Current and Emerging Therapies for and Uterine Fibroids What Do You Need to Know? Georgine Lamvu, MD, MPH Professor of Obstetrics and Gynecology University of Central Florida College of Medicine Gynecologic Surgery and Pelvic Pain Specialist Director of the Fellowship in Advanced and Minimally Invasive Gynecologic Surgery Orlando VA Medical Center Chair of the Board, International Pelvic Pain Society Orlando, Florida Disclosures

Georgine Lamvu, MD, MPH, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for AbbVie Inc. and Sola, LLC. Housekeeping Notes

Thank you for taking time out of your busy schedules to attend this virtual CME presentation, jointly provided by the Utah Academy of Family Physicians and PVI, PeerView Institute for Medical Education. We would like to thank AbbVie for making this event possible through the provision of an educational grant supporting this activity. I invite you to follow along on the PDF slides you received. You should have also received a link to the online program evaluation. Evaluation: PeerView.com/Endometriosis-survey Your evaluation of the program is very important in helping us to better meet your current and future medical education needs. We welcome your opinions and comments.

Uterine Fibroids A Common Scenario

• 33-year-old G0 presents with painful menstrual periods and heavy bleeding • Symptoms have worsened over the last 3 years and are causing her to miss work What are her options? • Married; interested in having children What do you recommend? • Negative pregnancy test • Enlarged and moderately tender uterus • Hemoglobin is 9 g/dL • A pelvic ultrasound shows three fibroids measuring 3 to 4 cm Uterine Fibroids1,2

• Detected in up to 80% of women by aged 50 years • 30%-50% of women are symptomatic – Heavy menstrual bleeding (HMB) – Dysmenorrhea – Pelvic pain – Infertility – Obstetric complications – Pelvic pressure – Urgency – Frequency

1. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 2. Donnez J, Dolmans MM. Hum Reprod Update. 2016;22:665-686. Types1

Intramural Submucosal

• Symptoms vary based on number, size, and location • Classified on degree of extension into the myometrium and/or the uterine cavity Subserosal Subserosal Peduncle

1. Donnez J, Dolmans MM. Hum Reprod Update. 2016;22:665-686. Pathophysiology of Fibroids1

• Monoclonal benign tumors resulting from mutations in uterine smooth muscle

– Mutations in meditator complex subunit 12 (MED12) are the most common mutation representing 70% of all uterine fibroids

– High mobility group AT-hook2 (HMGA2) gene mutation

– Collagen type IV alpha 5 chain (COL4A5) gene mutation

– Collagen type IV alpha 6 chain (COL4A6) gene mutation

• Fumarate hydrate (FH) group mutation is an autosomal dominant inherited, and not somatic, mutation associated with cutaneous leiomyomas and an increased risk of uterine and renal cancer

1. Laughlin-Tommaso SK, Stewart EA. Obstet Gynecol. 2018;132:961-971. Risk Factors for Uterine Fibroids1,2

Family Early Race history Age menarche (AA) and genetic (<10 y) factors

Caffeine Nulliparity Obesity Other factors and (ie, high BP) alcohol

1. Donnez J, Dolmans MM. Hum Reprod Update. 2016;22:665-686. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. Differential Diagnosis of Uterine Masses1

Benign Malignant

• Pregnancy • Leiomyosarcoma (myometrial neoplasm) – Intrauterine • Mixed mesodermal tumor – Ectopic • Uterine carcinosarcoma • (epithelial neoplasm)

• Fibroids (leiomyoma) • Endometrial adenocarcinoma • Endometrial polyps • Stromal sarcoma

1. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. Methods for Early Detection of Uterine Fibroids Diagnosis of Uterine Fibroids1-4

Screening Labs Pelvic Examination

• Abnormal bleeding • Pregnancy test • Bimanual evaluation (heavy, irregular) • CBC for pelvic mass • Pelvic pain • TSH /dysmenorrhea • Pap smear bulk symptoms • Pelvic ultrasound (pressure, frequency) • Endometrial biopsy (>40 y • Anemia with abnormal bleeding)

1. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 2. Donnez J, Dolmans MM. Hum Reprod Update. 2016;22:665-686. 3. Stoehr A et al. Arch Gynecol Obstet. 2019;300:1029-1043. 4. Moore KR et al. Fertil Steril. 2014;101:208-214. Diagnosis of Uterine Fibroids: Imaging1,2

Transvaginal Pelvic Ultrasound Magnetic Resonance Imaging • Preferred initial imaging (MRI)

• Evaluates fibroid size Fibroid Uterus and location • Provides information • 90%-99% sensitive on location, size, for detecting fibroids— and distance from the the gold standard Bladder endometrium, as well as • Sonohysterography, vascularization a 3D ultrasound improves • Indicated in women who detection of submucosal are considering surgery fibroids

1. Donnez J, Dolmans MM. Hum Reprod Update. 2016;22:665-686. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. Evaluating Risk for Uterine Malignancy1-3

• No single test accurately differentiates benign from malignant fibroids • ACOG recommends endometrial biopsy (cytology) in women aged >45 years with abnormal bleeding to rule out endometrial cancer or hyperplasia, even if fibroids are present; sensitivity for stromal malignancy (leiomyosarcoma) is low (~38%) • Revised Preoperative Sarcoma Score (rPRESS) evaluates risk factors for sarcoma – Cutoff value >4 points has positive predictive value (93.7%) and <4 points has negative predictive value (92%-94%) Predictors 0 point 2 points 4 points Age, y <49 ≥49 — Serum LDH level <279 — ≥279 Cytologic findings Negative — Positive Total 10 points — —

1. Bansal N et al. Gynecol Oncol. 2008;110:43-48. 2. ACOG Committee Opinion No. 557. Obstet Gynecol. 2013;121:891-896. 3. Nagai T et al. Springerplus. 2015;4:520. Evidence-Based Therapies for Managing Uterine Fibroids Medical, Interventional Nonsurgical, and Surgical Therapies for Uterine Fibroids1,2

Interventional Medical Surgical nonsurgical

• NSAIDs • Uterine artery • Myomectomy • Hormonal embolization • Hysterectomy contraceptives • Endometrial ablation • LNG-IUD • Myolysisa • Tranexamic acid • GnRH agonists • GnRH antagonists • SPRMs/SERMsa

Effective in reduction of HMB and dysmenorrhea Effective in reducing fibroid/uterine size a Not routinely available or currently under investigation. 1. Stewart E. N Engl J Med. 2015;372:1646-1655. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107.

. Management of HMB Associated With Fibroids1

Most effective

LNG-IUD Least effective CHCs, progestins, tranexamic acid NSAIDs

1. Stewart E. N Engl J Med. 2015;372:1646-1655. First-Line Medical Therapies1-3

NSAIDS Combination E+P, hormonal Tranexamic acida (Prostaglandin LNG-IUDa contraceptives, (Antifibrinolytic) inhibitor) and progestins 70% reduction 90% reduction <50% reduction 50% reduction in HMB; in HMB; in HMB; in HMB; dysmenorrhea; dysmenorrhea; dysmenorrhea; reversible effect reversible effect reversible effect no effect on fertility on fertility on fertility on fertility GI AEs, no reduction in fibroid GI-related AEs, size; risk of No reduction Minimal reduction no reduction thrombosis if used in fibroid size in fibroid size in fibroid size with COCs or in smokers aged >35 years a FDA-approved for management of HMB. 1. Maybin JA, Critchley H. Womens Health (Lond). 2016;12:27-34. 2 Stewart E. N Engl J Med. 2015;372:1646-1655. 3. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. RCT of LNG-IUD vs Low-Dose COCs1

Treatment Failure Rates • Reduction in monthly blood loss at 12 months: – LNG-IUD 90.9% ± 12.8% vs COC 13.4% ± 11.1% (P < .001) • No significant difference in reduction in fibroid size at 12 months • <12% IUD expulsion rates in women with fibroids

1. Sayed GH et. al. Int J Gynaecol Obstetr, 2011;112:126-130. Hormonal Management of HMB1-3

Bleeding may become more irregular in the first 3 months (especially with oral progestins)

Consistent 50%-60% reduction in blood loss occurs after 3-6 months of use Clinical pearls Continuous suppression is recommended in cases of dysmenorrhea and HMB

LNG-IUD showed a 90% reduction in menstrual blood loss and 20% complete amenorrhea after 9-12 months of use

1. Maybin JA, Critchley H. Womens Health (Lond). 2016;12:27-34. 2. Damm T et al. Contraception. 2019;1:100002. 3. Sergison JE et al. Am J Obstet Gynecol. 2019;220:440-448. Second-Line Medical Therapies1-7

GnRH GnRH SPRMs, SERMs, and antagonists agonists aromatase inhibitors

Reduces blood loss Reduce blood loss Reduce blood loss and dysmenorrhea; and dysmenorrhea; and dysmenorrhea; reversible effect reversible effect reversible effect on fertility on fertility on fertility

Initial increase in bleeding (flare Vasomotor symptoms Limited use, effect); vasomotor and bone density loss investigational symptoms; bone density loss

1. Maybin JA, Critchley H. Womens Health (Lond). 2016;12:27-34. 2. Stewart E. N Engl J Med. 2015;372:1646-1655. 3. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 4. Stewart EA et al. Nat Rev Dis Primers. 2016;2:16043. 5. Sohn GS et al. Obstet Gynecol Sci. 2018;61:192-201. 6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213388s000lbl.pdf. 7. Kumar P, Sharma A. J Hum Reprod Sci. 2014;7:170-174. Mechanism of GnRH Modulators1-3

Hypothalamus GnRH agonists GnRH • Initial overstimulation of GnRH receptors leading to an increase in LH/FSH (flare effect) Pituitary • Chronic administration eventually leads to suppression of LH/FSH and LH/FSH and progesterone

GnRH antagonists Ovaries • Immediately block release with rapid suppression of LH/FSH and estrogen and progesterone

Estrogen and progesterone 1. Maybin JA, Critchley H. Womens Health (Lond). 2016;12:27-34. 2. Sohn GS et al. Obstet Gynecol Sci. 2018;61:192-201. 3. Homburg R. In: von Dadelszen P, ed. The Global Library of Women’s Medicine. 2014. https://www.glowm.com/section_view/heading/the-mechanism-of-ovulation/item/289. Common GnRH Modulators1-3

GnRH Agonists GnRH Agonists • ~90% reduction in blood loss and improved • Leuprolide acetatea hemoglobin (Lupron Depot) • Reduction in fibroid size (~30%) • acetate (Synarel) • Effects are reversed if GnRH agonist is • acetate (Zoladex) stopped • Approved for short-term use GnRH Antagonists • Adding back progestin therapy is recommended • Elagolixb (Orilissa) • Adverse events • with add-back therapyc – Vasomotor symptoms (Oriahnn) – Loss of bone density • Relugolixd (Relumina)4 – Fibroid degeneration a FDA approved leuprolide acetate for the short term (up to 3 months). b FDA approved elagolix for management of endometriosis-related pain. c FDA approved elagolix with add-back therapy for the management of HMB associated with uterine fibroids in premenopausal women (up to 24 months). d Investigational use in trials, not yet FDA approved. 1. Maybin JA, Critchley H. Womens Health (Lond). 2016;12:27-34. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 3. https://www.accessdata.fda.gov/scripts/cder/daf/. 4. https://clinicaltrials.gov/. ELARIS UF-1 and ELARIS UF-2: Elagolix for HMB1,2

Patients Who Reached the Endpoint • Double-blind, randomized, placebo- of Decreased Bleeding After 6 Months, % controlled, 6-month, phase 3 trials – Two identical trials comparing placebo vs elagolix (300 mg BID) vs elagolix with E+P add-back therapy  ELARIS UF-1 N = 412  ELARIS UF-2 N = 378 • Primary endpoint: menstrual blood loss <80 mL and ≥50% reduction from baseline – On average, women had ~200 mL ELARIS UF-1 ELARIS UF-2 blood loss at baseline Elagolix Elagolix Elagolix Elagolix PBO Add-Back PBO Alone Alone Add-Back • 68%-77% of women in treatment group Therapy Difference from placebo, 75.4 59.8 66.4 66.0 — — reached the primary endpoint vs 10% % (95% CI) (66.2-84.6) (51.1-68.5) (55.5-77.3) (57.1-75.0) 9.7 7.9 7.1 7.2 of placebo group (P < .001) Risk ratio (95% CI) — — (5.0-18.9) (4.1-15.5) (3.8-13.4) (3.9-13.5) Two-sided P — — <.001 — — <.001 • Elagolix was FDA-approved elagolix HMB Patients, n 102 104 206 94 95 189 Imputed by multiple 8 3 16 6 11 12 and uterine fibroids in May 2020 imputation, n

1. Schlaff WD et al. N Engl J Med. 2020;382:328-340. 2. https://www.accessdata.fda.gov/scripts/cder/daf/. ELARIS UF-EXTEND Study1,2

• Initial ELARIS UF-1 and UF-2 trials Mean Percent Change From Baseline were extended (12 months total) in Menstrual Blood Loss by Month in Women Treated With Elagolix for Up to 12 Months3 • Patients on placebo were rerandomized to elagolix 300 mg twice daily with or without add-backa • At 12 months, 72%-88% of women on elagolix without and with add-back therapy continued to report reduced blood flow • Most frequent AEs: hot flush, night sweats, nausea, headache, nasopharyngitis, bone density loss (lowest with elagolix with add-back therapy than elagolix alone)

a 1.0 mg/norethindrone acetate 0.5 mg. 1. Lamb YN. Drugs. 2018;78:1501-1508. 2. https://clinicaltrials.gov/ct2/show/NCT02925494. 3. Simon JA et al. Obstet Gynecol. 2020;135:1313-1326. Mechanism of Action of GnRH Agonist vs SPRM1

Direct action on the pituitary; including down regulation GnRH and desensitization or blockage of the GnRH receptor Pituitary agonist producing a hypoestrogenic state with consequent reduction in estradiol

Direct action on the pituitary; inducing amenorrhea Pituitary by inhibiting ovulation and maintaining midfollicular phase levels of estradiol

SPRM Endometrium Direct effect on the endometrium; stops uterine bleeding and induces changes in endometrial tissue Fibroids Direct action on fibroids; inhibition of cell proliferation and induction of apoptosis resulting in reduction of fibroid size

1. Donnez J, Dolmans MM. Hum Reprod Update. 2016;22:665-686. Investigational Therapies1,2

SPRMs SERMs (eg, mifepristone, ulipristal) (eg, , raloxifene) Aromatase Inhibitors

• Reduces menstrual bleeding • Reduces bleeding • Insufficient evidence and may induce amenorrhea • Significant AEs to recommend in treatment • No hypoestrogenic AEs • Insufficient evidence of fibroids • Minimal reduction in fibroid to recommend in treatment size of fibroids • Treatment limited to 3 months • AEs: breast tenderness, headache, liver damagea

a Liver damage associated with ulipristal.3,4 1. Sohn GS et al. Obstet Gynecol Sci. 2018;61:192-201. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 3. Rozenberg S et al. Eur J Obstet Gynecol Reprod Biol. 2020;252:300-302. 4. Kang S et al. Drug Saf. 2020 Jul 9 [Epub ahead of print]. Interventional Fibroid Therapies: Uterine Fibroid Embolization1,2

• Performed by interventional radiology • Occluding agents injected into the uterine arteries • Requires overnight admission for pain control • Compared with hysterectomy: less time to return to normal activities • Reoperation rate of 20%-30% within 1.5-5 years • Insufficient evidence on how it affects fertility—may be associated with a higher rate of pregnancy complications (eg, miscarriage)

1. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 2. Khan AT et al. Int J Womens Health. 2014;6:95-114. Interventional Fibroid Therapies: Myolysis1

• Targeted destruction of fibroids using focused energy such as heat, laser, or MRgFUS • Less invasive than a hysterectomy • Reoperation rate 59% • Insufficient evidence on pregnancy outcomes

1. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. Surgical Management of Fibroids1,2

Myomectomy Hysterectomy Hysteroscopic (Laparoscopic, robotic, (Laparoscopic, robotic, myomectomy or abdominal) or abdominal) • Best for submucosal • Best for intramural • Definitive treatment fibroids or subserosal fibroids for HMB and fibroids • Reduces HMB • Reduces HMB • Permanent sterility • Fertility sparing and uterine size • Limited effect in large • Fertility sparing uteri (>4 fibroids) • Limited effect in large uteri with multiple small fibroids

1. Mas A et. al. Int J Womens Health. 2017;9:607-617. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. UFE vs Myomectomy vs Hysterectomy1

>80% Symptom relief 50% 100% Reduction in uterine/ fibroid size 50% Hysterectomy Myomectomy UFE

Need for reoperation 15% or additional 30% treatment <26% within 2 years Complications 17%

1. Keung JJ et al. Best Pract Res Clin Obstet Gynaecol. 2018;46:66-73. Best Practice Guidelines for Managing Uterine Fibroids Management Options for Women With Uterine Fibroids1

Medical Options Surgical Options Symptomatic bleeding and pain • Hysterectomy • Oral contraceptives Options for uterine • Laparoscopic • : oral, IUD fibroid management myomectomy • NSAIDs • Hysteroscopic • Tranexamic acid myomectomy • Others Etiologic treatment • GnRH agonists/antagonists Nonsurgical Options • SPRMs • Uterine artery embolization • Fibroid ablation (RF/MRgFUS)

1. Mas A et. al. Int J Womens Health. 2017;9:607-617. Selection of Therapy1

Depends on severity of symptoms and

Patient age Desire to preserve Fibroid (pre- or perimenopausal) uterus and/or fertility location and size

1. Mas A et. al. Int J Womens Health. 2017;9:607-617. Management of Uterine Fibroids1-4

Asymptomatic Symptomatic

• Desires to preserve uterus/fertility • Does not wish to preserve • Medical therapya uterus/fertility or failed uterine – NSAIDS preserving therapies – Tranexamic acid – UFE No intervention – CHCs – Myolysis – LNG-IUD – Endometrial – GnRH agonist/antagonist ablationa • Surgical therapy – Hysterectomy – Myomectomy

a Not effective for reducing bulk symptoms. 1. Maybin JA, Critchley H. Womens Health (Lond). 2016;12:27-34. 2. De La Cruz MSD, Buchanan EM. Am Fam Physician. 2017;95:100-107. 3. Simon JA et al. Obstet Gynecol. 2020;135:1313-1326. 4. Stewart E. N Engl J Med. 2015;372:1646-1655. Many options are available: A Common Scenario NSAIDS • 33-year-old G0 presents with painful menstrual periods and heavy bleeding CHCs Progestin • Symptoms have worsened over the last 3 years and are causing her to miss work TXA • Married; interested in having children LNG-IUD GnRH agonist/antagonist • Negative pregnancy test Hysteroscopy • Enlarged and moderately tender uterus (if submucosal fibroid) • Hemoglobin is 9 g/dL Myomectomy • A pelvic ultrasound shows three fibroids measuring 3 to 4 cm

Endometriosis Endometriosis1

Presence of endometrial-like tissue in aberrant locations outside the uterus

1. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline. Pathophysiology and Epidemiology1-5

• Estrogen stimulates lesion growth, inflammation, and pain

• 6%-10% of women of reproductive age in the United States have endometriosis

• On average, women experience pain for ~6-10 years

• 55% of women see three or more doctors before the diagnosis is made

1. Burney RO, Giudice LC. Fertil Steril. 2012;98:511-519. 2. Fuldeore MJ, Soliman A. Gynecol Obstet Invest. 2017;82:453-461. 3. Mowers EL et al. Obstet Gynecol. 2016;127:1045-1053. 4. Green R et al. Fertil Steril. 2009;91:32-39. 5. Zondervan KT et al. N Engl J Med. 2020;382:1244-1256. Mechanisms of Pain in Endometriosis1

Chronic

Chronic pelvic pain • Chronic inflammation characterized by systemic and local cytokines and growth factors resulting in pain • Long-term exposure to these pro-inflammatory substances can lead to peripheral and central sensitization, hyperalgesia, and chronic pain

1. Falcone T, Flyckt R. Obstet Gynecol. 2018;131:557-571. Variable Presentation of Endometriosisa

• No noninvasive tests available that can make a definitive diagnosis1 – Clinical evaluation can be used to initiate medical therapy, but laparoscopic diagnosis is the gold standard— appearance may vary though2-4 • Stage of disease does not correlate well with severity of pain1 • Other conditions may present with similar symptoms (dysmenorrhea, fibroids); 20% have other comorbidities (IBS, IC/BPS)3,4 • Patients may present with pain and no obvious pathology on laparoscopic examination1,5 a Image courtesy of Professor Phillipe Koninckx. 1. Rogers PA et al. Reprod Sci. 2009;16:335-346. 2. Acién P, Velasco I. ISRN Obstet Gynecol. 2013:242149. 3. Mao AJ, Anastasi JK. J Am Acad Nurse Pract. 2010;22:109-116. 4. Hsu AL et al. Clin Obstet Gynecol. 2010;53:413-419. 5. Walter AJ et al. Am J Obstet Gynecol. 2001;184:1407-1411. Methods for Detecting Endometriosis Symptoms of Endometriosis1-3

• Primary symptoms – Pain and infertility • Symptoms are more common in • Other common symptoms younger women (aged 18-29 years) – Painful menstrual cramps – 73% dysmenorrhea – Pain during/after sex – 57% noncyclical pelvic pain – Pain in the intestine or lower – 43% dyspareunia abdomen • In women of reproductive age, the triad – Painful bowel movements or of dysmenorrhea, noncyclic pelvic pain, urination during menstrual periods and dyspareunia (as well as infertility) should trigger an evaluation for – Heavy menstrual periods endometriosis to prevent delay in – Premenstrual spotting or bleeding diagnosis between periods

1. Fuldeore MJ, Soliman A. Gynecol Obstet Invest. 2017;82:453-461. 2. Mowers EL et al. Obstet Gynecol. 2016;127:1045-1053. 3. https://www.nichd.nih.gov/health/topics/endometri/conditioninfo/symptoms. Diagnosis1-3

• Patient history – Biopsychosocial evaluation: pain domains; affect on QOL – Key symptoms: dysmenorrhea, CPP, dyspareunia, infertility • Physical examination – Mood and affect (depression, anxiety, catastrophizing, rumination, poor coping) – Musculoskeletal (low back, abdomen, scars, trigger points, myalgias, neuralgia, hypersensitivity, allodynia) – Single-digit vaginal (myalgias, trigger points, nodularity, uterosacral tenderness, cervical tenderness, rectovaginal tenderness or masses, adnexal masses) – Speculum (cervical tenderness, posterior fornix nodules or masses)

1. Fuldeore MJ, Soliman A. Gynecol Obstet Invest. 2017;82:453-461. 2. Mowers EL et al. Obstet Gynecol. 2016;127:1045-1053. 3. Allaire C et al. J Endometr Pelvic Pain Disord. 2017;9:77-86. Endometriosis Diagnostic Testing1,2

• Transvaginal ultrasound: large lesions, including ovarian endometriomas, but not smaller implants or adhesions • MRI: deeply invasive endometriosis (eg, bowel, bladder) • Serum markers (CA-125, cytokines, MCP1, adhesion molecules): nonspecific Ovarian endometrioma • Consider CBC if concomitant anemia; urinalysis, pregnancy and STI testing if indicated Laparoscopy with pathologic confirmation; the goal of surgical intervention is diagnosis and excision

1. American College of Obstetricians and Gynecologists Practice Bulletin No. 218. Obstet Gynecol. 2020;135:e98-e109. 2. Seeber B et al. Fertil Steril. 2008;89:1073-1081. Treatment Recommendations for Endometriosis1-5

ACOG, ASRM, NICE, and ESHRE all endorse empiric medical therapy before definitive surgical diagnosis; however, they acknowledge that response to empiric therapy does not confirm the diagnosis of endometriosis, as there are other conditions that are not endometriosis that cause pelvic pain responsive to hormonal suppression

For patients who do not respond to initial medical therapy, surgery with staging and pathologic confirmation is highly recommended

1. Kuznetsof L et al. BMJ. 2017;358. 2. https://www.nice.org.uk/guidance/ng73/chapter/Recommendations. 3. ACOG Practice Bulletin No. 114. Obstet Gynecol. 2010;116:223-236. 4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2014;101:927-935. 5. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx. Evidence-Based Strategies for Managing Endometriosis Integrative Therapies for Pain Associated With Endometriosis1

Education and stress management

Activity and exercisea

Suppression of menstrual cycle

Surgery to remove lesions

Hysterectomy

a Evidence on the effect of exercise for endometriosis is limited. 1. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline. FDA-Approved Pharmacotherapy for Endometriosis (Suppression of Menstruation)1

Year Treatment Type Approved

Norethindrone (Aygestin)a Synthetic progestin 2005

Medroxyprogesterone acetate (Dep SubQ Provera 104) Progestin 2005

Leuprolide acetate (Lupron Depot) GnRH agonist 1999 Nafarelin acetate (Synarel) GnRH agonist 1990 Goserelin acetate (Zoladex) GnRH agonist 1989

Danazol () Synthetic 1971

Elagolix (Orlissa) GnRH antagonist 2018

Relugolix and linzagolix are not FDA-approved therapies and currently being studied a Aygestin has been discontinued. 1. https://www.accessdata.fda.gov/scripts/cder/daf/. Medical Management Options for Treatment of Endometriosis-Associated Symptoms (Pain and Bleeding)1-4

Continuous regimens preferred over cyclic NSAIDs Progestins COCs1-3 regimens for management of pain

GnRH GnRH Aromatase LNG-IUD agonists antagonists inhibitors

1 Casper R. Fertil Steril. 2017;107:533-536. 2. Jensen J et al. Fertil Steril. 2018;110:137-152. 3. Damm T et al. Contracept X. 2019;1:100002. 4. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline. LNG-IUD for Symptomatic Endometriosis Following Surgery1 Comparison 1 Postoperative Use of LNG-IUD Compared With No Postoperative Treatment in Women With Endometriosis, Outcome 1 Painful Symptoms

Comparison 1 Postoperative Use of LNG-IUD Compared With No Postoperative Treatment in Women With Endometriosis, Outcome 2 Painful Symptoms

1. Abou-Setta AM et al. Cochrane Database Syst Rev. 2013:CD005072 GnRH Antagonist: Elagolix1,2

Reduction of Dysmenorrhea and Nonmenstrual Pelvic Pain

• Double-blind, RCT; elagolix vs placebo • Various doses of elagolix (150 mg QD and 200 mg BID) • Primary endpoint: clinically meaningful reduction in pain • 872 patients randomized and followed over 6 months • Trial extended for additional 12 months • FDA approved for 24 months of use • AEs: hot flushes and mild bone density loss

1. Taylor HS et al. N Engl J Med. 2017;377:28-40. 2. https://www.accessdata.fda.gov/scripts/cder/daf/. Best Practice Guidelines for Managing Endometriosis Selection of Therapy1

Depends on

Presence Desire Patient of pain or to preserve AEs Efficacy Cost preference infertility, fertility or both

1. Zito G et al. Biomed Res Int. 2014:191967. Therapy Options for Endometriosis1-7

Aromatase inhibitors GnRH modulators LNG-IUD NSAIDS, progestins, COCs, tranexamic If no response, consider conservative Hysterectomy acid surgery with post-surgery suppression (+/- BSO)

Fertility is preserved Infertility

1. Kuznetsof L et al. BMJ. 2017;358. 2. ACOG Practice Bulletin No. 114. Obstet Gynecol. 2010;116:223-236. 3. https://www.eshre.eu/Guidelines-and- Legal/Guidelines/Endometriosis-guideline. 4. Hirsch M et al. BJOG. 2018;125:556-564. 5. Fuldeore MJ, Soliman A. Gynecol Obstet Invest. 2017;82:453-461. 6. Zondervan KT et al. Nat Rev Dis Primers. 2018;4:9. 7. Zondervan KT et al. N Engl J Med. 2020;382:1244-1256. Evidence on Endometriosis-Associated Chronic Pelvic Pain

• All treatments, except hysterectomy, are considered suppressive rather than curative; endometriosis is a chronic disease requiring sustained treatment and suppression of menstruation1-3

• Can have significant physical, sexual, psychological, and social effects requiring long-term treatment1-5 – Biopsychosocial evaluation6 ACOG bull #114, 2010; ACOG bull #110, 2010. • Progestins are preferred to COCs, and continuous suppression of menstruation is preferred over cyclic7,8

1. https://www.nice.org.uk/guidance/ng73/chapter/Recommendations. 2. https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline. 3. Abou-Setta AM et al. Cochrane Database Syst Rev. 2013;31:CD00572. 4. Falcone T, Flyckt R. Obstet Gynecol. 2018;131:557-571. 5. Vercellini P et al. Hum Reprod Update. 2009;15:177-188. 6. Allaire C et al. J Endometr Pelvic Pain Disord. 2017;9:77-86 7. Seracchioli R et al. Fertil Steril. 2010;94:856-861. 8. Muzii L et al. Am J Obstet Gynecol. 2016;214:203-211. Clinical Guidelines for Managing Patients With Endometriosis-Associated Chronic Pelvic Pain1-3

• Conservative surgery (laparoscopy or excision) can provide effective pain relief; however, up to 40% of patients do not respond – Recurrence rates are high; 15%-50% have recurrent pain or reoperation within 2 years – Medical suppression with progestins, LNG-IUD or combination contraceptives may delay recurrence of pain after conservative surgery • Hysterectomy is beneficial forACOG pain bull relief; #114, 2010;however, ACOG ovarianbull #110, preservation2010. is recommended in women aged <40 years as oophorectomy is associated with severe menopausal symptoms and increased all-cause mortality • In women who have undergone oophorectomy, HRT use should not be delayed; progestins and combination estrogen/progestin regimens can be used

1. Falcone T, Flyckt R. Obstet Gynecol. 2018;131:557-571. 2. Vercellini P et al. Hum Reprod Update. 2009;15:177-188. 3. Hickman TN et al. Obstet Gynecol. 1998;91:673-677. Conclusions

Uterine fibroids and endometriosis are common conditions that can have significantly negative effects on women’s lives

Both conditions have many medical and surgical treatment options

For all therapies, the management of heavy menstrual bleeding, pelvic pain, and desire for fertility are key factors to consider

Patient preferences and shared decision-making should guide individualized treatment selection Audience Q&A Please remember to complete and submit your Post-Test and Evaluation for CME credit.

Missed anything? Visit us at: PeerView.com/ZYV • Download slides and Practice Aids • Watch the online version of this activity • Join the conversation on Twitter @PeerView

Thank you and have a good day. Abbreviations

AA: African American G0: gravada 0 ACOG: American College of Obstetricians and GnRH: gonadotropin-releasing hormone Gynecologists GnRHa: gonadotropin-releasing hormone agonist ASRM: American Society for Reproductive GnRHan: gonadotropin-releasing hormone Medicine antagonist BID: twice daily HRT: hormone replacement therapy BSO: bilateral salpingo-oophorectomy IBS: irritable bowel syndrome CHCs: combined hormonal contraceptives IC/BPS: interstitial cystitis/bladder pain syndrome COC: combination oral contraceptive IUD: intrauterine device CPP: chronic pelvic pain LDH: lactate dehydrogenase E+P: estrogen and progesterone LH: ESHRE: European Society of Human LNG-IUD: levonorgestrel intrauterine device Reproduction and Embryology MRI: magnetic resonance imaging FSH: follicle-stimulating hormone Abbreviations

NICE: National Institute for Health and Care Excellence QD: once daily RCT: randomized controlled trial RF: radiofrequency SERMs: selective estrogen receptor modulators SPRMS: selective progesterone receptor modulator TSH: thyroid-stimulating hormone TXA: tranexamic acid UFE: uterine fibroid embolization