Learning Objectives HLRCC Appreciate the complex genetic and - - PowerPoint PPT Presentation

10/26/2016 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?

10/26/2016 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

• Incidence: 1.5 million/yr
• Prevalence: 13.6 million women

Predisposing Factors

• 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;159:113-123

10/26/2016 3 African-American women disproportionally affected by uterine fibroids

• Kjerulff KH et al Racial differences in severity, symptoms

and age of diagnosis. J Reprod Med 1996;41:483-490

• 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? Etiology of Uterine Fibroids

Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308:1589- 92

10/26/2016 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

Genetics of Fibroids

• Cytogentically abnormal: 40%
• > 200 chromosome abnormalities
• 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

10/26/2016 5 HLRCC Characteristic leiomyoma histology:

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

HLRCC Mutations in the Fumarate Hydratase gene

• FH encodes an enzyme in the

mitochondria involved in the Krebs Cycle

• Multiple different FH mutations-

all lead to absent, truncated or non-functioning

• FH acts like a tumor suppressor
• “2 Hit” theory

HLRCC Carrier Surveillance

• 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

Etiology of Uterine Fibroids

Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308:1589- 92

10/26/2016 6

Medical Management: Hormonal Manipulation

Drug Targets: Decrease hormone levels Selectively block hormone action

Estrogen Progesterone

Aromatase

Aromatase:

Fibroid

Aromatase Enzyme

Androgens Estrogen

• 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 women1
• Estrogen increases ER and PR

1Ishikawa H et al. J Clin Endocrinol Metab 2009:94;1752-6

Aromatase Inhibitors: Letrozole and Anastrozole

Fibroid

Aromatase

Androgens Estrogen

• Block action of aromatase enzyme in fibroids and to a lesser

extent in the ovaries

• Serum estradiol not significantly lower- no HF’s

X

10/26/2016 7

Letrozole: Decreases Fibroid Volume

Fibroid volume in cc Parsanezhad et al, Fert Ster: Jan 2010: 93:1

46% decrease

2 6 26 2 7 27

Progesterone Receptor Modulators (PRMs)

• Mifepristone, asoprisnil, ulipristal
• Reversibly binds to PR
• Equivalent fibroid size reduction as GnRHa
• Estradiol levels remain at premenopause levels

10/26/2016 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: 366:421-32.

Ulipristal Trials

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%

Hot flashes *p<.05 compared with

U 5mg

11% 40%* Donnez et al, NEJM, 2012: 366:421-32.

Progesterone Receptor Modulators: Ulipristal

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 Four 13 weeks courses of medication with 2 m drug free intervals

Donnez et al, Fertil Steril 2016: 105(1);165-173

10/26/2016 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);165-173

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
• utcomes, endometriosis, PCOS, cancer, auto immune

disorders, CV disease, DM

10/26/2016 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:E572-82

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;24:447-53
• Women with vitamin D deficiency were more likely to

have fibroids ( OR 2.4)

• Paffoni et al. J Clin Endocrinol Metab 2013;98:E1374-8
• Inverse relationship between vitamin D levels and

fibroid size

• Sabry et al. Int J Womens Health 2013;5:93-100

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;57:81-86

10/26/2016 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

• f 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

• Be aware of exciting prospects for medical therapy
• Ulipristal, aromatase inhibitors, vitamin D, green tea extract

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

10/26/2016 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

10/26/2016 13

Thank you