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Despite their importance for immunity against sexually transmitted infections, the composition of female reproductive tract (FRT) memory T-cell populations in response to changes within the local tissue environment under the regulation of the menstrual cycle remains poorly defined. Here, we show that in humans and pig-tailed macaques, the cycle determines distinct clusters of differentiation 4 T-cell surveillance behaviors by subsets corresponding to migratory memory (T MM ) and resident memory T cells. T MM displays tissue-itinerant trafficking characteristics, restricted distribution within the FRT microenvironment, and distinct effector responses to infection. Gene pathway analysis by RNA sequencing identified T MM -specific enrichment of genes involved in hormonal regulation and inflammatory responses. FRT T-cell subset fluctuations were discovered that synchronized to cycle-driven CCR5 signaling. Notably, oral administration of a CCR5 antagonist drug blocked T MM trafficking. Taken together, this study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of immune surveillance at the site of STI pathogen exposure., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The author declares no conflicts of interest.

Problem: Changes in sex hormones during the menstrual cycle and contraceptive vaginal ring (CVR) use influence immunity within the female genital tract, but the magnitude of these effects and their anatomical location are unclear., Method of Study: In a prospective study, 29 women were assessed at three-time points: follicular phase, luteal phase, and one month after initiation of the ethinyl estradiol/etonogestrel CVR (NuvaRing®, Merck). We performed microarrays on endocervical cytobrushes and measured immune mediators in cervicovaginal fluid, adjusting for bacterial vaginosis and the presence of blood. We compared these results to public gene expression data from the fallopian tubes, endometrium, endo- and ectocervix, and vagina., Results: Immune-related gene expression in the endocervix and immune mediators in cervicovaginal fluid increased during CVR use versus both menstrual phases, and in the follicular versus luteal phase. The antimicrobial protein granulysin was high during CVR use, intermediate in the follicular phase, and nearly absent from the luteal phase. Re-analysis of public gene expression data confirmed increased immune-related gene expression in the endocervix during the follicular phase. However, in the fallopian tube, endometrium, and vagina, the follicular phase showed immunosuppression., Conclusions: Immune-related genes in the cervicovaginal tract were highest during CVR use, intermediate in the follicular phase, and lowest in the luteal phase. Granulysin is a potential biomarker of menstrual phase: Frequently detected in follicular samples, but rare in luteal. Lastly, immunological differences between the follicular and luteal phases vary throughout the female genital tract., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autoimmune progesterone dermatitis (APD) is a rare skin disorder with varying presentations, resulting from hypersensitivity to endogenous progesterone during the luteal phase of the menstrual cycle. The diagnosis has been traditionally confirmed with intradermal progesterone testing (IPT) or intramuscular challenge with progesterone or its derivatives. We present a case of a 31-year-old woman with suspected APD who underwent IPT to progesterone. The patient's cyclical symptoms, positive skin reaction and symptoms following IPT were sufficient to make a diagnosis of APD. However, we also tested 10 healthy female controls without symptoms of APD, and found that 9 of these also developed positive skin reactions to intradermal progesterone at 15 min, 24 and 48 h, albeit to a lesser extent. Therefore, these results raise doubts about the validity of using IPT to make a diagnosis of APD. Further research on appropriate testing is needed., (© 2021 British Association of Dermatologists.)

Background: The menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time., Methods: Blood and vaginal lavage samples were collected from 18 pig-tailed macaques to evaluate immune changes over reproductive cycles, and from 5 additional animals undergoing repeated vaginal exposures to simian HIV (SHIV). Peripheral blood mononuclear cell (PBMC) samples from healthy women (n = 10) were prospectively collected over the course of a menstrual cycle to profile T cell populations. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Plasma progesterone was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression on CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was monitored in plasma by RT-PCR. Immune measures were compared using generalized estimating equations (GEE)., Findings: Macaques cycle-phases were associated with fluctuations in systemic immune properties and a type-1 inflammatory T cell response with corresponding CCR5+ memory CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis identified CCR5 oscillation frequencies synchronized with reproductive cycles. In a repetitive low-dose vaginal challenge model, productive SHIV 163P3 infection only occurred during intervals of mounting type-1 T cell responses (n = 5/5). Finally, we identify similar type-1 inflammatory T cell responses over the menstrual cycle are occurring in healthy women., Interpretation: These data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drives bystander CCR5+ CD4 T cell recruitment and HIV susceptibility in the female reproductive tract., Funding: This study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407 to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454])., Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Published by Elsevier B.V.)

Problem: To compare inflammatory- and immune-associated peritoneal cytokines of adolescents and adults with and without endometriosis., Methods of Study: In a nested case-control study in multiple university-affiliated scientific centers, ten adolescents and thirteen adults with visually and histologically confirmed endometriosis (cases), thirteen adolescents with visually suspected endometriosis but indeterminate (seven patients) or negative (six patients) histology, and fifteen adults undergoing surgery for non-malignant gynecologic disease without endometriosis (controls) underwent laparoscopic aspiration of peritoneal fluid (PF), from which PF and conditioned medium (CM) cytokine levels were assayed., Results: Compared to adults with endometriosis, MCP-3, IL-12p40, MIP-1β, and IL-15 were significantly higher among adolescents with endometriosis, while TNF-β and CTACK were lower among adolescents. These differences were similar comparing adolescents with endometriosis to adult controls except for MIP-1β, which was not statistically different. MIP-1β was, however, the only cytokine observed to differ between adult cases and controls. There were no significant differences in CM cytokines among the three groups. Results were similar when analyses were restricted to samples collected (a) during menstrual cycle days 1-10, (b) from patients unexposed to exogenous hormones, or (c) from all adolescents despite presence or absence of histologic endometriosis., Conclusion: Biologically relevant and statistically significant differences in six PF cytokines were observed and suggest a more pro-invasion cytokine profile among adolescents with endometriosis. Adolescents with endometriosis have unique peritoneal cytokine profiles and molecular behavior when compared to adults with and without endometriosis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immune cell differentiation is critical for adequate tissue-specific immune responses to occur. Here, we studied differentiation of human uterine natural killer cells (uNK cells). These cells reside in a tissue undergoing constant regeneration and represent the major leukocyte population at the maternal-fetal interface. However, their physiological response during the menstrual cycle and in pregnancy remains elusive. By surface proteome and transcriptome analysis as well as using humanized mice, we identify a differentiation pathway of uNK cells in vitro and in vivo with sequential acquisition of killer cell immunoglobulin-like receptors and CD39. uNK cell differentiation occurred continuously in response to the endometrial regeneration and was driven by interleukin-15. Differentiated uNK cells displayed reduced proliferative capacity and immunomodulatory function including enhanced angiogenic capacity. By studying human uterus transplantation and monozygotic twins, we found that the uNK cell niche could be replenished from circulation and that it was under genetic control. Together, our study uncovers a continuous differentiation pathway of human NK cells in the uterus that is coupled to profound functional changes in response to local tissue regeneration and pregnancy., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The peri-menopause or menopausal transition-the time period that surrounds the final years of a woman's reproductive life-is associated with profound reproductive and hormonal changes in a woman's body and exponentially increases a woman's risk of cerebral ischemia and Alzheimer's disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

Research Question: There is some controversy regarding the impact of ovarian stimulation on immune cells in women undergoing IVF. The study's aim was to determine whether ovarian stimulation affected immune uterine cells in healthy women undergoing IVF., Design: This prospective cohort study included 28 patients undergoing IVF and 47 healthy oocyte donors. Endometrial biopsies were taken in a natural cycle and after ovarian stimulation. All participants had a normal karyotype, pelvic ultrasound and cervical cytology results and thyroid-stimulating hormone concentration, as well as normal glucose and insulin concentrations and inherited and acquired thrombophilia test results. Screening tests including human papillomavirus were normal. Immune cells were analysed using three techniques: fluorescence-activated cell sorting, immunohistochemistry and gene expression. A human leukocyte antigen (HLA)-C tetramer was used as an 'artificial embryo'. The expression of genes including those for tumour necrosis factor (TNF)-α and interleukin-10 (IL-10) was analysed., Results: A comparison was made of the percentage and gene expression of CD56 bright CD16 - uterine natural killer (uNK), CD56 dim CD16 + natural killer cells, CD56 - CD16 + natural killer cells and TregCD25 + CD4 + FoxP3 + cells, uNK binding to the HLA-C tetramer, and TNF-α and IL-10 expression. No between- or within-group differences were observed in natural versus ovarian stimulation cycles., Conclusions: Ovarian stimulation does not affect the uterine immune cell population or HLA-C binding in healthy women undergoing ovarian stimulation. Further studies are underway to find out if different responses might be seen in women with previous autoimmune disorders., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The proper functioning of the monocyte-macrophage system, an important unit of innate immunity, ensures the normal course of pregnancy. In this review, we present the current data on the origin of the monocyte-macrophage system and its functioning in the female reproductive system during the ovarian cycle, and over the course of both normal and complicated pregnancy. Preeclampsia is a crucial gestation disorder characterized by pronounced inflammation in the maternal body that affects the work of the monocyte-macrophage system. The effects of inflammation at preeclampsia manifest in changes in monocyte counts and their subset composition, and changes in placental macrophage counts and their polarization. Here we summarize the recent data on this issue for both the maternal organism and the fetus. The influence of estrogen on macrophages and their altered levels in preeclampsia are also discussed.

Immune tolerance is crucial for the successful pregnancy, while immune effectors and their products are required to safeguard a fetus from the infectious pathogens. The key immune effectors, such as T, B, and natural killer (NK) cells, monocytes, macrophages, and dendritic cells take part in regulating the immune responses at the maternal-fetal interface. The immune effectors become involved in intraovarian reproductive processes as well, such as ovulation, production of corpus luteum (CL) and its degeneration and determine the quality and evolution of the oocyte during the folliculogenesis. In the cycling endometrium, NK cells are rapidly infiltrated into the endometrium after ovulation and participate in angiogenesis and spiral artery remodeling process. In this study, we reviewed the characteristics and action mechanisms of immune effectors and their products in the peripheral blood, ovary, and endometrium during the ovarian cycle, since a comprehensive understanding of immune responses during the ovarian cycle and the time of implantation can help us to predict the pregnancy outcome and take effective measures for the prevention of potential obstetrical complications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Many women experience some skin reaction or trouble in their monthly menstrual cycle, including the exacerbation of pre-existing diseases and skin eruptions directly associated with sex hormones. We herein report a Japanese woman who experienced repeated systemic urticaria in her premenstrual period, and was diagnosed as having estrogen dermatitis based on a positive result of intradermal estrogen skin test. Of note, the expression of estrogen receptor-β was increased in small dermal vessels of this case as well as in those of patients with other inflammatory skin diseases. These results suggest that inflammation may induce estrogen receptor-β expression in small dermal vessels, which potentially modifies the pathological skin inflammation during the menstrual period, leading to the development of estrogen dermatitis., (© 2019 Japanese Dermatological Association.)

Background: Inflammation and immune activation are key factors in sexual transmission of human immunodeficiency virus (HIV). We sought to define the impact of hormonal cycling on the mucosal immune environment and HIV risk in sex workers with a natural menstrual cycle., Methods: We compared soluble mucosal immune factors and cervical mononuclear cells during hormone titer-defined phases of the menstrual cycle among 37 sex workers from Nairobi, Kenya. Systemic and mucosal samples were collected 14 days apart to distinguish the follicular and luteal phases of the menstrual cycle, and phases were confirmed by hormone measurements. Vaginal concentrations of 19 immune modulators and cervical T-cell activation markers were measured., Results: The follicular phase signature was characterized by an elevated CCL2 level, decreased interleukin 1α and interleukin 1β cervical concentrations, and a significant increase in the proportion of CD4+ T cells that expressed CD69. The genital concentration of CCL2 was the best marker to distinguish the follicular from the luteal phase in univariate and multivariate analyses and remained independent of elevated genital inflammation and bacterial vaginosis., Conclusion: The follicular phase of the menstrual cycle was associated with an elevated CCL2 level and retention of resident memory CD4+ T cells, which has implications for increased susceptibility to HIV infection., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Sex-related differences in asthma prevalence are well established and change through the reproductive phases of life. As children, boys have increased prevalence of asthma compared to girls. However, as adults, women have increased prevalence of asthma compared to men. Many factors, including genetics, environment, immunological responses, and sex hormones, affect the sex disparity associated with the development and control of asthma and other allergic diseases. Fluctuations of hormones during puberty, menstruation, pregnancy, and menopause, alter asthma symptoms and severity. In this article, we review clinical and epidemiological studies that examined the sex disparity in asthma and other allergic diseases as well as the role of sex hormones on asthma pathogenesis.

IgG possesses an important yet little recognized effector function in mucus. IgG bound to viral surface can immobilize otherwise readily diffusive viruses to the mucin matrix, excluding them from contacting target cells and facilitating their elimination by natural mucus clearance mechanisms. Cervicovaginal mucus (CVM) is populated by a microbial community, and its viscoelastic and barrier properties can vary substantially not only across the menstrual cycle, but also in women with distinct microbiota. How these variations impact the "muco-trapping" effector function of IgGs remains poorly understood. Here we obtained multiple fresh, undiluted CVM specimens (n = 82 unique specimens) from six women over time, and employed high-resolution multiple particle tracking to quantify the mobility of fluorescent Herpes Simplex Viruses (HSV-1) in CVM treated with different HSV-1-binding IgG. The IgG trapping potency was then correlated to the menstrual cycle, and the vaginal microbial composition was determined by 16 s rRNA. In the specimens studied, both polyclonal and monoclonal HSV-1-binding IgG appeared to consistently and effectively trap HSV-1 in CVM obtained at different times of the menstrual cycle and containing a diverse spectrum of commensals, including G. vaginalis-dominant microbiota. Our findings underscore the potential broad utility of this "muco-trapping" effector function of IgG to reinforce the vaginal mucosal defense, and motivates further investigation of passive immunization of the vagina as a strategy to protect against vaginally transmitted infections.

Problem: To study the prevalence of HHV-6 in endometrial biopsies among women experiencing recurrent implantation failure (RIF) after IVF/ET compared with controls., Method of Study: Thirty women experiencing RIF after IVF/ET and 10 fertile women participated in the study. All women had endometrial biopsies taken in the luteal phase of their menstrual cycle for an endometrial immune profile (EIP) and HHV-6 mRNA as well as lymphocyte and granulocyte populations. The prevalence of HHV-6 in endometrial biopsies was determined, and biopsies for positive and negative expression of HHV-6 were compared with the results of their EIP and lymphocyte and granulocyte populations., Results: Thirty-seven percentage of women with a history of RIF and 0% of controls demonstrated the presence of HHV-6 in their endometrial biopsies. No associations were found when the results of the endometrial immune profile were compared with the presence or absence of HHV-6. Significant increase in neutrophil-specific CD16b mRNA was found in HHV-6-positive samples, and the levels of B cells-related CD19 mRNA were lower in biopsies from women with RIF in comparison with normal controls., Conclusion: HHV-6 infection is an important factor in RIF., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Why do some females menstruate at all? Answering this question has implications for understanding the tight links between reproductive function and organismal immunity. Here we build on the growing evidence that menstruation is the byproduct of a 'choosy uterus' to: (i) make the theoretical case for the idea that female immunity is cyclical in menstruating species, (ii) evaluate the evidence for the menstrual modulation of immunity and health in humans, and (iii) speculate on the implications of cyclical female health for female behaviour, male immunity, and host-pathogen interactions. We argue that an understanding of females' evolved reproductive system is foundational for both tackling the future challenges of the global women's health agenda and predicting eco-evolutionary dynamics in cyclically reproducing species., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To summarize the current literature on the sex disparity in asthma and the role of sex hormone signaling in allergic and neutrophilic airway inflammation., Data Sources: PubMed and Centers for Disease Control and Prevention health surveys were searched., Study Selections: Clinical and epidemiologic studies in children and adults as well as animal models of asthma were included in this review., Results: Compared with males, females have an increase in asthma prevalence starting around puberty, and fluctuations in hormones during menstruation, pregnancy, and menopause are associated with changes in asthma symptoms. Animal studies using genetic deletions of estrogen receptors or androgen receptors have shown that estrogen signaling promotes and androgen signaling attenuates allergen-mediated type 2 airway inflammation. Furthermore, animal studies have found that ovarian hormones are important for interleukin 17A-mediated airway inflammation., Conclusion: Sex hormones are important in regulating asthma pathogenesis. However, additional studies need to be conducted to further elucidate how sex hormones are initiating and driving the inflammatory response(s) in asthma. Determining these pathways will provide the foundation necessary for the development of treatment strategies and potentially new therapeutics for patients, in particular females, with asthma., (Copyright © 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The control of complement activation within embryo-endometrium environment is critical for embryo survival. Cell evasion from complement attack requires interaction of complement regulatory proteins (CRPs) with cell adhesion αvβ3 integrin. We aim to compare the expression of CRPs in endometria of women with and without endometriosis and to examine the molecular interaction of decay accelerating factor (DAF) with αvβ3 integrin. Endometrial expression of Membrane cofactor protein (CD46), Decay accelerating factor (DAF), Membrane attack complex inhibitory factor (CD59) and β3 integrin subunit were determined through menstrual cycle by immunohistochemistry. DAF protein quantity was determined by Western blot and mRNA levels measured in epithelial cells isolated by laser capture microdissection (LCM). Using in vitro assay, we examined DAF and β3 integrin expression through paracrine regulation between endometrial compartments. To determine whether β3 integrin and DAF interacts in vivo, endometrial samples were subjected to immunoprecipitation and colocalization using dual immunofluorescence technique. DAF and β3 integrin expression were significantly low in samples from women with endometriosis during mid secretory phase. This observation was supported by decreased DAF protein quantity; faint DAF and β3 integrin interaction and reduced mRNA levels in cells dissected by LCM. Moreover epithelial DAF and β3 integrin expression through paracrine regulation by progesterone from stromal compartment was disrupted in endometriosis. Endometria from women with endometriosis exhibits aberrant expression of complement proteins. The abnormal DAF expression potentially compromises embryo survival, contributing to understand the implantation failure in women with endometriosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Study Question: Is it possible to determine the receptivity status of an endometrium by combined quantitative reverse transcription PCR (RT-qPCR) expression analysis of genes involved in endometrial proliferation and immunity?, Summary Answer: The new ER Map®/ER Grade® test can predict endometrial receptivity status by RT-qPCR using a new panel of genes involved in endometrial proliferation and the maternal immune response associated to embryonic implantation., What Is Known Already: The human endometrium reaches a receptive status adequate for embryonic implantation around Days 19-21 of the menstrual cycle. During this period, known as the window of implantation (WOI), the endometrium shows a specific gene expression profile suitable for endometrial function evaluation. The number of molecular diagnostic tools currently available to characterize this process is very limited. In this study, a new system for human endometrial receptivity evaluation was optimized and presented for the first time., Study Design, Size, Duration: ER Map®/ER Grade® validation was achieved on 312 endometrial samples including fertile women and patients undergoing fertility treatment between July 2014 and March 2016. Expression analyses of 184 genes involved in endometrial receptivity and immune response were performed. Samples were additionally tested with an independent endometrial receptivity test., Participants/materials, Setting, Methods: A total of 96 fertile women and 120 assisted reproduction treatment (ART) patients participated in the study. Endometrial biopsy samples were obtained at LH + 2 and LH + 7 days in fertile subjects in a natural cycle and at the window of implantation (WOI) in patients in a hormone-replacement therapy (HRT) cycle. Total RNA was purified, quality-checked and reverse-transcribed. Gene expression was quantified by high-throughput RT-qPCR and statistically analyzed. Informative genes were selected and used to classify samples into four different groups of endometrial receptivity status., Main Results and the Role of Chance: Significantly different gene expression levels were found in 85 out of 184 selected genes when comparing LH + 2 and LH + 7 samples (paired t-test, P < 0.05). Gene ontology analyses revealed that cell division and proliferation, cell signaling and response, extracellular organization and communication, immunological activity, vascular proliferation, blood pressure regulation and embryo implantation are the most over-represented biological terms in this group of genes. Principal component analysis and discriminant functional analysis showed that 40 of the differentially expressed genes allowed accurate classification of samples according to endometrial status (proliferative, pre-receptive, receptive and post-receptive) in both fertile and infertile groups., Large Scale Data: N/A., Limitations, Reasons for Caution: To evaluate the efficacy of this new tool to improve ART outcomes, further investigations such as non-selection studies and randomized controlled trials will also be required., Wider Implications of the Findings: A new comprehensive system for human endometrial receptivity evaluation based on gene expression analysis has been developed. The identification of the optimal time for embryo transfer is essential to maximize the effectiveness of ART. This study is a new step in the field of personalized medicine in human reproduction which may help in the management of endometrial preparation for embryo transfer, increasing the chances of pregnancy for many couples., Study Funding/competing Interest(s): The authors have no potential conflict of interest to declare. No external funding was obtained for this study., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Problem: Fluctuating hormones regulate reproductive processes in the female genital tract. Consequent changes in the local immunological environment are likely to affect cellular interaction with infectious agents and the assessment of therapies that target mucosal infections., Method of Study: We compared Softcup and Weck-Cel sampling protocols and assessed the changes in the concentrations of 39 soluble proteins with menstrual cycle progression in the mucosal and peripheral compartments., Results: We demonstrate that the mucosal immunological profile is distinct from serum with inflammatory and migratory signatures that are localized throughout the cycle. The analytes highlighted in the mucosal compartment were generally highest at the follicular phase with a tendency to fall as the cycle progressed through ovulation to the luteal phase., Conclusion: Our results underscore the need to consider these localized cyclical differences in studies aimed at assessing the outcome of disease and the efficacy of mucosal vaccines and other therapies., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autoimmune progesterone dermatitis (APD) is an exceptional condition affecting young women of childbearing age with a high prevalence during the third decade of life. The diagnosis should be confirmed using an intradermal skin test to progesterone, during the follicular phase of the menstrual cycle. APD represents an early manifestation of autoimmune disease. A case of APD is presented who after curative treatment did not develop other autoimmune diseases during a 6-year follow-up. Dermatologists, gynecologists and obstetricians should be aware of this rare but highly invalidating entity.

Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.

Many women with endometriosis experience compromised fertility. This disease clearly exerts quantitative damage on the ovaries, and perhaps, also qualitative damage. However, it remains controversial whether endometrial receptivity is compromised. Here we review the evidence from basic transcriptomic signature data to clinical data from an oocyte donation model and find support for the concept that endometrial receptivity is not impaired in women with endometriosis when healthy embryos reach the endometrial cavity., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The endometrium maintains complex controls on proliferation and apoptosis as part of repetitive menstrual cycles that prepare the endometrium for the window of implantation and pregnancy. The reliance on inflammatory mechanisms for both implantation and menstruation creates the opportunity in the setting of endometriosis for establishment of chronic inflammation that is disruptive to endometrial receptivity, causing both infertility and abnormal bleeding. Clinically, there can be little doubt that the endometrium of women with endometriosis is less receptive to embryo implantation, and strong evidence exists to suggest that endometrial changes are associated with decreased cycle fecundity as a result of this disease. Here we provide unifying concepts regarding those changes and how they are coordinated to promote progesterone resistance and estrogen dominance through aberrant cell signaling pathways and reduced expression of key homeostatic proteins in eutopic endometrium of women with endometriosis., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Autoimmune estrogen dermatitis is a cyclical cutaneous eruption that occurs premenstrually and goes to the rapid resolution within a few days of menstrual cycles. The disorder has variable clinical manifestations consisting of macules, papules, vesicles, urticarial lesions, bullae, eczematous plaques, and erythema multiforme-like lesions. Herein, we present a case of a 30-year-old woman with attacks of edema and erosions involving the oral and genital mucosal sites on every first day of her menstruation period. She had also multiple endocrinological problems such as hypotroidism and infertility. To determine the sex hormon sensitivity, intradermal skin tests were performed. Based on her personal history and skin test findings, a diagnosis of autoimmune estrogen dermatitis was made. After the oophorectomy, she was free from the skin and mucosal symptoms. We propose that it is important to suspect the diagnosis of autoimmune estrogen dermatitis in patients who present with recurrent cylic eruptions and it must be kept in mind that these patients might have a concomitant infertility.

Objective: To examine differences in inflammation markers in sexually active versus abstinent women and observe changes in inflammation markers across the menstrual cycle. Cycle-related immune fluctuations may have evolved to reduce interference with conception. If so, reproductively active (i.e., sexually active) women should show the most variability in cytokine expression., Design: Participants provided serum samples at menses and ovulation (from which cytokines were assayed) and saliva samples at menses and during follicular, ovulation, and luteal phases (from which C-reactive protein [CRP] was assayed). Participants self-reported intercourse frequency during the study., Setting: Academic research laboratory., Patient(s): Thirty-two healthy, naturally cycling premenopausal women (sexually active, n = 15; abstinent, n = 17)., Intervention(s): Observational study., Main Outcome Measure(s): Levels of proinflammatory cytokines (interleukin-6 [IL-6], interferon γ [IFN-γ], tumor necrosis factor-α [TNF-α]), an anti-inflammatory cytokine (interleukin-4 [IL-4]), and a marker of total inflammation (CRP)., Result(s): Sexually active women had higher levels of all of the immune markers measured, including both pro- and anti-inflammatory cytokines, than abstinent women. Relative to sexually active women, abstinent women had less change across the menstrual cycle in levels of CRP. Among sexually active women, higher intercourse frequency predicted greater midcycle decreases in CRP, IL-6, and IFN-γ and midcycle increases in IL-4., Conclusion(s): Sexual activity may stimulate a complex interaction between pro- and anti-inflammatory cytokines that subsequently drives midcycle declines in inflammation., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Autoimmune progesterone dermatitis (APD) is rare autoimmune hypersensitivity reaction to the fluctuations of endogenous progesterone during a woman's menstrual cycle. It has a wide spectrum of clinical presentations including urticaria, eczema and vesiculobullous eruptions. The disease course depends on treatment modality. The pathogenic mechanisms of APD remain to be elucidated., Objective: We aim to review the literature on APD and evaluate the different theories of pathogenesis and treatments for this condition., Methods: A review of the English literature on APD was performed using PubMed, EMBASE and MEDLINE., Results: 89 patients are included in this review. Initial symptom development in association with the menstrual cycle was reported in 65 (73%) patients. In some patients, it occurred shortly after hormone therapy (8.9%) or in relation to a pregnancy (14.6%). Associated factors were not defined in three patients (3.4%). Nearly 45% had a history of exposure to exogenous progesterone. Diagnosis of APD was usually confirmed with an intradermal progesterone sensitivity test. The goal of treatment was to suppress progesterone secretion through anovulation. Some cases were controlled with oral contraceptives or conjugated estrogen, while some patients had complete resolution post-hysterectomy., Conclusion: The wide spectrum of clinical presentations, histology, and response to therapy would suggest that there are multiple subsets in APD. The increase in the levels of progesterone may also influence the clinical profile and the corresponding immunological response. Further research on the pathogenesis of APD is required to provide a satisfactory treatment modality., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To investigate if sexual activity moderated menstrual cycle-related shifts in cytokines associated with T-helper type 1 (TH1) cells (e.g., interferon [IFN] γ) and T-helper type 2 (TH2) cells (e.g., interleukin [IL] 4). Immune activity shifts across the menstrual cycle, with higher follicular-phase TH1-cell activity but higher luteal-phase TH2-cell activity. Little is known about how social behaviors alter TH1-TH2 ratios, despite evidence that psychosocial factors can influence immunity. Of particular interest is how sexual activity influences immune responses that may support conception, such as the TH1-TH2 balance., Design: Participants provided saliva samples at four time points (menstrual, follicular, ovulatory, and luteal phases), which were assayed by means of ELISA., Setting: Academic laboratory., Participant(s): Thirty healthy premenopausal women (16 sexually abstinent, 14 sexually active) not taking hormonal or immunoactive medications., Intervention(s): None., Main Outcome Measure(s): Salivary E2, P, IFN-γ, and IL-4., Result(s): Sexually active, but not abstinent, women were significantly more likely to express TH2-like cytokine ratios (IFN-γ < IL-4) in the luteal phase than in other phases. Similarly, sexually active women had significantly higher P, and higher P-E2 ratios, in the luteal phase than did abstinent women. The P-E2 ratio mediated menstrual variations in cytokine ratios in sexually active women., Conclusion(s): These results support the hypothesis that shifts in immune response across the menstrual cycle may reflect tradeoffs between reproduction and immunity. These findings point to the need for further research on the interaction between sexual behavior, the menstrual cycle, and immune response., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate differences in levels of serum and monocyte derived interleukin (IL)-1, IL-6 and neopterin (NPT) in women with normal or abnormal menstrual cycles and women with endometriosis. The women participating in this study were divided into 4 groups: 25 women with normal menstrual cycle; 25 women taking oral contraception (OC); 20 postmenopausal women and 25 endometriosis patients. IL-1beta, IL-6 and NPT levels in serum and monocyte culture media were measured with ELISA methods. The data collected showed the lowest serum NPT levels in women with follicular menstrual cycles. The levels of both types of interleukins in serum were the lowest in women using OC. In contrast, the highest concentrations of all cytokines were found in the serum of women with endometriosis. The lowest monocyte activity was observed in women with a follicular menstrual cycle phase and the highest in endometriosis. Monocytes from women using OC secreted similar amounts of cytokines to the cells during the follicular menstrual cycle phase. Changes occurring at the time of contraception, after menopause and during endometriosis, are followed by changed proinflammatory monocyte activity, which is associated with different secretion of cytokines. OC can inhibit inflammatory monocyte properties. Lower serum concentration of cytokines compared to cell secretion may suggest some control mechanisms of monocyte activity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Heavy menstrual bleeding (HMB) affects 30% of women of reproductive age and significantly interferes with quality of life. Altered endometrial vascular maturation has been reported in HMB and recurrent miscarriage, the latter associated with increased uterine natural killer (uNK) cell numbers. This study compared endometrial leukocyte populations in controls and women with HMB. Formalin-fixed paraffin-embedded endometrial biopsies from controls (without endometrial pathology) and HMB were immunostained for CD14 (macrophages), CD56 (uNK cells), CD83 (dendritic cells), FOXP3 (regulatory T cells/Tregs), CD3 and CD8 (T cells). Leukocyte numbers were analysed as a percentage of total stromal cells in five randomly selected fields of view in the stratum functionalis of each sample. In control women across the menstrual cycle, 2-8% of total stromal cells were CD3(+) cells, 2-4% were CD8(+) T cells and 6-8% were CD14(+) macrophages. Compared with controls, CD3(+) cells were reduced during the mid-secretory phase (4%, P<0.01) and increased in the late secretory phase (12%, P=0.01) in HMB. CD83(+) dendritic cells and FOXP3(+) Tregs were scarce throughout the menstrual cycle in both groups. In controls, 2% of stromal cells in proliferative endometrium were CD56(+) uNK cells, increasing to 17% during the late secretory phase. In HMB, CD56(+) uNK cells were increased in the proliferative (5%, P<0.01) and early secretory (4%, P<0.02) phases, but reduced (10%, P<0.01) in the late secretory phase. This study demonstrates dysregulation of uNK cells in HMB, the functional consequence of which may have an impact on endometrial vascular development and/or endometrial preparation for menstruation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Vaginal SHIVSF162P3 acquisition in pigtail macaques (Macaca nemestrina) is dependent on time point during the menstrual cycle. Susceptibility is higher around menstruation and lower at ovulation in mid cycle. This complicates the design of repeat low-dose (RLD) SHIV exposure studies because virus challenges given during low susceptibility periods have lower chances to infect. To account for fluctuating susceptibility, we analyzed menstrual cycles rather than exposures until infection following virus challenges. We first reanalyzed infection data of 41 macaques receiving placebo or no treatment during once (n=18) or twice (n=23) weekly virus exposures. The same number of cycles was required for infection with either challenge frequency, while it took a median four or six challenges for once or twice weekly exposures, respectively. More virus challenges to infection likely reflect frequent unsuccessful exposures in frequently exposed animals. When reanalyzing two previously reported biomedical HIV intervention studies, we found 1% tenofovir gel was 74% or 86% efficacious based on cycles or exposures (p=0.019 or p=0.003, respectively, Fisher's exact test), while 1% raltegravir gel was 84% or 89 % efficacious, respectively (p=0.047 or p=0.031). Evaluating the number of menstrual cycles rather than exposures until infection can account for varying susceptibility during the menstrual cycle. Our observations have implications for future study designs such as planning the frequency of virus exposures. Menstrual cycle analysis may also avoid potential overestimation of efficacy against vaginal challenges during low susceptibility periods in the cycle that are unlikely to cause infection.

The purpose of this study was to examine the effect of oral contraceptive (OC) use on salivary secretory immunoglobulin A (SIgA) levels at rest and in response to an acute bout of moderate-vigorous exercise during 2 phases of the 4-week OC cycle corresponding to different phases of the synthetic menstrual cycle. Ten healthy active females completed a cycling at 70% peak oxygen uptake for 45 min at 2 time points of an OC cycle: during the equivalent in time to the mid-follicular phase (day 8 ± 2) and the mid-luteal phase (day 20 ± 2). Timed unstimulated saliva samples were obtained before, immediately postexercise, and 1 h postexercise and analyzed for salivary SIgA. Salivary SIgA secretion rate was 26% (95% confidence limits (CI) 6-46) lower at postexercise compared with pre-exercise during the synthetic follicular phase (p = 0.019) but no differences were observed during the synthetic luteal trial. Saliva flow rate was 11% (95% CI, 8-30) lower at postexercise compared with pre-exercise (main effect for time; p = 0.025). In conclusion, the pattern of salivary SIgA secretion rate response to moderate-vigorous exercise varies across the early and late phases of a monophasic OC cycle, with a transient reduction in salivary SIgA responses during the synthetic follicular phase. These findings indicate that monophasic OC use should be considered when assessing mucosal immune responses to acute exercise.

Objective: Reproductive hormones are known to impact innate mucosal immune function of the lower genital tract. Our objectives were to determine the effect of hormonal status on intrinsic antiviral (herpes simplex virus [HSV]-1, HSV-2, and human immunodeficiency virus [HIV]-1) activity of cervicovaginal lavage (CVL)., Study Design: CVL was collected from 165 asymptomatic women including postmenopausal women (n = 29); women not on contraception in days 1-14 (n = 26) or days 15-28 (n = 27) of the menstrual cycle; and women using the levonorgestrel intrauterine device (n = 28), depot medroxyprogesterone acetate (n = 28), or combined oral contraceptives (n = 27). The anti-HSV-1/-2 and the anti-HIV-1 activity of the CVL were measured using plaque assays and the Jurkat-Tat-CCR5 assay, respectively., Results: CVL from all of the groups had modest antiviral activity. Anti-HIV-1 activity was decreased in CVL from postmenopausal women when compared to premenopausal women (11% vs 34%, P = .002). However, there was no difference in anti-HIV-1 activity among premenopausal women regardless of phase of menstrual cycle or contraceptive use. Anti-HIV-1 activity was associated with the protein content of the CVL (r = 0.44, P < .001). There was no difference in anti-HSV-1 or -2 activity by hormonal group., Conclusion: Menopause is associated with decreased innate HIV-1 activity in the lower genital tract, suggesting that factors in the vaginal fluid could play a role in increased susceptibility of HIV-1 infection in postmenopausal women. Hormonal contraceptive use, menopause, and phase of menstrual cycle did not have a measurable impact on the intrinsic anti-HSV-1 or -2 activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To investigate immunologic parameters and endoplasmic reticulum (ER) stress associated with unexplained infertility., Design: Case-control study., Setting: Academic center., Patient(s): Women with no fertility problems (FS) (n = 13), women with recurrent miscarriage (RM) (n = 15) and women with repeated in vitro fertilization failure (RIF) (n = 15)., Intervention(s): Endometrial biopsy and collection of peripheral blood during the midsecretory phase of menstrual cycle., Main Outcome Measure(s): Leptin, resistin, soluble tumor necrosis factor receptor (sTNF-R), myeloperoxidase (MPO), soluble intercellular adhesion molecule 1 (sICAM-1), and interleukin 22 (IL-22) concentration in peripheral blood, endometrial CD3(+), CD4(+), CD5(+), CD8(+), and FoxP3(+) T lymphocytes, and endometrial expression of HSPA5, a specific marker of ER stress., Result(s): We found an increase of proinflammatory molecules such as resistin, leptin, and IL-22 in both RM and RIF patients; sTNF-R and MPO only in RIF patients when compared with the FS women. We also found in endometria of infertile women a statistically significant increase of CD3(+), CD4(+), CD8(+) in both RM and RIF patients and CD5(+) in RM patients when compared with FS women. This was paralleled by a statistically significant reduction of infiltrating FoxP3(+) regulatory T cells. Finally, endometrial HSPA5 expression levels were statistically significantly up-regulated in both RM and RIF patients., Conclusion(s): Women with RM and RIF showed an increase of circulating proinflammatory cytokines, altered endometrial T lymphocytes subsets, and signs of endometrial ER stress., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Endometriosis is a chronic, hormone-dependent, inflammatory disease, characterized by the presence and growth of endometrial tissue outside the uterine cavity. It affects 5-10% of the female population of reproductive age and is frequently associated with moderate to severe pain, subfertility, and a marked reduction in health-related quality of life. Here, we propose a new pathophysiological concept of endometriosis, summarizing recent findings in one unifying picture. We propose menstruating tissue as the trigger for inflammatory pain in endometriosis through the activation of innate immune cells and peripheral nerve endings. We speculate how innovative treatment modalities beyond hormonal treatment will improve patients' lives., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Objective: The effects of different levels of steroid hormones, as experienced during puberty, pregnancy and menopause, on the periodontium have been demonstrated, but changes in sex hormone levels during the menstrual cycle, and the influence of these changes on the periodontium, remain unresolved. The aim of this study was to investigate the effect of the menstrual cycle on the levels of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in gingival crevicular fluid and on periodontal clinical parameters, including the gingival bleeding index (GBI) and the modified gingival index (MGI), in periodontally healthy women., Material and Methods: Twenty-seven periodontally healthy women with a regular menstrual cycle were included in the study. Clinical parameters, including the GBI, the MGI and the simplified oral health index, were recorded during menstruation, ovulation and premenstruation phases (e.g. on days 1-2, 12-14 and 22-24, respectively) of the menstrual cycle. Gingival crevicular fluid and unstimulated saliva were collected, at each study phase, for assessment of IL-1β, TNF-α, estrogen and progesterone., Results: Both the GBI and the MGI increased significantly during the menstrual cycle, and were significantly higher during ovulation than during menstruation or premenstruation (p < 0.001). No significant change in the simplified oral health index was observed during the menstrual cycle ( p = 0.18). The levels of IL-1β and TNF-α increased during the different phases of the menstrual cycle, but only the change in the TNF-α concentration was significant ( p < 0.05)., Conclusion: This study indicated that changes occurring during the menstrual cycle influence the periodontium and induce inflammatory conditions., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Most of the key physiological processes in the human reproductive tract involve a significant inflammatory component. These processes include follicle development, ovulation, implantation, pregnancy, labor, postpartum, remodeling and menstruation. In this context, the term 'inflammation' usually means an influx of leukocytes ('immune cells'), often of different types, into a reproductive tract tissue. These examples of inflammation are not overtly associated with any infective process. There may also be evidence that these invading leukocytes have altered their functions to take on specific and relevant local regulatory roles. Specific sequential changes in different leukocytes can be demonstrated within human endometrium during the different phases of the normal menstrual cycle. Leukocytes are fairly sparse in numbers through the proliferative phase, but increase substantially into and through the secretory phase, so much so that around 40% of all stromal cells in the premenstrual phase are leukocytes, mainly uterine natural killer cells, a large granulated lymphocyte. Other leukocytes which play key roles in menstruation appear to be macrophages, mast cells, dendritic cells, neutrophils, eosinophils and regulatory T cells. Premenstrual withdrawal of progesterone increases the endometrial expression of inflammatory mediators, including IL-8 and MCP-1, which are believed to drive endometrial leukocyte recruitment at this time. Macrophages and neutrophils are rich sources of defensins and whey acid protein motif proteins, which play important roles in ensuring microbial protection while the epithelial barrier is disrupted. Mast cells are increasingly activated as the menstrual phase approaches, and leukocyte proteases trigger a cascade of matrix metalloproteinases and degradation of extracellular matrix. Dendritic cells and other antigen-presenting cells (e.g. macrophages) almost certainly facilitate clearance of cellular debris from the uterine cavity, and reduce the amount of viable cellular material transiting the Fallopian tubes. All of these processes are influenced or controlled by regulatory T cells. Many of these leukocytes also have the potential to release regulatory molecules which stimulate endometrial repair mechanisms. Increasing recent evidence also implicates disturbances of immune cells and their cytokine mediators in contributing to symptoms of abnormal uterine bleeding and pelvic pain. These recent findings all point towards the importance of the 'inflammatory process' in both normal and abnormal endometrial bleeding.

Background: Hormonal changes during menstrual cycling may affect susceptibility to HIV., Methods: We determined the simian human immunodeficiency virus (SHIV) acquisition time point in 43 cycling pigtail macaques infected by repeated vaginal virus exposures initiated randomly in the cycle., Results: SHIV infection was first detected in the follicular phase in 38 macaques (88%), and in the luteal phase in five macaques (12%), indicating a statistically significant timing difference. Assuming a 7-day eclipse phase, most infections occurred during or following a high-progesterone period associated with menstruation, vaginal epithelium thinning, and suppressed mucosal immunity., Conclusions: This raises questions whether other high-progesterone conditions (pregnancy, hormonal contraception) similarly affect HIV risk., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

The immune system in the female reproductive tract (FRT) does not mount an attack against human immunodeficiency virus (HIV) or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the FRT. Working together, these antimicrobials along with mucosal antibodies attack viral, bacterial, and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus, has evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol (E2 ) and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells, fibroblasts and immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate and adaptive immune systems are under hormonal control, that protection varies with the stage of the menstrual cycle and as such, is dampened during the secretory stage of the cycle to optimize conditions for fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Menstruation is a complex process dependent on premenstrual release of inflammatory mediators and proteolytic enzymes from endometrial cells. Endometrial leukocytes are traditionally considered to be the major source of the inflammatory factors. However, evidence is emerging to suggest a role for decidualized endometrial stromal cells in the premenstrual inflammatory cascade. We sought to determine if withdrawal of hormone support (estrogen and progesterone) from decidualized endometrial stromal cells, in a model mimicking the precise timing leading to menstruation, activated inflammatory signaling pathways and downstream release of inflammatory mediators. Human endometrial stromal cells decidualized gradually over 12 days of estradiol and progestin treatment as evidenced by an increase in prolactin secretion. Withdrawal of hormone support from decidualized stromal cells resulted in a decrease in cytoplasmic IkappaB and a progressive increase in nuclear accumulation of NF-kappaB, as demonstrated by Western immunoblot and immunocytochemical analyses. Concomitant with nuclear translocation of NF-kappaB, hormone withdrawal led to production of a host of inflammatory mediators by the decidualized stromal cells, including IFN-alpha, IL-6, CCL11, GM-CSF, CCL2, IL1-RA, CXCL10, CXCL8, IL-12, IL-15, VEGF, and CCL5. Elevation of inflammatory mediators was not observed, however, upon hormone withdrawal in cells treated with the NF-kappaB inhibitor BAY 11-7085. Decidualized stromal cells are likely highly sensitive sensors of changing hormone levels. This provides a mechanism by which decidualized stromal cells may recruit inflammatory leukocytes into the premenstrual endometrium and contribute to the intense inflammation underlying this unique physiological process.

Salivary antimicrobial protein (AMP) expression is a primary determinant of mucosal immunity. This expression can be altered by exercise. While salivary IgA has been extensively studied, less is known about Lysozyme (Lys) and Lactoferrin (Lac). Knowledge on how sex and menstrual phase affect mucosal immunity is also limited. The purpose of this study was to examine how sex, menstrual phase, and exercise impact IgA, Lys, and Lac expression. Men (n = 9) and women (n = 9) ran for 45 min at 75% VO2(peak). Women were tested in the follicular and luteal phase. Saliva was collected pre-exercise, immediately post-exercise and 1 h postexercise. Pre-exercise, women had higher secretion rates of IgA compared to men (154 +/- 106 vs 85 +/- 44 microg/min) (p < 0.05). Lac secretion rate increased with exercise in both sexes and remained above baseline 1 h after exercise in men (7460 +/- 4839 ng/min), but had returned to pre-exercise levels at 1 h post-exercise in women (5720 +/- 4661 ng/min) (time * sex interaction, p < 0.05). Men had higher secretion rates of Lys (p < 0.05) at each time point compared to women (Men pre-exercise: 31042 +/- 23132, post-exercise: 29521 +/- 13205, 1 h post-exercise: 41229 +/- 31270 ng/min vs Women pre-exercise: 11585 +/- 10367, post-exercise: 22719 +/- 19452, 1 h post-exercise: 17303 +/- 11419 ng/min). Both sexes increased the secretion rate of Lys and Lac with exercise, whereas IgA was unchanged. Menstrual phase did not affect IgA, Lys, or Lac and men and women did not differ in saliva flow rates. In conclusion, regularly menstruating women who are not taking hormonal contraceptives differently express AMPs compared to men.

The effects of phorbol-12-myristate-13-acetate on functional activity and viability of neutrophil granulocytes in the saliva of women at various phases of menstrual cycle were studied using NBT-test and method for detection of neutrophil traps in mucosa secretions. The activator increased the number of neutrophil traps and parameters of neutrophil NBT-test.

Recent studies suggest that changes in certain uterine immune cell populations in endometrium of women with endometriosis are likely to precede changes at ectopic sites. This preliminary study is a first look into the function of uterine-draining lymph nodes (LNs) during the menstrual cycle and in the presence of endometriosis. Paraffin-embedded obturator LNs were obtained from women with (n = 7, mean age 44.3) and without (n = 9, mean age 38.4) endometriosis, who had undergone hysterectomy for cervical or ovarian cancer and in whom LN involvement was not detected. Immunohistochemical staining for endometrial stromal cells and a range of immune cell populations was performed. The CD10+ endometrial stromal cells were detected in uterine-draining LNs throughout the menstrual cycle with numbers peaking during menstruation. The inflammatory process of menstruation was also associated with increased numbers of CD3+, CD4+, Foxp3+, DC-Sign+, CD68+, CD20+, CD79+, and plasma cells. In endometriosis, CD10+ endometrial stromal cells were further increased in numbers, but CD3+, CD4+, DC-Lamp+, FoxP3+, and plasma cells were reduced. This study indicates that efficient immunological responses may be required to contain shed endometrial fragments within the draining uterine LNs thus preventing their further dissemination with establishment of ectopic lesions at distant sites.

The control of complement activation in the embryo-maternal environment has been demonstrated to be critical for embryo survival. Complement proteins are expressed in the human endometrium; however, the modulation of this expression by embryo signals has not been explored. To assess the expression of complement proteins in response to human chorionic gonadotropin (hCG), we designed an experimental study using in vivo and in vitro models. Twelve fertile women were treated with hCG or left untreated during the mid-luteal phase, and an endometrial biopsy was performed 24 hours later. The localizations of C3, membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55), and protectin (CD59) were assessed by immunohistochemistry, and the messenger RNA (mRNA) levels of these proteins were quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in cells harvested from endometrial compartments using laser capture microdissection. Endometrial explants were cultured with or without hCG for 24 hours, and the C3 and DAF protein levels were measured by Western blotting. Elevated C3 mRNA levels in stromal cells and elevated DAF levels in epithelial luminal cells were detected after hCG treatment. In the endometrial explant model, the progesterone receptor antagonist RU486 inhibited the increases in the levels of C3 and DAF in response to hCG. The findings of this study indicate that hCG plays a role in embryo-endometrium communication and affects the expression of complement proteins in endometrial compartments during the implantation window.

Reproductive senescence in women is a process that begins with regular menstrual cycles and culminates in menopause followed by gradual development of diseases such as autoimmune diseases, osteoporosis, neurodegenerative diseases, and hormone-dependent cancers. The age-associated impairment in the functions of neuroendocrine system and immune system results in menopause which contributes to subsequent development of diseases and cancer. The aim of this study is to characterize the alterations in immune responses, compensatory factors such as nerve growth factor (NGF) and antioxidant enzyme activities, and the molecular mechanisms of actions in the peripheral blood mononuclear cells (PBMCs) of young (follicular and luteal phases), middle-aged, and old healthy women. Peripheral blood mononuclear cells were isolated from young women in follicular and luteal phases of the menstrual cycle (n=20; 22.6±2.9 yrs), middle-aged women (n=19; 47.1±3.8 yrs; perimenopausal) and old (n=16; 63.2±4.7 yrs; post-menopausal) women and analyzed for Concanavalin (Con A)-induced proliferation of lymphocytes and cytokine (IL-2 and IFN-γ) production, expression of NGF, p-NF-κB, p-ERK, p-CREB, and p-Akt, antioxidant enzymes [superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), glutathione-S-transferase (GST)], extent of lipid peroxidation, and nitric oxide (NO) production. Serum gonadal hormones (17β-estradiol and progesterone) were also measured. A characteristic age- and menstrual cycle-related change was observed in the serum gonadal hormone secretion (estrogen and progesterone), T lymphocyte proliferation and IFN-γ production. Salient features include the age-related decline observed in target-derived growth factors (lymphocyte NGF expression), signaling molecules (p-ERK/ERK and p-CREB/CREB ratios) and compensatory factors such as the activities of plasma and PBMC antioxidant enzymes (SOD and catalase) and NO production. Further, an age-associated increase in p-NF-κB expression and lipid peroxidation was observed. Also, serum 17β-estradiol levels were positively correlated with IFN-γ production, SOD activity and NGF expression in the PBMCs. These results suggest that alterations in the levels of gonadal hormones are associated with immunosenescence characterized by decreased IFN-γ production and proliferation of T lymphocytes, decline in NGF expression, SOD and catalase activities, NO production, and signaling mechanisms and thus, may increase the incidence of diseases and cancer in women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Normal menstruation is an inflammatory process, where the endometrial concentrations and functions of several leukocyte types can change greatly through the menstrual cycle, especially during the premenstrual and menstrual phases. These leukocytes probably have a range of functions related to mucosal protection, decidualization, embryo implantation, and the process of menstrual tissue breakdown, repair and remodeling. Some of these leukocyte changes are apparently linked to changes in the pattern of circulating leukocytes. Many immune cells have been identified in the endometrium, and those with most relevance to the processes of menstruation include uterine natural killer cells, macrophages, mast cells, neutrophils, dendritic cells and Tregs. A range of disturbances in endometrial immune cell numbers, distributions and functions, and in a range of different inflammatory and other mediators, have been identified in women with heavy menstrual bleeding or endometriosis. Sufficient evidence exists to implicate these immune changes in some of the functional disturbances and symptoms identified in these women. This field is greatly under-researched, and ripe for the wider application of modern molecular and cellular techniques in human and animal model studies.