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PubMed2006

Possible involvement of 5alpha-reduced neurosteroids in adrenergic and serotonergic stimulation of GFAP gene expression in rat C6 glioma cells.

Influence of adrenergic and serotonergic stimulation on glial fibrillary acidic protein (GFAP) gene expression in rat C6 glioma cells was first examined as an in vitro model experiment for investigating the neuronal regulation of glial cell differentiation. Stimulation of these cells with isoproterenol and serotonin elevated GFAP mRNA levels followed by an increase in its protein contents, thus suggesting that both adrenergic and serotonergic stimulation might induce the differentiation of the glioma cells. In addition, progesterone and its 5alpha-reduced metabolite dihydroprogesterone also elevated GFAP mRNA levels in rat C6 glioma cells, consistent with their stimulatory actions on GFAP gene expression observed in rat astrocytes. Further studies showed that the elevation of GFAP mRNA levels induced by isoproterenol and serotonin as well as progesterone was abolished by pretreatment of the glioma cells with finasteride, an inhibitor of 5alpha-reduced steroid production. Moreover, the stimulatory actions of isoproterenol and serotonin on GFAP gene expression were inhibited by pretreatment with a GABA(A) receptor antagonist bicuculline and a progesterone receptor antagonist RU486. These findings suggest that both adrenergic and serotonergic stimulation may indirectly activate GFAP gene expression probably through the production of 5alpha-reduced steroid metabolites in rat C6 glioma cells, proposing the possibility that 5alpha-reduced neurosteroids may play a potential role in the neuronal regulation of glial cell differentiation.

20-alpha-Dihydroprogesterone↗
PubMed2004

Implementation of the Prostate Cancer Prevention Trial (PCPT).

The Prostate Cancer Prevention Trial is a randomized double blind chemoprevention trial of 18,882 men. It is designed to test the difference in the histologically proven prostate cancer prevalence between a group of participants given finasteride and another given placebo for 7 years. We present an overview of the study design, details of the administrative structure of the study and a description of the successful implementation of the accrual phase.

Chemoprevention↗
PubMed2004

5-Alpha reductase inhibition provides superior benefits to alpha blockade by preventing AUR and BPH-related surgery.

OBJECTIVES: This analysis examines the relative effectiveness of current medical therapies for BPH in preventing AUR, AUR-related catheterisation and surgery in real-life clinical practice. METHODS: This is a retrospective analysis of observational data from the General Practice Research Database (UK) (GPRD). The cohort contains 4500 patients experiencing BPH or lower urinary tract symptoms strongly suggestive of BPH, aged over 50 years, who were prescribed a 5ARI (finasteride) or an alpha-blocker (alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, terazosin) as their first BPH treatment between 1996 and 1999 inclusive. Cox regression and competing risks analyses, adjusted for age and year of first treatment, followed patients from the start of their first BPH treatment to AUR, catheterisation or surgery, or censoring. RESULTS: Patients prescribed an alpha-blocker were significantly more likely to experience AUR (hazard ratio 2.32, 95%CI 1.37, 3.94) or surgery (hazard ratio 1.78, 95%CI 1.30, 2.44) than patients prescribed a 5ARI. These differences were sustained with sensitivity analyses. CONCLUSION: Real-life clinical practice shows that significantly fewer BPH patients prescribed a 5ARI experienced serious complications associated with the progression of BPH compared with those prescribed an alpha-blocker.

5-alpha Reductase Inhibitors↗
PubMed2006

Looking back at PCPT: looking forward to new paradigms in prostate cancer screening and prevention.

OBJECTIVES: Provide a critical summary of the latest interpretation of findings from the Prostate Cancer Prevention Trial (PCPT). METHODS: Findings from PCPT and recently published post-hoc analyses are reviewed. RESULTS: PCPT demonstrated that finasteride can reduce the prevalence of prostate cancer, permitted the first large-scale assessment of the performance characteristics of prostate-specific antigen for prostate cancer screening, and identified new-onset erectile dysfunction as an early predictor of cardiovascular events. CONCLUSIONS: PCPT has and will continue to yield valuable information regarding future strategies for prostate cancer prevention and detection, benign prostatic hyperplasia, and other matters of public health importance.

5-alpha Reductase Inhibitors↗
PubMed2006

Endogenous neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy.

Neurosteroids modulate seizure susceptibility, but their role in the regulation of epileptogenesis is unknown. Status epilepticus (SE) induces temporal lobe epileptogenesis following a latent period in which glial cells are activated. Here, we found that P450scc, the rate-limiting enzyme in steroid synthesis, is upregulated in hippocampal glia during the latent period after pilocarpine-induced SE in rats. More prolonged SE was associated with greater P450scc expression and longer latencies to the development of seizures, suggesting that enhanced steroid synthesis retards epileptogenesis. The 5alpha-reductase inhibitor finasteride, which blocks neurosteroid synthesis, reduced the latent period, indicating that glia-derived neurosteroids may be antiepileptogenic.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Evaluation of an eucalyptus oil containing topical drug delivery system for selected steroid hormones.

In the present study the permeation and the chemical stability of 17-beta-estradiol, progesterone, cyproterone acetate and finasteride incorporated in an eucalyptus oil containing microemulsion system have been investigated. The formulations contained 1% (w/w) of the steroid hormones. Self diffusion coefficients determined by pulsed-field-gradient spin echo NMR spectroscopy were used to characterise the microemulsion. From these results a bicontinuous structure is proposed for the multicomponent system. However a correlation between the self diffusion of the hormones in the vehicle and the transdermal flux was not indicated. Explanations for this were self assembling, formation of aggregates between the components of the microemulsion and drugs and different effects because of different solubility of the drugs. By addition of certain polymers the skin permeation rates could be improved with exception of cyproterone acetate. Beside standard diffusion experiments, the residual drug content in the skin was investigated. Drug stability was monitored by analysing the steroid hormone content in the different formulations over an observation period of 6 weeks and could be improved by polymers. In addition, viscosity measurements were performed. They indicated an influence of the polymers and drugs on the viscosity in all formulations.

Administration, Topical↗
PubMed2004

Potent CYP17 inhibitors: improved syntheses, pharmacokinetics and anti-tumor activity in the LNCaP human prostate cancer model.

A facile preparation of azolyl steroids, VN/85-1 and VN/87-1 (potent inhibitors of CYP17) has been developed. This process without tedious chromatographic separations improved the overall yields from 55 and 45% to 70 and 65% for VN/85-1 and VN/87-1, respectively. Pharmacokinetic studies of VN/85-1 were conducted in male SCID mice. Following subcutaneous (s.c.) administration of 100mg/kg of VN/85-1, peak plasma level of 16.73 microg/ml occurred after 45 min, and the compound was cleared rapidly with a t(1/2) of 52.34 min. The bioavailability of VN/85-1 after s.c. administration was 83.0%. VN/85-1 was also rapidly metabolized to the corresponding 3-oxo-4-ene analog, 17-(1H-imidazol-1-yl)androsta-4,16-diene-3-one (VN/108-1). In our attempt to optimize the anti-tumor efficacy of these two CYP17 inhibitors, we studied their anti-tumor efficacies in male SCID mice bearing LNCaP tumor xenografts, utilizing various drug doses and drug scheduling. Three times a day dose regimen (3 x dose regimen) of VN/85-1 was more effective than a once daily dose. In contrast, 3 x dose regimen doses of VN/87-1 were less effective than the once daily dose. However, at their effective dosage regimes, VN/85-1 and VN/87-1 were each as effective as castration and more effective than finasteride or casodex, an anti-androgen used for prostate cancer (PC) therapy. For all of the treatments, there was a strong correlation between the tumor volumes and other associated parameters, such as, tumor weights, and serum testosterone (T) and PSA levels. These results indicate that VN/85-1 or VN/87-1 may be useful in the treatment of hormone-dependent prostate cancer.

Androstadienes↗
PubMed2006

Actions of 5alpha-reductase inhibitors on the epididymis.

Testosterone is converted to the more biologically active androgen, dihydrotestosterone (DHT), by steroid 5alpha-reductase. Two isozymes of 5alpha-reductase, types 1 and 2, are abundantly expressed in the epididymis. DHT is the androgen found in the nuclei of epididymal cells and is essential for the maturation of spermatozoa. Thus, one approach to block androgen action in the epididymis is to inhibit DHT formation. Several compounds have been reported to inhibit either one or both forms of 5alpha-reductase in many tissues. The first commercially available inhibitor of 5alpha-reductase, finasteride, has a predominant effect on the type 2 isozyme, while more recently developed agents, such as dutasteride, PNU157706 and FK143, act as dual inhibitors. We found that the treatment of adult rats with such agents results in pronounced effects on the expression of genes essential to the formation of the optimal luminal microenvironment that is required for proper sperm maturation. Furthermore, drug treatment caused a significant decrease in the percentage of progressively motile and morphologically normal spermatozoa in the cauda epididymides. Mating females to treated males resulted in fewer successful pregnancies and a higher rate of pre-implantation loss. Thus, there may be a role for dual 5alpha-reductase inhibitors as potential components of a male contraceptive.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2005

Anxiolytic activity of progesterone in progesterone receptor knockout mice.

Progesterone is an anxiolytic steroid that could play a role in the regulation of anxiety in women. However, the mechanism by which progesterone decreases anxiety is incompletely understood. Progesterone affects the function of the brain by two distinct mechanisms. Progesterone regulates reproductive behavior by activating intracellular progesterone receptors (PRs). In addition, progesterone is believed to influence neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABAA receptors. The extent to which the anxiolytic action of progesterone requires PRs is uncertain. In this study, we utilized PR knockout (PRKO) mice bearing a targeted null mutation of the PR gene that abrogates the function of both PR-A and PR-B subtypes to determine the requirement for PRs in the anxiolytic actions of progesterone. The absence of PR receptor protein expression in PRKO brain was confirmed by immunocytochemistry. In PRKO mice and their isogenic wild-type (WT) littermates, progesterone administration was associated with a dose-dependent rise in plasma allopregnanolone concentrations and corresponding anxiolytic effects in the elevated plus maze test. PRKO mice exhibited a greater anxiolytic response than WT animals although the allopregnanolone levels were similar in the two genotypes. Allopregnanolone also exhibited anxiolytic effects, but the magnitude of the response was similar in both genotypes. Pretreatment of PRKO mice with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone, completely prevented the anxiolytic activity of progesterone, but had no effect on the response to allopregnanolone, demonstrating that allopregnanolone (or other 5alpha-reduced metabolites of progesterone) accounts for the response to the parent steroid hormone. These results provide direct evidence that the anxiolytic action of progesterone does not require PRs. However, PR activation by progesterone may influence the anxiolytic response since PRKO mice were more sensitive to progesterone.

Analysis of Variance↗
PubMedDate not supplied

Evaluation of the rodent Hershberger assay using three reference endocrine disrupters (androgen and antiandrogens).

Three chemicals with known endocrine activities have been evaluated in the rat Hershberger assay for phase-2 of the international validation exercise within the Organization for Economic Cooperation and Development (OECD). The chemicals studied included the antiandrogens finasteride (FIN) and procymidone (PRO) and the androgen agonist 17alpha-methyltestosterone (MT). Castration of sexually immature Sprague-Dawley rats was performed between post-natal days 42 and 46 whilst dosing of the chemical over 10 days was performed between post-natal days 53 and 67. Rats were co-treated with testosterone propionate (TP) for the antiandrogenic activity evaluation. The endpoints examined for evaluation of the androgenic/antiandrogenic activity were changes in sex accessory tissue (SAT) weights supplemented with measurement of testosterone and luteinizing hormone (LH) levels at sacrifice. Changes in liver, adrenal, kidney and body weights were also monitored for general toxicity assessment. Statistically significant changes in the SAT weights were detected with the three chemicals tested. Hence, the rat Hershberger assay as defined by the OECD was demonstrated sensitive enough for the detection of the endocrine disrupting activity of the three reference chemicals evaluated.

Animals↗
PubMed2005

A high-performance liquid chromatography-tandem mass spectrometry assay of the androgenic neurosteroid 3alpha-androstanediol (5alpha-androstane-3alpha,17beta-diol) in plasma.

The testosterone metabolite 3alpha-androstanediol (5alpha-androstane-3alpha,17-diol) is a potential GABA(A) receptor-modulating neurosteroid with anticonvulsant properties and hence could act as a key neuromodulator in the central nervous system. However, there is no specific and sensitive assay for quantitative determination of the androgenic neurosteroid 3alpha-androstanediol in biological samples. We have established a liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay to measure 3alpha-androstanediol in rat plasma. Standard 3alpha-androstanediol added to rat plasma has been successfully analysed with excellent linearity, specificity, sensitivity, and reproducibility. The sensitivity of the method was < 10 ng/ml with a detection limit of 2 ng/ml (6.8 nmol/l) and a linear range of 10-2000 ng/ml. The method was used for the analysis of testosterone-induced increase in plasma 3alpha-androstanediol levels in rats. Testosterone produced a dose-dependent elevation in plasma 3alpha-androstanediol, which was almost completely prevented by pretreatment with the 5alpha-reductase inhibitor finasteride, indicating that 3alpha-androstanediol is synthesized from testosterone via a 5alpha-reductase pathway. This LC-MS-MS method allows accurate, high-throughput analysis of 3alpha-androstanediol in small amounts (200 microl) of plasma and possibly other biological samples.

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

Herbal and vitamin supplement use in a prostate cancer screening population.

OBJECTIVES: To report the observed usage trend of herbal and vitamin supplements in a population of men visiting a prostate cancer screening clinic and its relation to the Sexual Health Inventory for Men score and the American Urological Association Symptom Score (AUA-SS). METHODS: Men participating in the 2001 and 2002 Prostate Cancer Awareness Week screening for prostate cancer were given a self-administered questionnaire. The questions were designed to gather background health information and to determine the use of prescription medications for lower urinary tract symptoms (LUTS), as well as the use of herbal and vitamin supplements. In addition, the AUA-SS and Sexual Health Inventory for Men score were calculated for each participant in the study. RESULTS: The number of questionnaires completed was 12,457. Of the completed questionnaires, 70% of the participants reported the use of multivitamins, and 21% reported the use of herbal supplements. Ten percent of all men reported the use of prescription medications for LUTS (AUA-SS greater than 15). Of the men reporting the use of prescription medications, 19% were taking finasteride, 17% doxazosin, 20% terazosin, 23% tamsulosin, and 22% other prescription medications. Moreover, the average AUA-SS was greater for the men taking herbs or supplements than for those who did not take herbs or supplements (P <0.001). Nonetheless, the Sexual Health Inventory for Men score did not show a positive correlation between the intake of alternative medications and the severity of erectile dysfunction. CONCLUSIONS: We observed that a substantial proportion of men with LUTS participating in a national prostate cancer screening program were not taking prescription medications for these symptoms. Furthermore, we observed that men taking herbs or vitamin supplements tended to have higher AUA scores. Additional investigation is warranted into the reason some men are not receiving standard prescription medications for LUTS and whether reliance on alternative treatments is playing a role in this phenomenon.

Adenocarcinoma↗
PubMed2004

[The PCPT study: the viewpoint of an urologist involved].

The PCPT study investigating the possibility of decreasing the incidence of prostate cancer by daily administration of 5 mg of finasteride for 7 years appears to be a major clinical study in the management of this disease. Recently published in the New England Journal of Medicine, it makes difficult reading. The current article aims to demonstrate the main methodological characteristics of this study, to describe the most significant results and to discuss its clinical applications in daily urological practice.

Cholestenone 5 alpha-Reductase↗
PubMed1996

Inhibition of brain 5 alpha-reductase in pregnant rats: effects on enzymatic and behavioral activity.

Medial basal hypothalamic (MBH) 5 alpha-reductase activity was significantly blocked with a known inhibitor, Proscar (Finasteride), in pregnant rats while their open-field behavior was quantified during the last week of pregnancy. In control animals, open-field behavior significantly decreased (in a stair-step fashion) as a function of increasing gestational age. Conversely, in Proscar-treated animals open-field values significantly increased on day 15 and 17 of gestation compared to control values. These data indicate that inhibition of MBH 5 alpha-reductase during pregnancy significantly increased open-field activity levels during late gestation in rats and provides evidence for a link between the production of 5 alpha-reduced metabolites of progesterone in brain and behavioral activity during pregnancy.

5-alpha Reductase Inhibitors↗
PubMed1995

Benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a pathologic disorder that develops in response to the action of dihydrotestosterone on the aging prostate and to changes in stromal and epithelial cells in this exocrine gland. The current therapies for this disorder are chosen after other causes for irritative and obstructive symptoms have been excluded and the status of the urinary tract has been assessed. This evaluation includes a detailed medical history, a thorough genitourinary and neurological examination, assessment of serum prostate specific antigen and creatinine levels, as well as a urinalysis. A urodynamic evaluation consisting of a combined pressure-flow study is required if the diagnosis of obstruction is to be made. Patients with minimal symptoms and normal test results require no therapy. Mild to moderate symptoms can be controlled, at least temporarily, with alpha-adrenergic blockers such as terazosin or doxazosin. A subset of BPH patients with obstructive symptoms respond to the 5 alpha-reductase inhibitor finasteride. Early results with minimally invasive treatments such as laser prostatectomies, hyperthermia, and ultrasonic and radiofrequency ablation appear encouraging for those with moderate symptoms of prostatism. Severe symptoms, urinary retention, gross hematuria, recurrent urinary tract infections, bladder calculi, and hydronephrosis or renal insufficiency warrant transurethral incision, resection, vaporization, or open prostatectomy (for very large neoplasms). Although the morbidities of these latter surgical therapies are not insignificant, these treatments offer the best and most durable results for relief of obstruction and amelioration of symptoms.

Adrenergic alpha-Antagonists↗
PubMed1999

Physiological modulation of GABA(A) receptor plasticity by progesterone metabolites.

The possible functional relation between changes in brain and plasma concentrations of neurosteroids and the plasticity of gamma-aminobutyric acid type A (GABA(A)) receptors in the brain during pregnancy and after delivery was investigated in rats. The concentrations in the cerebral cortex and plasma of pregnenolone as well as of progesterone and its neuroactive derivatives allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and allotetrahydrodeoxycorticosterone (5alpha-hydroxy-3alpha,21-diol-20-one) increased during pregnancy, peaking around day 19, before returning to control (estrus) values immediately before delivery (day 21). In the postpartum period, steroid concentrations in plasma and brain did not differ from control values. The densities of [3H]GABA, [3H]flunitrazepam, and t-[35S]butylbicyclophosphorotionate (TBPS) binding sites in the cerebral cortex also increased during pregnancy, again peaking on day 19 and returning to control values on day 21; receptor density was decreased further 2 days after delivery and again returned to control values within 7 days. These changes were accompanied by a decrease in the apparent affinity of the binding sites for the corresponding ligand on day 19 of pregnancy. The amount of the gamma2L subunit mRNA decreased progressively during pregnancy, in the cerebral cortex and hippocampus, returned to control value around the time of delivery and did not change in the postpartum period. On the contrary, the amount of alpha4 subunit mRNA was not modified during pregnancy both in the cerebral cortex and hippocampus whereas significantly increased 7 days after delivery only in the hippocampus. No significant changes were apparent for alpha1, alpha2, alpha3, beta1, beta2, beta3 and gamma2S subunit mRNAs. Administration of finasteride, a specific 5alpha-reductase inhibitor, to pregnant rats from days 12 to 18 markedly reduced the increases in the plasma and brain concentrations of allopregnanolone and allotetrahydrodeoxycorticosterone as well as prevented both the increase in the densities of [3H]flunitrazepam and [35S]TBPS binding sites and the decrease of gamma2L mRNA normally observed during pregnancy. The results demonstrate that the changes in the plasticity of GABA(A) receptors that occur in rat brain during pregnancy and after delivery are related to the physiological changes in plasma and brain concentrations of neurosteroids.

Animals↗
PubMed1993

Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model.

Recent advances in molecular biology have enabled incorporation of proto-oncogenes into the mouse germline. In this study we use a transgenic mouse line that overexpresses the fibroblastic growth factor (FGF) family member, int-2, under the control of mouse mammary tumor virus (MMTV) regulatory elements. One of the tissues targeted by MMTV is the mouse prostate. Expression of the MMTV-int-2 transgene in male transgenic mouse carriers results in a dramatic enlargement of the prostate gland which on histologic examination closely resembles the epithelial/glandular BPH observed in human and canine models. Pre- and postpubertal transgenic (NR) and wild-type (WT) FVB/N male mice were evaluated for the effects of hormonal manipulation by orchiectomy and orchiectomy followed by androgen replacement. Orchiectomy results in a significant decrease in size of the prostate in both NR and WT mice (p < 0.05), regardless of sexual maturity. Exogenous hormonal replacement with testosterone or dihydrotestosterone following orchiectomy results in significant regrowth of the prostate in both NR and WT mice. Flutamide, a potent nonsteroidal anti-androgen, resulted in a 55% reduction in size of the NR prostate (p < 0.002) and a similar 44% reduction in size of the WT prostate. Similarly, treatment of both NR and WT mice with leuprolide, a GnRH agonist, resulted in a significant decrease in prostate size (p < 0.05). Treatment of both NR and WT mice with finasteride (MK-906), a 5-alpha reductase inhibitor, failed to produce any significant regression in prostatic tissue. Based upon these data, we conclude that this transgenic mouse model, expressing int-2, produces an epithelial BPH histologically similar to other animal models. This transgenic model is hormonally sensitive and appears to represent a unique model for the investigation of BPH and growth factor induced epithelial cell hyperplasia.

5-alpha Reductase Inhibitors↗