Effects of testosterone replacement therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity,voiding function and prostate safety parameters

Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function – erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.     

Effects of testosterone replacement therapy on nocturia and quality of life in men with hypogonadism: a subanalysis of a previous prospective randomized controlled study in Japan

Abstract

Objective: We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia.

Methods: From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n?=?31) and controls (n?=?33), were included in this analysis. The TRT group was administered 250?mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups.

Results: At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group.

Conclusions: Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.     

Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study

This observational post-marketing study of parenteral testosterone undecanoate (TU) in a non-selected population aimed to: examine the effectiveness of TU as treatment of hypogonadism; record adverse drug reactions (ADR) quantitatively particularly regarding polycythemia, prostate safety and cardiovascular-related metabolic risk factors; and verify whether recommended injection intervals apply to routine clinical practice. Eight hundred and seventy subjects from 259 outpatient units scheduled to visit the clinic six times were included. Effectiveness and tolerability of TU administration were assessed on a 4-point scale. Body weight, waist girth, blood pressure, hemoglobin levels, hematocrit, prostate-specific antigen (PSA), and digital rectal prostate examination were assessed. Over 90% of subjects completed the observational duration of 52.8?±?9.7 weeks (mean?±?SD) and 56% judged effectiveness as very good, 30.8% as good. 63.1% judged tolerability as very good, and 24.4% as good. No adverse effects on indicators of cardiovascular risk were observed. Polycythemia occurred in one subject and a supranormal hematocrit in one subject. Four subjects developed supranormal PSA levels. Prostate carcinoma was found in one subject, one subject had recurrence of a previously surgically treated prostate carcinoma, and the other two showed no indication of malignancy. Parenteral TU is safe, effective, and well-tolerated in clinical practice proving a good therapeutic option for hypogonadism.     

Clinical experiences with testosterone therapy: prostate safety

Due to a decrease in Leydig cell function, a considerable proportion of men over 50 years of age will develop hypogonadism. Consequently, loss of libido and several other testosterone-dependent symptoms may become evident. When decreased levels of biologically available testosterone are found, and corresponding symptoms are present, these men could be eligible for testosterone substitution therapy. Testosterone treatment in testosterone-deprived men has been shown to improve general well-being, osteoporosis, muscle atrophy, libido and - if present - anemia. Despite these positive effects, testosterone treatment has to be performed with caution. Although it has not been proven that elevation of the serum testosterone level to the normal range results in a greater risk of developing prostate cancer, the effects of testosterone on a prostate cancer already present are well established. Several studies have demonstrated that testosterone treatment does not result in a significant increase in serum levels of prostate-specific antigen (PSA) or prostate volume. The long-term effects, however, are currently unknown. For these reasons, testosterone treatment should be performed only when the presence of prostate cancer is unlikely; i.e. when PSA levels are within normal limits and digital rectal examination does not reveal any suspicious findings. These examinations may still miss some small prostate cancers that could be promoted by testosterone treatment. The determination of PSA levels under testosterone treatment is necessary every 3 months, at least for the first year. Steadily rising PSA levels require immediate cessation of testosterone administration and the initiation of further diagnostic procedures (prostate biopsy), to rule out prostate cancer.     

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

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.     

Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea

Objective: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea.

Methods: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12?months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17).

Results: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12?months.

Conclusion: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance.     

Testosterone,marital quality,and role overload

In a sample of established working‐ and middle‐class families with school‐aged children (N= 307 wives and 307 husbands), neither husbands’ nor wives’ testosterone showed a direct connection with marital quality. In contrast, the association between husbands’ testosterone and positive and negative marital quality (as evaluated by both spouses) was conditional on husbands’ role overload. When perceptions of role overload were elevated, higher testosterone levels were associated with lower levels of marital quality. When perceptions of role overload were low, higher testosterone was linked to greater marital quality. The study supports the biosocial model such that, depending on perceptions of the social context, testosterone enables positive behavior in some instances and negative behavior in others.     

ISA,ISSAM, EAU,EAA and ASA recommendations: investigation,treatment and monitoring of late-onset hypogonadism in males

Abstract

Hypogonadism or Testosterone Deficiency (TD) in adult men as defined by low levels of serum testosterone accompanied by characteristic symptoms and/or signs as detailed further on can be found in long-recognized clinical entities such as Klinefelter syndrome, Kallmann syndrome, pituitary or testicular disorders, as well as in men with idiopathic, metabolic or iatrogenic conditions that result in testosterone deficiency. These recommendations do not encompass the full range of pathologies leading to hypogonadism (testosterone deficiency), but instead focus on the clinical spectrum of hypogonadism related to metabolic and idiopathic disorders that contribute to the majority of cases that occur in adult men.     

Elevated high sensitivity C-reactive protein levels in aging men with low testosterone

Objective.?We examined baseline data from a lipid treatment study to assess the relationship between testosterone (T) and the cardiovascular inflammatory marker, high sensitivity C-reactive protein (hsCRP).

Methods.?The baseline T, hsCRP, lipid, glycemic, and anthropometric data were obtained from 467 men (mean age: 52 years). Inclusion criteria included low-density lipoprotein cholesterol ≥?3.4 to 4.9?mmol/l and triglycerides?≤?4.0?mmol/l. The baseline hsCRP levels were examined across the following T subgroups: <6.9?nmol/l (moderate to severe hypogonadism), 6.9 to <10.4?nmol/l (mild to moderate hypogonadism), 10.4 to <15?nmol/l (low-normal T), and?≥?15?nmol/l (normal T).

Results.?The median hsCRP levels were significantly (p?=?0.041) different across the four T subgroups; patients in the lower T subgroups had higher median hsCRP levels than patients in the higher T subgroups. The percentage of men with elevated hsCRP (>2?mg/l) was also significantly (p?=?0.038) different across the four T subgroups; 83% of men with T < 6.9?nmol/l had elevated hsCRP compared with 40% with T ≥ 15?nmol/l.

Conclusions.?This analysis demonstrated an inverse relationship between serum T and hsCRP in aging men. Urologists need to be aware that low T levels may not only adversely affect sexual function but also may worsen cardiovascular risk in aging, hypogonadal men.     

Testosterone therapy in erectile dysfunction

Studies in animals have indicated that the nitric oxide erectile pathway is testosterone-dependent. Castration induces erectile dysfunction and a reduction in nitric oxide synthase-stained nerves in erectile tissue. Furthermore, castration adversely affects penile hemodynamics and smooth muscle content, leading to veno-occlusive dysfunction. Testosterone replenishment reverses these physiological, biochemical and structural changes. Several clinical studies have demonstrated the benefits of a combination of testosterone and sildenafil. A recently published, multicenter study evaluated the safety and efficacy of testosterone gel 1% (Testogel®; Schering AG, Germany/AndroGel®; Solvay Pharmaceuticals) vs. placebo gel in conjunction with sildenafil, in producing an erectile response in hypogonadal men who did not respond to treatment with sildenafil alone for erectile dysfunction. The selection criteria required subjects to have had erectile dysfunction for at least 3 months, to be non-responsive to 100 mg sildenafil and to have low testosterone levels (&lt;?400 ng/dl). The primary efficacy measurement was the mean change from baseline in the Erectile Function domain of the International Index of Erectile Function (IIEF). Secondary outcome measures included the mean change from baseline in the other domains and the total sum of the IIEF. Subjects were randomized to receive either testosterone gel + sildenafil, or placebo gel + sildenafil for 12 weeks. Testosterone therapy with testosterone gel improved the erectile response to sildenafil. Therefore, testosterone therapy may be considered for the treatment of erectile dysfunction in men with low to low-normal testosterone levels, who have failed prior treatment with sildenafil alone. Consequently, it is important to screen for hypogonadism in men who fail PDE5 inhibitors.     

The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism

Objectives: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH).

Methods: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4?ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT.

Results: The mean serum total testosterone significantly increased from 178.04?±?51.92 to 496.28?±?103.73?ng/dl (p?=?0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT.

Conclusions: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.     

Examining the effect of the computer-based educational package on quality of life and severity of hypogonadism symptoms in males

Objective: The objective of this study was to determine the effect of the computer-based educational package on men’s QoL and the severity of their hypogonadism symptoms.

Methods: A quasi-experimental study was conducted on 80 male employees. The data collection tool included the ‘Aging Male Symptoms’ (AMS) and ‘Short Form-36’ (SF36) questionnaires. Four sessions were held for the intervention group over a period of 4 weeks. Two months after training, QoL and the severity of hypogonadism symptoms were measured in both the intervention and control groups. The data were analyzed with SPSS 22 software and statistical tests, such as χ², independent t-test, Fisher’s exact test, and paired t-tests.

Results: Significant statistical changes were observed in the intervention group before and 2 months after the training in the QoL score in the overall dimensions of physical–psychological health and all its domains except for three domains of emotional role, social function, and pain. Furthermore, the paired t-tests showed significant differences between 2 months before and after the training in all the domains and the overall hypogonadism score in the intervention group.

Conclusions: Based on our findings, the computer-based educational package has a positive effect on QoL and reduction of hypogonadism symptoms.     

Testosterone and men's quality of life

As the worldwide population ages, the emphasis on having a reasonable quality of life in old-age is increasing. In men, age-associated testosterone decline is one of the major factors that reduce quality of life. In patients and the physicians treating them, decreased energy levels and impairments to sex-life are perceived as the most important effects of hypogonadism. Two quality of life scales, the Aging Males' Symptoms (AMS) and the Age-Related Hormone Deficiency-Dependent Quality of Life (A-RHDQoL) scales, have recently been developed to specifically assess this patient population, and the A-RHDQoL found that memory, energy and physical capabilities, and sex-life were the factors most adversely affected by low testosterone levels. Unfortunately, there are limited data on the effects of testosterone on the quality of life of men with hypogonadism, but the information that exists suggests that testosterone can improve the quality of life significantly (to the same level as men with normal testosterone levels) and the more severe the symptoms before treatment, the greater the benefits of testosterone replacement. These promising early results need to be confirmed in more detailed quality of life studies.     

Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients who underwent prostate biopsy: a prospective data register

This study investigated the role of testosterone replacement therapy (TRT) in prostate safety and cancer progression. A cohort of 553 patients, 42 treated and 162 untreated hypogonadal men, and 349 eugonadal men were included. Pathological analysis of prostate biopsies examining the incidence and severity of PCa revealed that: 16.7% of treated hypogonadal men had a positive biopsy, a Gleason score of ≤6 in 71.4% and >6 in 28.6% of men, a predominant score of 3 and tumour staging of II in 85.7% men; 51.9% of untreated hypogonadal men had a positive biopsy, a Gleason score of ≤6 in 40.5% and >6 in 59.5% men, a predominant score of 3 (77.4%) and tumour staging of II (41.7%) or III (40.5%); 37.8% of eugonadal men had a positive biopsy, a Gleason score of ≤6 in 42.4% and >6 in 57.6% of men, a predominant score of 3 (82.6%) and tumour staging of II (44.7%) or III (47.7%). The incidence of positive prostate biopsies was lowest in hypogonadal men receiving TRT, with significantly lower severity of PCa in terms of staging and grading in the same group. These results suggest that TRT might have a protective effect against high-grade PCa.     

A randomized,double-blind,placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up

Introduction: The clinical significance of low to low-normal testosterone (T) levels in men remains debated. Aim: To analyze the effects of raising serum T on lean body mass (LBM), fat mass (FM), total body mass, and health-related quality-of-life (HRQoL). Methods: Randomized, double-blind, placebo-controlled study. Men, aged 50–80 years, with serum total T<15 nmol/L and bioavailable T < 6.68 nmol/L, and a Aging Males’ Symptoms (AMS) total score >36, received 6 months treatment with transdermal 1% T gel (5–7.5?mg/day; n =183) or placebo gel (n =179), followed by 12 months open-label with T in all. Results: After 6 months, LBM increased in T- treated patients by 1.28?±?0.15?kg (mean ± SE) and FM decreased by 1.16?±?0.16?kg, with minor changes with placebo (LBM +0.02?±?0.10?kg and FM ?0.14?±?0.12?kg; all p < 0.001, T group vs. placebo). Changes were largely similar across subgroups of age, baseline total testosterone, and baseline BMI. Total HRQoL improved compared with placebo (p < 0.05, T group vs. placebo). Conclusions: Six months 1% T gel improved body composition and HRQoL in symptomatic men with low to low-normal T, with further improvements over the following 12 months.     

Radical prostatectomy for clinically localized prostate cancer in patients aged 75 years or older: comparison with primary androgen deprivation therapy

Objective: To determine whether radical prostatetomy (RP) is suitable for prostate cancer patients with age ≥75 years in comparison to primary androgen deprivation therapy (PADT).

Patients and methods: A cohort study was conducted in clinically localized prostate cancer patients with ≥75 years of age who underwent RP or PADT at six institutions from 2005 to 2013. Patients who had less than 12 months of follow-up, or received neoadjuvant or adjuvant therapy were excluded. We compared clinical characteristics, cancer-specific and overall survivals, and post-treatment complication rates between two groups.

Results: We included 92 and 99 patients in the RP and PADT groups, respectively. In survival analyses, there were no significant differences in cancer-specific and overall survivals (p?=?.302 and .995, respectively). The incidence of serious adverse events (cardio- or cerebrovascular event, or bone fracture) was higher in the PADT group (p?=?.001). Multivariable analysis showed that PADT had a worse effect on the serious adverse events (OR 10.12, p?=?.038).

Conclusions: In selected elderly patients, RP was safe and effective for treatment of localized prostate cancer, as compared to PADT. Surgical treatment options should be considered in elderly patients with respect to life expectancy, rather than chronological age.     

Anaemia following initiation of androgen deprivation therapy for metastatic prostate cancer: A retrospective chart review

Objective. Haemoglobin levels often decline into the anaemic range with androgen deprivation therapy (ADT). We conducted a chart review of patients receiving ADT for metastatic prostate cancer to assess anaemia-related symptoms.

Methods. 135 stage IV prostate cancer cases were reviewed for treatment type; haemoglobin values before and after treatment; and symptoms of anaemia. Mean haemoglobin levels before and after for all treatment forms, for leuprolide alone, and for combination leuprolide/bicalutamide were calculated and evaluated for significant differences. The numbers of patients developing symptoms were recorded and the effects of specific therapies evaluated.

Results. For all ADT treated patients, mean haemoglobin declined by ?1.11 g/dL (p < .0001). Leuprolide-alone treated patients had a mean decline of ?1.66 g/dL (p < 0.0001). Leuprolide and bicalutamide combination treatment caused a mean decline of ?0.78 g/dL (p = 0.0426). 16 of 43 patients had anemia symptoms. Contingency analysis with Fisher's exact test shows patients receiving leuprolide therapy alone versus other forms of ADT were significantly less likely to have symptoms (χ² = 0.0190).

Conclusions. The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. A number of patients become symptomatic from this change. Practitioners should monitor haemoglobin levels, and treat symptomatic patients.     

The effect of 6 months of androgen deprivation therapy on muscle and fat mass in older men with localized prostate cancer

Objective.?To evaluate body composition changes, specifically skeletal muscle mass, in men receiving androgen deprivation with luteinizing-hormone releasing hormone-agonist (LHRH-A) for prostate cancer (PCa) in comparison with healthy controls.

Design.?Retrospective analysis of body composition changes in men with prostate cancer receiving LHRH-A therapy from 2 clinical trials compared to men without prostate cancer serving as a placebo-control in another clinical trial.

Setting.?Clinical Research Center in Connecticut.

Participants.?Thirty men (> 60 years) receiving 6 months of LHRH-A therapy for PCa were compared to a healthy group of 25 men without PCa.

Measurements.?Appendicular skeletal muscle/height² (ASM/ht²), lean and fat mass were assessed by dual energy x-ray absorptiometry. Total testosterone levels were assessed by enzyme immunoassay.

Results.?At baseline, 12/30 (40%) of the treatment group and 7/25 (28%) of the control group (p = 0.11) met criteria for sarcopenia. There were no differences between control groups in ASM/ht² or lean mass. The LHRH-A group had a higher percent body fat than the control group, 29.8 ± 6.3 versus 26.3 ± 4.6 (p = 0.02). ASM/ht² and lean mass decreased in the LHRH-A group from 7.5 ± 0.9 kg to 7.3 ± 0.9 kg (?2.3% ± 0.03; p ? 0.001) and 53.5 ± 5.4 kg to 52.3 ± 5.3 kg (?2.1% ± 0.03; p ? 0.001), respectively. There was no muscle loss in the control group. At 6 months, the LHRH-A group had increased percent body fat from 29.8 ± 6.4 to 32.2 ± 5.8 (9.5% ± 0.13; p ? 0.001), whereas the control group had decreased in percent body fat from 26.6 ± 4.6 to 25.3 ± 5.0 (?3.8% ± 0.08; p = 0.02).

Conclusions.?Men undergoing LHRH-A treatment for PCa decreased appendicular skeletal muscle and lean tissue and increased body fat within 6 months of initiation of therapy. Lifestyle changes or medical interventions to minimize the effects of androgen deprivation therapy for PCa deserve investigation.     

Comorbidities as predictors of incidental prostate cancer after Holmium laser enucleation of the prostate: diabetes and high-risk cancer

Prostate cancer can be diagnosed as an incidental finding during the pathological examination of benign prostatic hyperplasia (BPH) specimens by Holmium laser enucleation of the prostate (HoLEP). BPH and comorbidities such as hypertension, diabetes, and dyslipidemia often coexist in elderly people. We identified which comorbidities can be used to predict the presence of incidental prostate cancer, particularly high-risk cancer, in men who had undergone HoLEP. On the basis of pathological findings of HoLEP specimens, patients with incidental cancer were categorized as low-risk (Gleason ≤6 and T1a) or high-risk (all others). Of the 654 patients who underwent HoLEP, 41 patients (6.3%) were identified as having incidental cancer (25 low-risk and 16 high-risk). There were no significant factors for overall prostate cancers. However, a significantly higher frequency of diabetes was observed in patients with high-risk cancer compared to those with BPH (31% vs. 13%; p?=?.033). Logistic regression analysis using prostate-specific antigen (PSA) and prostate volume (PV), and smoking showed that diabetes was an independent predictor of high-risk cancer (odds ratio, 3.15; 95% confidence interval, 1.06–9.43). Diabetes may be an important predictor of the presence of high-risk prostate cancer in men with BPH who have undergone HoLEP.