Masculinities and Prostate Cancer

BACKGROUND: Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation. METHODS: A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC. RESULTS: The meta-analysis revealed that AR L702H (3.4%), AR H875Y (4.9%), and AR T878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for AR WT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs AR WT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate AR L702H , dexamethasone importantly does not. CONCLUSION: Both testosterone and 11KT effectively contribute to AR WT activation, while selective sensitization positions 11KT as a more prominent activator of AR H875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the AR L702H .

Ever since the introduction of androgen deprivation therapy (ADT) in prostate cancer, various controversial aspects of hormonal therapy have come to light. There has been tremendous progress in this area, marked by several important developments in the availability of various new androgen-suppressing agents and refinements to the existing therapies. Parallel to these developments, various more debatable aspects have arisen in the use of these therapies with regards to their negative impact on quality of life parameters. Various modifications in these hormonal agents, their doses, and protocols have been tried in different scenarios in order to improve ADT tolerability. As a result, these controversies continue to evolve even with optimal use of the androgen ablation therapy. This review assesses the present status of hormonal therapy in metastatic prostate cancer and specifically deals with those aspects of androgen ablation therapy that are still a subject of debate. In spite of th...

Although breast and prostate cancer are those most frequently diagnosed in Canada, information about the ways in which gender, class, race, culture, and other social determinants impact the experience of African Canadians living with cancer is lacking. This study began to address this gap by exploring cultured and gendered dimensions of African Nova Scotians’ experiences of these two cancers. Using a participatory action research approach, data were collected in two phases of focus group discussions in five African Nova Scotian communities from a total of 57 people, including those with breast or prostate cancer and their families and associates. Findings provide insight into how gender and meanings of masculinity and femininity in the African Nova Scotian community unavoidably interact with other social structures such as race and class to affect women and men’s perceptions and experiences of these two cancers. These insights point to the need for culturally appropriate and meaning...

Recent advances in understanding the mechanisms underlying the development and progression of castration resistant prostate cancer from androgen-sensitive prostate cancer have provided new avenues exploring efficacious therapies in a disease which is the second leading cause of cancer deaths among men in the western world. In the evolution of second generation anti-androgens, enzalutamide, a novel androgen-receptor signaling inhibitor, has emerged targeting multiple steps within the androgenic stimulation pathway. This review discusses what is currently known of the mechanisms surrounding castration resistant prostate cancer development and the current human clinical trials to determine whether enzalutamide presents a new hope for men with advanced prostate cancer. The issues of therapy resistance, withdrawal effects and cross-resistance are briefly touched upon.

The treatment of castration-resistant (CR) prostate cancer (PCa) is limited. A sub-population of CR PCa tumors can synthesize androgens for intracrine androgen receptor (AR) activation, thus targeting androgen biosynthesis could be an effective therapeutic option for these patients. We determined that androgen biosynthesis inhibitors simvastatin, atorvastatin, and ketoconazole directly inhibit growth, migration, and colony formation of LNCaP C-81 cells, which exhibit de novo androgen biosynthesis, with simvastatin being the most effective. Importantly, in combination treatments, statins specifically enhanced growth suppression with added effects by anti-androgen abiraterone acetate on the CR PCa cells. Thus, statins can be used in conjunction with abiraterone acetate to enhance anti-androgen therapy for CR PCa.

Enzalutamide, previously known as MDV300, is an oral, second-generation androgen receptor (AR) signaling inhibitor or antagonist that was approved by the Food and Drug Administration in 2012 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) postdocetaxel. Preclinical studies have demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. The landmark Phase III AFFIRM trial demonstrated improved overall survival benefit compared to placebo in addition to improvement in all tested parameters. Enzalutamide is currently being studied in several trials prechemotherapy and in earlier settings of prostate cancer. This review will discuss the mechanism of action of enzalutamide, its pharmacokinetics, the preclinical and clinical trials that led to its approval, the ongoing clinical trials, its safety and efficacy, as well as patterns of resistance, and discusses its place in therapy within the context of several recently approved agents for mCRPC.

Recently new drugs targeting androgen-dependent axis have been approved for the treatment of castration-resistant prostate cancer (CRPC)-Zytiga and Xtandi (formerly MDV3100), several other candidates (for example, ARN-509) are in early phases of clinical trials. However despite significant improvement in overall survival with new treatments it is evident that resistance to these drugs develops. One of the approaches to overcome it is combination therapy and from this point of view some potential for drug-drug interactions can limit the application of the drug. We describe here the preclinical development of ONC1-13B, antagonist of androgen receptor, with similar to MDV3100 and ARN-509 mechanism of action. It efficiently inhibits DHT-stimulated PSA expression and proliferation of prostate cancer cells, prevents binding of androgens to the AR ligand-binding domain, androgen-stimulated AR nuclear translocation and coactivator complex formation. In the LnCaP-Z2 xenograft model of prostate cancer ONC1-13B inhibits tumor growth and suppresses PSA expression. The in vivo activity of ONC1-13B is comparable to that of MDV3100 at similar doses, and even higher, calculated per unit of concentration in plasma. Distribution of ONC1-13B to the brain is less than that shown for MDV3100 and ARN-509, decreasing the risk of GABA-related seizure development. Additionally ONC1-13B induces significantly lower in vitro CYP3A activity than for example MDV3100 (known strong CYP3A inducer) or ARN-509 and could be well suited for co-therapy with drugs that are known CYP3A substrates. Thus ONC1-13B is a new promising antiandrogen demonstrating high efficacy in a preclinical model of prostate cancer, with lower potential for seizures and drug-drug interaction.

Abiraterone acetate, approved for patients with metastatic castration-resistant prostate cancer (mCRPC), blocks androgen byosinthesis. We aimed to describe changes determined by abiraterone in hormones implied in steroid biosynthesis, exploring association between hormonal levels and drug activity. Patients with mCRPC, receiving standard abiraterone + prednisone after docetaxel failure, were studied. We determined serum levels of progesterone, 17OH-progesterone, cortisol, ACTH, DHEA-sulphate, androstenedione, testosterone, sex hormone-binding globulin, aldosterone, plasma renin activity, and cholesterol, baseline and every 12 weeks. For each hormone, association with treatment activity was tested 1) comparing baseline values in responders vs. non-responders; 2) comparing progression-free survival (PFS) of patients with baseline low vs. high values; 3) comparing values after 12 weeks in responders vs. non-responders. Forty-nine patients were analyzed; 26 patients (53.1%) experienced ...

Prostate cancer is the most common type of cancer diagnosed in men worldwide and the second leading cause of death after lung cancer. Testosterone and dihydrotestosterone (DHT) have been known to play an essential role in prostate cancer. Androgen receptor (AR) binding to the ligand allows homodimerization and translocation to the nucleus, which acts as a transcription factor for androgen-responsive genes such as PSA (Prostate-specific antigen). Although many anti-androgens have been established, including Bicalutamide, Flutamide, and Abiraterone, the problem of non-specific cytotoxicity effects and cancer recurrence due to potential drug resistance remains a significant obstacle to establishing effective therapy. Plantago major L. is one of the plants that can choose anticancer therapy because, based on reports, it has anticancer activity through DNA damage in cancer cells. This study focused on the search for the potential phytochemical activity of Plantago major L. as an anti-and...

Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that are also highly expressed in the prostate. As a promising candidate, STAMP family genes STAMP1/STEAP2, STAMP2/STEAP4 and STEAP3 are involved in apoptosis and the cell cycle in metastatic prostate cancer. Vascular NADPH oxidase generates superoxide and other ROS, which stimulates IkappaB degradation and NF-kB activation by subunits of NADPH oxidases, namely p47phox and p67phox induced by different stimuli such as hydrogen peroxide. Hydrogen peroxide increased the expression levels of p67phox. They also have a role in redox-sensitive genes such as STAMP gene family. Flow cytometry analysis of LNCaP cells was performed using Annexin V staining and apoptotic index charts were drawn. STAMP1 and STAMP2 showed total anti-oxidant capacity versus control with hydrogen peroxide incubation. Using siRNA technology in LNCaP cells expressing mutant p53 silencing of p53 showed significant increase in MDM2 and decrease of caspase 9 mRNA levels at RT-PCR. Silencing of STAMP2, a significant decrease in p47phox was shown but STAMP1 silencing counteracted this effect on Cu/ZnSOD expression.As a conclusion, STAMP proteins have effects on oxidative stress-induced genes with significant and opposite changes.

Each year hundreds of thousands of males begin long-term androgen deprivation therapy (ADT), i.e. chemical or surgical castration, to slow the progress of prostate cancer. ADT causes loss of muscle mass and body hair; genital shrinkage and erectile dysfunction; variable amounts of breast growth and the development of a characteristically postmenopausal female pattern of fat distribution. ADT also changes mood and affect, most conspicuously seen as increased emotionality and depressed libido. Given these changes, it is not surprising that many patients on ADT no longer feel 'manly', yet do not experience themselves as women. For many, this gender liminality is psychologically and socially traumatic. Faced with these difficulties, how can castrated males understand themselves in a positive way? We explore the idea that some men may benefit from embracing the alternative gender identity of 'eunuch'. Unfortunately, due in part to the historic practice of forced castration, the word 'eunuch' is now largely pejorative, although it is the correct biological term for a castrated male. We examine the benefits and risks of contemporary castrated males accepting this identity to help them adapt to the changes they experience.

Each year hundreds of thousands of males begin long-term androgen deprivation therapy (ADT), i.e. chemical or surgical castration, to slow the progress of prostate cancer. ADT causes loss of muscle mass and body hair; genital shrinkage and erectile dysfunction; variable amounts of breast growth and the development of a characteristically postmenopausal female pattern of fat distribution. ADT also changes mood and affect, most conspicuously seen as increased emotionality and depressed libido. Given these changes, it is not surprising that many patients on ADT no longer feel 'manly', yet do not experience themselves as women. For many, this gender liminality is psychologically and socially traumatic. Faced with these difficulties, how can castrated males understand themselves in a positive way? We explore the idea that some men may benefit from embracing the alternative gender identity of 'eunuch'. Unfortunately, due in part to the historic practice of forced castration, the word 'eunuch' is now largely pejorative, although it is the correct biological term for a castrated male. We examine the benefits and risks of contemporary castrated males accepting this identity to help them adapt to the changes they experience.

The good news for prostate cancer patients currently
undergoing chemotherapy treatments is that, genetic markers
which once seemed the kiss of death may now permit classification
into a group of new prostate cancer treatments! Hospitals should
be made aware that if their prostate cancer patients are PTEN or
p53 mutant, these patients may benefit from therapy blocking
interleukin-6 (IL6)[1]. With our present-day individualized
approach to medicine, standard diagnostic tests can be employed,
such as a cheek swab, to flag patients who are candidates for this
novel treatment. This novel immunotherapy is presently in drug
development and will treat metastasis in the most refractory
prostate cancer patients. What does this novel IL6-based therapy
mean for a prostate cancer patient who is nearing Stage T3 or
T4 (TNM, Tumor/Nodes/Metastasis system [2]) or has already
entered it? It means a fighting chance.

Prostate Cancer is one of the common cancers in the world. It could primarily disseminate to the bone and can lead to death. In order to address its life-threatening distant metastasis, it is important to diagnose it earlier for timely treatment. Bone metastasis is usually diagnosed deploying bone scan imaging. However, interpretation of the bone scans is a tedious procedure for the physicians and often leads to misinterpretation either as overestimation or underestimation of the metastasis. To minimize the risk of misinterpretation, one of the accurate methods is quantitative analysis of the bone scans in order to ascertain, whether a metastatic lesion is present or not. There are several methods to-date which can be used to analyze the extent of such lesions. The aim of this study is to use %PAB (quantitative parameter) on a baseline bone scans. Moreover, an improved methodology is introduced by comparing the results with PSA levels. 141 patients with histopathologically proved prostate cancer were chosen to implement the % PAB on individual baseline bone scans. After which, for the calculation of risk of progression or regression of disease and survival rate, 40 patients were chosen from the same dataset. A serial follows up scan was performed to calculate 2-years survival rate. The dataset was again analyzed using the same quantitative parameter and the cut off were calculated as % PAB: 0.5. It was found out that the % PAB method is a good prognostic indicator in baseline scans. Moreover, the prostate cancer patients with the cut off % PAB > 0.5 showed increase risk of disease progression and less survival..

Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that are also highly expressed in the prostate. As a promising candidate, STAMP family genes STAMP1/STEAP2, STAMP2/STEAP4 and STEAP3 are involved in apoptosis and the cell cycle in metastatic prostate cancer. Vascular NADPH oxidase generates superoxide and other ROS, which stimulates IkappaB degradation and NF-kB activation by subunits of NADPH oxidases, namely p47phox and p67phox induced by different stimuli such as hydrogen peroxide. Hydrogen peroxide increased the expression levels of p67phox. They also have a role in redox-sensitive genes such as STAMP gene family. Flow cytometry analysis of LNCaP cells was performed using Annexin V staining and apoptotic index charts were drawn. STAMP1 and STAMP2 showed total anti-oxidant capacity versus control with hydrogen peroxide incubation. Using siRNA technology in LNCaP cells expressing mutant p53 silencing of p53 showed significant increase in MDM...

Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that are also highly expressed in the prostate. As a promising candidate, STAMP family genes STAMP1/STEAP2, STAMP2/STEAP4 and STEAP3 are involved in apoptosisand the cell cycle in metastatic prostate cancer. Vascular NADPH oxidase generates superoxide and other ROS, which stimulates IkappaB degradation and NF-kB activation by subunits of NADPH oxidases, namely p47phox and p67phox induced by different stimuli such as hydrogen peroxide. Hydrogen peroxide increased the expression levels of p67phox. They also have a role in redox-sensitive genes such as STAMP gene family. Flow cytometry analysis of LNCaP cells was performed using Annexin V staining and apoptotic index charts were drawn. STAMP1 and STAMP2 showed total anti-oxidant capacity versus control with hydrogen peroxide incubation. Using siRNA technology in LNCaP cells expressing mutant p53 silencing of p53 showed significant increase in MDM2...

Prostate Cancer is now the second biggest cause of cancer mortality in the UK. Media coverage has been rising, with some attributing to a rise in the cases diagnosed and treated in the NHS down to the "Fry and Turnbull effect". Our understanding of prostate cancer has increased tremendously in the past decades, with advances in molecular biology and genomics driving the way to new treatments and diagnostics. This Special Edition of Translational Andrology and Urology 2019: Prostate Cancer Biology and Genomics aims to review the current state of prostate cancer genomics, proteomics, diagnostics and treatment.

This article analyses the bibliographical production on the theme of gender, masculinities and health published in the journal Saúde e Sociedade. The method used was the literature review of narrative , of qualitative character, which addressed the search according to the descriptors " gender " and " masculinities " on all issues of the journal which are available in the SciELO system. 49 abstracts were selected for descriptive analysis; among these, 13 articles that focused on men and women or which used only men as subjects of analysis were analysed in depth. The narrative analysis of the articles and the comparison with the themes, objects and conceptual perspectives of the field of Public Health point to the expansion of the field of research on gender, masculinity and health, but also to the incipient character of conceptual approaches, especially regarding the intersectionality of gender and other social markers of difference, such as social class, generation and sexuality. This critical review evi-dences an expanding research field in terms of its strengths and weaknesses.

This article analyses the bibliographical production on the theme of gender, masculinities and health published in the journal Saúde e Sociedade. The method used was the literature review of narrative , of qualitative character, which addressed the search according to the descriptors " gender " and " masculinities " on all issues of the journal which are available in the SciELO system. 49 abstracts were selected for descriptive analysis; among these, 13 articles that focused on men and women or which used only men as subjects of analysis were analysed in depth. The narrative analysis of the articles and the comparison with the themes, objects and conceptual perspectives of the field of Public Health point to the expansion of the field of research on gender, masculinity and health, but also to the incipient character of conceptual approaches, especially regarding the intersectionality of gender and other social markers of difference, such as social class, generation and sexuality. This critical review evi-dences an expanding research field in terms of its strengths and weaknesses.

Prostate cancer studies focus on identification of androgen receptor (AR) regulated genes that are also highly expressed in the prostate. As a promising candidate, STAMP family genes STAMP1/STEAP2, STAMP2/STEAP4 and STEAP3 are involved in apoptosis and the cell cycle in metastatic prostate cancer. Vascular NADPH oxidase generates superoxide and other ROS, which stimulates IkappaB degradation and NF-kB activation by subunits of NADPH oxidases, namely p47phox and p67phox induced by different stimuli such as hydrogen peroxide. Hydrogen peroxide increased the expression levels of p67phox. They also have a role in redox-sensitive genes such as STAMP gene family. Flow cytometry analysis of LNCaP cells was performed using Annexin V staining and apoptotic index charts were drawn. STAMP1 and STAMP2 showed total anti-oxidant capacity versus control with hydrogen peroxide incubation. Using siRNA technology in LNCaP cells expressing mutant p53 silencing of p53 showed significant increase in MDM2 and decrease of caspase 9 mRNA levels at RT-PCR. Silencing of STAMP2, a significant decrease in p47phox was shown but STAMP1 silencing counteracted this effect on Cu/ZnSOD expression.As a conclusion, STAMP proteins have effects on oxidative stress-induced genes with significant and opposite changes.

and as a factor in men's perception of their bodies and assessment of the emotional and physiological care they receive. For men, losing control is seen as a negative experience, which may lead to negative experiences of preventative methods or care (Courtenay, 2000). Control is also a powerful metaphor for how current medicine, through increasingly technological interventions in the body, is being shaped by technoscience . This "virile" [our emphasis] biomedical agenda should be tempered by a t t e n t i o n t o w h a t s o m e c a l l " s u b j e c t i v e variables," which we call "social or cultural factors". These factors include how men experience different types of masculinities and how these experiences and values inform men's attitudes toward health . Social/cultural factors are relevant to every aspect of health and disease, and taking them into account will open professionals' perception to the complexity and richness of gender-related experiences of health practices.

Antiandrogens that block androgen action through the androgen receptor, often in conjunction with chemical or surgical castration, have been widely used for the treatment of advanced prostate cancer. Although this treatment produces a significant clinical response in most of the patients, the majority of the responders eventually develop recurrences termed castration-resistant prostate cancer. In addition, clinically available androgen receptor antagonists have been shown to possess agonist activity, resulting in an increase in serum prostate-specific antigen levels, which is known as the antiandrogen withdrawal syndrome. Recent studies have demonstrated that new types of androgen receptor signaling inhibitors improve survival in men with castration-resistant prostate cancer. Moreover, other drugs may have the potential of not inducing androgen withdrawal response. This article reviews the characteristics of classical and recent androgen receptor antagonists as well as their clinical efficacy in prostate cancer patients. Novel experimental compounds that may more specifically and effectively target androgens and/or androgen receptor signals in hormone-naive and possibly castration- resistant prostate cancer cells are also discussed.

Prostate Cancer -Diagnostic and Therapeutic Advances 38 cultural contexts and as a factor in men's perception of their bodies and assessment of the emotional and physiological care they receive. For men, losing control is seen as a negative experience, which may lead to negative experiences of preventative methods or care . Control is also a powerful metaphor for how current medicine, through increasingly technological interventions in the body, is being shaped by technoscience . This "virile" [our emphasis] biomedical agenda should be tempered by attention to what some call "subjective variables," which we call "social or cultural factors". These factors include how men experience different types of masculinities and how these experiences and values inform men's attitudes toward health . Social/cultural factors are relevant to every aspect of health and disease, and taking them into account will open professionals' perception to the complexity and richness of gender-related experiences of health practices.

Professionals and policy makers in a host society should pay attention to Latin American countries' ideas of masculinities because a significant proportion of men from these countries become immigrants. Social and health professionals need culture-specific information on ideas of masculinities to ensure that their educational approaches are appropriate for immigrant populations. The literature analysis in this article is a first step towards answering this need. In analyzing Latin American literature, we aimed to identify ideas of masculinities that might influence immigrant men's attitudes towards prostate cancer, and to uncover possible differences between the literature reviewed and the English-language literature available to professionals. Over 52 online reports, articles, and books (from 1991-2007), in Spanish and Portuguese, were examined. The thematic analysis method was used to guide reading, retrieval, and conceptual classification into 60 topics. Articles and books in English (from 2002-2008) were also examined. In the literature from Latin America, discourse about plural forms of masculinity co-exists with discourse about traditional masculinity. We identified an interactions / rights / affectivity triad that implies collective responsibility for promoting men's health. In the English-language literature, a persistent traditional view of masculinity may mask other aspects of these men's lives, limiting the scope of recommendations for professional practice. Men's health policies and preventive campaigns should take into account the ideas of masculinities particular to the nature and territories of social interaction of Latin American immigrant men. Questions about incorporation / resistance to immigrant men's values in a host society remained unanswered in this analysis.