finasteride, Propecia
Activation of caspases-3, -6, and -9 during finasteride treatment of benign prostatic hyperplasia.

Bozec A, Ruffion A, Decaussin M, Andre J, Devonec M, Benahmed M, Mauduit C.

Institut National de la Sante et de la Recherche Medicale U 407, Faculte de Medecine Lyon-Sud, BP 12, 69921 Oullins Cedex, France.

Benign prostatic hyperplasia (BPH) results from an increase in both epithelial and stromal compartments of the human prostate. Although inhibitors of 5alpha-reductase such as finasteride have been shown to reduce the size of BPH tissues by inducing apoptosis, their mechanisms of action still remain unknown. The present study supports that such a process triggered by finasteride is caspase dependent with a possible involvement of two effector caspases (caspase-3 and 6) and two initiator caspases (caspase-8 and 9). Indeed, by using tissues from patients affected by BPH and treated by finasteride (5 mg/d) for 2-3, 6-8, or 27-32 d, we observed that the 5alpha-reductase inhibitor induced apoptosis in epithelial cells (evaluated through cell number positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) as early as 2-3 d of treatment, with a maximal activity (250-fold increase, P < 0.0001) at 6-8 d of treatment. However, after 27-32 d of treatment, the number of apoptotic cells was reduced and was close to control. Caspases-3, -6, -8, and -9 were immunolocalized to (basal and secretory) epithelial cells and to a lesser extent to stromal cells. Activated caspase-3 immunoexpression was restricted to epithelial secretory cells, and its immunostaining intensity appeared to be higher in BPH tissues from patients treated for 2-3 or 6-8 d. Consistently, in Western blotting analyses, activated caspases-3 and -6 were detected as early as 2-3 d of treatment in BPH tissues, and their levels were increased after 6-8 d of treatment. In real time quantitative PCR experiments, caspase-3 and -6 mRNA levels were found to be unchanged after finasteride treatment. Activated caspase-8 was not detected in the different conditions tested, whereas activated caspase-9 protein levels were maximally enhanced after 2-3 d of finasteride treatment. In conclusion, we report here that finasteride treatment of BPH tissues induced a caspase-dependent apoptotic process restricted to epithelial cells by activating effector caspases-3 and -6 and exhibited a transient action because the apoptotic process was no longer observed after 27-32 d of treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15507514&dopt=Abstract finasteride Propecia



finasteride, Propecia
Exogenous Testosterone (T) Alone or with Finasteride Increases Physical Performance, Grip Strength, and Lean Body Mass in Older Men with Low Serum T.

Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL.

Departments of Medicine, Emory University School of Medicine (J.L.T.) and Biostatistics (F.D.B.), Rollins School of Public Health, Atlanta, Georgia, and Department of Medicine (S.T.P., J.K.A., B.D.A., A.M.M., W.J.B.), Veterans Affairs Puget Sound Health Care System (B.D.A. and A.M.M.), and Geriatric Research, Education and Clinical Center (A.M.M.), University of Washington School of Medicine, Seattle, WA.

Testosterone (T) therapy in older men with low serum testosterone (T) levels increases lean body mass (LBM) and decreases fat mass (FM). These changes might improve physical performance and strength; however, it has not been established whether T therapy improves functional outcome in older men. Moreover, concerns exist about the impact of T therapy on the prostate in older men. The administration of finasteride, which partially blocks the conversion of T to the more potent androgen, dihydrotestosterone (DHT), attenuates the impact of T replacement on prostate size and PSA. We hypothesized that T replacement in older hypogonadal men would improve physical function and that the addition of finasteride to this regimen would continue to provide the T-induced improvements in physical performance, strength, and body composition. Seventy men with low serum T (<350ng/dl), age 65 and older, were randomly assigned to receive one of three regimens for 36 months: T enanthate 200 mg intramuscularly every two weeks with placebo pills daily (T-only), T enanthate 200 mg every two weeks with 5 mg finasteride daily (T+F), or placebo injections and pills (placebo). We obtained serial measurements of timed physical performance, grip strength, lower extremity strength, body composition (by DEXA), fasting cholesterol profiles and hormones. Fifty men completed the 36-month protocol. After 36 months, T therapy significantly improved performance in a timed functional test when compared with baseline and placebo (4.3 +/- 1.6% [mean +/- SEM, T-only] and 3.8 +/- 1.0% [T+F] vs. -5.6 +/- 1.9% for placebo, [P < 0.002 for both T and T+F vs. placebo]), and increased handgrip strength compared with baseline and placebo [P < 0.05]. T therapy increased LBM (3.77 +/- 0.55 kg [T-only] and 3.64 +/- 0.56 kg [T+F] vs. -0.21 +/- 0.55 kg for placebo, [P < 0.0001]), decreased FM, and significantly decreased total cholesterol, low-density lipoprotein (LDL-C), and leptin, without affecting high-density lipoprotein (HDL), adiponectin or fasting insulin levels. These results demonstrate that T therapy in older men with low serum T improves physical performance and strength over 36 months both when administered alone or when combined with finasteride and suggest that high serum levels of DHT are not essential for these beneficial effect of T in men.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15572415&dopt=Abstract finasteride Propecia



finasteride, Propecia
Combination therapy with rofecoxib and finasteride in the treatment of men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).

Di Silverio F, Bosman C, Salvatori M, Albanesi L, Proietti Pannunzi L, Ciccariello M, Cardi A, Salvatori G, Sciarra A.

Department Urology, University La Sapienza, Urology U Bracci, V. Policlinico, 00161 Rome, Italy.

PURPOSE: Cyclooxygenase-2 (COX-2) is expressed in human BPH tissue and displays either a pro-inflammatory effect or a proliferative effect on prostate cells. The aim of this study is to analyze whether combination therapy with rofecoxib, a COX-2 inhibitor, and finasteride offers an advantage compared to finasteride monotherapy in patients with BPH. MATERIALS AND METHODS: This is a single centre unblinded trial. Forty-six consecutive men with LUTS and BPH were entered into the study and were randomized to receive rofecoxib 25mg/day plus finasteride 5mg/day (group B) versus finasteride 5mg/day alone (group A) for 24 weeks. Inclusion criteria included also a prostate size greater than 40 cc. The efficacy and safety of treatments were assessed at baseline and at week 4, 12 and 24. RESULTS: In our population, both treatments (groups A and B) produced statistically significant improvements in total IPSS and Q(max) from baseline during follow-up, although they were very low in particular for the finasteride alone group at 4 weeks. We found that finasteride monotherapy produces very little improvement at the 1 month interval. In comparing group A with group B, a significantly higher improvement in IPSS (p=0.0001) and Q(max) (p=0.03) was obtained in group B at 4 weeks interval (% cases with IPSS reduction >4 points: group B=34.7, group A=0; % cases with Q(max) improvement >3 ml/s: group B=8.7, group A=0), whereas at week 24, the differences between the two treatments were not significant (p>0.05). CONCLUSIONS: In our population, the advantage of the combination therapy compared to finasteride alone is significant in a short-term interval (4 weeks). It can be hypothesized that the association of rofecoxib with finasteride induces a more rapid improvement in clinical results until the effect of finasteride becomes predominant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15582252&dopt=Abstract finasteride Propecia



finasteride, Propecia
Co-administration of finasteride and the pure anti-oestrogen ICI 182,780 act synergistically in modulating the IGF system in rat prostate.

Huynh H, Alpert L, Alaoui-Jamali MA, Ng CY, Chan TW.

Molecular Endocrinology Laboratory, Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610. cmrhth nccs.com.sg

Prostate cancer is the most diagnosed invasive malignancy in males. Androgens and oestrogens have been implicated in the pathogenesis of prostate cancer. We report herein that the pure anti-oestrogen ICI 182,780 (ICI) reduces Ki-67 labelling index and IGF-I receptor levels in rat prostate. Increase of IGF-I mRNA and IGF-binding protein 3 (IGFBP-3) accumulation occur without any effect on prostate weight. Finasteride significantly decreases prostate weight and inhibits IGF-I gene expression. IGFBP-3 mRNA, Akt and phospho-Akt are not affected by finasteride. Co-administration of ICI plus finasteride reduces prostate weight by approximately 50% and causes acinar dilation with decreased luminal epithelial cell thickness. The acinar epithelial cells became atrophic and inactive with minimal cytoplasm. We also demonstrate a synergistic effect of ICI and finasteride on induction of IGFBP-3 accumulation and inhibition of Akt phosphorylation. Because the IGF and IGFBP-3 system plays an important role in prostate epithelial cell proliferation, apoptosis and tumour progression, the inhibitory effects of finasteride and ICI on IGF system may contribute to their anti-proliferative activity. These observations support a potential use of ICI in conjunction with finasteride in the prevention and/or treatment of prostate cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11572795&dopt=Abstract finasteride Propecia



finasteride, Propecia
Morphology of the testis and the epididymis in rats with dihydrotestosterone (DHT) deficiency.

Kolasa A, Marchlewicz M, Wenda-Rozewicka L, Wiszniewska B.

Department of Histology and Embryology, Pomeranian Medical University Szczecin, Poland.

The aim of the study was to estimate morphology in the testis and epididymis of adult rats, treated with finasteride for 28 days (the time period of two seminiferous epithelium cycles) and 56 days (the time period of one spermatogenesis). A 28 days long DHT deficiency did not significantly influence the structure of seminiferous epithelium. After 56 days of treatment, finasteride induced sloughing of immature genninal cells (spermatids and rarely pachytene spermatocytes) into the lumen of the seminiferous tubules. A reduced content of spermatozoa was observed in the lumen of rat epididymis in rats with 56-day-long deficiency. The results indicated that 5alpha-reductase 2 activity is important for the maintenance of spermatogenesis. The decreased content of spermatozoa in the epididymal lumen of rats, treated with finasteride during one course of spermatogenesis, could reflect seminiferous epithelium condition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15638393&dopt=Abstract finasteride Propecia



finasteride, Propecia
Efficacy and tolerability of drugs for treatment of benign prostatic hyperplasia.

Dutkiewics S.

Department of Urology, Central Clinical Hospital, Health Administration of the Capital, Ministry of Internal Affairs, Warsaw, Poland.

It has long been recognised that neural factors are of considerable importance in lower urinary tract function. Whilst reduction in the bulk of the human prostate is feasible, experience on this therapeutic approach proved to be disappointing. Existing trial data with the agent finasteride are reviewed. A number of formulations derived from plant extracts have been advocated but their mechanism of action remain largely obscure and there is a dearth of placebo controlled information to support their efficacy. Experience over the last 10 years has demonstrated efficacy with the use of alpha adrenoceptor blockade in the management of BPH. Alpha adrenoceptor antagonists relax the prostatic smooth muscle by interrupting the sympathetic pathway at the receptor level. Recent developments in this field include the recognition that there are alpha I adrenoceptor subtypes. The functional adrenoceptor in the human prostate is predominantly the alpha IA - subtype. Of the alpha 1-adrenoceptor antagonists only tamsulosin discriminates between the alpha 1-adrenoceptor subtypes. Alpha 1-blockers should be used in first-line medical therapy for BPH and 5-alpha-reductase inhibitors reserved for those patients in whom alpha-blocker therapy fails. Alpha I-blockers such as doxazosin, tamsulosin, terazosin, alfuzosin are effective in the treatment of BPH both in younger and in older men. The drugs are well tolerated. The majority of side effects were classified as minor and mild. The most common complaints, as with other alpha-blockers, are dizziness, fatigue and headache, and these are often transient. In contrast, finasteride can lead to impotence, reduced libido. gynaecomastia or ejaculatory disorders. Men with small prostates may not be suitable candidates for finasteride therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11583366&dopt=Abstract finasteride Propecia