Bazedoxifene–Conjugated Estrogens for Treating Endometriosis Endometriosis: Nina S
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Endometriosis: Case Report Bazedoxifene–Conjugated Estrogens Teaching Points for Treating Endometriosis 1. The estrogen receptor (ER) is a definitive down- stream target in endometriosis. As an endometrial ER antagonist, bazedoxifene assures not only block- Valerie A. Flores, MD, ade of estrogen binding, but it also has the ability to Nina S. Stachenfeld, PhD, degrade the receptor. This unique property of baze- and Hugh S. Taylor, MD doxifene blocks estrogen action and makes it an attractive treatment option for endometriosis. 2. Conjugated estrogens paired with bazedoxifene do BACKGROUND: Endometriosis is a gynecologic disorder not require a progestin to block endometrial affecting 6–10% of reproductive-aged women. First-line growth, thus avoiding the side effects associated therapies are progestin-based regimens; however, failure with progestin-based regimens. 08/19/2018 on BhDMf5ePHKbH4TTImqenVGLGjjqParD6K7Nl5tTGGFqgjMmLRmuIlIgbkUbgVXoQ by http://journals.lww.com/greenjournal from Downloaded rates are high, often requiring alternative hormonal agents, each with unfavorable side effects. Bazedoxifene with con- ’ 1 Downloaded that can have a significant effect on patients lives. jugated estrogens is approved for treatment of menopausal Treatment consists of agents that induce atrophy of symptoms, and use in animal studies has demonstrated from regression of endometriotic lesions. As such, it represents endometriotic lesions. There is tremendous need for http://journals.lww.com/greenjournal a potential treatment option for endometriosis. therapies that are effective, have favorable side effect profiles, and can be used long term in women with CASE: A patient with stage III endometriosis referred for symptomatic endometriosis, especially for those not management of dysmenorrhea and cyclic pelvic pain was treated with 20 mg bazedoxifene and 0.45 mg conjugated responding to progestin-based regimens. estrogens daily for more than 6 months. She noted Bazedoxifene with conjugated estrogens is the first Tissue Selective Estrogen Complex approved by by resolution of pelvic pain. There were no abnormal effects BhDMf5ePHKbH4TTImqenVGLGjjqParD6K7Nl5tTGGFqgjMmLRmuIlIgbkUbgVXoQ on hormonal, uterine, or ovarian parameters. the U.S. Food and Drug Administration for treatment of menopausal symptoms.2,3 Bazedoxifene is a selective CONCLUSION: Bazedoxifene with conjugated estro- estrogen receptor modulator (SERM) that, on binding gens may be an effective alternative to traditional to the ER, can exert agonist or antagonist effects. In endometriosis treatment options. – (Obstet Gynecol 2018;132:475–7) menopausal women, bazedoxifene conjugated estro- DOI: 10.1097/AOG.0000000000002739 gens improves hot flushes, vulvovaginal atrophy, and prevents bone loss with no associated adverse effects 3–5 ndometriosis is a debilitating disorder character- on the breast, uterus, or ovary. In eutopic endo- E ized by the growth of endometrial tissue outside metrium from women with endometriosis, we have the uterus.1 Pelvic pain, dyspareunia, and infertility previously demonstrated that cells expressing high are the most common symptoms of endometriosis levels of aromatase responded to bazedoxifene treatment.6 In a murine model of endometriosis, we have demonstrated that administration of bazedox- on 08/19/2018 From the Department of Obstetrics, Gynecology, and Reproductive Sciences and ifene with or without coadministration of conjugated the John B. Pierce Laboratory, Yale School of Medicine, New Haven, Connecticut. estrogens resulted in decreased size of endometrial 7,8 The authors thank Cheryl Leone, MS, for her assistance in blood sample collection implants. Furthermore, there was a uterine ER and data analysis. antagonistic effect in eutopic and ectopic endome- Each author has indicated that he or she has met the journal’s requirements for trium as well as decreased expression and degrada- authorship. tion of ER with treatment of bazedoxifene alone or Received March 31, 2018. Received in revised form May 9, 2018. Accepted May with conjugated estrogens.7,8 Given these findings, 17, 2018. we hypothesized bazedoxifene–conjugated estrogens Corresponding author: Valerie A. Flores, MD, Department of Obstetrics, would function similarly in premenopausal patients Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510; email: [email protected]. with endometriosis. Financial Disclosure CASE The authors did not report any potential conflicts of interest. © 2018 by the American College of Obstetricians and Gynecologists. Published A 36-year-old woman, gravida 0, was referred to our by Wolters Kluwer Health, Inc. All rights reserved. reproductive endocrinology center for management of ISSN: 0029-7844/18 endometriosis-associated pain. Her surgical history VOL. 132, NO. 2, AUGUST 2018 OBSTETRICS & GYNECOLOGY 475 Copyright ª by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. included a laparoscopy with excision of endometriosis and follicular phase, and midluteal phase of the menstrual removal of an endometrioma. Stage III endometriosis was cycle. There were no adverse effects on hormonal parame- documented, and histopathology confirmed the diagnosis ters, uterine, or ovarian morphology. Follicle-stimulating of endometriosis. She had a medical history of psoriatic hormone levels remained nearly constant throughout the arthritis for which she was treated with secukinumab for menstrual cycle, luteinizing hormone levels varied, and joint pain, yet she continued to note ongoing dysmenorrhea estradiol and progesterone levels demonstrated cyclic and cyclic pelvic pain related to endometriosis. She changes (Table 1). Endometrial thickness was never abnor- previously used combined oral contraceptives as well as mal (average thickness 4.2 mm), and no abnormal ovarian high-dose progestin therapy but reported continued pelvic cysts developed. Before starting any hormonal therapy, the pain on these regimens. She was subsequently started on patient reported painful menses lasting 7 days with heavy depot leuprolide acetate (11.25 mg) with norethindrone (5 flow, requiring oxycodone with acetaminophen for pain mg) add-back therapy. Her pelvic pain improved; however, control. Since starting bazedoxifene–conjugated estro- she represented with bothersome hot flushes. Symptomatic gens, she noted decreased flow and duration of menses and control was attempted with alternative add-back regimens: resolution of pelvic pain. Specifically, she noted menses conjugated estrogens with medroxyprogesterone and estra- lasting only 3 days that were light; she never required diol (oral and transdermal) with micronized progesterone; narcotics for dysmenorrhea, and she did not experience however, she noted continued hot flushes and break- breakthrough bleeding. Of note, while on leuprolide ace- through bleeding with associated pain. She also noted tate with add-back therapy, she had noted low libido; how- decreased libido. She was offered bazedoxifene– ever, while taking bazedoxifene–conjugated estrogens, she conjugated estrogens after reviewing potential risks as noted an increased libido. She has continued on this regi- well as the lack of efficacy data using this regimen for men for more than 6 months and reports satisfaction, endometriosis. Given the menopausal dose of estrogen in including normal menstrual cramping without pain. bazedoxifene–conjugated estrogens, she was counseled on the need for barrier contraception. She signed an informed consent form and agreed to publication of this report; the DISCUSSION institutional review board approved of this treatment. Although the etiology of endometriosis remains The patient had discontinued leuprolide acetate and largely unknown, the role of estrogens in the devel- add-back therapy 5 months prior and had resumed cycling opment and growth of endometriosis is well charac- at the time of initiation of bazedoxifene–conjugated estro- terized.1 Women with endometriosis can become gens. Treatment with bazedoxifene–conjugated estrogens, nonresponsive to progestin-based therapy as a result one tablet (20 mg bazedoxifene and 0.45 mg conjugated estrogens) daily, began in the early follicular phase. Serum of progestin resistance or to gonadotropin-releasing hormonal levels, including follicle-stimulating hormone hormone (GnRH) analogs as a result of aromatase 9 (FSH), luteinizing hormone, estradiol, and progesterone, expression in lesions. In addition to the were measured three times in each cycle for the first 2 progesterone-resistant phenotype, progesterone months of therapy. She also underwent transvaginal ultra- receptor gene polymorphisms can also affect risk of sonography to assess endometrial thickness, ovarian vol- endometriosis development. The PROGINS polymor- ume, and ovarian cyst or follicle formation. She phism can affect ligand binding and downstream sig- completed a clinical symptom survey at each clinical visit naling in endometriosis, and individuals with this in which she was asked a series of questions regarding polymorphism are at increased risk of endometri- potential changes in her menstrual cycles, including length, osis.10 With respect to GnRH analogs, decreased flow, menstrual symptoms, and cycle frequency. Blood FSH production resulting from treatment will sup- samples, ultrasonography, symptoms, and potential side ef- fects were assessed during the early follicular phase, late