Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci 2005;17:447-454.
23. Brooks BR, Crumpacker D, Fellus J, et al. PRISM: a novel research tool to assess the prevalence of pseudobulbar affect symptoms across neurological conditions. PLoS One 2013;8:e72232. 24. Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study. J Clin Endocrinol Metab 1999;84:573-577. 25. Shores MM, Sloan KL, Matsumoto AM, et al. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry 2004;61:162-167. 26. Smals AG, Weusten JJ, Benraad TJ, et al. The HMGCoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity. J Steroid Biochem Mol Biol 1991;38:465-468. 27. Raval AD, Hunter T, Stuckey B, et al. Statins for women with polycystic ovary syndrome not actively trying to conceive. Cochrane Database Syst Rev 2011;10: CD008565. 28. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-742. 29. Deng J, Wu Q, Liao Y, et al. Effect of statins on chronic inflammation and nutrition status in renal dialysis patients: a systematic review and meta-analysis. Nephrology 2012;17:545-551.