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PubMed2000

Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne.

BACKGROUND: Hirsutism is the presence of excessive hair growth in women and is an important cosmetic condition often resulting in severe distress. Hirsutism is most often caused by increased production of male sex hormones also known as androgens. It is also affected by increased sensitivity to androgens in the hair follicles, and the secretory glands around the hair follicles, called sebaceous glands. Spironolactone is an antiandrogen and aldosterone antagonist used to treat hirsutism. Since 1978, many studies have been conducted to determine its effectiveness. OBJECTIVES: The objective of this review was to investigate the effectiveness of spironolactone and/or in combination with steroids (oral contraceptive pill included) in reducing excess hair growth and/or acne in women. SEARCH STRATEGY: All publications of randomised controlled trials of spironolactone versus placebo and/or in combination with steroids (oral contraceptive pill included) were identified. Search strategy was developed by the Menstrual Disorder Group. All accessable electronic databases were searched. In addition, all reference lists of relevant trials were searched and drug companies contacted for details of unpublished trials. SELECTION CRITERIA: All randomised controlled comparisons of spironolactone versus: placebo steroids (oral contraceptive pill included)) spironolactone of varying dosages or spironolactone and steroids versus steroids alone when used to reduce hair growth and acne in women. DATA COLLECTION AND ANALYSIS: Four trials were included in the review, seven trials were excluded. Two other trials are awaiting assessment. All included trials were small (no more than 31 participants) randomised and controlled. Only one trial studied acne as an outcome, the remaining three were concerned with hirsutism. One trial investigated spironolactone versus placebo; one trial was a dosage studies of spironolactone; one trial compared spironolactone with spironolactone in combination with dexamethasone; the remaining trial used topical spironolactone for the treatment of acne. Major outcome measures include the following: - subjective observations - Ferriman and Gallwey hair scores - hormonal and biochemical parameters - side effects - sebum production measurement MAIN RESULTS: All sample populations were small and confidence intervals were wide. There was no significant difference between treatments for any of the observed outcomes. REVIEWER'S CONCLUSIONS: The effectiveness of treatment for either acne vulgaris or hirsutism cannot be determined due to the small sample populations involved in the trials. Its value in clinical practice is difficult to assess from currently available research.

Acne Vulgaris↗
PubMed1997

[Benign prostatic hyperplasia--the outcome of age-induced alteration of androgen-estrogen balance?].

Although human benign prostatic hyperplasia (BPH) is the most common tumor in men, its etiology is still unclear. At present, it is only widely accepted that BPH is under the endocrine control of the testes and strongly associated with aging. Therefore, in the human prostate we describe the impact of aging on the activity of various androgen metabolizing enzymes as well as on the endogenous androgen and estrogen levels. Moreover, the inhibition of 5 alpha-reductase by finasteride (Proscar) will be reported. Among all androgen metabolizing enzymes, within the human prostate 5 alpha-reductase is the most powerful one. Most of the androgen metabolizing enzymes undergo a significant age-dependent alteration. For distinct enzymes, the correlation with age is either negative (e.g. 5 alpha-reductase), or positive. Despite a complex pattern of age-dependent alterations, the dominance of 5 alpha-reductase among all androgen metabolizing enzymes is always maintained. This is underlined by a strong accordance between the age-dependent 5 alpha-reductase activity and the corresponding age-dependent endogenous DHT level. In epithelium, both the 5 alpha-reductase activity and the DHT level decrease with age, whereas in stroma not only the 5 alpha-reductase activity is rather constant over the whole age range but the DHT level as well. In contrast to the relatively unaltered DHT content in the stroma of the human prostate, the estrogen content follows an age-dependent increase. On the other side, in epithelium such a positive correlation between the estrogen level and age is not found. Thus, the age-dependent decrease of the DHT accumulation in epithelium and the concomitant increase of the estrogen accumulation in stroma will lead to a tremendous increase with age of the estrogen/androgen ratio in the human prostate. This could be of pathogenetic importance for BPH development if in fact a balanced androgen/estrogen synergism is necessary for the integrity of the normal human prostate. Finally, it is remarkable that the inhibition of 5 alpha-reductase activity by finasteride (Proscar) is significantly stronger in epithelium than in stroma. Therefore, it is conceivable that the global size-reduction of BPH under finasteride treatment is primarily due to the regression of BPH epithelium.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2002

Medical therapy for benign prostatic hyperplasia progression.

The vast majority of patients presenting to their physicians with concerns about voiding are seeking quick resolution of a disturbed urination pattern. The primacy of their concern over symptoms is appropriate, given the current focus on amelioration of voiding complaints in the treatment of lower urinary tract symptoms. Patients also ask about the risks of symptom progression and how this should impact their decision to choose either medical or surgical intervention. The concept of benign prostatic hyperplasia (BPH) progression has recently become a growing area of interest as new information emerges concerning the natural history of BPH and the identification of risk factors for progression. The impact of medical treatment on the prevention of BPH progression is slowly becoming apparent. The Proscar Long-Term Efficacy and Safety Study trial (Proscar; Merck & Co., Whitehouse Station, NJ) revealed a reduced risk of acute urinary retention and the requirement for invasive treatment with the long-term use of finasteride. More recent data from the Medical Therapy of Prostate Symptoms trial revealed that symptomatic men with BPH who were treated with a combination of an a-blocker and a 5-a reductase inhibitor showed significantly delayed clinical progression of their symptoms compared with treatment with each drug individually. Combination therapy appears to be more effective than doxazosin or finasteride alone in producing significant improvements in American Urological Association Symptom Index and flow rate changes. Interestingly, finasteride and combination therapy reduced the long-term risk of acute urinary retention.

Androgen Antagonists↗
PubMed2005

Neuroactive steroids attenuate oxytocin stress responses in late pregnancy.

In late pregnant rats neuroendocrine stress responses, expressed as increased oxytocin secretion and activation of the hypothalamo-pituitary-adrenal axis, are attenuated. These adaptations preserve the oxytocin store for parturition and prevent pre-term birth, and protect the fetuses from adverse programming by exposure to excess glucocorticoid. Mechanisms of adaptations for oxytocin neurones are reviewed, using challenge with systemic interleukin-1beta, simulating activation of immune signaling by infection, as a stressor of special relevance in pregnancy. In virgin rats, systemic interleukin-1beta stimulates the firing of oxytocin neurones, and hence oxytocin secretion, but interleukin-1beta has no effects in late pregnant rats. This lack of response is reversed by naloxone treatment just before interleukin-1beta administration, indicating endogenous opioid suppression of oxytocin responses in late pregnancy. This opioid presynaptically inhibits noradrenergic terminals impinging on oxytocin neurones. Finasteride pretreatment, inhibiting progesterone conversion to allopregnanolone, a positive GABA(A) receptor allosteric modifier, also restores an oxytocin response to interleukin-1beta. This finasteride effect is reversed by allopregnanolone treatment. In virgin rats allopregnanolone attenuates the oxytocin response to interleukin-1beta, which is exaggerated by naloxone. The effects of naloxone and finasteride in late pregnant rats in restoring an oxytocin response to interleukin-1beta are not additive. Accordingly, allopregnanolone may both enhance GABA inhibition of oxytocin neurone responses to interleukin-1beta, and induce opioid suppression of noradrenaline release onto oxytocin neurones.

Animals↗
PubMed2003

Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial.

Alpha-blockers and 5-alpha-reductase inhibitors are medical therapies that are being used as alternatives to surgical interventions to relieve symptoms of benign prostatic hyperplasia (BPH). Taken as monotherapy, alpha-blockers and 5-alpha-reductase inhibitors have each been shown to provide relief from BPH symptoms. Treatment with finasteride over 4 years has been shown to reduce both BPH symptoms and the likelihood of acute urinary retention and the need for surgery. Direct comparison of the alpha-blocker terazosin with finasteride has been done, but only for a period of 1 year. The Medical Therapy of Prostatic Symptoms (MTOPS) trial is a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to evaluate the long-term efficacy of the alpha-blocker doxazosin and the 5-alpha-reductase inhibitor finasteride, whether taken as a monotherapy or in combination, in preventing or delaying the progression of BPH. We describe in this paper the design of the MTOPS trial, the concept of BPH progression, the definition and methods of determining the primary outcome events and the proposed statistical analysis methods. A unique feature of MTOPS is the inclusion of prostate biopsies on a subgroup of randomized participants. Volunteers among randomized participants are to undergo a biopsy of the prostate at predetermined time points during the trial. Studies that will be conducted using the tissue specimens collected in MTOPS can potentially provide information at the molecular level on the natural history of BPH among medically treated and untreated men with moderate to severe symptoms of BPH.

Data Collection↗
PubMed2000

Prostatic disorders in the dog.

Common canine prostatic disorders include benign prostatic hypertrophy (BPH), prostatitis, prostatic cysts and prostatic adenocarcinoma. BPH is a spontaneous and age-related disorder of intact male dogs, which occurs in more than 80% male dogs over 5 years of age, and which is associated with clinical signs of sanguinous prostatic fluid, constipation and dysuria. BPH signs respond to castration or to finasteride treatment (0.1-0.5 mg/kg per os once daily), as finasteride inhibits conversion of testosterone to dihydrotestosterone, causing prostatic involution via apoptosis. BPH often occurs concurrently with prostatic infection, abscessation, cysts and neoplasia in the intact dog, and finasteride-induced prostatic involution may be beneficial in treatment of all of these conditions except neoplasia. Two studies suggest that risk of prostatic adenocarcinoma is increased in neutered, compared to intact male dogs. Although canine prostatic neoplasia, unlike human prostatic neoplasia, usually does not respond to androgen deprivation, recent reports of prostatic intraepithelial neoplasia (PIN) in a high percentage of older male dogs, with and without prostatic adenocarcinoma, suggests that PIN may be a precursor to adenocarcinoma in the dog as it is believed to be in man.

Adenocarcinoma↗
PubMed2006

Reducing the "risk" of chemoprevention: defining and targeting high risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture.

Two large-scale, phase III cancer prevention trials, the Breast Cancer Prevention Trial (BCPT) of tamoxifen and Prostate Cancer Prevention Trial (PCPT) of finasteride, concluded with strikingly positive and simultaneously problematic results: reduced cancer risks but a major adverse finding with each agent that prevented its widespread use in the community. For most moderate-risk people, such as those studied in the BCPT and PCPT, the benefit of reduced breast or prostate cancer does not outweigh the major risk of tamoxifen (endometrial cancer in the BCPT) or apparent risk of finasteride (high-grade prostate cancer in the PCPT). Promising interventions with biologically active substances are likely to have adverse, perhaps unforeseen effects, especially with long-term preventive use. Acceptance of such agents will depend heavily on the level of cancer risk of the target population. This article outlines research in molecularly identified high-risk oral intraepithelial neoplasia that creates the clinical opportunity for optimizing the risk-benefit ratio of agents to prevent oral cancer. Two other major research efforts focused on improving preventive agent risk-benefit ratios are molecular-targeted research designed to target away from known adverse signaling pathways and multidisciplinary research based on the PCPT that will develop comprehensive models of prostate cancer risk (especially of aggressive prostate cancer) and pharmacoecogenetic models for identifying high-risk men most likely to benefit from (and not be harmed by) finasteride or similar (5alpha-reductase inhibiting) agents. Defining and targeting high-risk populations, developing molecular-targeted approaches, and developing accurate pharmacoecogenetic models promise to reduce the risk of chemoprevention and ultimately to reduce the risk and burden of major cancers.

Anticarcinogenic Agents↗
PubMed1998

Medical therapy and quality of life.

The risk of mortality and long-term morbidity, including loss of sexual function, associated with surgical procedures for symptomatic benign prostatic hyperplasia (BPH) has prompted research into alternative medical therapies. Phytotherapy involves the use of herbal formulations, where the mechanisms of action are usually obscure and although studies have confirmed their effectiveness in symptom relief and improving quality of life (QOL), few placebo-controlled trials exist. Both the 5 alpha-reductase inhibitor finasteride and alpha 1-adrenoceptor antagonists (e.g. alfuzosin, doxazosin, prazosin, tamsulosin and terazosin) have been recommended as appropriate treatment options for patients with lower urinary tract symptoms (LUTS) associated with benign prostatic obstruction (BPO), and their efficacy has been proven in several placebo-controlled trials. Finasteride reduces the static component of BPO--by reducing the size of the prostate--and, as a result, symptom relief is slow (6-12 months) and is predominantly restricted to patients with large prostates (> 40 g). The alpha 1-adrenoceptor antagonists, on the other hand, reduce the dynamic component of obstruction--relaxation of smooth muscle in the prostate, urethra and bladder neck--and provide rapid symptom relief after only a few doses, relieving LUTS more effectively than finasteride and irrespective of prostate size. All of the various alpha 1-adrenoceptor antagonists provide effective and comparable relief of LUTS, and an improvement in bothersomeness and symptom-related QOL. However, it is also important that the therapy is fast acting and acceptable to the patient, in that it does not interfere with other medication or produce unpleasant side effects. These documented properties of the alpha 1A-adrenoceptor antagonists make them an ideal choice for the medical treatment of symptomatic BPH.

5-alpha Reductase Inhibitors↗
PubMed2001

Management of lower urinary tract symptoms of elderly men in Austria.

OBJECTIVES: The aim of this nation-wide study was to determine the current management of elderly men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE) in Austria, and to assess changes over a 4-year study period from 1995 to 1998. METHODS: The annual figures of prostatectomies performed in Austria from 1995 to 1998 were collected from the Austrian Institute for Health Affairs. Sales figures for finasteride, alpha(1)-receptor blockers and plant extracts were obtained from IMS market sales and Austrian regional compulsory insurance companies. These data were correlated with the number of males living in Austria during the study period and to the estimated numbers of elderly men with moderate and severe LUTS in this country. RESULTS: The annual number of transurethral resections of the prostate (TURPs) decreased from 6,302 in 1995 to 5,297 in 1998 (-16%), and the number of open prostatectomies from 506 to 469 (-7%). Extrapolation of these data to 100,000 men aged > or = 55 years revealed that 0.76% underwent TURP in 1995, this figure decreased to 0.59% in 1998. Market sales of alpha(1)-receptor blockers increased by 497% during the study period and those of finasteride by 1.6%, while plant extract market sales declined by 18.2%. In 1998, plant extracts comprised 43.3% of the total BPH market, alpha(1)-receptor blockers 41.5% and finasteride 15.2%. CONCLUSIONS: During the years 1995-1998, significant changes in medical and surgical BPH therapy were observed in Austria. These data provide the basis for a comparison to the situation in other countries and serve as a baseline investigation for future studies in this country.

Age Factors↗
PubMed2001

Lower urinary tract symptoms suggestive of benign prostatic obstruction: how can clinical expertise contribute to rational management?

OBJECTIVE: To perform a systematic analysis of clinical expertise on treatment for benign prostatic hyperplasia (lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO)) and to investigate the usefulness of these data in further guideline development. METHODS: A modified Delphi method was used to analyse the opinions of a panel of 15 European urologists on the appropriateness of 4 common treatments for 1,152 "indications" (hypothetical cases) for LUTS suggestive of BPO. Each indication consisted of a unique combination of 9 diagnostic variables, found to be relevant in treatment choice in previous research. The study population was restricted to patients for whom current guidelines do not provide clear indications on the most appropriate treatment. The panellists individually rated the appropriateness of three active treatments (surgery, alpha(1)-adrenoceptor antagonists, finasteride) using a 9-point scale, all in comparison with "watchful waiting". Aggregate panel judgements were calculated from individual ratings for each indication (appropriate, inappropriate, and uncertain). The relationship between diagnostic characteristics and panel opinions was analysed using logistic regression methods. The results were compared to those of an identical panel study including 12 Dutch urologists. RESULTS: Strong agreement existed for 42.5% of the indications, while strong disagreement was found in only 0.1%. For patients who had not previously been treated for LUTS, surgery was considered appropriate in 44% of the indications. For alpha(1)-adrenoceptor antagonists and finasteride these percentages were 56 and 6 respectively. Strong contra-indications were found only for finasteride (34%). Logistic regression analysis demonstrated consistent panel opinions, indicating a strong cumulative impact of almost all diagnostic variables on the panel judgement "appropriate". The figures on appropriateness were highly comparable to the results of the Dutch study (overall agreement 84%, kappa 0,76). A computer program was constructed to facilitate the implementation and evaluation of the panel recommendations in daily clinical practice. CONCLUSIONS: Given the consistency of the panel opinions, the results may be useful in complementing evidence-based guidelines for LUTS suggestive of BPO in the grey area of treatment choice.

Aged↗
PubMed1998

The regulation of gonadotropin-releasing hormone-induced calcium signals in male rat gonadotrophs by testosterone is mediated by dihydrotestosterone.

The biological effects of testosterone (T) may be mediated directly by T or indirectly by its metabolites, dihydrotestosterone (DHT) and estradiol. The present study examined whether the metabolism of T is involved in the regulation of GnRH-induced Ca2+ signaling at the pituitary. In gonadotrophs from castrated rats, a significantly greater percentage of gonadotrophs demonstrated oscillatory Ca2+ responses to 100 nM GnRH than cells from intact rats (72% vs. 24%; P < 0.05). This increase was prevented by the administration of T propionate (0.1 mg/kg x day), DHT benzoate (2 mg/kg x day,), estradiol benzoate (EB; 5 microg/kg x day), or the combination of the above doses of DHT benzoate and EB. In all cases the proportion of gonadotrophs from the steroid-treated rats having oscillatory Ca2+ responses to 100 nM GnRH was between 21-25% (P > 0.05, compared with intact rats). To assess the importance of T metabolism, intact male rats were treated with the aromatase inhibitor letrozole (1 mg/kg x day), the 5alpha-reductase inhibitor finasteride (50 mg/kg x day), or their respective vehicles for 7 days. Letrozole had no effect on GnRH-induced Ca2+ signals, serum LH concentrations, or ventral prostate or testes weight. Finasteride treatment, however, mimicked the effects of castration, with significantly more gonadotrophs exhibiting Ca2+ oscillations in response to 100 nM GnRH than gonadotrophs from the vehicle-treated group (71% vs. 20% respectively; P < 0.05). Finasteride also caused a significant (P < 0.05) decrease in prostatic weight and DHT concentration, but had no significant effect on either prostatic T or serum LH concentrations. These findings suggest that in the intact male rat, the effects of T on GnRH-induced Ca2+ signaling are preferentially mediated via DHT. The results of this study also show that in the absence of androgens, estradiol may regulate GnRH-induced Ca2+ signaling in the male rat pituitary.

Animals↗
PubMed1999

Androgen-induced regrowth in the castrated rat ventral prostate: role of 5alpha-reductase.

Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5alpha-reductase (5alpha-R) to be maximally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5alpha-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5alpha-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6-1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5alpha-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.

Androgens↗
PubMed2002

Human osteoblast-like cells express predominantly steroid 5alpha-reductase type 1.

In previous studies we established that human bone and human osteoblast-like cells (hOB cells) cultured from bone express 5alpha-reductase (5alpha-R) activity, as demonstrated by the conversion of testosterone and androstenedione to their corresponding 5alpha-reduced metabolites, 5alpha-dihydrotestosterone (DHT) and 5alpha-androstanedione. Two 5alpha-R isozymes (types 1 and 2) have been identified in various tissues. As their nature in bone is unknown, we investigated which isozymes were expressed in first passage hOB cells cultured from bone specimens obtained from six donors (five women and one man). For comparison, 5alpha-reductase isozyme expression in genital skin fibroblasts cultured from foreskin of three males was determined. Pharmacological and biochemical studies using selective inhibitors of the 5alpha-R isozymes were performed, and gene expression was assessed by RT-PCR. In hOB cells, LY191704, a potent nonsteroidal selective inhibitor of 5alpha-R type 1, and the 4-azasteroid 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one (a dual inhibitor of 5alpha-R types 1 and 2) inhibited 5alpha-R activity with a 50% inhibitory concentration (IC(50)) of approximately 4 nM. Finasteride, a selective inhibitor of 5alpha-R type 2, blocked 5alpha-R activity with an IC(50) of approximately 60 nM. The IC(50) of progesterone, a physiological substrate for 5alpha-R, was approximately 200 nM. In genital skin fibroblasts, LY191704 inhibited 5alpha-R with an IC(50) of more than 5000 nM, whereas finasteride and 17beta-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5alpha-androstan-3-one effectively inhibited 5alpha-R with IC(50) of approximately 4 nM. Experiments to determine 5alpha-reductase activity in homogenates of hOB cells as a function of pH showed very low activity at pH 5.5, but a broad shoulder of activity from pH 6.0-9.0, which was not inhibited by finasteride, but was nearly completely blocked by LY191704. RT-PCR revealed that 5alpha-R type 1 and 2 mRNAs were expressed in both bone and genital skin fibroblasts. Based on our pharmacological and biochemical studies, it appears that 5alpha-R activity in hOB cells is catalyzed predominantly by the type 1 rather than the type 2 isozyme. This expression pattern is in contrast to that in genital skin fibroblasts, where the activity of the type 2 isozyme prevails. As in most androgen target tissues DHT is biologically more active as an androgen than testosterone, DHT is formed in bone by 5alpha-R type 1 action from circulating testosterone, and bone cells also express the androgen receptor, local DHT production may play a physiological role in human bone homeostasis.

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

Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Androgen Antagonists↗
PubMed2002

Synthesis and pharmacological evaluation of new 16-methyl pregnane derivatives.

The pharmacological activity of several new pregnane derivatives 15-19 were determined on gonadectomized male hamster flank organs, seminal vesicles and in vitro conversion of testosterone (T) to dihydrotestosterone (DHT) as 5alpha-reductase inhibitors. Steroids 15-19 decreased the diameter of the pigmented spot in the flank organs as compared to the T treated animals; in this model, steroids 16 and 19 showed a higher activity than the commercially available finasteride 3. Injection of T increased the weight of the seminal vesicles. Compounds 15-19 when injected together with T decreased the weight of the seminal vesicles thus showing an antiandrogenic effect. The trienone 19 exhibited a considerably higher activity than finasteride. Steroids 15-19 inhibited the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. Compounds 18 and 19 showed a much higher antiandrogenic effect than finasteride. This enhancement of the biological activity could probably be attributed to the coplanarity of the steroidal skeleton as previously observed by our group. The high antiandrogenic activity of the epoxy compound 16 is probably the result of the ring opening of the oxiran ring with the nucleophilic part of the enzyme 5alpha-reductase thus leading to a stable adduct with concomitant deactivation of this enzyme.

5-alpha Reductase Inhibitors↗
PubMed1997

Benign prostatic hyperplasia. Practical treatment guidelines.

Symptomatic benign prostatic hyperplasia (BPH) is a common condition in older men and has a significant impact on their daily lives. Transurethral resection of the prostate (TURP) or open prostatectomy are currently the most effective therapies for BPH. TURP is, however, associated with clinically significant adverse events in 20% of patients. Therefore, patients who need treatment for BPH based on the presence of symptoms should also be offered other therapy options. Transurethral incision of the prostate is an effective therapy with minimal adverse effects in patients with a prostate not larger than 30 g. Minimally invasive procedures, such as electrovaporisation, laser prostatectomy, transurethral needle ablation, high intensity focused ultrasound, transurethral microwave therapy and insertion of prostatic stents, can be performed instead of the standard surgical procedures. They are either performed as outpatient procedures or are associated with shorter durations of hospitalisation than TURP; in addition, they can also be performed in high risk patients. The efficacy of these procedures lies between that of TURP and medical therapy. Medical therapy is becoming increasingly important in the treatment of patients with moderate symptoms of BPH. Both androgen-suppressing therapy and alpha-adrenoceptor blockade are well tolerated and effective modalities. Compared with placebo, both types of therapy produce improvements in maximum urinary flat rate and reductions in symptom scores of 15 to 20%. Finasteride, a potent 5 alpha-reductase inhibitor, must be given for 6 months before it effectiveness in a given patient can be assessed, and for at least 12 months to achieve maximum prostate shrinkage and the full extent of its other beneficial effects. This may be perceived as a disadvantage when compared with the rapid relief afforded by surgery or alpha-blockade. The efficacy of finasteride is also dependent on prostate size; it should not be tried in patients with a prostate volume of < 40 ml. On the other hand, finasteride may reverse the progression of the disease process. Of the alpha 1-adrenoceptor antagonists, terazosin, doxazosin and tamsulosin can be administered once daily. In contrast, prazosin, alfuzosin and indoramin must be administered twice daily, which may have a negative impact on patient compliance. Because of its specificity for alpha 1A-receptors, no dosage titration is needed when tamsulosin is used; in addition, in contrast with the other alpha-blockers used in BPH, tamsulosin lacks significant effects on blood pressure. On the other hand, nonselective alpha-blockers are preferable in hypertensive patients with BPH. The final decision about the best treatment for a particular patient must take into account the patient's preference after he has been informed of the different options.

Adrenergic alpha-Antagonists↗
PubMed1994

Benign prostatic hyperplasia. Current pharmacological treatment.

During the past decades, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become a fairly established modality. Approaches include blockade of alpha-adrenoreceptors and suppression of androgens. Patients eligible for drug treatment are those with mild to moderate symptoms of BPH and no strong indications for surgery. alpha-Receptor blockers generally improve urinary symptoms and peak urinary flow rates 2 to 4 weeks after introduction of therapy. Because of minor adverse effects, selective alpha 1-blockers are preferred over nonselective drugs. Prazosin, terazosin and alfuzosin are extensively studied and widely used in BPH treatment. Terazosin might be preferred to prazosin and alfuzosin because it can be administered once daily, but a disadvantage is higher cost. Doxazosin and tamsulosin (amsulosin; YM 617) are drugs currently under clinical investigation in the treatment of BPH. Antiandrogen therapy induces reduction in prostate volume and relief in symptoms of bladder outlet obstruction. However, the only drug which seems to be of major interest in BPH treatment is finasteride. Other drugs [gonadotrophin-releasing hormone (GnRH) agonists, progestogens and flutamide] are associated with frequent and sometimes severe adverse effects, such as impotence, flushing and loss of libido. Finasteride has fewer adverse effects and is well tolerated, but needs to be administered for at least 6 to 12 months to obtain maximum effect. Future approaches in medical treatment of BPH might be combination therapy of alpha 1-blockers and finasteride.

Adrenergic alpha-Antagonists↗
PubMed1999

Management of androgenetic alopecia.

BACKGROUND: Androgenetic alopecia (AGA) is the most frequent cause of hair loss affecting up to 50% of men and 40% of women by the age of 50. METHODS: This paper outlines the current status of diagnosis and offers guidelines for optimal management of AGA in both men and women. RESULTS: The diagnosis of AGA can usually be confirmed by medical history and physical examination alone. A trichogram can be useful to assess the progression of the hair loss. A scalp biospy is diagnostic but usually not required. In women with signs of hyperandrogenism, investigation for ovarian (polycystic ovarian disease) or adrenal (late-onset congenital adrenal hyperplasia) disorders is required. Mild to moderate AGA in men can be treated with oral finasteride or topical minoxidil. Oral finasteride at the dosage of 1 mg/day produced clinical improvement in up to 66% of patients treated for 2 years. The drug is effective for both frontal and vertex hair thinning. Medical treatment with finasteride or minoxidil should be continued indefinitely since interruption of therapy leads to hair loss with return to pretreatment status. Mild to moderate AGA in women can be treated with oral antiandrogens (cyproterone acetate, spironolactone) and/or topical minoxidil with good results in many cases. Hair systems and surgery may be considered for selected cases of severe AGA both in men and in women. CONCLUSIONS: Patients with AGA should be informed about the pathogenesis of the condition. If used correctly, available medical treatments arrest progression of the disease and reverse miniaturization in most patients with mild to moderate AGA.

Alopecia↗