finasteride, Propecia
Morphological and hormonal changes in the ventral and dorsolateral prostatic lobes of rats treated with finasteride, a 5-alpha reductase inhibitor.

Prahalada S, Rhodes L, Grossman SJ, Heggan D, Keenan KP, Cukierski MA, Hoe CM, Berman C, van Zwieten MJ.

Department of Safety Assessment, Merck Research Laboratory, West Point, Pennsylvania 19486, USA. Srinivasa_Prahalada merck.com

BACKGROUND: In rats, the prostate is divided into three distinct lobes, and the lobes are dependent on androgens [testosterone (T) and dihydrotestosterone (DHT)] as trophic hormones. However, the reasons for the difference in the incidence of proliferative changes reported are not well-understood. Administration of finasteride, a 5-alpha reductase (5alphaR) inhibitor which selectively inhibits the conversion of T to DHT, results in elevated intraprostatic T levels. However, long-term (2 years) administration of finasteride results in no increase in proliferative changes in the ventral lobes of the rat prostate. Therefore, studies were designed to determine the differences in intraprostatic hormonal levels, morphology, and 5alphaR activity in different lobes of the rat prostate. METHODS: Sexually mature male Sprague-Dawley rats were used in all studies. Finasteride was administered orally to rats. The methodology included determination of intraprostatic T and DHT levels by radioimmunoassay, qualitative and quantitative evaluation of prostatic morphology, and in vitro determination of 5alphaR activities in rat prostatic lobes. RESULTS: A significant amount of 5alphaR activity was observed in the dorsal, ventral, and lateral lobes of the rat prostate. Both 5alphaR isozymes (types 1 and 2) were present in all lobes, based on 5alphaR activities observed at both acidic and neutral pH. Oral administration of finasteride (160 mg/kg/day) for 15 days resulted in significant (P < or = 0.001) decreases in intraprostatic DHT levels and increases in T levels; when compared to controls, the mean decrease in DHT levels in the ventral and the dorsolateral lobes was 86% and 94%, respectively, and the mean increase in T levels in the ventral and the dorsolateral lobes was approximately 3 times and 20 times, respectively, higher than in controls. Chronic administration of finasteride (80 mg/kg/day) for 6 months resulted in significant (P < or = 0.001) decreases in the weights of the prostatic lobes, which correlated with significant (P < or = 0.001) decreases in the total number of epithelial and stromal cells per gland in both the ventral and dorsolateral lobes of the prostate. There were no qualitative differences in prostatic morphology between the control and finasteride-treated groups. A short-term study in control rats exposed to bromodeoxyuridine (Brdu) showed that the number of Brdu-labeled cells in the dorsolateral lobe was significantly (P < or = 0.05) greater than in the ventral lobe. CONCLUSIONS: This first comparative study has highlighted some of the similarities and differences among the prostatic lobes of the rat. Inhibition of conversion of T to DHT with finasteride resulted in a significant increase in intraprostatic T levels and a significant decrease in DHT levels in rats; despite a significant increase in intraprostatic T levels, the prostate remained atrophic, indicating that DHT alone has a trophic effect on the prostate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9582084&dopt=Abstract finasteride Propecia



finasteride, Propecia
Biologic variability of prostate-specific antigen and its usefulness as a marker for prostate cancer: effects of finasteride. Finasteride PSA Study Group.

Oesterling JE, Roy J, Agha A, Shown T, Krarup T, Johansen T, Lagerkvist M, Gormley G, Bach M, Waldstreicher J.

Mayo Clinic, Rochester, Minnesota, USA.

OBJECTIVES: The effects of finasteride on prostate-specific antigen (PSA) variability and usefulness in prostate cancer detection were examined. METHODS: Percent change and crossover of PSA levels between the low (1.0 to 3.9 ng/mL) and high (4.0 to 10.0 ng/mL) ranges were evaluated in 72 men with benign prostatic hyperplasia (BPH) and 77 men with both BPH and prostate cancer (PCa) treated with finasteride or placebo for 6 months. Patients with PCa were studied as a model for evaluating the effects on PSA levels in patients with BPH and latent PCa. As recommended on the product label, PSA levels for finasteride-treated patients were doubled for interpretation. RESULTS: In patients with BPH, most placebo- and finasteride-treated patients with low PSA levels at baseline had subsequent PSA levels below 4.0 ng/mL throughout the study. Among patients with high baseline PSA levels, only 1 of 17 finasteride-treated patients, compared with 8 of 13 placebo-treated patients, crossed into the low range. In the BPH/PCa study, most placebo-treated patients maintained PSA levels in the same range (15 of 19 less than 4.0 ng/mL; 14 of 16 greater than 4.0 ng/mL). Almost one third of finasteride-treated patients with low PSA levels at baseline crossed into the high range (8 of 22), whereas most patients with high PSA levels at baseline were not masked with treatment, with PSA levels remaining high (12 of 15). CONCLUSIONS: PSA levels cross between the low and high PSA ranges in both finasteride- and placebo-treated patients with BPH and those with both BPH and PCa. Doubling the PSA levels in finasteride-treated patients allows appropriate interpretation of PSA values and does not mask the detection of PCa.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9586598&dopt=Abstract finasteride Propecia



finasteride, Propecia
Androgen-independent basal cell re-epithelialization, c-erbB-2 mRNA expression and androgen-dependent EGFr mRNA expression in benign prostatic hyperplasia explant cultures treated with finasteride.

Schwartz S Jr, Caceres C, De Torres I, Morote J, Rodriguez-Vallejo JM, Gonzalez J, Reventos J.

Unitat de Recerca Biomedica, Centre d'Investigacions en Bioquimica i Biologia Molecular Vall d'Hebron, Barcelona, Spain. sschwartz ljcrf.edu

We have analyzed the effects of the 5alpha-reductase inhibitor, finasteride (MK906), on the mRNA expression of the epidermal growth factor receptor and c-erbB-2 genes, in benign prostatic hyperplasia explant cultures treated with testosterone and with testosterone plus finasteride. A decrease of the epithelial cell content and an androgen-independent basal cell re-epithelialization was observed during the first 10 days of culture, suggesting a role of basal cells as stem cells involved in androgen-independent epithelial regeneration. Using a semi-quantitative reverse transcription polymerase chain reaction technique, we observed a significant decrease in expression of the epidermal growth factor receptor in the cultures treated with finasteride whereas no effect of finasteride on c-erbB-2 transcription was detected, although the expression of both genes was increased by dihydrotestosterone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9590128&dopt=Abstract finasteride Propecia



finasteride, Propecia
PNU 157706, a novel dual type I and II 5alpha-reductase inhibitor.

di Salle E, Giudici D, Radice A, Zaccheo T, Ornati G, Nesi M, Panzeri A, Delos S, Martin PM.

Experimental Endocrinology, Research/Oncology, Pharmacia and Upjohn, Nerviano (MI), Italy. enrico.disalle eu.pnu.com

PNU 157706 is a novel dual inhibitor of 5alpha-reductase (5alpha-R), the enzyme responsible for the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5alpha-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5alpha-R type I and II isozymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isozyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate weight in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate weight, the ED50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5alpha-R with a very marked antiprostatic effect in the rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9605412&dopt=Abstract finasteride Propecia



finasteride, Propecia
Insulin-like growth factor binding protein 5 is associated with involution of the ventral prostate in castrated and finasteride-treated rats.

Thomas LN, Cohen P, Douglas RC, Lazier C, Rittmaster RS.

Department of Medicine and Physiology/Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.

BACKGROUND: Insulin-like growth factor binding protein (IGFBP)-5 has been proposed as a signal for apoptosis in the ovary. To determine the relationship between IGFBP-5 and apoptosis during regression of the androgen-deprived prostate, rats were castrated or treated with the 5alpha-reductase inhibitor finasteride for 4, 9, 14, 21, and 28 days. METHODS: Ventral prostate tissue was immunostained for IGFBP-5, and apoptotic cells were identified by in situ end-labeling of fragmented DNA (TUNEL). To compare the distribution of IGFBP-5 with the distribution of apoptotic cells, mirror-image serial sections of prostate tissues from normal and day 4 finasteride-treated rats were examined. RESULTS: In normal rats, 4+/-1% of prostate epithelial cells stained positively for IGFBP-5, and 0.1+/-0.03% demonstrated DNA fragmentation. IGFBP-5 staining peaked at day 9 with 93 +/-2% and 64+/-13% of epithelial cells staining positively in castrated and finasteride-treated rats, respectively. In contrast, DNA fragmentation peaked at day 4 in tissues from both castrated and finasteride-treated rats with 7+/-1% and 0.7+/-0.3% of epithelial cells, respectively, staining. In the serial sections, TUNEL and IGFBP-5 staining were not usually expressed in the same cells. CONCLUSIONS: Prostatic involution involves both programmed cell death and inhibition of cell growth. Because of the distribution of staining and the delayed expression of IGFBP-5 relative to initiation of apoptosis, we postulate that IGFBP-5 functions as an inhibitor of cell proliferation rather than as a signal for apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9609550&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effect of finasteride on serum concentrations of dihydrotestosterone and testosterone in three clinically normal sexually intact adult male dogs.

Kamolpatana K, Johnston SD, Hardy SK, Castner S.

Department of Veterinary Clinical Sciences, Washington State University, Pullman 99164, USA.

OBJECTIVE: To determine the effect of finasteride at dosages of 0, 10, 0.25, and 0.50 mg/kg of body weight, PO, q 24 h, for 7 days) in a Latin square design with repeated measures. Blood was obtained before and on days 1, 2, 4, and 7 of treatment; 3 blood samples were obtained at 20 minute intervals to detect pulsatile secretion of DHT and T. Dogs were untreated at least 2 weeks between treatments. RESULTS: Finasteride at all doses was associated with a mean decrease in concentration of DHT of 55% (range, 155 +/- 32.3 pg/ml to 70 +/- 15 pg/ml), but had no effect on concentration of T (before treatment, 2.6 +/- 0.38 ng/ml; after treatment, 2.2 +/- 0.63 ng/ml). CONCLUSIONS: Finasteride at these doses significantly decreased serum concentration of DHT in sexually intact adult male dogs. Concentrations of DHT and T before and 7 days after treatment did not differ by dosage of finasteride administered. CLINICAL RELEVANCE: Finasteride (5 mg; 1 tablet) may be a drug of choice for treatment of benign prostatic hypertrophy in 10- to 50-kg dogs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9622748&dopt=Abstract finasteride Propecia