bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2026–02–01
37 papers selected by
Chun-Chi Chang, Lunds universitet
  1. Sex Matters: Hormonal and Chromosomal Determinants of Autoimmunity and Anti-Cancer Immunity Across the Lifespan.
  2. Sex Differences in Response to Viral Vector Vaccines-Implications for Future Vaccine Design.
  3. Remodeling of androgen metabolism network mediated by UGT2B: a new perspective on treatment resistance in prostate cancer.
  4. Exploring Proteomic Differences in PBMCs for Sex-Specific Insights into Alzheimer's Disease.
  5. The effect of BCG vaccination on systemic inflammation in neonates.
  6. Single-nucleus resolution of sex-biased expression and dosage compensation in Drosophila melanogaster.
  7. Sex Differences in Alloimmunity and Other Immunological Considerations in Organ Transplantation.
  8. Exploring novel biomarkers for endocrine disruptor exposure: insights into extra-nuclear signaling pathways of estrogen and androgen receptors.
  9. Immunological Causes of Infertility: Diagnostic Perspectives.
  10. Host, microbial and environmental drivers of vaginal microbiota composition.
  11. Long-term sex differences in symptoms and immune profile in long COVID.
  12. X-inactive specific transcript (XIST) can determine sex differences in cardiovascular drug responses: focus on RNA therapeutics.
  13. Metabolic effects of testosterone therapy in transgender and gender diverse individuals with polycystic ovary syndrome.
  14. Neutrophils and NETosis in polycystic ovary syndrome: unraveling the immuno-metabolic thromboinflammatory axis.
  15. Sex Hormone Supplementation and Cardiovascular Disease Risk.
  16. Oxidative Stress and SIRT1-Nrf2 Anti-Ferroptotic Pathways in Granulosa Cells: A Molecular Key to Follicular Atresia and Ovarian Aging.
  17. The Role of Androgen Receptor and Antiandrogen Therapy in Breast Cancer: A Scoping Review.
  18. Glial activation and increased blood brain barrier permeability in the medial preoptic area of male mice lacking neural androgen receptor.
  19. Sex-Specific Differences in Gut Microbiota Composition in Adult Patients with Bronchial Asthma.
  20. Impact of female hormonal changes throughout life on oral health: A scoping review.
  21. Sex-dependent locus coeruleus vulnerability in Alzheimer's disease: gut dysbiosis as a driver and probiotic intervention as rescue.
  22. The relationship between sex hormones, metabolic markers, and cognitive linguistic functions in women with PCOS.
  23. Comment on "AMH predicts miscarriage in non-PCOS but not in PCOS related infertility ART cycles".
  24. Cardiovascular Dysfunction in Polycystic Ovary Syndrome: Mitochondrial and Inflammatory Mechanisms.
  25. The role of ovarian hormones in risk aversion in female rats.
  26. Effectiveness of exercise interventions on androgen and sex hormone-binding globulin levels in women with polycystic ovary syndrome: a systematic review and meta-analysis.
  27. Efficacy of Stop GnRH-Agonist/Antagonist versus GnRH-Antagonist Protocols in In Vitro Fertilization Cycles of Patients with Polycystic Ovary Syndrome: A Pilot Randomized Controlled Trial.
  28. Lactobacillus-Dominated Cervical Microbiota Revealed by Long-Read 16S rRNA Sequencing: A Greek Pilot Study.
  29. Sex-Dependent Microbial and Host Profiles Following Fecal Microbiota and Bifidobacterium longum Treatment in Stress-Induced Gut Dysbiosis.
  30. Role of reactive oxygen species in polycystic ovary syndrome: signalling pathways, mechanisms, and traditional Chinese medicine treatment strategies.
  31. Sex-Based Differences in Cell Types and Gene Expression within the Anterior Cruciate Ligament.
  32. Risk of bone fractures in patients with prostate cancer treated with maximal androgen blockade therapy: a systematic literature review and meta-analysis.
  33. The Vaginal Microbiome and Host Health: Implications for Cervical Cancer Progression.
  34. Sex-Specific Downregulation of CDK5RAP3 Exacerbates ER Stress-Mediated Inflammation and Apoptosis in CCl4-Induced Acute Liver Injury.
  35. Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC.
  36. Micro-Management: How the Male Reproductive Microbiome Shapes Male Fertility.
  37. Follicular Klotho in the Ovarian Microenvironment: Exploring Its Role in IVF Outcome Prediction.
  1. Immunol Rev. 2026 Mar;338(1): e70096
    Sex Matters: Hormonal and Chromosomal Determinants of Autoimmunity and Anti-Cancer Immunity Across the Lifespan.
    Christian G Bustillos, Esther M Peluso, Sophia L Cha, Melissa G Lechner, Maureen A Su.
      Sex plays a key role in shaping both anti-cancer immunity and autoimmunity. Biological factors underlying sexual dimorphism have now been identified in multiple aspects of anti-cancer immunity and autoimmunity. These factors include sex differences in hormone levels, chromosome complement, and expression of the long non-coding RNA XIST. In this review, we discuss recent advances delineating how these differences alter immune responses against cancer and autoimmune responses against healthy tissues. Moreover, we now understand that hormone levels change (e.g., in mini-puberty, menopause, and andropause) and that somatic alterations in chromosomal complement accumulate (e.g., loss of Y [LOY] chromosome) across the lifespan. We also include here a discussion of how these changes affect anti-cancer immunity and autoimmunity across a lifetime. These recent advances will set the stage for identifying immunotherapeutic approaches that optimize anti-cancer immunity while controlling the autoimmune responses.
    Keywords:  X chromosome; Y chromosome; autoimmunity; cancer; hormones; sex
    DOI:  https://doi.org/10.1111/imr.70096
  2. Immunol Rev. 2026 Mar;338(1): e70098
    Sex Differences in Response to Viral Vector Vaccines-Implications for Future Vaccine Design.
    Ilka Grewe, Tamara Zoran, Marylyn Martina Addo.
      Vaccination represents one of the most impactful public health achievements, preventing 3.5 to 5 million deaths annually according to estimates of the World Health Organization. Yet, recent outbreaks of emerging and reemerging infectious diseases highlight the need for rapid and strategic vaccine development using vaccine platforms technologies. Sexual dimorphism in vaccine-induced immune responses has received significant attention in recent years. To ensure vaccine safety and efficacy across sexes, sex-based differences should be considered in vaccine design, dosing, and regimen. Evidence on many traditional vaccines, such as the inactivated influenza vaccine, shows a female bias in innate and adaptive immune responses following vaccination. Thus, it has long been suggested that females universally develop stronger humoral and cellular immune responses to vaccines compared to males. However, compared to traditional vaccines, studies investigating sex differences following vaccination with next-generation platforms, such as viral vector vaccines, remain limited. This review provides an overview of clinical observations of sex differences in responses to replication-competent and replication-deficient, recombinant and nonrecombinant viral vaccines. Additionally, we describe the current state of knowledge on mechanisms of sex-based differences in immune responses and possible implications for future vaccine design.
    Keywords:  MVA; MVA‐MERS‐S; nonreplicating vaccines; replicating; sexual dimorphism; viral vector vaccines
    DOI:  https://doi.org/10.1111/imr.70098
  3. Eur J Pharmacol. 2026 Jan 23. pii: S0014-2999(26)00078-6. [Epub ahead of print] 178596
    Remodeling of androgen metabolism network mediated by UGT2B: a new perspective on treatment resistance in prostate cancer.
    YuanYuan Wang, Chenxi Tu, Hao Qin, Yingying Ma, Yukai Yang, Yinhua Xiong, Liang Peng, Lin Zhang.
      Prostate cancer (PCa) is the most common and aggressive malignancy in males worldwide, with its progression influenced by multiple factors. Androgens, the primary regulators of prostate cell growth and physiology, play a pivotal role in PCa pathogenesis through the androgen receptor (AR) signaling pathway, thus earning PCa designations as a hormone-sensitive or hormone-dependent cancer. Current anti-androgen therapies (e.g., androgen deprivation therapy, ADT) have demonstrated initial effectiveness but ultimately failed to prevent progression to castration-resistant prostate cancer (CRPC). Previous research has predominantly focused on AR and its associated signaling pathways. However, UGT2B15 and UGT2B17, as key members of the human UDP-glucuronosyltransferase (UGT) family, serve as critical catalytic enzymes in androgen metabolism. They both efficiently convert androgens into more excretable glucuronidated metabolites, thereby modulating systemic hormone levels, primarily affecting the activation of AR. This article systematically explores the association between the UGT2B subfamily and hormone-dependent prostate cancer, covering various aspects such as gene function, regulatory mechanisms, disease progression, and diagnosis. It elucidates the different roles of UGT2B genes and reveals their significant potential in being developed into biomarkers and therapeutic targets, paving the way for improvements in precision medicine for prostate cancer.
    Keywords:  UGT2B; androgen metabolism; biomarker; expression regulation; prostate cancer
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178596
  4. MicroPubl Biol. 2026 ;2026
    Exploring Proteomic Differences in PBMCs for Sex-Specific Insights into Alzheimer's Disease.
    Takako Ishida-Takaku, Colin Combs.
      Peripheral blood mononuclear cells (PBMCs) offer a minimally invasive window into systemic biology and immune dysregulation in Alzheimer's disease (AD). We performed quantitative proteomic profiling of PBMCs from male and female AD patients and controls to assess sex differences. AD was associated with proteomic remodeling, with complement activation, coagulation, and neuronal signaling enriched in males, whereas females showed increased steroid hormone secretion, lipid metabolism, and acute-phase response with reduced translation and DNA maintenance. Despite distinct patterns, both sexes exhibited immune and hemostatic activation, underscoring shared systemic mechanisms and the need for sex-specific biomarkers and therapeutic strategies in AD.
    DOI:  https://doi.org/10.17912/micropub.biology.001922
  5. Vaccine. 2026 Jan 26. pii: S0264-410X(26)00048-4. [Epub ahead of print]75 128241
    The effect of BCG vaccination on systemic inflammation in neonates.
    Valerie A C M Koeken, Thomas N Nissen, Nina M Birk, Collins K Boahen, Reinout van Crevel, Vinod Kumar, Yang Li, Peter Aaby, Christine S Benn, Mihai G Netea.
       OBJECTIVES: To assess the impact of BCG vaccination on systemic inflammation in neonates, focusing on sex-specific differences and the relationship between circulating inflammatory proteins and immune responses, including cytokine production and antibody levels.
    METHODS: A randomized clinical trial was conducted in Denmark involving newborns who were randomized to receive BCG vaccine or not. Blood samples were collected at 4 days, 3 months and 13 months post-randomization. In the current sub-study within the randomized clinical trial, ninety-two inflammatory proteins in plasma were measured using a proximity extension assay. We analysed the changes in these inflammatory markers and examined their association with immune markers.
    RESULTS: Before BCG vaccination, girls had slightly higher inflammatory marker levels than boys. Post-vaccination, a moderate decrease in circulating inflammatory markers was noted in BCG-vaccinated children, especially in girls, with the strongest effects observed at 3 months. By 13 months, following routine vaccinations, there was no longer any measurable effect of BCG vaccination. BCG seemed to modify the associations between inflammatory proteins and immune responses.
    CONCLUSIONS: This sub-study suggests that BCG vaccination could temporally reduce systemic inflammation in neonates, with the strongest effect observed in girls, who had the highest baseline levels. These findings seemingly replicate observations in adults, showing that BCG has a pronounced inflammation-dampening effect in those with higher pre-vaccination levels. The results further show that BCG vaccination could alter circulating inflammatory proteins in a time-dependent manner and potentially modulate the associations between inflammatory markers and immune function. These insights highlight the importance of sex-specific immune modulation by BCG in early life and underscore the value of personalised vaccination strategies that considers both timing and sex differences in immune responses.
    Keywords:  BCG; Inflammatory proteins; Sex-specific immune effects; Trained immunity; Vaccination
    DOI:  https://doi.org/10.1016/j.vaccine.2026.128241
  6. Proc Biol Sci. 2026 Jan 28. pii: 20252471. [Epub ahead of print]293(2063):
    Single-nucleus resolution of sex-biased expression and dosage compensation in Drosophila melanogaster.
    Carolina Barata, Beatriz Vicoso.
      In many species, sex-biased expression is widespread and thought to contribute to sexual dimorphism. While bulk RNA-sequencing has been instrumental in identifying strongly sex-biased genes, it lacks resolution to assess variation across cell-types and tissue compartments. Using single-nucleus expression data from the Fly Cell Atlas, we investigate sex differences in adult Drosophila melanogaster. We find that differences in cell-type composition between the sexes are not a major source of sex-bias, as for the vast majority of genes, the degree of sex-bias is similar regardless of whether sex differences in cell-type composition are controlled for or not. Our analysis confirms a deficit of X-linked male-biased genes in the body's somatic tissues that is widespread across cell-types. We also find the excess of X-linked female-biased genes to be associated with nervous system cells in the head but with epithelial cells in the body's somatic tissues, showing that single-nucleus data crucially resolves sex-bias at the cell-type level. We investigate dosage compensation (DC) across 15 tissues and 17 cell-types. We observe that it varies throughout the body. Surprisingly, we observe a lack of DC in a cluster of main cells within the male accessory glands. This result highlights the importance of understanding context-dependent DC.
    Keywords:  dosage compensation; fruit fly; sex-biased expression; sexual dimorphism
    DOI:  https://doi.org/10.1098/rspb.2025.2471
  7. Immunol Rev. 2026 Mar;338(1): e70104
    Sex Differences in Alloimmunity and Other Immunological Considerations in Organ Transplantation.
    Whitney A Perry, Pritha Sen.
      Sex-based differences in human immunity are well-described in the general population, cumulatively favoring a more hyperinflammatory immune response among females in different scenarios. It is imperative to understand how this applies in the setting of transplantation, where dynamic immune function determines key clinical outcomes, including graft rejection and responses to infection. Sex differences unique to transplant immunity begin at the chromosomal level and are influenced by steroid hormones and sex-specific factors ranging from pre-existing pregnancy-induced alloimmunization to differential metabolism of routine immunosuppressive medications. Given active efforts for greater sex and gender equity in transplantation, and with increasing transplantation of older candidates, the unique immunological considerations at the cross-roads of biological sex and age are also critical to consider. Age is an important modifier of the relationship between sex and immune-related outcomes as young females appear to have a greater risk for poor outcomes related to alloimmunity compared to similarly-aged male counterparts, particularly when receiving an organ from a male donor. However, this risk does not endure in post-menopausal age categories and there are some limited data to suggest, in fact, that post-menopausal women may have a greater risk for transplant-related infection. Greater efforts to incorporate sex as a biological variable into transplant research will lead to a more tailored strategy for immunosuppressive management, rejection surveillance, infection prophylaxis and other considerations for optimization of transplant outcomes.
    Keywords:  T cells; aging; cell lineages and subsets; infectious diseases; major histocompatibility complex; molecules; processes; therapeutic approaches; transplantation; viral
    DOI:  https://doi.org/10.1111/imr.70104
  8. Environ Toxicol Pharmacol. 2026 Jan 23. pii: S1382-6689(26)00027-X. [Epub ahead of print]122 104949
    Exploring novel biomarkers for endocrine disruptor exposure: insights into extra-nuclear signaling pathways of estrogen and androgen receptors.
    Manuela Cipolletti, Ilaria Campesi, Marco Pellegrini, Marco Fiocchetti, Filippo Acconcia, Maria Marino.
      Synthetic chemicals classified as endocrine disruptors (EDs) pose health risks by interfering with sex-steroid hormone signaling. This study evaluated bisphenol A (BPA) for its effects on ERα, ERβ, and AR expression and extranuclear signaling, including ERα phosphorylation, in human monocytes from healthy male and female donors, and assessed ten additional chemicals in ERα-positive breast cancer cell lines (MCF-7, T47D). BPA increased ERα phosphorylation in both male and female monocytes without altering receptor levels, while modulating downstream signaling in a sex-dependent manner and attenuating DHT- or E2-induced effects. The ten other chemicals similarly enhanced ERα phosphorylation, often independently of direct receptor binding. These findings indicate that ERα phosphorylation is a sensitive, early marker of ED activity across immune and epithelial cells and support its use as a receptor-proximal endpoint to complement conventional transcription-based assays in next-generation ED screening strategies.
    Keywords:  Endocrine disruptors; Exposure biomarkers; Human monocytes; Sex differences; Sex hormones receptors
    DOI:  https://doi.org/10.1016/j.etap.2026.104949
  9. Biomolecules. 2025 Dec 25. pii: 39. [Epub ahead of print]16(1):
    Immunological Causes of Infertility: Diagnostic Perspectives.
    Aleksandra M Kicińska, Radosław B Maksym, Grzegorz Szewczyk.
      From an immunological perspective, infertility mechanisms encompass not only fertilization but also implantation, as well as both early and late pregnancy loss. Growing attention is being directed towards the influence of systemic disorders on reproductive outcomes. The immune system plays a fundamental and regulatory role in human reproduction. Immunological factors may affect multiple stages of this process, potentially justifying their inclusion in extended diagnostic pathways. The impact of autoimmunity and the presence of various antibodies on reproductive functions is discussed. Special attention is given to the immunomodulatory role of progesterone in reproduction and a state of impaired progesterone action-luteal deficiency. Endometriosis is also highlighted as a disorder both associated with infertility and underpinned by a strong immunological basis. The usefulness of assessing lymphocyte subpopulation balance, cytokine profiles, and Th1/Th2 immune response in the diagnostic work-up of infertility is addressed. Furthermore, the prospect for a role of local and systemic infections, subclinical inflammation and microbial colonization is shown. Tests applied in the evaluation of implantation and placental development disorders are discussed. Adequate immunological diagnostics and accurate identification of the underlying causes of infertility facilitate effective therapeutic strategies and can substantially increase the likelihood of achieving a successful pregnancy.
    Keywords:  antisperm antibodies; autoimmune diseases; chronic endometritis; cytokines; endometriosis; infertility; inflammation; natural killer cells; progesterone; reproductive immunology; t-lymphocytes
    DOI:  https://doi.org/10.3390/biom16010039
  10. Fertil Steril. 2026 Jan 27. pii: S0015-0282(26)00049-X. [Epub ahead of print]
    Host, microbial and environmental drivers of vaginal microbiota composition.
    Remy B Young, Gonçalo D S Correia, David A MacIntyre.
      The human vagina harbours a microbial community that differs markedly in compositional structure from all mammals, including closely related primates. Lactobacilli are the most abundant vaginal species, and their dominance in this niche are associated with protection against adverse health outcomes including preterm birth, sexually transmitted infections and bacterial vaginosis. However, the vaginal environment can also support compositions of diverse anaerobic bacteria, which have been linked to poor reproductive health outcomes. Here, we review current knowledge on host and microbial determinants that influence microbial community structure within the vaginal niche, emphasising the interplay between host physiology, immune and metabolic interactions as well as lifestyle factors. This integrated understanding provides a foundation for linking vaginal microbiome compositions to clinically relevant phenotypes and highlights mechanisms that could be exploited to promote improved reproductive health.
    Keywords:  Vaginal microbiome; host-microbial co-evolution; microbial ecology; reproductive health
    DOI:  https://doi.org/10.1016/j.fertnstert.2026.01.020
  11. Biol Sex Differ. 2026 Jan 27.
    Long-term sex differences in symptoms and immune profile in long COVID.
    José Feliz, Juliana Gonçalves, Carolina Cabedo, José Brito, Maria Gamas, Maria Inês Neves, Helena Soares.
       BACKGROUND: Long COVID (LC) is a post-infectious condition affecting millions worldwide, characterized by persistent multisystem symptoms. Females are disproportionately affected, reporting higher symptom burden, particularly neurocognitive and neurosensory complaints. While short-term immunopathology has been described, the long-term clinical course, immune dysregulation, and sex-specific underpinnings remain poorly understood.
    METHODS: We analyzed 34 participants experiencing persisting symptoms from 9 months to 5 years post-SARS-CoV-2 infection, alongside 26 SARS-CoV-2-infected controls without symptoms. Clinical assessments, symptom inventories, comorbidity analysis, and work capacity evaluation were performed. Immune profiling included flow cytometry of CD4⁺ and CD8⁺ T cells, NK cells, and B cells, as well as quantification of plasma cytokines, soluble factors, and cytotoxic molecules, analyzed in a sex-disaggregated manner.
    RESULTS: Females with LC exhibited higher symptom burden, particularly persistent fatigue, neurocognitive and neurosensory complaints, which increased with age and tended to increase with disease duration, whereas males showed no clear age- or duration-related patterns. Comorbidities, especially affecting endocrine, metabolic, and circulatory systems, were more frequent in females and aligned with symptom severity. Immune profiling revealed subtle but sex-specific differences: females had reduced CD8⁺ T cell cytotoxic profile, lower NKG2D and granzyme K expression, increased sCD40L and sFAS, and decreased perforin, whereas males displayed elevated TNF-α. NK cell function, B cells, and humoral immunity remained largely intact. Over half of participants reported functional impairments affecting work capacity.
    CONCLUSIONS: Even though our cohort is small it suggests that prolonged LC is characterized by sex-specific differences in symptom burden and immune profiles. Reduced cytotoxic CD8⁺ T cell profile in females may contribute to viral persistence and neurological symptoms, whereas elevated inflammatory markers in males suggest distinct immune pathways. These findings highlight the need for sex- and duration-specific management strategies, the identification of biomarkers, and the development of personalized therapies targeting specific LC endotypes.
    Keywords:  Cellular and molecular signatures; Immune dysregulation; Long COVID; Long-term symptom persistence; Sex differential immunity
    DOI:  https://doi.org/10.1186/s13293-026-00825-9
  12. Front Pharmacol. 2025 ;16 1716863
    X-inactive specific transcript (XIST) can determine sex differences in cardiovascular drug responses: focus on RNA therapeutics.
    Timur O Yarovinsky, Vinod S Ramgolam, Iva R Knezevic, Nina S Stachenfeld, Jeffrey R Bender.
      Genetic, hormonal, anatomical, and environmental factors underlie sex differences in the prevalence and progression of cardiovascular disease and responses to therapeutics. The presence of two X chromosomes in the female genome decreases susceptibility to X-linked recessive disorders but imposes the need for random X chromosome inactivation as an epigenetic mechanism controlling gene dosage. Long non-coding RNA XIST is essential for transcriptional repression of genes on inactive X chromosome but may also act as a miRNA sponge for post-transcriptional regulation of gene expression and a scaffold for RNA binding proteins that provoke autoimmune responses. These features draw attention to XIST as an important drug development target by design or as an off target, including novel RNA therapeutics for genetic and cardiovascular diseases. Based on the extensive literature analysis, we postulate the hypothesis that XIST can determine sex differences in cardiovascular drug responses and propose several criteria for use in developing or evaluating responses to RNA therapeutics for cardiovascular disease in women. We hope that implementation of those criteria in the process of RNA therapeutics development may be helpful in reducing the risks of adverse effects in women.
    Keywords:  RNA therapeutics; X chromosome inactivation (XCI); XIST (X-inactive specific transcript); cardiovascular diseases; miRNA; sex as a biological variable (SABV)
    DOI:  https://doi.org/10.3389/fphar.2025.1716863
  13. J Clin Endocrinol Metab. 2026 Jan 28. pii: dgag032. [Epub ahead of print]
    Metabolic effects of testosterone therapy in transgender and gender diverse individuals with polycystic ovary syndrome.
    Justine Herndon, J Anderson McNeil, Salym Winter, Alice Y Chang.
       BACKGROUND: Polycystic ovary syndrome (PCOS) affects 10 to 13% of individuals assigned female at birth (AFAB), although a greater prevalence is reported in transgender/gender diverse individuals (TGD) (23.8%-38.8%). Testosterone therapy (TT) in TGD individuals is linked to worsening cardiovascular risk factors (CVRF) . Whether TT induces more adverse cardiometabolic changes in TGD with PCOS than TGD without PCOS remains uncertain.
    OBJECTIVE: To compare the effects of TT on CVRF in TGD with and without PCOS.
    METHODS: We retrospectively reviewed 373 records to identify 62 TGD with PCOS (withestablished guideline criteria) and 132 age-matched TGD without PCOS. Data included longitudinal anthropometric measurements, hormone and metabolic parameters, and CVRF before and after TT. Group comparison of PCOS vs. without PCOS before and after TT was conducted via independent t-tests, Mann-Whitney-U, and Chi-square.
    RESULTS: At baseline, TGD with PCOS had significantly greater body mass index (BMI), obesity prevalence, and, after controlling for BMI, baseline metformin use. There were no significant differences between TGD with and without PCOS when comparing intra-participant changes after TT. Controlling for BMI, TGD with PCOS on TT exhibited significantly greater hyperlipidemia prevalence, alanine transaminase (ALT) levels, and bioavailable testosterone concentrations than TGD without PCOS on TT.
    CONCLUSION: . Greater baseline cardiometabolic risk was largely BMI-related in TGD with PCOS compared to TGD without PCOS. Only hyperlipidemia and elevated ALT were more prevalent during TT after adjusting for BMI. These findings support cardiometabolic monitoring during TT in all TGD individuals without significant increased risk with PCOS history.
    Keywords:  Transmasculine; androgen excess; cardiovascular risk; gender-affirming hormone therapy
    DOI:  https://doi.org/10.1210/clinem/dgag032
  14. Eur J Med Res. 2026 Jan 27.
    Neutrophils and NETosis in polycystic ovary syndrome: unraveling the immuno-metabolic thromboinflammatory axis.
    Sahar Hosseini, Fatemeh Shabani, Mehrnaz Nayebzadeh, Fatemeh Asadi, Yasaman Kabiranaraki, Marziyeh Asadpour, Yasaman Golvar, Shafagh Asadi, Atoosa Etezadi.
      Polycystic ovary syndrome (PCOS), traditionally defined by its endocrine and reproductive hallmarks-hyperandrogenism, oligo-anovulation, and polycystic ovarian morphology-is increasingly viewed as a complex disorder associated with chronic low-grade immuno-metabolic inflammation. Emerging evidence suggests that neutrophils, the most abundant innate immune cells, may play a contributory role in linking metabolic stress, inflammatory signaling, and vascular dysfunction in PCOS. In women with PCOS, hyperandrogenism, insulin resistance, and adipose-derived inflammatory cues have been associated with altered neutrophil activation profiles, including increased oxidative stress, degranulation, and markers suggestive of neutrophil extracellular trap (NET) formation. While direct evidence for NET-driven pathology in PCOS remains limited, mechanistic insights from related inflammatory and metabolic diseases indicate that NET-associated pathways can amplify thrombo-inflammatory signaling, endothelial dysfunction, and tissue injury. This review synthesizes available PCOS-specific data on neutrophil activation alongside mechanistic frameworks inferred from other disease contexts, emphasizing cytokine- and adipokine-mediated priming, neutrophil heterogeneity, and potential NET-associated effects on reproductive, metabolic, and cardiovascular outcomes. We also highlight critical knowledge gaps, including the need for longitudinal studies, standardized NET biomarker assessment, and single-cell immune profiling to define neutrophil subsets and functional states in PCOS. Finally, we discuss translational perspectives, proposing neutrophil- and NET-focused strategies as potential adjuncts to existing hormone-centric management, rather than established therapeutic targets. By reframing PCOS through an immuno-metabolic lens centered on innate immune dysregulation, this review provides a cautious yet integrative conceptual framework to guide future mechanistic and clinical investigations.
    Keywords:  Endothelial dysfunction; Immune dysregulation; Neutrophil; Neutrophil extracellular trap; Polycystic ovary syndrome; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s40001-026-03927-7
  15. Medicina (Kaunas). 2026 Jan 09. pii: 134. [Epub ahead of print]62(1):
    Sex Hormone Supplementation and Cardiovascular Disease Risk.
    Zofia Kampka, Magdalena Balwierz-Podgórna, Maciej T Wybraniec.
      Background and Objectives: The fact that men are at a higher risk of cardiovascular disease (CVD) compared to women, regardless of concomitant risk factors, draws attention to the potential role of sex hormones in cardiovascular health. Hormonal therapies undoubtedly play a crucial role in reproductive and endocrine health; however, their cardiovascular implications remain complex and incompletely understood. This review aims at providing an updated overview of recent studies on this topic, highlighting the practical clinical aspects and knowledge gaps. Materials and Methods: This review synthesizes recent clinical studies regarding the cardiovascular impact of female hormone replacement therapy (HRT) and testosterone replacement therapy (TRT). Results: It seems that both hormonal deficiency and excess can exert detrimental effects on the cardiovascular system. While HRT and TRT offer benefits to specific patient populations, their broad biological actions can lead to adverse effects. This creates a sophisticated and delicate relationship between hormonal balance and heart health, complicating the determination of universal safety profiles and use indications. Conclusions: The risk-benefit ratio of hormonal therapies remains a critical concern in clinical practice. Because cardiovascular effects vary significantly based on individual patient profiles, a nuanced approach to prescribing is necessary. Further research is required to bridge knowledge gaps and refine safety guidelines for the use of sex hormones in cardiovascular prevention and treatment.
    Keywords:  cardiovascular disease; cardiovascular risk; hypogonadism; sex hormones; testosterone
    DOI:  https://doi.org/10.3390/medicina62010134
  16. Int J Mol Sci. 2026 Jan 18. pii: 950. [Epub ahead of print]27(2):
    Oxidative Stress and SIRT1-Nrf2 Anti-Ferroptotic Pathways in Granulosa Cells: A Molecular Key to Follicular Atresia and Ovarian Aging.
    Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Spyridon Polykalas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Charalampos Tsimpoukelis, Athanasios Karpouzos, Maria Anastasia Daskalaki, Nikolaos Kanakas, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis, Georgios Daskalakis.
      The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, reduced metabolic support for oocytes, and the activation of regulated apoptotic pathways that end in follicular atresia. Ferroptosis, an emergent type of iron-dependent lipid peroxidation, has been identified as a crucial mechanism contributing to chemotherapy-induced ovarian insufficiency, polycystic ovary syndrome (PCOS), and granulosa cell death in aging ovaries, in addition to conventional apoptosis. The SIRT1-Nrf2 axis acts as a crucial anti-oxidative and anti-ferroptotic system that protects GC viability, maintains mitochondrial homeostasis, and upholds redox equilibrium. SIRT1 promotes mitochondrial biogenesis and metabolic resilience by deacetylating downstream proteins, including FOXO3 and PGC-1α. Nrf2 simultaneously controls the transcriptional activation of detoxifying and antioxidant enzymes, including HO-1, SOD2, NQO1, and GPX4, which are critical inhibitors of ferroptosis. Disruption of SIRT1-Nrf2 signalling accelerates GC senescence, follicular depletion, and reproductive aging. In contrast, pharmaceutical and nutraceutical therapies, including metformin, melatonin, resveratrol, and agents that increase NAD+ levels, may reverse ovarian deterioration and reactivate SIRT1-Nrf2 activity. This narrative review highlights innovative treatment prospects for ovarian aging, fertility preservation, and assisted reproduction by synthesising current evidence on ferroptotic pathways, SIRT1-Nrf2 interactions, and oxidative stress in granulosa cells. An understanding of these interrelated biological networks enables the development of tailored therapies that postpone ovarian ageing and enhance reproductive outcomes for women receiving fertility therapy.
    Keywords:  IVF; Nrf2; SIRT1; antioxidants; ferroptosis; infertility; molecular research; ovarian aging; oxidative stress; reproductive endocrinology
    DOI:  https://doi.org/10.3390/ijms27020950
  17. Curr Oncol. 2026 Jan 12. pii: 41. [Epub ahead of print]33(1):
    The Role of Androgen Receptor and Antiandrogen Therapy in Breast Cancer: A Scoping Review.
    Antonio Ghidini, Roberta Bukovec, Luisa Roncari, Isabella Garassino, Fulvia Milena Cribiù, Fausto Petrelli.
      Breast cancer is a complex and highly heterogeneous disease, and its management is increasingly moving towards the principles of precision medicine. In this context, the androgen receptor (AR) has emerged as a promising therapeutic target, particularly within the challenging subgroup of triple-negative breast cancers (TNBCs) that express it. This scoping review provides a comprehensive and detailed analysis of the multifaceted role of AR in breast cancer. We delve into its intricate molecular structure, its differential function in ER-positive vs. TNBC subtypes, and the detailed molecular mechanisms that govern its activity. We provide a thorough examination of the landmark clinical trials with antiandrogen agents, including not only enzalutamide but also other first- and second-generation compounds, and discuss the emerging data on their efficacy. Furthermore, we will explore the critical challenges that hinder their widespread clinical adoption, such as primary and acquired resistance mechanisms, the need for robust predictive biomarkers, and the heterogeneity of AR expression. Finally, we outline future research directions, focusing on novel combination therapies and the development of next-generation agents and predictive tools to optimize patient selection and improve clinical outcomes.
    Keywords:  androgen receptor; antiandrogen therapy; bicalutamide; enzalutamide; hormone receptors; luminal androgen receptor; precision oncology; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/curroncol33010041
  18. Mol Cell Endocrinol. 2026 Jan 27. pii: S0303-7207(26)00019-5. [Epub ahead of print] 112742
    Glial activation and increased blood brain barrier permeability in the medial preoptic area of male mice lacking neural androgen receptor.
    Nida Karameh, Afnan Atallah, Danaé Nuzzaci, Valérie Grange-Messent, Sakina Mhaouty-Kodja.
      We have previously shown that testosterone depletion in adult male mice induced neural androgen receptor (Ar) down-regulation and led to neuroinflammation and increased blood brain barrier (BBB) permeability in the medial preoptic area. In the present study, we investigated the effects of neural Ar deletion on glial function and BBB integrity in male mice. For this purpose, we used control and mutant littermates obtained from a mouse line deleted for the Ar in neural progenitors by Cre-loxP technology. Neural Ar deletion induced glial activation evidenced by increased immunoreactivity against markers of astrocytes (glial fibrillary acidic protein -GFAP- and N-myc downstream-regulated gene 2) and microglia (ionized calcium binding adaptor molecule 1). Fluoro-Jade® C fluorescent labeling was increased and inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) were detected in the vicinity of capillaries in the male medial preoptic area of neural Ar knockout mice. Analysis of BBB integrity showed enhanced permeability for Evans Blue tracer and endogenous immunoglobulins in mutant animals compared to their control littermates. In addition, modifications in the ultrastructural organization of capillary endothelial tight junctions were observed by electron tomography. These effects were specific to neural Ar deletion since no changes were observed for GFAP-immunoreactivity, BBB permeability or Fluoro-Jade® C labeling in male mice expressing the wild type Ar allele and carrying the Cre transgene. Altogether, these data indicate the key role of the neural AR in testosterone-induced regulation of astrocyte, microglial and BBB functions in the medial preoptic area of male mice.
    Keywords:  Androgen receptor; Androgens; Astrocytes; Blood brain barrier; Brain; Microglia
    DOI:  https://doi.org/10.1016/j.mce.2026.112742
  19. Biomedicines. 2026 Jan 08. pii: 125. [Epub ahead of print]14(1):
    Sex-Specific Differences in Gut Microbiota Composition in Adult Patients with Bronchial Asthma.
    Chihiro Hirano, Yutaka Kozu, Yusuke Jinno, Yusuke Kurosawa, Shiho Yamada, Kouta Hatayama, Kanako Kono, Kenji Mizumura, Motoyasu Iikura, Shuichiro Maruoka, Hiroaki Masuyama, Yasuhiro Gon.
      Background: Gut microbiota dysbiosis has been associated with childhood asthma; however, its role in adult bronchial asthma (BA), particularly in Japanese populations, remains unclear. The potential influence of sex-based differences also warrants investigation. We aimed to investigate the association between gut microbiota composition and adult BA in a Japanese cohort, focusing on sex-specific differences. Methods: Stool samples from 108 Japanese adults with BA (48 male and 60 female individuals) and 210 healthy controls (90 male and 120 female individuals) were analyzed using 16S rRNA gene sequencing. Analyses were stratified by sex. β-diversity was assessed using non-metric multidimensional scaling and permutational multivariate analysis of variance. Genus-level taxonomic comparisons were conducted using the ANOVA-Like Differential Expression version 2 tool on centered log-ratio-transformed data. Results: β-diversity significantly differed between the groups among both male and female individuals. In male individuals, 11 taxa had absolute effect sizes of ≥0.2. In female individuals, 19 taxa met this threshold, with 8 reaching significance after Benjamini-Hochberg correction. Streptococcus and Blautia were enriched in the BA group in both sexes, whereas other taxa showed sex-specific patterns, such as Veillonella in male and Flavonifractor and Eggerthella in female individuals. Several short-chain fatty acid (SCFA)-producing taxa were depleted in the BA group. Conclusions: Our findings suggest that gut microbiota dysbiosis occurs in Japanese adults with BA, characterized by enrichment of taxa associated with respiratory diseases and depletion of SCFA-producing bacteria. The observed patterns highlight the importance of considering sex-specific differences in future research.
    Keywords:  bronchial asthma; dysbiosis; gut microbiota; sex differences; short-chain fatty acids
    DOI:  https://doi.org/10.3390/biomedicines14010125
  20. J Dent Sci. 2026 Jan;21(1): 31-48
    Impact of female hormonal changes throughout life on oral health: A scoping review.
    Inês Lopes Cardoso, Mayane Fryde, Maria Inês Guimarães, Fernanda Leal.
      This work looks at the impact of female hormonal fluctuations throughout life, during puberty, pregnancy and the menopause, on oral health. These physiological periods, marked by major variations in estrogen and progesterone levels, influence oral health, so the following question was formulated: to what extent do female hormonal fluctuations influence oral health? Through a scoping review of 37 scientific articles selected using a rigorous methodology (in particular using the Rayyan tool), it was possible to highlight clinical manifestations specific to each hormonal stage. In adolescent girls, puberty is frequently accompanied by exacerbated gingivitis, independent of dental plaque. During pregnancy, the increase in hormones leads to increased gingival inflammation and transient tooth mobility. Finally, the menopause is associated with a drop in female sex hormones, which can lead to dry mouth, altered salivary flora and accelerated bone loss, all of which contribute to the worsening of periodontal disease. These results underline the importance of a preventive and personalized approach to oral health care for patients, taking into account the hormonal context. They also highlight the collaboration between dentists, general practitioners and gynecologists, to optimize comprehensive care for women at every stage of their hormonal life.
    Keywords:  Hormonal changes; Hormonal fluctuations; Life cycle changes; Oral health; Women
    DOI:  https://doi.org/10.1016/j.jds.2025.09.016
  21. Biol Sex Differ. 2026 Jan 27.
    Sex-dependent locus coeruleus vulnerability in Alzheimer's disease: gut dysbiosis as a driver and probiotic intervention as rescue.
    Hannah M Stapleton, Dayanne S Borges, Erasmo B S M Trindade, Qi Yuan.
      Alzheimer's disease (AD) displays striking sex differences in incidence, progression, and resilience, yet the mechanisms that drive female-biased vulnerability remain incompletely understood. Emerging evidence indicates that gut dysbiosis, increasingly prevalent with ageing, acts as a systemic amplifier of neuroinflammation, vascular instability, and metabolic dysfunction. Here, we synthesize converging findings linking gut microbial alterations to noradrenergic pathology in the locus coeruleus (LC), one of the earliest brain regions affected in AD. We outline how dysbiosis-associated inflammatory signaling, including endotoxin exposure and impaired vagal-neuroimmune regulation, targets LC circuits. In parallel, disruptions in microbial metabolite pathways involving short-chain fatty acids, bile acids, and tryptophan metabolism further promote oxidative stress, tau phosphorylation, and neurodegeneration. We further argue that sex-dependent differences in immune reactivity, autonomic regulation, and hormonal transitions, particularly peri- and post-menopausal estrogen decline, render female LC neurons uniquely vulnerable to microbial and inflammatory perturbation. We propose a mechanistic framework in which gut dysbiosis destabilizes LC integrity through parallel immune-vascular, metabolite, endocrine, and vagal neural pathways, thereby accelerating cognitive decline and AD progression. Understanding how microbial signaling intersects with sex biology and neuromodulatory circuitry may reveal therapeutic windows for early intervention, including microbiome restoration, neuromodulatory tuning, and sex-specific metabolic targeting.
    Keywords:  Alzheimer’s disease; BBB; Dysbiosis; Gut microbiome; Inflammation; Locus coeruleus; Norepinephrine; Probiotics; Sex differences
    DOI:  https://doi.org/10.1186/s13293-026-00834-8
  22. Ginekol Pol. 2026 Jan 28.
    The relationship between sex hormones, metabolic markers, and cognitive linguistic functions in women with PCOS.
    Agnieszka Adamczak, Izabela Dymanowska, Aleksandra Glowinska, Wlodzimierz Plotek, Karolina Frankowska, Julia Spaczynska, Ewa Wysocka, Beata Banaszewska.
       OBJECTIVES: Polycystic ovary syndrome (PCOS) is a chronic endocrinopathy associated with a wide range of psychological disorders. Recent literature suggests a correlation between PCOS and cognitive linguistics disorders. This study aimed to analyze the relationship between sex hormones, metabolic markers, and cognitive linguistic performance in patients with PCOS.
    MATERIAL AND METHODS: 48 women with PCOS and 56 healthy control women were included in the study. Standardized questionnaires were used to assess depressive symptoms [the Beck Depression Inventory (BDI-II)] and linguistic capability [the Wechsler Vocabulary Subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) test and "Łatysz" non-word reading test]. Baseline cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Laboratory tests included measurements of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding globulin (SHBG), glucose, insulin, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC). Oral glucose tolerance test (OGTT) results were also obtained.
    RESULTS: We observed significant differences in testosterone, DHEA-S, SHBG, insulin, insulin measured in 120-minute post-OGTT, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values between women with and without PCOS. A negative correlation was found between the Wechsler Vocabulary Subtest of the WAIS-R test and testosterone, LDL, insulin, and HOMA-IR. Our study revealed a negative correlation between "Łatysz" non-word reading test and testosterone and a positive correlation between "Łatysz" non-word reading test and 120-minute post-OGTT blood glucose concentrations.
    CONCLUSIONS: Our results suggest that there is a relationship between hormonal, metabolic markers, and cognitive functions in patients suffering from PCOS.
    Keywords:  cognitive disorders; linguistic functions; metabolic markers; polycystic ovary syndrome; sex hormones
    DOI:  https://doi.org/10.5603/gpl.105502
  23. Reprod Biol Endocrinol. 2026 Jan 26. 24(1): 10
    Comment on "AMH predicts miscarriage in non-PCOS but not in PCOS related infertility ART cycles".
    Chang Liu.
      
    Keywords:  Anti-Müllerian hormone ; Assisted reproductive technology ; Diagnostic misclassification; Miscarriage ; Polycystic ovary syndrome
    DOI:  https://doi.org/10.1186/s12958-025-01518-5
  24. Biomed Res Int. 2026 ;2026 1110229
    Cardiovascular Dysfunction in Polycystic Ovary Syndrome: Mitochondrial and Inflammatory Mechanisms.
    Olabimpe Caroline Badejogbin, Mary Olaoluwa Agunloye, Ojichukwuka Ebere Chijioke-Agu, Makinde Vincent Olubiyi, Success Oluwanifesimi Olugbuyiro, Olaniyi Azeez Soetan, Opeyemi Abel Bamgbose, Tobi Opeyemi Olaleye.
       Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that significantly increases cardiovascular disease (CVD) risk in women. While insulin resistance and dyslipidemia are established contributors, growing evidence highlights mitochondrial dysfunction and chronic low-grade inflammation as central drivers of cardiovascular pathology in PCOS.
    Objective: This narrative review synthesizes current evidence on how mitochondrial dysfunction and inflammation interact to promote cardiovascular complications in women with PCOS while identifying potential therapeutic targets and areas requiring further investigation.
    Methods: A comprehensive review of clinical and experimental studies was conducted using PubMed, Scopus, and Web of Science databases. Relevant literature exploring mitochondrial alterations, oxidative stress, inflammatory cytokines, and endothelial function in PCOS, with emphasis on cardiovascular outcomes, was critically evaluated and summarized.
    Results: Women with PCOS exhibit altered mitochondrial dynamics, reduced ATP production, and elevated reactive oxygen species (ROS), which collectively impair vascular function. These mitochondrial abnormalities compromise oocyte quality and endometrial receptivity and activate proinflammatory signaling pathways, including the NLRP3 inflammasome, contributing to endothelial dysfunction and atherogenesis, and increased long-term cardiovascular risk, particularly in women with prior pregnancy complications. Elevated levels of cytokines including TNF-α, IL-6, and CRP further exacerbate cardiovascular risk. This bidirectional relationship between mitochondrial dysfunction and inflammation establishes a vicious cycle underlying cardiovascular deterioration in PCOS.
    Conclusion: Mitochondrial dysfunction and inflammation are interdependent mechanisms that contribute substantially to cardiovascular risk in women with PCOS. Targeting mitochondrial dysfunction and systemic inflammation presents a promising therapeutic strategy for reducing cardiovascular morbidity in PCOS. Future research should emphasize phenotype-specific interventions, biomarker discovery, and translational trials to improve long-term reproductive and cardiovascular outcomes.
    Keywords:  cardiovascular dysfunction; chronic inflammation; insulin resistance; mitochondrial dysfunction; oxidative stress; polycystic ovary syndrome; therapeutic targets
    DOI:  https://doi.org/10.1155/bmri/1110229
  25. Neuropsychopharmacology. 2026 Jan 26.
    The role of ovarian hormones in risk aversion in female rats.
    Leah M Truckenbrod, Nadia Carlos, Megan Kelly, Merrick Garner, Madeline Streifer, Andrea C Gore, Caitlin A Orsini.
      Decision making involving risk of punishment is a cognitive process characterized by sex-specific phenotypes, with females exhibiting greater risk aversion than males. Although prior research has demonstrated that ovarian hormones, and estradiol (E2) in particular, contribute to increased risk aversion in females, the receptor mechanisms underlying these effects remain unknown. Further, it is unclear what role the other key ovarian hormone progesterone (P4) plays in female risk aversion. Accordingly, the current set of experiments were designed to address these gaps in knowledge of the hormonal basis of female risk-taking behavior. Female rats were trained in a punishment-based risky decision-making task, ovariectomized, and then retested in the decision-making task. Rats were then treated with estradiol benzoate (Experiment 1; EB), estrogen receptor (ER) agonists (Experiment 2) or progesterone (Experiment 3; P4) after daily test sessions for 7 days. Consistent with prior work, OVX increased risk taking, and EB administration attenuated this effect. Administration of an ERα agonist, either alone or with an ERβ agonist, similarly mitigated the effects of OVX on risk taking. In contrast, the ERβ agonist alone was ineffective in restoring risk aversion in OVX females. Control tests confirmed that the effects of the ERα agonist on risk taking were not due to altered food motivation or footshock sensitivity. Finally, P4 administration did not alter risk taking in OVX females and did not inhibit EB's behavioral effects. Collectively, these data reveal that E2 is the critical ovarian hormone that promotes female risk aversion; further, they suggest that the likely mechanism by which E2 influences risk aversion in females is through activation of ERα.
    DOI:  https://doi.org/10.1038/s41386-026-02347-9
  26. Front Sports Act Living. 2025 ;7 1686566
    Effectiveness of exercise interventions on androgen and sex hormone-binding globulin levels in women with polycystic ovary syndrome: a systematic review and meta-analysis.
    Leman Atmaca, Shalini Chauhan, Sachal Sadiq Najaf, Mohammed Elmadani, Maha Al-Jawarneh, Anaam Soloh, Zsuzsanna Varga, József Vitrai, Viktoria Prémusz.
       Introduction: Polycystic ovarian syndrome (PCOS) is a common disorder typified by hyperandrogenism, ovarian dysfunction, and metabolic disorders. Elevated androgen and decreased Sex Hormone Binding Globulin (SHBG) levels are some of the main features contributing to its clinical manifestations. Lifestyle interventions, especially exercise, are considered first-line management methods due to their positive effects on hormonal regulation. Due to a lack of comprehensively synthesized data on the effects of exercise on androgen and SHBG levels, in this systematic review and meta-analysis, we aimed to evaluate the effects of structured exercise on Total Testosterone and Dehydroepiandrosterone (DHEA-S) as primary parameters, and SHBG levels as secondary parameters.
    Methods: Relevant databases (EMBASE, Scopus PubMed, Web of Science, Cochrane Trials) were searched for Randomized Clinical Trials (RCTs) and Controlled Clinical Trials (CCTs) on exercise in Rotterdam-diagnosed PCOS women. Study selection and data extraction were carried out by two separate reviewers. Risk of bias was assessed using Cochrane RoB 2. Meta-analyses, employing a random-effects model, calculated Mean Differences (MDs) for hormonal outcomes, with subgroup analyses for different exercise types [e.g., aerobic, high-intensity interval training (HIIT)].
    Results: A total of 23 studies involving women with PCOS were included. For the overall effect of exercise vs. control, meta-analysis of 12 studies (n = 563 participants) showed no significant effect on Total Testosterone, DHEA-S (5 studies, n = 231 participants), or SHBG (10 studies, n = 422 participants). However, subgroup analysis revealed that aerobic exercise led to a statistically significant reduction in Total Testosterone levels (4 studies, n = 212 participants). HIIT did not show a significant effect on Total Testosterone or SHBG.
    Conclusion: Aerobic exercise significantly reduces total testosterone levels in women with PCOS, according to this meta-analysis, indicating that it may be used as a non-pharmacological method of managing hyperandrogenism.
    Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024502657, PROSPERO CRD42024502657.
    Keywords:  androgens; exercise; physical activity; polycystic ovary syndrome; sex hormone-binding globulin
    DOI:  https://doi.org/10.3389/fspor.2025.1686566
  27. Int J Fertil Steril. 2026 Jan 05. pii: 722914. [Epub ahead of print]20(1): 62-68
    Efficacy of Stop GnRH-Agonist/Antagonist versus GnRH-Antagonist Protocols in In Vitro Fertilization Cycles of Patients with Polycystic Ovary Syndrome: A Pilot Randomized Controlled Trial.
    Azadeh Tarafdari, Fatemeh Keikhah, Maryam Bagheri, Masoumeh Masoumi, Rana Karimi, Mohammad Amin Prasaei, Mohadese Dashtkoohi, Marjan Ghaemi.
       Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting fertility. Controlled ovarian stimulation (COS) is a crucial step during in vitro fertilization (IVF) procedure to enhance oocyte retrieval and embryo generation. This study aims to compare the efficacy of the stop gonadotropin hormone-releasing hormone agonist (GnRH-agonist)/GnRH-antagonist protocol versus the conventional GnRH antagonist protocol in PCOS patients undergoing IVF.
    Materials and Methods: A pilot randomized controlled trial was conducted from March to December 2023 at ValiE-Asr Hospital, Tehran. Forty PCOS patients were randomized into two groups: stop GnRH-agonist/GnRH-antagonist (n=20) and conventional GnRH antagonist (n=20). Participants' demographics, hormonal profiles, and treatment outcomes were recorded. The primary outcome was the number of mature oocytes retrieved; secondary outcomes included the number of follicles >12 mm on human chorionic gonadotropin (hCG) administration day and ovarian hyperstimulation syndrome (OHSS) incidence. Data was analyzed using SPSS 21.0, employing t tests, Mann-Whitney tests, and Chi-square tests as appropriate.
    Results: Baseline characteristics were similar between groups. The conventional protocol group had significantly more 16-18 mm follicles but no differences in total oocytes retrieved, metaphase 1 and 2 oocytes, or degenerated oocytes. Stimulation duration was shorter in the conventional group. No significant differences were observed in OHSS incidence or total gonadotropin dose.
    Conclusion: The Stop GnRH-agonist/GnRH-antagonist protocol is a viable alternative for PCOS patients, offering comparable oocyte yields and safety profiles to the conventional GnRH antagonist protocol. Larger studies are needed to confirm these findings and evaluate long-term outcomes such as pregnancy and live birth rates (registration number: IRCT20180409039247N10).
    Keywords:  Gonadotropin-Releasing Hormone; In vitro fertilization; Ovarian Hyperstimulation Syndrome; Polycystic Ovary Syndrome; ovulation induction
    DOI:  https://doi.org/10.22074/ijfs.2025.2041275.1762
  28. Genes (Basel). 2025 Dec 26. pii: 18. [Epub ahead of print]17(1):
    Lactobacillus-Dominated Cervical Microbiota Revealed by Long-Read 16S rRNA Sequencing: A Greek Pilot Study.
    Despina Vougiouklaki, Sophia Letsiou, Konstantinos Ladias, Aliki Tsakni, Iliana Mavrokefalidou, Zoe Siateli, Panagiotis Halvatsiotis, Dimitra Houhoula.
      Background/Objectives: The vaginal microbiota constitutes a highly dynamic microbial ecosystem shaped by the distinct mucosal, hormonal, and immunological environment of the female genital tract. Accumulating evidence suggests that shifts in cervical microbial composition and function may influence host-microbe interactions and contribute to gynecological disease risk. Within this framework, the present study aimed to perform an in-depth genomic characterization of the cervical microbiota in a well-defined cohort of Greek women. The primary objective was to explore the functional microbial landscape by identifying dominant bacterial taxa, taxon-specific signatures, and potential microbial pathways implicated in cervical epithelial homeostasis, immune modulation, and disease susceptibility. Methods: Microbial genomic DNA was isolated from 60 cervical samples using the Magcore Bacterial Automated Kit and analyzed through full-length 16S rRNA gene sequencing using the Nanopore MinION™ platform, allowing high-resolution taxonomic assignment and enhanced functional inference. In parallel, cervical samples were screened for 14 HPV genotypes using a real-time PCR-based assay. Results: The cervical microbial communities were dominated by Lactobacillus iners, Lactobacillus crispatus, and Aerococcus christensenii, collectively representing over 75% of total microbial abundance and suggesting a functionally protective microbiota profile. A diverse set of low-abundance taxa-including Stenotrophomonas maltophilia, Stenotrophomonas pavanii, Acinetobacter septicus, Rhizobium spp. (Rhizobium rhizogenes, Rhizobium tropici, Rhizobium jaguaris), Prevotella amnii, Prevotella disiens, Brevibacterium casei, Fannyhessea vaginae, and Gemelliphila asaccharolytica-was also detected, potentially reflecting niche-specific metabolic functions or environmental microbial inputs. No HPV genotypes were detected in any of the cervical samples. Conclusions: This genomic profiling study underscores the functional dominance of Lactobacillus spp. within the cervical microbiota and highlights the contribution of low-abundance taxa that may participate in metabolic cross-feeding, immune signaling, or epithelial barrier modulation. Future large-scale, multi-omics studies integrating metagenomics and host transcriptomic data are warranted to validate microbial functional signatures as biomarkers or therapeutic targets for cervical health optimization.
    Keywords:  Lactobacillus crispatus; Lactobacillus iners; Oxford Nanopore MinION; cervical microbiota; full-length 16S rRNA sequencing
    DOI:  https://doi.org/10.3390/genes17010018
  29. Gut Liver. 2026 Jan 28.
    Sex-Dependent Microbial and Host Profiles Following Fecal Microbiota and Bifidobacterium longum Treatment in Stress-Induced Gut Dysbiosis.
    Chin-Hee Song, Nayoung Kim, Ryoung Hee Nam, Hoon Choi, Isom Jin, Eun Hye Kim, Sungchan Ha, Kisung Kang, Wonseok Lee, HyeLim Choi, Yeon-Ran Kim, Yeong-Jae Seok, Ho-Kyoung Lee, Cheol Min Shin, Dong Ho Lee.
       Background/Aims: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder influenced by stress, microbial dysbiosis, and immune activation. Microbiota-directed therapies, including fecal microbiota transplantation and probiotics, show promise, but their sex-specific effects remain unclear. We compared the therapeutic effects of lyophilized fecal microbiota (LFM) with Bifidobacterium longum BBH016 in male and female Wistar rats subjected to repeated water avoidance stress.
    Methods: Fecal pellet output (FPO), colonic mast cell infiltration, and fecal short-chain fatty acids were measured. Gut microbial composition and function were analyzed by 16S rRNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway prediction.
    Results: Both interventions significantly reduced FPO and mast cell infiltration in males but had less pronounced effects in females. Microbiota analyses revealed sex-dependent responses, with distinct microbial trajectories in each treatment group. Using linear discriminant analysis effect size, we identified seven key taxa with treatment- or sex-specific enrichment. Alistipes onderdonkii and Bacteroides uniformis consistently increased in both LFM- and B. longum-treated groups, regardless of sex. Bacteroides finegoldii and Barnesiella intestinihominis were specifically enriched in the LFM group. In males, Blautia faecis and Fusicatenibacter saccharivorans were enriched following the interventions, whereas Parabacteroides goldsteinii appeared exclusively in stressed males. Functional predictions revealed the enrichment of estrogen signaling and bile acid pathways in males and the attenuation of proinflammatory pathways in females following LFM. Correlations between microbial taxa and host outcomes were predominantly observed in male rats.
    Conclusions: These findings highlight sex-specific microbial and host responses to microbiota-targeted therapies in a stress-induced IBS model, emphasizing sex as a biological variable in designing personalized microbiome-based treatments.
    Keywords:   Bifidobacterium longum ; Fecal microbiota transplantation; Gastrointestinal microbiome; Irritable bowel syndrome; Water avoidance stress
    DOI:  https://doi.org/10.5009/gnl250440
  30. Int Immunopharmacol. 2026 Jan 23. pii: S1567-5769(26)00094-9. [Epub ahead of print]173 116251
    Role of reactive oxygen species in polycystic ovary syndrome: signalling pathways, mechanisms, and traditional Chinese medicine treatment strategies.
    Ziyi Wang, Shuyuan Liu, Mengyao Gao, Ying Shen, Miao Sun, Songli Hao.
      The biological role reactive oxygen species (ROS), both as byproduct of cellular respiration and as crucial secondary messengers, has been extensively acknowledged in scientific literature. Key ROS-generating enzymes and organelles, including mitochondria, NADPH oxidase, and the endoplasmic reticulum, have been found closely linked to the regulation of metabolic processes. An imbalance between oxidative and antioxidant systems, resulting from abnormal ROS production and leading to oxidative stress (OS), has been implicated as a significant pathogenic in a variety of diseases, such as polycystic ovary syndrome (PCOS). PCOS is a prevalent endocrine disorder that adversely affects reproductive health and metabolic homeostasis in women of reproductive age. This review provides a systematic examination of the three primary sources of ROS production, and explores the mechanisms through which excessive ROS production triggers the dysregulation of key signalling pathways. These pathways are central to the fundamental pathological features of PCOS, such as ovulatory dysfunction, obesity phenotype, insulin resistance, and hyperandrogenism, with a specific emphasis on the interactions within ROS signalling pathways. Grounded in the holistic regulation principles of Chinese medicine and targeting the core signalling pathway as the intervention focal point, we propose a comprehensive intervention strategy. This strategy incorporates natural compounds, herbal compounds, acupuncture, dietary supplements, and other therapeutic approaches, which will provide a new theoretical framework and research direction for enhancing the clinical management of PCOS.
    Keywords:  Natural compounds; Polycystic ovary syndrome; Reactive oxygen species; Signalling pathways; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.intimp.2026.116251
  31. J Bone Joint Surg Am. 2026 Jan 26.
    Sex-Based Differences in Cell Types and Gene Expression within the Anterior Cruciate Ligament.
    Steven M Garcia, Justin Lau, Aboubacar Wague, Sankalp Sharma, Kevin C Wang, Miguel Lizarraga, Cristhian Montenegro, Xuhui Liu, Grace O'Connell, Stephanie E Wong, Brian T Feeley.
       BACKGROUND: Sex-based disparities remain a major challenge in musculoskeletal medicine. Women and men experience different anterior cruciate ligament (ACL) injury rates and severity, but the causes remain unclear. We hypothesized that cellular differences in human progenitor cells contribute to the higher ACL tear risk observed in females.
    METHODS: ACL samples were collected from 4 male and 5 female patients undergoing ACL reconstruction surgery. Live cells were collected through flow cytometry and sent for single-cell RNA sequencing. Significantly greater expression in either sex relative to the other was defined as a >25% increase in expression level (log2 fold change > 0.32) and p < 0.05). Subpopulation characterization was performed with immunofluorescence on tissue sections.
    RESULTS: We discovered sex-based differences in all of the native cell types within the ACL. In particular, fibroblast progenitor-like (TPPP3+) cells from female patients expressed genes associated with dysregulation and degradation of collagen more highly than progenitor cells from male patients.
    CONCLUSIONS: These results highlight a ligament progenitor population with a sex-dependent gene expression profile. This work suggests that sex-based differences in stem cell populations may drive differential injury rates and outcomes between male and female patients with musculoskeletal injuries.
    CLINICAL RELEVANCE: The differential gene expression among TPPP3+ progenitor-like cells provides a possible target population for studying ligamentous injury and regeneration. Differential expression of collagen and extracellular matrix-related genes provides evidence of specific genes that could be therapeutically targeted to strengthen the ACL and reduce the risk of rupture, particularly in female athletes.
    DOI:  https://doi.org/10.2106/JBJS.25.00860
  32. Prostate Cancer Prostatic Dis. 2026 Jan 26.
    Risk of bone fractures in patients with prostate cancer treated with maximal androgen blockade therapy: a systematic literature review and meta-analysis.
    Isabella Saporita, Mariangela Calabrese, Federica Maria Carfi, Andrea Mogavero, Marialuisa Puglisi, Giorgio Treglia, Ursula Maria Vogl, Silke Gillessen, Ricardo Pereira Mestre, Martino Pedrani, Giovanna Pecoraro, Giuseppe Salfi, Caroline-Claudia Erhart, Hui-Ming Lin, Luigi Tortola, Massimo Di Maio, Marcello Tucci, Consuelo Buttigliero, Fabio Turco.
       BACKGROUND: Addition of an androgen receptor pathway inhibitor (ARPI) to androgen deprivation therapy (ADT) (ADT + ARPI, i.e., maximal androgen blockade, MAB) improves survival outcomes compared to ADT monotherapy in patients with prostate cancer (PC). It is known that ADT increases the risk of fractures in patients with PC, but it is unclear if this risk is higher with MAB. The aim of this study is to conduct a systematic review and meta-analysis to determine if MAB increases the incidence of fractures compared to ADT alone, and if the incidence of fractures was influenced by the type of ARPI.
    METHODS: Clinical trials assessing MAB versus ADT alone in patients with PC were identified using the PubMed/Medline and Cochrane library databases. The pooled odds ratio of developing fractures with MAB versus ADT alone was calculated for each type of ARPI in selected studies by random-effects modeling. The number of patients receiving bone-protecting agent (BPA) was also evaluated.
    RESULTS: We identified 17 studies comprising 16162 patients for the systematic review and meta-analysis (9240 patients treated with MAB, 6922 patients treated with ADT alone). Each type of ADT + ARPI resulted in a statistically significant increased risk of fractures compared to ADT alone (pooled OR ranging from 1.5 to 2.4). There was no difference in the magnitude of the risk of fractures among the different ARPIs. Only 7 studies reported the number of patients treated with a BPA.
    CONCLUSIONS: In our meta-analysis, MAB resulted in a statistically significant increase in fracture risk compared to ADT alone, regardless of the type of ARPI. Since long-term MAB represents the standard of care in various settings of PC, the use of a BPA should be generally recommended. Dosing and frequency of BPA need to be adapted according to the specific PC setting.
    DOI:  https://doi.org/10.1038/s41391-026-01077-9
  33. Int J Mol Sci. 2026 Jan 08. pii: 640. [Epub ahead of print]27(2):
    The Vaginal Microbiome and Host Health: Implications for Cervical Cancer Progression.
    María Del Carmen Lagunas-Cruz, Arturo Valle-Mendiola, Isabel Soto-Cruz.
      The vaginal microbiome plays a crucial role in maintaining host health by preserving a balanced microenvironment. Nevertheless, the definition of a "normal" vaginal microbiome remains controversial, as its composition varies depending on factors such as ethnicity and geographical origin. In most cases, members of the genus Lactobacillus predominate in healthy vaginal microbiomes, protecting against potential pathogens through specific mechanisms such as the secretion of lactic acid and bacteriocins, among others. A reduction in Lactobacillus abundance, accompanied by an increase in anaerobic organisms, predisposes the host to the development of various pathologies. Among these pathologies is infection with human papillomavirus (HPV) and the subsequent development of cervical cancer. A progressive decline in Lactobacillus has been observed as the lesion advances in different populations worldwide. In the case of the Mexican population, several Lactobacillus have been reported in healthy microbiomes: L. gasseri, L. fermentum, L. rhamnosus, L. jensenii, L. crispatus, L. delbrueckii, L. acidophilus, and L. brevis. In contrast, genera reported in dysbiosis include Sneathia, while Brevibacterium aureum and Brachybacterium conglomeratum have been associated with HPV16 infection and/or SIL. The mere presence of some bacteria is not sufficient to modulate the cellular activity of host cells; therefore, the expression, production and activity of different proteins could be affected by the vaginal microbiome. The impact of the microbiome on host cell function is the result of different metabolites produced by the bacteria, which suppress or activate different signaling and metabolic pathways. The molecular interactions between the host and microbiome, as well as their role in cervical carcinogenesis, are still unknown. In this review, we focus on the vaginal microbiome, HPV, and the impact that the interaction of the microbiome with HPV has in cervical cancer development.
    Keywords:  Lactobacillus; cervical cancer; dysbiosis; human papillomavirus; microbiome
    DOI:  https://doi.org/10.3390/ijms27020640
  34. Genes (Basel). 2026 Jan 08. pii: 73. [Epub ahead of print]17(1):
    Sex-Specific Downregulation of CDK5RAP3 Exacerbates ER Stress-Mediated Inflammation and Apoptosis in CCl4-Induced Acute Liver Injury.
    Jian Ruan, Qianyi Dong, Fangling Xu, Yufan Jin, Yuhong Yang, Jun Li, Yafei Cai.
       BACKGROUND/OBJECTIVES: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride (CCl4)-induced acute liver injury model and to explore the mechanisms underlying differential susceptibility between males and females.
    METHODS: Acute liver injury was induced in male and female mice by CCl4 administration. Liver injury was evaluated by serum biochemical parameters and histopathological analysis. CDK5RAP3 expression, inflammatory cytokines, and ER stress-related apoptotic markers were assessed. Hepatocyte apoptosis was examined by TUNEL staining. In addition, CDK5RAP3 was conditionally deleted in mouse embryonic fibroblasts (MEFs) using 4-hydroxytamoxifen to assess its direct role in regulating inflammatory and apoptotic responses in vitro.
    RESULTS: CCl4 exposure caused liver injury in both sexes, with male mice showing more severe biochemical and histological damage. CDK5RAP3 expression was significantly reduced after CCl4 treatment, particularly in males. Inflammatory mediators and ER stress-associated apoptotic markers were upregulated, accompanied by increased hepatocyte apoptosis. A similar enhancement of inflammatory and apoptotic signaling was observed in CDK5RAP3-deficient MEFs.
    CONCLUSIONS: Downregulation of CDK5RAP3 is associated with ER stress, inflammation, and apoptosis, contributing to increased susceptibility of male mice to acute liver injury. These findings provide insight into sex-specific mechanisms of hepatic injury and highlight CDK5RAP3 as a potential therapeutic target.
    Keywords:  CCl4; CDK5RAP3; liver; sex
    DOI:  https://doi.org/10.3390/genes17010073
  35. Front Oncol. 2025 ;15 1748527
    Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC.
    Ephraim J Gardner, Sasikumar Ponnusamy, Remi Adelaiye-Ogala.
      Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in the treatment of castration-resistant prostate cancer (CRPC). Emerging evidence suggests that Enzalutamide resistance is not solely due to the loss of AR dependency but can also arise from epigenomic reprogramming of the AR cistrome toward noncanonical gene networks. Recent studies have revealed that this reprogramming is mediated by previously unrecognized coactivators, including CXXC5, TET2, and EZH2, which cooperate with AR to establish a transcriptional landscape that supports lineage plasticity and therapeutic evasion. These noncanonical AR transcriptional programs enable CRPC cells to survive under continued AR blockade, acting as a transitional state towards neuroendocrine differentiation. Pharmacologic disruption of these coactivators abrogates noncanonical AR activity and suppresses tumor growth, highlighting a tractable vulnerability. These findings redefine AR signaling in advanced disease, suggesting that targeting noncanonical AR coactivators could offer a novel therapeutic paradigm to overcome resistance. Advances in single-cell and epigenomic profiling are poised to delineate further the heterogeneity and dynamics of AR cistrome remodeling in treatment-refractory prostate cancer.
    Keywords:  AR cistrome; advanced prostate cancer; androgen receptor; canonical and noncanonical AR cistrome; enzalutamide resistance; lineage plasticity; noncanonical AR coactivator; therapeutic strategies
    DOI:  https://doi.org/10.3389/fonc.2025.1748527
  36. Fertil Steril. 2026 Jan 27. pii: S0015-0282(26)00048-8. [Epub ahead of print]
    Micro-Management: How the Male Reproductive Microbiome Shapes Male Fertility.
    Sohei Kuribayashi, Noopur Naik, Aaron W Miller, Scott D Lundy.
       IMPORTANCE: One in six couples worldwide experience infertility, and male factors contribute to at least half of these cases. The pathophysiology of male infertility is complex and often multifactorial, and the male reproductive microbiome has now been implicated as a potentially critical component in male reproductive health and disease.
    OBJECTIVE: To summarize the emerging evidence describing the male reproductive microbiome with a focus on clinically relevant aspects within spermatogenesis and reproductive outcomes.
    EVIDENCE REVIEW: We performed a librarian-led search of MEDLINE, Embase, and Web of Science and a targeted PubMed search for antibiotic and probiotic trials, focusing on human studies that reported male reproductive microbiome data together with semen parameters, oxidative, DNA-damage, or inflammatory indices, or assisted reproduction outcomes. Given heterogeneity in design and laboratory methods, we conducted a narrative synthesis and integrated relevant mechanistic animal work.
    FINDINGS: Across heterogeneous cohorts, anaerobe-leaning seminal profiles (often with Prevotella or Atopobium) are more often linked to higher oxidative stress, greater sperm DNA fragmentation, and lower motility or total motile count. In contrast, Lactobacillus-rich profiles more often align with better redox status and DNA integrity. Couple-level data show rapid and robust partner microbiome exchange that can shift semen over short periods. Work on the gut-testis axis has identified a link between gut dysbiosis and systemic inflammation with semen quality via the gut-testis axis. Proposed mechanisms underlying the effect of the microbiome on fertility include local inflammation, oxidative injury, altered seminal rheology (e.g., viscosity/viscoelastic properties of seminal plasma), adherence/biofilms, and immune-metabolic crosstalk. Small trials to date using antibiotics and/or probiotics show variable benefits; durability and reproductive endpoints remain limited.
    CONCLUSION AND RELEVANCE: Emerging evidence supports a role for the male reproductive microbiome in sperm function and fertility and highlights it as a potential target for clinical intervention. However, predominantly small, cross-sectional studies and methodological heterogeneity limit causal inference and immediate translation, underscoring the need for longitudinal, couple-integrated cohorts and adequately powered randomized trials of targeted microbiome modulation.
    Keywords:  gut-testis axis; male infertility; male reproductive microbiome; probiotics; seminal microbiome
    DOI:  https://doi.org/10.1016/j.fertnstert.2026.01.019
  37. Medicina (Kaunas). 2026 Jan 09. pii: 139. [Epub ahead of print]62(1):
    Follicular Klotho in the Ovarian Microenvironment: Exploring Its Role in IVF Outcome Prediction.
    Mehmet Alican Sapmaz, Sait Erbey, Murat Polat, Selin Yıldız, İnci Kahyaoğlu, Ömer Osman Eroğlu, Emine Utlu Özen, Ayfer Bakır.
      Background and Objectives: Klotho (KL) is a multifunctional protein involved in reproductive physiology; however, its precise role in ovarian reserve and in vitro fertilization (IVF) outcomes remains unclear. This study aimed to evaluate the relationship between follicular fluid KL levels, ovarian reserve markers, and key IVF success parameters. Materials and Methods: This prospective study included a total of 150 women undergoing IVF, of whom 82 had diminished ovarian reserve (DOR) and 68 had normal ovarian reserve (NOR). All participants underwent controlled ovarian stimulation using a standard antagonist protocol. During oocyte pick-up (OPU), the first aspirated follicular fluid sample was collected, processed, and analyzed for KL concentrations using a Human Klotho ELISA kit. Hormonal profiles, ovarian reserve markers, and IVF outcomes were compared between groups. Results: Follicular fluid KL levels were significantly lower in the DOR group compared with the NOR group (117.07 ± 28.88 pg/mL vs. 266.13 ± 58.29 pg/mL; p < 0.001). Anti-Müllerian hormone (AMH) levels were reduced, whereas follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels were significantly higher in the DOR group (all p < 0.001). Implantation and clinical pregnancy rates were also significantly lower in the DOR group compared with the NOR group (p < 0.001 and p = 0.003, respectively). KL levels showed a strong positive correlation with the number of fertilized oocytes in both groups (DOR: r = 0.690; NOR: r = 0.552). Each one-unit increase in KL was associated with a 3.7% increase in implantation probability and a 3.2% increase in clinical pregnancy probability in the DOR group, and with corresponding increases of 4.4% and 1.2% in the NOR group (all p < 0.05). Conclusions: This study demonstrates significant associations between follicular fluid KL levels and fertilization, implantation, and clinical pregnancy outcomes. These associations appear to be more pronounced than those observed with traditional ovarian reserve markers such as AMH and antral follicle count. Reduced KL levels are associated with fewer fertilized oocytes, whereas higher KL concentrations correspond to increased implantation and clinical pregnancy probabilities. Nevertheless, similar to other non-invasive biomarkers, current evidence is insufficient to support routine clinical use of KL. Large-scale, well-designed, multicenter studies are therefore required to validate its clinical relevance and to determine whether KL can serve as a reliable and practical predictor of IVF success.
    Keywords:  clinical pregnancy; follicular fluid; implantation; in vitro fertilization; klotho protein
    DOI:  https://doi.org/10.3390/medicina62010139
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