The Molecular and Cellular Mechanisms of Endometriosis: From Basic Pathophysiology to Clinical Implications
Abstract
1. Introduction
2. Methods
3. Types of Endometrioses
3.1. Superficial Peritoneal Disease (SPD)
3.2. Deep Infiltrating Endometriosis (DIE)
3.3. Ovarian Endometriomas
4. The Pathophysiology of Endometriosis
4.1. Retrograde Menstruation Theory/Endometriotic Disease Theory (EDT)
4.2. Vascular and Lymphatic Dissemination
4.3. Coelomic Metaplasia/Mesothelial Cell Metaplasia Theory
4.4. Müllerian Remnants Theories/Embryonic Rest Theory
4.5. Genetic/Epigenetic Theory
5. Cellular Mechanisms
6. Molecular Mechanisms
6.1. Adhesion and Invasion
6.2. Proliferation and Apoptosis
6.2.1. Hormones
6.2.2. Cell Signaling Pathway
6.2.3. Growth Factors
6.3. The Role of Immune and Inflammatory Response in Endometriosis
6.4. Epigenetic Regulation and Gene Expression
7. Symptoms
8. Diagnosis of Endometriosis
8.1. ESHRE Guidelines [102]
8.2. ACOG Guidelines [103]
8.3. NICE Guidelines [104]
8.4. WES Guidelines [105]
9. Clinical Treatment of Endometriosis
9.1. Medical Management
9.1.1. Hormonal Therapies
- Combined Oral Contraceptives (COCs): COCs are a first-line treatment for endometriosis-associated pain. By suppressing ovulation and inducing decidualization and atrophy of endometrial tissue, COCs reduce pain severity [108]. Continuous regimens are often preferred to eliminate menstruation altogether.
- Progestins: Progestin-only therapies (e.g., medroxyprogesterone acetate and norethindrone acetate) act by inducing endometrial atrophy and suppressing gonadotropin secretion [109]. Dienogest, a novel synthetic progesterone, has shown good therapeutic effects in alleviating endometriosis-associated pain and reducing the progression and recurrence of endometriosis [110]. On the other hand, levonorgestrel-releasing intrauterine systems (LNG-IUSs) provide targeted progestin delivery, reducing systemic side effects while alleviating dysmenorrhea and pelvic pain [111].
- Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists: As a modulator of the hypothalamus–pituitary–gonadol axis, GnRH regulates the secretion of gonadotropins (FSH and LH) from the pituitary gland, which in turn control ovarian hormone production and affect the growth of ectopic endometrial tissues. GnRH agonists (e.g., leuprolide acetate) initially induce a flare-up of gonadotropin secretion, followed by the downregulation of pituitary receptors and the subsequent suppression of ovarian estrogen production [112]. Thus, GnRH agonists are used in the treatment of endometriosis to suppress ovarian function and reduce estrogen levels, thereby alleviating symptoms and inhibiting the growth of endometriotic lesions [113]. In contrast, GnRH antagonists (e.g., Elagolix) directly inhibit gonadotropin release, rapidly reducing estrogen levels without an initial flare-up [114]. These therapies are effective for refractory cases but may require add-back hormonal therapy to mitigate hypoestrogenic side effects such as bone loss and vasomotor symptoms.
- Aromatase Inhibitors: Aromatase inhibitors (e.g., letrozole, anastrozole) inhibit estrogen synthesis within ectopic endometrial tissue and the ovary [115]. These are used in combination with progestins or GnRH analogs for severe or refractory cases.
9.1.2. Non-Hormonal Pharmacological Options
- Neuromodulators: For chronic and neuropathic pain, medications such as gabapentin or amitriptyline may be employed as adjunctive therapies [118].
9.1.3. Emerging Medical Therapies
- Selective Progesterone Receptor Modulators (SPRMs): Agents such as ulipristal acetate are being investigated for their ability to modulate progesterone activity selectively, reducing lesion growth while preserving endometrial receptivity [119]. However, they are not used anymore because of the possible side effect of fulminant hepatitis.
- Immunomodulators: Therapies targeting inflammatory and immune pathways, such as tumor necrosis factor-alpha (TNF-α) inhibitors or interleukin antagonists, are in early-stage research for treating endometriosis [120].
9.2. Surgical Interventions
9.2.1. Laparoscopy
- Excision: Complete removal of endometriotic lesions is preferred over ablation to ensure thorough eradication of disease tissue and reduce recurrence [121].
- Adhesiolysis: Surgical removal of adhesions restores pelvic anatomy and improves organ function.
- Ovarian Cystectomy: Removal of endometriomas is recommended, especially in symptomatic cases, to relieve pain and improve fertility outcomes [122].
9.2.2. Laparotomy
9.2.3. Post-Surgical Considerations
9.3. Fertility Preservation and Management
- Ovulation Induction and Intrauterine Insemination (IUI): For minimal-to-mild endometriosis, controlled ovarian hyperstimulation with IUI can be effective [123].
- In Vitro Fertilization (IVF): For moderate-to-severe cases, IVF offers higher success rates. Pre-treatment with GnRH agonists for 2–3 months prior to IVF may improve outcomes [124].
- Ovarian Reserve Preservation: Early referral to fertility specialists and consideration of oocyte or embryo cryopreservation are crucial for patients at risk of diminished ovarian reserve due to surgical interventions or disease progression [125].
9.4. Adjunctive and Alternative Therapies
- Lifestyle Modifications: Regular exercise, a low-inflammatory diet, and stress management techniques may complement conventional treatments [126].
- Acupuncture and Physical Therapy: Evidence supports the role of acupuncture and pelvic floor physical therapy in reducing pain and improving quality of life [127].
- Psychological Support: Cognitive behavioral therapy (CBT) and counseling are beneficial for managing the emotional and psychological burden of chronic pain and infertility associated with endometriosis.
9.5. Future Perspectives in Endometriosis Treatment
- Precision Medicine: Advances in genomics and proteomics may enable the development of personalized therapeutic approaches targeting specific molecular pathways involved in endometriosis.
- Gene Editing and Stem Cell Therapy: Experimental therapies exploring gene-editing tools like CRISPR and stem cell-based regenerative approaches hold promise for future treatments.
- Non-Invasive Diagnostics: Liquid biopsy and biomarker-based diagnostics are under development to facilitate early detection and monitoring of treatment response, reducing reliance on invasive surgical procedures.
10. Discussion
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Organization | Key Diagnostic Points | Differences |
---|---|---|
ESHRE | - Emphasizes non-invasive imaging (transvaginal ultrasound, MRI). - Symptoms: chronic pain, infertility. | Recommends reducing reliance on routine laparoscopy for diagnosis. |
NICE | - Focuses on early symptom recognition (pelvic pain, dysmenorrhea). - Suggests timely specialist referral. | Highlights management pathways alongside diagnostic recommendations. |
ACOG | - Clinical evaluation as a primary tool. - Laparoscopy as the gold standard for confirmation. | Retains laparoscopy as a key diagnostic method, unlike ESHRE’s reduced emphasis on its routine use. |
WES | - Promotes unified, evidence-based diagnostic approaches globally. | Collaborates with multiple organizations to create international standards. |
Medication | Principles of Actions | Possible Side Effects |
---|---|---|
Combined Oral Contraceptives (COCs) | Suppress ovulation and induce decidualization and atrophy of endometrial tissue | Elevated risk of gall stone and deep vein thrombosis |
Progestins | Induce endometrial atrophy and suppress gonadotropin secretion | Irregular uterine bleeding; body weight gain |
Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists | As a modulator of the hypothalamus–pituitary–gonadol axis, GnRH regulates the secretion of gonadotropins (FSH and LH) from the pituitary gland, which in turn control ovarian hormone production and affect the growth of ectopic endometrial tissues | Menopausal syndrome and osteoporosis |
Aromatase Inhibitors | Inhibit estrogen synthesis within ectopic endometrial tissue and the ovary | Increased risk of osteoporosis and bone fracture; hot flashes; myalgia |
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) | Inhibit cyclooxygenase (COX) enzymes and reduce prostaglandin synthesis, alleviating inflammation and nociceptive signaling | Gastrointestinal tract bleeding and ulcer; heartburn |
Neuromodulators | May be employed as adjunctive therapies to alleviate chronic and neuropathic pain, | Nausea; headache; blurred vision |
Selective Progesterone Receptor Modulators (SPRMs) | Modulate progesterone activity selectively, reducing lesion growth while preserving endometrial receptivity | Fulminant hepatitis |
Immunomodulators | Target inflammatory and immune pathways, such as TNF-α inhibitors or interleukin antagonists | Fatigue; diarrhea; nausea |
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Mariadas, H.; Chen, J.-H.; Chen, K.-H. The Molecular and Cellular Mechanisms of Endometriosis: From Basic Pathophysiology to Clinical Implications. Int. J. Mol. Sci. 2025, 26, 2458. https://doi.org/10.3390/ijms26062458
Mariadas H, Chen J-H, Chen K-H. The Molecular and Cellular Mechanisms of Endometriosis: From Basic Pathophysiology to Clinical Implications. International Journal of Molecular Sciences. 2025; 26(6):2458. https://doi.org/10.3390/ijms26062458
Chicago/Turabian StyleMariadas, Heidi, Jie-Hong Chen, and Kuo-Hu Chen. 2025. "The Molecular and Cellular Mechanisms of Endometriosis: From Basic Pathophysiology to Clinical Implications" International Journal of Molecular Sciences 26, no. 6: 2458. https://doi.org/10.3390/ijms26062458
APA StyleMariadas, H., Chen, J.-H., & Chen, K.-H. (2025). The Molecular and Cellular Mechanisms of Endometriosis: From Basic Pathophysiology to Clinical Implications. International Journal of Molecular Sciences, 26(6), 2458. https://doi.org/10.3390/ijms26062458