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PubMed1993

Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens.

Androgens down-regulate the levels of androgen receptors (AR) and AR mRNA in the penis and prostate of castrated rats, and are assumed to cause their decrease during sexual maturation in the penile smooth muscle of intact rats. In order to determine whether these effects occur directly at the target cell level, and to what extent they are due to testosterone (T) or to their metabolites, we have measured AR mRNA in cultures of smooth muscle cells from the adult rat corpora cavernosa treated in vitro with sex steroids. T at high concentrations (100 nM) acted like dihydrotestosterone (DHT) in increasing moderately the levels of AR mRNA in both proliferating and contact-inhibited cells. However, when conversion of T to DHT was blocked by the 5-alpha reductase inhibitor finasteride, the levels of AR mRNA were considerably down-regulated by T (10-500 nM), particularly in the contact-inhibited cells. Finasteride by itself was inactive. These effects in both types of cultures were inhibited by platelet derived growth factor (PDGF) (20 ng/ml), a growth factor that up-regulates AR mRNA levels, and by fadrozole (100 nM), an aromatase inhibitor of the T/estrogen conversion. Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels. With the exception of PDGF none of the treatments affected significantly cell growth, as measured by DNA synthesis and content. Our results indicate that it is possible to modulate in vitro AR mRNA levels in the penile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the aromatization pathway of T to estradiol will prevail and induce a pronounced down-regulation of AR mRNA levels. We assume that the in vivo AR down-regulation in the penile smooth muscle by androgens is an indirect effect mediated by a paracrine or endocrine mechanism elicited in another tissue.

Animals↗
PubMed1993

Azasteroids as inhibitors of testosterone 5 alpha-reductase in mammalian skin.

Elevated levels of testosterone 5 alpha-reductase (5 alpha-R) and its product, dihydrotestosterone are associated with a number of androgen-dependent skin conditions. A series of 4-azasteroids were tested in vitro as inhibitors of 5 alpha-R in the isolated anagen human hair follicle. Major structural requirements for maximal 5 alpha-R inhibitory activity include a 4-methyl-4-aza moiety and a bulky, lipophilic side chain at C-17. Only one compound, 17 beta-N,N-diethylcarbamyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), was found to be a potent 5 alpha-R inhibitor in all tissues studied: human hair follicles, foreskin (Ki = 3 nM), genital fibroblasts (Ki = 12 nM), and prostate. 17 beta-Hydroxysteroid dehydrogenase activity was not inhibited by 4-MA. With the exception of 4-MA, azasteroid IC50s varied widely in human prostate vs skin, suggesting the possible existence in man of at least two 5 alpha-R isozymes. Finasteride [N(1,1-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide], a delta 1 orally active, specific 5 alpha-R inhibitor exhibiting no affinity for the androgen receptor, was only modestly active in the hair follicle microassay (IC50 = 200 nM). However, it was a potent in vitro inhibitor of human foreskin and prostate 5 alpha-R. Orally administered to rats finasteride inhibited 5 alpha-R in skin. A vasodilator used to treat male pattern baldness (MPB), minoxidil, was found to be a weak inhibitor of human hair follicle 5 alpha-R (IC50 = 1000 nM). 5 alpha-R activity in frontal scalp hair follicles from a MPB subject was four times higher than in occipital follicles. 4-Azasteroids are efficient inhibitors of human skin 5 alpha-R and offer promise for the treatment of acne, hirsutism and MPB.

5-alpha Reductase Inhibitors↗
PubMed2006

Treatment of lower urinary tract symptoms in benign prostatic hyperplasia and its impact on sexual function.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common disorder in older men and may be associated with lower urinary tract symptoms (LUTS) and sexual dysfunction. Men who present with symptomatic BPH and LUTS are at increased risk for sexual dysfunction, including erectile dysfunction (ED) and ejaculatory dysfunction (EjD). OBJECTIVE: This review describes treatment options recommended by the 2003 American Urological Association (AUA) guideline panel for the relief of LUTS associated with BPH, with a focus on the effects of each treatment on ED and EjD. METHODS: Relevant articles were identified via MEDLINE searches of all English-language articles published from January 1984 to January 2005 using the following search terms: benign prostatic hyperplasia and sexual dysfunction, lower urinary tract symptoms and sexual dysfunction, alfuzosin, doxazosin, terazosin, tamsulosin, dutasteride, finasteride, transurethral resection of prostate, erectile dysfunction, and ejaculatory dysfunction. Data on the effects of BPH treatments on sexual function were extracted from the articles and summarized. Because properly designed, adequately powered, direct-comparator studies have not yet been conducted, the AUA's report provides the most comprehensive analyses regarding the efficacy and safety of the current BPH treatment options. RESULTS: LUTS are an independent risk factor for sexual dysfunction in aging men, even after controlling for age and comorbidities. Although surgery, minimally invasive therapies, and pharmacologic therapies can all improve LUTS and the peak urinary flow rate, some can cause or exacerbate ED (incidence rates: surgery, 10%; minimally invasive therapies, 1%-3%; pharmacologic monotherapy or combination therapy, 3%-10%) and EjD (incidence rates: surgery, 65%; minimally invasive therapies, 4%-16%; pharmacologic monotherapy or combination therapy, 0%-10%). Among pharmacologic therapies for BPH, the frequency of EjD appears to be greater with tamsulosin (10%) than with other alpha(1)-blockers (0%-1%) or the 5alpha-reductase inhibitor finasteride (4%), based on data from a single-arm meta-analysis conducted by the AUA. CONCLUSION: Sexual function should be assessed and discussed with the patient when contemplating the appropriate management strategy for LUTS associated with BPH, as well as when evaluating the patient's response to treatment.

Adrenergic alpha-Antagonists↗
PubMed2006

Social isolation stress and neuroactive steroids.

Social isolation of rats immediately after weaning is associated to a reduction in the cerebrocortical and plasma concentrations of progesterone and its metabolites 3alpha,5alpha-TH PROG and 3alpha,5alpha-THDOC. Although we found that the basal plasma concentration of adrenocorticotropic hormone in isolated rats was slightly decreased compared with that in group-housed animals no other significant changes were found in the steroidogenic machinery (peripheral benzodiazepine receptors, steroidogenic regulatory protein (StAR)). However, the functional response of the hypothalamic-pituitary-adrenal axis HPA axis to an acute stressful stimulus (foot shock), or to an acute injection of ethanol or isoniazid is markedly increased in isolated rats. Behavioral studies have also indicated that the ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect of isolation is prevented by treatment with the 5alpha-reductase inhibitor finasteride. Social isolation modified the effects of ethanol on the amounts of StAR mRNA and protein in the brain suggesting an alteration in the mechanism of cholesterol transport in mitochondria. Moreover, the amounts of the alpha4 and delta subunits of the GABA(A) receptor in the hippocampus were increased in isolated rats, and these effects were accompanied by an increase in GABA(A) receptor-mediated tonic inhibitory currents in granule cells of the dentate gyrus. Ethanol also increased the amplitude of GABA(A) receptor-mediated miniature inhibitory postsynaptic currents (mIPSC) recorded from CA1 pyramidal neurons with a greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed, an effect inhibited by finasteride.

Animals↗
PubMed2005

Frontal fibrosing alopecia in postmenopausal women.

BACKGROUND: Frontal fibrosing alopecia is a variety of cicatricial alopecia characterized by a band of frontal/frontoparietal hair recession and marked decrease or a complete loss of the eyebrows, typically observed in women who are postmenopausal. OBJECTIVE: The purpose of this study was to report clinical and histopathologic findings and results of treatment in a group of women affected by the disease. METHOD: A total of 14 women with alopecia of the frontal hairline were evaluated from June 2000 through July 2003 in our outpatient consultation for hair disorders. RESULTS: Clinical examination revealed a band of symmetric recession of the frontoparietal hairline extending to the preauricular areas associated with loss of follicular orifices, mild skin atrophy, and perifollicular erythema at the scalp margin. In all, 9 patients also had partial or total loss of the eyebrows. The histologic features of the scalp specimens were similar in all our patients with a reduction of the number of hair follicles, and a high number of intermediate and velluslike follicles. Intemediate and velluslike follicles were more commonly affected than terminal follicles by the lymphocytic inflammatory infiltrate and perifollicular fibrosis. CONCLUSION: Frontal fibrosing alopecia is a cicatricial alopecia that follows destruction of hair follicles by an inflammatory lymphocytic infiltrate that is localized around the upper portion of the hair follicle. It differs from lichen planopilaris because the lymphocytic infiltrate and fibrosis affect selectively the intermediate and the velluslike follicles of the frontal margin and eyebrows. The reason for this selective involvement is still unknown. Frontal fibrosing alopecia may represent a variety of lichen planopilaris with selective involvement of certain androgen-dependent areas. The affected follicles may have typical biologic markers that could explain the clinical and histologic features found in the disease. It is interesting to note that some of the patients treated with finasteride (2.5 mg/d) showed an arrest in the progression of the disease. Even if there is no proof for a hormonal basis of the disease, the effectiveness of finasteride in some patients may indicate that androgens might be partially responsible of the pathogenesis of the disease.

Aged↗
PubMed2005

The epidemiology of sex steroid hormones and their signaling and metabolic pathways in the etiology of prostate cancer.

The purpose of this review is to discuss the epidemiologic literature on the association of sex steroid hormones and components of their signaling and metabolic pathways with prostate cancer and to describe data evaluating racial variation in sex steroid hormone pathways as a possible explanation for the notably higher risk of prostate cancer in African-American men compared to white or Asian men. Although sex steroid hormones likely contribute to the growth and progression of prostate cancer, associations between hormones and prostate cancer risk across the range of normal levels have been difficult to reliably demonstrate epidemiologically. Methodologic issues no doubt have made the detection of these associations difficult. Of particular importance are (1) the inadequacy of measuring circulating hormones in middle age as a surrogate for the exposure in the target cells in the prostate at the relevant time in life and (2) the current inability to integrate across components of the sex steroid hormone signaling pathway to fully capture target cell androgenic and estrogenic stimulation. Although the approach of evaluating polymorphisms in genes involved in sex steroid hormone signaling or metabolism as a way to minimize some of the issues in the direct measurement of hormones is logical, the findings among these studies are somewhat difficult to reconcile as well. The problems of the changing case mix due to screening for elevated PSA, small sample sizes increasing the likelihood of false negative and false positive results, the controls and their allele frequencies not being representative of the population at risk, and lack of knowledge of the functional consequence of a polymorphism in relation to other polymorphisms in that gene or without consideration of other genes involved in the same pathway may be contributory. The primary result of the Prostate Cancer Prevention Trial confirms that intraprostatic dihydrotestosterone levels in the normal range indeed do contribute to the growth of prostate adenocarcinoma. However, the secondary result of higher-grade disease in cases in the finasteride arm coupled with clinical studies showing higher grade disease in non-metastatic cases with lower serum androgens, if not a pathological artifact or detection bias in the finasteride arm, possibly suggests a complex relationship between androgens and the growth versus differentiation of a prostate tumor. Finally, racial variation in components of the sex steroid hormone pathway do appear to exist, but whether the extent of the variation is adequately great such that it accounts for some of the substantial differences in prostate cancer incidence among blacks, whites, and Asians is unclear.

Androgens↗
PubMed2006

Effects of various pesticides on human 5alpha-reductase activity in prostate and LNCaP cells.

Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens. While the different underlying mechanisms remain unclear, inhibition of 5alpha-reductase, the enzyme which is indispensable for the synthesis of DHT and thus normal masculinization, appears to be one of the sensitive targets for endocrine disruption. We therefore tested several endocrine disrupters with antiandrogenic effects in vivo for their influence on 5alpha-reductase activity in two different test systems: (a) an enzyme assay with human Lymph Node Carcinoma of Prostate (LNCaP) cells and (b) an enzyme assay with human prostate tissue homogenate. The selected pesticides and industrial compounds were monobutyltin (MBT), dibutyltin (DBT), tributyltin (TBT), triphenyltin (TPT), diuron, fenarimol, linuron, p,p'DDE, prochloraz and vinclozolin. The synthetic androgen methyltestosterone and the synthetic antiandrogen flutamide, as well as the 5alpha-reductase inhibitor finasteride served as control compounds. The effect of the organotin compounds DBT, TBT and TPT on enzyme activity was approximately the same in both test systems, with IC(50) values ranging between 2.7 and 11.2 microM, while in prostate tissue, methyltestosterone and prochloraz proved to be stronger inhibitors (IC(50) values of 1.9 and 12.4 microM) than in LNCaP cells (IC(50) values of 13.2 and 53.2 microM). The inhibitory impact of finasteride was approximately 130 times stronger in prostate tissue than in LNCaP cells. Fenarimol, flutamide, linuron and p,p'DDE inhibited 5alpha-reductase activity only at very high concentrations (IC(50)> or =24 microM) in prostate homogenates, and not at all in LNCaP cells. On average, the IC(20) values were 3.5 times lower than the IC(50) values. Diuron, MBT and vinclozolin exerted no effect in either of the test systems. The finding of pesticides acting as 5alpha-reductase inhibitors might be of clinical relevance. As a screening tool for putative ED, the tissue assay is the more practical and sensitive method. However, the cell assay can, to some extent, reflect particular cell processes since the living cell is able to compensate moderate toxicological effects of the ED on cell viability, and possibly also their impact on 5alpha-reductase activity.

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

Effect of androgen concentration on seminal vesicle blood flow in rats-establishment of new highly sensitive simultaneous androgen measurement method.

OBJECTIVES: To clarify the effect of androgen concentration on blood flow regulation in seminal vesicles and to identify the androgen most responsible for this effect. METHODS: The androgen concentrations in the seminal vesicles and the seminal vesicle blood flow were measured at 0, 3, 6, 12, 24, 48, and 72 hours after castration. The androgen concentration was measured with a newly developed highly sensitive simultaneous androgen quantification method that uses liquid chromatography-tandem mass spectrometry. The blood flow was measured with the radioactive microsphere injection method. The change in seminal vesicle blood flow in 6-hour castrated rats after administration of 3 mg/kg testosterone, 3 mg/kg dihydrotestosterone (DHT), 3 mg/kg dehydroepiandrosterone, or 3 mg/kg testosterone plus 20 mg/kg finasteride was evaluated. RESULTS: A correlation was observed between the DHT concentration and blood flow in the rat seminal vesicle after castration. The DHT concentration and blood flow decreased after castration to 31.6% and 37.9%, respectively, of the normal level at 6 hours. The decline in DHT concentration and blood flow decreased further thereafter to 2.2% and 18.1%, respectively, of the normal level at 72 hours. Both testosterone and DHT fully restored the organ blood flow in castrated rat seminal vesicles. However, the blood-flow-increasing effect of testosterone was attenuated by more than 50% when administered in combination with finasteride. Dehydroepiandrosterone did not increase seminal vesicle blood flow. CONCLUSIONS: The results of our study showed a strong correlation between the organ DHT concentration and blood flow in rat seminal vesicles. Of the various androgens, the most active androgen in the regulation of seminal vesicle blood flow was DHT.

Androgens↗
PubMed2004

Testosterone-stimulated weanlings as an alternative to castrated male rats in the Hershberger anti-androgen assay.

We showed previously that stimulation of weanling male rats with the synthetic androgen 17-methyltestosterone (17MT) caused premature growth of the sex accessory tissues such that the activity of the two anti-androgens flutamide and DDE could be demonstrated (Regul. Toxicol. Pharmacol. 35 (2002) 280). We suggested that that protocol should be evaluated as an alternative to the castrated male rat Hershberger assay. In the present paper we justify changing the assay protocol to use testosterone propionate (TP), in place of 17MT, as the stimulating androgen. This change enables biochemical formation of dihydrotestosterone from testosterone, a conversion not possible when using 17MT. This change in the protocol enables detection of the testosterone-5-reductase inhibitor finasteride. The modified TP-stimulated weanling male rat assay is shown to have similar sensitivity to that of the castrated male rat Hershberger assay in detection of the anti-androgens flutamide, procymidone, vinclozolin, and DDE, and of the biochemical inhibitor finasteride. The anti-androgen linuron and the anabolic steroid trenbolone were also detected as positive by the TP-stimulated weanling male assay. It is suggested that this modified assay for anti-androgens should be validated as an alternative to the Hershberger assay, thereby reducing animal stress by obviating the need for surgical castration.

Androgen Antagonists↗
PubMed2003

Neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one modulates ethanol-induced loss of righting reflex in rats.

Systemic ethanol administration elevates plasma and brain levels of GABAergic neuroactive steroids, including 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that contribute to specific behavioral actions of ethanol. The present study determined the effect of adrenalectomy and 5alpha-reductase type-1/type-2 enzyme inhibition, known to reduce neuroactive steroids, on ethanol-induced increases in cerebral cortical levels of 3alpha,5alpha-THP and hypnotic effects in male rats. Systemic ethanol administration to male rats increases plasma levels of progesterone and corticosterone similar to acute stress, indicating release of these steroids from adrenal glands. Adrenalectomy markedly reduced the elevation of cerebral cortical 3alpha,5alpha-THP and plasma progesterone levels and reduced the duration of ethanol-induced loss of righting reflex. Prior systemic administration of 5alpha-dihydroprogesterone (10 or 15 mg/kg, i.p.), an immediate precursor of 3alpha,5alpha-THP, to adrenalectomized rats not only restored the ethanol-induced increases in cerebral cortical 3alpha,5alpha-THP levels but also reversed the effect of adrenalectomy on ethanol-induced loss of righting reflex. Prior administration of the 5alpha-reductase inhibitor finasteride (2 x 25, 2 x 75 or 2 x 150 mg/kg, s.c.) and the 5alpha-reductase type-1 inhibitor SKF-105,111 (50 mg/kg, i.p.) did not reduce ethanol-induced increases in the cerebral cortical levels of 3alpha,5alpha-THP at hypnotic doses of ethanol. Furthermore, these drugs did not alter the duration of loss of righting reflex. However, significant correlations between cerebral cortical 3alpha,5alpha-THP levels and the duration of loss of righting reflex were obtained regardless of finasteride administration. These results demonstrate the contributory role of neuroactive steroids in the ethanol-induced loss of righting reflex and the source of ethanol-induced elevation of GABAergic neuroactive steroids. Ethanol-induced increases in neurosteroids could be pertinent to the etiology of sleep-related disorders associated with alcoholism.

Adrenalectomy↗
PubMed1996

Primary care practitioners: an analysis of their perceptions of voiding dysfunction and prostate cancer.

PURPOSE: We analyzed practice and referral patterns of primary care practitioners regarding the diagnosis of prostate cancer, and the evaluation and treatment of voiding dysfunction. MATERIALS AND METHODS: An anonymous multiple-choice questionnaire was mailed to all primary care practitioners in Brooklyn, New York who were registered with the Medical Society of the State of New York. RESULTS: More than 25% of primary care practitioners begin performing digital rectal examination after patient age 55 years. Compared to prostate specific antigen (PSA) 59% of practitioners believe that digital rectal examination is more sensitive or that the tests are equal, or they do not know. In regard to PSA 11% of respondents begin testing after patient age 60 years, 11% evaluate PSA only if digital rectal examination is abnormal and greater than 3% never evaluate PSA. Approximately 45% of primary care practitioners indicated that PSA of greater than 4.0 ng./ml. signifies prostate cancer regardless of patient age, prostate size or prostatis and 50% think that digital rectal examination elevates PSA in a clinically significant way. Although 93.2% of respondents refer a patient to a urologist after palpating a prostatic nodule, only 51.1% refer for an area of induration. Of the 47.2% of respondents who attempt pharmacotherapy for voiding dysfunction with finasteride, terazosin or both 15% do not know the agent mechanisms of action. Of those prescribing finasteride 68.6% are not aware of its effects on serum PSA. Overall 66.5% of primary care practitioners are not familiar with the American Urological Association Symptom Index while only 15% of those attempting pharmacotherapy use the index as a diagnostic tool. CONCLUSIONS: Primary care practitioners might require further education in regard to the use of PSA, digital rectal examination and pharmacotherapy in voiding dysfunction. Consideration should be given to the establishment of guidelines for urological referral.

Humans↗
PubMed2006

Evidence for a biopsy derived grade artifact among larger prostate glands.

PURPOSE: The PCPT has demonstrated a higher incidence of high grade (Gleason pattern 4 or greater) prostate cancers among men randomized to finasteride. One plausible explanation for this finding is that tumor grade as assigned by TRUS guided biopsy is artifactually associated with prostate volume. MATERIALS AND METHODS: We evaluated our institutional data set of TRUS guided biopsies in the last 3 years and identified 369 cases of prostate cancer that fit the criteria of PSA less than 10 ng/ml, biopsy at our center and RP at our center. We identified risk factors for Gleason pattern 4 or greater on biopsy and then on RP specimens from the same patients using univariate and multiple logistic regression analyses. Assessed covariates included patient age, PSA and TRUS volume. RESULTS: Risk factors for Gleason pattern 4 or greater in the biopsy specimens included age (p = 0.01), hypoechoic lesions on TRUS (p <0.001) and TRUS volume (p = 0.008). However, among RP specimens TRUS volume (p = 0.60) became nonsignificant of Gleason pattern 4 or greater on multivariable analysis. Although prostate volume was a predictor for biopsy derived high grade disease it was not predictive of true histological grade. CONCLUSIONS: These data suggest that simply having a larger prostate results in fewer high grade cancers diagnosed at biopsy. Prostatectomy results in the same men suggest sampling artifact, as the distribution of cancer grade is not associated with prostate volume. These findings provide evidence that the increase in higher grade tumors among men in the finasteride arm of PCPT may simply result from prostate volume reduction.

Adult↗
PubMed2006

The prostate cancer prevention trial: design, biases and interpretation of study results.

PURPOSE: We describe the complexities of the study design of the PCPT and how they influenced the end point chosen, trial implementation, analysis and interpretation of the results. MATERIALS AND METHODS: Data from the PCPT are provided to evaluate and quantify the potential biases of this trial design. RESULTS: Six potential sources of bias, including prostate specific antigen, digital rectal examination, prostate biopsy technique, study medication nonadherence and contamination, and transurethral prostate resection are presented. These biases resulted in the need for the end of study biopsy to evaluate the trial objectives. CONCLUSIONS: There were a large number of known and potential biases that worked for and against finasteride. Because of the trial design and inherent biases, it is imperative that interim biopsy results should be interpreted with caution. While the period prevalence end point that relied on an end of study biopsy was perhaps not the most clinically relevant, it was the only way to remove as much bias as possible and meet the study objective of determining if finasteride could decrease the risk of prostate cancer. The success of the PCPT depended on constant scrutiny by the Data and Safety Monitoring Committee to monitor these biases. The design and biopsy assumptions outlined at the inception of the trial were met, including adherence and contamination rates, the for-cause biopsy rate and the final percent of men with study end points.

Bias↗
PubMed2002

13C-NMR study of 4-azasteroids in solution and solid state.

A group of biologically active 4-azasteroids was studied by 13C-NMR spectroscopy in solution and in the solid phase. A full assignment of signals in the spectra of samples in chloroform was performed for thirteen 4-azasteroids using two-dimensional techniques. Substituent and steric effects of a nitrogen atom, and their influence on chemical shifts of the neighboring carbon atoms are discussed. CP MAS spectra were obtained for five 4-azasteroids including finasteride. The spectra confirmed polymorphism of the latter compound. In addition to the polymorphic forms that are already known, a new molecular complex of finasteride with dioxane is reported.

Azasteroids↗
PubMed2003

Lower urinary tract symptoms/benign prostatic hyperplasia: minimizing morbidity caused by treatment.

The beneficial effects of treatment for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), or LUTS/BPH, have to be balanced against the morbidity associated with treatment. Invasive surgery, such as transurethral resection of the prostate, has been associated with irreversible complications (eg, impotence and retrograde ejaculation). Alpha(1)-adrenoceptor antagonists provide effective and fast relief of LUTS/BPH. In contrast to finasteride, they are not associated with sexual dysfunction (eg, decreased libido or impotence). Alpha(1)-adrenoceptor antagonists induce adverse events associated with interference with blood pressure regulation. The alpha(1A)/alpha(1D)-adrenoceptor antagonist tamsulosin has the lowest potential to interfere with blood pressure regulation and induce related adverse events. In addition, tamsulosin seems to be as well tolerated as phytotherapy, except for a higher incidence of abnormal ejaculation. Abnormal ejaculation occurs in 4% to 11% of patients receiving a alpha(1)-adrenoceptor antagonist, which is, however, well tolerated; <1% of patients discontinue because of this adverse event. In placebo-controlled trials, abnormal ejaculation has been predominantly reported for tamsulosin, but in most direct comparative studies, the incidence was comparable to that of other alpha(1)-adrenoceptor antagonists. Men with LUTS/BPH have an increased risk of impaired sexual function. However, alpha(1)-adrenoceptor antagonists, such as tamsulosin, may slightly improve sexual dysfunction together with LUTS problems. Combination therapy of an alpha(1)-adrenoceptor antagonist and finasteride has a similar adverse-event profile as each monotherapy, except for an increased risk of abnormal ejaculation. The discontinuation rate because of adverse events does not seem to be higher than with monotherapy. Medical therapies, and particularly alpha(1)-adrenoceptor antagonists such as tamsulosin, can be considered a first-line treatment option for LUTS/BPH because they provide effective relief of bothersome LUTS with excellent tolerability.

5-alpha Reductase Inhibitors↗
PubMed2003

Lower urinary tract symptoms/benign prostatic hyperplasia: maintaining symptom control and reducing complications.

Because the average patient with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), or LUTS/BPH, has a remaining life expectancy of 15 to 20 years, both short-term and long-term outcomes matter in the management of LUTS/BPH. Sustained symptom control and improvement of quality of life (QOL), control of disease progression (ie, prevention or reduction of bladder wall hypertrophy [BWH]/increased bladder mass and reduction of the risk of serious complications), and minimization of the need to switch to other medical therapy or surgery are important. In this respect, alpha(1)-adrenoceptor antagonists, such as tamsulosin, have been shown to provide effective and rapid relief of symptoms and improvement in QOL, which is sustained in the long term (up to 6 years). Obstruction may, in the long term, induce changes in the bladder wall (eg, BWH), which may result in (irreversible) bladder damage and serious complications. Preliminary data suggest that alpha(1)-adrenoceptor antagonists prevent the development of BWH in rabbits and reduce existing BWH in obstructed LUTS/BPH patients. Pooled analyses and indirect comparisons of clinical studies up to 1 year have shown that alpha(1)-adrenoceptor antagonists, such as tamsulosin, reduce the risk of acute urinary retention and the need for surgery to at least the same extent as the 5alpha-reductase inhibitor finasteride. In addition, monotherapy with an alpha(1)-adrenoceptor antagonist reduces the risk of long-term clinical progression; the combination with finasteride may be more beneficial in patients at high risk (patients with large prostate volume, high level of prostate-specific antigen, high International Prostate Symptom Score, high postvoid residual amount, and low maximum flow rate). Therefore, alpha(1)-adrenoceptor antagonists, such as tamsulosin, are first-line therapy, not only in the short term but also in the long-term management of LUTS/BPH.

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

Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia.

Management of lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) has been central to urology for decades. The urologic community has increasingly come to realize that many men with LUTS do not have prostate enlargement and do not need their prostates debulked surgically. Of all the factors that have emerged to alter the trends associated with management of LUTS and BPH, none has had more impact than the advent of medical therapy. The selective, long-acting, alpha1-blocking agents terazosin, doxazosin, and tamsulosin have become most popular because of their specificity in the urinary tract, reduced side effects, and simplicity of dosage. In addition, finasteride, a 5-alpha-reductase inhibitor, was found to be effective in men with prostates of > or = 40 g. Furthermore, the larger the prostate at baseline, the greater the efficacy of finasteride on symptom relief and flow rate improvement. In addition to medical therapy, an array of device therapies has emerged in the management of LUTS and BPH. Laser prostatectomy is the oldest of the device therapies and includes transurethral vaporization of the prostate (VLAP), transurethral evaporation of the prostate (TUEP), and transurethral interstitial laser prostatectomy (TILP). Studies report beneficial outcomes approaching those achieved with transurethral resection of the prostate (TURP) with less morbidity and a shorter hospital stay. Common diseases contribute the most to national healthcare expenditures. The management of LUTS and BPH are such disorders and result in the expenditure of vast healthcare resources worldwide. The surgical strategies have an established record of outcomes documenting their potential for symptom relief and the avoidance of future complications. Medical and device therapies, although currently promising and attractive, therefore must prove comparable durability.

Costs and Cost Analysis↗
PubMed1998

Transurethral microwave thermotherapy: what role should it play versus medical management in the treatment of benign prostatic hyperplasia?

Both transurethral microwave thermotherapy (TUMT) and medical management by alpha-blockade or 5-alpha-reductase inhibition are increasingly being considered as alternatives to surgery for treatment of patients with benign prostatic hyperplasia (BPH). We review current evidence supporting the effectiveness and safety of TUMT and medical management. Factors for consideration in appropriately selecting patients for TUMT versus medical management are suggested. Available data indicate that TUMT confers greater long-term benefits than medical management as judged by symptom score and peak urinary flow rate improvements. TUMT-associated morbidity is comparatively low. Alpha-blockade affords more rapid relief than TUMT for patients with BPH; however, other strategies such as the use of temporary intraurethral endoprostheses during the acute post-TUMT recovery period may diminish or abolish the differences in time-course of symptom and flow rate improvement between TUMT and alpha-blockade. 5-Alpha-reductase inhibition with finasteride offers a favorable side-effect profile, although the magnitude of symptom and flow rate improvements is modest, and maximal effects of finasteride do not become manifest until after several months of treatment. As TUMT continues to evolve, increasing attention is being accorded the delivery of high thermal doses and precise targeting of the thermal energy delivered. The development of alpha-blockers with a more favorable side-effect profile continues to be a major focus of investigation. The potential clinical utility of combination therapy with TUMT and alpha-blockade is currently under investigation.

Clinical Trials as Topic↗