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At least 757 records · Page 42Linked to original sources
PubMed2005

Skin permeation of different steroid hormones from polymeric coated liposomal formulations.

In this study, the effect of various polymers (polycarbophil, chitosan-EDTA, polymeric emulsifier and carrageenan) on the permeation, the chemical and microbial stability of 17-beta-estradiol, progesterone, cyproterone acetate (cpa) and finasteride incorporated in DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) liposomes has been investigated. The liposomes contained 1% (w/w) of the steroid hormones. Standard diffusion experiments were performed. Drug stability was monitored by analysing the steroid hormone content in the different formulations over a time period of 8 weeks and visually inspecting for microbial contamination. In addition, viscosity measurements were performed. The permeation rate could be improved by addition of polymeric agents depending on their type and drug. In all tested formulations, finasteride exhibited the highest diffusion. Both the chemical and the microbial stability of the hormones were significantly improved by the polymers in comparison to the pure liposomes after an observation period of 8 weeks. After that time microbial stability was still evident for all semisolid formulations. In contrast to this in the pure liposomes already after 2 weeks the steroid drugs showed complete insufficient chemical stability and microbial contamination. Additional rheological measurements indicated an influence of the polymers and drugs on the viscosity in all formulations. The elasticity predominated in nearly all polymeric formulations.

Acrylic Resins↗
PubMed2005

In vivo evidence for an increase in 5alpha-reductase activity in the rat central nervous system following morphine exposure.

In the present study, the effects of acute and chronic morphine exposure on testosterone concentrations in the central nervous system (CNS) and serum were investigated in rats. Acute morphine administration (5 mg/kg, s.c.) reduced significantly testosterone levels in serum and spinal cord but not in the brain. Following chronic morphine administration (orally for 21 days), the brain testosterone was also significantly reduced as well as serum and spinal cord. Since, the decrease in testosterone levels following morphine exposure was more obvious in the CNS than serum, we suggested that it cannot be caused by only a direct decline in testosterone levels in periphery, and an increased local metabolism of testosterone in the CNS might be attributed in these effects. This hypothesis was supported with the findings that pretreatment with finasteride, a 5alpha-reductase inhibitor (5 mg/kg, s.c.) blocked testosterone elimination from the CNS following morphine exposure. Moreover, the serum concentration of 5alpha-reduced metabolites of testosterone, dihydrotestosterone and 3alpha-diol glucuronide was increased significantly following chronic morphine exposure, but not after co-treatment with finasteride. These results suggest that morphine exposure increase the CNS activity of 5alpha-reductase, which is an important metabolizing enzyme for testosterone.

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

Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3alpha-androstanediol and 17beta-estradiol.

Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17beta-estradiol. Reduction of testosterone by 5alpha-reductase generates 5alpha-dihydrotestosterone (DHT), which is then converted to 3alpha-androstanediol (3alpha-Diol), a powerful GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17beta-estradiol and 3alpha-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17beta-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5alpha-reductase inhibitor finasteride significantly reduced 3alpha-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5alpha-reduced metabolites of testosterone, DHT and 3alpha-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3alpha-Diol, but indomethacin partially reversed DHT actions. 3alpha-Diol but not 3beta-androstanediol, a GABA(A) receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3alpha-Diol and 17beta-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.

Androstane-3,17-diol↗
PubMed2004

Hippocampal 3alpha,5alpha-THP may alter depressive behavior of pregnant and lactating rats.

The 5alpha-reduced metabolite of progesterone (P), 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), may mediate progestins' effects to reduce depressive behavior of female rats in part through actions in the hippocampus. To investigate, forced swim test behavior and plasma and hippocampal progestin levels were assessed in groups of rats expected to differ in their 3alpha,5alpha-THP levels due to endogenous differences (pregnant and postpartum), administration of a 5alpha-reductase inhibitor (finasteride; 50 mg/kg sc), and/or gestational stress [prenatal stress (PNS)], an animal model of depression. Pregnant rats had higher plasma and hippocampal 3alpha,5alpha-THP levels and less depressive behavior (decreased immobility, increased struggling and swimming) in the forced swim test than did postpartum rats. Finasteride, compared to vehicle-administration, reduced plasma and hippocampal 3alpha,5alpha-THP levels and increased depressive behavior (increased immobility, decreased struggling and swimming). PNS was associated with lower hippocampal, but not plasma, 3alpha,5alpha-THP levels and increased swimming compared to that observed in control rats. Together, these data suggest that 3alpha,5alpha-THP in the hippocampus may mediate antidepressive behavior of female rats.

Animals↗
PubMedDate not supplied

Delivering prostate cancer prevention messages to the public: how the National Cancer Institute (NCI) effectively spread the word about the Prostate Cancer Prevention Trial (PCPT) results.

The Prostate Cancer Prevention Trial was the first clinical trial to show that a direct intervention (5 mg of finasteride daily for 7 years) could reduce a man's risk of developing prostate cancer. Initial results also suggested that men taking finasteride had an increased risk of developing what appeared to be higher-grade disease (Gleason score 7-10). The National Cancer Institute has a congressional mandate to communicate health information to the public and has established methods to reach the public directly and to reach information intermediaries in the media, professional societies, and advocacy groups. The groundbreaking yet complicated results of the Prostate Cancer Prevention Trial were widely disseminated by National Cancer Institute using the social marketing and public-relations strategies and tactics detailed here.

Clinical Trials as Topic↗
PubMed2004

[Use of 5-alpha-reductase inhibitors in the prevention of prostate cancer].

5-alpha-reductase inhibitors are now in widespread use for the treatment of benign prostatic hyperplasia (BHP) and these molecules have recently come under the spotlight in prostate cancer. Their peripheral "hormonal" action inducing reduced intraprostatic DHT synthesis seems to involve them in this hormone-dependant disorder. Finasteride evaluated in the treatment of BPH (PLESS study) was found to have a preventive effect on the incidence of cancer and this activity was assessed in a specific trial (PCPT study). Nevertheless, in the latter randomized study with a 7-year follow-up period, a reduction in the global incidence of the number of cases of cancers was associated with an increase in the number of high-grade cancers. A slight reduction in prostate cancer was also noted in the studies with dutasteride in BPH (ARIA3001, ARIA3002 and ARIB3003). An international multicenter study (REDUCE) is currently being conducted to confirm the preventive value of this molecule which has a more complete activity than finasteride with its inhibitory action on the two 5-alpha-reductase iso-enzymes, and may therefore have a clearer efficiency and rule out the risk of onset of high-grade cancer.

Aged↗
PubMed2002

Depletion of cortical allopregnanolone potentiates stress-induced increase in cortical dopamine output.

In freely moving rats finasteride markedly reduced the cortical content of allopregnanolone. This treatment significantly prolonged the increase in the extracellular concentration of dopamine in the prefrontal cortex induced by foot shock. Moreover, finasteride enhanced both maximal increase of dopamine and its duration elicited by a single injection of the anxiogenic drug FG 7142. These results suggest that endogenous allopregnanolone may modulate the excitatory response of cortical dopaminergic neurons to stressful and anxiogenic stimuli.

Animals↗
PubMed1998

The neurosteroids, progesterone and 3alpha,5alpha-THP, enhance sexual motivation, receptivity, and proceptivity in female rats.

The effects of progesterone (P) and the neurosteroid and P metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) on ovariectomized (ovx), estradiol-3-benzoate (EB)-primed rats on sexual motivation, receptivity, and proceptivity were examined. Changes in central P and 3alpha,5alpha-THP were measured following administration of EB, EB+P, EB+3alpha,5alpha-THP, or EB+inhibitor of 5alpha-reductase or P metabolism (epostane and finasteride)+P (Expt. 1). Partner preference was measured as the duration of time females in these different hormonal treatments spent in proximity to a male vs. female conspecific (Expt. 2). Receptivity (lordosis quotients and ratings) and proceptivity (darting, hopping, ear wiggling, and pacing), for different hormone treatments were assessed (Expt. 3 and Expt. 4, respectively). Conditioned place preference following hormone treatments and paced mating enabled assessment of sexual motivation (Expt. 5). Central P and 3alpha,5alpha-THP were measured in various combinations of hormone/mating conditions (Expt. 6). Studies revealed that 3alpha,5alpha-THP has a significant role in these reproductive measures. Brain concentrations of 3alpha, 5alpha-THP were significantly higher in animals receiving EB+P or EB+3alpha,5alpha-THP compared to animals receiving EB alone, or EB+P in conjunction with an inhibitor of P metabolism. EB+P and EB+3alpha, 5alpha-THP significantly increased time spent in proximity to the male, receptivity and proceptivity. When administered to ovx, EB-primed rats, the progestin metabolite, 3alpha,5alpha-THP, had effects on these behaviors similar to P. Epostane, an inhibitor of P and 3alpha,5alpha-THP biosynthesis, and finasteride, an inhibitor of P metabolism to 3alpha,5alpha-THP, administered to EB+P animals reduced male partner preference, proceptive, and receptive behaviors to levels seen in EB+vehicle animals. Notably, whole brain 3alpha, 5alpha-THP levels were significantly increased and whole brain P levels were significantly reduced in paced mated rats compared to standard mated, and receptive non-mated animals. These studies suggest that P and 3alpha,5alpha-THP may have some common effects on reproductive behavior, e.g., sexual motivation, receptivity, and proceptivity.

Androstenols↗
PubMed2003

Treatment of hyperandrogenic alopecia in women.

OBJECTIVE: To determine the effectiveness of various antiandrogens for the treatment of premenopausal women with hyperandrogenic alopecia. DESIGN: Randomized, unmasked trial of three treatments in 36 hyperandrogenic women with alopecia and observation, without treatment, in 12 other similar patients. SETTING: Endocrinologic outpatient practice in Italy. PARTICIPANT(S): A total of 48 hyperandrogenic women with alopecia and 30 age- and weight-matched controls for the assessment of androgen levels. INTERVENTION(S): Randomization to cyproterone acetate (50 mg) with ethinyl estradiol (EE) in a reverse sequential regimen; flutamide (250 mg) or finasteride (5 mg) daily; all for 1 year. Twelve similar patients were observed without treatment for 1 year. MAIN OUTCOME MEASURE(S): Ludwig scores for hair thinning as well as patient and investigator assessments of treatment effectiveness. RESULT(S): Flutamide resulted in a reduction of 21% in Ludwig scores (2.3 +/- 0.2 to 1.8 +/- 0.1). The other treatment effects were not statistically significant. Patient and investigator assessments showed a similar trend. CONCLUSION(S): Flutamide at a dose of 250 mg daily induced a modest improvement in alopecia after 1 year, whereas cyproterone acetate and finasteride were not effective. Treatment for more than 1 year may be required for better results.

5-alpha Reductase Inhibitors↗
PubMed2006

Baseline factors as predictors of clinical progression of benign prostatic hyperplasia in men treated with placebo.

PURPOSE: We analyzed data from the placebo arm of the MTOPS trial to determine clinical predictors of BPH progression. MATERIALS AND METHODS: A total of 3,047 patients with LUTS were randomized to either placebo, doxazosin (4 to 8 mg), finasteride (5 mg), or a combination of doxazosin and finasteride. Average length of followup was 4.5 years. The primary outcome was time to overall clinical progression of BPH, defined as either a confirmed 4-point or greater increase in AUA SS, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. We analyzed BPH progression event data from the 737 men who were randomized to placebo. RESULTS: The rate of overall clinical progression of BPH events in the placebo group was 4.5 per 100 person-years, for a cumulative incidence (among men who had at least 4 years of followup data) of 17%. The risk of BPH progression was significantly greater in patients on placebo with a baseline TPV of 31 ml or greater vs less than 31 ml (p <0.0001), a baseline PSA of 1.6 ng/dl or greater vs PSA less than 1.6 ng/dl (p = 0.0009), a baseline Qmax of less than 10.6 ml per second vs 10.6 ml per second or greater (p = 0.011), a baseline PVR of 39 ml or greater vs less than 39 ml (p = 0.0008) and baseline age 62 years or older vs younger than 62 years (p = 0.0002). CONCLUSIONS: Among men in the placebo arm, baseline TPV, PSA, Qmax, PVR and age were important predictors of the risk of clinical progression of BPH.

Adrenergic alpha-Antagonists↗
PubMed1993

Maximum urinary flow rate by uroflowmetry: automatic or visual interpretation.

We measured the maximum urinary flow rate monthly for 1 year by uroflowmetry in 1,645 patients in a double-blind, placebo-controlled study of finasteride therapy for benign prostatic hyperplasia. Patients were randomized to receive placebo (555) or finasteride (1,090). A total of 23,857 flow measurements was obtained. Because of the presence of artifacts on many uroflow curves, we read the maximum urinary flow rate values manually and compared them to the values provided electronically by the uroflowmeter. On average, the manually read values were 1.5 ml. per second lower than the machine read values. Artifacts causing a difference of 2 ml. per second or more between the 2 methods were found in 20% and of more than 3 ml. per second in 9% of the tracings. The difference between treatment groups in mean maximum urinary flow rate change at the end of the study was the same with both reading methods. However, confidence intervals were 15 to 25% larger for the machine read compared to the manually read values. This larger variability in machine read maximum urinary flow rate has a marked negative impact on the power of statistical tests to assess any given difference in maximum urinary flow rate between treatment groups. Furthermore, it increases sample size requirements by 50% to achieve any given statistical power. We conclude that maximum urinary flow rate artifacts contribute significantly to the variability of maximum urinary flow rate measurement by uroflowmetry. Manual reading of the maximum urinary flow rate eliminates an important fraction of such variability.

5-alpha Reductase Inhibitors↗
PubMed1994

Prostate-specific antigen: critical issues for the practicing physician.

BACKGROUND: Serum prostate-specific antigen (PSA), when used in combination with existing detection methods, improves the clinician's ability to detect early and potentially curable prostate cancer. FINDINGS: This report describes clinically important issues about use of the serum PSA concentration for detecting early prostate cancer. Other PSA-related factors--PSA density, PSA velocity, and age-specific reference ranges--seem to enhance the ability of clinicians to distinguish benign prostatic conditions from early prostate cancer. Because digital rectal examination only minimally affects the serum PSA concentration, delaying a determination after this examination is unnecessary. Finasteride therapy for benign prostatic hyperplasia should be initiated only after the prostate has been evaluated for cancer because this 5 alpha-reductase inhibitor lowers the serum PSA value by approximately 50%; however, reassessment of the prostate for cancer is necessary if the PSA level fails to decrease as expected or increases to more than 2 ng/mL during finasteride treatment. CONCLUSION: Currently, PSA is the most important, accurate, and clinically useful tumor marker for prostate cancer.

Adult↗
PubMed2001

Androgen antagonists: Potential role in prostate cancer prevention.

This article summarizes discussions of the importance of androgens and androgen antagonists in the genesis of prostate cancer. These discussions occurred at a recent symposium on prostate cancer chemoprevention sponsored by the National Cancer Institute. Considerable information exists indicating the importance of androgens in the development of prostate cancer. Trials in breast cancer indicate that estrogen antagonists prevent breast cancer-suggesting, by analogy, that the blockade of androgen action might prevent the emergence of prostate cancer. The 5alpha-reductase inhibitors block the intracellular metabolism of testosterone and inhibit the growth of the prostate. Limited data suggest that 5alpha-reductase inhibitors reduces prostate-specific antigen in men with localized and advanced, primary or recurrent prostate cancer. An ongoing national trial of 18,000 men over 50 years of age has completed accrual and will evaluate whether a standard dose of finasteride will prevent the development of prostate cancer. The toxicity profile of finasteride (Proscar, Merck & Co., West Point, PA), the only approved 5alpha-reductase inhibitor, is favorable leading to its evaluation as a potential chemopreventive agent for prostate cancer. Anti-androgens such as bicalutamide (Casodex, AstraZeneca, Wilmington, DE) are active in the treatment of prostate cancer and comparable, in some trials, to testicular androgen suppression. These data suggest that antiandrogens may be active in the prevention of prostate cancer; however, the toxicity of antiandrogens (gynecomastia, gastrointestinal toxicity) poses concerns for application in prevention studies. Opportunities for study of factors predictive or associated with the development of prostate cancer and new agents that may interrupt this process offer numerous leads that may reduce the incidence of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed2003

Lower urinary tract symptoms/benign prostatic hyperplasia: fast control of the patient's quality of life.

Fast control of bothersome symptoms and improvement in the patient's quality of life (QOL) are important treatment goals in lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia. Although voiding symptoms are most common, storage symptoms are most bothersome, interfere the most with daily life activities, and have a major effect on QOL. alpha(1)-Adrenoceptor antagonists, such as tamsulosin, improve the most bothersome storage symptoms to roughly the same extent as transurethral resection of the prostate (TURP), whereas the effect on voiding symptoms is slightly less. This may be because tamsulosin relieves storage symptoms as quickly and to the same extent as voiding symptoms, whereas TURP improves storage symptoms to a lesser extent and/or more slowly than voiding symptoms. In addition, alpha(1)-adrenoceptor antagonists have a more rapid onset of action and seem to be slightly more effective in improving LUTS, its bothersomeness, and QOL than 5alpha-reductase inhibitors, such as finasteride. It also seems that alpha(1)-adrenoceptor antagonists have a more rapid onset of action than the plant extract Serenoa repens. Because the alpha(1A)/alpha(1D)-adrenoceptor antagonist tamsulosin has a low risk for symptomatic orthostatic hypotension, it can be initiated at its full therapeutic dose immediately at the start of therapy. This enables faster relief of bothersome LUTS than non-subtype-selective alpha(1)-adrenoceptor antagonists that require dose titration to their full therapeutic dose. In the long term, adding finasteride to an alpha(1)-adrenoceptor antagonist may be beneficial in high-risk patients, but adding S repens does not seem to provide any additional benefit (up to 1 year). In conclusion, monotherapy with an alpha(1A)/alpha(1D)-adrenoceptor antagonist, such as tamsulosin, provides very effective and rapid relief of bothersome LUTS and so enables a rapid improvement of the patient's QOL.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1998

Army and Air Force leadership in the Prostate Cancer Prevention Trial.

Prostate cancer is now the most common solid tumor in men in the United States. Although the current public health approach to this disease is early diagnosis and treatment, investigations are also focusing on the possibility of disease prevention. The Prostate Cancer Prevention Trial, begun in 1993, has completed recruitment of 18,000 men who will be randomized to receive either finasteride or placebo to determine if finasteride can prevent the development of this disease. Both Army and Air Force institutions are participating in this trial, with four Department of Defense institutions contributing over 10% of the patients randomized. The results of this study may have a major impact on active duty personnel for whom prevention of prostate cancer may become possible.

Enzyme Inhibitors↗
PubMed1999

Impact of drug therapy on benign prostatic hyperplasia-specific quality of life.

Quality of life (QOL) is an important issue when assessing medical treatment of benign prostatic hyperplasia (BPH). There are many QOL questionnaires available, and disease-specific questionnaires are being developed. Currently, most patients undergoing treatment for BPH receive alpha-blockers or finasteride. To determine which QOL measures are being used, we did a Medline search covering the past 10 years and found 11 studies in which BPH-QOL was investigated. The wide variety of questionnaires used made comparison between drug studies difficult. When comparing studies that used at least one similar questionnaire to that of another drug study, we found alpha-blocker treatment excelled over finasteride in improving BPH-QOL in the areas of earlier response, larger decreases in mean changes, and reduced sexual side effects. QOL assessment should be a routine part of BPH treatment, and more standardized and validated measures should be used to allow for comparative, meaningful analyses.

Adrenergic alpha-Antagonists↗
PubMed2003

Analysis of genetic polymorphisms of steroid 5alpha-reductase type 1 and 2 genes in Korean men with androgenetic alopecia.

BACKGROUND: Genetic polymorphisms of steroid 5alpha-reductase have been studied in androgenetic alopecia in Caucasians, but the genes encoding the two isoenzymes were not associated with male pattern baldness. Genetic polymorphisms and ethnic variations have not been studied for Asians, although it is suggested that racial difference could exist and influence clinical phenotypes. OBJECTIVE: The purpose of our study is to investigate the genetic polymorphisms of steroid 5alpha-reductase type 1 and 2 (SRD5A1 and SRD5A2) genes in Korean population, and to study the association of these polymorphisms with the development, clinical types (female or male pattern) and therapeutic response of androgenetic alopecia. METHODS: Sixty-six patients with androgenetic alopecia and controls consisted of 92 healthy men were included. Twenty-four patients were treated with finasteride for at least 6 months, and clinical responses were assessed by a simple classification. For type 1 isoenzyme, HinfI and NspI restriction fragment length polymorphisms (RFLPs) were detected using polymerase chain reaction method. For type 2 isoenzyme, RsaI RFLPs detected valine/leucine polymorphisms at codon 89, and MowI RFLPs detected alanine/threonine polymorphisms at codon 49. RESULTS: We could not find any significant associations of the genetic polymorphisms of these two isoenzyme genes with androgenetic alopecia in Koreans (P>0.05). These polymorphisms were not associated with the clinical types of baldness or the response to finasteride (P>0.05). CONCLUSION: These results suggest that polymorphisms of SRD5A1 and SRD5A2 genes may not be directly associated with the development of baldness or generation of different clinical phenotypes.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1999

Validation of a population pharmacokinetic/pharmacodynamic model for 5 alpha-reductase inhibitors.

A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.

5-alpha Reductase Inhibitors↗