finasteride, Propecia
Effects of finasteride and bicalutamide on prostatic blood flow in the rat.

Lekas E, Bergh A, Damber JE.

Departments of Urology & Andrology, and Pathology, Umea University Hospital, Umea, Sweden.

OBJECTIVE: To determine whether finasteride and bicalutamide, both currently used in the clinical management of patients with prostate diseases because they have anti-androgenic properties, have any effects on prostatic blood flow in a rat prostate model, as androgens are known to be involved in the regulation of prostatic blood flow and angiogenesis. MATERIALS AND METHODS: Both finasteride and bicalutamide were supplied as oral suspensions in water and given daily to rats for 7 days by tube feeding. Blood flows to the ventral and dorsal prostates, and to the kidneys, were measured using the radioactive microsphere technique. In the bicalutamide experiments, some rats were treated with the Leydig cell toxin ethane dimethane sulphonate (EDS), to obtain a castration-like effect, and one group of these rats received testosterone. RESULTS: Finasteride induced a clear decrease in blood flow to the ventral and dorsal prostates after 7 days of treatment, with no significant changes in blood pressure or kidney blood flow. Bicalutamide inhibited the testosterone-induced increment of prostatic blood flow observed in EDS-treated animals. CONCLUSIONS: Finasteride, a blocker of 5alpha-reductase, decreases prostate blood flow after 7 days of administration. The response was slower than that after castration, but was of similar magnitude. Blood flow was also decreased after treatment with the androgen-receptor inhibitor bicalutamide. These observations suggest that prostatic blood flow is increased by dihydrotestosterone, and that the androgen receptor is responsible for mediating this effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10792183&dopt=Abstract finasteride Propecia



finasteride, Propecia
[Therapy of androgenetic alopecia with finasteride. What must be considered in consultation and drug prescribing]

[Article in German]

Wolff H, Kunte C.

Klinik und Poliklinik fur Dermatologie und Allergologie, Ludwig-Maximilians-Universitat, Munchen. hans.wolff lrz.uni-muenchen.de

Androgenetic alopecia in men is genetically determined, but occurs only when the testosterone metabolite dihydrotestosterone (DHT) is present in normal levels. The drug, finasteride, inhibits the enzyme 5-alpha-reductase II, which is responsible for converting testosterone to DHT. One 1 mg tablet (Propecia) of finasteride daily lowers serum DHT levels by about 70%, and increases serum testosterone by 10%. The efficacy of finasteride 1 mg has been demonstrated in a randomized, double-blind, placebo-controlled clinical trial involving more than 1,500 men in whom a significant increase in hair density over a specified area of the scalp, and a significant improvement in appearance was noted. Following one year to treatment 48%, and following 2 years 66%, of the finasteride patients (placebo group 7% after both treatment periods) presented with visibly thicker hair growth. Side effects such as decreased libido, ejaculation disorders and erectile dysfunction were seen in fewer than 2% of the men in both the finasteride and placebo groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10897972&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effects of the anti-androgen finasteride on 5 alpha-reduction of androgens in the presence of progesterone in human gingival fibroblasts: modulatory actions of the alkaline phosphatase inhibitor levamisole.

Tilakaratne A, Soory M.

Department of Periodontology, Faculty of Dental Science, University of Peradeniya, Sri-Lanka.

Oestrogens and androgens stimulate collagen matrix synthesis, while progesterone is a competitive inhibitor for the 5 alpha-reduction of testosterone to 5 alpha-dihydrotestosterone (DHT). The anti-androgen finasteride is a specific inhibitor of the 5 alpha-reductase type 2 isoenzyme, associated with anabolic functions. The aim of this investigation is to study the effects of progesterone and finasteride on 5 alpha-reduction of androgen substrates by human gingival fibroblasts. Monolayer cultures of human gingival fibroblasts (HGF) of the 4th 9th passage were established in Eagle's minimum essential medium (MEM). Duplicate incubations were performed with 14C-testosterone/14C-4-androstenedione as substrates and progesterone (P) or finasteride (F), at concentrations of 0.5, 1, 3 and 5 microg/ml, alone and in combination, for 24 h. Similarly, the effects of the alkaline phosphatase inhibitor levamisole (L, 30 microg/ml) and P were studied. Steroid metabolites were analysed and quantified, using a radioisotope scanner. Progesterone inhibited DHT synthesis in HGF from 14C-testosterone by 24-62% (n = 8; p < 0.01). Finasteride caused 59 82% inhibition (n=8;p<0.01). The combination of P+F showed a similar degree of inhibition (68-78%) of DHT synthesis to that of F alone (n = 8; p<0.01). There was 35-56% stimulation of 17beta-HSD (hydroxysteroid dehydrogenase) activity by P, F and P + F (n = 8; p < 0.01). When 14C-4-androstenedione was used as substrate there was 47% inhibition of 5 alpha-reductase activity at higher concentrations of P and 63 and 44% stimulation at 0.5 and 1 microg/ml (n = 8;p < 0.01). F and P + F caused 40-67% inhibition of this activity. P, F and P + F caused 2-2.7-fold stimulation of 17beta-HSD activity in response to all concentrations studied. L inhibited DHT synthesis from both substrates by 36-38%, with further inhibition of 55-70% (n = 4; p < 0.01), with P; this is suggestive of ligand-independent alkaline phosphatase activity mediated by 5 alpha-reductase. Inhibition of 5 alpha-reductase activity by finasteride in gingival fibroblasts is suggestive of target tissue anabolic functions in gingivae and competitive inhibition by progesterone, is suggestive of regulation of hormone mediated tissue responses during repair.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10983877&dopt=Abstract finasteride Propecia



finasteride, Propecia
Antiandrogenic effect of 16-substituted, non-substituted and D-homopregnane derivatives.

Bratoeff EA, Herrera H, Ramirez E, Solorzano K, Murillo E, Quiroz A, Cabeza M.

Department of Pharmacy, Faculty of Chemistry, Ciudad Universitaria, Mexico D.F. Mexico. eugene servidor.unam.mx

The pharmacological activities of 12 pregnane derivatives (4-15) were determined on gonadectomized male hamster flank organs and seminal vesicles as antiandrogens and as 5alpha-reductase inhibitors. The results from this study indicate that subcutaneous injection of testosterone for 3 d increased the diameter of the pigmented spot in the flank organs, whereas finasteride when injected with testosterone decreased the size of the spot significantly when steroids 4-15 were injected together with testosterone, the diameter of the flank organs of gonadectomized male hamsters, decreased significantly (p<0.005) compared to testosterone. Compound 11 was the most active steroid and reduced the diameter of the pigmented spot more than the other synthesized steroids or finasteride. Subcutaneous injections of testosterone to gonadectomized animals restore the seminal vesicle size lost upon castration. Injection of testosterone plus finasteride decreased significantly the weight of these glands (p<0.005). Steroids 5-15 when injected with testosterone decreased the weight of the seminal vesicles compared to testosterone. Finasteride is a good inhibitor of the conversion of testosterone to dihydrotestosterone (DHT) (low formation of DHT) measured as pmole of DHT/g of protein/h. Steroids 6-15 inhibited the conversion of testosterone to DHT as compared to testosterone however finasteride and 10 appeared to be the most effective compounds. Castration increases the protein content of the seminal vesicles (control) expressed as microg/mg of tissues. Testosterone tends to decrease it significantly, as did compounds 4, 5, 7, 9, and 15. We demonstrated that DHT as well as cyproterone acetate and steroids 5, 6, 8, 9, 11, and 14 at increasing non radioactive steroid concentration, inhibited the binding of [3H]DHT to cytosolic androgen receptor (AR), as indicated by its Ki values. However, 4, 7, 10, 12, and 13 did not have any inhibitory effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10993221&dopt=Abstract finasteride Propecia



finasteride, Propecia
Urethral development in the fetal rabbit and induction of hypospadias: a model for human development.

Kurzrock EA, Jegatheesan P, Cunha GR, Baskin LS.

Departments of Urology and Anatomy, University of California San Francisco, San Francisco, California, USA.

PURPOSE: To determine whether the development of the rabbit phallus would be an appropriate model of human phallic development, we evaluated the formation of the fetal rabbit phallus and attempted to induce hypospadias pharmacologically. MATERIALS AND METHODS: New Zealand rabbit fetuses were obtained on gestational days 20 to 24, 26, 28 and 31. Sex was determined by gonadal morphology, and 6 fetuses were obtained at each age. The perineum was dissected, fixed, sectioned and stained with hematoxylin and eosin, and monoclonal antibodies against neuronal specific enolase. Two pregnant rabbits were treated with 10 mg./kg. finasteride orally daily between gestational days 19 and 28. The development of the external genitalia was compared in treated and untreated control rabbits. RESULTS: The rabbit phallus contains 2 corpora cavernosa and dorsolateral nerves similar to the human. In male and female fetuses fusion of the urethral folds progressed in a proximal to distal sequence forming a seam at the point of ventromedial fusion. In male fetuses urethral fold and ventral preputial fusion continued more distally toward the glans compared to females. Thus, in mature males the urethral meatus and ventral prepuce extended to the tip of the phallus, whereas in females the urethral meatus opened on the proximal phallus and the prepuce was deficient ventrally forming a dorsal hood. Male offspring had a significantly larger anogenital distance postnatally than female offspring. In male fetuses exposed to finasteride urethral fusion did not extend distally and the prepuce was deficient ventrally. Also, male offspring exposed to finasteride in utero had a significantly shorter anogenital distance than females and untreated control males at all ages (p <0.05). CONCLUSIONS: Fetal development of the rabbit phallus and urethra is homologous to the human. Although the gestational period is significantly shorter, the temporospatial pattern of external genitalia development is analogous in these species. Feminization of the rabbit urethra, hypospadias, can be induced by inhibiting 5alpha-reductase. Use of this animal model will allow further study of molecular mechanisms involved in urethral fusion and the evaluation of the pathophysiological processes of hypospadias.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11025770&dopt=Abstract finasteride Propecia



finasteride, Propecia
Increased levels of clusterin (SGP-2) mRNA and protein accompany rat ventral prostate involution following finasteride treatment.

Astancolle S, Guidetti G, Pinna C, Corti A, Bettuzzi S.

Dipartimento di Scienze Biomediche, Universita di Modena e Reggio Emilia, Via G. Campi 287, 41100 Modena, Italy.

Finasteride is a well-known inhibitor of the prostatic enzyme 5 alpha-reductase type 2 which prevents conversion of testosterone into 5 alpha-dihydrotestosterone, the active intraprostatic androgen, which causes prostate involution through a combination of cell atrophy and cell death. The drug is widely used to improve symptoms of benign prostatic hyperplasia in man. Clusterin, a glycoprotein which is generally up-regulated under conditions inducing cell atrophy or organ involution, is produced at a high level in the regressing rat ventral prostate following androgen ablation. According to several authors, clusterin does not respond to finasteride treatment, suggesting a different action of testosterone and 5 alpha-dihydrotestosterone. We show here that, under our conditions, finasteride was capable of inducing production of both clusterin mRNA and protein in the rat ventral prostate. In fact, by using different and converging techniques, such as Northern hybridization, in situ hybridization histochemistry and immunohistochemistry, we were able to show a strong induction of the clusterin gene in the epithelial cell population of the gland. The response to finasteride, which was similar to that seen with castration, occurred with a delay of a few days. In situ and immunohistochemistry experiments indicated that both orchidectomy and finasteride administration resulted in increased transition of the epithelial cells from the columnar to the cuboidal (atrophic) shape, and this was accompanied by an increased intensity of the signal for clusterin. Thus, it appears that induction of clusterin is part of the molecular process leading to prostate involution caused by either orchidectomy or finasteride administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11054633&dopt=Abstract finasteride Propecia