KAT6B/A::KANSL1 fusion-positive uterine mesenchymal neoplasms are rare and may show overlapping endometrial stromal and smooth muscle features. We report a 47-year-old woman with regular menses, no dysmenorrhea, and a 7-year history of a presumed uterine fibroid. She underwent laparoscopic myomectomy at an outside hospital in November 2024. The fragmented specimen was interpreted as an endometrial stromal tumor with smooth muscle differentiation, but the tumor-myometrium interface could not be assessed, and an endometrial stromal nodule could not be distinguished from low-grade endometrial stromal sarcoma. Subsequent pelvic magnetic resonance imaging showed postoperative changes, possible residual leiomyomas, and heterogeneous enhancement at the uterine fundus. Pelvic computed tomography showed heterogeneous uterine enhancement without definite extrauterine disease. Because the original specimen was fragmented and a potentially malignant uterine mesenchymal neoplasm could not be excluded, completion hysterectomy with bilateral salpingo-oophorectomy was performed. The hysterectomy specimen contained multiple residual intramyometrial nodules with marked regional heterogeneity. One component showed fascicular smooth muscle morphology and diffuse desmin and h-caldesmon expression, whereas other nodules showed tongue-like myometrial infiltration, focal intravascular growth, spiral arteriole-like vessels, and diffuse ER, PR, CD10, and SMA expression. Whole-transcriptome sequencing identified an in-frame KAT6B::KANSL1 fusion involving KAT6B exon 3 and KANSL1 exon 11. Because the tumor expressed ER and PR, postoperative letrozole was administered for 30 days, after which surveillance was selected following review of the final pathologic and molecular findings. At 8 months after completion surgery, no clinical or radiologic recurrence was detected; this limited follow-up does not permit conclusions regarding long-term biological behavior or endocrine treatment benefit.

Breast cancer (BC) is the leading cause of cancer death among women worldwide with estrogen receptor positive (ER+) BC comprising 70-80% of all cases. Adjuvant therapy with aromatase inhibitors (AIs), such as letrozole (LTZ), is the standard of care in ER+ BC patients to prevent recurrence but many patients cease treatment prematurely due to the development of musculoskeletal side effects (i.e. arthralgia, myalgia, decreased grip strength) referred to as aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). The lack of efficacious treatments available for AIMSS and premature treatment cessation being linked to increased patient mortality highlights the critical importance of identifying new therapeutic targets for its management. Here, we directly link LTZ treatment with increased levels of sphingosine-1-phosphate receptor 1 (S1PR1) endogenous ligands in spinal cord tissue of female ovariectomized (OVX) ICR mice. We therefore investigated the impact of reducing S1PR1 activity as a potential therapeutic strategy for alleviating AIMSS-related behaviors. In C57BL/6J OVX female mice, we found that pharmacological inhibition using the selective and competitive S1PR1 antagonist, NIBR-0213, effectively alleviated AIMSS-like behaviors after acute and repeated dosing regimens, with limited therapeutic effectiveness when given prior to LTZ treatment. In a conditioned place preference (CPP) paradigm, LTZ- but not vehicle-treated animals preferred the NIBR-0213 paired chamber, unmasking the presence of a tonic-aversive state driven by LTZ treatment. These findings identify S1PR1 as an important mediator to AIMSS and suggest that S1PR1 antagonists may be most effective as acute interventions to provide relief from the sensory and affective burden of AIMSS.

Extrachromosomal circular DNA (eccDNA) serves as a vital regulator of gene expression and phenotypic plasticity. The Monopterus albus is a protogynous hermaphroditic fish, and the functional role of eccDNA during its female-to-male sex reversal remains poorly understood. We conducted Circle-seq analysis on gonadal tissues of super-female and male individuals and integrated our findings with previously published gonadal RNA-seq data. A total of 62,574 and 34,562 eccDNAs were, on average, identified in the two groups, and 7881 down-regulated and 2738 up-regulated differentially abundant eccDNAs were screened in male gonads. Three candidate eccDNAs, eccDNA[Dmrt1a], eccDNA[Sox9a1] and eccDNA[ZNF239], were selected for subsequent analysis. Quantitative real-time PCR was applied to detect the overall transcriptional levels of their corresponding host genes, covering transcripts derived from both genomic DNA and eccDNA. Spatiotemporal expression profiling and letrozole induction experiments revealed male-biased expression of Dmrt1a and Sox9a1, while ZNF239 was predominantly expressed in female gonads. Complete sex reversal was observed in female M. albus after 90-day letrozole treatment, accompanied by elevated Dmrt1a/Sox9a1 and reduced ZNF239 transcription. Fluorescence in situ hybridization localized these transcripts in gonadal germ cells and somatic cells across developmental stages. This study verifies the production of eccDNA during gonadal development. The results indicate that Dmrt1a and Sox9a1 may facilitate sex reversal and suggest that ZNF239 is likely involved in ovarian development. This work provides novel clues for deciphering the molecular mechanism underlying sex reversal from the eccDNA perspective.

Polycystic ovarian syndrome (PCOS) is a multifaceted reproductive endocrinopathy characterized by oligo/anovulation, cystic ovaries, and disrupted steroidogenesis. Inhibition of aromatase during steroidogenesis may be linked to dysregulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), which could lead to aberrant estradiol synthesis and contribute to PCOS pathophysiology. Therefore, we speculate that activation of PPAR-γ with propionic acid may, in part, help restore normal steroidogenesis. However, the expression levels of aromatase and PPAR-γ were not clearly understood with the currently used drugs (for PCOS) and propionic acid. Therefore, this study investigated ovarian expression of PPAR-γ and aromatase in zebrafish (Danio rerio) treated with various drugs (metformin, letrozole, clomiphene citrate, and the novel molecule, propionic acid) under normal conditions. Fifty female zebrafish were divided into five groups and treated with DMSO (control), metformin, letrozole, clomiphene citrate, and propionic acid for 14 days, followed by analysis of aromatase and PPAR-γ expression using RT-qPCR. Metformin treatment downregulated aromatase expression and upregulated PPAR-γ, whereas letrozole-mediated regulation of aromatase and PPAR-γ was reversed. Clomiphene citrate treatment upregulated both PPAR-γ and aromatase. Notably, propionic acid also upregulated both PPAR-γ and aromatase, suggesting a potential role as an ovarian microenvironment modulator. Further, molecular docking analysis of all compounds with PPAR-γ and aromatase revealed differential binding affinities, with metformin and propionic acid forming more hydrogen bonds than letrozole and clomiphene citrate. Collectively, these findings suggest that propionic acid may modulate ovarian steroidogenesis by regulating aromatase and PPAR-γ.

Age-related azoospermia is a clinically important cause of male infertility in dogs, yet effective pharmacological treatments for aged males remain limited. Whether transient aromatase inhibition can restore fertility in aged azoospermic dogs without prolonged exposure is unclear.

Hormone receptor-positive, human epidermal growth factor receptor 2-low (HER2-low) metastatic breast cancer (MBC) constitutes the predominant subtype of advanced breast cancer, with most patients eventually developing resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This case report describes a 64-year-old woman with hormone receptor (HR)-positive, HER2-low MBC involving lung, pleural, and lymph node metastases who achieved a remarkable and sustained radiographic complete response (rCR) to palbociclib plus fulvestrant, followed by letrozole after fulvestrant injection intolerance. The patient exhibited near-complete regression of metastatic lesions within 18 months and maintained remission for over 6 years, far exceeding the typical median progression-free survival observed in clinical trials. The prolonged remission observed underscores the existence of biologically distinct tumor subsets with exceptional sensitivity to CDK4/6 inhibition, warranting investigation into underlying molecular mechanisms.

Anovulation is a common and heterogenous cause of infertility with significant implications for metabolic health. Ovulatory disorders arise from disruption of the hypothalamic-pituitary-ovarian axis and are often characterized using the International Federation of Gynecology and Obstetrics hypothalamic dysfunction, pituitary dysfunction, ovarian dysfunction, and polyendocrine metabolic ovarian syndrome (PMOS) pathophysiologic framework. While many hypothalamic and pituitary causes of anovulatory infertility are treatable, primary ovarian insufficiency often requires assisted reproductive technology. In PMOS (formerly known as polycystic ovary syndrome), ovulation induction with an oral agent such as letrozole is considered first-line to reduce the risks of multiple gestation and ovarian hyperstimulation syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder marked by hyperandrogenism, ovulatory dysfunction, insulin resistance, chronic inflammation and oxidative stress, arising from dysregulation across several interconnected molecular pathways. Because its pathogenesis is multifactorial, therapies targeting diverse biological processes at once remain scarce. Nerolidol, a naturally occurring sesquiterpene alcohol with antioxidant, anti-inflammatory and cytoprotective properties, has an action against PCOS whose molecular basis remains unresolved. Transcriptomic differences associated with PCOS were examined using the Gene Expression Omnibus (GEO) dataset GSE34526. Exploratory differential-expression screening identified nominally altered probes using an unadjusted P < 0.05 and |log2FC| > 1; however, no individual probe remained significant after Benjamini-Hochberg correction at FDR < 0.05. Functional enrichment analysis was subsequently used to investigate biological processes and pathways represented by these exploratory transcriptional signals. Gene Ontology (GO) and KEGG enrichment were applied to pinpoint dysregulated biological processes and signalling pathways. Computational findings were tested in a letrozole-induced PCOS rat model treated with nerolidol, with efficacy judged from oestrous cyclicity, ovarian histopathology, reproductive hormone profiles, oxidative stress biomarkers, inflammatory mediators and metabolic parameters. Transcriptomic analysis showed marked enrichment of processes related to kinase regulation, insulin secretion, intrinsic apoptotic signalling, receptor-mediated signalling and the DNA damage response, while KEGG analysis pointed to pathways governing endocrine regulation, cell signalling and metabolic homeostasis. In animal experiments, nerolidol restored oestrous cyclicity, improved ovarian morphology, corrected endocrine disturbances, and reduced oxidative stress and PCOS-related pathology. These phenotypic effects were functionally concordant with several biological processes highlighted by the computational analyses. However, because the predicted signalling molecules and pathways were not directly measured in ovarian tissue following nerolidol treatment, the proposed molecular mechanisms remain hypotheses requiring targeted experimental validation.

Polyendocrine metabolic ovarian syndrome (PMOS; formerly polycystic ovary syndrome) is the most common endocrinopathy affecting women of reproductive age, characterized by ovarian dysfunction and hyperandrogenism, with metabolic disturbances including insulin resistance and obesity also present for 50% of PMOS patients. Effective preclinical models are crucial for evaluating therapeutic interventions. However, current mouse models of hyperandrogenemia induced by aromatase inhibition typically rely on subcutaneous letrozole implants, which require surgical procedures and struggle to sustain PMOS-like phenotypes over an extended period necessary for thorough drug assessment. We hypothesized that an oral letrozole administration would provide extended maintenance of syndrome-like features. Female mice received letrozole either via subcutaneous implant (~1.67 mg/kg/day for 70 days) or orally in drinking water (~1 mg/kg/day for up to 130 days). Estrous cyclicity was monitored by vaginal cytology. Hormonal, metabolic, and histological assessments were performed. While a subcutaneous letrozole implant only sustained hyperandrogenic, metabolic and reproductive phenotypes for ~50 days, oral letrozole administration sustained complete anovulation for at least 100 days, maintaining a persistent diestrus stage. The oral letrozole treatment produced comprehensive PMOS-like features, including significantly elevated testosterone levels, increased luteinizing hormone concentration, pulse frequency and amplitude, enhanced hypothalamic androgen receptor expression, decreased hypothalamic progesterone receptor expression, cystic-like ovarian morphology, increased body weight, impaired insulin sensitivity, and elevated adiposity during the entire time of the treatment period (18 weeks), compared to the placebo treatment. Uterine weight was not decreased, suggesting normal circulating estrogen concentrations. These findings demonstrate that oral letrozole delivery offers a more accessible method of administration, resulting in a sustained induction of PMOS-like phenotypes. This approach effectively maintains both reproductive and metabolic features essential for comprehensive evaluation, thereby enhancing the model's utility for investigating therapeutic interventions in PMOS.