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PubMed2000

How are lower urinary tract symptoms managed in real life practice? The French experience.

OBJECTIVES: We tried to outline the management of LUTS suggestive of BPO in real life practice in France. In addition, preliminary results regarding switch rates of different initial treatment approaches in primary care are given in order to assess the effectiveness of therapies. METHODS: IMS and GERS market data of drugs for LUTS suggestive of BPO in France are presented. In addition, data from the THALES database for 1997 and 1998 containing the patient medical records of 620 French GPs were analysed with special emphasis on the initial management by GPs and switch rate to another treatment option. RESULTS: The prevalence and incidence of LUTS suggestive of BPO is high and more than half of the French LUTS patients receive a medical treatment from their GP. alpha1-Adrenoceptor antagonists are prescribed most in the management of LUTS suggestive of BPO in France and their use is still increasing. Finasteride is prescribed much less whereas the use of phytotherapy is, although decreasing, still rather high. The switch rate of tamsulosin as initial treatment to another treatment option is low (14.4%), compared to other therapies like terazosin (26.5%), reflecting its favourable benefit/risk ratio in real life practice. CONCLUSIONS: In France, the prescription rate of alpha1-adrenoceptor antagonists, and especially tamsulosin, is high and still growing. Further information is however needed to study the impact of initial treatment choice on the progression of LUTS suggestive of BPO.

France↗

PubMed2001

Lower urinary tract symptoms suggestive of benign prostatic obstruction: what is the available evidence for rational management?

Because of the need for a more rational management of LUTS suggestive of BPO, EBM is receiving more attention. Treatment decisions should be based on scientific evidence more than on personal preferences of physicians and patients. EBM is more than following rigid treatment guidelines or published advice. It is a process of turning problems of clinical practice into well-defined questions and then finding and appraising available evidence and implementing it into clinical practice. In cases of LUTS suggestive of BPO, much evidence is available on the efficacy and tolerability of different treatment modalities in the short term, whereas long-term data on (cost)-effectiveness are rather scarce. From a patient's point of view, newer pharmacotherapeutic agents can be considered as an appropriate treatment option. alpha(1)-Adrenoceptor antagonists seem to be more efficacious than finasteride and within this group of drugs, selective alpha(1A)/alpha(1D)-adrenoceptor antagonists particularly show a favourable efficacy/tolerability ratio.

Evidence-Based Medicine↗

PubMed2001

Lower urinary tract symptoms suggestive of benign prostatic obstruction: what are the current practice patterns?

OBJECTIVE: The current clinical practice patterns for the management of LUTS suggestive of BPO in the US and in various European countries will be reviewed. METHODS: Information was obtained from published scientific articles and IMS/GERS market analysis data. RESULTS: Community-based surveys demonstrate that the prevalence of moderate to severe LUTS in elderly men is high and increases with age. The role of the GP in the initial management of LUTS is growing. In France, Italy and the UK, most patients with LUTS initially visit a GP. More and more patients in the US also first seek medical advice from a primary care physician or an internal medicine specialist. In Germany, both GPs and office-based urologists are involved in the initial management of LUTS. In Poland and Spain, office-based urologists initiate primary therapy for LUTS, although a trend towards involvement of GPs is also seen, especially in Poland. The shift in the initial management of LUTS from secondary to primary care accompanies a decreased incidence of surgery and a growing demand for medical therapy. Currently, there are considerable differences between the medical management of LUTS suggestive of BPO across Europe in real life practice. For example phytotherapy is particularly popular in countries such as Germany, France and Spain, whereas finasteride is more commonly used in Italy, Poland and the UK. alpha(1)-Adrenoceptor antagonists are used in most of these countries as the primary treatment modality. The data furthermore suggest that the current management of patients is often more opinion- than evidence-based, which may at least partly be due to the fact that data on long-term effectiveness of treatment options in real life clinical practice are largely lacking. CONCLUSIONS: [corrected] Due to the ageing and longevity of the population, the costs associated with the management of LUTS suggestive of BPO will rise in the future, whereas healthcare budgets will be relatively restricted. In order to improve cost-effective management of LUTS, more and better studies are needed in real life practice in primary care. These studies should not only be based on classical efficacy and safety data, but also on effectiveness of treatment in the long-term and the associated costs.

Europe↗

PubMed2005

Can we prevent prostate cancer? Rationale and current status of prostate cancer chemoprevention.

Prostate cancer has been one of the most frequent cancers among men in Western countries for the past decade. Investigation of prostate cancer prevention is very attractive, because prostate cancer has a high incidence, long-term natural history, regional difference in incidence, and is effected by sex steroids. Chemoprevention is defined as the use of specific agents to suppress or reverse carcinogenesis and to prevent the development of cancer. The development of chemoprevention strategies against prostate cancer would be of medical and economic importance. Basic and clinical research of chemoprevention of prostate cancer are under active investigation. This article aims to summarize and review the basic evidence and clinical trials on prostate cancer chemoprevention. Recent research has demonstrated that many agents, such as agents altering sex steroid signaling, drugs inducing antiproliferation/differentiation, retinoids, anti-inflammatory drugs, and antioxidants, could be potential preventatives for prostate cancer. Large-scale clinical trials have suggested that 5alpha-reductase inhibitor finasteride, selenium, and vitamin E can function as a chemopreventive agent. Although no definitely effective strategies of prostate cancer prevention have been identified yet, increasing evidence will provide effective and safe strategies that bring clinical benefits.

Anticarcinogenic Agents↗

PubMed2006

Questionnaire survey of urologists' initial treatment practices for acute urinary retention secondary to benign prostatic hyperplasia in Korea.

BACKGROUND: We undertook a survey of Korean urologists to establish initial treatment practices for acute urinary retention secondary to benign prostatic hyperplasia. METHODS: Probability samples were drawn from the Korean Urological Association Registry of Physicians, and a random sample of 850 Korean urologists were asked to complete a questionnaire that explored practice characteristics and treatment strategies in the management of acute urinary retention. The returned questionnaires were statistically analyzed. RESULTS: Of the 850 questionnaires sent, 302 were returned, and 277 of those were included in the final analysis (response rate 32.6%). Korean urologists preferred urethral catheterization as the initial management. Of respondents, 154 (55.6%) and 109 (39.4%) started their patients on alpha-blockers and alpha-blockers with finasteride, respectively. Nearly half (50.2%) used a trial without catheter 7 days after catheterization. One failed trial without catheter was an indication for surgery for only 69 (24.9%) of the respondents. A second trial without catheter was advocated by 108 (39.0%). Most urologists (82.3%) expected to be successful with the above management in 50% or greater. Physician's demographics or types of initial management did not influence physician's perception of expected success rate when the expected success rate was divided as < or =50% and >50. CONCLUSIONS: These data provide a picture of current practice regarding the management of acute urinary retention secondary to benign prostatic hyperplasia in Korea. There is no uniformity in the management of acute urinary retention in Korea.

Acute Disease↗

PubMed1993

Workshop summary: hormonal suppression in the neoadjuvant setting and advanced disease.

For advanced prostate cancer, hormonal suppression has long played an important role in patient management. Furthermore, the concept of combined androgen blockade using a luteinizing hormone-releasing hormone agonist in combination with an antiandrogen such as flutamide is gaining increasing acceptance. The novel regimen of finasteride (a 5-alpha-reductase inhibitor) plus flutamide may also have a role to play in the future. In the neoadjuvant setting, androgen suppression prior to radical prostatectomy is a novel approach. This strategy aims to reduce the size of the tumor as much as possible, hopefully downstaging the disease, and thus increasing the chances of a successful outcome at operation. Data from studies presented at this symposium revealed a clear reduction in tumor size by this method but the effects on both staging of disease and long-term outcome were not so definitive. Questions were put to the audience and the expert panel to assess their opinion of hormonal therapy and staging techniques, both in the neoadjuvant and advanced disease settings.

Androgen Antagonists↗

PubMed1992

Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase.

The enzyme steroid 5 alpha-reductase catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone, and impairment of this reaction causes a form of male pseudohermaphroditism in which genetic males differentiate predominantly as phenotypic females. We previously isolated cDNA clones that encode a human steroid 5 alpha-reductase enzyme. Here, we report molecular and genetic studies demonstrating that the gene encoding this cDNA is normal in subjects with the genetic disease steroid 5 alpha-reductase deficiency. We further show that in contrast to the major steroid 5 alpha-reductase in the prostate and cultured skin fibroblasts, the cDNA-encoded enzyme exhibits a neutral to basic pH optima and is much less sensitive to inhibition by the 4-aza steroid, finasteride (MK-906). The results provide genetic, biochemical, and pharmacological support for the existence of at least two steroid 5 alpha-reductase isozymes in man.

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

PubMedDate not supplied

Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.

Antiandrogenic chemicals alter sexual differentiation by a variety of mechanisms, and as a consequence, they induce different profiles of effects. For example, in utero treatment with the androgen receptor (AR) antagonist, flutamide, produces ventral prostate agenesis and testicular nondescent, while in contrast, finasteride, an inhibitor of 5 alpha-dihydrotestosterone (DHT) synthesis, rarely, if ever, induces such malformations. In this regard, it was recently proposed that dibutyl phthalate (DBP) alters reproductive development by a different mechanism of action than flutamide or vinclozolin (V), which are AR antagonists, because the male offsprings display an unusually high incidence of testicular and epididymal alterations--effects rarely seen after in utero flutamide or V treatment. In this study, we present original data describing the reproductive effects of 10 known or suspected anti-androgens, including a Leydig cell toxicant ethane dimethane sulphonate (EDS, 50 mg kg-1 day-1), linuron (L, 100 mg kg-1 day-1), p,p'-DDE (100 mg kg-1 day-1), ketoconazole (12-50 mg kg-1 day-1), procymidone (P, 100 mg kg-1 day-1), chlozolinate (100 mg kg-1 day-1), iprodione (100 mg kg-1 day-1), DBP (500 mg kg-1 day-1), diethylhexyl phthalate (DEHP, 750 mg kg-1 day-1), and polychlorinated biphenyl (PCB) congener no. 169 (single dose of 1.8 mg kg-1). Our analysis indicates that the chemicals discussed here can be clustered into three or four separate groups, based on the resulting profiles of reproductive effects. Vinclozolin, P, and DDE, known AR ligands, produce similar profiles of toxicity. However, p,p'-DDE is less potent in this regard. DBP and DEHP produce a profile distinct from the above AR ligands. Male offsprings display a higher incidence of epididymal and testicular lesions than generally seen with flutamide, P, or V even at high dosage levels. Linuron treatment induced a level of external effects consistent with its low affinity for AR [reduced anogenital distance (AGD), retained nipples, and a low incidence of hypospadias]. However, L treatment also induced an unanticipated degree of malformed epididymides and testis atrophy. In fact, the profile of effects induced by L was similar to that seen with DBP. These results suggest that L may display several mechanisms of endocrine toxicity, one of which involves AR binding. Chlozolinate and iprodione did not produce any signs of maternal or fetal endocrine toxicity at 100 mg kg-1 day-1. EDS produced severe maternal toxicity and a 45% reduction in size at birth, which resulted in the death of all neonates by 5 days of age. However, EDS only reduced AGD in male pups by 15%. Ketoconazole did not demasculinize or feminize males but rather displayed anti-hormonal activities, apparently by inhibiting ovarian hormone synthesis, which resulted in delayed delivery and whole litter loss. In summary, the above in vivo data suggest that the chemicals we studied alter male sexual differentiation via different mechanisms. The anti-androgens V, P, and p,p'-DDE produce flutamide-like profiles that are distinct from those seen with DBP, DEHP, and L. The effects of PCB 169 bear little resemblance to those of any known anti-androgen. Only in depth in vitro studies will reveal the degree to which one can rely upon in vivo studies, like those presented here, to predict the cellular and molecular mechanisms of developmental toxicity.

Aminoimidazole Carboxamide↗

PubMed1995

A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man.

This paper describes control of normal Leydig cell function and testosterone production. The macroscopic and histopathological appearances of spontaneous Leydig cell hyperplasias and tumors (LCT) in the rat are reviewed together with their incidence and hormonal status. Drugs which induce LCTs in chronic studies are discussed and include busereline, carbamazepine, cimetidine, finasteride, flutamide, gemfibrozil, histrelin, hydralazine, indomethacin, isradipine, lactitol, leuprolide, metronidazole, mesulergine, nafarelin, norprolac and vidarabine. The known mechanisms of LCT induction in the rat are reviewed together with other possible etiological factors. The incidence, clinical picture and etiological factors of LCTs in man are also surveyed. Hormone production in Leydig cells and LCTs in rats and man are compared. Differences between the two species are considered, particularly with regard to Leydig cell control mechanisms. The paper concludes that drug-induced LCTs in rats are most probably not predictive for man and their occurrence has little relevance in human safety assessment.

Animals↗

PubMed1997

Cancer Prevention: The Roles of Diet and Chemoprevention.

BACKGROUND: Reduction of cancer risk by either preventing carcinogenesis or stopping carcinogenesis in its early stages is a logical approach for reducing the cancer burden, both for high-risk individuals and for the general population. The areas of dietary modification and chemoprevention show considerable promise as effective approaches for cancer prevention and are a focus of research efforts. RESULTS: Diet and cancer studies show that, generally, vegetables and fruits, dietary fiber, and certain nutrients seem to be protective against cancer, whereas fat, excessive calories, and alcohol seem to increase cancer risk. Chemoprevention research is closely linked to diet and cancer research and represents a logical research progression. CONCLUSIONS: Dietary epidemiologic studies have helped to identify many naturally occurring chemopreventive agents. Currently, randomized clinical prevention trials sponsored by the NCI include dietary interventions (eg, low-fat and/or high-fiber vegetables and fruits) targeting breast and colorectal cancer, chemoprevention trials using micronutrients (eg, vitamin E, calcium, vitamin D) aimed at lung and colorectal cancer, and chemoprevention trials testing the effectiveness of pharmaceutical agents (eg, tamoxifen, finasteride, aspirin) for breast, prostate, and colorectal cancer.

Journal Article↗

PubMed1997

Chemoprevention of Bladder and Prostate Carcinoma.

BACKGROUND: The incidence of bladder and prostate cancer continues to rise, with little accompanying improvement in management strategies. Opportunities exist for testing various types of chemopreventive interventions. METHODS: The authors review the biology of progression to invasive disease for cancers of the bladder and the prostate and identify intermediate disease and surrogate endpoint markers. Candidate interventions and initial clinical trial results are described. RESULTS: Markers of cellular proliferation and differentiation, as well as antigens such as Le(x), M344, DD23, and bladder tumor antigen, are promising for bladder cancer. Testing with prostate-specific antigen and prostate-specific membrane antigen is promising for prostate cancer. Several prevention intervention trials are in progress for both cancers. CONCLUSIONS: Vitamins, polyamine synthesis inhibitors, and oltipraz are undergoing clinical tests for chemopreventive effects in bladder cancer, and a large trial of finasteride to prevent prostate cancer is completing accrual. Results from these studies will direct future research.

Journal Article↗

PubMed1994

Cancer chemoprevention.

PURPOSE: To review the most important recent advances in clinical trials and biologic studies within the growing field of chemoprevention. METHODS: The most critical methods issue concerns the definitive end point of phase III trials, which is now cancer incidence. This end point usually needs thousands of subjects monitored for 5 to 10 or more years to determine efficacy. Biologic markers of potential intermediate end points are under intensive study and may one day replace cancer incidence. Validated intermediate end point biomarkers could greatly reduce phase III trial populations, durations, and costs. RESULTS: Randomized clinical trials over the last 5 years have produced significant activity in reversing oral, skin, colon, and cervical premalignancy; in preventing primary skin and stomach cancer; and in preventing second primary tumors associated with head and neck and lung cancer. These clinical advances have been paralleled at the basic science level by elegant molecular studies of premalignant carcinogenesis and of chemopreventive agents' mechanisms of action. One major laboratory advance is the discovery of nuclear retinoic acid receptors and strong evidence of their roles both in carcinogenic progression and in its response to retinoids. CONCLUSION: Chemoprevention has matured greatly in recent years with the significant reversal or suppression of premalignancy by chemopreventive agents in several sites. The future of chemoprevention will be determined largely by several ongoing phase III trials, including trials of retinoids, beta-carotene, and alpha-tocopherol in the aerodigestive tract, of tamoxifen and fenretinide in the breast, and of finasteride in the prostate.

Anticarcinogenic Agents↗

PubMed2000

Profile of men randomized to the prostate cancer prevention trial: baseline health-related quality of life, urinary and sexual functioning, and health behaviors.

PURPOSE: To describe men who agreed to be randomized to the Prostate Cancer Prevention Trial (PCPT), a 7-year, double-blind placebo-controlled study of the efficacy of finasteride in preventing prostate cancer. METHODS: Comprehensive health-related quality-of-life data are presented for 18,882 randomized PCPT participants. RESULTS: PCPT participants are highly educated, middle to upper income, and primarily white (92%). Participants reported healthy lifestyles. The mean American Urological Association Symptom Index score was well below the maximum entry score of less than 19; existing urinary symptoms were generally not bothersome. The scores for two sexual functioning scales could range from 0 to 100, with higher scores reflecting worse sexual functioning. The mean score for the Sexual Problem Scale was 19.2 out of 100, and the mean Sexual Activities Scale was 44.1 out of 100. Scores for seven of the eight Medical Outcomes Study 36-item Short-Form Health Survey scales (higher scores are better) were 10 to 20 points higher than those reported by a general population sample and differed minimally by race but not by age. Previously reported associations between sexual dysfunction and hypertension, diabetes, and depression were also observed. Men who never smoked reported less sexual dysfunction than did those who either had quit or still smoked. CONCLUSION: Individuals who are likely to enroll in primary prevention trials have a high socioeconomic status, healthy lifestyle behaviors, and better health than the general population. These data help oncologists design chemoprevention trials with respect to the selection of health-related quality-of-life assessments and recruitment strategies.

Aged↗

PubMed2005

Phase III prostate cancer prevention trials: are the costs justified?

One randomized, prospective clinical trial for chemoprevention of prostate cancer has been completed, and two additional trials are ongoing. The investment, time, and effort for these trials are substantial. We reviewed the outcomes of these trials to address the value of the investment. The outcomes of the Prostate Cancer Prevention Trial (testing finasteride) and the design of the Selenium and Vitamin E Cancer Prevention Trial (SELECT; testing vitamin E and selenium) trial as well as the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (testing dutasteride) were reviewed. From a public health standpoint, there is tremendous potential for benefit from large-scale cancer prevention trials. Because of the volume of data that are collected, potential discoveries related to the biology of the disease are substantial. Translational scientific efforts are direct outgrowths of these studies. Prospective, randomized chemoprevention trials for prostate and other cancers are expensive and require long periods of time to conduct, yet the rewards are on a par with the investment.

Clinical Trials, Phase III as Topic↗

PubMed2005

Docetaxel followed by hormone therapy in men experiencing increasing prostate-specific antigen after primary local treatments for prostate cancer.

PURPOSE: Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC. PATIENTS AND METHODS: Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be > or = 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months. RESULTS: Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased > or = 50% in 17 of 35 patients (48.5%) and > or = 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%). CONCLUSION: Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.

Aged↗

PubMed2003

Inhibition of spontaneous and androgen-induced prostate growth by a nonhypercalcemic calcitriol analog.

We have recently found that analog V (BXL-353, a calcitriol analog) inhibits growth factor (GF)-stimulated human benign prostate hyperplasia (BPH) cell proliferation by disrupting signal transduction, reducing Bcl-2 expression, and inducing apoptosis. We now report that BXL-353 blocks in vitro and in vivo testosterone (T) activity. BPH cells responded to T and dihydrotestosterone (DHT) with dose-dependent growth and reduced apoptosis. Exposure of BPH cells to BXL-353 significantly antagonized both T- and DHT-induced proliferation and induced apoptosis, even in the presence of T. To verify whether BXL-353 reduced prostate growth in vivo, we administered it orally to either intact or castrated rats, supplemented with T enanthate. Nonhypercalcemic doses of BXL-353 time- and dose-dependently reduced the androgen effect on ventral prostate weight, similarly to finasteride. Comparable results were obtained after chronic administration of BXL-353 to intact rats. Clusterin (an atrophy marker) gene and protein were up-regulated by BXL-353 in rat prostate, and nuclear fragmentation was widely present. The antiandrogenic properties of BXL-353 did not interfere with pituitary and testis function, as assessed by serum determination of rat LH and T. BXL-353 did not compete for androgen binding to BPH homogenates and failed to inhibit 5alpha-reductase type 1 and type 2 activities. In conclusion, BXL-353 blocks in vitro and in vivo androgen-stimulated prostate cell growth, probably acting downstream from the androgen receptor, without affecting calcemia or sex hormone secretion. BXL-353 and other vitamin D(3) analogs might thus represent an interesting class of compounds for treating patients with BPH.

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

PubMed1990

Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone.

Testosterone and dihydrotestosterone are believed to exert their androgenic effects by interacting with a single intracellular receptor protein in androgen target tissues. During fetal life, however, testosterone mediates the virilization of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles, whereas the urogenital sinus and external genitalia require the in situ conversion of testosterone to dihydrotestosterone to undergo male development. The reason why the signal provided by testosterone needs to be amplified in some androgen target tissues but not in others remains an enigma. To provide insight into the different actions of these androgens we studied their interaction with the human androgen receptor in fibroblasts cultured from the genital skin of a patient with 5 alpha-reductase deficiency. Dihydrotestosterone was formed in negligible amounts in these cells, and in some experiments the residual 5 alpha-reductase activity was further blocked with the 5 alpha-reductase inhibitor finasteride. Saturation analysis in fibroblast monolayers disclosed similar amounts of binding with testosterone and dihydrotestosterone, and the affinity of binding of dihydrotestosterone was, on the average, about 2-fold greater than that of testosterone. [3H]Testosterone also exhibited a 5-fold faster dissociation rate from the receptor than [3H]dihydrotestosterone. In thermolability experiments the [3H]testosterone-receptor complex displayed marked instability at 42 C with 2 nM [3H] testosterone, whereas with 20 nM [3H]testosterone, receptor stability was similar to that seen with [3H]dihydrotestosterone. In up-regulation experiments, 2 nM [3H]testosterone produced a 34% increase in specific androgen receptor binding after 24 h, whereas 20 nM [3H]testosterone produced an average increase of 64%. Our results suggest that the weaker androgenic potency of testosterone compared to that of dihydrotestosterone resides in its weaker interaction with the androgen receptor, most clearly demonstrable as an increase in the dissociation rate of testosterone from the receptor. When present in relatively high concentrations, however, testosterone overcomes this defect by mass action.(ABSTRACT TRUNCATED AT 400 WORDS)

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

PubMed2000

In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism.

In the present study we characterized in detail the expression of aromatase P450 in leiomyomas to determine the role of in situ estrogen in the growth advantage of leiomyomas. The levels of aromatase P450 transcripts were determined by quantitative RT-PCR to be significantly higher in leiomyomas than in corresponding myometrium. The overexpression of aromatase P450 in leiomyomas was also confirmed by Western blot analysis. The estimated size of immunoreactive aromatase was 58 kDa, similar to that in placenta. To identify a cell type that express aromatase P450 in leiomyomas, histological specimens were stained for aromatase P450 using a polyclonal antibody. Strong immunoreactivity was detected in the cytoplasm of leiomyoma cells, whereas surrounding normal myometrium displayed weak or negative staining. Smooth muscle-like cells in culture obtained from leiomyomas, positive for actin D fiber, possessed immunoreactive granules of aromatase in the cytoplasm. Conversion of androgen to estrogen was effectively stimulated by phorbol myristate acetate and dexamethasone plus interleukin-1beta and was completely abolished by selective inhibitors of aromatase P450 (fadrozole and TZA-2209), but not by inhibitors of 5alpha-reductase (finasteride and flutamide). The apparent Km of androstenedione was 3 nM in the presence of dexamethasone and interleukin-1beta, corresponding to the plasma concentration of androstenedione in women of reproductive age. To determine whether endogenous aromatase P450 plays a role in the growth promotion of leiomyoma cells, we evaluated the cell growth of smooth muscle-like cells treated with various concentrations of estrogen and androgen using a WST-1 assay. Treatment with testosterone (10(-8) and 10(-7) M) and androstenedione (10(-8) and 10(-7) M) stimulated the growth of smooth muscle-like cells obtained from leiomyomas to the same extent as estradiol (10(-10)-10(-7) M), whereas dihydrotestosterone (10(-11)-10(-8) M) did not. The stimulatory effect of testosterone on cell growth was again abolished by cotreatment with fadrozole. The level of estradiol in the medium of testosterone (10(-8) M)-treated smooth muscle-like cells was 10(-11) M, which was 1 order lower than the minimum concentration of estradiol necessary to promote cell growth (10(-10) M). This indicates that estradiol synthesized in leiomyomas promotes their growth via an autocrine/intracrine mechanism. We conclude that myometrial cells of leiomyomas overexpress aromatase P450 and are able to synthesize sufficient estrogen to accelerate their own cell growth. Overexpression of aromatase P450 may play a role in the growth advantage of leiomyoma tissue over surrounding myometrium via an autocrine/intracrine mechanism.

Adult↗