Is Neonatal Uterine Bleeding Involved in Early-Onset Endometriosis?

BACKGROUND: There has been considerable progress in our understanding of endometriosis, but its pathophysiology remains uncertain. Uncovering the underlying mechanism of the rare instances of endometriosis reported in early postmenarcheal years and in girls before menarche can have wide implications. METHODS: We conducted a literature review of all relevant articles on Medline. RESULTS: In the review, we explore the pathogenetic theories of premenarcheal endometriosis, the role of retrograde menstruation in the adult and its potential role in early-onset disease, as well as the factors that argue against the existence of a link between early-onset endometriosis (EOE) and neonatal uterine bleeding (NUB). CONCLUSIONS: As with endometriosis in adult women, the pathogenesis of early-onset disease remains unclear. A link between NUB and EOE is plausible, but there are considerable challenges to collating supporting evidence. The state of our understanding of early uterine development and of the pathophysiology of NUB leaves many unknowns that need exploration. These include proof of the existence of viable endometrial cells or endometrial mesenchymal stem cells in NUB, their passage to the pelvic cavity, their possible response to steroids, and whether they can reside within the pelvic cavity and remain dormant till menarche.

Events Leading to the Establishment of Pregnancy and Placental Formation: The Need to Fine-Tune the Nomenclature on Pregnancy and Gestation.

Today, there is strong and diversified evidence that in humans at least 50% of early embryos do not proceed beyond the pre-implantation period. This evidence comes from clinical investigations, demography, epidemiology, embryology, immunology, and molecular biology. The purpose of this article is to highlight the steps leading to the establishment of pregnancy and placenta formation. These early events document the existence of a clear distinction between embryonic losses during the first two weeks after conception and those occurring during the subsequent months. This review attempts to highlight the nature of the maternal-embryonic dialogue and the major mechanisms active during the pre-implantation period aimed at "selecting" embryos with the ability to proceed to the formation of the placenta and therefore to the completion of pregnancy. This intense molecular cross-talk between the early embryo and the endometrium starts even before the blastocyst reaches the uterine cavity, substantially initiating and conditioning the process of implantation and the formation of the placenta. Today, several factors involved in this dialogue have been identified, although the best-known and overall, the most important, still remains Chorionic Gonadotrophin, indispensable during the first 8 to 10 weeks after fertilization. In addition, there are other substances acting during the first days following fertilization, the Early Pregnancy Factor, believed to be involved in the suppression of the maternal response, thereby allowing the continued viability of the early embryo. The Pre-Implantation Factor, secreted between 2 and 4 days after fertilization. This linear peptide molecule exhibits a self-protective and antitoxic action, is present in maternal blood as early as 7 days after conception, and is absent in the presence of non-viable embryos. The Embryo-Derived Platelet-activating Factor, produced and released by embryos of all mammalian species studied seems to have a role in the ligand-mediated trophic support of the early embryo. The implantation process is also guided by signals from cells in the decidualized endometrium. Various types of cells are involved, among them epithelial, stromal, and trophoblastic, producing a number of cellular molecules, such as cytokines, chemokines, growth factors, and adhesion molecules. Immune cells are also involved, mainly uterine natural killer cells, macrophages, and T cells. In conclusion, events taking place during the first two weeks after fertilization determine whether pregnancy can proceed and therefore whether placenta's formation can proceed. These events represent the scientific basis for a clear distinction between the first two weeks following fertilization and the rest of gestation. For this reason, we propose that a new nomenclature be adopted specifically separating the two periods. In other words, the period from fertilization and birth should be named "gestation", whereas that from the completion of the process of implantation leading to the formation of the placenta, and birth should be named "pregnancy".

An Appraisal of the Tissue Injury and Repair (TIAR) Theory on the Pathogenesis of Endometriosis and Adenomyosis.

As understanding their pathogenesis remains elusive, both endometriosis and adenomyosis are often referred to as "enigmatic diseases". The uncertainty and heightened interest are reflected in the range of expressed views and opinions. There is a sense of urgency because of the entailed patient suffering. The plethora of opinions calls for a critical analysis of proposed theories, both old and new. A series of papers published since 2009 proposed that both endometriosis and adenomyosis originate from the same aberrations occurring within the uterus. This came to be recognized as the tissue injury and repair theory, and the newly coined term "archimetrosis" posits that the two diseases share the same origin. While the theory opens an interesting channel for exploration, its claim as a unifying theory necessitates a critical appraisal. We, thus, undertook this review of the theory and analyzed its underpinnings based on a comprehensive review of the literature. Our appraisal indicates that the theory is open to a range of criticisms. Chief among these is the need for confirmatory evidence of features of abnormal uterine contractility and the lack of data addressing the question of causality. In addition, the theory has, as yet, no supporting epidemiological evidence, which is a major weakness. The theory suffers as it is not open to the test of falsifiability, and it lacks the ability to make useful predictions. It has not addressed the questions, such as why only a small percentage of women develop adenomyosis or endometriosis, given the ubiquity of uterine peristalsis. On the other hand, the triggers and prevention of hyper- or dys-peristalsis become critical to a theory of causation. We conclude that additional supportive evidence is required for the theory to be accepted.

From Retrograde Menstruation to Endometrial Determinism and a Brave New World of "Root Treatment" of Endometriosis: Destiny or a Fanciful Utopia?

Practically unknown outside of China, the "endometrial determinism" theory was proposed to account for the apparent gap between the relatively low prevalence of endometriosis and nearly universal retrograde menstruation. Attracting uncritical advocacy, the theory culminates in a recent consensus by elite Chinese gynecologists in favor of "root treatment", intended to nip endometriosis in the bud. Correcting endometrial "defects" can gain further momentum by the presence of cancer-driver mutations such as KRAS mutations in the endometrium of women with endometriosis and the recent introduction of therapeutics aiming to rectify the effect of these mutations for cancer treatment. We provide a critical appraisal of evidence for endometrial aberrations in endometriosis and relevant experimental evidence. All available evidence of endometrial "defect" is invariably post hoc and may well be secondary to induced endometriosis. We propose that the theory of "endometrial determinism" needs to demonstrate a clear causal and a phylogenetic relationship between endometrial aberrations and endometriosis. We argue that while it is highly likely that endometriosis is a consequence of retrograde menstruation, the case that molecular aberrations as a sole or a necessary determinant remains to be proven. "Root treatment" is a worthy ambition but as of now it is close to a fanciful Utopia.

Are Adenomyosis and Endometriosis Phenotypes of the Same Disease Process?

In recent literature reviews, we concluded that the possibility that endometrial molecular aberrations are the sole or a necessary determinant of endometriosis and the Tissue Injury and Repair (TIAR) theory are yet to be convincingly proven. Here, we critically examine the theory that adenomyosis and endometriosis represent different phenotypes of a single disease. A common etiopathology for adenomyosis and endometriosis has been suggested because both conditions entail the presence of endometrial tissue at locations other than the lining of the uterus. There are wide differences in reported disease incidence and prevalence and, consequently, in estimates of the coexistence of both conditions. There are some similarities but also differences in their clinical features and predisposing factors. Each condition has a range of subtypes. These differences alone pose the question of whether subtypes of endometriosis and adenomyosis have different etiopathologies, and, in turn, this raises the question of whether they all share a common etiology. It is debatable whether the recognized differences between the eutopic endometrium in adenomyosis and endometriosis compared to those in unaffected women are the cause or the effect of the disease. The finding of common mutations, particularly of KRAS, lend support to the notion of shared predisposing factors, but this alone is insufficient evidence of causation.

ENDO_STAGE Magnetic Resonance Imaging: Classification to Screen Endometriosis.

Introduction: Transvaginal sonography is the first-line imaging technique to diagnose endometriosis, but magnetic resonance imaging is more accurate in staging the extent of lesions, especially for deep pelvic endometriosis. The revised American Society for Reproductive Medicine and Enzian classifications are commonly used to stage the extent of endometriosis. However, a review underlined their weaknesses in terms of complexity, lack of clinical reproducibility and low correlation with surgical complications and fertility outcomes. Thus, to this day, in clinical practice, there is a lack of consensual, standardized or common nomenclature to stage the extent of endometriosis, posing a worldwide challenge. Objectives: The aims of our study were to: (i) develop a new classification (entitled Endo-Stage MRI) based on patterns of endometriosis as observed with magnetic resonance imaging; (ii) compare results with those of the rASRM classification; (iii) estimate the Endo-Stage MRI accuracy to predict the rate of surgical complications; and (iv) propose an Endo-Stage MRI system of triage (low, intermediate, high) that correlates with the risk of surgical complications. The goal is to improve the effectiveness of care pathways and allow for the planning of a multidisciplinary approach when necessary. Patients and methods: A single-center observational study using available clinical and imaging data. According to anatomical locations and the extent of endometriotic lesions, a standardized classification comprising six stages of severity (0-5) was designed. Results: A total of 751 patients with pelvic endometriosis underwent surgery from January 2013 to December 2018 in a tertiary care university hospital. Their Endo-Stage MRI classification was correlated with: (i) the rate of overall complications (grade I-IV Clavien-Dindo classification, (ii) the rate of major complications (grades III-IV) and (iii) the rate of voiding dysfunction requiring self-catheterization lasting more than one month. According to the Endo-Stage MRI classification, stages 0, 1, 2, 3, 4 and 5 were observed in 26 (3%), 156 (21%), 40 (5%), 22 (3%), 290 (39%) and 217 (29%) patients, respectively. Using the proposed Endo-Stage MRI system as triage, low (stages 0-2), intermediate (stages 3-4) and high-risk (stage 5), complications were observed in 29 (13%), 109 (34.9%) and 103 (47.4%) patients, respectively. In multivariate analysis, the Endo-Stage MRI system of triage was strongly predictive of surgical complications and achieved higher accuracy than the revised American Society for Reproductive Medicine classification (AUC: 0.78 (95% CI, 0.76-0.80) vs. 0.61 (95% CI, 0.58-0.64)). Conclusion: Our study proposes a new imaging classification of endometriosis coined Endo-Stage MRI classification. The results suggest that when applied to a clinical situation, it may improve care pathways by providing crucial information for identifying intermediate and/or high-risk stages of endometriosis with increased rates of surgical complications. To make this classification applicable, a multicentric validation study is necessary to assess the relevancy and clinical value of the current anatomical MRI classification.

Age-dependent phenotypes of ovarian endometriomas.

Purpose: To analyze the characteristics of the ovarian endometrioma (OE) across the life span of a woman. In the past, the OE has traditionally been viewed as a single, monolithic disease. Today, there are emerging data indicating that OE phenotypes differ according to the age of the woman. Method: A narrative review of original articles on OE indexed by PubMed. Results: When appearing in infancy and early adolescence, OE may be the consequence of endometrial cells retrogradely shed with neonatal uterine bleeding. The post-menarcheal variant, manifesting itself during full adolescence, is singularly frequent in the presence of vaginal or uterine outflow obstructive anomalies. The typical and most frequent adult phenotype is characterized by increasing fibrosis and a tendency to progress; its mere presence exerts a detrimental effect on the surrounding healthy ovarian tissue. In postmenopause, an old lesion may be reactivated in the presence of exogenous or endogenous estrogens, or even be produced ex novo; rarely, it can spread to a variety of organs and structures and even degenerate causing malignancies. Conclusions: Given the existence of these variants, it is important to agree on management guidelines that take into consideration these different phenotypes.

Unveiling the Pathogenesis of Adenomyosis through Animal Models.

BACKGROUND: Adenomyosis is a common gynecological disorder traditionally viewed as "elusive". Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power. METHODS: PubMed was exhaustively searched using the phrase "adenomyosis and animal model", "adenomyosis and experimental model", "adenomyosis and mouse", and "adenomyosis and rat", and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner. RESULTS: Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial-myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill's causality criteria. Other theories only partially satisfy Hill's criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis. CONCLUSIONS: EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis.

In Search of an Imaging Classification of Adenomyosis: A Role for Elastography?

Adenomyosis is a complex and poorly understood gynecological disease. It used to be diagnosed exclusively by histology after hysterectomy; today its diagnosis is carried out increasingly by imaging techniques, including transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). However, the lack of a consensus on a classification system hampers relating imaging findings with disease severity or with the histopathological features of the disease, making it difficult to properly inform patients and clinicians regarding prognosis and appropriate management, as well as to compare different studies. Capitalizing on our grasp of key features of lesional natural history, here we propose adding elastographic findings into a new imaging classification of adenomyosis, incorporating affected area, pattern, the stiffest value of adenomyotic lesions as well as the neighboring tissues, and other pathologies. We argue that the tissue stiffness as measured by elastography, which has a wider dynamic detection range, quantitates a fundamental biologic property that directs cell function and fate in tissues, and correlates with the extent of lesional fibrosis, a proxy for lesional "age" known to correlate with vascularity and hormonal receptor activity. With this new addition, we believe that the resulting classification system could better inform patients and clinicians regarding prognosis and the most appropriate treatment modality, thus filling a void.

Classifying Adenomyosis: Progress and Challenges.

Classically, the diagnosis of adenomyosis relied on histological examination of uteri following hysterectomy and classifications focused on the depth of endometrial invasion within the myometrium. There remain uncertainties around the cut-off point for the histological diagnosis. Imaging-based diagnosis enables recognition of the condition in women not undergoing surgery and facilitates the assessment of the extent of adenomyosis within the whole uterus, as well as of affections of the uterovesical pouch and of the pouch of Douglas. In this article, we explore the diagnostic uncertainties, the need to produce a classification of the condition and the challenges towards that goal. A distinction should be drawn between disease mapping and a classification that may link histological or image-based features with clinical characteristics, or with pathophysiology. An agreed system for reporting adenomyotic lesions may enable comparisons of research studies and thus contribute towards an informed classification. To this aim, we outline the features of the condition and explore the characteristics that are considered when producing a taxonomy. These include the latest proposal for subdivision of adenomyosis into an internal and an external variant. We also explore the uncertainties linked to classifying involvement of the uterovesical pouch, the pouch of Douglas and lesions in the outer myometrium. The limitations of currently available evidence suggest that agreement on a hypothesis to underpin a classification is unlikely at present. Therefore, current efforts will probably remain focused on disease mapping.

Neonatal Uterine Bleedings: An Ignored Sign but a Possible Cause of Early-Onset Endometriosis - A Systematic Review.

OBJECTIVE: Based on the hypothesis that neonatal uterine bleedings (NUB), occurring mostly in the first week after birth, could represent a pathogenetic mechanism for early-onset endometriosis, this systematic review (SR) was undertaken to evaluate the prevalence and screening strategies used to assess and quantify NUB. DESIGN: Both a SR and a sample literature search in PubMed and Embase were conducted to gather information on NUB prevalence and screening techniques. This was performed by an information specialist. Only full-text articles regarding the assessment of NUB in neonates in the first 2 weeks after birth were included. No limit on language or publication data was used. MATERIALS AND METHODS: The SR was registered in PROSPERO (CRD42019138121). Data was first assessed for eligibility on title and abstract by 2 blinded review authors. Any disagreements were discussed with a third reviewer if necessary. Subsequently, full-text articles were read and assessed for quality using the Cochrane Collaboration Handbook. RESULTS: Out of 1,988 articles in the systematic search, 10 relevant articles were selected, of which 8 were identified through the systematic search and 2 were found through other sources. The sample search of 4,445 articles did not bring up relevant articles. Results were not comparable due to the heterogeneity of screening techniques, although data showed consensus. The prevalence of visible bleeding ranged from 3.3 to 53.8% and the prevalence of occult bleeding from 25.4 to 96.7%. The occurrence was the highest between the 3rd and 7th day postpartum (PP) and the bleeding lasted for 3-4 days on average. Various screening techniques for detecting NUB were found in the literature, including the use of hemoglobin detection devices (such as Hemastix) in the vaginal vestibulum, comparison of diapers with stains of known volume, colposcopy, and ultrasonography. CONCLUSION: The reported prevalence of NUB varies considerably, with a consistent occurrence between the 3rd and the 7th day PP. Literature to assess NUB is dated. The techniques are poorly described and heterogeneous. Future research should focus on prospective cohort studies in order to attempt to correlate NUB cases to (early-onset) endometriosis.

The development of the human uterus: morphogenesis to menarche.

There is emerging evidence that early uterine development in humans is an important determinant of conditions such as ontogenetic progesterone resistance, menstrual preconditioning, defective deep placentation and pre-eclampsia in young adolescents. A key observation is the relative infrequency of neonatal uterine bleeding and hormone withdrawal at birth. The origin of the uterus from the fusion of the two paramesonephric, or Müllerian, ducts was described almost 200 years ago. The uterus forms around the 10th week of foetal life. The uterine corpus and the cervix react differently to the circulating steroid hormones during pregnancy. Adult uterine proportions are not attained until after puberty. It is unclear if the endometrial microbiome and immune response-which are areas of growing interest in the adult-play a role in the early stages of uterine development. The aim is to review the phases of uterine development up until the onset of puberty in order to trace the origin of abnormal development and to assess current knowledge for features that may be linked to conditions encountered later in life. The narrative review incorporates literature searches of Medline, PubMed and Scopus using the broad terms individually and then in combination: uterus, development, anatomy, microscopy, embryology, foetus, (pre)-puberty, menarche, microbiome and immune cells. Identified articles were assessed manually for relevance, any linked articles and historical textbooks. We included some animal studies of molecular mechanisms. There are competing theories about the contributions of the Müllerian and Wolffian ducts to the developing uterus. Endometrium features are suggestive of an oestrogen effect at 16-20 weeks gestation. The discrepancy in the reported expression of oestrogen receptor is likely to be related to the higher sensitivity of more recent techniques. Primitive endometrial glands appear around 20 weeks. Features of progestogen action are expressed late in the third trimester. Interestingly, progesterone receptor expression is higher at mid-gestation than at birth when features of endometrial maturation are rare. Neonatal uterine bleeding occurs in around 5% of neonates. Myometrial differentiation progresses from the mesenchyme surrounding the endometrium at the level of the cervix. During infancy, the uterus and endometrium remain inactive. The beginning of uterine growth precedes the onset of puberty and continues for several years after menarche. Uterine anomalies may result from fusion defects or atresia of one or both Müllerian ducts. Organogenetic differentiation of Müllerian epithelium to form the endometrial and endocervical epithelium may be independent of circulating steroids. A number of genes have been identified that are involved in endometrial and myometrial differentiation although gene mutations have not been demonstrated to be common in cases of uterine malformation. The role, if any, of the microbiome in relation to uterine development remains speculative. Modern molecular techniques applied to rodent models have enhanced our understanding of uterine molecular mechanisms and their interactions. However, little is known about functional correlates or features with relevance to adult onset of uterine disease in humans. Prepubertal growth and development lends itself to non-invasive diagnostics such as ultrasound and MRI. Increased awareness of the occurrence of neonatal uterine bleeding and of the potential impact on adult onset disease may stimulate renewed research in this area.

Effects of progestin-only contraceptives on the endometrium.

INTRODUCTION: The contraceptive activity of synthetic progestins is mediated through three basic mechanisms: (a) An anti-gonadotrophic action leading to the inhibition of ovulation; (b) Changes in cervical mucus characteristics that inhibit sperm penetration and (c) desynchronization of the endometrial picture necessary for implantation. AREAS COVERED: Mechanisms involved in the progestin-induced endometrium desynchronization are individually reviewed for each of the routes of administration and, whenever possible, by individual members of the various families of synthetic progestin derivatives. EXPERT OPINION: For contraceptive purposes, progestins are today administered through several routes: orally, as injections, subdermally and via the vagina or the uterine cavity. Given this variety of modalities, their effects may differ, depending on the route of administration, concentration reached at the level of the endometrium and the duration of use. These are characterized by inactivation of the endometrium. Progestin-only contraception provides a safe and effective control of fertility regulation, although, they are associated with the problem of endometrial break through bleeding that may lead to discontinuation. Unfortunately, in spite of a major research effort over two decades, there is not, as yet, an established long-term intervention available to manage bleeding irregularities, making mandatory a deeper understanding of the mechanisms involved is required.

Exploring the challenges for a new classification of adenomyosis.

The availability of non-invasive diagnostic tests is an important factor in the renewed interest in adenomyosis, as the disease can now be more accurately mapped in the uterus without a need for hysterectomy. An agreed system for classifying and reporting the condition will enhance our understanding of the disease and is envisaged to enable comparison of research studies and treatment outcomes. In this review, we assess previous and more recent attempts at producing a taxonomy, especially in view of the latest proposal for subdivision of adenomyosis into an internal and an external variant. In this context, we also explore the uncertainties linked to classifying involvement of the uterovesical pouch, the pouch of Douglas and lesions in the outer myometrium. Two opposing hypotheses are forwarded to explain the pathogenesis of these variants, namely that disease localized in these areas originates from an invasion by uterine adenomyosis of peritoneal organs; alternatively, that lesions present in the outer myometrium originate from peritoneal endometriosis. At the root of debates around these opposing theories of pathogenesis is fragmentary evidence. Because of the limitations of currently available evidence, and until this issue is resolved, broad agreement on a hypothesis to underpin any proposed classification is unlikely.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 4. Effects on uterine and cervical epithelia.

Introduction: Steroid hormones are responsible for specific changes in the endometrium during the menstrual cycle, when they are sequentially secreted and, because of this, in the early days sequential combined oral contraceptive regimens were utilized. The same basic concept has been utilized with multi-phasic regimens, in order to produce endometrial pictures mimicking the normal cycle.Areas covered: The Endometrial effects of progestins and estrogens; combined monophasic high- (50 µg), medium- (30 µg), low- (20 µg), ultralow- (15 µg) estrogen content; sequential regimens; multiphasic combinations; treatment schedules.Cervical effects of combined high-dose and sequential combinations, including evidence for an increase in malignant lesions.Expert opinion: Overall, combined oral contraceptives (COCs) inhibit normal proliferative changes and the endometrium becomes thin, narrow, with widely spaced glands and pre-decidual changes in the stroma. During the first few cycles the progestin induces a coexistence of proliferative and secretory features; with time, the picture changes because the progestin induces a down-regulation of estrogen receptors, resulting in tortuous glands similar to those in the secretory phase, but characterized by a quiescent, atrophic glandular epithelium.In the cervical epithelium, under the influence of high-dose COCs, endocervical glands became hypersecretory and in some instances, distinctive type of atypical polypoid endocervical hyperplasia is found.

Placental bed research: II. Functional and immunological investigations of the placental bed.

Research on the placenta as the interface between the mother and the fetus has been undertaken for some 150 years, and in 2 subsequent reviews, we attempted to summarize the situation. In the first part, we described the discovery of unique physiological modifications of the uteroplacental spiral arteries, enabling them to cope with a major increase in blood flow necessary to ensure proper growth of the fetus. These consist of an invasion of the arterial walls by trophoblast and a progressive disappearance of its normal structure. Researchers then turned to the pathophysiology of the placental bed and in particular to its maternal vascular tree. This yielded vital information for a better understanding of the so-called great obstetrical syndromes (preeclampsia, fetal growth restriction, premature labor and delivery, placenta accreta). Systematic morphological investigations of the uteroplacental vasculature showed that preeclampsia is associated with decreased or failed transformation of spiral arteries and the persistence of endothelial and smooth muscle cells in segments of their myometrial portion. Here we report on recent functional investigations of the placental bed, including in situ biophysical studies of uteroplacental blood flow and vascular resistance, and manipulation of uteroplacental perfusion. These new methodologies have provided a novel way of identifying pregnancies in which remodeling is impaired. In animals it is now possible to manipulate uteroplacental blood flow, leading to an enhancement of fetal growth; this opens the way to trials in abnormal human pregnancies. In this second part, we explored a new, extremely important area of research that deals with the role of specific subsets of leukocytes and macrophages in the placental bed. The human first-trimester decidua is rich in leukocytes called uterine natural killer cells. Both macrophages and uterine natural killer cells increase in number from the secretory endometrium to early pregnancy and play a critical role in mediating the process of spiral artery transformation by inducing initial structural changes. It seems therefore that vascular remodeling of spiral arteries is initiated independently of trophoblast invasion. Dysregulation of the immune system may lead to reproductive failure or pregnancy complications, and in this respect, recent studies have advanced our understanding of the mechanisms regulating immunological tolerance during pregnancy, with several mechanisms being proposed for the development of tolerance to the semiallogeneic fetus. In particular, these include several strategies by which the trophoblast avoids maternal recognition. Finally, an important new dimension is being explored: the likelihood that pregnancy syndromes and impaired uteroplacental vascular remodeling may be linked to future maternal and even the child's cardiovascular disease risk. The functional evidence underlying these observations will be discussed.

Autoimmune diseases: Role of steroid hormones.

Autoimmune diseases (AIDs) are a heterogeneous group of disorders in terms of clinical manifestations, pathogenesis, and prevalence, and there is no agreement to date on a common classification. Adaptive immune responses are responsible for the existence of AIDs, although innate immunity is also involved in misguiding the immune response against self-antigens. Hormones, in general, and in particular steroid hormones, play a critical role in the physiology and pathology of the immune system, especially in adaptive immunity. Hormonal factors, alone or in relation to age, sex, and reproductive status, are involved in conditioning the onset of a number of AIDs. There is a well-defined sexual dimorphism for human AIDs. At the same time, the classic view has been that steroid hormones have well-defined effects, with one type, estrogens, being "pro-inflammatory" and the other two progestogens (progesterone and its synthetic analogs) and androgens being "anti-inflammatory." Although this view has been considered too simplistic and seems contradicted by numerous observations, it remains valid: progestogens and androgens are immunosuppressive and therefore protective against AIDs, whereas estrogens are immune-stimulatory and therefore pathogenic in AIDs.

Uncommon Mixed Endometrial-Myometrial Benign Tumors of the Reproductive Tract: Literature Review.

BACKGROUND: We reviewed published cases of uterus-like mass (U-LM), endomyometriosis, polypoid adenomyoma (PA), adenomyomatous polyp, atypical PA (APA), and adenomyoma. SEARCH METHODS: PubMed, Medline, and Scopus searches of all cases published in the databases till November 26, 2018. RESULTS: We identified 45 case reports of U-LM in the pelvis, 10 cases of endomyometriosis, 44 cases of adenomyomatous polyp, 466 cases of APA and case series of adenomyoma and PA. Most case reports focused on histological description of removed lesions with no or very limited clinical correlates. Histological descriptions were often used interchangeably, which creates considerable confusion. It is unclear if endomyometriosis warrants inclusions as a distinct entity, since the distinction is blurred between adenomyomatous polyp and PA. The glandular epithelium in atypical polypoid adenomyoma exhibits atypia and the lesions have a tendency to recur with a risk of malignant transformation. Smooth muscle metaplasia and Müllerian fusion defects have been proposed as etiology, but it is possible that the lesions do not share a common origin. CONCLUSION: There is need for more detailed and structured description of reported cases including clinical presentation and associated pathology.