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American Journal of Obstetrics and... Nov 2020Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of... (Review)
Review
Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation-a fast, scarless healing process in healthy individuals-will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, "Menstruation: Science and Society" with an aim to "identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field." Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration-and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids-to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent "menstrual equity" and "period poverty" movements spreading across high-income countries.
Topics: Adenomyosis; Attitude; Biological Evolution; Biomedical Research; Congresses as Topic; Developing Countries; Education; Endometriosis; Endometrium; Female; Global Health; Health Literacy; Humans; Leiomyoma; Menstrual Hygiene Products; Menstruation; Menstruation Disturbances; Mesenchymal Stem Cells; Microbiota; Microfluidic Analytical Techniques; National Institute of Child Health and Human Development (U.S.); Regeneration; Stem Cells; Terminology as Topic; Tissue Engineering; United States; Uterine Hemorrhage; Uterine Neoplasms; Uterus; Women's Health
PubMed: 32707266
DOI: 10.1016/j.ajog.2020.06.004 -
Fertility and Sterility Mar 2021Congenital and acquired uterine anomalies are associated with recurrent pregnancy loss (RPL). Relevant congenital Müllerian tract anomalies include unicornuate,... (Review)
Review
Congenital and acquired uterine anomalies are associated with recurrent pregnancy loss (RPL). Relevant congenital Müllerian tract anomalies include unicornuate, bicornuate septate, and arcuate uterus. Recurrent pregnancy loss has also been associated with acquired uterine abnormalities that distort the uterine cavity such as, notably, intrauterine adhesions, polyps, and submucosal myomas. Initial evaluation of women with RPLs should include an assessment of the uterine anatomy. Even if proof of efficacy of surgical management of certain uterine anomalies is often lacking for managing RPLs, surgery should be encouraged in certain circumstances for improving subsequent pregnancy outcome. Uterine anomalies such as uterine septa, endometrial polyps, intrauterine adhesions, and submucosal myomas are the primary surgical indications for managing RPLs.
Topics: Abortion, Habitual; Female; Humans; Hysteroscopy; Pregnancy; Urogenital Abnormalities; Uterus
PubMed: 33712099
DOI: 10.1016/j.fertnstert.2020.12.003 -
Frontiers in Immunology 2019The female reproductive tract harbors distinct microbial communities, as in the vagina, cervical canal, uterus, and fallopian tubes. The nature of the vaginal microbiota... (Review)
Review
The female reproductive tract harbors distinct microbial communities, as in the vagina, cervical canal, uterus, and fallopian tubes. The nature of the vaginal microbiota is well-known; in contrast, the upper reproductive tract remains largely unexplored. Alteration in the uterine microbiota, which is dependent on the nutrients and hormones available to the uterus, is likely to play an important role in uterine-related diseases such as hysteromyoma, adenomyosis, and endometriosis. Uterine mucosa is an important tissue barrier whose main function is to offer protection against pathogens and other toxic factors, while maintaining a symbiotic relationship with commensal microbes. These characteristics are shared by all the mucosal tissues; however, the uterine mucosa is unique since it changes cyclically during the menstrual cycle as well as pregnancy. The immune system, besides its role in the defense process, plays crucial roles in reproduction as it ensures local immune tolerance to fetal/paternal antigens, trophoblast invasion, and vascular remodeling. The human endometrium contains a conspicuous number of immune cells, mainly Natural Killers (NK) cells, which are phenotypically distinct from peripheral cytotoxic NK, cells and macrophages. The endometrium also contains few lymphoid aggregates comprising B cell and CD8 T cells. The number and the phenotype of these cells change during the menstrual cycle. It has become evident in recent years that the immune cell phenotype and function can be influenced by microbiota. Immune cells can sense the presence of microbes through their pattern recognition receptors, setting up host-microbe interaction. The microbiota exerts an appropriately controlled defense mechanism by competing for nutrients and mucosal space with pathogens. It has recently been considered that uterus is a non-sterile compartment since it seems to possess its own microbiota. There has been an increasing interest in characterizing the nature of microbial colonization within the uterus and its apparent impact on fertility and pregnancy. This review will examine the potential relationship between the uterine microbiota and the immune cells present in the local environment.
Topics: Adaptive Immunity; Endometrium; Female; Host-Pathogen Interactions; Humans; Immunity; Immunity, Innate; Leukocytes; Lymphocytes; Microbiota; Mucus; Pregnancy; Semen; Uterus
PubMed: 31681281
DOI: 10.3389/fimmu.2019.02387 -
Fertility and Sterility Nov 2021There are many proposed classification systems for müllerian anomalies. The American Fertility Society (AFS) Classification from 1988 has been the most recognized and...
There are many proposed classification systems for müllerian anomalies. The American Fertility Society (AFS) Classification from 1988 has been the most recognized and utilized. The advantages of this iconic classification include its simplicity, recognizability, and correlation with clinical pregnancy outcomes. However, the AFS classification has been criticized for its focus primarily on uterine anomalies, with exclusion of those of the vagina and cervix, its lack of clear diagnostic criteria, and its inability to classify complex aberrations. Despite this classification and others, the wide range of müllerian anomalies is still largely unknown and confusing to many providers. Consequently, müllerian anomalies may go undiagnosed for extended periods, receive inappropriate or inadequate surgical interventions, and result in persistent issues such as pain or loss of reproductive function. The American Society for Reproductive Medicine Task Force on Müllerian Anomalies Classification was formed and charged with designing a new classification. The Task Force set goals for a new classification and chose to base it on the iconic AFS classification from 1988 because of its simplicity and recognizability, while expanding and updating it to include all categories of anomalies. In addition, this was recognized as an opportunity to raise awareness of this area of medicine, educate providers and learners, and promote patient advocacy. Presented here is the new American Society for Reproductive Medicine Müllerian Anomalies Classification 2021.
Topics: Cervix Uteri; Decision Support Techniques; Female; Humans; Magnetic Resonance Imaging; Male; Mullerian Ducts; Predictive Value of Tests; Terminology as Topic; Ultrasonography; Urogenital Abnormalities; Uterus; Vagina
PubMed: 34756327
DOI: 10.1016/j.fertnstert.2021.09.025 -
Annual Review of Cell and Developmental... Oct 2023The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during... (Review)
Review
The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.
Topics: Female; Animals; Humans; Endometrium; Uterus; Fibrosis; Mammals
PubMed: 37843929
DOI: 10.1146/annurev-cellbio-011723-021442 -
Nature Communications Jul 2019The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression,...
The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.
Topics: Adult; Base Sequence; Endothelial Cells; Female; Granulosa Cells; Humans; Myocytes, Smooth Muscle; Ovarian Follicle; Ovulation; Sequence Analysis, RNA; Theca Cells; Uterus
PubMed: 31320652
DOI: 10.1038/s41467-019-11036-9 -
Endocrine Reviews Oct 2019All mammalian uteri contain glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is... (Review)
Review
All mammalian uteri contain glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is intrinsically regulated by proliferation, cell-cell interactions, growth factors and their inhibitors, as well as transcription factors, including forkhead box A2 (FOXA2) and estrogen receptor α (ESR1). Extrinsic factors regulating adenogenesis originate from other organs, including the ovary, pituitary, and mammary gland. The infertility and recurrent pregnancy loss observed in uterine gland knockout sheep and mouse models support a primary role for secretions and products of the glands in pregnancy success. Recent studies in mice revealed that uterine glandular epithelia govern postimplantation pregnancy establishment through effects on stromal cell decidualization and placental development. In humans, uterine glands and, by inference, their secretions and products are hypothesized to be critical for blastocyst survival and implantation as well as embryo and placental development during the first trimester before the onset of fetal-maternal circulation. A variety of hormones and other factors from the ovary, placenta, and stromal cells impact secretory function of the uterine glands during pregnancy. This review summarizes new information related to the developmental biology of uterine glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
Topics: Animals; Developmental Biology; Embryo Implantation; Female; Hormones; Humans; Infertility; Mammals; Mice; Pregnancy; Sheep; Signal Transduction; Uterus
PubMed: 31074826
DOI: 10.1210/er.2018-00281 -
Nature Jul 2023Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large,...
Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR). However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.
Topics: Female; Humans; Pregnancy; Arteries; Decidua; Pregnancy Trimester, First; Trophoblasts; Uterus; Maternal-Fetal Exchange; Time Factors; Proteomics; Gene Expression Profiling; Datasets as Topic; Gestational Age
PubMed: 37468587
DOI: 10.1038/s41586-023-06298-9 -
Fertility and Sterility Jul 2019Uterus transplantation is the first available treatment for absolute uterine factor infertility. Live births have been reported after transplantation of uteri both from...
Uterus transplantation is the first available treatment for absolute uterine factor infertility. Live births have been reported after transplantation of uteri both from live and deceased donors. Although this novel infertility treatment is still at its experimental stage, with human attempts performed within clinical trials, there is a rapid development in the field. Up until June 2019 more than 60 human uterus transplantation attempts have been performed and the scientific data of the published cases will be reviewed in relation to surgery and outcome. The assisted reproductive technologies that are used before and after uterus transplantation have to be modified for this patient group. The special demands for in vitro fertilization in a patient with no uterus and with embryo transfer in a transplanted uterus will be discussed. Traditionally, uterus transplantation has been performed through laparotomy in both the donor and the recipient. There is now a move to introduce minimally invasive surgery in live donor surgery transplantation, and in the future this may also be applied to recipient surgery. There is a continuous debate whether live donor or deceased donor uterus is the organ source for optimal outcome. Ongoing studies and the general development of the uterus transplantation field will shed light on the pros and cons of each donor source.
Topics: Female; Fertility; Graft Survival; Humans; Infertility, Female; Live Birth; Living Donors; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted; Tissue Donors; Treatment Outcome; Uterus
PubMed: 31277760
DOI: 10.1016/j.fertnstert.2019.05.032 -
International Journal of Gynaecology... Oct 2021Endometrial cancer is the most common gynecological malignancy in high- and middle-income countries. Although the overall prognosis is relatively good, high-grade...
Endometrial cancer is the most common gynecological malignancy in high- and middle-income countries. Although the overall prognosis is relatively good, high-grade endometrial cancers have a tendency to recur. Recurrence needs to be prevented since the prognosis for recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal strategy to balance treatment efficacy against toxicity. Since The Cancer Genome Atlas defined four molecular subgroups of endometrial cancers, the molecular factors are increasingly used to define prognosis and treatment. Standard treatment consists of hysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy (and increasingly sentinel node biopsy) enables identification of lymph node-positive patients who need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant therapy is used for Stage I-II patients with high-risk factors and Stage III patients; chemotherapy is especially used in non-endometrioid cancers and those in the copy-number high molecular group characterized by TP53 mutation. In advanced disease, a combination of surgery to no residual disease and chemotherapy with or without radiotherapy results in the best outcome. Surgery for recurrent disease is only advocated in patients with a good performance status with a relatively long disease-free interval.
Topics: Chemotherapy, Adjuvant; Endometrial Neoplasms; Female; Humans; Hysterectomy; Lymph Node Excision; Neoplasm Recurrence, Local; Neoplasm Staging; Radiotherapy, Adjuvant; Retrospective Studies; Uterus
PubMed: 34669196
DOI: 10.1002/ijgo.13866