Drugs targeting the androgen receptor (AR) are important therapeutics for castration-resistant prostate cancer (CRPC) but are vulnerable to resistance due to AR mutations. Previously, we reported that the (5R/5S) enantiomer pairs of four novel 3-pyrrolazole carboxamide derivatives 9ab-12ab are antagonists and agonists, respectively, of AR, as demonstrated by transcriptional assays supported by fluorescence microscopy and proliferation studies. Herein, we describe the synthesis and stereochemical characterization of these compounds and document their enantiospecific effect on enzalutamide-resistant AR.

Environmental factors can influence the epigenetic inheritance of pathology across generations. Prior studies found various toxicants increased pathology in their descendants through epigenetic transgenerational inheritance. Previously, three generations of rats were exposed separately to vinclozolin (F0 generation), a jet fuel hydrocarbon mixture (F1 generation), and dichlorodiphenyltrichloroethane (DDT) (F2 generation), producing a transgenerational F5 generation. The current study extends this study by breeding this transgenerational F5 generation with wild-type rats to create maternal and paternal outcross lineages, labeled MOC and POC, respectively. In the current study, we examined the differential DNA methylated regions (DMRs) in the outcross F6 generation offspring to detect potential parent-of-origin lineage‑specific inheritance impacts. When comparing both outcross MOC and POC lineages of the F6 generation to a control outcross F3 generation from the same lineage, with no toxicant exposure, a higher number of DMRs were observed in the F6 generation lineages. Additionally, while there was some common overlap between the two MOC and POC outcross generations, only the F6 POC generation had overlaps with the F5 multigenerational exposure lineage generation of the previous study, which was also a paternal outcross. Since previous pathology analysis has been extensive, limited pathology (e.g. obesity) was performed in the current study to primarily confirm the transgenerational pathology in the F6 generation outcross lineages. Comparisons between the control same lineage F3 generation and both of the outcross F6 generations identified outcross‑specific results, suggesting sex-specific epigenetic inheritance after ancestral toxicant exposure. Therefore, both the oocyte and sperm facilitate epigenetic transgenerational inheritance.

To evaluate whether an integrated classification combining the CHAARTED and LATITUDE criteria improves prognostic stratification and to explore treatment effects across risk groups, including further stratification by metastasis timing, in metastatic castration-sensitive prostate cancer (mCSPC). This post hoc analysis included 1,052 patients from the TITAN trial (NCT02489318) randomized to receive apalutamide plus androgen deprivation therapy (ADT) or placebo plus ADT. Patients were classified into double low, intermediate, and double high groups based on the CHAARTED and LATITUDE criteria and further stratified by metastasis timing. Model discrimination was assessed using Harrell's concordance index (C-index). Overall survival (OS) was analyzed using Kaplan-Meier curves and Cox proportional hazards models, with baseline imbalances adjusted by inverse probability of treatment weighting. The integrated classification based on the CHAARTED and LATITUDE criteria significantly improved prognostic stratification, yielding a higher C-index for OS (0.645) than the CHAARTED (0.628; p = 0.011) or LATITUDE (0.621; p = 0.003) criteria alone. When further stratified by metastasis timing, apalutamide was associated with improved OS across most subgroups; however, no clear benefit was observed in the double low group with synchronous metastasis (hazard ratio: 0.93; 95% confidence interval [CI]: 0.48-1.79; p = 0.8). Integrating the CHAARTED and LATITUDE criteria significantly improves prognostic stratification in patients with mCSPC. While further stratification by metastasis timing suggested no clear survival benefit in the double low synchronous subgroup, wide CIs indicate substantial uncertainty. These exploratory findings require prospective validation.Clinical Trial Registration: NCT02489318.

Androgen deprivation therapy (ADT) represents a cornerstone in the treatment of prostate cancer (PC); however, its use is associated with an accelerated deterioration of bone health as a consequence of treatment-induced hypogonadism. Patients receiving ADT experience a rapid loss of bone mineral density (BMD), especially during the first year of therapy, leading to a clinically significant increase in the risk of osteoporosis and fragility fractures. These bone complications are associated with a significant negative impact on quality of life, morbidity and mortality, and healthcare costs. This article aims to provide a critical and practical review of pathophysiology, risk factors, assessment methods, and strategies for the prevention and treatment of ADT-induced bone loss in patients with prostate cancer. Current recommendations from major clinical guidelines are analyzed, highlighting the importance of systematic bone risk assessment using bone densitometry and risk stratification tools like Fracture Risk Assessment Tool (FRAX®). Evidence-based interventions are also reviewed, ranging from lifestyle modifications and calcium and vitamin D supplementation to the use of antiresorptive therapies in selected patients, to provide a comprehensive and clinically applicable approach for daily practice.

Prostate cancer is the second most common cancer in US men. Guidelines for screening vary, underscoring the need to engage patients in shared decision-making and counsel them about potential benefits and harms. When screening is undertaken, it is based on the prostate-specific antigen test, with digital rectal examination used selectively as an adjunct. Men with an abnormal prostate-specific antigen level should have a repeat test within a few months, before proceeding to biomarker testing, referral to urology, biopsy, and potentially imaging. Patients with newly diagnosed prostate cancer should be risk-stratified using clinical tumor (T) stage as determined by digital rectal examination, International Society of Urological Pathology grade group (Gleason score), prostate-specific antigen level, and tumor volume on biopsy. Treatment options vary by risk. Active surveillance is recommended for patients with low-risk disease, typically those with grade group 1/Gleason score of 6 (3 + 3). For patients with favorable intermediate-risk prostate cancer, treatment options are active surveillance, radiation therapy, or radical prostatectomy. For patients with unfavorable intermediate- or high-risk prostate cancer and estimated life expectancy greater than 10 years, options are radical prostatectomy or radiation therapy plus androgen deprivation therapy. For patients with prostate-specific antigen levels greater than 40 ng/dL, a Gleason score of 9 or higher, or locally advanced prostate cancer, treatment with radiation therapy and androgen deprivation therapy can additionally include concurrent abiraterone plus prednisone for 2 years. Focal ablation is also an option for some patients. Prognosis varies by disease features; men with low-risk prostate cancer are much more likely to die from other causes, whereas those with distant metastases have a 5-year relative survival rate of 38.3%.

Breast cancer (BC) is the most incidental cancer in women. Patients' living conditions and survival rates have significantly improved with the success of two first-line endocrine therapies of selective estrogen-receptor modulators (SERMs from 1977) and aromatase inhibitors (AIs from 1995). Unfortunately, both therapies have produced significant resistance. AI resistance reaches 50% in metastatic estrogen-dependent BC cases, leading oncologists to seek a substitute for current therapies. We target the reductive 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), which stimulates the synthesis of the active estrogen estradiol (E2) and reduces the potent androgen dihydrotestosterone (DHT) simultaneously, triggering negative feedback on 17β-HSD7 expression. INH7(464), an improved 17β-HSD7 inhibitor, efficiently blocks estrogen conversion at an IC50 of 92 ± 8 nM. INH7(464) inhibited cell proliferation by decreasing E2 levels and restoring DHT, successively arresting the cell cycle in G0/G1 phase. In vivo, INH7(464) reduced tumor size by 49% on Day 22 in BC xenografts with T47D. INH7(464) reduced E2 levels in mouse blood circulation and xenograft tumor tissue. There is no demonstrated cytotoxicity or cardiotoxicity of INH7(464) on cellular levels and mouse models under the experimental conditions. 17β-HSD7 is a potential target for estrogen-dependent BC therapy, while INH7(464) is promising for a preclinical lead compound (PCT/CA2022/050966).

Female-pattern hair loss is common in obese women with polycystic ovary syndrome (PCOS), recently proposed as polyendocrine metabolic ovarian syndrome (PMOS) and is often associated with hypertriglyceridemia (TG), although the underlying mechanisms remain unclear. This study investigated how metabolic factors and androgens contribute to hair loss in female mice exposed to a high-fat diet (HFD). A controlled, parallel-group study using 8-week-old female C57BL/6 mice fed either an HFD (60% kcal fat) or a standard diet for 16 weeks. Mice were sacrificed at baseline and 4-week intervals for serial evaluation of metabolic, hormonal and skin changes (n = 6/group/time point). Hair loss was quantified from digital photographs using the ImageJ and further supported by histological examination. Circulating metabolic and hormonal profiles were measured. In dorsal skin, oxidative stress (malondialdehyde, MDA) and androgen-related markers-5-alpha-reductase type II (5αR2), dihydrotestosterone (DHT) and androgen receptor (AR)-were evaluated using immunohistochemistry, Western blot and enzyme-linked immunosorbent assay. From Week 12 onward, HFD-fed mice exhibited greater weight gain, pronounced dorsal hair thinning and elevated TG, insulin and free androgen index (FAI) levels. Skin MDA, 5αR2, DHT and AR levels also progressively increased. In the second experiment, 8-week-old female mice were assigned to four groups (n = 6/group): HFD with N-acetylcysteine (NAC), finasteride, spironolactone, or vehicle administered by oral gavage for 12 weeks. Compared with HFD-vehicle, antioxidant or anti-androgen co-treatment significantly lowered serum TG, tissue MDA and ameliorated hair thinning despite similar weight gain and 5αR2 levels. NAC reduced TG, FAI and decreased tissue MDA, DHT and AR. Finasteride lowered TG, MDA, DHT and AR, whereas spironolactone reduced TG and MDA. HFD-induced obesity exacerbates hair loss in female mice by enhancing oxidative stress and activating androgen signalling in the skin. Targeting these pathways, such as antioxidants and antiandrogens, may mitigate HFD-accelerated hair loss.

Congenital adrenal hyperplasia (CAH) comprises a group of rare autosomal recessive disorders and is a leading cause of primary adrenal insufficiency in children. Most cases are due to classic 21-hydroxylase deficiency. Earlier diagnosis has been made possible with newborn screening, which has also reduced the risk of adrenal crises. This review is based on a search of PubMed, Embase, Scopus, and Medline for articles published from 2000 to 2025, using the terms "congenital adrenal hyperplasia", "21-hydroxylase deficiency", "primary adrenal insufficiency", and "steroidogenesis" with a focus on paediatric studies, clinical trials, systematic reviews, and consensus guidelines.

Drug resistance to the androgen receptor (AR) antagonist is a critical obstacle in the clinic for advanced prostate cancers. Especially, AR antagonist treatment-induced neuroendocrine progression represents a lethal and therapy-resistant subtype. Although transcriptional and epigenetic lineage plasticity have been extensively implicated in treatment-induced neuroendocrine progression, the contribution of metabolic adaptation remains incompletely understood. Here, we identified a previously unrecognized metabolic reprogramming mechanism induced by AR antagonists in castration-resistant prostate cancer (CRPC) models. AR antagonist treatment markedly enhanced glycolytic activity and induced glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Genetic depletion of GAPDH suppressed AR antagonist-induced glycolytic activation, altered transcriptomic and metabolic programs, reduced neuroendocrine-associated marker expression, and inhibited xenograft tumor growth. Mechanistically, GAPDH promoter pulldown coupled with mass spectrometry, siRNA screening, and chromatin immunoprecipitation assays identified myeloid zinc finger-1 (MZF1) as a key transcription factor for Enzalutamide-induced GAPDH gene expression. Pharmacological inhibition of GAPDH using koningic acid (KA) or penta-O-galloyl-β-D-glucopyranose (PGG) significantly suppressed tumor growth and attenuated neuroendocrine-associated molecular programs in CRPC cell-derived xenograft and patient-derived t-NEPC xenograft models. Collectively, our findings identify an AR antagonist-induced MZF1-GAPDH signaling axis that promotes glycolytic activation and neuroendocrine-associated metabolic adaptation during treatment resistance. These results support targeting GAPDH-dependent metabolic reprogramming as a potential therapeutic strategy for treatment-resistant prostate cancer.