bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2025–08–10
nine papers selected by
Chun-Chi Chang, Lunds universitet
  1. Emerging Mechanisms of NK Cell Dysfunction in Endometriosis: The Role of Autophagy, Metabolism, Cytokines, Exosomes, and Trogocytosis.
  2. Sex differences in tissue-specific immunity and immunology.
  3. Impact of subclinical hypothyroidism on endocrine features in patients with polycystic ovary syndrome.
  4. Sex differences in pulmonary (arterial) hypertension: does it matter?
  5. Regulatory KIR+CD8+ T cells are elevated during human pregnancy.
  6. Testosterone Suppresses IL-17 Expression by Targeting RORγt Functions.
  7. Association between menopause-related symptoms and muscle mass index among perimenopausal and postmenopausal women and the mediating role of estrogen levels.
  8. Modulating endoplasmic reticulum stress and NLRP3 inflammasome in polycystic ovary syndrome: a review of natural and synthetic compounds.
  9. Sex, hormones, and lung health.
  1. Am J Reprod Immunol. 2025 Aug;94(2): e70138
    Emerging Mechanisms of NK Cell Dysfunction in Endometriosis: The Role of Autophagy, Metabolism, Cytokines, Exosomes, and Trogocytosis.
    Mohammad Abbaszadeh, Mojdeh Soltani, Sara Falahi, Nafiseh Esmaeil.
      Endometriosis (EMS) is a persistent, inflammatory condition that relies on estrogen and is distinguished by the proliferation of endometrial tissue outside the confines of the uterus. The impact on the well-being of individuals affected can be significant, as it is linked to pelvic pain and reduced fertility in women of reproductive age. Over 30 years have passed since initially discovering a malfunction in the activity of natural killer (NK) cells in individuals with EMS. Several aspects that contribute to NK cell dysfunction have been explored by researchers over the years, such as the upregulation of inhibitory receptors, downregulation of activating receptors, and the exhaustion process. Nonetheless, there are still many aspects that have yet to be identified. The objective of this review is to explore whether there is a connection between mechanisms that have not yet been explored and the malfunctioning of EMS-derived NK cells. Autophagy, metabolism, trogocytosis, tunneling nanotubes (TNT), and exosomes are among the factors that play a role in these processes. The primary objective of this publication is to provide valuable insights for future research on NK cells, with the aim of enhancing our understanding of the disease's causes and identifying more effective targets for immunotherapy.
    Keywords:  NK cell; TNTs; autophagy; cytokines; endometriosis; exosomes; metabolism; trogocytosis
    DOI:  https://doi.org/10.1111/aji.70138
  2. Science. 2025 Aug 07. 389(6760): 599-603
    Sex differences in tissue-specific immunity and immunology.
    Sonia Sharma, Alicia Gibbons, Erica Ollmann Saphire.
      Biological sex exerts a substantial influence on the immune system and immune-related diseases. Males are more susceptible to the acute effects of viral disease and certain cancers, whereas females exhibit a more robust immune response that can make them prone to developing autoimmune complications. We reflect on the emerging appreciation of sex differences-governed by genetics, sex hormones, and environmental factors-in tissue immunity and immunology. Understanding these tissue context-dependent sex differences in the immune system is critical to deciphering the exact mechanisms that determine why women and men experience organ-specific infections, autoimmune or inflammatory diseases, and cancers differently. Only by parsing distinction at the tissue level can the development of personalized and precision immunotherapy approaches be conceived and then achieved.
    DOI:  https://doi.org/10.1126/science.adx4381
  3. Eur J Med Res. 2025 Aug 08. 30(1): 725
    Impact of subclinical hypothyroidism on endocrine features in patients with polycystic ovary syndrome.
    Rui Hua, Jing-Jun Li, Wei Yang, Yun Hua, Yu-Long Ma.
       BACKGROUND: Polycystic ovary syndrome (PCOS) and subclinical hypothyroidism (SCH) are both common endocrine disorders. This study investigates the impact of SCH on the endocrine features of patients diagnosed with PCOS.
    METHODS: This retrospective study included 124 women diagnosed with PCOS between January 2020 and November 2022. Participants were divided into two groups: those with PCOS alone (n = 93) and those with both PCOS and SCH (n = 31).Clinical parameters (age, body mass index, blood pressure, age at menarche) and endocrine markers were collected. Hormonal measurements included follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), testosterone (TES), progesterone (PRG), TSH, free triiodothyronine (FT3), FT4, and Anti-Müllerian hormone (AMH). Thyroid autoantibodies, including antithyroid peroxidase (TPO-Ab) and antithyroglobulin antibody (TG-Ab), were also assessed. Antral follicle count (AFC) was evaluated using transvaginal ultrasound.
    RESULTS: The study found that patients with PCOS and SCH exhibited significantly higher levels of TSH and PRL compared to those with PCOS alone. However, there were no significant differences in PRG, LH, FSH, TES, and E2 levels between the groups. The PCOS group showed a moderate positive correlation between TSH and AMH, whereas the PCOS with SCH group demonstrated a negative correlation between TSH and FSH, albeit not statistically significant.
    CONCLUSIONS: Subclinical hypothyroidism in women with PCOS is associated with altered thyroid-prolactin axis activity and a disrupted correlation between TSH and AMH, while gonadotropin levels and ovarian morphology appear unaffected. These findings warrant confirmation through prospective studies.
    Keywords:  Endocrine features; Polycystic ovary syndrome; Subclinical hypothyroidism
    DOI:  https://doi.org/10.1186/s40001-025-02910-y
  4. Curr Opin Pulm Med. 2025 Sep 01. 31(5): 411-428
    Sex differences in pulmonary (arterial) hypertension: does it matter?
    Corey E Ventetuolo, Alexis E Sherman-Roe.
       PURPOSE OF REVIEW: This review synthesizes the current prevailing theories behind the 'sex paradox' or 'sex puzzle' in pulmonary arterial hypertension (PAH), a disease marked by sexual dimorphism. To a lesser extent, we also review sex differences in other forms of pulmonary hypertension.
    RECENT FINDINGS: Although more females than males develop PAH worldwide, female sex is associated with improved right ventricular (RV) function and survival. We review the role of sex chromosomes and sex hormones and their relationships to genomic and epigenetic regulation, immune function, and RV function, sex-based differences in therapeutic response and social determinants of health and intersectionality with gender in PAH pathobiology, prevalence and outcomes. We include experimental studies and observational human data that have led to the study of sex hormone modulation as a treatment strategy in PAH, with recently completed clinical trials. In addition, we explore potential future directions to help understand the mechanisms that underpin sex biases in pulmonary vascular disease, as well as those that may inform potential therapeutic targets.
    SUMMARY: Survival in PAH depends on RV function, and females have improved survival despite increased prevalence for reasons that remain unclear. While knowledge gaps remain, recent advancements offer promise and many future directions.
    Keywords:  pulmonary arterial hypertension; right ventricle; sex chromosomes; sex differences in pulmonary arterial hypertension; sex hormones
    DOI:  https://doi.org/10.1097/MCP.0000000000001197
  5. Sci Transl Med. 2025 Aug 06. 17(810): eadm7697
    Regulatory KIR+CD8+ T cells are elevated during human pregnancy.
    Jing Li, Xuerui Wang, Andreas I Lackner, Purnima Narasimhan, Lin Li, Vamsee Mallajosyula, Mary M Johnson, Anna-Lena Höbler, Adam S Kirosingh, Amy E Braun, Felistas Nankya, Kenneth Musinguzi, Abel Kakuru, Moses Kamya, Philip J Rosenthal, Grant Dorsey, Prasanna Jagannathan, Michael Angelo, Jürgen Pollheimer, Stephanie L Gaw, Virginia D Winn, Kari C Nadeau, Mark M Davis.
      During pregnancy, immune responses must balance protection from infections with tolerance of the semiallogeneic fetus. However, the mechanisms regulating maternal-fetal tolerance remain poorly understood. Recently, we identified CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) as a regulatory subset important for suppressing self-reactivity in human autoimmune and infectious diseases. To better understand what other roles these cells might play, we asked whether they are active during pregnancy. We first observed an increased frequency of KIR+CD8+ T cells in the peripheral blood of pregnant people in the second trimester, especially in those carrying a male fetus. In vitro, KIR+CD8+ T cells inhibited the alloreactive responses of maternal T cells against irradiated cord blood cells and selectively suppressed CD8+ T cells targeting male-specific proteins in mothers with male pregnancies. Therefore, the higher induction of KIR+CD8+ T cells in mothers carrying a male fetus may help suppress additional allogeneic responses triggered by male-specific alloantigens. Longitudinal analysis showed that KIR+CD8+ T cells undergo expansion and differentiate into functional cytotoxic cells during pregnancy. Single-cell RNA sequencing of decidual CD8+ T cells from early pregnancy revealed elevated numbers and increased expression of activation markers in KIR+CD8+ T cells at the maternal-fetal interface. In addition, a higher frequency of KIR+CD8+ T cells was associated with spontaneous abortion and preeclampsia. Together, our findings suggest that KIR+CD8+ T cells may contribute to maternal tolerance by modulating fetal-specific alloreactive T cell responses. They may also be useful as candidate biomarkers or therapeutic targets for human pregnancy disorders.
    DOI:  https://doi.org/10.1126/scitranslmed.adm7697
  6. Eur J Immunol. 2025 Aug;55(8): e70016
    Testosterone Suppresses IL-17 Expression by Targeting RORγt Functions.
    Akshay Binayke, Rajdeep Dalal, Charu Suri, Jyotsna Dandotiya, Srikanth Sadhu, Yashwant Kumar, Shailendra Asthana, Deepak Kumar Rathore, Amit Awasthi.
      Th17 cells play a crucial role in autoimmune disease pathogenesis. However, the mechanisms behind the sex differences in immune responses, particularly women's higher susceptibility to autoimmune diseases, remain unclear. This study investigated the role of testosterone in modulating the IL-17 response. IL-17 levels and IL-17-expressing cells were compared between males and females, and testosterone's effect on Th17 differentiation was evaluated. In an imiquimod-induced psoriasis mouse model, testosterone supplementation reduced psoriasis severity in female mice, whereas castration of male mice exacerbated psoriasis. Testosterone inhibited both in vitro Th17 differentiation and in vivo IL-17 expression, correlating with reduced psoriasis severity. Molecular studies indicated that testosterone is an inverse agonist of related orphan receptor gamma (RORγt), a key transcription factor for IL-17 expression. These findings offer mechanistic insights into how testosterone limits tissue inflammation in psoriasis and suggest a basis for developing novel testosterone derivatives to target RORγt and suppress Th17-mediated inflammation.
    Keywords:  IL‐17 | immune sex bias | immune sex dimorphism | psoriasis | testosterone | Th17
    DOI:  https://doi.org/10.1002/eji.70016
  7. Front Endocrinol (Lausanne). 2025 ;16 1628612
    Association between menopause-related symptoms and muscle mass index among perimenopausal and postmenopausal women and the mediating role of estrogen levels.
    Xiaoyi Wang, Dongjian Yang, Jiahui Li, Lei Jin, Shuhua Xia, Furui Jin.
       Background: The decline in muscle mass is a common concern among perimenopausal women. However, the association between menopause-related symptoms and muscle mass remains inconclusive, and the mechanistic role of estrogen is still unclear.
    Methods: The study included 407 peri- and postmenopausal women aged 40-60 years who visited the International Peace Maternity and Child Health Hospital. Menopausal symptoms were assessed using the modified Kupperman Index (KMI). Muscle mass was evaluated using the InBody 270 analyzer, and sex hormone levels were determined by chemiluminescent immunoassay. Multiple linear regression and Mediation analysis were conducted to examine the association of KMI with MMI and the mediation of estrogen.
    Results: A total of 407 valid cases were collected. The mean age of the patients was 49.96 ± 3.25 years, with an average body weight of 58.02 ± 7.36 kg and an average BMI of 22.50 ± 2.61 kg/m². The findings showed that advanced age, lower education level, and reduced muscle mass index (MMI) were linked to elevated KMI scores (p<0.05). Patients with hypertension had higher KMI scores (p<0.05). Additionally, decreased estradiol (E2) levels correlated with heightened menopausal symptoms (p<0.05). After controlling for confounding factors such as age, educational level, menopausal stage, history of hypertension, follicle-stimulating hormone (FSH), and E2, KMI was negatively correlated with MMI (β=-1.612, 95% CI: -2.677 to -0.546, p=0.003). Specifically, for each unit increase in MMI, KMI decreased by 1.612 points (R²=0.186, p=0.003). Stratified analysis showed that the negative correlation between KMI and MMI was significant only in premenopausal women. Both the direct and indirect effects of MMI and E2 on KMI were statistically significant (p<0.01). The mediating effect of MMI on KMI through E2 accounted for 26.9% (p=0.001).
    Conclusions: Lower muscle mass is associated with severe menopausal symptoms, partially mediated by estrogen. Maintaining muscle mass may alleviate symptoms, highlighting the importance of resistance training and hormone regulation in perimenopausal women. However, due to the cross-sectional nature of the study, causality cannot be inferred. Longitudinal or interventional studies are warranted to further validate these associations and explore underlying mechanisms.
    Keywords:  estradiol; mediation; menopause-related symptoms; muscle mass index; peri- and post-menopause
    DOI:  https://doi.org/10.3389/fendo.2025.1628612
  8. Inflammopharmacology. 2025 Aug 04.
    Modulating endoplasmic reticulum stress and NLRP3 inflammasome in polycystic ovary syndrome: a review of natural and synthetic compounds.
    Arfah Siddiqua, Abdul Malik, Urooj Iqbal.
      Polycystic ovary syndrome (PCOS) is the most prevalent multifactorial endocrine disorder which affects 6% to 20% of females which are of reproductive age, depending on diagnostic criteria. The symptoms typically evident during early adolescence are irregular menstrual cycles, anovulation, and acne. Although promising developments have been made in PCOS over the past decades, the distinct etiologies and pathophysiology of this syndrome are not fully revealed. Various contributing factors to the development of PCOS were precisely examined, including epigenetic mechanisms, unhealthy lifestyles, environmental poisons, tension, nutrition, inflammation, oxidative stress, obesity, insulin resistance, and hyperandrogenism. Recent studies suggest that endoplasmic reticulum stress plays a major role in the development of PCOS. It has been observed that NLRP3 inflammasome is activated in PCOS and is responsible for chronic inflammation and metabolic disturbances. This review illustrates the relationship between ER stress and activation of NLRP3 inflammasomes and investigates the therapeutic targets that regulate endoplasmic function and reduce inflammation. The endoplasmic reticulum generates numerous reactive oxygen species, which stimulates the activation of the NLRP3 pathway responsible for the pathogenesis of various metabolic and reproductive disturbances in PCOS. In this review, we will discuss the natural and synthetic drugs that reduce endoplasmic reticulum stress and prevent the initiation of NLRP3 inflammasomes. This review emphasizes that approaches for PCOS are pivoting toward personalized therapies, genetic and epigenetic approaches, and stem cell therapies to generate effective treatments. These approaches may have more potential to improve the metabolic and endocrine functions of PCOS.
    Keywords:  Endoplasmic reticulum stress; IL-1β; Inflammation; NLRP3 inflammasome; Polycystic ovary syndrome
    DOI:  https://doi.org/10.1007/s10787-025-01875-y
  9. Physiol Rev. 2025 Aug 06.
    Sex, hormones, and lung health.
    Patricia Silveyra, Maksat Babayev, Carolyn Damilola Ekpruke.
      Sex plays an essential role as a biological variable in lung health, leading to observed differences in lung disease susceptibility. Some respiratory conditions are more common in women than men, especially after puberty, indicating the influence of ovarian hormones on disease mechanisms. Other conditions display sex disparities that begin in utero and progress throughout the life span. Preclinical and clinical studies have indicated that both sex chromosomes and hormones can influence lung disease outcomes, immune responses, susceptibility to viral and bacterial infection, and responses to environmental challenges. This review summarizes the latest research on how sex affects lung physiology and health, drawing on a wide range of studies in respiratory physiology and anatomy, genetics, molecular and cellular biology, environmental health, and immunity. We emphasize how biological sex, gonadal hormones, and occupational and environmental exposures can impact disease mechanisms and outcomes. As clinical outcomes among women have not improved at the same rate as men have over the past few decades, it is crucial to understand the role played by the sex variable in designing strategies to prevent and mitigate disease. The collective research indicates that sex-induced differences in the respiratory system are essential determinants of physiological responses and clinical outcomes.
    Keywords:  lung disease; lung inflammation; sex chromosomes; sex hormones; sex steroids
    DOI:  https://doi.org/10.1152/physrev.00026.2024
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