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

Figures & data

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).

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