Areas of Future Research RFTS Blacks in Fibroid Therapy Blacks - - PDF document

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Areas of Future Research RFTS Blacks in Fibroid Therapy Blacks - - PDF document

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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

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Areas of Future Research in Fibroid Therapy

William H. Catherino, MD, PhD Professor and Chair, Research Division Uniformed Services University Associate Program Director 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

  • f the Department of the Army, Department of Defense, or the US Government.

RFTS Blacks Whites Seveso Italy CARDIA Age 33-46 Whites Blacks Sweden/Whites (Age 33-40) Whites Blacks UFS

Cumulative Incidence of Fibroids over Reproductive Lifespan

Laughlin Seminars Reprod Med 2010;28: 214

Fibroids Increase Miscarriage Rate

Guben Reprod Biol Endocrinol 2013;11:102

Odds of miscarriage decreased with no myoma compared to myoma Not Impacting the Cavity OR = 0.737 [0.647, 0.840]

Obstetric Complications of Fibroids

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

Biderman-Madar Arch Gynecol Obstet 2005;272:218 Ciavattini J Matern Fetal Neonatal Med 2015;28:484-8 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 Stout Obstet Gynecol 2010;116:1056 Qidwai Obstet Gynecol 2006;107:376

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Best Studied Therapies

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

Hysterectomy Option over Time

Medical Therapy

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 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

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GnRH Analogues

Leuprolide Acetate

Visual Analog Scale: 1-10, patient reported

Palomba Fertil Steril 1998;70:111

Elagolix

Archer Fertil Steril 2017;108:152

Selective Progesterone Receptor Modulators

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How do sPRMs work?

Bouchard Fertil Steril 2011;96:1175

Chemical Structures: Selective Progesterone Receptor Modulators (SPRMs)

Ulipristal

O N CH3 H3C C OH C CH3

Mifepristone

O N CH3 H3C OCH3 OCCH3 O O O S O OH F F F F F

Vilaprisan

O O OCH3 N OCH2CH3 CH3 H3C

Telapristone Asoprisnil

O N OCH3 HO CH2OCH3

Progesterone

O O O O S H OH F F F F F

Clinical efficacy of each SPRM for fibroid treatment

Mifepristone

N = 14 Age: 40.8 BMI: 25.9 Decrease in fibroid size: 28%

Engman Hum Reprod 2009;

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Asoprisnil

Chwalisz Fertil Steril 2007;87:1399

Bleeding Suppression Uterine Volume

PEARL I: Ulipristal Controls bleeding faster than Placebo

Donnez NEJM 2012;366:

Donnez N Engl J Med 2012;366:409

PEARL II: Ulipristal Controls Bleeding Faster than Leuprolide Acetate

Donnez NEJM 2012;366:421-32

Donnez N Engl J Med 2012;366:421

Vilaprisan: Optimal Dose approximately 1-2 mg to induce Non-Bleeding Event

Schütt Hum Reprod 2016;31:1703

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Vilaprisan: 1-2 mg decreases mean number of Bleeding Days

Schütt Hum Reprod 2016;31:1703

Potential Future Therapies

Simvastatin

  • hmg-CoA

inhibitor

  • Hyperlipidemia

therapy

  • Antitumor

properties

Borahay J Biol Chem 2014;289:35075 Borahay Am J Obstet Gynecol 2015;213:196.e1-8

Retinoic Acid

  • Differentiating

agent

  • Relatively toxic
  • Compounds that

increase intracellular retinoic acid available for study

Catherino WH, Malik M. Fertil Steril 2007;87:1388 Ben-Sasson Fertil Steril 2011;95:2080 Gilden Fertil Steril 2012;98:1557

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Vitamin D

  • Has

antiproliferative and apoptotic function

  • Vit D depletion

associated with high risk of fibroids

Halder Biol Reprod 2012;86:116 Halder Biol Reprod 2013;89:150

Green Tea Extract

  • High therapeutic

index

  • Consumption

associated with lower cancer incidence

Zhang Am J Obstet Gynecol 2010;202:289 Roshdy Int J Womens Health 2013;5:477

Berberine

  • Chinese herb
  • Anti-inflammatory
  • Used to treat

chronic inflammatory conditions

Chuang Reprod Sci 2017;24:1005 Wu Fertil Steril 2015;103:1098

Tranilast

  • Anti-allergic
  • Inhibits mast cell

degranulation

  • Inhibits release of

inflammatory mediators

  • Prevents keloid

tumor formation

Islam Fertil Steril 2014;102:597

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Cabergoline / Aromatase Inhibitor

  • Dopamine

receptor agonist

  • Combined with

aromatase inhibitor

  • No value in

addition of cabergoline

Vahdat Eur J Obstet Gynecol Reprod Biol 2016;206:74 Sayyah-Melli Eur J Obstet Gynecol Reprod Biol 2017;210:257

50 Con trol Cab ergo lin e Bef

  • re

Afte r

Summary

  • There is an increasing interest in moving from surgical

to medical management.

  • GnRH analogues and SPRMs effectively decrease

menorrhagia and leiomyoma size

  • Novel therapies that function without regulating

gonadal hormones are currently under investigation

Thank you!