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PubMed2000

The novel drug CS-891 inhibits 5alpha-reductase activity in freshly isolated dermal papilla of human hair follicles.

The local conversion of testosterone (T) to the more potent androgen dihydrotestosterone (DHT) by 5alpha-reductase (5aR) is implicated in the pathogenesis of androgenetic alopecia (AGA). Recently, the clinical effectiveness of finasteride, a selective type II 5aR inhibitor, in treating AGA has been documented, and these clinical studies have shown that circulating DHT is lowered by 60-70% in men taking finasteride. The source of the residual circulating DHT is presumed to be due to type I 5aR activity which is not affected by finasteride. Several novel compounds with potent dual inhibitory activity on both isoenzymes have been described and CS-891 is one of them. This compound may be likewise effective in the prevention or treatment of AGA. As a prerequisite for such an action CS-891 should be able to inhibit 5aR activity in its target tissue: the hair follicles (HF). Here we report on the capability of CS-891 to inhibit 5aR activity in dermal papillae (DP) of human HF.

Adult↗
PubMed2003

Benign prostatic hyperplasia: does prostate size matter?

Recent studies and analyses have confirmed that baseline prostate volume is related to progression of benign prostatic hyperplasia (BPH) as well as to negative outcomes related to BPH, such as acute urinary retention (AUR) and need for surgery, and can also predict response to therapy. Other investigations have determined that prostate-specific antigen (PSA) level has good predictive value for assessing prostate volume. Strong evidence exists that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. Randomized placebo-controlled finasteride trials have shown that men with larger prostate volumes and higher PSA levels experience a clinically significant response to therapy compared with those with smaller prostate volumes and lower PSA levels. It has also been demonstrated that men with larger prostate glands and higher PSA levels are at increased risk for AUR and BPH-related surgery but that finasteride reduces these risks. Moreover, doxazosin and finasteride, alone and in combination, have been shown to significantly reduce BPH clinical progression.

Journal Article↗
PubMed2003

Landmark studies impacting the medical management of benign prostatic hyperplasia.

The treatment of benign prostatic hyperplasia (BPH) has changed dramatically over the past 10 years. Phase 3 studies of the safety and effectiveness of alpha-blockers (eg, terazosin and doxazosin) and 5-alpha-reductase inhibitors (eg, finasteride) for the treatment of BPH began to appear in the literature in 1992. This article reviews the results of landmark studies of these agents, either separately as monotherapy or as combined therapy, for the treatment of BPH. The relationship between prostate size and lower urinary tract symptoms (LUTS) is discussed. Although prostate volume is not as strongly correlated with these symptoms as was once believed, it has been shown to be an important predictor of risk for developing acute urinary retention. alpha-Blockers represent an effective treatment for LUTS independent of prostate volume; the clinical benefit of finasteride for LUTS is limited primarily to men with large prostates. Finasteride decreases the risk of progression to acute urinary retention and the requirement for surgical intervention; this benefit is greatest in men with enlarged prostates.

Journal Article↗
PubMed2003

Landmark studies impacting the medical management of benign prostatic hyperplasia.

The treatment of benign prostatic hyperplasia (BPH) has changed dramatically over the past 10 years. Phase 3 studies of the safety and effectiveness of alpha-blockers (eg, terazosin and doxazosin) and 5-alpha-reductase inhibitors (eg, finasteride) for the treatment of BPH began to appear in the literature in 1992. This article reviews the results of landmark studies of these agents, either separately as monotherapy or as combined therapy, for the treatment of BPH. The relationship between prostate size and lower urinary tract symptoms (LUTS) is discussed. Although prostate volume is not as strongly correlated with these symptoms as was once believed, it has been shown to be an important predictor of risk for developing acute urinary retention. alpha-Blockers represent an effective treatment for LUTS independent of prostate volume; the clinical benefit of finasteride for LUTS is limited primarily to men with large prostates. Finasteride decreases the risk of progression to acute urinary retention and the requirement for surgical intervention; this benefit is greatest in men with enlarged prostates.

Journal Article↗
PubMed1997

Pharmacological and molecular evidence for the expression of the two steroid 5 alpha-reductase isozymes in normal and hyperplastic human prostatic cells in culture.

BACKGROUND: Whereas the embryological development of the human prostate is clearly dependent on steroid 5 alpha-reductase (5 alpha-R) type 2 expression, the respective expression of the two known isoforms (types 1 and 2) of 5 alpha-R in the adult human prostate remains unclear. METHODS: 5 alpha-R isoform mRNA expression (Northern blots and reverse transcriptase-polymerase chain reaction [RT-PCR]) and enzyme activity were studied in immortalized epithelial cells (NE) and in fibroblasts from normal (NF) or hyperplastic (BPHF) human prostates. RESULTS: 5 alpha-R activity (fmol/microgram DNA/hr) was 1.43 +/- 0.5 in NE, 10.7 +/- 4.7 in NF, and 79 +/- 37 in BPHF. mRNAs for both 5 alpha-R isoforms were expressed in the three cell types, as shown by Northern blot and RT-PCR analysis. LY306089, a selective 5 alpha-R type 1 inhibitor, strongly inhibited 5 alpha-R activity in all cell types (IC50: 10 nM), confirming the predominant expression of 5 alpha-R type 1 in these cells. Finasteride, a 5 alpha-R type 2 inhibitor, was less efficient (IC50: 45, 35, and 65 nM in NE, NF, and BPHF, respectively). In addition, the inhibition by finasteride decreased with serial subculture in NF only, suggesting an effect of age in culture on the expression of 5 alpha-R type 2 in these cells. SKF105657, also a 5 alpha-R type 2 inhibitor, was a poor inhibitor in this system. CONCLUSIONS: These studies demonstrate that human prostate cells in culture express both isoforms of 5 alpha-R and suggest a balance in the expression of the two isoforms as a function of various regulatory factors.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Chemoprevention of prostate cancer: the Prostate Cancer Prevention Trial.

BACKGROUND: A variety of innovative approaches to the prevention of prostate cancer are now available, including selenium, alpha tocopherol, dietary interventions, and vitamin D. Perhaps the most promising opportunity is based upon considerable evidence that cumulative androgen exposure of the prostate contributes to the age-related risk of prostate cancer. METHODS: The Prostate Cancer Prevention Trial has completed randomization of over 18,000 healthy men to either finasteride or placebo. CONCLUSIONS: While the primary objective of this study is to determine whether finasteride can reduce the period prevalence of prostate cancer over a 7-year period, the biologic and data resources of this study will provide multiple opportunities to better understand this most common cancer in U.S. men.

Aged↗
PubMed1998

Effect of dual inhibition of 5-alpha-reductase and aromatase on spontaneously developed canine prostatic hypertrophy.

BACKGROUND: Our aim was to assess the effect of dual inhibition of 5-alpha-reductase and aromatase on prostate glands. METHODS: We investigated the morphological changes in the prostate gland and the changes in the hormonal environment after administration of finasteride and arimidex to intact canine specimens. The study consisted of four groups: a 5-alpha-reductase only group (5RI only, n = 5); a 5RI plus aromatase-inhibitor combination group (5RI + ARI combination, n = 5); a BPH control group (n = 3); and a castration control group (n = 3). Finasteride (1 mg/kg/day) and the same dose of arimidex were orally administered for 80 days. RESULTS: In the 5RI group, a significant decrease in the serum dihydrotestosterone (DHT) level was found, and prostatic volume was significantly decreased. However, significant increases in serum testosterone (T) and DHT levels were observed, with a concomitant increase in prostatic volume in the 5RI + ARI combination group. Morphometric analysis showed that histopathological findings in the 5RI + ARI combination group were similar to those in the BPH control group. CONCLUSIONS: Dual inhibition of 5-alpha-reductase and aromatase resulted in a significant increase in prostate volume, accompanied by a 3-10-fold increase in serum testosterone levels and a significant increase in testicular volume.

Anastrozole↗
PubMed2003

Impact of a novel neoadjuvant and adjuvant hormone-deprivation approach on quality of life, voiding function, and sexual function after prostate brachytherapy.

BACKGROUND: Data demonstrate a benefit from neoadjuvant and adjuvant hormone-deprivation therapy with luteinizing hormone-releasing hormone agonists in patients who are treated with radiotherapy for localized prostate carcinoma; however, this approach has detrimental effects on quality of life (QOL). A cross-sectional study was undertaken to evaluate the impact on QOL, voiding function, and sexual function of an alternative hormone-deprivation approach. METHODS: Three hundred fifty patients with clinical T1c-T2b prostate carcinoma were treated from March 1997 to August 2000 either with palladium 103 brachytherapy (BTM) without hormone therapy or with 8 months of adjuvant and neoadjuvant hormone-deprivation therapy with an antiandrogen and finasteride (BTM+H), were mailed the Functional Assessment of Cancer Therapy (FACT) global well being QOL instrument (FACT-G), the American Urological Association symptom score (AUASS), and specific items addressing urinary control and sexual function from validated instruments. Differences between treatment groups were assessed as a function of time since treatment. RESULTS: Seventy-two percent of patients responded to the questionnaire. No differences in overall FACT-G scores, AUASS scores, or AUASS subscale scores between the BTM group and the BTM+H group were found. The BTM+H group initially had lower personal well being FACT-G subscale scores, more urinary incontinence, and lower odds of attaining an erection sufficient for intercourse initially, although these differences disappeared with longer follow-up. CONCLUSIONS: The use of neoadjuvant and adjuvant antiandrogen and finasteride with brachytherapy is associated with QOL equal to that of brachytherapy alone for the treatment of patients with localized prostate carcinoma, allowing the advantages of hormone manipulation in terms of tumor control without its downside.

5-alpha Reductase Inhibitors↗
PubMed2001

Replacement of surgical castration by GnRH-inhibition or Leydig cell ablation in the male rat Hershberger antiandrogen assay.

An obstacle to the widespread adoption of the Hershberger antiandrogen assay is the surgical castration procedure required to produce androgen deficiency in the test animals. Here we describe two chemical treatments that produce similar effects to surgical castration. The first is use of ethane dimethane sulphonate (EDS), a specific toxin to the testosterone-producing Leydig cells of the mature testes. The second class of compound is the decapeptide inhibitors of the gonadotrophin-releasing hormone (GnRH), compounds such as Antarelix and Antide. Administration of either EDS or the GnRH inhibitors results in loss of weight of the testes, epididymides, and sex-associated tissues. Co-administration of testosterone to these animals leads to reversal of the induced effects. The basic test protocol for both of these assay modifications is described. Flutamide was used as a representative potent antiandrogen, and DDE as an example of a weakly active antiandrogen. The 5alpha-reductase inhibitor finasteride was used to inhibit the transformation of testosterone to dihydrotestosterone. It is shown that the EDS assay is sensitive to the antiandrogen flutamide, but that it fails to detect the weaker antiandrogen DDE. In contrast, the Antarelix assay performs as well as does the classical castration assay, leading to the detection as antiandrogens of flutamide, DDE, and finasteride. It is concluded that the GnRH inhibition Hershberger assay is more convenient to conduct than the original surgical castration assay, and it involves less stress to the test animals.

5-alpha Reductase Inhibitors↗
PubMed1997

Pharmacotherapy of benign prostatic hyperplasia: inhibitor of 5 alpha-reductase.

We studied the effects of 5 alpha-reductase inhibitor (finasteride) in the treatment of benign prostatic hyperplasia (BPH). This study is a randomized controlled trial. Sixty-two patients were treated with 5 alpha-reductase (finasteride 5 mg/day) and 61 patients (control group) with placebo for one year. Prostatic volume, maximal urine flow rate, AUA symptom scoring, residual urine volume and prostate-specific antigen (PSA) levels were evaluated at 3, 6, 9 and 12 months. In the first 6 months prostatic volume decreased rapidly (20.5%), in the second 6 months it decreased slowly and reached the maximal rate (23.3%). Maximal urine flow rate increased in the second 6 months. AUA symptom scores decreased first at 3 months and were 4.6 points lower at the end of the 12th month. There were no significant changes in residual volume. The 5 alpha-reductase inhibitor caused a 50% decrease in PSA levels, like in other studies. Because of the prolonged use of the drug, treatment with 5 alpha-reductase inhibitor is not tolerated by many patients and being expensive its future in the pharmacotherapy of BPH is unclear.

Aged↗
PubMed1996

Economics of different treatment options of benign prostatic hyperplasia in Turkey.

Benign prostatic hyperplasia (BPH) has an important impact on the national health economics and can be managed in a large spectrum of modalities from simple follow-up to surgery. In this study, we aimed to compare different treatment options of BPH in terms of cost effectiveness in Turkey. The first evaluation of a BPH patient has a cost of $200. The cost of TURP or open prostatectomy (OP) in our hospital including all the expenses is $740. Finasteride has an annual cost nearly equal to TURP and OP. Considering the expenses of the close follow-up studies and regular visits, one-year lasting Finasteride treatment is two times more expensive than surgery. In comparison with medical treatment options, TURP as the gold standard of treatment of BPH is cost effective when long-term expenses are considered.

Cost-Benefit Analysis↗
PubMed2002

[Drug therapy of benign prostatic hyperplasia. Is combination therapy with 5 alpha-reductase inhibitors and alpha-receptor blockers effective?].

5 alpha-reductase inhibitors and alpha 1-receptor blockers are the two main drug therapies used in the management of symptomatic benign prostatic hyperplasia. As alpha-reductase inhibitors and alpha 1-receptor blockers act through different mechanisms, a combination of the two agents might be promising. The potential benefits of combination therapy with selective alpha 1-receptor blockers and finasteride, a 5 alpha-reductase inhibitor, are currently being evaluated in several placebo-controlled prospective multicenter studies (VA Study, ALFIN Study, PREDICT Study, and MTOPS Study). The data from these studies available so far demonstrate a statistically significant benefit for the study groups receiving alpha 1-receptor blockers and combination therapy vs placebo and finasteride monotherapy in terms of symptom scores and peak urine flow rates. However, none of the studies yielded a statistically significant advantage of combination therapy over treatment with alpha 1-receptor blockers. These results should be interpreted with reference to the prostatic volume, which in the studies mentioned above was relatively low. From the results of all these studies, it can be concluded that in symptomatic patients with prostate volumes of up to 40-45 ml a combination of 5 alpha-reductase inhibitors with alpha 1-receptor blockers does not appear to provide any benefit. Yet, it can be assumed that in symptomatic patients with prostate volumes of more than 60 ml combination therapy may indeed prove more effective.

5-alpha Reductase Inhibitors↗
PubMed1997

[Significance of 5-alpha-reductase inhibitors in therapy of benign prostatic hyperplasia with mild to modern symptoms].

Medical therapy in the treatment of symptomatic benign prostatic hyperplasia has changed very much during the last few years. Finasteride is a 5-alpha-reductase inhibitor, which inhibits the predominant intraprostatic isoenzyme II of 5-alpha-reductase and therefore DHT, which is-among other factors-essential for the physiological growth of the prostate. However, it also has an important influence on developing BPH. It was shown in several studies that finasteride can increase urinary flow rates, decrease the prostate volume, and improve the symptom score and PSA value. The objective improvement in urinary flow rates was only moderate, but better results were obtained in the improvement of patient symptoms. Large multicenter studies will be conducted to see if the efficacy of treatment can be improved by combination therapy with alpha-1-blockers.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2004

Benign prostate hyperplasia: evaluation of treatment response with DCE MRI.

Benign prostate hyperplasia (BPH) is a major disease and its non-surgical therapy a major area of interest. The purpose of this study was to establish perfusion parameters in beagles with BPH using dynamic contrast-enhanced (DCE) MRI and to investigate changes due to the effects of finasteride treatment. Twelve male beagles (mean age 4.4 +/- 0.9,years) were divided into a control and treatment group that received a daily dose of 1 mg/kg finasteride. DCE MRI was carried out in a clinical scanner using a 3D spoiled gradient echo sequence prior to and during treatment. 0.2 mmol/kg contrast agent (gadoteridol) was administered with an injection rate of 0.2 ml/s followed by a 15 ml flush of saline. Contrast enhancement was evaluated by pharmacokinetic mapping of a two-compartment model with colour overlay images in addition to regional ROI analysis. Quantitative parameters were defined by the amplitude of contrast enhancement A, the exchange rate k(ep) and the time to maximum signal enhancement. Dynamic contrast-enhanced MRI investigations of the prostate revealed two distinct zones, an inner, periurethral zone and an outer, parenchymal zone. The periurethral zone is highly vascularized, whereas the parenchymal zone is moderately vascularized when compared to other parenchymal organs. During treatment, in the parenchymal zone the intensity of enhancement (amplitude A) and the time to maximum signal enhancement increased, while the exchange rate k(ep) decreased. Dynamic contrast-enhanced MRI of BPH reveals distinct differences between individual zones within the prostate. Moreover, changes during successful treatment suggest increased blood volume per volume of tissue and decreased vessel leakiness.

Animals↗
PubMed1995

Current treatment of BPH.

Benign prostatic hypertrophy (BPH) is one of the most common diseases of adult males which increases with age. Effective therapeutic agents are an attractive option for patients for whom surgery is not a necessity, improving quality of life when compared with watchful waiting. Epidemiological studies show that 88% of patients over 80 years of age present anatomical BPH. This prevalence is similar in male populations throughout the world. Surgical treatment (transurethral resection of the prostate: TURP) has been the gold standard for over 50 years in patients with an enlarged prostate and obstructive symptoms but 20% of patients remain unsatisfied with surgery. Various medicinal preparations have been used since biblical times, in particular plant extracts which are still prescribed in Europe. Some claim to have an enzymatic inhibitory effect, but currently have not demonstrated objective efficacy. Alpha-blockers act on bladder and prostate smooth muscle, the contraction of which is mediated through alpha 1-receptors. Treatment has shown increased uroflow, decreased residual volume and a decrease in symptoms of BPH. Alpha-blockers; however, have shown no effect on prostate volume nor a reduction in the need for surgery for these patients. Finasteride, currently the only 5 alpha-reductase inhibitor approved for treatment of symptomatic BPH, has been widely investigated. The drug has been shown to decrease prostate volume, improve symptoms, uroflow and invasive urodynamic parameters in the majority of patients. Dihydrotestosterone (DHT) is decreased but the level of serum testosterone is maintained. Prostatic specific antigen is decreased by 50% as an effect of the drug on epithelial cells. Overall, the drug is well tolerated but some patients have shown decreased libido and/or impotency; however, two-thirds of these patients improved when the treatment was continued. Two effective medical therapies are currently available for treating symptomatic BPH: finasteride and alpha antagonists. Studies are now in progress to determine whether a combination of these therapies would be an effective alternative to surgery or watchful waiting.

Adrenergic alpha-Antagonists↗
PubMed1995

Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts.

We compare testosterone (T) metabolism in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy (BPH) and prostate cancer tissues. In all cultures, androstenedione (delta 4) formed by oxidation of T by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) represented 80% of the metabolites recovered. The amounts of 5 alpha-dihydrotestosterone (DHT), formed by reduction of T by 5 alpha-reductase (5 alpha-R), were small: 5 and 2% (BPH) and 8 and 15% (adenocarcinoma) for epithelial cells and fibroblasts, respectively. Northern blot analysis of total RNA from epithelial cells (BPH or adenocarcinoma) attributed the reductive activity to the 5 alpha-reductase type 1 isozyme and oxidative activity to the 17 beta-HSD type 2. In cancer fibroblasts, only little 17 beta-HSD type 2 mRNA was detected. The 5 alpha-reductase inhibitors, 4-MA (17 beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and finasteride, inhibited DHT formation with a preferential action of 4-MA on epithelial cells (BPH or adenocarcinoma) and of finasteride on fibroblasts from adenocarcinoma. Neither inhibitor acted on delta 4 formation. On the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon) inhibited the formation of all the T metabolites studied [IC50 S = 40 and 200 micrograms/ml (BPH) and 90 and 70 micrograms/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively]. These results have important therapeutic implications when selecting appropriate treatment options for BPH.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

Androgens are not major down-regulators of androgen receptor levels during growth of the immature rat penis .

This study was undertaken to investigate the prevalent hypothesis that androgens are responsible for the organ-specific down-regulation of penile androgen receptors (ARs) and decline of penile growth in the rat during sexual maturation. Sexually immature male rats (21 days old) were castrated and treated for 3 days ("short-term"), with high doses of: (a) testosterone and the alpha-reductase inhibitor finasteride (T/F); (b) dihydrotestosterone (DHT); or (c) finasteride alone (F). Intact and castrate controls received vehicle only. PolyA + RNA was analysed by Northern blot hybridization and ARs were estimated in the penis and ventral prostates by (3-H)R-1881 binding in the cytosol. Short-term castration, with or without F, increased penile AR mRNA, whereas high doses of T/F and DHT reduced it considerably. Although penile cytosol AR concentration in the control castrates, with or without F, paralleled the AR mRNA rise, treatment with androgens left cytosol AR content per organ and AR concentration above those of the intact rat penis despite the drop in AR mRNA. A "long-term" treatment (10 days) on 19-day-old rats with either medium or high doses of T/F and DHT also failed to down-regulate penile cytosol ARs below the intact controls. Western blot analysis of penile cytosol AR levels confirmed these results. Block of pituitary FSH and LH release by a GnRH antagonist in castrates receiving T/F or DHT at high doses did not modify the response. In the case of intact rats, high doses of T/F or DHT actually increased penile cytosol AR content. No difference was observed between T/F and DHT effects. In contrast to what occurs during sexual maturation, the prostate ARs and growth rate responded to all treatments in a similar way to what was observed in the penis. Our results suggest that increases in serum T or DHT are not major factors in the physiological down-regulation of ARs and androgen-dependent growth in the rat corpora cavernosa.

Androgens↗
PubMed1996

Synthesis of 4,17-diazasteroid inhibitors of human 5 alpha-reductase.

The synthesis of the 17-aza isomer of finasteride is described. With the side chain amide group of the compound existing in the Z configuration the structure is similar to one of the two favored conformations of finasteride. A series of 4,17-diazasteroids was assayed against the isoenzymes of human 5 alpha-reductase.

5-alpha Reductase Inhibitors↗