Uterine Fibroids: No financial disclosures. Current Challenges, Promising Future. Off-label uses of drugs. Alison Jacoby, MD.

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Uterine Fibroids: Current Challenges, Promising

Obstetrics, Gynecology and Reproductive Sciences No

1 Uterine Fibroids: Current Challenges, Promising Future Alison Jacoby, MD Professor, Dept of Obstetrics, Gynecology and Reproductive Sciences No financial disclosures Off-label uses of drugs The BIG Questions What causes fibroids? How can they be prevented? Why are African American women disproportionally affected? 1

HLRCC Learning Objectives Appreciate the complex genetic and molecular changes that

prevalence, age of onset and severity of fibroid disease Be aware of exciting prospects

for women with fibroids Predisposing Factors Incidence: 1.5 million/yr Prevalence: 13.

2 HLRCC Learning Objectives Appreciate the complex genetic and molecular changes that lead to fibroid development Gain insight into the causes of racial disparities in prevalence, age of onset and severity of fibroid disease Be aware of exciting prospects for medical therapy Imagine a paradigm shift that would minimize the burden of disease for women with fibroids Predisposing Factors Incidence: 1.5 million/yr Prevalence: 13.6 million women Sex hormone status Race/ethnicity Family history Parity Obesity Sex hormone exposure Wise LA et al. Reproductive factors, hormonal contraception, and risk for uterine leiomyoma in African-American women: a prospective study. Am J Epidemiol 2004;159:

African-American women disproportionally affected by uterine fibroids Increased incidence of fibroids Fibroids diagnosed at a younger age More

surgical complication rates What exactly are fibroids? Kjerulff KH et al Racial differences in severity, symptoms and age of diagnosis.

3 African-American women disproportionally affected by uterine fibroids Increased incidence of fibroids Fibroids diagnosed at a younger age More numerous and larger compared to Caucasian women Higher risk for hysterectomy due to sx fibroids Worse disease at time of hysterectomy Higher surgical complication rates What exactly are fibroids? Kjerulff KH et al Racial differences in severity, symptoms and age of diagnosis. J Reprod Med 1996;41: Etiology of Uterine Fibroids Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308:

4 What causes the transformation from myometrial to myoma cells? Combination of factors: Genetic and epigenetic changes Hyper-responsiveness to steroid hormones and growth factors Extracellular matrix dysregulation Alterations in cell cycle and apoptosis Cytogentically abnormal: 40% > 200 chromosome abnormalities Genetics of Fibroids Non-random translocations, rearrangements and deletions Cytogenetically normal (46XX): 60% Molecular Effects of Genetic Mutations t(12;14)(q14 15;q23 24) Most common mutation in uterine fibroids Found in other solid benign tumors such as lipomas, salivary gland adenomas, pulmonary hamartomas and epithelial breast tumors Translocation results in transcription of HMG genes HMG proteins involved in cell growth, proliferation, differentiation and cell death Hereditary Leiomyomata and Renal Cell Carcinoma (HLRCC) Autosomal dominant with incomplete penetrance Cutaneous smooth muscle tumors High prevalence of uterine fibroids Earlier age of onset More severe symptoms Increased risk for LMS Papillary renal cell carcinoma Women at increased risk compared to male family members 4

5 HLRCC Characteristic leiomyoma histology: HLRCC Mutations in the Fumarate Hydratase gene Mann M et al. Fumarate hydratase mutation in a young woman with uterine leiomyomas and a family history of renal cell cancer. Obstet Gynecol 2015;126:90-2 FH encodes an enzyme in the mitochondria involved in the Krebs Cycle Multiple different FH mutationsall lead to absent, truncated or non-functioning FH acts like a tumor suppressor 2 Hit theory HLRCC Carrier Surveillance Etiology of Uterine Fibroids If HLRCC suggested by histology or family hx, refer to Cancer Risk Program for testing Refer to Urology for RCC screening Recommend hysterectomy, rather than uterine sparing treatments High risk for new fibroid growth Increased risk for leiomyosarcoma Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308:

Medical Management: Hormonal Manipulation Aromatase Estrogen Progesterone Drug Targets: Decrease hormone levels Selectively block hormone action Aromatase: Catalyzes the

Estrogen increases ER and PR Aromatase Inhibitors: Letrozole and Anastrozole Block action of aromatase enzyme in fibroids and to a lesser extent in the ovaries Serum

6 Medical Management: Hormonal Manipulation Aromatase Estrogen Progesterone Drug Targets: Decrease hormone levels Selectively block hormone action Aromatase: Catalyzes the conversion of androgens to estrogen in ovaries, adipose tissue and fibroids High levels of aromatase in fibroids High aromatase expression in fibroid tissue of AA women 1 Estrogen increases ER and PR Aromatase Inhibitors: Letrozole and Anastrozole Block action of aromatase enzyme in fibroids and to a lesser extent in the ovaries Serum estradiol not significantly lower- no HF s Fibroid Fibroid Androgens Aromatase Enzyme Estrogen Androgens X Aromatase Estrogen 1 Ishikawa H et al. J Clin Endocrinol Metab 2009:94;

7 Letrozole: Decreases Fibroid Volume Fibroid volume in cc 46% decrease Parsanezhad et al, Fert Ster: Jan 2010: 93: Progesterone Receptor Modulators (PRMs) Mifepristone, asoprisnil, ulipristal Reversibly binds to PR Equivalent fibroid size reduction as GnRHa Estradiol levels remain at premenopause levels

8 Progesterone Receptor Modulators: Ulipristal Two randomized trials, industry funded, in Europe Placebo vs. Ulipristal (n=242) GnRHa vs. Ulipristal (n=307) Participants had heavy bleeding, anemia, uterus <16 weeks 13 weeks of medication Donnez et al, NEJM, 2012: 366: Ulipristal Trials Progesterone Receptor Modulators: Ulipristal Ulipristal vs. Placebo Ulipristal vs. Lupron U 5mg N=95 Placebo N=48 U 5mg N=93 Lupron N=93 Amenorrhea 73% 6%* 75% 80% Menstrual bleeding became normal 91% 19%* 90% 89% Change in fibroid volume -21% +3%* -36% -53% Phase III Randomized trial, industry funded, in Europe Ulipristal 5 mg vs. Ulipristal 10 mg (n=451) Participants had heavy bleeding, fibroids >3 cm & < 12 cm, uterus <16 weeks Hot flashes *p<.05 compared with U 5mg Donnez et al, NEJM, 2012: 366: % 40%* Four 13 weeks courses of medication with 2 m drug free intervals Donnez et al, Fertil Steril 2016: 105(1);

Progesterone Receptor Modulators: Ulipristal Results 5 mg vs 10 mg- no clinical difference Significant fibroid

pre-menopausal range No endometrial hyperplasia/cancer Donnez et al, Fertil Steril 2016: 105(1);165-173 The

African-American women 10x more likely to be Vitamin D deficient than Caucasian women Vitamin D involved in

9 Progesterone Receptor Modulators: Ulipristal Results 5 mg vs 10 mg- no clinical difference Significant fibroid size reduction High rates of amenorrhea UFS-QOL scores improved to that of healthy subjects Estradiol in pre-menopausal range No endometrial hyperplasia/cancer Donnez et al, Fertil Steril 2016: 105(1); The Vitamin D Hypothesis Vitamin D Does it play a role in fibroid development? African-American women 10x more likely to be Vitamin D deficient than Caucasian women Vitamin D involved in regulation of gene transcription and ER/PR Insufficient Vit D levels linked to adverse pregnancy outcomes, endometriosis, PCOS, cancer, auto immune disorders, CV disease, DM 9

10 Mechanisms of vitamin D action in uterine fibroid development Vitamin D In vitro Studies Exposure to vitamin D reduces # of ER and PR in human leiomyoma cells Vitamin D inhibits growth and promotes apoptosis Vitamin D decreases production of ECM proteins, eg collagen and fibronectin Al-Hendy et al. J Clin Endocrinol Metab 2015;100:E Vitamin D Epidemiologic Sutdies Women with sufficient levels of vitamin D were less likely to have uterine fibroids (OR 0.68) Baird et al. Epidemiology 2013;24: Women with vitamin D deficiency were more likely to have fibroids ( OR 2.4) Paffoni et al. J Clin Endocrinol Metab 2013;98:E Inverse relationship between vitamin D levels and fibroid size Sabry et al. Int J Womens Health 2013;5: Vitamin D Epidemiologic Studies Data from NHANES found no relationship between serum vitamin D and self-reported dx of fibroids Mitro SD and Zota AR Reproductive Toxicology 2015;57:

The Vitamin D Hypothesis Learning Objectives Appreciate the complex genetic and molecular changes that lead to fibroid development Transformation from myometrial to myoma cells is assoc d with a

prevalence, age of onset and severity of fibroid disease Different genes and genetic polymorphisms, inclucing increases in aromatase, signal transduction genes and transcription factors may underlie

11 The Vitamin D Hypothesis Learning Objectives Appreciate the complex genetic and molecular changes that lead to fibroid development Transformation from myometrial to myoma cells is assoc d with a complex network of factors including genetic mutations, epigenetic influences, dysregulation of growth factors and overproduction of ECM Gain insight into the causes of racial disparities in prevalence, age of onset and severity of fibroid disease Different genes and genetic polymorphisms, inclucing increases in aromatase, signal transduction genes and transcription factors may underlie the more severe form of fibroid disease in AA women Learning Objectives Appreciate the complex genetic and molecular changes that lead to fibroid development Gain insight into the causes of racial disparities in prevalence, age of onset and severity of fibroid disease Be aware of exciting prospects for medical therapy Imagine a paradigm shift that would minimize the burden of disease for women with fibroids Be aware of exciting prospects for medical therapy Ulipristal, aromatase inhibitors, vitamin D, green tea extract 11

12 Current State of Affairs Treat fibroids when symptoms interfere with quality of life What if Elevated blood sugar was treated only when peripheral vascular disease and loss of vision affected a person s QOL Hypertension was treated only after an MI or stroke HIV was treated only after the first opportunistic infection What if. Women were treated when fibroids first detected? Women at high risk for developing fibroids, were treated prophylactically? Women received medical treatment following uterine preserving treatments? Combination therapy worked better than monotherapy? There was an implantable delivery system- Ulipristal IUD Thank you 12

13 Thank you 13

Management of Uterine Myomas

Management of Uterine Myomas Deidre D. Gunn, MD Assistant Professor Division of Reproductive Endocrinology & Infertility February 16, 2018 Disclosures I have no relevant financial relationships to disclose.