Endometriosis in the era of precision medicine and impact on sexual and reproductive health across the lifespan and in diverse populations

Abstract

Endometriosis is a common estrogen-dependent disorder wherein uterine lining tissue (endometrium) is found mainly in the pelvis where it causes inflammation, chronic pelvic pain, pain with intercourse and menses, and infertility. Recent evidence also supports a systemic inflammatory component that underlies associated co-morbidities, e.g., migraines and cardiovascular and autoimmune diseases. Genetics and environment contribute significantly to disease risk, and with the explosion of omics technologies, underlying mechanisms of symptoms are increasingly being elucidated, although novel and effective therapeutics for pain and infertility have lagged behind these advances. Moreover, there are stark disparities in diagnosis, access to care, and treatment among persons of color and transgender/nonbinary identity, socioeconomically disadvantaged populations, and adolescents, and a disturbing low awareness among health care providers, policymakers, and the lay public about endometriosis, which, if left undiagnosed and under-treated can lead to significant fibrosis, infertility, depression, and markedly diminished quality of life. This review summarizes endometriosis epidemiology, compelling evidence for its pathogenesis, mechanisms underlying its pathophysiology in the age of precision medicine, recent biomarker discovery, novel therapeutic approaches, and issues around reproductive justice for marginalized populations with this disorder spanning the past 100 years. As we enter the next revolution in health care and biomedical research, with rich molecular and clinical datasets, single-cell omics, and population-level data, endometriosis is well positioned to benefit from data-driven research leveraging computational and artificial intelligence approaches integrating data and predicting disease risk, diagnosis, response to medical and surgical therapies, and prognosis for recurrence.

Keywords: access; biomarkers; diagnosis; diversity; endometriosis; equity; health disparities; precision medicine; therapies.

FIGURE 1

Model of pelvic endometriosis pathogenesis and pathophysiology. Origins of endometriotic lesions include transplantation of endometrial tissue fragments and cells via retrograde menstruation and coelomic metaplasia of the peritoneal mesothelium; and stem and progenitor cell differentiation. Vascular and lymphatic metastasis likely give rise to disease in extra‐pelvic sites. When superficial and deeply invasive lesions develop, they are maintained via molecular mechanisms that promote cellular adhesion cell proliferation, a localized inflammatory response, immune dysregulation, neoneuroangiogenesis, and systemic and localized steroidogenesis. Dashed arrow shows postulated effects. ER, estrogen receptor; HSD17β2, 17β‐hydroxysteroid dehydrogenase 2; ICAM, intercellular adhesion molecule; IGF, insulin‐like growth factor; NF‐κB, nuclear factor κB; NGF, nerve growth factor; PR, progesterone receptor; SF1, steroidogenic factor; STAR, steroidogenic acute regulatory protein; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. From Ref. [3]: Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382(13):1244–1256. 10.1056/NEJMra1810764, with permission.

FIGURE 2

Theories regarding endometriosis pathogenesis. Multiple theories of endometriosis prevail and shown here include: retrograde deposition of menstrual blood and tissue into the pelvis, lymphatic and/or hematogenous spread to distant sites, bone marrow mesenchymal and hematopoietic stem cell migration to the pelvic cavity and/or endometrium, endothelial cell transformation to endometrial cells, induction of disease by remnant Mullerian rests, metaplasia of mesothelium by uncertain triggers, and estrogenic endocrine disrupters, excessive estradiol (E2), inflammation accompanying and sustaining disease, and a genetic predisposition to disease. From Ref. [4]: Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility. 2012;98(3):511–519. 10.1016/j.fertnstert.2012.06.029, with permission.

FIGURE 3

Models of inflammation and aberrant steroid hormone signaling in the pathophysiology of endometriosis. A. Inflammation, enhanced estrogen signaling. Panel A depicts retrograde menstruation resulting in inflammatory stress and associated cytokines, inflammatory mediators, and macrophage recruitment to lesions, altered nuclear receptors and co‐activators, and methylation defects resulting in altered gene transcription and enhanced estrogen signaling. B. Mechanisms of disrupted progesterone signaling. Mechanisms include (indicated by numbers in ovals): (1) Inhibition of PR transcription by increased PG promotor DNAme and altered DMNT1 and DMNT3A and B; (2) stimulation of cell membrane receptors by hormones, cytokines, and growth factors; (3) activation of AKT, ERK1, MAPK that suppress PR activity via increased phosphorylation and degradation via proteasome pathways; (4) Inflammation stimulates NF‐kB activation and NF‐kB interacts with PR, leading to reduced PR expression; and (5) Non‐AKT, MEK, ligand binding‐induced degradation can also regulate PR protein levels. AKT, akt serine/threonine protein kinase; AROM, aromatase; COX‐2, cyclooxygenase 2; DMNT, DNA methyl transferase; DNAme, DNA methylation, EGF, epidermal growth factor; E₂, estradiol; ERβ, estrogen receptor beta; ERK1, extracellular signal‐regulated kinase; FGF, fibroblast growth factor; Il1b, interleukin 1 beta; MAPK, mitogen‐activated protein kinase; mir, microRNA; NF‐kB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; PGE₂, prostaglandin E2; PR, progesterone receptor; pPR, phosphorylated PR; RARs, retinoic acid receptors; SF1, steroidogenic factor 1; SRC‐1, steroid receptor coactivator‐1; TNF‐α, tumor necrosis factor alpha. Adapted from Ref. [54]: Dyson MT, Bulun SE. Cutting SRC‐1 down to size in endometriosis. Nat Med. 2012;18(7):1016–1018. doi:10.1038/nm.2855 (Panel A), with permission, and from Ref. [55]: McKinnon B, Mueller M, Montgomery G. Progesterone resistance in endometriosis: an acquired property? Trends Endocrinol Metab. 2018;29(8):535–548. 10.1016/j.tem.2018.05.006 (Panel B), with permission.

FIGURE 4

Models of inflammation leading to pain and infertility. Panel A: Inflammatory environment in the peritoneal cavity leading to disease formation and pain symptoms; Panel B: inflammatory environment affecting the ovary relevant to fertility; Panel C: inflammation in the uterine cavity leading to compromised embryo implantation and predisposing to poor pregnancy outcomes and dysregulated tissue homeostasis (See text for details). From Ref. [71]: Lin YH, Chen YH, Chang HY, Au HK, Tzeng CR, Huang YH. Chronic Niche Inflammation in Endometriosis‐Associated Infertility: Current Understanding and Future Therapeutic Strategies. Int J Mol Sci. 2018;19(8). 10.3390/ijms19082385, with permission.

FIGURE 5

Algorithm for clinical diagnosis of endometriosis. The algorithm shows sequence of clinical diagnosis beginning with evaluation of symptoms (section 1), review patient history (section 2), perform physical examination (section 3), and performing/order imaging (section 4). Items on the left side of the figure are informative about possible endometriosis diagnosis. Items on the right side may co‐exist with endometriosis but do not rule it out. From Ref. [115]: Agarwal SK, Chapron C, Giudice LC, et al. Clinical diagnosis of endometriosis: a call to action. Am J Obstet Gynecol. 2019;220(4):354.e1‐354.

FIGURE 6

Some medical therapies for endometriosis‐related pelvic pain. The figure shows classes of drugs to treat endometriosis‐related pain, ranging from NSAIDs, CHCs, progestins, GnRH analogs, aromatase inhibitors, danazol, SERMs, and SPRMs. CHCs, combined hormonal contraceptives; GnRH, gonadotropin‐releasing hormone; LH, luteinizing hormone; NSAIDs, non‐steroidal anti‐inflammatory drugs; P₄, progesterone; SERMs, selective estrogen receptor modulators; SPRMs, selective progesterone receptor modulators.

FIGURE 7

Potential indications for artificial intelligence applications in endometriosis. Artificial intelligence, combining supervised and unsupervised machine learning and natural language processing, with foundational input selections, training, and validation, is proposed to lead to improved diagnostics, therapeutics, post‐operative outcome predictions, disease pathophysiology understanding, and phenotyping of endometriosis. From Ref. [202]: Sivajohan B, Elgendi M, Menon C, Allaire C, Yong P, Bedaiwy MA. Clinical use of artificial intelligence in endometriosis: a scoping review. NPJ Digit Med. 2022;5(1):1–17. 10.1038/s41746‐022‐00638‐1, with permission.