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Effects of 5-Year Treatment With Testosterone Undecanoate on Lower Urinary Tract Symptoms in Obese Men With Hypogonadism and Metabolic Syndrome

Published:October 17, 2013DOI:https://doi.org/10.1016/j.urology.2013.08.019

      Objective

      To investigate the possible effects of testosterone undecanoate (TU) injections in a population of obese (mean age 57) hypogonadal men with lower urinary tract symptoms (LUTS) in a long-term observational study.

      Methods

      Twenty obese hypogonadal men with metabolic syndrome were treated with TU injections every 12 weeks for 60 months; also 20 matched subjects in whom TU was unaccepted or contraindicated were used as controls. LUTS severity and the impact of TU injections were assessed by differences in International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) rate in milliliters, post-void residual (PVR) volume, and prostate size every 12 months in a 5-year controlled study.

      Results

      TU injections did not produce differences in IPSS, Qmax, PVR, and prostate size in both groups. No modification in prostate-specific antigen (PSA) and hematocrit levels was also found between the 2 groups. Interestingly, controls showed increased incidence of prostatitis than TU-treated men (10% vs 30%, P <.01).

      Conclusion

      We showed that 5 years of TU treatment did not change IPSS, PVR, Qmax, or prostate size in obese hypogonadal men with metabolic syndrome and moderate LUTS at baseline. Therefore, long-term TU replacement therapy is a safe and effective treatment for reverting hypogonadal features related to metabolic syndrome and does not impact negatively on LUTS and prostate volume.
      Recent data suggest that hypogonadism can be considered a clinical additional feature of metabolic syndrome, which also seems to be one of the factors involved in the pathogenesis and progression of benign prostate hyperplasia (BPH). This latter is commonly regarded as a benign disease with a progressive character in which the slow but steady growth of the prostate gland results in a spectrum of clinical symptoms that highly affect the quality of life of the patient and it is commonly known as lower urinary tract symptoms (LUTS). Recent studies indicate that 8%-31% of middle-aged men suffer from LUTS ranging from moderate-to-severe, which increases to 27%-44% of men in their 70s, representing an important determinant of the quality of life.
      • Robertson C.
      • Link C.L.
      • Onel E.
      • et al.
      The impact of lower urinary tract symptoms and comorbidities on quality of life: the BACH and UREPIK studies.
      Hypogonadism affects approximately one-fifth of elderly men with LUTS, but it has no impact on symptom severity.
      • Schatzl G.
      • Madersbacher S.
      • Temml C.
      • et al.
      Serum androgen levels in men: impact of health status and age.
      An increasing number of men experience symptoms of LUTS much earlier in life, particularly those affected by metabolic syndrome. Many studies have established a clear relationship between levels of sex steroids and BPH, but few studies have analyzed the relationship between circulating testosterone and LUTS symptoms. There is a gradual increase in prostate volume concomitant with the progressive decline in testosterone from middle age, reflecting the evolution of BPH, a common disease of the older men.
      • Berry S.J.
      • Coffey D.S.
      • Walsh P.C.
      • Ewing L.L.
      The development of human benign prostatic hyperplasia with age.
      Thus, it seems that the presence of low serum levels of testosterone may be the common link between advancing age, metabolic syndrome, and LUTS.
      There are several similarities in the etiology of erectile dysfunction and LUTS, and recent studies suggest that BPH/LUTS are significantly associated with metabolic syndrome also; patients with LUTS may share the same metabolic abnormalities as those with metabolic syndrome.
      • Paick J.S.
      • Yang J.H.
      • Kim S.W.
      • et al.
      Are age, anthropometry and components of metabolic syndrome-risk factors interrelated with lower urinary tract symptoms in patients with erectile dysfunction? A prospective study.
      It is well known that testosterone replacement therapy (TRT) yields significant benefits to hypogonadic patients affected by metabolic syndrome, including the improvement of metabolic parameters (fasting glucose, glucose tolerance, abdominal circumference, triglycerides, and high-density lipoprotein [HDL] cholesterol), but the concerns of potential side effects at both the prostate and the bladder levels have severely limited the use, especially in the presence of obesity.
      Therefore, the potential concerns about the effects of testosterone on prostate disease and LUTS should be reassessed. In the present study, we have investigated the effects of TRT during 5 years of treatment for hypogonadism associated with metabolic syndrome and its impact on urinary function and symptoms.

      Patients and Methods

      Inclusion Criteria

      Forty patients, aged 45 to 65 years, were enrolled into this observational study. Patients were included in the study if they were between 45 and 65 years of age, had metabolic syndrome, and/or type 2 diabetes mellitus defined by the International Diabetes Federation,
      • Alberti K.G.
      • Zimmet P.
      • Shaw J.
      IDF Epidemiology Task Force Consensus Group
      The metabolic syndrome–a new worldwide definition.
      and total serum testosterone level <320 ng/dL (11 nmol/L) or calculated free-testosterone levels <255 pmol/L (74 pg/mL) on 2 separate early morning days (between 8:00 and 11:00 AM) at least 1 week apart, and at least 2 symptoms of hypogonadism.

      Exclusion Criteria

      Patients were not included in the study in case of: use of TRT or anabolic steroids in the previous 12 months; history of prostate or breast cancer or other tumors; drug or alcohol abuse; blood coagulation alterations; symptomatic obstructive sleep apnea syndrome; hematocrit level ≥52% at baseline; age-adjusted elevated prostate-specific antigen (PSA) level or abnormal digital rectal examination (DRE) of the prostate suspicious for cancer or severe symptomatic BPH; an International Prostate Symptom Scale (IPSS) >13 at baseline; use of 5-α-reductase inhibitors; presence of any uncontrolled endocrine disorder including diabetes (HbA1c ≥9); presence of New York Heart Association III or IV heart failure; hepatic insufficiency; severe neurological and/or psychiatric disease; or requiring or undergoing fertility treatment. We also excluded men who had diseases potentially affecting the skeleton, such as chronic renal disease or malabsorption, or were taking medications or drugs affecting bone turnover, or had >3 alcoholic drinks a day. All concomitant oral hypoglycemic, anti-hypertensive, and lipid-lowering medications were permitted if started within the previous 12 months and continued throughout the study without dose adjustments. Subjects were asked to maintain their usual physical exercise and lifestyle for the duration of the study. Written informed consent was obtained from each patient before commencement of the study according to Protocol and Good Clinical Practice on the conducting and monitoring of clinical studies, and was approved by our University Ethics Committee.

      Primary Outcome Measures

      The primary outcomes were variations from baseline of the IPSS, a questionnaire to assess the severity of irritative (frequency, urgency, and/or nocturia) and obstructive LUTS (incomplete emptying, intermittency, weak stream, and/orstraining), which were attributable to bladder outlet obstruction caused by prostatic enlargement. Symptoms were classified as mild (score 0-7), moderate (8-19), or severe (20-35).
      • el Din K.E.
      • Koch W.F.
      • de Wildt M.J.
      • et al.
      Reliability of the International Prostate Symptom Score in the assessment of patients with lower urinary tract symptoms and/or benign prostatic hyperplasia.
      Uroflowmetry parameters were measured by the maximum urine flow (Qmax) rate maintained for 2 seconds with a minimal voided volume of 150 mL (MicroFlow II)
      • Marks L.S.
      • Mazer N.A.
      • Mostaghel E.
      • et al.
      Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial.
      and post-void residual (PVR) after micturition (as evaluated by ultrasound) were also investigated. At baseline and every 12 months, the following evaluations were assessed: general physical examination and anthropometric parameters (ie, weight, height, body mass index [BMI], and waist circumference), systolic and diastolic blood pressure, heart rate, blood samples for chemical and hormonal analyses, and DRE. Only medical personnel performed testosterone undecanoate (TU) injections according to the procedures recommended by the manufacturer, by a deep intramuscular injection in the buttock level, with slow infusion, and while the patient is standing. The study was carried out for 60 months. The control group underwent the same evaluations including transrectal ultrasonography (TRUS) at baseline and annually.

      Modality of Treatment

      After screening any patient for the presence of hypogonadism, 20 of 72 patients met the inclusion/exclusion criteria and entered into the study. Patients received TU (TRT group) administered intramuscularly at a dose of 1000 mg every 6 weeks for the first 2 injections and then every 12 weeks, according to recommendations, for a period of 60 months. Twenty patients not fulfilling inclusion/exclusion criteria or refusing TRT were observed throughout the time and served as controls.

      Evaluations

      Total prostate volume (TPV) was investigated by TRUS of the prostate. The same operator performed the TRUS every time. Patients were scanned in the left lateral decubitus position using a 3.6-7 MHz multiplanar rectal probe (HDI 5000; Philips Medical System, Eindhoven, The Netherlands). The TPV measurement by TRUS is a well-established diagnostic test for men with LUTS because of BPH. The standardized measurement technique and calculation formula using anterioposterior and transverse diameters, both in the transverse image and the craniocaudal scans, were measured in the largest area in the sagittal plane. The TPV was calculated by timing these diameters: height × width × length × π/6 (the ellipsoid method). The transitional zone was measured in the same way except that the craniocaudal diameter was measured in the sagittal plane where the transitional zone is seen at its largest. Furthermore, attention was placed on the presence of hypoechogenic lesions in the prostate.
      • Chenven E.S.
      • Glazier D.B.
      • Krisch E.B.
      • et al.
      Evaluation of prostate volume by transrectal ultrasonography for use in a brachytherapy program.
      If abnormalities were found, patients were sent to the urology out-patient clinic for further evaluation and the prostate was examined systematically at DRE.
      Qmax, mean urine flow rate, and voided volume measurements have been obtained with a prevoid total bladder volume (assessed by ultrasound) of 150-550 mL inclusive and minimum void volume of ≥125 mL. The same investigator interpreted uroflowmetry results. Qmax is defined as the peak urine flow rate (measured in milliliters/second using a standard calibrated flowmeter). mean urine flow rate, is defined as the mean urine flow rate (measured in milliliters/second using a standard calibrated flowmeter). Vcomp is defined as the volume of voided urine (measured in milliliters).
      • Kaplan S.A.
      • Roehrborn C.G.
      • McConnell J.D.
      • et al.
      Long-term treatment with finasteride results in a clinically significant reduction in total prostate volume compared to placebo over the full range of baseline prostate sizes in men enrolled in the MTOPS trial.
      Prostatitis (bacterial and nonbacterial) was defined by the presence or the absence of increased leukocytes in prostate secretions in a man complaining of pain in the prostate (prostatodynia), or with symptoms of urinary urgency, dysuria, poor urine flow, or prostatic discomfort.

      Grabe M, Bjerklund-Johansen TE, Botto H, et al. European Association of Urology. Guidelines on urological infections. Available at: http://www.uroweb.org/gls/pockets/english/17%20Urological%20Infections_LR.pdf. Accessed August 1, 2013.

      Total testosterone was measured by electrochemiluminescence (Immulite 2000, Siemens, Milan, Italy; within and between-assay coefficients of variation were 5.1% and 7.2%, respectively). Insulin and PSA were analyzed by immunometric assay based on chemioluminescence using an automated clinical chemistry analizer (Immulite 2000, Diagnostic Product Corp., Los Angeles, CA). Plasma glucose was measured by an automated clinical chemistry analyzer (Modular P and Modular E for PSA, Roche Diagnostics GmbH, Mannheim, Germany). HbA1c was measured by high-performance liquid chromatography (Bio-Rad Laboratories, Hercules, CA). To assess insulin sensitivity, we calculated the homeostatic measurement assessment-insulin resistance (HOMA-IR) using the formula [fasting insulin in mU/l × fasting glucose in mmol/l]/22.5.

      Statistical Analysis

      Differences between characteristics of each group were investigated using the unpaired t test. Multiple regression analysis was performed for PSA, prostate volume, IPSS scores, and bladder PVR volume. A P value <.05 was considered statistically significant. Statistical analysis was performed using the computer statistical package SPSS 11.0 (SPSS Inc., Chicago, IL).

      Results

      At baseline, no significant differences between the 2 groups were found. Baseline characteristics of the study population are summarized in Table 1.
      Table 1Demographic characteristics of patients at baseline
      VariablesControl Group (20)Treatment Group (20)
      Age (y)57 ± 858 ± 10
      BMI (kg/m3)31 ± 6.230 ± 5.5
      Only metabolic syndrome, no. (%)14 (70)14 (70)
      T2DM + metabolic syndrome, no. (%)6 (30)6 (30)
      Smokers, no. (%)4 (20)4 (20)
      Treatments
       None (%)8 (40)6 (30)
       Metformin (%)8 (40)8 (40)
       Antihypertensives (%)12 (60)8 (40)
       Statins (%)4 (20)5 (25)
       Fibrates (%)0 (0)2 (10)
       Others (%)4 (20)5 (25)
      BMI, body mass index; T2DM, type 2 diabetes mellitus.

      LUTS and Urinary Function

      Total IPSS (Fig. 1A), Qmax (Fig. 1B) and PVR (Fig. 1C) were unaltered in both treatment and control. In particular, there were no modifications in IPSS subscores (data not shown), and the domains that affect the phase of filling, emptying, and irritative symptoms were not altered by any treatment. After 60 months, both groups did not shown any variation in prostate volume (Table 2).
      Figure thumbnail gr1
      Figure 1(A) Variations in total International Prostate Symptom Score (IPSS), (B) maximum urine flow (Qmax, mL/sec), and (C) post-void residual (PVR, mL) in hypogonadal men treated with testosterone undecanoate therapy (TRT) injections and control group (CTRL).
      Table 2Metabolic and inflammatory parameters, body weight, and prostate volumes in testosterone replacement therapy and control groups
      Baseline12 Mo24 Mo36 Mo48 Mo60 Mo
      CTRLTRTP ValueCTRLTRTP ValueCTRLTRTP ValueCTRLTRTP ValueCTRLTRTP ValueCTRLTRTP Value
      BMI (kg/m2)31 ± 630.5 ± 5.45NS−0.1 ± 6−1.8 ± 3.1NS1 ± 5.5−2.5 ± 2.2.011 ± 4.4−1.8 ± 1.6NS0.8 ± 4.4−2.6 ± 1.3NS1 ± 4.4−2.9 ± 1.4NS
      WC (cm)108 ± 5.7105 ± 4.8NS0.3 ± 6.2−3.8 ± 5.3.0011.0 ± 5.5−5.5 ± 4.1.00010.9 ± 5.2−6.5 ± 4.1.00011.8 ± 4.7−7.8 ± 3.2.00013.1 ± 4.1−9.6 ± 3.8.0001
      Weight (kg)111 ± 6.3107 ± 5.9NS−0.2 ± 6.1−5.7 ± 5.3.0010.4 ± 1.1−9.6 ± 4.8.00010.4 ± 1.2−11.1 ± 3.3.00010.6 ± 0.8−13.7 ± 3.1.00010.9 ± 0.7−15.4 ± 2.8.0001
      HbA1C (%)6.7 ± 1.36.6 ± 1.5NS0.3 ± 0.8−0.9 ± 0.4.010.4 ± 1.1−1.1 ± 0.4.0010.4 ± 1.2−1.4 ± 0.5.0010.5 ± 0.8−1.3 ± 0.5.0010.3 ± 0.7−1.6 ± 0.5.001
      Total cholesterol (mg/dL)238 ± 30237 ± 31NS5 ± 32−52 ± 30.00110 ± 28−61 ± 24.0001−9 ± 2.6−63 ± 20.0001−8 ± 2.9−67 ± 23.00015 ± 38−66 ± 19.0001
      LDL cholesterol (mg/dL)160 ± 27161 ± 29NS−2 ± 25−26 ± 23.0012 ± 31−31 ± 23.0001−9 ± 27−41 ± 21.00015 ± 20−50 ± 18.00018 ± 26−51 ± 16.0001
      HDL cholesterol (mg/dL)33 ± 732 ± 8NS3 ± 915 ± 10.0012 ± 1116 ± 11.0001−2 ± 1118 ± 9.0001−3 ± 1119 ± 9.00012 ± 1121 ± 11.0001
      Triglicerides (mg/gL)187 ± 28196 ± 31NS6 ± 21−29 ± 21.00110 ± 24−4.3 ± 22.0001−6 ± 25−45 ± 21.00012 ± 23−49 ± 19.0001−5 ± 23−41 ± 19.0001
      Systemic BP (mm Hg)149 ± 11147 ± 13NS−3 ± 11−12 ± 10.001−2 ± 9−15 ± 10.0001−5 ± 12−16 ± 14.0001−1 ± 13−18 ± 9.0001−3 ± 13−23 ± 10.0001
      Diastolic BP (mm Hg)97 ± 1198 ± 10NS1 ± 8−7 ± 11.0011 ± 10−14 ± 10.0001−3 ± 11−16 ± 8.0001−1 ± 9−14 ± 9.00010 ± 11−17 ± 10.0001
      HOMA-IR4.25 ± 0.354.2 ± 0.3NS0.2 ± 0.3−2.1 ± 0.3.00010.6 ± 0.5−2.07 ± 0.4.00010.9 ± 0.4−2.5 ± 0.6.0001−0.9 ± 0.7−2.6 ± 0.6.00011.1 ± 0.6−2.8 ± 0.6.0001
      Total testosterone (nmol/L)9 ± 1.78.3 ± 2.4NS0.35 ± 1.47.4 ± 1.4.0001−0.4 ± 1.28.5 ± 1.7.0001−1.1 ± 0.89.3 ± 1.5.0001−0.9 ± 1.68.8 ± 1.7.0001−1.3 ± 1.49.1 ± 1.7.0001
      Fbn (mg/dL)685 ± 79690 ± 63NS14 ± 68−200 ± 59.000118 ± 51−212 ± 77.0528 ± 60−231 ± 70.000124 ± 71−255 ± 58.000121 ± 68−268 ± 46.0001
      Hs-CRP (mg/mL)3.4 ± 1.53.6 ± 1.8NS0.05 ± 1.7−0.55 ± 1.3.0010.1 ± 1.2−0.75 ± 1.1.0010.15 ± 1.7−0.79 ± 1.3.0010.09 ± 1.7−0.93 ± 1.3.0010.18 ± 1.4−1.13 ± 1.3.001
      TPV (mL)31.5 ± 2.532 ± 3NS1.2 ± 2.51.1 ± 3NS1.1 ± 2.51.3 ± 3NS1.2 ± 2.51.2 ± 3NS0.8 ± 2.51.2 ± 3NS0.9 ± 2.51.1 ± 3.5NS
      Total PSA (ng/mL)0.98 ± 0.251.05 ± 0.21NS−0.07 ± 0.270.31 ± 0.31.010.05 ± 0.180.30 ± 0.24.010.01 ± 0.190.29 ± 0.29.010.04 ± 0.210.32 ± 0.22.010.06 ± 0.250.37 ± 0.29.01
      HCT (%)42.5 ± 0.2843.8 ± 0.21NS−0.6 ± 0.192.29 ± 0.85.001−0.7 ± 0.272.34 ± 0.72.0010.5 ± 0.342.57 ± 0.63.0010.6 ± 0.672.68 ± 0.59.0010.9 ± 0.272.76 ± 0.93.001
      BP, blood pressure; CTRL, control group; Fbn, fibrinogen; HCT, hematocrit; HDL, high-density lipoprotein; HOMA-IR, homeostatic measurement assessment-insulin resistance; Hs-CRP, high sensitivity C-reactive protein; LDL, low-density lipoprotein; NS, not significant; PSA, prostate-specific antigen; TPV, total prostate volume; TRT, testosterone replacement therapy group; WC, waist circumference; other abbreviation as in Table 1.
      Baseline and variation changes are reported.
      P values refer to statistical significance between controls vs treatmnet group at each time point.

      Metabolic Parameter and Inflammatory Markers

      As expected, at the end of the study, the values of total testosterone were higher in the TRT group compared to the control group (+9.1 ± 1.7 nmol/L, P <.0001). Only the TRT group showed a significant reduction of BMI and waist circumference (WC, −2.9 ± 1.4, P <.0001 and −9.6 ± 3.8 cm, P <.0001, respectively). There was a significant reduction of blood glucose, as evaluated by HbA1c, during the 60-month study follow-up period (−1.6 ± 0.5%, P <.001) for the TRT group only. In this latter group, significant reduction in insulin sensitivity, as evaluated by HOMA-IR (−2.8 ± 0.6, P <.0001), lipid profile (total cholesterol, −66 ± 19 mg/dL, P <.0001), HDL cholesterol, (+21 ± 11 mg/dL, P <.0001) low-density lipoprotein cholesterol, (−51 ± 16 mg/dL, P <.0001), inflammatory markers (fibrinogen, −268 ± 46 mg/dL, P <.0001) and high sensitive C-reactive protein (−1.13 ± 1.3 mg/mL, P <.0001) were found (Table 2).

      Safety

      No significant variation in prostate volume was found. A significant increase in hematocrit values(+2.76 ± 0.93%, P >.001) and PSA levels (+0.37 ± 0.29 ng/mL, P <.01) within the normal reference range values were found in the TRT group only. This increase occurred within the first 12 months of treatment, and remained stable throughout the remaining period of the study (Table 2). Interestingly, patients on active TRT developed fewer incidence of prostatitis compared to the control group (CTRL: 6/20 = 30% vs TRT: 2/20 = 10%, P <.01, data not shown).

      Comment

      Epidemiological studies suggest that circulating levels of sex hormones are generally not significant predictors of LUTS in men after adjustment for age, and that the pathophysiology of LUTS is complex and probably includes more factors other than circulating sex steroid levels.
      • Litman H.J.
      • Bhasin S.
      • O'Leary M.P.
      • et al.
      An investigation of the relationship between sex-steroid levels and urological symptoms: results from the Boston Area Community Health survey.
      Also, no consistent relationship exists between total- or free-testosterone circulating levels and LUTS in another cross-sectional study.
      • Rohrmann S.
      • Nelson W.G.
      • Rifai N.
      • et al.
      Serum sex steroid hormones and lower urinary tract symptoms in Third National Health and Nutrition Examination Survey (NHANES III).
      In addition, some studies have indicated inverse associations between total testosterone, bioavailable-testosterone, and free-testosterone with LUTS. One prospective study revealed a significant inverse association between dihydrotestosterone and LUTS and indicated that men with higher concentrations of bioavailable testosterone had a 56% decreased risk of LUTS compared with those with hypogonadal concentrations, but no relationship between total testosterone and LUTS were found.
      • Trifiro M.D.
      • Parsons J.K.
      • Palazzi-Churas K.
      • et al.
      Serum sex hormones and the 20-year risk of lower urinary tract symptoms in community-dwelling older men.
      Furthermore, Tan et al
      • Tan M.O.
      • Karabiyik I.
      • Uygur M.C.
      • et al.
      Serum concentrations of sex hormones in men with severe lower urinary tract symptoms and benign prostatic hyperplasia.
      reported that the decrease in serum-free testosterone concentrations with a relative rise in serum estradiol levels with advancing age may be an important factor in the development of BPH in a population of 61 men aged 60-69 years. Schatzl et al
      • Schatzl G.
      • Brössner C.
      • Schmid S.
      • et al.
      Endocrine status in elderly men with lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary tract function. The Prostate Study Group of the Austrian Society of Urology.
      reported that hypogonadism was detected in 22.1% of 312 men with LUTS but had no impact on IPSS, maximum flow rate, prostate volume, or PSA level.
      The theoretical basis to explain the improvement of metabolic syndrome features has been addressed in our previous clinical studies in which we demonstrated that intramuscular instead of oral TU is able to determine advantages on body composition and sexual function in hypogonadal men with metabolic syndrome.
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome.
      In another study, we demonstrated that the administration for 24 months of intramuscular TU in hypogonadal men with metabolic syndrome is able to improve insulin sensitivity and body composition regardless of diet and physical exercise, causing a reduction of the risk factors for atherosclerosis and cardiovascular disease,
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
      and an increase in bone mineral density after 36 months.
      • Aversa A.
      • Bruzziches R.
      • Francomano D.
      • et al.
      Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study.
      In the present study, we investigated, for the first time, the effects of long-acting TRT after 60 months on urinary function in a population of hypogonadal men affected by metabolic syndrome. No evidences regarding the urinary function for such a long time period with long-acting TRT are present yet in the literature. We demonstrated for the first time that the normalization of total testosterone levels, after 5 years of TRT with intramuscular TU, did not negatively impact urinary function, as evaluated by IPSS and uroflow, and this was confirmed by no variations in prostate volume. Also not one patient showed alteration of safety parameters (hematocrit and PSA). Interestingly, the TU-treated group showed a significantly lower incidence of prostatitis than the controls during the follow-up period, thus suggesting that testosterone may play an important role in preventing prostate inflammation.
      The hypothesis on the pathogenic mechanism that links metabolic syndrome hypogonadism with LUTS,
      • Yassin A.A.
      • El-Sakka Al
      • Saad F.
      • et al.
      Lower urinary-tract symptoms and testosterone in elderly men.
      suggests that testosterone may act on the structures of the lower urinary tract because of the presence of androgen receptors on urethral and bladder epithelial cells.
      • Chavalmane A.K.
      • Comeglio P.
      • Morelli A.
      • et al.
      Sex steroid receptors in male human bladder: expression and biological function.
      Also, testosterone and its metabolites have been shown to be able to maintain the reflex activity of the pelvic autonomic nervous system. Indeed, animal studies suggest that testosterone directly regulates urinary function through its nongenomic action on postsynaptic receptors on the cell surface of ganglionic neurons that suppress detrusor activity.
      • Watkins T.W.
      • Keast J.R.
      Androgen-sensitive preganglionic neurons innervate the male rat pelvic ganglion.
      Juan et al,
      • Juan Y.S.
      • Onal B.
      • Broadaway S.
      • et al.
      Effect of castration on male rabbit lower urinary tract tissue enzymes.
      showed that castration led to a significant alteration of cellular functions with reduced mitochondrial function, disturbance of storage of calcium in the sarcoplasmic reticulum, alterated relaxation of microtubules, and a slowing of the muscarinic transmission of the bladder, urethra, and corpora cavernosa, in a rabbit model. Rats affected by metabolic syndrome induced with high-calorie meals demonstrated high messenger RNA (mRNA) levels of the proinflammatory interleukins (IL-8, IL-6, tumor necrosis factor [TNF]-alpha, and IL-1 beta), turned out to be important in determining hystopathological findings of enlarged prostate.
      • Vignozzi L.
      • Morelli A.
      • Sarchielli E.
      • et al.
      Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit.
      Interestingly, TRT in these animals completely prevented the development of prostatic alterations and had similar beneficial effect at the level of the bladder. Other experimental studies have shown that TRT improved the control of the response of bladder smooth muscle after acute administration of phosphodiesterase-5-inhibitors and this occurred to a greater extent in men than in women even when treated with testosterone and letrozole.
      • Vignozzi L.
      • Filippi S.
      • Morelli A.
      • et al.
      Testosterone/estradiol ratio regulates no-induced bladder relaxation and responsiveness to PDE5 inhibitors.
      Also, epidemiological and histopathological studies have shown that intraprostatic chronic inflammation is the “triggering” proliferative stimulus for prostatic epithelial and stromal cell growth that typically occurs in BPH and may also play a role in determining LUTS.
      • Fibbi B.
      • Penna G.
      • Morelli A.
      • et al.
      Chronic inflammation in the pathogenesis of benign prostatic hyperplasia.
      Interventional studies with testosterone in men with LUTS and hypogonadism are scarce. In a placebo-controlled study, the weekly testosterone-enanthate administration for 3 months did not show any increase in TPV or an increase of PVR.
      • Tenover J.S.
      Effects of testosterone supplementation in the aging male.
      Franchi et al
      • Franchi F.
      • Luisi M.
      • Kicovic P.M.
      Long-term study of oral testosterone undecanoate in hypogonadal males.
      showed that the oral administration of increasing doses of TU in hypogonadal men for 8 months did not cause an increase in prostate volume, or a worsening of emptying symptoms. Behre et al,
      • Behre H.M.
      • Bohmeyer J.
      • Nieschlag E.
      Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls.
      did not show significant difference in the uroflow data, PSA values, and TRUS among subjects with hypogonadotropic hypogonadism treated for 6 months and controls. In an elegant study, Marks et al,
      • el Din K.E.
      • Koch W.F.
      • de Wildt M.J.
      • et al.
      Reliability of the International Prostate Symptom Score in the assessment of patients with lower urinary tract symptoms and/or benign prostatic hyperplasia.
      demonstrated that 6 months of TRT normalizes serum testosterone concentrations to the mid-normal range but does not accumulate within the prostate, does not producing abnormal levels of dihydrotestosterone, and does not induce any major biological change within the gland. Other studies showed the beneficial effects of TRT without significant exacerbation of LUTS or complications, such as urinary retention, compared to controls. These studies have therefore shown that TRT had negligible negative effects on urinary function, on LUTS, and prostate volume in adult men treated for about 1 year.
      • Takao T.
      • Tsujimura A.
      • Nakayama J.
      • et al.
      Lower urinary tract symptoms after hormone replacement therapy in Japanese patients with late-onset hypogonadism: a preliminary report.
      Only Gooren
      • Gooren L.J.
      A ten-year safety study of the oral androgen testosterone undecanoate.
      provided some evidence for a longer period study, showing no significant worsening of urinary function measured with uroflowmetry during the follow-up period of 10 years in a small cohort of hypogonadal patients treated with oral TU. Despite these studies, evidence is consistent, at present, no meta-analysis data are available on this topic and TRT is still contraindicated in individuals who have BPH/LUTS with symptoms of urinary retention.
      We acknowledge some study limitations because of the small sample of the study, and to the lack of urodynamic evaluations, thus, we are unable to provide data on the pathophysiological mechanism(s) of testosterone on the bladder neck.

      Conclusions

      LUTS is frequently present in male aging, especially in the presence of metabolic syndrome and hypogonadism. The common denominator of these conditions is the presence of insulin resistance and chronic inflammation. We hypothesize that, in hypogonadal men, the prostate gland may become more susceptible to inflammations and that TRT may exert a protective effect over time, as evidenced in the present study, and, likewise, already demonstrated in animal models. Our 5-year study showed, we believe for the first time, a stability of LUTS as evaluated by IPSS score and uroflowmetry in hypogonadal men with metabolic syndrome in the absence of urinary obstructive symptoms at baseline, and a less frequencies of prostatitis. Therefore, we suggest that the improvement of the inflammatory status, along with the reversion of the metabolic syndrome and it's related features, may have played some role in maintaining unaltered urinary function and protecting the prostate gland from inflammation during TU treatment. Larger population studies are needed to clarify the role of TRT in the pathophysiology of LUTS, especially in men with different severity of urinary obstructive symptoms.

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      • Editorial Comment
        UrologyVol. 83Issue 1
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          A decade ago, The Institute of Medicine Report on Testosterone and Aging1 indicated that “the potential for testosterone therapy to increase risk for symptomatic prostatic hypertrophy is of major concern… but quantifying these risks will require randomized trials that include large number of men followed for multiple years.” In relation to the development of prostate cancer, the report drew attention to the need for a study including a population of 5000 men followed for 3 to 5 years. The logistic and financial implications of such undertakings are enormous and little progress has occurred since.
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