What is the best treatment approach for a female of reproductive age with endometriosis?

Treatment of Endometriosis in Reproductive-Age Women

For reproductive-age women with endometriosis, initiate treatment with NSAIDs for immediate pain relief, followed by combined oral contraceptives or progestins as first-line hormonal therapy, reserving GnRH agonists for refractory cases and surgery for severe disease or when medical management fails. 1

First-Line Medical Management

NSAIDs for Immediate Pain Control

• Start with naproxen 550 mg twice daily or ibuprofen 600-800 mg three times daily for immediate pain relief 1, 2, 3
• NSAIDs can be initiated even without surgical confirmation of endometriosis 1

Hormonal Suppression as Primary Therapy

• Combined oral contraceptives provide effective pain relief compared to placebo and are as effective as GnRH agonists while causing far fewer side effects 1, 2
• Continuous (rather than cyclic) oral contraceptive use is preferred for endometriosis pain management 1
• Progestins (oral or depot medroxyprogesterone acetate) demonstrate similar efficacy to oral contraceptives in reducing pain and lesion size 1, 2
• For norethindrone acetate specifically, FDA labeling recommends starting at 5 mg daily for two weeks, increasing by 2.5 mg every two weeks until reaching 15 mg daily, maintaining this dose for 6-9 months 4

Network Meta-Analysis Evidence

• A 2025 network meta-analysis of 1680 patients across 15 trials demonstrated that hormonal treatments (combined oral contraceptives, progestins, and GnRH agonists) led to clinically significant pain reduction compared with placebo, with mean differences ranging between 13.15 and 17.6 points on a 0-100 visual analog scale 5
• Little difference in effectiveness exists among the various hormonal options, making tolerability and cost the primary differentiators 5

Second-Line Medical Management

GnRH Agonists for Refractory Cases

• Reserve GnRH agonists (leuprolide 3.75 mg IM monthly or 11.25 mg every 3 months) for patients who fail first-line therapies 1, 3
• Mandatory add-back therapy with norethindrone acetate 5 mg daily (with or without low-dose estrogen) must be implemented to prevent bone mineral loss without reducing pain relief efficacy 1, 2, 3
• GnRH agonists require at least 3 months of treatment to provide significant pain relief 1, 2

Surgical Management

Indications for Surgery

• Consider surgical excision by an endometriosis specialist when medical treatment is ineffective, contraindicated, or for severe endometriosis 1, 2
• Surgical excision by a specialist is the definitive treatment for endometriosis, while medical therapies only temporize symptoms but cannot eradicate the disease 1, 2
• Surgery provides significant pain reduction during the first 6 months following the procedure 2, 3

Preoperative Planning

• Obtain high-quality preoperative imaging with pelvic MRI to map disease extent, identify deep infiltrating lesions, and plan surgical approach 1, 2
• Preoperative imaging reduces morbidity and mortality by decreasing incomplete surgeries and need for repeat procedures 1, 2

Surgical Classification

• Complete r-ASRM scoring for general staging during surgery 6
• Add Enzian classification when deep endometriosis is present to give complete description of operative findings 6
• Calculate the Endometriosis Fertility Index (EFI) for women with future fertility concerns, as it is a simple, robust, and validated clinical tool that predicts fertility outcomes and has considerable utility in developing treatment plans 6, 2

Special Considerations for Fertility

Critical Fertility Management Principles

• Medical hormonal treatment does not improve future fertility outcomes and should be avoided in women actively seeking pregnancy 2
• Hormonal suppression should not be used in women actively trying to conceive 1, 2
• For infertility concerns, proceed directly to surgical excision by a specialist followed by assisted reproduction techniques if spontaneous pregnancy does not occur within 6 months post-surgery 2

Definitive Surgical Options

Hysterectomy Considerations

• Hysterectomy with bilateral salpingo-oophorectomy remains the definitive approach for women with completed childbearing 1
• If hysterectomy is performed without oophorectomy, ongoing medical suppression may still be required as residual ovarian function can stimulate remaining endometriotic tissue 1
• Hormone replacement therapy with estrogen is not contraindicated following hysterectomy and bilateral salpingo-oophorectomy for endometriosis 1, 2

Critical Pitfalls and Limitations

Treatment Limitations

• No medical therapy completely eradicates endometriotic lesions; hormonal treatments only temporize symptoms 1, 2
• 11% to 19% of individuals with endometriosis have no pain reduction with hormonal medications 5
• 25% to 34% experience recurrent pelvic pain within 12 months of discontinuing hormonal treatment 5
• Up to 44% of women experience symptom recurrence within one year after surgery 1, 2, 3
• Approximately 25% of patients who undergo hysterectomy for endometriosis experience recurrent pelvic pain and 10% undergo additional surgery 5

Diagnostic Considerations

• Pain severity correlates poorly with laparoscopic appearance but correlates with lesion depth, not with the type of lesions seen 1, 2
• Normal physical examination and imaging do not exclude the diagnosis 5
• Diagnostic delay averages 5 to 12 years after onset of symptoms, with most women consulting 3 or more clinicians prior to diagnosis 5

Adjunctive Non-Pharmacologic Measures

• Heat application to the abdomen or back may reduce cramping pain 3
• Acupressure on Large Intestine-4 (LI4) or Spleen-6 (SP6) points may help reduce cramping pain 3
• Aromatherapy with lavender may increase satisfaction and reduce pain or anxiety 3