Lower urinary tract symptoms following discontinuation of long-term non-medical use of testosterone preparations

INTRODUCTION

The aging process in men is accompanied by a progressive decrease in serum testosterone (Ts) level [1][2]. In addition to chronological aging, various somatic diseases (diabetes mellitus, arterial hypertension, obesity, etc.) and some pharmacological drugs used to treat these conditions (atenolol, anapriline, verospiron, hypothiazid, etc.) contribute to a decline in circulating Ts levels [2–6]. In eugonadal men, transitory hypogonadotropic hypogonadism can develop because of any severe acute disease or injury [7][8]. In addition, harmful habits (smoking, drug addiction, alcohol abuse) and eating behavior (from malnutrition to obesity) increase age-related decrease in androgen levels. For these reasons, diseases associated with Ts deficiency are frequently diagnosed in young men.

A widely discussed issue among the factors that decrease endogenous Ts levels in young people is the long-term non-medical use of testosterone preparations (TPs) [9][10]. Risk groups for non-medical application of Ts include amateur sportsmen and people who train in sports centers for recreational physical activity [11][12].

Long-term TP application models, including supratherapeutic doses and TPs combinations, with further discontinuation, increase the risk of unfavorable psychological and other Ts-deficiency-associated complications. Consumers of TPs for non-medical purposes more often apply to physicians for non-psychiatric medical complications than for changes in their psychological status. At the same time, despite the unfavorable consequences, the motivation for the constant application of TPs is mainly maintained by psychological factors [12].

The most common adverse events for the urinary tract and reproductive organs associated with discontinuation of long-term intake of TPs, which inhibit endogenous Ts synthesis, include erectile dysfunction, decreased libido, infertility, and lower urinary tract symptoms (LUTS) [11][13][14].

The study aimed to evaluate the lower urinary tract symptoms character in men after the discontinuation of long-term non-medical use of testosterone preparations.

MATERIALS AND METHODS

The clinical-statistical analysis included the examination results of 31 men aged 22–46 years old, who received TPs for non-medical use during training in the gym and referred to a urologist with complaints about LUTS. TP intake was initiated without medical indications by men or sports centers personnel. Men developed LUTS after the discontinuation of TPs intake. Medical records said that before TPs usage, the hormonal status (Ts, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol) agreed with the reference values. There were no signs of the infectious-inflammatory process of the urinary tract and prostate. Ten men took TPs for 2 years (32.3%), eight men – for 2 – 4 years (25.8%), and 13 men – for over 4 years (41.9%).

The examination of patients included the International Prostatic Symptom Score Scale (IPSS). For each patient, the total LUTS score was calculated (max score = 35). Additionally, storage symptoms (max score 20) and voiding symptoms (max score 15) were evaluated separately. Participants underwent laboratory and instrumental examinations: general urine examination, general blood examination, prostate secretion microscopy, evaluation of serum total Ts, FSH, LH, prolactin, estradiol, prostate and bladder ultrasound, uroflowmetry.

Hormonal tests were performed with a fully automated Cobas 6000 immunochemical analyzer («Roche Diagnostics International Ltd.», Rotkreuz, Switzerland), an innovative patented electrochemiluminescence (ECL) technology and a quantitative antigen assessment method based on changes in the signal of ECL before and after immunoreaction.

Statistical analysis. The study results were processed using Microsoft Excel tables from the software package Microsoft Office, 2007. Statistical analysis of the data was performed using the Statistica ver.6.1 software («StatSoft Inc.», Tulsa, OK, USA). The normality of the distribution was evaluated using the Shapiro-Wilk test. All qualitative data were described as the mean (M) ± standard deviation (SD). Qualitative data were described with absolute values (n) and percent (%).

RESULTS

Clinical and laboratory parameters gathered when the participants first referred for medical help are presented in the Table.

IPSS score analysis showed that 27 (87.1%) patients had moderate symptoms (8–9 score) and 4 (12.9%) patients had light symptoms (0–7 score) (Fig. 1). The evaluation of the LUTS character showed that patients had primarily irritative symptoms by the number of cases and expression (Figs. 2, 3)

In 13 (41.9%) patients, total Ts in serum was 8–11 nmol/L, in 18 (58.1%) patients, it was < 8 nmol/L. An increase in FHS levels was higher than the reference values in 5 (16.1%) men, LH and prolactin – in 9 (29.0%) and 5 (16.1%) men, respectively. A decrease in the estradiol level below the reference values was revealed in 6 (19.4%) men.

Prostate US revealed low blood flow areas in 24 (77.4%) cases: 11 (35.5%) unilateral localizations and 13 bilateral localizations (Fig. 4A). In 8 (25.8%) patients, these areas visualized in the transitory zone, and 4 (12.9%) patients — in the central zone, and 12 (38.7%) patients — in both prostate zones. Additionally, 21 (67.7%) patients had prostate fibrosis. In 7 (22.6%) patients, fibrosis was revealed in the single prostate lobe, and in 14 (45.2%) patients — in both lobes (Fig. 4B, 4C).

DISCUSSION

There are few publications on pathogenetic mechanisms of adverse events in patients who received long-term therapy with TPs, including for the urinary tract and reproductive organs. However, it is known that the pathogenesis of LUTS associated with Ts deficiency has complicated neuroendocrine mechanisms, and endothelial dysfunction is the leading one. Ts deficiency is associated with a decrease or complete loss of endothelial cells capacity to provide an adequate synthesis of vasoconstricting and vasodilating factors that determine the structural-functional integrity of the endothelium and preventive anti-atherogenic effects [15][16]. Furthermore, it was shown that the functional activity of the detrusor, prostate, and urethra decreased in men with a Ts deficiency. In the conditions of a long-term decrease in serum Ts levels, the synthesis of nitrogen oxide (NO) is impaired in the vascular neuroendothelium, which leads to a persistent spasm of vascular walls in various organs and systems. This contributes to the development of vascular and cellular-tissue hypoxia. Additionally, local, and systemic ischemia (in particular, pelvic ischemia) develops, leading to hypoxia of the pelvic, urethral, and prostatic areas, which is considered the most important inducer of LUTS [13].

LUTS is an important determinant of the quality of life of any aged men [17][18]. In the present study, men, who used TPs for non-medical purposes for a long time, were primarily at the young age (aged 18 – 44 years) group (87.1%). In all cases, the registered LUTS had an irritative character. In 24 (77.4%) cases, they were combined with voiding symptoms. The total score of irritative symptoms in 22 (71.0%) patients was > 7 points, and in 9 (29.0%) patients, 5–7 points. The total score of obstructive symptoms in the examined men was < 7. In 77.4% of the patients, low blood flow and avascular areas were detected in the prostate, which are US signs of ischemia and could be the initiators of the clinical manifestation of LUTS. Additionally, in 29.0% of men, a Ts decrease and other hormone levels was registered, which are important links in the functioning of the urinary and reproductive organs.

CONCLUSION

Men who receive TPs for non-medical purposes for a long time develop secondary hypogonadism associated with adverse events for urinary tracts and reproductive organs. LUTS are one such adverse event that worsens the quality of life of men after discontinuation of TPs intake. They have a primarily irritative character and are caused by hypovascular and avascular changes in the prostate transitory and central zones, which should be considered before the indication of the required therapy. Furthermore, an interdisciplinary system of therapeutic measures should be proposed for such patients.