EDITORIAL

Optimize your treatment of endometriosis by using an FDA-approved hormonal medication For women with endometriosis, if one estrogen-progestin contraceptive results in suboptimal control of pelvic pain, do not prescribe a different brand of the same contraceptive type. In this situation, prescribe one of the US Food and Drug Administration (FDA) approved treatments for pelvic pain caused by endometriosis.

Robert L. Barbieri, MD Chair Emeritus, Department of Obstetrics and Gynecology Interim Chief, Obstetrics Brigham and Women’s Hospital Kate Macy Ladd Distinguished Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School Boston, Massachusetts

omen with endometriosis initially improve with estrogen-pro- decrease in pain symptoms and often present for medical gestin contraceptives, many women improvement in the patient’s quality W care for one or more of the on this medication will eventually of life. following health issues: pelvic pain, report that they have worsening Other FDA-approved options infertility, and/or an adnexal cyst pelvic pain that adversely impacts to treat pelvic pain caused by endo- (endometrioma). For women with their daily activities. Surprisingly, metriosis include depot medroxy- moderate or severe pelvic pain and clinicians often continue to prescribe progesterone acetate injectable laparoscopically diagnosed endo- estrogen-progestin contraceptives suspension, depot leuprolide ace- metriosis, hormone therapy is often even after the patient reports that the tate, goserelin implant, and dan- necessary to achieve maximal long- treatment is not effective, and their azol. I do not routinely prescribe term reduction in pain and optimize pain continues to be bothersome. depot medroxyprogesterone acetate health. I focus on opportunities to Patients benefit when they have because some patients report new optimize hormonal treatment of access to the full range of hormone onset or worsening symptoms of endometriosis in this editorial. treatments that have been approved depression on the medication. I pre- by the FDA for the treatment of mod- scribe depot-leuprolide acetate less erate to severe pelvic pain caused by often than in the past, because many When plan A is endometriosis (TABLE). In the situ- patients report moderate to severe not working, move ation where an estrogen-progestin hypoestrogenic symptoms on this expeditiously to plan B contraceptive is no longer effective medication. In women taking depot- Cyclic or continuous combination at reducing the pelvic pain, I will leuprolide acetate, moderate to estrogen-progestin contraceptives often offer the patient the option severe vasomotor symptoms can be are commonly prescribed to treat of norethindrone acetate (NEA) or improved by prescribing NEA pills, pelvic pain caused by endometriosis. elagolix treatment. My experience is but the alternative of norethindrone Although endometriosis pain may that stopping the estrogen-progestin monotherapy is less expensive. I contraceptive and starting NEA or seldom use goserelin or danazol in doi: 10.12788/obgm.0084 elagolix will result in a significant my practice. The needle required

8 OBG Management | April 2021 | Vol. 33 No. 4 mdedge.com/obgyn TABLE Hormone treatments approved by the FDA to treat moderate to severe pain caused by endometriosis FDA-approved medication Route of administration Dose Relative costa Progestins Norethindrone acetate Oral 5 mg daily $ Medroxyprogesterone acetate Subcutaneous injection 104 mg every 3 months $$ injectable suspension GnRH analogues Nafarelin acetate Intranasal spray One spray twice daily $$$$ Depot-leuprolide acetate Intramuscular injection 3.75 mg monthly $$$$ Goserelin Subcutaneous implant 3.6 mg monthly $$$$ Elagolix Oral 150 mg daily or 200 mg twice daily $$$$ Androgens Danazol Oral 200 mg twice daily $$$

aRelative 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. goodrx.com). Accessed February 19, 2021.

Abbreviations: FDA, US Food and Drug Administration; GnRH, gonadotropin-releasing hormone.

to place the goserelin implant has a explored.2 The initial dose of NEA flashes (8%), depression (6%), scalp diameter of approximately 1.7 mm was 5 mg daily. If the patient did not hair loss (4%), headache (4%), nau- (16 gauge) or 2.1 mm (14 gauge), for achieve a reduction in pelvic pain sea (3%), and deepening of the voice the 3.6 mg and 10 mg doses, respec- and amenorrhea on the NEA dose of (1%). (In this study women could tively. The large diameter of the 5 mg daily, the dose was increased by report more than one side effect.) needle can cause pain and bruising 2.5 mg every 2 weeks, up to a maxi- In another cohort study of at the implant site. As a comparison, mum of 15 mg, until amenorrhea 52 women with pelvic pain and sur- the progestin subdermal implant and/or a decrease in pelvic pain gically confirmed endometriosis, needle is approximately 2.1 mm in was achieved. Ninety-five percent NEA treatment resulted in pain relief diameter. Danazol is associated with of the women in this cohort had in 94% of the women.3 Breakthrough weight gain, and most women prefer previously been treated with an bleeding was a common side effect, to avoid this side effect. estrogen-progestin contraceptive or reported by 58% of participants. a GnRH antagonist and had discon- The investigators concluded that Norethindrone acetate tinued those medications because NEA treatment was a “cost-effective NEA 5 mg daily is approved by the of inadequate control of pelvic pain alternative with relatively mild side FDA to treat endometriosis.1 NEA or because of side effects of the effects in the treatment of symptom- was approved at a time when large medication. atic endometriosis.” A conclusion controlled clinical trials were not In this large cohort, 65% which I endorse. routinely required for a medicine of women reported significant NEA has been reported to effec- to be approved. The data to sup- improvement in pelvic pain, with a tively treat ovarian endometriomas port NEA treatment of pelvic pain median pain score of 5 before treat- and rectovaginal endometriosis.4,5 caused by endometriosis is based ment and 0 following NEA treatment. In a cohort of 18 women who had on cohort studies. In a study of About 55% of the women reported previously had the surgical resec- 194 women, median age 21 years no side effects. The most commonly tion of an ovarian endometriosis cyst with moderate to severe pelvic pain reported side effects were weight and had postoperative recurrence of and surgically proven endometriosis, gain (16%; mean weight gain, 3.1 kg), pelvic pain and ovarian endometrio- the effect of NEA on pelvic pain was acne (10%), mood lability (9%), hot sis, treatment was initiated with an

mdedge.com/obgyn Vol. 33 No. 4 | April 2021 | OBG Management 9 EDITORIAL

escalating NEA regimen.4 Treatment as a contraceptive. However, noreth- groups. Bone density was measured was initiated with NEA 5 mg daily, indrone 0.35 mg daily, also known as at baseline and after 6 months of with the dosage increased every the “mini-pill”, is approved as a pro- treatment. Lumbar bone density 2 weeks by 2.5 mg until amenor- gestin-only contraceptive.9 NEA is changes were -2.61%, -0.32%, and rhea was established. Most women rapidly and completely deacetylated +0.47% and hip femoral neck bone achieved amenorrhea with NEA 5 mg to norethindrone, and the disposi- density changes were -1.89%, -0.39%, daily, and 89% had reduced pelvic tion of oral NEA is indistinguish- and +0.02% in the high-dose elago- pain. The investigators reported com- able from that of norethindrone.1 lix, low-dose elagolix, and placebo plete regression of the endometriosis Since norethindrone 0.35 mg daily groups, respectively. cyst(s) in 74% of the women. In my is approved as a contraceptive, it is Another large clinical trial of experience, NEA does not result in highly likely that NEA 5 mg has con- elagolix for the treatment of pelvic pain complete regression of endometriosis traceptive properties if taken daily. caused by endometriosis, Elaris EM-II, cysts, but it does cause a reduction in involving 817 women, produced cyst diameter and total volume. Elagolix results very similar to those reported in In a retrospective cohort study, Elagolix is FDA approved for the Elaris EM-I. The elagolix continuation 61 women with pelvic pain and rec- treatment of pelvic pain caused by studies, Elaris EM-III and -IV, demon- tovaginal endometriosis had 5 years endometriosis. I reviewed the key strated efficacy and safety of elagolix of treatment with NEA 2.5 mg or studies resulting in FDA approval through 12 months of treatment.12 5.0 mg daily.5 NEA treatment resulted in the November 2018 issue of OBG In my 2018 review,10 I noted that in a decrease in dysmenorrhea, deep Management.10 elagolix dose adjustment can be uti- dyspareunia, and dyschezia. The In the Elaris Endometriosis-I lized to attempt to achieve maximal most common side effects attrib- study, 872 women with endometrio- pain relief with minimal vasomotor uted to NEA treatment were weight sis and pelvic pain were randomly symptoms. Elagolix at 200 mg twice gain (30%), vaginal bleeding (23%), assigned to treatment with 1 of daily produces a mean estradiol decreased libido (11%), headache 2 doses of elagolix (high-dose concentration of 12 pg/mL, whereas (9%), bloating or swelling (8%), [200 mg twice daily] and low-dose elagolix at 150 mg daily resulted in depression (7%), and acne (5%). In [150 mg once daily]) or placebo.11 a mean estradiol concentration of women who had sequential imag- After 3 months of therapy, a clinically 41 pg/mL.13 The estrogen threshold ing studies, NEA treatment resulted meaningful reduction in dysmenor- hypothesis posits that in women in a decrease in rectovaginal lesion rhea pain was reported by 76%, 46%, with endometriosis a stable estra- volume, stable disease volume, or an and 20% of the women in the high- diol concentration of 20 to 30 pg/mL increase in lesion volume in 56%, 32%, dose elagolix, low-dose elagolix, and is often associated with decreased and 12% of the women, respectively. placebo groups, respectively (P<.001 pain and fewer vasomotor events.14 The investigators concluded that for for comparisons of elagolix to pla- To achieve the target estradiol range women with rectovaginal endome- cebo). After 3 months of therapy, a of 20 to 30 pg/mL, I often initiate triosis, NEA treatment is a low-cost clinically meaningful reduction in elagolix treatment with 200 mg twice option for long-term treatment. nonmenstrual pain or decreased or daily. This enables a rapid onset of In my practice, I do not prescribe stable use of rescue analgesics was amenorrhea and a reduction in pel- NEA at doses greater than 5 mg daily. reported by 55%, 50%, and 37% of vic pain. Once amenorrhea has been There are case reports that NEA at the women in the high-dose elago- achieved and a decrease in pelvic a dose of ≥10 mg daily is associated lix, low-dose elagolix, and placebo pain has occurred, I adjust the dose with the development of a hepatic groups, respectively (P<.01 low-dose downward to 200 mg twice daily on adenoma,6 elevated liver transami- elagolix vs placebo and P<.001 high- even calendar days of each month nase concentration,7 and jaundice.8 dose elagolix vs placebo). and 200 mg once daily on odd calen- If NEA 5 mg daily is not effective in Hot flashes that were severe dar days each month. Some women controlling pelvic pain caused by enough to be reported as an adverse will have continued pain relief and endometriosis, I stop the NEA and event by the study participants were amenorrhea when the dose is fur- start a GnRH analogue, most often reported by 42%, 24%, and 7% of ther decreased to 200 mg once daily. elagolix. the women in the high-dose elago- If bothersome bleeding recurs and/ NEA 5 mg is not FDA approved lix, low-dose elagolix, and placebo or pain symptoms increase in

CONTINUED ON PAGE 12

10 OBG Management | April 2021 | Vol. 33 No. 4 mdedge.com/obgyn EDITORIAL

CONTINUED FROM PAGE 10 severity, the dose can be increased were 81,000 opioid-related deaths, rence was 10, assuming a recurrence to 200 mg twice daily or an alternat- the greatest number ever reported in rate of 25% in the placebo treatment ing regimen of 200 mg twice daily a 12-month period.21 Many authori- or expectant management groups. and 200 mg once daily, every 2 days. ties believe that in the United States For women with pelvic pain An alternative to dose adjustment is opioid medications have been over- caused by endometriosis who to combine elagolix with NEA, which prescribed, contributing to the opi- develop a recurrence of pelvic pain can reduce the severity of hot flashes oid misuse epidemic. There is little while on postoperative hormone and reduce bone loss caused by evidence that chronic pelvic pain is treatment, it is important for the pre- hypoestrogenism.15,16 optimally managed by chronic treat- scribing clinician to be flexible and Health insurers and pharmacy ment with an opioid.22,23 Prescribing consider changing the hormone regi- benefits managers may require a prior opioids to vulnerable individuals to men. For example, if a postoperative authorization before approving and treat chronic pelvic pain may result patient is treated with a continuous dispensing elagolix. The prior autho- in opioid dependency and adversely estrogen-progestin contraceptive and rization process can be burdensome affect the patient’s health.It is best develops recurrent pain, I will stop for clinicians, consuming limited to pledge not to prescribe an opi- the contraceptive and initiate treat- healthcare resources, contributing oid medication for a woman with ment with either NEA or elagolix. to burnout and frustrating patients.17 chronic pelvic pain caused by endo- Elagolix is less expensive than depot- metriosis. In situations when pelvic leuprolide acetate and nafarelin nasal pain is difficult to control with hor- Capitalize on spray and somewhat more expensive monal therapy and nonopioid pain opportunities to than a goserelin implant.18,19 medications, referral to a specialty improve the medical Elagolix is not approved as a pain practice may be warranted. care of women with contraceptive. In the Elaris EM-I and endometriosis -II trials women were advised to use Early diagnosis of endometriosis 2 forms of contraception, although Post–conservative can be facilitated by recognizing that pregnancies did occur. There were 6 surgery hormone the condition is a common cause of pregnancies among 475 women tak- treatment reduces pelvic moderate to severe dysmenorrhea. ing elagolix 150 mg daily and 2 preg- pain recurrence In 5 studies involving 1,187 women, nancies among 477 women taking In a meta-analysis of 14 studies that the mean length of time from onset elagolix 200 mg twice daily.20 Women reported on endometriosis recur- of pelvic pain symptoms to diagnosis taking elagolix should be advised to rence rates following conservative of endometriosis was 8.6 years.25 If a use a contraceptive, but not an estro- surgery, recurrence (defined as woman with pelvic pain caused by gen-progestin contraceptive. recurrent pelvic pain or an imaging endometriosis has not had sufficient study showing recurrent endometri- pain relief with one brand of continu- osis) was significantly reduced with ous estrogen-progestin contraceptive, Do not use opioids to the use of hormone treatment com- it is best not to prescribe an alterna- treat chronic pelvic pain pared with expectant management tive brand but rather to switch to a caused by endometriosis or placebo treatment.24 The postop- progestin-only treatment or a GnRH One of the greatest public health erative relative risk of endometriosis antagonist. If plan A is not working, tragedies of our era is the opioid recurrence was reduced by 83% with move expeditiously to plan B. ● misuse epidemic. Hundreds of thou- progestin treatment, 64% with estro- sands of deaths have been caused gen-progestin contraceptive treat- by opioid misuse. The Centers for ment, and 38% with GnRH analogue Disease Control and Prevention treatment. Overall, the number of [email protected] reported that for the 12-month patients that needed to be treated Dr. Barbieri reports no financial rela- period ending in May 2020, there to prevent one endometriosis recur- tionships relevant to this article.

References 1. Aygestin [package insert]. Barr Laboratories: norethindrone acetate alone for postoperative 3. Muneyyirci-Delale O, Karacan M. Effect of noreth- Pomona, NY; 2007. suppression of endometriosis symptoms. J Pediatr indrone acetate in the treatment of symptomatic 2. Kaser DJ, Missmer SA, Berry KF, et al. Use of Adolesc Gynecol. 2012;25:105-108. endometriosis. Int J Fertil Womens Med. 1998;43:

12 OBG Management | April 2021 | Vol. 33 No. 4 mdedge.com/obgyn 24-27. of endometriosis-associated pain with elago- 2021. 4. Muneyyirci-Delale O, Anopa J, Charles C, et al. lix, an oral GnRH antagonist. N Engl J Med. 19. Goserelin. Good Rx website. https://www Medical management of recurrent endometri- 2017;377:28-40. .goodrx.com/. Accessed January 22, 2021 oma with long-term norethindrone acetate. Int J 12. Surrey E, Taylor HS, Giudice L, et al. Long-term 20. Taylor HS, Giudice LC, Lessey BAet al. Treat- Women Health. 2012;4:149-154. outcomes of elagolix in women with endome- ment of endometriosis-associated pain with 5. Morotti M, Venturini PL, Biscaldi E, et al. Effi- triosis: results from two extension studies. Obstet elagolix, an oral GnRH antagonist. N Engl J Med. cacy and acceptability of long-term norethin- Gynecol. 2018;132:147-160. 2017;377:28-40. drone acetate for the treatment of rectovaginal 13. Orilissa [package insert]. AbbVie Inc; North Chi- 21. Centers for Disease Control and Prevention. endometriosis. Eur J Obstet Gynecol Repro Biol. cago, IL; 2018. Overdose deaths accelerating during COVID- 2017;213:4-10. 14. Barbieri RL. Hormonal treatment of endome- 19. https://www.cdc.gov/media/releases/2020 6. Brady PC, Missmer SA, Laufer MR. Hepatic ade- triosis: the estrogen threshold hypothesis. Am J /p1218-overdose-deaths-covid-19.html. nomas in adolescents and young women with Obstet Gynecol. 1992;166:740-745. Reviewed December 18, 2020. Accessed March endometriosis treated with norethindrone ace- 15. Hornstein MD, Surrey ES, Weisberg GW, et 24, 2021. tate. J Pediatr Adolesc Gynecol. 2017;30:422-424. al. Leuprolide acetate depot and hormonal 22. Till SR, As-Sanie S. 3 cases of chronic pelvic pain 7. Choudhary NS, Bodh V, Chaudhari S, et al. Nor- add-back in endometriosis: a 12-month study. with nonsurgical, nonopioid therapies. OBG ethisterone related drug induced liver injury: a Lupron Add-Back Study Group. Obstet Gynecol. Manag. 2018;30:41-48. series of 3 cases. J Clin Exp Hepatol. 2017;7:266- 1998;91:16-24. 23. Steele A. Opioid use and depression in chronic 268. 16. Gallagher JS, Missmer SA, Hornstein MD, et al. pelvic pain. Obstet Gynecol Clin North Am. 8. Perez-Mera RA, Shields CE. Jaundice associated Long-term effects of gonadotropin-releasing hor- 2014;41:491-501. with norethindrone acetate therapy. N Engl J mone agonists and add-back in adolescent endo- 24. Zakhari A, Delpero E, McKeown S, et al. Endo- Med. 1962;267:1137-1138. metriosis. J Pediatr Adolesc Gynecol. 2018;31:376- metriosis recurrence following post-operative 9. Camila [package insert]. Mayne Pharma Inc: 381. hormonal suppression: a systematic review and Greenville, NC; 2018. 17. Miller A, Shor R, Waites T, et al. Prior authoriza- meta-analysis. Hum Reprod Update. 2021;27:96- 10. Barbieri RL. Elagolix: a new treatment for pel- tion reform for better patient care. J Am Coll Car- 107. vic pain caused by endometriosis. OBG Manag. diol. 2018;71:1937-1939. 25. Barbieri RL. Why are there delays in the diagnosis 2018;30:10,12-14, 20. 18. Depot-leuprolide acetate. Good Rx website. of endometriosis? OBG Manag. 2017;29:8, 10-11, 11. Taylor HS, Giudice LC, Lessey BA, et al. Treatment https://www.goodrx.com/. Accessed January 22, 16.

mdedge.com/obgyn Vol. 33 No. 4 | April 2021 | OBG Management 13