finasteride, Propecia
Human osteoblast-like cells express predominantly steroid 5alpha-reductase type 1.

Issa S, Schnabel D, Feix M, Wolf L, Schaefer HE, Russell DW, Schweikert HU.

Department of Internal Medicine, University of Bonn, Bonn, Germany.

In previous studies we established that human bone and human osteoblast-like cells (hOB cells) cultured from bone express 5alpha-reductase (5alpha-R) activity, as demonstrated by the conversion of testosterone and androstenedione to their corresponding 5alpha-reduced metabolites, 5alpha-dihydrotestosterone (DHT) and 5alpha-androstanedione. Two 5alpha-R isozymes (types 1 and 2) have been identified in various tissues. As their nature in bone is unknown, we investigated which isozymes were expressed in first passage hOB cells cultured from bone specimens obtained from six donors (five women and one man). For comparison, 5alpha-reductase isozyme expression in genital skin fibroblasts cultured from foreskin of three males was determined. Pharmacological and biochemical studies using selective inhibitors of the 5alpha-R isozymes were performed, and gene expression was assessed by RT-PCR. In hOB cells, LY191704, a potent nonsteroidal selective inhibitor of 5alpha-R type 1, and the 4-azasteroid 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one (a dual inhibitor of 5alpha-R types 1 and 2) inhibited 5alpha-R activity with a 50% inhibitory concentration (IC(50)) of approximately 4 nM. Finasteride, a selective inhibitor of 5alpha-R type 2, blocked 5alpha-R activity with an IC(50) of approximately 60 nM. The IC(50) of progesterone, a physiological substrate for 5alpha-R, was approximately 200 nM. In genital skin fibroblasts, LY191704 inhibited 5alpha-R with an IC(50) of more than 5000 nM, whereas finasteride and 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one effectively inhibited 5alpha-R with IC(50) of approximately 4 nM. Experiments to determine 5alpha-reductase activity in homogenates of hOB cells as a function of pH showed very low activity at pH 5.5, but a broad shoulder of activity from pH 6.0-9.0, which was not inhibited by finasteride, but was nearly completely blocked by LY191704. RT-PCR revealed that 5alpha-R type 1 and 2 mRNAs were expressed in both bone and genital skin fibroblasts. Based on our pharmacological and biochemical studies, it appears that 5alpha-R activity in hOB cells is catalyzed predominantly by the type 1 rather than the type 2 isozyme. This expression pattern is in contrast to that in genital skin fibroblasts, where the activity of the type 2 isozyme prevails. As in most androgen target tissues DHT is biologically more active as an androgen than testosterone, DHT is formed in bone by 5alpha-R type 1 action from circulating testosterone, and bone cells also express the androgen receptor, local DHT production may play a physiological role in human bone homeostasis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12466325&dopt=Abstract finasteride Propecia



finasteride, Propecia
Inhibiting progesterone metabolism in the hippocampus of rats in behavioral estrus decreases anxiolytic behaviors and enhances exploratory and antinociceptive behaviors.

Rhodes ME, Frye CA.

State University of New York, Albany, New York, USA.

Blocking progesterone's metabolism to 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) with finasteride, a 5 alpha-reductase inhibitor, and effects on anxiolytic, exploratory, and antinociceptive behaviors of rats in behavioral estrus were examined. Rats in behavioral estrus received finasteride systemically (SC), to the hippocampus, or to control implant sites, the nucleus accumbens (NA) or ventral tegmental area (VTA), and were tested in horizontal crossing, open-field, elevated plus-maze, emergence, holeboard, social interaction, tailflick, pawlick, and defensive freezing tasks. Finasteride, SC or intrahippocampally, reduced 3 alpha,5 alpha-THP in the hippocampus relative to vehicle implants or finasteride to the NA or VTA. Systemic or intrahippocampal finasteride decreased central entries in the open field and open-arm time on the elevated plus-maze and increased freezing in response to shock relative to vehicle. Finasteride to the hippocampus decreased emergence latencies and increased social interaction, pawlick, and tailflick latencies relative to all other groups. Finasteride to the hippocampus of rats in behavioral estrous decreased anxiolysis and enhanced exploration and analgesia. In summary, these data demonstrate that decreases in anxiolytic behavior of behavioral estrous rats can be produced by reductions in 3 alpha,5 alpha-THP in the hippocampus, which suggest that elevations in 3 alpha,5 alpha-THP in the hippocampus may give rise to anxiolysis seen during behavioral estrus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12467128&dopt=Abstract finasteride Propecia



finasteride, Propecia
Finasteride in the treatment of Taiwanese men with androgenetic alopecia: a 12-month open-label study.

Lin JH, Chen WC.

Department of Dermatology, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan.

Finasteride 1 mg/day is effective in the treatment of androgenetic alopecia (AGA). Our open-label study assessed the efficacy and safety of finasteride for the treatment of Taiwanese men with AGA. We enrolled 34 Taiwanese men (aged 18-40 yr) with AGA of modified Norwood/Hamilton scale (MNHS) grade II-V. In investigator assessments at 12 months, five of 21 subjects (23.8%) had two-grade improvement in MNHS grade and 12 of 21 subjects (57.1%) had one-grade improvement; the others remained at the same grade. In global photographic evaluation, five of 31 subjects (15.1%) had observable hair growth at 6 months and 11 of 21 subjects (52.4%) had observable hair growth at 12 months. Patient self-assessment of hair growth was favorable across all questions in the treatment course, more significantly at 12 months than at 6 months; nine of 21 subjects (42.9%) were satisfied with their overall appearance at 12 months. Serum prostate specific antigen levels had decreased by 23.4% at 12 months. Adverse effects, including abnormal liver function (5/34), were minimal, and the causal relationship with finasteride could not be established. Thus, in Taiwanese men with AGA, finasteride 1 mg/day for 1 year slowed the progression of hair loss and increased hair growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12476680&dopt=Abstract finasteride Propecia



finasteride, Propecia
Haematuria associated with BPH-Natural history and a new treatment option.

Kashif KM, Foley SJ, Basketter V, Holmes SA.

Department of Urology, St. Mary's Hospital, Portsmouth, Hants PO3 6AD, UK.

Bleeding of prostatic origin is usually caused by the friable hypervascularity of the prostate, the vessels of which are easily disrupted by physical activity. The condition is often ignored after the patient has been fully investigated and more serious causes for bleeding excluded and treatment is often withheld unless the bleeding becomes excessive. We analysed the clinical effect of finasteride in the treatment of this condition. We retrospectively reviewed 42 patients diagnosed as having haematuria secondary to bleeding from a benign prostate. Eighteen patients were simply reassured and given no treatment. Twenty-four patients with prostatic bleeding were treated using finasteride. All case notes were reviewed and the patients were contacted by telephone. Of 18 patients who had prostatic bleeding but did not receive treatment the mean age was 70 y and the mean follow-up was 10 months; two had died, nine had no further bleeding, two had a single episode of bleeding requiring no treatment, six had several bleeding episodes of whom one started finasteride, one refused treatment, and three required TURP. In the group treated with finasteride the mean follow up was 9 months, the mean age of the patients was 75 y. Twenty patients had no further bleeding, one patient experienced minor intermittent bleed and required no further treatment. Two patients died of non-urological causes, one patient stopped the treatment because of impotence and one patient had mild gynecomastia. Haematuria secondary to prostatic bleeding can be significant if not treated. Finasteride appears to be effective in suppressing haematuria caused by benign prostatic hyperplasia and should be considered in treating this problem.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12496909&dopt=Abstract finasteride Propecia



finasteride, Propecia
Combined analysis of two multicenter studies of finasteride 5 mg in the treatment of symptomatic benign prostatic hyperplasia.

Byrnes CA, Liss CL, Tenover JL, Lippert MC, Gillenwater JY.

Clinical Development, US Human Health, Merck & Co., Inc., P.O. Box 4, West Point, 19486-0004, PA, USA.

The purpose of this paper is to examine effects of finasteride 5 mg across different age groups in an ethnically diverse population of men with symptomatic benign prostatic hyperplasia (BPH) seen in community urology and primary care practices. Data were combined from two previous placebo-controlled randomised trials of finasteride that evaluated changes in urinary symptoms, blinded global assessments of urologic status, adverse experiences, and effects on dihydrotestosterone (DHT) and prostate-specific antigen (PSA) in over 4500 men. Finasteride showed a favourable efficacy and tolerability profile in this large ethnically diverse population and was similarly effective in middle-aged and older men with BPH and prostate gland enlargement.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12496930&dopt=Abstract finasteride Propecia



finasteride, Propecia
A prospective randomized trial evaluating tissue effects of finasteride therapy in benign prostatic hyperplasia.

Feneley MR, Span PN, Schalken JA, Harper M, Griffiths K, Holmes K, Kirby RS.

St Bartholomew's Hospital, London, UK.

Finasteride is widely used for the treatment of benign prostatic hyperplasia (BPH). Its therapeutic efficacy is believed to be mediated through selective inhibition of prostatic 5alpha-reductase (type II). This prospective, controlled, randomized study examines various relationships between changes in tissue 5alpha-reductase isozyme activity, epithelial proliferative index and morphology in men with BPH treated with finasteride for 6 months, and correlates these with clinical response. Thirty-one patients presenting with symptomatic bladder outflow obstruction were prospectively randomized to receive either finasteride or placebo (2:1) for 24 weeks. Of these, 27 men aged 55-80 y (median 69 y) completed the study, including 18 patients on treatment. Symptom score determination, uroflow and prostate volume were assessed at baseline and end of study. Prostatic tissue was obtained by ultrasound-guided needle biopsy at baseline and by transurethral resection (TURP) at end of study for biochemical and morphometric analysis. Epithelial proliferation was examined quantitatively in the resected tissue using MIB-1 antibody to Ki-67 and counting the percentage of positively staining cells. Type II 5alpha-reductase activity was strongly inhibited by finasteride in resected BPH tissue, with over 100-fold decrease in V(max) (P=0.001), whereas the type I isozyme was inhibited 5-fold (P=0.005). Selective inhibition of type II 5alpha-reductase was demonstrated in all treated patients. No significant difference in epithelial proliferation was observed between the finasteride and placebo groups. Epithelial proliferation was, however, greater in prostatic tissue with histological manifestation of inflammation (2.02% vs 0.89%, P=0.001). Positive correlation between the total epithelial volume and the ratio of transition zone volume/total prostate volume was observed in the placebo group (r=0.834), whereas there was no such correlation in men taking finasteride (r=-0.300), consistent with a reduction in epithelial content in the treatment group. Improvement in uroflow and reduction in prostatic volume in patients treated with finasteride did not reach statistical significance. This study shows that finasteride causes inhibition of 5alpha-reductase activity in human BPH tissue with selectivity for the type II isozyme. In spite of this, no significant effects in epithelial proliferation or tissue morphology were demonstrated. The presence of inflammation was, however, associated with significantly greater proliferative activity. The power of this study was limited by the small number of recruited patients, and a larger study would be required for further investigation of morphological changes induced by finasteride in BPH tissue and their biochemical basis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12497174&dopt=Abstract finasteride Propecia



finasteride, Propecia
Early diagnosis of prostate cancer in finasteride treated BPH patients.

Tarle M, Kraus O, Trnski D, Reljic A, Ruzic B, Katusic J, Spajic B, Kusic Z.

University Hospital Sestre Milosrdnice, 29 Vinogradska St, Zagreb 10000, Croatia. marko_tarle yahoo.com

A total of 37 patients with well-documented benign prostatic hypertrophy (BPH) were referred to finasteride. In all subjects the prostate volume was > 60 cc. Serum total PSA (TPSA) and free/total PSA (%FPSA) values were recorded at 3-month intervals. After 6 months of treatment, the patients were divided into two groups in accordance with the numerical values of these two parameters. In the first group (25 patients), a drop in TPSA approached 50% reduction while the %FPSA level remained at the initial level. No malignancy was detected in these patients after 9 months of finasteride treatment and in 4-18 months additional follow-up. The second group (12 patients), consisted of subjects with a less pronounced decrease in TPSA concentration (ca. 28%) and a significant reduction in %FPSA mostly to values < 18% (cut-off point dividing BPH from cancer) during a 6-month monitoring period. During the extended part of the investigation, prostate cancer was diagnosed in 7 out of 11 of these latter patients (63.6%), or overall in 7 out of 30 (23.3%) patients who reached the end-point of the study. Accordingly, serial assessments of total and free PSA are necessary and sufficient clinical means to detect early prostate cancer in patients with a large benign prostate referred to finasteride.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12680169&dopt=Abstract finasteride Propecia