Effects of testosterone administration (and its 5-alpha-reduction) on parenchymal organ volumes in healthy young men: findings from a dose-response trial.

Animal data shows that testosterone administration increases the volume of some parenchymal organs. However, the effects of exogenous testosterone on solid abdominal organs in humans remain unknown. The present study evaluated the effects of testosterone administration on the volume of liver, spleen and kidneys in a dose-response trial. Young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone secretion and weekly injections of 50, 125, 300 or 600 mg of testosterone enanthate, and were randomized to receive either 2.5 mg dutasteride (5 α-reductase inhibitor) or placebo daily for 20 weeks. Liver, spleen and kidney volumes were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose-effect of testosterone on changes in the volume of parenchymal organs was evaluated by linear regression model. The association between changes in total testosterone (TT) levels and changes in organ volumes were assessed. Testosterone administration increased liver volume dose-dependently (17.4 cm3 per 100 mg of weekly testosterone enanthate; p = 0.031); the increase in liver volume was positively associated with changes in TT levels (R2  = 0.08, p = 0.024). A dose-dependent, but non-significant, increase in kidney volumes was also seen. Inclusion of dutasteride use into the models showed an independent association of randomization to dutasteride group with liver volume increase. In conclusion, Testosterone administration increased the liver volume in a dose-dependent manner. The potential changes in parenchymal organs should be considered when interpreting apparent changes in lean mass in response to anabolic interventions.

Evaluating use patterns of and adherence to medications for benign prostatic hyperplasia.

PURPOSE: We investigated adherence to benign prostatic hyperplasia medications in a California Medicaid population. MATERIALS AND METHODS: Using California Medicaid data on 1995 to 2004 we identified adult males 40 years old or older with 1 or more diagnosis and 2 or more prescription fills for benign prostatic hyperplasia. Patients with 2 fills on the same day were assigned to the multiple medication cohort. Adherence was measured using the medication possession ratio for the index medication and the proportion of days covered for any benign prostatic hyperplasia medication. Patients with a medication possession ratio or proportion of days covered of 0.8 or greater were considered adherent. A Cox proportional hazards model was used to assess the relative hazards associated with discontinuation. Multiple logistic regression was used to investigate factors associated with nonadherence or a benign prostatic hyperplasia related procedure. RESULTS: Of the total population of 2,640 men 40% were adherent with any benign prostatic hyperplasia medication. A significantly greater proportion of patients using multiple medications and finasteride were adherent with any benign prostatic hyperplasia medication (62% and 55%, respectively, p <0.0001). Doxazosin, terazosin and tamsulosin use was associated with nonadherence (p = 0.008, 0.04 and 0.03, respectively). Younger patients and those changing medications were more likely to discontinue (p = 0.01 and <0.0001), while patients using multiple medications and those experiencing a gap were at lower risk for discontinuation (p = 0.01 and <0.0001, respectively). Predictors of a procedure included an index prescription in 1999 or later, a urologist visit and nonadherence to any benign prostatic hyperplasia medication (p = 0.01, <0.0001 and <0.0001, respectively). CONCLUSIONS: Adherence to alpha-blockers was less than adherence to finasteride or multiple medications and nonadherence was significantly associated with a procedure. Interventions focused on improving adherence to benign prostatic hyperplasia medications are clearly needed.

Pharmacological approaches to reducing the risk of prostate cancer.

CONTEXT: It is now possible to reduce a man's risk of developing biopsy-detectable prostate cancer. This review addresses the evidence and issues surrounding prostate cancer risk reduction. OBJECTIVE: The scientific basis, therapeutic approach, and risks and benefits of prostate cancer prevention are reviewed. Special attention is given to data on 5alpha-reductase inhibitors (5-ARIs). EVIDENCE ACQUISITION: Medline searches consisted of articles published since 2003 regarding prostate cancer chemoprevention, prevention, or risk reduction, as well as searches around specific topics within this review. EVIDENCE SYNTHESIS: Current data support the use of finasteride for prostate cancer risk reduction in appropriately selected men. The initial concern that finasteride increased the incidence of high-grade prostate cancer has not been confirmed by subsequent analyses. The efficacy of dutasteride, a dual 5-ARI, for prostate cancer risk reduction is currently being evaluated in men with elevated prostate-specific antigen (PSA). Other medical approaches to prostate cancer risk reduction, including statins, cyclooxygenase-2 (COX-2) inhibitors, selective estrogen receptor modulators, and dietary supplements, await validation in controlled clinical trials. CONCLUSIONS: It is now possible to reduce an individual man's risk of developing biopsy-detectable prostate cancer. The greatest benefit arises from decreasing the amount of unnecessary treatment in men harboring low-risk cancers. Presently, there is no evidence that 5-ARIs or any other approach to prostate cancer risk reduction will reduce the risk of lethal prostate cancers. Finasteride, however, does enhance the utility of PSA for diagnosing high-grade cancers.

[Factors determining treatment strategies for patients with benign prostatic hyperplasia. The DUO study]. / Facteurs déterminant le choix thérapeutique des urologues pour la prise en charge des patients ayant une hypertrophie bénigne de la prostate. L'étude DUO.

OBJECTIVES: The DUO study sought to identify the factors determining diagnostic and treatment strategies for benign prostatic hyperplasia (BPH) in daily practice. METHODS: Observational study conducted in France (from June 2004 through March 2005) among a representative sample of French urologists. RESULTS: Two hundred two urologists included 1027 BPH patients (mean age: 68 years +/-9), 856 of whom were seen again six months later. The mean International Prostatic Symptom Score (IPSS) was 14.9 (+/-6.7) at inclusion and 10.5 (+/-6.7) at the follow-up visit. At inclusion, pharmacologic treatment was prescribed to 84% of patients, surgery was recommended to 13% and no treatment to 3%. Factors favoring surgery (versus drugs) were BPH severity (OR=2.5 for IPSS>or=20), patient choice (OR=2.5), expected quality of life improvement (OR=2.2), post-void residual (OR=2.1) and dribbling (OR=1.6). This choice was not associated with patient age, prostatic volume or active sex life. Choice of a 5alpha reductase inhibitor (versus alpha-blocker) was associated with large prostatic volume (OR=7.6), PSA results (OR=5.8), and patient age (OR=5.5 for >or=74 years, OR=2.1 for >or=68 years). Prescription of a combination of alpha-blocker plus 5alpha-reductase inhibitor (versus alpha-blocker alone) was associated with severity of BPH (OR=7.9), prostatic volume (OR=7.8), prevention of complications (OR=3.1), patient age (OR=3.0 if >or=74 years) and post-void residual (OR=2.3). DISCUSSION: Both medical and surgical treatment of BPH resulted in improved IPSS scores at 6 months. Patient age and prostatic volume are reasons urologists prescribe 5alpha reductase inhibitors, but they do not affect the decision about surgical treatment. Surgery is performed in severe BPH or when patients choose surgery in the expectation of improving their quality of life. The factors determining treatment strategies identified in this study are patient age, BPH severity, prostatic volume, patients' wishes, PSA results and post-void residual.

Estudio in vitro de tres antiandrógenos empleados en la actualidad en enfermedades andrógenodependientes / In vitro assay of three antiandrogens presently used in the treatment of androgen dependent diseases

Objetivo: Analizar el efecto in vitro del acetato de ciproterona, finasteride y flutamida, sobre la enzima 5Ó-reductasa, principal indicador bioquímico responsable del potente efecto andrógenico de la tetosterona, al convertirla en dihidrotestosterona. Material y Métodos: Se midio la actividad de la enzima 5Ó-reductasa en la próstata de ratas de macho adultos, utilizando concentraciones de 20 a 500µM de cada antiandrógeno. Resultados: El análisis estadístico muestra que la flutamina presenta mejor actividad antiandrogénica a medida que se incrementa su concentración, mientras que en el acetato de ciproterona y el finasteride, el efecto antiandrogénico fue menor a diferentes concentraciones (p<0.05); probablemente por una mayor velocidad de disociación de estos compuestos con su receptor

Determination of turosteride, a new inhibitor of 5 alpha-reductase, in human plasma by high-performance liquid chromatography with ultraviolet detection.

A sensitive and specific HPLC method for the determination of turosteride in human plasma was developed and validated. Turosteride was extracted from plasma with diethyl ether. Further purifications of the fraction extracted were performed sequentially by solid-phase extraction using a CN cartridge and by liquid-liquid partition between n-hexane and acetonitrile. Finally the acetonitrile solution containing the test compound was evaporated to dryness and the residue dissolved in the mobile phase, then injected onto the HPLC system. The chromatographic separation was performed isocratically by a reversed-phase column filled with ODS using a water-acetonitrile-methanol mixture. The eluate was monitored at 210 nm. No peak interfering with that of turosteride was observed when blank human plasma was assayed. Linearity was obtained in the turosteride concentration range of 5-1000 ng/ml plasma. Six calibration curves in plasma prepared and run on six different days showed correlation coefficients higher than 0.99 and good reproducibility of the slope (C.V. = 4.3%). The intra-day precision, evaluated at three concentrations (in the low, mid and high range of the standard curve) and expressed as C.V., ranged from 0.81 to 13.25%. The inter-day precision evaluated at the same concentrations was better than 10.7%. The inter-day accuracy evaluated in the same samples and expressed as the ratio of found/added amount of turosteride ranged from 97.66 to 98.38%. The limit of quantitation was 5 ng/ml plasma. The HPLC method described was successfully employed for the determination of turosteride in plasma samples obtained during a phase I clinical trial with the test compound.

Pharmacokinetics and absolute bioavailability of epristeride in healthy male subjects.

The objective of the current investigation was to describe the pharmacokinetics and absolute oral bioavailability of epristeride. Twelve healthy male subjects (mean (SD) age, 27 (6.2) years) received a single oral dose of 5 mg and an intravenous infusion of 4.5 mg over 30 min in a crossover fashion. Blood samples were obtained over 72h for the determination of epristeride plasma concentrations using a sensitive high-performance liquid chromatography assay. The lower limit of quantification was 5 ng mL-1. Pharmacokinetic analysis of the plasma concentration-time data was performed by both non-compartmental and compartmental methods. Absolute bioavailability was determined using dose-normalized AUC values following oral and intravenous administration. Epristeride plasma concentrations declined in a biexponential fashion with secondary peaks evident around 24 h in a majority of subjects following both routes of administration. Maximal plasma concentrations were typically achieved approximately 4 h after oral dosing. The mean apparent terminal elimination half-life estimates were similar following intravenous and oral administration and were 27.3 and 26.2 h, respectively. The mean plasma clearance and steady-state volume of distribution were 0.33 (0.09) mL min-1 kg-1 and 0.54 (0.17) L kg-1, respectively. The mean absolute bioavailability was 93% (95% CI: 84%, 104%). Following compartmental analysis of the intravenous data, the mean (SD) lambda 1 and lambda 2 half-life estimates were 2.74 (0.48) and 31.8 (19.5) h, respectively. The % AUC associated with the lambda 2 exponential phase was approximately 68%. This long half-life allows for once-daily dosing of epristeride.

High-performance liquid chromatographic method for the determination of finasteride in human plasma at therapeutic doses.

A high-performance liquid chromatographic (HPLC) method with ultraviolet detection for the determination of a novel 4-aza-steroidal inhibitor of 5 alpha-reductase in human plasma has been developed. The assay is based on a single solid-phase extraction and an efficient HPLC separation on two analytical columns in series. The assay has been fully validated and used to support Phase II and III clinical pharmacokinetic studies. The lowest limit of quantification was found to be at 1 ng/ml and allowed pharmacokinetic evaluation of the drug at doses down to 5 mg.