Are combined hormonal contraceptives the neglected treatment for symptomatic endometriosis?
2018; Elsevier BV; Volume: 110; Issue: 1 Linguagem: Inglês
10.1016/j.fertnstert.2018.03.038
ISSN1556-5653
Autores Tópico(s)Uterine Myomas and Treatments
ResumoI want a new drug.—Huey Lewis and the News (Chrysalis, UK, 1984)An approximate answer to the right question is worth a great deal more than a precise answer to the wrong question.—John Tuckey, American statistician (https://en.wikiquote.org/wiki/John_Tukey. Accessed March 18, 2018) There is good and bad news for women needing medical treatment for endometriosis. The good news is that, based on the results of the systematic review conducted by Jensen and coworkers (1Jensen J.T. Schlaff W. Gordon K. The use of combined hormonal contraceptives for the treatment of endometriosis-related pain: a systematic review of the evidence.Fertil Steril. 2018; 110: 136-151Abstract Full Text Full Text PDF Scopus (45) Google Scholar), "combined hormonal contraceptives (CHC) treatment, administered cyclically or continuously, results in clinically important and statistically significant reductions from baseline in endometriosis-related pain" and "CHC treatment also resulted in improvements from baseline in quality of life in most studies that measured this outcome." The bad news is that the data supporting the use of CHC were judged of low quality, mainly due to nonrandom allocation of treatments, absence of treatment concealment, and lack of a placebo arm in most studies. Why are data on CHC for endometriosis still of "low quality," whereas those on GnRH agonists and antagonists and dienogest are considered of "high quality"? A tentative answer is that pharmaceutical industries, which have the organization and money to conduct costly double-blind, placebo-controlled, multicenter, randomized controlled trials (RCTs), have limited interest in CHC as a treatment for endometriosis, whereas independent investigators interested in CHC struggle with the overwhelming administrative and financial burden associated with the planning of such RCTs. Therefore, research groups without industry support either take the long and winding road to public funding or choose observational designs that provide low-quality evidence. In fact, of the 18 included studies in the Jensen et al. review, only five were fully or partly industry sponsored, whereas the remaining 13 (72%) were conducted by independent groups without industry support. Only one RCT was funded by the National Institutes of Health (1Jensen J.T. Schlaff W. Gordon K. The use of combined hormonal contraceptives for the treatment of endometriosis-related pain: a systematic review of the evidence.Fertil Steril. 2018; 110: 136-151Abstract Full Text Full Text PDF Scopus (45) Google Scholar). Pharma industries are unlikely to invest in CHC for endometriosis because the extra revenues from this indication, in addition to contraception, would not compensate for the cash outflow necessary for the organization of RCTs (2Quaas A.M. Weedin E.A. Hansen K.R. On-label and off-label drug use in the treatment of endometriosis.Fertil Steril. 2015; 103: 612-625Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Historically, novel medications for endometriosis have always been high priced. The price of new drugs can be negotiated with regulatory authorities, whereas that of already marketed, and generally inexpensive, CHC cannot be augmented. Jensen and coworkers have not exploited the label of "low-quality evidence" to put CHC out of play, thus freeing the market from low-cost competitors and leaving it open for more lucrative drugs. However, should the popularly accepted equivalence RCT = high-quality data, and observational studies = low-quality data be challenged here? Even when a faultless methodology is adopted, the practical value of the resulting evidence relies on the formulation of research questions that are relevant to patients, the selection of a study population that is representative of women with endometriosis also outside research settings, and the choice of a comparator that most patients actually use. How should the evidence originating from methodologically impeccable RCTs be considered in case an outcome is chosen that addresses patient health issues only partly, or if generalization of results is limited by recruitment of highly selected participants, or when the comparator is a medication that is not commonly used as a first-line option? Should the results of observational studies be put in the background because treatments were neither allocated randomly nor concealed, despite the fact that these studies may adequately reflect real-world conditions, thus providing concrete, albeit imprecise, answers to questions that matter to women? Obviously, the ideal scenario would be systematically conducting pragmatic RCTs where novel drugs for endometriosis are tested against a CHC, and not a placebo or GnRH agonist. This would allow the definition of the incremental benefit, if any, of the new compound over a really standard comparator and the generalization of valuable comparative effectiveness research findings and would enable women to decide whether the magnitude of the additional effect justifies the extra costs. Given the limited industry interest, it is not surprising that CHC use for endometriosis is off label (2Quaas A.M. Weedin E.A. Hansen K.R. On-label and off-label drug use in the treatment of endometriosis.Fertil Steril. 2015; 103: 612-625Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Nevertheless, CHCs are recommended as first-line medications by several authoritative scientific organizations. In particular, recommendation no. 37 of the recent guideline NG73 "Endometriosis: diagnosis and management," issued by the United Kingdom National Institute for Health and Care Excellence (NICE), states, "At the time of publication (September 2017), none of these medicines [CHC and progestins] had UK marketing authorisations for this indication. The General Medical Council (GMC), in its Prescribing Guidance: Prescribing Unlicensed Medicines, states that although doctors should usually prescribe licensed medicines for their licensed indications, they may prescribe unlicensed medicines when it is necessary to do so to meet the specific needs of the patient. […] It also states that when prescribing an unlicensed medicine is supported by authoritative clinical guidance (such as a NICE guideline), it may be sufficient to describe in general terms why the medicine is not licensed for the proposed use or patient population" (https://www.nice.org.uk/guidance/ng73/evidence/full-guideline-pdf-4550371315; p. 238. Accessed March 18, 2018). The off-label use of CHC should be in accordance with local regulations. In the same vein, progestins and GnRH agonists and antagonists cannot be formally described as contraceptive. The need for barrier contraception may potentially decrease patient satisfaction and adherence. Casper questions the use of CHC as a first-line treatment for endometriosis, because the usual 20–30 μg ethinyl E2 (EE) content is supraphysiologic. In fact, 5 μg of EE are equivalent to about 1 mg of micronized E2 or 0.625 mg of conjugated equine estrogens (3Casper R.F. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills.Fertil Steril. 2017; 107: 533-536Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). As the estrogen and P receptors would be, respectively, over- and underexpressed in endometriotic lesions, the use of CHC, contrary to progestins, would create an estrogen-dominant hormonal environment that might increase the risk of lesion progression (3Casper R.F. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills.Fertil Steril. 2017; 107: 533-536Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). However, CHCs are available with only 15 μg of EE or 1.5 mg of E2 (4Vercellini P. Buggio L. Frattaruolo M.P. Borghi A. Dridi D. Somigliana E. Medical treatment of endometriosis-related pain.Best Pract Res Clin Obstet Gynaecol. 2018 Feb 15; ([Epub ahead of print.])https://doi.org/10.1016/j.bpobgyn.2018.01.015Crossref Scopus (68) Google Scholar). Moreover, a cheap estrogen-progestin combination containing 1 mg of E2 valerate (corresponding to 0.76 mg E2) and precisely 2 mg of dienogest is used in Europe for hormone replacement therapy. Such very low estrogen doses should not promote endometriosis progression, given the predominantly progestogenic effect of these combinations. In addition, provided ovulation and endometrial bleeding are prevented, it is still unclear whether it is more advantageous to induce a profound hypoestrogenic state or keep the hormonal status stable independently of the degree of hypoestrogenism induced. No available drug for endometriosis is curative; therefore medications may be needed for years. Exposing reproductive-age women to prolonged hypoestrogenism may cause unfavorable long-term consequences. Thus, a balance should be found between the pursuit of the maximum endometriotic lesion quiescence and the maintenance of the best possible overall patient health. In this regard, the evidence on the safety of prolonged CHC use is abundant and that on progestins without estrogens less so. Hence, very-low-dose CHC may be preferred in women with superficial peritoneal lesions or with small typical endometriomas and for the prevention of postoperative endometrioma recurrence, whereas progestins may be indicated selectively in patients with deep infiltrating lesions (4Vercellini P. Buggio L. Frattaruolo M.P. Borghi A. Dridi D. Somigliana E. Medical treatment of endometriosis-related pain.Best Pract Res Clin Obstet Gynaecol. 2018 Feb 15; ([Epub ahead of print.])https://doi.org/10.1016/j.bpobgyn.2018.01.015Crossref Scopus (68) Google Scholar). When faced with unaffordable options, some women with endometriosis may choose to forgo care (5Vercellini P. Frattaruolo M.P. Buggio L. Toward minimally disruptive management of symptomatic endometriosis: reducing low-value care and the burden of treatment.Expert Rev Pharmacoecon Outcomes Res. 2018; 18: 1-4Crossref PubMed Scopus (11) Google Scholar). This must be taken into account when considering the results of head-to-head comparisons. Jensen and coworkers maintain that "in RCTs comparing cyclic CHC with GnRH agonist treatment, the latter treatment showed superiority in most studies" (1Jensen J.T. Schlaff W. Gordon K. The use of combined hormonal contraceptives for the treatment of endometriosis-related pain: a systematic review of the evidence.Fertil Steril. 2018; 110: 136-151Abstract Full Text Full Text PDF Scopus (45) Google Scholar). However, demonstrating that an experimental drug provides an incremental benefit over CHC in terms of pain relief does not mean that all candidates to medical treatment should use the new medication, especially if its overall therapeutic value is limited and its cost substantially higher. More effective, but potentially less safe and more costly compounds should be used selectively in those women who do not respond to, do not tolerate, or have contraindications to CHC. As about two thirds of patients with endometriosis appear satisfied with CHC use (4Vercellini P. Buggio L. Frattaruolo M.P. Borghi A. Dridi D. Somigliana E. Medical treatment of endometriosis-related pain.Best Pract Res Clin Obstet Gynaecol. 2018 Feb 15; ([Epub ahead of print.])https://doi.org/10.1016/j.bpobgyn.2018.01.015Crossref Scopus (68) Google Scholar), especially when used continuously, alternative therapeutic options are needed only in the remaining third. The adoption of a stepped-care approach based on the use of very-low-dose CHC as the first step, progestins as the second step, and GnRH agonists and antagonists as the third step can limit the financial burden of medical treatment on individual families and reduce the opportunity costs for national health services (4Vercellini P. Buggio L. Frattaruolo M.P. Borghi A. Dridi D. Somigliana E. Medical treatment of endometriosis-related pain.Best Pract Res Clin Obstet Gynaecol. 2018 Feb 15; ([Epub ahead of print.])https://doi.org/10.1016/j.bpobgyn.2018.01.015Crossref Scopus (68) Google Scholar, 5Vercellini P. Frattaruolo M.P. Buggio L. Toward minimally disruptive management of symptomatic endometriosis: reducing low-value care and the burden of treatment.Expert Rev Pharmacoecon Outcomes Res. 2018; 18: 1-4Crossref PubMed Scopus (11) Google Scholar). According to the Practice Committee of the American Society of Reproductive Medicine, "endometriosis should be viewed as a chronic disease that requires a lifelong management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures" (http://www.fertstert.org/article/S0015-0282(14)00150-2/pdf. Accessed March 27, 2018). Importantly, Jensen and coworkers conclude that "combined and progestin-only hormonal contraception present affordable and effective treatment options for women with endometriosis. Our review supports that these methods reduce menstrual and nonmenstrual pain and improve quality of life. Continuous use may result in amenorrhea and further improve outcomes compared with cyclic use. Overall, the available literature is limited, but a consistency of effect is observed supporting these recommendations" (1Jensen J.T. Schlaff W. Gordon K. The use of combined hormonal contraceptives for the treatment of endometriosis-related pain: a systematic review of the evidence.Fertil Steril. 2018; 110: 136-151Abstract Full Text Full Text PDF Scopus (45) Google Scholar). The authors should be commended for a well-performed analysis of the available data. Women with endometriosis will benefit from this effort. Use of combined hormonal contraceptives for the treatment of endometriosis-related pain: a systematic review of the evidenceFertility and SterilityVol. 110Issue 1PreviewTo review the available clinical evidence on the use of combined hormonal contraceptive (CHC) agents (estrogen [E]-progestin combinations) for the treatment of endometriosis-related pain. Full-Text PDF Open Access
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