Optimising Hormonal Therapy Before Declaring Failure in Endometriosis‐Associated Pain

Dear Dr. Papageorghiou, We applaud Vincent and Horne for clearly explaining the different mechanisms of endometriosis-associated pain, and for stating ‘there is already enough evidence that endometriosis-associated pain is similar in so many ways to other forms of chronic pain that we should feel confident in taking a pain-focussed approach’ 1 Accordingly, they advocate treatments targeted both at lesions for the nociceptive component of pain and at pain itself for the neuropathic-nociplastic component. Regarding nociceptive pain, the authors propose moving away from excisional surgery as the optimal primary choice and initiating hormonal treatment early instead 1. However, they also emphasise that over 40% of patients reportedly fail to improve with medical therapy. When assessing the effect of any treatment, it is assumed that it has been correctly indicated and completed. As no surgeon is eager to publish poor results, the postoperative outcomes reported in meta-analyses may represent overestimates, reflecting the excellent technical capabilities of a few experts. We hypothesise that the opposite is true of hormonal therapies for endometriosis. These medications can be prescribed by all gynaecologists and GPs. As drugs are usually prepackaged and provided with approved administration schedules, specific experience may not be deemed necessary. However, we challenge the notion that findings from general clinical practice surveys reflect the true potential effect of hormonal treatment for endometriosis-associated pain. First-line medications include combined oral contraceptives (COCs) and progestogens, with gonadotropin-releasing hormone (GnRH) agonists and antagonists constituting second-line treatments. The choice of specific first-line components (e.g., ethinyl-oestradiol versus bioidentical 17β-oestradiol or oestetrol), doses (e.g., regular versus ultra-low-dose COCs) and the modality of use (e.g., cyclic vs. continuous use of COCs, or the adoption of tailored cycling regimens) may influence the outcome. The same applies to whether GnRH analogues are systematically used for patients who do not respond to or tolerate first-line medications. Notably, ‘hormonal therapy failure’ should not usually be concluded before amenorrhoea has been achieved or if a GnRH analogue has not been used, that is, if all the medical treatment options have not been tried. Before referring a patient to pain management services, referral to services specialising in medical treatments for endometriosis is recommended. Medical treatment experts could thus co-manage care, requesting consultations with pain management experts for non-responders to second-line drugs 2. Patients may feel ‘abandoned’ when referred to a pain management service, as they may believe that the cause of their symptoms has been overlooked or that their condition has a particularly poor prognosis. This may increase anxiety, depression, and catastrophising, which could worsen nociplastic pain. Unfortunately, little evidence supports the pharmacological treatment of non-nociceptive pain in women with endometriosis. Vincent and Horne ask: ‘How do we identify those who may still benefit from a lesion-focused approach?’ 1. To this end, we suggest conducting a 3-month GnRH analogue ex-juvantibus test, as non-responders are more likely to experience non-nociceptive pain and benefit most from a multidisciplinary approach 3. This could also prevent the ‘scapegoat’, described by Hudelist et al. 4, of attributing pain to ectopic lesions when it is not caused by endometriosis. P.V. conceived the text and drafted the original version of the letter. V.B., N.S., P.Vi. and E.S. participated in conceiving and drafting part of the letter and critically revising it. All authors approved the final version of the letter. The authors have nothing to report. P.V. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource up-to-date; and maintains both a public and private gynaecological practice. P.Vi. is co-editor-in-chief of the Journal of Endometriosis and Uterine Disorders. E.S. is editor-in-chief of Human Reproduction Open; discloses payments from Ferring and Theramex for research grants and personal honoraria from Merck-Serono, Ibsa, and Gedeon-Richter; and maintains both a public and private gynaecological practice. V.B. and N.S. declare they have no Conflicts of Interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.