Abstract
Testosterone deficiency (TD) is common and impairs quality of life (QoL) in patients with chronic kidney disease (CKD). However, there are no studies about whether testosterone replacement therapy (TRT) can improve QoL in patients with CKD. Therefore, we investigated the effect of TRT on the QoL of patients with CKD and confirmed the safety of TRT. Twenty-five male patients with stages III–IV CKD whose serum testosterone levels were <350 ng/dl (TD) were enrolled and treated with testosterone gel for 3 months (group II). Age-matched controls with stages III–IV CKD and TD (group I) were recommended to exercise for the same period. Before and after the treatment, the BMI and handgrip strength were checked, serological tests were performed, and questionnaires were administered in both groups. Compared to baseline, there was no significant difference in serum testosterone levels, scores of the 36-Item Short Form Health Survey (SF-36), Aging Males’ Symptoms Scale (AMS), and International Prostate Symptom Score (IPSS), and grip strength in group I after 3 months. In group II, a significant increase in testosterone, hemoglobin (Hb), and hematocrit (Hct) was observed, and grip strength significantly increased after TRT. Significant improvement in scores of SF-36, AMS, and IPSS was also confirmed after TRT in group II. There was a significant difference in testosterone, Hb, Hct, grip strength, and scores of SF-36, AMS, and IPSS between the two groups after 3 months. The patients in group II showed positive results and continued with TRT. Therefore, we conclude that TRT safely improves the QoL and TD symptoms in patients with moderate-to-severe CKD.
Keywords
The prevalence of testosterone deficiency (TD) is reported to be 6%–9% in men in general, and it increases in men with diabetes or obesity (Hackett, 2019; Tostain, 2008). The prevalence further increases to as high as 44% in patients with severe renal function impairment, which corresponds to stage V chronic kidney disease (CKD; Carrero, 2011). According to a study conducted by the authors in 2013, TD prevalence among stage V CKD patients was up to 95% (Park et al., 2013), and patients undergoing hemodialysis presented with much more severe climacteric symptoms and lower serum testosterone levels (Park et al., 2013). The pathophysiological mechanism by which TD prevalence increases in CKD patients has not yet been clearly identified. However, it is speculated that TD may be induced by inadequate production and distribution of testosterone due to a dysfunctional hypothalamic–pituitary–gonadal axis, as CKD progresses (Dunkel et al., 1997; Schmidt et al., 2002).
Since TD prevalence is high in CKD patients in particular and symptom severity increases in accordance with the extent of renal dysfunction, as already mentioned, it is highly likely that stages III–IV CKD patients show more severe climacteric symptoms than other TD patients in general (Park et al., 2013). Moreover, because CKD can be neither cured nor improved but typically worsens over the long term, TD symptoms, too, may gradually worsen and affect quality of life (QoL) in most CKD patients. However, few attempts have been made in the past to focus on and enhance the QoL of CKD patients. Some studies have reported that regular exercise could increase QoL and physical function of CKD patients (Aoike et al., 2018; Tang & Yang, 2017); however, an attempt to improve QoL through testosterone replacement therapy (TRT) has not been tried, other than in studies in which TRT was administered for the purpose of improving hypogonadal symptoms (Inoue, 2018) or sexual function (Canguven, 2010).
Accordingly, the present study was conducted to explore the effect of TRT on QoL and investigate the safety of the therapy in patients with impaired renal function, by administering hormone therapy using testosterone gel over a relatively short term of 3 months to stages III–IV CKD patients who were diagnosed with TD.
Material and Methods
Subjects
Twenty-five male patients with stages III–IV CKD whose serum total testosterone (TT) levels were lower than 350 ng/dl with more than 1 TD symptom were consecutively enrolled in this study. The cutoff level for TT was set according to the European Association of Urology (EAU) guidelines for TD (Dohle et al., 2018). Stage III–IV CKD was defined as Modification of Diet in Renal Disease (MDRD) Study glomerular filtration rate (GFR) of 15–59 ml/min/1.73 m2. Then, age-matched 25 male CKD patients with same conditions (TD) were consecutively enrolled as controls (group I). Patients who met any of the following exclusion criteria were excluded from the study: having undergone TRT using testosterone in any form within the past 3–6 months, having been diagnosed with or treated for prostate cancer or breast cancer, a serum prostate-specific antigen (PSA) >3.0, hepatic dysfunction, thyroid dysfunction, a hematocrit (Hct) level of 50% or more, and severe sleep apnea. Patients received a full explanation of the content and purpose of the study before the trial and were enrolled after signing informed consent. Group I patients were recommended to exercise regularly and group II patients were treated with 2% testosterone gel at 60 mg/day for 3 months. Before and after treatment, body mass index (BMI), vital signs (blood pressure, heart rate, and body temperature), and hand grip strength were checked, and serological tests including hemoglobin (Hb), Hct, PSA, blood urea nitrogen (BUN), creatinine (Cr), GFR, glucose, total cholesterol, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and TT were also carried out. Self-administered questionnaires such as the 36-Item Short Form Health Survey (SF-36), Aging Males’ Symptoms Scale (AMS), International Prostate Symptom Score (IPSS), and Center for Epidemiologic Studies Depression Scale (CES-D) were also administered to the participants. SF-36, which has been widely used as the tool for estimating the QoL of CKD and hypogonadal patients (Katznelson, 2006; Lausevic et al., 2007; Santos, 2008), consisted of a total of 36 items across the following 8 sections: (a) Physical Functioning, (b) Physical Role, (c) Bodily Pain, (d) General Health, (e) Vitality, (f) Social Functioning, (g) Emotional Role, and (h) Mental Health. Two summary measures—physical and mental component summary scores—were computed based on the 36 items. Each of the summary scores was transformed into a linear scale ranging from 0 to 100 points, with higher scores indicating better QoL. For group II patients, a global assessment question (GAQ; “Do you want to continue testosterone treatment?”) was additionally asked. Electrocardiogram (EKG) was recorded before and after the testosterone treatment and side effects related to testosterone treatment were investigated.
Ethics Statement
The present study protocol was reviewed and approved by the Institutional Review Board of Seoul Paik Hospital and it complied with the Declaration of Helsinki.
Statistical Analyses
To conduct statistical analysis to examine changes in the parameters in the pre and posttreatment period and to compare between groups, Kolmogorov–Smirnov test was first performed to test for normality in distributions. Continuous variables that were confirmed to follow a normal distribution were then subjected to paired t test, independent t test, or chi-square test to test for pre- and posttreatment changes and between-group differences. Statistical significance was determined if a p value was less than .05.
Results
Twenty-three patients in group I and 22 patients in group II completed the 3-month-long therapy. Three patients who dropped out from testosterone treatment were not related to the side effects of testosterone gel. The mean age of patients was 68.54 years (55–84) in group I and 69.72 (58–86) in group II. The continuous variables among the assessment items were confirmed to follow a normal distribution. There was no significant difference between the two groups in age, comorbidities, BMI, and vital signs at baseline. There were also no significant differences in hand grip strength, scores of SF-36, IPSS, AMS, and CES-D, Hb, Hct, GFR, glucose, total cholesterol, TG, LDL, HDL, PSA, TT, and stage of kidney function between the two groups at baseline (Table 1). Compared to baseline, there was no significant difference in serum testosterone,Hb, Hct, GFR, glucose, total cholesterol, TG, LDL, HDL, and PSA levels, scores of SF-36, AMS, IPSS, and CES-D, and hand grip strength in group I after 3 months.
Comparison Between the Parameters in the Two Groups at Baseline.
Note. AMS = Aging Males’ Symptoms Scale; BMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale; GFR = glomerular filtration rate; Hb = hemoglobin; Hct = hematocrit; HDL = high-density lipoprotein; IPSS = International Prostate Symptom Score; LDL = low-density lipoprotein; PSA = prostate-specific antigen; SF-36 = 36-Item Short Form Health Survey.
In group II, testosterone level statistically significantly increased posttreatment with TRT, and hand grip strength also increased on both sides. The SF-36 score, a measure that assessed QoL, improved statistically significantly in both physical and mental components. Urinary function, assessed with IPSS, improved significantly after the 3-month-long treatment as well. The results of AMS, an assessment of hypogonadal symptoms, showed that prior to the treatment, the patients manifested moderate (AMS scores of 37–49) or severe symptoms, whereas after the treatment, mental, physical, and sexual functions all significantly improved, with the mean AMS score indicating mild symptoms (scores of 27–36). As shown in the CES-D score, depression also statistically significantly improved. Hb was also statistically significantly elevated. Regarding lipid profile, TG statistically significantly decreased, while blood glucose, PSA, GFR, and the severity of CKD did not show a statistically significant difference (Table 2).
Changes in Group II After 3 Months of Testosterone Treatment.
Note. AMS = Aging Males’ Symptoms Scale; BMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale; GFR = glomerular filtration rate; Hb = hemoglobin; Hct = hematocrit; HDL = high-density lipoprotein; IPSS = International Prostate Symptom Score; LDL = low-density lipoprotein; PSA = prostate-specific antigen; SF-36 = 36-Item Short Form Health Survey.
In comparison of the two groups at 3 months, there was a significant difference in grip strength and scores of SF-36, IPSS, AMS, and CES-D. There were also significant differences in Hb, Hct, TG, and TT. No significant difference in GFR and grade of kidney function was observed between the two groups at 3 months (Table 3). All patients in group II were satisfied and wanted to continue TRT. Five patients of group II complained of rashes or itching sensation where the testosterone gel was applied; however, they were all resolved by changing the gel application site and short-term treatment with antihistamine drugs. There was also no significant change in EKG and other cardiovascular events during the treatment.
Comparison Between the Parameters in the Two Groups at 3 Months.
Note. AMS = Aging Males’ Symptoms Scale; BMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale; GFR = glomerular filtration rate; Hb = hemoglobin; Hct = hematocrit; HDL = high-density lipoprotein; IPSS = International Prostate Symptom Score; LDL = low-density lipoprotein; PSA = prostate-specific antigen; SF-36 = 36-Item Short Form Health Survey.
Discussion
As predicted, the study findings show that stages III–IV CKD patients in the climacteric period manifested moderate-to-severe hypogonadal symptoms and experienced low QoL, but after 3-month-long TRT, scores indicative of mental and physical QoL improved significantly, and the patients expressed high satisfaction with the treatment. Moreover, male hypogonadal symptoms improved in all areas, and the level of severity decreased from moderate or severe to mild.
It is very common for CKD patients showing imbalance between protein synthesis and degradation to present with sarcopenia accompanying skeletal muscle atrophy, and sarcopenia is reported to be strongly linked to morbidity and mortality in CKD patients (Kalantar-Zadeh et al., 2013; Watanabe, 2019). Accordingly, the current study finding of significant enhancement in grip strength due to testosterone treatment suggests that from the standpoint of sarcopenia, TRT may be a useful solution in moderate-to-severe CKD patients.
Elevated serum testosterone level is known to enhance vitality, overall patient condition, and libido in a relatively early point in treatment (Ng Tang Fui & Hoermann, 2017; Park et al., 2019). A similar pattern of TRT effects was also found in patients with moderate-to-severe CKD, and the effect of TRT was confirmed in QoL improvement as well. Since CKD patients have high risk for cardiovascular events, adverse events due to this treatment should be closely observed. However, no major complications were reported in a recently conducted pilot study in which patients undergoing hemodialysis were treated with testosterone enanthate intramuscular injection, which has higher testosterone treatment–related risk (Inoue, 2018). In the present study too, major complications such as worsening renal function and cardiovascular events did not occur following TRT. With respect to renal function, there was no change in serum Cr level, GFR, and grade of renal function. No patients in group II showed significant abnormal elevation of PSA and Hct levels after testosterone treatment. Some patients only complained of mild skin rashes and itching sensation; however, none dropped out from the study due to side effects of testosterone gel. In addition, treatment compliance and satisfaction were excellent, a finding that confirms that TRT can be used to improve QoL of CKD patients.
Increased quality of physical and mental life was found to have a positive effect not only on overall male hypogonadal symptoms but also on urinary function and mood. With regard to lower urinary tract symptoms (LUTS) in CKD patients, Chen et al. (Chen, 2019) proposed bladder urothelial dysfunction, chronic inflammation, and change in sensory protein in the bladder urothelium as the mechanisms of bladder instability in patients with CKD and end-stage renal disease (ESRD). Some recent studies have reported that testosterone treatment improved LUTS (Okada et al., 2018; Yucel et al., 2017). Although more research is necessary on LUTS in CKD patients with TD, the opinion stated in the current guidelines is that in general, testosterone treatment does not greatly affect LUTS induced by BPH (Bhasin et al., 2018; Morgentaler et al., 2019).
With respect to depression, a recent study by Agrawaal et al. (2019) reported that the prevalence of depression in stage V CKD patients undergoing hemodialysis was 78%, with helplessness (82%) being the most common symptom. The present study was conducted with stages III–IV CKD patients only. However, since it is well known that depression and anxiety co-occur with TD in itself (Berglund et al., 2011), the likelihood for CKD patients with TD, like this study’s subjects, to present with depression symptoms is sufficiently high. Significant improvement in CES-D score over a short treatment duration of 3 months suggests that testosterone treatment may be a useful therapy for CKD patients complaining of depression and anxiety.
It is a well-known fact that CKD patients and those undergoing hemodialysis in particular present with anemia due to erythropoietin deficiency (Palmer, 2017). Two mechanisms by which testosterone treatment corrects anemia have been proposed. One mechanism involves increased production of endogenous erythropoietin, and the other mechanism suggests that androgens may increase the sensitivity of erythroid progenitors to the effects of erythropoietin (Gaughan, 1997). In this study, Hb and Hct were significantly elevated in group II patients, who had TRT, in comparison to group I patients, who performed exercise only. This finding suggests that although, generally, increased Hct is an adverse effect of testosterone treatment that should be observed closely, in CKD patients, Hct may be elevated for the purpose of correcting anemia.
It is reported that it takes a minimum of 3 months to a maximum of 2 years for testosterone treatment to have a significant effect, depending on the hypogonadal symptoms or relevant parameters and that testosterone treatment has a positive impact on metabolic components as well (Lunenfeld et al., 2015). Ultimately, improvement in metabolic parameters will reduce the risk of cardiovascular disease and, hence, the mortality rate. In the present study, parameters that evaluate the components of metabolic syndrome, such as BMI, glucose, and lipid profile, were not significantly improved, with the exception of TG. Even glucose levels in the testosterone treatment group showed an insignificant increase at 3 months in some patients, with poorly controlled diabetes mellitus. It is speculated that a treatment duration of 3 months may not have been long enough for improving metabolic components. Indeed, in another study conducted by the current authors, in which TRT was administered to non-CKD patients for 3 months, BMI, blood glucose, and lipid profile did not significantly change either (Cho et al., 2017). Furthermore, in group I subjects who performed exercise, metabolic components did not show changes. However, in a study where supervised exercise and diet were performed for over 1 year, metabolic components were found to improve (Heufelder et al., 2009).
The present study was conducted as a pilot study and it has a few limitations such as the following: The target population was small, TRT was administered for a short time, and the observation period after TRT was short. Additionally, muscle mass was not measured to assess the extent of sarcopenia, aside from using grip strength. Uroflowmetry, which is an objective assessment of LUTS, and prostate volume measurement (which is closely linked to LUTS) were not performed. However, the present study provided evidence that TRT can effectively enhance QoL in moderate-to-severe CKD patients without notable safety problems. In the future, research should be conducted to investigate the effect of TRT in stage V CKD and patients undergoing hemodialysis.
Conclusions
Testosterone treatment safely improves QoL as well as TD symptoms in patients with moderate-to-severe CKD and it is also expected to have a good effect on the improvement of anemia, which is also a common condition in CKD. More studies will be needed in the future to elucidate the mechanisms that underlie this beneficial effect of testosterone.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
