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The urological management of men with lower urinary tract symptoms, recorded using an interactive computer program.

OBJECTIVE: To analyse the level of agreement among urologists from the industrialized world in the management of men with lower urinary tract symptoms (LUTS). METHODS: Thirty-three urological departments participated in the study. A computer program was used to provide an unbiased format of 18 simulated cases of men with LUTS which individual urologists then evaluated diagnostically and made therapeutic decisions about their management. The management of the patients was assessed for the probability that a diagnostic test was used, that a therapy was offered to a particular patient, the first-choice therapies selected, the mean cost and range for the diagnostic process per patient and the number of first-choice therapies offered by one urologist for all the patients. Various discriminators for these therapeutic decisions were evaluated, analysing the correlations between the information provided by the diagnostic tests and the probability of a particular therapy. RESULTS: For the 18 patients, the urologists, as a first choice, treated a mean (SD, range) of 8.3 (3.4, 3-16) patients with TURP, 3.9 (3.6, 0-11) with alpha-blockers, 2.3 (1.7, 0-6) with watchful waiting and 1.7 (2.4, 0-9) with finasteride. The other therapy options were only offered as a first choice by a few of the urologists in a few of the cases. The mean (SD, range) cost per patient of the diagnostic process was US$ 594 (209, 326-1350). CONCLUSION: There was considerable disagreement among the urologists about the management of men with LUTS, which included both the choice of diagnostic tests and the criteria for offering therapy to patients. If such disagreement prevails generally, it may be detrimental for the outcome of patients seeking medical attention for LUTS, and the cost of the medical care of these patients will be unnecessarily high.

Adrenergic alpha-Antagonists↗

Placebo therapy of benign prostatic hyperplasia: a 25-month study. Canadian PROSPECT Study Group.

OBJECTIVE: To analyse the efficacy, correlations and adverse-event profile of placebo therapy from the initial placebo run-in period to beyond 2 years of treatment. PATIENTS AND METHODS: The effects of placebo therapy on prostate size, maximum urinary flow rate (Qmax) and symptoms were analysed, and adverse drug experiences documented, for a period of 25 months in 303 patients randomized to the placebo arm of a controlled trial evaluating finasteride in the treatment of BPH (the Canadian PROSPECT study). RESULTS: For all variables, the values during follow-up were significantly different from baseline (P < or = 0.001). Transrectal ultrasonography confirmed a progressive increase in prostate volume over 25 months (+8.4%) but Qmax improved for the first 5 months (to 1.4 mL/s over baseline) and remained 1.0 mL/s more than baseline at 25 months. The total symptom score improved by -2.9 points in the first 2 months on placebo and was ultimately 2.3 points below baseline at 25 months. The extent of the placebo response for symptoms (r=0.08, P=.180) and Qmax (r=0.04, P=0.550) was independent of age, but the response correlated with the initial severity of symptoms (r= -0.394, P < or = 0.001) and initial Qmax (r= -0.134, P=0.023). Patients with a prostate of < or = 40 mL had a clinically more important placebo response than those with larger prostates. In all, 246 patients (81.2%) reported adverse events thought to be secondary to placebo therapy. The most common complaint was urogenital (40.3%), specifically impotence (6.3%) and decreased libido (6.3%); 13.2% of patients discontinued placebo therapy because of significant adverse reactions. CONCLUSIONS: Placebo therapy rapidly produces a significant improvement in Qmax and symptoms of BPH but also causes clinically important adverse effects. The beneficial effect fades but remains after 2 years.

Aged↗

Chronic prostatitis and chronic pelvic pain in men: aetiology, diagnosis and management.

Patients with chronic prostatitis/pelvic pain syndrome typically report genital or pelvic pain (in or around the penis, perineum, scrotum) lasting > 3 months. Whereas true chronic bacterial prostatitis is an uncommon condition characterised by recurrent prostatic and urinary infection, chronic pelvic pain syndrome (CPPS) is a common condition in which no infection is found. Recent surveys suggest a prevalence of 2.5-3% for CPPS. The four-glass test, traditionally used to distinguish inflammatory and inflammatory forms of CPPS, has not been adequately validated; whether the distinction is clinically meaningful is increasingly questioned. The aetiology of CPPS is not known; urodynamic studies imply a neuromuscular origin. More recent work supports a role for proinflammatory cytokines in the pathogenesis. In the management of chronic bacterial prostatitis, trials support the use of quinolone antibiotics as first-line treatment. In contrast, the management of CPPS is generally unsatisfactory, as no reliable treatment has been identified. Treatments commonly tried include antibiotics (notably tetracyclines, quinolones and macrolides), anti-inflammatory agents, and alpha blockers. Newer approaches include trials of finasteride, quercetin and rofecoxib. A recent systematic review demonstrated that none of the current diagnostic and treatment methods for CPPS is supported by a robust evidence base.

Adrenergic alpha-Antagonists↗

Changes in expression of the neuropeptide Y Y1 receptor gene in the medial amygdala of transgenic mice during pregnancy and after delivery.

Long-term administration of progesterone or allopregnanolone was previously shown to increase Y1 receptor gene expression in the medial amygdala of Y1R/LacZ transgenic mice, which harbor a construct comprising the murine Y1 receptor gene promoter and a lacZ reporter. We have now investigated the effects of physiological fluctuations in the cerebrocortical concentrations of neuroactive steroids during pregnancy on Y1R/LacZ transgene expression by quantitative histochemical analysis of beta-galactosidase activity. Cerebrocortical concentrations of progesterone and its metabolites allopregnanolone and allotetrahydrodeoxycorticosterone were increased on day 18 of pregnancy and had returned to control values 2 days after delivery. Transgene expression in the medial amygdala was also increased on day 18 of pregnancy and had returned to control values 2 days after delivery. Similar results were obtained after analysis of Y1R mRNA levels in the medial amygdala of pregnant mice by in situ hybridization. Administration of the 5alpha-reductase inhibitor finasteride to pregnant mice prevented both the increase in the cerebrocortical concentrations of neuroactive steroids as well as the increase in transgene expression. These data suggest that fluctuations in the brain concentrations of endogenous neuroactive steroids during pregnancy are associated with changes in Y1 receptor gene expression in the medial amygdala, further supporting a functional interaction between the GABAergic and NPY-Y1 receptor systems.

Amygdala↗

TrichoScan: a novel tool for the analysis of hair growth in vivo.

Hair loss or hair thinning is a common complaint in clinical dermatology, and patients seeking advice for hair loss are not necessarily bald. Because the effects of treatment attempts are hard to measure, there is need for a sensitive tool to monitor hair loss and treatment responses. Such a method must be able to analyze the biologic parameters of hair growth, which are: (i) hair density (n per cm2); (ii) hair diameter (microm); (iii) hair growth rate (mm per day); and (iv) anagen/telogen ratio. Herein we present the TrichoScan as a method that combines epiluminescence microscopy with automatic digital image analysis for the measurement of human, and potentially animal hair, in situ. The TrichoScan is able to analyze all four parameters of hair growth with a so-called intraclass correlation of approximately 91% within the same TrichoScan operator and an intraclass correlation of approximately 97% for different TrichoScan operators. The application of the technique is demonstrated by comparing the hair parameters in individuals without apparent hair loss, men with untreated androgenetic alopecia, and men after treatment with finasteride (1 mg per day). We were able to detect a significant increase in hair counts and cumulative hair thickness 3 and 6 mo after treatment. Advantages of the TrichoScan are that it can be used for clinical studies to compare placebo versus treatment, to compare different capacities of hair growth promoting substances, to study androgenetic alopecia and other forms of diffuse hair loss, and to study the effects of drugs and laser treatment on hypertrichosis and hirsutism.

Adult↗

The potential role of minoxidil in the hair transplantation setting.

BACKGROUND: Over the last decade surgical management of hair loss has become an increasingly popular and satisfying procedure for both men and women, as innovations in donor harvesting, graft size, and hairline design have resulted in consistently natural-appearing hair restoration. OBJECTIVE: In addition, a better understanding of the regulation of the hair-growth cycle has led to advances in the pharmacologic treatment of androgenetic alopecia. METHODS: Currently there are two U.S. Food and Drug Administration (FDA)-approved agents that promote hair regrowth: over-the-counter topical minoxidil solution for men and women and prescription oral finasteride tablets for men. In October 2001, a group of 11 international experts on hair loss and hair transplantation convened to review the physiology and effects of pharmacologic treatments of hair loss and to discuss the value of administering topical minoxidil therapy as an adjunct to hair transplantation. RESULTS: This article presents the key findings and consensus points among the participants, including their current use of pharmacologic treatments, strategies for optimal results both pre- and postsurgery, and the importance of realistic patient expectations and compliance. CONCLUSIONS: Based on the surgeons' clinical experience, the use of approved hair regrowth agents in hair transplant patients with viable but suboptimally functioning follicles in the region to be transplanted can increase hair density, speed regrowth in transplanted follicles, and complement the surgical result by slowing down or stopping further hair loss.

Administration, Oral↗

Androgenetic alopecia: combining medical and surgical treatments.

BACKGROUND: Medical treatment or surgical reconstruction is used separately to treat androgenetic alopecia. Two drug molecules (5% minoxidil solution and oral finasteride 1 mg) have proven efficacy to stabilize hair loss and promote hair regrowth. Microtransplant of one to three hair follicular unit grafts can provide a definitive hair restoration with a natural appearance. OBJECTIVES: Aesthetic results can be optimized with a combination of drugs and transplantation of follicular unit grafts. The Dynamic Multifactorial Classification is used to select suitable candidates for this combined approach and also to assess follow-up results. RESULTS: Dynamic Multifactorial Classification assists the evaluation of the natural history of androgenetic alopecia evolution and also the effects of treatment. Regression of male androgenetic alopecia from Hamilton type V to type III can be achieved by combining drugs with hair grafts. CONCLUSION: Improvement of investigative methods and especially the Dynamic Multifactorial Classification makes it easier for a patient to follow the results of treatment adapted to their case.

Alopecia↗

Inhibitors of 5alpha -reductase type I in LNCaP cells from the roots of Angelica koreana.

A prenylated coumarin, osthenol (1) and a sesquiterpene, bisabolangelone (2) have been isolated as active principles with 5alpha-reductase type I inhibitory effects in LNCaP cells from the roots of Angelica koreana Max. by bioassay-guided chromatographic fractionation. Osthenol exhibited a highly potent inhibitory activity on 5alpha-reductase type I in LNCaP cells with an IC50 value of 0.1 microg/ml, which is about 200 times more potent than the positive control, finasteride (IC50 = 19.8 microg/ml). Bisabolangelone also inhibited the activity of 5alpha-reductase type I in LNCaP cells (IC50 = 11.6 microg/ml), indicating that these compounds are possible candidates for the development of new drugs to treat human endocrine disorders associated with overproduction of DHT by 5 alpha-reductase type I. In addition, four compounds isooxypeucedanin, oxypeucedanin hydrate, oxypeucedanin and isoimperatorin were also isolated and found to be inactive in the 5alpha-reductase assay systems used in the present study.

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

Torilin from Torilis japonica, as a new inhibitor of testosterone 5 alpha-reductase.

The methanolic extract of the fruits of Torilis japonica showed a potent inhibition against 5 alpha-reductase activity in vitro. Bioassay-guided fractionation of the methanol extract of the fruits followed by repeated silica gel chromatography led to the isolation of an active principle and its structure was identified as torilin on the basis of spectroscopic data. Torilin (IC50 = 31.7 +/- 4.23 microM) showed a stronger inhibition of 5 alpha-reductase than alpha-linolenic acid (IC50 = 160.3 +/- 24.62 microM) but was weaker than finasteride. (IC50 = 0.38 +/- 0.06 microM). Simple guaiane-type compounds, such as (-)-guaiol and guaiazulene showed weak inhibitory effects on the 5 alpha-reductase activity with IC50 values of f 81.6 microM and 100.8 microM, respectively, while azulene was not active. These results suggest that both degrees of unsaturation and the side-chain in the guaiane skeleton are important for the manifestation of 5 alpha-reductase inhibition.

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

Kinetic studies on rabbit liver glucocorticoid 5alpha-reductase.

The serum concentration of active glucocorticosteroids depends not only on adrenal synthesis but also on enzymatic activation of 11-dehydro-glucocorticoids in the liver by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In order to define the respective involvement of other regulative enzymes in the metabolism of 11-dehydro-glucocorticoids in the liver, the objective of this study was to evaluate the kinetic behavior of NADPH:delta 4-3-ketosteroid-5alpha-reductase (5alpha-reductase, EC 1.3.99.5). The interrelations to liver 11beta-HSD1 will be discussed. The kinetic properties of 5alpha-reductase of the rabbit liver were measured by a radioenzymatic assay and characterized with respect to protein-, substrate-, cosubstrate-, and pH-dependence. Michaelis-Menten enzyme kinetic parameters (Km and Vmax) were obtained for the formation of 5alpha-reduced 11-dehydrocorticosterone and corticosterone metabolites. We found that both 11-dehydrocorticosterone (Km 4.2 x 10(-6) mol/l, Vmax 2,600 pmol x min(-1) x mg(-1)) and corticosterone (Km 0.5 x 10(-6) mol/l, Vmax 38 pmol x min(-1) x mg(-1)) exhibit a high affinity to 5alpha-reductase. With respect to cosubstrate-, pH-dependence and finasteride inhibition, it is likely that 11-dehydrocorticosterone metabolism is primarily controlled by isoenzyme 5alpha-reductase type 1. This study shows that the deactivation of GCS especially of 11-dehydro-glucocorticoids via 5alpha-reductase is an important metabolic pathway in the liver. The metabolic activation of GCS by 11beta-HSD could possibly lead to an excess of GCS in the hepatocytes. Due to 5alpha-reductase activity this excess can be limited - on the level of CORT as well as of 11-DHC.

11-beta-Hydroxysteroid Dehydrogenases↗

Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery.

The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.

Animals↗

Stable expression of the human 5alpha-reductase isoenzymes type I and type II in HEK293 cells to identify dual and selective inhibitors.

A eucaryotic cell assay was established to identify novel, dual and selective inhibitors of human 5alpha-reductase. For this purpose the cDNAs encoding 5alpha-reductase type I and type II were inserted into a pRcCMV vector and expressed in human embryonic kidney (HEK293) cells. Single cell clones with substantially high enzymatic activity were selected and established as permanent cell lines. KM values were determined for both isozymes. The inhibitory potency of several steroidal and non-steroidal compounds synthesized in our group, as well as finasteride and 4MA as controls, were tested by measuring the conversion of [3H]androstenedione. Reaction products were quantified by a HPLC reversed phase technique. Using the new cell assays, selective as well as novel dual 5alpha-reductase inhibitors with IC50 values between 1.0 and 2.5 microM were identified.

Azasteroids↗

Evaluation of the EDSTAC female pubertal assay in CD rats using 17beta-estradiol, steroid biosynthesis inhibitors, and a thyroid inhibitor.

The Endocrine Disrupter Screening and Testing Advisory Committee has recommended the female pubertal onset assay as a Tier I test to detect potential endocrine-disrupting chemicals (EDs). We evaluated this assay's ability to detect EDs acting through various mechanisms. In two similar experiments, weanling female rats were dosed for 20 days by gavage with vehicle (0.5% methocel) or the following test compounds (mg/kg/day): 17beta-estradiol (E2; 0.1, 2, or 4), ketoconazole (KETO; 24, 50, or 100), finasteride (FIN; 20), testolactone (TL; 220), fadrozole (FAD; 0.6, 1.2, or 6.0) or 6-propylthiouracil (PTU; 240). In vehicle-treated females, mean age at pubertal onset, as evidenced by vaginal opening (VO), varied interexperimentally from 32.3+/-1.6 days to 33.5+/-1.8 days. At 0.1 mg/kg E2, age at VO was reduced slightly to 31.0+/-1.6 days, but not significantly (alpha=0.05). Higher E2 doses (2.0 and 4.0) reduced age at VO to 28 days. KETO delayed VO, but this delay was significant only at 100 mg/kg (39.7+/-2.4 days). FIN and TL had no effect on age at pubertal onset; however, FAD significantly delayed VO. PTU delayed VO to 34.2+/-1.1 days and altered thyroid weight, histology, and hormone levels. With each compound, significant changes in age at VO were accompanied by decreased uterine or ovarian weights. Thus, although this assay did not detect TL or lower doses of E2 (0.1 mg/kg) or KETO (< or = 50 mg/kg), it was capable of detecting EDs operating through a variety of mechanisms.

5-alpha Reductase Inhibitors↗

Evaluation of the male pubertal onset assay to detect testosterone and steroid biosynthesis inhibitors in CD rats.

The male pubertal onset assay has been recommended by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) as an alternate Tier I screening assay to detect potential endocrine-active chemicals (EACs). Recently, this assay was evaluated by several laboratories using a variety of dosing schemes. This study used a 30-day dosing period to confirm and extend previous work on the assay's ability to detect steroid biosynthesis inhibitors. Weanling male rats were dosed by gavage from 21 to 50 days of age with vehicle (0.5% methocel) or chemicals from the following EAC classes: an androgen (testosterone propionate [TP], 0.1 or 0.4 mg/kg/day), a broad-spectrum steroid biosynthesis inhibitor (ketoconazole [KETO], 24 mg/kg/day), a 5alpha-reductase inhibitor (finasteride [FIN], 20 or 80 mg/kg/day), a moderately specific aromatase inhibitor (testolactone [TL], 220 mg/kg/day), or a highly specific aromatase inhibitor (fadrozole [FAD], 0.6 or 6.0 mg/kg/day). None of these treatments altered relative thyroid weights. However, TL, KETO, and FIN were positive for endocrine activity based on decreases in one or more reproductive or accessory sex gland organ weights. Of these three inhibitors, only TL significantly increased the age at PPS, indicating that PPS was less sensitive for detecting these EACs. Based on its profile of effects, TL may have been detected as an antiandrogen. TP and FAD were negative in this assay, even at doses that caused effects in other studies. With TP, oral administration limited assay sensitivity such that higher TP doses would be needed for detection. FAD decreased body weight gains, but did not significantly alter any other assay end points; thus, the capacity of this assay to detect aromatase inhibitors remains in question.

Animals↗

Effects of prenatal treatment with antiandrogens on luteinizing hormone secretion and sex steroid concentrations in adult spotted hyenas, Crocuta crocuta.

Prenatal androgen treatment can alter LH secretion in female offspring, often with adverse effects on ovulatory function. However, female spotted hyenas (Crocuta crocuta), renowned for their highly masculinized genitalia, are naturally exposed to high androgen levels in utero. To determine whether LH secretion in spotted hyenas is affected by prenatal androgens, we treated pregnant hyenas with antiandrogens (flutamide and finasteride). Later, adult offspring of the antiandrogen-treated (AA) mothers underwent a GnRH challenge to identify sex differences in the LH response and to assess the effects of prenatal antiandrogen treatment. We further considered the effects of blocking prenatal androgens on plasma sex steroid concentrations. To account for potential differences in the reproductive state of females, we suppressed endogenous hormone levels with a long-acting GnRH agonist (GnRHa) and then measured plasma androgens after an hCG challenge. Plasma concentrations of LH were sexually dimorphic in spotted hyenas, with females displaying higher levels than males. Prenatal antiandrogen treatment also significantly altered the LH response to GnRH. Plasma estradiol concentration was higher in AA-females, whereas testosterone and androstenedione levels tended to be lower. This trend toward lower androgen levels disappeared after GnRHa suppression and hCG challenge. In males, prenatal antiandrogen treatment had long-lasting effects on circulating androgens: AA-males had lower T levels than control males. The sex differences and effects of prenatal antiandrogens on LH secretion suggest that the anterior pituitary gland of the female spotted hyena is partially masculinized by the high androgen levels that normally occur during development, without adverse effects on ovulatory function.

Age Factors↗

Testosterone, cytochrome P450, and cardiac hypertrophy.

Cytochrome P450 mono-oxygenases (CYP) play an essential role in steroid metabolism, and there is speculation that sex hormones might influence cardiac mass and physiology. As CYP mono-oxygenases activity is frequently altered during disease, we tested our hypothesis that CYP mono-oxygenase expression and testosterone metabolism are altered in cardiac hypertrophy. We investigate major CYP mono-oxygenase isoforms and other steroid-metabolizing enzymes and the androgen receptor in normal, hypertrophic, and assist device-supported human hearts and in spontaneously hypertensive rats (SHR). We show increased and idiosyncratic metabolism of testosterone in hypertrophic heart and link these changes to altered CYP mono-oxygenase expression. We show significant induction of 5-alpha steroid reductase and P450 aromatase gene expression and enhanced production of dihydrotestosterone, which can be inhibited by the 5-alpha reductase inhibitor finasteride. We show increased gene expression of the androgen receptor and increased levels of lipid peroxidation in diseased hearts, the latter being markedly inhibited by CYP mono-oxygenase inactivation. We show alpha-MHC to be significantly repressed in cardiac hypertrophy and restored to normal on testosterone supplementation. We conclude that heart-specific steroid metabolism is of critical importance in cardiac hypertrophy

17-Hydroxysteroid Dehydrogenases↗

Transurethral resection of the prostate: the new old standard.

A literature search was performed for articles between June 2000 and July 2001 pertaining to transurethral resection of the prostate. Eight of the most interesting and/or groundbreaking articles, as deemed by the authors, were selected for review. Topics discussed include transurethral vaporization of the prostate, laser prostatectomy, preoperative finasteride, pelvic floor rehabilitation, the impact of the quantity of tissue removed, bladder infusion prior to catheter removal, and ethanol-glycine in assessment of the absorption of irrigation fluid.

Blood Loss, Surgical↗

Chemotherapeutic prevention studies of prostate cancer.

PURPOSE: Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, ie the administration of agents that inhibit 1 or more steps in the natural history of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe. MATERIALS AND METHODS: Published studies were identified in a search of MEDLINE. Information about ongoing studies was provided by author access to protocols. RESULTS: A variety of chemoprevention studies have focused on the role of dietary factors, vitamins and trace elements in prostate cancer. Some of these studies have been prospective, randomized and double-blinded, while others have used retrospective or epidemiological approaches. Large scale randomized studies are also evaluating the role of 5alpha-reductase inhibitors, which inhibit the conversion of testosterone to the more potent androgen dihydrotestosterone. CONCLUSIONS: Robust evidence is lacking for the value of chemopreventive agents in prostate cancer. Current evidence does suggest that vitamin E and selenium may have a role in prostate cancer chemoprevention. Data from 2 studies, 1 examining the type 1 5alpha-reductase selective inhibitor finasteride and the other using the dual 5alpha-reductase inhibitor dutasteride, will determine the benefits of androgen inhibition strategies for prostate cancer chemoprevention.

Anticarcinogenic Agents↗