bims-simsho 2025-07-20 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–07–20
twenty-six papers selected by
Chun-Chi Chang, Lunds universitet

Proinflammatory Cytokines in Women with PCOS in Atypical Pathogen Infections.
Enhancing the potency of 5T4 mRNA vaccine by CD70 mRNA-LNPs through ADCC and T cell boosting in prostate cancer therapy.
Innate Lymphoid Cells in Reproductive Health and Disease.
Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation.
Immunopathological insights into endometriosis: from research advances to future treatments.
The quantity and quality of B-cell immunity against SARS-CoV-2 in children with cancer and hematological diseases.
Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance-Insights and Therapeutic Advances.
Comparison of the effects of laparoscopic sleeve gastrectomy and endoscopic intragastric balloon placement on hormone profile and menstrual cycle in obese women with polycystic ovary syndrome.
Applying a life course approach to elucidate the biology of sex differences in frailty: early-life gonadectomy diminishes late-life robustness in male and female dogs in the Exceptional Aging in Rottweilers Study.
Sex Differences in B Cell Dynamics after Seasonal Influenza Vaccination are Dependent on the Age and Hormonal Profile of Vaccinees.
Predicting in vitro fertilization success: the role of hyperglycosylated human chorionic gonadotropin to beta-human chorionic gonadotropin ratio in implantation and early pregnancy outcomes at a private in vitro fertilization center in Baghdad.
Platelets and platelet-leukocyte interactions in infectious diseases.
The protective role of BMP-15 in infertility development with NLRP3 and IL-18 in infertility development in obese patients with PCOS: clinical and mouse model investigations.
MODULATION OF PD-L1 EXPRESSION IN PROSTATE CANCER CELLS THROUGH ANDROGEN RECEPTOR INHIBITION DIFFERS DEPENDING ON RECEPTOR STATUS.
Evaluation of Th1-Th2 Balance in Patients With Unexplained Recurrent Spontaneous Abortion: A Systematic Review and Meta-Analysis.
Cracking the Code of Oocyte Quality: The Oxidative Stress Link to IVF Success.
Endocrine traits during pregnancy in women with polycystic ovary syndrome - insights from a prospective cohort study in China.
Stability of cytokine and immunoglobulin concentrations in the general population: prepandemic basal concentrations and intraindividual changes until the COVID-19 pandemic.
Epigenetic age and fertility timeline: testing an epigenetic clock to forecast in vitro fertilization success rate.
ERβ limits T cell-mediated inflammation to maintain immune homeostasis.
S1PR1, an endothelial-immune influencer.
Metabolic comparison of minimally to noninvasive urogenital sample types for studying gynecologic health: A pilot study.
Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.
Adverse Birth Outcomes Associated with SARS-CoV-2 Infection Among Pregnant Women with and without HIV: A Longitudinal Cohort Study.
Sex hormones and serotonin 4 receptor brain binding in men with and without major depressive disorder.
Aging murine peritoneal macrophages undergo female-specific remodeling driven by hormone-dependent and independent mechanisms.

Diagnostics (Basel). 2025 Jun 30. pii: 1669. [Epub ahead of print]15(13):

Proinflammatory Cytokines in Women with PCOS in Atypical Pathogen Infections.

Izabela Chudzicka-Strugała, Iwona Gołębiewska, Grzegorz Brudecki, Wael Elamin, Beata Banaszewska, Marta Chudzicka-Adamczak, Dominik Strugała, Barbara Zwoździak.

  Background/Objectives: Polycystic ovary syndrome (PCOS) is one of the most frequently diagnosed endocrine and metabolic disorders in women of reproductive age before menopause. It is associated with excess androgens and ovarian dysfunction, reduced fertility, the presence of obstetric disorders, but also metabolic disorders, and, among others, insulin resistance, obesity and type II diabetes. Its close relationship with changes in the diversity of the vaginal microbiome, vaginal inflammation and changes in the vaginal microenvironment, which can pave the way for pathogenic microorganisms, is emphasized. Methods: The research in the presented paper focuses on a group of women with PCOS (n = 490) of reproductive age (26-43 years), in whom the frequency of infections of the reproductive system caused by atypical pathogens, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma spp., were analyzed, and then the immune system response was assessed in terms of the level of serum proinflammatory cytokines, IL-1β, IL-6 and TNF-α. Results: Our results showed a 40% infection rate in the studied group of patients with PCOS, with C. trachomatis being the most common pathogen (17.7%), followed by Ureaplasma spp. (10%) and M. hominis (4.9%). In some cases, co-infections such as Mycoplasma and Ureaplasma were also observed in 3.1% or all three atypical bacteria, M. hominis, Ureaplasma spp. and C. trachomatis, in 4.3% of patients with PCOS. In our study, in women with PCOS and confirmed infection with any atypical pathogen (n = 196), we analyzed the levels of proinflammatory cytokines, IL-1 β a, IL-6 and TNF-α. The results were compared with a control group (control group A) consisting of patients with the same underlying disease, i.e., PCOS (n = 39), who did not experience infection with atypical pathogens or symptoms of gynecological infection. Additionally, a control group B (n = 28) consisting of healthy women (without PCOS and without infection) was introduced. The results regarding the levels of cytokines studied in this work (IL-1β, IL-6, TNF-α) may suggest that the presence of intracellular C. trachomatis in the infection will play a dominant role in the immune system response. In the infections with atypical pathogens analyzed in this study in patients with PCOS, no characteristic clinical features were observed, apart from indications in the form of an increase in the number of leukocytes in the assessment of the vaginal biocenosis, suggesting cervicitis and reported reproductive failure or lower abdominal pain. An additional problem is the inability to detect the presence of atypical pathogens in routine microbiological tests; therefore, confirmation of such etiology requires referral of the patient for targeted tests. Conclusions: Invasion of host cells by atypical pathogens such as C. trachomatis and infections with "genital mycoplasmas" can disrupt the function of these cells and lead to many complications, including infertility. The immune response with the production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, observed in response to infection with C. trachomatis, M. hominis, and Ureaplasma spp., induces or amplifies inflammation by activating immune cells or controlling infection, but may lead to the facilitation of the survival of pathogenic microorganisms and irreversible damage to fallopian tube tissues. Especially in the case of the proinflammatory cytosine TNF-α, there seems to be a close correlation with infections with atypical pathogens and a marked immune response, as well as with increased IL-1β and IL-6 values compared with the absence of infection (both in the presence and absence of PCOS). The presented study may suggest the importance of extended diagnostics to include atypical pathogens in the case of PCOS and the importance of research in this area also from the point of view of the immune response.

Keywords:  BV; Chlamydia trachomatis; IL-1β; Il-6; Mycoplasma hominis; PCOS; TNF-α; Ureaplasma parvum; Ureaplasma spp.; Ureaplasma urealyticum; atypical pathogen infections; cytokines; infertility; inflammation of the genital tract; vaginal dysbiosis; vaginal microbiome

DOI:  https://doi.org/10.3390/diagnostics15131669
J Nanobiotechnology. 2025 Jul 18. 23(1): 523

Enhancing the potency of 5T4 mRNA vaccine by CD70 mRNA-LNPs through ADCC and T cell boosting in prostate cancer therapy.

Fei Cao, Yuandong Xu, Yupeng Guan, Kexin Zhang, Haowei Qiu, Zhen Xu, Yunru He, Ze Xiu Xiao, Gao-Feng Zha, Jun Pang.

BACKGROUND: Prostate cancer remains a significant health challenge, as conventional treatments often fail to provide long-term benefits in the advanced stages. This study explored the potential of mRNA vaccines as novel therapeutic strategies, specifically focusing on the combination of 5T4 and CD70 mRNA delivered via lipid nanoparticles (LNPs). 5T4, which is highly expressed in various tumors but minimally expressed in normal tissues, is an ideal target for immunotherapy. CD70 was selected for its capacity to enhance T cell activation and augment the overall immune response.
RESULTS: Our findings demonstrated that the combination of 5T4 and CD70 mRNA-LNPs significantly enhanced both humoral and cellular immunity, resulting in improved tumor suppression and prolonged survival in a prostate cancer mouse model. Mechanistically, these LNPs increased the immune responses, including elevated 5T4-specific antibodies, enhanced CD8 + T cell activity, and more active natural killer (NK) cells.
CONCLUSIONS: These results suggest that this combined mRNA vaccine strategy may offer more effective and durable treatments for prostate cancer and that CD70 mRNA, as an immune activator, has broader potential for cancer immunotherapy.

DOI: https://doi.org/10.1186/s12951-025-03607-4
Eur J Immunol. 2025 Jul;55(7): e70007

Innate Lymphoid Cells in Reproductive Health and Disease.

Francesco Colucci, Marco Botta.

  Half a kilogram of immune cells reside in tissues. In the uterus, innate lymphoid cells (ILC) contribute to the cyclic destruction and repair of the mucosa. During pregnancy, uterine ILC support the formation of the placenta and the growth of the fetus. They also contribute to immune responses to pathogens. ILC respond quickly to signals of tissue perturbations and, by influencing other immune cells, they organise responses that help maintain tissue health. Their functions have been determined in the respiratory and intestinal tracts, skin, liver and adipose tissue. It is challenging to determine the function of uterine ILC because of the cyclic changes of the endometrium and the difficulties in accessing human tissues during pregnancy. We review the existing literature on the involvement of uterine ILC in physiology and pathology of the non-pregnant endometrium as well as in pregnancy, from implantation of the fertilised egg to the tissue remodelling occurring during the first trimester and that leads to the formation of the placenta which sustains fetal growth, until parturition.

Keywords:  NK cells; innate immunity; placenta; reproductive immunology; trophoblast

DOI:  https://doi.org/10.1002/eji.70007
Sci Immunol. 2025 Jul 18. 10(109): eadq3066

Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation.

Nagisa Yoshida, Anna Appios, Qian Li, Joseph P Hutton, George Wood, Martin Potts, Julia Aleksandrowicz, Enrico R Barrozo, Freya Dover, Holly Anderson, Katie Stephens, Irving L M H Aye, Jake R Thomas, Hannah C M Schenk, Adam M Bourke, Catherine E Aiken, Ashley Moffett, Andrew Sharkey, Anna V Protasio, Kjersti M Aagaard, James R Edgar, Betty Y W Chung, Naomi McGovern.

Hofbauer cells (HBCs) are extraembryonic macrophages generated de novo within the human placenta. In this study, we explored how the properties of HBCs change throughout gestation. Our analysis revealed transcriptomic differences between first-trimester and term HBCs, with many of the altered genes linked to immune responses. As pregnancy progresses, HBCs exhibit a marked decrease in phagosome maturation and acidification. We show that the differences between first-trimester and term HBCs are important in the context of infection with Listeria monocytogenes, a pathogen that crosses the placenta and replicates within macrophages. Specifically, we observed reduced colony-forming units and diminished actin recruitment by L. monocytogenes in first-trimester HBCs compared with term HBCs. Our findings indicate that the ability of L. monocytogenes to escape from vacuoles is impaired within first-trimester HBCs. Thus, the changes in HBC biology across pregnancy are important in shaping their interactions with L. monocytogenes.

DOI: https://doi.org/10.1126/sciimmunol.adq3066
Semin Immunopathol. 2025 Jul 18. 47(1): 31

Immunopathological insights into endometriosis: from research advances to future treatments.

Yangyang Dai, Zi Ye, Xiang Lin, Songying Zhang.

  Endometriosis is a chronic gynecological disease and a major global concern for women's health. With advancing knowledge of the condition, the classic definition of endometriosis as "endometrium-like tissue outside the uterus" now appears insufficient to explain its pathophysiology, as it overlooks the complex involvement of multiple systems in disease development. Immunological changes have been recognized in endometriosis for decades, and growing evidence substantiates that immunopathological alterations are a hallmark of the disease. Imbalanced immune cell populations and cellular dysfunctions within both the innate and adaptive immune systems, along with aberrant inflammatory cytokines, contribute to the inflammation associated with endometriosis. Moreover, immune cell dysfunctions such as reduced natural killer (NK) cell activity, impaired dendritic cell (DC) maturation and inhibited T cell function via immune checkpoints (ICPs) make the microenvironment also immune-suppressive, facilitating the immune evasion of endometriotic lesions. Endometriosis associated inflammation also sabotages female fertility across multiple stages, including ovarian function, fertilization, embryo development and pregnancy complications. Recognition of the inflammatory and immune-suppressive microenvironment associated with endometriosis leads to the discovery of potential immunotherapeutic targets. Established treatments like non-steroid anti-inflammatory drugs (NSAIDs) and hormone therapies harbor immunomodulatory properties. Other immune-based therapies such as immune cell therapies, cytokine-targeting therapies and immune checkpoint inhibitors (ICIs), which have demonstrated significant efficacy in many chronic inflammatory diseases including cancers, may hold substantial promise as future treatments for endometriosis.

Keywords:  Endometriosis; Fertility; Immune; Immunotherapy; Inflammation

DOI:  https://doi.org/10.1007/s00281-025-01058-5
Front Immunol. 2025 ;16 1613778

The quantity and quality of B-cell immunity against SARS-CoV-2 in children with cancer and hematological diseases.

Eva Tiselius, Emil Sundberg, Amanda Ramilo Amor, Hanna Andersson, Renate Varnaite, Linda Kolstad, Dario Akaberi, Jiaxin Ling, Arja Harila, Shanie Saghafian-Hedengren, Tove Hoffman, Anna Nilsson.

   Background: Our understanding of protective immunity after natural viral infections in children with cancer and hematological diseases is restricted. Current cancer treatments cause significant immunosuppression, affecting both innate and adaptive immunity which leads to reduced B-cell and antibody responses. The aim of this study was to characterize SARS-CoV-2 immune response in children with cancer or hematological disease.
Methods: A single-center study was conducted from June 2020 to June 2023, including 135 patients and 14 healthy siblings. Blood samples were obtained for serological analysis and cell-based assays. SARS-CoV-2 IgG and IgA responses were quantified using suspension multiplex immunoassay (SMIA) and enzyme-linked immunosorbent assay (IgG ELISA) while neutralizing antibody (nAb) responses were assessed by plaque reduction neutralization tests (PRNT). The memory B-cell (MBC) population was evaluated through flow cytometry and MBC responses through FluoroSpot, respectively.
Results: In total, 78 patients seroconverted in response to SARS-Co-V-2 but neither immunosuppression nor cancer diagnosis significantly affected seroconversion. SARS-CoV-2 IgG and IgA levels correlated positively with increasing age, and IgA seroconversion was significantly associated with the presence of nAbs. Antigen-specific MBC responses against both spike and receptor-binding domain (RBD) were elevated in older children, while children on immunosuppression had significantly lower RBD IgG-secreting cells.
Conclusion: Our results show that most pediatric oncological and hematological patients can mount a broad antibody response upon SARS-CoV-2 natural infection or vaccination, although there is a variability in their responses influenced by increasing age. MBC responses in children with immunosuppression were blunted with fewer RBD IgG-secreting cells. Essentially, our findings underscore that young children with severe treatment-related immunosuppression are at risk for less effective B-cell responses upon viral infection.

Keywords:  SARS-CoV-2 infection; antibody responses; childhood cancer; hematological disease; memory B cells

DOI:  https://doi.org/10.3389/fimmu.2025.1613778
Int J Mol Sci. 2025 Jun 28. pii: 6233. [Epub ahead of print]26(13):

Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance-Insights and Therapeutic Advances.

Samia Palat Tharayil, Pallavi Shukla.

  Insulin resistance (IR) frequently develops in women with polycystic ovary syndrome (PCOS), an endocrinological disorder typified by hyperandrogenaemia, erratic menstrual cycles, and the presence of multiple cysts in the ovaries. It results in elevated androgen production contributing to the clinical manifestations of the syndrome including associated co-morbidities such as obesity and type 2 diabetes (T2D). Mounting data suggest the involvement of free fatty acids, reactive oxygen species (ROS) signalling, and mitochondrial dysfunction with IR. In recent years, numerous reports have suggested that mitochondrial dysregulation is associated with the pathogenesis of PCOS. Increased ROS, mutations/variants in mitochondrial DNA (mtDNA), and the altered expression of nuclear-related mitochondrial genes in insulin-resistant women with PCOS provide sufficient evidence for mitochondrial dysfunction as one of the factors contributing to PCOS pathogenesis. Despite the advancements in the field of interconnecting links between mitochondrial dysfunction, IR, and PCOS, various underlying mechanisms needs to be elucidated. Advancements in therapeutic interventions showed promising results in improving mitochondrial functions and IR in PCOS pathogenesis, including evolving mitochondrial transfer approaches that may improve in vitro fertilisation (IVF) outcomes in obese and insulin-resistant women with PCOS in future.

Keywords:  ROS; hyperandrogenism; insulin resistance; mitochondrial dysfunction; polycystic ovary syndrome

DOI:  https://doi.org/10.3390/ijms26136233
BMC Surg. 2025 Jul 16. 25(1): 297

Comparison of the effects of laparoscopic sleeve gastrectomy and endoscopic intragastric balloon placement on hormone profile and menstrual cycle in obese women with polycystic ovary syndrome.

Omer Tammo, Esra Söylemez, Hüseyin Bayhan.

   BACKGROUND AND AIM: Obesity is a significant public health problem with increasing prevalence worldwide, and polycystic ovary syndrome (PCOS) is a common comorbidity in obese women. PCOS is characterized by hormonal imbalances, menstrual irregularities, infertility, and metabolic disorders. Weight management is critical in obese women with PCOS to improve both reproductive health and achieve metabolic and hormonal balance. To this end, surgical treatments have come to the forefront, and procedures such as laparoscopic sleeve gastrectomy (LSG) and endoscopic intragastric balloon (EIB) placement are being used increasingly.
METHODS AND RESULTS: This is a retrospective study conducted at [Blinded for review] between January 2022 and October 2024. It compares the effects of laparoscopic sleeve gastrectomy and endoscopic intragastric balloon placement in female patients aged 18-40 who were diagnosed with PCOS and obesity. In the study, anthropometric measurements, hormonal parameters, and menstrual cycles were evaluated before treatment and 6 months after treatment and analyzed between the two groups. There was no difference in age between patients who underwent laparoscopic sleeve gastrectomy and endoscopic intragastric balloon placement (p = 0.424). The preoperative BMI and the difference between preoperative and postoperative BMI were higher in the LSG group (p < 0.001), but the postoperative BMI values were similar between the two groups (p = 0.583). The waist/hip ratio was higher in the LSG group (p < 0.001, p = 0.010, p < 0.001). While both surgeries showed a reduction in free androgen index and AMH, this reduction was not statistically significant (p > 0.05), both surgeries increased SHBG (p > 0.05). The decrease in AMH was greater in the LSG group (p = 0.020). Total testosterone decreased in the sleeve gastrectomy group (p < 0.001) and the menstrual cycle improved (p = 0.035).
CONCLUSION: In summary, both laparoscopic sleeve gastrectomy and endoscopic intragastric balloon placement led to positive changes in hormone profiles and menstrual cycle characteristics. However, LSG was found to be more effective on these parameters.

Keywords:  AMH; Androgens; Bari̇atri̇c surgery; Obesi̇ty; PCOS

DOI:  https://doi.org/10.1186/s12893-025-03039-9
Biol Sex Differ. 2025 Jul 16. 16(1): 52

Applying a life course approach to elucidate the biology of sex differences in frailty: early-life gonadectomy diminishes late-life robustness in male and female dogs in the Exceptional Aging in Rottweilers Study.

David J Waters, Aimee H Maras, Rong Fu, Andres E Carrillo, Emily C Chiang, Cheri L Suckow.

   BACKGROUND: Frailty refers to a state of increased vulnerability to mortality and other adverse outcomes as a consequence of age-related physiological decline. Sex differences in frailty have been reported; women are usually more frail than men. Physical frailty in men and women is the result of both sociobehavioral and biological factors, making the deciphering of the biology of sex differences in frailty challenging. Investigators have measured frailty in aging animals, including mice and dogs. We posited that companion dogs provide a useful opportunity to study sex differences in the biology of frailty, circumventing many of the sociobehavioral determinants of frailty that complicate human studies.
METHODS: Male-female differences in the relationship between lifetime gonad hormone exposure and late-life robustness were studied in the Exceptional Aging in Rottweilers Study (EARS), a lifetime cohort study of companion dogs with a broad range of lifetime gonad exposure. Late-life frailty was assessed by scoring dogs (135 females, 87 males) for deficit accumulation using a 34-item clinical frailty index previously developed and validated in dogs. The study outcome, late-life robustness, was defined as the lowest tertile of frailty index in the study population. Logistic regression models were constructed to assess differences in the likelihood of late-life robustness in dogs stratified into low, middle, and high lifetime gonad exposure groups. Male-female differences were probed after controlling for age at frailty scoring, gonad exposure, and other covariates.
RESULTS: In both male and female dogs, there was a strong association between longer lifetime gonad exposure and increased likelihood of late-life robustness. Compared to dogs in the lowest gonad exposure group, dogs with highest gonad exposure had a statistically significant 3-fold (females) to 10-fold (males) higher likelihood of late-life robustness. Notably, after controlling for gonad exposure and age at frailty scoring, no male-female difference in late-life robustness was found.
CONCLUSIONS: The research extends current interest in the biology of sex differences in frailty and provides rationale for further inquiry into the role that the hypothalamic-pituitary-gonadal axis plays in supporting late-life robustness. Studies with companion dogs represent a unique investigative opportunity to enhance our understanding of biological factors that impact sex differences and to spur the development of sex-specific anti-frailty interventions.

Keywords:  Aging; Companion dogs; HPG axis; Male-Female differences; Neutering; Preclinical models; Sex hormones; Spay; Timing of gonadectomy; Translational

DOI:  https://doi.org/10.1186/s13293-025-00735-2
medRxiv. 2025 May 23. pii: 2025.05.22.25328179. [Epub ahead of print]

Sex Differences in B Cell Dynamics after Seasonal Influenza Vaccination are Dependent on the Age and Hormonal Profile of Vaccinees.

Han-Sol Park, Anna Yin, Weiqiang Zhou, Eliane F E Wenstedt, Anne Jedlicka, Amanda Dziedzic, Annie Werner, Katherine Z J Fenstermacher, Huifen Li, Patrick J Shea, John S Lee, Patricia Gearhart, Robert W Maul, Sjoerd A A Van Den Berg, Richard E Rothman, Hongkai Ji, Sean X Leng, Andrew Pekosz, Sabra L Klein.

Sex differences in the humoral immune responses to the seasonal quadrivalent influenza vaccine (QIV) in young adults (YA; 18-49yo) or high dose QIV in old adults (OA; 75+yo) were analyzed to evaluate how age-related changes in steroids impact sex differences in B cell responses. Prior to vaccination, CD19+ B cells from OAs, regardless of sex, showed greater enrichment of hallmark pathways associated with inflammatory responses than YAs. Among YAs, females had greater H3N2, but not H1N1, neutralizing antibody titers and greater proportions of hemagglutinin (HA)+CD19+ B cells and HA+ memory B cells than males through 28 days post-vaccination (DPV), which was not observed among OAs. CD19+ B cells from YA females had greater transcriptional activity at 7 DPV than YA males, with upregulation of estrogen-responsive genes and NF-κB-mediated inflammatory pathways in B cell subsets. HA stimulation and treatment of antibody secreting cells (ASCs) from YAs and OAs with estradiol increased the number and size of HA+IgG+ ASCs from YA females and to a lesser extent OA females, but not males, which was inhibited by estrogen receptor antagonism. Machine learning algorithms illustrated that baseline (0 DPV) steroids, including 17-hydroxyprogesterone, estrogens, and testosterone, as well as HA+CD19+ B cells and HA+ ASCs were major predictors of subsequent seroconversion at 28 DPV, particularly in YA. This study provides mechanistic insights into steroid mediation of greater influenza vaccine-induced immunity among reproductive-aged females as compared with age-matched males and explains how sex differences in vaccine-induced immunity are reduced with old age.
One Sentence Summary: Estrogenic activity in B cells causes greater influenza vaccine-induced immunity in young adult females than age-matched males, with these sex differences being mitigated in old adults.

DOI: https://doi.org/10.1101/2025.05.22.25328179
AJOG Glob Rep. 2025 Aug;5(3): 100531

Predicting in vitro fertilization success: the role of hyperglycosylated human chorionic gonadotropin to beta-human chorionic gonadotropin ratio in implantation and early pregnancy outcomes at a private in vitro fertilization center in Baghdad.

Rasha Fadhil Abas, Maad Mahdi Shallal.

   Background: This study explores the role of human chorionic gonadotropin (hCG) isoforms in predicting implantation success and early pregnancy outcomes in in vitro fertilization (IVF) patients. Despite advances in reproductive medicine, implantation failure, and early pregnancy loss remain significant challenges. Hyperglycosylated hCG (hCG-H) facilitates trophoblast invasion and angiogenesis, while beta-hCG (β-hCG) supports progesterone production, crucial for pregnancy maintenance. This study assesses the predictive value of these biomarkers in IVF success.
Methods: A prospective cohort study was conducted at Al-Binuk Private IVF Center in Baghdad from January to December 2024, including 100 women aged 20 to 44 years with primary or secondary infertility and normal uterine cavities. Women with endocrine disorders or uterine abnormalities were excluded. All transferred embryos were frozen day 4 or day 5 embryos and were implanted into a prepared uterus. Serum hCG levels, including hCG-H and β-hCG, were measured 10 to 11 days after embryo transfer. Data were analyzed using SPSS, and logistic regression was performed to evaluate the predictive value of these biomarkers.
Results: The mean age of participants was 34.3 years, with 54% having a normal BMI. Primary infertility was more common (73%), with an average infertility duration of 5.9 years. Half of the participants underwent their first IVF attempt. Among pregnancies, 73% resulted in a single embryo, 13% in twins, and 14% experienced pregnancy failure. Higher hCG-H and β-hCG levels were significantly associated with implantation success, and an increased hCG-H to β-hCG ratio further enhanced prediction. Logistic regression showed that higher hCG levels improved implantation success, while age negatively affected outcomes.
Conclusion: Serum hCG-H and β-hCG levels measured postembryo transfer serve as strong predictors of IVF success. Their ratio further enhances predictive accuracy, emphasizing their role in assessing pregnancy viability. Further research is needed to refine diagnostic thresholds and enhance fertility treatment strategies.

Keywords:  IVF; early pregnancy outcomes; hCG-H; implantation success; β-hCG

DOI:  https://doi.org/10.1016/j.xagr.2025.100531
Curr Opin Hematol. 2025 Jul 03.

Platelets and platelet-leukocyte interactions in infectious diseases.

Marcelo Miranda Lima de Paula, Renata Tôrres Rêgo Oliveira, Eugenio D Hottz.

   PURPOSE OF REVIEW: Platelets are essential effector cells in the immune continuum. Understanding platelet roles during infectious diseases is paramount to understanding pathological and protective immune responses. In this review, we compiled recent data about platelets in immune response to infectious diseases.
RECENT FINDINGS: Platelets recognize and respond to pathogens, including viruses, bacteria and parasites, contributing to the assembly of the immune response. Platelet activation and platelet-leukocyte aggregates formation have been observed in naturally infected humans and in experimental models of diseases. In this review we discuss recent findings on the mechanisms and outcomes of platelet activation and platelet-leukocyte interaction in infectious diseases and response to vaccine. Pathogens may modulate platelet response to escape immune surveillance, but platelets still contribute to host defense. We compiled evidence of platelet mediated-pathological responses, but also their contributions to pathogen clearance. We focused on the participation of platelets in pathophysiological and protective responses in infectious diseases of global impact such as COVID-19, HIV-1, viral hemorrhagic fevers, bacterial sepsis and parasite infections.
SUMMARY: Platelets contribute to protective and pathological responses by regulating innate and adaptive immunity through activation, hyperaggregability and directly interacting with pathogens. Even though many mechanisms underlying platelet roles in infectious disease have been revealed, much remains to be investigated.

Keywords:  bacteria; parasites; platelet activation; thromboinflammation; virus

DOI:  https://doi.org/10.1097/MOH.0000000000000878
Gynecol Endocrinol. 2025 Dec;41(1): 2530571

The protective role of BMP-15 in infertility development with NLRP3 and IL-18 in infertility development in obese patients with PCOS: clinical and mouse model investigations.

Qiaohong Guo, Yongjun Zhou, Lingli Li, Xi Chen, Liang Sun.

  Background: Obesity-related polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with infertility and metabolic dysfunction. While bone morphogenetic protein-15 (BMP-15) plays a recognized role in ovarian function, its specific impact on infertility in obese PCOS patients remains unclear Objective: This study aimed to investigate the influence of BMP-15, NOD-like receptor protein 3 (NLRP3), and interleukin-18 (IL-18) on infertility in this population and to evaluate their predictive clinical value. Methods: Clinical data from 185 obese PCOS patients were retrospectively analyzed. Univariate and logistic regression analyses identified infertility-related factors. Results: Results showed an infertility rate of 34.43%, with significant differences in BMP-15, NLRP3, IL-18, Morisky Medication Adherence Scale (MMAS-8), and Connor-Davidson Resilience Scale (CD-RISC) scores between infertility and non-infertility groups. NLRP3, IL-18, and MMAS-8 emerged as risk factors, while BMP-15 and CD-RISC were protective.In an obese PCOS mouse model, BMP-15 administration improved metabolic parameters, restored hormonal balance, reduced ovarian inflammation, and preserved fertility. Conclusion: These findings suggest that BMP-15 plays a protective role in PCOS-related infertility by modulating metabolic and inflammatory pathways. BMP-15 may serve as a valuable biomarker and therapeutic target for early identification and intervention in obese PCOS patients at risk of infertility.

Keywords:  BMP-15; Obese patients with PCOS; infertility; metabolic disorders

DOI:  https://doi.org/10.1080/09513590.2025.2530571
Exp Oncol. 2025 Jul 11. 47(1): 60-67

MODULATION OF PD-L1 EXPRESSION IN PROSTATE CANCER CELLS THROUGH ANDROGEN RECEPTOR INHIBITION DIFFERS DEPENDING ON RECEPTOR STATUS.

Н Наджафзаде, Е Озьгюр, С Б Газіоглу, Е Е Йорукер, У Гезер.

BACKGROUND: Immune checkpoint blockade (ICB) therapy targeting the PD-1/PD-L1 axis results in poor outcomes in prostate cancer (PCa). PD-L1, the most commonly used predictive marker for the efficacy of PD-1/PD-L1-targeted immunotherapy, appears to be rarely or at low levels expressed in primary androgen-responsive PCa tumors, with higher levels in advanced PCa. PD-L1 expression has not yet been studied regarding the androgen receptor (AR) status.
MATERIALS AND METHODS: We investigated the effect of hormone stimulation by dihydrotestosterone (DHT) and AR inhibition by enzalutamide on PD-L1 expression in LNCaP and LNCaP-AR+ cells, the latter overexpressing AR. Cells were grown for 24 h under hormone-free conditions and then for 24 h in the presence of DHT (10 nM) and/or enzalutamide (10 μM). Cell viability was assessed by Annexin V and propidium iodi de staining. PD-L1 expression was determined semiquantitatively at the mRNA level. ANOVA and independent t-tests were used to compare experimental results between different treatment modalities.
RESULTS: DHT treatment induced some degree of apoptosis in AR-overexpressing LNCaP-AR + cells, but not in parental LNCaP cells. We found low basal expression of PD-L1 in both cell lines, with 2.7-fold higher levels in LNCaP-AR+ cells. DHT treatment increased PD-L1 expression by approximately three-fold in LNCaP cells, while in enzalutamide-treated cells, the expression was lower than the basal level. In LNCaP cells treated concomitantly with DHT and enzalutamide, AR inhibition reduced DHT-induced PD-L1, suggesting an androgen-dependent expression of PD-L1. Unlike in LNCaP cells, androgen stimulation did not increase PD-L1 expression in LNCaP-AR+ cells, and enzalutamide did not affect PD-L1 expression either.
CONCLUSION: Our data reveal that PD-L1 is expressed in an AR-dependent manner in PCa cells, and its expression in AR-overexpressing cells is not modulated by receptor inhibition.

DOI: https://doi.org/10.15407/exp-oncology.2025.01.060
Am J Reprod Immunol. 2025 Jul;94(1): e70125

Evaluation of Th1-Th2 Balance in Patients With Unexplained Recurrent Spontaneous Abortion: A Systematic Review and Meta-Analysis.

Reza Kargar, Zahra Yahoo, Hosein Rafiemanesh, Saeed Aslani, Atefeh Shamosi, Hamed Mohammadi.

   OBJECTIVE: Unexplained recurrent spontaneous abortion (URSA) poses a major challenge in reproductive medicine, with increasing evidence of maternal immune dysregulation. This systematic review and meta-analysis assessed differences in T helper (Th) 1 and Th2 cell frequencies and their ratio between women with URSA and healthy fertile controls.
METHODS: A comprehensive search of PubMed, Scopus, and Web of Science (WoS), up to October 2024, included studies evaluating peripheral blood Th subsets by flow cytometry.
RESULTS: Meta-analyses were performed for Th1(IFN-γ), Th1(TNF-α), Th2(IL-4), Th2(IL-10), and Th1/Th2 ratios. Th1(IFN-γ) frequencies were significantly higher in URSA (mean difference [MD] = 2.31, 95% CI = 0.30-4.33, p = 0.02), while Th2(IL-4) levels were lower (MD = -0.51, 95% CI = -0.91 to -0.11, p = 0.01). No significant differences were observed for Th1(TNF-α) (SMD = 0.25, 95% CI = -0.06 to 0.55, p = 0.11) and Th2(IL-10) (SMD = -0.28, 95% CI = -0.62 to 0.05, p = 0.10). The Th1(IFN-γ)/Th2(IL-4) ratio was significantly elevated (MD = 5.37, 95% CI = 1.47-9.27, p = 0.007), reflecting a shift toward a Th1-dominant immune profile.
CONCLUSIONS: These findings support the role of Th1/Th2 imbalance in URSA and suggest its potential value as a diagnostic or prognostic marker.

Keywords:  Infertility; Recurrent spontaneous abortion; Th1‐Th2 balance

DOI:  https://doi.org/10.1111/aji.70125
Int J Mol Sci. 2025 Jul 02. pii: 6377. [Epub ahead of print]26(13):

Cracking the Code of Oocyte Quality: The Oxidative Stress Link to IVF Success.

Charalampos Voros, Diamantis Athanasiou, Ioannis Papapanagiotou, Despoina Mavrogianni, Antonia Varthaliti, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Georgios Papadimas, Athanasios Gkirgkinoudis, Kyriaki Migklis, Dimitrios Vaitsis, Aristotelis-Marios Koulakmanidis, Charalampos Tsimpoukelis, Sofia Ivanidou, Anahit J Stepanyan, Maria Anastasia Daskalaki, Marianna Theodora, Panagiotis Antsaklis, Dimitrios Loutradis, Georgios Daskalakis.

  The success of in vitro fertilization (IVF) and female reproductive capacity are significantly determined by oocyte quality. Increasing data highlights the significance of oxidative stress-a state of imbalance between reactive oxygen species (ROS) and antioxidant defenses-in regulating oocyte competence. Normal folliculogenesis and ovulation rely on optimal ROS levels; excessive oxidative stress (OS) can lead to DNA fragmentation, undermine meiotic spindle integrity, and trigger apoptosis in cumulus and granulosa cells. Molecular insults impair nuclear and cytoplasmic maturation, thereby impacting fertilization potential and embryonic development. Individuals with polycystic ovarian syndrome (PCOS), endometriosis, advanced maternal age, and metabolic disorders-conditions associated with suboptimal IVF outcomes-frequently exhibit redox imbalance. This narrative review examines significant oxidative markers in the follicular environment, exploring the molecular processes linking OS to diminished oocyte quality and discussing therapy techniques aimed at mitigating oxidative damage. Maintaining redox homeostasis in the ovarian milieu appears to be an effective strategy for enhancing oocyte competence and optimizing outcomes in assisted reproduction.

Keywords:  endocrine disruptors; female infertility; in vitro fertilization (IVF); ovarian function; perfluoroalkyl substances

DOI:  https://doi.org/10.3390/ijms26136377
Gynecol Endocrinol. 2025 Dec;41(1): 2530566

Endocrine traits during pregnancy in women with polycystic ovary syndrome - insights from a prospective cohort study in China.

Qi Cao, Dong Liu, Huili Zhu, Qiuyi Wang, Jing Tan, Xin Huang, Yujing Li, Ruiying Wang, Rong Zhou, Wei Huang.

  Pregnant women with Polycystic ovary syndrome (PCOS) often experience exacerbated endocrine and metabolic dysfunction. While existing studies lack prospective data exist for Chinese populations. Our study aimed to characterize endocrine profiles in Chinese PCOS pregnancies using a prospective cohort. Ninety-one participants (33 PCOS, 58 non-PCOS) were enrolled. Endocrine and metabolic parameters were measured at three trimesters (12-16, 24-28, 32-36 weeks). Primary outcomes included total testosterone (T), sex hormone-binding globulin (SHBG), and free androgen index (FAI). Secondary outcomes covered fasting insulin (FINS), fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), LDL, and HDL. Logistic regression models adjusted for confounders were used for group comparisons. Women with PCOS exhibited higher T and FAI levels compared to women without PCOS across all gestational windows, even after adjusting for factors including pre-pregnancy BMI. Women with PCOS exhibited elevated FINS levels and HOMA-IR at 12-16 weeks and 32-36 weeks of gestation. After adjustment for pre-pregnancy BMI, initial glucose metabolism differences were attenuated and no longer statistically significant. Women with PCOS displayed minor lipid metabolic differences in lipid metabolism. This study highlights complex metabolic changes in PCOS pregnancies, characterized by persistent hyperandrogenism and altered glucose metabolism. Pre-pregnancy BMI might emerge as the key driver of exacerbated glucose dysregulation.

Keywords:  Insulin resistance; Polycystic ovary syndrome; androgen; endocrine traits; pregnancy

DOI:  https://doi.org/10.1080/09513590.2025.2530566
Front Public Health. 2025 ;13 1548379

Stability of cytokine and immunoglobulin concentrations in the general population: prepandemic basal concentrations and intraindividual changes until the COVID-19 pandemic.

Magda Gasull, José Pumarega, Ruth Aguilar, Laura Campi, David Prieto-Merino, Judit Villar-García, Cristina Rius, Francisco Bolúmar, Leonardo Trasande, Carlota Dobaño, Gemma Moncunill, Miquel Porta.

   Background: While there is wide evidence on concentrations of cytokines in patients attending health care facilities, evidence is scant on physiological, basal concentrations of cytokines in the general population and across sociodemographic groups, as well as on their potential stability over time. Furthermore, from a public health perspective it is remarkable that no studies have analyzed intraindividual changes in such concentrations from before the COVID-19 pandemic until its outbreak.
Objectives: To investigate: (a) prepandemic concentrations of cytokines and immunoglobulins to viral exposures in a general, non-institutionalized population, and their associated sociodemographic variables; (b) the intraindividual change in such concentrations between a prepandemic period (2016-17) and the initial pandemic period (2020-21); and (c) whether such change was similar in participants who in 2020-21 were SARS-CoV-2 seronegative and seropositive, and between participants who did and did not develop COVID-19.
Methods: We conducted a prospective cohort study in 240 individuals from the general population of Barcelona, Spain. Thirty cytokines and 31 immunoglobulins were measured in paired serum samples collected in 2016-17 and 2020-21 in the same individuals.
Results: The median value of the relative intraindividual change in cytokine concentrations between 2016 and 2020 was <15% for 29 of the 30 cytokines. A substantial number of participants had an intraindividual increase or decrease ≥15% in some cytokines. No major differences in intraindividual changes of cytokine and immunoglobulin levels between 2016 and 2020 were observed between participants who did and did not develop COVID-19.
Conclusion: We provide novel information on physiological, basal ex-vivo concentrations of cytokines and immunoglobulins in a general population, which should be relevant for clinical practice and public health. Intraindividual changes in cytokines and immunoglobulins during the 4 years from 2016-17 to 2020-21 were moderate, and they did not differ between participants who in 2020-21 were SARS-CoV-2 seropositive and seronegative, nor between participants who did and did not develop COVID-19 disease. These findings are also novel and relevant for medicine and public health. In particular, the stability in the biomarkers is relevant to assess the role of the immunological and inflammatory state (measured through baseline levels of cytokines and immunoglobulins) in the development of SARS-CoV-2 seropositivity and COVID-19 disease, as well as in the susceptibility to other infections and pathologies.

Keywords:  COVID-19; SARS-CoV-2; cytokines; immunoglobulins; population-based

DOI:  https://doi.org/10.3389/fpubh.2025.1548379
Reprod Biol Endocrinol. 2025 Jul 14. 23(1): 99

Epigenetic age and fertility timeline: testing an epigenetic clock to forecast in vitro fertilization success rate.

Davide Marinello, Marco Reschini, Giorgia Di Stefano, Giorgia Carullo, Maíra Casalechi, Letizia Tarantini, Benedetta Albetti, Valentina Bollati, Paola Viganò, Edgardo Somigliana, Letizia Li Piani.

   BACKGROUND: In the field of in vitro fertilization (IVF), the search for reliable success predictors is ongoing, with novel biomarkers gaining increasing attention. Epigenetic clocks, mathematical models based on DNA methylation (DNAm) patterns, have revolutionized aging research by providing insights into biological aging. However, the magnitude of the benefit of the use of a simplified and non-specific epigenetic clock is still insufficient to claim for its clinical use. We investigated the potential role of epigenetic clocks in predicting IVF success.
METHODS: This prospective observational study involved 379 women of reproductive age who underwent IVF treatment. On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. Epigenetic age was calculated using an algorithm based on the methylation patterns of 5 specific CpG sites and derived by pyrosequencing technique ("Zbieć-Piekarska2" model). Epigenetic age acceleration (EPA) was estimated from the residuals of a linear model, with epigenetic age regressed on chronological age. We compared the resulting epigenetic age and EPA between women who achieved a live birth and those who did not, alongside traditional ovarian reserve parameters (antral follicular count AFC; anti-müllerian hormone AMH).
RESULTS: Among 379 women, 204 (54%) achieved LB. They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. 39 ± 5 years, p < 0.001) with moderate predictive power (area under the curve AUC = 0.652). After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve. This association was lost in subgroup analysis by infertility cause. In women aged 31-35, epigenetic age and EPA were the best predictors (AUC = 0.637). Combining epigenetic age with ovarian reserve markers slightly improved predictive accuracy (AUC = 0.692 with AFC, 0.693 with AMH) over chronological age alone (AUC = 0.672).
CONCLUSIONS: Epigenetic clocks may enhance IVF success prediction, particularly in women between 31 and 35. Our findings support the need for further research in this area and emphasize the importance of developing epigenetic models specifically tailored to fertility outcomes.

Keywords:  ART; Epigenetic clock; IVF; Infertility; Live birth; Predictor

DOI:  https://doi.org/10.1186/s12958-025-01429-5
bioRxiv. 2025 Jun 26. pii: 2025.06.21.660869. [Epub ahead of print]

ERβ limits T cell-mediated inflammation to maintain immune homeostasis.

Sarah K McNeer, Alyssia V Broncano, Sarah M Stark, Caroline M Schlessman, Michelle R Raymond, William B Tran, Adrian D Kocinski, Nicholas P Ziats, Wendy A Goodman.

Many autoimmune diseases exhibit a female sex bias in prevalence and severity, yet the mechanisms for this remain unclear. 17β-estradiol, a steroid sex hormone with established immunomodulatory roles, signals through the nuclear receptors ERα and ERβ, which are expressed by CD4 + T cells. Expression of ERβ is reduced in CD4 + T cells isolated from autoimmune disease patients, suggesting that dysregulated E2 signaling contributes to inflammation. We previously identified a novel role for ERβ in promoting the TGFβ-dependent differentiation of Foxp3 + Tregs, supporting the idea that ERβ has anti-inflammatory functions. In this study, we investigated the functional role of ERβ in effector T cells, which drive pathogenesis of many autoimmune diseases. We found that CD4+ T cells isolated from mice globally deficient in ERβ exhibit enhanced proliferation and Th1 polarization ex vivo , together with elevated levels of proinflammatory cytokines in response to T cell receptor (TCR) stimulation. We also found that transfer of ERβ-KO T cells to immunodeficient mice results in significantly worse inflammation in a murine model of colitis. Together, these findings suggest that T cell-specific ERβ functions as a brake on T cell-mediated inflammation, thereby helping to maintain immune homeostasis.
Highlights: CD4+ T cells express the nuclear estrogen receptor ERβ ERβ-deficient T cells express higher levels of inflammatory cytokines and are hyperproliferative ex vivo Deletion of ERβ increases T cell-mediated inflammation in a murine model of colitis.
CRediT authorship contribution statement: SKM: investigation, formal analysis, visualization, writing - original draft; AVB: investigation, formal analysis, visualization, writing - original draft and review and editing; SMS: investigation and formal analysis; CMS: investigation and formal analysis, ADK: investigation, MLR: investigation, WBT: investigation; WAG: conceptualization, funding acquisition, project administration, resources, supervision, formal analysis, visualization, writing-review and editing.

DOI: https://doi.org/10.1101/2025.06.21.660869
J Exp Med. 2025 Sep 01. pii: e20251056. [Epub ahead of print]222(9):

S1PR1, an endothelial-immune influencer.

Samantha Mahfoud, Timothy P Padera.

Lymphatic dysfunction has been associated with tertiary lymphoid structure (TLS) formation in the mesentery. However, our understanding of TLS formation is mainly focused on inflammatory signaling. Here, Geng et al. (https://doi.org/10.1084/jem.20241799) show that lymphatic endothelial cell (LEC) S1P/S1PR1 signaling plays a role in mesenteric TLS formation in the absence of subclinical inflammation and, importantly, is a key regulator of lymphatic valve development.

DOI: https://doi.org/10.1084/jem.20251056
iScience. 2025 Jul 18. 28(7): 112938

Metabolic comparison of minimally to noninvasive urogenital sample types for studying gynecologic health: A pilot study.

Holly Chatenoud, Paweł Łaniewski, Nichole D Mahnert, Melissa M Herbst-Kralovetz.

  In this pilot study, we investigated three minimally to noninvasive biospecimens: cervicovaginal lavages (CVLs), vaginal swabs, and urine, from 18 premenopausal women using untargeted metabolomics to inform future gynecologic research. Metabolic profiles were compared between specimen types and between participants grouped based on vaginal microbiome composition and body mass index (BMI). We identified metabolites altered in the groups in all sample types; however, different metabolites were uniquely detected in each biospecimen. Within CVLs, key amino acid signatures (i.e., polyamines) were identified in women with dysbiosis. While polyamines were also detected in vaginal swabs, this sample type exhibited more lipid signatures. In urine, we specifically detected estrogenic steroids, endocrine-disrupting compounds, and certain drugs. Overall, each urogenital biospecimen type exhibits unique metabolic profiles and, based on metabolic alteration in the context of vaginal microbiome and BMI, can be valuable tools in answering questions related to gynecologic health.

Keywords:  Metabolomics; Microbiome; Women’s health

DOI:  https://doi.org/10.1016/j.isci.2025.112938
Semin Immunopathol. 2025 Jul 18. 47(1): 30

Macrophage clock of pregnancy: circadian and metabolic control of decidual macrophage.

Dongyong Yang, Kristin Thiele, Tailang Yin, Lianghui Diao.

  The temporal regulation of immune responses during pregnancy is crucial for successful gestation. Yet, the specific mechanisms controlling macrophage function across gestational stages remain poorly understood. Here, we introduce the concept of the "macrophage clock of pregnancy", describing how molecular clock and cellular metabolism coordinate macrophage function across gestational stages. The molecular mechanisms underlying circadian control of macrophage function are examined, as well as hormones secreted by the pineal gland and their relevance to pregnancy-related processes. These pathways orchestrate key macrophage functions in pregnancy: modifying the uterine epithelium during implantation, supporting spiral artery remodeling, maintaining fetal tolerance, and initiating labor. Recent evidence shows that environmental factors such as shift work and extension of artificial light exposure can disturb macrophage function. The temporal regulation of macrophages also depends on metabolic signals, with distinct patterns of glycolysis, oxidative phosphorylation, and fatty acid metabolism corresponding to different gestational phases. Disruption of these temporal and metabolic signals - whether through circadian misalignment or metabolic dysfunction - correlates with pregnancy complications including recurrent pregnancy loss, preeclampsia, and preterm birth. We propose that monitoring macrophage temporal dynamics could provide early indicators of pregnancy complications, while targeting clock-controlled pathways may offer new therapeutic strategies. Understanding the temporal aspects of macrophage function opens new approaches for treating pregnancy disorders through precise immunological timing.

Keywords:  Circadian rhythms; Decidual macrophage; Maternal-fetal interface; Metabolic dysfunction; Molecular clock; Pregnancy complications

DOI:  https://doi.org/10.1007/s00281-025-01057-6
Res Sq. 2025 Jul 08. pii: rs.3.rs-6787028. [Epub ahead of print]

Adverse Birth Outcomes Associated with SARS-CoV-2 Infection Among Pregnant Women with and without HIV: A Longitudinal Cohort Study.

Ibrahim Ahmed El-Imam, Abra Rachida Koudjra, Nginache Nampota-Nkomba, Felix Mkandawire, Osward Nyirenda, Rhoda Masonga, Cristiana Cairo, Melissa Gladstone, Miriam K Laufer, Andrea G Buchwald.

Introduction Both COVID-19 disease and HIV infection in utero are associated with increased risk of adverse pregnancy outcomes. However, there is limited evidence on the impact of mild SARS-CoV-2 infection during pregnancy in sub-Saharan Africa, particularly among women living with HIV (WLWH), who may face heightened risk of adverse effects due to immune dysregulation and elevated obstetric risks. Methods We conducted a prospective cohort study of pregnant women enrolled at 20-36 weeks gestation at two health facilities in southern Malawi between 2018 and 2022. SARS-CoV-2 infection was determined via serologic testing at enrollment and delivery. Participants were enrolled into three groups based on HIV status and viral suppression: (1) WLWH with detectable viral load (VL), (2) WLWH with undetectable VL, and (3) HIV-negative women. We used multivariable logistic regression with adjustment for confounding to evaluate the impact of SARS-CoV-2 infection on the following adverse birth outcomes: low birth weight (LBW), preterm birth, small-for-gestational-age (SGA), stillbirth or early neonatal death, and a composite outcome. We further assessed any interaction between SARS-CoV-2 infection and HIV infection on adverse birth outcomes. Results Among 905 women, 29% tested positive for SARS-CoV-2 during pregnancy. Most (87%) infections were mild or asymptomatic. In the total population, SARS-CoV-2 infection was significantly associated with SGA births (adjusted OR [aOR]: 1.49, 95% CI: 1.03-2.13) but was not associated with other adverse outcomes. Among WLWH, SARS-CoV-2 positivity was significantly associated with increased odds of LBW (aOR: 2.07, 95% CI: 1.10-3.91) and SGA births (aOR: 1.73, 95% CI: 1.01-2.91). The effect of SARS-CoV-2 infection among WLWH did not differ based on VL. Conclusion Mild SARS-CoV-2 infection during pregnancy was associated with adverse birth outcomes, particularly among WLWH, suggesting HIV-related immune modulation may heighten vulnerability to adverse pregnancy outcomes in the context of other infectious exposures. These findings underscore the need for integrated antenatal care and targeted infection prevention strategies for pregnant women with HIV in high-burden settings. Additionally, in light of recent changes in recommendations for COVID-19 vaccinations, these findings highlight the ongoing need for infection prevention among pregnant women globally.

DOI: https://doi.org/10.21203/rs.3.rs-6787028/v1
Neurosci Appl. 2025 ;4 105517

Sex hormones and serotonin 4 receptor brain binding in men with and without major depressive disorder.

Malene Ravn Aarestrup, Kristian H Reveles Jensen, Søren Vinther Larsen, Brice Ozenne, Kristin Köhler-Forsberg, Gitte Moos Knudsen, Martin Balslev Jørgensen, Vibe G Frokjaer.

  Sex hormones may contribute to the pathophysiology of Major Depressive Disorder (MDD) through effects on the serotonergic brain system. Estradiol is associated with serotonergic neurobiology in rodent models and humans across sexes. In healthy men, we have previously observed a negative association between testosterone and serotonin 4 receptor (5-HT4R) levels, a receptor implicated in depression and a promising novel antidepressant target. Here, we investigate the associations between sex hormone levels and 5-HT4R binding in unmedicated men with MDD compared to healthy men. We used a latent variable model to evaluate the association between estradiol and testosterone, and cerebral 5-HT4R binding based on [11C]SB207145 Positron Emission Tomography (PET) data from 25 males with MDD from the Neuropharm trial and 52 healthy males (aged 18-49), which included 38 healthy males from our previous study. As previously shown in the complete group of men and women with MDD from the Neuropharm trial, we here confirm that a lower cerebral 5-HT4R level is also observed in the male MDD population alone compared to healthy men (β = -0.07, p = 0.012). In addition to the previously shown negative association between global 5-HT4R levels and testosterone (β = -0.007, p = 0.006) in healthy men, we also observe a positive association with estradiol (β = 1.74, p = 0.001). However, we do not observe this in men with MDD (testosterone: β = 0.0001, p = 0.97; estradiol: β = 0.64, p=0.36). There was a trend towards a group difference in the association between testosterone and global 5-HT4R (β = 0.008, p = 0.082). In summary, we found evidence for a coupling between 5-HT4R and sex hormone levels in healthy men. This neuroendocrine connection appeared unclear in unmedicated men with depression, possibly due to a different and weaker coupling.

Keywords:  5-HT4 receptor; Estrogen; Major depressive Disorder (MDD); Positron emission tomography (PET); Sex Hormones; Testosterone

DOI:  https://doi.org/10.1016/j.nsa.2025.105517
bioRxiv. 2025 Jun 27. pii: 2025.06.11.659200. [Epub ahead of print]

Aging murine peritoneal macrophages undergo female-specific remodeling driven by hormone-dependent and independent mechanisms.

Ryan J Lu, Shiqi Chen, Minhoo Kim, Nirmal K Sampathkumar, Evelyn H Lee, Amy Christensen, Eric E Wang, Isabella Y Lau, Shivay Parihar, Charan K Ravikumar, Jane Jung, Shelby Brown, Alan Xu, Julio L Alvarenga, Kristen Mehalko, Changhan D Lee, Helen S Goodridge, Bérénice A Benayoun.

Aging is a complex process characterized by a progressive decline in physiological functions driven by both biological and environmental factors, with notable differences between sexes. Immune function is strongly influenced by biological sex, affecting both innate and adaptive immune responses, including macrophage behavior. In this study, we investigated the effects of age and sex on the immune cell composition within the peritoneal cavity niche and identified macrophages as the most affected cell type. Macrophages, as central components of the innate immune system, play critical roles in maintaining tissue homeostasis and responding to infections. Here, we find that aging induces sex-specific remodeling of murine peritoneal macrophage transcriptomic and epigenomic landscapes. Consistently, peritoneal macrophages undergo sex-specific functional remodeling with aging ( i.e . female-specific phagocytic decline and metabolic rewiring). Modulation of gonadal hormone signaling showed that changes in circulating estrogen levels likely contribute to aspects of female-specific macrophage age-related changes. Importantly, multi-omic analysis identified candidate transcription factors whose sex-specific age-regulated expression may drive aspects of sex-specific 'omic' remodeling with aging. Specifically, Irf2 downregulation in female macrophages recapitulates distinct transcriptomic and metabolic aspects of macrophage female aging phenotypes. These findings suggest that female-specific age-related functional remodeling arises through hormone-dependent and -independent mechanisms in peritoneal macrophages.

DOI: https://doi.org/10.1101/2025.06.11.659200