PCOS Challenge & Thomas Jefferson University PCOS ... · Conclusion: Screen aggressively, treat...
Transcript of 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
PCOS & Population Health 2566 women – 25,660 age-matched controls 1997-2011
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
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) <.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
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) <.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
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 (<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
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) <.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
Hyperinsulinemia Weight gain
↑ Testosterone
Irregular menses
Infertility
IRS-1 mutation
Pathophysiology: Metabolic
Insulin resistance
Hyperinsulinemia Weight gain
↑ 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