Thai Interest Group for Endometriosis (TIGE) consensus statement on endometriosis-associated pain

Abstract

This consensus statement has been developed by the Thai Interest Group for Endometriosis (TIGE) for use by Thai clinicians in the diagnosis and management of endometriosis. TIGE is a group of clinical and academic gynaecologists with a particular interest in endometriosis. Endometriosis is an oestrogen-dependent inflammatory disease which causes chronic symptoms such as dysmenorrhoea, chronic pelvic pain, dyspareunia and subfertility, and it is common in reproductive-age women. There is limited overall data on its prevalence in different clinical settings in Thailand, but it is clear that the disease causes significant problems for patients in terms of their working lives, fertility, and quality of life, as well as placing a great burden on national healthcare resources. Decisions about selecting the appropriate treatment for women with endometriosis depend on many factors including the age of the patient, the extent and severity of disease, concomitant conditions, economic status, patient preference, access to medication, and fertility need. Several hormonal treatments are available but no consensus has been reached about the best option for long-term prevention of recurrence. Bearing in mind differences in environment, genetics, and access to the healthcare system, this treatment guideline has been tailored to the particular circumstances of Thai women.

Keywords:

• Clinical
• guideline
• endometriosis
• gynaecology
• gynaecology
• thailand

Introduction

Endometriosis is an oestrogen-dependent inflammatory disease which causes chronic symptoms such as dysmenorrhoea, chronic pelvic pain, dyspareunia and subfertility. It is defined as the presence of endometrium-like tissue outside of the uterine cavity (Vercellini et al. 2014). The pathogenesis of endometriosis is complex and somewhat controversial. The proposed hypotheses for the aetiology of endometriosis can be categorized into two main theories: the retrograde menstruation theory and the in-situ theory. The retrograde menstruation theory is the most convincing, but it is not sufficient to explain the pathogenesis of the different presentations. This theory proposes that endometriosis is caused by the retrograde passage of eutopic endometrium through the fallopian tubes into the pelvic cavity during menstruation, establishing ectopic implants. This may also occur with endometrial stem cells in a similar manner. The in-situ theory proposes that endometriosis is caused by metaplastic cells differentiated from either coelomic epithelium or Müllerian remnants by environmental, endocrine, immune and (epi)genetic processes (Vercellini et al. 2014; Lagana et al. 2018). Epigenetic mechanisms regulate many of the processes involved in the immunological, immunohistochemical, histological, and biological changes of the metaplastic ectopic endometrium (Lagana et al. 2018, 2020).

The disease detrimentally affects patients in terms of their working lives, their fertility and their quality of life, as well as placing a great burden on national healthcare resources. The prevalence of endometriosis in reproductive age women is approximately 5–10% (Anon 2010; Leyland et al. 2010; Naphatthalung and Cheewadhanaraks 2012). However, it is impossible to determine an accurate prevalence because of a silent clinical presentation in some patients. With limited overall data in reproductive-age women in Thailand, the prevalence of endometriosis has been reported in various specific conditions: 8.6% from hospital-based data (Thailert et al. 1992), 25.6% in infertile women (Chiamchanya and Su-angkawatin 2008), 30.5% in benign gynaecological disease (Tanmahasamut et al. 2014), 60.9% in patients with chronic pelvic pain who underwent laparoscopic surgery (Bunyavejchevin et al. 2003), and 78.4% in patients with severe dysmenorrhoea (Cheewadhanaraks et al. 2004). Bearing in mind differences in environment, genetics, and access to the healthcare system, a treatment algorithm for endometriosis should be tailored to the particular circumstances of Thai women. Accordingly, the Thai Interest Group for Endometriosis (TIGE) has developed these guidelines for Thai clinicians on the diagnosis and management of endometriosis.

Diagnosis

The estimated duration from initial symptoms to diagnosis is approximately 4–8 years (Hadfield et al. 1996; Arruda et al. 2003; Husby et al. 2003; Soliman et al. 2017). Early diagnosis is essential so that immediate treatment can be offered to improve health-related quality of life and to decrease healthcare utilization. Improvements in time-to-diagnosis have been made in recent years (Soliman et al. 2017). TIGE recommends general practitioners and family physicians immediately refer suspected endometriosis cases to a gynaecologist in order to expedite diagnosis.

TIGE classifies the diagnosis of endometriosis as clinical or definitive. A clinical diagnosis is sometimes referred to as suspected, predictive, or considered, which is determined by the patient’s history, clinical examination and ultrasonography (US). Definitive diagnosis requires clinical symptoms, physical examination and US findings which are suggestive of endometriosis, as well as laparoscopy with or without pathologic confirmation. Clinical symptoms suggesting the presence of endometriosis include chronic pelvic pain, dysmenorrhoea, infertility, painful defaecation and dyspareunia (Riazi et al. 2015).

Pelvic and rectal examination can demonstrate a fixed and retroverted uterus, the presence of uterine motion tenderness, tenderness or nodularity of the cul-de-sac and uterosacral ligament, as well as adnexal masses. Our group suggests performing both pelvic and rectal examination in women with suspected endometriosis because (1) normal pelvic examination does not exclude the presence of endometriosis, and (2) combined pelvic and rectal examination helps assess the severity and extent of disease involving the parametrium, bladder or rectum (deep endometriosis) which requires further investigation and a multidisciplinary approach.

TIGE recommends transvaginal US (TVUS) or transrectal US (TRUS) in non-sexually active women as the first-line approach because of its high sensitivity and specificity. The sonographic appearance ranges from an anechoic, internal homogenous ground-glass or low-level echo without internal colour Doppler flow or calcification, to a complex cyst with heterogeneous appearance and septations (Hoyos et al. 2017). However, the presence of blood flow may increase the suspicion of malignancy. Approximately 1% of endometriomas will develop malignancy, especially in women older than 45, and in endometriomas larger than 9 cm (Hoyos et al. 2017).

It is important to consider the differential diagnosis between endometriosis and interstitial cystitis/painful bladder syndrome, a condition that is well known to cause chronic pelvic pain in women, and may sometimes be seen in association with endometriosis (the so-called ‘evil twin syndrome’) (Cervigni and Natale 2014; Patnaik et al. 2017).

A process of pelvic pain mapping which focuses on the tender areas evoked by the application of gentle pressure with the TVUS probe allows the presence of endometriotic implants to be suspected and identified (Hoyos et al. 2017).

Although laparoscopy is the gold standard diagnostic tool for endometriosis (Riazi et al. 2015; Nisenblat et al. 2016a), it is an invasive and costly procedure. Therefore, TIGE recommends it as a second-line diagnosis and treatment method. At laparoscopy, the endometriotic lesions can present with a variety of appearances ranging from white, yellow, or non-pigmented lesions, to blue, powder-burn black, red or brown lesions (Mishra et al. 2017). The suspected lesion should be excised and confirmed by microscopic examination. However, it is possible that occult microscopic endometriosis may sometimes be reported as undetectable by the laparoscopy (Khan et al. 2014).

Magnetic resonance imaging (MRI) is an alternative investigation for detecting deeply infiltrating endometriosis (DIE) involving the rectosigmoid, uterosacral ligaments and the rectovaginal septum (Guerriero et al. 2018). However, the accuracy of MRI depends on the experience of the radiologist.

Biological markers are not recommended by TIGE for the diagnosis of endometriosis. In a wide-ranging Cochrane review, anti-endometrial antibodies, interleukin-6 and cancer antigens CA-19.9 and CA-125 showed low sensitivity for the diagnosis of endometriosis (Nisenblat et al. 2016b). However, CA-125 with a serum level more than 30 units/ml may be used as an initial rule-in test for women presenting with symptoms of endometriosis, though a level below 30 units/ml cannot rule out endometriosis (Hirsch et al. 2016). In addition, the diagnostic performance of CA-125 may be more accurate than that of interleukin-6 in detecting cases of endometriosis in ASRM (American Society for Reproductive Medicine) stages III and IV (Tanmahasamut et al. 2018). Serum markers are not recommended by TIGE for diagnosis of endometriosis because of their low sensitivity and specificity.

Treatment

The mainstays of endometriosis management include medical and/or surgical treatment to remove all of the visible endometriotic lesions. Although superficial peritoneal lesions and ovarian endometriomas represent the majority of endometriotic implants within the pelvis, deep infiltrating endometriosis and extra-pelvic endometriosis are the most challenging conditions to treat. Medical therapy may be enough to reduce symptoms and signs (Sansone et al. 2018), but in a large number of patients a complete eradication, with a nerve- and vascular-sparing approach is needed to restore normal pelvic anatomy and function (Raffaelli et al. 2018). Endometriosis is a chronic disease and requires lifelong treatment. Therefore, TIGE recommends long-term medication in order to avoid repeated surgery and disease progression with its consequences. Additionally, our group recommends the choice of treatment should take into account the age of the patient, the extent of disease, the severity of symptoms, fertility need, previous treatments and adverse effects, concomitant disease, contraindications to hormonal treatments, body image, economic status, patient preference, and competency of healthcare providers.

Empirical treatment of endometriosis-associated pain

Empirical treatment should be considered when endometriosis is suspected, and other causes of pelvic pain should be excluded. Analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), or hormonal treatments such as combined oral contraceptives (COCs), progestin, gonadotropic releasing hormone agonist (GnRHa), etc. are recommended (Dunselman et al. 2014; Bedaiwy et al. 2017). Although NSAIDs may be used for pain relief, they do not prevent disease progression.

Medical treatment of endometriosis-associated pain

After endometriosis is definitively diagnosed, medical treatment should be considered for the treatment of pain and prevention of recurrence after surgery (Dunselman et al. 2014) because recurrence rates of pain after surgical treatment are up to 50% within 5 years (Cheewadhanaraks 2013; Bedaiwy et al. 2017). The choices of medication for endometriosis-associated pain can be classified as first- and second-line medications. First-line medication includes progestin and continuous COCs containing low oestrogen, while second-line medications are GnRHa with add-back therapy and the levonorgestrel-releasing intrauterine system (LNG-IUS). See Table 1.

Table 1. Drugs for the management of endometriosis-associated pain.

Drug	Recommendation
NSAIDs	There is no high-quality evidence to prove the efficacy of NSAIDs in managing endometriosis-associated pain (Brown et al. 2017). TIGE recommends their use in symptomatic treatment only.
COCs	There are few published randomized controlled trials of COCs in endometriosis (Brown et al. 2018). However, COCs decrease endometriosis-associated dysmenorrhoea and endometriotic cyst volume (Harada et al. 2008). Continuous COCs may have better efficacy than a cyclic regimen, although with more unexpected uterine bleeding (Hwang et al. 2018).
Progesterone, progestogens (natural metabolites of progesterone) and progestins (synthetic progestogens)	Progesterone/progestogens/progestins are available in different forms including oral, injectable, transdermal patches, vaginal rings, intrauterine devices and subcutaneous implants. They have demonstrable benefits in reducing pain and suppressing the extent of endometriotic lesions. Progestins used include dienogest (2 mg per day), medroxyprogesterone acetate (MPA) (150 mg intramuscularly every three months or oral 10 mg per day), norethindrone acetate (NETA) (5-15 mg per day), 52 mg levonorgestrel-releasing intrauterine system (LNG-IUS), etonogestrel (ENG)-releasing contraceptive implant, cyproterone acetate, dydrogesterone, gestrinone, lynesterole, megesterol acetate, etc. (Gheorghisan-Galateanu and Gheorghiu 2019) Medroxyprogesterone acetate (MPA) Depot medroxyprogesterone acetate (DMPA) is a commonly used progestin in Thailand. It has better compliance among patients compared to oral MPA (Attaran and Gidwani 2003). However, DMPA may not be a good choice for women wanting a pregnancy in the immediate future, as ovulation may be inhibited for up to 12 months (Cheewadhanaraks et al. 2012) and care should be exercised regarding long-term treatment – especially in adolescents – due to a reduction in bone density (Cheewadhanaraks et al. 2012). DMPA treatment can reduce endometriosis-associated pain to an extent comparable to oral contraceptives (OCs) and it may help significantly improve dysmenorrhoea compared to OCs in long-term treatment (Cheewadhanaraks et al. 2012). Treatment with DMPA is associated with bone mineral density (BMD) deficits during treatment, with the greatest BMD loss occurring during the first 2 years of treatment. However, the bone mineral deficits return to baseline levels after discontinuation, but this can take more than 2 years, depending on the extent of BMD loss (Clark et al. 2006). Treatment with DMPA is also associated with a slightly increased risk of fractures, especially for long-term treatment (Meier et al. 2010). Norethindrone acetate (NETA) NETA is effective in treating endometriosis-associated pain. The most common adverse events are weight gain, breakthrough bleeding, and decreased libido (Barra et al. 2018). Dienogest Dienogest is effective in reducing pelvic pain and endometriotic lesions. In addition, it is as effective as gonadotropin releasing hormone agonist (GnRHa) in controlling endometriosis-associated pain (Ota et al. 2015; Barra et al. 2018). The most common adverse events in long-term treatment are metrorrhagia (including spotting), reductions in BMD and depression. There are no abnormalities in serum lipid concentrations or liver enzymes after long-term treatment (Ota et al. 2015). LNG-IUD The LNG-IUD is as effective in reducing pain after surgery as GnRHa (Song et al. 2018) and it significantly decreases the recurrence rate of symptoms when compared to danazol. Furthermore, it shows higher satisfaction ratings than COCs. There is some data showing that the LNG-IUD causes a reduction in uterine volume in women with endometriosis and adenomyosis (Bahamondes et al. 2007). Vaginal bleeding is significantly higher in LNG-IUS than GnRHa but does not lead to patient dissatisfaction or early removal of the device (Song et al. 2018). ENG-releasing implant The ENG-releasing implant is effective in controlling endometriosis-associated pain and dysmenorrhoea, and in improving quality of life similarly to the LNG-IUD (Carvalho et al. 2018; Sansone et al. 2018). However, it has no effect on endometriotic cysts (Sansone et al. 2018) but can reduce the volume of rectovaginal nodules (Ferrero et al. 2019).
GnRHa	GnRHa is an effective medical treatment for endometriosis-related pain. Treatment with GnRHa often leads to hypoestrogenic side effects including hot flushes, bone loss and mood swings (Bedaiwy et al. 2017). In general, GnRHa treatment can be continued for 3–6 months and even extended to one year if appropriate add-back therapy is used concomitantly. To minimize vasomotor symptoms and maximize bone density preservation, add-back therapy should be started at the same time as GnRHa therapy. The options for add-back therapy regimens include progestin-only (typically NETA), or a combination of oestrogen/progestin in doses used for regular hormone therapy (Bedaiwy et al. 2017). The data for the outcome on bone density in adolescents with endometriosis and treated with GnRHa is limited. However, it is recommended for adolescents with endometriosis if other treatments have failed. Add-back therapy should be prescribed if prolonged (>6 months) GnRHa therapy is used, and monitoring of BMD by dual-energy X-ray absorptiometry of the total hip and lumbar spine is required for these patients if GnRHa treatment exceeds 8–9 months (DiVasta and Laufer 2013).
Danazol	Danazol is effective in endometriosis-associated pain. However, a large number of patients discontinue long-term treatment with danazol because of side effects such as weight gain, acne, changes in lipid profile, hirsutism and permanent deepening of the voice (Barbieri 1990; Selak et al. 2007; Tosti et al. 2017; Ferrero et al. 2018).

Surgical treatment of endometriosis-associated pain

Surgical treatment should be considered in patients with endometriosis-associated pain for whom medication is ineffective or contraindicated, and those with suspected malignancy, large endometriomas or co-incidental surgical disease (Chapron et al. 2002). The goal of surgical treatment is to remove all visible lesions. Surgical options, whether conservative (e.g. ovarian cystectomy) or radical (e.g. hysterectomy and bilateral salpingo-oophorectomy), depend on the location, extent and severity of the disease, the need for fertility, and patient preference. The recurrence rate of endometriosis after surgery varies between studies from 6–69% (Taylor and Williams 2010; Bozdag 2015). Laparoscopic cystectomy should be preferred to drainage and coagulation especially when cysts are larger than 4 cm, due to better outcomes in terms of infertility and pelvic pain (Beretta et al. 1998; Chapron et al. 2002).

Conclusion

Endometriosis is a common disease in reproductive-age women. It affects quality of life, fertility, and imposes an enormous economic burden on society. Decisions about selecting the appropriate treatment for women with endometriosis depend on the age of the patient, the extent of disease, the severity of symptoms, previous treatments and any adverse effects, coincidental disease, contraindications to hormonal treatment, body image, economic status, patient preference, the skill and experience of physicians, access to medication, and fertility need. Several hormonal treatments are available but no consensus has been reached about the best option for long-term prevention of recurrence. TIGE has developed this guideline for Thai clinicians to help with the management of patients with endometriosis.

Acknowledgements

David Engert MBBS, MFPM, medical writer and editor.

Puttavee Charoenwanthanang, M.Sc., manuscript coordinator.

Disclosure statement

The authors declare they have no conflicts of interest and nothing to disclose.

Additional information

Funding

This consensus statement is supported by Bayer Thai Company Limited.