A woman goes to five doctors, each of whom tells her it's “just bad period cramps.” Maybe she’s stressed, or maybe she’s just sensitive. But she’s missing school, struggling to get out of bed, and no one can explain why. What she doesn’t know is that her body is waging a silent war on itself, a war called endometriosis. Endometriosis is a condition where tissue similar to the uterine lining grows outside of the uterus, causing pain, inflammation, and even infertility. The tissue behaves as it would during a normal menstrual cycle, thickening, breaking down, and bleeding. However, this excess tissue has no means of exiting the body, leading to further inflammation and pain.1 Endometriosis is difficult to diagnose, since there are many different clinical presentations and patients may even present as asymptomatic. Understanding the hormonal complexities associated with endometriosis helps explain why the chronic condition is often overlooked, especially when symptoms mimic normal menstrual cycles.
The Two Key Players: Estrogen and Progesterone
Endometriosis can be characterized by two key hormonal imbalances: estrogen and progesterone. Estrogen, one of the main female reproductive hormones, helps regulate the menstrual cycle, prepare the uterus for pregnancy, and facilitate the development of female traits during puberty. In individuals with endometriosis, estrogen promotes the growth of endometrial-like tissue outside the uterus.2 This ectopic tissue survives due to angiogenesis, or the formation of new blood vessels stimulated by estrogen production.3 Additionally, due to the overexpression of aromatase, an enzyme responsible for converting androgens into estrogen, endometriotic lesions can produce estrogen independent of ovarian estrogen, creating a self-sustaining cycle of growth and inflammation. Estrogen further upregulates the enzyme cyclooxygenase-2 (COX-2), increasing the synthesis of an inflammatory mediator, prostaglandin E2 (PGE2). PGE2 stimulates aromatase expression, which amplifies estrogen production and inflammation.4 Endometriotic tissue expresses two primary estrogen receptors: ER-α, a regulator of reproductive tissue growth, and ER-ꞵ, expressed in endometriotic lesions.2 An observed underexpression of ER-α and overexpression of ER-ꞵ contribute to increased inflammation, preventing the body’s immune system from clearing abnormal tissue.5 This continuous, positive feedback loop drives excessive estrogen production, promoting lesion growth and intensifying pain.
Progesterone, the second critical hormone, works to regulate the menstrual cycle and prepare the uterine lining for pregnancy. In a healthy reproductive system, it functions to counterbalance estrogen, acting as an anti-inflammatory agent that regulates tissue growth. However, in endometriosis, estrogen-driven changes in gene expression lead to a reduction in progesterone receptor expression.6 As a result, progesterone becomes resistant, impairing the body’s ability to respond to progesterone’s regulatory signals. Progesterone resistance allows estrogen-fueled tissue to persist outside of the uterine cavity.7 This is a key factor underlying the limited effectiveness of many hormonal treatments, given the compromised nature of progesterone’s therapeutic action.
Medical Dismissal and Diagnostic Delay
One of the primary challenges associated with diagnosis lies in the variability of symptoms experienced by patients. Common manifestations, including pelvic pain, inflammation, heavy periods, fatigue, and bloating, mimic other conditions such as irritable bowel syndrome, pelvic inflammatory disease, or even typical menstrual cramps.1 The combination of diagnostic ambiguity and the absence of reliable non-invasive tools further complicates treatment, leading to minimization of symptoms. Cultural norms exacerbate dismissal, often normalizing painful periods and downplaying the severity of pain women experience. Consequently, diagnosis can be delayed as long as 7-10 years, leaving millions of women burdened by life-altering symptoms.8 While hormonal therapies, such as birth control, may offer temporary relief, they fail to address the complex pathology of endometriosis and ultimately provide no definitive cure.9
The hormonal and clinical complexities of this chronic condition impose detrimental effects on the well-being of the patient. The combined effects of estrogen dominance and progesterone resistance drive the growth of endometrial-like tissue outside the uterus, leading to chronic pain, infertility, and psychological distress. The disconnect between symptoms and measurable biomarkers makes diagnosis especially challenging, and patients are frequently misdiagnosed or dismissed. Endometriosis should be recognized not only as a gynecological condition but a hormonally driven, systemic disease. Until clinical treatments evolve to meet the biological complexity of this condition, endometriosis will thrive in silence and women will continue to suffer.
References
- Mayo Clinic. Endometriosis. Mayo Clinic. Published August 30, 2024. https://www.mayoclinic.org/diseases-conditions/endometriosis/symptoms-causes/syc-20354656
- Chantalat E, Valera MC, Vaysse C, et al. Estrogen Receptors and Endometriosis. Int J Mol Sci. 2020;21(8):2815. Published 2020 Apr 17. doi:10.3390/ijms21082815
- Chung MS, Han SJ. Endometriosis-Associated Angiogenesis and Anti-angiogenic Therapy for Endometriosis. Front Glob Womens Health. 2022;3:856316. Published 2022 Apr 5. doi:10.3389/fgwh.2022.856316
- Bulun SE, Zeitoun K, Takayama K, et al. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999;6(2):293-301. doi:10.1677/erc.0.0060293
- Bulun SE, Monsavais D, Pavone ME, et al. Role of estrogen receptor-β in endometriosis. Semin Reprod Med. 2012;30(1):39-45. doi:10.1055/s-0031-1299596
- Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. Int J Mol Sci. 2023;24(8):6992. Published 2023 Apr 10. doi:10.3390/ijms24086992
- MacLean JA 2nd, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells. 2022;11(4):647. Published 2022 Feb 13. doi:10.3390/cells11040647
- De Corte P, Klinghardt M, von Stockum S, Heinemann K. Time to Diagnose Endometriosis: Current Status, Challenges and Regional Characteristics-A Systematic Literature Review. BJOG. 2025;132(2):118-130. doi:10.1111/1471-0528.17973
Lindeman T. Millions of people take birth control to treat endometriosis — but it doesn’t work. STAT. Published April 4, 2023. https://www.statnews.com/2023/04/04/birth-control-for-endometriosis-does-it-work/