Markers and Interventions for Nonobese Women with Polycystic

Ovarian SyndromeZoë Wasserman

What is Polycystic Ovarian Syndrome?

What is Polycystic Ovarian Syndrome?

Polycystic Ovaries Hyperandrogenism

Infrequent/Absent menses

What is Polycystic Ovarian Syndrome?

Polycystic Ovaries Hyperandrogenism

Infrequent/Absent menses

5-6 Million Reproductive Age American Women

What is Polycystic Ovarian Syndrome?

Polycystic Ovaries Hyperandrogenism

Infrequent/Absent menses

5-6 Million Reproductive Age American Women

Exclusionary Diagnosis

PCOS = Exclusionary DiagnosisCongenital Adrenal Hyperplasia

PCOS = Exclusionary DiagnosisCongenital Adrenal Hyperplasia

Adrenal Tumor

PCOS = Exclusionary DiagnosisCongenital Adrenal Hyperplasia

Hypothyroidism:Low Production of Thyroid HormoneAdrenal Tumor

PCOS = Exclusionary DiagnosisCongenital Adrenal Hyperplasia

Cushing Syndrome:Excessive Cortisol Production

Hypothyroidism:Low Production of Thyroid HormoneAdrenal Tumor

Rotterdam Criteria: Hyperandrogenism>80% cases

Roe & Dokras, (2011).

Rotterdam Criteria: Oligo-Anovulation

(Roe & Dokras, 2011).

Rotterdam Criteria: Oligo-Anovulation

→ Earliest Clinical Sign

→ ~ 6-8 week cycles

→ 75% cases(Roe & Dokras, 2011).

Rotterdam criteria: polycystic ovaries

PCOS Phenotypes● Obese vs Nonobese (overweight, normal, lean)● Hyperandrogen + PCO● Hyperandrogen + Anovulation● Anovulation + PCO● Hyperandrogen + PCO + Anovulation

Significance● 60% PCOS patients Obese in USA● 90-95% Anovulatory at fertility Clinics ● 3 x rate of miscarriage● 3x endometrial cancer● Cardiovascular DIsease & Diabetes

Lashen, (2010);Sirmans & Pate, (2013);McGowan, (2011).

Are the metabolic risk Factors due to PCOS or Obesity?

Are the metabolic risk Factors due to PCOS or Obesity?

?

DyslipidemiaInsulin ResistanceDiabetesGestational DiabetesHIgh blood PressureHeart Disease Chronic Inflammation

Are the metabolic risk Factors due to PCOS or Obesity?

DyslipidemiaInsulin ResistanceDiabetesGestational DiabetesHIgh blood PressureHeart Disease Chronic Inflammation

RISK IS INDEPENDENTOF OBESITY!

Are the metabolic risk Factors due to PCOS or Obesity?

DyslipidemiaInsulin ResistanceDiabetesGestational DiabetesHIgh blood PressureHeart Disease Chronic Inflammation

RISK IS INDEPENDENTOF OBESITY!

WHY???

Are the metabolic risk Factors due to PCOS or Obesity?

DyslipidemiaInsulin ResistanceDiabetesGestational DiabetesHIgh blood PressureHeart Disease Chronic Inflammation

RISK IS INDEPENDENTOF OBESITY!

INNATE INSULINRESISTANCE

WHAT IS INSULIN RESISTANCE?

Sirmans & Pate, (2014); Johnson, (2014).

How does insulin resistance effect PCOS?

Kilic et al,(2010)

Polycystic Ovaries: ● No dominant

follicle chosen● Follicles don’t

undergo cell death

Treatments studied:

MetforminStop Gluconeogenesis:Lower Glucose Levels

Decrease Insulin Production

(Genazzani et al, 2004).

Increase Production of Sex hormone Binding Globulin (SHBG)

MetforminStop Gluconeogenesis:Lower Glucose Levels

Decrease Insulin Production

(Genazzani et al, 2004).

Increase Production of Sex hormone Binding Globulin Hyperandrogenism

Ovulation

Oral Contraceptives● Great at creating Menstrual cyclicity &

Preventing Pregnancy● Decrease androgens (increase SHBG)● Decrease hirsutism in 80%● Decreased glucose tolerance● Increase chronic inflammation and BMI● Worsen dyslipidemia Morin-Papunen et al., (2003);Elter, Imir, & Durmusoglu, (2002).

Oral Contraceptives and Metformin● Reduction in:

○ Hyperandrogenism○ Waist: Hip○ BMI○ Pregnancy

Increases in:

○ Insulin Sensitivity○ SHBG Elter, Imir, & Durmusoglu, (2002)

Clomiphene Citrate● Antiestrogenic: normalizes FSH & LH● faster than metformin● Does not Decrease long term morbidity and Mortality risks

○ Ovarian hyperstimulation syndrome, multiple birth pregnancies & Endometrial thinning

○ Pregnancy rate increased 3.5X when used with metformin

Palomba et al., (2005).; Johnson, (2014)

Ovulation

Supplements: Inositol

Oner & Muderris, (2013).

Supplements: Inositol ● 1200 mg of D-chiro-inositol, ~ 2 months

○ Serum Androgen

○ Triglycerides

○ 86% Ovulated!

● 2-4g, Myo-Inositol

○ Oocyte quality

○ Ovulation

○ Dyslipidemia & Hyperandrogenism Nestler et al, (1999). & Unfer et al, (2012).

Hyperandrogenism Infrequent/Absent menses

Supplements: Vitamin D

Oner & Muderris, (2013).

Supplements: Vitamin D ● Deficiency common in PCOS Obese &

Nonobese● Insulin resistance is an independent

predictor of Deficiency● Increase [SHBG]

Velija-Ašimi, (2014).

Hyperandrogenism

Supplements: Omega-3

Oner & Muderris, (2013).

Supplements: Omega-3 1500 mg/day/6 months

● Hirsutism● BMI● LH ● Testosterone● SHBG Oner & Muderris, (2013).

Hyperandrogenism

In Vitro Fertilization & MEtformin● Decrease Ovarian Hyperstimulation

Syndrome: ovaries painful & swollen● Increase oocyte quality● Increase Embryo viability

Kumbak & Kahraman, (2009); Lashen, (2010)

Laparoscopic Ovarian DrillingBest Predictor Of Success:● BMI● Androgen Levels● Normal & Overweight

○ 81% Ovulation○ 57% pregnancy

*Lower Variables = Higher Success*Li, & Ledger, W.L., (2004)

Gestational Diabetes and Metformin

Diet & Exercise

McGowan, (2011) ; Parker, (2015).

Diet & Exercise

McGowan, (2011) ; Parker, (2015).

LOw carbohydrate Diets:○ HDL-c○ Triglycerides○ Systolic Blood Pressure○ Weight

Exercise○ Insulin○ Glucose○ Weight

Public Health Implications● Holistic Approach to health● Direct health Care costs > $4.36 billion (2005).

○ Diagnosis○ Treatment○ comorbidities

● 7 x suicide rates● Diabetes occurs in 40% < 50 years old● Persistence of Obesity

Parker, (2015); Caglar et al, (2013); McGowan, (2010).