History of Endometriosis: Unraveling the Theories and Advances

Endometriosis is a complex condition that affects a significant number of women (XX) and on average takes 7-10 years for a diagnosis. The majority of people date their symptoms back to adolescence though go years seeking answers. Throughout their journey, many people  receive either a wrong diagnosis or were simply dismissed altogether.  In recent years, there has been a marked improvement in the recognition of the word ‘endometriosis’ but why does this disease remain such an enigma to so many healthcare professionals? Furthermore, endometriosis has been a subject of medical investigation for over a century with debates about how to approach treatment, understanding of the pathogenesis, clinical manifestations, and treatment methods.

Research in this field has evolved over time, but are we really that much further along than we were a century ago? One of the most frustrating concepts for those of us who truly understand endo, is the regurgitation of the theory of retrograde menstruation postulated in the 1920’s by Dr. John A. Sampson. The theory that endometriosis is derived from retrograde menstruation is an incomplete understanding of this original theory, that has perpetuated misinformation and our current recommended treatments – hormonal suppression and hysterectomies. Sampon’s original theory was more involved, but future research into alternative theories seems much more promising. Even so, our current “validated or trusted treatments” are still rooted in early understanding. This article delves into the intricate history of endometriosis, tracing its theories and advances, or lack thereof, to provide a comprehensive overview of this complex condition.

The Early Recognition of Endometriosis

Initial Observations and Descriptions

The first description of a disease resembling endometriosis can be attributed to Thomas Cullen in the early 20th century.¹ Cullen identified endometriosis and adenomyosis as a single disease, characterized by the presence of endometrium-like tissue outside the uterine cavity.² This breakthrough laid the foundation for future research and understanding of endometriosis.

Sampson’s Theory of Retrograde Menstruation

The term “endometriosis” was coined by John A. Sampson in the late 1920s.³ Sampson proposed the theory of retrograde menstruation as the primary cause of endometriosis, due to the observation during surgery of the similarity in endometriosis lesions and the endometrium, suggesting that endometrial cells are transported to ectopic locations via menstrual flow. This theory gained widespread acceptance and significantly influenced the direction of endometriosis research. Though he did note early on that there were additional factors to allow the growth of these lesions to transform, similar to more current theories and the immune system involvement.

Advances in Diagnosing Endometriosis

The Advent of Laparoscopy

The introduction of laparoscopy in the 1960s revolutionized the diagnosis of endometriosis.⁴ This minimally invasive surgical procedure allowed physicians to visually identify and classify endometriosis lesions, leading to a significant increase in the diagnosis of the disease.

Differentiating Clinical Presentations

With the advent of laparoscopy, three distinct clinical presentations of endometriosis were identified: peritoneal, deep adenomyotic, and cystic ovarian.⁵ These classifications, along with advances in imaging techniques such as ultrasound and magnetic resonance imaging (MRI), have improved the precision of endometriosis diagnosis.

Development of Medical Therapies for Endometriosis

Early Interventions

The first attempts at treating endometriosis with synthetic steroids began in the 1940s.⁶ Initially, androgenic substances were used, but their side effects led to a search for more effective and tolerable treatments. Fun fact: testosterone was actually the first hormone used in attempts to “treat” the disease. 

The Pseudo-pregnancy Regimen

The 1950s saw the advent of the “pseudo-pregnancy” regimen, where hormones were used to mimic the hormonal environment of pregnancy, thereby suppressing ovulation and endometrial growth.⁷ During this time, there were limited options and this suggestions came from the observation that symptoms were improved when pregnancy occurred. This approach utilized a combination of estrogen and progestin medications and marked a significant advance in the medical management of endometriosis. At this time, birth control was becoming more widespread and more options were being developed. The myth that is still perpetuated today by uninformed practitioners and society of “just get pregnant, it will cure your endo” or “just have a baby” stems from this belief. In 1953 a physician legitimized the limited options and made recommendations suggesting that frequent and often pregnancy was one of the only options and “subsidize your children” was the solution for the increased financial burden. There are so many infuriating suggestions at this recommendation, but the 50’s were a different time, with limited research and options. 

Gonadotropin-Releasing Hormone (GnRH) Agonists

Gonadotropin-releasing hormone (GnRH) agonists emerged as a primary medical therapy for endometriosis in the late 20th century.⁸ These drugs work by reducing the production of estrogen, thereby limiting the growth of endometriotic tissue, at least in theory. However, the side effects of hypoestrogenism led to the development of ‘add-back’ therapies to mitigate these effects.Not to mention poor regulation and research practices present in the 1990’s including falsified data on the true impact of these drugs. 

Evolution of Surgical Treatments

Conservative Surgery & Advancements in Endoscopic Surgery

The development of laparoscopy also transformed the surgical management of endometriosis. Conservative surgical techniques, including the excision of visible endometriosis lesions and adhesion lysis, became feasible.⁹ These procedures aimed to preserve fertility while effectively managing the disease. The late 20th century saw further advancements (again, in theory) in laparoscopic surgery for endometriosis. Techniques such as CO2 laser vaporization and the use of circular staplers for bowel resection improved the effectiveness and safety of surgery.¹⁰

Unraveling the Pathogenesis of Endometriosis

The Role of the Peritoneal Environment

Research in the 1980s began to focus on the peritoneal environment’s role in endometriosis. Studies found evidence of a local peritoneal inflammatory process, including increased activation of peritoneal macrophages and elevated cytokine and growth factor concentrations.¹¹

Endometrial Dysfunctions

Investigations also revealed biochemical differences between eutopic and ectopic endometrium in women with endometriosis. These differences suggested that endometriosis might be associated with endometrial dysfunction, contributing to both the pathogenesis and sequelae of the disorder.¹² While research exists that shows differences in BOTH the endometriosis lesions and the endometrial environment, this is correlational research, and does not imply causation. 

Immunological Factors

The involvement of the immune system in the pathogenesis of endometriosis was another significant discovery. Altered immune responses, including decreased T-cell and natural killer cell cytotoxicities, were observed in those with endometriosis.¹³

The Connection Between Endometriosis and Adenomyosis

In the late 20th century, researchers revisited the connection between endometriosis and adenomyosis, suggesting that the two conditions might represent different phenotypes of the same disorder.¹⁴ This theory proposed that both endometriosis and adenomyosis are primarily diseases of the junctional zone myometrium.

Modern Approaches to Endometriosis Treatment

Use of Gonadotropin-Releasing Hormone Agonist and Levonorgestrel-Releasing Intrauterine System

In more recent years, GnRHa therapy, often combined with ‘add-back’ therapy, has become a popular “treatment” for endometriosis.¹⁵ The levonorgestrel-releasing intrauterine system (LNG-IUS), which releases a progestin hormone into the uterus, has also shown promise in the management of endometriosis-associated chronic pelvic pain.¹⁶ In reality, this may be more true for adenomyosis and further research is needed. Research with less bias seems to oppose these claims stating that “GnRH drugs show marginal improvement over no active treatment” when compared with other hormonal suppression medications. Thanks to marketing, this is not well known among consumers. ¹⁹ Not to mention the significant side effects that further contribute to the various chronic overlapping pain syndromes associated with endometriosis. 

The Future of Endometriosis Research and Treatment

The evolution of endometriosis theories and advances underscores the complexity of this condition. As we continue to unravel the mysteries of endometriosis, there is an ongoing need for research into its pathogenesis, diagnosis, and treatment. The future of endometriosis research and treatment lies in a deeper exploration of its genetic-epigenetic aspects, the role of oxidative stress, and the impact of the peritoneal and upper genital tract microbiomes.¹⁸

Conclusion

The history of endometriosis is marked by a continual evolution of theories, advancements in diagnostic and therapeutic approaches, and an expanding understanding of the disease’s complex pathogenesis. From the initial descriptions by Thomas Cullen to the modern laparoscopic techniques and hormonal therapies, the journey of understanding and treating endometriosis has indeed been a frustrating one.

One of the most frustrating aspects is that when we really understand the first observations of endometriosis in the 1800’s into the early 1900’s, it is not far from where we are today. This demonstrates the serious need for more research, better research, and more in depth understanding of the pathogenesis and treatment approaches for endometriosis. While this has improved in the last five years, it is not enough. We need to do more, and we need to do better. Healthcare policy change is an extremely slow process and in my personal observation, decided among individuals who show less understanding than those with the disease. 

10. References

Disclaimer: This article is intended to provide general information on the topic and should not be used as a substitute for professional medical advice. Always consult with your healthcare provider for personal medical advice.

1. Cullen, T. (1920). Adenomyoma of the Uterus. WB Saunders.
2. Sampson, J.A. (1927). Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. American Journal of Pathology, 3(2), 93–110.
3. Sampson, J.A. (1927). Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics & Gynecology, 14, 422–469.
4. Brosens, I., & Benagiano, G. (2011). Endometriosis, a modern syndrome. Indian Journal of Medical Research, 133(6), 581–593.
5. Amro, B., et al. (2022). New Understanding of Diagnosis, Treatment and Prevention of Endometriosis. International Journal of Environmental Research and Public Health, 19(11), 6725.
6. Miller, E.J. (1944). The use of testosterone propionate in the treatment of endometriosis. American Journal of Obstetrics & Gynecology, 48(2), 181–184.
7. Kistner, R.W. (1958). The use of newer progestins in the treatment of endometriosis. American Journal of Obstetrics & Gynecology, 75(2), 264–278.
8. Hughes, E., et al. (2007). Ovulation suppression for endometriosis for women with subfertility. Cochrane Database of Systematic Reviews, (3), CD000155.
9. Brosens, I., et al. (2022). New Understanding of Diagnosis, Treatment and Prevention of Endometriosis. International Journal of Environmental Research and Public Health, 19(11), 6725.
10. Keckstein, J., & Becker, C.M. (2020). Endometriosis and adenomyosis: Clinical implications and challenges. Best Practice & Research Clinical Obstetrics & Gynaecology, 69, 92–104.
11. Dmowski, W.P., & Braun, D.P. (1997). Immunology of endometriosis. Best Practice & Research Clinical Obstetrics & Gynaecology, 11(3), 365–378.
12. Lebovic, D.I., et al. (2001). Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. Seminars in Reproductive Medicine, 19(2), 105–112.
13. Dmowski, W.P., & Braun, D.P. (1997). Immunology of endometriosis. Best Practice & Research Clinical Obstetrics & Gynaecology, 11(3), 365–378.
14. Leyendecker, G., et al. (2009). Endometriosis results from the dislocation of basal endometrium. Human Reproduction, 24(9), 2130–2137.
15. Surrey, E.S., & Soliman, A.M. (2019). Endometriosis and fertility: A review of the evidence and an approach to management. Journal of the Society of Laparoendoscopic Surgeons, 23(2), e2018.00087.
16. Vercellini, P., et al. (2003). Endometriosis and pelvic pain: relation to disease stage and localization. Fertility and Sterility, 79(2), 156–160.
17. Sutton, C.J., et al. (1994). Laser laparoscopy in the treatment of endometriosis: a 5 year study. British Journal of Obstetrics and Gynaecology, 101(3), 216–220.
18. Brosens, I., & Benagiano, G. (2011). Endometriosis, a modern syndrome. Indian Journal of Medical Research, 133(6), 581–593.
19. Johnson, N. P., Hummelshoj, L., & World Endometriosis Society Montpellier, C. (2013). Consensus on current management of endometriosis. Hum Reprod, 28(6), 1552-1568.