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Endometriosis

Endometriosis is a chronic, estrogen-dependent inflammatory disease defined by endometrial-like tissue outside the uterine lining, affecting approximately 10% of reproductive-age women (~9 million in the U.S.). It is the most common cause of chronic pelvic pain in women and is associated with infertility in 30–50% of affected individuals. There is currently no medical or surgical cure, and diagnosis is delayed an average of 5 to 12 years from symptom onset.[1] For the urogynecologist and pelvic reconstructive surgeon, endometriosis is unavoidable: deep infiltrating disease causes ureteral obstruction and bladder-detrusor invasion that drive partial cystectomy and ureteroneocystostomy referrals, IC/PBS frequently coexists through shared central-sensitization pathways, and 40–50% of patients return to the operating room within 5–7 years for recurrent pain.

Pathophysiology​

The most widely accepted theory is retrograde menstruation (Sampson's theory), in which shed endometrial tissue travels through the fallopian tubes into the peritoneal cavity, where it implants, proliferates, and provokes an inflammatory response.[2][3] Additional mechanisms include:

  • Epigenetic reprogramming of endometrial mesenchymal progenitor / stem cells, with overexpression of steroidogenic factor-1 driving excessive local estrogen production via estrogen receptor-β, and progesterone receptor deficiency causing progesterone resistance.[3]
  • Immune dysregulation with proinflammatory cytokines, altered circulating immune cell populations, and aberrant microRNA expression creating a systemic inflammatory environment.[4]
  • Neurogenesis within lesions, with new nerve fiber growth contributing to nociceptive and neuropathic pain mechanisms; central sensitization (nociplastic pain) explains why lesion burden correlates poorly with pain severity.[1]

Three pain mechanisms — nociceptive (lesion-driven inflammation), neuropathic (lesion-associated nerve fiber injury and infiltration), and nociplastic (central sensitization) — coexist and explain the disconnect between disease stage and symptom severity.

Clinical Presentation​

Approximately 90% of women with endometriosis report pelvic pain, and 50% report moderate to severe fatigue.[1] Key symptoms:

  • Dysmenorrhea — progressive, often starting in adolescence
  • Nonmenstrual chronic pelvic pain
  • Deep dyspareunia
  • Dyschezia — painful defecation, often cyclic
  • Dysuria — cyclic
  • Infertility — reported in 26% at diagnosis[1]

Endometriosis exists in three phenotypes: superficial peritoneal lesions, ovarian endometriomas, and deep infiltrating endometriosis (involving the rectovaginal septum, bladder, ureters, or bowel).[2][4]

Diagnosis​

A clinical diagnosis can now be made based on symptoms, physical examination, and imaging — surgical confirmation is no longer required to initiate treatment.[1][5] Key diagnostic considerations:

  • Physical examination. Tenderness in the posterior fornix, uterosacral nodularity, fixed retroverted uterus, or adnexal masses; a normal exam does not exclude the diagnosis.[1]
  • Transvaginal ultrasound (TVUS). First-line imaging; can identify endometriomas and deep infiltrating endometriosis with high sensitivity in experienced hands.[6][5]
  • Pelvic MRI. Useful for mapping deep infiltrating endometriosis, particularly when surgical planning is needed or TVUS is inconclusive.[5]
  • Laparoscopy with biopsy. Remains the gold standard for definitive histologic diagnosis but is no longer required before initiating empiric treatment.[6][7]
  • Biomarkers. No serum biomarker (including CA-125) has sufficient sensitivity or specificity for clinical use.[3]

Treatment: Medical Management​

Hormonal therapy is the mainstay of treatment for endometriosis-associated pain in women not seeking immediate pregnancy. All hormonal treatments target the estrogen-dependent pathophysiology by suppressing ovarian activity. A network meta-analysis of 1,680 women from 15 RCTs found that all hormonal treatments produced clinically significant pain reduction (13–18 points on a 0–100 VAS) compared with placebo, with little difference among classes.[1]

First-Line Therapies​

  • Combined oral contraceptives (20–30 μg ethinyl estradiol). Continuous use provides better pain control than cyclic regimens. Mean pain reduction vs. placebo: 15.1 points (95% CI, −20.8 to −9.3).[1][8]
  • Progestin-only options. Norethindrone acetate (oral), depot medroxyprogesterone acetate (IM), etonogestrel implant, or the 52-mg levonorgestrel IUD. The LNG-IUD reduced pain by 17.7 points vs. placebo but does not suppress ovulation.[1][8]
  • NSAIDs. Commonly used adjunctively, though a Cochrane review found insufficient evidence that they significantly reduce endometriosis-specific pain.[8][9]

Second-Line Therapies: GnRH Agonists and Antagonists​

Two FDA-approved oral GnRH antagonists represent a major advance:

  • Elagolix (Orilissa). Low dose 150 mg daily (up to 24 months) or high dose 200 mg twice daily (up to 6 months without add-back). Dysmenorrhea response rates of 42–47% (low dose) and 75–77% (high dose) vs. 23–25% placebo. High-dose elagolix with add-back therapy (estradiol 1 mg / norethindrone acetate 0.5 mg) showed sustained efficacy at 12 months with preserved bone mineral density.[1][10][11]
  • Relugolix combination therapy (Myfembree). Relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg, once daily. In the SPIRIT 1 and 2 trials, 75% had clinically significant improvement in dysmenorrhea vs. 27–30% placebo, with sustained efficacy at 2 years and minimized BMD loss due to integrated add-back.[1][12][13]

A meta-analysis of all oral GnRH antagonists found a pooled NNT of 2 for dysmenorrhea response and 5 for nonmenstrual pelvic pain response, with no significant heterogeneity across agents.[14]

GnRH agonists (leuprolide acetate) remain an option but require injection, cause an initial flare, and are limited to 12 months with add-back therapy due to bone loss concerns.[8][9]

Third-Line Therapy​

  • Aromatase inhibitors (off-label). Block estrogen production within lesions; reserved for refractory cases. Must be combined with a GnRH agonist or OCP to prevent follicular cyst development. Limited by bone loss with prolonged use.[9][8]

Approximately 11–19% of patients have no pain reduction with hormonal medications, and 25–34% experience recurrent pain within 12 months of discontinuation.[1][8]

Treatment: Surgical Management​

Surgery is indicated when medical therapy is ineffective or contraindicated, for large endometriomas, deep infiltrating lesions causing organ compromise, or for infertility.[5][8]

  • Laparoscopic excision / ablation. Standard surgical approach. Excision may be preferred over ablation for endometriomas (lower recurrence, higher spontaneous pregnancy rates), though the comparison for superficial peritoneal disease is debated.[4][8][9]
  • Recurrence rates. 40–45% of women have pain recurrence after laparoscopic surgery; the probability of repeat surgery is 15–20% within 2 years and up to 50% within 5–7 years. Postoperative hormonal therapy is recommended to reduce recurrence.[4]
  • Hysterectomy. Considered when all other treatments fail and future pregnancy is not desired. Approximately 25% of patients who undergo hysterectomy for endometriosis experience recurrent pelvic pain, and 10% require additional surgery. Ovarian preservation is recommended in premenopausal women when possible, as surgical menopause contributes to approximately half of the 60% elevated cardiovascular disease risk observed in women with endometriosis.[1][9]
  • Endometrioma excision and fertility. Cystectomy adversely affects ovarian reserve (lower AMH, reduced antral follicle counts), requiring careful risk-benefit discussion before surgery in women desiring fertility.[9]

In a large population-based cohort (n = 84,885, median follow-up 10 years), up to 1 in 4 women who underwent minor conservative surgery and 1 in 5 who underwent major conservative surgery required additional endometriosis surgery.[15]

Urologic involvement​

Approximately 1–2% of endometriosis cases involve the urinary tract, with the bladder most commonly affected (~85% of urinary endometriosis), followed by the ureter, kidney, and urethra. Bladder endometriosis presents with cyclic dysuria, hematuria, and suprapubic pain; deep detrusor involvement typically requires partial cystectomy with primary closure. Ureteral endometriosis (intrinsic vs. extrinsic) carries a high risk of silent renal loss — periodic upper-tract surveillance is mandatory in deep infiltrating disease, and ureterolysis is often insufficient for intrinsic disease, which requires segmental resection and ureteroneocystostomy with psoas hitch or Boari flap. See Ureteral Stricture and UPJ Obstruction for the reconstructive techniques.

Endometriosis and Infertility​

Infertility occurs in 30–50% of women with endometriosis through multiple mechanisms: chronic inflammation impairing folliculogenesis and implantation, distorted pelvic anatomy, diminished ovarian reserve, and altered endometrial receptivity.[16][4]

  • Medical therapy for endometriosis is contraceptive and should not be used before attempting conception, with one exception: GnRH agonist pretreatment for 3–6 months before IVF significantly increases pregnancy likelihood.[4]
  • Mild–moderate disease (rASRM I–II). Surgical excision / ablation may improve spontaneous pregnancy rates. Ovulation induction with IUI increases fecundity (limit to 3–4 cycles).[4][17]
  • Moderate–severe disease (rASRM III–IV). IVF is the most effective treatment. ART outcomes are similar to other causes of infertility in stage I–II disease but show reduced live birth rates and oocyte yields in stage III–IV.[16][18]
  • Endometriomas and IVF. Insufficient evidence that removal improves IVF success; surgery should be considered for endometriomas >4 cm to confirm histology and improve follicle access, with counseling about potential ovarian-reserve compromise.[17]
  • The Endometriosis Fertility Index (EFI) can help guide management decisions after surgery.[16]

Systemic Comorbidities and Long-Term Risks​

Endometriosis is increasingly recognized as a systemic inflammatory disease with effects extending beyond the pelvis:[4][1]

  • Ovarian cancer. 93% greater risk overall; 3.4-fold risk of clear-cell and 2.3-fold risk of endometrioid subtypes. Absolute lifetime risk remains low (1.8% vs. 1.1% in the general population), and prophylactic oophorectomy is not recommended.[1]
  • Cardiovascular disease. Significantly elevated risk of MI and stroke, partly mediated by chronic inflammation and partly by high rates of surgical menopause.[9][1]
  • Autoimmune conditions. Increased risk of SLE, rheumatoid arthritis, and other autoimmune diseases.[9][1]
  • Mental health. Depression and anxiety, with evidence of altered brain gene expression and decreased volume in emotional-processing regions.[4]
  • Coexisting pain conditions. Migraine, irritable bowel syndrome, interstitial cystitis / painful bladder syndrome, and fibromyalgia are common comorbidities, reflecting shared central-sensitization pathways.[9]

Emerging Concepts​

  • Classification. The revised ASRM staging system correlates poorly with symptoms and prognosis. Newer frameworks including the ENZIAN classification for deep endometriosis and the Endometriosis Fertility Index aim to better guide clinical decisions.[6][16]
  • Noninvasive diagnosis. Research into circulating biomarkers (miRNAs, proteomics) and advanced imaging continues, though none have reached clinical utility.[3][4]
  • Multimodal pain management. Given the contribution of central sensitization, interdisciplinary approaches incorporating pelvic-floor physical therapy, cognitive behavioral therapy, and neuromodulatory agents are increasingly emphasized alongside hormonal treatment.[1][9]

Cross-references​

  • Chronic Pelvic Pain — biopsychosocial framework, central sensitization, and the multidisciplinary CPP workup.
  • IC/PBS — frequent comorbidity through shared central-sensitization pathways.
  • Ureteral Stricture — reconstructive approach for endometriosis-related ureteral obstruction.
  • UPJ Obstruction — extrinsic compression by endometriotic implants.
  • Opportunistic Adnexal Surgery — endometriosis-related adnexal surgery considerations.
  • GSM — vaginal estrogen counseling after surgical menopause / oophorectomy for endometriosis.

References​

1. As-Sanie S, Mackenzie SC, Morrison L, et al. "Endometriosis." JAMA. 2025;334(1):64-78. doi:10.1001/jama.2025.2975

2. Veth VB, van de Kar MM, Duffy JM, et al. "Gonadotropin-Releasing Hormone Analogues for Endometriosis." Cochrane Database Syst Rev. 2023;6:CD014788. doi:10.1002/14651858.CD014788.pub2

3. Bulun SE, Yilmaz BD, Sison C, et al. "Endometriosis." Endocr Rev. 2019;40(4):1048-1079. doi:10.1210/er.2018-00242

4. Taylor HS, Kotlyar AM, Flores VA. "Endometriosis Is a Chronic Systemic Disease: Clinical Challenges and Novel Innovations." Lancet. 2021;397(10276):839-852. doi:10.1016/S0140-6736(21)00389-5

5. Voelker R. "What Is Endometriosis?" JAMA. 2025. doi:10.1001/jama.2025.14241

6. Chen I, Veth VB, Choudhry AJ, et al. "Pre- and Postsurgical Medical Therapy for Endometriosis Surgery." Cochrane Database Syst Rev. 2020;11:CD003678. doi:10.1002/14651858.CD003678.pub3

7. Grammatis AL, Georgiou EX, Becker CM. "Pentoxifylline for the Treatment of Endometriosis-Associated Pain and Infertility." Cochrane Database Syst Rev. 2021;8:CD007677. doi:10.1002/14651858.CD007677.pub4

8. Edi R, Cheng T. "Endometriosis: Evaluation and Treatment." Am Fam Physician. 2022;106(4):397-404.

9. Zondervan KT, Becker CM, Missmer SA. "Endometriosis." N Engl J Med. 2020;382(13):1244-1256. doi:10.1056/NEJMra1810764

10. U.S. Food and Drug Administration. "Orilissa (elagolix) prescribing information." Updated December 2025.

11. Miller CE, Kim JH, Kroll R, et al. "Efficacy, Tolerability, and Bone Density Outcomes of Elagolix With Add-Back Therapy for Endometriosis-Associated Pain: Twelve Months of an Ongoing Randomized Phase 3 Trial." Am J Obstet Gynecol. 2024;231(6):630.e1-630.e13. doi:10.1016/j.ajog.2024.06.040

12. Giudice LC, As-Sanie S, Arjona Ferreira JC, et al. "Once Daily Oral Relugolix Combination Therapy Versus Placebo in Patients With Endometriosis-Associated Pain: Two Replicate Phase 3, Randomised, Double-Blind Studies (SPIRIT 1 and 2)." Lancet. 2022;399(10343):2267-2279. doi:10.1016/S0140-6736(22)00622-5

13. Blair HA. "Relugolix / Estradiol / Norethisterone Acetate: A Review in Endometriosis-Associated Pain." Drugs. 2024;84(4):449-457. doi:10.1007/s40265-024-02018-3

14. Hsu R, Han ES, Farrow M, et al. "Oral Gonadotropin-Releasing Hormone Antagonists for the Treatment of Endometriosis-Associated Pain: A Systematic Review and Meta-Analysis." J Minim Invasive Gynecol. 2026. doi:10.1016/j.jmig.2026.04.004

15. Bougie O, McClintock C, Pudwell J, Brogly SB, Velez MP. "Long-Term Follow-Up of Endometriosis Surgery in Ontario: A Population-Based Cohort Study." Am J Obstet Gynecol. 2021;225(3):270.e1-270.e19. doi:10.1016/j.ajog.2021.04.237

16. Colombo GE, Salmeri N, Leonardi M. "Integrating IVF and Surgical Management in Endometriosis-Associated Infertility: A Review." Adv Ther. 2026;43(3):1004-1015. doi:10.1007/s12325-025-03489-w

17. Practice Committee of the American Society for Reproductive Medicine. "Endometriosis and Infertility: A Committee Opinion." Fertil Steril. 2012;98(3):591-598. doi:10.1016/j.fertnstert.2012.05.031

18. Santoro N, Polotsky AJ. "Infertility Evaluation and Treatment." N Engl J Med. 2025;392(11):1111-1119. doi:10.1056/NEJMcp2311150