Endometriosis: Classification, symptoms, diagnosis, treatment

Endometriosis is a chronic inflammatory gynecologic disease characterized by the presence of endometrial glands and stroma outside the uterine cavity and myometrium. The exact prevalence of endometriosis is unknown. However, it is thought to affect approximately 10% of women of reproductive age and up to 50% of women with infertility.

Pathogenesis of endometriosis

The pathogenesis of endometriosis is complex and involves many factors and processes that occur simultaneously. There are many interactions of the immune system, hormones, genes, local and stem cells – all of which influence the development of endometriosis and its further progression.

Many theories have been studied in recent years, but there is no single theory that can explain all aspects of endometriosis. Currently, there are several hypotheses that explain its development:

• Retrograde menstrual flow theory: it is hypothesized that during menstruation, some endometrial cells may be taken back into the fallopian tubes and ovaries, leading to their incorporation into other tissues.
• Metastatic spread theory: small amounts of endometrial tissue can spread through the lymphatic vessels of the uterus to other parts of the body, such as the pelvic organs, which also contributes to the disease.
• Immune dysregulation theory: a disturbed immune response may prevent normal removal of endometrial tissue from extrauterine sites, favoring its growth and development.
• The theory of coelomic metaplasia: it is hypothesized that cells that are normally unrelated to the endometrium can turn into endometrial cells under the influence of certain factors.
• Hormonal imbalance theory: changes in the levels of hormones such as estrogen can contribute to the growth and progression of endometriosis.
• Theory of stem cell involvement and changes in epigenetic regulation: stem cells may play a role in the development of endometriosis because they are able to turn into endometrial cells, which promotes the spread of the disease.

Classification of endometriosis

Superficial endometriosis

Superficial endometriosis – superficial peritoneal foci of endometrial tissue with < 5 mm peritoneal invasion. This is the most common type of the disease.

According to the ENZIaN classification, three stages are distinguished:

• 1 – total size of masses up to 3 cm;
• 2 – lesion from 3-7 cm;
• 3 – pathologic focus or total size of lesions more than 7 cm.

Endometriomas

Endometriomas are thick-walled, cavitary ovarian lesions containing viscous protein and hemorrhagic products. They are often bilateral (in 50% of cases). According to the classification of Adamyan L.V., the following stages are distinguished:

• 1 – small point endometrioid masses on the surface of ovaries, peritoneum of rectovaginal-uterine space without formation of cystic cavities.
• 2 – endometrioid cyst of one ovary not more than 5-6 cm in size with small endometrioid inclusions on the pelvic peritoneum. Minor adhesions in the area of uterine appendages without intestinal involvement.
• 3 – endometrioid cysts of both ovaries (cyst diameter of one ovary more than 5-6 cm and small endometrioma of the other). Endometrioid heterotopias of small size on the pelvic parietal peritoneum. Expressed adhesions in the area of uterine appendages with partial involvement of the intestine.
• 4 – bilateral endometrioid ovarian cysts of large size (more than 6 cm) with transition of the pathological process to the neighboring organs – bladder, rectum and sigmoid colon. Disseminated adhesions.

3D Models of the stages of ovarian endometriosis:

Stage 1 ovarian endometriosis

Stage 2 ovarian endometriosis.

Stage 3 ovarian endometriosis.

Stage 4 ovarian endometriosis.

According to the ENZIaN classification, three stages are distinguished:

• 1 – endometrioma up to 3 cm;
• 2 – endometrioma from 3-7 cm (or several endometriomas with total diameter less than 7 cm);
• 3 – endometrioma more than 7 cm.

Deep infiltrative endometriosis

Deep infiltrative endometriosis are foci consisting of fibromuscular hyperplasia surrounding the gland on the peritoneum. These lesions are more than 5 mm deep. The ENZIaN classification provides a more detailed understanding of the location of the pathologic foci. This classification is based on the location of the infiltrate, the depth of its invasion into the pelvic cavity, as well as infiltration into adjacent abdominal organs and violation of their functions. The designation is made using the Latin alphabet and Arabic numerals, where:

• E – endometrioid focus;
• E 1a is a unit center in Douglas space;
• E 1c – foci in the area of one sacrococcygeal ligament up to 1 cm in diameter;
• E 1vv – bilateral lesion of the sacrococcygeal ligament. Heterotopia up to 1 cm in diameter;
• E 1c – single foci in the area of rectovaginal septum;
• E 2a is a lesion of the upper third of the vagina;
• E 2c – foci in the area of one sacrococcygeal ligament measuring more than 1 cm in diameter;
• E 2vv – bilateral lesions of the sacrococcygeal ligaments. Heterotopia more than 1 cm in diameter;
• E 2c – foci on the rectum up to 1cm in diameter;
• E 3a – the infiltrate is located in the middle third of the vagina;
• E 3c – infiltration of the cardinal ligament on one side without development of hydronephrosis;
• E 3vc – infiltration of both cardinal ligaments without hydronephrosis;
• E 3c – infiltration of the rectum over 1-3 cm, without stenosis;
• E 4a – infiltration of the posterior surface of the uterus and/or lower third of the vagina;
• E 4c – infiltration of the cardinal ligament on one side with the development of hydronephrosis;
• E 4vv – bilateral lesion of the cardinal ligaments with development of hydronephrosis;
• E 4c – rectal infiltrate larger than 3 cm and/or with development of stenosis;
• F – lesions of other adjacent organs;
• FA is adenomyosis;
• FB is a deep bladder lesion;
• FU is ureteral infiltration;
• FI – colorectal involvement (upper ampullary rectum and involvement of the sigmoid colon);
• FO is a different localization.

The American Society for Reproductive Medicine has developed its own classification. This system rates the stages of endometriosis according to a point scale, which is determined according to surgical assessment of the size, location, severity of endometriotic lesions and the occurrence of adhesions. Thus, women with endometriosis are categorized into four stages: I (1-5 points), II (6-15 points), III (16-40 points), and IV (>40 points).

Clinical Manifestations

Endometriosis can be accompanied by various symptoms such as:

• Chronic pelvic pain;
• Dysmenorrhea;
• Dyspareunia;
• Metrorrhagia;
• Menorrhagia;
• Infertility;
• Postcoital bleeding.

Non-gynecologic symptoms:

• Dyschezia;
• Dysuria;
• Hematuria;
• Pain in my side;
• Fatigue.

Pain is a major symptom for many women with endometriosis. The perception of pain can vary individually in intensity, location, time of onset, and duration. In addition, the quality of pain and the associated sympathetic and parasympathetic responses can sometimes differ.

The more symptoms present, the more likely the diagnosis. In a prospective study by Forman and colleagues that only severe dysmenorrhea was a predictor of endometriosis in women who underwent laparoscopy for infertility. This is also supported by other studies that suggest that increased severity of dysmenorrhea may indicate the presence of endometriosis.

However, there is no convincing correlation between the stage of the disease and the severity of symptoms, making the prognosis for each individual patient much more difficult. The growth, frequency and progression of endometrioid lesions, cysts and nodules, remain incompletely understood. This is due to the lack of understanding of pathophysiology, lack of standardized clinical indicators.

Studies suggest that endometriosis may progress in about one-third of women within six to twelve months, while similar forms of endometriosis have been observed to be non-progressive or even regressive. However, these reports should be interpreted with caution because they are few in number and do not take into account the biological activity of individual lesions.

Diagnosis of endometriosis

Late diagnosis of endometriosis is a hallmark of the disease. Numerous studies have demonstrated a significant period of time between the onset of the first symptoms and a definitive diagnosis. These studies rely on data that use surgical confirmation as the gold standard.

Imaging modalities such as:

• Transvaginal ultrasound (TV-US);
• Triggered transvaginal ultrasound (TV-US);
• Transrectal ultrasound;
• Magnetic resonance imaging (MRI).

Standard transvaginal ultrasound remains the first-line diagnostic method due to its ability for real-time evaluation in addition to reproducibility, accessibility, cost, and non-invasiveness.

The International Consensus on Deep Endometriosis Analysis (IDEA) has developed a systematic sonographic approach to improve the detection of endometriosis on pelvic ultrasound by evaluating four components: uterus and appendages, deep infiltrative endometriosis, sliding sign, and soft markers. Thus, the components of this specialized ultrasound examination exceed those of the “standard” ultrasound examination.

Diagnosis of superficial peritoneal endometriosis (SPE)

Superficial peritoneal endometriosis (SPE) has traditionally been described as undetectable by any imaging modality because the size of the foci in the peritoneum is less than 5 mm. Modern equipment and specialist skills allow visualization of SPE lesions at the utero-sacral ligament (USL), parametrium and Douglas space (POD). SPE lesions appear as avascular hypoechogenic areas with irregular borders, less than 5 mm deep. In addition, ovarian motility and local soreness (SST) are two commonly assessed soft markers that are associated with the presence of SPEs.

Diagnosis of endometrioma

The sensitivity and specificity of transvaginal ultrasound for detecting endometriomas approaches 90%. Endometriomas have different appearances depending on the degree of viscous proteinaceous material, blood products, and blood degradation. As free fluid is reabsorbed into the cyst, protein and iron concentrations increase. Cyclic bleeding will contribute to the variety of echogenicity, but typically, as bleeding becomes chronic, endometriomas produce a lot of hemorrhagic debris, taking on the appearance of classic frosted glass.

However, early in their formation, the sonographic characteristics of endometriomas may be indistinguishable from hemorrhagic ovarian cysts. They may be unicameral or multicameral (usually less than 5 chambers), and 50% of endometriomas are bilateral. Typically, an endometrioma is a homogeneous cyst with low internal echo, with a wall without solid areas or internal vascularization.

Atypical endometriomas may occur in 50% of patients, more commonly in the postmenopausal age group. Features include:

• The presence of a fluid level;
• Avascular internal nodule;
• Papillary outgrowths in endometriomas.

During pregnancy, endometrioma may undergo decidualization and mimic malignancy due to the presence of vascularized solid areas.

Diagnosis of deep infiltrative endometriosis (DIE)

Lesions appear as hypoechogenic thickening of the wall of the lesions or as hypo- or isoechogenic solid nodules that may vary in size and have smooth or irregular contours. The intestinal form of DIE occurs in approximately 8-12% of patients with endometriosis. Rectal and rectosigmoid endometriosis are considered severe forms of DIE, and these forms account for 70-93% of intestinal endometriosis cases.

It is recommended to always include renal ultrasound to evaluate hydronephrosis to assess the urinary tract involvement. Ureteral dilation > 6 mm and detection of nodules > 17 mm in patients scheduled for surgery due to DIE was associated with ureteral endometriosis in 100% of cases.

It is worth noting that the sensitivity of ultrasound varies considerably depending on the location of the DIE.

The sign of a slipping uterus

The uterine slip sign is a real-time dynamic TV-US sign. There are two separate stages:

1. In the first step, the transvaginal transducer is placed in the posterior vaginal arch, where gentle pressure is applied to mobilize the uterus to determine whether the anterior wall of the rectum slides freely over the posterior wall of the vagina and cervix.
2. In the second step, the technician places a free hand on the lower anterior abdominal wall to palpate the uterus and determine if the anterior rectosigmoid wall slides freely over the posterior uterine wall.

The sliding sign is considered positive if smooth sliding occurs between the posterior wall of the uterus/cervix and the anterior wall of the sigmoid/rectum.

If there is no sliding, it is usually due to the formation of adhesions or nodules that cause fibrosis between the two structures.

Preoperative knowledge of POD obliteration is important because it allows for appropriate surgical planning and patient counseling involving colorectal surgeons.

Pelvic organ mobility can also be detected on MRI, either directly (using a cine loop) or indirectly (identification of bowel distortion). Direct mobility assessment on MRI has been reported, with absent MRI slip sign correlating well with absent TV-US slip sign and organ fixation detectable on laparoscopy.

Soft markers

Although superficial peritoneal lesions are difficult to visualize with TV-US, there are some soft markers that can help determine the presence or absence of superficial endometriosis.

Ovarian mobility and local soreness (SST) are two commonly evaluated soft markers that are associated with the presence of SPE. In addition, studies suggest that SST may be a marker of endometriosis of the peritoneal lateral pelvic wall.

Thus, in the absence of hard markers of TV-US such as endometrioma/deep endometriosis/obliterated POD, soft markers may provide insight into associated superficial lesions, aiding in the management of chronic pelvic pain.

Ovarian immobility in preoperative TV-US is also significantly associated with the need for complex laparoscopic pelvic lateral wall surgery, including ureterolysis and tuboovariolysis. Therefore, ovarian immobility in TV-US should be considered not only a red flag of increased risk of endometriosis/pelvic lateral wall adhesion, but also a necessity for complex surgery and advanced laparoscopic skills.

Additional methods and assessments

1. Advanced TV-US technologies

These techniques include TV-US-guided rectal contrast injection, sonovaginography, and bowel preparation before TV-US (diet for 1-3 days, oral laxative the day before the examination, rectal enema). These techniques are mainly used as additional information for surgical planning, in particular to determine the number of affected intestinal layers and the distance from the lesion to the anal verge.

2. Use of MRI

MRI for endometriosis is complementary to ultrasound. MRI can be used for diagnosis but is most often required for preoperative determination of the extent of disease, both for surgical planning and patient counseling. However, if conservative treatment is planned, dynamic ultrasound scans are usually performed at 6-12 months. MRI can detect endometrioid lesions in the small bowel, sigmoid colon and/or cecum, as well as endometriosis of the abdominal wall or diaphragm.

3. Laparoscopic identification

Laparoscopic identification of endometrioid lesions with histologic diagnosis has been described as the gold standard for diagnosis in the past. However, advances in the quality and availability of imaging techniques for some forms of endometriosis, surgical risk, limited access to highly skilled surgeons, and financial implications have relegated this method of diagnosis to last place, but laparoscopy still remains the most reliable diagnostic method.

It is worth mentioning that serum CA-125 determination has no diagnostic value. An elevated CA-125 concentration (i.e. 35 IU/mL or more) can be detected in endometriosis, but endometriosis can also be present despite normal CA-125 values (less than 35 IU/mL).

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Treatment endometriosis

The choice of treatment will depend on the severity of the symptoms, the extent and location of the disease, the desire to become pregnant and the age of the patient. There are medical and surgical treatments, as well as a combination of both.

Medical Therapy

Pharmacologic therapy for endometriosis is aimed at improving symptoms or preventing recurrence postoperatively.

• Hormonal treatment takes the lead: it acts by suppressing fluctuations in gonadotropic and sex hormones, resulting in inhibition of ovulation, menstruation and reduction of inflammation.
• Combined oral contraceptives and progestins and antiprogestagens are the drugs of choice. They work by inhibiting ovulation, lead to decidualization and reduce the size of the lesions. They are also available in a variety of dosage forms, take away painful symptoms in most patients, are well tolerated and inexpensive. However, 25% of patients do not respond to treatment, in addition to side effects such as: sudden bleeding, breast soreness, nausea, headaches, mood swings and others.
• GnRH agonists are a hypoestrogenic therapy that represents a second line of treatment. It is an effective treatment for women who do not respond to combined oral contraceptives or progestins. GnRH agonists provide a negative feedback mechanism in the pituitary gland, inhibiting gonadotropin secretion and subsequently reducing steroid hormone synthesis by the ovaries. One major disadvantage of these drugs is that they are not administered orally because they are destroyed during digestion, so their use is indicated parenterally, subcutaneously, intramuscularly, by nasal spray, or intravaginally. The use of these drugs is associated with poorly tolerated side effects such as vasomotor symptoms, genital hypotrophy, and mood instability. In addition, GnRH agonists cause negative calcium balance with an increased risk of osteopenia, although bone loss is reversible with short-term treatment or administration of add-back therapy.
• GnRH antagonists – may be considered as a second line therapy to reduce endometriosis foci, concomitant pain syndrome, although data regarding dosage and duration of treatment are limited.
• Hyperandrogenic therapy induces pseudomenopause by inhibiting the release of GnRH and peak luteinizing hormone (LH) increases androgen levels (free testosterone) and decreases estrogen levels, which causes atrophy of endometrioid foci. However, this class of drugs is not suitable for long-term treatment, mainly because of androgenic effects, i.e. seborrhea, hypertrichosis, weight gain, and adverse effects on serum cholesterol and lipoprotein distribution (decreased HDL levels and increased LDL levels).
• Aromatase inhibitors (AIs) are a class of drugs that are very specific and act by inhibiting the aromatase P450 enzyme, the final enzyme in the estrogen biosynthesis pathway, which reduces the local synthesis of estrogen in endometriosis. Use of these drugs significantly reduces lesion size as well as pelvic pain. However, in premenopausal women, AI needs to be combined with other classes of drugs such as progestin, combined oral contraceptives or GnRH agonist. It was noted that the best combination with minimal side effects was with oral contraceptives or progestins. Side symptoms include increased risk of osteoporosis, vaginal mucosal dryness, insomnia, vasomotor symptoms, nausea and headache.
• Non-steroidal anti-inflammatory drugs are used in combination with all the other classes mentioned above. They are widely used to treat chronic inflammatory conditions and are effective in relieving primary dysmenorrhea. However, they only help to minimize symptoms. Patients using these drugs should consider side effects such as exacerbation of peptic ulcers, cardiovascular events, and acute renal failure.

Surgical treatment

Surgical treatment is indicated when symptoms persist or when the side effects of drug therapy outweigh its therapeutic effect. Patients with anatomical changes in pelvic structures, adhesions, bowel or urinary tract obstruction are also indicated for surgical treatment.

• Conservative surgery

Conservative surgery consists of coagulation of endometrioid foci and restoration of normal pelvic anatomy. When ectopic foci are excised, there is a significant reduction in pelvic pain and improvement in fertility.

Despite this, the risk of symptom recurrence after surgery remains high.

Ablation of endometriosis foci is applicable in women with superficial endometriosis. The evidence in favor of ablation over excision is based on studies involving women with heterogeneous endometriosis.

Some of these studies excluded women with deep endometriosis, in whom ablation is not usually used. The excisional approach is likely to be more appropriate for deep foci, as it is impossible to know whether the entire nidus has been destroyed by ablation.

• Surgery for ovarian endometriomas

When intervening in women with ovarian endometrioma, cystectomy is preferred over drainage and coagulation because it reduces the risk of recurrence and pain.

Alternatively, CO2 laser vaporization may be performed. Both techniques have similar recurrence rates in the first year after surgery, but the early postoperative recurrence rate may be lower after cystectomy.

When performing surgery for ovarian endometrioma, extreme care should be taken to minimize damage to healthy ovarian tissue.

• Radical surgical treatment

The final surgical treatment includes hysterectomy with or without ovarian removal, which depends on the age of the patient.

Hysterectomy with bilateral salpingo-oophorectomy and excision of all foci of endometriosis showed effective cure in 90% of cases.