Various types of adenomyosis and endometriosis: in search of optimal management.
Fertility and sterility
Currently, hormonal drugs are the mainstay for treating endometriosis or adenomyosis. Aside from staying within the "therapeutic window" and cutting off the hormonal support to the ectopic endometrium, none of these treatments were developed with a previously identified target. The current lack of innovation is humbling, especially considering that among >34,000 PubMed-indexed publications on endometriosis or adenomyosis, approximately 65% of them were published in the last 2 decades, many of them presumably with all the benefits of omics and molecular biology. One major reason for so many doomed research and development (R&D) projects on nonhormonal drugs is the failure to understand the natural history of the ectopic endometrium. Other reasons include, but are not limited to, the number of side effects that these nonhormonal drug candidates presented, which the developers were either unaware of or simply had ignored when pursuing a too narrowly minded development-a common cognitive trap known as invisible gorillas. Unless we have a clear global picture with a good grasp of the natural history of ectopic endometrium, "potholes" and "blind alleys" in drug R&D are difficult to avoid. This review shall explore some new concepts in the progression of ectopic endometrium and explain how these new perspectives offer insights for devising better therapeutic options, explain why some drug R&D projects for endometriosis or adenomyosis have failed, provide a critical analysis of some issues encountered in everyday practice, expose knowledge gaps in need of further research, and, finally, offer possible ways to circumvent hurdles and potholes and avoid cul-de-sacs in nonhormonal drug R&D.
10.1016/j.fertnstert.2023.03.021
Metabolomics for the identification of biomarkers in endometriosis.
Archives of gynecology and obstetrics
BACKGROUND:Endometriosis affects the quality of life in women during their reproductive years, causing immense pain and can result in infertility. It is characterized by inflammation and the growth of the endometrium outside the uterine cavity. Metabolomics has the potential to resolve the major bottleneck of endometriosis which is delay in diagnosis due to the invasive diagnostic approach.In this review, the author has summarized the identified biomarkers of endometriosis from different bodily fluids. Metabolomics promises a non-invasive diagnostic approach for endometriosis that could aid in earlier diagnosis and prognosis. METHODS:Patients with endometriosis keywords were searched in correspondence with the assigned keywords, including metabolomics from PubMed, from its inception to Dec 2023. The relevant studies from this search were extracted and included in the study. RESULTS:This article provides information regarding metabolomics studies in endometrisis. CONCLUSIONS:We demonstrated that metabolomics is about to change the world of endometriosis by analyzing and detecting the diagnosis, prognosis, mortality and treatment response biomarkers.
10.1007/s00404-024-07796-5
Nonsurgical approaches to the diagnosis and evaluation of endometriosis.
Fertility and sterility
An inability to make the diagnosis of endometriosis or evaluate lesion response to treatment without surgery is a clear impediment to understanding the disease and to developing new therapies. The need is particularly strong for rASRM Stage 1 or 2 disease, since higher stage (rASRM Stage 3 or 4) endometriosis can often be diagnosed by ultrasound or other imaging techniques. Despite promising findings in association studies, no biomarkers or nonsurgical diagnostic or evaluation methods for Stage 1 or Stage 2 endometriosis has yet been clinically validated. Admittedly, validation is difficult, since surgery is required as a gold standard diagnostic method for comparison. This manuscript is aimed as a succinct review of what is known about nonsurgical approaches to detect and assess endometriosis, with an emphasis on Stage 1 and 2.
10.1016/j.fertnstert.2023.12.020
Endometriosis: Future Biological Perspectives for Diagnosis and Treatment.
International journal of molecular sciences
Endometriosis is an oestrogen-dependent inflammatory disease affecting menstruating women, with varying levels of severity. Oestrogen dysregulation is responsible for chronic inflammation, angiogenesis, endometrial lesion development, progression, and infertility during menarche in afflicted women. The inflammatory mediators associated with this chronic painful disease have been established, with research also indicating the relationship between dysbiosis and disease manifestation. Endometriosis is also present with several painful comorbidities, including endometrial cancer, cardiovascular disease, and autoimmunity. The lack of specific and sensitive non-invasive diagnostic procedures, coupled with poor response to current therapeutic approaches, means that treatment needs remain unmet. Surgical procedures are performed to remove endometriosis ectopic lesions, for which the recurrence rate of disease is up to 50%, with certain patients exhibiting no alleviation of symptoms. This review aims to outline the aetiology of endometriosis, detailing novel diagnostic approaches and potential therapeutic approaches, namely advanced therapeutic medical products (ATMPs), including stem cell therapy and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing. This timely review also provides novel insights into the important recent modalities which may be applied for the diagnosis and therapeutic response of endometriosis, including biomarkers, microfluidic platforms, and organoid systems. Undoubtedly, reliable, reproducible, sensitive, and specific models of endometriosis in humans are urgently needed to investigate and detail the aetiology of this debilitating disease.
10.3390/ijms252212242
The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study.
BMC medicine
BACKGROUND:Endometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6-10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis. METHODS:To investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran's Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis. RESULTS:Our two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses. CONCLUSIONS:Our MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.
10.1186/s12916-023-02881-z
Endometriosis: pathogenesis and treatment.
Vercellini Paolo,Viganò Paola,Somigliana Edgardo,Fedele Luigi
Nature reviews. Endocrinology
Endometriosis is defined as the presence of endometrial-type mucosa outside the uterine cavity. Of the proposed pathogenic theories (retrograde menstruation, coelomic metaplasia and Müllerian remnants), none explain all the different types of endometriosis. According to the most convincing model, the retrograde menstruation hypothesis, endometrial fragments reaching the pelvis via transtubal retrograde flow, implant onto the peritoneum and abdominal organs, proliferate and cause chronic inflammation with formation of adhesions. The number and amount of menstrual flows together with genetic and environmental factors determines the degree of phenotypic expression of the disease. Endometriosis is estrogen-dependent, manifests during reproductive years and is associated with pain and infertility. Dysmenorrhoea, deep dyspareunia, dyschezia and dysuria are the most frequently reported symptoms. Standard diagnosis is carried out by direct visualization and histologic examination of lesions. Pain can be treated by excising peritoneal implants, deep nodules and ovarian cysts, or inducing lesion suppression by abolishing ovulation and menstruation through hormonal manipulation with progestins, oral contraceptives and gonadotropin-releasing hormone agonists. Medical therapy is symptomatic, not cytoreductive; surgery is associated with high recurrence rates. Although lesion eradication is considered a fertility-enhancing procedure, the benefit on reproductive performance is moderate. Assisted reproductive technologies constitute a valid alternative. Endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer, but preventive interventions are feasible.
10.1038/nrendo.2013.255
Endometriosis is a chronic systemic disease: clinical challenges and novel innovations.
Taylor Hugh S,Kotlyar Alexander M,Flores Valerie A
Lancet (London, England)
Endometriosis is a common disease affecting 5-10% of women of reproductive age globally. However, despite its prevalence, diagnosis is typically delayed by years, misdiagnosis is common, and delivery of effective therapy is prolonged. Identification and prompt treatment of endometriosis are essential and facilitated by accurate clinical diagnosis. Endometriosis is classically defined as a chronic, gynaecological disease characterised by endometrial-like tissue present outside of the uterus and is thought to arise by retrograde menstruation. However, this description is outdated and no longer reflects the true scope and manifestations of the disease. The clinical presentation is varied, the presence of pelvic lesions is heterogeneous, and the manifestations of the disease outside of the female reproductive tract remain poorly understood. Endometriosis is now considered a systemic disease rather than a disease predominantly affecting the pelvis. Endometriosis affects metabolism in liver and adipose tissue, leads to systemic inflammation, and alters gene expression in the brain that causes pain sensitisation and mood disorders. The full effect of the disease is not fully recognised and goes far beyond the pelvis. Recognition of the full scope of the disease will facilitate clinical diagnosis and allow for more comprehensive treatment than currently available. Progestins and low-dose oral contraceptives are unsuccessful in a third of symptomatic women globally, probably as a result of progesterone resistance. Oral gonadotropin-releasing hormone (GnRH) antagonists constitute an effective and tolerable therapeutic alternative when first-line medications do not work. The development of GnRH antagonists has resulted in oral drugs that have fewer side-effects than other therapies and has allowed for rapid movement between treatments to optimise and personalise endometriosis care. In this Review, we discuss the latest understanding of endometriosis as a systemic disease with multiple manifestations outside the parameters of classic gynaecological disease.
10.1016/S0140-6736(21)00389-5
Rethinking mechanisms, diagnosis and management of endometriosis.
Chapron Charles,Marcellin Louis,Borghese Bruno,Santulli Pietro
Nature reviews. Endocrinology
Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility. This disease should be viewed as a public health problem with a major effect on the quality of life of women as well as being a substantial economic burden. In light of the considerable progress with diagnostic imaging (for example, transvaginal ultrasound and MRI), exploratory laparoscopy should no longer be used to diagnose endometriotic lesions. Instead, diagnosis of endometriosis should be based on a structured process involving the combination of patient interviews, clinical examination and imaging. Notably, a diagnosis of endometriosis often leads to immediate surgery. Therefore, rethinking the diagnosis and management of endometriosis is warranted. Instead of assessing endometriosis on the day of the diagnosis, gynaecologists should consider the patient's 'endometriosis life'. Medical treatment is the first-line therapeutic option for patients with pelvic pain and no desire for immediate pregnancy. In women with infertility, careful consideration should be made regarding whether to provide assisted reproductive technologies prior to performing endometriosis surgery. Modern endometriosis management should be individualized with a patient-centred, multi-modal and interdisciplinary integrated approach.
10.1038/s41574-019-0245-z