Camran Nezhat, MD (1, 2); Shruti Agarwal, DO (1, 2)
Camran Nezhat Institute, Center for Special Minimally Invasive and Robotic Surgery, Palo Alto, CA
Endometriosis is an estrogen-dependent, progressive chronic inflammatory disease that affects an estimated 1 in 6-8 of women, girls, transgender, and non-binary people, and an unknown number of men and intersex people as well. In the U.S., this works out to an estimated 10-15 million people and around 400-700 million worldwide.
Contrary to popular myths, endometriosis is not a period or reproductive disease, but a whole-body (systemic) chronic disease that can cause incapacitating pain and severe destruction to nerves, musculoskeletal structures, and multiple organs throughout the body. In fact, you do not need to menstruate or have a uterus to have endometriosis. For example, men can develop endometriosis, as can women born without a uterus, such as those with complete Mullerian agenesis or Mayer-Rokitansky-Kuster-Hauser syndrome. As well, an estimated 15% (possibly more) of those who have undergone surgical removal of their uterus (hysterectomy) can also still have endometriosis.
Thankfully, too, the harmful and outdated notion that endometriosis only affects people of ‘reproductive age’ is also now known to be incorrect, as endometriosis can manifest at any age. For example, there have been documented cases of endometriosis occurring in premenarcheal girls (prior to menstruation). The incidence is still not currently known, but early investigators in the 20th century actually reported on this phenomenon. Unfortunately, for many years these cases were generally brushed off by researchers and healthcare professionals alike as one-off anomalies. Thanks to the advocacy efforts of patients themselves, premenarcheal endometriosis has recently regained attention and is finally being taken more seriously as a potential cause of severe disability and chronic illness in children. Moreover, endometriosis also affects approximately 5% (and potentially more) of individuals in menopause, including severe cases that lead to hospitalization and life-threatening bowel obstructions. In postmenopausal patients, the cases include those newly diagnosed or with suspected recurrent disease. And finally, supporting the notion of an embryological (congenital) origin as one of several potential etiologies, there have been instances of endometriosis discovered in fetuses, as is reported here and here and here.
As mentioned, endometriosis has been reported in every organ in the human body, with clinically significant extragenital endometriosis leading to genitourinary, gastrointestinal, thoracic, and/or nervous system dysfunction. Those affected can present with non-menstrual pelvic and abdominal pain, dysmenorrhea, dyspareunia, ovulatory pain, dyschezia, and/or changes to bowel or bladder function which can be exacerbated during ovulation or menses. One can also see extragenital symptoms like shoulder pain with diaphragmatic endometriosis; chest pain, hemoptysis and lung collapse in cases of pulmonary endometriosis, upper abdominal pain with pancreatic endometriosis and lumbar pain with sciatic nerve endometriosis (2-5). The severity of symptoms can vary from debilitating to mild, with up to 25% of women being completely asymptomatic (6). Endometriosis in some may only present with unexplained infertility, with an increased suspicion arising only after multiple failed in vitro fertilization (IVF) treatments.
Endometriosis is in fact a leading cause of unexplained infertility, accounting for up to 50 – 80% of patients seeking fertility care. (7). Some theories that can explain how endometriosis can affect fertility include abnormal utero-tubal transport, ovulatory dysfunction, dyssynchronous oocyte maturation, altered cell-mediated immunity, distorted pelvic anatomy, decreased oocyte quality, and altered endometrial receptivity (8). Currently, altered endometrial receptivity and progesterone resistance describe the leading mechanisms behind endometriosis-related implantation failure. Adequate progesterone levels and endometrial receptor expression are needed for embryo implantation, endometrial stabilization and maintenance of pregnancy; any mechanism that interferes with progesterone signaling can cause implantation failure. (9-12)
Endometriosis has been associated with aberrant humoral and cellular immunity. (12). B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL-6) is a protein encoded by a proto-oncogene present on chromosome 3 (3q27.3) that stimulates inflammatory cytokines such as interleukin-6 (IL-6), IL-8, and IL-17 in the peritoneal fluid of people with endometriosis. In the endometrium, BCL-6 forms a complex that binds to and inactivates regulators of the progesterone pathway, leading to progesterone resistance, implantation failure, aberrant decidualization, and recurrent miscarriages in people with endometriosis. (8, 10-14).
The gold standard for the diagnosis of endometriosis is still a surgical diagnosis consisting of laparoscopy with or without histologic confirmation. This can prove to be difficult when endometriomas are involved as different subtypes of endometriomas are treated differently in patients desiring to preserve fertility. Type I endometriomas arise from implanted endometrial-like tissue on the ovarian cortex (Figure 1-3). To minimize adverse effects on ovarian reserve and fertility, these are treated by brushing or washing off the lesions. Type II endometriomas arise from functional cysts that are invaded by endometrial-like implants. When less than 50% invasion is involved, excision can be performed successfully without compromising ovarian reserve. (19-22).
Recently there has been increased development of noninvasive screening and diagnostic tests to accurately identify patients with endometriosis14. A screening test for endometriosis called ReceptivaDx (CiceroDx, Huntington Beach, CA) has been developed to detect endometrial BCL-6 overexpression in asymptomatic women with unexplained infertility or recurrent pregnancy loss15. This test also detects beta-3 integrin expression, a cell adhesion molecule integral to successful implantation. (11, 13). Positive endometrial BCL-6 testing, defined as an HSCORE >1.4, has been associated with recurrent miscarriages and poor IVF outcomes. (13, 16-17). An improvement in subsequent live birth rates was seen (LBR) (50 –76%) when compared to controls (7.4%) when the underlying cause of endometrial inflammation secondary to endometriosis was treated. In this study, 93.8% of patients that tested positive for BCL-6 had laparoscopic findings of endometriosis. (15). A recent retrospective study by Camran Nezhat et. al. on reproductive- age people assigned female at birth going through IVF treatment with endometrial BCL-6 overexpression who underwent laparoscopic surgery for treatment of suspected endometriosis showed that three-quarters of patients (74.7%, n = 56) had a histologically confirmed diagnosis, while 21.3% were diagnosed visually through the presence of ovarian endometriotic implants (n= 16). Those with at least 6 months of postoperative follow-up were assessed for reproductive outcomes (n = 40), resulting in a clinical pregnancy rate (CPR) of 90.0%. The PPV of BCL-6 testing was found to be as high as 96% for the diagnosis of endometriosis, similar to previously reported rates. (15, 18).
According to ASRM, approximately 50% of patients with unexplained infertility having endometriosis. (8). Although those diagnosed with unexplained infertility and recurrent pregnancy loss do not typically seek surgical diagnosis of endometriosis, persistent endometriosis could affect the success rate of IVF. Testing for endometrial BCL-6 may help determine which patients are high risk for endometriosis and other inflammatory pathologies and may need counseling for surgical treatment. Endometrial BCL-6 testing has a high PPV that could help guide physicians and patients undergoing infertility treatment to consider surgical evaluation for endometriosis, which may assist in achieving successful reproductive outcomes. (18). If you are experiencing repeat failed IVF or have been diagnosed with unexplained infertility, many have found it helpful to to download Dr. Nezhat’s free Endometriosis Advisor App , which can assess your risk of having endometriosis with over 90% accuracy. Once you assess your risk, the app will give you an option to email your results to your healthcare provider or to Dr. Nezhat at email@example.com.
- Nezhat C, Li A, Abed S, et al. Strong association between endometriosis and symptomatic leiomyomas. JSLS. 2016;20:1–7. [PMCID: PMC5019190] [PubMed: 27647977]
- Veeraswamy A, Lewis M, Mann A, Kotikela S, Hajhosseini B, Nezhat C. Extragenital endometriosis. Clin Obstet Gynecol. 2010;53:449–466. [PubMed: 20436322]
- Nezhat C, Falik R, McKinney S, King LP. Pathophysiology and management of urinary tract endometriosis. Nat Rev Urol. 2017;14:359–372. [PubMed: 28467398]
- Nezhat C, Li A, Falik R, et al. Bowel endometriosis: diagnosis and management. Am J Obstet Gynecol. 2018;218:549–562. [PubMed: 29032051]
- Nezhat C, Lindheim SR, Backhus L, et al. Thoracic endometriosis syndrome: a review of diagnosis and management. JSLS. 2019;23:1–8.
- Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010;27:441–447. [PMCID: PMC2941592] [PubMed: 20574791]
- Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fert Steril. 2005;84:1574–1578. [PubMed: 16359945]
- Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fert Steril. 2012;98:591–598. [PubMed: 22704630]
- Macer ML, Taylor HS. Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39:535–549.[PMCID: PMC3538128] [PubMed: 23182559]
- Burney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148:3814–3826. [PubMed: 17510236]
- Lessey BA, Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why. Fert Steril. 2017;108:19–27. [PMCID: PMC5629018] [PubMed: 28602477]
- Miller JE, Ahn SH, Monsanto SP, Khalaj K, Koti M, Tayade C. Implications of immune dysfunction on endometriosis associated infertility. Oncotarget. 2017;8:7138–7147. [PMCID: PMC5351695] [PubMed: 27740937]
- Lessey BA, Young SL. What exactly is endometrial receptivity? Fert Steril. 2019;111:611–617. [PubMed: 30929718]
- Agarwal SK, Chapron C, Giudice LC, et al. Clinical diagnosis of endometriosis: a call to action. AJOG. 2019;220:354e.1–354e.12. [PubMed: 30625295]
- Evans-Hoeker E, Lessey BA, Jeong JW, et al. Endometrial BCL6 overexpression in eutopic endometrium of women with endometriosis. Reprod Sci. 2016;23:1234–1241. [PMCID: PMC5933165][PubMed: 27222232]
- Almquist LD, Likes CE, Stone B, et al. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study. Fertility and Sterility 2017;108:1063–1069. [PMCID: PMC5726554] [PubMed: 29126613]
- Likes CE, Cooper LJ, Efird J, et al. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet. 2019;36:483–490. [PMCID: PMC6439015] [PubMed: 30610661]
- Nezhat C, Rambhatla A, Miranda-Silva C, Asiaii A, Nguyen K, Eyvazzadeh A, Tazuke S, Agarwal S, Jun S, Nezhat A, Roman RA. BCL-6 Overexpression as a Predictor for Endometriosis in Patients Undergoing In Vitro Fertilization. JSLS. 2020 Oct-Dec;24(4):e2020.00064. doi: 10.4293/JSLS.2020.00064. PMID: 33414614; PMCID: PMC7757768.
- Nezhat F, Nezhat C, Allan CJ, Metzger DA, Sears DL. Clinical and histologic classification of endometriomas. Implications for a mechanism of pathogenesis. J Reprod Med. 1992;37(9):771–776. [PubMed: 1453396]
- Nezhat C, Nezhat F, Nezhat C, Seidman DS. Classification of endometriosis. Improvingthe classification of endometriotic ovarian cysts. Hum Reprod. 1994;9(12):2212–2213. [PubMed: 7714131]
- Falik RC, Li A, Farrimound F, Razavi GM, Nezhat C, Nezhat F. Endometriomas: classification and surgical management. OBG Management. 2017;29:39–43.
- Donnez J, Lousse JC, Jadoul P, Donnez O, Squifflet J. Laparoscopic management of endometriomas using combined technique of excisional (cystectomy) and ablative surgery. Fert Steril. 2010;94(1):28–32.[PubMed: 19361793]