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Seminars in Reproductive Medicine May 2020Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is... (Review)
Review
Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. These include intrinsic or induced (1) microtrauma of the endometrial-myometrial interface; (2) enhanced invasion of endometrium into myometrium; (3) metaplasia of stem cells in myometrium; (4) infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; (5) induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and (6) abnormal uterine development in response to genetic and epigenetic modifications. Dysmenorrhea, HMB, and infertility are likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components. Elucidating mechanisms underlying the pathogenesis of adenomyosis raise possibilities to develop targeted therapies to ameliorate symptoms beyond the current agents that are largely ineffective. Herein, we address these possible etiologies and data that support underlying mechanisms.
Topics: Adenomyosis; Animals; Cell Movement; Dysmenorrhea; Endometrium; Female; Humans; Infertility, Female; Menorrhagia; Myometrium
PubMed: 33032339
DOI: 10.1055/s-0040-1716687 -
American Family Physician Jul 2019Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires... (Review)
Review
Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires evaluation if menarche has not occurred by 15 years of age or three years post-thelarche. Secondary amenorrhea is characterized by cessation of previously regular menses for three months or previously irregular menses for six months and warrants evaluation. Clinicians may consider etiologies of amenorrhea categorically as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, sequelae of chronic disease, physiologic, or induced. The history should include menstrual onset and patterns, eating and exercise habits, presence of psychosocial stressors, body weight changes, medication use, galactorrhea, and chronic illness. Additional questions may target neurologic, vasomotor, hyperandrogenic, or thyroid-related symptoms. The physical examination should identify anthropometric and pubertal development trends. All patients should be offered a pregnancy test and assessment of serum follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, should be individualized. Patients with primary ovarian insufficiency can maintain unpredictable ovary function and may require hormone replacement therapy, contraception, or infertility services. Functional hypothalamic amenorrhea may indicate disordered eating and low bone density. Treatment should address the underlying cause. Patients with polycystic ovary syndrome should undergo screening and intervention to attenuate metabolic disease and endometrial cancer risk. Amenorrhea can be associated with clinically challenging pathology and may require lifelong treatment. Patients will benefit from ample time with the clinician, sensitivity, and emotional support.
Topics: Amenorrhea; Diagnosis, Differential; Female; Humans; Medical History Taking; Physical Examination; Practice Guidelines as Topic
PubMed: 31259490
DOI: No ID Found -
Fertility and Sterility May 2023A narrative review of endometrial receptivity in adenomyosis and/or endometriosis revealed that this parameter is difficult to assess in natural conception because both... (Review)
Review
A narrative review of endometrial receptivity in adenomyosis and/or endometriosis revealed that this parameter is difficult to assess in natural conception because both disorders alter natural fertility. Recent data emanating from assisted reproductive technology have allowed the study of endometrial receptivity in women affected by adenomyosis and endometriosis. This has upended our views on the effects of these 2 disorders on embryo implantation. Today, the very existence of altered receptivity in assisted reproductive technology is questioned. In this context, we now know that frozen euploid blastocyst transfers in estradiol and progesterone cycles have unaltered outcomes in both adenomyosis and endometriosis.
Topics: Female; Humans; Pregnancy; Endometriosis; Adenomyosis; Embryo Implantation; Embryo Transfer; Reproductive Techniques, Assisted; Endometrium; Pregnancy Rate; Retrospective Studies
PubMed: 36914148
DOI: 10.1016/j.fertnstert.2023.03.004 -
International Journal of Molecular... Apr 2020Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the... (Review)
Review
Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.
Topics: DNA Methylation; Endometrium; Epigenesis, Genetic; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation; Humans; Receptors, Estrogen; Stromal Cells
PubMed: 32316608
DOI: 10.3390/ijms21082815 -
F1000Research 2019Adenomyosis is a benign uterine disorder in which endometrial glands and stroma are pathologically demonstrated in the uterine myometrium and it is considered a specific... (Review)
Review
Adenomyosis is a benign uterine disorder in which endometrial glands and stroma are pathologically demonstrated in the uterine myometrium and it is considered a specific entity in the PALM-COEIN FIGO (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified - International Federation of Gynecology and Obstetrics) classification of causes of abnormal uterine bleeding (AUB). Although it has always been considered the classic condition of multiparous women over 40 years old who have pain and heavy menstrual bleeding, diagnosed at hysterectomy, the epidemiological scenario has completely changed. Adenomyosis is increasingly identified in young women with pain, AUB, infertility, or no symptoms by using imaging techniques such as transvaginal ultrasound and magnetic resonance. However, there is no agreement on the definition and classification of adenomyotic lesions from both the histopathology and the imaging point of view, and the diagnosis remains difficult and unclear. A uniform and shared reporting system needs to be implemented in order to improve our understanding on imaging features, their relationship with pathogenic theories, and their importance in terms of clinical symptoms and response to treatment. In fact, adenomyosis pathogenesis remains elusive and not a single theory can explain all of the different phenotypes of the disease. Furthermore, adenomyosis often coexists with other gynecological conditions, such as endometriosis and uterine fibroids, increasing the heterogeneity of available data. Treatment requires a lifelong management plan as the disease has a negative impact on quality of life in terms of menstrual symptoms, fertility, and pregnancy outcome and has a high risk of miscarriage and obstetric complications.
Topics: Adenomyosis; Adult; Cesarean Section; Female; Humans; Pregnancy; Quality of Life; Reproducibility of Results
PubMed: 30918629
DOI: 10.12688/f1000research.17242.1 -
Human Reproduction Update Sep 2019Endometriosis, a common oestrogen-dependent inflammatory disorder in women of reproductive age, is characterized by endometrial-like tissue outside its normal location... (Review)
Review
BACKGROUND
Endometriosis, a common oestrogen-dependent inflammatory disorder in women of reproductive age, is characterized by endometrial-like tissue outside its normal location in the uterus, which causes pelvic scarring, pain and infertility. While its pathogenesis is poorly understood, the immune system (systemically and locally in endometrium, pelvic endometriotic lesions and peritoneal fluid) is believed to play a central role in its aetiology, pathophysiology and associated morbidities of pain, infertility and poor pregnancy outcomes. However, immune cell populations within the endometrium of women with the disease have had incomplete phenotyping, thereby limiting insight into their roles in this disorder.
OBJECTIVE AND RATIONALE
The objective herein was to determine reproducible and consistent findings regarding specific immune cell populations and their abundance, steroid hormone responsiveness, functionality, activation states, and markers, locally and systemically in women with and without endometriosis.
SEARCH METHODS
A comprehensive English language PubMed, Medline and Google Scholar search was conducted with key search terms that included endometriosis, inflammation, human eutopic/ectopic endometrium, immune cells, immune population, immune system, macrophages, dendritic cells (DC), natural killer cells, mast cells, eosinophils, neutrophils, B cells and T cells.
OUTCOMES
In women with endometriosis compared to those without endometriosis, some endometrial immune cells display similar cycle-phase variation, whereas macrophages (Mø), immature DC and regulatory T cells behave differently. A pro-inflammatory Mø1 phenotype versus anti-inflammatory Mø2 phenotype predominates and natural killer cells display abnormal activity in endometrium of women with the disease. Conflicting data largely derive from small studies, variably defined hormonal milieu and different experimental approaches and technologies.
WIDER IMPLICATIONS
Phenotyping immune cell subtypes is essential to determine the role of the endometrial immune niche in pregnancy and endometrial homeostasis normally and in women with poor reproductive history and can facilitate development of innovative diagnostics and therapeutics for associated symptoms and compromised reproductive outcomes.
Topics: Dendritic Cells; Endometriosis; Endometrium; Estrogens; Female; Humans; Inflammation; Killer Cells, Natural; Macrophages; Pregnancy; T-Lymphocytes, Regulatory
PubMed: 31424502
DOI: 10.1093/humupd/dmz018 -
Human Reproduction Update Oct 2021Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most... (Review)
Review
BACKGROUND
Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging uterine disorders in terms of diagnosis and management. Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility. The relative contributions of abnormal endometrial tissue and myometrial smooth muscle cells to the development and growth of adenomyosis are not well understood. Moreover, there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium.
OBJECTIVE AND RATIONALE
A recent series of next-generation sequencing (NGS) studies have provided the best scientific evidence thus far regarding the cellular origins of adenomyosis and the contributions of new signaling pathways to its pathogenesis, survival, and growth. These seminal studies on endometrium, adenomyosis and endometriosis demonstrate or support the following key points. (i) Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis. Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis. (ii) KRAS and other less frequent mutations are limited to endometrial-type epithelial cells. They are also observed in endometriosis, indicating that the disease process in adenomyosis is similar to that in endometriosis and distinct from that of uterine fibroids. (iii) Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis. Together, these findings suggest that distinct cell populations in eutopic endometrial tissue play key roles in the etiology of adenomyosis. Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis. In this context, common patterns of aberrant gene expression have been reported both in adenomyosis and endometriosis. These include pathways that favor increased estrogen biosynthesis, decreased estradiol metabolism, a unique estrogen receptor beta (ESR2)-driven inflammatory process, and progesterone resistance due to decreased progesterone receptor expression. Since adenomyosis exhibits a uniquely estrogen-driven inflammatory process and progesterone resistance, we discuss the interactions between these molecular characteristics and signaling pathways induced by the newly discovered KRAS mutations.
SEARCH METHODS
We conducted a comprehensive search using PubMed for human and animal studies published until 2020 in the following areas: adenomyosis, endometriosis, endometrium, NGS, whole-exome sequencing, whole-genome sequencing, RNA sequencing, targeted deep sequencing, epigenetics, driver mutation, KRAS, progesterone resistance, estrogen action and steroid production.
OUTCOMES
Targeted deep sequencing analyses of epithelial cells in adenomyosis and adjacent basalis endometrial glands demonstrated recurring KRAS mutations in both cell types. This finding suggests that adenomyosis originates from basalis endometrium. Epithelial cells of the endometrium, adjacent adenomyosis and co-occurring endometriosis also share identical KRAS mutations. These findings suggest both adenomyosis and endometriosis are oligoclonal tissues that arise from endometrial cell populations carrying a specific driver mutation that most commonly affects the KRAS gene.
WIDER IMPLICATIONS
Adenomyosis usually follows an event such as pregnancy that has disrupted the integrity of the endometrial-myometrial junction followed by repetitious menstrual episodes that increase the likelihood of the entrapment of the basalis endometrium within the myometrium. Glandular epithelial cells carrying KRAS mutations and located within the deep crypts of basalis endometrium may become entrapped and invade myometrial tissue to give rise to adenomyosis. Evidence suggests that KRAS mutations may be responsible, in part, for previously observed phenomena such as prolonged cell survival and progesterone resistance in adenomyosis.
Topics: Adenomyosis; Animals; Endometriosis; Endometrium; Female; High-Throughput Nucleotide Sequencing; Humans; Uterine Diseases
PubMed: 34131719
DOI: 10.1093/humupd/dmab017 -
Reviews in Endocrine & Metabolic... Jun 2022Endometriosis is a benign uterine disorder characterized by menstrual pain and infertility, deeply affecting women's health. It is a chronic disease and requires a long... (Review)
Review
Endometriosis is a benign uterine disorder characterized by menstrual pain and infertility, deeply affecting women's health. It is a chronic disease and requires a long term management. Hormonal drugs are currently the most used for the medical treatment and are based on the endocrine pathogenetic aspects. Estrogen-dependency and progesterone-resistance are the key events which cause the ectopic implantation of endometrial cells, decreasing apoptosis and increasing oxidative stress, inflammation and neuroangiogenesis. Endometriotic cells express AMH, TGF-related growth factors (inhibin, activin, follistatin) CRH and stress related peptides. Endocrine and inflammatory changes explain pain and infertility, and the systemic comorbidities described in these patients, such as autoimmune (thyroiditis, arthritis, allergies), inflammatory (gastrointestinal/urinary diseases) and mental health disorders.The hormonal treatment of endometriosis aims to block of menstruation through an inhibition of hypothalamus-pituitary-ovary axis or by causing a pseudodecidualization with consequent amenorrhea, impairing the progression of endometriotic implants. GnRH agonists and antagonists are effective on endometriosis by acting on pituitary-ovarian function. Progestins are mostly used for long term treatments (dienogest, NETA, MPA) and act on multiple sites of action. Combined oral contraceptives are also used for reducing endometriosis symptoms by inhibiting ovarian function. Clinical trials are currently going on selective progesterone receptor modulators, selective estrogen receptor modulators and aromatase inhibitors. Nowadays, all these hormonal drugs are considered the first-line treatment for women with endometriosis to improve their symptoms, to postpone surgery or to prevent post-surgical disease recurrence. This review aims to provide a comprehensive state-of-the-art on the current and future hormonal treatments for endometriosis, exploring the endocrine background of the disease.
Topics: Aromatase Inhibitors; Endometriosis; Endometrium; Female; Humans; Infertility; Uterine Diseases
PubMed: 34405378
DOI: 10.1007/s11154-021-09666-w -
Cell Dec 2019Endometriosis is chronic disorder with high socioeconomic impact defined by the presence of endometrial-like tissue ("lesions") outside the uterus. Genetic, hormonal,... (Review)
Review
Endometriosis is chronic disorder with high socioeconomic impact defined by the presence of endometrial-like tissue ("lesions") outside the uterus. Genetic, hormonal, and immunological factors as well as endometrial progenitor cells are implicated in development of lesions. A hallmark of the disorder is chronic pain associated with neuroinflammation and changes in the CNS. Women with endometriosis are at increased risk of infertility. Current therapies are inadequate. To view this SnapShot, open or download the PDF.
Topics: Endometriosis; Female; Humans
PubMed: 31951524
DOI: 10.1016/j.cell.2019.11.033 -
Theranostics 2022Despite great advances in assisted reproductive technology (ART), recurrent implantation failure (RIF) cannot be effectively avoided. Notably, cellular characteristics...
Despite great advances in assisted reproductive technology (ART), recurrent implantation failure (RIF) cannot be effectively avoided. Notably, cellular characteristics and communication that regulate endometrial receptivity and differentiation, and its disorders in RIF at window of implantation (WOI) remain rudimentary. In this study, we profiled the endometrial cells present at the WOI timing in RIF patients and healthy controls using single-cell RNA sequencing (scRNA-seq) and provided a detailed molecular and cellular map of a healthy and RIF endometrium at the WOI. In the current study, the endometrium from RIF patient (n = 6; age range, 32 - 35 years) and control (Ctrl) (n = 3; age range, 29 - 35 years) groups were studied at a single-cell resolution. single-cell RNA-seq and analysis were performed on the endometrium of patients with RIF and Ctrl. Immunofluorescence, flow cytometry assays, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to verify cellular identity and function. We profiled the transcriptomes of 60222 primary human endometrial cells isolated from control and RIF patients at a single-cell resolution. We discovered dramatic differential expression of endometrial receptivity-related genes in four major endometrial fibroblast-like cells from RIF patients compared to the control endometrium. We observed that CD49aCXCR4NK cells were diminished in proportion with RIF. The decrease in subset of CD63PGR endometrial epithelial cells with high levels of progesterone receptor, autophagy and exosomes should contribute to the decrease in subset of NK cells. Additionally, we characterized aberrant molecular and cellular characteristics and endometrial cell-cell communication disorders in RIF patients. Our study provides deeper insights into endometrial microenvironment disorder of RIF that are potentially applicable to improving the etiological diagnosis and therapeutics of unexplained RIF.
Topics: Adult; Embryo Implantation; Endometrium; Female; Gene Expression Profiling; Humans; Integrin alpha1; Receptors, Progesterone
PubMed: 36185612
DOI: 10.7150/thno.74053