Definition and Classification
Endometriosis is a chronic inflammatory condition defined by the presence of endometrial tissue outside the uterine cavity. The endometrium, which physiologically lines the interior of the uterus, is an estrogen-dependent tissue whose growth and activity are regulated by hormonal stimulation.
Endometriosis affects approximately 10% of women of reproductive age and tends to diminish after menopause. In many patients, it represents a significant cause of chronic abdominopelvic pain and may be associated with other comorbidities, including infertility.
Based on the location of ectopic endometrial tissue, genital and extragenital forms are distinguished.
Genital endometriosis
It may present in an internal form, termed adenomyosis, when endometrial tissue involves the myometrium, or it may affect other structures of the female reproductive system, including the ovaries, uterosacral ligaments, pouch of Douglas, vaginal fornices, portio, vagina, vulva, perineum, and round ligament.
Extragenital endometriosis
Located outside the reproductive tract, it may involve the bowel, diaphragm, and urinary tract, particularly the bladder and ureters.
Iatrogenic endometriosis
Consists of endometrial tissue located at surgical scars, following cesarean section or other gynecologic procedures.
Etiology
The etiology of endometriosis has not yet been definitively clarified; however, several pathogenetic hypotheses have been proposed.
Theory of retrograde menstruation
Proposes that endometrial cells from the uterine cavity may reach ectopic sites during menstrual flow, implanting on peritoneal and ovarian surfaces.
Coelomic metaplasia theory
Hypothesizes the development of endometrial or endometrial-like tissue outside the uterus, arising from other cell groups, under the influence of hormonal or immunologic factors.
Lymphatic-vascular transport theory
According to this hypothesis, endometrial cells may spread through the blood or lymphatic circulation, explaining rare distant locations such as diaphragmatic or pulmonary involvement.
Immune tolerance
Proposes that endometriosis may result from a reduced capacity for peritoneal clearance of endometrial cells from retrograde menstruation, related to alterations in normal immunologic mechanisms.
Symptoms
The clinical presentation of endometriosis is heterogeneous. In some cases the disease may be asymptomatic; more frequently it is associated with the following manifestations:
(painful menstruation)
pain
(pain during intercourse)
In extragenital forms, urinary symptoms may appear, such as pain during urination, urinary urgency, and renal failure in cases of urinary tract involvement, or bowel symptoms, such as diarrhea, tenesmus, rectal bleeding, and bowel obstruction in cases of intestinal involvement.
Symptom intensity does not necessarily correlate with disease extent: patients with severe endometriosis may present modest symptoms, while women with apparently mild forms may report highly debilitating complaints. Endometriosis is considered a disease with high social impact, due to its repercussions on quality of life, personal relationships, and productivity.
Diagnosis
The diagnosis of endometriosis is based on a thorough medical history, gynecologic examination, and imaging studies including ultrasound, MRI, CA125 plasma level measurement, and laparoscopy. The first-level diagnostic approach consists of a gynecologic examination combined with transvaginal ultrasound, which allows evaluation of reproductive tract involvement, such as the presence of ovarian cystic formations, and potential infiltration of adjacent structures.
If this examination is negative in the presence of strong clinical suspicion, MRI may be performed, useful for evaluating peritoneal implants, rectosigmoid endometriosis, the ileocecal region, and urinary tract lesions. The most accurate diagnostic method is laparoscopy, a minimally invasive surgical procedure that involves introducing instrumentation equipped with a camera into the abdominal cavity through small skin incisions, allowing both diagnostic confirmation and surgical treatment.
A potentially useful test is the measurement of CA125, a marker often elevated in patients with endometriosis. However, elevated values may also be found in other conditions, including malignancies and inflammatory conditions, which is why it is not used as a diagnostic test. It may have a role in follow-up, since serum levels may correlate with disease stage, treatment response, and identification of potential recurrences after medical or surgical treatment.
Staging classification
Endometriosis may be classified by severity into four stages:
Medical Therapy
Treatment choice depends on the severity of symptoms, the extent and location of the disease, the desire for pregnancy, and the patient's age. In cases of minimal or mild endometriosis, the primary indication is medical therapy, aimed at reducing estrogen production and, consequently, limiting both the growth and inflammatory activity of the endometriotic tissue.
Comparison of combined oral contraceptives, progestins, and intrauterine system — evidence from network meta-analyses and recent randomized trials
There is no definitive ranking of efficacy among different combined oral contraceptives (COCs) and different progestins for endometriosis, as available evidence shows overall similar efficacy among various formulations. However, some recent studies suggest relevant differences related to the type of estrogen used, tolerability, and therapeutic persistence.
A network meta-analysis of 1,680 women showed that all COCs significantly reduce pelvic pain compared with placebo (mean reduction: 15.1 points on a 0–100 VAS scale), without substantial differences among formulations. Progestins also demonstrated a significant benefit. Results for the main options are:
| Option | Formulation | VAS Reduction (95% CI) |
|---|---|---|
| Levonorgestrel intrauterine system | 52 mg | −17.7 points (−25.5 / −9.8) |
| Intramuscular progestins | Medroxyprogesterone acetate 150 mg every 3 months | −13.2 points (−16.2 / −10.1) |
| Oral progestins | Norethindrone acetate, medroxyprogesterone acetate, dienogest, drospirenone | −12.6 points (−15.3 / −9.8) |
Ref.: [1]
A 2025 comparative study showed that COCs containing natural estradiol (E2) or estetrol (E4) may be more effective than COCs with ethinylestradiol in treating chronic pelvic pain. Estetrol 15 mg/drospirenone 3 mg showed improvement similar to dienogest at 3 and 6 months, and superior to COCs with natural estradiol at 6 months. COCs with ethinylestradiol showed the most modest efficacy. A Cochrane review, however, concluded that direct comparative evidence between different COCs remains insufficient to establish a definitive hierarchy.
Ref.: [2, 3]
A 2025 randomized study of dienogest vs norethindrone acetate demonstrated that both effectively reduce pain (dysmenorrhea scores reaching 0.00 in both groups at 12 months). Norethindrone acetate 5 mg/day showed greater endometrioma reduction (p=0.037) and lower discontinuation rate (23.3% vs 47.5% at 6 months). An Italian study reported similar clinical satisfaction (71% vs 72%), but dienogest was better tolerated (80% vs 58%). In patients with ovarian endometriomas, dienogest showed greater symptom reduction. Compared with medroxyprogesterone acetate, dienogest demonstrated significantly superior pain reduction in some post-surgical series.
Ref.: [4, 5, 6, 7]
Dienogest is among the most studied progestins in endometriosis. It increases PR-B receptor expression in endometriotic tissue, counteracting progesterone resistance. In several randomized studies it has shown efficacy comparable to GnRH agonists with a more favorable tolerability profile. A 2025 network meta-analysis identified it among the pharmacologic treatments with the most robust scientific support for endometriosis-related pain.
Ref.: [8, 9]
The LNG-IUS showed the greatest pain reduction in the network meta-analysis (−17.7 points). Long-term data document sustained efficacy up to 10 years, with 91.5% of patients maintaining treatment beyond 5 years (vs 21.9% with COCs or dienogest), fewer systemic side effects, and better therapeutic persistence. However, it is not the treatment of choice for ovarian endometriomas, as it does not consistently suppress ovulation.
Ref.: [1, 10]
For COCs, continuous use is superior to cyclic use in pain control: residual dysmenorrhea 9.4% vs 20.9%, non-menstrual pelvic pain 9.4% vs 23.9%. Therefore, monophasic formulations are preferred. For progestins, the main differences concern tolerability, cost, route of administration, and persistence. Between 11% and 34% of patients do not respond to first-line hormonal therapies, due to possible progesterone resistance or intolerable side effects.
Ref.: [1, 8, 11]
Based on current evidence, COCs containing natural estradiol or estetrol represent an emerging prospect. Among progestins, dienogest and the levonorgestrel intrauterine system are the options with the most robust scientific support. Therapeutic choice must be individualized based on clinical presentation, disease phenotype, tolerability, and reproductive desire.
Evidence on adjuvant therapies for chronic pelvic pain: from selective use of neuromodulators to the role of supplements
Neuromodulators are not a first-line therapy for endometriosis but may play a role in persistent pain phenotypes with a neuropathic or nociplastic component, or in chronic pelvic pain refractory to hormonal and/or surgical therapies. The biologic rationale is solid: a proportion of patients with endometriosis develop central sensitization that reduces response to lesion-directed therapies. In clinical practice, neuromodulators make most sense when pain appears "decoupled" from the cycle, with allodynia, hyperalgesia, overlapping pain comorbidities, or persistence after surgery.
Among the medications, amitriptyline, duloxetine, and venlafaxine show more favorable clinical signals, while the empiric use of gabapentin was strongly downgraded by the multicenter randomized GaPP2 trial (Lancet 2020), which showed no clinically relevant benefit in female chronic pelvic pain and recorded more adverse events compared with placebo. The SOGC 2024 guidelines recommend considering tricyclics for neuropathic pelvic pain and SNRIs in selected cases, but advise against gabapentin as a routine choice.
Overall evidence on neuromodulators in female chronic pelvic pain remains of low-to-moderate quality; the most favorable results come primarily from small-scale studies. Their use is appropriate in a multidisciplinary pain setting, not as standard endometriosis treatment.
The ESHRE 2022 guidelines explicitly state that no specific nutritional intervention can be recommended to reduce pain or improve quality of life in women with endometriosis, due to insufficient and heterogeneous evidence. The main supplements studied are:
| Supplement | Available evidence |
|---|---|
| N-acetylcysteine (NAC) | Most interesting clinical signal among supplements: some studies report pain reduction and endometrioma size decrease, but evidence quality remains low (small or observational studies). |
| Omega-3 / fish oil | Possible modest benefit on pain in preliminary reviews, but the randomized SAGE trial (AJCN 2020) did not demonstrate a clear advantage over placebo. |
| Vitamin D | Solid immuno-inflammatory rationale, contradictory clinical data; some trials report pain reduction, others results similar to placebo. |
| Curcumin | Strong preclinical anti-inflammatory rationale; a triple-blind trial showed no clear benefit, while an add-on study to dienogest reported improvements in pain and quality of life. |
| Antioxidants (vit. C and E) | 2024 meta-analysis of RCTs: possible reduction of pain symptoms, but with strong heterogeneity and low-to-moderate certainty of evidence. |
Neuromodulators: to be considered only in selected patients with suspected neuropathic component or persistent pain unexplained by anatomic burden; avoid routine empiric use of gabapentin. Supplements: none are recommended as standard of care; NAC, omega-3, and vitamin D remain adjuvant options to be discussed case by case, clarifying the limitations of the evidence. The strategy with the most robust evidence remains pain phenotype assessment, appropriate hormonal therapy, and a multidisciplinary approach.
| Option | Possible clinical role | Evidence quality | Practical message |
|---|---|---|---|
| Oral neuromodulators (amitriptyline, duloxetine, venlafaxine) | Persistent pain with neuropathic/nociplastic component or refractory CPP | Low–moderate | In multidisciplinary setting; gabapentin not routine |
| Gabapentin | Downgraded by GaPP2 trial (Lancet 2020); no relevant benefit in female CPP | Moderate (negative) | Not recommended routinely; more AEs vs placebo |
| NAC | Favorable signal on pain and endometrioma size | Low | Interesting as add-on; not universally recommended |
| Vitamin D | Conflicting data; some positive studies, others similar to placebo | Low | Correct documented deficiency; not as specific therapy |
| Omega-3 / fish oil | Possible modest benefit on pain; SAGE trial does not confirm | Low | Not routinely recommended |
| Antioxidants (vit. C, E) | 2024 meta-analysis: possible pain reduction, strong heterogeneity | Low–moderate | Promising, but evidence still insufficient |
Surgical Therapy
Surgical therapy is reserved for cases of severe endometriosis, in patients unresponsive to pharmacologic therapy, in the presence of distorted pelvic anatomy, adhesions, bowel obstruction, or obstructive involvement of the urinary tract. The procedure is performed laparoscopically.
Treatment may initially be conservative, through cauterization of endometriotic foci, a procedure associated with an increase in fertility rates and a reduction in pain, although symptom recurrence is possible in some cases.
When the disease presents a severe picture, with persistent debilitating symptoms despite medical therapy and conservative surgery, definitive surgery may become necessary. This consists of removal of the uterus (hysterectomy), with preservation of the tubes and ovaries in women of reproductive age, or removal of the uterus, tubes, and ovaries (hysterectomy with salpingo-oophorectomy) in postmenopausal women.
Hysterectomy with salpingo-oophorectomy combined with complete excision of all endometriotic foci has a cure rate of 90%.
For information on gynecologic examination and the initial diagnostic pathway for endometriosis, visit the portal dedicated to clinical gynecology.
iltuoginecologo.it → Clinical Gynecology
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