Origin Theories of Endometriosis

Where does endometriosis come from? 

There are several theories as to why and when endometriosis develops, although none have been proven definitively. Latest research demonstrates endometriosis lesions can be found in embryos thus highlighting that it can be laid down before birth. 

• Crispi, S., Piccolo, M. T., D’avino, A., Donizetti, A., Viceconte, R., Spyrou, M., … & Signorile, P. G. (2013). Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. Journal of cellular physiology, 228(9), 1927-1934. https://doi.org/10.1002/jcp.24358

“Our group has recently described the presence of ectopic endometrium in a consistent number of human female foetuses analysed by autopsy, reinforcing the hypothesis that endometriosis may be generated by defects during the organogenesis of the female reproductive trait….These data support the theory that embryological defects could be responsible of the endometriosis generation.” 

Why does it matter?

Many treatments (such as hysterectomy) are based on the oldest theory of the origins of endometriosis (Sampson’s theory) that menstrual blood backflows into the pelvis and once there attaches and grows. However, this retrograde menstruation occurs in most women but only around 10% develop endometriosis. In addition, endometriotic lesions have distinct characteristics from that of regular endometrial tissue from the uterus (see “Role of Estrogen Receptor” and “Progesterone Resistance in Endometriosis“). Hysterectomy can be useful for diseases of the uterus, such as fibroids or adenomyosis, but may not put an end to endometriosis symptoms or progression. Endometriosis is complicated and no one has the definitive answer, but new studies are highlighting new information that can help guide further care.

Links:

• “Mülleriosis: The best-fit theory of the origin of endometriosis”
• Video: “Mullerianosis: embryonic endometriosis, adenomyosis, endosalpingiosis, and endocervicosis”

Studies:

• Sourial, S., Tempest, N., & Hapangama, D. K. (2014). Theories on the pathogenesis of endometriosis. International journal of reproductive medicine, 2014. https://doi.org/10.1155/2014/179515 

In this study, the different theories of the origins of endometriosis as well as contributing factors are discussed. The authors state that “The aetiology of endometriosis is complex and multifactorial, where several not fully confirmed theories describe its pathogenesis.” The topics discussed does not imply that they are necessarily the CAUSE of endometriosis, but that they may CONTRIBUTE to the proliferation and to the symptoms of endometriosis. The authors discuss:

1. retrograde menstruation (“the oldest…theory proposes that endometriosis occurs due to the retrograde flow of sloughed endometrial cells/debris via the fallopian tubes into the pelvic cavity during menstruation [18]. However, retrograde menstruation occurs in 76%–90% of women with patent fallopian tubes and not all of these women have endometriosis.”) 
2. metaplasia (“residual embryonic cells of the Wolffian or Mullerian ducts persist and develop into endometriotic lesions that respond to oestrogen”)
3. hormones (“Oestrogen is the driving force of endometrial proliferation and ectopic lesions may have an increased responsiveness to oestrogen, thus enhancing the development of endometriosis”)
4. oxidative stress and inflammation (“accumulation of ROS may contribute to the propagation and maintenance of endometriosis and associated symptoms”)
5. immune dysfunction (“women with endometriosis have higher expression of cytokines and vascular endothelial growth factors in their peritoneal fluid, which promote proliferation of endometrial cells and angiogenesis”)
6. apoptosis suppression and alteration of endometrial cell fate (“inhibition of the apoptosis of endometrial cells may also be mediated by the transcriptional activation of genes that normally promotes inflammation, angiogenesis, and cell proliferation”)
7. genetics (“different types of endometriosis may be associated with altering different gene clusters that regulate specific cellular functional aberrations”)
8. stem cells (“due to their natural ability to regenerate, these stem cells may give rise to new endometriotic deposits”)

The theory of endometriosis being laid down during development of the fetus is evidenced in different studies:

• Crispi, S., Piccolo, M. T., D’avino, A., Donizetti, A., Viceconte, R., Spyrou, M., … & Signorile, P. G. (2013). Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. Journal of cellular physiology, 228(9), 1927-1934. https://doi.org/10.1002/jcp.24358 
• Laganà, A. S., Vitale, S. G., Salmeri, F. M., Triolo, O., Frangež, H. B., Vrtačnik-Bokal, E., … & Sofo, V. (2017). Unus pro omnibus, omnes pro uno: a novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Medical hypotheses, 103, 10-20. https://doi.org/10.1016/j.mehy.2017.03.032 
• Signorile, P. G., Baldi, F., Bussani, R., Viceconte, R., Bulzomi, P., D’Armiento, M., … & Baldi, A. (2012). Embryologic origin of endometriosis: analysis of 101 human female fetuses. Journal of Cellular Physiology, 227(4), 1653-1656.  https://doi.org/10.1002/jcp.22888
• Schuster, M., & Mackeen, D. A. (2015). Fetal endometriosis: a case report. Fertility and sterility, 103(1), 160-162. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S0015028214022274

Genetic associations with endometriosis can be seen the following studies:

•  European Society For Human Reproduction And Embryology. “Genetic Link To Endometriosis – Unique Icelandic Study Provides Further Proof.” ScienceDaily. ScienceDaily, 5 March 2002. www.sciencedaily.com/releases/2002/02/020228073008.htm

“… among sisters there was a 5.2-fold increase in the risk of being diagnosed with endometriosis”

• Dun, E. C., Taylor, R. N., & Wieser, F. (2010). Advances in the genetics of endometriosis. Genome medicine, 2(10), 75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988445/#!po=0.609756

(This study composites several previous studies on the familial tendencies for endometriosis.)

“They found a sixfold increased risk for first-degree relatives of women with laparoscopically confirmed diagnosis of endometriosis. Moen and Magnus [14] conducted a large Norwegian study composed of 522 cases, which supported the findings of earlier studies looking at familial aggregation; 3.9% of mothers and 4.8% of sisters of affected individuals had endometriosis compared with only 0.6% of sisters in the control group. Interestingly, this Norwegian study [14] also concluded that symptom severity was increased among women who had relatives with endometriosis, a conclusion originally reported in a smaller study by Malinak et al. [12].”

• Nouri, K., Ott, J., Krupitz, B., Huber, J. C., & Wenzl, R. (2010). Family incidence of endometriosis in first-, second-, and third-degree relatives: case-control study. Reproductive Biology and Endocrinology, 8(1), 85. https://pubmed.ncbi.nlm.nih.gov/20618992/

“Endometriosis was found in 8/136 (5.9%) first-degree relatives of patients and in 4/134 (3.0%) first-degree relatives of controls in the real-case analysis” 

• 23andMe. (2017). New genetic variants found to influence endometriosis risk. Retrieved from https://blog.23andme.com/23andme-research/endometriosis/

“…the study identified 19 genetic variants associated with endometriosis, and many of those variants are also associated with other serious health conditions such as ovarian cancer, cardiovascular disease and high cholesterol….In this case the study found several variants in genes involved in sex hormone metabolism, specifically the genes GREB1, FN1, KDR, CCDC170, ESR1, SYNE1, and FSHB.”  

• Stefansson, H., Geirsson, R. T., Steinthorsdottir, V., Jonsson, H., Manolescu, A., Kong, A., … & Stefansson, K. (2002). Genetic factors contribute to the risk of developing endometriosis. Human reproduction, 17(3), 555-559. Retrieved from https://academic.oup.com/humrep/article/17/3/555/642154

“CONCLUSIONS: This is the first population-based study using an extensive genealogy database to examine the genetic contribution to endometriosis. A genetic factor is present, with a raised risk in close and more distant relatives, and a definite kinship factor with maternal and paternal inheritance contributing.”

• Rahmioglu, N., Montgomery, G. W., & Zondervan, K. T. (2015). Genetics of endometriosis. Women’s health, 11(5), 577-586. Retrieved from https://journals.sagepub.com/doi/pdf/10.2217/whe.15.41

“The heritable component of endometriosis has been illustrated by many different studies [2–4]. Higher rates of endometriosis among relatives of endometriosis cases compared with controls was shown, with risk ratio compared with general population risk for sisters estimated at 5.2 and for cousins 1.6 in a population-based study in Iceland [3]. In addition, in a hospital-based study in the UK, consisting of 230 women with surgically confirmed endometriosis in 100 families, familial aggregation of endometriosis was shown [4]. However, estimates of familial aggregation in human populations are likely to be affected – to an unknown extent – by the fact that endometriosis is only reliably diagnosed through laparoscopy. The chance of being diagnosed with endometriosis may be influenced by having a family member already diagnosed with disease and it is difficult to get an accurate population-based estimate of disease risk [5]. Stronger evidence of heritability is provided by twin studies, that have shown higher concordance in monozygotic twins compared with dizygotic twins, a finding less likely to be affected by selection biases operating on diagnostic opportunity [6,7]. The largest twin study, among 3096 Australian female twins, estimated the heritable component of endometriosis at 51%.”

• Sapkota, Y., Attia, J., Gordon, S. D., Henders, A. K., Holliday, E. G., Rahmioglu, N., … & Scott, R. J. (2015). Genetic burden associated with varying degrees of disease severity in endometriosis. Mhr: Basic science of reproductive medicine, 21(7), 594-602. Retrieved from https://academic.oup.com/molehr/article/21/7/594/2459755

“For the minimal disease, genetic factors may contribute to a lesser extent than other disease categories. Mild and moderate endometriosis appeared genetically similar, making it difficult to tease them apart. Consistent with our previous reports, moderate and severe endometriosis showed greater genetic burden than minimal or mild disease.”

• Hansen, K. A., & Eyster, K. M. (2010). Genetics and genomics of endometriosis. Clinical obstetrics and gynecology, 53(2), 403. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346178/

“Studies have demonstrated the familial nature of endometriosis and suggest that inheritance occurs in a polygenic/multifactorial fashion. Studies have attempted to define the gene or genes responsible for endometriosis through association or linkage studies with candidate genes or DNA mapping technology. A number of genomics studies have demonstrated significant alterations in gene expression in endometriosis….A number of studies have demonstrated the familial clustering of endometriosis and that first-degree relatives of affected women are 5 to 7 times more likely to have surgically confirmed disease….Other findings support polygenic/multifactorial inheritance of endometriosis. First endometriosis that occurs in families tends to be more severe compared to sporadic cases. This suggests that there is more genetic propensity or liability in individuals with severe disease, and hence there is more likelihood to have affected sibs or offspring. Other factors which suggest a genetic predisposition to endometriosis include the similar and earlier age of onset of symptoms in affected families. Twin studies have demonstrated a higher concordance for endometriosis in monozygotic versus dizygotic twins, which suggested increased heritability….

“Another method used to investigate for gene mutations or polymorphisms associated with endometriosis involves gene mapping….A number of candidate genes have been evaluated for their association with endometriosis and include genes involved in inflammation, steroid-synthesis, detoxification, hormone receptors, estrogen metabolism, growth factors, adhesion molecules, apoptosis, cell-cycle regulation, oncogenes, other enzymes and metabolic systems. These studies have a priori defined the gene of interest which is then tested for association in a case-control or in a linkage study in individuals from an affected family. Most of these studies have failed to support or confirm an association between the candidate gene and endometriosis with a few interesting exceptions….

“Another gene mapping technique which holds promise in investigating the inheritance of endometriosis is Genome-wide Association scans. This is a very powerful, hypothesis free technique using single nucleotide polymorphisms (SNPs) to evaluate the genome for risk-associated variations….Further studies will help define these associations and determine the significant genes involved in the pathogenesis of endometriosis….

“Whereas genetics refers to the heritability of a trait, genomics refers to how genes are expressed….All of the cells in our bodies contain the same set of chromosomes with the same set of genes, the genome, but each differentiated cell type expresses only a fraction of the total available genes….angiogenic factors, growth factors, and hormone receptor genes are also up-regulated in the genomic studies. ¹⁸ Perhaps the most interesting aspect of the gene expression studies is the highlighting of the up-regulation of inflammatory response gene.^25, 33 The inflammatory nature of endometriosis has long been recognized³²; the genomics studies further advance the concept that aberrant communication between ectopic endometrial cells and immune system cells participating in the inflammatory response contribute to the development and persistence of endometriosis. ^25, 34 Collectively, the studies cited above support the hypothesis that endometriosis is the result of abnormal expression or regulation of certain key genes.”