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PubMed1991

Time-specific androgen blockade with flutamide inhibits testicular descent in the rat.

Inhibition of androgen action by flutamide, a nonsteroidal antiandrogen, blocked testicular descent in 40% of the testes exposed to this agent continuously from gestational day 13 through postpartal day 28. By contrast, only 11% of the testes failed to descend when blocked by 5 alpha-reductase inhibitors during the same period. Flutamide administration over narrower time intervals (gestational day 13-15, 16-17, or 18-19) revealed maximal interference with testicular descent after androgen inhibition during gestational days 16-17. No significant differences in testicular or epididymal weights were evident between descended and undescended testes; furthermore, no correlation was detected between the presence of epididymal abnormalities and testicular descent. These findings indicate that androgen inhibition during a brief period of embryonic development can block testicular descent. The mechanism through which this inhibition occurs remains to be elucidated.

5-alpha Reductase Inhibitors↗
PubMed1999

Characterization of aromatase cytochrome P450 activity in the human temporal lobe.

Local aromatase-mediated conversion of androgens plays an important role in androgen action on the brain. To characterize estrogen formation in the human brain, we measured the microsomal aromatase activity of temporal lobe biopsies and compared it to that of human placenta using a highly sensitive 3H2O assay with [1beta-3H]androstenedione as substrate. Brain tissue was removed neurosurgically from 23 patients with epilepsy. Data of kinetic studies were analyzed with a computer-assisted, nonlinear, curve-fitting method using the Michaelis-Menten plus a nonspecific metabolism model. In contrast to data for placental aromatase activity, that for brain always had to be corrected for nonspecific tritium release. The mean K, values were 22.2 nmol/L in brain and 49.6 nmol/L in placenta. Inhibition experiments with atamestane, an inhibitor of aromatase cytochrome P450, revealed specific, dose-responsive, and competitive inhibition of both brain and placental aromatase activities. Placental aromatase activity was completely suppressible by atamestane, whereas in brain tissue there remained a residue of nonspecific tritium release. Subsequent experiments with cerebral cortex and subcortical white matter specimens of children and adults revealed a significantly higher aromatase activity in cerebral cortex than in subcortical white matter, but no sex or age differences were found.

Adolescent↗
PubMed2001

Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain.

Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We therefore investigated 5alpha-reductase and colocalized 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity in cerebral neocortex (CX) and subcortical white matter (SC) specimens neurosurgically removed from 44 patients suffering from epilepsy. We could demonstrate the presence of the 5alpha-reductase-3alpha-HSD complex in the biopsies of all patients under investigation. Inhibition experiments with specific inhibitors for 5alpha-reductase type 1 and type 2 revealed strong evidence for the exclusive activity of the type 1 isoform. We detected a significantly higher 5alpha-reductase activity in CX than in SC (P< 0.0001), but no sex-specific differences were observed. Furthermore, we found that, in contrast to liver, only 3alpha-HSD type 2 messenger RNA is expressed in the brain and that its expression is significantly higher in SC than in CX without sex-specific differences. The present study is the first to systematically characterize the 5alpha-reductase-3alpha-HSD complex in the human brain. The lack of sex-specific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g. the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.

3-Hydroxysteroid Dehydrogenases↗
PubMed2004

Dutasteride: a potent dual inhibitor of 5-alpha-reductase for benign prostatic hyperplasia.

Dutasteride is a 5alpha-reductase inhibitor that inhibits both types 1 and 2 isozymes of 5alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone in the prostate and other tissues. Dihydrotestosterone is the primary cause of prostate growth and has been proven to play a key role in the development and progression of benign prostatic hyperplasia. Dutasteride has been investigated in three multicenter studies involving 4325 men aged 50 years and above with benign prostatic hyperplasia. Data from these two-year, placebo-controlled studies demonstrated that dutasteride 0.5 mg once daily reduced the risk of both acute urinary retention and the need for benign prostatic hyperplasia-related surgical intervention, improved benign prostatic hyperplasia-related symptoms, decreased prostate volume and increased maximum urinary flow rates with a low incidence of generally mild to moderate adverse events.

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

Noninvasive management of lower urinary tract symptoms and sexual dysfunction associated with benign prostatic hyperplasia in the primary care setting.

Most men who live to middle age and beyond will ultimately develop lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), and many will also experience sexual dysfunction. Clinical studies indicate that most patients will experience improvement in BPH-related LUTS with alpha-adrenergic blockade or 5alpha-reductase inhibition. Recent studies suggest that alpha-blockers and 5alpha-reductase inhibitors may help to slow the progression of LUTS; 5alpha-reductase inhibitors reduce the need for surgery and complications, such as acute urinary retention. Third-generation alpha-blockers (alfuzosin, tamsulosin) are infrequently associated with cardiovascular side effects, in contrast to their predecessors (doxazosin, terazosin, prazosin). This may provide an advantage for consideration as firstline therapy. alpha-Blocker therapy may also improve sexual functioning, with the exception of ejaculation disorders, predominantly associated with subtypeselective alpha-blockers. By contrast, 5alpha-reductase inhibition is not recommended for men without demonstrable prostatic enlargement, may be associated with a long delay between treatment initiation and LUTS improvement, and is clearly associated with sexual side effects, including decreased libido, ejaculatory dysfunction, and erectile dysfunction. When choosing appropriate pharmacotherapy, the clinician should consider not only the expeditious relief of the presenting symptoms but also the patient's quality of life, including sexual function and potential long-term outcomes, such as acute urinary retention and the need for surgical intervention.

Adrenergic alpha-Antagonists↗
PubMed2001

Pharmacogenetics of human androgens and prostatic diseases.

Prostate cancer (PCa) and benign prostatic hypertrophy (BPH) are two common and growing public health problems in the Western world. We review here the recent biochemical and pharmacogenetic literature related to these two prostatic disorders. We focus first on constitutional ('germline') single nucleotide polymorphism (SNPs) at the steroid 5 alpha-reductase (SRD5A2) locus, which encodes the human prostatic (or Type II) steroid 5 alpha-reductase enzyme. The investigations reviewed point to several uses of personalised medicine at the SRD5A2 locus. In addition, we report on recent identification of somatic pharmacogenetic alterations at the androgen receptor (AR) locus, which encodes the human androgen receptor, suggesting that this also may be a fruitful field of investigation, with important clinical applications. Pharmacogenomic investigation of constitutional and somatic DNA changes in human genes predisposing to cancer may lead to significant advances in chemoprevention, presymptomatic diagnosis and improved treatment of PCa.

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

Emerging drug therapies for benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland caused by increases in number of both epithelial and stromal cells. Clinically, BPH leads to voiding dysfunction, which is most often referred to as lower urinary tract symptoms (LUTS). Historically, the only treatments for LUTS due to BPH were watchful waiting or surgery (transurethral or open prostatectomy). However, over the last 20 years medical therapy has taken a prominent role in the management of BPH. Current medical treatments for BPH include alpha-adrenergic receptor antagonists, inhibitors of the 5-alpha reductase enzyme and various phytotherapies. These agents are generally effective and safe; however, many patients are unable to tolerate the side effects or are refractory to medical management and require surgery. In light of this, many potential new therapies for the treatment of BPH are under development. Some represent a variation of current treatments, whereas others target novel molecular pathways within the prostate. The aim of this review is to examine current pharmacotherapies as well as to highlight emerging drugs that may improve our treatment of patients with LUTS secondary to BPH.

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

Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus.

An interaction with the GABA type A (GABA(A)) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA(A) receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABA(A) receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3alpha,5alpha-THP as well as the amplitude of GABA(A) receptor-mediated IPSCs recorded from CA1 pyramidal neurons in isolated hippocampal slices. These effects are shared by the neurosteroid precursor progesterone, the peripheral benzodiazepine receptor-selective agonist CB34, and gamma-hydroxybutyrate, all of which are known to increase the formation of neuroactive steroids in plasma and in the brain. The action of ethanol on GABA(A) receptor-mediated IPSC amplitude is biphasic, consisting of a rapid, direct effect on GABA(A) receptor activity and an indirect effect that appears to be mediated by neurosteroid synthesis. Furthermore, ethanol affects GABA(A) receptor activity through a presynaptic action, an effect that is not dependent on neurosteroid formation. These observations suggest that ethanol may modulate GABA(A) receptor function through an increase in de novo neurosteroid synthesis in the brain that is independent of the HPA axis. This novel mechanism may have a crucial role in mediating specific central effects of ethanol.

Animals↗
PubMed2001

Steroid-sensitive gene-1 is an androgen-regulated gene expressed in prostatic smooth muscle cells in vivo.

Steroid-sensitive gene-1 (SSG1) is a novel gene we cloned, found regulated by 17beta-estradiol in the rat uterus and mammary gland, and over-expressed in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. We show here that SSG1 mRNA and protein expression are regulated by androgens in the rat ventral prostate. Increases in SSG1 mRNA levels were detected by Northern blotting after 24 h and reached a 27-fold peak 96 h following castration, relative to SSG1 mRNA expression in sham-operated rats. Dihydrotestosterone or testosterone supplementation of castrated rats prevented this rise in SSG1 mRNA. In contrast with SSG1 mRNA expression, SSG1 protein was decreased 16-fold 2 weeks following castration but was at control levels in the prostates of castrated rats receiving dihydrotestosterone or testosterone. Although SSG1 is regulated by androgens in vivo, treatment of LnCap cells with dihydrotestosterone, cyproterone acetate or flutamide did not result in the regulation of SSG1 protein levels in vitro. Immunofluorescence studies show that SSG1 is mainly expressed in prostatic smooth muscle cells. These results indicate that SSG1 is an androgen-regulated gene that is expressed in the smooth muscle component of the rat ventral prostate in vivo.

Amino Acid Sequence↗
PubMed1994

Role of reductase and aromatase in sex determination in the red-eared slider (Trachemys scripta), a turtle with temperature-dependent sex determination.

In many turtles the temperature during the middle of incubation determines the gonadal sex of the hatchling. In the red-eared slider turtle (Trachemys scripta), an incubation temperature of 26 degrees C results in all male offspring, whereas an incubation temperature of 31 degrees C results in all female offspring; at temperatures intermediate to these (e.g. 29, 29.2, 29.4 degrees C) a mixed sex ratio is obtained. Administration of exogenous oestrogens will overcome the effects of an all-male producing incubation temperature to cause female sex determination, whereas administration of exogenous dihydrotestosterone (DHT) or testosterone to eggs incubating at an all-female temperature will have no discernible effect. Administration of DHT will cause male sex determination only if administered at intermediate incubation temperatures whereas administration of testosterone to eggs incubating at all male-producing and male-biased intermediate temperatures results in a significant number of female offspring, an effect presumably due to aromatization of testosterone to oestradiol (OE2). Since testosterone serves as the precursor to both DHT and OE2, being metabolized by reductase and aromatase respectively, three experiments were conducted to determine whether various putative reductase and aromatase inhibitors would overcome the effect of incubation temperature. First, while administration of testosterone to eggs incubating at all male-producing and male-biased intermediate temperatures produced females in a dose- and temperature-dependent manner, significant numbers of intersex individuals resulted from high dosage testosterone treatment to eggs incubating at a female-biased intermediate temperature. The reductase inhibitors 4MA and MK906 were capable of producing female offspring if administered at intermediate temperatures, but not in a dose-dependent fashion. Administration of the aromatase inhibitors CGS16949A and CGS20267 resulted in male offspring at both female-biased intermediate and at all female-producing temperatures in a dose-dependent fashion. Second, similar findings were obtained with combined doses of testosterone and reductase or aromatase inhibitors. Combined treatment of eggs at male-biased intermediate incubation temperatures with testosterone and reductase inhibitor resulted in female hatchlings, whereas combined treatment of testosterone and aromatase inhibitor at both female-biased intermediate and at all female-producing temperatures resulted in male hatchlings.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids.

Important gender differences in mood disorders result in a greater susceptibility for women. Accumulating evidence suggests a reciprocal modulation between the 5-hydroxytryptamine (5-HT) system and neuroactive steroids. Previous data from our laboratory have shown that during pregnancy, the firing activity of 5-HT neurons increases in parallel with progesterone levels. This study was undertaken to evaluate the putative modulation of the 5-HT neuronal firing activity by different neurosteroids. Female rats received i.c.v. for 7 days a dose of 50 micro g/kg per day of one of the following steroids: progesterone, pregnenolone, 5beta-pregnane-3,20-dione (5beta-DHP), 5beta-pregnan-3alpha-ol,20-one, 5beta-pregnan-3beta-ol,20-one, 5alpha-pregnane-3,20-dione, 5alpha-pregnan-3alpha-ol,20-one (allopregnanolone, 3alpha,5alpha-THP), 5alpha-pregnane-3beta-ol,20-one and dehydroepiandrosterone (DHEA). 5beta-DHP and DHEA were also administered for 14 and 21 days (50 micro g/kg per day, i.c.v.) as well as concomitantly with the selective sigma 1 (sigma1) receptor antagonist NE-100. In vivo, extracellular unitary recording of 5-HT neurons performed in the dorsal raphe nucleus of these rats revealed that DHEA, 5beta-DHP and 3alpha,5alpha-THP significantly increased the firing activity of the 5-HT neurons. Interestingly, 5beta-DHP and DHEA showed different time-frames for their effects with 5beta-DHP having its greatest effect after 7 days to return to control values after 21 days, whereas DHEA demonstrated a sustained effect over the 21 day period. NE-100 prevented the effect of DHEA but not of 5beta-DHP, thus indicating that its sigma1 receptors mediate the effect of DHEA but not that of 5beta-DHP. In conclusion, our results offer a cellular basis for potential antidepressant effects of neurosteroids, which may prove important particularly for women with affective disorders.

5-alpha-Dihydroprogesterone↗
PubMed1995

Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review.

During recent years, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become the primary treatment choice for an increasing number of patients. The 2 principal drug classes employed are alpha 1-blockers and 5 alpha-reductase inhibitors. Current information from placebo-controlled double-blind clinical trials is reviewed. The effect of alpha 1-blockers on symptoms and objective parameters for bladder outlet obstruction is well documented. However, alpha 1-blockers carry a small but significant incidence of adverse effects. Parameters for identification of patients who will respond well to alpha 1-blockers have yet to be identified, and data concerning the long term effects of these drugs are not yet available. 5 alpha-Reductase inhibitors have a slow onset of effect, but treatment leads to improvement in symptoms, reduction of the size of the prostate gland and improvement in objective parameters for bladder outflow obstruction. Approximately 30 to 50% of patients will respond to treatment with 5 alpha-reductase inhibitors. The definitive role of pharmacological treatment in symptomatic BPH remains to be established, although it seems that patients unfit or unwilling to undergo surgical resection of the prostate will benefit from such therapy.

5-alpha Reductase Inhibitors↗
PubMed2001

Quality-of-life assessment in patients with benign prostatic hyperplasia: effects of various interventions.

A literature search was conducted to review quality-of-life (QOL) measurement in patients with benign prostatic hypertrophy (BPH). The different QOL instruments are discussed in relation to their correlation with symptom evaluation in studies of treatment options for BPH. Symptom evaluation of BPH has been standardised internationally with the International Prostatic Symptom Score (IPSS), but there is neither agreement nor data to decide which QOL instrument is preferable. The most widely used QOL instrument is the disease-specific QOL single question added to the IPSS. Other QOL instruments have been used, but none has gained unanimous approval. The results of QOL assessments obtained from comparative clinical studies of treatment options for BPH are discussed. These studies compare treatment options such as watchful waiting, drug treatment and surgery. Disease-specific QOL domains (interference with daily activities) tend to improve more with treatment interventions than general health measures (i.e. general well-being). The use of QOL instruments to evaluate patients with BPH, and their many treatment options, is still open to debate with regard to which instruments are preferred and their importance to the clinical evaluation of the patient. The challenge remains to find an acceptable disease-specific QOL instrument that adds information to currently used disease measures of BPH.

Doxazosin↗