Endometriosis: Classification, Symptoms, Diagnosis, Treatment

Endometriosis is a chronic inflammatory gynecological condition 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 estimated to affect approximately 10% of reproductive-age women and up to 50% of women with infertility.

Pathogenesis of Endometriosis

The pathogenesis is complex and involves many factors and processes that occur simultaneously. The development and progression of the disease are influenced by various interactions between the immune system, hormones, genetic factors, local cells, and stem cells.

Several theories have been proposed over the recent years, but none of them can explain all the aspects of endometriosis. Currently, the following theories exist:

• Retrograde menstruation theory: It is assumed that during menstruation, some endometrial cells may be flushed back into the fallopian tubes and ovaries, leading to their implantation in other tissues.
• Metastatic spread theory: A small amount of endometrial tissue may spread through the uterine lymphatic vessels to other parts of the body, such as the pelvic organs, which also contributes to the development of the disease.
• Immune dysregulation theory: An impaired immune response may prevent the normal removal of endometrial tissue from extrauterine sites, thereby promoting its growth and development.
• Coelomic metaplasia theory: It is assumed that non-endometrial cells may transform into endometrium-like cells under the influence of certain factors.
• Hormonal imbalance theory: Changes in hormone levels, such as estrogen, may contribute to the growth and progression of endometriosis.
• Stem cell and epigenetic theory: Stem cells may play a role in the development of endometriosis, as they are capable of transforming into endometrial cells.

Classification of Endometriosis

Superficial Endometriosis

Superficial endometriosis is characterized by lesions with less than 5 mm depth of invasion. This is the most common type.

ENZIAN classification distinguishes three stages of endometrioma:

• Stage 1 – total size of lesions up to 3 cm;
• Stage 2 – total size of lesions from 3 to 7 cm;
• Stage 3 – a pathological focus or total size of lesions exceeding 7 cm.

Endometriomas

Endometriomas are thick-walled ovarian cysts containing viscous hemorrhagic and proteinaceous material. They are often bilateral (in 50 percent of cases). According to Adamyan classification the following stages are distinguished:

• Stage 1 – small, isolated endometrial implants on the surface of the ovaries and the peritoneum of the rectouterine space without cyst formation;
• Stage 2 – unilateral ovarian cyst less than 5–6 cm in size with small endometriotic inclusions on the pelvic peritoneum. Minor adhesions may be present in the area of the uterine appendages without involvement of the bowel;
• Stage 3 – bilateral ovarian cysts (cyst diameter in one ovary greater than 5–6 cm and a small endometrioma in the other one). Small endometriotic heterotopias on the parietal peritoneum of the pelvis are usually present. There are significant adhesions in the area of the uterine appendages with partial involvement of the bowel;
• Stage 4 – large bilateral ovarian cysts (over 6 cm) with spread to adjacent organs — the bladder, rectum, and sigmoid colon. Extensive adhesions are present.

3D-models of endometrioma stages:

Stage 1 endometrioma

Stage 2 endometrioma

Stage 3 endometrioma

Stage 4 endometrioma

ENZIAN classification distinguishes three stages of endometrioma:

• Stage 1 – up to 3 cm in size;
• Stage 2 – 3-7 cm in size (or multiple cysts with the total diameter of less than 7 cm);
• Stage 3 – larger than 7 cm.

Deep Infiltrating Endometriosis

Deep infiltrating endometriosis presents as lesions consisting of fibromuscular hyperplasia on the peritoneum. These lesions are more than 5 mm deep. The ENZIAN classification provides a more detailed description of lesions location. It 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 impairment of their function. The notation uses the Latin alphabet and Arabic numerals, where:

• Е — endometrioid lesion;
• Е 1а — single lesion in the pouch of Douglas;
• Е 1в — lesion involving one uterosacral ligament, less than 1 cm in diameter;
• Е 1вв — bilateral uterosacral ligament involvement. Lesion diameter – up to 1 cm;
• Е 1с — solitary lesion in the rectovaginal septum;
• Е 2а — involvement of the upper third of the vagina;
• Е 2в — lesion involving one uterosacral ligament, more than 1 cm in diameter;
• Е 2вв — bilateral uterosacral ligament involvement. Lesion diameter – more than 1 cm;
• Е 2с — lesion involving the rectum, less than 1 cm in diameter;
• Е 3а — infiltrate involving the middle third of the vagina;
• Е 3в — unilateral cardinal ligament infiltration without hydronephrosis;
• Е 3вв — bilateral cardinal ligament infiltration without hydronephrosis;
• Е 3с — rectal infiltration measuring 1–3 cm, without stenosis;
• Е 4а — infiltration of the posterior uterine wall and/or lower third of the vagina;
• Е 4в — unilateral cardinal ligament infiltration with hydronephrosis;
• Е 4вв — bilateral cardinal ligament involvement with hydronephrosis;
• Е 4с — rectal infiltrate measuring more than 3 cm and/or with stenosis;
• F — involvement of other adjacent organs;
• FA — adenomyosis;
• FB — deep bladder involvement;
• FU — ureteral infiltration;
• FI — involvement of the colon (upper segment of the ampulla and the sigmoid colon);
• FO — other locations.

The American Society for Reproductive Medicine has developed its own classification system. It assesses the stages of endometriosis using a scoring scale determined by surgical evaluation of the size, location, and severity of lesions, as well as the extent of adhesions. Thus, this scale distinguishes four stages of endometriosis: I (score 1–5), II (score 6–15), III (score 16–40), and IV (score > 40).

Endometriosis Fertility Index

The Endometriosis Fertility Index (EFI) is a tool for predicting the likelihood of spontaneous pregnancy in women who have undergone surgical treatment for endometriosis. Developed by G.D. Adamson and D.J. Pasta in 2010, the EFI integrates clinical and surgical parameters to quantitatively assess a patient’s fertility potential.

EFI Components

EFI is calculated based on the following factors:

1. Клинические параметры: 
   • Patient age — as age increases, the likelihood of natural conception decreases;
   • Duration of infertility — infertility lasting more than 5 years is associated with a poor prognosis;
   • Reproductive history — a history of previous pregnancies has a positive effect on EFI.
2. Surgical:

• rASRM score — endometriosis stage and extent of lesions, including ovarian cysts, deep lesions and adhesions;
• Condition of the reproductive organs — is determined during laparoscopy, including fallopian tube patency, condition of ovaries and fimbriae. Each organ is assigned a score from 0 to 4; the scores are summed to calculate the EFI.

Calculation and Interpretation

The total EFI score ranges from 0 to 10. A high score correlates with an increased probability of pregnancy following surgical intervention. Medical literature provides the following interpretation:

• 9–10: high probability of natural pregnancy (> 75 percent within 3 years);
• 7–8: moderately high probability (50–75 percent);
• 4–6: moderate probability (25–50 percent);
• 0–3: low probability (< 25 percent); assisted reproductive technologies may be considered.

Application and Clinical Significance

The EFI is a valuable tool for:

• Predicting the likelihood of natural conception following surgical treatment of endometriosis;
• Planning further reproductive strategies (natural conception or IVF);
• Informing patients about realistic fertility prospects.

An advantage of EFI is the integration of clinical and surgical parameters into a single quantitative assessment, which improves predictive accuracy compared to only using the rASRM score. The main limitations of the method are that it can only be applied after surgical intervention and that it does not account for male fertility factors.

Clinical presentation

Endometriosis may present with a variety of symptoms.

Gynecological symptoms:

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

Non-gynecological symptoms:

• Dyschezia;
• Dysuria;
• Hematuria;
• Flank pain;
• Fatigue.

Pain is the primary symptom for many women with endometriosis. The perception of pain can vary in intensity, location, timing, and duration. Additionally, the nature of pain and associated sympathetic and parasympathetic responses may sometimes differ.

The more symptoms a person has, the higher the likelihood of a proper diagnosis. In a prospective study conducted by Forman and colleagues, it was found that only severe dysmenorrhea is a predictor of endometriosis in women who underwent laparoscopic surgery for infertility. This is also supported by other studies suggesting that an increase in the severity of dysmenorrhea may be indicative of endometriosis.

However, there is no clear correlation between the stage of the disease and the severity of symptoms, which significantly complicates the prognosis for each individual patient. The growth, incidence, and progression of endometriotic lesions, cysts, and nodules remain underinvestigated. This is due to an incomplete understanding of the disease’s pathophysiology and the lack of standardized clinical indicators.

Studies show that endometriosis may progress in approximately one-third of women within 6–12 months, while in other patients the disease remains stable or even regresses. However, these reports should be interpreted with caution, as the number of studies is small and they do not account for the biological activity of individual lesions.

Diagnosis of Endometriosis

Delayed diagnosis of this condition is common. Numerous studies confirm a significant time lag between the first symptoms and the final diagnosis. These studies are based on data that use surgical confirmation as the gold standard.

At present, imaging modalities are preferred for the diagnosis:

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

Standard transvaginal ultrasound remains the first-line diagnostic method due to real-time assessment, reproducibility, accessibility, low cost and non-invasiveness.

The International Deep Endometriosis Analysis (IDEA) group issued a consensus opinion on systematic ultrasound approaches to improve endometriosis detection. The assessment includes four components: the condition of the uterus and adnexa, presence of deep infiltrative endometriosis, sliding sign, and soft markers. Thus, the components of this specialized ultrasound go beyond the scope of a standard ultrasound procedure.

Diagnosis of Superficial Peritoneal Endometriosis (SPE)

Superficial peritoneal endometriosis (SPE) has traditionally been described as undetectable by imaging methods, since the size of lesions in the peritoneum is less than 5 mm. Modern equipment and the expertise of specialists make it possible to visualize SPE lesions on the uterosacral ligament (USL), in the parametrium, and in the pouch of Douglas (POD). SPE lesions appear as avascular hypoechoic areas with irregular borders, less than 5 mm deep. In addition, ovarian mobility and site-specific tenderness (SST) are two commonly evaluated soft markers associated with the presence of SPE.

Diagnosis of Endometrioma

The sensitivity and specificity of transvaginal ultrasound for detecting endometriomas approach 90 percent. Endometriomas vary in appearance depending on the amount of viscous proteinaceous material, blood products, and their degradation. As free fluid is reabsorbed within the cyst, the concentration of proteins and iron increases. Cyclic bleeding contributes to variable echogenicity; however, as bleeding becomes chronic, endometriomas accumulate a large amount of hemorrhagic debris, taking on the classic “ground-glass” appearance.

Early in their development, the sonographic characteristics of endometriomas may be indistinguishable from those of hemorrhagic ovarian cysts. They may be unilocular or multilocular (usually less than 5 chambers), and in 50 percent of cases endometriomas are bilateral. Typically, an endometrioma is a homogeneous cyst with low level of internal echo, no solid parts in its walls and no internal vascularization.

Atypical endometriomas may occur in 50 percent of patients, more commonly in postmenopausal women. Their characteristics include:

• Presence of fluid;
• Presence of an avascular internal nodule;
• Presence of papillary projections within the endometrioma.

During pregnancy, an endometrioma may undergo decidualization and mimic a malignant neoplasm due to the presence of vascularized solid areas.

Diagnosis of Deep Infiltrative Endometriosis (DIE)

Lesions appear as hypoechoic wall thickening of the affected structures or as hypo- or isoechoic solid nodules that may vary in size and have smooth or irregular contours. The intestinal form of DIE occurs in approximately 8–12 percent of patients with endometriosis. Endometriosis of the rectum and rectosigmoid region is considered a severe form of DIE, accounting for 70–93 percent of intestinal endometriosis cases.

It is recommended to always include renal ultrasound to assess hydronephrosis and detect urinary tract involvement. Ureteral dilation greater than 6 mm and detection of nodules larger than 17 mm in patients scheduled for surgery due to DIE were associated with ureteral endometriosis in 100 percent of cases.

It should be noted that ultrasound sensitivity varies significantly depending on the location of DIE.

Uterine Sliding Sign

The uterine sliding sign is a real-time dynamic sign assessed with transvaginal ultrasound. There are two distinct steps:

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

The sliding sign is considered positive if smooth sliding occurs between the posterior uterine/cervical wall and the anterior sigmoid/rectal wall.

If there is no sliding, this is usually associated with the formation of adhesions or nodules that cause fibrosis between the two structures.

Preoperative knowledge of POD obliteration is crucial, as it allows for appropriate surgical planning and patient counseling in collaboration with colorectal surgeons.

On MRI, pelvic organ mobility can also be assessed both directly (using cine loops) and indirectly (by identifying bowel distortion). Direct mobility assessment on MRI has been reported, with an absent MRI sliding sign correlating well with an absent TV-US sliding sign and organ fixation observed during laparoscopy.

Soft Markers

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

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

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

Ovarian immobility on preoperative TV-US is also strongly associated with the need for complex laparoscopic pelvic sidewall surgery, including ureterolysis and tubo-ovariolysis. Therefore, ovarian immobility on TV-US should be considered not only a red flag for increased risk of pelvic sidewall endometriosis/adhions, but also an indicator of the need for complex surgery and advanced laparoscopic skills.

Additional Methods and Assessments

1. Advanced TV-US techniques

These methods include rectal contrast administration under TV-US guidance, sonovaginography, and bowel preparation prior to 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, particularly to determine the number of affected bowel layers and the distance from the lesion to the anal verge.

2. Use of MRI

MRI in endometriosis complements ultrasound examination. MRI can be used for diagnosis but is most often required for preoperative staging of the disease, both for surgical planning and patient counseling. However, when planning conservative treatment, dynamic ultrasound scanning is usually performed over 6–12 months. MRI can detect endometriotic involvement of the small intestine, sigmoid colon, and/or cecum, as well as endometriosis of the abdominal wall or diaphragm.

3. Laparoscopic identification

Laparoscopic identification of endometriotic lesions with histological confirmation has long been considered the gold standard of diagnosis. However, advances in imaging quality and availability for certain forms of endometriosis, surgical risks, limited access to highly skilled surgeons, and financial implications have relegated this diagnostic method to a secondary role; nevertheless, laparoscopy remains the most reliable diagnostic method.

It should be noted that serum CA-125 measurement has no diagnostic value. Elevated CA-125 levels (i.e., 35 IU/mL or higher) may be seen in endometriosis, but the disease may also be present despite normal CA-125 levels (less than 35 IU/mL).

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Treatment of Endometriosis

The choice of treatment depends on the severity of symptoms, the extent and location of the disease, the desire to get pregnant, and the patient’s age. There are pharmacological and surgical treatment options, as well as combinations of both.

Medical therapy

Pharmacological therapy aims to improve symptoms or prevent recurrence after surgical treatment.

• Hormonal therapy plays a leading role: It works by suppressing fluctuations of gonadotropins and sex hormones, which leads to inhibition of ovulation and menstruation, and a reduction in the inflammatory process.
• Combined oral contraceptives and progestines, as well as antiprogestins — are the drugs of choice. They act by inhibiting ovulation, leading to decidualization and reduction in lesion size. In addition, they are available in various dosage forms, relieve pain symptoms in most patients, are well tolerated, and inexpensive. However, 25 percent of patients do not respond to treatment; moreover, side effects may occur, such as breakthrough bleeding, breast tenderness, nausea, headaches, mood swings, and others.
• GnRH agonists — a hypoestrogenic therapy that represents the second line of treatment. These are effective drugs for women who do not respond to combined oral contraceptives or progestins. GnRH agonists provide a negative feedback mechanism at the pituitary level, inhibiting gonadotropin secretion and subsequently reducing steroid hormone synthesis by the ovaries. One of the main disadvantages of these drugs is that they cannot be taken orally, as they are destroyed during digestion; therefore, they are administered parenterally, subcutaneously, intramuscularly, via nasal spray, or intravaginally. Their use is associated with poorly tolerated side effects such as vasomotor symptoms, genital atrophy, and mood instability. In addition, GnRH agonists cause a negative calcium balance with an increased risk of osteopenia, although bone loss is reversible with short-term treatment or with add-back therapy.
• GnRH antagonists — may be considered as a second-line therapy to reduce endometriotic lesions and associated pain, although data regarding dosage and duration of treatment are limited.
• Hyperandrogenic therapy induces a pseudomenopausal state by inhibiting GnRH release; the luteinizing hormone (LH) surge increases androgen levels (free testosterone) and reduces estrogen levels, leading to atrophy of endometriotic lesions. However, this class of drugs is not suitable for long-term treatment, mainly due to androgenic effects such as seborrhea, hypertrichosis, weight gain, and adverse effects on cholesterol and lipoprotein distribution in the blood serum (decreased HDL and increased LDL).
• Aromatase inhibitors (AIs) — a class of drugs that are highly specific and act by inhibiting the aromatase P450 enzyme, the final enzyme in the estrogen biosynthesis pathway, thereby reducing local estrogen synthesis in endometriosis. The use of these drugs significantly reduces lesion size and pelvic pain. However, in premenopausal women, AIs must be combined with other drug classes such as progestins, combined oral contraceptives, or GnRH agonists. The best combination with minimal side effects has been observed with oral contraceptives or progestins. Side effects include an increased risk of osteoporosis, vaginal dryness, insomnia, vasomotor symptoms, nausea, and headache.
• Nonsteroidal anti-inflammatory drugs are used in combination with all the other medications mentioned above. They are widely used to treat chronic inflammatory conditions and are effective in relieving primary dysmenorrhea. However, such medications only help minimize symptoms. Patients should also consider side effects, such as exacerbation of gastric ulcers, cardiovascular events, and acute renal failure.

Surgical therapy

Surgical treatment is indicated when symptoms persist or when the side effects of medical therapy outweigh its therapeutic benefits. It is also indicated for patients with anatomical changes in pelvic structures, adhesions, bowel obstruction, or urinary tract obstruction.

Conservative surgery

Conservative surgery consists of coagulation of endometriotic lesions and restoration of normal pelvic anatomy. Excision of ectopic lesions results in significant reduction of pelvic pain and improvement in fertility.

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

Ablation of endometriosis lesions is applicable in women with superficial endometriosis. Evidence supporting ablation versus excision is based on studies involving women with heterogeneous forms of endometriosis.

Some of these studies excluded women with deep endometriosis, in whom ablation is usually not used. The excisional approach is likely more appropriate for deep lesions, as it is not possible to determine whether the entire lesion has been destroyed using ablation.

Surgery for ovarian endometriomas

When performing surgery in women with ovarian endometriomas, cystectomy is preferred over drainage and coagulation, as it reduces the risk of recurrence and pain.

Alternatively, CO₂ laser vaporization may be performed. Both methods have similar recurrence rates within the first year after surgery; however, the rate of early postoperative recurrence may be lower for cystectomy.

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

Radical Surgical Treatment

Definitive surgical treatment includes hysterectomy with or without removal of the ovaries, depending on the patient’s age.

Hysterectomy with bilateral salpingo-oophorectomy and excision of all endometriotic lesions has shown a cure rate of 90 percent.