The endometrium is ground zero when it comes to understanding how implantation occurs and how it might also fail, resulting in infertility or pregnancy loss. Many of the causes of diminished uterine ...receptivity are acquired during a woman's lifetime. Endometriosis, a major inflammatory disease affecting women, is also a leading cause of infertility and miscarriage. Once established, the inflammatory changes can, in some women, lead to progesterone resistance and downstream changes in endometrial gene expression. Much is now known about how inflammation translates to progesterone resistance and infertility, but much remains to be learned. In this review we provide an overview for understanding how the endometrium becomes dysfunctional, what biomarkers may hold promise for the diagnosis of endometriosis, and how progesterone resistance leads to infertility. Understanding the pathophysiology of this disease will likely lead to better treatment options.
Progesterone resistance, a known pathologic condition associated with a reduced cellular response to progesterone and heightened estrogen responses, appears to have a normal physiologic role in ...mammalian reproduction. The molecular mechanism responsible for progesterone resistance in normal and abnormal endometrium remains unclear.
To examine the roles of sirtuin-1 (SIRT1) in normal endometrium as well as endometrium associated with infertility and endometriosis, as an epigenetic modulator associated with progesterone resistance.
SIRT1 expression was examined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemistry in mouse uterus and human endometrium. Mice with uterine specific Sirt1 overexpression were developed to examine SIRT1's role in endometrial function and endometriosis development. EX-527, a SIRT1 inhibitor, and SRT1720, a SIRT1 agonist, were also used to evaluate SIRT1 effect on endometriosis.
In normal healthy women, endometrial SIRT1 is expressed only during menses. SIRT1 was dramatically overexpressed in the endometrium from women with endometriosis in both the epithelium and stroma. In mice, SIRT1 is expressed at the time of implantation between day 4.5 and 5.5 of pregnancy. Overexpression of SIRT1 in the mouse uterus leads to subfertility due to implantation failure, decidualization defects and progesterone resistance. SIRT1 overexpression in endometriotic lesions promotes worsening endometriosis development. EX-527 significantly reduced the number of endometriotic lesions in the mouse endometriosis model.
SIRT1 expression and progesterone resistance appears to play roles in normal endometrial functions. Aberrant SIRT1 expression contributes to progesterone resistance and may participate in the pathophysiology of endometriosis. SIRT1 is a novel and targetable protein for the diagnosis as well as treatment of endometriosis and the associated infertility seen in this disease.
Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus. It affects many women during their reproductive age, causing years of pelvic pain and potential ...infertility. Its pathophysiology remains largely unknown, which limits early diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared them to matched eutopic endometrium, unaffected endometrium and organoids derived from these tissues, generating data on over 122,000 cells across 14 individuals. We spatially localized many of the cell types using imaging mass cytometry. We identify a perivascular mural cell specific to the peritoneal lesions, with dual roles in angiogenesis promotion and immune cell trafficking. We define an immunotolerant peritoneal niche, fundamental differences in eutopic endometrium and between lesion microenvironments and an unreported progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment that represents a comprehensive cell atlas of the disease in individuals undergoing hormonal treatment, providing essential information for future therapeutics and diagnostics.
Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we ...perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10
), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.
Women with endometriosis typically present with pelvic pain, infertility, or an adnexal mass, and may require surgery. Treatment of endometriosis in the setting of infertility raises a number of ...complex clinical questions that do not have simple answers. This document replaces the 2006 ASRM Practice Committee document of the same name.
Abstract Objective(s) To evaluate the prevalence of adenomyosis in patients undergoing surgery for endometriosis. Study design Retrospective study including 1618 women with preoperative clinical and ...ultrasound diagnosis of endometriosis. As preoperative assessment, all patients underwent ultrasound to assess endometriosis and all features associated with adenomyosis (heterogeneous myometrial echotexture, globular-appearing uterus, asymmetrical thickness of anteroposterior wall of the myometrium, subendometrial myometrial cysts, subendometrial echogenic linear striations or poor definition of the endometrial–myometrial junction). Results Adenomyosis was present in 353/1618 (21.8%) women included in the study. Multivariate analysis showed that the prevalence of adenomyosis was significantly associated with deep infiltrating endometriosis, parity, dysmenorrhea intensity and women's age ( P < 0.0001). Conclusion(s) Adenomyosis is a common condition but its aetiology and natural history are still unknown. Our experience showed a 21.8% of prevalence of adenomyosis in patients affected by endometriosis and its association with parous women, increasing age, dysmenorrhea intensity and with the presence of deep infiltrating endometriosis.
STUDY QUESTION
Is the decreased natural killer (NK) cell cytolytic activity in the peritoneal fluid (PF) of endometriosis patients due to primary cytokine activity?
SUMMARY ANSWER
An increased level ...of interleukin-6 (IL-6) in the PF of patients with endometriosis suppresses NK cell cytolytic activity by down-regulating cytolytic granule components, such as granzyme B and perforin, through the modulation of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) expression.
WHAT IS ALREADY KNOWN
Endometriosis is known to be related to a defect in NK cell cytolytic activity. Additionally, the levels of inflammatory cytokines are elevated in the PF of women with endometriosis.
STUDY DESIGN, SIZE, DURATION
The effects of PF on the differentiation and functional activity of NK cells were investigated in patients with or without endometriosis, and cytokines that reduce NK cell cytolytic activity in endometriosis patients were examined. The study included women who underwent laparoscopic examination for the diagnosis of endometriosis from August 2012 to July 2013 (33 women with, and 15 women without, endometriosis).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women of reproductive age (20–40 years old) who underwent laparoscopic examination for endometriosis were included. Cytokines present in the PF were identified by enzyme-linked immunosorbent assay. The cytolytic activity of NK cells in the PF was also analyzed using a calcein-acetoxy methyl ester (AM) release assay.
MAIN RESULTS AND THE ROLE OF CHANCE
PF from patients with endometriosis suppressed the differentiation and cytotoxicity of NK cells compared with PF from controls (P < 0.05). Increased levels of IL-6 were also found in the PF of patients with endometriosis (P < 0.01), and IL-6 levels were negatively correlated with the cytolytic activity of NK cells (rs = −0.558, P = 0.03). Furthermore, IL-6 reduced the cytolytic activity of NK cells, concomitantly with the down-regulation of granzyme B and perforin (P < 0.05), by modulating SHP-2. Importantly, the addition of anti-IL-6 to the PF of endometriosis patients restored the activity of NK cells (P < 0.01), suggesting that IL-6 plays a crucial role in the reduction of NK cell activity in the PF of patients with endometriosis.
LIMITATIONS, REASONS FOR CAUTION
PF contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the differentiation and activity of NK cells.
WIDER IMPLICATIONS OF THE FINDINGS
Our results imply that the suppression of IL-6 using an anti-IL-6 antibody or soluble IL-6 receptor could rescue the impairment of NK cell activity in patients with endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the KRIBB Creative Research Program (KCS3051312); the STP project (DTM0111221) of the Ministry of Knowledge & Economy and the Basic Science Research Program (RBM0271312) of the National Research Foundation of Korea (NRF) from the Ministry of Education, Science & Technology. There are no conflicts of interest.
This article aims to provide a systematic review of estimates and methodology of studies quantifying the costs of endometriosis. Included studies were cost-of-illness analyses quantifying the ...economic impact of endometriosis and cost analyses calculating diagnostic and treatment costs of endometriosis. Annual healthcare costs and costs of productivity loss associated with endometriosis have been estimated at $2801 and $1023 per patient, respectively. Extrapolating these findings to the US population, this study calculated that annual costs of endometriosis attained $22 billion in 2002 assuming a 10% prevalence rate among women of reproductive age. These costs are considerably higher than those related to Crohn's disease or to migraine. To date, it is not possible to determine whether a medical approach is less expensive than a surgical approach to treating endometriosis in patients presenting with chronic pelvic pain. Evidence of endometriosis costs in infertile patients is largely lacking. Cost estimates were biased due to the absence of a control group of patients without endometriosis, inadequate consideration of endometriosis recurrence and restricted scope of costs. There is a need for more and better-designed studies that carry out longitudinal analyses of patients until the cessation of their symptoms or that model the chronic nature of endometriosis.
Deep endometriosis remains a source of controversy. A number of theories may explain its pathogenesis and many arguments support the hypothesis that genetic or epigenetic changes are a prerequisite ...for development of lesions into deep endometriosis. Deep endometriosis is frequently responsible for pelvic pain, dysmenorrhea, and/or deep dyspareunia, but can also cause obstetrical complications. Diagnosis may be improved by high-quality imaging. Therapeutic approaches are a source of contention as well. In this issue's Views and Reviews, medical and surgical strategies are discussed, and it is emphasized that treatment should be designed according to a patient's symptoms and individual needs. It is also vital that referral centers have the knowledge and experience to treat deep endometriosis medically and/or surgically. The debate must continue because emerging trends in therapy need to be followed and investigated for optimal management.
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