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Current and Emerging Treatment Options for Endometriosis

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Current and Emerging Treatment Options for Endometriosis Expert Opinion on Pharmacotherapy ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20 Current and emerging treatment options for endometriosis Simone Ferrero, Giulio Evangelisti & Fabio Barra To cite this article: Simone Ferrero, Giulio Evangelisti & Fabio Barra (2018): Current and emerging treatment options for endometriosis, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2018.1494154 To link to this article: https://doi.org/10.1080/14656566.2018.1494154 Published online: 05 Jul 2018. Submit your article to this journal View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 EXPERT OPINION ON PHARMACOTHERAPY https://doi.org/10.1080/14656566.2018.1494154 REVIEW Current and emerging treatment options for endometriosis Simone Ferrero a,b, Giulio Evangelistia,b and Fabio Barra a,b aAcademic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genoa, Italy; bDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy ABSTRACT ARTICLE HISTORY Introduction: Pharmacotherapy has a pivotal role in the management of endometriosis with long-term Received 8 June 2018 treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the Accepted 25 June 2018 disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors KEYWORDS including age and patient preference, reproductive plans, intensity of pain, severity of disease and Endometriosis; combined incidence of adverse effects. oral contraceptives; Areas covered: The aim of this review is to provide the reader with a complete overview of drugs that progestins; gonadotropin- are currently available or are under investigation for the treatment of endometriosis highlighting on- releasing hormone agonist; going clinical trials. aromatase inhibitors; Expert opinion: Almost all of the available treatment options for endometriosis suppress ovarian gonadotropin-releasing function and are not curative. Combined oral contraceptives and progestins are commonly adminis- hormone antagonist; anti- tered to these patients in order to ameliorate pain symptoms. Gonadotropin-releasing hormone- angiogenetic; anti-oxidant; immunomodulators agonists are prescribed when first-line therapies are ineffective, not tolerated or contraindicated. Aromatase inhibitors should be reserved only for women who are refractory to other treatments. Amongst the drugs under development, gonadotropin-releasing hormone antagonists have shown the most promising results. Presently, are a number of potential therapies currently in pre-clinical or early clinical studies which may alter treatment strategies in the future although further studies are necessary. 1. Introduction ‘cure’ the disease which may not only persist but may also progress [8] despite the use of endocrine therapies Endometriosis is defined by the presence of endometriotic and the improvement of pain symptoms. As a conse- glands and stroma outside the uterine cavity. quence, pain usually recurs when patients discontinue Endometriotic lesions may have various locations; they hormonal treatment either because of the adverse effects are found more frequently on the pelvic peritoneum, ovar- (AEs) or because of the desire to conceive. ies, and uterosacral ligaments, in the rectovaginal septum Estradiol (E ) is of paramount importance in the main- and in the vesico-uterine fold, and more rarely in the 2 tenance of endometriosis. Hormonal therapies currently bowel, diaphragm, umbilicus, pericardium and pleura. used to treat endometriosis-related pain primarily acts by Endometriosis may be asymptomatic in some women. suppressing ovulation and, thus, inducing a relatively However, more frequently, this condition causes pain hypoestrogenic state [6]. First-line hormonal therapies symptoms (such as dysmenorrhea, deep dyspareunia, used to treat pain in women with endometriosis are com- non-menstrual pelvic pain, dyschezia) and infertility [1]. bined with oral contraceptives (COCs) and progestins. The Pain is the most debilitating complaint of patients with current guidelines recommend an accurate diagnostic endometriosis and it negatively affects quality of life, sex- workup of women with endometriosis prior to administer- ual function, working efficiency and social life. ing second-line hormonal treatments, which include gona- Surgical excision of endometriosis significantly amelio- dotropin releasing hormone analogues (GnRH-as) or ratespainsymptoms[2]; however, it may be associated aromatase inhibitors (AIs). with complications. Moreover, the recurrence rate of pain However, since the original description of endometriosis by symptoms after surgery is not negligible [3]. In addition, in Sampson [9], our knowledge of the molecular pathways the case of ovarian endometriomas, one concern is the risk involved in the pathogenesis of the disease has largely of damage to the ovarian reserve [4]. Therefore, medical increased. Based on these molecular studies, several new therapy has a pivotal role in the long-term treatment of drugs have been tested in vitro and in animal models of endometriosis [5,6]. Current hormonal therapies used to endometriosis [10,11]. treat endometriosis have no role in improving endometrio- A comprehensive literature research was conducted to sis-related infertility [7] and they aim only to alleviate pain identify the published studies evaluating the drugs used or symptoms [5]. Thus, these therapies do not definitively CONTACT Simone Ferrero [email protected] Academic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Largo R.Benzi 10, 16132 Genoa, Italy © 2018 Informa UK Limited, trading as Taylor & Francis Group 2 S. FERRERO ET AL. 2. Current therapies for the treatment of Article highlights endometriosis-related pain ● Pharmacotherapy plays a pivotal role in the management of patients 2.1. Non-steroidal anti-inflammatory drugs with endometriosis and long-term treatments should balance clinical efficacy (controlling pain symptoms and preventing recurrence of Table 1 summarizes the characteristics of main drug classes disease after surgery) with an acceptable safety-profile; ● Combined oral contraceptives and progestins are commonly adminis- used for the treatment of endometriosis. Non-steroidal anti- tered as first-line therapies for the management of endometriosis- inflammatory drugs (NSAIDs) are widely used to treat endo- associated pain. However, between one-fourth and one-third of metriosis-related pain symptoms. Surprisingly, there is little patients do not respond to these treatments. ● Gonadotropin-releasing hormone-agonists are prescribed when first- evidence to support the use of NSAIDs in the treatment of line therapies are ineffective, not tolerated or contraindicated. AIs endometriosis [12]. Tolfenamic acid (200 mg three times per should be reserved for patients who are refractory to other treat- day) [13] and naproxen sodium (275 mg four times per day) ments only in a research environment. It is important to note that all of these drugs have a number of common AEs; [14] have been shown to be superior to placebo for the ● Almost all of the currently available treatment options for endome- treatment of dysmenorrhea secondary to endometriosis. triosis suppress ovarian function and are not curative. For this reason, Moreover, rofecoxib (25 mg per day) was shown to improve research into new drugs is unsurprisingly demanding. Amongst the drugs currently under investigation, gonadotropin-releasing hormone pelvic pain and dyspareunia caused by endometriosis [15], antagonists, which are currently in late stage clinical development This drug, however, was withdrawn from the market after a have shown most promise; study showed an increased cardiovascular risk after long-term ● There are a number of potential future therapies currently tested only in vitro, in animal models of endometriosis or in early clinical studies use [16]. There is no evidence that one NSAID is more effective with a small sample size. Further studies are necessary to conclude than another. Furthermore, patients using in long-term whether these treatments would be of value for the treatment of NSAIDs must be aware that these drugs may be responsible endometriosis. significant AEs (such as gastrointestinal ulcers, cardiovascular This box summarizes key points contained in the article. events, hypertension, and acute renal failure) [12]. 2.2. Estroprogestins under investigation to treat endometriosis. The database of Estroprogestins (using oral formulations, vaginal rings or trans- the National Library of Medicine (MEDLINE, 1950–February dermal patches), either sequential or continuous, are com- 2018), EMBASE (1974–February 2018) and the Cochrane monly administered for treating endometriosis-related pain. Database (February 2018) were used to identify the papers They have some practical advantages, including contracep- that were published on this topic. The reference lists of all tion, long-term safety and control of the menstrual cycle [10]. known primary and review articles were examined for addi- A double-blind, placebo-controlled, multicenter rando- tional relevant citations and recent book chapters were mized controlled trial (RCT) evaluated the efficacy of cyclic reviewed. The database of clinicaltrial.gov was also reviewed low-dose COC
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