Abstract
Objective: We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia.
Methods: From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n = 31) and controls (n = 33), were included in this analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups.
Results: At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group.
Conclusions: Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.
Introduction
It is well known that serum testosterone levels decrease with age by 2–3% annually in men, and this is associated with specific symptoms, namely late-onset hypogonadism (LOH) syndrome [Citation1]. The clinical signs of LOH syndrome are widely recognized and include decreased libido and sexual desire, muscle weakness and increased visceral fat, obesity, osteoporosis, anemia and deterioration of insulin resistance [Citation1–3]. Testosterone replacement therapy (TRT) improves many of the LOH-associated symptoms and conditions, and its clinical use has increased substantially over the past several years.
On the other hand, concomitant with this progressive decline in testosterone concentrations after 50 years, prostate volume has gradually increased, as reflected by the appearance of lower urinary tract symptoms (LUTS). The incidence of LUTS increases with aging, with an overall prevalence >50% in men aged > 50 years. In particular, nocturia is a common symptom of LUTS in elderly men and has a pronounced impact on sleep conditions and quality of life (QOL) and general health [Citation4]. When nocturnal awakenings occur two or more times, nocturia is correlated with a 10–21% increased risk of falling, limb fractures, excessive daytime somnolence and nocturnal enuresis [Citation5]. Moreover, nocturia can lead to increased mortality among elderly men even after adjusting for several possible contributing co-morbidities and lifestyle factors [Citation6]. Nocturia is generally caused by various factors, such as decreased bladder volume capacity, increased nocturnal urine volume, congestive heart failure, diabetes mellitus, chronic kidney disease, sleep disorder, bladder storage disorder and aging. To improve QOL in the patients with nocturia, this symptom is generally addressed by restricting night-time water intake, in addition to treatment with medications, such as α1-blockers, anticholinergic drugs, desmopressin and drugs to induce sleep, among others. However, a recent report demonstrated that nocturia treatment only reduced nocturnal voiding frequency without improving QOL [Citation5].
Recently, it was reported that testosterone deficiency was also closely linked with the development of LUTS [Citation7], and some clinical trials demonstrated that TRT contributed to the improvement of LUTS in men with LOH syndrome and benign prostatic hyperplasia [Citation8,Citation9]. Furthermore, testosterone itself has been reported to be potentially correlated with the circadian rhythm and sleep quality. Low testosterone may affect overall sleep quality, which may be improved by TRT [Citation10–12]. Therefore, there may be an association among nocturia, testosterone deficiency, LUTS and sleep disorders.
We recently conducted a randomized controlled study (EARTH study) to evaluate the effects of long-term TRT on the physical and mental statuses of hypogonadal men in Japan [Citation13]. This previous study demonstrated that TRT contributed to a significant decrease in waist circumstance and serum triglycerides, a significant increase in muscle mass volume and serum hemoglobin, and some degree of improvement in erectile function and QOL among 334 hypogonadal Japanese men, which were randomly assigned to the TRT group (n = 169) and control one (n = 165). In this study, we conducted a subanalysis of the EARTH study population to investigate the effects of TRT on nocturia and QOL among men with hypogonadism and nocturia.
Methods
Study subjects
From the EARTH study population, we included hypogonadal patients with a clinical diagnosis of nocturia in this study. A biochemical diagnosis of hypogonadism was made based on the Japanese biochemical criteria as follows: free testosterone (FT) ≤8.5 pg/ml (TRT is the first choice of treatment for hypogonadism) and FT 8.5–11.8 pg/ml (TRT is a relative choice) [Citation14]. Some of the guidelines used overseas base the diagnosis of LOH syndrome on the level of serum TT or calculated FT value. The measurement of the sex hormone binding globulin has not been approved by health insurance companies as a biochemical diagnostic indicator in Japan, and therefore, it is not commonly used. A large epidemiological study found that the FT value, but not TT value, showed a significant correlation with age among Japanese men [Citation15]. In addition, favorable correlations between calculated FT and analog FT values have been shown [Citation15,Citation16]. Thus, the Japanese guideline for the management of LOH syndrome recommends the use of the FT value to establish the diagnosis.
The International Continence Society defines nocturia as “the complaint that the individual has to wake at night one or more times for voiding” [Citation17]. However, most people seek clinical treatment for severe nocturia, when the awakenings for voiding are as frequent as two or more times per night and are generally associated with a decreased health status and QOL. Therefore, in this study, nocturia was defined as the need to wake at night more than two times for voiding [Citation5,Citation6].
In the EARTH study, patients with prostate cancer, prostate-specific antigen (PSA) level ≥ 2.0 ng/ml, sleep apnea syndrome, severe chronic kidney disease, unstable chronic heart disease, severe hypertension (systolic blood pressure ≥180 mmHg), polycythemia (hemoglobin ≥18.0 g/dl), mental illness history requiring regular psychotropic medication, administration of testosterone, or anti-androgenic agents within 6 months were excluded. Additionally, we also excluded patients with history of pelvic surgery or definite neurogenic disorders in this study. All the medications associated with voiding or storage functions of lower urinary tract, such as α-1 blockers and anticholinergic agents, remained unchanged in the study period. Patients who underwent dosing changes or were prescribed additional medications were excluded from this analysis. Patients under treatment for any sleeping disorders were not eligible to participate in this study.
The study protocol was approved by Kanazawa University Hospital Institutional Review Board, and all subjects gave informed written consent before participation in the study. Data of 31 hypogonadal patients with nocturia that received TRT for 6 months were extracted, and that of 33 men, without TRT, who met the same inclusion criteria were comparatively selected as a control group.
Protocol
Initially, a complete medical history and physical examination were obtained before patient enrollment in the study. Additionally, all participants underwent general blood tests, including TT and FT value measurements. FT value was measured in the serum obtained from blood samples collected from each patient between 8:30 am and 10:30 am. Serum samples were stored at −20 °C until the assay was performed. FT values were measured by radioimmunoassay, using the DPC Free Testosterone Kit (Mitsubishi Kagaku, Tokyo, Japan). Additionally, all patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score, and Short Form-36 (SF-36) health survey at baseline and 6-month visit.
The TRT group received intramuscular testosterone enanthate (250 mg; Enarmon Depot; ASKA Pharmaceutical Co., Ltd., Tokyo, Japan) intramuscular injection every 4 weeks.
Frequency of nocturnal voiding was evaluated by IPSS question no. 7 as a primary end point. The secondary end points were set as the changes from baseline in IPSS, AMS and SF-36. Sleep quality was estimated by question no. 4 of the AMS score as follows: difficulty in falling asleep, difficulty in sleeping through, waking up early and feeling tired, poor sleep and sleeplessness. Changes in these variables from baseline to the 6-month visit were compared between the TRT and control groups.
Statistical analysis
The background data of each group were compared using the Mann–Whitney test. For each group, the changes in parameters were compared by the Wilcoxon's signed rank test, and changes from baseline were evaluated using the unpaired t-test. All statistical analyses were performed using SPSS™ version 17.0 Medical Model (SPSS Inc., Chicago, IL). In all analyses, p < 0.05 was considered as statistically significant.
Results
The characteristics of the patients in both groups are summarized in . Patients in the TRT and control groups had a mean [standard deviation (SD)] age of 69.5 ± 6.5 and 72.1 ± 8.0 years, respectively. Mean (SD) FT values were 7.18 ± 1.70 and 6.95 ± 1.72 in TRT and control groups, respectively. Patients in the TRT and control groups had a nocturnal voiding frequency of 2.6 ± 0.8 and 2.6 ± 0.8, respectively. There were no statistically significant differences between these two groups in any of the baseline characteristics.
Table 1. Patient characteristics.
At the 6-month visit, the score of IPSS question no. 7 (frequency of nocturnal voiding) was significantly decreased in the TRT group (from 2.6 ± 0.8 to 2.0 ± 0.7; p = 0.0237), whereas a significant increase was observed in the control group (from 2.6 ± 0.8 to 2.8 ± 0.8; p = 0.0289; ). The score AMS question no. 4, which indicates “sleep quality”, also improved significantly from 2.6 ± 0.8 to 2.3 ± 0.9 (p = 0.0355), with improving nocturia among the patients in the TRT group. However, there were no significant changes for this score in the control group. There were no significant changes in the total AMS score, total IPSS and each IPSS subscore, excluding question no. 7 from baseline to the 6-month visit among both groups.
Table 2. Comparison of changes before and after TRT in both groups.
Regarding the evaluation of QOL, TRT contributed to a significant improvement in SF-36 score in role limitation because of health programs (RP), vitality (VT), mental health (MH) domains, and led to a slight but not significant improvement in the role limitation because of health programs (RE) domain. Control patients had no significant changes in any other category of the SF-36 ().
Table 3. Comparisons of changes from baseline to 6-month visit between TRT and control groups.
Comparisons of changes from baseline to the 6-month visit between TRT and control groups also showed significant differences in IPSS question no. 7 (−0.61 ± 0.79 versus 0.37 ± 0.89; p ≤ 0.001), AMS score question no. 4 (−0.30 ± 0.86 versus 0.07 ± 0.68; p = 0.024), RP domain (3.3 ± 10.5 versus −0.9 ± 5.6; p = 0.0367) and MH domain of the SF-36 (2.6 ± 10.3 versus −0.3 ± 8.7; p = 0.0411). There were no significant differences in changes from baseline to the 6-month visit in the total AMS score, total IPSS and SF-36 domain, except for RP and MH in both groups.
None of the patients enrolled in this study discontinued the study because of any adverse effects, such as polycythemia, worsening of urinary symptoms, sudden elevation of serum PSA value or the development of sleep apnea syndrome.
Discussion
The previous EARTH study to investigate the effects of TRT on health and prolong active lifestyles among 334 Japanese aging men with LOH syndrome demonstrated that TRT significantly affected physical functioning (PF) subdomain of SF-36 (p = 0.0318) [Citation13]. In addition, TRT could also contribute to significant decreases in waist circumstance (p = 0.002) and serum triglyceride (p = 0.013), and to significant increases in whole-body muscle mass volumes (p = 0.071), serum hemoglobin (p < 0.001), IPSS voiding score (p = 0.0418) and the second question on IIEF-5 (p = 0.0049). Overall, there was no significant difference between TRT and control groups in IPSS, AMS score and any other subdomain of SF-36. On the other hand, some detailed analysis regarding the effects of TRT on IPSS-subscores and AMS-subdomains has been not shown in the EARTH study.
This study results showed that TRT could reduce frequency of nocturnal voiding (IPSS question no. 7 score) and sleeping nuisance (AMS-4 score) among hypogonadal men with nocturia, who were extracted from the EARTH study population. One of the reasons may be that TRT had a direct beneficial effect on LUTS for men with nocturia. Nocturia, including nocturnal frequency and nocturnal polyuria, is commonly prevalent among elderly men with LUTS and can result in decreased quality of sleep, which has a negative effect on daytime activities [Citation18,Citation19]. Some recent studies have suggested that testosterone may be associated with lower urinary tract functions in men. Androgen receptors are widely distributed in the urothelium, urinary bladder, prostate and urethra. Testosterone presumably exerts an effect on the autonomic nervous system, bladder smooth muscle differentiation, nitric oxide synthase, phosphodiesterase-5 and Rho/Rho-kinase activities and pelvic blood flow [Citation20]. Indeed, some recent studies have shown that TRT improved LUTS in hypogonadal men [Citation8,Citation9,Citation21]. Amano et al. [Citation9] reported that TRT, by application of testosterone ointment during 3 months, contributed to increase the serum testosterone levels and was effective in improving LUTS and nocturia in 41 patients with LOH syndrome. Karazindiyanoğlu et al. [Citation21] found that TRT with transdermal testosterone gel (50–100 mg) per day for 1 year in 25 men with LOH syndrome improved IPSS with an increase in maximal bladder capacity and compliance. Furthermore, our previous randomized controlled trial indicated that TRT for 1 year could be effective in improving LUTS and increasing the maximum flow rate and voided volume among hypogonadal men with mild benign prostatic hyperplasia [Citation8]. These findings suggest that a decline in frequency of nocturnal voiding by TRT could contribute to better sleeping conditions in this study.
However, we found no significant changes in any other subscores of IPSS, excluding IPSS question no. 7. Our study included a population with relatively moderate LUTS, with the average scores of 14.7 and 14.8 in the TRT and control groups. Additionally, the chief compliant of these patients was nocturia and not voiding symptoms. Furthermore, the patients with benign prostatic hyperplasia were not entirely the target of our study population. Thus, further studies, including a large number of patients with various LUTS, should reach more definitive conclusions.
Another explanation is that TRT could have a direct positive effect on sleep quality and sleep disorders. Sleep disorders are also significantly correlated with nocturia [Citation22]. It is known that testosterone has an important impact on sleep [Citation10,Citation23–25]. Actually, some categories of the AMS score are associated with a sleep condition and are commonly used for screening specific symptoms of LOH syndrome. A previous study demonstrated that men aged ≥65 years with lower testosterone level had a reduction in sleep efficiency and nonrapid eye movement (non-REM) sleep and had increased nocturnal awakenings [Citation23]. Experimental data indicated that the quality and quantity of non-REM sleep were reduced considerably in mice lacking of testosterone after gonadectomy, which could be recovered by TRT [Citation24]. Another study found that healthy young men with high endogenous testosterone levels could have increased sleepiness after 5 d of sleep restriction compared with those with low testosterone levels [Citation25]. Testosterone itself is likely to play a role in sleep, especially in hypogonadal men. Therefore, improved sleep conditions as a result of TRT may have a favorable effect on nocturia.
An alternative mechanism may possibly be the effect of testosterone, to a certain extent, on the urine concentrating ability of the kidneys. Testosterone has been reported to play a physiological role in the maintenance of vasopressin and in the normal urinary concentrating ability of the kidneys [Citation26–28]. In contrast, the serum d-arginine-vasopressin concentration was decreased in male rats after orchiectomy but increased after TRT [Citation26]. Another previous report indicated that the number of vasopressin-binding sites of the kidney that were decreased by aging could be restored by TRT in male rats [Citation27]. Moreover, Ikeda et al. [Citation28] studied vasopressin concentrations by hypertonic saline infusions in hypogonadal men and concluded that TRT improved the subnormal vasopressin response in aging men with hypogonadism. However, this study was limited by the lack of assessment of urine concentration disorders at night time with a voiding diary. Further studies are likely to be required to warrant this hypothesis.
The psychological and physical stresses caused by sleep disorders due to nocturia may lead to decreased endogenous testosterone secretion. A few previous reports suggest that nocturia may induce testosterone deficiency. Kim et al. reported that storage symptoms of IPSS were significantly associated with total testosterone level, and testosterone was significantly decreased in patients with four or more episodes of nocturia [Citation29]. Another study reported that serum TT level was significantly associated with a frequency of nocturia of two or more times per night. Furthermore, men with serum TT levels in the greatest quartile had a 44% reduced risk of nocturia compared with those in the lowest quartile [Citation30]. Furthermore, TT levels were significantly increased in men with low TT levels that were probably attributed to nocturia treatment using desmopressin [Citation31]. Therefore, nocturia may also affect QOL indirectly by decreasing testosterone levels in elderly men.
We found that some domains of SF-36, such as RP, VT and MH domains, in addition to IPSS question no. 7 and AMS question no. 4, were improved by 6-month TRT in hypogonadal men with nocturia. TRT is a widely accepted tool to improve many of the LOH-associated symptoms and conditions, and thus, the 6-month TRT had a direct impact on improvement of QOL as shown in this study. However, our study population had mild hypogonadal symptoms with a low score of AMS at baseline, and there were no significant changes in AMS after 6 months of TRT. Nonetheless, these findings suggest that the improvement of nocturia may have a potential effect on the QOL of our study participants. Nocturia causes daytime drowsiness and reduces daytime activities that can lead to depression [Citation18,Citation19], which is consistent with our findings that the TRT group had a significant improvement in the categories of RP, VT and MH of the SF-36 together with the improvement of nocturia and sleep conditions.
In conclusion, TRT during 6 months may improve nocturia and sleep conditions in hypogonadal men with nocturia and may contribute to the enhancement of their QOL.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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