Overview of Pathogenesis,Symptoms,Diagnosis,Management,and Prognosis of Endometriosis and Its Role in Infertility

Introduction

Affecting 10%–15% of all women of reproductive age, endometriosis is a disease conventionally thought of being comprised of endometrial glands and stroma located outside the uterus. ¹ The majority of individuals suffer from chronic pelvic pain, dysmenorrhea, dyspareunia, and/or infertility. This disorder carries a high individual and societal cost and is associated with a significant economic burden. Due to both health care costs and loss of productivity, the estimated cost of endometriosis is almost $70 billion dollars annually in the United States. ²

Pathogenesis

Although there is currently no definitive explanation for the origin of endometriosis, many theories do exist that hypothesize how endometriosis lesions may develop. The most popular theory is retrograde menstruation. This is the oldest theory, initially proposed by John Sampson, MD, in the 1920s and supported by menstrual blood seen in fallopian tubes in menstruating women during laparotomy. ³ This theory proposes that a retrograde flow of endometrial cells through the fallopian tubes and into the pelvic cavity during menstruation is the cause of endometriosis. However, retrograde menstruation occurs in a large majority of women, 76%–90%, with patent fallopian tubes, and not all of these women have endometriosis. ⁴

It is hypothesized that inherent dysfunction of the peritoneal system is the reason why only a small percentage of women develop endometriosis that results from retrograde menstruation. ⁵

The coelomic metaplasia theory describes metaplasia of specialized cells in the mesothelial lining of the abdominal peritoneum causing endometriosis, which may explain the occurrence of the disease in prepubertal girls. ⁶ The theory of Müllerianosis proposes that misplaced endometrial tissue at the time of fetal organogenesis develops into endometriosis, providing a better explanation for lesions in the cul de sac and uterosacral ligaments. ⁵

Alternatively, it is thought that steroid hormones, specifically estrogen, are central to the development of endometriosis, as it is most commonly seen in women of reproductive age and it is likely that ectopic lesions have an increased responsiveness to estrogen. ⁶ Other theories include hematogenous or lymphatic transport, oxidative stress and inflammation, immune dysfunction, apoptosis suppression, genetics, and involvement of stem cells. Additionally, progesterone typically counteracts the proliferative actions of estrogen in healthy endometrium, and it is believed that endometriosis may be related to resistance of endometrium to progesterone. ⁷

Unfortunately, each of these theories only account for a partial understanding of the etiology of endometriosis, rather than providing an etiology for all women affected by the disease, given that there is such a wide range of clinical presentations and pathologic findings.

Symptoms and Diagnosis

Endometriosis primarily affects women of reproductive age. Of those women, 30%–50% suffer from chronic pelvic pain and/or infertility, the two major clinical symptoms. ⁸ The clinical presentation of endometriosis often varies, but the hallmark symptoms are chronic abdominal–pelvic pain, specifically painful periods (dysmenorrhea), painful intercourse (dyspareunia), painful urination (dysuria), and painful defecation (dyschezia). Given that endometriosis is an estrogen-dependent disease, ⁴ it is typically suspected in women with cyclic pain associated with heavy menses.

One must consider all potential alternative causes of pelvic pain in the differential diagnosis when considering endometriosis. Cyclic pain can also be seen in women with fibroids and adenomyosis. Associated symptoms, including constipation, diarrhea, or urinary symptoms should lead to consideration of gastrointestinal or genitourinary diseases. There may also be associated pain syndromes such as irritable bowel syndrome, fibromyalgia, or interstitial cystitis. ⁹ Though women with endometriosis can have benign physical examination results, findings may include tenderness on palpation of the posterior fornix, adnexa, uterosacral ligaments, or pelvic masses when endometriomas or deep infiltrating endometriosis (DIE) occur. Long-term exposure can lead to secondary pain syndromes, pelvic-floor myalgia, and central sensitization. ⁸

There are 3 primary types of endometriosis: (1) superficial peritoneal lesions; (2) ovarian endometriomas; and (3) DIE. The location and extent of these lesions do not correlate well with the severity or location of the pain but may be associated with infertility. The lesions are primarily found in the pelvis, as well as on the appendix, large bowel, ureters, bladder, or rectovaginal septum, with very rare lesions occurring in extrapelvic locations. ⁹

Pelvic ultrasound can additionally identify endometriomas and DIE. ⁸ Although ultrasound is more readily available and inexpensive, its accuracy is reliant on expert technicians. Therefore, magnetic resonance imaging (MRI) can be used for a more-accurate diagnosis, especially to detect DIE and rectosigmoid lesions. Computed tomography (CT) scans can be used to detect ureteral involvement but are not as helpful because CT scans do not visualize the pelvic organs as well as MRI. ⁹

Imaging can aid in diagnosis of DIE, but the “gold standard” for diagnosing endometriosis is surgery. Diagnosis is defined by histology identifying extrauterine lesions with endometrial glands, stroma, or hemosiderin-laden macrophages with further descriptions of the locations and depths of these lesions. The lack of obvious lesions does not eliminate the diagnosis of endometriosis, and there is poor correlation between severity of the disease and women's symptoms. While surgery is the gold standard for diagnosis and treatment, it comes with risks and potential decreases in ovarian reserve, especially in the case of endometriomas. ⁵

Effects of Endometriosis on Fertility

For many years, research has examined the role endometriosis plays in fertility. Data from 2017 indicate that ∼30%–50% of women diagnosed with endometriosis also struggle with infertility. ¹⁰ Additionally, there is speculation that, although there is limited evidence, failure of timely diagnosis and management of endometriosis may compromise fertility further and increase the risk of continued chronic pelvic pain. ¹¹

Compared with women without histories of endometriosis, women with endometriosis had an age-adjusted twofold increased risk of infertility. However, a study also showed that, among women with primary infertility, 50% became parous after endometriosis diagnosis, and, among all women with endometriosis, 83% were parous by age 40. ¹² It has been noted that women with endometriomas have lower anti-Müllerian hormone levels than women without endometriosis prior to surgery. ⁵ However, even minor endometriosis has been associated with subfertility. ¹³

The mechanism explaining infertility due to endometriosis is controversial, but involves abnormal folliculogenesis, oxidative stress, and immune dysfunction that lead to poor oocyte quality, impaired fertilization, and implantation. ¹³ Additionally, peritoneal adhesions and inflammation may lead to sperm DNA damage and abnormal oocyte cytoskeletons. ⁵

While the exact mechanism of how endometriosis plays a role in infertility has been elusive, there are many different proposed theories. A study in Fertility and Sterility in 1984 first explored this investigation on monkeys and found that impaired fertility in monkeys with endometriosis was mediated by failure of follicular rupture and/or pelvic adhesions. ¹⁴

Toya et al. then looked specifically at the cell cycle in granulosa cells and found that patients with endometriosis had a higher portion of granulosa cells trapped in the S-phase, subsequently leading to apoptosis and therefore reduced folliculogenesis. ¹⁵ Natural-killer (NK) cells have also been implicated in infertility. A study reviewed NK cells in both benign and endometriosis populations and revealed a reduced cytotoxic function in women with endometriosis. This decreased cytotoxic function is thought to be connected to the associated infertility. ¹⁶

More-recent data have indicated specific anatomical findings and suggested how they related to infertility in patients with endometriosis. For example, a retrospective study by Rubod et al. revealed that the presence of a rectouterine nodule is associated with a lower chance of pregnancy after in vitro fertilization (IVF). ¹⁷ With these studies examining the causes of infertility in endometriosis patients, ranging from microscopic changes to anatomical changes of scar and nodule formation, research is focusing on how to treat each one of these causes to decrease infertility rates and improve the success of IVF.

Management of Endometriosis

Treatment options for endometriosis are both medical and surgical. From symptom and inflammation control with nonsteroidal anti-inflammatory drugs to medications that suppress ovulation, medical management has been a staple in treatment for women who wish to avoid surgery. Women for whom first-line management with medical treatment fails often proceed to surgical management. Surgery not only provides the benefit of symptom relief but also the advantage of tissue diagnosis. Surgical management can be thought of as conservative, definitive, or radical. Conservative management includes resection or ablation of lesions, with definitive surgery including hysterectomy with possible oophorectomy, and radical being the removal of all visible endometriosis implants during surgery.

Management of Endometriosis in Patients with Infertility

For many years, women struggling with infertility and endometriosis have turned to IVF. A large meta-analysis reviewed IVF therapy as an appropriate method for achieving pregnancy in women suffering from endometriosis. The data revealed that women with and without endometriosis have comparable assisted reproductive technology (ART) outcomes in terms of live births; however women with severe endometriosis have inferior outcomes. ¹⁸ With this meta-analysis, subsequent studies have reviewed ways to improve IVF outcomes. A recent Cochrane review examined long-term gonadotropin-releasing hormone–agonist therapy before IVF treatment and revealed that there were not enough data to determine if this intervention affected clinical pregnancy rates, multiple pregnancy rates, miscarriage rates, mean numbers of oocytes, and mean numbers of embryos. ¹⁹

Given the paucity of data on medical management and its effect on infertility, more recent studies have examined surgical management. Bianchi et al. compared the outcomes of IVF treatments in women with infertility-associated DIE who underwent extensive laparoscopic excision of endometriosis before IVF with those who underwent IVF only and revealed that extensive laparoscopic excision of DIE significantly improved IVF pregnancy rates of women with infertility-associated DIE. ²⁰

A large meta-analysis also showed that, for women with infertility and symptoms of endometriosis, primary surgery to resect or ablate endometriosis nearly doubled live birth or ongoing pregnancy rates. ²¹ Other studies have also examined fertility rates after repeat surgery if primary surgery did not lead to pregnancy. Both Rizk et al. and Vercellini et al. described reoperations that did not increase fertility while showing a small amount of pain relief.^22,23

Another way of examining outcomes came from the endometriosis fertility index (EFI) and subsequently developing treatment plans. The EFI was first described in 2010 as a simple, robust, and validated clinical tool that predicts pregnancy rates after diagnostic laparoscopy to determine long term prognosis. ²⁴ A recent analysis revealed that patients with unfavorable EFIs require ART at higher rates than patients with favorable EFIs and, therefore, should be referred for ART shortly after surgery. Patients with favorable EFIs may attempt spontaneous pregnancy for 24 months before referral. ²⁵ Evaluation of the EFI and creating patient-specific treatment plans can lead to better patient outcomes.

Prognosis

Although surgery may reduce symptoms and increase likelihood to conceive, Prescott et al. concluded that surgery provides only an 8% increase in the conception rate among patients with Stages I–II endometriosis. ¹² In a study comparing women with mild endometriosis and women without endometriosis, implantation and pregnancy rates were similar in a donor egg program using oocytes of women with advanced endometriosis and in those without disease. ²⁶ Another study showed that using sibling oocytes from the same donor in recipients with and without endometriosis resulted in lower implantation and pregnancy rates, suggesting an endometrial defect. ³ It is possible that these lower implantation rates may be due to other simultaneous endometrial defects, such as adenomyosis.

With respect to pain and symptoms associated with endometriosis, not all patients experience relief following surgery. Many undergo conservative surgery and uterine preservation due to desired future fertility. Current studies show that one-fourth of women continue to have endometriosis-associated pain following surgery, with more than 10% reporting no improvement of pain. Additionally, one-fifth of women undergo further surgery. The likelihood of recurrence at 3 years after surgical excision is 24%. ²⁷ That systematic review also showed that women with DIE have a good prognosis following surgery, and that women who underwent hysterectomy with ovarian preservation were more than twice as likely to require further surgical treatment than those who underwent surgery without ovarian preservation (18% versus 9%). ²⁷

A further concern with endometriosis is the possibility of malignant transformation. Interestingly, tumor cells are programmed by transforming growth factor (TGF)–β1 to use aerobic glycolysis, which results in increased lactate secretion. ⁶ Both increased TGF-β1 and lactate have been seen in the peritoneal fluid of women with endometriosis. ⁶ Although it is a benign disease, there is evidence that women with endometriosis have a fourfold increased risk of epithelial ovarian malignancy, specifically clear-cell and endometrioid carcinomas. ⁵ The small increased risk of cancer in these patients does raise concern regarding hormone therapy. However, hormone therapy for symptomatic reproductive-age women with postsurgical menopause is still recommended. ⁵