Commentary on the new 2022 European Society of Human Reproduction and Embryology (ESHRE) endometriosis guidelines

Endometriosis is a prevalent benign illness defined by the presence of endometrial glands and stroma outside of the uterine cavity, primarily on the ovary, pelvic peritoneum, and rectovaginal septum [ 1 ]. It is linked to infertility and a variety of problems, including chronic pelvic pain, dysmenorrhea, deep dyspareunia, dysuria, dyschezia, and fatigue [ 2 , 3 ]. However, symptom severity is not usually proportional to the endometriosis stage, and some women with endometriosis may be asymptomatic. Traditionally, endometriosis has been diagnosed through diagnostic laparoscopy or the histological identification of lesions. However, with recent developments in imaging modalities, the necessity for diagnostic laparoscopy in cases where endometriosis is relatively obvious has been questioned, and concerns have been raised regarding delays in the endometriosis diagnosis due to the diagnostic laparoscopic and histological confirmation criteria. In 2022, the new European Society of Human Reproduction and Embryology (ESHRE) guidelines were published [ 4 ]. Although the new guidelines are not perfect, they provide clearer guidance on many difficult issues, such as medication selection among combined oral contraceptives (COCs), progestogen, and gonadotropin-releasing hormone (GnRH) agonists, and surgical indications for endometrioma in patients preparing for pregnancy. The ESHRE guidelines are one of the most frequently cited endometriosis-related guidelines. It is believed that referring to representative changes in the new guidelines and major updates will be beneficial for diagnosing and treating endometriosis ( Table 1 ). This paper provides a brief overview of these developments.

The objective of primary prevention is to prevent healthy and asymptomatic women from developing endometriosis. Although there is no direct proof of the efficacy of a healthy lifestyle and diet in preventing endometriosis, women can be counseled to adopt a healthy lifestyle and diet, including reduced alcohol use and regular physical activity. The efficacy of hormonal contraceptives for the primary prevention of endometriosis is uncertain. Genetic testing of women with suspected or proven endometriosis should only be undertaken in a research context, citing the newly added text.

The previous ESHRE guidelines suggested that laparoscopic histologic confirmation of endometriosis was the gold standard for an endometriosis diagnosis. In contrast, according to the new ESHRE guidelines, laparoscopy is no longer the diagnostic gold standard and is now only advised for patients with negative imaging results and/or when empirical treatment is ineffective or unsuitable. This change was based on a meta-analysis regarding endometriosis diagnostic tools. According to a Cochrane review, imaging modalities such as transvaginal ultrasonography and magnetic resonance imaging showed sensitivity and specificity for diagnosing endometrioma and deep endometriosis comparable to a surgical diagnosis ( Table 2 ) [ 5 ]. As an added explanation in the new guidelines, the difficulties and limitations of making a noninvasive diagnosis of a superficial disease are described. Despite these limitations, stating that diagnostic laparoscopy is not the gold standard emphasizes the usefulness of imaging modalities for diagnosing endometrioma and deep endometriosis.

The GDG recommends that the decision to perform surgery should be made in consideration of some factors such as the presence or absence of pain symptoms, patient age and preferences, history of previous surgery, presence of other infertility factors, ovarian reserve, and the estimated Endometriosis Fertility Index (EFI). The EFI was added to the new guidelines for the first time. The EFI staging system predicts non- in vitro fertilization pregnancy rates following surgical endometriosis staging and treatment [ 9 ]. The EFI is determined by historical variables (age, number of years of infertility, and prior pregnancy) and surgical variables (the American Society for Reproductive Medicine [ASRM] overall score, the ASRM endometriosis score, and the least function score). The extended administration of a GnRH agonist prior to assisted reproductive technology treatment to increase the live birth rate in infertile women with endometriosis (ultra-long protocol) is no longer suggested due to the lack of evidence supporting its benefits. The previous recommendation was based on an older Cochrane review regarding GnRH agonist pre-treatment, which included 228 patients from three studies and showed an increased likelihood of clinical pregnancy by more than 4-fold [ 10 ]. However, an updated Cochrane review that included eight parallel-design RCTs with a total of 640 participants, concluded that the effect of GnRH agonist pre-treatment (for at least 3 months) was very uncertain, both on the live birth rate as the primary outcome and on secondary outcomes (clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, the mean number of oocytes, and the mean number of embryos) [ 11 ]. Another meta-analysis of studies comparing different GnRH agonist protocols (short, long, and ultra-long) also found that different down-regulation protocols did not significantly improve clinical outcomes (implantation rate, fertilization rate, and clinical pregnancy rate) by analyzing RCTs and observational studies (n=21) [ 12 ]. Prior ESHRE guidelines on fertility preservation considered benign disorders to be an indication for fertility preservation, but did not address whether endometriosis was a reason for fertility preservation in particular [ 13 ]. A recent large retrospective study by Cobo et al. [ 14 ] evaluated the outcome of fertility preservation utilizing vitrified oocytes in 485 patients with endometriomas of at least 1 cm and an antral follicular count of at least 3, finding oocyte survival rates of 83.2% after warming and a cumulative live birth rate of 46.4%. They concluded that fertility preservation was a valid treatment option in patients with endometriosis. Although several issues such as cost-effectiveness and specific indications remain unsolved, practitioners should explore the advantages and disadvantages of fertility preservation with endometriosis patients who have severe ovarian endometriosis. Sparse data with low and moderate quality indicated that the behavior of endometriotic lesions during pregnancy was diverse, ranging from complete elimination to increasing growth [ 15 ]. Patients should not be encouraged to become pregnant with the primary aim of treating endometriosis because pregnancy does not necessarily result in symptom improvements or slow disease progression. The decidualization of an endometrioma during pregnancy may resemble malignant ovarian tumors in some circumstances, providing a diagnostic conundrum. However, the incidence of this event is unknown (0%–12% prevalence, 17 studies reporting 60 cases) [ 16 ]. Endometrioma can manifest differently throughout pregnancy. If an ultrasound examination during pregnancy reveals atypical endometrioma, it is recommended that the patient be referred to a center with the necessary expertise. Complications directly connected to pre-existing endometriosis lesions are uncommon and likely underreported. These issues may result from decidualization, adhesion formation/stretching, and endometriosis-related chronic inflammation [ 16 ]. Although uncommon, these may pose life-threatening conditions that necessitate surgical treatment. Clinicians should be aware that women with endometriosis may have a higher risk of miscarriages and ectopic pregnancies during the first trimester. They should also be informed of uncommon endometriosis-related problems during pregnancy, which include gestational diabetes, preterm birth, premature rupture of membranes, placenta previa, hypertensive disorders and pre-eclampsia, stillbirth, cesarean section, obstetric hemorrhage (placental abruption, antepartum and postpartum bleeding), small for gestational age, admission to the neonatal intensive care unit, and neonatal death. However, since these results are based on low- or moderate-quality research, they should be regarded with caution, and additional antenatal monitoring is not recommended.

The new ESHRE recommendations are clearer and more practical than their predecessors and other guidelines. However, as stated on the opening page of the ESHRE guidelines, clinical practice guidelines do not supersede the clinical decisions made by a healthcare professional for diagnosis and treatment. Ultimately, healthcare professionals must make their own clinical decisions case by case, with consideration of various circumstances.

Clinicians should not regularly perform surgical excision/ablation for asymptomatic endometriosis discovered incidentally during surgery. Practitioners should not suggest medical therapy to women with an incidental endometriosis diagnosis, but routine ultrasound surveillance must be recommended. Even in the absence of convincing data on the benefits of monitoring asymptomatic endometriosis, the GDG recommends considering ultrasound surveillance due to its low cost and safety.

Clinicians should be aware of the symptoms of extra-pelvic endometriosis, which include cyclical shoulder discomfort, cyclical spontaneous pneumothorax, cyclical cough, and enlargement of nodules during menstruation. The diagnosis and treatment of extra-pelvic endometriosis should be discussed by a multidisciplinary team at an institution with sufficient expertise. When possible, surgical excision is the best treatment for alleviating symptoms in women with abdominal extra-pelvic endometriosis. If surgery is inapplicable or unacceptable, hormonal therapy may also be an alternative.

According to the 2014 recommendations, ovarian cancer and non-Hodgkin lymphoma were slightly prevalent among endometriosis patients. Nevertheless, according to a recent systematic review and meta-analysis of 49 cohort or case-control studies, endometriosis was related to a very slight and not statistically significant higher risk of cancer overall (summary relative risk [SRR], 1.07; 95% confidence interval [CI], 0.96–1.16) [ 20 ]. Endometriosis was related to an increased risk of ovarian cancer (SRR, 1.93), especially clear-cell (SRR, 3.44) and endometrioid (SRR, 2.33) histotypes, breast cancer (SRR, 1.04) and thyroid cancer (SRR, 1.39) [ 20 ]. Although endometriosis is associated with an elevated risk of certain cancers, given the low absolute risks of ovarian, breast, and thyroid cancer in people with endometriosis relative to those without (increases of 1.2%p, 0.5%p, and 0.5%p, respectively) and the uncertainty regarding the risk of other cancers, endometriosis patients can be reassured that their cancer risk is low and comparable to that of people without the disease. Clinicians should educate women with endometriosis who request information on their cancer risk that endometriosis is not associated with an increased risk of cancer. Although endometriosis is related to a somewhat higher risk of ovarian, breast, and thyroid malignancies, the absolute increase in risk relative to the general female population is minimal ( Table 3 ).