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Annual Review of Pathology Jan 2020Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to... (Review)
Review
Recent molecular genetic findings on endometriosis and normal endometrium suggest a modified model in which circulating epithelial progenitor or stem cells intended to regenerate uterine endometrium after menstruation may become overreactive and trapped outside the uterus. These trapped epithelium-committed progenitor cells form nascent glands through clonal expansion and recruit polyclonal stromal cells, leading to the establishment of deep infiltrating endometriosis. Once formed, the ectopic tissue becomes subject to immune surveillance, resulting in chronic inflammation. The inflammatory response orchestrated by nuclear factor-κB signaling is exacerbated by aberrations in the estrogen receptor-β and progesterone receptor pathways, which are also affected by local inflammation, forming a dysregulated inflammation-hormonal loop. Glandular epithelium within endometriotic tissue harbors cancer-associated mutations that are frequently detected in endometriosis-related ovarian cancers. In this review, we summarize recent advances that have illuminated the origin and pathogenesis of endometriosis and have provided new avenues for research that promise to improve the early diagnosis and management of endometriosis.
Topics: Endometriosis; Endometrium; Estrogen Receptor beta; Female; Humans; Menstruation; Ovarian Neoplasms; Receptors, Progesterone; Signal Transduction; Stromal Cells; Uterus
PubMed: 31479615
DOI: 10.1146/annurev-pathmechdis-012419-032654 -
Current Topics in Developmental Biology 2017The hormone estrogen is involved in both female and male reproduction, as well as numerous other biological systems including the neuroendocrine, vascular, skeletal, and... (Review)
Review
The hormone estrogen is involved in both female and male reproduction, as well as numerous other biological systems including the neuroendocrine, vascular, skeletal, and immune systems. Therefore, it is also implicated in many different diseases and conditions such as infertility, obesity, osteoporosis, endometriosis, and a variety of cancers. Estrogen works through its two distinct nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Various transcriptional regulation mechanisms have been identified as the mode of action for estrogen, mainly the classical mechanism with direct DNA binding but also a nongenomic mode of action and one using tethered or indirect binding. The expression profiles of ERα and ERβ are unique with the primary sites of ERα expression being the uterus and pituitary gland and the main site of ERβ expression being the granulosa cells of the ovary. Mouse models with knockout or mutation of Esr1 and Esr2 have furthered our understanding of the role of each individual receptor plays in physiology. From these studies, it is known that the primary roles for ERα are in the uterus and neuroendocrine system, as female mice lacking ERα are infertile due to impaired ovarian and uterine function, whereas female mice lacking ERβ are subfertile due to ovarian defects. The development of effective therapies for estrogen-related diseases has relied on an understanding of the physiological roles and mechanistic functionalities of ERα and ERβ in human health and disease.
Topics: Animals; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Humans; Mice; Ovary; Uterus
PubMed: 28527569
DOI: 10.1016/bs.ctdb.2016.12.005 -
Fertility and Sterility Mar 2018The appropriate surgical treatment of adenomyosis, a benign invasion/infiltration of endometrial glands within the underlying myometrium, remains a subject of... (Review)
Review
The appropriate surgical treatment of adenomyosis, a benign invasion/infiltration of endometrial glands within the underlying myometrium, remains a subject of discussion. Since 1990, in place of the classical V-shaped resection method, various kinds of surgical management have been attempted, including a uterine muscle flap method that emphasizes fertility preservation, an asymmetric dissection method, and various modified reduction methods. Laparoscopic adenomyomectomy has also become an alternative to laparotomy for surgically managing the focal type of adenomyosis, although it seems to be associated with a higher risk of uterine rupture than laparotomy. This article reviews the surgical treatment of adenomyosis, including 23 uterine rupture cases that occurred during post-adenomyomectomy pregnancies, and provides an updated picture of the state of the field.
Topics: Adenomyosis; Dissection; Female; Fertility Preservation; Humans; Laparoscopy; Postoperative Complications; Risk Factors; Surgical Flaps; Treatment Outcome; Uterine Diseases; Uterine Myomectomy; Uterus
PubMed: 29566853
DOI: 10.1016/j.fertnstert.2018.01.032 -
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 -
Cellular & Molecular Immunology Sep 2021Tissues are the new frontier of discoveries in immunology. Cells of the immune system are an integral part of tissue physiology and immunity. Determining how immune... (Review)
Review
Tissues are the new frontier of discoveries in immunology. Cells of the immune system are an integral part of tissue physiology and immunity. Determining how immune cells inhabit, housekeep, and defend gut, lung, brain, liver, uterus, and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies. The uterine microenvironment modulates the development and function of innate lymphoid cells [ILC, largely represented by natural killer (NK) cells], macrophages, T cells, and dendritic cells. These immune cells, in turn, contribute to tissue homeostasis. Regulated by ovarian hormones, the human uterine mucosa (endometrium) undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause, with its fibroblasts, glands, blood vessels, and immune cells remodeling the tissue into the transient decidua. Even more transformative changes occur upon blastocyst implantation. Before the placenta is formed, the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin. This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells, chiefly uterine NK (uNK) cells, which also assist fetal growth. The transformed arteries no longer respond to maternal stimuli and meet the increasing demands of the growing fetus. This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua, placenta development, and fetal growth. Determining these pathways will help understand the causes of major pregnancy complications.
Topics: Biology; Decidua; Female; Humans; Immunity, Innate; Killer Cells, Natural; Pregnancy; Uterus
PubMed: 34426671
DOI: 10.1038/s41423-021-00739-z -
Proceedings of the National Academy of... Nov 2019The human endometrium is essential in providing the site for implantation and maintaining the growth and survival of the conceptus. An unreceptive endometrium and...
The human endometrium is essential in providing the site for implantation and maintaining the growth and survival of the conceptus. An unreceptive endometrium and disrupted maternal-conceptus interactions can cause infertility due to pregnancy loss or later pregnancy complications. Despite this, the role of uterine glands in first trimester human pregnancy is little understood. An established organoid protocol was used to generate and comprehensively analyze 3-dimensional endometrial epithelial organoid (EEO) cultures from human endometrial biopsies. The derived EEO expand long-term, are genetically stable, and can be cryopreserved. Using endometrium from 2 different donors, EEO were derived and then treated with estrogen (E2) for 2 d or E2 and medroxyprogesterone acetate (MPA) for 6 d. EEO cells were positive for the gland marker, FOXA2, and exhibited appropriate hormonal regulation of steroid hormone receptor expression. Real-time qPCR and bulk RNA-sequencing analysis revealed effects of hormone treatment on gene expression that recapitulated changes in proliferative and secretory phase endometrium. Single-cell RNA sequencing analysis revealed that several different epithelial cell types are present in the EEO whose proportion and gene expression changed with hormone treatment. The EEO model serves as an important platform for studying the physiology and pathology of the human endometrium.
Topics: Endometrium; Epithelium; Estrogens; Female; Gene Expression Profiling; Humans; Organoids; Progesterone; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 31666317
DOI: 10.1073/pnas.1915389116 -
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.ELife Sep 2021Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust...
Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterized endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.
Topics: Cellular Senescence; Coculture Techniques; Decidua; Embryo Implantation; Endometrium; Female; Humans; Organoids; Pregnancy; Stromal Cells
PubMed: 34487490
DOI: 10.7554/eLife.69603 -
Annual Review of Nutrition Aug 2023The placenta is the gatekeeper between the mother and the fetus. Over the first trimester of pregnancy, the fetus is nourished by uterine gland secretions in a process... (Review)
Review
The placenta is the gatekeeper between the mother and the fetus. Over the first trimester of pregnancy, the fetus is nourished by uterine gland secretions in a process known as histiotrophic nutrition. During the second trimester of pregnancy, placentation has evolved to the point at which nutrients are delivered to the placenta via maternal blood (hemotrophic nutrition). Over gestation, the placenta must adapt to these variable nutrient supplies, to alterations in maternal physiology and blood flow, and to dynamic changes in fetal growth rates. Numerous questions remain about the mechanisms used to transport nutrients to the fetus and the maternal and fetal determinants of this process. Growing data highlight the ability of the placenta to regulate this process. As new technologies and omics approaches are utilized to study this maternofetal interface, greater insight into this unique organ and its impact on fetal development and long-term health has been obtained.
Topics: Female; Pregnancy; Humans; Placenta; Placentation; Pelvis; Uterus; Mothers
PubMed: 37603428
DOI: 10.1146/annurev-nutr-061121-085246 -
Endocrinology Mar 2022Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous...
Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By age 20 weeks, uterine gland development was comparable to controls, but pathologies, including cribriform glandular structures, were observed. Induction of ovulations by periodic human chorionic gonadotropin treatment did not rescue postpubertal uterine gland development. Interestingly, progesterone receptor knockout mice, which lack progesterone signaling, also have defects in postpubertal uterine gland development. However, progesterone treatment did not rescue postpubertal uterine gland development. These studies indicate that chronically elevated levels of estradiol with low progesterone and therefore an absence of cyclic ovarian hormone secretion disrupts postpubertal uterine gland development and homeostasis.
Topics: Animals; Chorionic Gonadotropin; Estradiol; Estrus; Female; Infertility, Female; Mice; Mice, Knockout; Ovarian Follicle; Ovulation; Progesterone; Receptors, LHRH; Uterus
PubMed: 35134138
DOI: 10.1210/endocr/bqac011 -
Biomolecules Nov 2022Common uterine diseases include endometriosis, uterine fibroids, endometrial polyps, endometrial hyperplasia, endometrial cancer, and endometrial dysfunction causing... (Review)
Review
Common uterine diseases include endometriosis, uterine fibroids, endometrial polyps, endometrial hyperplasia, endometrial cancer, and endometrial dysfunction causing infertility. Patients with uterine diseases often suffer from abdominal pain, menorrhagia, infertility and other symptoms, which seriously impair their health and disturb their lives. Androgens play important roles in the normal physiological functions of the uterus and pathological progress of uterine diseases. Androgens in women are synthesized in the ovaries and adrenal glands. The action of androgens in the uterus is mainly mediated by its ligand androgen receptor (AR) that regulates transcription of the target genes. However, much less is known about the signaling pathways through which androgen functions in uterine diseases, and contradictory findings have been reported. This review summarizes and discusses the progress of research on androgens and the involvement of AR in uterine diseases. Future studies should focus on developing new therapeutic strategies that precisely target specific AR and their related signaling pathways in uterine diseases.
Topics: Humans; Female; Androgens; Uterine Diseases; Endometrium; Uterus; Infertility
PubMed: 36358974
DOI: 10.3390/biom12111624