Long-term adherence to topical psoriasis treatment can be abysmal: a 1-year randomized intervention study using objective electronic adherence monitoring.

BACKGROUND: Most people with psoriasis have limited disease that could be treated with topicals, but topical efficacy is limited by low short-term adherence. Psoriasis is a chronic disease, and long-term adherence is an even bigger problem. OBJECTIVES: To determine how well medication is used in the long-term topical treatment of psoriasis and to assess the potential of an internet-based reporting intervention to improve treatment adherence and outcomes. METHODS: An investigator-blinded, prospective study evaluated topical fluocinonide adherence in 40 patients with mild-to-moderate psoriasis over 12 months. Subjects were randomized in a 1 : 1 ratio to standard-of-care or internet-based reporting group. Adherence was objectively monitored with Medication Event Monitoring System® caps. RESULTS: Fifty per cent of subjects discontinued the treatment. Greater adherence was seen in the intervention group compared with the standard-of-care group (50% vs. 35%, P = 0·08). Psoriasis Area and Severity Index improved more in the intervention group at month 1 (1·61 vs. -0·12, P = 0·003), month 3 (2·50 vs. 0·79, P = 0·025) and month 12 (3·32 vs. 0·34, P = 0·038) than in the standard-of-care group. CONCLUSIONS: This study likely underestimates the challenge of long-term adherence, as adherence tends to be better in research studies than in clinical practice. This study also did not fully account for primary nonadherence. Adherence to topical treatment is low in the short term and decreased further in the long term, a considerable challenge for dermatologists to address. A reporting intervention may be one of the ways we can improve our patients' treatment outcomes.

Effect of frequency on entrance and propagation pattern of high-frequency (radiofrequency) electrical currents in biologic tissues.

BACKGROUND: Radiofrequency electrical currents have a tendency to move toward the center of the bulk of biologic tissues. OBJECTIVES: To evaluate the effect of the frequency of currents on their entrance and propagation pattern in biologic tissues. MATERIALS AND METHODS: Three electrosurgical generators with 0.4, 1.5, and 3 MHz frequency outputs were studied. Current was applied using a metallic needle introduced into a piece of cow liver, with different amounts of energy delivered at multiple points. Cross-sections of the liver were then studied for tissue effect. The diameters of the coagulated areas at the deepest and most superficial parts were measured. The tendency of the currents for penetration in the deeper layers of tissue rather than in the superficial layers was assessed using the superficial diameter/deep diameter ratio. RESULTS: Diameter of coagulated area was larger around deeper parts than around superficial parts of the electrode. No correlation between frequency of current and the superficial/deep diameter ratio of the coagulation zone was found. CONCLUSION: Radiofrequency currents have a tendency to move toward the center of the tissue. Frequency of current over the range of 0.4-3 MHz did not show any effect on this tendency.

Oncology in midlife and beyond.

The onset of the menopause is often a time when women's concerns can act as a powerful trigger to encourage healthy modifications in lifestyle which will maintain, or improve, their general health. This document aims to help women to understand their potential risks, to encourage them to find proactive preventive strategies by modifying some of their attitudes, and to use health resources (when available) to be screened. Cancer is an important cause of death but not the primary cause of mortality. Cardio/circulatory diseases represent 35-40% of causes of death in most developed countries and 20-25% of women will die from cancers in Western Europe, Australasia, high-income North America, high-income Asia Pacific, East Asia and Southern Latin America. Breast cancer, lung cancer and colorectal cancer are prevalent in most regions of the world. Cervical cancer remains a hallmark of low access to health care. Preventive strategies (decreasing smoking and alcohol consumption, losing weight, eating a healthy diet and undertaking physical activity) and implementation of screening could help to significantly decrease the incidence of and mortality from cancer. The mortality/incidence ratio is higher in developing countries compared to high-income regions as well as in subgroups of populations in developed countries with lower socioeconomic levels. Implementation of better diagnostic methods and management of cancer according to the local resources will help to decrease the mortality rate in developing countries, and effort has to be made to decrease social inequities and improve access to health care for low-income groups. In conclusion, cancer incidence is increasing as a consequence of longer life expectancy all over the world. National health programs are mandatory to implement screening and to improve individual management. Finally, educating women so that they are aware of ways to improve their general health, to minimize their own risk factors and to identify signs of change in their own health which may be markers of impending cancer will help to reduce the burden of disease and improve the prognosis for tumors detected at an earlier stage.

Androgen receptor inclusions acquire GRP78/BiP to ameliorate androgen-induced protein misfolding stress in embryonic stem cells.

Commitment of differentiating embryonic stem cells (ESCs) toward the various lineages is influenced by many factors, including androgens. However, the mechanisms underlying proteotoxic stress conferred by androgen receptor (AR) actions on embryonic cell fate remains unclear. Here we show that mouse ESCs display stress-related cellular phenotypes in response to androgens during early phase of differentiation. Androgen induced a significant increase in the percentage of ESCs and embryoid bodies with the intranuclear and juxtanuclear AR inclusions, which were colocalized with the E3 ubiquitin ligase, C terminus of Hsc70-interacting protein. Caspase-3 activity corresponded with AR expression, was enhanced in cells engaged more differentiation phenotypes. Androgen-mediated accumulation of AR aggregates exacerbated endoplasmic reticulum (ER) stress and rendered ESCs susceptible to apoptosis. Increasing expression levels of the ER chaperones, GRP78/BiP and GRP94, as well as ER stress markers, such as ATF6, phosphorylated PERK, GADD153/CHOP and spliced XBP-1 mRNA, were dramatically elevated in ESCs overexpressing AR. We found that androgen induced GRP78/BiP to dissociate from ATF6, and act as an AR-interacting protein, which was recruited into AR inclusions in ESCs. GRP78/BiP was also colocalized with AR inclusions in the cells of spinal bulbar muscular atrophy transgenic mouse model. Overexpression of GRP78/BiP suppressed ubiquitination of AR aggregates and ameliorated the misfolded AR-mediated cytopathology in ESCs, whereas knockdown of GRP78/BiP increased the accumulation of AR aggregates and significantly higher levels of caspase-3 activity and cell apoptosis. These results generate novel insight into how ESCs respond to stress induced by misfolded AR proteins and identify GRP78/BiP as a novel regulator of the AR protein quality control.

Risk of refracture associated with compliance and persistence with bisphosphonate therapy in Taiwan.

SUMMARY: Bisphosphonates have been used for the treatment of postmenopausal osteoporosis since the early 1990s and studies show that compliant patients experience a lower fracture rate. This cohort study showed that the compliance of Taiwanese patients was poor and the refracture risk was related to compliance with bisphosphonate therapy. INTRODUCTION: Bisphosphonates are potent inhibitors of osteoclast activity, and reduce bone turnover by inhibiting bone resorption. According to Taiwanese reimbursement guidelines, patients with osteoporosis-related fractures are eligible for bisphosphonate treatment. This study aimed to elucidate the relationship of refracture risk with compliance/persistence with bisphosphonate therapy in Taiwan. METHODS: This was a retrospective, administrative, database analysis measuring the adherence status and impact of poor adherence to bisphosphonate therapy in Taiwan. Study data derived from the National Health Insurance Research Database (NHIRD) were used to assemble a cohort of all osteoporosis patients who initiated bisphosphonate treatment between January 1, 2004, and December 31, 2005. Patients were followed until death, end of registration in NHIRD, or end of study period (December 31, 2006), whichever occurred first. Compliance was calculated as medication possession ratio (MPR; sum of days of supply of osteoporosis medications divided by follow-up duration). RESULTS: The refracture rates for osteoporosis patients were 5.15 %, 7.36 %, and 8.49 % in the first, second, and third year, respectively, and were significantly lower for patients with >80 % compliance than with <80 % compliance (p < 0.05). Nearly 50 % patients were noncompliant (MPR < 80 %) at 3 months, and only around 30 % patients were adherent at 1 year. Refracture risk increased with MPR < 80 %, age, and co-morbidities like diabetes mellitus or dementia. Patients with concomitant statin medication had significantly lower refracture risk. CONCLUSIONS: The compliance of Taiwanese patients with osteoporosis medication is poor, and refracture risk is related to compliance with bisphosphonate therapy.

Evidence-based assessment of the impact of the WHI on women's health.

Following the announcement of the first results of the Women's Health Initiative (WHI) to the media in 2002, prior to their scientific publication, the resulting panic headlines had an immediate and lasting negative effect on use of menopausal hormone replacement therapy (HRT) around the world. Rates of use dropped by 40-80%. Symptomatic women then sought multiple alternative therapies but the majority of these have no greater effect than the effect seen from placebo in well-conducted trials of HRT. Some of these therapies have risks. Although anecdotally most menopause practitioners after 2002 can attest to having to counsel large numbers of women with debilitating menopausal symptoms who were too frightened to consider HRT, it is difficult to document loss of health-related quality of life in large population studies as they were not conducted. Similarly, the positive or negative effects of the marked decline in HRT on long-term morbidities and mortality have yet to be fully assessed. Recent studies have shown an increase in postmenopausal fractures and in some, but not all, populations a small temporary decline in breast cancer. Cardiovascular outcomes may not be apparent for another decade. Short-term, randomized, placebo-controlled trials confirm that HRT is the only therapy that effectively improves health-related quality of life in symptomatic women through a reduction in vasomotor and urogenital symptoms, joint pains and insomnia, while improving sexuality. The results of the re-analyses of the WHI data and new data from other studies do not justify the continuing negative attitude to HRT in symptomatic women who start HRT near menopause.

The assessment of efficacy of Diascorea alata for menopausal symptom treatment in Taiwanese women.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of Diascorea alata for treatment of menopausal symptoms. MATERIALS AND METHODS: Two-center, randomized, double-blind, placebo-controlled clinical investigation on 50 menopausal women randomly assigned to two groups, treated for 12 months with either placebo or two sachets daily of Diascorea extracts containing 12 mg/sachet. Primary outcome measures were changes in the Greene Climacteric Scale caused by Diascorea compared with placebo; secondary outcomes were changes in plasma hormone profiles. One-way ANCOVA test was performed to investigate the significance. RESULTS: At 6 months and at the end of treatment, those women who received Diascorea showed general improvement in almost all the clinical symptoms investigated. A significant reduction was noted in the total Greene scores in the Diascorea group assessed at the end of 12 months' treatment (p < 0.01). This phenomenon was more significant for the psychological parameters of anxiety than for other parameters. Apparent improvements were noted in the parameters 'feeling tense or nervous' (p = 0.007), 'insomnia' (p = 0.004), 'excitable' (p = 0.047) and 'musculoskeletal pain' (p = 0.019) among those receiving Diascorea. Diascorea consumption also resulted in positive effects on blood hormone profiles. CONCLUSIONS: Compared with placebo, Diascorea alata improves symptoms, particularly the psychological parameters in menopausal women. Safety monitoring indicated that standardized extracts of Diascorea alata were safe during daily administration over a period of 12 months.

Updated clinical recommendations for the use of tibolone in Asian women.

Tibolone, which is indicated for the relief of climacteric symptoms and the prevention of osteoporosis in postmenopausal women, has a tissue-specific mode of action different to that of conventional hormone replacement therapy (HRT). A large proportion of Asian postmenopausal women experience symptoms that most frequently include musculoskeletal pain, insomnia, forgetfulness, hot flushes and sexual dysfunction, and there is a need to address their specific requirements. Recent studies show that, in comparison to HRT, tibolone is as effective in alleviating menopausal symptoms and preventing bone loss, has a greater positive effect on sexual dysfunction and is associated with less vaginal bleeding, but it is rarely mentioned in guidelines for menopausal treatment. Levels of awareness amongst women about treatments for menopausal symptoms vary between Asian countries but, even in countries where awareness is high, HRT usage is much lower than in the West. To provide a practical approach to the use of tibolone in Asian postmenopausal women, a panel of experts in the management of menopause from 11 Asia Pacific countries has developed recommendations for its use, based on the evidence from clinical studies published since 2005. However, as much of the clinical data reviewed are from international studies, the recommendations and the treatment algorithm presented here are widely applicable.

Guidelines for hormone replacement therapy of Asian women during the menopausal transition and thereafter.

These Guidelines summarize the position of an Expert Panel on Menopause in Asian Women regarding the use of hormone replacement therapy (HRT) during the menopausal transition and thereafter. They are intended to aid gynecologists, family physicians and other health-care professionals in providing optimal care to menopausal Asian women who desire HRT.

Flow resistance in carotid and middle cerebral arteries in postmenopausal women: a comparative study of tibolone and continuous combined hormone replacement therapy.

OBJECTIVE: The study sought to compare the vascular resistance and serum lipids of postmenopausal women assigned to tibolone therapy or continuous combined hormone replacement therapy. DESIGN: This was a 6-month, prospective, single-blind, single-center, randomized study. A total of 50 healthy postmenopausal women were enrolled. At study end, 40 women had completed a 6-month follow-up. The first group (23 subjects) received conjugated equine estrogens (CEE) 0.625 mg/day and medroxyprogesterone acetate (MPA) 5 mg/day. The second group (17 subjects) received tibolone 2.5 mg/day. The pulsatility and resistance indexes of the carotid and middle cerebral arteries, and serum lipid profiles were monitored. RESULTS: Comparisons demonstrated that there were no significant differences between the groups in terms of changes in the pulsatility index (PI) and the resistance index (RI) of the common carotid artery (CCA), internal carotid artery (ICA), and middle cerebral artery (MCA) within the study period. Both treatments effectively reduced the total cholesterol level and with no significant differences found between the two regimens. However, in comparing the two groups, we found that high-density lipoprotein (HDL) cholesterol levels were significantly lower in the tibolone group at either 3 months or 6 months after treatment, whereas a significantly higher triglycerides level was observed in the CEE + MPA group after 3 months of treatment. Low-density lipoprotein (LDL) cholesterol levels indicated no significant differences between the two groups after treatment. CONCLUSIONS: The study demonstrated that major neck and cerebral vascular impedance was not influenced significantly by either regimen. Nonetheless, lipid profiles were affected differently by tibolone and by continuous combined CEE + MPA. However, whether or not these findings might modify cardiovascular risk is still unknown.

Short- and long-term effects of hormone replacement therapy on cardiovascular risk factors in postmenopausal women.

BACKGROUND: The beneficial effect of hormone replacement therapy (HRT) on cardiovascular disease has been documented in postmenopausal women, but has a significant time trend. Thus, it is worthwhile to further study whether there are different effects on cardiovascular factors between short- and long-term use of HRT. METHOD: Prospective study of the changes on lipoprotein profile, hemostatic factors, and platelet aggregation was evaluated in 21 postmenopausal women receiving oral E2 valerate (2 mg/d) combined with medroxyprogesterone acetate (10 mg/d) during the last 10 days of each 21-day cycle. The treatment period was 24 months. RESULTS: During the 24 months of treatment, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and atherogenic indices- total cholesterol-to-high-density lipoprotein cholesterol (HDL-C) and LDL-C-to-HDL-C, were significantly reduced. The concentrations of tissue plasminogen activator and plasminogen activator inhibitor-1 were significantly reduced after 12 months of HRT. In addition, the concentrations of antithrombin III were significantly increased, but protein S was statistically decreased during the 18 months of HRT. The maximum aggregation and slope of platelet aggregation were significantly reduced only during the first 12 months of HRT. CONCLUSION: This study demonstrates that there were some differences in cardiovascular risk factors between short- and long-term HRT, especially in changes in platelet aggregation and hemostatic factors. However, the long-term favorable effect on lipoprotein metabolism and fibrinolytic activity among hormone users may explain, in part, the inverse association between HRT and cardiovascular disease.

Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors.

OBJECTIVE: To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women. DESIGN: Twenty subjects were treated with oral E2 valerate (2 mg) combined with cyproterone acetate (1 mg) (group I) and 21 with transdermal E2 (1.5 mg) plus oral medroxyprogesterone acetate (5 mg) (group II). The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3, 6, and 12 months of treatment. RESULTS: Group I showed a stronger increase of high-density lipoprotein (HDL) cholesterol levels (2-8%) and stronger reduction of atherogenic indices (total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol) than group II. Group II showed a more pronounced reduction of triglyceride (21-31%) and factor VII (6-10%) levels than group I. Both groups showed reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, and protein S, whereas protein C was increased after 12 months of treatment. CONCLUSIONS: The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity. Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration, but transdermal medication had a stronger effect on triglyceride and coagulation factors. However, it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment.

From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells.

Although transforming growth factor-beta (TGF-beta) has been identified to mainly inhibit cell growth, the correlation of elevated TGF-beta with increasing serum prostate-specific antigen (PSA) levels in metastatic stages of prostate cancer has also been well documented. The molecular mechanism for these two contrasting effects of TGF-beta, however, remains unclear. Here we report that Smad3, a downstream mediator of the TGF-beta signaling pathway, functions as a coregulator to enhance androgen receptor (AR)-mediated transactivation. Compared with the wild-type AR, Smad3 acts as a strong coregulator in the presence of 1 nM 5alpha-dihydrotestosterone, 10 nM 17beta-estradiol, or 1 microM hydroxyflutamide for the LNCaP mutant AR (mtAR T877A), found in many prostate tumor patients. We further showed that endogenous PSA expression in LNCaP cells can be induced by 5alpha-dihydrotestosterone, and the addition of the Smad3 further induces PSA expression. Together, our findings establish Smad3 as an important coregulator for the androgen-signaling pathway and provide a possible explanation for the positive role of TGF-beta in androgen-promoted prostate cancer growth.

Quality of life and sexuality changes in postmenopausal women receiving tibolone therapy.

OBJECTIVE: The goal of this study was to investigate the effects of hormone replacement therapy (HRT) and tibolone on the sexuality and quality of life of Taiwanese postmenopausal women. METHODS: Forty-eight postmenopausal women were enrolled and prospectively randomized to receive either HRT or tibolone for 3 months. At the end of the 3-month period, quality of life measures were assessed using the Greene Climacteric Scale and attitudes of sexuality were evaluated using the McCoy Sex Scale. RESULTS: Based on subjective qualitative scores, tibolone treatment was at least as effective as continuous combined HRT in improving quality of life. It also effectively prevented withdrawal bleeding, which may occur during HRT use. Compared with continuous combined HRT, tibolone treatment was also associated with perceived improvement of sexual performance, including general sexual satisfaction, sexual interest, sexual fantasies, sexual arousal and orgasm, with decreased frequencies of vaginal dryness and painful intercourse. CONCLUSIONS: The findings of this study indicate that both tibolone and continuous combined HRT have positive effects on the quality of life of Taiwanese postmenopausal women. Sexuality is affected more by tibolone than by HRT.

Raloxifene versus continuous combined estrogen/progestin therapy: densitometric and biochemical effects in healthy postmenopausal Taiwanese women.

We treated 116 healthy postmenopausal women (age 47-66 years, mean 57 years) in Taiwan with either raloxifene (RLX) 60 mg (n = 92) or 0.625 mg conjugated equine estrogen plus 5 mg medroxyprogesterone acetate (CCEP, n = 24) daily for 12 months in a randomized, double-masked, active-controlled fashion. The results showed that both regimens increased bone mineral density (BMD) at hip sites (means: RLX 2.5-4.9%, CCEP 4.6-7.9%, all p<0.005 compared with baseline), and the difference between the two regimens was not significant. The spinal BMD increased significantly in both groups (1.4% with RLX and 6.0% with CCEP, both p<0.01), and more with CCEP (p<0.003). Osteocalcin levels and urinary type I collagen C-telopeptide/creatinine ratios decreased significantly in both regimens, but the decreases were significantly larger with CCEP. Compared with baseline, both RLX and CCEP decreased the total cholesterol (median 4.9% and 8.6% respectively, p<0.001) and LDL-cholesterol (median 11% and 19% respectively, p<0.001), and increased HDL-cholesterol (median 8.6% and 10.7% respectively, p<0.01). Both regimens increased triglyceride levels (median 3.2% and 18.9% respectively, both p<0.05), although to a lesser extent with RLX than with CCEP (p<0.05). Only 3 subjects (3.3%) reported vaginal bleeding in the RLX group, as compared with 31% (7/22) with CCEP (p<0.05). We conclude that in healthy, postmenopausal Taiwanese women, RLX 60 mg given daily has favorable results in BMD, bone turnover and serum lipids, although the dosage we used showed a potency less than that of conventional CCEP.

Percutaneous epididymal sperm aspiration versus microsurgical epididymal sperm aspiration for irreparable obstructive azoospermia--experience with 100 cases.

PURPOSE: This study investigated the sperm retrieval success rates, fertilization rates, pregnancy rates, and complications of percutaneous epididymal sperm aspiration (PESA) and microsurgical epididymal sperm aspiration (MESA) in cases of irreparable obstructive azoospermia. METHODS: During a period of 36 months, 100 men with irreparable obstructive azoospermia underwent 109 cycles of sperm retrieval procedures and intracytoplasmic sperm injection (ICSI). We routinely performed PESA first in each retrieval cycle; MESA and/or testicular sperm extraction (TESE) were performed if PESA failed. The sperm retrieval success rates, mean fertilization rates, and pregnancy rates of PESA and MESA were evaluated. RESULTS: PESA was performed in all 109 retrieval cycles with a successful sperm retrieval rate of 61%. When PESA failed to retrieve a sufficient number of viable sperm, MESA was subsequently performed with a sperm retrieval rate of 93%. Three cases, which had failed retrieval with both the PESA and MESA procedures, received TESE successfully. The rates of fertilization and pregnancy were 56% and 39% in the 66 PESA-ICSI cycles, respectively, and 47% and 45% in the 40 MESA-ICSI cycles. No significant differences were found in fertilization rates or pregnancy rates among the various sperm retrieval methods and obstruction etiologies. The overall mean fertilization rate and pregnancy rate were 51% and 41%, respectively. CONCLUSION: Both PESA and MESA can be used successfully to obtain sufficient sperm for ICSI. PESA cannot replace MESA in some cases as some epididymal pathologies prevent its success. The results of this study indicate that PESA should be the treatment of choice for patients with ductal obstruction distal to the epididymis, owing to its higher initial success rate. In contrast, patients with irreparable epididymal obstruction might achieve better success rates with MESA.

Functional analysis of androgen receptor N-terminal and ligand binding domain interacting coregulators in prostate cancer.

Several new androgen receptor (AR) coregulators, including ARA70, ARA55, ARA54, ARA160 and ARA24, associated with the N-terminal or the ligand-binding domain (LBD) of AR, have been identified by our group. We first identified the AR-LBD coregulators ARA70, ARA55, and ARA54. Our previous reports suggest that ARA70 can enhance the androgenic activity of 17 beta-estradiol (E2) and antiandrogens toward AR. It is of interest to compare and determine if the specificity of sex hormones and antiandrogens can be modulated by different coregulators. Our results indicate that, ARA70 is the best coregulator for increasing the androgenic activity of E2. Only ARA70 and ARA55 were able to significantly increase the androgenic activity of hydroxyflutamide, the active metabolite of a widely-used antiandrogen for the treatment of prostate cancer. Furthermore, our results suggest that among the LBD coregulators, ARA70 has a relatively high specificity for AR in the human prostate cancer cell line DU145. Together, our data suggest that the androgenic activity of some sex hormones and antiandrogens can be modulated by selective AR coactivators. In addition to the AR-LBD associated proteins, ARA24 and ARA160 have been identified as AR coregulators, interacting with the AR N-terminal instead of the LBD. Functional analysis revealed that the AR N-terminal coregulator ARA160 could cooperate with the AR LBD-associated coregulator ARA70. Our data indicate that ARA24 could also interact with AR, and that this binding is decreased by an expanding poly-glutamine (Q) length within AR. The length of the poly-Q stretch in the AR N-terminal domain is inversely correlated with the transcriptional activity of AR. Our data suggest that optimal AR transactivation may require interaction of AR with AR coregulators. The identification of factors or peptides that can interrupt androgen-mediated AR-ARA interactions may be useful in the development of better antiandrogens for treating androgen-related diseases, such as prostate cancer.

Suppression of Delta(5)-androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells.

Our earlier report suggested that androst-5-ene-3beta,7beta-diol (Delta(5)-androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the Adiol-induced androgen receptor (AR) transactivation in prostate cancer cells. Here, we report the development of a reporter assay to screen several selective steroids with anti-Adiol activity. Among 22 derivatives/metabolites of dehydroepiandrosterone, we found 4 steroids [no. 4, 1,3,5(10)-estratriene-17alpha-ethynyl-3, 17beta-diol; no. 6, 17alpha-ethynyl-androstene-diol; no. 8, 3beta, 17beta-dihydroxy-androst-5-ene-16-one; and no. 10, 3beta-methylcarbonate-androst-5-ene-7,17-dione] that have no androgenic activity and could also block the Adiol-induced AR transactivation in prostate cancer PC-3 cells. Interestingly, these compounds, in combination with hydroxyflutamide, further suppressed the Adiol-induced AR transactivation. Reporter assays further showed that these four anti-Adiol steroids have relatively lower glucocorticoid, progesterone, and estrogenic activity. Together, these data suggest some selective steroids might have anti-Adiol activity, which may have potential clinical application in the battle against the androgen-dependent prostate cancer growth.