Oral Antiandrogens Research Articles

Conventional androgen deprivation therapy is associated with an increased risk of cardiovascular disease in advanced prostate cancer, a nationwide population-based study.

PurposeAndrogen Deprivation Therapy (ADT) is the mainstay treatment in advanced prostate cancer. We conducted a nationwide population-based study to evaluate the association of ADT and cardiovascular diseases.MethodsBetween 2005 and 2009, patient data from the National Health Insurance database were obtained. We divided newly diagnosed prostate cancer patients into four groups, injection of gonadotropin-releasing hormone agonists and antagonists, oral antiandrogens, orchiectomy and radical prostatectomy only. Another matched non-cancerous control group was also assigned for comparison purposes. Study outcomes were newly onset Cardiovascular Diseases (CVD) and hospital admissions. Multi-variant Cox proportional regression analysis and the Kaplan–Meier method for cumulative incidence were performed.ResultsA total of 17,147 newly diagnosed prostate cancer patients were found. After exclusion criteria was considered, the 2,565 remaining patients were then divided into 1,088 subjects in the injection group, 286 in the orchiectomy group, 812 in the oral group and 379 in the radical prostatectomy only group. The mean age of all the patients was 71.2 years. Multi-variant analysis showed a significantly increased risk of CVD in the injection group, orchiectomy group, oral group and radical prostatectomy group (HR = 2.94, 95% CI 2.51 to 3.45, p<0.001, HR = 3.43, 95% CI 2.69 to 4.36, p<0.001, HR = 2.87, 95% CI 2.42 to 3.39, p<0.001, HR = 1.93, 95% CI 1.5 to 2.48, p<0.001, respectively). A time dependent increased risk of CVD was also observed amongst the study groups (p<0.001).ConclusionsADT is associated with an increased risk of CVD. For long-term prostate cancer castration therapy, doctors should be aware of this complication and arrange for proper management.

Risk of Fatigue and Anemia in Patients With Prostate Cancer Treated With Novel Oral Anti-androgens: A Meta-Analysis of Randomized Controlled Trials.

Novel oral anti-androgens (NOAAs) represent a new class of drugs that are being approved for prostate cancer. However, fatigue and anemia are among the most common treatment-related symptoms. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the relative risks (RRs) of fatigue and anemia associated with NOAAs. PubMed, Cochrane, EMBASE, and abstracts presented at the annual meeting of the American Society of Clinical Oncology and European Society of Clinical Oncology were searched for phase III and V RCTs of NOAAs from January 2000 to March 2020. Safety profile from each selected study was evaluated for all-grade and high-grade fatigue and anemia adverse events. The RRs with 95% confidence intervals (95% CIs) were calculated using random-effects for all-grade and high-grade events.Our analysis involved 15 RCTs, including 16,795 patients. Overall, 9,177 patients were treated with NOAAs in the experimental arm, whereas 7,095 received a standard of care in the control arm. The RR of all-grade and high-grade fatigue was 1.26 (95% CI 1.15-1.38) and 1.24 (95% CI 0.83-1.84), and that of all-grade and high-grade anemia was 0.81 (95% CI 0.77-1.19) and 0.81 (95% CI 0.61-1.06), respectively. Our findings suggest that NOAAs are associated with an increased risk of fatigue but decreased risk of anemia. Patients should be frequently monitored to identify adverse events to improve oncological outcomes and optimize the overall treatment efficacy and safety. Not all the RCTs addressed fatigue and anemia simultaneously as side effects of NOAA treatment.

Patients with undetectable PSA 2 years after docetaxel for metastatic castration sensitive prostate cancer (mCSPC).

e17044 Background: Patients with mCPSC have multiple treatment options to combine with androgen deprivation therapy (ADT) including docetaxel, abiraterone, enzalutamide and apalutamide, all of which have demonstrated a survival advantage. While oral anti-androgens are administered daily until progression but are less toxic, docetaxel has more upfront side effects. One of the advantages of using docetaxel is that the 6-cycle regimen (over approximately 4 months) potentially affords patients a respite from daily therapies thereafter. Furthermore, docetaxel may be more cost-effective. In this prospective study, mCSPC patients were treated with docetaxel and Prostvac, a therapeutic cancer vaccine. Since this study was initiated, Prostvac did not demonstrate independent clinical activity in a phase 3 trial in metastatic castration resistant prostate cancer. Nonetheless, this study provides an opportunity to evaluate responses to docetaxel-based therapy in mCSPC. Methods: Eligible patients included those with mCSPC and ECOG of ≤ 2. All patients were treated with docetaxel and were planned to receive 75mg/m2 for 6 cycles within 4 months of starting ADT, as per the CHAARTED regimen. Patients were randomized to receive Prostvac prior to, concurrent with or after docetaxel. Patients were restaged annually with CT and Tc99 bone scan. The study was powered to evaluate immunologic responses, which is ongoing. For the purposes of this analysis, all patients were analyzed as one group and long-term PSA responses were evaluated. Results: The study enrolled 73 patients. Age range was 41-86 with a median of 63 years. Race distribution was 71.6% White, 20.3% Black, 4.1% other, and 4.1% unknown. Gleason scores were 6 (4.1%), 7 (21.6%), and 8-10 (68.9%), with 5.4% being unknown. Median pre-ADT PSA was 34.75 ng/mL. Low-volume disease represented 41.1% of patients and high-volume was 58.9%. After 2 years from the start of ADT, 22% of all patients had PSA values of ≤ 0.2 ng/mL. This included 37% of the low-volume group and 12% of the high-volume group. Three years from the start of ADT, 14% of all patients had PSA values ≤ 0.2 ng/mL (20% of the low-volume group, 9% of the high-volume group). Conclusions: These data highlight long-term outcomes of 6 cycles of docetaxel for men with mCSPC. Although there are concerns about the short-term toxicity of docetaxel, there is potential for prolonged stable disease after ̃4 months of chemotherapy that allows these patients to defer additional oral anti-androgen therapy for years in some patients. The proportions of patients presented here are an underestimate of those who could continue to be monitored for slowly rising, but low PSAs, before starting the next line of therapy. Additional research is required to determine the optimal therapeutic sequence for men diagnosed with mCSPC and long-term implications for quality of life and cost-effectiveness. Clinical trial information: NCT02649855.

Quantifying observational evidence for risk of dementia following androgen deprivation therapy for prostate cancer: an updated systematic review and meta-analysis.

Androgen deprivation therapy (ADT) administration was recently reported and might be positively associated with dementia. However, the existing studies showed controversial results. The aim of this study was to evaluate the relationship between ADT and the risk of dementia through a meta-analysis. Original articles published up to March 2020 were retrieved from Embase, Pubmed, the Cochrane library, and Web of Science for studies focusing on associations between ADT for prostate cancer (PCa) and incidence of dementia. A meta-analysis was conducted using a hazard ratio (HR) and 95% confidence interval (CI) as effect measures. Heterogeneity between the studies was examined using I2 statistics. Subgroup analyses, sensitivity analyses, and meta-regression were conducted, and publication bias was assessed by Egger's test. Thirteen studies were included in this systematic review. Eleven cohort studies involving 339,400 cases and 436,851 controls were included in the main meta-analysis. ADT administration was associated with a 21% increase in dementia risk (pooled HR = 1.21, 95% CI: 1.13-1.30, P < 0.001). Subgroup analyses based on ADT types showed that luteinizing hormone-releasing hormone agonists (HR = 1.14, P < 0.001), bilateral orchiectomy (HR = 1.42, P < 0.001), oral antiandrogens (HR = 1.35, P = 0.138), and combined androgen blockade (HR = 1.22, P = 0.097) were positively related to subsequent risk of dementia, although the differences were not statistically significant with oral antiandrogens and combined androgen blockade. The current study indicated that ADT administration, no matter with types of ADT, is associated with the risk of dementia in patients with PCa. Future studies are needed to determine whether ADT causes dementia or is merely associated with increased risk.

Androgen Deprivation Therapy and the Risk of Stroke in Patients with Prostate Cancer: An Updated Systematic Review and Meta-Analysis

Background: The aim of this article was to review the association between androgen deprivation therapy (ADT) and the risk of stroke in patients with prostate cancer (PC). Thus, we performed this study to understand the impact of ADT on the incidence of stroke in PC patients. Methods: A comprehensive literature search was performed in June 2019 based on PubMed, EMBASE, and Web of science databases. Pooled rate ratio (RR), hazard ratio (HR), and their 95% confidence intervals (95% CIs) were calculated with a DerSimonian and Laird random effects. Result: A total of 239,099 patients from 10 studies were included in this analysis. There was no significant association in pooled RR analysis. Pooled HR analysis showed that ADT treatment increased the risk of stroke (HR = 1.129, 95% CI: 1.019–1.251, p = 0.02). In a subgroup analysis of RR results, we found that different ADT treatments had no significant effect on increasing the risk of stroke. And in the subgroup analysis of HR results, only PC patients treated with gonadotropin-releasing hormone (GnRH) agonists, orchiectomy, or oral antiandrogen had significantly higher risk of stroke. In addition, we observed the result from another comparison that PC patients treated with GnRH agonists combined with oral antiandrogens might have a lower risk of stroke compared with using GnRH agonists alone. Conclusion: Our results showed that GnRH agonists, orchiectomy, or oral antiandrogen might play an important role in the incidence of stroke. We still need further studies to clarify the role of ADT in the increased risk of stroke.

Female Androgenetic Alopecia: An Update on Diagnosis and Management.

Female androgenetic alopecia (FAGA) is a common cause of non-scarring alopecia in women. The onset may be at any age following puberty and the frequency increases with age. Clinically, it shows a diffuse hair thinning over the central scalp, while the frontal hairline is usually retained. FAGA can have a significant psychological impact, leading to anxiety and depression. For this reason, early diagnosis is very important to stop the progression of the disease. The sex hormonal milieu is the main pathogenetic mechanism studied in FAGA. The role of androgens is not clearly defined and only one-third of women with FAGA show abnormal androgen levels. Endocrinological diseases with hyperandrogenism associated with FAGA comprise polycystic ovarian syndrome (PCOS), hyperprolactinemia, adrenal hyperplasia and, rarely, ovarian and adrenal tumours. Usually the diagnosis of FAGA is made clinically. A complete clinical examination and a blood examination can reveal other signs of hyperandrogenism. Trichoscopy shows the typical hair miniaturization. A scalp biopsy can be useful when the clinical evaluation does not provide a definitive diagnosis or when cicatricial alopecias with hair loss in the distribution of FAGA or alopecia areata are suspected. FAGA is a slowly progressive disease. The goal of therapy is to stop the progression and to induce a cosmetically acceptable hair regrowth. The most important drugs are topical minoxidil and oral anti-androgens. The purpose of this review is to provide an update on FAGA and to create a guideline on diagnosis and management of this frequent hair disease, not always easily recognizable from cicatricial alopecias with a similar distribution.

面部毛孔粗大的治疗进展

Enlarged facial pores remain a common skin concern. Its occurrence is mainly associated with increased sebum production, skin aging (skin laxity and decreased skin elasticity) , increased hair follicle size and other factors, and current treatments for enlarged facial pores mainly target these factors. This review retrospectively summarizes current common treatments, including oral antiandrogens, topical retinoids, chemical peels, lasers, radiofrequency and focused ultrasound. The increasing development of photoelectric devices offers newer and more reliable choices. Key words: Hair follicle; Sebaceous glands; Skin aging; Enlarged pores; Treatments

Management of teenagers with polycystic ovarian syndrome

Abstract Polycystic ovary syndrome (PCOS) is a common, complex endocrine and metabolic disorder with a prevalence of 20%. It is variable in aetiology, clinical presentation and prognosis, making it a challenging disease to understand and manage in teenagers. It results from a defect in steroidogenesis, leading to excess luteinising hormone and hyperandrogenism. PCOS is also associated with insulin resistance and compensatory hyperinsulinism. The Rotterdam criteria are the most widely used criteria for diagnosing PCOS, however it is typically challenging to diagnose in teenage girls due to the overlap of symptoms with normal pubertal changes. Importantly, PCOS is also a diagnosis of exclusion. Management strategies for PCOS should be tailored to the presenting symptoms, and can include lifestyle modifications, cosmetic hair removal and pharmacological management, for example, the combined oral contraceptive pill, anti-androgens and insulin sensitizers. An assessment of psychological well-being, and contraceptive or fertility needs is also an important aspect of managing PCOS in adolescents. This short review offers guidance and practical advice about diagnosis, investigation and treatment for healthcare practitioners working with children and young people.

Androgen deprivation therapy for prostate cancer and risk of dementia.

ObjectivesTo study whether androgen deprivation therapy (ADT), the mainstay treatment for advanced and disseminated prostate cancer, is associated with risk of dementia.MethodsRisk of dementia in men with prostate cancer primarily managed with ADT or watchful waiting (WW) in the Prostate Cancer Database Sweden, PCBaSe, was compared with that in prostate cancer‐free men, matched on birth year and county of residency. We used Cox regression to calculate the hazard ratios (HRs) for Alzheimer's and non‐Alzheimer's dementia (vascular dementia, dementia secondary to other diseases or unspecified dementias) for different types and duration of ADT and oral antiandrogens (AAs) as well as for men managed with WW.ResultsA total of 25 967 men with prostate cancer and 121 018 prostate cancer‐free men were followed for a median of 4 years. In both groups 6% of the men were diagnosed with dementia. In men with prostate cancer, gonadotropin‐releasing hormone agonist treatment ( HR 1.15, 95% confidence interval [CI] 1.07–1.23) and orchiectomy (HR 1.60, 95% CI 1.32–1.93) were associated with an increased risk of dementia, as compared to no treatment in prostate cancer‐free men; however, this increase in risk was only observed for non‐Alzheimer's dementia and occurred from year 1–4 after start of ADT. No increase in risk for any type of dementia was observed for men treated with AAs or for men on WW.ConclusionThis population‐based cohort study does not support previous observations of an increased risk of Alzheimer's dementia for men on ADT; however, there was a small increase in risk of non‐Alzheimer's dementia.

Platelet-rich plasma on female androgenetic alopecia: Tested on 10 patients.

Recently, platelet-rich plasma (PRP) injection has been proposed as a potential adjuvant therapy to treat androgenetic alopecia. Investigate the efficacy, tolerability, and clinical improvement of PRP for the treatment of female AGA. A total of 10 female patients affected by AGA and not responding to treatment with minoxidil and/or oral antiandrogens were enrolled. The clinical improvement was evaluated by pull test, global photographs, and Trichoscan at weeks 9, 12, and 24, and hair measurements were performed at baseline and 12 and 24weeks after the first session. After 24weeks, the median relative percentage change (%RC) for all the parameters of hair density was mostly positive. After 12weeks, the medium hair diameter in frontal area showed a significant increase (%RD=12.5, with P-value<.05), and after 24weeks (%RD=14.6, P-value<.05), the vellus relative change instead showed a decrease, especially in the front and the central area, while for the vertex, the decrease was mainly visible at the end (-6.6%). No adverse events were reported. Platelet-rich plasma injections have a positive therapeutic effect on hair density and hair diameter improvement.

Clinical Case Seminar: Postmenopausal androgen excess-challenges in diagnostic work-up and management of ovarian thecosis.

Postmenopausal hyperandrogenism can be tumour- or non-tumour-related, with pathology residing either in the ovary or adrenal gland(s). The tempo of investigation is determined by the clinical severity of hyperandrogenism (presence/absence of actual virilisation) and degree of serum testosterone elevation. When clinical or biochemical hyperandrogenism is severe, rapidly developing, or associated with hypercortisolism, screening for adrenocortical or ovarian carcinoma with cross-sectional imaging should be prioritised over detailed biochemical evaluation. Adrenal hyperandrogenism is readily characterised, both biochemically and radiologically. By contrast, even a combination of high-resolution imaging with laboratory evaluation, including dynamic endocrine testing, often cannot distinguish between ovarian hyperthecosis (OH) and virilising ovarian tumour (VOT); a definitive diagnosis usually emerging only after histological examination of excised ovaries. VOTs are typically below the resolution-limit of current imaging modalities and exhibit suppression of gonadotropin-dependent androgen secretion with GnRH-analogue therapy. Thus, for well-characterised ovarian hyperandrogenism, laparoscopic bilateral salpingo-oophorectomy may serve both as a diagnostic and therapeutic procedure. Nevertheless, women unable or unwilling to undergo ovarian surgery can be reassured that malignant VOTs are exceedingly rare and that long-term medical therapy with oral antiandrogens or GnRH-analogues is safe and well-tolerated. OH is strongly associated with insulin-resistance, with hyperinsulinaemia acting synergistically with raised gonadotropin levels to stimulate thecal cell hyperplasia and androgen secretion by the postmenopausal ovary, which lacks granulosa cell aromatase activity and thus cannot convert testosterone to 17 beta estradiol. Thus, features of metabolic syndrome may indicate OH, and significant reductions in androgens can thereby potentially be achieved with lifestyle measures and/or insulin-sensitising drugs.

European evidence-based (S3) guideline for the treatment of acne - update 2016 - short version.

European evidence-based (S3) guideline for the treatment of acne - update 2016 - short version.

Hair Restoration in Androgenetic Alopecia: Looking Beyond Minoxidil, Finasteride and Hair Transplantation

Patterned hair loss (PHL) is one of the most commonly encountered problems for dermatologists. PHL at an early age is often cosmetically unacceptable, tends to be persistent and inflicts a profound negative impact on one’s quality of life. Androgenetic alopecia (AGA) affects both genders in a distinctive pattern of hair loss from the scalp (MPHL for male PHL and FPHL or female PHL). The etiopathogenesis of AGA is complex, so far the major factor emphasized to be involved has been the undesirable androgen metabolism at the hair follicle level. In this review article, we shall dwell upon the relatively newly understood pathophysiological factors behind the genesis of AGA apart from the hormonal factors like the Wnt/β-catenin pathway, follicular micro-inflammation, prostaglandin imbalance, loss of extracellular matrix and oxidative stress. Based on the sound understanding of these factors we will be elaborating upon therapies for treatment of AGA beyong minoxidil, finasteride and hair transplantation. Amongst the therapeutic options discussed include topical 5alpha reductase (AR) inhibitors like finasteride, oral 5AR inhibitor – dual receptor antagonist dutasteride, botanical 5AR inhibitors, oral anti-androgens and estrogens for FPHL like spiranolactone, drospirenone etc. Wnt/β-catenin activators like topical valproic acid, hair stem cell based therapies, prostaglandin based therapies, tetrapeptides, nutritional and anti-oxidants and many more.

Androgen Deprivation Therapy and Risk of Acute Kidney Injury in Patients With Prostate Cancer

The use of androgen deprivation therapy (ADT) in the treatment of advanced prostate cancer has been shown to delay the clinical progression of the disease. However, the testosterone suppression associated with this therapy may lead to a hypogonadal condition that can have detrimental effects on renal function, thus raising the hypothesis that ADT-induced hypogonadism could potentially lead to acute kidney injury (AKI). To determine whether the use of ADT is associated with an increased risk of AKI in patients newly diagnosed with prostate cancer. A nested case-control analysis using medical information extracted from the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database. Men newly diagnosed with nonmetastatic prostate cancer between January 1, 1997, and December 31, 2008, were selected and followed up until December 31, 2009. Cases were patients with incident AKI during follow-up who were randomly matched with up to 20 controls on age, calendar year of prostate cancer diagnosis, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% CIs of AKI associated with the use of ADT. ADT was categorized into 1 of 6 mutually exclusive groups: gonadotropin-releasing hormone agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, estrogens, and combination of the above. RESULTS A total of 10,250 patients met the study inclusion criteria. During a mean follow-up of 4.1 (SD, 2.9) years, 232 incident cases of AKI were identified (rate, 5.5/1000 person-years). Overall, current use of any ADT was associated with an increased risk of AKI when compared with never use (OR, 2.48 [95% CI, 1.61-3.82]), generating a rate difference of 4.43/1000 persons per year (95% CI, 1.54-7.33). This association was mainly driven by a combined androgen blockade consisting of gonadotropin-releasing hormone agonists with oral antiandrogens (OR, 4.50 [95% CI, 2.61-7.78]), estrogens (OR, 4.00 [95% CI, 1.06-15.03]), other combination therapies (OR, 4.04 [95% CI, 1.88-8.69]), and gonadotropin-releasing hormone agonists (OR, 1.93 [95% CI, 1.20-3.10]). In a cohort of patients with newly diagnosed nonmetastatic prostate cancer, the use of ADT was significantly associated with an increased risk of AKI. These findings require replication in other well-designed studies as well as further investigation of their clinical importance.

Diagnosis and management of hirsutism

Hirsutism is a frequent medical complaint that usually results from relatively benign functional disorders including the polycystic ovary syndrome, which is the most frequent etiology. The essential tool for the diagnosis of hirsutism is a complete clinical history and physical examination, because functional causes begin peripubertally and progress slowly, whereas the very rare androgen-secreting neoplasms have a sudden onset and a rapid progression of hirsutism, and usually associate clinical signs of virilization and defeminization. In all cases, diagnosis requires quantification of hirsutism using the modified Ferriman-Gallwey score, measurement of circulating androgen concentrations, a detailed study of ovaulatory function, and possibly an ovarian ultrasound. Treatment must consider not only amelioration of hirsutism but also treatment of the underlying etiology and of any metabolic associations. When caused by a functional disorder, treatment of hirsutism should be chronic and should include cosmetic as well as pharmacological interventions such as oral contraceptives and antiandrogens. For nonfunctional disorders, treatment should focus on solving the underlying etiology as hirsutism is usually responsive to the elimination of the source of androgen excess.

170 ANDROGEN DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER IS ASSOCIATED WITH AN INCREASED RISK OF PERIPHERAL ARTERIAL DISEASE AND VENOUS THROMBOEMBOLISM

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History I1 Apr 2012170 ANDROGEN DEPRIVATION THERAPY FOR NON-METASTATIC PROSTATE CANCER IS ASSOCIATED WITH AN INCREASED RISK OF PERIPHERAL ARTERIAL DISEASE AND VENOUS THROMBOEMBOLISM Jim Hu, Stephen Williams, A. O'Malley, Matthew Smith, Paul Nguyen, and Nancy Keating Jim HuJim Hu Boston, MA More articles by this author , Stephen WilliamsStephen Williams Orange, CA More articles by this author , A. O'MalleyA. O'Malley Boston, MA More articles by this author , Matthew SmithMatthew Smith Boston, MA More articles by this author , Paul NguyenPaul Nguyen Boston, MA More articles by this author , and Nancy KeatingNancy Keating Boston, MA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.221AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Previous studies demonstrate that androgen deprivation therapy (ADT) with gonodotropin-releasing hormone (GnRH) agonists and orchiectomy for prostate cancer (CaP) is associated with cardiovascular disease. However, few studies have examined its effect on the peripheral vascular system. The objective of the surrent study was to assess the risk of peripheral arterial disease (PAD) and venous thromboembolism (VTE) associated with ADT for prostate cance CaP. METHODS Population-based observational study of 182,757 U.S. men aged 66 years and older who were diagnosed with nonloco-metastaticregional prostate cancer CaP from 1992 to 2007, of whom 47.8% received GnRH agonists and 2.2% orchiectomy. We used Cox proportional hazards models with time-varying treatment variables to assess whether treatment with GnRH agonists or orchiectomy was associated with PAD and/or VTE. RESULTS GnRH agonist use was associated with an increased risk of incident PAD (adjusted hazard ratio [HR], 1.16, 95% confidence interval [CI] 1.09-1.21) and incident VTE (adjusted HR, 1.09, 95% CI 1.04-1.15). In addition, orchiectomy was associated with an increased risk of PAD (adjusted HR, 1.13, 95% CI 1.02-1.26) and VTE (adjusted HR, 1.21, 95% CI 1.05-1.38). Limitations include the observational study design, inability to assess the use of oral anti-androgens as monotherapy or combined androgen deprivation. CONCLUSIONS ADT for loco-regional non-metastatic CaP is associated with an increased risk of peripheral artery disease and VTE. Additional research is needed to better understand the potential risks and benefits, so that these treatments can be targeted to patients where the benefits are most clear. Table 1. Adjusted association of the duration of GnRH Agonist therapy and outcomes⁎ Duration of GnRH agonist Incident PAD Incident VTE Treatment (Months)† Adjusted HR 95% CI p-value⁎ Adjusted HR 95% CI p-value⁎ No Treatment Ref – Ref – 1-4 1.11 1.05–1.19 0.002 0.88 0.80–0.96 0.003 5-12 1.22 1.15–1.29 <0.001 1.18 1.08–1.29 <0.001 13-24 1.13 1.05–1.22 0.008 1.27 1.15–1.41 <0.001 >25 1.17 1.09–1.26 <0.001 1.18 1.06–1.30 0.002 ⁎ Using time-varying Cox proportional hazards models adjusting for all variables in Table 1 and orchiectomy. † For the peripheral artery disease cohort, the proportion of patient time contributed by duration categories was: no treatment 84.3%; 1-4 months 4.5%; 5-12 months 4.7%; 13-24 months 3.0%; and >25 months 3.5%. For the VTE cohort, the proportion of patient time contributed by duration categories was: no treatment 84.2%; 1-4 months 4.6%; 5-12 months 4.8%; 13-24 months 3.0%; and >25 months 3.5%. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e71 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jim Hu Boston, MA More articles by this author Stephen Williams Orange, CA More articles by this author A. O'Malley Boston, MA More articles by this author Matthew Smith Boston, MA More articles by this author Paul Nguyen Boston, MA More articles by this author Nancy Keating Boston, MA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Androgen-Deprivation Therapy for Nonmetastatic Prostate Cancer Is Associated With an Increased Risk of Peripheral Arterial Disease and Venous Thromboembolism

BackgroundPrevious studies demonstrate that androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and orchiectomy for prostate cancer (PCa) is associated with cardiovascular disease. However, few studies have examined its effect on the peripheral vascular system. ObjectiveTo study the risk of peripheral artery disease (PAD) and venous thromboembolism associated with ADT for PCa. Design, settings, and participantsThis was a population-based observational study of 182 757 US men ≥66 yr of age who were diagnosed with nonmetastatic PCa from 1992 to 2007, with a median follow-up of 5.1 yr, of whom 47.8% received GnRH agonists and 2.2% orchiectomy. MeasurementsWe used Cox proportional hazards models with time-varying treatment variables to adjust for demographic and tumor characteristics in assessing whether treatment with GnRH agonists or orchiectomy were associated with PAD and/or venous thromboembolism. Results and limitationsGnRH agonist use was associated with an increased risk of incident PAD (adjusted hazard ratio [HR]: 1.16; 95% confidence interval [CI], 1.12–1.21) and incident venous thromboembolism (adjusted HR: 1.10; 95% CI, 1.04–1.15). In addition, orchiectomy was associated with an increased risk of peripheral arterial disease (adjusted HR: 1.13; 95% CI, 1.02–1.26) and venous thromboembolism (adjusted HR: 1.27; 95% CI, 1.11–1.45). Limitations include the observational study design and the inability to assess the use of oral antiandrogens. ConclusionsADT for nonmetastatic PCa is associated with an increased risk of PAD and venous thromboembolism. Additional research is needed to better understand the potential risks and benefits of ADT, so that this treatment can be targeted to patients for whom the benefits are clearest.

Androgens and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a mainly hyperandrogenic disorder and is possibly the most frequent endocrinopathy in premenopausal women. Androgen excess is the primary defect in PCOS, because ovarian theca cells secrete increased amounts of androgens even after several passes in primary culture. Excessive androgen amounts might favor the visceral deposition of body fat in affected women, resulting in insulin resistance, compensatory hyperinsulinism and further androgen excess. This vicious circle starts early during life in women with PCOS, even during fetal development, manifests clinically during puberty and does not end after menopause. All the steps in the vicious circle contribute to the association of PCOS with metabolic dysfunction and cardiovascular risk factors. Fortunately, most, if not all, of the therapeutic strategies currently in use for the management of PCOS, including lifestyle modification and diet, oral contraceptives, antiandrogens and insulin sensitizers, may ameliorate androgen excess and its long-term consequences.

Androgen-Deprivation Therapy and the Risk of Stroke in Patients With Prostate Cancer

BackgroundSome evidence indicates that androgen-deprivation therapy (ADT) increases the risk of diabetes and cardiovascular disease. To date, few studies have investigated whether this therapy also increases the risk of cerebrovascular events. ObjectiveTo determine whether different types of ADT increase the risk of stroke/transient ischaemic attacks (TIAs) in patients with prostate cancer. Design, setting, and participantsWe conducted a population-based cohort study using a nested case-control analysis within the United Kingdom's General Practice Research Database population. The cohort included all patients at least 40 yr of age newly diagnosed with prostate cancer between January 1, 1988, and December 31, 2008, and followed until December 31, 2009. Cases consisted of those who experienced a first-ever stroke/TIA during follow-up. Up to 10 controls were matched to each case on age, year of cohort entry, and duration of follow-up. MeasurementsAdjusted rate ratios (RRs) of stroke/TIA associated with the use of different ADTs (gonadotropin-releasing hormone [GnRH] agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, and others) were estimated using conditional logistic regression. Results and limitationsThe cohort included 22 310 patients with prostate cancer, followed for a mean of 3.9 yr, where 938 patients experienced a first-ever stroke/TIA (rate: 10.7 per 1000/yr). Compared with nonusers of ADT, current users of GnRH agonists (adjusted RR: 1.18; 95% confidence interval [CI], 1.00–1.39), oral antiandrogens (adjusted RR: 1.47; 95% CI, 1.08–2.01), and those who underwent bilateral orchiectomy (adjusted RR: 1.77; 95% CI, 1.25–2.39) were at an increased risk of stroke/TIA. No statistically significant increased risks were observed for patients on combined androgen blockade and other ADTs, but the small numbers do not rule out a possible association. ConclusionsThe results of this large population-based study provide additional evidence that different forms of ADT may increase the risk of stroke/TIA.

Old issues and new perspectives on prostate cancer hormonal therapy: the molecular substratum

Secondary hormonal therapy is a treatment option in patients with castration-resistant prostate cancer (CRPC); however, it is underutilized and is room for optimization and improvement. In this context, androgen receptor (AR) is the Achilles' heel, being critically important and various mechanisms ranging from receptor mutations to secondary signaling pathways are responsible for some of the biological heterogeneity, demanding a multimodal approach. A comprehensive review of the peer-reviewed literature is performed on the topic of molecular mechanisms supporting secondary hormonal therapies, including expanded alternative hormonal therapies for CRPC. Essential concepts in clinical treatment of patients with progression on primary hormonal therapy are maintaining the castrate state, accounting for the intermittency phenomenon and sequentially using oral antiandrogens and adrenolytics heading to androgen depletion microenvironment. Survival prolongation, pain relief or measurable improvement in tumor-related symptoms should be persecuted and are considered to be a tangible benefit of obvious worth to the patient. Understanding the underlying molecular substratum is of paramount importance to hormonal therapy optimization in this context once current androgen-depletion strategies are incomplete, and residual androgens as well as alternative routes contribute to sustained AR activity and disease progression to a lethal phenotype. One or many mechanisms may be playing a role, even within the same patient and lastly are potential targets for treatment. Five fundamental mechanisms mediated through the AR to promote tumor growth (three of which depend on ligand signaling) added to the stem cell pathway must be recognized in CRPC. They are persistence of intratumoral androgens as a result of in situ steroidogenesis or adrenal source; AR mutations that allow promiscuous activation by otherwise nonsignaling ligands; wild-type AR gene amplification; alterations in AR coactivator-to-corepressor ratio that impact transcription; outlaw AR pathways that bypass the need for androgens by signaling through crosstalk with other ligand-bound receptors, cytokines, or transactivation of activated tyrosine kinase receptors in the cytosol.