The effect of testosterone therapy on lower urinary tract symptoms/bladder and sexual functions in men with symptomatic late-onset hypogonadism

Abstract

Objective. To prospectively investigate the effect of testosterone therapy on lower urinary tract symptoms (LUTS)/bladder and sexual functions in men with symptomatic late-onset hypogonadism (SLOH).

Methods. The study included 25 men (age range 38 to 73 years) presented with sexual dysfunction, having SLOH, at a single university hospital. All men received testosterone replacement therapy with transdermal testosterone 50–100 mg gel per day for one year. Urodynamic studies with pressure-flow analysis, measurement of prostate volume, prostate specific antigen (PSA) and free PSA level, International Prostate Symptom Score (IPSS), Aging Male Symptom (AMS) scale and International Index of Erectile Function (IIEF-5) score were recorded in all men before and after one year of the treatment.

Results. The mean AMS score significantly decreased from 40.4 ± 7.3 to 28.8 ± 5.31 (p = 0.001), and mean IIEF-5 score significantly increased from 8.84 ± 3.76 to 14.36 ± 3.62 (p = 0.001). The mean maximal bladder capacity and compliance significantly increased (p = 0.007 and p = 0.032, respectively), and mean detrusor pressure at Qmax significantly decreased from pre-treatment to post-treatment (p = 0.017).

Conclusion. This study suggests that in addition to improvement in sexual functions, testosterone therapy may also improve LUTS/bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow in men with SLOH.

Keywords:

• Hypogonadism
• testosterone
• bladder
• sexual function

Introduction

Symptomatic late-onset hypogonadism (SLOH) is defined a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels [1]. Both the conditions of androgen deficiency and erectile dysfunction are highly prevalent medical disorders in aging men with associated multiple risk factors. Prevalence of androgen deficiency, defining testosterone level below 3 ng/ml, is 12% of 7,000 men with sexual dysfunction from 9 large series [2], varying 1.7 to 35% in different studies, depending on the study sample and design [3]. SLOH is characterized by diminished libido and erectile quality and frequency, changes in mood, sleep disturbances, decrease in lean body mass, increase in visceral fat, decrease in body hair and skin alterations, and decreased bone mineral density [1],[4].

Androgens play an important role in the physiology of erectile function, and androgen replacement therapy results in improvement in erectile functions and libido [1],[4-6]. Studies suggest that testosterone replacement therapy may promote prostate enlargement resulting in lower urinary tract symptoms. However, no clinical study has reported the effect of testosterone on LUTS/bladder functions.

The aim of this study was to prospectively investigate the effect of testosterone therapy on lower urinary tract symptom (LUTS)/bladder and sexual functions in men with SLOH.

Methods

The study included 25 hypogonadal men presenting with sexual dysfunction having SLOH at a single university hospital. The study was approved by the ethical committee of the university hospital. All men enrolled in the study were evaluated by a single physician (SÇ) with a detailed history, physical examination including a digital rectal examination of the prostate, International Prostate Symptom Score (IPSS), Aging Male's Symptoms (AMS) scale, International Index of Erectile Function (IIEF-5) score, urinary ultrasound and laboratory tests. Transrectal ultrasound was performed for measurement of prostate volume. Laboratory tests included measurement of serum testosterone, lipid profile, blood glucose, haemoglobin and haematocrit level, liver function tests, and prostate-specific antigen (PSA) and free PSA level. Blood sample for laboratory tests was taken in the early morning between 8:00 and 10:00 a.m. These laboratory tests and digital rectal examination of the prostate were repeated at three-month intervals for one year.

Men with personal or family history of prostate or breast cancer, significant polycythemia, untreated sleep apnea, severe heart failure, impaired liver and renal functions, severe symptoms of lower urinary tract obstruction were not included in the study.¹ Men who underwent transrectal ultrasound guided biopsy of the prostate for abnormal digital rectal examination of the prostate and/or elevated PSA level were not included in the study because bladder functions would be affected by the biopsy procedure. Men receiving any kind of treatment such as alpha-blockers or 5-alpha reductase inhibitors for lower urinary tract symptoms, or men receiving phosphodiesterase type 5 (PDE-5) inhibitors for erectile dysfunction were excluded from this prospective study because bladder functions would be affected by these drugs.

The study included only men with SLOH, complaining of sexual dysfunction (decreased libido and erectile dysfunction). Hypotestosteronemia was considered as serum total testosterone value of <3 ng/mL [1]. All men received testosterone therapy with transdermal testosterone (Testogel®, Bayer Schering Pharma, Germany) 50–100 mg gel per day for one year. Sexual function assessment was performed using the IIEF-5 and AMS scale at baseline and after one year of the testosterone treatment. Urodynamic studies included cystometry (maximal bladder capacity and compliance) and pressure-flow analysis. Urodynamic studies with pressure-flow analysis, measurement of prostate volume, PSA and free PSA level, IPSS, AMS and IIEF-5 score were compared in all men before and after one year of the treatment.

Statistical analyses were performed using “paired t-test” to compare total testosterone, IIEF-5 score, AMS scale, IPSS, prostate volume, PSA and free PSA level, average flow rate, maximal bladder capacity, bladder compliance, detrusor pressure at Qmax and post-voided residual volume in all men from baseline to the post-treatment. Probability values of < 0.05 were considered significant. The values are given as the mean ± standard deviation (SD).

Results

The mean age of the patients and mean duration of the sexual dysfunction were 56.5 ± 7.8 years (range 38 to 73) and 16.9 ± 8.1 months (range 12 to 42), respectively. Table I shows comparison of total testosterone, AMS and IIEF-5 scores, IPSS, measurement of prostate volume, PSA and free PSA level, average flow and urodynamic studies with pressure-flow analysis before and after the testosterone treatment.

Table I.  Comparison of total testosterone, AMS and IIEF-5 scores, IPSS, measurement of prostate volume, PSA and free PSA level, average flow and urodynamic studies with pressure-flow analysis before and after the testosterone treatment

	Pre-treatment	Post-treatment	p-value
Total testosterone (ng/ml)	2.14 ± 0.53	5.09 ± 2.13	0.001
AMS score	40.4 ± 7.3	28.8 ± 5.31	0.001
IIEF-5	8.84 ± 3.76	14.36 ± 3.62	0.001
IPSS	9.72 ± 7.52	8.16 ± 6.19	0.029
Prostate volume (cc)	25.24 ± 6.74	28.8 ± 7.01	0.001
PSA (ng/ml)	1.26 ± 0.9	1.44 ± 0.87	0.121
Free PSA (ng/ml)	0.42 ± 0.41	0.39 ± 0.38	0.067
Average flow rate (ml/sec)	19.88 ± 8.21	19.48 ± 7.2	0.499
Maximal bladder capacity (ml)	564 ± 175.9	628.6 ± 139.6	0.007
Bladder compliance (ml/cmH2O)	46.02 ± 45.89	76.4 ± 72.78	0.032
P detrusor at Qmax (cmH2O)	41.48 ± 14.92	33.72 ± 13.35	0.017
Post-voided residual volume (ml)	2.8 ± 8.9	2.8 ± 7.91	0.991

As shown in the table, the mean total testosterone significantly increased from 2.14 ± 0.53 ng/ml to 5.09 ± 2.13 ng/ml (p = 0.001). The mean AMS score significantly decreased from 40.4 ± 7.3 to 28.8 ± 5.31 (p = 0.001). The mean IIEF-5 significantly increased from 8.84 ± 3.76 to 14.36 ± 3.62 after the testosterone treatment (p = 0.001). Of the 25 patients, 23 (92%) had improvement in erectile function based on IIEF-5 score. The mean maximal bladder capacity and compliance significantly increased from 564 ± 175.9 ml to 628.6 ± 139.6 ml and from 46.02 ± 45.89 ml/cmH₂O to 76.4 ± 72.78 ml/cmH₂O, respectively (p = 0.007 and p = 0.032, respectively). The mean detrusor pressure at Qmax significantly decreased from 41.48 ± 14.92 cmH₂O to 33.72 ± 13.35 cmH₂O, revealing statistical significance (p = 0.017). Although prostate volume significantly increased from 25.24 ± 6.74 cc to 28.8 ± 7.01 cc (p = 0.001), mean IPSS significantly decreased from 9.72 ± 7.52 to 8.16 ± 6.19 (p = 0.029), and average flow rate and post-voided residual volume did not change from pre-treatment to post-treatment (p = 0.499 and p = 0.991, respectively).

Discussion

SLOH is defined as a clinical and biochemical syndrome associated with advancing age and characterized by sexual dysfunction and other typical symptoms and a deficiency in serum testosterone levels [1]. SLOH is diagnosed with a decreased sense of well-being, reduced libido and erectile function, a decrease in muscle mass, strength, energy and bone mass, and increased sweating, mood changes, fat mass, dry skin and anaemia. Testosterone replacement therapy is indicated in the presence of both clinical symptoms suggestive of hormone deficiency and decreased testosterone level [1],[5]. Although several testosterone formulations are available, testosterone topical gel and long-term depot injections are the most commonly used treatment options, due to their favourite pharmacokinetic profile characterized by relatively constant plasma levels, avoiding wide fluctuations and minimal side effects [3]. In the present study, we administered 50–100 mg of testosterone topical gel for one year, and mean testosterone level increased from 2.14 ng/ml to 5.09 ng/ml after the treatment. Testosterone therapy in men with SLOH should restore serum testosterone levels into the physiologic range. A single daily application of 50–100 mg testosterone gel can rapidly restore testosterone to physiologic levels, remaining stable for 24 hours.

Cellular and molecular mechanisms of erectile physiology by androgens include regulation of nerve structure and function, nitric oxide synthase expression and activity, PDE-5 and also regulation of cellular growth and differentiation [7]. Androgens are critical not only for regulating NOS activity, but also in modulating PDE-5 activity. Androgens have a profound effect on cellular structure and organization of the corpus cavernosum, and these alterations may contribute to the loss of erectile function [7]. Testosterone treatment improves neuropsychological function (cognition and mood), libido and sexual functioning, and enhances quality of life [4]. In a meta-analysis by Isidori et al., consisting of 17 randomized controlled trials, testosterone replacement therapy provided a significant improvement of all aspects of sexual function in men with low and low-normal testosterone level in any age [8]. Greenstein et al. reported 31 men with erectile dysfunction, receiving testosterone therapy alone for six months, and they found an improvement in sexual desire score from a mean of 4.2 to 8.6 and of erectile function from 13.6 to 27 [9]. In the present study, mean IIEF score significantly increased from 8.84 to 14.36. In addition, mean AMS score significantly decreased from 40.4 to 28.8. Testosterone replacement therapy alone may be insufficient to restore erectile function in every case, since erectile dysfunction is often multi-factorial in aging men [2]. In addition, testosterone therapy may have more significant effects on libido than on erectile function [10]. Beneficial effects of combination therapy with PDE-5 inhibitors to improve erectile functions have been reported in patients with co-morbid conditions. However, in this prospective study, we did not include combination therapy of testosterone and PDE-5 inhibitors, because bladder functions would be affected with these drugs.

Prostate volumes have been reported to increase with testosterone replacement therapy, and therefore obstructive BPH has been reported as a contraindication [5]. However, testosterone replacement therapy does not appear to cause a rapid increase in prostate size or to be associated with the development of benign prostatic hyperplasia [11,12]. In the present study, prostate volume significantly increased from mean of 25.24 cc to mean of 28.8 cc. However, mean IPSS significantly decreased from 9.72 to 8.16, and mean average flow rate and post voided residual volume did not change.

PSA levels are dependent on natural testosterone levels, and are correlated with the risk of prostate cancer [13]. Monitoring PSA therefore provides the safety of administering exogenous testosterone. An increase in PSA (the velocity) of > 1 ng/ml in the first six months of therapy or > 0.4 ng/ml/year while on therapy is an indication for stopping the treatment and obtaining a prostate biopsy [14]. Although testosterone replacement therapy in men with SLOH has been reported to be associated with a minor PSA elevation [15], available data support the safety of testosterone replacement therapy in the short term [16]. Gerstenbluth et al. investigated PSA changes in hypogonadal men treated with testosterone, and mean PSA level significantly increased with a mean follow-up of 30.2 months [15]. In another study, Wang et al. treated 163 hypogonadal men with 1% testosterone gel for up to 42 months, and during this time, the mean PSA level remained within the normal range for the majority of patients [17]. A recent article found no evidence of an increased prevalence rate of prostate cancer in a total of 461 men, receiving testosterone replacement therapy, followed for 6–36 months [14]. Finally, in a recent randomized controlled trial, Marks et al. investigated effect of testosterone replacement therapy on prostate tissue in men with LOH, and no treatment related change was observed in prostate histology, tissue biomarkers (androgen receptor and gene expression) or cancer incidence or severity [18]. In addition, they found minor treatment-related changes in prostate volume, serum PSA level, voiding symptoms and urinary flow. In the present study, we found no significant changes in PSA and free PSA levels. Similarly to our study, Yassin and Saad reported improvement of sexual desire in all men, but improvement of erectile function in 12 of 22 men with late-onset hypogonadism treated with testosterone only, and they found no significant changes in serum PSA or prostate volume [6]. Hwang et al. evaluated combined therapy with testosterone and sildenafil in 32 hypogonadal men not responding to sildenafil, based on the variables of the IIEF, IPSS, and urinary flow rate [19]. While the IIEF score significantly increased, there were no statistical differences for the IPSS or urinary flow rate.

Androgen deprivation may inhibit the smooth muscle differentiation pathway. Androgens, through the activation of androgen receptors, may stimulate stromal precursor cells to differentiate into smooth muscle cells [7]. Such studies have not been performed in bladder tissue. Androgens also regulate growth and differentiation of vascular smooth muscle cells. In the literature, although the effect of testosterone therapy on prostate related symptoms has been studied, no clinical study has investigated the effect of testosterone treatment on LUTS/bladder functions. In the present study, we performed a urodynamic study with pressure-flow analysis before the treatment as baseline and at one year of the treatment. We found significant increases in maximal bladder capacity (from mean of 564 to 628.6 ml) and bladder compliance (from mean of 46.02 to 76.4 ml/cmH₂O), and significant decrease in detrusor pressure at maximal flow (from mean of 41.48 to 33.72 cmH₂O). Our findings suggest that testosterone replacement therapy in men with SLOH may significantly improve bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow. Our clinical findings confirm the findings of a recent male rabbit study showing that after the injection of testosterone, bladder capacity and compliance increased with high blood testosterone levels in male rabbits undergoing bilateral orchiectomy [20]. There can be increased rho-kinase activity, and consequently calcium sensitivity of the contractile machinery in prostate and bladder smooth muscle in bladder outlet obstruction, in corpus cavernosum in erectile dysfunction [21]. One possible explanation for the improvement of LUTS/bladder functions would be that testosterone therapy may also alleviate pelvic ischaemia by increasing nitric oxide synthase expression and activity as well as reducing rho-kinase activity in bladder and prostate smooth muscle.

There is evidence suggesting that hypogonadism is a risk factor for unfavourable changes in high-density lipoprotein cholesterol, and coronary artery disease [22]. In the present study, we observed no significant changes in lipid profiles between baseline and at one year of the treatment. Testosterone therapy may also significantly increase red blood cell and haemoglobin levels [23]. We did not need dose adjustments or discontinuation of the testosterone treatment due to polycythaemia or hyperlipidemia during the treatment.

Conclusions

This study suggests that in addition to improvement in sexual functions, testosterone therapy may also improve LUTS/bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow in men with SLOH. However, the longer-term effects on lower urinary tract system such as bladder and prostate are yet to be determined.