Beneficial effects of testosterone administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: A pilot study

Abstract

Introduction. Elderly men are bothered by lower urinary tract complaints designated as lower urinary tract symptoms (LUTS). In epidemiological studies LUTS appears strongly associated with erectile dysfunction, and also with metabolic syndrome. LUTS occurs at an age at which plasma testosterone levels decline, in some men to hypogonadal values.

Objectives. This pilot study tested whether testosterone administration to elderly men complaining of LUTS and whose plasma testosterone levels are below normal, might alleviate LUTS.

Methods. Group 1 (n = 10) received treatment with testosterone gel (50 mg) daily for three months; group 2 (n = 20) received treatment with injections of testosterone undecanoate 1000 mg for 26 weeks.

Results. Upon these interventions, plasma testosterone increased to the normal range. Symptoms of LUTS, measured by the International Prostate Symptoms Score, improved significantly, and also scores of the Aging Males’ Symptoms scale and international index of erectile function improved. There were no untoward effects on the prostate over this period of time of the study.

Conclusion. Testosterone administration improved symptoms of LUTS in men with late-onset hypogonadism. The mechanism of action is as yet not understood, but it may be connected with or parallel with the effects of testosterone on penile tissues in hypogonadal men, such as on nitric oxide and phosphodiesterase.

Keywords:

• Testosterone
• late-onset hypogonadism
• LUTS
• erectile function
• Aging Male Symptoms scale

Introduction

Many aging men experience voiding problems which originate from two categories: 1) irritative: ranging from nocturia, increased frequency of micturition, urgency, hesitancy, and/or 2) obstructive: such as poor stream, postmicturition dribbling, loss of bladder control resulting in incontinence, and retention. ‘Narrowing’ or obstruction of bladder neck and/or prostatic urethra may be either static, based on mechanical obstruction due to prostate enlargement, or dynamic, due to spasms or constrictions of bladder neck caused by the increase of the stroma or collagen compartment leading to higher expression and activity of alpha-adrenoceptors [1]. This results in vaso-constriction and local ischemia. Many of these complaints were previously referred to as ‘prostatism’. But these complaints may not be caused by disease of the prostate itself and, therefore, now the umbrella term ‘lower urinary tract symptoms’ (LUTS) is preferred to describe these voiding problems. LUTS may have a considerable impact on quality of life of the patient. The degree of bothersomeness rather than the objective magnitude of LUTS, is the indication for diagnostic and therapeutic interventions.

Population studies show a frequency of moderate to severe LUTS from 8–31% in men in their fifties, increasing to 27–44% of men in their seventies. But many men experience symptoms of LUTS much earlier in life [1].

Several symptom scores have been developed as tools to quantify LUTS. The best known is the International Prostate Symptoms Score (IPSS) [2-4] produced by task forces of the American Urological Association. The specificity is rather low because of the non-specificity of LUTS itself as a complaint. The IPSS has therefore been criticized as lacking specificity, and for lacking usefulness for screening, and for not including symptoms such as dribbling and incontinence. Therefore, bothersomeness and disease-specific or non-specific quality of life indices have been added as tools in the management of LUTS and benign prostate hypertrophy [5]. Drug treatment is often helpful. A study in six European countries reported an improvement of LUTS/BPH of drug treatment over watchful waiting [6].

Aging is characterized by a progressive decline of virtually all physiological functions. Among them is the secretory capacity of the endocrine glands. Several studies in men show that testosterone, particularly free, bioactive levels of testosterone, decline with aging, though there is considerable inter-individual variation [7]. LUTS occurs in elderly populations at an age when serum testosterone levels are declining.

Apart from their obvious reproductive and sexual functions, androgens have a large number of non-reproductive effects; they are important anabolic factors in the maintenance of muscle mass and bone mass and in non-sexual psychological functioning [7-9]. The decline in plasma testosterone levels and the emergence of LUTS largely coincide in the lives of men. Yet their interrelationship has only been recently investigated [10]. Several community-based studies have reported a statistically significant association between LUTS and erectile dysfunction (ED) [11-13]. Furthermore, recent studies have suggested that benign prostate hyperplasia (BPH) and LUTS are components of metabolic syndrome and that BPH and LUTS patients may share the same metabolic abnormalities as patients with metabolic syndrome [14-16]. These interrelationships suggest that features of metabolic syndrome, particularly in association with testosterone deficiency result in microanatomical changes leading to tissue fibrosis and loss of elasticity, explaining the lower urinary tract symptoms often encountered in testosterone-deficient men.

This pilot study tested whether administration of testosterone to elderly men with lower-than-normal testosterone levels and LUTS improved their symptoms.

Study methods

30 men, mean age 51 years (range 41–65) with clinical and biochemical symptoms of late-onset hypogonadism (LOH) as well as symptoms of LUTS were included in the study. Their plasma testosterone levels at inclusion were below10.8 nmol/L and considered subnormal. Seventy per cent of the men had received drug treatment for LUTS, but largely unsuccessfully. At the time of the inclusion of the study patients were not using medications for LUTS (such as alpha-adrenergic blockers or anticholinergic drugs). Exclusion criteria were pathologies associated with impairment in androgen secretion or action, such as hyperprolactinemia, hyper/hypothyroidism, liver and renal insufficiency, as well as contraindications to testosterone therapy, such as prostate cancer, male breast cancer, benign prostate hyperplasia with symptoms of static infravesical obstruction. All patients had given their informed consent to participate in this study which was approved by the institute's ethical review board on investigations in humans.

There were two groups of patients: group 1 (n = 10) received treatment with testosterone gel (Androgel®/Testogel®) (50 mg) daily; group 2 (n = 20) received treatment with testosterone undecanoate (Nebido®) for 26 weeks. Resulting plasma testosterone levels are usually higher with parenteral testosterone undecanoate than with testosterone gel [17] and this allowed, to a degree, assessment of dose-response effects.

Erectile function was assessed with the International Index of Erectile Function (IIEF-5). The scale measures the effects of interventions. The Aging Males’ Symptoms (AMS) scale was used which has been designed and standardized as a self-administered scale (a) to assess symptoms of aging (independent from those which are disease-related) between groups of males under different conditions, (b) to evaluate the severity of symptoms over time, and (c) to measure changes pre- and post-androgen therapy [18]. The International Prostate Symptoms Score (IPSS) was used to measure effects of the intervention on LUTS.

It was analysed whether there was a relationship between severity of LUTS on the one hand and baseline testosterone values and AMS scores on the other. Results are expressed as median and quartile range. The quartile range of a variable is calculated as the value of the 75th percentile minus the value of the 25th percentile. Thus it is the width of the range about the median that includes 50% of the cases.

Statistical analysis was done with STATISTICA (StatSoft Inc. USA, version 6.0) software. Wilcoxon matched pairs test was used to compare two dependent samples. Mann-Whitney U-test was used to compare two independent samples.

Correlation analysis was performed using the Spearman correlation test. A p-value <0.05 was considered to be statistically significant.

Results

Results are presented in Tables IIII. Characteristics of patients in groups 1 and 2 were similar (Table I). Before testosterone administration, plasma total testosterone and sex hormone binding globulin (SHBG) levels and scores were similar in the two groups. As a result of the intervention, plasma testosterone levels rose in both groups to levels within references values (11–33 nmol/L) but plasma levels of testosterone were higher in the group receiving parenteral testosterone undecanoate than testosterone gel (p < 0.05) (Tables II and III). Following the intervention there was a significant improvement of the LUTS assessed with the IPSS. The same was true for the AMS and the IIEF-5. The improvements in scores of the AMS, the IPSS and the IIEF-5 were not significantly different between the groups treated with parenteral testosterone undecanoate and testosterone gel. No relationship between severity of LUTS and baseline testosterone values or AMS scores could be demonstrated in these rather small numbers of men. There was no significant change in prostate volume during administration of testosterone with either type of treatment modality, notably no increase (Table II), and, remarkably, plasma prostate-specific antigen (PSA) levels decreased (Table II).

Table I.   Characteristics before treatment. Results are expressed as median and quartile range.

Parameters	Group 1 (n=10) T gel	Group 2 (n=20) TU	p
Age	43.5 (39.0–54.0)	53.5 (43.5–66.0)	0.3
AMS score	40.0 (34.0–44.0)	39.5 (35.0–44.0)	0.86
IPSS score	12.0 (9.0–19.0)	11 (8–18.5)	0.66
Irritative symptoms (questions 2,4,7)	7.5 (6.0;11.0)	5.5 (2.0;10.0)	0.1
Obstructive symptoms (questions 1,3,5,6)	4.5 (3.0;7.0)	5.5 (5.0;7.5)	0.17
Nocturia	2.5 (1.0;4.0)	2.0 (1.0;3.0)	0.54
IIEF-5 score	12.0 (2.0–15.0)	14.5 (6.0–18.0)	0.3
Total testosterone level (nmol/L)	6.65 (5.6–9.4)	8.3 (5.7–10.8)	0.5
Calculated free testosterone level (pmol/L)	139.5 (115.0–161.0)	149.5 (115.5–177.0)	0.57
SHBG (nmol/L)	30.2 (25.6–40.9)	34.3 (27.05–53.2)	0.32
total PSA (pg/mL)	0.85 (0.5–1.5)	0.65 (0.4–1.21)	0.4

Table II.   Results of treatment in group 1 treated with Tgel during 26 weeks of treatment. Results are expressed as median and quartile range.

	Before treatment	16 weeks	26 weeks	p
AMS score	39.5 (35.0–44.0)	30.5 (22.0–36.0)	23.5 (20.0–25.5)	<0.00001
IPSS score	11 (8–16.5)	6.0 (3.0–7.5)	4.0 (1.5–7.0)	<0.00001
Irritative symptoms (questions 2,4,7)	5.5 (2.0;10.0)	4.0 (2.0;5.0)	2.0 (1.0;4.0)	<0.001
Obstructive symptoms (questions 1,3,5,6)	5.5 (5.0;7.5)	2.0 (1.0;3.0)	1.0 (0.0;2.0)	<0.001
Nocturia	2.0 (1.0;3.0)	1.5 (1.0–2.0)	0.5 (0.0;1.0)	<0.001
IIEF-5 score	14.5 (6.0–18.0)	17.5 (12.5–24.0)	22.5 (19.5–24.0)	<0.016
Total testosterone level (nmol/l)	8.3 (5.7–10.8)	13.05 (9.9–16.0)	17.05 (15.2–20.7)	<0.00001
Calculated free testosterone level (pmol/l)	149.5 (115.5–177.0)	244 (176–291)	382 (320.5–469.0)	<0.00001
SHBG (nmol/l)	34.3 (27.05–53.2)	38.8 (27.1–55.5)	30.2 (35.2–34.3)	0.76
Total PSA (pg/ml)	0.65 (0.4–1.21)	0.60 (0.4–1.25)	0.68 (0.4–1.3)	0.08

Table III.   Parameters during treatment in group 2 treated with TU injections. Results are expressed as median and quartile range.

	Before treatment	26 weeks of treatment	p
AMS score	40.0 (34.0–44.0)	24.0 (20.0–25.5)	0.004
IPSS score	12.0 (9.0–19.0)	6.5 (3.0–11.0)	0.004
Irritative symptoms (questions 2,4,7)	7.5 (6.0;11.0)	3.5 (2.0;7.0)	0.005
Obstructive symptoms (questions 1,3,5,6)	4.5 (3.0;7.0)	3.0 (1.0;4.0)	0.018
Nocturia	2.5 (1.0;4.0)	1.0 (0;2)	0.005
IIEF-5 score	12.0 (2.0–15.0)	19.5 (16.0–22.0)	0.004
Total testosterone level (nmol/l)	6.65 (5.6–9.4)	19.5 (16.7–21.7)	0.005
Calculated free testosterone level (pmol/l)	139.5 (115.0–161.0)	441.5 (387–524)	0.004
SHBG (nmol/l)	30.2 (25.6–40.9)	30.15 (25.6–33.8)	0.4
total PSA (pg/ml)	0.85 (0.5–1.5)	0.80 (0.5–1.4)	0.9

Discussion

This pilot study tested whether normalization of plasma testosterone levels in men suffering from clinical signs of LOH, substantiated by laboratory evidence of lower-than-normal testosterone levels, would potentially experience an improvement of LUTS. LUTS is a complex of complaints which are bothering a substantial number of elderly men, in a period in their lives when plasma testosterone levels decline. Our study confirms this assumption. There is preliminary evidence that men with LUTS benefit from treatment with testosterone, so far only in the form of abstracts awaiting peer-reviewed publication. Early data appearing on this subject have shown that normalization of testosterone levels has a positive effect on LUTS in men with BPH and late-onset hypogonadism [19]. A recent presentation confirmed the positive effects of testosterone treatment on bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow in men with SLOH [20]. The results of pilot studies [21],[22] also showed positive effects of testosterone undecanoate therapy on LUTS in men with LOH. If indeed testosterone treatment improves symptoms of LUTS, this would benefit patients since pharmacological treatment of LUTS (α1-adrenergic receptor antagonists and 5α-reductase inhibitors) often leads to sexual complaints [23]. And testosterone appears to have a wide range of effects in hypogonadal elderly men, such as on features of metabolic syndrome, mood, erectile function and anabolic effects on muscle and bone.

It is not yet possible to identify the pathophysiological basis of the intervention, but androgen receptors have been found to be present to a large extent in the epithelial cells of the urethra and bladder [24]. In another study the role of testosterone and its metabolites on maintaining the reflex activity in the pelvic part of the autonomic nervous system could be demonstrated [25]. Others have postulated the influence of testosterone on postsynaptic non-genomic receptors which are suppressing detrusor activity [26],[27]. Not only the penis but also in other parts of the urogenital tract, nitric oxide (NO) acts as a non-adrenergic non-cholinergic neurotransmitter in the urogenital tract, and the action of testosterone on the urogenital tract may be mediated by this system [28] In nNOS-deficient mice, testosterone administration decreased urinary frequency [29]. Studies treating one condition (e.g. ED) and measuring the impact on the other (e.g. LUTS) should further contribute to support this common link [30]. But as yet it is not possible to provide a comprehensive picture of the impact of androgen (and its deficiency) on the lower urinary tract.

Admittedly, our study was not blinded and not placebo-controlled but was directed to explore this issue. Naturally, methodologically more rigorous studies should be undertaken to test this challenging and clinically relevant question further. The men in our study were not suffering from a severe degree of LUTS (IPSS scores between 6 and 19, average 11–12). The groups were, unfortunately, too small to allow a sub-analysis of men with the higher scores. In this study, our treatment appeared to have no negative effect on prostate volume and on PSA levels. Other interventional studies of longer duration have not unveiled untoward effects on the prostate, reviewed in [30],[31], so there are no immediate concerns regarding testosterone administration to elderly men.