Endometriosis is an estrogen-dependent chronic inflammatory disease characterized by the extrauterine presence of functioning endometrial glands and stroma. It is most commonly found along the pelvic peritoneum, but also located in the ovaries, the pouch of Douglas, vesicouterine space, and uterosacral ligaments. It is less commonly seen in laparotomy and episiotomy scars, on bowel, diaphragm, appendix, pleural and pericardial cavities, and the cervix.
Theories of the Pathogenesis of Endometriosis
The etiology of endometriosis is unknown and multifactorial. Anatomic, immunologic, hormonal, and genetic mechanisms have been implicated.
Sampson's Theory of Retrograde Menstruation. Retrograde menstruation is the leading theory and suggests that endometriosis is due to the backward flow of endometrial tissue through the fallopian tubes, seeding the peritoneal cavity during menses. Support for this theory is as follows:
Blood flowing freely from the fimbriated ends of fallopian tubes has been visualized during laparoscopy (seen in 90% of patients with patent fallopian tubes).
Endometriosis is most often found in the dependent portions of the pelvis.
Incidence of endometriosis is higher in patients with obstruction to normal outward menstrual flow (eg, cervical stenosis).
Coelomic metaplasia. Totipotential cells of the ovary and peritoneum are transformed into endometriotic lesions by hormonal influence and menstrual efflux. This may explain the finding of endometriosis in mature teratomas and extraperitoneal sites as well as the incidence of endometriosis in premenarchal girls, those with congenital absence of the uterus, and rarely men.
Lymphatic and vascular spread. One study showed that at time of autopsy, 29% of patients with endometriosis had positive pelvic lymph nodes for the disease. Thus, lymphatic spread may explain endometriotic implants found in remote anatomic areas, such as the lung.
Immunologic factors. Increasing data suggest that specific immunologic factors play a major role in determining whether and to what extent a patient will develop the disease. These factors are thought to influence the attachment and proliferation of the endometriotic cells through upregulation of angiogenic and proliferative cytokines and downregulation of cells involved in the destruction of the aberrant tissue.
Hormonal factors. Unlike normal endometrial tissue, endometriotic implants can produce aromatase and 17β-hydroxysteroid dehydrogenase type 1, leading to local estrogen production. In addition, implants do not adequately express 17β-hydroxysteroid dehydrogenase type 2, the enzyme responsible for inactivating estrogen, leading to a high estrogen environment. Implants demonstrate reduced levels of progesterone receptors and are therefore relatively resistant to the estrogen-antagonizing effects of progesterone seen in normal endometrium.
Inflammatory factors. Elevated levels of interleukin-6 and tumor necrosis factor-α have been noted in the peritoneal fluid of endometriosis patients. Prostaglandin E2 (PGE2), a proinflammatory compound, has been shown to be a powerful inducer of aromatase activity in endometriotic implants. PGE2 effects are augmented by endometriotic aromatase activity. This positive feedback loop amplifies the proliferative effects of estradiol.
Genetic factors. Patients with a first-degree relative with endometriosis have a seven-fold greater risk of developing endometriosis. The mode of inheritance is likely multifactorial.
Patient Characteristics
Mean age at diagnosis is 25 to 30 years. Delays in diagnosis, estimated up to 12 years following symptom onset, is common and problematic. Nulliparous patients with early age at menarche and shorter menstrual cycles have the highest incidence. Increased parity and greater cumulative lactation protect against endometriosis.
Studies have demonstrated an inverse relationship between the incidence of endometriosis and current body mass index (BMI) as well as BMI at 18 years of age. This relationship appears to be augmented in the subgroup of patients who experience infertility.
Clinical Presentation
Although some patients with endometriosis are asymptomatic, the most common symptoms are pelvic pain and infertility.
Infertility. Incidence of endometriosis is believed to be present in up to 50% of infertile couples.
Pelvic pain. Up to 70% of patients with chronic pelvic pain and/or dysmenorrhea have endometriosis. Endometrial lesions can lead to chronic inflammation with increases in inflammatory cytokines and subsequent overproduction of prostaglandins, both of which can be a source of pain. Central sensitization and pain may result from nerve growth within the implants and exposure to a chronic inflammatory milieu. The severity of pelvic pain does not correlate with the amount of endometriosis present. The pain typically associated with endometriosis is central, deep, and often in the rectal area.
Other symptoms. Depending on site of implantation, patients can experience additional symptoms. Implantation in the anterior abdominal wall or thorax can lead to abdominal pain and chest or shoulder pain, respectively. Implants in the thorax can result in hemoptysis or pneumothorax (catamenial endometriosis).
Diagnosis of Endometriosis
Definitive diagnosis is made only through histologic examination of lesions removed at the time of surgery. Histology reveals endometrial glands and stroma. Hemosiderin-laden macrophages are identified in 77% of endometriosis biopsy specimens.
Clinical diagnosis. Approximately one-third of patients with endometriosis are asymptomatic. Heightened suspicion is warranted in patients presenting with the symptoms described above, namely cyclic pelvic pain especially deep pelvic pain, and infertility. Experienced clinicians often presumptively diagnose endometriosis based on clinical history, timing of symptoms, and exclusion of other causes of pelvic pain.
Physical exam findings. Tenderness and nodularity along the posterior pelvic structures may be noted in patients with endometriosis. Limited mobility of the uterus or adnexa fixed to the sidewall may be found on bimanual exam depending on the degree of scarring and presence of ovarian endometriomas.
Diagnostic imaging. Imaging may help evaluate causes of pelvic pain and may identify endometriotic lesions; however, imaging cannot be used to rule out endometriosis. In addition, ultrasound and MRI can assist in surgical planning.
Transvaginal ultrasound. The gold standard to visualize ovarian endometriomas, which appear as homogenous cystic lesions with low-level echoes. Although highly operator-dependent, ultrasound has demonstrated fair sensitivity and high specificity for detecting deep infiltrating endometriosis especially of rectosigmoid disease.
MRI. Often used as confirmatory imaging in equivocal cases and provides the best overall imaging modality for endometriosis. Peritoneal implants appear as a high-intensity signal on T1-weighted imaging similar to fat and hypointense signal on T2-weighted imaging.
CT imaging. Generally, of limited utility but can help in evaluating thoracic endometriosis and abdominal wall endometriomas.
Diagnostic laparoscopy. Endometriotic lesions classically appear as blue-black powder-burn implants on visual inspection. However, lesions can have varying appearances including vesicular, red, white, tan, nonpigmented, stellate lesions cause peritoneal puckering and/or fibrosis. The presence of defects in the peritoneum (usually scarring overlying endometrial implants) is known as Allen–Masters syndrome. Endometriomas, or “chocolate cysts,” appear filled with dark brown blood. Pathologic confirmation of suspicious lesions is preferred for diagnosis but not required.
Surgical staging of endometriosis
The American Society for Reproductive Medicine (ASRM) Revised Scoring System (1996) consists of four stages following numeric grading of endometriotic lesions, degree of posterior cul-de-sac obliteration and adhesions. It provides a standardized method to report operative findings but does not correlate with type or severity of symptoms, nor does it predict future fertility following treatment.
Enzian Classification System (2005) consists of four stages to describe deep infiltrating endometriosis.
Endometriosis Fertility Index (EFI) (2009) provides numerical measurement of functional anatomy to predict pregnancy rates following surgery. A low EFI (0 to 3) correlates with a low pregnancy rate (∼10%) over 3 years and a high EFI (9 to 10) with improved pregnancy rates (∼75%).
The American Association of Gynecological Laparoscopists (AAGL) Endometriosis Scoring System (2021) grades surgical complexity with high reliability. It corresponds with symptoms comparable to the ASRM system.
Treatment
Expectant management. Asymptomatic patients or patients with mild symptoms can be managed expectantly.
Medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal suppression remains the mainstay of therapy ranging from combined hormonal therapy, progesterone-only therapy, and GnRH agonist and antagonists. There has not been proven superiority of one over another and selection should be driven by efficacy and safety as well as the need for contraceptive protection, anticipated duration of treatment, tolerability, and cost. Estrogen stimulates the growth of endometriotic implants similar to its effect on normal endometrial tissue. Medical therapy is aimed at suppressing ovarian estrogen stimulation by interrupting the hypothalamic–pituitary–ovarian axis. Inhibition of ovulation by gonadotropin suppression removes the stimulation of endometriosis by cycling sex steroids.
NSAIDs are a common first-line agent for symptomatic relief of endometriosis-related pain and inflammation. NSAIDs inhibit prostaglandin production by ectopic endometrium.
Estrogen-progesterone contraceptives. Combined contraceptives are often the treatment of choice for endometriosis-related pain and can provide pain relief from dysmenorrhea. Combined contraceptives suppress gonadotropin release and subsequently cause decidualization and atrophy of endometrial implants. Symptomatic relief of pelvic pain and dysmenorrhea is reported in 60% to 95% of patients.
Progestins. Progestins inhibit ovulation by suppressing luteinizing hormone (LH) and may induce amenorrhea. They also suppress endometriosis through decidualization and atrophy of endometrial tissue. Progesterone therapy can be continued for suppression of endometriosis symptoms; however, there is a potential for bone demineralization with long-term use. Various forms of progestin can be used, including oral progestin pills, depot medroxyprogesterone acetate, norethindrone acetate, or a levonorgestrel-releasing intrauterine device (IUD).
Gonadotropin-releasing hormone (GnRH) agonists. Long-acting GnRH is all parenteral medications that suppress pituitary function by downregulating pituitary GnRH receptors. This interruption of the hypothalamic–pituitary–ovarian axis produces a “medical oophorectomy” or “pseudo-menopause.” Three available agents are leuprolide acetate (Lupron Depot), nafarelin acetate nasal spray (Synarel), and goserelin acetate (Zoladex). Side effects are related to the hypoestrogenic state. The FDA has approved up to a 12-month course in combination with add-back therapy to avoid the long-term consequences of the hypoestrogenic state on bone metabolism. Recurrence rates following discontinuation of therapy have been quoted as high as 73% after a 5-year follow-up period.
Add back therapy. Used to minimize hypoestrogenic side effects and bone loss at a dose below the threshold needed to stimulate endometriosis growth. Patients receiving add-back therapy have significantly less vasomotor side effects and bone mineral density loss over a 6-month period while still achieving pain relief. Add-back therapies include norethindrone acetate 5 mg daily (a progestin with estrogenic metabolites) and conjugated estrogen 0.625 mg together with medroxyprogesterone acetate 5 mg daily.
GnRH antagonists. Elagolix, the first oral, nonpeptide GnRH antagonist acts similarly to GnRH agonists in suppressing gonadotropin production and circulating estradiol levels. GnRH antagonists can be given at a low (150 mg daily) or high dose (200 mg twice daily) with fewer side effects in the low dose group but also less efficacy. High-dose GnRH may require add-back therapy. GnRH antagonists, however, provide an immediate effect without the initial flare effect seen in nonpulsatile dosing of GnRH agonists. They are also better tolerated than GnRH agonists even with high-dose administration.
Danazol (Danocrine). A derivative of the synthetic steroid 17α-ethinyltestosterone. It suppresses the mid-cycle LH surge, inhibits steroidogenesis in the human corpus luteum, and produces a high-androgen and low-estrogen environment. Despite high rates of improvement in symptoms, androgenic side effects (acne, hirsutism, decrease in breast size, deepening of voice) greatly reduce compliance.
Aromatase inhibitors. Third-generation aromatase inhibitors, letrozole and anastrozole, have been used in combination with other agents for treatment of endometriosis refractory to other modalities. They decrease circulating estrogen by blocking conversion of androgens to estrogens. Side effects include decreased bone density, vaginal spotting, hot flashes, headaches, and mood swings.
Surgical Treatment
Definitive surgery entails total abdominal hysterectomy with bilateral salpingo-oophorectomy, excision of peritoneal surface lesions or endometriomas, and lysis of adhesions. In patients with normal appearing ovaries, a hysterectomy with ovarian conservation should be considered pending the age of the patient, comorbidities, and family history. While there is a sixfold increased risk of developing recurrent symptoms and an eightfold reoperation rate to remove the remaining ovary, most patients do not require reoperation.
Hormone therapy (HT) with estrogen after definitive surgery should be used to reduce surgical menopausal symptoms pending patient age. Although endometriosis is an estrogen dependent disease, HT does not appear to increase the risk for recurrence of endometriosis.
Conservative surgery is usually reserved for patients with endometriosis-related pain who desire future fertility. The goals of surgery are to restore normal anatomy and remove and treat visible disease. A Cochrane review demonstrated improvement in pain with removal of disease but no clear benefit of excision versus ablation. However, excision is imperative for removal of deep infiltrating lesions (>5 mm depth) and to obtain a pathology specimen. Those favoring excision note that the depth of the lesion cannot be ascertained visually and thus disease may persist following ablation. Recurrence over a 5-year period is approximately 40% and may require reoperation. Postoperative medical suppressive therapy lowers recurrence of dysmenorrhea and endometrioma formation and should be routinely used to prevent recurrence except in patients actively trying to conceive.
Endometrioma resection. Surgical resection of endometriomas is pursued based on patient symptoms, size of endometrioma, fertility goals, and/or suspicion of malignancy. Cystectomy can be recommended regardless of symptoms when size approaches approximately 5 cm, although the decision to proceed with surgical intervention for an endometrioma alone depends on symptoms, if they have trialed medical therapy, and/or fertility plans. Recent data supports that medical management of endometriomas can modestly reduce their size over time. Cystectomy can improve pain relief, rates of subsequent spontaneous pregnancy and reduces recurrence compared to aspiration and should be the primary form of endometrioma management when appropriate. Patients should be counseled on the risk of reducing ovarian reserve or increasing adhesions, both of which could reduce future fertility. If active surveillance is chosen over resection, endometriomas should be followed with at least annual imaging.
Endometriosis and Infertility
The exact incidence of infertility caused by endometriosis is unknown, although endometriosis is found in up to 50% of couples with infertility. Infertility can increase with severity of disease.
The effect of endometriosis on fertility is likely multifactorial including anatomic, inflammatory, cell signaling and epigenetic effects on ovarian, tubal and endometrial function. Chronic inflammation may affect folliculogenesis, fertilization, and implantation. Specific mechanisms include alterations in peritoneal fluid cytokines, decreased presence of integrins during the implantation phase, and progesterone resistance leading to abnormal endometrial matrix metalloproteinase activity. Adhesions and resulting distorted anatomy may impair oocyte release and transport.
Fewer oocytes are retrieved when an endometrioma is present but the pregnancy rate with in vitro fertilization (IVF) is not greatly altered and the risk of removing segments of normal ovarian cortex along with the cystectomy must be weighed against the benefits.
Endometriosis and Ovarian Malignancy
Endometriosis is associated with an increased risk of ovarian cancer, especially endometroid and clear cell types. The relative risk of ovarian cancer in patients with endometriosis is up to 1.42 based on recent meta-analyses. The overall risk, however, remains low and no additional cancer screening is recommended.
The pathology of endometriosis exhibits many of the characteristics of neoplastic lesions: reduced cell cycle inhibitor activity, ability to resist apoptosis, angiogenic potential, and ability to invade surrounding tissue.
Malignant transformation of endometriotic lesions is a recognized but rare mechanism in the development of ovarian cancer. Definitive surgery to remove all visible evidence of endometriosis is not recommended as a prophylactic means of reducing the development of ovarian malignancy. Rather, long-term use of oral contraceptives is the preferred method of cancer risk reduction as an 80% lower occurrence of ovarian cancer in patients with endometriosis has been shown in patients using the drug for >10 years.
Endometriosis as a Systemic Disease
Endometriosis is associated with an increased risk of anxiety and depression, in addition to alteration in pain sensitivity. This may result from alterations in gene expression in the brain.
Chronic inflammation associated with endometriosis can alter cytokine profiles in systemic circulation. This may increase the risk of cardiovascular disease and cancer. In addition, if the treatment for endometriosis induces early menopause, the risk of cardiovascular disease is increased.
Sexual health may be impacted not only through pelvic pain but due to the mental comorbidities associated with the disease.
A holistic approach to addressing care for patients with endometriosis involves addressing the physical, psychological, and social effects of this disease. Complementary therapies, especially acupuncture, have shown improvement in quality of life in well-designed studies.