The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia

The dual 5alpha-reductase inhibitor, dutasteride has been shown to suppress serum dihydrotestosterone (DHT) by >90%. In the present study, the effect of dutasteride 0.5 mg/day on intraprostatic DHT levels was investigated. In this multicenter, double-blind trial, 43 men with benign prostatic hyperplasia (BPH) scheduled to undergo transurethral resection of the prostate (TURP) were randomized to receive dutasteride, 0.5 mg/day or placebo for 3 months before surgery. Intraprostatic DHT, testosterone and dutasteride levels were determined at the time of TURP. Changes in serum DHT and testosterone from baseline, and both serum and intraprostatic dutasteride levels at the time of TURP were also assessed. Dutasteride reduced intraprostatic DHT by 94% relative to placebo (P<0.001); the adjusted mean intraprostatic DHT concentration was 3.23 and 0.209 ng/g in the placebo and dutasteride groups, respectively. In the dutasteride group, serum DHT was reduced from baseline by 93% at month 3, a significantly greater reduction (P<0.001) than the 15% decrease observed in the placebo group. There was a reciprocal increase in intraprostatic testosterone but the level of intraprostatic testosterone in the dutasteride group tended to be lower than the intraprostatic DHT level in the placebo group (P=0.06). Significant intraprostatic DHT suppression was achieved in all subjects who received dutasteride, regardless of the level of intraprostatic dutasteride. There was a strong positive correlation between serum and intraprostatic dutasteride concentrations (R(2)=0.73). After 3 months of treatment, dutasteride 0.5 mg/day provided near-complete suppression of both intraprostatic and serum DHT in men with BPH.     

Histological and hormonal testicular function in oligo/azoospermic infertile men

We characterised and correlated the histological and hormonal aspects of a cohort of 261 azo/oligozoospermic men, applying a quantitative/qualitative evaluation of testicular tissue and serum and intratesticular hormonal measurements. One hundred and 93 azo?oligozoospermic patients were diagnosed as: complete sertoli cell only syndrome (cSCOS), n = 76; focal SCOS, n = 31; maturation arrest, n = 34; hypospermatogenesis, n = 17; mixed atrophy, n = 25; and severe atrophy, n = 10. Normal spermatogenesis was observed in 68 infertile men (controls). Patients with cSCOS, focal SCOS, mixed and severe atrophy had larger LC/clusters (11.5; 11.0; 10.7; 18.9 LC/cluster) than controls (6 LC/cluster; P < 0.001). cSCOS, focal SCOS, mixed and severe atrophy patients had higher FSH, LH and lower T/LH ratio serum levels than the other groups. Intratesticular testosterone concentrations were higher in tissues with complete or focal SCOS (45.6 ng mg^?1 protein) and mixed atrophy (79.0 ng mg^?1 protein) than normal tissues (20.3 ng mg^?1 protein; P = 0.03 and P = 0.007). Considering all subjects, significant correlations were found between T/LH ratio and Leydig cells/cluster (r = 0.510, P < 0.001), FSH levels (r = ?0.692, P < 0.001) and with intratesticular testosterone (r = ?0.354, P = 0.001); these correlations follow the pattern of severity of spermatogenic damage. By a thorough histological evaluation, we validate the concept that the severity of spermatogenic impairment is associated with major morphological and functional disturbance of the Leydig cell compartment.     

Serum testosterone levels in diabetic men with and without erectile dysfunction

Diabetes mellitus is a common chronic disease, affecting 0.5–2% worldwide. The Massachusetts Male Aging Study reported that up to 75% of men with diabetes have a lifetime risk of developing ED. Type 2 diabetes is associated with low total serum testosterone (TT) identified in several cross‐sectional studies and systemic analyses. There is a lack of consensus regarding what constitutes the lowest level of testosterone within the boundaries of normality. In this retrospective study, we sought to evaluate the effect of associated co‐morbidities on serum total testosterone (TT) level in men with type 2 diabetes DM, either with or without erectile dysfunction (ED). Three hundred and ninety‐one patients were evaluated for erectile function using an abridged, five‐item version of the International Index of Erectile Function‐5. Measurements of TT, fasting lipid profile, blood sugar and glycated haemoglobin (HbA1c) were conducted. Penile hemodynamics was assessed using intracavernosal injection and penile duplex study. Hypogonadism was found in 126 cases (33.2%), and normal TT was observed in 254 (66.8%). ED was detected in 119 cases in the hypogonadal group (94.4%) as compared to 155/254 (61.0%) in eugonadal group, P = 0.0001. TT was lower in diabetic men with ED as compared to those with normal erectile function (EF), 392.4 ± 314.9 versus 524.3 ± 140.2 ng dl^?1, respectively, P < 0.0001. After exclusion of patients with hypertension and dyslipidaemia, 185 men were evaluated, and there was no difference in the mean TT level among men with ED 490.6 ± 498.2 ng dl^?1 versus normal EF 540.6 ± 133.4 ng dl^?1 although, HbA1c remained lower in men with normal erectile function. Receiver operating characteristic (ROC) curve of TT in men without associated co‐morbidities showed that EF was compromised at TT = 403.5 ng dl^?1 or less. Sensitivity of 63.3% and a specificity of 94.0% were detected. At this level, ED was found in 33/38 (86.8%) men with TT 403.5 ng dl^?1, whereas ED was observed in 57/147 (38.8%) men with TT ≥ 403.5 ng dl^?1 (P < 0.0001). We propose a cut‐off value of 403.5 ng dl^?1 of TT blood levels as an indicator for initiation of testosterone replacement therapy in diabetic men with ED. Further prospective controlled trials are recommended.     

Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial

What’s known on the subject? and What does the study add? Treatment of benign prostatic hyperplasia (BPH) centres on two drug classes, 5α‐reductase inhibitors and α‐blockers. The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study investigated whether the combination of dutasteride and tamsulosin was more effective than either monotherapy in reducing the relative risk of AUR, BPH‐related surgery, and BPH clinical progression in men with moderate‐to‐severe LUTS who were at increased risk of disease progression. Data from the 2‐ and 4‐year, pre‐planned primary and secondary endpoint analyses for the CombAT study have been reported previously. This study reports the outcomes of post hoc analyses of the influence of baseline parameters on the incidence of AUR, BPH‐related surgery, and overall clinical progression in patients treated with tamsulosin, dutasteride, or combination therapy with both agents.

OBJECTIVE

? To investigate the influence of baseline variables on the 4‐year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)‐related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both.

PATIENTS AND METHODS

? The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double‐blind, parallel‐group study of clinical outcomes in men aged ≥50 years with symptomatic (International Prostate Symptom Score [IPSS]≥12) BPH, with prostate‐specific antigen (PSA) levels of ≥1.5 ng/mL and ≤10 ng/mL, and a prostate volume (PV) of ≥30 mL. ? Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. ? The primary endpoint was time to first AUR or BPH‐related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health‐related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q_max] and body‐mass index [BMI]) on the incidence of AUR or BPH‐related surgery, clinical progression of BPH, and symptoms were performed.

RESULTS

? There were 4844 men in the intent‐to‐treat population. Overall baseline characteristics were similar across all patient groups. ? Regardless of baseline subgroup, the incidence of AUR or BPH‐related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. ? Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH‐related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P≤ 0.001). ? Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of <20 or IPSS HRQL score of <4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of <40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. ? Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of <40 mL) and compared with dutasteride in most subgroups.

CONCLUSIONS

? Men with a baseline PV of ≥40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH‐related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. ? These analyses support the long‐term use of combined therapy with dutasteride plus tamsulosin in men with moderate‐to‐severe BPH symptoms and a slightly enlarged prostate.     

The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? Long‐term treatment with combination therapy (dutasteride plus tamsulosin) is significantly superior to tamsulosin but not dutasteride at reducing the relative risk of AUR or BPH‐related surgery. Furthermore, combination therapy is significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression, and provides significantly greater reductions in IPSS. In addition, combination therapy significantly improves patient‐reported, disease specific QoL and treatment satisfaction compared with either monotherapy. Two‐year results from the CombAT study showed that combination therapy was more effective than either monotherapy in controlling both storage and voiding symptoms, irrespective of baseline prostate volume (for men with prostate volume ≥30 cc). This post‐hoc two‐year analysis also showed that treatment with dutasteride not only improved voiding symptoms, as would be expected from its effects on prostate volume, but was also as effective as the α‐blocker tamsulosin in the control of storage symptoms.

OBJECTIVE

• ? To assess the effects of combined therapy with dutasteride and tamsulosin on voiding and storage symptoms compared with those of dutasteride or tamsulosin alone, using 4‐year data from the Combination of Avodart and Tamsulosin (CombAT) study.

PATIENTS AND METHODS

• ? Men (n = 4844) aged ≥50 years with moderate‐to‐severe lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH), a prostate volume of ≥30 mL, and a serum prostate‐specific antigen level of 1.5–10 ng/mL.
• ? CombAT was a multicentre, double‐blind, parallel‐group study.
• ? Oral dutasteride (0.5 mg) or tamsulosin (0.4 mg) alone or in combination was taken daily for 4 years.
• ? Mean changes from baseline in storage and voiding symptoms at 4 years were assessed using subscales of the International Prostate Symptom Score.

RESULTS

• ? At 4 years, the mean reduction in the storage subscore was significantly greater in the combined therapy group vs the dutasteride (adjusted mean difference ?0.43) and tamsulosin (adjusted mean difference ?0.96) monotherapy groups (P < 0.001).
• ? Also at 4 years, the mean reduction in the voiding subscore was significantly greater in the combined therapy group vs the dutasteride (adjusted mean difference ?0.51) and tamsulosin (adjusted mean difference ?1.60) monotherapy groups (P < 0.001).
• ? The improvement in the storage subscore with combined therapy was significantly better (P < 0.001) than dutasteride and tamsulosin from 3 months and 12 months, respectively. Similarly, the improvement in the voiding subscore with combined therapy was significantly better than dutasteride (P < 0.001) and tamsulosin (P ≤ 0.006) from 3 months and 6 months, respectively.
• ? Improvements in the storage and voiding symptom subscores with combined therapy were achieved irrespective of prostate volume, although in men with the highest baseline prostate volumes (≥58 mL), combined therapy was not better than dutasteride.

CONCLUSIONS

• ? In men with a prostate volume of ≥30 mL, combined therapy with dutasteride plus tamsulosin provided better long‐term (up to 4 years) control of both storage and voiding LUTS compared with tamsulosin monotherapy.
• ? Combined therapy was better than dutasteride monotherapy in men with prostate volumes of ≥30 to <58 mL, but not in men with a prostate volume of ≥58 mL.

     

The micronutrient supplements,zinc sulphate and folic acid,did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men

We investigated the effects of folic acid and zinc sulphate supplementation on the improvement of sperm function in subfertile oligoasthenoteratozoospermic (OAT) men. Eighty‐three OAT men participated in a 16‐week intervention randomised, double‐blind clinical trial with daily treatment of folic acid (5 mg day^?1) and zinc sulphate (220 mg day^?1), or placebo. Before and after treatment, semen and blood samples were obtained for determining sperm concentration, motility, and morphology, sperm viability, sperm mitochondrial function, sperm chromatin status using toluidine blue, aniline blue, acridine orange and chromomycin A₃ staining; and semen and blood folate, zinc, B₁₂, total antioxidant capacity ( TAC) and malondialdehyde (MDA) concentrations. Sperm concentration (×10⁶ ml^?1) increased in subfertile men receiving the combined treatment of folic acid and zinc sulphate and also in the group receiving only folic acid treatment; however, it was not statistically significant (P = 0.056 and P = 0.05, respectively). Sperm chromatin integrity (%) increased significantly in subfertile men receiving only zinc sulphate treatment (P = 0.048). However, this improvement in sperm quality was not significant after adjusting placebo effect. This study showed that zinc sulphate and folic acid supplementation did not ameliorate sperm quality in infertile men with severely compromised sperm parameters, OAT. Male infertility is a multifactorial disorder, and also nutritional factors play an important role in results of administration of supplementation on sperm parameters. However, these results should be confirmed by multiple studies in larger populations of OAT men.     

Dutasteride monotherapy in men with serologic relapse following radical therapy for adenocarcinoma of the prostate: A pilot study

ObjectiveThe objective of this study was to assess the effect of dutasteride on serum prostate specific antigen (PSA) levels in men with serologic relapse following radical prostatectomy and/or radiation therapy for clinically localized adenocarcinoma of the prostate.MethodsA prospective, single institution, IRB approved trial was conducted. Entry criteria required that all participants have serologic disease relapse only with serum PSA levels between 0.4 and 10.0 ng/ml. Enrolled participants were treated with 0.5 mg dutasteride daily. The primary endpoints were serum PSA level and clinical recurrence. The rate of durable decline in PSA was assessed according to the recommendations of the Prostate-Specific Antigen Working Group.ResultsThirty-five patients provided informed consent and participated in the present study. At a median follow-up duration of 27 months (range, 4–42 months), 46% of enrolled men had a serum PSA decrease of greater than 10%, and 25% had a serum PSA decrease of greater than 50% (P < 0.001). Pre-study PSA doubling time (PSADT) (≥12 months vs. <12 months), and Gleason score (≤6 vs. ≥7) were associated with a better response to dutasteride, but only PSADT was statistically significant (P < 0.001). Thirty percent of patients experienced PSA progression (increase in serum PSA of greater than 50%). Two (6%) patients developed bone metastasis. No patient was removed from the study for drug-related toxicity.ConclusionsIn the present pilot study, treatment with dutasteride resulted in a significant decrease in serum PSA in men with serologic relapse following radical treatment for adenocarcinoma of the prostate. These data appear to suggest that dutasteride may delay or prevent progression of prostate cancer in some men with biochemical relapse after radical therapy. These findings require confirmation in the setting of a larger, longer trial.     

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Previous studies used the decrease in PSA after 6 months of dutasteride treatment as a new ‘baseline’ PSA value from which subsequent rises may serve as a warning for prostate cancer; however, PSA tends to continue to decrease as dutasteride treatment continues. By comparing positive biopsy rates in the REDUCE study using any rise from nadir in the dutasteride arm and standard PSA decision criteria (NCCN) in the placebo arm, we demonstrated that the ability to detect prostate cancer and high grade prostate cancer is maintained with dutasteride treatment.

OBJECTIVES

? To determine if dutasteride‐treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. ? To analyse whether the use of treatment‐specific criteria for repeat biopsy maintains the usefulness of prostate‐specific antigen (PSA) level for detecting high grade cancers.

PATIENTS AND METHODS

? The REDUCE study was a randomized, double‐blind, placebo‐controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy‐detectable prostate cancer in men with a previous negative biopsy. ? The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. ? The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. ? Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds.

RESULTS

? Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. ? If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8–10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8–10 cancers would have been missed in the placebo group. ? In both groups, the incidence of Gleason 7 and Gleason 8–10 cancers generally increased with greater rises in PSA. ? Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7–10 cancers in men treated with dutasteride vs placebo. ? Men with Gleason 7 and Gleason 8–10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds.

CONCLUSION

? Using treatment‐specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. ? The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8–10) or higher than (Gleason 7–10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.     

Obesity Is Associated with Increased Prostate Growth and Attenuated Prostate Volume Reduction by Dutasteride

Background

Although obesity has been associated with larger prostate volumes (PV), few studies have actually investigated whether obesity enhances PV growth, especially among men using 5α-reductase inhibitors.

Objective

To examine whether obesity is associated with enhanced PV growth measured by serial transrectal ultrasound (TRUS) measurements.

Design, setting, and participants

We conducted a secondary analysis of the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, which was originally aimed at cancer risk reduction among high-risk men with a single negative prestudy biopsy.

Intervention

Per-protocol randomization to placebo or dutasteride and mandatory TRUS-guided biopsies at 2 yr and 4 yr.

Outcome measurements and statistical analysis

Percentage change in PV at 2 yr and 4 yr from baseline. We tested its association with baseline body mass index (BMI) groups of <25, 25–29.9, and ≥30 kg/m² using multivariable linear regression. Secondarily, we tested whether BMI was associated with the likelihood of having no PV reduction among men randomized to dutasteride using multivariable logistic regression.

Results and limitations

Of 8122 participants, we analyzed 71.8% and 54.5% with complete 2-yr and 4-yr PV data, respectively. In multivariable analysis, men on placebo with BMI ≥30 versus <25 kg/m² had enhanced PV growth from baseline (at 2 yr: 17.0% vs 10.7%, p < 0.001; at 4 yr: 29.4% vs 20.1%; p = 0.001). Men on dutasteride with BMI ≥30 versus <25 kg/m² had attenuated PV reduction from baseline (at 2 yr: −14.3% vs −18.5%; p = 0.002; at 4 yr: −13.2% vs −19.3%; p = 0.001) and higher likelihood of having no PV reduction (at 2 yr: odds ratio [OR]: 1.44; 95% confidence interval [CI], 1.08–1.93; p = 0.014; at 4 yr: OR: 1.62; 95% CI, 1.18–2.22; p = 0.003). We found no significant interactions between BMI and dutasteride on PV change at 2 yr and 4 yr (p interaction ≥0.36). No clinical outcomes or effects of weight change were assessed.

Conclusions

Obesity enhanced PV growth and attenuated PV reduction by dutasteride. The null interaction between obesity and dutasteride for PV change implies that the effect of obesity on dutasteride-treated men is likely a combination of dutasteride-driven PV reduction with obesity-driven PV growth rather than decreased dutasteride efficacy.

ClinicalTrials.gov identifier

NCT00056407.     

Clinical usefulness of serum prostate specific antigen for the detection of prostate cancer is preserved in men receiving the dual 5alpha-reductase inhibitor dutasteride

PURPOSE: We determined whether the decrease in serum PSA seen with 5alpha-reductase inhibitors affects the clinical usefulness of PSA for prostate cancer screening using data from 2 dutasteride benign prostatic hyperplasia studies. MATERIALS AND METHODS: A total of 2,802 men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia, no history of prostate cancer, PSA 1.5 to 10 ng/ml, prostate volume 30 cc or greater, an American Urological Association symptom score of 12 or greater and peak urinary flow rate 15 ml per second or less were randomized to 0.5 mg dutasteride daily or matching placebo for 24 months. Increases in PSA from baseline and the maximum increase from nadir to month 24 were compared between the groups and analyzed by prostate cancer status, as determined by PSA driven biopsy and an advised cutoff of more than 4 ng/ml after doubling to correct for dutasteride treatment with sensitivity and specificity calculated for each. RESULTS: In placebo treated men without prostate cancer there was an 8.3% median increase in PSA at month 24 compared with -59.5% in those who received dutasteride, using doubled values to correct for dutasteride treatment. In those with prostate cancer these changes were 23.8% and -37.2%, respectively. Using the upper PSA limit of 4 ng/ml sensitivity for prostate cancer in men receiving dutasteride vs placebo was 0.737 vs 0.804, while specificity was 0.671 vs 0.578. Using a PSA increase from nadir of 0.8 ng/ml the sensitivity of dutasteride was 0.548 and its specificity was 0.795. CONCLUSIONS: A doubling factor is effective for maintaining the sensitivity and specificity of PSA for prostate cancer detection in men on dutasteride. Increases in serum PSA in men receiving dutasteride should be considered suspicious and serial PSA measurements should be used to evaluate changes from nadir.     

Effect of Coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double‐blind randomised clinical trial

Low seminal plasma concentrations of coenzyme Q10 (CoQ10) have been correlated with impaired sperm parameters, but the exact mechanism remains of dominating interest. This randomised, placebo‐controlled study examined the effect of CoQ10 on catalase, superoxide dismutase (SOD) and F₂‐isoprostanes in seminal plasma in infertile men and their relation with CoQ10 concentration. Sixty infertile men with idiopathic oligoasthenoteratozoospermia (OAT) were randomised to receive 200 mg d^?1 of CoQ10 or placebo for 3 months. 47 persons of them completed the study. Semen analysis, anthropometric measurements, diet and physical activity assessment were performed for subjects before and after treatment. Independent and paired t‐test, chi‐square test and ancova were compared outcomes of supplementation between two groups. CoQ10 levels increased from 44.74 ± 36.47 to 68.17 ± 42.41 ng ml^?1 following supplementation in CoQ10 (P < 0.001). CoQ10 group had higher catalase and SOD activity than the placebo group. There was a significant positive correlation between CoQ10 concentration and normal sperm morphology (P = 0.037), catalase (P = 0.041) and SOD (P < 0.001). Significant difference was shown between the mean of changes in seminal plasma 8‐isoprostane in two groups (P = 0.003) after supplementation. Three‐month supplementation with CoQ10 in OAT infertile men can attenuate oxidative stress in seminal plasma and improve semen parameters and antioxidant enzymes activity.     

Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS)

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Both dutasteride and finasteride inhibit type 2 5α‐reductase, the dominant form of 5α‐reductase in benign prostatic tissue, making these effective treatments for BPH. In comparison with finasteride, dutasteride has a longer half‐life and leads to a greater and more consistent suppression of serum and intraprostatic DHT. EPICS is currently the only prospective, randomized, double‐blind study of finasteride vs dutasteride for BPH endpoints conducted for longer than a few months. Over a one‐year period, treatment with dutasteride and finasteride led to similar reductions in prostate volume, and improvements in peak urine flow and urinary symptoms associated with BPH in men with an enlarged prostate. Men treated with finasteride and dutasteride also experienced similar rates of adverse events over the course of one year, which suggests that inhibition of both type 1 and type 2 5α‐reductase, resulting in greater DHT suppression than type 2 inhibition alone, does not confer an increase in adverse events. Given the long‐term, progressive nature of BPH, the one‐year duration of EPICS may limit the potential to observe major differences between dutasteride and finasteride treatment.

OBJECTIVE

• ? To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months.

PATIENTS AND METHODS

• ? The Enlarged Prostate International Comparator Study was a multicentre, randomized, double‐blind, 12‐month, parallel‐group study.
• ? Men aged ≥50 years with a clinical diagnosis of BPH received once‐daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4‐week placebo run‐in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24‐month, open‐label phase, during which patients received dutasteride 0.5 mg once daily.
• ? The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA‐SI) scores, improvement in maximum urinary flow rate (Q_max) and long‐term safety in the 24‐month open‐label phase.

RESULTS

• ? Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study.
• ? Similar reductions in mean AUA‐SI scores and Q_max were also observed for men in both treatment groups.
• ? A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open‐label phase.

CONCLUSION

• ? Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Q_max and urinary symptoms associated with BPH in men with an enlarged prostate.

     

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate

Objectives. Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide.Methods. Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride 5, mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first second nadir PSA values.Results. The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 ± 38.2 ng/mL at baseline and 7.8 ± 2.7 and 4.7 ± 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 ± 3.1% with flutamide alone and 94.0 ± 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 ± 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 ± 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 ± 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 ± 4.7% (P = 0.0009).Conclusions. Finasteride and flutamide were safe and well tolerated at AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.     

Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer

PURPOSE: In the prostate testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase (5alphaR) types 1 and 2 (5alphaR1 and 5alphaR2). Suppression of DHT formation by 5alphaR inhibition may be beneficial in early treatment or prevention of prostate cancer. Although 5alphaR2 is the dominant enzyme in the prostate, evidence indicates that 5alphaR1 may be up-regulated in some prostate cancers. This suggests that dual inhibition of both isoenzymes may be more effective than suppression of 5alphaR2 alone in prostate cancer treatment or prevention. In this short-term pilot study we examined the effect of the dual 5alphaR inhibitor dutasteride on markers of tumor regression. MATERIALS AND METHODS: A total of 46 men with clinically staged T1 or T2 prostate cancer were randomized to receive 5 mg per day of placebo or dutasteride for 6 to 10 weeks before radical prostatectomy. Resected tissues were analyzed to determine the effect of dutasteride on intraprostatic androgen levels, and indices of apoptosis and microvessel density (MVD) in malignant tissue, as well as degree of atrophy in benign tissue. RESULTS: Treatment with dutasteride caused a 97% decrease in intraprostatic DHT and was associated with a trend toward increased apoptosis. In patients receiving dutasteride for 45 days or more, a significant increase in apoptosis and a trend toward decreased MVD in prostate cancer tissue was observed. Dutasteride treatment was also associated with an 18% decrease in mean benign epithelial cell width compared with placebo (p < 0.0001). CONCLUSIONS: In this pilot study dutasteride treatment resulted in almost complete suppression of intraprostatic DHT, increased apoptosis and a trend toward decreased MVD. These findings suggest that short-term treatment with dutasteride can cause regression in some prostate cancers.     

The efficacy,bioavailability and safety of a novel hydroalcoholic testosterone gel 2% in hypogonadal men: results from phase II open‐label studies

Pharmacokinetics, pharmacodynamics and safety of a novel hydroalcoholic testosterone gel 2% (TG) were evaluated in phase II sequential dose escalation studies using 3 application sites (thigh, abdomen and shoulder/upper arm) and 2 application methods. Hypogonadal men (n = 40), 18–75 years, with serum testosterone <300 ng dl^?1 were included in both studies. Study 1 evaluated hand‐applied multiple doses of TG 1.25, 2.50 and 3.75 ml (23, 46 and 70 mg of testosterone, respectively), once daily for 10 days to shoulder/upper arm. Study 2 evaluated applicator‐applied (TG 1.25, 2.50 and 3.75 ml) versus hand‐applied (TG 2.5 ml) doses, once daily for 7 days to shoulder/upper arm. Primary endpoint for both studies was responder rate (C_ave testosterone levels between 298 and 1050 ng dl^?1). In Study 1 following multiple applications, >70% participants in each group were responders. Dose‐dependent increase was observed in PK values for total testosterone, free testosterone and DHT. In Study 2, responder rate was dose proportional: 16.7%, 50.0% and 77.8% responders in TG 1.25, 2.50 and 3.75 ml groups respectively. The bioavailability was highest for the shoulder application. There was a significant improvement in almost all the domains of sexual functioning. Applicator‐application was preferred over hand‐application by majority of the participants. TG was found to be safe and well tolerated in hypogonadal men.     

A study on the association between serum amyloid A and sperm concentration

Our aim was to compare peripheral blood and seminal fluid serum amyloid A (SAA) protein levels in men classified on the basis of sperm concentration and investigate whether SAA protein is an important marker of male infertility. A total of 74 first‐attempt IVF male partners of infertile couples classified as azoospermic (n = 25), oligozoospermic (n = 25) and normozoospermic group (n = 24) were recruited for this cross‐sectional study. There was no difference with respect to age, BMI, infertility period and smoking ratio. No difference in haematologic parameters including white blood cell count, neutrophil ratio, lymphocyte ratio, neutrophil‐to‐lymphocyte ratio and blood SAA level was found between the groups. Seminal fluid SAA level was 17.85 ± 2.21 ng ml^?1 in azoospermics, 16.13 ± 3.58 ng ml^?1 in oligozoospermics and 15.67 ± 4.77 ng ml^?1 in normozoospermics, showing no significant difference. Seminal SAA level was found to be not correlated with blood SAA levels. Therefore, we could not find any associations between these parameters at all. However, further studies with more participants are needed to address the exact action of SAA on spermatogenesis.     

Can testosterone level be a good predictor of late‐onset hypogonadism?

Androgens are essential for the development and growth of the genitalia. They regulate the erectile physiology by multiple mechanisms. Several studies have examined associations among sex hormones' serum levels, erectile function and sex drive. We sought to identify a protocol for using testosterone in men with erectile dysfunction and late‐onset hypogonadism (LOH). During a 16‐month period, men with erectile dysfunction who presented to the andrology clinic were selected. They underwent a complete physical examination and filled out the International Index of Erectile Function‐5 questionnaire. Serum luteinising hormone (LH) and testosterone levels were evaluated. Patients received a single intramuscular injection of 250 mg testosterone. Thereafter, serum levels of LH and testosterone were measured 3 weeks later. The mean age was 53 years old. After treating patients with testosterone, 45 (94%) showed improvement in LOH symptoms including libido, loss of energy, irritability and quality of life. The mean International Index of Erectile Function was 9 and 13.1, prior to and after treatment respectively. Mean serum testosterone levels before and after treatment were 4.2 and 4.1 ng ml^?1 respectively (P = 0.849). Mean serum LH revealed a significant decrease after the study (P = 0.004) (6.12 and 5.1 ng ml^?1, before and after the study respectively). Our findings suggested that testosterone replacement therapy improves libido and LOH symptoms in individuals with almost normal or lower limit normal value of serum testosterone levels.     

Seminal level of clusterin in infertile men as a significant biomarker reflecting spermatogenesis

The objective of this study was to assess the impact of seminal clusterin level on spermatogenesis in infertile men. This study included 89 men who visited our clinic due to infertility, consisting of 28, 33, and 28 diagnosed with normospermia, oligozoospermia and nonobstructive azoospermia (NOA) respectively. The seminal clusterin concentrations measured by enzyme‐linked immunosorbent assay were 47.9, 28.2 and 18.4 ng ml^?1 in men with normospermia, oligozoospermia and NOA, respectively, with significant differences among these three groups (P < 0.01). Microdissection testicular sperm extraction (MD‐TESE) was performed in the 28 men with NOA, and spermatozoon was successfully retrieved from 9. There was a significant correlation between seminal clusterin level and testicular clusterin protein expression evaluated by immunohistochemical staining in these men with NOA (P = 0.026). Of several parameters available before MD‐TESE, the univariate analysis identified serum follicle‐stimulating hormone (FSH) level <10 IU ml^?1 and seminal clusterin level ≥18 ng ml^?1 as significant predictors of sperm retrieval, and of these, only serum FSH level <10 IU ml^?1 was shown to be independently associated with sperm retrieval in the multivariate analysis. Accordingly, it might be worthy to further evaluate the significance of seminal clusterin level as a biomarker for the assessment of spermatogenic status in infertile men.     

INFLUENCE OF FINASTERIDE ON FREE AND TOTAL SERUM PROSTATE SPECIFIC ANTIGEN LEVELS IN MEN WITH BENIGN PROSTATIC HYPERPLASIA

Purpose

Finasteride therapy for benign prostatic hyperplasia (BPH) results in a marked lowering of serum prostate specific antigen (PSA) levels. However, little is known about the effect of finasteride on unbound or free serum levels of PSA. Such information would be important since percent free PSA may substantially improve the cancer specificity of PSA testing. Thus, we prospectively studied the effect of finasteride therapy on total and free serum PSA levels.

Materials and Methods

In a randomized, placebo controlled, double-blind trial 40 men with histologically confirmed BPH (age range 52 to 78 years) were treated with either 5 mg. finasteride daily (26 patients) for 9 months or placebo (14) for 6 months. Prostate volume was assessed by transrectal ultrasound. Serum levels of free and total PSA were measured from archived serum samples stored at −70C at baseline and for as long as 9 months of treatment.

Results

In the finasteride group mean total PSA levels declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6 months of treatment (50% decrease, p < 0.01). In the placebo group, with similar baseline levels, no significant change was observed. PSA density declined significantly in finasteride treated men (p <0.01) but not in men receiving placebo. The mean percent free PSA (13 to 17% at baseline) was not altered significantly by finasteride or placebo.

Conclusions

Total PSA serum levels decreased by an average of 50% during finasteride therapy but percent free PSA did not change significantly. This information is potentially useful in the interpretation of PSA data used for early detection of prostate cancer in men receiving finasteride. However, further studies are required to demonstrate the use of percent free PSA to detect the development of cancer.     

Alendronate for osteoporosis in men with androgen-repleted hypogonadism

Male hypogonadism is associated with low bone mineral density (BMD) and an increased risk of fractures. Testosterone replacement therapy improves BMD in young hypogonadal men. This effect is milder in older patients, who are at greater risk for fractures. We studied the effects of alendronate or placebo on BMD in 22 osteoporotic men, 29–69 years of age (mean, 50.2±11.2 years) with long-standing hypogonadism, receiving standard testosterone replacement treatment. Alendronate 10 mg daily ( n =11) increased lumbar-spine BMD by 6.0 and 8.4% at 6 and 12 months, respectively, compared with –0.5% at 6 months and +3.3% at 12 months in the placebo group ( n =11; P <0.005). Alendronate also increased mean femoral-neck BMD by 1.9% after 1 year, compared to a 1.4% decrease with placebo ( P <0.005), and increased the total body bone mineral content by 4.4%, compared to a 0.6% decrease with placebo ( P =0.07). After 6 months alendronate suppressed urinary deoxypyridinoline by 50% ( P <0.005), compared to a 24% decrease in the placebo group. Both the alendronate and placebo groups continued with alendronate 70 mg once weekly for the following 2 years. Lumbar-spine BMD during this open-label study phase did not change significantly in the group originally treated with alendronate, but continued to increase in the placebo-alendronate group by 5.4, 6.5, and 6.2% after 18 (6 months of alendronate), 24 and 36 months, respectively ( P <0.05). Femoral-neck BMD continued to increase in both groups receiving active therapy; in the alendronate-alendronate group by 3.7, 2.7, and 5.2% after 18, 24, and 36 months, respectively ( P =0.01), and in the placebo-alendronate group by 0.7 and 1.9% at 24 (first 12 months of alendronate) and 36 months, respectively ( P <0.05). Our results support the long-term administration of alendronate along with testosterone replacement to men with hypogonadism-induced osteoporosis.