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PubMed1995

An overview of clinical cancer chemoprevention studies with emphasis on positive phase III studies.

Cancer prevention aims to halt or reverse the development and progression of precancerous cells through the use of noncytotoxic nutrients and/or pharmacologic agents during the lengthy time period between tumor initiation and frank malignancy. This paper reviews cancer chemoprevention studies and focuses on Phase III trials, which are large, randomized, placebo-controlled studies that usually last several years. Studies may include multiple agents and dose levels, long-term toxicity evaluations or the modulation of surrogate endpoint biomarkers. Sample sizes of individual studies vary depending on statistical concerns and the demographics of the subject population. Recent Phase III trials include several promising agents: retinol; the retinoids 13-cis retinoic acid, all-trans-retinoic acid and 4-hydroxyphenyl retinamide; beta-carotene; finasteride and tamoxifen. Because one of the many actions of retinoids is the induction of epidermal differentiation, clinical trials with this class of agents have largely been conducted in epithelial or squamous cell tumor types. Several Phase III studies that have targeted the reversal of premalignant lesions or the prevention of second primary tumors have shown promising positive results. In contrast, some studies have shown that chemopreventive agents may have limited activity against the recurrence or progression of cells that have already undergone malignant transformation. Thus, the role of chemoprevention appears to lie in reversal of the premalignant process rather than suppression of malignant growth.

Antineoplastic Agents↗
PubMed2004

Clinical trials in cancer prevention: current results and perspectives for the future.

Cancer prevention remains the ideal strategy for reducing the burden of cancer on society. Progress in cancer prevention has been accelerated as prevention clinical trials are completed and reported. A promising strategy is the identification of cancer risk factors through epidemiologic and experimental research with lifestyle and medical approaches that allow translation of clinical trial results to clinical practice. A major focus of cancer prevention clinical trials has been on modulation of hormones and nutritional modifications using natural or synthetic bioactive food components for breast and prostate cancer. Breast cancer prevention clinical trials have investigated the role of estrogen antagonists with agents such as tamoxifen, raloxifene, and newer agents such as aromatase inhibitors and bioactive food components. Among the promising bioactive food components being investigated at the National Cancer Institute in prevention clinical trials to reduce breast cancer risk are indole-3-carbinol, sulforaphanes, phytoestrogen isoflavones, perillyl alcohol, and green tea polyphenols. Prostate cancer prevention trials have focused on hormone modulation with the 5-alpha-reductase inhibitor finasteride and bioactive food components such as selenium and vitamin E. Soy isoflavones, green tea polyphenols, and doxercalciferol also are being investigated for prostate cancer prevention. Future prevention clinical trials will rely on multidisciplinary medical approaches that bring together expertise in many fields to address disease across the cancer spectrum. Nutritional science can play an important role in this effort through the use of new and emerging technologies to better understand the influence of bioactive food components on the genes, proteins, and cellular processes that are associated with cancer risk.

Breast Neoplasms↗
PubMed1997

Inhibition of rat prostate carcinogenesis by a 5alpha-reductase inhibitor, FK143.

BACKGROUND: Androgen levels in the prostate may influence carcinogenesis in this organ. Inhibitors of the enzyme 5alpha-reductase block conversion of testosterone to the more active androgen dihydrotestosterone. The use of a 5alpha-reductase inhibitor, finasteride, in the chemoprevention of prostate cancer is being evaluated in a clinical trial. PURPOSE: This study was conducted to determine if a 5alpha-reductase inhibitor, FK143, inhibits the development of prostate cancer in rats. METHODS: Male ACI/Seg rats, which spontaneously develop prostate cancer, were randomly assigned at 80 weeks of age to receive one of three diets (n = 35/group) containing 0 (i.e., control group), 20, or 200 ppm FK143. At 140 weeks of age, the animals were killed, and the prostates were removed and examined for histopathologic features in addition to being assayed for androgen concentrations. Two-sided statistical tests were used to calculate all P values. RESULTS: The incidence of prostate carcinoma in the control group was 62.9% (22 of 35 rats); in the group fed the 20 ppm FK143-containing diet, it was 45.7% (16 of 35); and in the group fed the 200 ppm FK143-containing diet, it was 67.6% (23 of 34) (overall, P = .153). The corresponding incidences of macroscopic lesions were 17.1% (six of 35 rats), 0% (none of 35), and 23.5% (eight of 34), respectively (overall, P = .004). The incidence of macroscopic lesions in the prostates of rats in the 20-ppm diet group was significantly lower than that in the control group (P = .029) or that in the 200-ppm diet group (P = .003). Intraprostatic dihydrotestosterone content was significantly lower in rats in the groups fed diets containing 20 or 200 ppm FK143 (mean values: 4.51 and 4.33 pg/mg wet weight of prostate tissue, respectively) than in the control group (6.10 pg/mg) (overall, P<.001); by contrast, testosterone was higher in the 200-ppm diet group (2.09 pg/mg) than in the control group (1.08 pg/mg) or the 20-ppm diet group (1.21 pg/mg) (overall, P<.001). CONCLUSIONS: FK143, when fed to rats at 20 or 200 ppm, significantly reduced the level of dihydrotestosterone in their prostate tissue. However, the incidence of macroscopic cancer in the prostate was suppressed in rats consuming the 20 ppm FK143-containing diet but not in those consuming the 200-ppm diet. The lack of dose dependence for the chemopreventive activity of FK143 may be explained by the reciprocal increase of tissue testosterone in the 200-ppm diet group. IMPLICATIONS: The 5alpha-reductase inhibitor FK143 may, at specific doses, reduce the incidence of spontaneously developing prostate cancer; however, whether these findings in rats will apply to humans remains to be determined.

5-alpha Reductase Inhibitors↗
PubMed2000

Cellular and molecular mechanisms of action of linuron: an antiandrogenic herbicide that produces reproductive malformations in male rats.

Antiandrogenic chemicals alter sex differentiation by several different mechanisms. Some, like flutamide, procymidone, or vinclozolin compete with androgens for the androgen receptor (AR), inhibit AR-DNA binding, and alter androgen-dependent gene expression in vivo and in vitro. Finasteride and some phthalate esters demasculinize male rats by inhibiting fetal androgen synthesis. Linuron, which is a weak competitive inhibitor of AR binding (reported Ki of 100 microM), alters sexual differentiation in an antiandrogenic manner. However, the pattern of malformations more closely resembles that produced by the phthalate esters than by vinclozolin treatment. The present study was designed to determine if linuron acted as an AR antagonist in vitro and in vivo. In vitro, we (1) confirmed the affinity of linuron for the rat AR, and found (2) that linuron binds human AR (hAR), and (3) acts as an hAR antagonist. Linuron competed with an androgen for rat prostatic AR (EC(50) = 100-300 microM) and human AR (hAR) in a COS cell-binding assay (EC(50) = 20 microM). Linuron inhibited dihydrotestosterone (DHT)-hAR induced gene expression in CV-1 and MDA-MB-453-KB2 cells (EC(50) = 10 microM) at concentrations that were not cytotoxic. In short-term in vivo studies, linuron treatment reduced testosterone- and DHT-dependent tissue weights in the Hershberger assay (oral 100 mg/kg/d for 7 days, using castrate-immature-testosterone propionate-treated male rats; an assay used for decades to screen for AR agonists and antagonists) and altered the expression of androgen-regulated ventral prostate genes (oral 100 mg/kg/d for 4 days). Histological effects of in utero exposure to linuron (100 mg/kg/d, day 14-18) or DBP (500 mg/kg/d, day 14 to postnatal day 3) on the testes and epididymides also are shown here. Taken together, these results support the hypothesis that linuron is an AR antagonist both in vivo and in vitro, but it remains to be determined if linuron alters sexual differentiation by additional mechanisms of action.

Abnormalities, Drug-Induced↗
PubMed2000

Rapid androgen actions on calcium signaling in rat sertoli cells and two human prostatic cell lines: similar biphasic responses between 1 picomolar and 100 nanomolar concentrations.

Androgen-induced calcium fluxes and gap junctional intercellular communication (GJIC) were studied in three different cell types. A transient (2-3 min duration) increase in intracellular calcium levels was observed within 20-30 sec of androgen addition, which was followed by a plateau phase with steroid concentrations higher than 1 nM. The kinetics of the calcium responses were similar in immature rat Sertoli cells, which contain normal nuclear receptors; the human prostatic tumor cell line, LNCaP, which contains a mutated nuclear receptor; and the human prostatic cell line, PC3, which does not contain a nuclear receptor. The human A431 tumor cell line did not respond to androgens. Concentrations of testosterone and the synthetic androgen, R1881, between 1-1000 pM induced transient calcium increases with ED(50) values near 1 pM and 1 nM, whereas dihydrotestosterone (DHT) was not active at these concentrations. At concentrations higher than 1 nM, testosterone, R1881, and DHT were equipotent in stimulating an increase in calcium that lasted for more than 10 min, with ED(50) values between 5 and 20 nM. Testosterone covalently bound to albumin was also active, whereas 11 related androstane compounds as well as progesterone and estradiol-17beta were inactive at 1000 nM. The calcium response induced by the three androgens (10 nM) was abolished in all cell types by hydroxyflutamide (1000 nM) and finasteride (1000 nM), but not by cyproterone acetate (1000 nM). The calcium response was also abolished in the absence of extracellular calcium and strongly inhibited by the presence of verapamil. Exposure of the responsive cells to brief (150-sec) pulses of androgens generated calcium responses that were similar to those after continuous exposure. After exposure of Sertoli cells for only 30 sec to 100 nM testosterone, the calcium response lasted for at least 50 min. Although nuclear binding of androgens could be demonstrated, there was no evidence for tight binding to the plasma membrane under similar conditions. When protein synthesis was inhibited, an enhancement of GJIC between rat Sertoli cells, but not between LNCaP cells or PC3 cells, was observed within 15 min of the addition of 10 nM testosterone. Because nuclear androgens are not present in PC3 cells and many functional properties of the responsive system are different from the nuclear receptor in all three cell types, we postulate the existence of an alternative cell surface receptor system with biphasic response characteristics (high and low affinity). The calcium signals are probably coupled to the regulation of gap junctional efficiency between Sertoli cells. The low-affinity receptors may convey complementary androgen signals at elevated local levels such as in the testis, when nuclear receptors are (over)saturated.

Androgen Antagonists↗
PubMed2004

Advances in prostate cancer.

PURPOSE OF REVIEW: The purpose of this review is to highlight the most important developments in the diagnosis, prevention, and management of prostate cancer reported in the past year that have been published in the medical literature. RECENT FINDINGS: Recent research has yielded important insights into the effects of lowering the serum prostate-specific antigen threshold for prostate biopsy on the incidence of prostate cancer and suggests that a cutoff value of 2.5 ng/mL would double the rate of diagnosis of the disease in young men. Other developments demonstrate that oral finasteride reduces the incidence of the disease but increases the proportion of high-grade tumors. The incidence of mutations of the androgen receptor gene has been shown to be lower than was previously thought. New randomized data suggest that for patients with high-risk localized prostate cancer treated with radiation, 4 months of androgen deprivation in combination with whole pelvis radiotherapy confers a clinical benefit. The clinical benefits associated with chemotherapy and supportive care therapies such as the bone targeting bisphosphonates continue to be refined. SUMMARY: The data reported in the past year have widespread implications for all clinicians involved in the management of prostate cancer, ranging from primary care physicians who screen for and diagnose the disease to those who manage localized as well as systemic disease. Several of the year's findings will result in significant changes in the manner in which the disease is treated.

Humans↗
PubMed1997

Resistance to apoptosis and up regulation of Bcl-2 in benign prostatic hyperplasia after androgen deprivation.

PURPOSE: Benign prostatic hyperplasia (BPH) is related to advancing age and the presence of androgens and occurs in virtually all older men. BPH causes morbidity, most often by urinary obstruction, in a substantial fraction of men over sixty. Both finasteride and androgen ablation induce partial diminution in BPH that occurs over weeks to months. This is in contrast to the often rapid involution seen in both normal prostatic epithelium and prostatic carcinoma in response to androgen withdrawal. This study was performed to analyze the response of prostatic cells, and in particular BPH, to acute androgen ablation. MATERIALS AND METHODS: We subjected a cohort of 26 men to androgen ablation with goserelin, a gonadotrophin releasing hormone agonist, for 3-4 weeks prior to radical prostatectomy for prostate cancer. Preablation biopsy specimens and prostatectomy specimens were immunohistochemically stained for apoptotic cells and for expression of apoptosis regulatory proteins Bcl-2, Bax, Bcl-x, and Bak. RESULTS: Normal prostatic epithelial cells and prostate cancer responded to hormone deprivation by undergoing apoptosis, but in 19/26 specimens prostatic hyperplasia had a total absence of apoptosis. In all 26 specimens, benign prostatic hyperplasia demonstrated increased expression of the Bcl-2 protein, but no change in the expression of Bax, Bcl-x, and Bak. In contrast, adjacent normal and malignant prostatic epithelium showed positive staining for apoptosis and did not alter Bcl-2 expression in response to androgen ablation. CONCLUSIONS: BPH demonstrated increased staining for Bcl-2 after androgen deprivation that may render hyperplastic epithelium relatively resistant to apoptosis induced acutely by androgen withdrawal.

Apoptosis↗
PubMed2000

Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II.

Human prostatic steroid 5alpha-reductase, encoded by the SRD5A2 gene on chromosome band 2p23, catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH as its cofactor. This enzyme has never been purified but a number of competitive inhibitors have been developed for this enzyme since increased steroid 5alpha-reductase activity may cause benign prostatic hypertrophy and prostate cancer. We report here the detailed biochemical and pharmacogenetic dissection of the human enzyme by analysing 10 missense substitutions and three double mutants which are all naturally found in humans. Nine of these 13 mutants reduce activity (measured as Vmax) by 20% or more, three increase steroid 5alpha-reductase by more than 15% and one results in essentially unaltered kinetic properties suggesting that it is a truly neutral ('polymorphic') amino acid substitution. Substantial pharmacogenetic variation among the mutants was also observed when three competitive inhibitors, finasteride, GG745 (dutasteride) and PNU157706, were investigated. Our studies not only define the substrate and cofactor binding sites of human steroid 5alpha-reductase, but also have significant consequences for the pharmacological usage of steroid 5alpha-reductase inhibitors in human patients treated for prostatic conditions.

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

5alpha-reductase 2 polymorphisms as risk factors in prostate cancer.

Prostate cancer is a significant cause of death in Western countries and is under the strong influence of androgens. The steroid 5alpha-reductase 2 catalyzes the metabolism of testosterone into the more potent androgen dihydrotestosterone in the prostate gland. The enzyme is a target in pharmacological treatment of benign prostatic hyperplasia using specific inhibitors such as finasteride. Makridakis et al. have characterized the V89L and A49T polymorphisms in recombinant expression systems. The L allelic variant has a lower Vmax/Km ratio than the V variant. In the A49T polymorphism, the T variant has an increased Vmax/Km ratio. We performed a population-based case-control study of the impact of the SRD5A2 V89L and A49T polymorphisms on the risk of prostate cancer. We also studied the relation between the genotypes and age at diagnosis, tumor, node, metastasis stage, differentiation grade, prostate specific antigen and heredity. The study included 175 prostate cancer patients and 159 healthy controls that were matched for age. There was an association with SRD5A2 V89L LL genotype and metastases at the time of diagnosis, OR 5.67 (95% CI 1.44-22.30) when adjusted for age, differentiation grade, T-stage and prostate specific antigen. Heterozygous prostate cancer cases that carried the SRD5A2 A49T AT genotype were significantly younger than cases that carried the AA genotype, (mean age 66 years vs 71, P = 0.038). The SRD5A2 V89L and A49T polymorphisms were, however, not associated with altered prostate cancer risk. Further studies of the V89L polymorphism may lead to better understanding of the etiology of prostate cancer metastases.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1999

Alternative methods for management of prostatic outflow obstruction.

During the past year no new therapies for prostatic outflow obstruction were introduced. Instead, research focused on refinement of treatments previously available. Further reports on the efficacy and safety of alpha 1-adrenergic receptor subtype selective agents have appeared. The long-term effects of finasteride on the natural history bladder outflow obstruction have become clearer. The clinical efficacy of device therapy has evolved, and information regarding intermediate-term outcomes is now available.

Drug Therapy↗
PubMed2004

Real life practice in the management of benign prostatic hyperplasia.

PURPOSE OF REVIEW: To review the current diagnostic and treatment options of lower urinary tract symptom due to benign prostatic hyperplasia and to put data from real life practice into perspective. RECENT FINDINGS: The overall incidence rate of lower urinary tract symptom/benign prostatic hyperplasia was found at 15 per 1000 man-years (95% CI 14.8-16.1). The incidence increases with age from 3/1000 man-years at 45-49 years to 38/1000 man-years at 75-79 years. Recent diagnostic studies include the use of PSA to estimate prostate volume and its predictive value for the long-term risk of prostate enlargement. Variability of the International Prostate Symptom Score when filled at home and in the hospital is discussed. The first-line treatment option remains medical therapy. The most prescribed alpha-blockers are terazosin, alfuzosin, and tamsulosin, which are comparable in efficacy. The efficacy of finasteride is also confirmed, especially for enlarged prostates with the possibility of volume reduction up to 30%. Interventional therapy begins when there is evidence of moderate to severe symptoms. Long term results put transurethral microwave thermotherapy in advantage over other minimally invasive modalities. Surgical treatment remains the procedure with the best results. Open prostatectomy is still indicated for severely enlarged prostates. Transurethral resection for medium-sized prostates and bladder-neck incision for small prostates also remain the best option. SUMMARY: Real life practice studies in the last few years have broadened our insight into the application of different diagnostic and treatment modalities. Since results from randomized controlled trials can not always be extrapolated to daily urological practice, real life practice studies made data available to complement data from randomized controlled trials.

Aged↗
PubMed2005

Role of phytotherapy in men with lower urinary tract symptoms.

PURPOSE OF REVIEW: Serenoa repens extract is a popular phytotherapeutic agent in men with lower urinary tract symptoms. Although the exact mechanism of action is unknown, the agent is generally well accepted for its easy availability and good tolerability. This paper reviews the evidence of its efficacy in comparison with placebo, 5-alpha reductase inhibitor and alpha-1 adrenoreceptor antagonist. RECENT FINDINGS: Serenoa repens extract is comparable with 5-alpha reductase (finasteride) and alpha-1 antagonist in the treatment of benign prostatic hyperplasia in terms of symptom score and peak urinary flow rate improvement, but has a lower incidence of associated sexual dysfunction. Furthermore, long-term usage (36 months) of Serenoa repens decreases the progression rate of the condition as compared with watchful waiting. In addition, the efficacies of Serenoa repens are proven in several placebo-controlled trials. SUMMARY: Serenoa repens has proven its role in the management of benign prostatic hyperplasia and will remain as a viable first-line treatment option.

5-alpha Reductase Inhibitors↗
PubMed2003

5alpha-reductase type 1 immunostaining is enhanced in some prostate cancers compared with benign prostatic hyperplasia epithelium.

PURPOSE: In the prostate testosterone is converted to the more potent androgen dihydrotestosterone by the enzymes 5alpha-reductase (5alphaR) types 1 (5alphaR1) and 2 (5alphaR2). Since 5alphaR2 is the dominant prostatic enzyme, the 5alphaR2 selective inhibitor finasteride has been widely used to treat benign prostatic hyperplasia (BPH). However, inhibition of both 5alphaR enzymes provides a greater decrease in serum dihydrotestosterone. We developed a specific antibody to 5alphaR1 and assessed expression in BPH and prostate cancer (pCa) tissue. The presence of this isoenzyme in localized prostate cancer would provide a rationale for assessing the efficacy of dual inhibition for prostate cancer prevention. MATERIALS AND METHODS: A polyclonal antibody to 5alphaR1 was developed and validated using 5alphaR1 and 5alphaR2 transfected COS-1 cells. A total of 26 BPH and 53 pCa specimens were assessed for 5alphaR1 protein expression using immunocytochemical methods. Also, 29 BPH and 37 pCa specimens were assayed for 5alphaR1 and 5alphaR2 enzyme activity. RESULTS: Specificity of the 5alphaR1 antibody was confirmed using transfected COS-1 cells. Cells transfected with 5alphaR1 showed specific staining in immunocytochemistry experiments and on Western blotting of cell lysates the expected 24 kDa band was observed. High intensity immunoreactivity for 5alphaR1 was observed in the tumor epithelium of 28% of pCa specimens. No high intensity epithelial staining was observed in BPH specimens. In 19% of pCa and 7% of BPH specimens 5alphaR1 enzyme activity was detected. CONCLUSIONS: The presence of increased 5alphaR1 in some prostatic malignancies suggests that it is worthwhile to investigate the use of a dual 5alphaR inhibitor to prevent or treat early stage prostate cancer.

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

Prostate cancer chemoprevention: an overview of United States trials.

PURPOSE: We review the current status of clinical trials investigating the use of interventions designed to reduce the risk of prostate cancer. MATERIALS AND METHODS: A comprehensive review of the literature was conducted, which included the Ovid database and recent abstract proceedings from national meetings relevant to chemoprevention trials in prostate cancer. All clinical trials sponsored by the National Institutes of Health and National Cancer Institute in the United States were included. RESULTS: A total of 11 randomized controlled trials were found to be currently recruiting patients in the United States. These randomized controlled trials are designed to investigate the efficacy of a variety of agents ranging from dietary supplements to laboratory manufactured drugs, such as finasteride and cyclooxygenase-2 inhibitors, for the primary chemoprevention of prostate cancer. CONCLUSIONS: Chemoprevention of prostate cancer is currently being tested in a wide range of clinical trials. These studies have the potential to fundamentally alter the current approach to prostate cancer management.

Animals↗
PubMed2004

Statistical design issues and other practical considerations for conducting phase III prostate cancer prevention trials.

PURPOSE: We briefly describe the purpose of phase II studies as a source of preliminary data for phase III prevention trials, and address statistical and other practical considerations for phase III prostate cancer prevention trials. MATERIALS AND METHODS: Objectives of 2 types of phase II studies and general criteria for validating surrogate end points are described, and statistical considerations needed for planning a phase III prevention trial are explained, including selection of an appropriate study population and end point, the corresponding expected event rate, estimates of loss to followup, and death and compliance rates. If a preventive agent has an impact on the ability to detect prostate cancer, additional study design considerations are then made. Other practical issues are addressed, including collection of biological materials for correlative studies, assessment of quality of life measures and the addition of ancillary studies that may include the collection of additional end points unrelated to prostate cancer. RESULTS: The Southwest Oncology Group is coordinating 2 recently reported phase III prostate cancer prevention trials. The Prostate Cancer Prevention Trial final results of 18,882 men randomized to either finasteride or placebo, and the Selenium and Vitamin E Cancer Prevention Trial has accrued more than half of its goal of 32,400 men. These studies are used to illustrate some statistical design features. CONCLUSIONS: The aforementioned trials provide valuable lessons in the successful design and conduct of phase III prostate cancer prevention trials.

Anticarcinogenic Agents↗
PubMed2005

The relationship among lower urinary tract symptoms, prostate specific antigen and erectile dysfunction in men with benign prostatic hyperplasia: results from the proscar long-term efficacy and safety study.

PURPOSE: We evaluated the associations among lower urinary tract symptoms, prostate specific antigen (PSA) and erectile dysfunction (ED) in men with benign prostatic enlargement enrolled in the Proscar (Merck, Whitehouse Station, New Jersey) Long-Term Efficacy and Safety Study. MATERIALS AND METHODS: The Proscar Long-Term Efficacy and Safety Study was a 4-year, randomized, double-blind, placebo controlled study that enrolled 3,040 men with moderate to severe lower urinary tract symptoms and an enlarged prostate gland. Two questions assessed ED. A logistic regression model, including the effect of patient age, was used to examine the relationships among quasi-American Urological Association Symptom Score (AUASS), PSA, and ED at baseline. Changes in ED scores from baseline to study closeout were analyzed with ANOVA. RESULTS: A total of 2,981 patients had baseline data available for analysis. Mean age was 64 years, mean quasi-AUASS was 15, mean PSA was 2.8 ng/ml and mean prostate volume was 55 cm. At baseline every 1 point increase in quasi-AUASS was associated with a 2% increased risk of ED even after controlling for age (p <0.001). At 48 months in placebo but not in finasteride treated men a 1-unit decrease in quasi-AUASS was associated with a slight but statistically significant decrease in ED. No association existed between increasing PSA and ED on baseline or longitudinal analysis. CONCLUSIONS: We found a moderately strong association between baseline quasi-AUASS and the ED rate in men with an enlarged prostate, a finding that was supported by longitudinal data in the placebo arm. The absence of a relationship between PSA and ED highlights the need for further investigation into the mechanisms of benign prostatic hyperplasia related sexual dysfunction.

Aged↗
PubMed1995

Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin.

The presence of 5 alpha-reductase (5 alpha-R) in skin may indicate that the androgen regulation of sebaceous glands and sebum production requires the local conversion of testosterone to dihydrotestosterone. The goals of this study were to identify which isozyme of 5 alpha-R (type 1 or type 2) is expressed in sebaceous glands from facial areas, scalp, and non-acne-prone areas; to determine if 5 alpha-R activity is concentrated in sebaceous glands; to assess whether there are regional differences in this enzyme's activity; and to test the effects of azasteroid inhibitors and 13-cis retinoic acid on 5 alpha-R in these tissues. Sebaceous glands were microdissected from facial skin, scalp, and non-acne-prone skin (arm, breast, abdomen, leg), and the activity of 5 alpha-R was determined. A total of 49 samples from 23 male and 21 female subjects without acne (age range, 16 to 81 years, 56 +/- 20 years [mean +/- SD]) was analyzed. The biochemical properties of the enzyme in each of the samples tested are consistent with those of the type 1 5 alpha-R. Minimal to no type 2 5 alpha-R was detected. The level of 5 alpha-R activity was significantly higher in the sebaceous glands compared to whole skin in facial skin (p = 0.047), scalp (p = 0.039), and non-acne-prone skin (p = 0.04). Enzyme activity in sebaceous glands from facial skin and scalp was significantly higher than in a comparable amount of sebaceous gland material obtained from non-acne-prone areas (32 +/- 6 [mean +/- SEM]), 35 +/- 7 (mean +/- SEM) versus 6.0 +/- 3.0 (mean +/- SEM) pmol/min/mg protein, p = 0.014 and 0.007, respectively). Finasteride and 13-cis retinoic acid were poor inhibitors of the enzyme with 50% inhibitory concentration values greater than 500 nM. These data demonstrate that in the skin from older patients without acne the type 1 isozyme of 5 alpha-R predominates, its activity is concentrated in sebaceous glands and is significantly higher in sebaceous glands from the face and scalp compared to non-acne-prone areas, and the action of 13-cis retinoic acid in the control of acne is not at the level of 5 alpha-R. Furthermore, we suggest that specific inhibition of the type 1 5 alpha-R may offer a viable approach to the management of sebum production and, hence, acne.

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

Testosterone therapy in the ageing male: what about the prostate?

The concerns about testosterone therapy in ageing men with late-onset hypogonadism mainly address the risk of prostatic disease, i.e. either benign prostatic hyperplasia (BPH) or prostate cancer (PCa). Both conditions are highly dependent on androgen action and recent clinical data on the cancer-preventive effect of the 5alpha-reductase inhibitor finasteride have supported the possible role of androgens in PCa. However, the clinical data especially on the long-term effects of exogenous androgen substitution in regard to prostate safety are nonconclusive in many respects. As sufficient clinical studies on these risks will not be available in the near future, the approach of testosterone therapy towards prostate complications should be kept on a safe but practical basis. This review includes some recommendations in regard to testosterone therapy and prostate monitoring in patients with BPH and bladder outlet obstruction, with previous history of curative treatment for PCa or with prostatic intraepithelial neoplasia.

Humans↗