Treatment of Benign Prostatic Hyperplasia by Natural Drugs.

Benign prostatic hyperplasia (BPH) is one of the most common urinary diseases affecting men, generally after the age of 50. The prevalence of this multifactorial disease increases with age. With aging, the plasma level of testosterone decreases, as well as the testosterone/estrogen ratio, resulting in increased estrogen activity, which may facilitate the hyperplasia of the prostate cells. Another theory focuses on dihydrotestosterone (DHT) and the activity of the enzyme 5α-reductase, which converts testosterone to DHT. In older men, the activity of this enzyme increases, leading to a decreased testosterone/DHT ratio. DHT may promote prostate cell growth, resulting in hyperplasia. Some medicinal plants and their compounds act by modulating this enzyme, and have the above-mentioned targets. This review focuses on herbal drugs that are most widely used in the treatment of BPH, including pumpkin seed, willow herb, tomato, maritime pine bark, Pygeum africanum bark, rye pollen, saw palmetto fruit, and nettle root, highlighting the latest results of preclinical and clinical studies, as well as safety issues. In addition, the pharmaceutical care and other therapeutic options of BPH, including pharmacotherapy and surgical options, are discussed, summarizing and comparing the advantages and disadvantages of each therapy.

GABAA receptor currents in the dorsal motor nucleus of the vagus in females: influence of ovarian cycle and 5α-reductase inhibition.

The dorsal motor nucleus of the vagus (DMV) contains the preganglionic motor neurons important in the regulation of glucose homeostasis and gastrointestinal function. Despite the role of sex in the regulation of these processes, few studies examine the role of sex and/or ovarian cycle in the regulation of synaptic neurotransmission to the DMV. Since GABAergic neurotransmission is critical to normal DMV function, the present study used in vitro whole cell patch-clamping to investigate whether sex differences exist in GABAergic neurotransmission to DMV neurons. It additionally investigated whether the ovarian cycle plays a role in those sex differences. The frequency of phasic GABAA receptor-mediated inhibitory postsynaptic currents in DMV neurons from females was lower compared with males, and this effect was TTX sensitive and abolished by ovariectomy (OVX). Amplitudes of GABAergic currents (both phasic and tonic) were not different. However, females demonstrated significantly more variability in the amplitude of both phasic and tonic GABAA receptor currents. This difference was eliminated by OVX in females, suggesting that these differences were related to reproductive hormone levels. This was confirmed for GABAergic tonic currents by comparing females in two ovarian stages, estrus versus diestrus. Female mice in diestrus had larger tonic current amplitudes compared with those in estrus, and this increase was abolished after administration of a 5α-reductase inhibitor but not modulation of estrogen. Taken together, these findings demonstrate that DMV neurons undergo GABAA receptor activity plasticity as a function of sex and/or sex steroids.NEW & NOTEWORTHY Results show that GABAergic signaling in dorsal vagal motor neurons (DMV) demonstrates sex differences and fluctuates across the ovarian cycle in females. These findings are the first to demonstrate that female GABAA receptor activity in this brain region is modulated by 5α-reductase-dependent hormones. Since DMV activity is critical to both glucose and gastrointestinal homeostasis, these results suggest that sex hormones, including those synthesized by 5α-reductase, contribute to visceral, autonomic function related to these physiological processes.

The effect of early-life stress and chronic high-sucrose diet on metabolic outcomes in female rats.

Early-life stress affects metabolic outcomes and choice of diet influences the development of metabolic disease. Here we tested the hypothesis that chronic sugar intake exacerbates metabolic deficits induced by early-life stress. Early-life stress was induced in Sprague-Dawley rats using limited nesting material in early lactation (LN, postnatal days 2-9), and siblings were given chow alone or with additional sucrose post weaning (n = 9-17 per group). Female control and LN siblings had unlimited access to either chow plus water, or chow and water plus 25% sucrose solution (Sucrose), from 3-15 weeks of age. Weekly body weight and food intake were measured. Glucose and insulin tolerance were tested at 13 and 14 weeks of age, respectively. Rats were killed at 15 weeks. Hepatic triglyceride and markers of lipid synthesis - fatty acid synthase, acetyl-CoA carboxylase alpha and oxidation - and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) were examined. Mediators of hepatic glucocorticoid metabolism, specifically 11-beta hydroxysteroid dehydrogenase-1 (11ßHSD-1), 5-α reductase, and glucocorticoid and mineralocorticoid receptor mRNAs were also measured. Sucrose increased caloric intake in both groups, but overall energy intake was not altered by LN exposure. LN exposure had no further impact on sucrose-induced glucose intolerance and increased plasma and liver triglycerides. Hepatic markers of fat synthesis and oxidation were concomitantly activated and 11ßHSD-1 mRNA expression was increased by 53% in LN-Sucrose versus Con-Sucrose rats. Adiposity was increased by 26% in LN-Sucrose versus Con-Sucrose rats. Thus, LN exposure had minimal adverse metabolic effects despite high-sugar diet postweaning.

Methods to predict and lower the risk of prostate cancer.

Chemoprevention for prostate cancer (PCa) continues to generate interest from both physicians and the patient population. The goal of chemoprevention is to stop the malignant transformation of prostate cells into cancer. Multiple studies on different substances ranging from supplements to medical therapy have been undertaken. Thus far, only the studies on 5 alpha-reductase inhibitors (the Prostate Cancer Prevention Trial [PCPT] and Reduction by Dutasteride of Prostate Cancer Events [REDUCE] trial) have demonstrated a reduction in the risk of PCa, while results from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) concluded no decreased risk for PCa with selenium or vitamin E.

Extracts of Phyllostachys pubescens Leaves Represses Human Steroid 5-Alpha Reductase Type 2 Promoter Activity in BHP-1 Cells and Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia in Rat Model.

Benign prostatic hyperplasia (BPH) is the most common symptomatic abnormality of the human prostate characterized by uncontrolled proliferation of the prostate gland. In this study, we investigated the effect of bamboo, Phyllostachys pubescens, leaves extract (PPE) on human 5α-reductase type 2 (SRD5A2) gene promoter activity in human prostate cell lines and the protective effect of PPE on a testosterone-induced BPH rat model. PPE repressed human SRD5A2 promoter activity and its mRNA expression. The rats treated with PPE for 4 weeks showed a significantly attenuated prostate weight compared to vehicle control. PPE-treated rats also showed reduced serum dihydrotestosterone, testosterone, prostate-specific antigen, and SRD5A2 levels by testosterone injection. Quantitative real-time polymerase chain reaction showed that PPE treatment significantly decreased mRNA expression of SRD5A2, androgen receptor (AR), proliferating cell nuclear antigen (PCNA), and fibroblast growth factor 2 compared with the vehicle-treated, testosterone-injected rats in the prostate. Furthermore, PPE treatment showed reduced AR, PCNA, and tumor necrosis factor alpha expression in the prostate via immunohistofluorescence staining. In conclusion, oral administration of PPE prevented and inhibited the development and progression of enlarged prostate lesions in testosterone-induced animal models through various anti-proliferative and anti-inflammatory pharmacological effects and induced suppression of SRD5A2 gene expression.

Complete NMR assignment and absolute configuration of k4610422, a norditerpenoid inhibitor of testosterone-5α-reductase originally from Streptosporangium: rediscovery from a thermophilic Actinomadura.

A norditerpenoid k4610422 (1), an inhibitor of testosterone-5α-reductase originally discovered from a mesophilic rare actinomycete of the genus Streptosporangium, was isolated from the culture extract of a thermophilic actinomycete Actinomadura sp. The complete 1H and 13C NMR assignment and absolute configuration of 1 were addressed by spectroscopic measurements including NOESY and CD spectra coupled with ECD calculation, which allowed to establish the (5 R,9 S,10 R,13 S)-configuration. Compound 1 was moderately cytotoxic against P388 murine leukemia cells with IC50 30 µM.

Baicalin alleviates benign prostate hyperplasia through androgen-dependent apoptosis.

BPH is a disease prevalent among elderly men that is characterized by abnormal proliferation of prostatic epithelial and stromal tissues. No effective treatment exists for BPH owing to lack of a clear understanding of its molecular etiology. Although several studies have reported therapeutic effects of baicalin against numerous diseases, including prostate cancer, its beneficial effects on BPH have not yet been explored. The present study investigated the therapeutic effects of baicalin on the development of BPH and its mechanism of action. We established a testosterone-treated BPH animal model and DHT-stimulated prostate cell lines, including RWPE-1 and WPMY-1. Administration of baicalin ameliorated the pathological prostate enlargement, suppressed the production of DHT, and inhibited the activity of 5α- reductase Type II in the animal model. BC exerted these effects via its anti-proliferative effects by restoring the Bax/Bcl-2 ratio, activating caspase-3 and caspase-8, and inducing the phosphorylation of AMPK. In vitro studies using DHT-stimulated prostate cells demonstrated an up-regulation of BPH-related and proliferation markers, whereas baicalin clearly reduced the overexpression of AR, PSA, PCNA, and Bcl-2. These results suggested that baicalin could suppress androgen-dependent development of BPH both in vivo and in vitro by inducing apoptosis.

Progesterone pretreatment enhances serotonin-stimulated BDNF gene expression in rat c6 glioma cells through production of 5alpha-reduced neurosteroids.

Tricyclic antidepressants and selective serotonin reuptake inhibitors are considered in theory to induce the outflow of neurotransmitters, norepinephrine, and serotonin from the synapses as a consequence of inhibiting their reuptake into the nerve terminals, resulting in the stimulation of glial cells surrounding the synapses in the brain. Then, we have investigated the direct actions of neurotransmitters on glial cell metabolism and function using rat C6 glioma cells as an in vitro model system and suggested that these neurotransmitters induce their differentiation probably through the production of 5alpha-reduced neurosteroids. On the other hand, the stimulation of the glioma cells with serotonin has been reported to enhance brain-derived neurotrophic factor (BDNF) gene expression, which may be closely related to the beneficial effects of antidepressant drugs. In the present study, to evaluate BDNF expression in differentiated glial cells, the glioma cells were pretreated with progesterone, and the effect of serotonin on BDNF messenger RNA levels in these cells was examined. Progesterone pretreatment enhanced the stimulatory action of serotonin on BDNF gene expression, and the enhancement of serotonin action observed in the cells pretreated with progesterone was almost completely abolished by finasteride, an inhibitor of the enzyme involved in the production of 5alpha-reduced neurosteroids. These findings propose the possibility that neurosteroid-mediated glial cell differentiation may result in the enhancement of serotonin-stimulated BDNF gene expression, which is considered to contribute to the survival, regeneration, and plasticity of neuronal cells in the brain, and hence, leading to the improvement of mood disorders and other symptoms in depressive patients.

[Benign prostatic hyperplasia: medical therapy]. / Prostatagrösse, PSA-Wert, Leidensdruck. Die Wegweiser für die medikamentöse Therapie.

Primary aims of the medical therapy for BPH are improvement of subjective symptoms and quality of life as well as the prevention of long-term complications such as acute urinary retention and renal failure. Secondary goal is inhibition of disease progression. The medical therapy should be tailored to each patient according to the individual complaints and risk of progression. Plant extracts, alpha-blockers and 5-alpha reductase inhibitors represent the most common prescribed substances. Recent data suggest beneficial effects for the use of antimuscarinic agents and phosphodiesterase type 5 inhibitors.

Cyclophosphamide modulates rat hepatic cytochrome P450 2C11 and steroid 5 alpha-reductase activity and messenger RNA levels through the combined action of acrolein and phosphoramide mustard.

Cyclophosphamide treatment of adult male rats leads to sustained decreases in several liver microsomal cytochrome P450 (CYP) activities, including CYP 2C11-catalyzed cyclophosphamide activation, via a process that is associated with a feminization of the overall pattern of liver enzyme expression (G. A. LeBlanc and D. J. Waxman, Cancer Res., 50:5720-5726, 1990). The present study compares the effects of cyclophosphamide and its isomeric analogue ifosphamide on the gender-dependent expression of hepatic CYP 2C11 and steroid 5 alpha-reductase in adult male rats and also examines the role of the cyclophosphamide metabolites acrolein and phosphoramide mustard in feminizing the expression of these liver enzymes. Ifosphamide (a) suppressed the male-specific CYP 2C11 mRNA and CYP 2C11-catalyzed liver microsomal testosterone 2 alpha-hydroxylation and cyclophosphamide and ifosphamide 4-hydroxylation and (b) elevated the female-dominant liver enzyme steroid 5 alpha-reductase and its mRNA 7-9 days after drug treatment, both occurring in a manner similar to that of cyclophosphamide, but requiring a 50% higher dose (180 mg/kg, single i.p. injection) to achieve these effects. This pattern of response could not be achieved by treatment of rats with acrolein or with cyclophosphamide analogues that decompose to acrolein without formation of phosphoramide mustard. In contrast, phosphoramide mustard treatment (100 mg/kg) did modulate microsomal CYP 2C11 and steroid 5 alpha-reductase activities. Treatment with a lower dose (50 mg/kg) of phosphoramide mustard or with the acrolein precursor 4-hydroperoxydechlorocyclophosphamide (200 mg/kg) alone did not affect liver enzyme expression, whereas the combination of these agents produced an overall pattern of response that was similar to that conferred by cyclophosphamide. These studies establish that ifosphamide is less potent than cyclophosphamide in modulating the pattern of cytochrome P450 and steroid 5 alpha-reductase expression and that phosphoramide mustard is responsible for the modulation of liver enzyme expression by cyclophosphamide, with acrolein potentiating the modulating activity of the mustard.

Regulation of aromatase and 5alpha-reductase by 25-hydroxyvitamin D(3), 1alpha,25-dihydroxyvitamin D(3), dexamethasone and progesterone in prostate cancer cells.

Estrogens and androgens are proposed to play a role in the pathogenesis of prostate cancer. The effective metabolites, estradiol and 5alpha-dihydrotestosterone are produced from testosterone by aromatase and 5alpha-reductase, respectively. Metabolites of vitamin D have shown to inhibit the growth of prostate cancer cells. The aim of the present study was to verify whether 25-hydroxyvitamin D(3) (25OHD(3)), 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)], dexamethasone, and progesterone regulate the expression of aromatase and 5alpha-reductase in human prostate cancer cells. LNCaP and PC3 cells were treated with 25OHD(3), 1alpha,25-(OH)(2)D(3), dexamethasone, or progesterone. Aromatase and 5alpha-reductase mRNA was quantified by real-time RT-PCR and aromatase enzyme activity was measured by the [(3)H] water assay. Aromatase enzyme activity in LNCaP and PC3 cells was increased by both 10nM dexamethasone, 1-100 nM 1alpha,25-(OH)(2)D(3) and 100 nM-10 microM progesterone. The induction was enhanced when hormones were used synergistically. Real-time RT-PCR analysis showed no regulation of the expression of aromatase mRNA by any steroids tested in either LNCaP or PC3 cells. The expression of 5alpha-reductase type I mRNA was not regulated by 1alpha,25-(OH)(2)D(3) and no expression of 5alpha-reductase type II was detected in LNCaP.

The effects of progesterone, 4,16-androstadien-3-one and MK-434 on the kinetics of pig testis microsomal testosterone-4-ene-5alpha-reductase activity.

The enzyme 3-oxo-steroid: NADP+ 4-oxidoreductase (EC 1.3.1.22; 5alpha-reductase) was assayed in testicular microsomes of pigs of 3, 20 and 24 weeks of age. The activity was very low in 3-week-old animals and approximately 10-fold higher in 5- and 6-month-old pigs. The pH optimum was 6.3 in 6-month-old animals, 5.7 in 5-month-old animals, but could not be reliably determined in 3-week-old animals. The kinetic parameters for 5alpha-reductase in testis microsomes from 6-month-old animals were; K((m)(app)), 8.0 micromol/l, V((max)(app)), 6.7 nmoles/90 min/mg protein. Progesterone was a competitive inhibitor of testosterone 5alpha-reduction with an apparent K((i)(app)) of 0.86 micromol/l. However, 4,16-androstadien-3-one (dienone), which undergoes 5alpha-reduction in the biosynthesis of the pheromonally active 16-androstenes, was a comparatively poor inhibitor with a K((i)(app)) of 4.9 micromol/l. Similarly, MK434, which is a selective inhibitor of the human type 2 5alpha-reductase, but which inhibits both types 1 and 2 in the rat, was also a poor competitive inhibitor of testosterone 5alpha-reductase in the pig testis (K((i)(app)), 3.1 micromol/l). It would appear from these studies that the pig testis microsomal 5alpha-reductase corresponds to a type 1 isozyme that is not capable of reducing dienone other than under conditions where the dienone concentration would be in considerable excess of testosterone. It is, therefore, probable that substrate-specific 5alpha-reductases exist in the pig testis for the 5alpha-reduction of testosterone and dienone.

Effects of sex steroids on skin 5 alpha-reductase activity in vitro.

Skin 5 alpha-reductase activity is the major factor influencing the manifestation of androgen excess. Although oral contraceptives have been useful for the treatment of androgen excess, little is known of the independent effects of the various progestins and estrogens on inhibition of skin 5 alpha-reductase activity. We incubated minces of normal genital and pubic skin with physiologic concentrations of 3H-testosterone to assess 5 alpha-reductase activity by its conversion to 3H-dihydrotestosterone. In separate experiments, 5 alpha-reductase activity was assessed before and after the addition of progesterone, medroxyprogesterone acetate, levonorgestrel, norethindrone, 17 beta-estradiol, and ethinyl estradiol. Progesterone, levonorgestrel, and norethindrone demonstrated 97 +/- 5.3%, 47.9 +/- 6.3%, and 59 +/- 4.6% inhibition, respectively, of genital skin 5 alpha-reductase activity at 10(-4) mol/L (P less than .01). Medroxyprogesterone acetate, however, failed to affect 5 alpha-reductase activity at similar doses. Estradiol exhibited 40.8 +/- 14.2% inhibition at 10(-4) mol/L (P less than .01), whereas ethinyl estradiol at concentrations from 10(-8) to 10(-4) mol/L failed to inhibit 5 alpha-reductase activity. We conclude that progesterone and the 19-nor-derivatives inhibit 5 alpha-reductase activity at high doses, whereas medroxyprogesterone acetate does not. Therefore, the 19-nor-progestin component may expand the usefulness of oral contraceptives in the treatment of hirsutism by an inhibitory action on skin 5 alpha-reductase activity.

Influence of 17beta-estradiol on the synthesis of reduced neurosteroids in the brain (in vivo) and in glioma cells (in vitro): possible relevance to mental disorders in women.

Brain neurosteroids modulate gamma-aminobutyric acid type A (GABAA) receptor activity, thereby playing a role in mood disorders. Alterations in 17beta-estradiol (E2) and progesterone (P) are also known to play a significant role in psychopathology in women. The aim of the present study was to evaluate the synthesis of dihydroprogesterone (DHP), tetrahydroprogesterone (THP), and the activity of 5alpha-reductase (5alphaR) which regulates the reduction of P to DHP on exposure to supraphysiological levels of E2 in vitro (C6 glioma cells) and in vivo (mouse brain). The results showed that supraphysiological levels of E2 induced a decrease in the accumulation of both neurosteroids, probably by decreasing the activity of 5alphaR. We hypothesize that the high levels of E2 in pregnancy attenuate the increase in the conversion of P to THP in the brain and that the ratio of E2/P modulates the sedative effect of THP. This process may be relevant to psychopathological disorders that are ascribed to drastic alterations in estrogen levels, such as premenstrual syndrome, pregnancy-related mental disorders, and postpartum "blues".

Synthesis of bioactive polyheterocyclic ring systems as 5α-reductase inhibitors.

Simple synthetic strategies for the hitherto unreported [1,2,4]triazolo[4,3-a]pyrido[4,3-d]pyrimidines 8 and [1,2,4]triazolo[4',3':1,2]pyrimido[4,5-b][1,6]naphthyridine-5-one 15 are described based on reaction of thione 3 and 12 with hydrazonoyl chloride 1a-h, respectively. The structures of products 8 and 15 were confirmed by spectroscopic and X-ray crystallographic analyses. Also, the mechanism of such reactions was discussed. In addition, reaction of compound 12 with bromoacetic acid and hydrazine hydrate was investigated. Compounds were screened against 5α-reductase and showed activities with good LD(50) and LD(90) for all compounds.

Finasteride, a 5alpha-reductase inhibitor, potentiates antinociceptive effects of morphine, prevents the development of morphine tolerance and attenuates abstinence behavior in the rat.

It has been shown that morphine increases 5alpha-reductase enzyme activity in the rat central nervous system; however importance of this finding on morphine analgesia, tolerance and dependence has not been reported. In the present study, we investigated inhibition of 5alpha-reductase enzyme on morphine effects using finasteride. To determine whether the 5alpha-reductase enzyme interact with morphine analgesia, finasteride (5 mg/kg, i.p.) was administrated with morphine (5 and 7 mg/kg, i.p.). The tail-flick test was used to assess the nociceptive threshold, before and 15, 30, 45, 60 and 90 min after drug administration. In tolerance experiments, morphine 20 mg/kg was injected i.p., twice daily for 4 days. The development and expression of dependence were assessed in the naloxone precipitation test 5 days after the morphine (20-30 mg/kg, i.p.) administration. We found that finasteride could potentiate the antinociceptive effect of morphine. In addition, chronic finasteride administration effectively blocked development of tolerance and dependence to morphine. Following chronic morphine administration, single dose injection of finasteride failed to reverse tolerance but prevented naloxone precipitate withdrawal syndrome. Therefore, it was concluded that there is a functional relationship between 5alpha-reductase enzyme and morphine.

A preliminary investigation of the enzymatic inhibition of 5alpha-reduction and growth of prostatic carcinoma cell line LNCap-FGC by natural astaxanthin and Saw Palmetto lipid extract in vitro.

UNLABELLED: Inhibition of 5alpha-reductase has been reported to decrease the symptoms of benign prostate hyperplasia (BPH) and possibly inhibit or help treat prostate cancer. Saw Palmetto berry lipid extract (SPLE) is reported to inhibit 5alpha-reductase and decrease the clinical symptoms of BPH. Epidemiologic studies report that carotenoids such as lycopene may inhibit prostate cancer. In this investigation the effect of the carotenoid astaxanthin, and SPLE were examined for their effect on 5alpha-reductase inhibition as well as the growth of prostatic carcinoma cells in vitro. These studies support patent #6,277,417 B1. The results show astaxanthin demonstrated 98% inhibition of 5alpha-reductase at 300 microg/mL in vitro. Alphastat, the combination of astaxanthin and SPLE, showed a 20% greater inhibition of 5alpha-reductase than SPLE alone n vitro. A nine day treatment of prostatic carcinoma cells with astaxanthin in vitro produced a 24% decrease in growth at 0.1 mcg/mL and a 38% decrease at 0.01 mcg/mL. SPLE showed a 34% decrease at 0.1 mcg/mL. CONCLUSIONS: Low levels of carotenoid astaxanthin inhibit 5alpha-reductase and decrease the growth of human prostatic cancer cells in vitro. Astaxanthin added to SPLE shows greater inhibition of 5alpha-reductase than SPLE alone in vitro.

Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.

The development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens and the ageing process. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play, at least, a permissive role. The principal prostatic androgen is dihydrotestosterone. Although not elevated in human benign prostatic hyperplasia, dihydrotestosterone levels in the prostate remain at a normal level with ageing, despite a decrease in the plasma testosterone. Dihydrotestosterone (DHT) is generated by a reduction in testosterone. Two isoenzymes of 5alpha-reductase have been discovered. Type 1 is present in most tissues in the body where 5alpha-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 5alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5alpha-reductase inhibitor that has been used to treat BPH and male-pattern baldness. At doses used clinically, its major effect is to suppress type 2 5alpha-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85%-90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 5alpha-reductase. The suppression of both 5alpha-reductase isoenzymes with GI198745 results in greater and more consistent containment of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5alpha-reductase within the prostate. There have been two large, international multicentre, phase III trials published documenting the safety and efficacy of finasteride in treating human benign prostatic hyperplasia. Combining these two studies, randomised, controlled data are available for 12 months. Non-controlled extension of these data from a subset of patients, who elected to continue on the drug for 3, 4 and 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints, such as acute urinary retention or surgery. According to the meta-analysis of six randomised, clinical trials with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5alpha-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydrotestosterone. A clinical evaluation of potent dual 5alpha-reductase inhibitors may help to define the relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases.

Torilin from Torilis japonica, as a new inhibitor of testosterone 5 alpha-reductase.

The methanolic extract of the fruits of Torilis japonica showed a potent inhibition against 5 alpha-reductase activity in vitro. Bioassay-guided fractionation of the methanol extract of the fruits followed by repeated silica gel chromatography led to the isolation of an active principle and its structure was identified as torilin on the basis of spectroscopic data. Torilin (IC50 = 31.7 +/- 4.23 microM) showed a stronger inhibition of 5 alpha-reductase than alpha-linolenic acid (IC50 = 160.3 +/- 24.62 microM) but was weaker than finasteride. (IC50 = 0.38 +/- 0.06 microM). Simple guaiane-type compounds, such as (-)-guaiol and guaiazulene showed weak inhibitory effects on the 5 alpha-reductase activity with IC50 values of f 81.6 microM and 100.8 microM, respectively, while azulene was not active. These results suggest that both degrees of unsaturation and the side-chain in the guaiane skeleton are important for the manifestation of 5 alpha-reductase inhibition.