9/18/18 Cumulative Incidence of Fibroids over Reproductive Lifespan Areas of Future Research RFTS Blacks in Fibroid Therapy Blacks UFS Whites CARDIA Age 33-46 William H. Catherino, MD, PhD Professor and Chair, Research Division Whites Seveso Italy Uniformed Services University Blacks Whites Associate Program Director Sweden/Whites ( Age 33-40) Division of REI, PRAE, NICHD, NIH The views expressed in this article are those of the author(s) and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government. Laughlin Seminars Reprod Med 2010;28: 214 Obstetric Complications of Fibroids Fibroids Increase Miscarriage Rate Complication Fibroid No Fibroid OR Abnormal labor 49.6% 22.6% 2.2 Cesarean Section 46.2% 23.5% 2.0 Preterm delivery 13.8% 10.7% 1.5 Breech position 9.3% 4.0% 1.6 pp Hemorrhage 8.3% 2.9% 2.2 PROM 4.2% 2.5% 1.5 Placenta previa 1.7% 0.7% 2.0 Abruption 1.4% 0.7% 2.3 Guben Reprod Biol Endocrinol 2013;11:102 Odds of miscarriage decreased with no myoma compared to myoma Biderman-Madar Arch Gynecol Obstet 2005;272:218 Ciavattini J Matern Fetal Neonatal Med 2015;28:484-8 Not Impacting the Cavity Coronado Obstet Gynecol 2000;95:764 Kramer Am J Obstet Gynecol 2013;209:449.e1-7 Navid Ayub Med Coll Abbottabad 2012;24:90 Sheiner J Reprod Med 2004;49:182 OR = 0.737 [0.647, 0.840] Stout Obstet Gynecol 2010;116:1056 Qidwai Obstet Gynecol 2006;107:376 1
9/18/18 Best Studied Therapies Hysterectomy Option over Time Surgical Radiologic Medical >100 years of study Hysterectomy Open myomectomy G n R H a g o n is ts 25-34 years of study Endometrial Ablation GnRH agonists 20-24 years of study Laparoscopic myomectomy Uterine artery embolization Retinoic acid 10-19 years of study Uterine artery obstruction SPRMs: Mifepristone, ulipristal Robotic myomectomy GnRH antagonists 5-9 years of study Cryomyolysis MRI-guided high frequency ultrasound SPRMs: Asoprisnil, Telapristone, Laparoscopic ablation Vilaprisan SERMs: Tamoxifen, Raloxifene, Letrozole, Genistein Pitter MC, Simmonds C, Seshadri-Kreaden U, Hubert HB. J Jacoby VLObstet Gynecol 2009;114:1041-8 2011 2012 2013 2014 2015 2016 2017 2018 Elagolix Vilaprisan Vilaprisan Vilaprisan Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Cetrorelix Cetrorelix Cetrorelix Cetrorelix Cetrorelix Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid ECGC ECGC ECGC Berberine Berberine Tranilast Halofuginone Halofuginone Halofuginone >100 pubs Medical Therapy Levonorgestrel Levonorgestrel Levonorgestrel Levonorgestrel Levonorgestrel 70-99 pubs Triptorelin Triptorelin Triptorelin Triptorelin Triptorelin 10-69 pubs Letrozole Letrozole Letrozole Letrozole 1-9 pubs AG1478 AG1478 Last Pub Simvastatin Tamoxifen 2001 Goserelin Goserelin Goserelin Goserelin Targretin 2004 Raloxifene Raloxifene Raloxifene Raloxifene Pioglitazone 2005 Tibolone Tibolone Tibolone Tibolone Resveratrol 2005 Asoprisnil Asoprisnil Asoprisnil Asoprisnil E. alatus 2006 Liarozole Liarozole TKS050 2007 Celecoxib Celecoxib Ciglitazone 2007 Telapristone Telapristone Telepristone Isoliquiritigenin 2008 Lynesterol Lynesterol Curcumin 2011 Methoxyestradiol Methoxyestradiol Fulvestrant 2011 Buserelin Buserelin Perfenidone 2011 CDB-4124 2011 2
9/18/18 Leuprolide Acetate Visual Analog Scale: 1-10, patient reported GnRH Analogues Palomba Fertil Steril 1998;70:111 Elagolix Selective Progesterone Receptor Modulators Archer Fertil Steril 2017;108:152 3
9/18/18 Chemical Structures: Selective Progesterone Receptor Modulators (SPRMs) How do sPRMs work? CH 3 O O O O N S S F F H 3 C F F F F OCH 3 H OH OH F F OCCH 3 F F O CH 3 N H 3 C OH O O O O C C CH 3 Ulipristal Vilaprisan CH 3 OCH 3 HO N N O O H 3 C OCH 2 CH 3 Mifepristone OCH 3 CH 2 OCH 3 Progesterone O O Telapristone Asoprisnil Bouchard Fertil Steril 2011;96:1175 Mifepristone Clinical efficacy of each SPRM for fibroid N = 14 treatment Age: 40.8 BMI: 25.9 Decrease in fibroid size: 28% Engman Hum Reprod 2009; 4
9/18/18 PEARL I: Asoprisnil Ulipristal Controls bleeding faster than Placebo Uterine Volume Bleeding Suppression Donnez NEJM 2012;366: Donnez N Engl J Med 2012;366:409 Chwalisz Fertil Steril 2007;87:1399 PEARL II: Vilaprisan: Optimal Dose Ulipristal Controls Bleeding Faster approximately 1-2 mg to induce than Leuprolide Acetate Non-Bleeding Event Donnez NEJM 2012;366:421-32 Donnez N Engl J Med 2012;366:421 Schütt Hum Reprod 2016;31:1703 5
9/18/18 Vilaprisan: 1-2 mg decreases mean number of Bleeding Days Potential Future Therapies Schütt Hum Reprod 2016;31:1703 Simvastatin Retinoic Acid • hmg-CoA • Differentiating inhibitor agent • Hyperlipidemia • Relatively toxic therapy • Compounds that • Antitumor increase properties intracellular retinoic acid available for study Catherino WH, Malik M. Fertil Steril 2007;87:1388 Borahay J Biol Chem 2014;289:35075 Ben-Sasson Fertil Steril 2011;95:2080 Borahay Am J Obstet Gynecol 2015;213:196.e1-8 Gilden Fertil Steril 2012;98:1557 6
9/18/18 Vitamin D Green Tea Extract • Has • High therapeutic antiproliferative index and apoptotic • Consumption function associated with • Vit D depletion lower cancer associated with incidence high risk of fibroids Halder Biol Reprod 2012;86:116 Zhang Am J Obstet Gynecol 2010;202:289 Halder Biol Reprod 2013;89:150 Roshdy Int J Womens Health 2013;5:477 Berberine Tranilast • Chinese herb • Anti-allergic • Anti-inflammatory • Inhibits mast cell degranulation • Used to treat chronic • Inhibits release of inflammatory inflammatory conditions mediators • Prevents keloid tumor formation Chuang Reprod Sci 2017;24:1005 Wu Fertil Steril 2015;103:1098 Islam Fertil Steril 2014;102:597 7
9/18/18 Cabergoline / Aromatase Inhibitor Summary Bef ore 50 0 • Dopamine Afte r receptor agonist • There is an increasing interest in moving from surgical • Combined with to medical management. aromatase 0 • GnRH analogues and SPRMs effectively decrease Con trol Cab ergo lin e inhibitor menorrhagia and leiomyoma size • No value in • Novel therapies that function without regulating addition of gonadal hormones are currently under investigation cabergoline Vahdat Eur J Obstet Gynecol Reprod Biol 2016;206:74 Sayyah-Melli Eur J Obstet Gynecol Reprod Biol 2017;210:257 Thank you! 8
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