pcos challenge & thomas jefferson university pcos ... · conclusion: screen aggressively, treat...

Saturday, April 16th, 2016

PCOS Challenge & Thomas Jefferson University

PCOS Awareness Symposium Philadelphia

The Impact of Insulin Resistance on Long-Term Health in PCOS

Katherine Sherif, MD Professor & Vice Chair, Department of Medicine Director, Jefferson Women’s Primary Care Sidney Kimmel Medical College, Thomas Jefferson University

Question #1

Polycystic ovary syndrome is

1. The most common cause of anovulatory infertility

2. Associated with a high rate of miscarriages

3. Associated with a higher incidence of type 2 diabetes

4. Characterized by high androgens

5. All of the above

Question #2

PCOS is associated with

1. Endometrial carcinoma

2. Endometriosis

3. Coronary artery disease

4. All of the above

Question #3

Initial testing for irregular menses includes

1. Thyroid stimulating hormone

2. Cortisol

3. 17-alpha-hydroxyprogesterone

4. All of the above

Question #4

Diagnostic criteria for PCOS include:

1. A history of irregular menstrual intervals

2. Signs of high androgens or elevated levels of androgens

3. Characteristic polycystic ovaries by ultrasound

4. All of the above

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

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

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 - 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 & 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) <.001 6.87 6.25–7.56

Endometrial

hyperplasiaa 24 (0.1) 46 (1.8) <.001 19.45 11.9–31.9

Menstrual problems 1269 (4.9) 520 (20.3) <.001 4.65 4.20–5.15

Hysteroscopy 1965 (7.7) 1107 (43.1) <.001 7.37 6.84–7.93

D&C 5695 (22.2) 1641 (64.0) <.001 3.83 3.62–4.05

Endometrial

ablation 244 (1.0) 94 (3.7) <.001 3.94 3.11–5.00

Data are shown as number (percentage) with χ2 test P values, and HRs and their 95% CI values adjusted for birth epochs (<1972, 1973–1979, 1980–1994).

aEndometrial adenomatous hyperplasia found in one control and four cases, respectively. - See more at: http://press.endocrine.org/doi/full/10.1210/jc.2014-3886#sthash.5aDRlI61.dpuf

Hart et al., JCEM 100(3):911-919, 2015


Hysterectomy 649 (2.5) 204 (8.0) <.001 3.36 2.87–3.93

Infertility 1188 (4.6) 1050 (40.9) <.001 11.44 10.5–12.4

Miscarriage 1572 (6.1) 286 (11.1) <.001 1.86 1.64–2.11

Ectopic pregnancy 386 (1.5) 97 (3.8) <.001 2.54 2.03–3.17

Procreative

management 668 (2.6) 527 (20.5) <.001 8.74 7.78–9.78

Investigation-

testing

91 (0.4) 93 (3.6) <.001 10.34 7.74–13.80

IVF 518 (2.0) 445 (17.2) <.001 9.38 8.26–10.65

Pregnancy ≥ 20 wk 16 132 (62.9) 1786 (69.6) <.001 1.10 1.05–1.15

Hart et al., JCEM 100(3):911-919, 2015


Diagnoses Non-PCOS PCOS P Value HR 95% CI

Endocrine

Obesity (3.7) 411 (16.0) <.001 4.71 4.19–5.28

Late-onset diabetes 980 (3.8) 321 (12.5) <.001 2.84a 2.49–3.23

Other endo, nutr,

metab 1873 (7.3) 521 (20.3) <.001 2.96a 2.69–3.27

Circulatory

Hypertension 192 (0.7) 98 (3.8) <.001 3.20a 2.47–4.13

IHD 50 (0.2) 21 (0.8) <.001 2.89a 1.68–4.97

CVA 51 (0.2) 15 (0.6) .002 2.58a 1.43–4.67

Other cardiac 266 (1.0) 44 (1.7) .013 1.49a 1.09–2.05

Arterial/venous dis 1497 (5.8) 275 (10.7) <.001 1.81a 1.59–2.05

Hart et al., JCEM 100(3):911-919, 2015


Diagnoses Non-PCOS PCOS P Value HR 95% CI

Musculoskeletal

4167 (16.2) 661 (25.8) <.001 1.55a 1.43–1.68

Mental disorders

Stress/anxiety

1525 (5.9) 358 (14.0) <.001 2.50 2.19–2.76

Depression

1116 (4.3) 252 (9.8) <.001 2.32 2.03–2.67

Drug use-related

1161 (4.5) 227 (8.8) <.001 2.00 1.74–2.31

Other disorder

1704 (6.6) 353 (13.8) <.001 2.16 1.92–2.42

Hart et al., JCEM 100(3):911-919, 2015


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 (<0.01) 9 (0.4) <.001 22.52 6.94–73.14

Breast cancer 88 (0.3) 8 (0.3) .801 0.91 0.44–1.88

Skin cancer 169 (0.7) 14 (0.5) .641 0.83 0.48–1.43

Other cancers* 165 (0.6) 24 (0.9) .083 1.45 0.95–2.23

Hart et al., JCEM 100(3):911-919, 2015


Diagnoses

Non-PCOS PCOS P Value HR 95% CI

External

causes

Adverse

outcome of

medical

treatment

1936 (7.5) 486 (18.9) <.001 2.68 2.43–2.97

Self-harm 750 (2.9) 185 (7.2) <.001 2.52 2.14–2.96

Land transport

accident

victim

982 (3.8) 134 (5.2) .001 1.37 1.15–1.65

Respiratory

Asthma 1160 (4.5) 271 (10.6) <.001 2.51 2.18–2.88

Other

respiratory 3635 (14.2) 585 (22.8) <.001 1.67 1.53–1.82

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

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

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

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

“I can’t be insulin resistant, my sugar is fine.”

• After years of being insulin resistant….

• Beta cells in the pancreas die

• Now the pancreas cannot produce enough insulin to metabolize nutrients and get them into the cells

• The blood sugar is high (because the sugar is in the blood, not in the cells of the body as fuel)

• You are told you are diabetic…..

How do we prevent becoming diabetic?

• Keep the pancreatic beta cells happy

• Become insulin sensitive so the beta cells don’t have to work as hard

• How do you become insulin sensitive?

Key: improve insulin sensitivity • Nutrition

• Decrease both calories & simple carbohydrates

• Increase physical activity and muscle mass

• Sleep 8 hours per night – treat sleep apnea

• Insulin-sensitizing medications

• Insulin-sensitizing supplements

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

endothelium ovary

acne, hirsutism,

alopecia

infertility

anovulation dyslipidemia diabetes

testosterone

ovary

endothelial dysfunction

hyperinsulinemia

Overweight Acanthosis nigricans

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 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

pcos challenge & thomas jefferson university pcos ... · conclusion: screen aggressively, treat...

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