10/26/2016 ✔ No financial disclosures Uterine Fibroids : ✔ Off-label uses of drugs Current Challenges, Promising Future Alison Jacoby, MD Professor, Dept of Obstetrics, Gynecology and Reproductive Sciences The BIG Questions What causes fibroids? • How can they be prevented? • Why are African American women disproportionally • affected? 1
10/26/2016 Learning Objectives HLRCC • 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 • Sex hormone status • Race/ethnicity • Family history • Parity • Obesity • Incidence: 1.5 million/yr • Sex hormone exposure • Prevalence: 13.6 million women 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 2
10/26/2016 African-American women disproportionally What exactly are fibroids? 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 • Kjerulff KH et al Racial differences in severity, symptoms and age of diagnosis. J Reprod Med 1996;41:483-490 Etiology of Uterine Fibroids Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308:1589- 92 3
10/26/2016 What causes the transformation from Genetics of Fibroids myometrial to myoma cells? Combination of factors: • Cytogentically abnormal: 40% • Genetic and epigenetic changes • > 200 chromosome abnormalities • Hyper-responsiveness to steroid hormones and growth factors • Non-random translocations, rearrangements and deletions • Extracellular matrix dysregulation • Cytogenetically normal (46XX): 60% • Alterations in cell cycle and apoptosis Hereditary Leiomyomata and Renal Cell Molecular Effects of Genetic Carcinoma (HLRCC) Mutations • Autosomal dominant with incomplete t(12;14)(q14–15;q23–24) penetrance • • Cutaneous smooth muscle tumors • Most common mutation in uterine fibroids • High prevalence of uterine fibroids Found in other solid benign tumors such as lipomas, • • Earlier age of onset salivary gland adenomas, pulmonary hamartomas and epithelial breast tumors • More severe symptoms • Increased risk for LMS Translocation results in transcription of HMG genes • • Papillary renal cell carcinoma • HMG proteins involved in cell growth, proliferation, differentiation and cell death • Women at increased risk compared to male family members 4
10/26/2016 HLRCC HLRCC Mutations in the Fumarate Hydratase gene Characteristic leiomyoma histology: • FH encodes an enzyme in the mitochondria involved in the Krebs Cycle • Multiple different FH mutations- all lead to absent, truncated or non-functioning • “ 2 Hit ” theory • FH acts like a tumor suppressor 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 Etiology of Uterine Fibroids 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 Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005;308:1589- 92 5
10/26/2016 Medical Management: Hormonal Manipulation Aromatase Estrogen Progesterone Drug Targets: Decrease hormone levels Selectively block hormone action Aromatase: Aromatase Inhibitors: Letrozole and Anastrozole • Catalyzes the conversion of androgens to estrogen in ovaries, adipose tissue and fibroids • Block action of aromatase enzyme in fibroids and to a lesser Serum estradiol not significantly lower- no HF ’ s • High levels of aromatase in fibroids extent in the ovaries • High aromatase expression in fibroid tissue of AA women 1 • • Estrogen increases ER and PR Fibroid Fibroid Aromatase Androgens Estrogen Androgens Estrogen Aromatase Enzyme X 1 Ishikawa H et al. J Clin Endocrinol Metab 2009:94;1752-6 6
10/26/2016 Letrozole: Decreases Fibroid Volume Fibroid volume in cc 46% decrease 26 2 Parsanezhad et al, Fert Ster: Jan 2010: 93:1 6 Progesterone Receptor Modulators (PRMs) Mifepristone, asoprisnil, ulipristal • Reversibly binds to PR • • Equivalent fibroid size reduction as GnRHa Estradiol levels remain at premenopause levels • 27 2 7 7
10/26/2016 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. Progesterone Receptor Modulators: Ulipristal Trials Ulipristal Ulipristal vs. Placebo Ulipristal vs. Lupron U 5mg Placebo U 5mg Lupron N=95 N=48 N=93 N=93 Phase III Randomized trial, industry funded, in Europe 73% 6%* 75% 80% Amenorrhea • Ulipristal 5 mg vs. Ulipristal 10 mg (n=451) Menstrual bleeding became 91% 19%* 90% 89% normal Participants had heavy bleeding, fibroids >3 cm & < 12 cm, uterus Change in -21% +3%* -36% -53% <16 weeks fibroid volume Hot flashes Four 13 weeks courses of medication with 2 m drug free intervals 11% 40%* * p<.05 compared with U 5mg Donnez et al, Fertil Steril 2016: 105(1);165-173 Donnez et al, NEJM, 2012: 366:421-32. 8
10/26/2016 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 • outcomes, endometriosis, PCOS, cancer, auto immune disorders, CV disease, DM 9
10/26/2016 Mechanisms of vitamin D action in Vitamin D uterine fibroid development 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 Vitamin D Epidemiologic Sutdies Epidemiologic Studies Women with sufficient levels of vitamin D were less • Data from NHANES found no relationship between • likely to have uterine fibroids (OR 0.68) serum vitamin D and self-reported dx of fibroids • Baird et al. Epidemiology 2013;24:447-53 • Mitro SD and Zota AR Reproductive Toxicology 2015;57:81-86 • 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 10
10/26/2016 The Vitamin D Hypothesis Learning Objectives Learning Objectives Appreciate the complex genetic and molecular changes • • Appreciate the complex genetic and molecular changes that lead to fibroid development that lead to fibroid development Gain insight into the causes of racial disparities in • • Transformation from myometrial to myoma cells is assoc’d with a complex network of factors including genetic mutations, epigenetic influences, dysregulation prevalence, age of onset and severity of fibroid disease of growth factors and overproduction of ECM • Be aware of exciting prospects for medical therapy • Gain insight into the causes of racial disparities in prevalence, age of onset and severity of fibroid disease Imagine a paradigm shift that would minimize the • burden of disease for women with fibroids • 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 11
10/26/2016 Current State of Affairs What if… • Elevated blood sugar was treated only when peripheral vascular disease and loss of vision affected a person’s • Treat fibroids when QOL symptoms interfere with Hypertension was treated only after an MI or stroke • quality of life 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 Thank you preserving treatments? Combination therapy worked better than • monotherapy? There was an implantable delivery system- Ulipristal • IUD 12
Recommend
More recommend
