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Frontiers in Endocrinology 2023Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS... (Review)
Review
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS over the past decades, the distinct etiologies of this syndrome are not fully elucidated. Prenatal factors, genetic variation, epigenetic mechanisms, unhealthy lifestyles, and environmental toxins all contribute to the development of this intricate and highly heterogeneous metabolic, endocrine, reproductive, and psychological disorder. Moreover, interactions between androgen excess, insulin resistance, disruption to the hypothalamic-pituitary-ovary (HPO) axis, and obesity only make for a more complex picture. In this review, we investigate and summarize the related molecular mechanisms underlying PCOS pathogenesis from the perspective of the level of signaling pathways, including PI3K/Akt, TGF-β/Smads, Wnt/β-catenin, and Hippo/YAP. Additionally, this review provides an overview of prospective therapies, such as exosome therapy, gene therapy, and drugs based on traditional Chinese medicine (TCM) and natural compounds. By targeting these aberrant pathways, these interventions primarily alleviate inflammation, insulin resistance, androgen excess, and ovarian fibrosis, which are typical symptoms of PCOS. Overall, we hope that this paper will pave the way for better understanding and management of PCOS in the future.
Topics: Pregnancy; Female; Humans; Polycystic Ovary Syndrome; Insulin Resistance; Hyperandrogenism; Androgens; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 37929034
DOI: 10.3389/fendo.2023.1191759 -
Cureus Jul 2023Androgenic alopecia (AGA), commonly known as male pattern baldness (MPB), is a hereditary condition characterized by hair follicles that are sensitive to androgens. This... (Review)
Review
Androgenic alopecia (AGA), commonly known as male pattern baldness (MPB), is a hereditary condition characterized by hair follicles that are sensitive to androgens. This article focuses on examining the recent advancements in the comprehension and management of AGA. The genetic factors and pathophysiology of AGA, including the role of dihydrotestosterone (DHT) and the androgen receptor gene, are discussed. The consequences of hair loss on self-esteem and identity, as well as on mental health, are examined. Diagnostic methods, such as the hair-pull test and trichoscopy, are discussed. The article also presents the Hamilton-Norwood classification, which is the most commonly employed system for classifying MPB. The article then delves into the various treatment options available, including topical minoxidil, oral finasteride, platelet-rich plasma therapy, low-level light therapy, hair transplant, and other alternative treatments. The efficacy and combination therapies for these treatments are examined. Additionally, emerging treatments such as caffeine-based solutions and prostaglandin inhibitors are discussed. By examining the recent advancements in AGA treatment, this article provides a comprehensive overview for healthcare professionals to make informed decisions when selecting the best treatment options for their patients.
PubMed: 37663989
DOI: 10.7759/cureus.42768 -
The Journal of Clinical Endocrinology... Oct 2023Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital...
CONTEXT
Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH.
METHODS
This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone.
CONCLUSION
Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.
Topics: Male; Adult; Humans; Female; Adolescent; Androgens; Adrenal Hyperplasia, Congenital; Androstenedione; 17-alpha-Hydroxyprogesterone; Testosterone; Adrenocorticotropic Hormone
PubMed: 37216921
DOI: 10.1210/clinem/dgad270 -
Cancer Research Aug 2023Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor...
UNLABELLED
Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated Krüppel-like factor 5 (KLF5) as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease.
SIGNIFICANCE
Comprehensive characterization of the five subtypes of metastatic castration-resistant prostate cancer identified transcription factors that drive each subtype and showed that the double-negative subtype has the worst prognosis.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Epigenomics; Androgen Antagonists; Androgens; Genomics; Neuroendocrine Tumors
PubMed: 37289025
DOI: 10.1158/0008-5472.CAN-23-0593 -
Cancer Cell Nov 2023When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune...
When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Prostatic Neoplasms, Castration-Resistant; Androgens; Immunotherapy; Castration; Tumor Microenvironment
PubMed: 37922910
DOI: 10.1016/j.ccell.2023.10.006 -
Cancer Research Oct 2023Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression.
SIGNIFICANCE
Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.
Topics: Male; Humans; Receptors, Androgen; Androgen Antagonists; Androgens; Prostatic Neoplasms, Castration-Resistant; Ferroptosis; Nitriles; Castration; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 37527336
DOI: 10.1158/0008-5472.CAN-23-0285 -
International Journal of Molecular... Jul 2023Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis... (Review)
Review
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Receptors, Androgen; Signal Transduction; Orchiectomy; Protein Serine-Threonine Kinases
PubMed: 37446279
DOI: 10.3390/ijms241311100 -
JAMA Oncology Jul 2023The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed.
OBJECTIVE
To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects.
DATA SOURCES
PubMed, EMBASE, and Scopus (inception to September 12, 2022).
STUDY SELECTION
Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, fatigue, weakness), or falls were evaluated.
DATA EXTRACTION AND SYNTHESIS
Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Enhancing the Quality and Transparency of Health Research reporting guidelines. Tabular counts for all-grade toxic effects were determined to test the hypothesis formulated before data collection.
MAIN OUTCOMES AND MEASURES
Risk ratios (RRs) and SEs were calculated for cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the asthenic toxic effect extracted from all studies, data on fatigue are specified in the results. Meta-analysis and meta-regression were used to generate summary statistics.
RESULTS
The systematic review included 12 studies comprising 13 524 participants. Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR, 2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001) was noted among individuals treated with second-generation AAs vs those in the control arms. The findings were consistent in studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79; P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression supported that, across studies, increased age was associated with a greater risk of fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In addition, the use of second-generation AAs was associated with an increased risk of falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001).
CONCLUSIONS AND RELEVANCE
The findings of this systematic review and meta-analysis suggest that second-generation AAs carry an increased risk of cognitive and functional toxic effects, including when added to traditional forms of hormone therapy.
Topics: Humans; Male; Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Cognition; Fatigue; Prospective Studies; Prostatic Neoplasms; Quality of Life; Retrospective Studies
PubMed: 37227736
DOI: 10.1001/jamaoncol.2023.0998 -
European Urology Aug 2023Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment.
OBJECTIVE
To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT.
DESIGN, SETTING, AND PARTICIPANTS
This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896).
INTERVENTION
Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1-5 metastases) or polymetastatic (≥6 metastases).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values.
RESULTS AND LIMITATIONS
Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16-0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40-0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23-0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41-0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases.
CONCLUSIONS
This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous.
PATIENT SUMMARY
This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Disease-Free Survival; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 37179240
DOI: 10.1016/j.eururo.2023.04.002