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Current Oncology Reports Sep 2023There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer.... (Review)
Review
PURPOSE OF THE REVIEW
There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer. While this may result from the direct effects of androgen suppression in the cardiovascular systems, there are ADT-type-specific distinct cardiovascular complications suggestive of mechanisms beyond androgen-mediated. Thus, it is critical to understand the biological and clinical impact of ADT on the cardiovascular system.
RECENT FINDINGS
Gonadotropin-releasing hormone (GnRH) agonists cause increased cardiovascular events compared to GnRH antagonists. Androgen receptor antagonists are linked to an increased risk of long QT syndrome, torsades de pointes, and sudden cardiac death. Androgen synthesis inhibitors are associated with increased rates of hypertension, atrial tachyarrhythmia, and, in rare incidences, heart failure. ADT increases the risk of cardiovascular disease. The risk among ADT drugs differs and must be evaluated to develop a medically optimal plan for prostate cancer patients.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Androgen Antagonists; Gonadotropin-Releasing Hormone; Cardiovascular System; Biology
PubMed: 37273124
DOI: 10.1007/s11912-023-01424-2 -
Reviews in Endocrine & Metabolic... Dec 2022In men > ~35 years, aging is associated with perturbations in the hypothalamus-pituitary-testicular axis and declining serum testosterone concentrations. The... (Review)
Review
In men > ~35 years, aging is associated with perturbations in the hypothalamus-pituitary-testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism-a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65-70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism-a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment for symptoms, signs and causes of male hypogonadism. In older men with a body mass index (BMI) ≥ 30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.
Topics: Male; Humans; Aged; Androgens; Testosterone; Aging; Gonadotropin-Releasing Hormone; Hypogonadism
PubMed: 36459352
DOI: 10.1007/s11154-022-09765-2 -
International Journal of Molecular... Jun 2013The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma,... (Review)
Review
The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma, breast and prostate cancer. In the present review, recent advances in an understanding of the involvement of autophagy in prostate cancer treatment are described. The regulatory effects of androgens on prostate cancer cell autophagy are particularly discussed in order to highlight the effects of autophagy modulation during androgen deprivation. A critical evaluation of the studies examined in the present review suggests the attractive possibility of autophagy inhibition combined with hormonal therapy as a promising approach for prostate cancer treatment.
Topics: Androgens; Animals; Autophagy; Disease Progression; Humans; Immunity; Male; Models, Biological; Prostatic Neoplasms
PubMed: 23743823
DOI: 10.3390/ijms140612090 -
Reproductive Biology and Endocrinology... Jul 2023Although psychoactive drugs have their therapeutic values, they have been implicated in the pathogenesis of male infertility. This study highlights psychoactive drugs... (Review)
Review
Although psychoactive drugs have their therapeutic values, they have been implicated in the pathogenesis of male infertility. This study highlights psychoactive drugs reported to impair male fertility, their impacts, and associated mechanisms. Published data from scholarly peer-reviewed journals were used for the present study. Papers were assessed through AJOL, DOAJ, Google Scholar, PubMed/PubMed Central, and Scopus using Medical Subjects Heading (MeSH) indexes and relevant keywords. Psychoactive drugs negatively affect male reproductive functions, including sexual urge, androgen synthesis, spermatogenesis, and sperm quality. These drugs directly induce testicular toxicity by promoting ROS-dependent testicular and sperm oxidative damage, inflammation, and apoptosis, and they also suppress the hypothalamic-pituitary-testicular axis. This results in the suppression of circulating androgen, impaired spermatogenesis, and reduced sperm quality. In conclusion, psychoactive drug abuse not only harms male sexual and erectile function as well as testicular functions, viz., testosterone concentration, spermatogenesis, and sperm quality, but it also alters testicular histoarchitecture through a cascade of events via multiple pathways. Therefore, offering adequate and effective measures against psychoactive drug-induced male infertility remains pertinent.
Topics: Male; Humans; Androgens; Semen; Testis; Spermatogenesis; Infertility, Male; Fertility; Psychotropic Drugs
PubMed: 37507788
DOI: 10.1186/s12958-023-01098-2 -
FEBS Letters Mar 2022The mechanisms through which the androgen-dependent activation of the androgen receptor (AR) regulates gravid uterine ferroptosis remain unknown. We show that while...
The mechanisms through which the androgen-dependent activation of the androgen receptor (AR) regulates gravid uterine ferroptosis remain unknown. We show that while co-exposure of pregnant rats to the androgen 5α-dihydrotestosterone (DHT) and insulin (INS) triggered uterine ferroptotic signaling cascades, additional treatment with the anti-androgen flutamide increased expression of the key ferroptosis-inhibitory proteins SLC7A11, GSH, and GPX4; reduced iron content; normalized levels of ferroptosis-associated Tfrc, Fpn1, and Ho1 mRNAs; reduced levels of proteins modified by 4-HNE (a marker of ferroptosis); and restored protein levels of NRF2, a key transcription factor regulating antioxidant defense signaling, in the gravid uterus. Furthermore, exposure to DHT alone increased uterine ferroptosis, and NRF2 abundance was negatively correlated with AR status. Co-immunoprecipitation and Western blot assays revealed that the AR physically interacted with endogenous NRF2, and this interaction was increased by DHT exposure in vivo. Our results suggest that AR overactivation and NRF2 suppression cooperate in the regulation of NRF2-targets in uterine ferroptosis.
Topics: Androgens; Animals; Dihydrotestosterone; Female; Ferroptosis; NF-E2-Related Factor 2; Pregnancy; Rats; Receptors, Androgen; Signal Transduction; Uterus
PubMed: 35038776
DOI: 10.1002/1873-3468.14289 -
Breast Cancer Research : BCR 2009Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of... (Review)
Review
Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.
Topics: Androgens; Breast Neoplasms; Female; Humans; Mammary Glands, Human
PubMed: 19889198
DOI: 10.1186/bcr2413 -
The Journal of Clinical Investigation Dec 2022Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously...
Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.
Topics: Male; Humans; Receptors, Androgen; Androgens; Prostatic Neoplasms, Castration-Resistant; Androgen Receptor Antagonists; Nitriles; Testosterone; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 36194476
DOI: 10.1172/JCI162396 -
Cell Death & Disease Jun 2023The incidence of bladder cancer (BLCA) in men is higher than that in women. Differences in androgen levels between men and women are considered the main causes of...
The incidence of bladder cancer (BLCA) in men is higher than that in women. Differences in androgen levels between men and women are considered the main causes of incidence rate differences. In this study, dihydrotestosterone (DHT) significantly increased the proliferation and invasion of BLCA cells. In addition, BLCA formation and metastatic rates were higher in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-treated male mice than in female and castrated male mice in vivo. However, immunohistochemistry showed that androgen receptor (AR) was expressed at low levels in normal and BLCA tissues of men and women. The classical AR pathway considers that DHT binds to AR and induces it to enter the nucleus, where it functions as a transcription factor. Here, a non-AR combination pathway of androgen that promoted BLCA development was investigated. The EPPK1 protein was bombarded with DHT, as determined by biotinylated DHT-binding pull-down experiments. EPPK1 was highly expressed in BLCA tissues, and EPPK1 knockdown significantly inhibited BLCA cell proliferation and invasion promoted by DHT. Moreover, JUP expression was elevated in DHT-treated high-EPPK1 expressing cells, and JUP knockdown inhibited cell proliferation and invasion. EPPK1 overexpression increased tumour growth and JUP expression in nude mice. Furthermore, DHT increased the expression of the MAPK signals p38, p-p38, and c-Jun, and c-Jun could bind to the JUP promoter. However, the promotion of p38, p-p38, and c-Jun expression by DHT was not observed in EPPK1 knockdown cells, and a p38 inhibitor suppressed the DHT-induced effects, indicating that p38 MAPK may be involved in the regulation of DHT-dependent EPPK1-JUP-promoted BLCA cell proliferation and invasion. The growth of bladder tumours in BBN-treated mice was inhibited by the addition of the hormone inhibitor goserelin. Our findings indicated the potential oncogenic role and mechanism of DHT in BLCA pathogenesis through a non-AR pathway, which may serve as a novel therapeutic target for BLCA.
Topics: Animals; Female; Male; Mice; Androgens; Cell Line, Tumor; Cell Proliferation; Dihydrotestosterone; Mice, Nude; Receptors, Androgen; Urinary Bladder Neoplasms; Humans
PubMed: 37328487
DOI: 10.1038/s41419-023-05882-1 -
Endocrine-related Cancer Sep 2020The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral... (Review)
Review
The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.
Topics: Androgen Antagonists; Androgens; Angiotensin-Converting Enzyme 2; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Hypothalamo-Hypophyseal System; Male; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Prostatic Neoplasms; SARS-CoV-2; Serine Endopeptidases
PubMed: 32508311
DOI: 10.1530/ERC-20-0165 -
International Journal of Molecular... Jul 2021Ovarian cancer (OVCA) arises from three cellular origins, namely surface epithelial cells, germ cells, and stromal cells. More than 85% of OVCAs are EOCs (epithelial... (Review)
Review
Ovarian cancer (OVCA) arises from three cellular origins, namely surface epithelial cells, germ cells, and stromal cells. More than 85% of OVCAs are EOCs (epithelial ovarian carcinomas), which are the most lethal gynecological malignancies. Cancer stem/progenitor cells (CSPCs) are considered to be cancer promoters due to their capacity for unlimited self-renewal and drug resistance. Androgen receptor (AR) belongs to the nuclear receptor superfamily and can be activated through binding to its ligand androgens. Studies have reported an association between AR expression and EOC carcinogenesis, and AR is suggested to be involved in proliferation, migration/invasion, and stemness. In addition, alternative AR activating signals, including both ligand-dependent and ligand-independent, are involved in OVCA progression. Although some clinical trials have previously been conducted to evaluate the effects of anti-androgens in EOC, no significant results have been reported. In contrast, experimental studies evaluating the effects of anti-androgen or anti-AR reagents in AR-expressing EOC models have demonstrated positive results for suppressing disease progression. Since AR is involved in complex signaling pathways and may be expressed at various levels in OVCA, the aim of this article was to provide an overview of current studies and perspectives regarding the relevance of androgen/AR roles in OVCA.
Topics: Androgens; Carcinogenesis; Female; Gene Expression Regulation, Neoplastic; Humans; Ovarian Neoplasms; Receptors, Androgen; Signal Transduction
PubMed: 34299364
DOI: 10.3390/ijms22147748