pcos challenge & thomas jefferson university pcos ......pcos challenge & thomas jefferson university...
TRANSCRIPT
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Saturday, April 16th, 2016
PCOS Challenge & Thomas Jefferson University
PCOS Awareness Symposium Philadelphia
Preventing Long-Term Cardiometabolic Complications in PCOS
Katherine Sherif, MD Professor & Vice Chair, Department of Medicine Director, Jefferson Women’s Primary Care Sidney Kimmel Medical College, Thomas Jefferson University
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The Key to Preventing Cardiometabolic Complications:
Early Recognition & Aggressive Treatment
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PCOS: Background
• The intersection of sex hormones & metabolism
• Reproductive and cardiovascular features • Reproductive consequences
• Endocrine/metabolic consequences
• Cardiovascular associations
• A multi-factorial, polygenic disorder with variable phenotypes
• PCOS is under-diagnosed and under-treated • Multiple cardiovascular risk factors
• High conversion to diabetes
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Polycystic Ovary Syndrome
• 2003 ESHRE/ASRM Consensus Conference Definition: 2 of 3 criteria
• Irregular menstrual intervals
• Hyperandrogenemia
• Polycystic ovaries *In absence of other etiologies
• 2011 AES criteria: presence of three features
• androgen excess (clinical and/or biochemical hyperandrogenism)
• ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology)
• exclusion of other androgen excess or ovulatory disorders
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Polycystic Ovary Syndrome
• Endocrine Society 2013 • Adult
• ESHRE/ASRM criteria
• Adolescent • presence of clinical and/or biochemical evidence of
hyperandrogenism (after exclusion of other pathologies) in the presence of persistent oligomenorrhea
• Perimenopausal & menopausal women • well-documented long-term history of oligo/amenorrhea
and hyperandrogenism during reproductive years
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Polycystic Ovary Syndrome
• Prevalence is high
• Essential to diagnose early to prevent metabolic sequelae
• Earlier: Infertility, acne, hirsutism, alopecia
• Later: Significant metabolic abnormalities & morbidity
• Dyslipidemia, IR/IGT/T2D, hypertension, obesity, fatty liver
• Obstructive sleep apnea
• Eating disorders
• Endometrial carcinoma, dysfunctional uterine bleeding
• Miscarriages, preterm births, stillbirth, gestational diabetes
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Why are so many women with PCOS undiagnosed?
• Lack of agreement on defining criteria
• Variable phenotype
• No firm radiologic criteria for “polycystic ovaries”
(ovarian appearance not pathognomonic in US)
• Serum sex hormone assays notoriously inaccurate
• Existence of traditional silos in medicine
• Most importantly:
• Clinicians’ lack of recognition
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It’s
acne
Hirsutism
Ovarian
Cysts
It’s fatty
liver
Obesity
It’s
diabetes
The Challenge of PCOS: Recognition
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PCOS - Economic Cost to Health Care
Annual costs = $4.3 billion • Initial evaluation: $93 million (2%) • Treat hirsutism: $622 million (14%) • Infertility costs: $533 million (12%) • Treat irregular bleeding: $1.35 billion (31%) • T2D in PCOS: $1.77 billion (40%) Conclusion: Screen aggressively, treat aggressively & prevent sequelae Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span, JCEM 2005, 90(8):4650–4658.
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PCOS: a reproductive disorder • Oligomenorrhea, amenorrhea
• Infertility (50 – 60% of all infertility in the US)
• Pregnancy loss (30-50%), preterm and stillbirths
• Polycystic ovaries
• Endometrial carcinoma?
• Gestational diabetes (30% GD are PCOS)
• …with hirsutism, acne and weight gain
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Cardiometabolic Disorder
• Elevated blood pressure 50%
• Abnormal glucose metabolism 50-70% • insulin resistance, IFG, IGT, diabetes
• Abnormal lipids 70%
• High triglycerides, low HDL-C
• Obesity 40-80%
• Sleep apnea ?
• Fatty liver ?
J Intern Med 1996, 239:105–110, J Clin Epidemiol 1998, 51:415–422
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Figure 1 Natural history of PCOS. PCOS has a multifactorial aetiology that includes intra-
uterine, genetic and environmental factors which might or might not be interrelated.
Anderson Sanches de Melo et al. Reproduction 2015;150:R11-R24
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Weight gain and/or androgens cause adiopose tissue hypertrophy,
followed by release of adipokines and inflammatory mediators that
cause insulin resistance, weight gain and androgen excess
Poli Mara Spritzer et al. Reproduction 2015;149:R219-R227
© 2015 Society for Reproduction and Fertility
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PCOS & weight-matched controls
• PCOS women have a higher prevalence of hyperinsulinemia • Clin Endocrinol Metab 1987;65:499–507
• PCOS women have a greater degree of hyperinsulinemia • Diabetes 1989;38:1165–1174
• 16% of PCOS developed diabetes at menopause compared to 6% of obese women
• Fertil Steril 1992;57(3):505-13
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Obstetric Complications N = 4982 PCOS, N = 119,692 Controls
• RISK OR 95% CI
• Gestational DM 3.43 2.49 – 4.74
• PIH 3.43 2.49 – 4.74
• Preeclampsia 2.17 1.91 – 2.46
• Preterm birth 1.93 1.45 – 2.57
• C-section 1.74 1.38 – 2.11
• NICU admission 2.32 1.40 – 3.85
Qin JZ, Reprod Biol Endocrin 2013
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PCOS & Coronary Artery Disease
• No prospective study linking PCOS with CAD has ever been published
• Lack of consensus on definition and evolving definition hampers ability to compare studies
• Long duration between diagnosis and cardiovascular disease outcomes
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Link with Coronary Artery Disease
• Coronary angiography: women with polycystic ovaries have more extensive CAD • “extensive” = number of segments with >50% stenosis
• NHS: oligomenorrheic women followed for 8 years had double the risk of fatal MI
• Retrospective study – oligomenorrheic women in the 1950’s were 7.4 x’s more likely to have MI in their 50’s and 60’s
Birdsall, Annals Int Med, 1997
Dahlgren, Acta Obstet Gynecol Scand, 1992
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CVD risk factors/markers
• Increased levels of PAI – 1: risk of intravascular thrombosis • Gyn Endocrin 2003;17(3):231-7
• Smaller, denser LDL particles
• Clin Endocrinol 2001;54:447–453
• homocysteine – may be more significant in women • Human Reprod 2003;18(4):721
• left ventricular size & diastolic dysfunction
• lipoprotein (a) – may be more significant in women
• Minassian 2002, Endo Soc
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CVD risk factors/markers
• Elevated C-reactive protein • J Clin Endocrinol Metab 2001; 86:2453–2455
• Endothelial dysfunction • Circ 2001;103:1410–1415
• Increased endothelin – 1 • Clin Endocrinol Metab 2001;86:4666–4673
• Increased intima-media wall thickness • Arteriosler Thromb Vasc Biol 1995;15:821-826
• Decreased adiponectin
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LH pulsatility in PCOS and normals
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Pathophysiology
Follicle
Theca cell
androstenedione testosterone estradiol
Insulin
LH
Progesterone 17 - OH P testosterone
estrone
GnRH
pulsatility
↓ SHBG Free T
X
X
Peripheral conversion
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Pathophysiology
Insulin resistance in muscle
Hyperinsulinemia Weight gain
Larger adipocytes
Insulin Receptor Substrate-1 gene mutation (G972R)
IRS-1 is in muscle cells and adipocytes
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Pathophysiology: Reproduction
Insulin resistance
Hyperinsulinemia Weight gain
↑ Testosterone
Irregular menses
Infertility
IRS-1 mutation
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Pathophysiology: Metabolic
Insulin resistance
Hyperinsulinemia Weight gain
↑ Blood pressure
↑ Triglycerides, ↓ HDL
β –cell dysfunction
↑ Coagulation
Obesity
Acanthosis nigricans
IRS-1 mutation
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Primary: Secondary: Hereditary defect Acanthosis nigricans
in insulin action Ovarian Dysfunction
Hyperlipidemia
Hypertension
Central obesity
Coagulopathy
compensatory hyperinsulinemia
obesity insulin resistance
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Role of PCOS in Childhood Obesity
• In utero androgen excess may trigger insulin resistance
• Androgen excess may cause adipocytes to hypertrophy
• Hypertrophied adipose tissue
• SGA babies
• rapid growth & weight gain first two years
• premature pubarche/adrenarche
• Androgen excess leads to insulin resistance
Reproduction 2015, 149:R219
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PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
Gynecological
Diagnoses Non-PCOS (25 660) PCOS (2560) P Value HR 95% CI
Endometriosis 1121 (4.4) 677 (26.4)
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PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
Hysterectomy 649 (2.5) 204 (8.0)
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PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
Diagnoses Non-PCOS PCOS P Value HR 95% CI
Endocrine
Obesity (3.7) 411 (16.0)
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PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
Diagnoses Non-PCOS PCOS P Value HR 95% CI
Musculoskeletal
4167 (16.2) 661 (25.8)
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PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
Diagnosis Non-PCOS PCOS P Valu
e HR 95% CI
n 25 660 2566
Cervical cancer 970 (3.8) 67 (2.6) .003 0.69 0.54–0.88
Endometrial cancer 4 (
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PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
Diagnoses
Non-PCOS PCOS P Value HR 95% CI
External
causes
Adverse
outcome of
medical
treatment
1936 (7.5) 486 (18.9)
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endothelium
ovary
acne, hirsutism,
alopecia
infertility
anovulation dyslipidemia diabetes
testosterone
ovary
endothelial dysfunction
hyperinsulinemia
hypertension
Sherif 2016 ©
cysts
Androgen Excess
Adipocyte dysfunction
Inflammatory
mediators
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History • Abnormal menses:
• Oligomenorrhea or amenorrhea • Menorrhagia and metrorrhagia
• Reproductive abnormalities:
• Infertility ** • Multiple miscarriages • Preterm births and stillbirths
• Endocrine disturbances:
• Rapid weight gain • Gestational diabetes • Diabetes
• Family history of premature cardiac disease
• Mothers or sisters with PCOS or infertility (24%) • Battaglia 2002 Human Repro
• Brothers with early balding (age
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Physical Examination
• Elevated blood pressure
• Signs of hyperandrogenism • Alopecia - depends on androgen receptors • Hirsutism - diffuse • Acne, often in an androgenic distribution • Seborrhea
• Signs of insulin resistance • Acanthosis nigricans – depends on pigmentation • Skin tags
• Central obesity (lean with abdominal fat)
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Frequently observed lab abnormalities
• High TSH with normal free T4
• Elevated ALT & AST
• Elevated WBC’s and CRP
• Dyslipidemia
• High TG and low HDL
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Traditional Treatment
• Oral contraceptives Oligomenorrhea Hirsutism Acne Alopecia • Anti-androgens Hirsutism Alopecia • Clomiphene Infertility
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Oral contraceptives: benefits
• Increase SHBG & decrease free testosterone
• Improve hirsutism, alopecia & acne
• Decrease risk of endometrial cancer
• Regulate cycles Sherif, Am J Ob/Gyn 180, 1999
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Oral Contraceptive Pills
• Risks:
• Worsen insulin sensitivity – cause glucose intolerance
• Increase triglycerides
• Microalbuminuria
• Unmask thrombophilias – more common in PCOS?
• Double relative risk of MI/stroke in high-risk group
• Advantages of some formulations?
Sherif, Am J Obstet Gyn 1999
Nestler, JCEM 2005
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Anti-androgens
• Spironolactone 100mg BID
• As long as 3-6 months to see improvement, especially in alopecia
• Alpha-reductase inhibitors: flutamide, finasteride
• Transaminase elevations
• Ornithine decarboxylase inhibitors: eflornithine
• 30% response rate at six months
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endothelium ovary
acne, hirsutism,
alopecia
infertility
anovulation dyslipidemia diabetes
testosterone
ovary
endothelial dysfunction
hyperinsulinemia
Overweight Acanthosis nigricans
hypertension
Sherif 2006 ©
cysts
Traditional treatment does not address cardiometabolic issues
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Key: improve insulin resistance • Nutrition
• Decrease both calories & simple carbohydrates
• Increase physical activity and muscle mass
• Sleep 8 hours per night
• Insulin-sensitizing medications
• Insulin-sensitizing supplements
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Metformin
• Benefits: • Weight loss (minimal)
• Improved lipid profile
• Improved acne, hirsutism and alopecia
• Normalization of transaminases
• Ovulation & pregnancy
• Cochrane meta-analysis: first-line agent for anovulation
• Side effects • Gastrointestinal: diarrhea, nausea
• Decreased B-12 absorption and homocysteine
Lord, BMJ, 2003
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Treatment with unapproved indications
• Metformin ER: 500mg titrated up to 2000mg/day
• Pioglitazone and rosiglitazone • Associated with fluid retention
• Byetta, Symlin, Victoza, Bydureon etc.
• Spironolactone: 100mg BID
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endothelium ovary
acne, hirsutism,
alopecia
infertility
anovulation dyslipidemia diabetes
testosterone
ovary
endothelial dysfunction
hyperinsulinemia
Adipocyte dysfunction hypertension
Sherif 2006 ©
cysts
Insulin sensitizers improve metabolic & reproductive problems
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Supplements with insulin-sensitizing properties
• Cinnamon
• Vitamin D
• Chromium 250mg TID
• N-acetyl cysteine 500mg
• Alpha lipoic acid
• Resveratrol
• D - chiro inositol & myo-inositol
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Summary
• PCOS is a multifactorial polygenic disorder with variable phenotypes and long-term consequences
• PCOS is common: 6 – 10% of the US population
• PCOS is underdiagnosed and undertreated
• PCOS has reproductive, metabolic and cardiovascular consequences
• Insulin plays a central role in the pathophysiology
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Summary of Management
1. Nutrition counseling & increase physical activity
2. Metformin for metabolic abnormalities
3. Consider supplements
4. Hormonal contraception for dermatologic problems
5. Screen early for
• Type 2 diabetes – A1c
• Fatty Liver - transaminases
• Hypothyroidism – TSH, free T4
• Sleep apnea – STOP BANG
• Depression
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We need to educate our colleagues about PCOS
• Internist, Family Medicine, Pediatrician
• Obstetrician/Gynecologist
• Reproductive Endocrinologist
• Psychiatrist, Psychologist
• Dermatologist
• Endocrinologist
• Gastroenterologist/Hepatologist
• Pulmonologist/Sleep Medicine
• Cardiologist
• Oncologist
• Surgeon(Bariatric Surgery)
• Radiologist