Endometriosis is a chronic oestrogen-dependent condition characterised by the presence of endometrial-like tissue outside the uterus. Although benign, the associated chronic inflammation and fibrosis can result in substantial symptomatic burden, including chronic pelvic pain, menorrhagia, dysmenorrhoea and dyspareunia. Adenomyosis, which commonly co-exists with endometriosis, is defined by endometrial glands within the myometrium, causing chronic inflammation and fibrosis. Symptoms overlap with endometriosis, including heavy menstrual bleeding, dysmenorrhoea and chronic pelvic pain. Historically, laparoscopy with histological confirmation was considered the diagnostic gold standard for endometriosis. However, imaging now plays an essential role in noninvasive diagnosis and preoperative planning. Transvaginal ultrasound remains the first-line imaging modality in the diagnosis of endometriosis due to its accessibility, cost-effectiveness and real-time dynamic assessment. Certain forms of deep endometriosis, particularly rectal and bladder involvement, are more readily detected with ultrasound when performed by an expert operator using a structured approach that includes assessment of sliding signs and detailed evaluation of each pelvic compartment. Similarly, the Morphological Uterus Sonographic Assessment (MUSA) consensus provides a standardised ultrasound approach for the diagnosis of adenomyosis, incorporating both direct and indirect signs. Magnetic resonance imaging (MRI) offers excellent soft tissue contrast and multiplanar capability, enabling assessment of the entire pelvis and characterisation of indeterminate lesions. MRI allows the comprehensive evaluation of the parametria, ureters, nerves and bowel muscle invasive lesions beyond the reach of ultrasound. Standardised reporting systems, including the #Enzian classification, now enable a unified language between radiologists and the multidisciplinary team. Comprehensive compartment-based disease mapping is essential for accurate surgical planning and improving patient outcomes. This review illustrates the typical US and MRI appearances of endometriosis and adenomyosis, using a compartment-based approach.

Ferroptosis, often characterized by glutathione depletion-associated oxidative stress and lipid peroxidation, contributes importantly to many pathological conditions, including drug-induced liver injury. Protein disulfide isomerase (PDI or PDIA1) has emerged as a pivotal upstream regulator of chemically-triggered ferroptosis and also an important therapeutic target. In this work, we identified raloxifene (RAL), a clinically-used selective estrogen receptor modulator, as a suppressor of chemically-induced oxidative ferroptosis and liver toxicity both in vitro and in vivo. Mechanistically, RAL can interact directly with PDI in both purified systems and cultured hepatocytes, leading to inhibition of its enzymatic activity. This inhibition decreases the dimerization (i.e., catalytic activation) of the inducible nitric oxide synthase (iNOS) and the subsequent buildup of cellular nitric oxide (NO), and these changes are associated with reduced accumulation of cellular reactive oxygen species, including lipid peroxides. RAL treatment markedly mitigates acetaminophen-evoked liver injury in vivo, as reflected by normalized serum enzyme levels, decreased lipid oxidative damage, and improved tissue morphology. Together, these results reveal that RAL can effectively limit oxidative ferroptotic injury in hepatocytes in both cellular and animal settings via its direct inhibition of PDI-mediated oxidative signaling cascade. The findings reveal a novel estrogen receptor-independent, PDI-targeted mechanism for the hepatoprotective actions of RAL, and also illustrate its promise for treating ferroptosis-associated liver injuries.

Sex differences in cancer therapy response remain poorly understood. Using a "phase II-like preclinical trial" across 55 CLDN18.2+ pancreatic cancer patient-derived xenografts, we identify marked female-biased resistance to CLDN18.2-targeted antibody-drug conjugate (ADC) therapy despite equivalent antigen expression. Mechanistically, estrogen signals through GPER1 to upregulate TRAF6, redirecting tumor-intrinsic STING signaling from IRF3-mediated interferon production toward nuclear factor κB (NF-κB) activation. This drives CXCL1 secretion, neutrophil recruitment, and neutrophil extracellular trap (NET) formation. NETs form a charged extracellular network that restricts antibody access to tumor-cell-surface antigens-a mechanism we term functional antigen shielding-reducing ADC cytotoxicity independently of antigen expression. The NET burden also correlated with poorer responses to trastuzumab, cetuximab, and enfortumab vedotin across three clinical cohorts. Pharmacologic NET disruption with sivelestat restored ADC efficacy in female mice. These findings reveal an estrogen-driven resistance mechanism with broad implications for antibody-based cancer therapy.

Wastewater treatment performance is commonly evaluated based on contaminant removal, although environmental protection ultimately depends on reducing the cumulative ecological risk imposed by complex pharmaceutical mixtures. Here, we investigated the barrier-specific attenuation of estrogens, antidepressants, and antiretrovirals in a full-scale lagoon treatment system coupled to a pilot-scale constructed wetland by integrating repeated-measures ANOVA, barrier-specific log removal values (LRV), deterministic ecological risk assessment, and probabilistic mixture modeling using species sensitivity distributions (SSDs), and multisubstance potentially affected fraction (msPAF). Mean influent concentrations were 31.07 μg L⁻¹ for lamivudine and 322.75, 119.52, and 33.73 ng L⁻¹ for estrone, 17β-estradiol, and estriol, respectively. Pharmaceutical attenuation differed markedly among treatment barriers, with limited removal under anaerobic conditions and substantially greater attenuation during oxidative treatment and tertiary polishing. The constructed wetland provided the greatest incremental ecological protection, accounting for approximately 91.4% of the total cumulative deterministic ecological risk attenuation. Deterministic ecological risk identified efavirenz as the dominant contributor to cumulative long-term ecological risk, accounting for approximately 99.9% of the cumulative long-term deterministic risk throughout the wastewater treatment train. The short-term probabilistic mixture risk declined progressively from 0.651 in the influent to 0.602 after secondary treatment and was modeled as zero following tertiary wetland polishing. These findings demonstrate that wastewater treatment performance is more appropriately evaluated through barrier-specific ecological risk attenuation than concentration removal alone and highlight nature-based tertiary treatment as a highly effective strategy for mitigating pharmaceutical risks before environmental discharge.

Oral contraceptives (OCs) are composed of artificial estrogen (ethinyl-estradiol) and/or progesterone (progestin), which can attach to receptors in the brain and potentially influence cognition. One prior study suggested that OC use was associated with increased mind-wandering - implying that OC use was associated with detriments to attention. In contrast, two subsequent well-powered conceptual replications of this initial finding revealed little evidence that OC use was related to increases in inattentiveness (including mind-wandering). However, these later studies collapsed across different OC formulations, which may obscure effects specific to particular formulations. In the present study, we investigated the possibility that OC formulation might differentially relate to attention-related traits. To do this, we collected trait-level reports of the tendency to experience attention related errors, attention lapses, spontaneous and deliberate mind-wandering, boredom, and flow in undergraduate females using OCs, and we collected the brand of OC used from which it was possible to derive the formulation. OC formulations differed in ethinyl-estradiol dose, progestin dose, dosing schedule, hormonal activity (or potency), and the type (or 'generation') of progestin used. We found no evidence that different OC formulations were related to differences in attention-related traits, which suggests that OC users can be treated as a homogenous group when examining trait-level attention. Comparisons of OC users (collapsing across formulation) to non-users again revealed no significant differences in trait-level attention.

Epidemiological studies show that more men are hospitalized for severe hepatitis A than women. However, the extent to which social and behavioral differences versus intrinsic biological mechanisms account for this disparity in disease incidence remains unclear. To better define how sex influences infection outcome, we challenged male and female Ifnar1-/- mice with HAV and quantified virus replication and liver injury. Male mice replicated and shed more virus than female mice, and demonstrated both accelerated and more severe liver injury, as evidenced by increased serum alanine aminotransferase (ALT) activity, greater immune cell infiltration in the liver, and higher intrahepatic expression of chemokines and interferon-stimulated genes. Sex differences were apparent in young and older adult mice, indicating that age did not significantly influence these effects. Ovariectomized female mice had higher intrahepatic viral loads, greater serum ALT elevation, and more severe pathology, compared to surgical controls. Conversely, ovariectomized mice given estradiol implants showed reduced viral loads and ALT activity, indicating that estrogen exerts a protective effect. Female Ifnar1-/- mice lacking hepatocellular expression of estrogen receptor were phenotypically similar to those expressing Esr1, indicating that direct ESR1 signaling in hepatocytes is not essential for protection against pathogenesis. Collectively, these findings indicate that sex influences the pathogenesis and outcome of HAV infection and that female sex hormones protect against severe liver injury.

Secretory carcinoma of the breast is a rare histological subtype in women and is uncommon in female dogs and cats, with only two cases described in female dogs and one case described in a cat. This report describes the histopathological and immunohistochemical features of secretory carcinoma of the mammary gland in a domestic rabbit (Oryctolagus cuniculus). Microscopic evaluation revealed a non-encapsulated, well-demarcated neoplastic proliferation composed of epithelial cells arranged in solid and tubular patterns, supported by a delicate fibrous connective tissue stroma. The neoplastic cells had slightly eosinophilic cytoplasm, frequently containing large, well-demarcated vacuoles that displaced the nucleus to the periphery, giving the cells a signet-ring-like appearance. Periodic acid-Schiff (PAS) histochemical staining, performed with and without diastase digestion, showed positivity in the intracellular and extracellular secretory material in both approaches. Immunohistochemical evaluation was performed for the markers α-lactalbumin, Ki-67, estrogen receptor, progesterone receptor, and COX-2. Positive cytoplasmic immunolabeling for α-lactalbumin was observed in neoplastic cells and in intracellular and extracellular secretory material, confirming their secretory nature. The diagnosis of secretory carcinoma was established based on the association of histopathological, histochemical, and immunohistochemical features. Considering the secretory features of the mammary gland in rabbits, secretory carcinoma should be included in the differential diagnosis of mammary carcinomas with prominent secretory activity in this species.

Paraben esters are endocrine disruptors linked to breast cancer, yet their role in other estrogen-mediated cancers remains limited. Preclinical evidence suggests that parabens accumulate in tissues and may promote carcinogenesis, while clinical data indicate widespread exposure. Our re-analysis of cervicovaginal metabolomes revealed elevated paraben metabolites in endometrial and cervical cancer patients compared with controls. Overall, longitudinal studies considering intrinsic and environmental factors are needed in assessing paraben-related cancer risk.

Endometriosis is a heterogeneous gynecological disorder for which experimental model development is often limited by diagnostic ambiguity and the restricted lifespan of primary epithelial cultures. Although immortalization strategies enable long-term expansion of patient-derived cells, concerns remain regarding the preservation of disease-specific biological characteristics and the risk of model misclassification in the absence of definitive pathological confirmation. In the present study, immortalized ovarian epithelial cell lines from clinically suspected ovarian cystic lesions representing endometriosis were established and it was evaluated whether disease-intrinsic biological features were preserved following immortalization, as determined by definitive histopathological stratification. Primary epithelial cells were isolated from two ovarian cystic lesions and immortalized via lentiviral co-expression of constitutively active cyclin-dependent kinase 4 (CDK4[R24C]), cyclin D1 and human telomerase reverse transcriptase. One lesion was subsequently identified as an ovarian endometrioma, and the other as a mature cystic teratoma, in postoperative histopathology. The endometriosis-derived immortalized epithelial line iEn1 exhibited sustained proliferative capacity (Cell Counting Kit-8 assay), maintained epithelial lineage characteristics (western blotting for pan-cytokeratin, β-catenin and claudin-1), and retained a stable 46,XX karyotype. These cells demonstrated epithelial-mesenchymal plasticity evidenced by co-expression of epithelial markers with vimentin and N-cadherin, and formed microscopic glandular structures resembling endometriosis-like lesions in an estrogen-supplemented xenograft model. However, immunohistochemistry revealed that estrogen receptor β and interleukin-6, both frequently implicated in endometriosis-associated inflammation, were not detected in either the original tissue or the xenografted lesions, indicating that this particular inflammatory phenotype is not intrinsic to this model. By contrast, the teratoma-derived line iEn2 displayed marked chromosomal instability and phenotypic heterogeneity, demonstrated by karyotyping, consistent with its germ cell origin. Thus, immortalization alone does not determine the biological validity of patient-derived cellular models; rather, accurate interpretation requires integration with definitive histopathological classification. The present study established a pathology-validated immortalized epithelial model of ovarian endometriosis and highlighted the importance of pathology-integrated frameworks for improving experimental rigor in disease modeling.

Pure metaplastic squamous cell carcinomas (MSCC) of the breast are rare. We report the case of a 57-year-old woman who presented with a breast abscess in whom a papillomatous lesion was identified during incision and drainage. The initial biopsy demonstrated hyperplastic squamous epithelium with koilocytic atypia, raising the possibility of condylomata acuminata. Subsequent wide excision revealed extensive squamous metaplasia with invasive squamous cell carcinoma arising within a cystic papillary lesion consistent with pure MSCC of the breast. Immunohistochemistry revealed positivity for p63 and negativity for p16, estrogen receptor, progesterone receptor, and human epidermal growth receptor 2. The investigations excluded human papillomavirus infections, cutaneous origins, and extramammary primary squamous cell carcinomas. Following early local recurrence, the patient underwent mastectomy and axillary dissection. Adjuvant radiotherapy and chemotherapy were also administered. This case highlights the diagnostic challenges and aggressive behavior of pure MSCC and emphasizes the importance of clinicopathological correlations and multidisciplinary management.