The Role of Estrogen Receptor-β in Endometriosis
Endometriosis is a complex and often painful condition characterized by the presence of tissue similar to the uterine lining (endometrium) outside the uterus. This study delves into the molecular differences between endometriosis lesions and normal uterine tissue, particularly focusing on hormonal receptors and their role in treatment resistance.
Differences in Hormonal Receptors and Treatment Resistance
Endometriosis lesions differ fundamentally from eutopic endometrium in their response to hormones. Estrogen is a key driver of endometriosis, fueling the growth and persistence of lesions. Unlike normal uterine tissue, endometriosis lesions have a unique hormonal receptor profile, notably with higher levels of estrogen receptor-β (ERβ) and lower levels of estrogen receptor-α (ERα) and progesterone receptors (PRs).
This hormonal imbalance contributes to the resistance seen in conventional hormonal treatments such as synthetic progestins, oral contraceptives, and gonadotropin-releasing hormone (GnRH) analogs. These treatments often fail in nearly half of patients, leaving a significant gap in effective management strategies. Aromatase inhibitors, in combination with ovulation suppressors, have shown promise for cases resistant to traditional treatments.
Unique Characteristics of Endometriosis Lesions
Endometriosis lesions can produce their own estrogen, exacerbating inflammation and pain. They exhibit high levels of ERβ, which is more than 100 times higher than in normal endometrium. This overexpression is believed to be influenced by defective DNA methylation and other epigenetic mechanisms. Conversely, ERα and PR expression are significantly reduced in endometriosis lesions. The imbalance between ERα and ERβ disrupts normal hormonal responses, including the ability of estradiol to induce PR expression.
The suppression of PR-B, in particular, contributes to progesterone resistance, a hallmark of endometriosis. Progesterone resistance makes it difficult to manage the condition with conventional hormonal therapies, as the body does not respond effectively to progesterone’s regulatory effects.
The Impact of Estrogen and Prostaglandins on Pain and Inflammation
Estradiol, a potent form of estrogen, is a key hormone in endometriosis. It reaches the lesions either through circulation or is produced locally via aromatase activity. This local estrogen production promotes inflammation, pain, and growth of the lesions. ERβ overexpression stimulates prostaglandin production by inducing COX2 expression, further amplifying pain and inflammation.
Insights into Molecular Differences
The study highlights several molecular differences between endometriotic and eutopic tissues. Key findings include:
- ERβ overexpression: This suppresses ERα expression, leading to high ERβ-to-ERα ratios in endometriotic cells.
- Progesterone resistance: Reduced PR-B levels impair the ability of progesterone to regulate endometriotic growth.
- Steroidogenic activity: The orphan nuclear receptor SF1 is overexpressed in endometriotic tissue, driving local estrogen production.
A Shift in Hormonal Dynamics
The authors speculate that the high ERβ-to-ERα ratio may shift the hormonal balance in endometriotic stromal cells, inhibiting PR expression and further contributing to progesterone resistance. This dynamic underscores the critical role of ERβ in the pathology of endometriosis, with broad implications for understanding the disease and developing targeted therapies.
Conclusion
High estrogen production and unique receptor profiles are defining features of endometriosis. The overexpression of ERβ and the suppression of PR-B highlight the complexity of the condition and its resistance to conventional treatments. Addressing these molecular differences holds the key to developing more effective management strategies and improving outcomes for women with endometriosis.
Reference:
Bulun, S. E., Monsavais, D., Pavone, M. E., Dyson, M., Xue, Q., Attar, E., … & Su, E. J. (2012). Role of estrogen receptor-β in endometriosis.
Seminars in Reproductive Medicine, 30(01), 39-45.
Read more.
Leptin and Its Role in Endometriosis
We’ve heard about leptin and its role in weight gain/loss, but did you know leptin does more than that?
“Subsequent work has confirmed that leptin has a pleiotrophic role on the immune response and can rightly be considered, both structurally and functionally, as a proinflammatory cytokine (Lord, 2006, p. 151).” (Note: Pleiotrophic means one gene that influence many, so leptin can influence lots of different things.) Also, in a very small study, leptin was tied to greater fatigue in CFS patients: “Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology (Stringer et al., 2013, p.1).
So, leptin can be proinflammatory and influence many different responses in the body (including energy/fatigue and immune response). The following studies demonstrate that leptin (similar to the effects of estrogen) can cause endometriosis lesions to proliferate (to get bigger and bulkier).
This study explores leptin’s role in endometriosis and its effect on inflammation and angiogenesis (creating new blood vessels). It also found that leptin had a different effect on cells in the uterus versus endometriosis lesions (highlighting that endometriosis cells have distinct differences from the lining of the uterus).
- Wu, M. H., Chuang, P. C., Chen, H. M., Lin, C. C., & Tsai, S. J. (2002). Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Molecular human reproduction, 8(5), 456-464. Retrieved from https://academic.oup.com/molehr/article/8/5/456/1030708
“Leptin has been reported to exert immunoregulatory, proinflammatory, mitogenic and angiogenic effects in several tissues (Gainsford et al., 1996; Wolf et al., 1999; Caprio et al., 2001). This makes it a potential candidate for contributing to the progress of endometriosis. A recent report even demonstrated that leptin levels in peritoneal fluid and serum of patients with pelvic endometriosis are increased (Matarese et al., 2000). However, the cellular origin and mechanism by which leptin modulates the formation of endometriosis is not clear. We herein present evidence showing that leptin and its receptor are differentially expressed in endometriosis and are involved in the proliferation of endometrial stromal cells….
“…leptin stimulated a significant increase in eutopic as well as ectopic endometrial stromal cell proliferation. However, this mitogenic effect of leptin was somewhat different in eutopic endometrial stromal cells compared with ectopic endometriotic stromal cells. In eutopic endometrial stromal cells, leptin caused a greater extent of cell proliferation and at much lower doses (Figure 8A). In stromal cells obtained from ectopic endometriotic implants, only high doses of leptin (3 and 10 ng/ml) induced cell proliferation and the induction was less pronounced (Figure 8B)….
“…we showed that both leptin transcripts and protein are highly expressed in ectopic endometriotic lesions. In eutopic endometrium, leptin was not detected in a half of the samples and only extremely low amounts of leptin were detected in the other half of the endometria. In concordance with our finding, contradictory reports have shown either positive or negative leptin expression in normal human endometrium (Alfer et al., 2000; Gonzalez et al., 2000a; Kitawaki et al., 2000). The reasons for differences in leptin transcript expression in eutopic endometrium are not known. Nevertheless, leptin was highly expressed in ectopic endometriotic lesions. The elevation of leptin in ectopic endometriosis was not due to differences in the stages of menstrual cycles or body mass as evidenced by marked increase of leptin in ectopic endometriotic tissues as compared to the eutopic endometrium collected from the same patients (n = 4). In addition, the mean BMI was not different between eutopic and endometriosis groups. Thus, elevated expression of leptin in ectopic endometriotic tissues may reflect the distinct biochemical nature of endometriotic lesions. Our result showing that leptin is markedly expressed in ectopic endometriotic lesions supports previous reports that the peritoneal fluid concentration of leptin was increased in women with endometriosis (Matarese et al., 2000; De Placido et al., 2001)….One of the examples is the acquisition of estrogen-producing ability in ectopic endometriotic implants (Noble et al., 1996; Bulun et al., 1999, 2000). Our recent data have also indicated that ectopic endometriotic cells of early endometriosis express high quantities of steroidogenic acute regulatory protein and produce high levels of progesterone (Tsai et al., 2001c). As a consequence, the ectopic endometriotic tissues become independent of the survival factors generated from gonads, and proliferate continuously throughout the cycle….In summary, differential expression of leptin and its receptor in eutopic and ectopic endometrium suggests that leptin may have a critical role in endometriosis development. Elevated leptin expression by endometriosis lesions appears to enhance the proliferation of ectopic endometriotic stromal cells. Our findings may open a new field of investigation into the actions of leptin in the pathogenesis of endometriosis and provide a reasonable rationale for developing a therapeutic regime for endometriosis by targeting leptin and its action.”
In the following study, the authors further investigate the role of leptin in endometriosis through its inflammatory and angiogenic properties:
- Nácul, A. P., Lecke, S. B., Edelweiss, M. I., Morsch, D. M., & Spritzer, P. M. (2013). Gene expression of leptin and long leptin receptor isoform in endometriosis: a case-control study. Obstetrics and gynecology international, 2013. Retrieved from http://www.hindawi.com/journals/ogi/2013/879618/
“It (Leptin) may also play a role in endometriosis through its inflammatory and angiogenic properties…. Moreover, the possibility of an association between PF leptin levels and severity of endometriosis is also controversial, with some studies suggesting a negative correlation [2, 6, 8] and others showing a positive correlation with more severe forms of peritoneal endometriosis [5, 7, 13, 15]….Conclusions: The present data suggest that serum leptin/BMI ratio is associated with the presence of endometriosis. Nevertheless, the clinical applicability of the leptin/BMI ratio for prediction of endometriosis still requires confirmation. Moreover,the increased expression of leptin and OB-RL in ectopic endometrium suggests a modulatory interaction between leptin and its active receptor and a role of leptin, an inflammatory and angiogenic cytokine, in the initiation or development of endometrial implants.”
In this study, the authors elaborate on the increased leptin expression in endometriosis cells causing them to proliferate:
- Wu, M. H., Chuang, P. C., Chen, H. M., Lin, C. C., & Tsai, S. J. (2002). Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Molecular human reproduction, 8(5), 456-464. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11994543/
“Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Abstract: Endometriosis is a polygenic disease with complex, multifactorial aetiologies affecting approximately 10% of women of reproductive age. Leptin is the product of the ob gene, which is related to reproductive function and immunological alteration. The angiogenic and mitogenic action of leptin may influence the formation of endometriosis. This study was aimed at determining whether leptin and leptin receptor expression differs in eutopic and ectopic endometria collected from laparoscopy and at investigating the pathophysiological role of leptin in the development of endometriosis. Leptin mRNA was undetectable in seven out of 14 eutopic endometria and only a minute amount was detected in the remaining samples. In contrast, there was a marked increase in leptin mRNA and protein expression in ectopic endometriotic lesions of patients with endometriosis (P < 0.05). Receptors for leptin were immunologically stained in eutopic endometrium as well as in ectopic endometriotic implants. However, the levels of mRNA for the long and total forms of leptin receptors were suppressed in association with the severity of endometriosis (P < 0.05). Administration of leptin stimulated its own mRNA expression in ectopic endometriotic stromal cells but decreased steady-state concentrations of mRNA encoding for leptin receptor (n = 6). In addition, leptin significantly enhanced both eutopic and ectopic endometrial stromal cell proliferation (P < 0.05). In conclusion, the differential distribution of mRNA for leptin and its receptor suggests an important autocrine and paracrine role for leptin in human endometriosis. The mitogenic and auto-augmentation effects of leptin may further contribute to the pathogenesis of endometriosis.”
The following study discusses leptin stimulating the increased growth of endometriosis cells:
- Oh, H. K., Choi, Y. S., Yang, Y. I., Kim, J. H., Leung, P. C., & Choi, J. H. (2012). Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. MHR: Basic science of reproductive medicine, 19(3), 160-168. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23184927
“Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Leptin acts as a potential growth stimulator in several normal and neoplastic cells. Recent studies have shown the presence of increased levels of leptin in the peritoneal fluid of patients with endometriosis, implicating leptin in the pathogenesis of endometriosis. However, the specific function of leptin in the induction of mitogenesis in endometriosis is not known. This study investigated the expression of the leptin receptor (ObR) in endometrioma tissues and immortalized endometriotic cells, and the effect of leptin on cell growth. ObR expression was higher in endometriomas than in the normal endometrium, and it was detected in 74% of epithelial and 30% of stromal endometrioma tissues. In addition, human endometriotic epithelial cells (11Z and 12Z) showed a high level of ObR when compared with endometrial cells and endometriotic stromal cells (22B). Furthermore, leptin treatment stimulated the growth of 11Z and 12Z cells, but not that of 22B cells. Knockdown of the ObR in 11Z and 12Z cells impaired the ability of leptin to induce cell growth. Leptin induced the activation of Janus Kinases 2 (JAK2), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) in endometriotic epithelial cells. Moreover, pretreatment with the JAK2/STAT3 inhibitor AG490 and the ERK inhibitor PD98059 significantly inhibited leptin-induced cell growth. The present results show that the ObR is induced in endometriosis, and that leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways.”
References
Lord, G. M. (2006). Leptin as a proinflammatory cytokine. In Obesity and the Kidney (Vol. 151, pp. 151-164). Karger Publishers. Retrieved from https://pubmed.ncbi.nlm.nih.gov/16929139/
Stringer, E. A., Baker, K. S., Carroll, I. R., Montoya, J. G., Chu, L., Maecker, H. T., & Younger, J. W. (2013). Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. Journal of translational medicine, 11(1), 93. Retrieved from http://www.translational-medicine.com/content/11/1/93
Progesterone Resistance in Endometriosis
The following studies elaborate on progesterone resistance in endometriosis lesions. This progesterone resistance could provide a clue as to why some people do not respond to progestin therapy. It also is a clue as to why estrogen exerts such a strong role on endometriosis- because there is not a balancing progesterone effect.
- Cheng, Y. H., Imir, A., Fenkci, V., Yilmaz, M. B., & Bulun, S. E. (2007). Stromal cells of endometriosis fail to produce paracrine factors that induce epithelial 17β-hydroxysteroid dehydrogenase type 2 gene and its transcriptional regulator Sp1: a mechanism for defective estradiol metabolism. American journal of obstetrics and gynecology, 196(4), 391-e1. Retrieved from http://www.ncbi.nlm.nih.gov/m/pubmed/17403431/?i=5&from=/9851796/related
“CONCLUSION: A stromal cell defect in endometriosis blocks formation of progesterone-dependent production of factors leading to 17beta-hydroxysteroid dehydrogenase type 2 deficiency and defective conversion of estradiol to estrone in epithelium.”
- Bruner-Tran, K. L., Herington, J. L., Duleba, A. J., Taylor, H. S., & Osteen, K. G. (2013). Medical management of endometriosis: emerging evidence linking inflammation to disease pathophysiology. Minerva ginecologica, 65(2), 199. Retrieved from http://europepmc.org/articles/PMC3718308
“…initial studies comparing endometrial tissues from women with and without endometriosis examined circulating progesterone levels relative to expected histological responses across the secretory phase of the menstrual cycle 27–29. These investigations revealed that while women with endometriosis exhibit normal circulating ovarian progesterone levels, the endometrium’s ability to respond appropriately to this steroid appeared to be reduced 27–29. Subsequent studies confirmed that endometrial tissues from women with endometriosis did not exhibit the changes in specific gene and protein expression normally expected during the progesterone-dominated secretory phase 12, 30–31. Perhaps not surprisingly, altered expression of genes and proteins in endometriosis patients was reported to be associated with changes in the expression pattern of progesterone receptor (PR) isotypes (PR-A and PR-B), at both eutopic and ectopic sites of endometrial growth11, 32–33….At present, the biological origin of reduced endometrial progesterone responsiveness among women with endometriosis remains to be fully elucidated; however, a number of research groups have begun to examine whether chronic inflammatory processes may promote the development of endometrial resistance to this steroid. Within the reproductive tract, an important component of steroidal regulation of inflammation involves cellular signaling by members of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) family. This signaling network has been suggested to play a critical role in triggering, or enhancing, the inflammatory processes…Although the studies noted above support the concept that inflammatory processes may represent a potential trigger for the loss of progesterone sensitivity related to endometriosis, the precise cellular and molecular mechanisms leading to this disease phenotype remain elusive. In this regard, a number of recent observations suggest that epigenetic modification, mediated by chronic inflammation, could explain the progesterone resistant endometrial phenotype observed in women with endometriosis. ”
- Al-Sabbagh, M., Lam, E. W. F., & Brosens, J. J. (2012). Mechanisms of endometrial progesterone resistance. Molecular and cellular endocrinology, 358(2), 208-215. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22085558
“Throughout the reproductive years, the rise and fall in ovarian hormones elicit in the endometrium waves of cell proliferation, differentiation, recruitment of inflammatory cells, apoptosis, tissue breakdown and regeneration. The activated progesterone receptor, a member of the superfamily of ligand-dependent transcription factors, is the master regulator of this intense tissue remodelling process in the uterus. Its activity is tightly regulated by interaction with cell-specific transcription factors and coregulators as well as by specific posttranslational modifications that respond dynamically to a variety of environmental and inflammatory signals. Endometriosis, a chronic inflammatory disorder, disrupts coordinated progesterone responses throughout the reproductive tract, including in the endometrium. This phenomenon is increasingly referred to as ‘progesterone resistance’. Emerging evidence suggests that progesterone resistance in endometriosis is not just a consequence of perturbed progesterone signal transduction caused by chronic inflammation but associated with epigenetic chromatin changes that determine the intrinsic responsiveness of endometrial cells to differentiation cues.”
Why is this progesterone resistance in endometriosis lesions important? Because progesterone helps in the process of metabolizing estrogen:
- Bulun, S. E., Cheng, Y. H., Yin, P., Imir, G., Utsunomiya, H., Attar, E., … & Kim, J. J. (2006). Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Molecular and cellular endocrinology, 248(1-2), 94-103. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16406281
“The biologically active estrogen estradiol (E2) is the best-defined mitogen for the growth and inflammation processes in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Progesterone and progestins may relieve pain by limiting growth and inflammation in endometriosis but a portion of patients with endometriosis and pelvic pain do not respond to treatment with progestins. Moreover, progesterone-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptors (PRs) and the lack of the PR isoform named progesterone receptor B (PR-B). In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factor(s). These unknown factor(s) act on neighboring epithelial cells to induce the expression of the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2), which metabolizes the biologically active estrogen E2 to estrone (E1). In endometriotic tissue, progesterone does not induce epithelial 17beta-HSD-2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17beta-HSD-2 may be due to the lack of PR-B and very low levels of progesterone receptor A (PR-A) observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this local mitogen.”
- Zeitoun, K., Takayama, K., Sasano, H., Suzuki, T., Moghrabi, N., Andersson, S., … & Bulun, S. E. (1998). Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol. The Journal of Clinical Endocrinology & Metabolism, 83(12), 4474-4480. Retrieved from http://www.ncbi.nlm.nih.gov/m/pubmed/9851796/?i=3&from=/16406281/related
“In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17betaHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17betaHSD-2 expression.”
- Matsuzaki, S., Canis, M., Pouly, J. L., Déchelotte, P. J., & Mage, G. (2006). Analysis of aromatase and 17β-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection. Fertility and sterility, 85(2), 308-313. Retrieved from http://www.ncbi.nlm.nih.gov/m/pubmed/16595205/?i=2&from=/9851796/related
“CONCLUSION(S): Local estrogen concentration may be much higher in epithelial cells than in stromal cells in deep endometriotic tissue.”
Furthermore (part of this is particular for those with infertility):
- Sirota, I., Zarek, S. M., & Segars, J. H. (2014, January). Potential influence of the microbiome on infertility and assisted reproductive technology. In Seminars in reproductive medicine (Vol. 32, No. 01, pp. 035-042). Thieme Medical Publishers. Retrieved from https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1361821
“On the basis of the role of inflammation in the induction of a progesterone-resistant endometrium, we hypothesize that failure of implantation might be explained, perhaps in part, by alteration in the uterine microbiome in response to inflammation…This hypothesis finds support in the ability of environmental factors to alter progesterone sensitivity…A very important finding derived from this study demonstrated that TCDD-mediated P4 resistance might increase sensitivity to inflammation, even in subsequent generations not exposed to the toxicants, resulting in PTB.[98] By means of extrapolation, these data support the hypothesis that a combination of environmental factors, taken together, are a risk for recurrent pregnancy loss and PTB in humans; the mechanism being creation of a P4-resistant endometrium and the presence of inflammation. Therefore, we conclude that the association between the microbiome of the reproductive tract and circulating serum E2 concentrations may reflect the environment and availability of glycogen. However, progesterone resistance, albeit an unproven relationship to the microbiome, might contribute to implantation failure and infertility. This putative role of undetected endometrial colonization and progesterone resistance requires further investigation.”
- Houshdaran, S., Oke, A. B., Fung, J. C., Vo, K. C., Nezhat, C., & Giudice, L. C. (2020). Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis. PLoS genetics, 16(6), e1008601. https://doi.org/10.1371/journal.pgen.1008601
“The cells were derived from normal woman and those with endometriosis, an E2-responsive, P4-resistant, inflammatory disorder with implantation-based infertility and poor pregnancy outcomes.”
Weird places endometriosis has been found
Endometriosis Where?!?
Although very rare, endometriosis can show up in surprising places. Here are a few case studies:
Vaginal Cuff
- Arkerson, B. J., Wyckoff, E. T., & Moawad, N. S. (2018). Vaginal Cuff Endometriosis with Endometrial Hyperplasia: A Rare Cause of Post-Hysterectomy Vaginal Bleeding. Journal of Gynecologic Surgery, 34(2), 92-94. https://www.liebertpub.com/doi/abs/10.1089/gyn.2017.0075
“A 53-year-old female presented with postmenopausal bleeding. She had undergone a total TAH/BSO in 2001 for menorrhagia and uterine fibroids. The operative report described an uncomplicated procedure, and pathology was remarkable for inactive endometrium, adenomyosis, small fibroids, and normal ovaries, without evidence of endometriosis. Since then, the patient had used oral estrogen replacement. On presentation, ultrasonography showed no pelvic masses or fluid collections. She did have vaginal cuff granulation tissue and tenderness on bimanual examination. A vaginal cuff biopsy revealed endometriosis with simple hyperplasia without atypia. The patient elected to have laparoscopic vaginal cuff revision with removal of the vaginal cuff endometriosis that was demarcated by injectable dye as a guide. Results: The patient’s postoperative recovery was uneventful. No bleeding or pain was noted during a 2-year follow-up period. She was not restarted on estrogen replacement to minimize the risk of recurrence. Conclusions: Laparoscopic vaginal cuff revision with the use of injectable dye to ensure complete excision of cuff endometriosis is a feasible and safe method for the management of symptomatic vaginal cuff lesions following hysterectomy.”
Inguinal Hernia
- Yu, M., & McKay, G. (2018, September). Inguinal Endometriosis; Diagnostic Considerations & Management. In AUSTRALIAN & NEW ZEALAND JOURNAL OF OBSTETRICS & GYNAECOLOGY (Vol. 58, pp. 88-88). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY. Retrieved from https://www.ranzcogasm.com.au/wp-content/uploads/2018/09/Yu-Michelle-193.pdf
“A 20 year old nulliparous female presented with a right sided inguinal lump, her pain and swelling worse during menstruation. She had no other previous surgical or medical history. The mass was non-reducible with features of a femoral hernia. Ultrasound reported a lobulated hypoechoic fluid filled structure within the inguinal canal above the superficial ring. Further imaging modalities were considered but not deemed suitable in this particular case with consideration of future fertility. Based on clinical findings suspecting groin hernia, the patient underwent laparoscopic mesh repair of hernia. Surgery confirmed a right side indirect inguinal hernia arising from a patent indirect sac. The sac was reduced with traction and on routine transection chocolate brown fluid escaped. Mesh was placed in the pre-peritoneal plane over the defect to complete the hernorrhaphy. Histopathology of sac and cystic contents showed an inguinal hernia sac with endometriosis. Her postoperative recovery was unremarkable.”
Lungs (Pulmonary):
- Foster, D. C., Stern, J. L., Buscema, J., Rock, J. A., & Woodruff, J. D. (1981). Pleural and parenchymal pulmonary endometriosis. Obstetrics & Gynecology, 58(5), 552-556. Retrieved from https://journals.lww.com/greenjournal/abstract/1981/11000/pleural_and_parenchymal_pulmonary_endometriosis.3.aspx
“Sixty-five cases of pulmonary endometriosis are reviewed for characteristics of age, parity, prior surgery, prior endometriosis, location of pulmonary disease, and documentation of disease. Two categories of pulmonary endometriosis are defined: 1) pleural and 2) parenchymal. Age, history of pelvic endometriosis, and location of disease were found to be significantly different between the 2 groups.”
Liver (Hepatic):
- Roesch-Dietlen, F., Jiménez-García, A., Pérez-Morales, A., Grube-Pagola, P., Ramírez-Cervantes, K. L., & Remes-Troche, J. M. (2016). Hepatic endometriosis. Annals of hepatology, 10(3), 347-348. Retrieved from https://www.medigraphic.com/pdfs/hepato/ah-2011/ah113n.pdf
“Here, we present a case of an incidental intraparenchymal hepatic endometriosis in a young woman who presented with only right upper quadrant pain. A 25-year-old nulliparous woman was referred to our unit due to an 8-month history of relapsing and remitting right upper quadrant pain. In the last month, these episodes occurred more often and were related to the ingestion of fatty foods. There were no other symptoms.”
Skin (Cutaneous):
- Steck, W. D., & Helwig, E. B. (1965). Cutaneous endometriosis. JAMA, 191(3), 167-170. Retrieved from https://jamanetwork.com/journals/jama/article-abstract/654568
“A clinicopathologic study of cutaneous endometriosis in 82 patients includes 28 lesions of the umbilicus, 42 of the lower abdominal wall, and 12 in the inguinal area, labia, and perineum. With the exception of five endometriomas of the inguinal area, every lesion occurred in a scar. Twenty-one arose without a preceding operation in the physiologic scar of the umbilicus, and 56 in surgical scars. The umbilical lesions were too precisely located to be logically explained by lymphatic spread, unless only the cells that find scar tissue are able to proliferate. Cesarean-section scars of 26 patients were involved, indicating a vastly greater incidence of endometriosis in cesarean scars than previously reported. This either casts doubt on the theory of transplantation as the usual pathogenetic mechanism for the lesions in surgical scars, or suggests that the endometrium of pregnancy is easier to transplant than is commonly believed.”
Sciatic Nerve:
- Lomoro, P., Simonetti, I., Nanni, A., Cassone, R., Di Pietto, F., Vinci, G., … & Sammarchi, L. (2019). Extrapelvic Sciatic Nerve Endometriosis, the Role of Magnetic Resonance Imaging: Case Report and Systematic Review. Journal of Computer Assisted Tomography, 43(6), 976-980. Retrieved from https://journals.lww.com/jcat/Abstract/2019/11000/Extrapelvic_Sciatic_Nerve_Endometriosis,_the_Role.25.aspx
“Endometriosis (EN) is a common gynecological condition characterized by the presence of functional endometrium located outside the uterine cavity. Sciatic nerve (SN) is rarely affected by EN. Magnetic resonance imaging allows a direct visualization of the spinal and SN, and it is the modality of choice for the study of SN involvement in extrapelvic EN. We report a case of an endometrioma located in the right SN with a systematic review of the literature.”
- Roca, M. U., Bandeo, L., Saucedo, M. A., Bala, M., Binaghi, D., Chertcoff, A., … & Pardal, M. F. (2019). Cyclic Sciatica: Presentation of a Case With Intra and Extrapelvic Endometriosis Affecting the Sciatic Nerve and Utility of MR Neurography (P3. 4-026). Retrieved from https://n.neurology.org/content/92/15_Supplement/P3.4-026.abstract
“A 35-year-old female patient consulted for right low back pain extending along her posterior thigh, calf and foot since 2 years. The pain was recurrent, acute in onset, lasted several days and gradually diminished until disappearing. It was refractory to common analgesics and during the crisis she had difficulties to walk. Neurologist requested a calendar of pain in which the relationship between the menstrual cycle and the pain became evidenced. We performed MRN of the lumbo sacral plexus that showed multiple endometriotic implants in ovaries, L5-S1 roots and a huge one on the sciatic nerve (intra and extrapelvic segment). The patient started oral contraceptives but presented progressive worsening of pain until it became constant and developed step page. Electromyogram showed acute and chronic axonal damage in the sciatic nerve distribution. Medical treatment was changed to leuprolide acetate. The patient evolved with improvement of ovarian endometriosis but persistence of sciatic nerve lesions, leg pain and weakness up to now. Surgical option was considered.”
- Yanchun, L., Yunhe, Z., Meng, X., Shuqin, C., Qingtang, Z., & Shuzhong, Y. (2019). Removal of an endometrioma passing through the left greater sciatic foramen using a concomitant laparoscopic and transgluteal approach: case report. BMC women’s health, 19(1), 95. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624926/
“A 20-year-old woman presented with complaints of severe dysmenorrhea lasting for more than 6 years and dysfunction of her left lower limb lasting for approximately 4 months. Both CT and MRI demonstrated a suspected intrapelvic and extrapelvic endometriotic cyst (7.3 cm × 8.1 cm × 6.5 cm) passing through the left greater sciatic foramen. Laparoscopic exploration showed a cyst full of dark fluid occupying the left obturator fossa and extending outside the pelvis. A novel combination of transgluteal laparoscopy was performed for complete resection of the cyst and decompression of the sciatic nerve. Postoperative pathology confirmed the diagnosis of endometriosis. Long-term follow-up observation showed persistent pain relief and lower limb function recovery in the patient.”
Brain
- Meggyesy, M., Friese, M., Gottschalk, J., & Kehler, U. (2020). Case Report of Cerebellar Endometriosis. Journal of Neurological Surgery Part A: Central European Neurosurgery. Retrieved from https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0040-1701622
“We describe a case of cerebellar endometriosis in a 39-year-old woman who underwent posterior fossa decompression multiple times without establishing a correct diagnosis. Her neurologic status progressively worsened due to chronic hydrocephalus and brainstem compression by cysts. Late in the clinical course, histology from the cyst wall was taken that revealed endometriosis with clear cells and positive immunohistology for progesterone and estrogen receptors. Treatment with gestagens was started but did not improve the patient’s status. In patients with chronic recurring intracranial cysts and hydrocephalus, cerebral endometriosis should be considered.”
Heart (Cardiac):
- Sarmast, H., & Takriti, S. Z. (2019). Cardiac Involvement Resulting from Thoracic Endometriosis. Cardiovasc Surg Int, 1(1), 1002. Retrieved from https://www.researchgate.net/profile/Hossein_Sarmast2/publication/338832751_Cardiac_involvement_resulting_from_thoracic_endometriosis/links/5e2ea4ad299bf1e929d93270/Cardiac-involvement-resulting-from-thoracic-endometriosis.pdf
“We reported a 28-years old woman who suffered from thoracic endometriosis syndrome accompanied by cardiac involvement. Also our patient is the third report of surgically documented thoracic endometriosis syndrome, involving right side pleura and pericardium.”
- Video of pericardial endometriosis surgery
- Video of pericardial and diaphragmatic endometriosis surgery
Locations of endometriosis
Studies:
- Charatsi, D., Koukoura, O., Ntavela, I. G., Chintziou, F., Gkorila, G., Tsagkoulis, M., … & Daponte, A. (2018). Gastrointestinal and urinary tract endometriosis: a review on the commonest locations of extrapelvic endometriosis. Advances in medicine, 2018. Retrieved from https://www.hindawi.com/journals/amed/2018/3461209/
“Endometriotic lesions have been reported in every part of the female human body and in some instances in males. Organs that are close to the uterus are more often affected than distant locations. Extrapelvic endometriosis affects a slightly older population of women than pelvic endometriosis….The gastrointestinal tract is the most common location of extrapelvic endometriosis with the urinary system being the second one. However, since sigmoid colon, rectum, and bladder are pelvic organs, extragenital pelvic endometriosis may be a more suitable definition for endometriotic implants related to these organs than extrapelvic endometriosis. The sigmoid colon is the most commonly involved, followed by the rectum, ileum, appendix, and caecum. Most lesions are confined in the serosal layer; however, deeper lesion can alter bowel function and cause symptoms. Bladder and ureteral involvement are the most common sites concerning the urinary system. Unfortunately, ureteral endometriosis is often asymptomatic leading to silent obstructive uropathy and renal failure. Surgical excision of the endometriotic tissue is the ideal treatment for all types of extrapelvic endometriosis.
“Pelvic endometriosis usually refers to lesions proximal to the uterus such us the ovaries, the fallopian tubes, the uterine ligaments, and the surrounding pelvic peritoneum. Extrapelvic endometriosis on the other hand, is affecting other areas of the body, including the vagina, vulva, cervix and perineum, the urinary system, the gastrointestinal tract, the thoracic cavity including lung and pleura, extremities, skin, and central nervous system. Nevertheless, the term of extragenital pelvic endometriosis describes in a more accurate way endometriotic lesions involving pelvic organs such as rectum, sigmoid, and bladder.”
Histology of Endometriosis
Histological appearance of endometriosis refers to what it looks like under the microscope. This is done when a biopsy or removed tissue (excised tissue) is sent to the pathologist for confirmation.
Overall histological appearance:
- Busca, A. and Parra-Herran, C. (2017). Ovary: Other nonneoplastic: Endometriosis. PathologyOutlines.com. Retrieved from http://www.pathologyoutlines.com/topic/ovarynontumorendometriosis.html
“At least two of the following three microscopic features: Endometrial type glands, Endometrial type stroma, Evidence of chronic hemorrhage (hemosiderin laden macrophages)
- Glandular epithelium commonly has metaplastic changes (tubal, mucinous, squamous, hobnail)
- Atypical endometriosis: epithelial lining of the glands may show enlargement with abundant eosinophilic cytoplasm, cellular stratification and hyperchromatic nuclei; can be reactive but also has malignant potential and is considered the precursor lesion for endometriosis associated carcinomas (clear cell or endometrioid) (Histopathology 1997;30:249, Case Rep Oncol 2013;6:480)
- Burnt out endometriosis: this term has been proposed for changes suggestive of endometriosis, namely central necrosis with surrounding fibrosis and pseudoxanthoma cells but lacking confirmatory features as listed above
- Liesegang rings: acellular ring-like structures seen in areas of chronic inflammation”
Smooth muscle fibers in deep infiltrating endometriosis (DIE):
- Anaf, V., Simon, P., Fayt, I., & Noel, J. C. (2000). Smooth muscles are frequent components of endometriotic lesions. Human reproduction, 15(4), 767-771. Retrieved from https://academic.oup.com/humrep/article/15/4/767/706409
“Deep infiltrating endometriosis (deeper than 5 mm under the peritoneum) often takes the form of a nodular lesion (or `adenomyotic nodule’) consisting of smooth muscles and fibrosis with active glands and scanty stroma. Thus, among endometriotic lesions, a certain distinction is drawn between musculo-glandular lesions and glandular lesions composed of endometrial-like epithelium surrounded by a cell-producing (cytogenous) stroma. The aim of this study was to detect by immunohistochemistry, with a monoclonal antibody against muscle-specific actin, the presence of smooth muscles in 54 endometriotic lesions originating from four different pelvic locations (peritoneum, ovary, rectovaginal septum and uterosacral ligaments) and to quantify the smooth muscle content. Smooth muscles were frequent components of endometriotic lesions in pelvic locations. In addition, smooth muscles were significantly (P < 0.001) more abundant in endometriotic lesions than in their respective unaffected sites. This finding supports, at least partially, the occurrence of a metaplastic phenomenon in the pathogenesis of endometriotic lesions. The definition of distinct endometriotic entities based on the difference in the tissue composition of the lesions (endometriotic nodules versus adenomyotic nodules) is inconsistent with the very frequent presence of smooth muscle cells in endometriosis irrespective of its localization.”
The Many Appearances of Endo
Endometriosis has been described as appearing in many different colors: clear, white, red, yellow, brown, and black (Yeung, Sinervo, Winer, & Albee, 2011). Lesions have also been described as “petechial, vesicular, polypoid, hemorrhagic, red flame-like” (Agarwal & Subramanian, 2010). The appearance of endometriosis is important when surgery is performed to diagnose and treat endometriosis- otherwise it might be missed.
Links:
Studies:
- Yeung Jr, P., Sinervo, K., Winer, W., & Albee Jr, R. B. (2011). Complete laparoscopic excision of endometriosis in teenagers: is postoperative hormonal suppression necessary?. Fertility and sterility, 95(6), 1909-1912. Retrieved from https://www.fertstert.org/article/S0015-0282(11)00335-9/fulltext
“Endometriosis has many different appearances that can make the diagnosis challenging and may necessitate histologic confirmation. “Subtle” or “atypical” appearance has been described as “red” or “white” lesions, or “clear” vesicles. Endometriosis in teenagers has been found to be more atypical in appearance. Some believe that with enhanced magnification available with modern-day laparoscopy, virtually all endometriosis can be identified.”
- Agarwal, N., & Subramanian, A. (2010). Endometriosis–morphology, clinical presentations and molecular pathology. Journal of laboratory physicians, 2(1), 1. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147077/
“…black, dark-brown, or bluish puckered lesions, nodules or small cysts containing old hemorrhage surrounded by a variable extent of fibrosis. Atypical or ‘subtle’ lesions are also common, including red implants (petechial, vesicular, polypoid, hemorrhagic, red flame-like) and serous or clear vesicles. Other appearances include white plaques or scarring and yellowish brown peritoneal discoloration of the peritoneum. Endometriomas usually contain thick fluid like tar; such cysts are often densely adherent to the peritoneum of the ovarian fossa and the surrounding fibrosis may involve the tubes and bowel. Deeply infiltrating endometriotic nodules extend >5 mm beneath the peritoneum and may involve the uterosacral ligaments, vagina, bowel, bladder, or ureters. The depth of infiltration is related to the type and severity of symptoms.”
- Demco, L. (2000). Review of pain associated with minimal endometriosis. JSLS: Journal of the Society of Laparoendoscopic Surgeons, 4(1), 5. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015350/
“The classic black lesions were found to be painful in only 11% of patients when the lesion was touched. Similarly, white lesions were painful in 20% of patients with red lesions at 37%, and clear lesions at 32% were the most painful. These results added further reason as to why initial therapy had such poor results. Surgeons would only “see” the black lesions and removed them, but these were the least painful lesions. The most painful clear lesions were not “seen” at laparotomy and therefore remained, as did the pain.”
- Donnez, J., Squifflet, J., Casanas-Roux, F., Pirard, C., Jadoul, P., & Van, A. L. (2003). Typical and subtle atypical presentations of endometriosis. Obstetrics and gynecology clinics of North America, 30(1), 83-93. Retrieved from http://europepmc.org/article/med/12699259
“The diagnosis of peritoneal endometriosis at the time of laparoscopy is often made by the observation of typically puckered black or bluish lesions. There are also numerous subtle appearances of peritoneal endometriosis. The lesions are frequently non-pigmented. Red flame-like lesions, glandular excrescences, and subovarian adhesions must be considered as the most active lesions. Sometimes, however, subtle endometriotic lesions can be the only lesions seen at laparoscopy.”
- Farrugia, M., Nair, M. S., & Kotronis, K. V. (2007). Narrow band imaging in endometriosis. Journal of minimally invasive gynecology, 14(4), 393-394. Retrieved from https://www.jmig.org/article/S1553-4650(06)00663-7/abstract
“Endometriosis is a disease of protean appearances and, when present on the superficial peritoneum, may assume a range of coloration, from the obvious to the very subtle. The exact extent of a lesion may be difficult to judge because subtle lesions merge with normal peritoneum. An inflammatory reaction occurs in most, but not all superficial lesions. Endometriotic lesions are angiogenic and create an altered microvascular pattern on the peritoneal lining.”
- Albee Jr, R. B., Sinervo, K., & Fisher, D. T. (2008). Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis. Journal of Minimally Invasive Gynecology, 15(1), 32-37. Retrieved from https://www.sciencedirect.com/science/article/pii/S1553465007010205
“The greatest number of patient lesions were excised from cul-de-sac (n = 309). For this site, using visual criteria for diagnosis of endometriosis, positive predictive value was 93.9%, sensitivity was 69.3%, negative predictive value was 41.9%, and specificity was 83.1%. Prevalence was noted to be 79.0% and accuracy was 72.2%. In addition, atypical-appearing tissue not presumed to be endometriosis was confirmed to be endometriosis histologically in 24.3%. In examining tissue specimens from multiple anatomic sites, laparoscopic visual diagnosis of typical endometriosis generally had high positive predictive value. However, both sensitivity and negative predictive value were lower than expected because of atypical lesions subsequently diagnosed as endometriosis. Conclusions: These data suggest that when the surgical objective is complete eradication of endometriosis, the surgeon must be prepared to excise all lesions suggestive of endometriosis and tissue atypical in appearance as in most anatomic sites approximately 25% of atypical specimens proved to be endometriosis.”
More Evidence Against Reflux Theory of Origin
Age-stratified Laterality of Endometriosis Does Not Support Reflux Menstruation as the Origin of Endometriosis
Unpublished Scientific Article
MDDavid B Redwine MD
Funding: none
Synopsis
The age-stratified laterality of distribution of endometriosis refutes the peritoneal circulation modification of the theory of reflux menstruation as the origin of endometriosis.
Abstract
Objective: To tabulate the frequencies of involvement of left and right sided uterosacral and ovarian endometriosis in age-group intervals.
Design: Retrospective review of contemporaneously-tabulated data.
Setting: Tertiary international referral practice specializing in the surgical treatment of endometriosis.
Patients: All patients with no previous surgical treatment of endometriosis.
Interventions: Pelvic mapping of anatomic sites involved by endometriosis.
Outcome measures: Tabulation of unilateral uterosacral and ovarian disease.
Results: There was a small and mostly statistically insignificant predominance of left sided lesions that did not diverge with increasing age.
Conclusions: The incidence of left-sided disease did not increase with advancing age as would be predicted by the peritoneal circulation modification of Sampson’s theory of origin of endometriosis.
Introduction
The origin of endometriosis has been the subject of intense speculation for decades. Sampson’s theory of reflux menstruation is favored by many researchers and clinicians. This theory asserts that during menstruation, viable endometrial cells or small endometrial tissue fragments pass from the uterine cavity, through the fallopian tubes, and exit the fimbriated ends of the tubes into the peritoneal cavity. Once these viable cells enter the peritoneal cavity, three sequential steps occur: 1. Viable cells or tissue fragments must attach to intraperitoneal surfaces; 2. These cells or tissue fragments must then proliferate and invade the surfaces to which they have attached; 3. The autotransplant disease called endometriosis becomes established. There is universal agreement that the only acceptable scientific proof of this theory would be robust photomicrographic evidence of the first two steps occurring in vivo. Since such required scientific proof of Sampson’s theory is absent, support for this theory comes from circumstantial evidence.
A recent argument offered as circumstantial evidence of the theory of reflux menstruation is the peritoneal circulation modification of Sampson’s theory. This modification is based on mapping of the frequency of involvement of anatomic sites by endometriosis, such as the uterosacral ligaments and ovaries (1,2,3,4), ureter (5), intestines (6), and sciatic nerve (7). In this type of study, it has been observed among women with surgically diagnosed endometriosis that when only one uterosacral ligament or one ovary is involved, the left side is more commonly involved than the right side, whereas the right sciatic nerve is involved more commonly than the left. It is argued that these differences in laterality of involvement of pelvic structures are due to the alteration of a clockwise flow (as an observer faces a patient) of peritoneal fluid by the sigmoid colon. In this model, a putative peritoneal circulation of fluid descending along the left abdominal wall is directed medially by the presence of the sigmoid colon. Endometrial cells or tissue fragments entering the pelvis via reflux menstruation from the left fallopian tube are thus alleged to remain in a protected microenvironment, trapped in an eddy lateral to the sigmoid colon. This allows these cells to remain in contact with the left side of the pelvis for a longer length of time since they not swept away by the current, resulting in an increased likelihood of attachment, proliferation and invasion and subsequent development of endometriosis on the left side of the pelvis. Each month, when reflux menstruation takes place, the left side of the pelvis is preferentially seeded by the refluxed cells or tissue fragments which are allowed to remain in contact with pelvic surfaces for a longer length of time. The end result of this model is that the left uterosacral ligament and left ovary are more commonly involved than their contralateral twin structures.
It is further argued that the sigmoid colon simultaneously protects the area of the roots of the sciatic nerve on the left side, thus protecting them from reflux menstruation. This concept of an organ simultaneously promoting and inhibiting the occurrence of a disease on the same side of the body is unique in medicine. Since the area of the right sciatic nerve roots is not protected by the sigmoid colon, endometrial cells or tissue fragments refluxed from the right tube can attach to the area of these nerve roots, thus explaining the greater frequency of right-sided sciatic nerve endometriosis according to this theory.
The pelvic mapping studies offered in support of the peritoneal circulation modification of Sampson’s theory have looked at the cumulative frequency of involvement of pelvic sites of interest in populations of women with endometriosis. Most studies have concentrated on the unilateral involvement of these sites, especially the uterosacral ligaments and ovaries.
There is more information to be obtained from pelvic mapping than such simple overall observations of the distribution of unilateral disease in a large group of women.
Age-stratified pelvic mapping would allow new insight into the validity of the pelvic circulation/sigmoid obstruction modification of Sampson’s theory. If with every menstrual flow new endometrial cells were deposited and preferentially allowed to attach and propagate into lesions of endometriosis, then as women get older the left side of the pelvis should be progressively more commonly diseased than the right side of the pelvis. As a result, as older age groups of women with endometriosis are examined, the difference between left and right-sided pelvic involvement should progressively increase. This paper examines the frequency of unilateral endometriosis involving the uterosacral ligaments and ovaries by five-year age intervals to determine if a significant difference of laterality of involvement exists and to determine if this difference progressively increases with advancing age.
Materials and Methods
The computerized database of the Endometriosis Institute of Oregon contains detailed, prospectively-obtained information on over 2,800 women with surgically-diagnosed endometriosis operated on by the senior author (DBR). This is the largest such database in the world, and the details of its management have been described in previous publications (8,9,10).
In addition to administrative information on each patient such as name, birthdate, address, etc, an important component of each patient record is mapping of sites of involvement by biopsy-confirmed endometriosis. Excision of endometriosis has been performed exclusively, with all reported visual manifestations of endometriosis subject to aggressive excision. The pelvic and intestinal sites of involvement by biopsy-proved endometriosis were then entered into fields in the database according to individual anatomic sites of involvement as previously described (11). Institutional review board approval for this study was not sought since pelvic mapping did not affect patient treatment, did not violate patient confidentiality, and is an extension of the revised American Fertility Society classification system of endometriosis, which is a recommended routine part of patient record-keeping.
The database was queried for patients with no previous surgical therapy who had been found to have histologically documented endometriosis of the uterosacral ligaments and ovaries. Patients were stratified into five-year age intervals.
Statistical analysis was performed using McNemar’s chi-square analysis to accept or exclude the null hypothesis that there is no significant difference in laterality of disease for each age interval. A significance level of p<0.05 was chosen in order to match most previous publications on this topic. A significance level of p>0.05 would therefore indicate that the difference in involvement of a left sided pelvic structure versus its twin on the right side was not statistically significant. Also, for each age interval, the amount (positive or negative) by which the frequency of left sided disease exceeded that of the right side was observed to see if it remained positive across all age groups and increased progressively across advancing age groups, which would be an inevitable result of the peritoneal circulation modification of Sampson’s theory.
Results
A total of 2841 patients were in the database, 1471 of whom had no previous surgical therapy for endometriosis or pelvic pain. Of these, 845 patients had biopsy proven endometriosis involving either one or both uterosacral ligaments. Overall, 224 had only left sided disease, and 165 had only right sided disease, with 456 having bilateral disease of the uterosacral ligaments.
When patients with unilateral disease of the uterosacral ligaments were stratified into eight five-year age intervals (Table 1), five of the eight age intervals had disease more commonly found on the left side, although this finding was statistically significant only for the 25 – 29 year age interval. When the chi square analysis was performed for the entire group of patients with uterosacral ligament disease, the chi square level was 8.95, p <0.005. However, this significance for the entire population was due entirely to the effect of the findings in the 25 – 29 year age interval. The difference between the frequencies of left and right sided disease of the uterosacral ligaments did not increase sequentially with, instead varying positively or negatively among the age groups.
Four hundred and three patients had biopsy proven endometriosis of the ovaries, with 130 involving the left ovary only, 122 the right ovary only, and 151 with bilateral ovarian endometriomas, a non-significant difference in laterality. Four of the eight age group intervals had ovarian disease more commonly found on the left side than on the right. None of these differences was statistically significant, and an increasing frequency of involvement of the left ovary vs the right ovary was not seen with advancing age. As with uterosacral ligament involvement, the differences between the frequencies of left and right-sided ovarian endometriosis varied positively and negatively across the age intervals and did not show a progressive increase with age as the peritoneal circulation model predicts.
Discussion
The peritoneal circulation modification of Sampson’s theory of origin of endometriosis is refuted by these findings. The laterality of involvement of pelvic structures cannot be used as circumstantial evidence for Sampson’s theory.
Many authors have described trends related to laterality of endometriosis lesions involving various organs and structures. The slight left-sided predominance has been championed as strong circumstantial evidence in favor of Sampson’s theory. These authors commonly cite studies which they believe establish the existence of a peritoneal circulation that supposedly runs clockwise as an observer looks at a patient. If this notion were true, then each month with the menstrual flow, endometrial cells or tissue fragments should preferentially accumulate in areas protected from this circulation, such as the left side of the pelvis which allegedly is protected by the sigmoid colon. Since this process is argued to begin with menarche, progressively older age groups of women should have progressively more disease in those protected areas. This is because each month refluxed cells are preferentially allowed to remain in longer contact with pelvic surfaces in such a protected area, allowing the cells an increased opportunity to attach and then to proliferate and invade. With each passing menstrual flow, as more disease accumulates in such a susceptible protected location, the difference in frequency of involvement of the left vs right side of the pelvis should increase as older age groups are examined. Our results indicate clearly that this does not occur.
Our age-stratified results forcefully contradict the notion that the frequency of involvement of the left side of the pelvis is statistically different from the right side, since such statistical significance was found in only one age group of patients with unilateral uterosacral ligament disease and in none of the age groups with ovarian disease. Additionally, our results indicate that an increasing frequency of involvement of the left side of the pelvis does not occur with advancing age, a direct refutation of one of the inevitable predictions of the simplistic peritoneal circulation modification of Sampson’s theory. These results were revealed by age-stratified analysis of patients with endometriosis, illustrating the imprecision and misleading results which can result from collapsing all data into one large data set as has been done with most previous papers.
One other paper presented results with findings similar to ours. Bazi et al (3) found that patients less than 35 years of age had a statistically significant predilection of endometriomas for the left ovary than patients 35 and older, although the numerical basis for their calculation was not presented and patients less than 26 years of age were not included in the analysis.
A two-part question arises in considering the alleged peritoneal circulation: What evidence has been published which supports the existence of this peritoneal circulation in the first place, and does this evidence support the contention of champions of the peritoneal circulation modification of Sampson’s theory? The literature was searched for papers which might shed light on the existence of the type of peritoneal circulation alleged to exist by supporters of the peritoneal circulation modification of Sampson’s theory.
Mitchell (12) studied the patterns of spread of intraperitoneal fluid in a rather unphysiologic way. Working on stillborn infants, artificial perforations were created in the intestinal tract and barium was injected in to the intestines over three hours, during which x-rays were taken. Depending on where the perforation was created, barium could flow literally in any direction. In one female stillborn, he injected barium into the uterus at 100 mm Hg pressure and noted that the barium flowed from the right tube up the right colonic gutter toward the right subphrenic space. He mentioned this single instance of intrauterine injection in his paper, but did not include this in his discussion, since he considered this single observation to be unphysiologic due to the high pressure of injection. The methodology in this paper is unphysiologic and cannot be accepted as what happens in living adult females. However, if the evidence observed during the single case of intrauterine injection were to be accepted as valid, it would predict that involvement of the right colonic gutter and right upper quadrant would be more frequent than involvement of the right hemipelvis, and this does not occur.
Drye (13) found that in the standing position, the hydrostatic pressure in the bottom of the human pelvis was higher than the hydrostatic pressure in the epigastrium as measured by balloon catheters. When subjects were upright, this pressure difference remained constant, other than slight respiratory variations. This pressure difference went away when the subjects were supine. These results are unsurprising and straightforward manifestations of basic physics. The increased pressure in the pelvic region in the standing position is not evidence of a peritoneal circulation, nor would it force fluid out of the pelvic region into the upper abdomen any more than fluid in the bottom of a glass would be forced to the surface by the pressure difference alone. The unvarying difference of pressure between the upper abdomen and lower abdomen is proof that a circulation does not exist in the upright position.
Meyers in 1970 (14) studied the distribution of radioopaque dye injected into the peritoneal cavity in 20 patients with intraperitoneal effusions and abscesses. Dye was injected into the abdomen through the left upper quadrant. This was done in various positions on a tilt table but not in the upright position. Fluoroscopy revealed the dye to initially sink into the pelvis, then rise up both colonic gutters as the table was tilted, with more pronounced upward flow on the right than the left. The fluid ascending the right gutter pooled preferentially in Morrison’s pouch beneath the liver, from where it could then drift into the sub-phrenic space on the right. This study by Meyers was rather unphysiologic since patients had intraperitoneal pathological conditions, and the patient’s position was changed at will on a tilt table. Also, the observations during the short duration of a radiological exam would not necessarily be an accurate indication of what happens over several years in vivo. For these reasons, this study cannot be accepted as evidence of a natural peritoneal circulation as envisioned by supporters of the peritoneal circulation modification of Sampson’s theory. However, for the sake of argument, if this study by Meyers were accepted as proving that a natural peritoneal circulation exists, then it could not be characterized as clockwise since fluid flowed up the left colonic gutter also. The fact that dye ascended from the left side of the pelvis up the left paracolic gutter means that there is not a “protected microenvironment” on the left side of the pelvis due to the presence of the sigmoid colon. Therefore, the inference that the sigmoid colon offers a protected environment on the left side of the pelvis is false, based on Meyers’ findings. If the peritoneal circulation modification of Sampson’s theory were true, there should be some substantial involvement of the left colonic gutter in the lower abdomen due to the flow upward along the left pelvic and abdominal sidewall, but disease in that area is rare. Also, involvement of Morrison’s pouch by endometriosis would be more common than diaphragmatic disease since particles of endometrium should be carried there first, yet involvement of Morrison’s pouch by endometriosis is extremely rare, if in fact it has ever been reported. Therefore, sites of pelvic and abdominal involvement by endometriosis are not accurately predicted by the patterns of artificially induced peritoneal flow described in this study.
A subsequent study by Meyers (15) correlated sites of metastatic cancer with the flow of intraperitoneal dye. Again, dye was injected into the abdomen and x-rays were taken in multiple positions, including Trendelenberg and oblique views. Up to 200 mL of dye was injected, and the hypertonicity of the dye induced mild ascites, which may have altered the results. The dye collected in the cul-de-sac, the termination of the small bowel mesentery (terminal ileum), the superior aspect of the sigmoid mesocolon, and the right paracolic gutter. These findings were correlated with metastatic implants from ovarian, pancreatic, gastric, and colon cancer. Not surprisingly, among 15 patients with ovarian cancer (the closest approximation to what is alleged to result from reflux menstruation) nine had seeding of the cul-de-sac, 7 had seeding of the small bowel mesentery near the ileocecal junction, 1 had seeding of the medial aspect of the sigmoid mesentery, and 4 had seeding of the right colonic gutter. Once again, the nature of the investigation was unphysiologic due to the tilting of the table during the short duration of the exam, and no clockwise circulation of fluid was expressly described, so this paper cannot be accepted as evidence of a clockwise circulation. However, if the results of this study were to be accepted as predicting where endometriosis would likely occur by virtue of Sampson’s theory, endometriosis should occur preferentially in the cul-de-sac, small bowel mesentery, medial sigmoid colon, and right colonic gutter, following the patterns seen with ovarian cancer. While endometriosis is most commonly found in the cul-de-sac, it rarely involves the small bowel mesentery near the ileocecal junction, and involvement of the medial sigmoid colon and right colonic gutter are uncommon. Once again, sites of pelvic and abdominal involvement by endometriosis are not accurately predicted by the patterns of peritoneal flow described in this study.
Rosenshein et al (16) conducted a study in anesthetized rhesus monkeys where two catheters were inserted into the abdominal cavity. One catheter was inserted in the right upper quadrant and advanced down into the pelvis. The second catheter was inserted in the left upper quadrant and not advanced. Radioactive albumen was injected through the left upper quadrant catheter in a volume of 250 mL in three animals and 10 mL in two animals. Over the course of almost three hours of observation, various maneuvers were applied to the monkeys, including abdominal massage for five minutes, and various position changes including 30 degree Trendelenburg and reverse Trendelenburg positions. The fluid was noted to settle in the cul-de-sac and eventually track up the course of the right-sided catheter when 250 mL was injected, with less pronounced distribution of the smaller volume of fluid. This finding is unsurprising since it demonstrates that fluid will take the path of least resistance, unphysiologic since menstruating women don’t usually have such catheters in place and probably don’t have 250 mL of refluxed menses in their peritoneal cavity, and therefore unhelpful as evidence supporting either a clockwise peritoneal circulation or Sampson’s theory. The authors of this study said nothing about a clockwise circulation existing in the peritoneal cavity of rhesus monkeys.
Rosenshein et al, (17) in a discussion of the diffusion of radiocolloids in the peritoneal cavity describes the actions of the diaphragm as a ‘pump, draining the peritoneal fluid upwards with each inspiration.’ There is nothing in the context of the rest of this paper which would lead anyone to conclude that there is a clockwise or counterclockwise current in the abdominal cavity.
Foster et al (18) published a paper commenting on the right-sided predilection of thoracic endometriosis. Citing Rosenshein et al (17), they presented a schematic diagram of a clockwise circulation of peritoneal fluid, although they presented no evidence of their own to suggest that this circulation existed. This schematic diagram, a crude and incomplete explanation of Rosenshein’s findings, cannot be accepted as scientific evidence of a clockwise peritoneal circulation.
McQueen et al (19) placed 1.5 mL of radionuclide in the vaginas of 23 women without endometriosis and found that after one hour, the material had collected in the cervix, uterus, and around the adnexae bilaterally. A peritoneal circulation was not being sought and such a circulation was not mentioned in this paper.
From this review of the literature it is clear that there is no scientific evidence of the existence of a clockwise peritoneal circulation which is alleged to exist by proponents of the peritoneal circulation modification of Sampson’s theory. Supporters of this theory do not cite any reference with scientific evidence of this circulation. Any arguments which are based on the alleged existence of such a circulation are therefore without foundation.
The peritoneal circulation modification of Sampson’s theory is overly simplistic and does not address fundamental questions which arise from it. For example, is the alleged peritoneal circulation a stronger force on the tissue fragments than that exerted by surface tension of moist surfaces? Are the effects of gravity stronger than the alleged circulation?
The statistics which have been used to support the peritoneal circulation modification of Sampson’s theory are inconsistent with our findings and occasionally internally contradictory. Most of the published papers on the laterality of endometriosis have focused on the cumulative frequencies of involvement of the uterosacral ligaments and ovaries, since these are distinctly lateral structures about which there would be no confusion over assignment of laterality. Most of the papers on the subject have examined the relative left vs right laterality of involvement of paired pelvic structures by McNemar’s chi square test (although this was not specifically mentioned in the Methods sections of these papers.). The schematic formula for this statistic is (L – R)2/T, where L is the number of patients with left-sided unilateral disease and R is the number of patients with right-sided unilateral disease and T is the sum of L + R.
One paper published in support of the peritoneal circulation modification of Sampson’s theory actually contains statistical evidence refuting that theory. Parazzini, et al, (20) wrote a paper comparing the incidence of endometriosis in the left vs. right hemipelvis. Rather than using McNemars’s chi square test (which was used in all other papers published previously on this subject by members of this writing group and numerous other authors) to analyze their data, they instead used the binomial distribution and Poisson’s approximation to measure the significance of their findings that the left side was more commonly involved than the right side. However, when the traditionally-used McNemar’s chi-square test is applied to their data, the chi-square value is 2.58 (p>0.1) which is not significant. Thus, this paper actually refutes its authors’ claims when the correct statistical test is run. In order for a theory to be valid, it should be consistently supported by the same statistical test used to support it in other publications rather than searching for a different statistical test which might give support.
Papers championing the peritoneal circulation modification of Sampson’s theory have avoided the question of the large percentage of patients with bilateral disease. For a theory to be valid, it must include an explanation for all observations, not just a selected portion such as those with only unilateral disease.
Reflux menstruation itself as a theory of origin of endometriosis remains unproven, supported only by many lines of circumstantial evidence. The peritoneal circulation modification of this theory has introduced a new, strained attempt to support this theory by circumstantial evidence. If such a peritoneal circulation were to exist, our findings would suggest that this circulation reverses direction at various times in a woman’s lifespan, then eventually slows. Such variation of an unproven circulation seems unlikely and has not been proposed by supporters of this concept.
The peritoneal circulation modification of Sampson’s theory of reflux menstruation as the origin of endometriosis has resulted in an unusual situation in scientific publication. A long-standing but scientifically unproven theory of origin (Sampson’s theory) of an important disease seeks support from inconsistent and contradictory statistical evidence of laterality of disease which infers the physical results of a peritoneal circulation which has not been scientifically proven to exist. Since the peritoneal circulation modification of Sampson’s theory is based on a scientifically unproven fiction, it should be abandoned.
Summary
There is a slight left sided predominance of endometriosis involving the uterosacral ligaments and ovaries. The difference between the frequency of left-sided involvement and right-sided involvement does not increase with advancing age. The frequency of involvement of the left side of the pelvis does not increase linearly with advancing age. A clockwise circulation of peritoneal fluid has not been scientifically proven to exist. Supporters of the peritoneal circulation modification of Sampson’s theory have selected portions of studies which support their contentions and have ignored those portions that do not. The laterality of distribution of endometriosis does not support Sampson’s theory via the peritoneal circulation model. Future papers on the theory of reflux menstruation as the origin of endometriosis should focus on the most easily obtainable scientific evidence of all: robust photomicrographic evidence of the in vivo occurrence of the two missing steps of this theory, adhesion and implantation of the endometrial cells at their final resting sites within the pelvis.
References
Vercellini P, Busacca M, Aimi G, Bianchi S, Frontino G, Crosignani PG. Lateral distriburion of recurrent ovarian endometriotic cysts. Fertil Steril 2002;77:848-9.
Vercellini P, Aimi G, De Giorgi O, Maddalena S, Carinelli S, Crosignani PG. Is cystic ovarian endometriosis an asymmetric disease? Br J Obstet Gynaecol 1998;105:1018-21.
Bazi T, Nader KA, Seoud MA, Charafeddine M, Rechdan JB, Zreik TG. Lateral distribution of endometriomas as a function of age. Fertil Steril 2007;87:419-21.
Al-Fozan H, Tulandi T. Left lateral predisposition of endometriosis and endometrioma. Obstet Gynecol 2003;101:164 – 6.
Vercellini P, Pisacreta A, Pesole A, Vicentini S, Stellato G, Crosignani PG. Is ureteral endometriosis an asymmetric disease? Br J Obstet Gynaecol 2000;107:559 – 61.
Vercellini P, Chapron C, Fedele L, Gattei U, Daguati R, Crosignani PG. Evidence for asymmetric distribution of lower intestinal tract disease. Br J Obstet Gynaecol 2004;111:1213-7.
Vercellini P, Chapron C, Fedele L, Frontino G, Zaina B, Crosignani PG. Evidence for asymmetric distribution of sciatic nerve endometriosis. Obstet Gynecol 2003 102:383-7.
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Rosenshein NB, Leichener PK, Vogelsang G. Radiocolloids in the treatment of ovarian cancer. Obstet Gynecol Surv 1979;34:708 – 20.
Foster DC, Stern JL, Bescema J, Rock JA, Woodruff JD. Pleural and parenchymal pulmonary endometriosis. Obstet Gynecol 1981; 58:552 – 6.
McQueen D, McKillop JH, Gray HW, Callaghan M, Monaghan C, Bessent RG. Radionuclide migration through the genital tract in infertile women with endometriosis. Hum Reprod 1993;8:1910 – 4.
Parazzini F, et al. Left:right side ratio of endometriotic implants in the pelvis. Eur J Obstet Gynecol 111(2003) 65-67.
WEBLINK TO ARTICLE http://pacificendometriosis.com/age-stratified-laterality-of-endometriosis-does-not-support-reflux-menstruation-as-the-origin-of-endometriosis/
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. 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:
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:
- 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.”)
- metaplasia (“residual embryonic cells of the Wolffian or Mullerian ducts persist and develop into endometriotic lesions that respond to oestrogen”)
- 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”)
- oxidative stress and inflammation (“accumulation of ROS may contribute to the propagation and maintenance of endometriosis and associated symptoms”)
- 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”)
- 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”)
- genetics (“different types of endometriosis may be associated with altering different gene clusters that regulate specific cellular functional aberrations”)
- 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.”
Staging and Categories of Endometriosis
Staging
So you’ve been told your endometriosis is a certain stage, but what does that mean?
The most widely used staging system for endometriosis, the American Society of Reproductive Medicine’s (ASRM), is based on how it affects fertility, not how it affects symptoms. Others systems of classification/staging focus on fertility or how the anatomy is affected (such as the Enzian classification for deep endometriosis, the endometriosis fertility index (EFI), and the American Association of Gynecological Laparoscopists (AAGL) classification) (Johnson et al., 2017). These do not take into consideration the biochemical effects of endometriosis (Imanaka, 2020). None of the systems “predicts pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality of life measures, and other endpoints important to women and health care providers for guiding appropriate therapeutic options and prognosis” (Johnson et al., 2017, para. 3).
The ASRM’s classification system “classifies the disease as minimal (Stage I), mild (Stage II), moderate (Stage III) or severe (Stage IV)” based on a point system for how deep lesions go, the number of lesions, if cysts are on the ovaries, and adhesions (Khine, Taniguchi, & Harada, 2016, para. 12). A newer staging system called the endometriosis fertility index (EFI) “was developed…to predict fecundity after endometriosis surgery” and “could be useful as a clinical tool for counseling patients with endometriosis after surgery about their fertility prognosis and eventual need for fertility treatment” (Khine, Taniguchi, & Harada, 2016, para. 13).
None of these predict how you will respond to treatments or predict the symptoms experienced. Some will have Stage IV but have minimal symptoms. Others will have “minimal” disease but severe symptoms.
Endometriosis is divided into three main phenotypes: ovarian endometrioma (OMA), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE). Here we’ll briefly discuss SPE and DIE.
Categories of Endometriosis
Superficial peritoneal endometriosis
Superficial peritoneal endometriosis (SPE) is defined as lesions less than 5 mm deep (Daly, 2018). Although superficial, SPE can cause moderate to severe symptoms as well as infertility (Reis et al., 2020). The appearance or staging of endometriosis does not reflect the biochemical mechanisms of endometriosis (Imanaka, 2020).
Deep Infiltrating Endometriosis
“Deep infiltrating endometriosis (DIE) represents 15 to 30% of endometriosis cases and is defined as endometriosis infiltrating the peritoneum by more than 5 mm. DIE is characterized by nodules infiltrating the rectosigmoid, uterosacral ligaments (USL), vaginal fornix, rectovaginal septum (RVS) and/or bladder.”
(Daly, 2018, para. 1)
(For reference, a millimeter is 0.039 of an inch. 5 mm would be about the length of a pencil’s eraser.)
DIE is associated with severe pain, and it has been noted to be important to resect (i.e. remove) these lesions in order to treat the pain (Yi, Leng, Lang, Ll, & Zhang, 2012). Your surgeon should be skilled and work with a multi-disciplinary team if DIE is present, because it can affect areas such as the bowel and ureters (Yi et al., 2012). Your surgeon should also know that ovarian endometriosis (or endometriomas) is associated with pelvic endometriosis and DIE, and should be prepared to address endometriosis in other areas as well (Exacoutos et al., 2018).
“Of the 177 DIE patients, 336 lesions were proved both histologically and laparoscopically as DIE lesions. The anatomical distributions of all DIE endometriotic lesions (number of patients, percentage) were as follows: bladder (5, 1.58%), uterosacral ligament (95, 67.08%), cul-de-sac (37, 12.02%), recto-vaginal septum (40, 12.66%), rectum and rectosigmoid junction (9, 2.85%) and ureter (12 lesions, 3.80%). Twenty-seven (67.5%) recto-vaginal septum lesions infiltrated deeply into the vaginal fornix. The 139 deeply infiltrating lesions on uterosacral ligaments (USL) included 29 on the left side, 37 on the right side and 73 were bilateral. The bladder was only anterior pelvic lesions in the DIE patients. While posterior pelvic lesions were more widespread and more severe in this group of DIE patients.”
(Yi et al., 2012, para. 15)
Ovarian Endometrioma
Endometriomas are a type of endometriosis found as a cyst on the ovary. It “contains thick, brown, tar-like fluid, which may be referred to as a ‘chocolate cyst'” (UpToDate, 2021). “Ovarian endometriomas are found in up to 44% of women with endometriosis, and are significantly associated with the presence of pelvic deep infiltrating endometriosis, ovarian adhesions, and pouch of Douglas obliteration” (Cranney, Condous, & Reid, 2017).
References
Cranney, R., Condous, G., & Reid, S. (2017). An update on the diagnosis, surgical management, and fertility outcomes for women with endometrioma. Acta obstetricia et gynecologica Scandinavica, 96(6), 633-643. Retrieved from https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/aogs.13114
Daly, S. (2018). Imaging in Endometrioma/Endometriosis. Medscape. Retrieved from https://emedicine.medscape.com/article/403435-overview#a1
Demco, L. (2000). Review of pain associated with minimal endometriosis. JSLS: Journal of the Society of Laparoendoscopic Surgeons, 4(1), 5. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015350/
Exacoustos, C., De Felice, G., Pizzo, A., Morosetti, G., Lazzeri, L., Centini, G., … & Zupi, E. (2018). Isolated ovarian endometrioma: a history between myth and reality. Journal of minimally invasive gynecology, 25(5), 884-891. Retrieved from https://www.jmig.org/article/S1553-4650(18)30042-6/fulltext?fbclid=IwAR1yOvqvObWgpldiQ-VAwvju8uGNqQz0-edmbhZluYmDvTfanlCQJcniTEQ
Imanaka, S., Maruyama, S., Kimura, M., Nagayasu, M., & Kobayashi, H. (2020). Towards an understanding of the molecular mechanisms of endometriosis-associated symptoms. World Academy of Sciences Journal, 2(4), 1-1. Retrieved from https://www.spandidos-publications.com/10.3892/wasj.2020.53
Johnson, N. P., Hummelshoj, L., Adamson, G. D., Keckstein, J., Taylor, H. S., Abrao, M. S., … & Rombauts, L. (2017). World Endometriosis Society consensus on the classification of endometriosis. Human reproduction, 32(2), 315-324. Retrieved from https://academic.oup.com/humrep/article/32/2/315/2631390
Khine, Y. M., Taniguchi, F., & Harada, T. (2016). Clinical management of endometriosis-associated infertility. Reproductive medicine and biology, 15(4), 217-225. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715862/
UpToDate. (2021). Endometriosis: Management of ovarian endometriomas. Retrieved from https://www.uptodate.com/contents/endometriosis-management-of-ovarian-endometriomas
Reis, F. M., Santulli, P., Marcellin, L., Borghese, B., Lafay-Pillet, M. C., & Chapron, C. (2020). Superficial peritoneal endometriosis: clinical characteristics of 203 confirmed cases and 1292 endometriosis-free controls. Reproductive Sciences, 27(1), 309-315. Retrieved from https://link.springer.com/article/10.1007/s43032-019-00028-1
Yi, D. A. I., Leng, J. H., Lang, J. H., LI, X. Y., & Zhang, J. J. (2012). Anatomical distribution of pelvic deep infiltrating endometriosis and its relationship with pain symptoms. Chinese medical journal, 125(2), 209-213. Retrieved from https://journals.lww.com/cmj/Fulltext/2012/01020/Anatomical_distribution_of_pelvic_deep.10.aspx
Endometriosis Overview
Endometriosis is an inflammatory disorder defined by the presence of glandular endometrial and stromal cells outside the uterine cavity (Becker, 2015). An estimated 11% of women have endometriosis with varying degrees of severity of symptoms and infertility; the severity of symptoms does not necessarily correlate with extent of lesions (McCance & Huether, 2014). Despite the high incidence of endometriosis, diagnosis is often delayed by 10 years due to symptoms being misdiagnosed or dismissed as normal menstrual cramps, by the lack of satisfactory biomarkers to diagnose, and by the definitive diagnostic standard being surgical visualization with histological confirmation (Ahn, Singh, & Tayade, 2017; Schliep, 2015). While endometriosis is a benign condition, it is related to higher incidence of ovarian carcinomas, autoimmune disorders, and cardiovascular disease (Kvaskoff, Mu, Terry, Harris, Poole, Farland, & Missmer, 2015).
Precipitating Factors
The cause of endometriosis is unknown, but it is likely to be multi-factorial, including environmental and genetic factors (Ashrafi, Sadatmahalleh, Akhoond, & Talebi, 2016). Being female is a significant risk factor as endometriosis is mainly seen in females; however, it has been in seen in men, usually those undergoing chemotherapy for prostate cancer (Jabr & Mani, 2014; Martin & Hauck, 1985). Several risk factors have been associated to be relational to endometriosis but not causative. Patient gravidity has been negatively associated with endometriosis with the thought that pregnancy provided suppression due to anovulation and amenorrhea as well as metabolic, hormonal, immune and angiogenesis changes (Maggiore et al., 2015). However, this lack of pregnancy can also be considered as a symptom as endometriosis is highly related to infertility with up to 50% of infertility cases being related to endometriosis (Dunselman et al., 2014).
A family history of endometriosis is also a risk factor, with one study reporting a rate of 56% of patients studied with endometriosis having a family history (Dun, Kho, Morozov, Kearney, Zurawin, & Nezhat, 2014). Some studies have reported the proportion of endometriosis cases due to genetic factors to be in the range of 52% (Rahmioglu, Nyholt, Morris, Missmer, Montgomery, & Zondervan, 2014; Chettier, Albertsen, & Ward, 2014). However, while multiple genetic aberrations have been identified, none have been proven conclusive enough to be a biomarker for endometriosis (Rahmioglu, Nyholt, Morris, Missmer, Montgomery, & Zondervan, 2014). One theory of the origin of endometriosis is Mullerian rests that allows for endometriosis to be laid down during fetal development and is associated with other Mullerian disorders (Acién & Velasco, 2013).
There is an increased risk of endometrial polyps with endometriosis (Wang, Zhang, & Liu, 2016; Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). Evidence of similar pathologies, such as estrogen driven proliferation of tissue, between endometriosis and endometrial polyps are noted (Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). This association with endometriosis and endometrial polyps is important in infertility (Galal, 2016). Other risk factors include early age of menarche, short menstrual cycles, long duration of menstrual flow, and defects in the uterus or fallopian tubes (Ashrafi, Sadatmahalleh, Akhoond, & Talebi, 2016).
Cellular Analysis
Endometriotic lesions on a cellular level are not the same as the endometrium as endometriotic lesions are capable of high estrogen production, high prostaglandin production, and have a resistance to progesterone (Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). This is important in the symptoms seen. The endometriotic lesions respond to estrogen which signals to increase lesion size, fluid volume, increased epithelial cell height, and epithelial cell proliferation (Burns, Rodriguez, Hewitt, Janardhan, Young, & Korach, 2012). However, the endometriosis lesions are capable of estrogen production, have decreased responsiveness to progesterone, can produce cytokines and prostaglandins, and are capable of angiogenesis and neurogenesis (Hey-Cunningham, Peters, Zevallos, Berbic, Markham, & Fraser, 2013; Reis, Petraglia, & Taylor, 2013; Bulun et al., 2012; Chaban, 2012). These capabilities of the endometriotic lesions are thought to be responsible for the symptoms noted with endometriosis.
The location of the lesions and the presence of adhesions can also affect the symptomology seen (Lu, Zhang, Jiang, Zou, & Li, 2014). Most symptoms arise from a chronic inflammatory state, noxious chemical release such as prostaglandins, musculoskeletal sequelae, and/or adhesions. An estimated 30-50% of patients with endometriosis are infertile due to the inflammatory environment and physical abnormalities such as adhesions (Koga, Yoshino, Hirota, Hirata, Harada, & Osuga, 2014).
Pain:
- Chronic pelvic pain:
Chronic pelvic pain is strongly associated with endometriosis (Donnelly & Yeung, 2015). Pain with endometriosis is related to increased inflammation, nociceptors, and noxious stimuli (Alvarez, Bogen, & Levine, 2014; McKinnon, Bertschi, Bersinger, & Mueller, 2015). Morotti, Vincent, Brawn, Zondervan, and Becker (2014) note higher nerve fiber production and density, increased neurotrophins, and the location of lesions in proximity to areas such as the bowel to be contributory to pain in endometriosis. These nerve fibers are found within and near the endometriotic lesions as well as in the peritoneum and endometrium of those with endometriosis (Fraser & Berkley, 2013). In patients with endometriosis, increased pro-inflammatory estrogen unchecked by antiinflammatory progesterone (due to progesterone resistance) has also been hypothesized to be problematic in endometriosis pain (Bruner-Tran, Herington, Duleba, Taylor, & Osteen, 2013; Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). The peritoneal fluid of endometriosis patients has been noted to have higher amounts of tumor necrosis factor-α, several interleukins, RANTES, monocytes, and prostaglandins (Aredo, Heyrana, Karp, Shah, & Stratton, 2017). Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, and Pop (2013) describe an “overproduction of estrogen in endometriotic stromal cells with high local production of prostaglandins” (p. 95) as well as overproduction of prostaglandins PGE2 and PGF2-alpha not only in the endometriotic lesions but also in the uterus. Pain can be either cyclical or acyclical. Pelvic floor muscle dysfunction has been shown to be pathologic in pain with endometriosis patients (Raimondo et al., 2016). Most often hypertonicity of the pelvic floor is implicated in the musculoskeletal pain experienced (Aredo, Heyrana, Karp, Shah, & Stratton, 2017).
- Dysmenorrhea:
Dysmenorrhea is a classic signal for endometriosis. Erasmo and Ferrero (2015) state that “in patients suffering from dysmenorrhea, the incidence of endometriosis ranges from 40% to 60% and the 70% of adolescents who experience dysmenorrhea are diagnosed with endometriosis” (p. 63). Erasmo and Ferrero (2015) note the pain to be visceral and somatic. They also indicate that inflammation, prostaglandins, nerve growth factors, deep infiltrating lesions, and increased uterine contractility to be causes of dysmenorrhea in endometriosis (Erasmo & Ferrero, 2015).
- Intermenstrual pain
Pain between menstruations can be caused by the factors already mentioned of inflammation, nociceptors, noxious stimuli, and musculoskeletal dysfunctions.
- Pain during exercise
The location of the lesions, the presence of adhesions, and other factors such as pelvic floor dysfunction, trigger points, and muscles spasms can all factor into pain with exercise (Hartmann & Sarton, 2014; Aredo, Heyrana, Karp, Shah, & Stratton, 2017). High impact exercises can affect the tonicity of the pelvic floor. Adhesions can cause pulling sensations as well as musculoskeletal imbalances.
- Fatigue:
Pain is one factor leading to fatigue (Morotti, Vincent, Brawn, Zondervan, & Becker, 2014). Luisi et al. (2015) also noted hormonal alterations, chronic inflammation and impaired immune function as causes of fatigue in endometriosis.
- Menstrual:
- Premenstrual spotting:
Spotting for greater than two days prior to menstruation has been associated as a strong indicator for endometriosis (Heitmann, Langan, Huang, Chow, & Burney, 2014). Although hormonal and inflammatory alterations could play a part in spotting, in this case, the presence of an endometrial polyp is the most likely cause of spotting in this patient (Thubert, Demoulin, Lamazou, Rivain, Trichot, Faivre, & Deffieux, 2014).
- Menorrhagia
While dysmenorrhea is defined as a classic sign of endometriosis, menorrhagia is more often associated with conditions that frequently coexist with endometriosis. Adenomyosis, leiomyomas, and endometrial polyps are often comorbidities of endometriosis and have the primary symptom of menorrhagia (Habiba & Benagiano, 2016; Nezhat et al, 2016; Thubert, Demoulin, Lamazou, Rivain, Trichot, Faivre, & Deffieux, 2014). It may also be noted that polycystic ovarian syndrome is also frequently seen in endometriosis patients which can contradict this symptom (Likes & Lessey, 2014).
- Gastrointestinal:
- Dyschezia
Elevated prostaglandin levels within the peritoneal fluid are seen in patients with endometriosis, and these prostaglandins affect gastrointestinal motility (McAllister, Giourgas, Faircloth, Leishman, Bradshaw, & Gross, 2016). The irritation of the gastrointestinal tract from the cytokines released can also contribute to dyschezia, particularly seen if lesions are located within the posterior cul de sac (Avila, Filogônio, Costa, & Carneiro, 2016). Hypertonic pelvic floor muscles can contribute to the pain and spasms felt upon defecation (Preil, Belkin, & Goldstein, 2016).
- Bloating
The exact cause of the bloating experienced with endometriosis is unknown. Some contribute it to the inflammatory process while others cite the coexistence of irritable bowel syndrome; however, many patients experience gastrointestinal symptoms cyclically which might indicate the inflammatory and/or hormonal impact (Ek, Roth, Ekström, Valentin, Bengtsson, & Ohlsson, 2015). Ek, Roth, Ekström, Valentin, Bengtsson, and Ohlsson (2015) identify mast cells as possible contributors from the inflammatory spectrum, but they also point out that hormonal receptors in the gastrointestinal tract could also explain the symptoms.
- Alternating constipation/diarrhea
Again, prostaglandins and inflammatory markers are contributory to altered bowel function as is pelvic floor muscular dysfunction. Endometriosis on or near the bowel has been seen as contributory to bowel symptoms, even to the extent of bowel obstruction due to lesion growth (Ruffo et al., 2014).
- Urinary:
- Pain on micturition
While endometriosis of the urinary tract is rare, the most common site is the bladder (Knabben, Imboden, Fellmann, Nirgianakis, Kuhn, & Mueller, 2015). Estay et al. (2015) describes bladder symptoms as cyclical dysuria, dyspareunia, or resembling recurrent cystitis, and more rarely hematuria. Estay et al. (2015) described ureteral obstruction from endometriosis lesions presenting more as the loss of kidney function including anuria and hydronephrosis. Knabben, Imboden, Fellmann, Nirgianakis, Kuhn, and Mueller (2015) point out that bladder symptoms are usually symptomatic whereas ureteral are often not symptomatic. Again, irritation of the urinary tissue from the inflammatory markers described above can cause symptoms, particularly of the bladder. Endometriosis of the ureters would present more from obstruction due to lesion growth versus inflammation. In this case, endometriosis of the bladder would be suspected, however interstitial cystitis would need to be ruled out as it is frequently seen in endometriosis patients as well (Chen, Lee, & Wu, 2016).
- Examination:
- Tenderness with palpation
Tenderness can be due to pelvic floor muscular dysfunction and/or to lesion location (Yamamoto, Carillo, & Howard, 2014). Particularly tenderness is noted in the rectovaginal area, bladder, and close to the uterosacral ligaments in many patients with endometriosis (Nourmoussavi, Bodmer‐Roy, Mui, Mawji, Williams, Allaire, & Yong, 2014; Yamamoto, Carillo, & Howard, 2014; Williams et al., 2016). If a patient had been sexually active, the symptom of dyspareunia might also have been described. In addition to the contributory causes of inflammation, muscular dysfunction, and adhesions, Williams et al. (2016) also describe increased nerve bundle density noted in endometriosis patients with dyspareunia. This could also cause pain upon pelvic examination.
- Diagnostic laparoscopic findings:
- Glands and stroma in the pelvic cavity
Endometriosis is diagnosed by the visualization and preferably the histological confirmation of endometrial glands and/or stroma outside of the uterus (Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). Visually, endometriosis can vary from the clear, white, red, tan, and black colorations that may be very small to blister like formations to polypoid masses (Kondi-Pafitis, 2012). Kondi-Pafitis (2012) describes the histological presentation as “one or more endometrioid glands surrounded by stromal cells, resembling the endometrial stromal cells of the proliferative phase…. consistent with inactive or irregular proliferative endometrium, although typical proliferative or secretory changes may be observed” (p. 106). Kondi-Pafitis (2012) also notes that inflammatory cells and fibrosis may be present. An older study, but worth noting, performed by Demco (2000) utilized patients under conscious sedation to perform pain mapping of the lesions. The study found that the different colored lesions produced different amounts of pain, that the pain extended beyond the visible border of the lesion, and that palpation of the endometriotic lesions produced “cramps” (Demco, 2000). This information is important in understanding the symptomology and in treating the disease.
o Endometrial polyp
As noted previously, endometrial polyps are frequently seen with endometriosis (Wang, Zhang, & Liu, 2016; Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015). Estrogen driven proliferation of tissue is seen in endometrial polyps as well as endometriosis (Zheng, Mao, Zhao, Zhao, Wei, & Liu, 2015).
Medical Management
Pharmalogical
Hormonal: Balancing hormones is reasoned to be beneficial in alleviating symptoms; however, it does not rid the patient of the disease. Most efforts are concentrated on lowering estrogen in order to alleviate symptoms, particularly pain. Birth control pills, progestins, gonadotropin-releasing hormone antagonists, aromatase inhibitors, selective estrogen receptor modulators, and oral and intravaginal danazol are different hormonal therapies trialed to decrease symptoms and slow progression of the disease. However, some of these therapies have limited evidence and many have untoward side effects, so much so that some are only recommended if all other medical and surgical options fail (Tosti, Biscione, Morgante, Bifulco, Luisi, & Petraglia, 2016; Dunselman, et al., 2014; Brown & Farquhar, 2015). Also note that the resistance to progesterone seen in endometriosis lesions can cause some patients to be refractive to the effect of progestins (Cristescu, Velişcu, Marinescu, Pătraşcu, Traşcă, & Pop, 2013). In the following order, depending on patient tolerance, hormonal therapy could be trialed:
- Oral contraceptives: Oral contraceptives are useful for dysmenorrhea, reduction of pelvic pain, and reduction in the recurrence rate for endometriomas (ovarian cyst endometriosis) (Zorbas, Economopoulos, & Vlahos, 2015).
- Progestins (oral, intrauterine, injections): These can be useful for pain reduction (Gezer & Oral, 2015).
- Gonadotropin-releasing hormone analogs: These are as effective as other hormonal methods for endometriosis pain, but associated with a significant reduction in bone mineral density (Jeng, Chuang, & Shen, 2014). The most commonly prescribed is sold under the brand name Lupron, who recommends a lifetime maximum of 12 months of treatment (Lupron, n.d.).
- Danazol: Danazol is useful for decreasing pain and lowering inflammation (shown via a lowered CA-125) (Szubert, Suzin, Duechler, Szuławska, Czyż, & KowalczykAmico, 2014). However, danazol can have strong androgenic side effects (deepening of voice, facial hair growth) (Godin & Marcoux, 2015). Vaginally administered danazol might help decrease the pain and the nodule size in rectovaginal endometriosis (Godin & Marcoux, 2015).
- Aromatase inhibitors: These are only used if other hormonal methods and surgical therapies have failed but can be useful for pain (Hashim, 2014).
- Selective estrogen receptor modulators: Their effectiveness and safety are not established and have shown an increased risk for thromboembolism, vaginal dryness, rash and abdominal cramps (Chen, Zheng, & Wan, 2014).
Surgical
As discussed, surgical visualization is the definitive method for diagnosing endometriosis. Surgical intervention within the diagnostic surgery is preferable and is aimed at removing the endometriotic lesions. Surgical treatment can help prevent the reoccurrence of endometriosis without the use of hormones afterwards (Jovanovic, Dikic, Janković-Raznatovic, Savija, & Radaković, 2015). While ablation of endometriosis has been utilized extensively, newer data suggests excising the lesions may lead to a better long term outcome for patients. Ablation may or may not destroy the full thickness of the lesion while excision allows for better margins and provides samples for histological study.
A randomized, double-blind, five year follow up study concluded that surgical intervention was effective for at least up to five years and demonstrated that in some areas excision was more effective than ablation (Healey, Cheng, & Kaur, 2014). Excision is preferred in order for all tissue to be sent for histological review and confirmation (Dunselman et al., 2014; Donnelly & Yeung, 2015). Complete excision of deep infiltrating endometriosis has shown better outcomes versus incomplete surgical removal coupled with postoperative hormonal therapy (Angioni, Pontis, Dessole, Surico, Nardone, & Melis, 2015). Mackenzie (2015) suggests that excision be the standard of care for bowel endometriosis. Several other studies also suggest that excision is the preferable treatment method (Laganà, 2016; Alvarez, Giudice, & Levine, 2015; Koninckx, Donnez, & Brosens, 2016; Gingold & Falcone, 2016).
Other
- Dietary: Several dietary changes are suggested to alleviate symptoms. A diet rich in vegetables, fruit, and omega-3 fatty acids is recommended due to the oxidative stress created by the chronic inflammatory state (Gupta, Harlev, Agarwal, Al Safaar, Gupta, & Hack, 2015; Halpern, Schor, & Kopelman, 2015). Celiac disease has been connected with endometriosis through inflammatory markers and genetics and a gluten free diet has been shown to decrease painful symptoms (Santoro et al., 2014; Mormile & Vittori, 2013; Marziali, 2012). A study cites the role of inflammation and oxidative stress from endometriosis as factors leading to an increase in the risk of coronary heart disease in endometriosis patients, therefore a heart healthy diet would be beneficial as well (Mu, Rich-Edwards, Rimm, Spiegelman, & Missmer, 2016). A low fat diet is suggested as high fat consumption has been associated with increased inflammatory markers (Heard, Melnyk, Simmen, Yang, Pabona, & Simmen, 2016). Due to the frequent diagnosis of irritable bowel syndrome in endometriosis patients, a low FODMAPs diet is suggested (Moore, Gibson, & Burgell, 2014).
- Physical Activity: As noted, endometriosis patients can be susceptible to pelvic musculoskeletal disorders, so physical therapy with a women’s health qualified physical therapist would be beneficial (DeBevoise, Dobinsky, McCurdy-Robinson, McGee, McNeely, Sauder, & Sullivan, 2015). This might include retraining of the pelvic floor muscles to prevent spasms, reestablishing musculoskeletal balance, trigger point therapy, and other pain relieving modalities (dos Bispo et al., 2016). Yoga therapy has been shown to decrease menstrual pain and increase quality of life (Yonglitthipagon et al., 2017; Gonçalves, Barros, & Bahamondes, 2016).
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