Endometriosis

Etiology

Endometriosis develops through a combination of hormonal and inflammatory mechanisms. Endometriosis is a multifactorial condition with no single explanatory mechanism. Several theories have been proposed. The most widely accepted theory is retrograde menstruation, in which viable endometrial cells reflux through the fallopian tubes and implant within the peritoneal cavity; however, as this occurs in many individuals without disease, additional factors are necessary for lesion development. Alternative mechanisms include coelomic metaplasia, stem cell recruitment theory, embryogenetic, and lymphatic or hematogenous dissemination, which may account for extrapelvic disease. The following are the proposed theories of the etiology of endometriosis, as well as the possible mechanisms involved:

• Retrograde menstruation: This theory was first described by Sampson. Menstrual tissue flows backward through the fallopian tubes into the pelvic cavity, where endometrial cells implant and grow on peritoneal surfaces.[6][7][6]
• Coelomic metaplasia: Cells lining the peritoneum transform into endometrial-like tissue in response to specific biological or environmental influences.[6][7][6]
• Hematogenous/lymphatic dissemination: Endometrial cells spread through blood vessels or lymphatic channels, leading to implantation at distant or extrapelvic sites.
• Stem cell recruitment: Circulating or endometrial stem/progenitor cells migrate and differentiate into endometriotic lesions at various locations.
• Embryologic (Müllerian/Wolffian remnant): Residual embryonic ductal cells persist and later develop into endometriotic tissue, potentially stimulated by hormonal factors, eg, estrogen.[6][7][6]

Epidemiology

Endometriosis affects an estimated 10% of reproductive-aged females worldwide, making it one of the most common gynecologic disorders. In the United States, approximately 9 million females have endometriosis.[8] Worldwide, endometriosis affects 190 million reproductive-aged females.[9][10] Prevalence is substantially higher, up to 35% to 50%, among patients with chronic pelvic pain or infertility. The disease is most often diagnosed in females between the ages of 25 and 45, though symptoms frequently begin in adolescence.[11]

The risk for developing endometriosis is increased in individuals with early menarche (before age 10), short menstrual cycles, heavy or prolonged bleeding, low body mass index (BMI), nulliparity, and a first-degree family history, reflecting both hormonal and genetic influences. Endometriosis occurs across all racial and ethnic groups, though diagnostic delays and access to care vary widely.[12][13] Additional potential risk factors include Müllerian duct anomalies and prenatal exposure to diethylstilbestrol. Genetic contributions are supported by twin studies and genome-wide analyses, with a family history of endometriosis in a first-degree relative increasing the risk by 3- to 9-fold.[14]

Pathophysiology

Endometriosis involves disturbances of the immune system, including both adaptive and innate immunity.[15] Disease establishment and progression are influenced by stem/progenitor cells, a proinflammatory peritoneal environment, and immune dysregulation, contributing to lesion persistence and survival. Immune dysregulation, with elevated inflammatory cytokines and macrophage activation, sustains local inflammation, while genetic, epigenetic, and environmental factors modulate individual susceptibility and disease heterogeneity.[11][16][17][11] These ectopic implants are driven by estradiol, which promotes cellular proliferation, adhesion, fibrosis, inflammation, immune dysfunction, and the development of neovascularization and neurogenesis. Beyond the lesions themselves, systemic and local alterations occur, including disrupted immune function and progesterone signaling within the eutopic endometrium, as well as increased inflammatory and angiogenic activity within the pelvic peritoneal environment.[8]

Histopathology

Histopathologic evaluation remains the gold standard for confirming the diagnosis of endometriosis. Classic microscopic findings include endometrial-type glands and stroma located outside the uterine cavity, often accompanied by hemorrhage, hemosiderin-laden macrophages, fibrosis, and chronic inflammatory changes. However, lesion morphology is variable, and some specimens may show only partial features, particularly in longstanding or hormonally suppressed disease, thereby reducing diagnostic sensitivity.[18] Ovarian endometrioma, superficial peritoneal endometriosis, and deep infiltrating endometriosis comprise the 3 different endometriosis phenotypes.[19]

Recent molecular studies further demonstrate that eutopic endometrium commonly acquires somatic mutations, particularly within epithelial cells, beginning early in life and increasing with age. Mutations in genes, eg, PIK3CA, are frequently observed across individuals, while alterations in KRAS appear more prevalent in patients with endometriosis. Notably, endometriotic lesions often share identical epithelial mutations with the patient’s eutopic endometrium, supporting a clonal origin in which mutated endometrial cells implant and persist outside the uterus. These findings highlight the biologic heterogeneity of the disease and underscore the importance of integrating histopathologic, clinical, and molecular data in diagnosis and management.[18]

History and Physical

Endometriosis most often affects females in their 20s to 40s, with a higher prevalence in caucasian patients. The hallmark symptoms are chronic, cyclic pelvic pain, dysmenorrhea, dyspareunia, dyschezia, dysuria, and infertility, though symptom severity does not correlate with disease extent. Some patients develop neuropathic pain or allodynia, especially with deep infiltrating disease involving nerve fibers.[20] Physical exam may reveal uterine or adnexal tenderness, reduced uterine mobility, uterosacral ligament nodularity, or adnexal masses from ovarian endometriomas. Bowel or rectovaginal involvement can produce gastrointestinal symptoms or cyclic rectal bleeding, whereas superficial peritoneal lesions may be asymptomatic and found incidentally.[21][1]

Endometriosis commonly presents with pelvic pain, affecting the vast majority of diagnosed individuals, while many also report significant fatigue and a substantial proportion experience infertility. The condition is associated with reduced quality of life and imposes a significant economic burden in the United States due to both healthcare costs and lost productivity. Diagnosis is frequently delayed, often taking several years from initial symptom onset, with many patients consulting multiple clinicians before the condition is identified and confirmed.[8][22]

Evaluation

The initial assessment for endometriosis should include a comprehensive review of the patient’s medical, gynecologic, menstrual, and family history, along with a thorough evaluation of symptoms. This includes the location, severity, frequency, and duration of pain or other symptoms, as well as their impact on quality of life. While many symptoms overlap with other gynecologic or nongynecologic conditions, the presence of multiple characteristic symptoms increases the likelihood of endometriosis and warrants further investigation. Pain can be quantified using tools, eg, a visual analog scale or numerical rating scale, and validated symptom questionnaires may support history-taking and help patients communicate how symptoms affect daily functioning and quality of life.[14][20]

Imaging in Endometriosis Evaluation

Transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) are the primary imaging tools for evaluating suspected endometriosis. Imaging is recommended early, even when physical examination is normal, to detect endometriomas and deep pelvic lesions, identify other potential causes of pelvic pain, guide management decisions, and assist with preoperative planning. Empiric medical therapy should begin alongside imaging to avoid delays in symptom relief.[14]

TVUS is the preferred first-line modality due to its accessibility, lower cost, and accuracy comparable to MRI, particularly for identifying endometriomas.[23] Examination should include assessment of the uterus, ovaries, fallopian tubes, anterior and posterior pelvic compartments, and peritoneum, as well as evaluation for ultrasonographic markers of deep disease (eg, abnormal organ mobility, bowel tethering, adenomyosis). TVUS has high specificity but variable sensitivity, performing best for endometriomas and moderate for deep endometriosis; superficial peritoneal lesions are often missed. TVUS can also aid preoperative staging, particularly in identifying early- and late-stage disease.[14]

MRI is recommended as a secondary imaging option when further characterization of deep endometriosis is required, such as for surgical planning.[23] MRI generally provides greater sensitivity for deep lesions, including the uterosacral ligaments and vaginal wall, but like TVUS, MRI is limited in detecting superficial peritoneal disease. Both imaging modalities are influenced by operator expertise, and negative imaging results do not exclude endometriosis; symptomatic patients should still be considered for treatment regardless of findings.[14]

Historically, endometriosis diagnosis depended on surgical confirmation, which often delays treatment and overlooks its systemic, chronic nature.[22] While laparoscopy remains useful in certain cases, current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional societies emphasize the use of patient history, symptom assessment, and physical examination to make a clinical diagnosis. This approach allows for earlier intervention and management, without waiting for surgical confirmation.[14]

Diagnostic Laparoscopy in Endometriosis

The decision to perform diagnostic laparoscopy versus initiating empiric medical therapy should be individualized through shared decision-making, weighing the benefits and risks of each approach. While laparoscopy can confirm endometriosis even when physical exam and imaging are inconclusive, laparoscopy is not required to start medical treatment. Laparoscopy may be particularly useful when the diagnosis is uncertain, when patients want definitive confirmation, or if symptoms persist despite empiric therapy. It also allows identification and treatment of other causes of pelvic pain.[14]

Surgical evaluation should be conducted by a clinician experienced in endometriosis, with systematic inspection of the pelvis and documentation of lesion appearance, location, extent, and disease stage. Lesions can vary in color and morphology, with differences noted between adult and adolescent patients. Biopsy of suspicious lesions is recommended for histopathologic confirmation; however, a negative result does not exclude disease, as sampling limitations, prior hormonal therapy, or superficial lesion characteristics can yield false negatives. Visual diagnosis alone may sometimes suffice to guide treatment.[14]

Early superficial endometriotic lesions may appear clear or translucent at laparoscopy before the development of new blood vessels. As inflammation in the peritoneal environment increases, local estrogen production and inflammatory mediators promote cellular proliferation and angiogenesis, causing lesions to appear red. As blood breakdown products accumulate, lesions darken to brown or black. Over time, these lesions may become pale or white as fibrosis develops and pigment is replaced by scar tissue, often decreasing in size as stromal elements are lost.[23] Older lesions may regress, while new lesions form in other areas, contributing to a dynamic disease process. Overall, superficial endometriosis can present with a range of laparoscopic appearances, including clear vesicles, red inflammatory lesions, dark “powder-burn” spots, and fibrotic plaques.[24][14][24]

Atypical endometriosis is a precursor to endometriosis-associated ovarian cancer, most commonly endometrioid and clear-cell ovarian cancer types. Because of this association, biopsy with histopathologic analysis is advised when malignancy is suspected.[25] Concurrent treatment of lesions during laparoscopy is recommended whenever feasible to reduce the need for repeat surgery. Preoperative imaging can support surgical planning and improve intraoperative decision-making.[14]

Treatment / Management

Management of endometriosis follows a stepwise approach that includes medical therapy, surgical intervention, and interprofessional support, consistent with major national and international guidelines from ACOG, ESHRE, and the National Institute for Health and Care Excellence (NICE).[26] Treatment is individualized based on symptom severity, fertility goals, lesion location, and patient preference. Because endometriosis is a chronic inflammatory condition, therapy focuses on symptom control, improving quality of life, and optimizing fertility, rather than a cure.[4](B3)

Recent updates in clinical guidelines and expanding pharmacologic evidence have refined the management of endometriosis. First-line treatments, including nonsteroidal anti-inflammatory drugs, combined hormonal contraceptives, and progestins, eg, dienogest, remain foundational for symptom control. For patients with persistent or refractory symptoms, additional options include GnRH agonists and antagonists, aromatase inhibitors, and the use of add-back therapy to mitigate adverse effects. Emerging therapies targeting inflammation, fibrosis, angiogenesis, and the microbiome are under investigation. Future management is expected to move toward more individualized care, incorporating precision medicine approaches, nonhormonal therapies, and advanced tools to support fertility-focused, patient-centered treatment strategies.[27](B3)

Medical Management

Medical therapy is appropriate for patients with pain symptoms and may be initiated without surgical confirmation of endometriosis, a practice supported by updated ACOG guidance. Medical therapy does not usually enhance fertility, so patients desiring pregnancy may require surgical or assisted reproductive approaches.

First-line therapy

The following options are preferred treatments for endometriosis as these agents suppress ovulation, reduce estrogen-driven proliferation, and decrease inflammatory activity:

• Combined hormonal contraceptives (cyclic or continuous pills, patches, or ring)
• Progestins (norethindrone, medroxyprogesterone acetate, dienogest)
• NSAIDs for analgesia

Second-line therapy

The following agents induce a hypoestrogenic state and are effective for pain, but are less favored due to notable adverse-effect profiles and do not improve fertility:

• GnRH agonists (leuprolide, goserelin) with or without add-back therapy (estrogen or progestin)
• GnRH antagonists (elagolix, relugolix) 
• Danazol (limited by androgenic adverse effects and rarely used currently) [28]
(B3)

An off-label option for third-line refractory cases includes medical therapy with aromatase inhibitors like letrozole (used in select refractory cases, often with combined hormonal contraceptives, progestogens, GnRH agonists, or GnRH antagonists).[29] Overall, GnRH antagonist therapy has been shown to specifically reduce non-menstrual pelvic pain, while dienogest was most beneficial for dyspareunia treatment, and GnRH agonists have the poorest safety profile.[30](A1)

Oral medications like cyclobenzaprine, which share similarities with tricyclic antidepressants, can help decrease overall muscle tension and are frequently administered at night due to their calming, sedative effects. For more targeted relief, intravaginal muscle relaxants, eg, diazepam or baclofen, can be used in suppository or compounded cream formulations. These are generally well tolerated, with drowsiness being the most commonly reported adverse effect. Additionally, internal application of topical lidocaine may help alleviate discomfort during sexual activity or before pelvic floor physical therapy sessions that involve internal manual techniques.[26]

Surgical Management

Surgery is considered for patients with persistent pain, infertility, or anatomically significant disease. NICE guidelines emphasize offering surgery when symptoms are refractory or when fertility is a priority. Laparoscopic excision or ablation of lesions is the standard first-line approach. Excision reduces inflammatory burden and may improve spontaneous conception rates. Ovarian endometriomas are treated with cystectomy as the preferred method over drainage or ablation due to lower recurrence and better pain control, though it may reduce ovarian reserve. Deep infiltrating endometriosis requires specialized surgical expertise and may involve resection of bowel, bladder, or ureteral lesions when symptomatic. Surgery carries risks, and decisions should be made collaboratively, balancing symptom relief, fertility goals, and potential complications.[31](B2)

Interprofessional and Supportive Care

Optimal management often includes:

• Pelvic floor physical therapy
• Pain management specialists
• Gastroenterology or urology for organ-specific involvement
• Reproductive endocrinology for fertility planning

Updated ACOG recommendations emphasize earlier diagnosis, symptom-based treatment, and improved access to care, reflecting a shift toward reducing diagnostic delay and initiating appropriate therapy sooner.[32] 

Management of deep infiltrating endometriosis should be individualized based on symptom severity, disease extent, fertility goals, and comorbidities. As mentioned above, medical therapy, including combined hormonal contraceptives, progestins, and GnRH agonists or antagonists, aims to suppress estrogen activity, reduce inflammation, and improve pain, with most patients experiencing at least partial symptom relief. Hormonal suppression is also useful for preventing recurrence, particularly in patients not seeking immediate pregnancy.[19]

Surgery is often indicated for patients with persistent symptoms, organ involvement (especially bowel or urinary tract), or failure of medical therapy. The goal is to remove lesions and restore normal anatomy while preserving function. Surgical options range from conservative approaches (eg, shaving or disc excision) to more extensive procedures such as segmental bowel resection, depending on lesion size, depth, and location. Conservative techniques are generally associated with fewer complications and better functional outcomes. In contrast, more radical surgery may be necessary for large, obstructive, or multifocal disease but carries higher risks, including fistula, anastomotic leak, and bowel dysfunction.[19]

Decision-making should incorporate symptoms, imaging findings, and patient preferences, with careful counseling regarding risks, benefits, and potential impact on quality of life. An interprofessional approach is often required, particularly for complex diseases involving the bowel, urinary tract, or pelvic nerves.[19]

A recent network meta-analysis compared multiple pharmacologic approaches for managing endometriosis-related pain, providing practical insights for clinical decision-making. The combination of leuprolide with a combined oral contraceptive (OCP) demonstrated the greatest effectiveness for pelvic pain, likely due to synergistic suppression of sex hormone production. While combined OCPs alone are ineffective in roughly one-third of patients and may lose efficacy over time, they remain a low-cost, well-tolerated option within combination regimens.[33](A1)

For dysmenorrhea, elagolix showed the strongest benefit, consistent with its role in suppressing pituitary GnRH receptor activity and lowering estrogen and progesterone levels. Dyspareunia was alleviated by antioxidant therapy, including vitamins C and E, which reduce oxidative stress and the release of inflammatory mediators. Nonmenstrual pelvic pain responded best to gestrinone, a synthetic steroid with anti-estrogenic and weak androgenic properties, which decreases estrogen through inhibition of pituitary gonadotropins, thereby limiting ectopic endometrial growth.[33](A1)

Combination therapies, including relugolix or elagolix with OCP or add-back therapy, were generally less effective than monotherapy for pelvic pain and dyspareunia, likely due to interactions that disrupt hypothalamic-pituitary-gonadal regulation. These findings highlight the need to tailor treatment plans to individual patients' symptoms, drug efficacy, safety profiles, and personal preferences.[33](A1)

Differential Diagnosis

Endometriosis must be distinguished from other causes of infertility and chronic cyclic pelvic pain, including:

• Primary dysmenorrhea
• Adenomyosis
• Uterine fibroids
• Cervical stenosis
• Pelvic inflammatory disease
• Endometritis
• Pelvic adhesions
• Ovarian cysts
• Irritable bowel syndrome
• Constipation
• Inflammatory bowel disease
• Appendiceal pathology
• Interstitial cystitis
• Recurrent urinary tract infections
• Ureteral stones or obstruction with pelvic floor myalgia
• Pudendal neuralgia
• Lumbar or sacroiliac disorders within the neurologic and musculoskeletal systems

Psychosocial contributors, eg, somatic symptom disorders and central sensitization, may mimic or amplify pelvic pain, and in reproductive-age patients, ectopic pregnancy and early pregnancy complications must also be excluded.[34]

Pertinent Studies and Ongoing Trials

Several studies and ongoing clinical trials have evaluated the efficacy of reproductive and hormonal therapies in managing endometriosis-related pain and fertility outcomes. Evidence demonstrates that reproductive and hormonal therapies, including combined hormonal contraceptives, progestins, and gonadotropin-releasing hormone agonists, can reduce lesion-associated inflammation, decrease pain, and improve quality of life. Randomized controlled trials and longitudinal studies support reproductive and hormonal therapies as a first-line strategy for symptom control and as an adjunct for patients seeking fertility, with ongoing trials investigating optimized regimens, long-term safety, and combination approaches to further improve both pain and reproductive outcomes.[35]

Endometriosis is common but has a highly variable presentation, and diagnosis is challenging due to the lack of reliable noninvasive biomarkers. Early and accurate detection is essential for optimal management. Emerging noninvasive approaches under investigation include blood-based assays, immunomodulatory strategies, stem cell therapies, biosensors, and nanotechnology-based diagnostics.[36]

Toxicity and Adverse Effect Management

Toxicities associated with endometriosis management arise not only from the disease process but also from the adverse-effect profiles of hormonal therapies, analgesics, and surgical interventions. Combined estrogen–progestin regimens may cause breakthrough bleeding, breast tenderness, nausea, mood changes, and an increased risk of thromboembolism. Progestin-only therapies can lead to irregular bleeding, weight or mood changes, and acne. With depomedroxyprogesterone, reversible bone mineral density loss, weight gain, and a small increased risk of meningiomas with prolonged use have been associated.

GnRH agonists and antagonists produce hypoestrogenic effects, eg, vasomotor symptoms, vaginal dryness, sleep disturbance, mood changes, and accelerated bone loss, often requiring add-back therapy with estrogen or progesterone to mitigate symptoms and protect bone health. Aromatase inhibitors may contribute to arthralgias, hot flashes, fatigue, and bone loss when used without ovarian suppression. Analgesic strategies, including NSAIDs and neuromodulators, carry risks of gastrointestinal irritation, renal effects, sedation, dizziness, and weight or mood changes.

Surgical management, particularly excision of deep infiltrating disease, may result in bleeding, infection, injury to bowel, bladder, or ureters, adhesion formation, and reduced ovarian reserve after ovarian endometrioma cystectomy. Chronic pain, infertility, and repeated interventions may also contribute to anxiety, depression, and sexual dysfunction, underscoring the need for anticipatory counseling, interprofessional care, and early integration of pelvic floor physical therapy and psychosocial support.[37][38]

Some patients with endometriosis-related chronic pelvic pain receive opioids, with these women being significantly more likely than those without endometriosis to use them, often at higher doses or alongside benzodiazepines. Their risk of developing long-term opioid dependence is substantially increased. Evidence supporting chronic opioid therapy for pelvic pain is limited, and potential harms, eg, immune suppression, hormonal disturbances, and increased pain sensitivity, likely outweigh the benefits.[26]

Staging

No single system captures all stages of endometriosis; therefore, using a combination of anatomic (Enzian), radiologic (dPEI), and surgical (rASRM, VNESS) tools may offer the best option.[19] Endometriosis staging is most commonly described using the revised American Society for Reproductive Medicine (rASRM) system, which classifies the disease into 4 stages based on the number, depth, and location of implants, as well as the presence and severity of adhesions. The rASRM system assigns a numerical score that corresponds to stage I (minimal), stage II (mild), stage III (moderate), and stage IV (severe) disease. Minimal and mild stages typically involve superficial peritoneal implants with few or no adhesions, whereas moderate and severe stages include deep implants, ovarian endometriomas, and dense adhesions affecting pelvic organs. Although widely used, the rASRM system does not reliably correlate with symptom severity and may underrepresent deeply infiltrating disease.[6]

Because of these limitations, complementary systems such as the ENZIAN classification have been developed to better characterize deep infiltrating endometriosis, but rASRM remains the standard for clinical documentation and research reporting.[38][20] The Endometriosis Fertility Index (EFI), introduced in 2010, is a tool designed to estimate the chances of achieving pregnancy in individuals with endometriosis. EFI incorporates factors, eg, age, duration of infertility, prior pregnancies, tubal and ovarian function, and disease staging based on the revised American Society for Reproductive Medicine (r-ASRM) classification, which reproductive surgeons commonly use.[6]

Prognosis

Deep endometriosis shows variable behavior. About half of the cases remain stable over time, and hormonal therapy can significantly slow disease progression. Treatment with hormonal agents, particularly combined contraceptives and progestins, can modestly reduce lesion volume, often within 6 months, with effects persisting for several years. Regardless of changes in lesion size, most hormonal therapies provide meaningful symptom relief and improvements in quality of life.[39]

Patients with endometriosis have reduced fertility and experience higher rates of miscarriage and ectopic pregnancy compared with individuals without the disease, reflecting both inflammatory and anatomic disruptions of reproductive function. Endometriotic lesions may spontaneously regress in approximately one-third of untreated patients, although the condition more commonly follows a chronic, relapsing course. Recurrence after surgical management varies widely, with reported rates ranging from 6% to 67%, likely due to differences in disease severity, completeness of excision, and follow-up duration. Recurrent lesions may arise from either residual microscopic implants or de novo disease. Medical therapy is effective for many patients, yet 5% to 59% continue to experience pain despite treatment, and pain recurrence after discontinuation occurs in 17% to 34%, underscoring the need for long-term, individualized management strategies. Overall prognosis depends on disease phenotype, reproductive goals, and access to interprofessional care, with many patients achieving meaningful symptom control despite the chronic nature of the disorder.[40]

Complications

Complications of endometriosis arise from chronic inflammation, adhesions, and distortion of pelvic anatomy, leading to a broad range of reproductive, gastrointestinal, urinary, and psychosocial consequences. Infertility is one of the most significant complications, affecting up to one-third of patients, and is driven by impaired tubal function, altered peritoneal environment, and anatomic distortion; risks of miscarriage and ectopic pregnancy are also increased. Chronic pelvic pain, dyspareunia, dyschezia, and dysuria result from deep infiltrating disease and adhesion formation, which may also contribute to bowel dysfunction, partial obstruction, or urinary tract involvement, eg, hydronephrosis from ureteral compression.[20] Surgical management carries risks as noted above. Beyond physical morbidity, endometriosis is associated with anxiety, depression, sexual dysfunction, and reduced quality of life due to persistent pain, infertility, and repeated interventions.[41]