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PubMed2001

Executive Summary of the National Cancer Institute Workshop: Highlights and recommendations.

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.

Anticarcinogenic Agents↗
PubMed2001

Effect of androgen deprivation therapy on prostatic intraepithelial neoplasia.

There is a marked decrease in the prevalence and extent of high-grade prostatic intraepithelial neoplasia (PIN) in men with prostate cancer after androgen deprivation therapy (ADT) when compared with untreated cases. Basal cell hyperplasia, cytoplasmic clearing, and prominent atrophy of benign acini, with decreased ratio of acini to stroma, accompany this decrease. These findings indicate that the benign and dysplastic prostatic epithelium is androgen dependent. In the normal prostatic epithelium, luminal secretory cells are more sensitive to the absence of androgen than basal cells, and the proliferative cells of high-grade PIN share this androgen sensitivity. The loss of some normal, hyperplastic, and dysplastic epithelial cells with ADT is probably because of acceleration of programmed single-cell death. Remarkably little is known about the comparative effect of different forms of chemical ADT on PIN and cancer, although there appears to be a limited and consistent repertoire of morphologic responses to all forms of this therapy. Conversely, blockade of 5alpha-reductase with finasteride has little or no effect on PIN (or benign epithelium and cancer), unlike other forms of ADT. A recent international consensus conference sponsored by the World Health Organization concluded that identification of high-grade PIN offered the possibility of chemoprevention with hormonal therapy to block the development of clinical cancer. Multiple chemoprevention trials are planned or under way to address this hypothesis.

Adenocarcinoma↗
PubMed2001

Minimally invasive therapies for benign prostatic hyperplasia.

Currently, 3 categories of treatment are available for men with benign prostatic hyperplasia (BPH): (1) medicine, such as alpha-blockers and finasteride; (2) minimally invasive treatment, such as transurethral microwave thermotherapy and interstitial ablation using either radiofrequency or laser; and (3) surgical therapy. The 1990s have seen an explosion of transurethral technology to treat symptoms caused by bladder outlet obstruction secondary to BPH. Unlike surgical debulking procedures, the minimally invasive therapies attempt to treat patients without general or regional anesthesia, and even ambulatory procedures are performed in the office. Because of the demographics of patients with BPH, it is hoped that these minimally invasive options will relieve symptoms without any surgical complications and the side effects and compliance issues associated with medical therapy. It is important that urologists have a clear understanding of the clinical usefulness of these devices, so that the overall role of such treatment may be determined by science rather than marketing. Clinically, the degree of symptom score, peak flow, and quality-of-life improvement seen with all the minimally invasive techniques are similar. The techniques may differ in their ability to reach the maximum number of responders and achieve an acceptable duration of response, and the need for analgesia/sedation associated with each technique. This study will define the minimally invasive therapies and present the differences in catheter design and technique. The pathologic basis for these therapeutic options and the advantages and disadvantages of each will be discussed. Urologists must decide which therapy can be used in their office practice. The maximum numbers of responders and enhanced durability of the treatment can be achieved based on realistic expectations, proper selection of patients, and complete information on the potential of these devices.

Adrenergic alpha-Antagonists↗
PubMed2003

Familial aggregation of bothersome benign prostatic hyperplasia symptoms.

OBJECTIVES: To evaluate familial aggregation and the mode of inheritance of bothersome benign prostatic hyperplasia (BPH). METHODS: During an extension of the North American Finasteride Trial, 301 of 895 patients and 158 spousal controls completed a family history questionnaire. Segregation analysis was performed to examine the mode of inheritance in first-degree relatives of the 301 probands. RESULTS: The lifetime cumulative probability of bothersome BPH was similar in relatives of those with BPH (0.35; 95% confidence interval [CI] 0.28 to 0.44) and spousal controls (0.36; 95% CI 0.22 to 0.56), but the age of onset was significantly earlier in relatives of cases than controls (P = 0.001). Fathers of those with BPH had a significantly elevated risk of bothersome BPH (unadjusted odds ratio [OR] 2.1; 95% CI 1.2 to 3.8) and brothers had a significantly elevated risk of both bothersome BPH (OR 3.5; 95% CI 1.7 to 7.3) and transurethral resection of the prostate (OR 3.6; 95% CI 1.4 to 8.8). After adjusting for family size, the risk of bothersome BPH increased approximately twofold with each additional affected first-degree relative (0 relatives, OR 1.0; 1 relative, OR 1.7; 2 relatives, OR 4.7). Segregation analysis suggested a rare autosomal codominant allele (frequency 0.0004). CONCLUSIONS: These findings confirm previous findings that family history and early age of onset are associated with an increased risk of BPH and that the most likely mode of inheritance is autosomal dominant or codominant. Bothersome BPH appears to have a weaker genetic component than more restrictive definitions of hereditary BPH. Thus, linkage studies are more likely to be successful if they focus on stricter definitions of hereditary BPH (eg, early onset, large volume, strong family history) rather than symptomatic or clinical BPH.

Adult↗
PubMed1998

Accurate determination of prostate size via digital rectal examination and transrectal ultrasound.

Previously, prostate size did not play a significant role in the choice of treatment for benign prostatic hyperplasia (BPH). It has been postulated that prostate size does not correlate with symptom severity, flow rate, or the presence or absence of obstruction. However, in a published study of community-dwelling men, the odds of having moderate to severe symptoms were five times higher for men with enlarged prostates than for those with normal prostates. Response to certain types of BPH therapy, especially finasteride, depends on actual prostate volume. Therefore, it is important to have a simple way to accurately determine if a patient's prostate is enlarged. In an analysis of four studies, there was a distinct underestimation of prostate size by digital rectal examination (DRE) when compared with transrectal ultrasound (TRUS) measurement. The underestimation of prostate volume increased with increasing TRUS volume, particularly if the volume was greater than 30 mL. The average underestimation was between 9% and 12% for prostate volumes 30 to 39 mL and between 17% and 27% for prostate volumes 40 to 49 mL. Because of these results, a prospective study is currently in progress to develop models or visual aids to assist physicians in more accurately predicting a threshold prostate volume via DRE.

Humans↗
PubMed1995

Effect of demographic factors, urinary peak flow rates, and Boyarsky symptom scores on patient treatment choice in benign prostatic hyperplasia.

OBJECTIVES: To determine the effect of patient's age, race, Boyarsky score, and urinary flow rate on type of treatment selected for benign prostatic hyperplasia (BPH) and to evaluate maintenance of treatment at 1-year follow-up. METHODS: Subjects in this prospective study, conducted in a referral center prostate clinic, were 174 consecutive patients, aged 67.6 +/- 10.8 years (mean +/- SD), with previously untreated BPH. Patients underwent structured interviews and uroflowmetry, then completed the Boyarsky Symptom Index. Blinded to these data, one physician described four treatment categories in a nonjudgmental fashion, always using the same order: watchful waiting; finasteride and alpha-blocker; thermal therapy, balloon dilation, and a prostate stent; and transurethral prostate resection. Treatment choice was entirely that of the patient. Independent variables were patient's age, race, symptom score, and uroflow; the dependent variable was treatment choice. At 1 year, the same physician interviewed patients to evaluate maintenance of therapy. RESULTS: Only symptom score and flow rate were predictive of treatment choice, high scores and low flow being associated with more aggressive treatment choices (P = 0.001). Most patients, regardless of symptom severity, chose interventions less aggressive than surgery and more aggressive than watchful waiting. At 1 year, 85% of patients continued to be maintained on their original treatment. CONCLUSIONS: Men with mild or moderate BPH prefer interventions of moderate aggressiveness; race and age make little or no difference. If maintenance of treatment indicates patient satisfaction, most patients appear to remain satisfied with therapy they select.

Adult↗
PubMedDate not supplied

A cost density analysis of benign prostatic hyperplasia.

We assessed the frequency and cost of care for benign prostatic hyperplasia (BPH) among approximately 165,000 subscribers to Fallon Community Health Plan (FCHP), a group model health maintenance organization located in central Massachusetts. We computed rates of episodes of medical services for BPH using automated utilization files, and we estimated costs using Medicare reimbursement schedules and medication average wholesale prices. We identified 3919 men who visited a physician for BPH from January 1, 1991, until December 31, 1994, during which time they contributed 8336 person-years to the analysis. This population comprises approximately 12% of men at least 40 years old at FCHP. From 1991 to 1994, 696 (18%) men received terazosin, 219 (6%) men underwent a prostatectomy, and 41 (1%) men received finasteride. Men averaged 1.66 office visits per year to a physician for BPH. Most office visits (61%) were to a primary care physician, with 39% of the visits to a urologist. Among patients who received terazosin, the frequency of office visits increased slightly after receiving terazosin, from 2.14 to 2.62 visits per year. Among surgery patients, the frequency of visits declined after prostatectomy, from 6.31 visits per year to 1.67 visits. The individual annual cost rate for BPH care ranged from $25.00 to $25,352.00, with an average of $364.00 per person and a median cost of $126.00. The major components of the overall costs were hospital admissions (35%), terazosin dispensings (29%), and physician office visits (19%), with outpatient hospital care and ambulatory procedures accounting for the remaining 17%. Among men receiving terazosin, the average cost was $1190.00 per person-year, and among patients undergoing prostatectomy, the cost was $2630.00 per person-year. The prostatectomy rate declined by nearly 80% during the study period, while the dispensing rate for terazosin doubled, resulting in an overall decline in the total cost of care for BPH from 1991 to 1994.

Adult↗
PubMedDate not supplied

The economics of benign prostatic hyperplasia treatment: a literature review.

Benign prostatic hyperplasia (BPH) is one of the most common benign neoplasms in elderly men in the United States; it has been estimated that the annual costs of caring for these men exceed $4 billion. This condition is rarely life threatening, but often affects the individual's quality of life in varying degrees. There are several treatments for this condition, including surgery, with the most common procedure being transurethral resection of the prostate. Other treatment options include medication (such as finasteride and terazosin), balloon dilation, and watchful waiting. The cost associated with BPH depends on the severity of the disease and the appropriate course of treatment. The objective of this paper is to identify and evaluate the economic research papers that have considered either the economic burden or costs associated with alternative BPH therapy options and to identify key areas for future economic research. This review indicates that the economic studies of BPH are diverse in nature and greater attention needs to be placed on the societal appraisal of competing BPH therapies. Other research areas include the economic analysis of both short- and long-run BPH treatment options, increased cost-utility analysis, and the use of retrospective claims database analysis using regression techniques.

Aged↗
PubMed2001

The appropriateness of treatment of benign prostatic hyperplasia: a comparison of Dutch and multinational criteria.

Over the last decade, a number of organisations have developed clinical guidelines, typically at a national level, in order to increase appropriate health care. This raises the question as to whether it is possible to develop guidelines, applicable on the national level, at an international level. In order to examine this, we compared the appropriateness criteria for the treatment of benign prostatic hyperplasia ratings developed by two panels, one a single-nationality (Dutch) panel, the other a multinational (European) panel. The panels, both consisting of experienced urologists, used a modified Delphi process to rate 1152 indications for the most common treatments (surgery, alpha-blocker, finasteride and watchful waiting) on a nine-point scale. This article describes the similarities and differences between the ratings produced by the panels. The appropriateness ratings were identical for 84% of the indications (kappa=0.76). The difference in the scores for individual indications was zero in 41% of indications and less than or equal to two in 99% of indications. This study provides strong evidence that a multinational panel can deliver essentially the same appropriateness ratings for BPH as a national panel. Developing appropriateness criteria on an international level may result in significant savings and may help contribute to the reduction of undesirable practice variation.

Aged↗
PubMed2004

[Estimation of the cost in the medical treatment of benign prostatic hyperplasia in Navarre, Spain].

We evaluate the cost and trends in the medical treatment of out patients suffering from lower urinary tract symptoms suggestive of clinical benign prostatic hyperplasia in Navarre (Spain) between 1998/2002. The estimated number of patients increased each year, to 10% of the male population over the age of 50 in 2002, with a cost of Euros 2,557,236 equivalent to 2.4% of the total drug expenditure spending of out patients (Euros 106.6 million). The use of tamsulosin tripled and the cost doubled to Euros 807,467 (31.5%) of the total), while the rest of alpha-blockers, wit the exception of doxazosin, was stationary. Phytotherapy decreased by a third and finasteride follows a slow upward trend. The introduction of reference prices set by the Health Department in 2001 to reduce medical budget, led to an initial decrease in cost, offsetted in the following year due to the incorporation of new patients. In this period, surgery for prostate adenoma diminished from 382 patients in 1998 to 270 in 2002 (-30%).

Costs and Cost Analysis↗
PubMed2006

[Clinicopathological study of incidental cancer prostate in patients undergoing surgery for symptomatic diagnosis of BPH].

UNLABELLED: OBJECTIVES-INTRODUCTION: Retrospective study of a series of patients with prostate surgery (suprapubic prostate adenomectomy -APS-, and prostate transurethral resection -RTU-P-) for presumed BPH symptomatic non-respondent to the conservative medical treatment. Analysis of prevalence, incidence, clinical-pathological, treatment, tumor progression and evolution of the patients with incidental prostate cancer (CPI) detected. MATERIAL AND METHODS: 1593 patients with prostate surgery (APS and RTU-P) during 6 years (1996-2001) were revised. APS 35%, RTU-P 65%. Revision of all pathological anatomy of surgical specimens and the evolutions of the patients with CPI. RESULTS: 78 CPI; Prevalence 4,89%; Incidence 13 cases/year. Mean age 73.6 years. Digital rectal examination was normal in 100%, mean PSA 6 ng/ml (0.5-30). Group APS: 25 CPI (32%); prevalence 4.55%; incidence 4 cases/year; mean PSA 7.7 ng/ml (2.8-30); mean weight resection 65 gs. Group RTU-P: 53 CPI (68%); prevalence 5,07%; incidence 9 cases/year; mean PSA 5.2 ng/ml (0,5-29); mean weight resection 20 gs. 22% biopsy previously by high PSA, mean PSA 14 ng/ml (4,8-30). Gleason average 5 (mean 4.8), rank 3-8. pTla 66%, pTlb 33%. TREATMENT: 57% follow-up watched without treatment (wait and see); 18% hormonal treatment; 3% finasteride; 9% Radical Prostatectomy; 9% radiotherapy. Follow Lost 4%. Mean follow-up 47.19 months (12-96). Tumor progression 13.3% (10 patients). Specific CPI mortality 2.6% (2 patients). CONCLUSIONS: We didn't observe significant differences between the prevalence of CPI in both groups (APS and RTU-P). The detected tumours were mainly well differentiated and in stage pTla. In more than half of the cases an expectant attitude without treatment was decided. 13,3% of tumor progression after 47.19 months of follow mean and specific CPI mortality 2.6%.

Aged↗
PubMed2003

Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia.

OBJECTIVE: The objective of this paper is to examine safety and tolerability data from a number of recently completed clinical trials with the novel, dual 5alpha-reductase inhibitor, dutasteride. METHODS: Intent-to-treat analyses were conducted on data for dutasteride 0.5 mg/day for drug-related adverse events, clinical laboratory test results, and prostate-specific antigen (PSA) levels derived from four large, randomised, double-blind clinical trials (n=5655). Further data were derived from a randomised, double-blind combination study of dutasteride 0.5 mg/day and tamsulosin 0.4 mg/day (n=327), and several safety studies conducted in healthy volunteers. RESULTS: Data from two-year blinded clinical studies demonstrate that dutasteride is well tolerated, with a profile comparable with that of placebo. The exception is a modestly elevated incidence of impotence, decreased libido, ejaculation disorders, and gynaecomastia. Clinical laboratory test abnormalities were reported by <1% of patients treated with dutasteride, and abnormal values occurred with similar frequency versus placebo-treated patients. In a healthy volunteer study, when dutasteride was administered daily for 1 year, it did not significantly affect bone metabolism markers, bone mineral density or lipid profiles. Dutasteride reduced total serum PSA concentrations by approximately 50% following 6, 12, and 24 months of treatment but had no effect on free-to-total PSA levels. The safety profile of dutasteride did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride was used in combination with an alpha(1)-blocker, the drug-related adverse event profiles were as would be expected for the individual agents. CONCLUSIONS: Considered together, these data demonstrate dutasteride to be well-tolerated.

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

Des (1-3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D3 analogue.

Prostate growth and differentiation is under the control of androgens not only during fetal life and childhood but also in adulthood, and it has been proposed that increased prostatic concentration of androgens, or increased androgen responsiveness, causes benign prostatic hyperplasia (BPH). However, different androgen ablation strategies such as treatment with GnRH agonists and finasteride resulted in a modest decrease of the hyperplastic prostate volume. In the last few years it became evident that both androgen-dependent and androgen-independent growth factors promote prostate enlargement by inducing cell proliferation or reducing apoptosis. Therefore, new therapeutic strategies, aimed at reducing intraprostatic growth factor signaling, are under investigation. In this study, we report further evidence that a non hypercalcemic-analogue of vitamin D(3), analogue (V) decreases growth factor-induced human BPH cell proliferation and survival. We found that Des (1-3) insulin-like growth factor [Des (1-3) IGF-I], an IGF-I analogue, which does not bind to IGF-binding proteins, is a potent mitogen for BPH stromal cells via a dual mechanism: stimulation of cell growth and inhibition of apoptosis. Similar results were previously reported for another growth factor for BPH cells, keratinocyte growth factor (KGF). Accordingly, we speculate that both KGF and IGF might be involved in the pathogenesis of BPH. We also found analogue (V) not only inhibits the mitogenic activity of growth factors on BPH cells, but even decreased the basal expression of bcl-2, and induced apoptosis. Therefore, vitamin D(3) analogues might be considered for the medical treatment of BPH.

Animals↗
PubMed1998

A new look at an old option in the treatment of early-stage prostate cancer: hormone therapy as an alternative to watchful waiting.

Watchful waiting is an attractive option in the management of early-stage, low-grade prostate cancer because of the high financial costs and complication risks associated with surgery and radiotherapy. Despite the drawbacks of current local therapy, neither treatment can demonstrate a discernible survival benefit over observation alone. Even the slowest progressing disease, however, can potentially develop into a deadly medical problem. As a result, physicians and patients frequently have difficulty accepting untreated cancer. Therefore, we propose that another option be considered in cases of prostate cancer that would otherwise qualify for observation alone: the use of two oral hormonal agents, flutamide and finasteride, to achieve complete androgen blockade. Some evidence exists which suggests that such therapy may improve symptom-free survival, and perhaps overall survival as well. This 'aggressive' form of 'conservative' therapy may satisfy patient concerns that are not adequately addressed by current forms of therapy.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

Molecular mechanisms of androgenetic alopecia.

Androgenetic alopecia (AGA) is hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern. While the genetic involvement is pronounced but poorly understood, major advances have been achieved in understanding principal elements of the androgen metabolism involved: androgen-dependent processes are predominantly due to the binding of dihydrotestosterone (DHT) to the androgen receptor (AR). DHT-dependent cell functions depend on the availability of weak androgens, their conversion to more potent androgens via the action of 5 alpha-reductase, low enzymatic activity of androgen inactivating enzymes, and functionally active AR present in high numbers. The predisposed scalp exhibits high levels of DHT, and increased expression of the AR. Conversion of testosterone to DHT within the dermal papilla plays a central role, while androgen-regulated factors deriving from dermal papilla cells are believed to influence growth of other components of the hair follicle. Current available treatment modalities with proven efficacy are oral finasteride, a competitive inhibitor of type 2 5 alpha-reductase, and topical minoxidil, an adenosine-triphosphate-sensitive potassium channel opener which has been reported to stimulate the production of vascular endothelial growth factor in cultured dermal papilla cells. Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA.

Alopecia↗
PubMed1996

Antiandrogen and hormonal treatment of acne.

In the treatment of acne in women, the use of antiandrogens and other hormonal approaches is a valuable alternative to standard therapy. These treatments that are based on physiologically sound principles produce gratifying results in selected women with acne, and are the primary treatment for women with hirsutism. The drugs discussed in this article include spironolactone, cyproterone acetate, flutamide, oral contraceptives, corticosteroids, finasteride, and gonadotropin-releasing hormone agonists. Patient selection, pretreatment evaluation, and case studies also are discussed with an emphasis on practical applications.

Acne Vulgaris↗
PubMed1994

Role of 5 alpha-reductase in health and disease.

The mechanism of androgen action varies in different tissues, but in the majority of androgen target tissues either testosterone or 5 alpha-dihydrotestosterone (DHT) binds to a specific androgen receptor to form a complex that can regulate gene expression. Testosterone is metabolized to DHT by the enzyme 5 alpha-reductase. The autosomal recessive genetic disorder of 5 alpha-reductase deficiency has clearly shown that the requirement for DHT formation varies with different tissues. In this syndrome genetic males contain normal male internal structures including testes, but exhibit ambiguous or female external genitalia at birth; at puberty they undergo partial virilization which includes development of a male gender identity even if brought up as females. Their development suggests that testosterone itself is able to stimulate psychosexual behaviour, development of the embryonic wolffian duct, muscle development, voice deepening, spermatogenesis, and axillary and pubic hair growth; DHT seems to be essential for prostate development and growth, the development of the external genitalia and male patterns of facial and body hair growth or male-pattern baldness. How different hormones operate to regulate genes via the same receptor is currently unknown, but appears to involve cell-specific factors. The 5-alpha-reductase enzyme has proved difficult to isolate biochemically, but recently at least two human isoenzymes have been identified using molecular biological methods. All the various 5 alpha-reductase-deficient kindreds have been shown to have mutations in 5 alpha-reductase 2, the predominant form in the prostate. The biological role of 5 alpha-reductase 1 has not yet been ascertained, but at present it cannot be ruled out that some of the actions ascribed to testosterone are indeed in cells producing DHT via this enzyme. The activity of 5 alpha-reductase is also implicated in benign prostatic hypertrophy, hirsutism and possibly male-pattern baldness; recent evidence discounts the role of 5 alpha reductase 2 in sebaceous glands and acne. Specific inhibitors of both enzymes are now available and finasteride, a 5 alpha-reductase 2 inhibitor, has been used successfully in clinical trials of benign prostatic hypertrophy. Knowledge of 5 alpha-reductase is expanding dramatically at the moment with the application of molecular biological methods. The advent of antibodies to the isoenzymes should herald further understanding of their biological and clinical roles.

Animals↗
PubMedDate not supplied

Expression of aromatase cytochrome P450 in rat H540 Leydig tumor cells.

The rat H540 Leydig cell tumor has been shown to express cholesterol side-chain cleavage and 17alpha-hydroxylase cytochrome P450s, 3beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, and steroid 5alpha-reductase, making it a useful model in which to study steroidogenesis. In the current studies, we report that cultured H540 cells express high levels of aromatase cytochrome P450 (P450arom), which converts androgens to estrogens. Levels of aromatase activity varied from 9.4 to 51.7 pmol/h/mg protein and inhibition of 5alpha-reductase with finasteride did not significantly effect aromatase measurements, indicating that 5alpha-reductase is not competing for the substrate used in the aromatase assays. Aromatase activity was decreased 95% by preincubating the cells with 4-hydroxyandrostenedione, an aromatase inhibitor. Characterization of the aromatase mRNA expressed in the H540 cell line demonstrates that, like R2C cells and rat ovarian tissue, three distinct P450arom mRNA species are detected by Northern analysis, and that these transcripts are derived from the same site of transcription initiation. Despite these similarities, the regulation of aromatase activity by 8-bromo-cAMP in H540 cells differs from both R2C cells and rat ovarian tissue. As the H540 and R2C cell lines appear to have distinct origins, H540 is the second rat Leydig tumor cell line characterized that constitutively expresses high levels of aromatase.

8-Bromo Cyclic Adenosine Monophosphate↗