finasteride, Propecia
Effects of flutamide and finasteride on rat testicular descent.

Spencer JR, Torrado T, Sanchez RS, Vaughan ED Jr, Imperato-McGinley J.

James Buchanan Brady Foundation, Department of Surgery, New York Hospital/Cornell University Medical College, New York 10021.

The endocrine control of descent of the testis in mammalian species is poorly understood. The androgen dependency of testicular descent was studied in the rat using an antiandrogen (flutamide) and an inhibitor of the enzyme 5 alpha-reductase (finasteride). Androgen receptor blockade inhibited testicular descent more effectively than inhibition of 5 alpha-reductase activity. Moreover, its inhibitory effect was limited to the outgrowth phase of the gubernaculum testis, particularly the earliest stages of outgrowth. Gubernacular size was also significantly reduced in fetuses exposed to flutamide during the outgrowth period. In contrast, androgen receptor blockade or 5 alpha-reductase inhibition applied after the initiation of gubernacular outgrowth or during the regression phase did not affect testicular descent. Successful inhibition of the development of epididymis and vas by prenatal flutamide did not correlate with ipsilateral testicular maldescent, suggesting that an intact epididymis is not required for descent of the testis. Plasma androgen assays confirmed significant inhibition of dihydrotestosterone formation in finasteride-treated rats. These data suggest that androgens, primarily testosterone, are required during the early phases of gubernacular outgrowth for subsequent successful completion of testicular descent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1677329&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effect of finasteride, a 5 alpha-reductase inhibitor on prostate tissue androgens and prostate-specific antigen.

Geller J.

Department of Medical Education, Mercy Hospital and Medical Center, San Diego, California 92103-2180.

Whole tissue dihydrotestosterone (DHT) and testosterone (T) concentrations have been measured after finasteride, a 5 alpha-reductase inhibitor, and this was compared to other methods of androgen inhibition. In 10 patients treated for 1 week with finasteride, whole tissue DHT decreased to a mean of 0.302 ng/g. This value was significantly less than DHT values in control patients (mean, 4.5 ng/g) and patients treated with either surgical castration (mean, 1.14 ng/g), megestrol (160 mg/day) plus diethylstilbestrol (0.1 mg), or megestrol plus ketoconazole (1200 mg/day; mean, 0.609). Tissue T levels were significantly increased in finasteride-treated patients (1.18 ng/g) compared to a mean of 0.171 ng/g in controls and 0.105 ng/g in megestrol-treated patients. Part of the prostate tissue obtained at surgery was mechanically separated into epithelium and stroma. The epithelial cells were homogenized, the supernate was assayed for prostate-specific antigen (PSA), an androgen-dependent protein, and the pellet was assayed for DHT and DNA. Epithelial cell PSA and DHT values significantly decreased in finasteride- and megestrol- plus estrogen-treated patients compared to controls. However, the slope and position of the regression lines for DHT vs. PSA in patients treated with megestrol plus low dose estrogen (r = 0.79) differed significantly (P less than 0.05) from the regression line relating epithelial DHT to PSA in patients treated with finasteride (r = 0.82). Since the regression slope for finasteride described a greater increase in PSA per unit change in DHT compared to the slope for megestrol plus estrogen, which lowers both DHT and T, finasteride, despite its drastic lowering of DHT, may have a modest residual androgenic effect related to its effect on tissue T.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1699965&dopt=Abstract finasteride Propecia



finasteride, Propecia
Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.

Rittmaster RS, Magor KE, Manning AP, Norman RW, Lazier CB.

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

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1719382&dopt=Abstract finasteride Propecia



finasteride, Propecia
External genitalia of the rat: normal development and the histogenesis of 5 alpha-reductase inhibitor-induced abnormalities.

Anderson CA, Clark RL.

Department of Safety Assessment, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.

The normal histogenesis of the rat genital tubercle and the effect of exposure in utero to the 5 alpha-reductase inhibitor finasteride (L-652,931; MK-0906; Proscar) on that process were studied. In normal males and females, the genital tubercle was first seen on Day 14.25 of gestation. It contained a urethral plate which extended from the cloaca (and after Day 15.25, from the urogenital sinus) to the tip of the tubercle. On Day 18.25 the glans lamellae, which would separate the glans penis or the clitoris from the prepuce, began to develop in both sexes. Also on Day 18.25 a dense, midline plate of mesenchymal cells was first evident between the urogenital sinus and the rectum in normal males. This plate acted as a wedge, first increasing the separation between the rectum and the urogenital sinus, and subsequently separating the urethral plate from the surface epithelium in the genital tubercle. As a result, by Day 21.25 the urethra in males followed an "S"-shaped course, extending from the pelvis through the center of the glans penis to an orifice near the tip of the genital tubercle. In females, in which a mesenchymal plate did not develop, the urethral orifice remained at the base of the tubercle, and the clitoris contained the remnants of the urethral plate, extending as an open groove from the urethral orifice to the tip of the tubercle. Finasteride did not affect development of the genital tubercle in females. However, in males exposed to finasteride in utero, there was variable failure of the mesenchymal wedge to develop. As a result, the urethral plate remained in contact with the surface epithelium and eventually opened to form a groove on the ventral surface of the glans penis (hypospadias). Also, the persistence of the urethral plate along the ventral midline in finasteride-treated male fetuses and its subsequent opening as a groove interfered with development of the glans lamellae, causing displacement of the frenulum distally on the glans penis and the development of a cleft in the prepuce.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2177574&dopt=Abstract finasteride Propecia



finasteride, Propecia
Changes in progesterone metabolites in the hippocampus can modulate open field and forced swim test behavior of proestrous rats.

Frye CA, Walf AA.

Department of Psychology, The University at Albany-SUNY, 1400 Washington Avenue, New York, 12222, USA. cafrye cnsunix.albany.edu

The purpose of these experiments was to test the hypothesis that attenuating the endogenous increase of the 5alpha-reduced progesterone metabolite 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) in the hippocampus will alter anxiety and depression behavior of proestrous rats. In Experiment 1, anxiety (open field) and depression (forced swim test) behavior was compared of rats that should have high (proestrous) and low (diestrous and male rats) endogenous hippocampal 3alpha,5alpha-THP. Proestrous rats exhibited more anxiolytic-like (increased central entries in the open field) and anti-depressant-like (less immobility in the forced swim test) behavior than diestrous or male rats. In Experiments 2 and 3, respectively, systemic and intrahippocampal finasteride, a 5alpha-reductase inhibitor which attenuates progesterone's metabolism to 3alpha,5alpha-THP, versus vehicle administration to proestrous rats was compared for effects on open field and forced swim test behavior. Systemic or intrahippocampal finasteride decreased central entries in the open field and increased immobility in the forced swim tests compared to vehicle administration. In Experiment 4, the effects of systemic and intrahippocampal finasteride vs vehicle administration on hippocampal 3alpha,5alpha-THP of proestrous rats was examined. Finasteride, SC or intrahippocampally, reduced 3alpha,5alpha-THP in the hippocampus compared to vehicle administration. Together these data suggest that variations in 3alpha,5alpha-THP levels in the hippocampus may mitigate proestrous changes in anxiety and depressive behavior of cycling rats. (c) 2002 Elsevier Science (USA).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11971664&dopt=Abstract finasteride Propecia



finasteride, Propecia
Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results.

Fleshner NE, Trachtenberg J.

Division of Urology, Toronto Hospital, Ont., Canada.

In an attempt to maximize the quality of life of advanced prostate cancer patients on prolonged total androgen ablation and to minimize side effects, we have devised a strategy of 'sequential androgen blockade'. Animal studies have demonstrated that the combination of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide was as effective as a luteinizing hormone-releasing hormone analog and flutamide in inhibiting the growth of the prostate. In a pilot trial, 10 potent patients with clinical stage C and D1 prostate cancer were given the combination of finasteride (5 mg b.i.d.) and flutamide (125-250 mg t.i.d.). Eight of ten men remained potent. At 3 months the mean prostate-specific antigen level of all patients was 3.8 ng/ml (34 ng/ml prior to therapy). In all patients serum testosterone increased and those with the highest increase demonstrated gynecomastia. The combination was easily tolerable and side effects were few. This treatment regime appears to offer the benefits of total androgen blockade, is less expensive and has fewer side effects. Further trials are warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7505229&dopt=Abstract finasteride Propecia