finasteride, Propecia
Seizure activity is increased in endocrine states characterized by decline in endogenous levels of the neurosteroid 3 alpha,5 alpha-THP.

Frye CA, Bayon LE.

Neuroscience Program, Connecticut College, New London, Conn., USA.

To examine the role of progesterone (P) and its 5alpha-reduced metabolite, the neurosteroid 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP), in endogenous variations in ictal activity rats were tested for kainic acid-induced seizures in different hormonal milieu. Corresponding plasma and central P and 3alpha,5alpha-THP levels were measured. Cycling Long-Evans rats in estrus and proestrus had seizures of significantly shorter duration and more central and plasma 3alpha,5alpha-THP and P than animals in metestrus or diestrus. Females with luteal functioning had seizures of significantly shorter duration and increased central and plasma 3alpha,5alpha-THP and P compared to animals that recently had luteal functioning discontinued. Pregnant rats had significantly shorter seizures and greater central and plasma 3alpha,5alpha-THP and central P than animals tested 1-2 days postparturition. In all test paradigms, seizure activity was increased in animals that had decreased 3alpha, 5alpha-THP or P; overall, central 3alpha,5alpha-THP was more inversely related to ictal activity than central P or plasma P and 3alpha,5alpha-THP. To investigate a causal relationship between 3alpha,5alpha-THP and seizures, a 5alpha-reductase inhibitor, finasteride, or vehicle was administered to pregnant rats. Finasteride administration significantly decreased central and plasma 3alpha,5alpha-THP, but had no significant effect on plasma or central P of pregnant rats. Finasteride, but not vehicle administration, to pregnant rats significantly increased seizure duration. These findings support the hypothesis that variations in seizure threshold over endogenous hormonal milieu may be related to endogenous 3alpha,5alpha-THP. Of all of the endocrine conditions, seizure durations were greatest in diestrus animals; this group did not experience the lowest or the greatest decrease in 3alpha, 5alpha-THP concentrations; however, of all of the endocrine conditions, cycling rats experienced the most rapid cycles of 3alpha, 5alpha-THP variation. This suggests that cycles of endogenous variations in 3alpha,5alpha-THP may influence seizure threshold.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9772342&dopt=Abstract finasteride Propecia



finasteride, Propecia
In vitro inhibition of androstenedione 5alpha-reduction by finasteride in epithelium and stroma of human benign prostatic hyperplasia.

Weisser H, Krieg M.

Institute of Clinical Chemistry, Transfusion and Laboratory Medicine, University Clinic Bergmannsheil, Bochum, Germany. heike.weisser ruhr.uni.bochum.de

Finasteride is a well known steroid 5alpha-reductase inhibitor. In this context, recently we have shown that in human benign prostatic hyperplasia (BPH) finasteride inhibits the 5alpha-reduction of testosterone to dihydrostestosterone (DHT) more effectively in the epithelium as compared to the stroma. The aim of the present study was to describe in epithelium and stroma of human BPH the effect of finasteride on the 5alpha-reduction of androstenedione, that is the second main circulating androgen in men, to androstanedione. Using a finasteride concentration of 75 nM and an androstenedione concentration of 220 nM, the mean inhibition [% +/- SEM] of 5alpha-reductase activity was significantly higher in epithelium (69 +/- 2) than in stroma (52 +/- 4). Both in epithelium and stroma, this inhibition of 5alpha-reductase activity was dose-dependent and competitive. Dixon plots as well as slope replots of Lineweaver-Burk plots showed that the mean inhibition constant Ki (nM +/- SEM) was significantly lower in epithelium (10 +/- 1 and 11 +/- 2, respectively) than in stroma (33 +/- 7 and 28 +/- 4, respectively) indicating a significantly stronger inhibitory effect of finasteride in epithelium. From those mean Ki values, it follows that in human BPH finasteride inhibits equally well both the 5alpha-reduction of androstenedione to androstanedione and testosterone to DHT. Based on these inhibition studies, there is no evidence for the coexistence of substrate-specific 5alpha-reductases converting either testosterone or androstenedione. However, the striking difference in finasteride sensitivity of the 5alpha-reduction between epithelium and stroma could be due to a cell-type specific expression of structurally different 5alpha-reductases as well as to a different access of finasteride to 5alpha-reductase in epithelium and stroma where, compared to each other, the lipid environment is significantly different.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9780029&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effects of finasteride on apoptosis and regulation of the human hair cycle.

Sawaya ME, Blume-Peytavi U, Mullins DL, Nusbaum BP, Whiting D, Nicholson DW, Lotocki G, Keane RW.

ARATEC Research, Ocala, Florida 34478, USA. ARATEC worldnet.att.net

BACKGROUND: A number of studies have provided evidence that apoptosis is a central element in the regulation of hair follicle regression. In androgenetic alopecia (AGA), the exact location and control of key players in the apoptotic pathways remains obscure. OBJECTIVE: In the present study, we used a panel of antibodies and investigated the spatial and cellular pattern of expression of caspases and inhibitors of apoptosis (IAPs), such as XIAP and FLIP, in men with normal scalp and in men with AGA before and after 6 months of treatment with 1 mg oral finasteride treatment. METHODS AND RESULTS: Constitutive expression of caspases-1, -3, -8, and -9 and XIAP was detected predominantly within the isthmic and infundibular hair follicle area, basilar layer of the epidermis, and eccrine and sebaceous glands. AGA-affected tissues showed an increase in caspase (-1, -3, -6, -9) immunoreactivity with a concomitant decrease in XIAP staining. After 6 months of finasteride treatment, both caspases and XIAP were similar to levels exhibited by normal subjects. Immunoblot analysis was performed to determine antibody specificity and cellular expression of caspases. Purified populations of keratinocytes, melanocytes, dermal papilla, and dermal fibroblasts derived from human hair follicles were cultured in vitro and treated with 0.5 mm staurosporin. Time-course experiments revealed that processing of caspase-3 is a principal event during apoptosis of these hair cell types. CONCLUSION: These data suggest that alterations in levels of caspases and IAPs regulate hair follicle homeostasis. Moreover, finasteride appears to influence caspase and XIAP expression in hair follicle cells thus signaling anagen, active growth in the hair cycle.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11896416&dopt=Abstract finasteride Propecia



finasteride, Propecia
Proscar (Finasteride) inhibits 5 alpha-reductase activity in the ovaries and testes of Lytechinus variegatus Lamarck (Echinodermata: Echinoidea).

Wasson KM, Watts SA.

Department of Biology, University of Alabama at Birmingham 35294-1170, USA. kwasson uab.edu

Recent investigations into the steroid metabolic pathway in the echinoid Lytechinus variegatus demonstrated the capacity of the gonads to convert androstenedione, the classical mammalian precursor to bioactive androgens, into testosterone and a variety of 5 alpha-reduced androgens including 5 alpha-androstane-3 beta, 17 beta-diol and 5 alpha-androstane-3 alpha, 17 beta-diol. The synthesis of these steroids, which requires 5 alpha-reductase activity, varies with sex and reproductive state in L. variegatus, suggesting that these steroids may be involved in reproductive processes. The classical method of castration followed by steroid replacement therapy to determine the biological role of steroids in the gonads of higher vertebrates is not possible in echinoids. Therefore, this study was designed to determine the efficacy of finasteride, a selective 5 alpha-reductase inhibitor in the mammalian prostate gland, on 5 alpha-reductase activity in the gonads of L. variegatus. Finasteride inhibits echinoid 5 alpha-reductase in a dose-dependent manner with IC50 approximately 2.7 microM for both ovaries and testes. These echinoid IC50s are significantly higher than those reported for humans and rats. In addition, oral administration of finasteride to the echinoids appeared to inhibit 5 alpha-reductase with no apparent stress (no spine loss) to the animals. These data suggest that finasteride may be used to selectively and chemically ablate 5 alpha-reduced androgen synthesis in the gonads of L. variegatus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9827060&dopt=Abstract finasteride Propecia



finasteride, Propecia
Identification of genes expressed in the rat prostate that are modulated differently by castration and Finasteride treatment.

Avila DM, Fuqua SA, George FW, McPhaul MJ.

Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235-8857, USA.

In mammals, testosterone and 5alpha-dihydrotestosterone (DHT) are the principal male hormones (androgens). Testosterone is the most abundant circulating androgen, and is converted in specific tissues to DHT by the 5alpha-reductase enzymes. Although each of these androgens binds to the same receptor protein (androgen receptor, AR), each exerts biologically distinct effects. Theories to explain the specific effects of testosterone and DHT have centered on kinetic differences of binding of androgens to the receptor or differences in the metabolic fates of the two hormones. In the current experiments, differential display PCR (ddPCR) was used to identify genes regulated differently by testosterone and DHT. Adult male rats were treated as follows: castrated, treated with Finasteride (an inhibitor of 5alpha-reductase) or left intact for ten days. RNA was prepared from the dissected prostates of these animals and used for ddPCR. Genes exhibiting four distinct patterns of regulation were observed among the mRNAs. Class 1 genes showed equivalent expression in intact and Finasteride-treated animals, but were absent in castrated animals (mRNAs D1, D2, D6, D10). Class 2 genes showed higher expression in intact animals, intermediate levels following Finasteride treatment, but were absent in castrated animals (mRNA D8). Two classes of gene were particularly intriguing: class 3 showed gene expression only in the intact animal (mRNA D7, D9) and class 4 showed increased gene expression following Finasteride treatment (mRNA D3). While the patterns observed for some of these genes (e.g. D8) suggest that the different biological effects of testosterone and DHT may be due to the lower affinity of the AR for testosterone and limiting tissue concentrations of androgen, our results also suggest that some genes expressed in the rat prostate may be regulated in fundamentally different ways in response to testosterone and DHT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9834458&dopt=Abstract finasteride Propecia



finasteride, Propecia
Effect of finasteride in idiopathic hirsutism.

Faloia E, Filipponi S, Mancini V, Di Marco S, Mantero F.

Istituto di Medicina Clinica, University of Ancona, Italy.

Increased 5 alpha-reductase activity has been found in hair follicles of hirsute women, suggesting a pathogenetic role. The aim of the present study was to evaluate the effect of finasteride in the treatment of idiopathic hirsutism. Twenty-seven women with idiopathic hirsutism, aged 16-35 years, were treated for 6 months with finasteride, 5 mg once daily. Fourteen patients were on finasteride alone (group A), while the remaining received in addition an oral contraceptive (group B). Clinical, hormonal and biochemical evaluation were performed before, and after 3 and 6 months of treatment. Clinical evaluation was repeated 6 months after drug discontinuation in seven patients. Treatment was well tolerated by all patients; no side effects or adverse reactions were reported. A significant improvement of hirsutism was obtained by finasteride; clinical score observed at the 6th month of therapy was reduced from 11.71 +/- 2.23 to 7.92 +/- 1.81 (p < 0.05) and from 14.92 +/- 6.13 to 9.3 +/- 2.75 (p < 0.05) in group A and B, respectively. Clinical score in seven patients was still 8.61 +/- 2.28 (p < 0.05) 6 months after the end of therapy. Finasteride treatment alone (group A) induced a slight increase, though not significant, in serum androgens; DHT and SHBG did not change. In group B (finasteride plus oral contraceptive) total testosterone and free testosterone showed no significant decrease; after 6 months of therapy DHT was reduced significantly, while SHBG levels were increased. These data demonstrate that 5 alpha-reductase inhibition may be an effective treatment in women suffering from idiopathic hirsutism. This approach may be attractive due to the absence of adverse reactions, although the necessity of an adequate contraception should be kept in mind.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9854686&dopt=Abstract finasteride Propecia