Exploring endometriosis: a surprisingly common disease

Endometriosis is a chronic inflammatory disease where cells belonging inside a woman’s* uterus are found in other parts of the body. This condition is characterized by debilitating pelvic pain during menstruation, sex, excretion or urination, as well as heavy menstrual flow, fatigue and infertility [1,2,3]. Consequently, the quality of life can be severely impacted [4,5,6]. What may be most surprising about the disease is that little is known about its cause, even though it affects one in ten American women of reproductive age [7], or 1 in 9 Australian women under 44 years [8], for example. As a result, the road to diagnosis is often long and difficult [9], stressing the need for potential sufferers to know the difference between bad cramps and endometriosis. In this article, we cover the latest research on the origin of endometriosis, how the disease is diagnosed, and what treatment options are available.

The first hypothesis for endometriosis was proposed by John A. Sampson in 1927 and is still the most widely accepted one. Retrograde menstruation, when a woman’s menses flows in the wrong direction, can carry viable pieces of cells from the lining of the uterus, called the endometrium. Since ovaries are not directly attached to the fallopian tubes, retrograde menstruation allows menses to flow into the pelvis for endometrial cells to invade other tissues, subsequently forming scar tissue named endometrial lesions [10]. The effect of gravity, the clockwise flow of fluid around the abdomen, and the anatomy of the pelvis then fits the typical distribution of endometrial lesions in the body, for instance the fallopian tubes, ovaries and the space between the uterus and rectum or bladder [10,11, 12]. However, lesions can also appear – more rarely – on the cervix, or even around the stomach, intestines and lungs, which are less accessible from the pelvis [1,10]. Therefore, the Sampson hypothesis is still incomplete.

It is also plausible that genetics, inflammation, immunity, hormones and environmental factors could all act together to cause endometriosis. Genetically, there is a sixfold higher chance of displaying endometriosis if a first-degree relative has it [13], with researchers currently focusing on identifying “endometriosis genes” and markers to diagnose the disease [14,15,16]. An overview of studies between 1991 and 2011 suggests that the female-associated hormone estrogen is involved in enhancing inflammation and improving the survival of endometrial cells, which would contribute to symptoms such as pelvic pain and infertility [17].  The activity of white blood cells in charge of eliminating unwanted cells in the body may have impaired activity in women with endometriosis, which can lead to wayward cells from the endometrium escaping detection. Endometrial lesions persistently release molecules that promote inflammation and the formation of new blood vessels as well, producing a chronic inflammatory response in the body [18].  In a study of 161 patients with endometriosis, environmental factors like premature birth and formula feeding correlated with a higher chance of having the disease, hence this may affect endometriosis development before and after birth [19]. In addition, all known risk factors for increased menstrual flow, such as short menstrual cycles and early age for a first period, overlap with risk for endometriosis [20]. Scientific articles extensively reviewing studies on endometriosis are published periodically and can offer further examples, though a common theme persists that the exact biological mechanisms behind endometriosis are still unclear or need validation [21].

As a result of these knowledge gaps, and the overlap of symptoms like pelvic pain with other gastrointestinal and urinary disorders [22], the diagnosis of endometriosis can be a long and tricky process. Diagnosis time can range from 4-11 years, and 65% of women are initially misdiagnosed [9]. There are three main types of endometriosis: superficial peritoneal lesions (SUP), ovarian endometriomas (OMA) and deep infiltrating endometriosis (DIE) [21]. The current gold standard for diagnosis involves a minimally invasive surgery, where a thin, lighted tube with a camera takes pictures from a small cut made in the abdomen to find evidence of endometrial lesions [1]. However, imaging techniques such as ultrasound taken from within the vagina and magnetic resonance imaging (MRI) can also suitably identify OMA- and DIE-type endometriosis [23,24,25]. Researchers from the University of Paris Descartes argue that consistent records of a woman’s medical history, such as pain associated with monthly cycles, can significantly contribute to initiating a timely diagnosis for endometriosis as well [21].

Once endometriosis is diagnosed, focus can be put on symptom management, as there is currently no cure. The first line of therapy is usually pain killers and oral birth control, especially when used without a break for menstruation, as these reduce inflammation and therefore pain [26,27]. However, this option is not suitable for women that wish to become pregnant. In addition, one quarter to one third of patients do not respond to the treatment, have adverse side effects, or other medical reasons not to take hormonal birth control [28]. In these cases, a different class of hormones called gonadotropin-releasing hormone analogues (GnRHa for short) can be prescribed that relieves pain in 85% of women, though it is more expensive than first-line therapy [26,29]. Alternatively, surgery via the same camera-guided method as the diagnosis can be used to remove lesions partially or fully and may even be performed during the diagnostic surgery. Evidence for long-term pain relief and help with infertility is contested though, and recurrence of endometriosis is also possible [30,31]. As a last resort, the uterus or the ovaries can be removed [32].

Overall, endometriosis is a difficult disease affecting menstruating women worldwide. Research is continuing to reduce  the knowledge gaps, but in the meantime, improving outreach and education is an important first step in raising awareness for such a common disorder [8].

*Disclaimer: this article will use women as a catch-all term for persons that menstruate, to reflect the terms used in scientific literature.

All images are the work of Dr. Marco Garbelli, a member of the Facts&Reasons graphics team.

References:

1. John Hopkins Medicine. Endometriosis. Retrieved July 13, 2023, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/endometriosis

2. NHS. Endometriosis. Retrieved July 13, 2023, from https://www.nhs.uk/conditions/endometriosis/

3. World Health Organization. Endometriosis. Retrieved July 13, 2023, from https://www.who.int/news-room/fact-sheets/detail/endometriosis

4. Hämmerli, S., Kohl Schwartz, A. S., Geraedts, K., Imesch, P., Rauchfuss, M., Wölfler, M. M., Haeberlin, F., von Orelli, S., Eberhard, M., Imthurn, B., & Leeners, B. (2018). Does Endometriosis Affect Sexual Activity and Satisfaction of the Man Partner? A Comparison of Partners From Women Diagnosed With Endometriosis and Controls. The Journal of Sexual Medicine, 15(6), 853–865.

5. Nnoaham, K. E., Hummelshoj, L., Webster, P., D’Hooghe, T., De Cicco Nardone, F., De Cicco Nardone, C., Jenkinson, C., Kennedy, S. H., & Zondervan, K. T. (2011). Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertility and Sterility, 96(2).

6. Simoens, S., Dunselman, G., Dirksen, C., Hummelshoj, L., Bokor, A., Brandes, I., Brodszky, V., Canis, M., Colombo, G. L., Deleire, T., Falcone, T., Graham, B., Halis, G., Horne, A., Kanj, O., Kjer, J. J., Kristensen, J., Lebovic, D., Mueller, M., … Dhooghe, T. (2012). The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Human Reproduction (Oxford, England), 27(5), 1292–1299.

7. Buck Louis, G. M., Hediger, M. L., Peterson, C. M., Croughan, M., Sundaram, R., Stanford, J., Chen, Z., Fujimoto, V. Y., Varner, M. W., Trumble, A., & Giudice, L. C. (2011). Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertility and Sterility, 96(2), 360–365. https://doi.org/10.1016/J.FERTNSTERT.2011.05.087

8. Australian Institute of Health and Welfare. Endometriosis in Australia: prevalence and hospitalisations. 16.

9. Greene, R., Stratton, P., Cleary, S. D., Ballweg, M. Lou, & Sinaii, N. (2009). Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertility and Sterility, 91(1), 32–39.

10. Sampson, J. A. (1927). Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics and Gynecology, 14(4), 422–469.

11. Bricou, A., Batt, R. E., & Chapron, C. (2008). Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: why Sampson seems to be right. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 138(2), 127–134.

12. Chapron, C., Chopin, N., Borghese, B., Foulot, H., Dousset, B., Vacher-Lavenu, M. C., Vieira, M., Hasan, W., & Bricou, A. (2006). Deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. Human Reproduction (Oxford, England), 21(7), 1839–1845.

13. Stefansson, H., Geirsson, R. T., Steinthorsdottir, V., Jonsson, H., Manolescu, A., Kong, A., Ingadottir, G., Gulcher, J., & Stefansson, K. (2002). Genetic factors contribute to the risk of developing endometriosis. Human Reproduction (Oxford, England), 17(3), 555–559. https://doi.org/10.1093/HUMREP/17.3.555

14. Treloar, S. A., Wicks, J., Nyholt, D. R., Montgomery, G. W., Bahlo, M., Smith, V., Dawson, G., Mackay, I. J., Weeks, D. E., Bennett, S. T., Carey, A., Ewen-White, K. R., Duffy, D. L., O’Connor, D. T., Barlow, D. H., Martin, N. G., & Kennedy, S. H. (2005). Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. American Journal of Human Genetics, 77(3), 365–376.

15. Treloar, S., Hadfield, R., Montgomery, G., Lambert, A., Wicks, J., Barlow, D. H., O’Connor, D. T., & Kennedy, S. (2002). The International Endogene Study: A collection of families for genetic research in endometriosis. Fertility and Sterility, 78(4), 679–685.

16. Zondervan, K. T., Treloar, S. A., Lin, J., Weeks, D. E., Nyholt, D. R., Mangion, J., MacKay, I. J., Cardon, L. R., Martin, N. G., Kennedy, S. H., Montgomery, G. W., Wicks, J., Wainwright, B. J., Henders, A., Zabaneh, D., Dawson, G., Smith, V., Carey, A., Bennett, S. T., … Ewen-White, K. R. (2007). Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15. Human Reproduction (Oxford, England), 22(3), 717–728.

17. Reis, F. M., Petraglia, F., & Taylor, R. N. (2013). Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Human Reproduction Update, 19(4), 406–418.

18. Giudice, L. C., & Kao, L. C. (2004). Endometriosis. The Lancet, 364(9447), 1789–1799. https://doi.org/10.1016/S0140-6736(04)17403-5

19. Vannuccini, S., Lazzeri, L., Orlandini, C., Tosti, C., Clifton, V. L., & Petraglia, F. (2016). Potential influence of in utero and early neonatal exposures on the later development of endometriosis. Fertility and Sterility, 105(4), 997–1002.

20. Vercellini, P., Viganò, P., Somigliana, E., & Fedele, L. (2014). Endometriosis: pathogenesis and treatment. Nature Reviews. Endocrinology, 10(5), 261–275.

21. Chapron, C., Marcellin, L., Borghese, B., & Santulli, P. (2019). Rethinking mechanisms, diagnosis and management of endometriosis. Nature Reviews Endocrinology 2019 15:11, 15(11), 666–682.

22. Sinaii, N., Plumb, K., Cotton, L., Lambert, A., Kennedy, S., Zondervan, K., & Stratton, P. (2008). Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertility and Sterility, 89(3), 538–545.

23. Guerriero, S., Condous, G., van den Bosch, T., Valentin, L., Leone, F. P. G., Van Schoubroeck, D., Exacoustos, C., Installé, A. J. F., Martins, W. P., Abrao, M. S., Hudelist, G., Bazot, M., Alcazar, J. L., Gonçalves, M. O., Pascual, M. A., Ajossa, S., Savelli, L., Dunham, R., Reid, S., … Timmerman, D. (2016). Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound in Obstetrics & Gynecology : The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology, 48(3), 318–332.

24. Guerriero, Stefano, Alcázar, J. L., Pascual, M. A., Ajossa, S., Perniciano, M., Piras, A., Mais, V., Piras, B., Schirru, F., Benedetto, M. G., & Saba, L. (2018). Deep Infiltrating Endometriosis: Comparison Between 2-Dimensional Ultrasonography (US), 3-Dimensional US, and Magnetic Resonance Imaging. Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine, 37(6), 1511–1521.

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31. Vercellini, P., Barbara, G., Abbiati, A., Somigliana, E., Viganò, P., & Fedele, L. (2009). Repetitive surgery for recurrent symptomatic endometriosis: what to do? European Journal of Obstetrics, Gynecology, and Reproductive Biology, 146(1), 15–21.

32. Chapron, C., Fauconnier, A., Vieira, M., Barakat, H., Dousset, B., Pansini, V., Vacher-Lavenu, M. C., & Dubuisson, J. B. (2003). Anatomical distribution of deeply infiltrating endometriosis: surgical implications and proposition for a classification. Human Reproduction (Oxford, England), 18(1), 157–161.