Endometriosis

> What is the burden of endometriosis?

It is estimated that endometriosis affects approximately 10% of women of reproductive age, and an unknown number of people of gender diversity. Case series have identified endometriosis in 40%-50% of women and adolescents with persistent pelvic pain, and in 30-40% of women with infertility. The condition can cause severe dysmenorrhea, profound dyspareunia, and chronic pelvic pain, as well as bowel and bladder symptoms, and fatigue.

The severity of symptoms does not correlate with the extent of the disease; Patients with significant disease may be asymptomatic, which adds to the puzzle of this condition.

Endometriosis can involve multiple organ systems and symptoms are often chronic, which can significantly impact work productivity and social life, intimate relationships, and mental health. Its social costs are substantial. Endometriosis also affects fertility by altering the peritoneal environment or distorting pelvic anatomy. About 30% of patients with endometriosis have difficulty conceiving.

> What causes endometriosis?

Many theories have been proposed to explain the development of endometriosis, but none are definitive. The most accepted is that endometrial cells reach the peritoneal cavity through retrograde menstruation.

Generally, these cells are altered and eliminated. It is believed that endometriosis develops from the alteration of this process favored by factors such as cell adhesion and proliferation, somatic mutations, inflammation, localized steroidogenesis, neurogenesis and immune deregulation.

Endometrium-like cells can implant outside the uterus and respond to estrogenic stimulation of the ovaries and the cells themselves, leading to inflammation and subsequent scarring and adhesions.

Other theories include coelomic metaplasia, whereby normal peritoneal tissue (i.e., mesothelium) transforms into endometrial-like tissue due to ectopic metaplastic transition. It is postulated that extra-pelvic endometriosis is due to hematogenous or lymphatic dissemination.

> What are the known risk factors for endometriosis?

Risk factors for endometriosis include low birth weight, Müllerian anomalies, early menarche, short menstrual cycles, increased menstrual flow, low body mass index, and nulliparity.

People with endometriosis may have a genetic predisposition. Twin studies showed a 50% heritability while epidemiological studies confirmed a 3 to 15 times greater risk of disease in first-degree relatives of patients with endometriosis.

Different racial and ethnic prevalence of diagnosed endometriosis have been reported. A systematic review found that Asian women had a higher risk and black women had a lower risk of endometriosis than white women, but these estimates may reflect bias related to access to care.

> What are the subtypes of endometriosis and its clinical manifestations?

It is important to recognize 3 subtypes of pelvic endometriosis as they can affect the presentation of symptoms and the method of diagnosis. The most common subtype is superficial peritoneal endometriosis, which consists of various colored lesions located on the surface of the peritoneum. Endometriomas are ovarian cysts that contain a dark, blood-stained fluid (often called chocolate cysts).

Deep endometriosis ( previously called deep infiltrating endometriosis) is identified by lesions that extend beyond the peritoneum. These lesions are usually nodular and fibrotic and have the capacity to invade adjacent pelvic organs, such as the rectosigmoid, ureter or bladder.

Subtypes may overlap; some patients may have more than 1 manifestation of the disease at the same time. The coexistence of endometriomas and deep endometriosis is common; The finding of an endometrioma on ultrasound requires further investigation, especially if the patient reports severe pain.

Deep endometriosis has the capacity to cause target organ damage, such as kidney failure (due to ureteral obstruction) or intestinal obstruction, so timely diagnosis and management are important. The clinical presentation of extra-pelvic endometriosis is less common and can occur in sites such as the diaphragm, thoracic cavity, and surgical scars.

The symptoms of endometriosis can vary and change over time. Endometriosis is sometimes diagnosed incidentally during surgery performed for other indications, in asymptomatic patients, regardless of subtype.

Most (90%) symptomatic patients have secondary dysmenorrhea, which can be disabling and is often their current problem.

This can be distinguished from primary dysmenorrhea, which is usually shorter in duration and responds well to nonsteroidal anti-inflammatory drugs.

Deep dyspareunia ( shooting pain in the upper part of the vagina during intercourse), chronic pelvic pain, and infertility are also common symptoms and may coexist with dysmenorrhea. Less commonly, any of these 3 symptoms may be the main presenting problem in the absence of dysmenorrhea.

Deep endometriosis that invades adjacent organs can cause symptoms at the time of menstruation, such as dyschezia, hematochezia, dysuria or hematuria. Diaphragmatic or thoracic implants may cause cyclical dyspnea, chest or shoulder pain, hemoptysis, and pneumothorax. Other less specific but common symptoms are: abdominal pain and distension, abnormal uterine bleeding, lower back pain and fatigue. Given the heterogeneity of this symptomatology, it is important that providers have a high index of suspicion of endometriosis.

> What is the natural history and prognosis of endometriosis?

The natural history of disease was observed by laparoscopy, repeated at 6-12 months, in patients enrolled in the no-treatment group of 2 randomized trials evaluating surgical treatment of patients with minimal to moderate disease.

Endometriosis progressed in 29% to 45% of patients, remained unchanged in 33% to 42%, and regressed in 22% to 29%. This information changed the long-held belief that endometriosis is always progressive.

Most patients report that their symptoms began in adolescence and improved at menopause, although some patients continue to have pain after menopause. The improvement in menopause is likely due to the lack of estrogenic stimulation.

Although current medical and surgical therapies are not curative, they provide considerable symptom relief for many patients. However, some people with endometriosis develop more complex persistent pain (despite complete treatment) that may be secondary to central sensitization or nociplastic pain, recently defined by the International Association for the Study of Pain as “pain arising from “altered nociception despite no evidence of actual or potential tissue damage causing activation of peripheral nociceptors, or evidence of disease or injury to the somatosensory system causing pain.”

Mechanisms of central sensitization in endometriosis include reduced downward modulation of peripheral signals (gating theory) and cross-sensitization, leading to visceral symptoms and somatic structures (via viscero/visceral and visual crosstalk). zero/somatic in the spinal cord).

The development of central sensitization may explain the evolution of cyclic pain to chronic pelvic pain and the development of other chronic pain conditions. In 2015, the National Institutes of Health recognized the entity of overlapping chronic pain conditions as a group of chronic pain conditions that often coexist, occur predominantly in women, and likely share common immune, neural, and endocrine mechanisms.

Endometriosis was one of these conditions, along with commonly co-occurring conditions such as vulvodynia, irritable bowel syndrome, and painful bladder syndrome. Other overlapping chronic pain conditions include chronic migraine, low back pain, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, and temporomandibular disorders.

Patients who do not respond or who have only a short-term response to targeted endometriosis treatments with coexisting pain conditions may have developed a central sensitization or nociplastic pain process. Evidence suggests that early treatment of endometriosis and associated pain may decrease the risk of developing chronic pain, further supporting the importance of early screening and intervention.

> How is endometriosis diagnosed?

Despite research on biomarkers, no blood test reliably diagnoses endometriosis.

For a long time it has been considered that the gold standard of diagnosis after having visualized the lesions laparoscopically is histological confirmation. However, recent guidelines recommend a nonsurgical (clinical) diagnosis based on symptoms and findings on physical examination and imaging. This change is the result of recognition that surgery is not considered curative and carries risks, and that reliance on surgery to make the diagnosis can lead to an unacceptably long delay (up to 11 years) between the onset of symptoms and the diagnosis. initiation of appropriate treatment.

Other factors that contribute to delay in diagnosis, including symptom variability, suboptimal healthcare provision, patient awareness and knowledge of this condition, stigma around discussing gynecological symptoms, and social normalization of pain in women. women. To overcome some of these factors, doctors should routinely ask about the menstrual cycle and the symptoms associated with endometriosis and their impact on quality of life. Diagnosis in adolescents can be particularly difficult, since acyclic pain is more common in this population.

History and physical examination are essential in making the diagnosis of endometriosis. A UK case-control study of more than 5,000 patients with endometriosis found that patients were more likely to have dysmenorrhea, dyspareunia or postcoital bleeding, abdominopelvic pain, menorrhagia, and a history of subfertility than controls.

A pelvic exam can be very uncomfortable for a patient with symptoms of pelvic pain, and in some circumstances it may not be possible. It should be performed with informed consent and carried out gradually depending on the tolerance of each step (single digit, then bimanual, then speculum), with frequent check-ups with the patient.

In patients with endometrioma , examination may reveal adnexal masses or a fixed retroverted uterus or, in patients with deep endometriosis, a firm nodule of the palpable posterior vaginal fornix (corresponding to the posterior fornix of the pelvis). Posterior vaginal fornix nodules can sometimes be visualized on speculum examination, often with a bluish tint. In patients affected by endometriosis, sensitivity of the posterior vaginal fornix (corresponding to the uterosacral ligaments) or the lateral vaginal fornix (corresponding to the adnexa) may be found.

The clinical examination has a low diagnostic accuracy, so a normal examination does not rule out endometriosis.

The exam can help detect other possible causes of pelvic pain, such as tenderness in the pelvic floor (pelvic floor myalgia) or at the base of the bladder (painful bladder syndrome).

Transvaginal imaging is an important modality for nonsurgical diagnosis. The first-line investigation is ultrasound, an inexpensive and easily accessible test. Basic transvaginal ultrasound, as performed in most ultrasound units, can be used to diagnose endometriomas, with high accuracy, and can also rule out other pelvic pathologies.

Advanced transvaginal ultrasound — which incorporates the sliding sign between the uterus and sigmoid colon, and examination of the anterior and posterior compartments, for endometriosis nodules—systematic reviews have been shown to detect deep endometriosis. This type of ultrasound is performed by sonographers, radiologists or gynecologists with special interest and training in endometriosis imaging, but is not routinely available in many regions of Canada.

The criteria for performing and reporting transvaginal ultrasounds for patients with suspected endometriosis has been published, and is expected to be adopted by all sonographers. If a pelvic examination or transvaginal ultrasound is not possible or acceptable to the patient, a transabdominal or transrectal ultrasound may be performed.

Magnetic resonance imaging can also be used to diagnose endometriosis , as it has similar sensitivity and specificity (>90%) to advanced transvaginal ultrasound, although its accuracy is affected by the protocols used and the experience of the reader. Both modalities are excellent for detecting adenomyosis, a condition that commonly occurs along with endometriosis, and is also a cause of severe dysmenorrhea.

Healthcare providers may need to contact their local radiologist to find out which imaging modality is most available in their region for the detection of deep endometriosis. No imaging modality can reliably detect superficial peritoneal endometriosis; It may be suspected based on symptoms suggesting endometriosis and tenderness of the vaginal fornices on pelvic examination. Definitive diagnosis can only be made at surgery, but current guidelines recommend that the diagnosis not be based solely on laparoscopy.

The current recommendation to provide a clinical diagnosis of endometriosis based on symptoms, signs and imaging, without the need for pathological confirmation, is important because this approach facilitates validation of symptoms, empowers clinicians to initiate treatment early, and provides information to patients about their health, allowing them to make more informed decisions about their treatment. Providing first-line treatment on the basis of a clinical diagnosis also reduces delays in treatment and therefore decreases the likelihood of long-term sequelae.

> How should endometriosis be managed?

Therapeutic options for patients with symptomatic endometriosis are hormonal therapies that suppress ovulation and menstruation, surgery, or a combination of both. Diet and lifestyle modifications may also be helpful, but have not been well studied. Diets that target co-occurring conditions such as irritable bowel syndrome and painful bladder syndrome have more evidence supporting their usefulness.

Lay health providers should feel empowered to diagnose endometriosis and initiate management. Non-steroidal anti-inflammatory drugs may be a useful first line of treatment for symptoms of dysmenorrhea but no evidence suggests that they improve non-menstrual symptoms.

There are many hormones that can be used to treat endometriosis; all have comparable efficacy, 60% to 80%, and are recommended by clinical practice guidelines. However, they have variable costs and adverse effects. The goal of hormone therapy is to suppress the menstrual cycle, induce amenorrhea, and preferably stop ovulation when it is painful.

Hormonal therapies are contraceptive and therefore are not appropriate for patients who are trying to conceive.

Non-hormonal medical therapies targeting inflammatory or angiogenic pathways are currently being explored, but none are yet available.

Hormonal suppression can be achieved with combined estrogen-progestin contraceptives (cyclic or continuous) or progestin-only medications (oral, injectable, subcutaneous implants, or intrauterine device). Evidence supports their effectiveness for endometriosis symptoms, and current guidelines consider them acceptable first-line options.

Two systematic reviews and a Cochrane review (including 5 randomized controlled trials) have concluded that treatment with hormones combined with contraception reduces pain associated with endometriosis, including dysmenorrhea, non-cyclic pelvic pain and dyspareunia, with improvement in quality of life, compared to placebo. However, these reviews also noted that the studies were of low quality, with a high risk of bias and short duration of follow-up (3-11 months).

The efficacy of several progestins was evaluated in a Cochrane review and a systematic review focusing on dienogest. Continuous progestins were found to be effective for the treatment of pain associated with endometriosis, with variable adverse effects, with no evidence of greater efficacy of one oral progestin than another. A systematic review comparing levonorgestrel combined with an intrauterine system that releases gonadotropin-releasing hormone (GnRH) agonists included 5 randomized studies that showed similar efficacy for the relief of pain associated with endometriosis.

It is necessary to focus on the patient and choose between the two. Discussions should include information about individual risk factors and patient preferences. Several treatments may be needed before one is found that provides cycle suppression, with acceptable adverse effects. Once a first line medication is found that is effective it can be continued for many years.

Second-line therapies include GnRH agonists and antagonists, as well as aromatase inhibitors. GnRH agonists, and at higher doses GnRHb antagonists, require additional hormone replacement therapy to counteract the adverse effects of severe hypoestrogenism. Today the use of oral danazol, a synthetic androgen, is not supported due to its adverse effects.

Second-line therapeutic options are generally initiated by a gynecologist, especially when endometriosis is confirmed by imaging or surgery. Prolonged use of second-line agents is sometimes required and therefore ongoing management may be provided by the primary care provider.

Surgical treatment is indicated when pharmacological therapies are contraindicated (e.g., if the patient is planning to conceive) or were not tolerated or failed to provide adequate relief. Most international guidelines consider that the best practice is a minimally invasive and complete approach to the disease.

Some patients may choose surgery as their first option after being informed about its benefits (including fertility benefits, which are affected by factors such as age) and its risks and limitations, including disease recurrence and persistence. of pain from other causes. For patients in whom endometriosis has caused ureteral or intestinal obstruction, the only management option may be surgery.

The American Society for Reproductive Medicine (ASRM) classification allows us to distinguish minimal, mild, moderate or severe endometriosis (stages I-IV). This system reflects the extent of disease and anatomical distortion, and correlates with surgical complexity. On the other hand, it is poorly correlated with the severity of pain and fertility.

The Endometriosis Fertility Index, a tool that combines patient history, revised ASRM staging, and anatomical status of the adnexa at the end of surgery, has been shown to be reliable in predicting the likelihood of conceiving without resorting to fertilization. in vitro after surgery.

In the context of infertility, surgery for superficial peritoneal endometriosis or endometriomas can improve the likelihood of natural conception, but must be balanced with other options such as assisted reproductive technologies.

A Cochrane systematic review concluded that surgery was effective for pain symptoms, but included only 3 small randomized studies with follow-up of 6 to 12 months. Other systematic reviews have shown a persistence or recurrence rate of 22% at 2 years and 40-50% at 5 years after surgery.

Treating patients with hormonal management after surgery may decrease the rate and speed of recurrence of pain symptoms. Due to the surgical complexity and higher risks associated with deep endometriosis surgery, detection of deep endometriosis on imaging allows for improved surgical planning and timely referral to surgeons or specialized centers.

Laparoscopic hysterectomy , with or without removal of one or both ovaries, may also be an option for select patients, such as those who have ongoing dysmenorrhea or heavy menses, adenomyosis, or recurrence of the disease, and who have no desire to conceive in the future. of adequate advice on the benefits and risks.

Hysterectomy with concomitant endometriosis treatment has better results in pain relief than conservative surgery alone, but is still not curative. Removal of both ovaries causes premature surgical menopause, with potential adverse effects on bone and heart health (low adherence to hormone replacement therapy) and provides little additional pain relief compared to hysterectomy alone.

Some patients may not respond to medical or surgical treatment and develop persistent pelvic pain, which may reflect central sensitization or nociplastic pain, with accompanying overlapping chronic pain conditions.

In patients with complex pain, multidisciplinary care for pain management, based on current guidelines for the treatment of chronic pelvic pain, may improve quality of life. This may include pain education, pelvic physical therapy, psychological therapy (such as cognitive behavioral therapy, acceptance and commitment therapy, or mindfulness therapy), and specific interventions for other contributors to pain.

It has been recognized that the best practice for chronic pain is to have a multidisciplinary, multimodal, patient-focused center. Primary care providers often play a central role in coordinating this care or referring to a specialized center.

> Which patients should be referred to a gynecologist?

If a patient has symptoms and signs of deep endometriosis or investigations reveal endometrioma , she should be referred to a gynecologist for evaluation, who will likely order further imaging, including pelvic MRI or advanced transvaginal ultrasound.

Depending on wait times for specialist consultation or imaging results, it may be appropriate to request both at the same time and begin first-line medical therapy.

Patients with suspected superficial peritoneal endometriosis who do not respond to, have contraindications to, or refuse first-line therapeutic options for medical management, and those who are actively trying to conceive or have infertility, would also benefit from gynecologic evaluation and management.

Endometriosis is a common and complex condition that can cause considerable distress and lead to the development of chronic pelvic pain, infertility or target organ damage. Early recognition and diagnosis are key to providing timely treatment.

Primary care providers can make a clinical diagnosis of endometriosis and initiate first-line medical management. In indicated cases, it is important to make referral to a gynecologist for second-line hormone therapy or surgery.

Hormonal or surgical treatments can provide symptom relief and are part of a long-term therapeutic plan for this chronic condition. Multidisciplinary care may be necessary to treat complex persistent pain.