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

In mammals, testosterone and alpha-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 alpha-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 alpha-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.

Effects of the anti-androgen finasteride on the modulatory actions of oestradiol on androgen metabolism by human gingival fibroblasts.

5 alpha-Reduction of androgen substrates results in the formation of the biologically active androgen 5 alpha-dihydrotestosterone (DHT), while 17 beta-hydroxysteroid dehydrogenase metabolises androgen substrates to 4-androstenedione or testosterone. The aim here was to study the effect of the anti-androgen finasteride on 5 alpha-reduction of androgens by human gingival fibroblasts (HGF) and its modulation by oestradiol-17 beta. Duplicate cultures of HGF were incubated with [14C]testosterone/[14C]4-androstenedione in Eagle minimum essential medium (n=6) in the presence or absence of oestradiol-17 beta (O) or finasteride (F; 0.1-3 microg/ml) for 24 h. The steroid metabolites were analysed and quantified using a radioisotope scanner. With [14C]testosterone as substrate, oestradiol stimulated the formation of DHT by 63% (n=6; P<0.01). In contrast, finasteride inhibited this activity by 61% (n=6; P<0.01). The combination of O+F produced 43% less inhibition than finasteride alone (n=6; P<0.01). There were 200-300% increases in the formation of 4-androstenedione in response to O and F, being less pronounced in combination. Oestradiol stimulated the formation of DHT from [14C]4-androstenedione by 300-600% and finasteride reduced the yield of DHT by 40-64%; there was less inhibition in combination with O. There were 300-700% increases in the formation of testosterone in response to F and O alone and in combination (n=6; P<0.01). Oestradiol-induced stimulation of 5 alpha-reductase activity on androgen substrates by HGF is suggestive of hormone modulatory mechanisms in the healing periodontium of both sexes. Its inhibition by finasteride is suggestive of type 2 isoenzyme activity, confirming target-tissue functions in the gingiva.

The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides).

Finasteride, a 5 alpha-reductase inhibitor, was administered orally (1 mg/kg.day) for 6 months to six male and five female stumptail macaques. Vehicle was given to five male and five female animals over the same period of time. Hair weights in a defined 1-in.2 area of frontal scalp were measured periodically every 1-2 months, and serum was collected for measurement of testosterone and dihydrotestosterone. In addition, scalp biopsies were taken before and 6 months after treatment to evaluate the micromorphometry of hair follicles. Results showed that both male and female serum dihydrotestosterone levels were significantly reduced (60-70%) by finasteride treatment. Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034). In addition, there was a statistically significant increase in mean follicle length (measured histologically in scalp biopsies) compared to baseline in the finasteride-treated animals (P = 0.028). These data show that an inhibition of 5 alpha-reductase in the stumptail macaque can reverse the balding seen with age in both the male and female animals.

Finasteride (Proscar) for benign prostatic hypertrophy

Several alternatives to surgery for benign prostatic hypertrophy (BPH) were studied during the past few years. Finasteride (Proscar), a 4-azosteroid, is an inhibitor of the enzyme 5-alpha reductase, which is responsible for the conversion of testosterone to the biologically more active dihydrotestosterone (DHT). We report 3 years of experience with the drug in 23 men. Persistent significant decreases in serum DHT and prostate-specific antigen (PSA) were documented. Prostatic volume decreased by about 25% after 1 year, and remained fairly constant thereafter. Urination improved, as evidenced by increased maximal flow rate and decreased volume of residual urine. Symptoms were affected favorably, but only mildly. One of the main advantages of the drug is its lack of side-effects. More data on a larger number of patients with a longer follow-up are needed before finasteride can be established as having a role as an alternative treatment for BPH.