Bazedoxifene–Conjugated Estrogens for Treating Endometriosis Endometriosis: Nina S

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1 475 lives. ’ In eutopic endo- conjugated estro- – 5 – 3 conjugated estrogens Given these findings, – 7,8 Bazedoxifene is a selective 2,3 OBSTETRICS & GYNECOLOGY Furthermore, there was a uterine ER In a murine model of endometriosis, we 6 7,8 stream target inER endometriosis. antagonist, bazedoxifene As assures an notade only of endometrial block- estrogen binding, butdegrade it the also receptor. has This the uniquedoxifene ability property to blocks of baze- estrogenattractive treatment action option and for endometriosis. makes itnot an requiregrowth, thus a avoidingwith progestin progestin-based the regimens. side to effects block associated endometrial Bazedoxifene with conjugated estrogens is the 1. The estrogen receptor (ER) is a definitive down- 2. Conjugated estrogens paired with bazedoxifene do Teaching Points we hypothesized bazedoxifene antagonistic effect intrium eutopic as and well as ectopiction decreased of endome- expression ER and withwith degrada- treatment conjugated of estrogens. bazedoxifene alone or estrogen receptor modulatorto (SERM) that, the on ER,menopausal binding can exert women, agonistgens bazedoxifene or improves antagonist hotprevents effects. flushes, bone vulvovaginal In loss atrophy,on with and the no breast, associated uterus, adverse or effects ovary. metrium from womenpreviously with endometriosis, demonstrated we that have levels cells expressing of high treatment. aromatase responded to bazedoxifene CASE A 36-year-old woman,reproductive gravida endocrinology 0,endometriosis-associated center was for pain. referred management to of Her our surgical history responding to progestin-based regimens. first Tissue Selectivethe Estrogen U.S. Food Complex and Drug approvedmenopausal Administration for by symptoms. treatment of Treatment consists ofendometriotic agents lesions. that There induce istherapies atrophy that tremendous are of need effective, for profiles, have and favorable can sidesymptomatic effect be endometriosis, used long especially term for in those women not with have demonstrated thatifene administration with of or without bazedox- coadministrationestrogens of resulted conjugated inimplants. decreased size of endometrial would function similarly inwith endometriosis. premenopausal patients that can have a significant effect on patients s requirements for ’ he American College of Obstetricians t by ª , MD PhD , Case Report MD Endometriosis is a gynecologic disorder Bazedoxifene with conjugated estro- Copyright Unauthorized reproduction of this article is prohibited. Pelvic pain, dyspareunia, and infertility 1 and Gynecologists. Published by Wolters Kluwer Health, Inc. A patient with stage III endometriosis referred for ized by the growth of endometrial tissue outside ndometriosis is a debilitating disorder character- are the most common symptoms of endometriosis and Hugh S. Taylor, the uterus. VOL. 132, NO. 2, AUGUST 2018 The authors did not report any© potential 2018 conflicts by of theby interest. American Wolters College Kluwer of Health, ObstetriciansISSN: Inc. and 0029-7844/18 All Gynecologists. rights Published reserved. Corresponding author:Gynecology Valerie and A. ReproductiveStreet, Flores, Sciences, New Haven, Yale MD, CT School 06510; Department email:Financial of [email protected]. Disclosure Medicine, of 333 Obstetrics, Cedar authorship. Received March 31, 2018. Received17, in 2018. revised form May 9, 2018. Accepted May Connecticut. The authors thank Cheryl Leone,and MS, for data her analysis. assistance in blood sample collection Each author has indicated that he or she has met the journal From the Department ofthe Obstetrics, Gynecology, John and Reproductive B. Sciences and Pierce Laboratory, Yale School of Medicine, New Haven, DOI: 10.1097/AOG.0000000000002739 E CONCLUSION: gens mayendometriosis be treatment options. an(Obstet Gynecol effective 2018;132:475–7) alternative to traditional estrogens daily forresolution of pelvic more pain. There than wereon no hormonal, abnormal 6 effects uterine, or months. ovarian parameters. She noted CASE: management of dysmenorrhea and cyclictreated pelvic with pain 20 was mg bazedoxifene and 0.45 mg conjugated symptoms, and useregression in of endometriotic animal lesions.a studies As potential has such, treatment it option demonstrated represents for endometriosis. therapies are progestin-basedrates regimens; are however, high, often failure requiringeach alternative with hormonal unfavorable agents, side effects.jugated Bazedoxifene estrogens with is con- approved for treatment of menopausal BACKGROUND: affecting 6–10% of reproductive-aged women. First-line Valerie A. Flores, Bazedoxifene–Conjugated Estrogens for Treating Endometriosis Endometriosis: Nina S. Stachenfeld,

Downloaded from http://journals.lww.com/greenjournal by BhDMf5ePHKbH4TTImqenVGLGjjqParD6K7Nl5tTGGFqgjMmLRmuIlIgbkUbgVXoQ on 08/19/2018 Downloaded from http://journals.lww.com/greenjournal by BhDMf5ePHKbH4TTImqenVGLGjjqParD6K7Nl5tTGGFqgjMmLRmuIlIgbkUbgVXoQ on 08/19/2018 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 effects were assessed during the early follicular phase, late press ovarian estradiol production but will not inhibit local estrogen production by aromatase in endometri- Table 1. Reproductive Hormones otic lesions.1 Aromatase inhibitors can therefore help prevent endometriosis progression by lowering estro- Cycle Phase gen concentrations, but must be given with an oral Early Late contraceptive, progestin, or GnRH analog to prevent Hormone Follicular Follicular Midluteal an increase in FSH and stimulation of follicular development.9,11 Despite suppression of systemic and FSH (milli-international 10 10 7 peripheral estrogen production by existing therapies, units/mL) LH (milli-international 7.5 12 5 endometriotic lesions may still produce sufficient 11 units/mL) amounts of estradiol to promote ectopic growth. Estradiol (pg/mL) 46.5 181 90 The estrogen receptor is a downstream target in endo- Progesterone (ng/mL) 0.05 1 7 metriosis. As an endometrial ER antagonist, bazedox- FSH, follicle-stimulating hormone; LH, luteinizing hormone. ifene assures not only blockade of estrogen action, but

476 Flores et al Bazedoxifene-Conjugated Estrogen Therapy for Endometriosis OBSTETRICS & GYNECOLOGY

Copyright ª by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. it also has the ability to degrade the receptor. This contraception. Although our findings in a single patient unique property of bazedoxifene prevents the possi- are provocative, bazedoxifene–conjugated estrogens for bility of estrogen action and makes bazedoxifene an endometriosis-associated pelvic pain need to be further attractive treatment option. tested to determine the efficacy and safety profile. NotallSERMspairedwithconjugatedestrogens function in the same way. Administration of conjugated REFERENCES estrogens with the SERM raloxifene results in pro- 1. Giudice LC. Clinical practice. Endometriosis. N Engl J Med liferation of the endometrium.12 In a randomized 2010;362:2389–98. placebo-controlled trial using raloxifene for the treatment 2. 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Copyright ª by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.