PCOS Challenge & Thomas Jefferson University PCOS ......PCOS Challenge & Thomas Jefferson University PCOS Awareness Symposium Philadelphia Preventing Long-Term Cardiometabolic Complications

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

The Key to Preventing Cardiometabolic Complications:

Early Recognition & Aggressive Treatment

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

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


• 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


• 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

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

It’s

acne

Hirsutism

Ovarian

Cysts

It’s fatty

liver

Obesity

It’s

diabetes

The Challenge of PCOS: Recognition

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.

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

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

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

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

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

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

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

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

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

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

LH pulsatility in PCOS and normals

Pathophysiology

Follicle

Theca cell

androstenedione testosterone estradiol

Insulin

LH

Progesterone 17 - OH P testosterone

estrone

GnRH

pulsatility

↓ SHBG Free T

X

X

Peripheral conversion

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

Pathophysiology: Reproduction

Insulin resistance


↑ Testosterone

Irregular menses

Infertility

IRS-1 mutation

Pathophysiology: Metabolic

Insulin resistance


↑ Blood pressure

↑ Triglycerides, ↓ HDL

β –cell dysfunction

↑ Coagulation

Obesity

Acanthosis nigricans

IRS-1 mutation

Primary: Secondary: Hereditary defect Acanthosis nigricans

in insulin action Ovarian Dysfunction

Hyperlipidemia

Hypertension

Central obesity

Coagulopathy

compensatory hyperinsulinemia

obesity insulin resistance

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

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)


Hysterectomy 649 (2.5) 204 (8.0)


Diagnoses Non-PCOS PCOS P Value HR 95% CI

Endocrine

Obesity (3.7) 411 (16.0)


Diagnoses Non-PCOS PCOS P Value HR 95% CI

Musculoskeletal

4167 (16.2) 661 (25.8)


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 (


Diagnoses

Non-PCOS PCOS P Value HR 95% CI

External

causes

Adverse

outcome of

medical

treatment

1936 (7.5) 486 (18.9)

endothelium

ovary

acne, hirsutism,

alopecia

infertility

anovulation dyslipidemia diabetes

testosterone

ovary

endothelial dysfunction

hyperinsulinemia

hypertension

Sherif 2016 ©

cysts

Androgen Excess

Adipocyte dysfunction

Inflammatory

mediators

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

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)

Frequently observed lab abnormalities

• High TSH with normal free T4

• Elevated ALT & AST

• Elevated WBC’s and CRP

• Dyslipidemia

• High TG and low HDL

Traditional Treatment

• Oral contraceptives Oligomenorrhea Hirsutism Acne Alopecia • Anti-androgens Hirsutism Alopecia • Clomiphene Infertility

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

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

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

endothelium ovary

acne, hirsutism,

alopecia

infertility


testosterone

ovary


hyperinsulinemia

Overweight Acanthosis nigricans

hypertension

Sherif 2006 ©

cysts

Traditional treatment does not address cardiometabolic issues

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

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

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

endothelium ovary

acne, hirsutism,

alopecia

infertility


testosterone

ovary


hyperinsulinemia

Adipocyte dysfunction hypertension

Sherif 2006 ©

cysts

Insulin sensitizers improve metabolic & reproductive problems

Supplements with insulin-sensitizing properties

• Cinnamon

• Vitamin D

• Chromium 250mg TID

• N-acetyl cysteine 500mg

• Alpha lipoic acid

• Resveratrol

• D - chiro inositol & myo-inositol

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

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

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

Documents

PCOS Challenge & Thomas Jefferson University PCOS ......PCOS Challenge & Thomas Jefferson University PCOS Awareness Symposium Philadelphia Preventing Long-Term Cardiometabolic Complications