{"paper_id":"fb60431c-2e0a-4352-8afe-244df2de0e4c","body_text":"EDITORIAL\n8  OBG Management  |   April 2021  |   Vol. 33  No. 4  mdedge.com/obgyn\nOptimize your treatment of  \nendometriosis by using an FDA-approved \nhormonal medication\nFor women with endometriosis, if one estrogen-progestin contraceptive \nresults in suboptimal control of pelvic pain, do not prescribe a different \nbrand of the same contraceptive type. In this situation, prescribe one of the \nUS Food and Drug Administration (FDA) approved treatments for pelvic pain \ncaused by endometriosis.\nRobert L. Barbieri, MD\nChair Emeritus, Department of Obstetrics and Gynecology  \nInterim Chief, Obstetrics \nBrigham and Women’s Hospital \nKate Macy Ladd Distinguished Professor of Obstetrics,  \n   Gynecology and Reproductive Biology  \nHarvard Medical School \nBoston, Massachusetts\nW\nomen with endometriosis \noften present for medical \ncare for one or more of the \nfollowing health issues: pelvic pain, \ninfertility, and/or an adnexal cyst \n(endometrioma). For women with \nmoderate or severe pelvic pain and \nlaparoscopically diagnosed endo -\nmetriosis, hormone therapy is often \nnecessary to achieve maximal long-\nterm reduction in pain and optimize \nhealth. I focus on opportunities to \noptimize hormonal treatment of \nendometriosis in this editorial.\nWhen plan A is \nnot working, move \nexpeditiously to plan B\nCyclic or continuous combination \nestrogen-progestin contraceptives \nare commonly prescribed to treat \npelvic pain caused by endometriosis. \nAlthough endometriosis pain may \ninitially improve with estrogen-pro -\ngestin contraceptives, many women \non this medication will eventually \nreport that they have worsening \npelvic pain that adversely impacts \ntheir daily activities. Surprisingly, \nclinicians often continue to prescribe \nestrogen-progestin contraceptives \neven after the patient reports that the \ntreatment is not effective, and their \npain continues to be bothersome.\nPatients benefit when they have \naccess to the full range of hormone \ntreatments that have been approved \nby the FDA for the treatment of mod-\nerate to severe pelvic pain caused by \nendometriosis ( TABLE ). In the situ -\nation where an estrogen-progestin \ncontraceptive is no longer effective \nat reducing the pelvic pain, I will \noften offer the patient the option \nof norethindrone acetate (NEA) or \nelagolix treatment. My experience is \nthat stopping the estrogen-progestin \ncontraceptive and starting  NEA or \nelagolix will result in a significant \ndecrease in pain symptoms and \nimprovement in the patient’s quality \nof life. \nOther FDA-approved options \nto treat pelvic pain caused by endo -\nmetriosis include depot medroxy -\nprogesterone acetate injectable \nsuspension, depot leuprolide ace -\ntate, goserelin implant, and dan -\nazol. I do not routinely prescribe \ndepot medroxyprogesterone acetate \nbecause some patients report new \nonset or worsening symptoms of \ndepression on the medication. I pre-\nscribe depot-leuprolide acetate less \noften than in the past, because many \npatients report moderate to severe \nhypoestrogenic symptoms on this \nmedication. In women taking depot-\nleuprolide acetate, moderate to \nsevere vasomotor symptoms can be \nimproved by prescribing NEA pills, \nbut the alternative of norethindrone \nmonotherapy is less expensive. I \nseldom use goserelin or danazol in \nmy practice. The needle required doi: 10.12788/obgm.0084\n\nmdedge.com/obgyn  Vol. 33  No. 4  |   April 2021   |   OBG Management   9\nto place the goserelin implant has a \ndiameter of approximately 1.7 mm \n(16 gauge) or 2.1 mm (14 gauge), for \nthe 3.6 mg and 10 mg doses, respec -\ntively. The large diameter of the \nneedle can cause pain and bruising \nat the implant site. As a comparison, \nthe progestin subdermal implant \nneedle is approximately 2.1 mm in \ndiameter. Danazol is associated with \nweight gain, and most women prefer \nto avoid this side effect. \nNorethindrone acetate\nNEA 5 mg daily is approved by the \nFDA to treat endometriosis. 1 NEA \nwas approved at a time when large \ncontrolled clinical trials were not \nroutinely required for a medicine \nto be approved. The data to sup -\nport NEA treatment of pelvic pain \ncaused by endometriosis is based \non cohort studies. In a study of  \n194 women, median age 21 years \nwith moderate to severe pelvic pain \nand surgically proven endometriosis, \nthe effect of NEA on pelvic pain was \nexplored.2 The initial dose of NEA \nwas 5 mg daily. If the patient did not \nachieve a reduction in pelvic pain \nand amenorrhea on the NEA dose of \n5 mg daily, the dose was increased by  \n2.5 mg every 2 weeks, up to a maxi -\nmum of 15 mg, until amenorrhea \nand/or a decrease in pelvic pain \nwas achieved. Ninety-five percent \nof the women in this cohort had \npreviously been treated with an \nestrogen-progestin contraceptive or \na GnRH antagonist and had discon -\ntinued those medications because \nof inadequate control of pelvic pain \nor because of side effects of the  \nmedication. \nIn this large cohort, 65% \nof women reported significant \nimprovement in pelvic pain, with a \nmedian pain score of 5 before treat -\nment and 0 following NEA treatment. \nAbout 55% of the women reported \nno side effects. The most commonly \nreported side effects were weight \ngain (16%; mean weight gain, 3.1 kg), \nacne (10%), mood lability (9%), hot \nflashes (8%), depression (6%), scalp \nhair loss (4%), headache (4%), nau -\nsea (3%), and deepening of the voice \n(1%). (In this study women could \nreport more than one side effect.) \nIn another cohort study of  \n52 women with pelvic pain and sur -\ngically confirmed endometriosis, \nNEA treatment resulted in pain relief \nin 94% of the women. 3 Breakthrough \nbleeding was a common side effect, \nreported by 58% of participants. \nThe investigators concluded that \nNEA treatment was a “cost-effective \nalternative with relatively mild side \neffects in the treatment of symptom -\natic endometriosis. ” A conclusion \nwhich I endorse. \nNEA has been reported to effec -\ntively treat ovarian endometriomas \nand rectovaginal endometriosis. 4,5 \nIn a cohort of 18 women who had \npreviously had the surgical resec -\ntion of an ovarian endometriosis cyst \nand had postoperative recurrence of \npelvic pain and ovarian endometrio-\nsis, treatment was initiated with an  \nTABLE  Hormone treatments approved by the FDA to treat moderate to severe pain caused by \nendometriosis\nFDA-approved medication Route of administration Dose Relative costa\nProgestins\nNorethindrone acetate Oral 5 mg daily $\nMedroxyprogesterone acetate \ninjectable suspension\nSubcutaneous injection 104 mg every 3 months $$\nGnRH analogues\nNafarelin acetate Intranasal spray One spray twice daily $$$$\nDepot-leuprolide acetate Intramuscular injection 3.75 mg monthly $$$$\nGoserelin Subcutaneous implant 3.6 mg monthly $$$$\nElagolix Oral 150 mg daily or 200 mg twice daily $$$$\nAndrogens\nDanazol Oral 200 mg twice daily $$$\naRelative cost: $, < $50 per month; $$, $50 to $100 per month; $$$, > $100 and < $200 per month; $$$$, ≥ $500 per month. Prices are from the Good Rx website (www.\ngoodrx.com). Accessed February 19, 2021.\nAbbreviations: FDA, US Food and Drug Administration; GnRH, gonadotropin-releasing hormone. \n\nEDITORIAL\n10  OBG Management  |   April 2021  |   Vol. 33  No. 4  mdedge.com/obgyn\nCONTINUED ON PAGE 12\nescalating NEA regimen.4 Treatment \nwas initiated with NEA 5 mg daily, \nwith the dosage increased every \n2 weeks by 2.5 mg until amenor -\nrhea was established. Most women \nachieved amenorrhea with NEA 5 mg \ndaily, and 89% had reduced pelvic \npain. The investigators reported com-\nplete regression of the endometriosis \ncyst(s) in 74% of the women. In my \nexperience, NEA does not result in \ncomplete regression of endometriosis \ncysts, but it does cause a reduction in \ncyst diameter and total volume. \nIn a retrospective cohort study, \n61 women with pelvic pain and rec -\ntovaginal endometriosis had 5 years \nof treatment with NEA 2.5 mg or  \n5.0 mg daily.5 NEA treatment resulted \nin a decrease in dysmenorrhea, deep \ndyspareunia, and dyschezia. The \nmost common side effects attrib -\nuted to NEA treatment were weight \ngain (30%), vaginal bleeding (23%), \ndecreased libido (11%), headache \n(9%), bloating or swelling (8%), \ndepression (7%), and acne (5%). In \nwomen who had sequential imag -\ning studies, NEA treatment resulted \nin a decrease in rectovaginal lesion \nvolume, stable disease volume, or an \nincrease in lesion volume in 56%, 32%, \nand 12% of the women, respectively. \nThe investigators concluded that for \nwomen with rectovaginal endome -\ntriosis, NEA treatment is a low-cost \noption for long-term treatment.\nIn my practice, I do not prescribe \nNEA at doses greater than 5 mg daily. \nThere are case reports that NEA at \na dose of ≥10 mg daily is associated \nwith the development of a hepatic \nadenoma,6 elevated liver transami -\nnase concentration, 7 and jaundice. 8 \nIf NEA 5 mg daily is not effective in \ncontrolling pelvic pain caused by \nendometriosis, I stop the NEA and \nstart a GnRH analogue, most often \nelagolix. \nNEA 5 mg is not FDA approved \nas a contraceptive. However, noreth-\nindrone 0.35 mg daily, also known as \nthe “mini-pill” , is approved as a pro-\ngestin-only contraceptive. 9 NEA is \nrapidly and completely deacetylated \nto norethindrone, and the disposi -\ntion of oral NEA is indistinguish -\nable from that of norethindrone. 1 \nSince norethindrone 0.35 mg daily \nis approved as a contraceptive, it is \nhighly likely that NEA 5 mg has con -\ntraceptive properties if taken daily. \nElagolix\nElagolix is FDA approved for the \ntreatment of pelvic pain caused by \nendometriosis. I reviewed the key \nstudies resulting in FDA approval \nin the November 2018 issue of OBG \nManagement. 10 \nIn the Elaris Endometriosis-I \nstudy, 872 women with endometrio -\nsis and pelvic pain were randomly \nassigned to treatment with 1 of  \n2 doses of elagolix (high-dose  \n[200 mg twice daily] and low-dose \n[150 mg once daily]) or placebo. 11 \nAfter 3 months of therapy, a clinically \nmeaningful reduction in dysmenor -\nrhea pain was reported by 76%, 46%, \nand 20% of the women in the high-\ndose elagolix, low-dose elagolix, and \nplacebo groups, respectively (P<.001 \nfor comparisons of elagolix to pla -\ncebo). After 3 months of therapy, a \nclinically meaningful reduction in \nnonmenstrual pain or decreased or \nstable use of rescue analgesics was \nreported by 55%, 50%, and 37% of \nthe women in the high-dose elago -\nlix, low-dose elagolix, and placebo \ngroups, respectively (P<.01 low-dose \nelagolix vs placebo and P<.001 high-\ndose elagolix vs placebo). \nHot flashes that were severe \nenough to be reported as an adverse \nevent by the study participants were \nreported by 42%, 24%, and 7% of \nthe women in the high-dose elago -\nlix, low-dose elagolix, and placebo \ngroups. Bone density was measured \nat baseline and after 6 months of \ntreatment. Lumbar bone density \nchanges were -2.61%, -0.32%, and \n+0.47% and hip femoral neck bone \ndensity changes were -1.89%, -0.39%, \nand +0.02% in the high-dose elago -\nlix, low-dose elagolix, and placebo \ngroups, respectively. \nAnother large clinical trial of \nelagolix for the treatment of pelvic pain \ncaused by endometriosis, Elaris EM-II, \ninvolving 817 women, produced \nresults very similar to those reported in \nElaris EM-I. The elagolix continuation \nstudies, Elaris EM-III and -IV , demon-\nstrated efficacy and safety of elagolix \nthrough 12 months of treatment.12  \nIn my 2018 review,10 I noted that \nelagolix dose adjustment can be uti -\nlized to attempt to achieve maximal \npain relief with minimal vasomotor \nsymptoms. Elagolix at 200 mg twice \ndaily produces a mean estradiol \nconcentration of 12 pg/mL, whereas \nelagolix at 150 mg daily resulted in \na mean estradiol concentration of \n41 pg/mL. 13 The estrogen threshold \nhypothesis posits that in women \nwith endometriosis a stable estra -\ndiol concentration of 20 to 30 pg/mL \nis often associated with decreased \npain and fewer vasomotor events. 14 \nTo achieve the target estradiol range \nof 20 to 30 pg/mL, I often initiate \nelagolix treatment with 200 mg twice \ndaily. This enables a rapid onset of \namenorrhea and a reduction in pel -\nvic pain. Once amenorrhea has been \nachieved and a decrease in pelvic \npain has occurred, I adjust the dose \ndownward to 200 mg twice daily on \neven calendar days of each month \nand 200 mg once daily on odd calen-\ndar days each month. Some women \nwill have continued pain relief and \namenorrhea when the dose is fur -\nther decreased to 200 mg once daily. \nIf bothersome bleeding recurs and/\nor pain symptoms increase in \n\nEDITORIAL\n12  OBG Management  |   April 2021  |   Vol. 33  No. 4  mdedge.com/obgyn\nseverity, the dose can be increased \nto 200 mg twice daily or an alternat -\ning regimen of 200 mg twice daily \nand 200 mg once daily, every 2 days. \nAn alternative to dose adjustment is \nto combine elagolix with NEA, which \ncan reduce the severity of hot flashes \nand reduce bone loss caused by  \nhypoestrogenism.15,16 \nHealth insurers and pharmacy \nbenefits managers may require a prior \nauthorization before approving and \ndispensing elagolix.  The prior autho-\nrization process can be burdensome \nfor clinicians, consuming limited \nhealthcare resources, contributing \nto burnout and frustrating patients.17 \nElagolix is less expensive than depot-\nleuprolide acetate and nafarelin nasal \nspray and somewhat more expensive \nthan a goserelin implant.18,19 \nElagolix is not approved as a \ncontraceptive. In the Elaris EM-I and \n-II trials women were advised to use \n2 forms of contraception, although \npregnancies did occur. There were 6 \npregnancies among 475 women tak -\ning elagolix 150 mg daily and 2 preg -\nnancies among 477 women taking \nelagolix 200 mg twice daily.20 Women \ntaking elagolix should be advised to \nuse a contraceptive, but not an estro-\ngen-progestin contraceptive. \nDo not use opioids to \ntreat chronic pelvic pain \ncaused by endometriosis\nOne of the greatest public health \ntragedies of our era is the opioid \nmisuse epidemic. Hundreds of thou-\nsands of deaths have been caused \nby opioid misuse. The Centers for \nDisease Control and Prevention \nreported that for the 12-month \nperiod ending in May 2020, there \nwere 81,000 opioid-related deaths, \nthe greatest number ever reported in \na 12-month period. 21 Many authori -\nties believe that in the United States \nopioid medications have been over-\nprescribed, contributing to the opi -\noid misuse epidemic. There is little \nevidence that chronic pelvic pain is \noptimally managed by chronic treat-\nment with an opioid. 22,23 Prescribing \nopioids to vulnerable individuals to \ntreat chronic pelvic pain may result \nin opioid dependency and adversely \naffect the patient’s health. It is best \nto pledge not to prescribe an opi -\noid medication for a woman with \nchronic pelvic pain caused by endo -\nmetriosis. In situations when pelvic \npain is difficult to control with hor -\nmonal therapy and nonopioid pain \nmedications, referral to a specialty \npain practice may be warranted.\nPost–conservative \nsurgery hormone \ntreatment reduces pelvic \npain recurrence\nIn a meta-analysis of 14 studies that \nreported on endometriosis recur -\nrence rates following conservative \nsurgery, recurrence (defined as \nrecurrent pelvic pain or an imaging \nstudy showing recurrent endometri -\nosis) was significantly reduced with \nthe use of hormone treatment com -\npared with expectant management \nor placebo treatment. 24 The postop -\nerative relative risk of endometriosis \nrecurrence was reduced by 83% with \nprogestin treatment, 64% with estro -\ngen-progestin contraceptive treat -\nment, and 38% with GnRH analogue \ntreatment. Overall, the number of \npatients that needed to be treated \nto prevent one endometriosis recur -\nrence was 10, assuming a recurrence \nrate of 25% in the placebo treatment \nor expectant management groups. \nFor women with pelvic pain \ncaused by endometriosis who \ndevelop a recurrence of pelvic pain \nwhile on postoperative hormone \ntreatment, it is important for the pre-\nscribing clinician to be flexible and \nconsider changing the hormone regi-\nmen. For example, if a postoperative \npatient is treated with a continuous \nestrogen-progestin contraceptive and \ndevelops recurrent pain, I will stop \nthe contraceptive and initiate treat -\nment with either NEA or elagolix. \nCapitalize on \nopportunities to \nimprove the medical \ncare of women with \nendometriosis\nEarly diagnosis of endometriosis \ncan be facilitated by recognizing that \nthe condition is a common cause of \nmoderate to severe dysmenorrhea. \nIn 5 studies involving 1,187 women, \nthe mean length of time from onset \nof pelvic pain symptoms to diagnosis \nof endometriosis was 8.6 years. 25 If a \nwoman with pelvic pain caused by \nendometriosis has not had sufficient \npain relief with one brand of continu-\nous estrogen-progestin contraceptive, \nit is best not to prescribe an alterna -\ntive brand but rather to switch to a \nprogestin-only treatment or a GnRH \nantagonist. If plan A is not working, \nmove expeditiously to plan B. ●\nCONTINUED FROM PAGE 10\nReferences\n1. Aygestin [package insert]. Barr Laboratories: \nPomona, NY; 2007. \n2. Kaser DJ, Missmer SA, Berry KF , et al. Use of  \nnorethindrone acetate alone for postoperative \nsuppression of endometriosis symptoms. J Pediatr  \nAdolesc Gynecol. 2012;25:105-108.\n3. Muneyyirci-Delale O, Karacan M. Effect of noreth-\nindrone acetate in the treatment of symptomatic \nendometriosis. Int J Fertil Womens Med. 1998;43: \nRBARBIERI@MDEDGE.COM\nDr. Barbieri reports no financial rela-\ntionships relevant to this article.\n\nmdedge.com/obgyn  Vol. 33  No. 4  |   April 2021   |   OBG Management   13\n24-27.\n4. Muneyyirci-Delale O, Anopa J, Charles C, et al. \nMedical management of recurrent endometri-\noma with long-term norethindrone acetate. Int J \nWomen Health. 2012;4:149-154.\n5. Morotti M, Venturini PL, Biscaldi E, et al. Effi-\ncacy and acceptability of long-term norethin-\ndrone acetate for the treatment of rectovaginal \nendometriosis. Eur J Obstet Gynecol Repro Biol. \n2017;213:4-10.\n6. Brady PC, Missmer SA, Laufer MR. Hepatic ade-\nnomas in adolescents and young women with \nendometriosis treated with norethindrone ace-\ntate. J Pediatr Adolesc Gynecol. 2017;30:422-424.\n7. Choudhary NS, Bodh V , Chaudhari S, et al. Nor-\nethisterone related drug induced liver injury: a \nseries of 3 cases. J Clin Exp Hepatol. 2017;7:266-\n268.\n8. Perez-Mera RA, Shields CE. Jaundice associated \nwith norethindrone acetate therapy. N Engl J \nMed. 1962;267:1137-1138.\n9. Camila [package insert]. Mayne Pharma Inc: \nGreenville, NC; 2018. \n10. Barbieri RL. Elagolix: a new treatment for pel-\nvic pain caused by endometriosis. OBG Manag. \n2018;30:10,12-14, 20.\n11. Taylor HS, Giudice LC, Lessey BA, et al. Treatment  \nof endometriosis-associated pain with elago-\nlix, an oral GnRH antagonist. N Engl J Med.  \n2017;377:28-40.\n12. Surrey E, Taylor HS, Giudice L, et al. Long-term \noutcomes of elagolix in women with endome-\ntriosis: results from two extension studies. Obstet \nGynecol. 2018;132:147-160.\n13. Orilissa [package insert]. AbbVie Inc; North Chi-\ncago, IL; 2018. \n14. Barbieri RL. Hormonal treatment of endome-\ntriosis: the estrogen threshold hypothesis. Am J \nObstet Gynecol. 1992;166:740-745.\n15. Hornstein MD, Surrey ES, Weisberg GW, et \nal. Leuprolide acetate depot and hormonal \nadd-back in endometriosis: a 12-month study. \nLupron Add-Back Study Group. Obstet Gynecol. \n1998;91:16-24.\n16. Gallagher JS, Missmer SA, Hornstein MD, et al. \nLong-term effects of gonadotropin-releasing hor-\nmone agonists and add-back in adolescent endo-\nmetriosis. J Pediatr Adolesc Gynecol. 2018;31:376-\n381. \n17. Miller A, Shor R, Waites T , et al. Prior authoriza-\ntion reform for better patient care. J Am Coll Car-\ndiol. 2018;71:1937-1939. \n18. Depot-leuprolide acetate. Good Rx website. \nhttps://www.goodrx.com/. Accessed January 22, \n2021.\n19. Goserelin. Good Rx website. https://www  \n.goodrx.com/. Accessed January 22, 2021\n20. Taylor HS, Giudice LC, Lessey BAet al. Treat -\nment of endometriosis-associated pain with \nelagolix, an oral GnRH antagonist. N Engl J Med. \n2017;377:28-40. \n21. Centers for Disease Control and Prevention. \nOverdose deaths accelerating during COVID-\n19. https://www.cdc.gov/media/releases/2020  \n/p1218-overdose-deaths-covid-19.html. \nReviewed December 18, 2020. Accessed March \n24, 2021. \n22. Till SR, As-Sanie S. 3 cases of chronic pelvic pain \nwith nonsurgical, nonopioid therapies. OBG \nManag. 2018;30:41-48. \n23. Steele A. Opioid use and depression in chronic \npelvic pain. Obstet Gynecol Clin North Am.  \n2014;41:491-501. \n24. Zakhari A, Delpero E, McKeown S, et al. Endo-\nmetriosis recurrence following post-operative \nhormonal suppression: a systematic review and \nmeta-analysis. Hum Reprod Update. 2021;27:96-\n107.\n25. Barbieri RL. Why are there delays in the diagnosis \nof endometriosis? OBG Manag. 2017;29:8, 10-11, \n16.","source_license":"CC0","license_restricted":false}