Lower urinary tract symptoms are associated with clinically relevant depression, anxiety, and stress symptoms

Abstract Objectives To investigate the correlation between lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and testosterone deficiency (TD) with depressive, stress, and anxiety symptoms. Material and methods From October 2019 to March 2020, 113 males were included. Inclusion criteria: age 40–75, no clinical suspicion of prostate cancer, no serious cardiovascular comorbidities. All patients completed a set of questionnaires: International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5), and Depression Anxiety Stress Scales (DASS-21). Results Median age was 62 years (range 40–74), mean IPSS score was 10.94 (SD 7.75), mean IIEF-5 score 13.12 (SD 7.08), and mean DASS-21 score 11.35 (SD 8.24). According to DASS-21 subscales, 28 (24.8%) patients had depressive symptoms, 25 (22.1%) anxiety symptoms, and 25 (22.1%) stress symptoms. Depression was associated with LUTS (14.5 vs. 8 score, p = .002). Similarly, stress symptoms were associated with LUTS (IPSS 15 vs. 7 score, p = .0001) and with ED (IIEF-5 5 vs. 15 score, p = .01). Positive Spearman's rho correlations between LUTS and all three, depression, anxiety, and stress symptoms were found (p values <.001). Conclusions LUTS is associated with depression, anxiety, and stress symptoms. Screening for these symptoms could help with individual counseling and management.


Introduction
Lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and testosterone deficiency (TD) are frequent complaints in adult men and have complex multifactorial etiologies [1]. Diagnosis and treatment planning is mostly based on medical and sexual history as well as validated questionnaires, together with a focused physical examination and laboratory assessment [2]. All three of these symptoms complexes/entities have been shown to result in psychologic distress and unwell being [3][4][5].
The association between LUTS with depressive symptoms has been investigated, but not in correlation with the presence of TD and ED nor the impact of LUTS on stress and anxiety [6][7][8][9].
Therefore, in this study, we aimed to investigate the correlation between LUTS, TD, and ED with depressive, stress, and anxiety symptoms at time of diagnosis. We focused on men coming to the outpatient clinic for LUTS, TD, and/or ED. criteria and agreed to enter the study after having signed an informed consent (Ethical Committee approval no. 9973/2019). Inclusion criteria included: age 40-75 years, no clinical suspicion of prostate cancer, and no serious cardiovascular comorbidities. Agerelated TD was defined both according to the latest American Urological Association (AUA) guideline as <300 ng/dl at two consecutive determinations [10] and also according to the latest European Association of Urology (EAU) guideline as <350 ng/dl at two consecutive determinations [11].

Validated questionnaires
All patients completed a set of self-reported validated questionnaires: International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5), and Depression Anxiety Stress Scales (DASS-21).

Statistical analysis
Data were considered as nominal or quantitative variables. Nominal variables were characterized using frequencies. Quantitative variables were tested for normality of distribution using Kolmogorov-Smirnov's test and were characterized by median and percentiles (25-75%) or by mean and standard deviation (SD), when appropriate. A chi-square test was used in order to compare the frequencies of nominal variables. Quantitative variables were compared using t-test, Mann-Whitney's test, ANOVA test, or the Kruskal-Wallis test, when appropriate. The correlation between quantitative variables was assessed using Pearson's correlation or Spearman's rho, when appropriate. The level of statistical significance was set at p<.05 and all tests are two-sided. Statistical analysis was performed using SPSS 17.0 (SPSS Inc., Chicago, IL).

Association of depressions symptoms with LUTS, TD, and ED
Patients with depressive symptoms were more likely to have LUTS and vice-versa: median IPSS score was 14.5 in males with depressive symptoms compared to eight in those without (p ¼ .002). In contrast, depression symptoms severity was not associated with TD (both 300 or 350 ng cut-offs for testosterone), ED or severe LUTS associated with moderate or severe ED (Table 1). These associations remained when analyzing according to the severity of symptoms with a median IPSS score of 21 in patients with severe depression (p ¼ .01). A positive Spearman's rho correlation between IPSS score and DASS-depression subscale was observed (K ¼ 0.313, p ¼ .001). LUTS was also correlated with the global DASS-21 score (K ¼ 0.41, p<.001).

Association of anxiety symptoms with LUTS, TD, and ED
Anxiety symptoms were not associated with LUTS, TD, or ED (Table 2). IPSS score increased with worsening severity of anxiety symptoms (median score 14 vs. 9, p<.05) and IPSS score was correlated with the DASSanxiety subscale (K ¼ 0.319, p ¼ .001).

Association of stress symptoms with LUTS, TD, and ED
Stress symptoms were associated with LUTS; the median IPSS score was 15 in males with stress symptoms compared to seven in those without (p ¼ .0001).
Stress symptoms were not associated with TD (both 300 and 350 ng cut-offs for testosterone), ED or severe LUTS associated with moderate or severe ED (Table 3). These associations remained when analyzing according to the severity of symptoms with a median IPSS score of 21 in patients with severe stress, p ¼ .001. This was also true regarding IIEF-5 scores (five in those with severe stress vs. 15 in those without symptoms, p ¼ .01). When analyzing according to severity of stress symptoms patients with both severe LUTS and moderate or severe ED were more likely to suffer from severe stress (two out 10 vs. one out 103, p ¼ .004). A positive Spearman's rho correlation between IPSS  score and DASS-stress subscale was observed (K ¼ 0.39, p<.001).

Discussion
We found that LUTS was associated with depression, anxiety, and stress symptoms. In addition, patients with severe depressive symptoms had severe LUTS. Similarly, a nationwide, population-based study in Taiwan found that patients with LUTS had a significantly higher prevalence of anxiety and depression than matched controls even after adjusting for the effects of socio-demographic variables and other systemic diseases [17]. Another study of 602 patients with multiple sclerosis reported an association of LUTS severity with anxiety, depression, and stress [18]. A similar association between depressive symptoms and LUTS was investigated in a survey on 5506 subjects in Boston Area Community Health. The survey found that depressive symptoms were associated with increased odds of LUTS across all gender and racial/ethnic groups [overall odds ratio (95% confidence interval): 2.4 (1.9-3.2), p<.001] [6]. In contrast, using a mediation model to explore the interrelationships between LUTS severity, mental health, and health-related quality of life (HRQOL), Choi et al. reported that only anxiety symptoms fully mediated the relationship between LUTS severity and HRQOL in males [3]. We found a significant association between ED severity and stress symptoms, even more when associated with severe LUTS symptoms. Similar findings were reported in a study that included 60 patients with ED, which revealed a significant relationship between ED, hyperprolactinemia, and stress symptoms [19]. In contrast, in a cohort study from China (153 males), the authors observed a negative correlation between ED and psychological stress [20]. Currently, the 2021 EAU Guideline recommends by the time of ED diagnosis to use for depression mood assessment Beck Depression Inventory [11], but it seems that psychological stress represents also an important factor that should also be investigated.
We found out that approximately 1/4 of men presenting for a urologic consult have concomitant depressive, anxiety, or stress symptoms. This suggests a need for screening for these symptoms at diagnosis of LUTS, ED, and TD. A close collaboration with a clinician psychologist may lead to early detection of patients at risk and help address all dimensions needed by the patient [21]. By using DASS-21 questionnaire, clinicians are able to screen for all three important mood aspects: depression, anxiety, and stress, and further to tailor treatment to patient's needs.
The results of our study should be considered taking into consideration a number of limitations. First, all subjects were recruited from public-sector outpatient's clinics and the results may not be generalizable to LUTS patients receiving care in the private-sector. Second, the DASS-21 is an instrument designed to assess mental health and psychological distress; however, it is not a diagnostic tool and the final patient's mental health status should always be doubled by a clinical diagnostic interview. In the present study, symptoms were measured only by self-reported instruments DASS-21, IPSS, and IIEF-5.

Conclusions
We found LUTS to be correlated with depression, anxiety, and stress symptoms. Interestingly, 1/4 of men presenting for a urologic consult have concomitant depressive, anxiety, or stress symptoms. Screening for these symptoms could help with individual counseling and management as well as improve patient satisfaction.

Disclosure statement
The authors report there are no competing interests to declare.

Funding
The author(s) reported there is no funding associated with the work featured in this article.

Data availability statement
Liliana Vartolomei had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.