Search

Prostate cancer (PCa) represents the most common tumor in male and one of the most relevant causes of death in Western countries. Androgen deprivation therapy (ADT) constitutes a widely used approach in advanced PCa. When PCa progresses in spite of ADT and castrate levels of testosterone, the severe clinical condition termed as metastatic castration-resistant prostate cancer (mCRPC) takes place. The only approach to mCRPC has been represented by chemotherapy with taxanes for many years. Nevertheless, recently introduced treatments such as 2nd generation antiandrogens (i.e. enzalutamide and abiraterone), cell immunotherapy with sipuleucel-T or targeted alpha therapy with 223Ra-dichloride, have dramatically changed mCRPC prognosis. These novel therapies call for an unmet need for imaging biomarkers suitable for patients’ pre-treatment stratification and response assessment. In this scenario, nuclear medicine can provide several metabolic and molecular probes for investigating pathological processes at a cellular and sub-cellular level. The aim of this paper is to review the most relevant findings of the literature published to date on this topic, giving particular emphasis to the pros and cons of each tracer and also covering future prospects for defining personalized therapeutic approaches.

La castración constituye una de las medidas más antiguas en la lucha contra la delincuencia sexual, cuya aplicación resurge a finales del siglo pasado en su versión química, a través del tratamiento farmacológico con antiandrógenos. En el presente trabajo se abordan los problemas de carácter médico, ético y jurídico que plantea esta medida, tanto en su modalidad química como quirúrgica, analizando el tratamiento jurídico que recibe en el Derecho comparado y la distinta finalidad (incapacitante, rehabilitadora o de instrumento de control del riesgo) a la que responde. Asimismo, se consideran las posibles vías de aplicación en nuestro vigente orden penal -al albur principalmente de la medida de seguridad de libertad vigilada y los programas de tratamiento penitenciario-, así como la previsión que en este sentido se recoge en el Anteproyecto de Ley Orgánica integral de la libertad sexual. Se concluye que su administración solo tiene sentido con un enfoque rehabilitador, sobre una base voluntaria, y respecto de una categoría muy concreta de delincuente sexual. Castration constitutes one of the oldest measures in the fight against sexual delinquency, whose application resurfaces at the end of the last century in its chemical version, through pharmacological treatment with anti-androgens. This paper addresses the problems of medical, ethical and legal nature posed by this measure, both in its chemical and surgical modalities, analyzing the legal and medical treatment in comparative Law and the different purpose (incapacitation, rehabilitation and risk control) to which it responds. Likewise, the possible means of application in our criminal system are considered -at the risk mainly of the security measure of probation and the prison treatment programs-, as well as the provision that in this sense is included in the Draft Organic Law comprehensive sexual freedom. It is concluded that its implementation only makes sense with a rehabilitative approach, on a voluntary basis, and with respect to a very specific category of sex offender. Artículo realizado en el seno del PID2019-107974RB-100: “Derecho penal y distribución de la riqueza en la sociedad tecnológica”.

Most prostate cancer patients who undergo androgen-deprivation therapy or orchiectomy will eventually develop castration-resistant prostate cancer (CRPC), often preceded by a nonmetastatic CRPC state known as M0CRPC. The recent development of second-generation antiandrogens provides clinicians with efficacious and safe treatments for M0CRPC. However, the complexity of these patients, who typically have to deal with underlying comorbidities and polypharmacy, often challenges therapeutic decisions in this setting. The recent development of novel imaging techniques also provides clinicians with tools for detecting metastases with high sensitivity and specificity. However, the lack of evidence on the early detection of metastases and the corresponding impact on therapeutic decisions makes these techniques a double-edged sword that must be managed appropriately. Here, we present the expert view of the rapidly evolving concept of M0CRPC and provide recommendations for the identification of these patients, the appropriate use of the emerging imaging modalities, and patients’ management, particularly considering their clinical complexity and the recent development of next-generation antiandrogens.

Modern antiandrogens: abiraterone acetate (inhibitor of CYP17 cytochrome) and enzalutamide (irreversible inhibitor of androgen receptor) are the drugs that are increasingly often administered in treatment of castration-resistant prostate cancer. Despite their clinical efficacy, especially in terms of prolonged survival and improved quality of life of patients, they pose of problem for a practicing oncologist such as possible cardiovascular complications (particularly arterial hypertension), which may lead to the cessation of this form of therapy. This article provides a brief overview of the mechanisms responsible for the above complications, including practical recommendations in the event such complications arise. A simple scheme of action for control of cardiovascular risk factors has been presented, which can improve the prognosis in this population of patients.

Context: Polycystic Ovarian Syndrome (PCOS) is a common multisystem disease that causes reproductive, metabolic and psychological changes. Lately, the use of medicinal plants has grown considerably in the hope of reducing the side effects of synthetic drugs and in an attempt to reduce harm and costs. Objective: Analyze the use of medicinal plants that are used in PCOS from an integrative literature review, in order to verify the pharmacological effects caused by their use in PCOS. Methodology: An integrative literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines through searches in PubMed, Scielo and Scopus databases to select ethnobotanical, ethnopharmacological, preclinical and clinical studies, published in full in the last 10 years (2012 – 2022), in English, Portuguese and Spanish using health descriptors. Results: The ten publications analyzed showed ten families and 11 plant species, which, in general, showed antiandrogenic activities. Conclusions: With the exception of Foeniculum vulgare, all other medicinal plants analyzed in this study have anti-androgenic effects on PCOS. However, these species need better clinical and toxicological evaluations regarding their use in order to provide a safe and effective therapy. Contexto: El síndrome de ovario poliquístico (SOP) es una enfermedad multisistémica común que causa cambios reproductivos, metabólicos y psicológicos. Últimamente, el uso de plantas medicinales ha crecido considerablemente con la esperanza de reducir los efectos secundarios de las drogas sintéticas y en un intento por reducir daños y costos. Objetivo: Analizar el uso de las plantas medicinales que se utilizan en el SOP a partir de una revisión integrativa de la literatura, con el fin de verificar los efectos farmacológicos provocados por su uso en el SOP. Metodología: Se realizó una revisión integrativa de la literatura utilizando las guías Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) a través de búsquedas en las bases de datos PubMed, Scielo y Scopus para seleccionar estudios etnobotánicos, etnofarmacológicos, preclínicos y clínicos, publicados íntegramente en el últimos 10 años (2012 – 2022), en inglés, portugués y español utilizando descriptores de salud. Resultados: Las diez publicaciones analizadas mostraron diez familias y 11 especies de plantas, las cuales, en general, mostraron actividades antiandrogénicas. Conclusiones: Con la excepción de Foeniculum vulgare, todas las demás plantas medicinales analizadas en este estudio tienen efectos antiandrogénicos sobre el SOP. Sin embargo, estas especies necesitan mejores evaluaciones clínicas y toxicológicas con respecto a su uso para brindar una terapia segura y efectiva. Contexto: A Síndrome do Ovário Policístico (SOP) é uma doença multissistêmica comum, que causa alterações reprodutivas, metabólicas e psicológicas. Ultimamente, o uso de plantas medicinais vêm crescendo consideravelmente na esperança de reduzir os efeitos colaterais das drogas sintéticas e na tentativa de redução dos danos e custos. Objetivo: Analisar o uso de plantas medicinais que são utilizadas na SOP a partir de uma revisão integrativa da literatura, com a finalidade de verificar os efeitos farmacológicos ocasionados a partir do uso na SOP. Metodologia: Foi realizada uma revisão integrativa da literatura utilizando as diretrizes Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) através de pesquisas nas bases de dados PubMed, Scielo e Scopus para seleção de estudos etnobotânicos, etnofarmacológicos, pré-clínico e clínico, publicados na íntegra nos últimos 10 anos (2012 – 2022), nos idiomas Inglês, Português e Espanhol a partir de descritores em saúde. Resultados: As dez publicações analisadas evidenciaram dez famílias e 11 espécies de plantas, que, de modo geral, apresentaram atividades antiandrogênicas. Conclusões: Com exceção de Foeniculum vulgare, todas as demais plantas medicinais analisadas neste estudo possuem efeitos anti androgênicos na SOP. Porém, essas espécies necessitam de melhores avaliações clínicas e toxicológicas quanto ao seu uso para que seja possível proporcionar uma terapia segura e eficaz.

SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19., TMPRSS2 is regulated by androgen receptor signalling in the prostate, however it is unclear if blocking this signalling is beneficial in the context of SARS-CoV-2 lung infection. Here the authors show that antiandrogen treatment downregulates TMPRSS2 in the lung and reduces viral entry and infection.

[Image: see text] Androgen receptor (AR) transcriptional reactivation plays a key role in the development and progression of lethal castration-resistant prostate cancer (CRPC). Recurrent alterations in the AR enable persistent AR pathway signaling and drive resistance to the treatment of second-generation antiandrogens. AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure–activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC.

Androgen deprivation therapy (ADT) combined with docetaxel or antiandrogens (abiraterone, enzalutamide, or apalutamide) improved the outcomes in men with metastatic hormone-sensitive prostate cancer (mHSPC). When multiple options are available, the dilemma remains how to choose among these options. Similarly, issues of bone health, long-term side effects of therapies, and hereditary risk need to be discussed for comprehensive care. In the present article, we reviewed the relevant evidence for the treatment of mHSPC. ADT alone is not the current standard of care for most patients. In these times of plenty and price crisis, it is imperative to find the best option for treating these patients.

Background: Antiandrogen withdrawal (AAW) response is the paradoxical decrease in prostate-specific antigen (PSA) following the withdrawal of antiandrogen in patients with advanced prostate cancer. Currently, the reported literature on the proportion of patients exhibiting AAW response and the differences in PSA response between the types of antiandrogens is unclear. Methods: This review aimed to explore the PSA response to AAW and to identify if the response depends on the type of antiandrogens. A literature search was performed using databases PubMed, Cochrane and EMBASE with a cut-off date of 23rd of November 2020. Studies reporting on outcomes of AAW and prostate cancer were included. Studies were screened by two reviewers and relevant data extracted. Meta-analysis of outcomes was reported using random-effects and fixed-effects model. A subgroup analysis was performed for type of antiandrogen. Results: From 450 studies, 23 were included with a total of 1474 patients with advanced prostate cancer were available for further analysis. Overall, 395 (26%) patients had any reduction in PSA levels (95% CI: 20–32%) and 183 (11%) patients had a ≥50% reduction in PSA levels (95% CI: 6–16%). Among the 1212 patients on first-generation antiandrogens, 30% (95% CI: 23–38%) had any PSA decline with 15% patients having a ≥50% PSA decline (95% CI: 8–22%). In contrast, among the 108 patients on second-generation antiandrogens, 7% (95% CI: 0–13%) had any PSA decline and only 1% (95% CI: 0–5%) had a ≥50% PSA decline. Also, among the 154 patients on androgen synthesis inhibitors, 26% (95% CI: 19–33%) had any PSA decline and only 4% (95% CI: 0–13%) had a ≥50% PSA decline. Conclusions: One-fourth of patients treated with AAW show a PSA response. However, PSA response to AAW is uncommon with second-generation antiandrogens and androgen synthesis inhibitors. Further research is required to understand the differences in response between the types of antiandrogen. Refereed/Peer-reviewed

The ligand-binding domain of the androgen receptor (AR) is a target for drugs against prostate cancer and offers three distinct binding sites for small molecules. Drugs acting on the orthosteric hormone binding site suffer from resistance mechanisms that can, in the worst case, reverse their therapeutic effect. While many allosteric ligands targeting either the activation function-2 (AF-2) or the binding function-3 (BF-3) have been reported, their potential for simultaneous administration with currently prescribed antiandrogens was disregarded. Here, we report results of 60 μs molecular dynamics simulations to investigate combinations of orthosteric and allosteric AR antagonists. Our results suggest BF-3 inhibitors to be more suitable in combination with classical antiandrogens as opposed to AF-2 inhibitors based on binding free energies and binding modes. As a mechanistic explanation for these observations, we deduced a structural adaptation of helix-12 involved in the formation of the AF-2 site by classical AR antagonists. Additionally, the changes were accompanied by an expansion of the orthosteric binding site. Considering our predictions, the selective combination of AR-targeting compounds may improve the treatment of prostate cancer.

Синдром полікістозних яєчників (СПКЯ) є однією з найчастіших причин гіперандрогенії, порушення менструального циклу та кардіометаболічної дисфункції в жінок. Повна клінічна картина включає нерегулярний менструальний цикл, гірсутизм, ожиріння, інсулінорезистентність та ановуляторне безпліддя. Ця стаття висвітлює основні дискусійні питання щодо визначення синдрому полікістозних яєчників, підкреслюючи його фенотипічну неоднорідність. Наведені основні діагностичні критерії, які в свою чергу визначають різні фенотипи даного синдрому. На теперішній час з метою покращення діагностики та лікування СПКЯ ідентифіковано чотири різних фенотипи, які включають певні комбінації діагностичних критеріїв: 1) гіперандрогенізм (клінічний або біохімічний) та хронічна ановуляція; 2) гіперандрогенізм та полікістоз яєчників при УЗД, але з овуляторними циклами; 3) хронічна ановуляція і полікістозні яєчники без гіперандрогенемії; 4) гіперандрогенемія, хронічна ановуляція та полікістозні яєчники. В статті наведені основні групи препаратів, які слід застосовувати при лікуванні даної патології згідно з останніми міжнародними рекомендаціями, систематичними оглядами та мета-аналізами. Зокрема, зазначені особливості застосування інсулінових сенсибілізаторів та інших антидіабетичних препаратів, аналогів глюкагоноподібного пептиду-1, оральних контрацептивів і прогестинів, антиандрогенів. Особлива увага приділена вибору лікування залежно від фенотипу та індивідуальних потреб пацієнтки. Окремо висвітлено терапевтичний підхід до метаболічного, гіперандрогенного та репродуктивного фенотипу. Ановуляція або рідкісна овуляція є головною причиною порушення репродуктивної функції в жінок із СПКЯ. В статті наведені основні методи і препарати, які слід застосовувати в жінок із метою індукції овуляції, в тому числі розглянуто особливості індукції овуляції в жінок із резистентністю до кломіфену. Наріжним каменем лікування жінок із СПКЯ та ожирінням, зокрема при абдомінальному фенотипі, є модифікація способу життя, в тому числі дієта і фізичні вправи. Наведені в статті клінічні рекомендації засновані на принципах доказової медицини

BACKGROUND: Gender-affirming hormone therapy for transgender women includes estrogen and antiandrogens (cyproterone acetate, spironolactone, or gonadotropin-releasing hormone agonists). Both estrogen and antiandrogens are reported to increase prolactin levels. The objective is to systematically review the evidence of the effects of antiandrogens on prolactin levels, hyperprolactinemia, and prolactinomas among transgender women on estrogen therapy. METHODS: We searched PubMed, Embase, and PsycInfo up to May 2020. We included studies with at least 3 months follow-up that evaluated the effects of antiandrogens among transgender women and reported on prolactin levels, hyperprolactinemia, or image-confirmed prolactinomas. Two reviewers independently screened studies for eligibility, serially abstracted data, and independently assessed risk of bias and graded strength of evidence. FINDINGS: We included 17 studies (16 publications): 8 prospective cohorts, 8 retrospective cohorts, and 1 cross-sectional study, each with a moderate to serious risk of bias. Among transgender women on estrogen, prolactin levels increased by over 100% with cyproterone acetate and by up to 45% with spironolactone. However, we were unable to isolate the effects of antiandrogens from estrogen therapy. We were unable to draw conclusions about effects of antiandrogens on hyperprolactinemia and prolactinomas. INTERPRETATION: Prolactin levels may be increased in transgender women who are taking both estrogens and an antiandrogen. Future research is needed to determine the effects of different antiandrogens on prolactin levels separately from estrogen therapy. Ideally, future studies would be prospective, provide either a comparison of two different antiandrogens or compare combination of estrogen and antiandrogen therapy to estrogen alone, and control for possible confounders.

Androgenetic alopecia (AGA) is the most common type of hair loss in adults and may be particularly distressing for gender minority patients, given the close relation between hair and gender expression. Furthermore, use of gender affirming hormones such as testosterone in transmen and estrogen/antiandrogens in transwomen has a direct effect on hair growth distribution and density. Clinicians should thus be knowledgeable about the effects of sex hormones on the hair growth cycle to comfortably diagnose and treat AGA in gender minority patients.

Purpose: To conduct a population-based study to determine whether the use of GnRH agonist and antiandrogens are associated with an increased risk of cardio-cerebrovascular disease (CCVD) in Asian patients with prostate cancer using the National Health Insurance Service-Elderly Cohort Database (NHIS-ECD). Materials and Methods: We included a total of 2,413 men aged 60 years or older with prostate cancer between January 2003 and December 2008. Outcomes of interest included the first occurrence of cardiovascular events [acute myocardial infarction (AMI), ischemic heart disease (IHD)] and cerebrovascular events [ischemic stroke (IS), and cerebrovascular disease (CVD)]. Results: The 5-year AMI-free rates of patients diagnosed with prostate cancer and treated with GnRH agonists, antiandrogens alone, or androgen deprivation therapy (ADT)-naive interventions were 97.0%, 96.5%, and 98.3%, respectively, while the 5-year IHD-free rates were 93.2%, 92.3%, and 94.5%, respectively. Exposure to GnRH agonists or antiandrogen regimens did not significantly increase the risk of AMI or IHD compared to ADT-naive treatment in multivariate Cox proportional-hazards models after adjusting for other covariates. Five-year IS-free rates of patients exposed to GnRH agonists, antiandrogens alone, and those with ADT-naive prostate cancer were 94.8%, 94.7%, and 95.5%, respectively, while the five-year CVD-free rates were 92.9%, 93.3%, and 94.6%, respectively. Cox proportional-hazards models also failed to show that men who received GnRH agonist or antiandrogen treatment alone carried a significantly increased risk for IS or CVD compared to ADT-naive patients. Conclusions: The current study based on Asian population suggests that treatment with neither GnRH agonist nor antiandrogens increases the risk of cardio-cerebrovascular disease compared to patients with ADT-naive prostate cancer.

For a particular subgroup of individuals with severe paraphilic disorders and a high risk of sexual recidivism, the combination of sex drive–reducing medications and psychotherapy is a promising treatment approach. The present quasi-experimental study aims at comparing differences in clinical characteristics and dynamic risk factors between persons receiving (+TLM, n = 38) versus not receiving (−TLM, n = 22) testosterone-lowering medications (TLMs). Individuals receiving TLM were more frequently diagnosed with paraphilic disorders. Neither the criminal history nor average risk scores differed between the two groups. In the +TLM, Stable-2007 scores showed a stronger decrease after TLM treatment was started. This accounted especially for the general and sexual self-regulation subscales. Individual variations in risk, however, were not predicted by TLM but were significantly related to treatment duration and Psychopathy Checklist–Revised (PCL-R) Factor I. Paraphilic patients with problems in self-regulatory abilities seem to profit most from pharmacological sex drive–reducing treatment. Furthermore, therapists seem to underestimate deviant sexual fantasies in medicated patients.

Background The role of androgens on COVID-19 is well established. Proxalutamide is a second-generation, non-steroidal antiandrogen (NSAA) with the highest antiandrogen potency among NSAAs and concurrent regulation of angiotensin-converting enzyme 2 (ACE2) expression and inflammatory response. Proxalutamide has been demonstrated to be effective to prevent hospitalizations in early COVID-19 in randomized clinical trials (RCTs). Conversely, in hospitalized COVID-19 patients, preliminary results from two different arms of an RCT (The Proxa-Rescue AndroCoV Trial) also demonstrated a reduction in all-cause mortality. This study aims to report the final, joint results of the two arms (North arm and South arm) of the Proxa-Rescue AndroCoV trial of the two arms (North and South arms) combined, and to evaluate whether COVID-19 response to proxalutamide was consistent across different regions (Northern Brazil and Southern Brazil). Materials and methods Upon randomization, hospitalized COVID-19 patients received either proxalutamide 300mg/day or placebo for 14 days, in addition to usual care, in a proxalutamide:placebo ratio of 1:1 in the North arm and 4:1 in the South arm (ratio was modified due to preliminary report of high drug efficacy). Datasets of the South and North arms were combined, and statistical analysis was performed for the overall study population. Proxalutamide was compared to placebo group for 14-day and 28-day recovery (discharge alive from the hospital) and mortality rates, and overall and post-randomization hospitalization stay. Results of proxalutamide and placebo groups were also compared between the North and South arms. Analysis was also performed stratified by sex and baseline WHO COVID Ordinary Score. Results A total of 778 subjects were included (645 from the North, 317 from the proxalutamide group and 328 from the placebo group; 133 from the South arm, 106 from the proxalutamide group and 27 from the placebo group). Recovery rate was 121% higher in proxalutamide than placebo group at day 14 [81.1% vs 36.6%; Recovery ratio (RecR) 2.21; 95% confidence interval (95% CI), 1.92-2.56; p

Objective: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering and psychotropic drugs. Material and methods: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class. Results: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs was available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found. Conclusions: Antiandrogens and to a lesser extent 5 alphareductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated to the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.

Per- and poly-fluoroalkyl substances (PFASs) are used extensively in a broad range of industrial applications and consumer products. While a few legacy PFASs have been voluntarily phased out, over 5000 PFASs have been produced as replacements for their predecessors. The potential endocrine disrupting hazards of most emerging PFASs have not been comprehensively investigated. In silico molecular docking to the human androgen receptor (hAR) combined with machine learning techniques were previously applied to 5206 PFASs and predicted 23 PFASs bind the hAR. Herein, the in silico results were validated in vitro for the five candidate AR ligands that were commercially available. Three manufactured PFASs namely (9-(nonafluorobutyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one (NON), 2-(heptafluoropropyl)-3-phenylquinoxaline (HEP), and 2,2,3,3,4,4,5,5,5-nonafluoro-N-(4-nitrophenyl)pentanamide (NNN) elicited significant antiandrogenic effects at relatively low concentrations. We further investigated the mechanism of AR inhibition and found that all three PFASs inhibited AR transactivation induced by testosterone through a competitive binding mechanism. We then examined the antiandrogenic effects of these PFASs on AR expression and its responsive genes. Consistently, these PFASs significantly decreased the expression of PSA and FKBP5 and increased the expression of AR, similar to the effects elicited by a known competitive AR inhibitor, hydroxyflutamide. This suggests they are competitive antagonists of AR activity and western blot analysis revealed these PFASs decreased intracellular AR protein in androgen sensitive human prostate cancer cells. Hence, the findings presented here corroborate our published in silico approach and indicate these emerging PFASs may adversely affect the human endocrine system.

Orientador: Sebastião Roberto Taboga Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: O crescimento normal, a diferenciação e a manutenção da integridade morfofuncional da glândula prostática são dependentes das interações de concentrações constantes de andrógenos com seus receptores. A necessidade de se estudar esta glândula em resposta aos hormônios e o efeito do bloqueio destes, deve-se ao fato da próstata humana ser o sítio de um grande número de doenças relacionadas à idade, sendo que as de maior importância clínica são o câncer prostático e a hiperplasia prostática benigna, as quais podem ser tratadas por estratégias de remoção de andrógenos. Este estudo teve por objetivo a análise imuno-histoquímica do grau de expressão do receptor androgênico (RA) no lóbulo ventral prostático do gerbilo após terapias de bloqueios androgênicos. Setenta e cinco gerbilos machos foram distribuídos, aleatoriamente, em 3 grupos de 25 animais, cada grupo representando uma fase do desenvolvimento pós-natal: jovem, adulto e senil. Em cada fase foi realizada uma análise morfológica e estereológica dos compartimentos prostáticos, bem como a análise imuno-histoquímica da expressão do RA. Além disso, estabeleceu-se a dosagem hormonal das concentrações séricas de testosterona, como método para verificar a relação da quantidade desse andrógeno com a expressão dos RA. Os resultados demonstraram haver um padrão heterogêneo de distribuição dos RA no lóbulo ventral ao longo do desenvolvimento pós-natal, em que quanto mais jovem for o animal maior a interação de andrógenos estimulando a expressão de RA nos compartimentos prostáticos. As terapias de bloqueios androgênicos diminuíram a expressão de RA no lóbulo ventral e a reposição androgênica após esses bloqueios não apresentou o mesmo grau de intensidade de expressão de RA próximo às condições fisiológicas normais. A regulação e a distribuição do RA nos tecidos prostáticos do gerbilo são mecanismos complexos e que, provavelmente, são geneticamente regulados por andrógenos antes do nascimento ou por outros fatores ainda desconhecidos. O gerbilo parece ser um modelo valioso na tentativa de melhorar o conhecimento do comportamento morfofisiológico e patológico dessa importante glândula em humanos ao longo do envelhecimento e da formulação de novas idéias de terapias de combate ao câncer de próstata Abstract: The normal growth, differentiation and maintenance of the morphofunctional integrity of the prostate gland are dependent on the interaction of constant levels of androgens with their receptors. The need to study the responses to hormones under several conditions and the effect of their blockage is due to the fact that the human prostate is the site of a great number of age-related diseases, and the ones with a major medical importance are prostate cancer and benign prostatic hyperplasia, which can both be treated with androgen suppression. The aim of this study was to analyze immunohistochemical degree of expression of androgen receptor (AR) of the ventral lobe of the gerbil prostate during different phases of the postnatal development employing differents treatments for androgen blocking. Seventy-five male gerbils were distributed, randomly, into 3 groups of 25 animals each, where each group corresponded to one phase of postnatal development: young, adult and aged phase. In each phase, it was possible to morphologically and stereologically analyze the compartments of prostatic ventral lobe, as well as to immunohistochemically analyze the degree of expression of androgen receptor. In addition, it was possible to establish the hormonal dosage of serum testosterone concentrations given the comparative approach of the expression of androgen receptors. There is a heterogeneous pattern of AR distribution in the prostatic ventral lobe throughout postnatal development, in which the younger animal is the higher, the interaction of circulating androgens that stimulate the AR expression in the compartments prostatics. The androgen blockage therapies decreased AR expression in the ventral lobe, but the androgen reposition after these blockages was not showed the same the degree of expression of androgen receptor near normal physiological conditions. The regulation and distribution of AR along the gerbil prostatic tissues are complex mechanisms that are likely to be genetically regulated by androgens prenatally or by other factors that are still unknown. The gerbil seems to be a valuable model in the attempt to improve the understanding of the morphophysiological and pathological behavior of this important gland in humans throughout aging and to stimulate new therapeutic ideas to fight prostate cancer Doutorado Biologia Celular Doutor em Biologia Celular e Estrutural

Orientador: Sebastião Roberto Taboga Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: A próstata é uma glândula exócrina túbulo-alveolar composta, do sistema genital masculino, que secreta parte do líquido seminal. Sua diferenciação dá-se no início do desenvolvimento embrionário e termina na puberdade, sendo que a testosterona (T) tem papel fundamental no seu desenvolvimento e em sua manutenção, após sua conversão pela enzima 5a.-redutase para uma isoforma cerca de 10 vezes mais potente, a dihidrotestosterona (DHT). Uma série de doenças podem acometer a próstata, dentre elas o câncer e a Hiperplasia Benigna Prostática (HBP), e a principal forma de controle dessas doenças é a diminuição dos níveis séricos de T, que pode ser conseguida através da castração cirúrgica (orquiectomia) e da administração de antiandrógenos (castração química). Algumas das drogas mais usadas na castração química são a flutamida e o acetato de ciproterona. A primeira é um antiandrógeno não-esteroidal que compete com a T e com a DHT pelo receptor de andrógeno (RA) nas células da próstata, e a segunda é uma droga esteroidal que além de competir pelo RA inibe a produção de Hormônio Luteinizante (LH) pela hipófise, o que por sua vez inibe a produção de T pelos testículos. O objetivo desse trabalho foi avaliar, morfológica e histoquimicamente o comportamento do tecido prostático regredido após 30 dias de ablação de T, tanto pela orquiectomia quanto pela castração química, ambas seguidas de administração de T exógena e suspensão do tratamento, respectivamente. Para tanto foram usados 40 gerbilos (Meriones unguiculatus, Criscetidae, Gerbilinae) machos adultos, os quais foram divididos em dois grupos experimentais (G.Ex. 01 e G.Ex. 02) e dois grupos controle (G.e. 01 e G.e. 02). G.Ex. 01 foi constituído por 20 animais os quais sOITeramorquiectomia bilateral e após 30 dias receberam doses de cipionato de testosterona (TC) a uma concentração de 25mm/Kg, em intervalos de 48 horas, durante 21 dias, e os animais foram sacrificados após O,7, 14 e 21 dias do inicio do tratamento com Te. G.Ex 02 (20 animais) recebeu doses semanais e alternadas dos antiandrógenos acetato de ciproterona e flutamida (0,3ml/animal/dia numa concentração de 25mgIKg) diluídos em óleo de milho, durante 30 dias, e após a suspensão do tratamento anti-androgênico os animais foram sacrificados após de O,7, 14 e 21 dias. O 8 G.C. 01 foi constituído por 5 animais adultos não castrados e o G.c. 02 por 5 animais adultos castrados que receberam óleo de milho, o veículo de diluição das drogas. Os resultados demonstraram que, tanto a castração cirúrgica quanto a química provocaram uma drástica regressão do peso do complexo prostático após 30 dias quando comparados com o grupo controle. A dosagem hormonal mostrou uma redução na quantidade de T circulante no caso da castração cirúrgica e na castração química e o L.H. apresentou um aumento durante a castração cirúrgica e uma diminuição durante a castração química. Após 30 dias de castração, em ambos os grupos, houve uma drástica diminuição na altura epitelial, que foi mais intensa em G.Ex 02, que, juntamente com a pequena quantidade de retículo endoplasmático rugoso (RER), caracterizou uma pouca atividade secretora dessas células. As células musculares lisas (CML) apresentaram um fenótipo estrelado e irregular, e houve um pregueamento da membrana basal (MB) acompanhada de uma diminuição na quantidade de vesículas secretoras. Após a reposição hormonal, em G.Ex O1 pôde ser notado um aumento na altura epitelial, acompanhado da presença de numerosas e alargadas cisternas de RER. As CML retomaram seu fenótipo característico, mas passaram a apresentar uma enorme quantidade de RER em seu citoplasma, caracterizando uma modulação de seu fenótipo contrátil para um fenótipo secretor. A suspensão do tratamento antiandrogênico em G.Ex 02 promoveu a retomada da altura do epitélio e um aumento na quantidade de RER, e estas células passaram a apresentar uma grande quantidade de vesículas lipídicas em seu citoplasma basal. Como em G.Ex O1 as CML retomaram seu fenótipo característico, e também apresentaram um aumento na quantidade de RER. Assim, estes dados nos permitem assumir que o tecido prostático apresentou uma notável capacidade de involução após supressão androgênica e uma capacidade de reorganização após reposição hormonal, e os eventos decorrentes da orquiectomia e da subseqüente administração de T mostraram mais intensos para o tecido prostático Abstract: The prostate is an exocrine gland of the male genital system, which secretes part of seminal liquidolts differentiation initiates in the beginning of the embryonic development and finishes during the puberty. Testosterone (T) plays an essential role in prostate maintenance, after transformation, by 5a-reductase enzyme, to dehidrotestostorone (DHT) an more potent isoform. As Benign Prostatic Hyperplasia (BPH) and cancer may attack prostate gland, the down regulation of T levels by surgical castration (orchiectomy) or by the administration of anti-androgens drugs, such as flutamide and cyproterone acetate (chemical castration) have been the principal therapies to control these disease. The nonsteroidal antiandrogen flutamide acts by competitive inhibition of the androgen receptors (AR) in the prostate cells. The cyproterone acetate is a steroidal drug besides competing for the AR inhibits Luteinizant Hormone (LH) production on the pituitary gland that themselves inhibit T production by testis. The aim of this work was to evaluate morphologically and histochemically the behavior of prostatic tissue regression after 30 days of T ablation by orchiectomy and by chemical castration, both followed by T administration and suspension oftreatment, respectively. Two experimental groups (Ex.G. 01 and Ex.G. 02) of 20 adult gerbil (Meriones unguiculatus) each were employed. ln the Ex.G.Ol the animais underwent bilateral orchiectomy and after 30 days they received testosterone cipionate (TC) doses (25mm/Kg) during 21 days every 48 hours. They were sacrificed at O, 7, 14 and 21 days of the TC treatment beginning. Ex.G. 02 received altemates doses of cyproterone acetate and flutamide (0,3mI/animaI/day, at 25mg/Kg) dissolved in com oil, during 30 days weekly. They were sacrificed at O,7, 14 and 21 days after treatment interruption. As control group 5 animaIs not castrated (C.G.Ol) and 5 castrated animaIs (C.G.02) received com oil, the drug dilution vehicIe. Results showed that after 30 days of both surgical and chemical castration a drastic regression in the prostate weight occurred. Hormonal dosages reveled serum T leveI reduction in both surgical and chemical castration, while serum LH leveI increased during surgical castration and decreased during chemical castration. After 30 days of castration in both groups there were10 intense decreases of epithelium height, more intensive in EX.G. 02, and notable small amount of rugous endoplasmatic reticulum (RER), which characterized a low secretory activity of those cells. Some smooth muscle cells (SMC) showed a spinous and irregular phenotype along with infolding basal membrane and decrease of secretory vesicle amount. After hormonal replacement in EX.G. 01 were noted an increase in epithelial height and a greater RER quantity. Those altered SMC recovered its normal pattem and the considerable number of RER observed in the cytoplasm suggests a modulation of these cells ITom contractile to secretory phenotype. In EX.G. 02 the treatment interruption promoted an increase in epithelial height and in the amount ofRER, besides lots oflipid vesicles at basal cytoplasm. Like in EX.G. 01 SMC retook its normal phenotype, but showed an increase of RER amount to. These data leads to conclude that prostatic tissue showed a high capacity of involution after androgenic ablation and a capacity or reorganization after hormonal replacement, but the events promoted by orchiectomy and T administration appear to be more aggressive to the tissue Mestrado Biologia Celular Mestre em Ciências Biológicas

The COVID-19 pandemic has derailed the management of many cancers. Prostate cancer although a disease known for good response to treatment has posed unique challenges in this pandemic in view of the co-morbidities associated with these elderly patients. A pandemic specific treatment approach following the RADS (Remote, Avoid, Defer, Shorten) principle is required while dealing with these patients. Very low, low and favourable intermediate risk cancers may be kept on active surveillance rather than active treatment. Unfavourable intermediate, high and very high risk cases may follow the ‘defer’ policy by initiating hormonal therapy for 6-8 months to defer radiotherapy. When radiation is planned for these patients extreme or moderate hypo fractionation may be used to follow the ‘shorten’ policy. Metastatic hormone sensitive cancers may be initiated on hormonal therapy avoiding antiandrogens like Abiraterone and chemotherapy upfront. In the castration resistant phase the antiandrogens like Abiraterone or Enzalutamide may be given preference over chemotherapy. In the post operative settings early salvage may be preferred over adjuvant that too, using hypofractionation. Symptomatic patients require prompt attention and radiation should not be delayed for palliation of impending spinal compression or fracture or for local symptoms. Aggressive histologies like small cell types also need prompt treatment. Other general measures like universal masking, hand hygiene, physical distancing, respiratory etiquettes, etc., must also be emphasised keeping in mind the vulnerability of these patients.

Terminalia chebula (Haritaki) is known as the “King of Medicines” in Tibet because of its extraordinary powers of healing. It is extensively used in ayurveda, unani and homoeopathic medicine. It is listed first in Ayurvedic literatures due to its multifarious use in treating diseases. However continuous usage of this herb was known to cause decrease in sexual strength and infertility problems in males. Around 150 phytoconstituents have been isolated and characterised from T. chebula having various pharmacological activities. Some of the characterized compounds from T. chebula esp. the flavonoids and phenolics were found to have either antiestrogenic or antiandrogenic effects. This points to the fact that such compounds can function as endocrine disruptors which limits the long term use of this wonder drug. In this study an attempt is made to screen the potential antiandrogenic compounds from T. chebula using molecular docking. Two classes of compounds viz. triterpenoids and ellagitannin metabolites that are known to act as antiandrogens were selected for docking. A total of 17 triterpenoids and 13 ellagitannin metabolites were docked to the three binding sites (viz. ABS, BF3 and AF2 sites) in LBD of Rat and Human AR using AutoDock Vina. Also known agonists and antagonists of AR were docked to the above mentioned binding sites to draw a comparison. Eventhough both triterpenoids and ellagitannin metabolites showed comparable affinity to the binding sites with respect to the reference antagonists, urolithins and its derivatives showed the best binding. This point to the possibility that urolithins and its derivatives can function as potent antiandrogens. At a time when urolithins and ellagitannins are rising as promising nutraceuticals, more studies have to be done on its long term endocrine disrupting effects to ensure safety.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

The use of antiandrogens is gaining significance in dermatology practice these days. Though once considered a domain of endocrinologists and gynecologists, these drugs now constitute an important category while treating a number of dermatologic conditions. A thorough knowledge of these drugs, as well as their applications in dermatology would therefore be of immense value for the practicing dermatologist. This review will throw a bird's eye view on the salient aspects of these drugs and their importance in those conditions, where their usage in applicable.

The Androgen Receptor (AR) pathway plays a major role in both the pathogenesis and progression of prostate cancer. In particular, AR is chiefly involved in the development of Castration-Resistant Prostate Cancer (CRPC) as well as in the resistance to the secondgeneration AR antagonist enzalutamide, and to the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Several small molecules acting as AR antagonists have been designed and developed so far, also as a result of the ability of cells expressing this molecular target to rapidly develop resistance and turn pure receptor antagonists into ineffective or event detrimental molecules. This review covers a survey of most promising classes of non-steroidal androgen receptor antagonists, also providing insights into their mechanism of action and efficacy in treating prostate cancer.

Prostate cancer (PCa) is one of the most common cancers and the fifth most common reason for cancer deaths in the males. Surgical castration combined with androgen deprivation therapy, antiandrogens, and androgen synthesis inhibitors is the current therapeutic modalities for PCa. These strategies inhibit androgen synthesis or reduce its binding to the androgen receptor (AR) but the development of resistance to these therapies and transient responsiveness are challenging issues in the treatment of this cancer. Deregulation of ARs has a vital role in the initiation and progression of PCa. Also, recent findings imply that micro RNAs (miRNAs) are involved in the evolution of PCa and mediate drug resistance in different cancers. Hence, discovering and targeting miRNAs might represent a novel therapeutic approach. This review paid particular attention to the AR pathway and existing information on the possible roles of miRNAs associated with AR pathway and drug resistance to two second-generation antiandrogens, that is, enzalutamide and abiraterone.

Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearing prostate cancer xenografts with RO4929097 display significantly impaired tumor growth. Loss of NOTCH1 additionally decreased metastatic potential of prostate cancer cells in invasion assays in vitro as well as in vivo experiments. Moreover, treatment with gamma secretase inhibitors or NOTCH1 gene deletion synergized with antiandrogen therapies, enzalutamide or abiraterone, to decrease the growth of prostate cancer cells. Combination of gamma secretase inhibitors with abiraterone significantly inhibited cell migration and invasion, while combination with enzalutamide reversed enzalutamide-induced migration and invasion. These collective findings suggest loss of NOTCH1 delays growth of CRPC and inhibits metastasis, and inhibition of Notch1 activation in conjunction with second-generation antiandrogen therapies could delay growth and progression of prostate cancer.

Androgens are important determinants of normal and malignant prostate growth. They function by binding to the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR). All clinically approved AR-targeting antiandrogens for prostate cancer therapy function by competing with endogenous androgens. Despite initial robust responses to androgen deprivation therapy, nearly all patients with advanced prostate cancer relapse with lethal castration-resistant prostate cancer (CRPC). Progression to CRPC is associated with ongoing AR signaling, which in part, is due to the expression of constitutively active AR splice variants that contain the N-terminus of the receptor but lack the C-terminus. Currently, there are no approved therapies specifically targeting the AR N-terminus. Current pharmacologic targeting strategies for inhibiting the AR N-terminal region have proven difficult, due to its intrinsically unstructured nature and lack of enzymatic activity. An alternative approach is to target key molecules such as the cochaperone BAG1L that bind to and enhance the activity of the AR AF1. Here, we review recent literature that suggest Bag-1L is a promising target for AR-positive prostate cancer.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder. Patients may present with a combination of hyperandrogenism symptoms, menstrual irregularities, metabolic syndrome, infertility, acne, and obesity. PCOS diagnosis is based on three diagnostic guidelines. Treatment options include oral contraceptive pills, antiandrogens, and metformin. NPs can improve diagnosed patients' quality of life through education about this disorder.

Antiandrogen therapy is a primary treatment for patients with metastasized prostate cancer. Whilst the biologic mechanisms of antiandrogens have been extensively studied, the operating protocols used for the characterization of these drugs were not identical, limiting their comparison. Here, the antiandrogens Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide were systematically compared using identical experimental setups. Androgen-dependent LNCaP and LAPC4 cells as well as androgen-independent C4-2 cells were treated with distinct concentrations of antiandrogens. Androgen receptor (AR)-mediated gene transactivation was determined using qPCR. Cell viability was measured by WST1 assay. Protein stability and AR localization were determined using western blot. Response to the tested antiandrogens across cellular backgrounds differed primarily in AR-mediated gene transactivation and cell viability. Antiandrogen treatment in LNCaP and LAPC4 cells resulted in AR protein level reduction, whereas in C4-2 cells marginal decreased AR protein was observed after treatment. In addition, AR downregulation was already detectable after 4 h, whereas reduced AR-mediated gene transactivation was not observed before 6 h. None of the tested antiandrogens displayed an advantage on the tested parameters within one cell line as opposed to the cellular background, which seems to be the primary influence on antiandrogen efficacy. Moreover, the results revealed a prominent role in AR protein stability. It is one of the first events triggered by antiandrogens and correlated with antiandrogen efficiency. Therefore, AR stability may surrogate antiandrogen response and may be a possible target to reverse antiandrogen resistance.

Polycystic ovarian syndrome (PCOS) is the most common endocrine condition in women, affecting anywhere from 3% to 13% depending on the population being studied. PCOS often begins in adolescence, but diagnosis is difficult due to the overlap of symptoms with normal puberty. It is also necessary to rule out other potential causes of these symptoms before diagnosis. Once diagnostic criteria have been met, there are many treatment options to consider including lifestyle changes, combined oral contraceptive pills, metformin, and in some cases, antiandrogens. [ Pediatr Ann . 2021;50(7):e272–e275.]

Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (clinicaltrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale P < 0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03–0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost during follow-up, and 2 patients died from acute respiratory distress syndrome. Here we demonstrate the hospitalization rate in proxalutamide treated men was reduced by 91% compared to usual care.

A acne vulgar é uma patologia crónica da unidade pilossebácea caracterizada por polimorfismo cutâneo, sendo das mais prevalentes na adolescência. Pode originar sequelas físicas, como cicatrizes desfigurantes, e psicológicas, nomeadamente diminuição da qualidade de vida e função psicossocial. Assim, torna-se fundamental uma estratégia terapêutica eficaz de modo a promover a sua resolução e, simultaneamente, minimizar a presença destas sequelas. Atualmente, os fármacos disponíveis são diversos, obrigando, na sua seleção, à avaliação biopsicossocial do doente. Estudos recentes têm apontado novos agentes terapêuticos promissores, nomeadamente alternativas aos retinóides tópicos, isotretinoína oral, antiandrogénios orais e antibióticos. Estes poderão permitir uma redução da resistência antibiótica e consequente aumento da eficácia com redução substancial dos efeitos adversos. O melhor perfil de segurança e tolerabilidade poderá otimizar a abordagem terapêutica atual.

Pharmaceuticals and personal care products, antibiotics, estrogens, and antiandrogens are found widely in aquatic environments. Monitoring studies by sampling surface water and effluents of wastewater treatment plants (WWTPs) have been conducted recently to monitor antiandrogens, which, along with estrogens, cause endocrine disruption. However, few studies have investigated antiandrogenic activity (AA) combined with a chemical analyses of emerging antiandrogens. Therefore, we analyzed the presence and persistence of 12 types of antiandrogens, atrazine, and carbamazepine using grab sampling and polar organic chemical integrative sampler (POCIS) along a river affected by WWTP discharges. Water and sediment samples were collected from the WWTP effluent (WW), as well as upstream (US) and downstream (DS) of the WWTP. We detected only tebuconazole, triclosan, propiconazole, and fluconazole during the two sampling campaigns in 2016 and 2017. Grab sampling of the site WW detected tebuconazole (7–77 ng/L), propiconazole (5–47 ng/L), and fluconazole (6–45 ng/L). However, the concentrations in the river water were below the detection limits. Nevertheless, fluconazole and triclosan were detected by POCIS in the site WW (45.7 and 26.8 ng/L, respectively) and all river samples ranges of 0.3–9.3 and 2.4–3.7, respectively. This detection was attributed to the limit of quantification of POCIS being lower than that of grab sampling. Nilutamide and triclosan were detected in the river sediment, suggesting that their concentrations in the water column were at least partly attenuated through sediment sorption. We also observed AA by analyzing POCIS extracts with the yeast androgen screen assay. The highest AA was found in the site WW and it was still observable several kilometers downstream of the point of discharge despite decreasing. Therefore, the WWTP effluent was most likely contributor to the persistent AA in the river.

International audience; Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter-and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and vemurafenib; two active metabolites of them: N-desmethyl imatinib, N-oxide sorafenib; and two AAs: abiraterone and enzalutamide; with short pre-treatment and run time in order to be easily used in clinical practice for their therapeutic drug monitoring (TDM) and facilitating pharmacokinetics and pharmacokinetics/pharmacodynamics studies. Plasma samples were prepared by a single-step protein precipitation. Analytes were separated on a Waters Acquity UPLC ® T3 HSS C18 column by non-linear gradient elution; with subsequent detection by Xevo ® TQD triple quadrupole tandem mass spectrometer in a positive ionization mode. Analysis time was 2.8 minutes per run, and all analytes eluted within 1.46-1.97 minutes. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-500 ng/mL for abiraterone, dasatinib and ibrutinib; 5-500 ng/mL for cobimetinib and palbociclib; 10-5,000 ng/mL for imatinib, N-desmethyl imatinib, nilotinib, sorafenib, N-oxide sorafenib and ruxolitinib; 100-50,000 ng/mL for enzalutamide and 100-100,000 ng/mL for vemurafenib with coefficient of correlation above 0.995 for all analytes. This novel method was successfully applied to TDM in clinical practice.

Gender Identity Dysphoria (GID) is a condition characterized by a strong and persistent identification with the opposite sex. These people consider themselves victims of a sort of biological accident: "a soul in a wrong body". There are numerous theories on the origin of transsexualism: genetic, hormonal and psychological causes have been hypothesized, but those currently most accredited are the neuroanatomical ones. The cornerstones of hormone conversion therapy (Gender Affirming Hormone Therapy, GAHT) are feminizing hormones for transgender women (MtFs) and virilizing for transgender males (FtMs). GID can be present among adolescents and older people. For adolescents is now accepted reversible treatment of puberty withdrawal with hormones that stops the progression of pubertal development in the biological direction not accepted; for elderly people is suggested GAHT in reduced doses. Physicians should consider and discuss with people with GID about fertility preservation, general and cancer risks. We present also data of 127 transsexual patients enrolled at the Garibaldi-Nesima Andrology Clinic in Catania (Italy) from 2003 to 2020. To optimize the conversion treatment with sex hormones, transsexuals require long-term follow-up. GAHT must be performed by a doctor who is familiar with these problems. Therefore, the “do-it-yourself” trend and the lack of medical and laboratory checks over time should be absolutely discouraged. Before proceeding with the surgical sex reassignment, it is recommended to refer to an endocrinologist and psychologist or psychiatrist for a period of 2-3 years. The transition surgical conclusion process must be practiced by a quality surgical team.

Androgen receptor is an important target for the treatment of prostate cancer, and mutations in the androgen receptor have an important impact on the resistance of existing drugs. In this work, we performed molecular dynamics simulations of the existing marketed antiandrogens flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide and its main metabolite ORM15341 in complex with the wild-type and F876L mutant androgen receptor. We calculated the residue-specific binding free energy contribution of the wild-type and mutant androgen receptors with the AS-IE method, and analyzed the hot-spot residues and the binding free energy contributions of specific residues before and after the mutation. In addition, we analyzed the total binding obtained by adding residue binding energy contributions and compared the results with experimental values. The obtained residue-specific binding information should be very helpful in understanding the mechanism of drug resistance with respect to specific mutations and in the design of new generation drugs against possible new mutations.

Background Medical castration, gonadotropin‐releasing hormone agonists, and antiandrogens have been widely applied as a treatment for prostate cancer. Sex steroid hormones influence cardiac ion channels. However, few studies have examined the proarrhythmic properties of medical castration. Methods and Results This study included 149 patients who underwent medical castration using gonadotropin‐releasing hormones with/without antiandrogen for prostate cancer. The changes in the ECG findings during the therapy and associations of the electrocardiographic findings with malignant arrhythmias were studied. The QT and corrected QT (QTc) intervals prolonged during the therapy compared with baseline (QT, 394±32 to 406±39 ms [ P P 80 ms. However, in patients without TdP/VF, the prevalence of an increase in the QTc interval from the pretreatment value of >50 ms was 11%, and an increase in the QTc interval from the pretreatment value >80 ms was found in only 4 (3%) patients. Conclusions Medical castration prolongs the QT/QTc intervals in most patients with prostate cancer, and it could cause TdP/VFs even in patients with no risk of QT prolongation before the therapy. An increase in the QTc interval from the pretreatment value >50 ms might become a predictor of TdP/VF. Much attention should be paid to the QTc interval throughout all periods of medical castration to prevent malignant arrhythmias.

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.

Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.

Testosterone derivatives and related compounds (such as anabolic-androgenic steroids—AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.

Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate cancer halted prostate cancer cell growth and migration in vitro and tumor growth in vivo. These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation antiandrogens as novel therapeutic strategies for advanced prostate cancer. Significance: These findings reveal that induction of ferroptosis is a new therapeutic strategy for advanced prostate cancer as a monotherapy and in combination with second-generation antiandrogens.

The androgen receptor (AR) plays a crucial role in the occurrence and development of prostate cancer (PCa), and its signaling pathway remains active in castration-resistant prostate cancer (CRPC) patients. The resistance against antiandrogen drugs in current clinical use is a major challenge for the treatment of PCa, and thus the development of new generations of antiandrogens is under high demand. Recently, strategies for downregulating the AR have attracted significant attention, given its potential in the discovery and development of new antiandrogens, including G-quadruplex stabilizers, ROR-γ inhibitors, AR-targeting proteolysis targeting chimeras (PROTACs), and other selective AR degraders (SARDs), which are able to overcome current resistance mechanisms such as acquired AR mutations, the expression of AR variable splices, or overexpression of AR. This review summarizes the various strategies for downregulating the AR protein, at either the mRNA or protein level, thus providing new ideas for the development of promising antiandrogen drugs.

The therapeutic action of nitroaromatic antiandrogens nilutamide and flutamide may be complicated by their cytotoxicity, whose mechanisms are still incomprehensively understood. In particular this concerns the enzymatic redox cycling of flutamide and its metabolites, and its impact on their cytotoxicity. In this work, we examined the single-electron reduction of nilutamide, flutamide, its metabolites 2-hydroxyflutamide and 4-nitro-3-trifluorormethyl-phenylamine, and a topical antiandrogen (3-amino-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl)-phenyl) propanamide by NADPH:cytochrome P-450 reductase and adrenodoxin reductase/adrenodoxin. The obtained steady-state bimolecular rate constants of oxidant reduction (kcat/Km) enabled to establish single-electron reduction midpoint potentials (E17) of compounds, −0.377 – −0.413 V, which were in line with enthalpies of formation of their free radicals, obtained by quantum mechanical calculations. Using murine hepatoma MH22a cells, the obtained cytotoxicity vs. E17 correlation based on the data of model nitroaromatic compounds shows that redox cycling and oxidative stress could be the main factor of cytotoxicity of nitroaromatic antiandrogens. Other minor cytotoxicity factors could be their redox metabolism involving NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P-450.

Simple Summary Prostate cancer is the second most common cancer in men world-wide, with nearly 1.3 million new cases each year, and over the next twenty years the incidence and death rate are predicted to nearly double. For decades, this lethal disease has been more or less successfully treated using hormonal therapy, which has the ultimate aim of inhibiting androgen signalling. However, prostate tumours can evade such hormonal therapies in a number of different ways and therapy resistant disease, so-called castration-resistant prostate cancer (CRPC) is the major clinical problem. Somewhat counterintuitively, the androgen receptor remains a key therapy target in CRPC. Here, we explain why this is the case and summarise both new hormone therapy strategies and the recent advances in knowledge of androgen receptor structure and function that underpin them. Abstract Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic disease were sensitive to the presence or absence of androgenic hormones. The first hormonal therapy for PCa was thus castration. In the subsequent eighty years, targeting the androgen signalling axis, where possible using drugs rather than surgery, has been a mainstay in the treatment of advanced and metastatic disease. Androgens signal via the androgen receptor, a ligand-activated transcription factor, which is the direct target of many such drugs. In this review we discuss the role of the androgen receptor in PCa and how the combination of structural information and functional screenings is continuing to be used for the discovery of new drug to switch off the receptor or modify its function in cancer cells.

Ilustraciones y fotografías With the objective to contribute the discovering of drugs to treat the disorders endogen androgen-dependent like prostate cancer (CP) and prostatic benign hyperplasia, which are public health problem worldwide and in Colombia because their high morbidity and mortality in mature men, in this investigation the in vivo activity of the lichen origin compounds sphaerophorin (1) and atraric acid (2) was evaluated. These compounds have been active in vitro on targets involved in the biosynthesis and action of endogen androgens. The compounds 1 y 2 were obtained from the lichens Bunodophoron melanocarpum and Stereocaulon strictum using phytochemical techniques. Their identity was confirmed by their spectroscopic RMN 1H and 13C data that was compared with the literature. The in vivo activity on the biosynthesis and action of endogen androgens was determined by Hershberger bioassay using male Wistar rats. The animals were castrated under anesthesia (Ketamine 75 mg/kg and xilacine 10 mg/kg) intraperitoneal ten days before the experiment. Then, the rats were distributed randomly in 5 groups of 7 individuals each one. Three groups were the controls: vegetal oil (AV) (200 µL, vehicle); testosterone propionate (TP) (0.4 mg/kg dissolved in the vehicle); and TP (0.4 mg/kg) + finasteride (F) (positive control) (1 mg/kg dissolved in 200 µL of vehicle) subcutaneously. The fourth and fifth groups had the test compounds (both 2 mg/kg dissolved in 200 µL of vehicle) + TP (0.4 mg/kg) that were administrated once daily for 10 days subcutaneously. The day after the last administration, the animals were sacrificed and their organs androgen dependents (prostate, seminal vesicles, bulbocavernosus muscle, Cowper glands and glans) and no androgen dependents (adrenal glands, kidneys, and liver) were obtained and weight. This data was expressed as mg of organ per 100 grams of corporal weight. Additionally, the prostates were analyzed semiquantitatively using histoscore to observe some characteristics that could be a possible antiandrogenic effect in that organ. Considering that 1 and 2 did not decrease significatively (p