presented by

Martha McKittrick RD, CDE

Website: MarthaMcKittrickNutrition.comBlog: CityGirlBites.com Contact: mmckittnyc@gmail.com Twitter: @citygirlbites

Provide background information on PCOS

Discuss the role of insulin resistance in PCOS

Diagnosing & treating PCOS

Provide the RD with guidance for lifestyle education for the patient with PCOS

 

Part One: Background Information on PCOS

PCOS was first identified by Stein & Leventhal in 1935

They described a group of women who were obese and infertile, with enlarged ovaries and multiple cysts

Few of these original features are now considered consistent findings in PCOS

PCOS is possibly the most common hormone abnormality that exists!

Up to 10% of all females have PCOS

6 million American women have PCOS

#1 cause of anovulatory infertility

PCOS is a complex hormonal disturbance that affects the entire body

It has numerous implications for general health and well being

It can affect all females – from adolescence to post menopause

Accounts for ~ $40 billion yearly in the U.S. Dr. Azziz

80%+ show PCO on ultrasound (but having PCO does not mean PCOS!)

40 – 80% will have a fertility problem

60 - 80% hirsuitism

40 - 70% scalp hair thinning (alopecia)

75 - 90% irregular menstrual periods

40 - 60% acne

70% - hyperlipidemia (often low HDL, high LDL)*

10% - acanthosis nigricans

* Legro RS, et al, Am. J. Med. 111, 607-613 (2001).

Acanthosis nigricans

Hirsutism

Alopecia

Insulin resistance (up to 80% of women with PCOS)

Metabolic syndrome (~ 1 in 3 women with PCOS)

Increased risk of diabetes/prediabetes (> 50% will get this by age 40)

Obesity (~ 50% of women with PCOS)

Endometrial Cancer

Obstructive sleep apnea

HTN

Mood disorders

Increased incidence of mood disorders (i.e. depression or anxiety, or to engage in bingeing). Certain features of PCOS may contribute to the increased risk of mood disorders. For example:

Abnormal levels of androgens and other hormones are related to mood disorders

Obesity is linked to mood disorders as well as to abnormal hormone levels. Studies show that the risk of mood disorders is even greater among women with PCOS who are also obese

http://www.nichd.nih.gov/health/topics/PCOS/conditioninfo/Pages/default.aspx

Heart disease

Inflammation

Pregnancy complications

Conclusions: Women with PCOS

Obesity, Cig. Smoking, Dyslipidemia, HTN, IGT, Subclinical Vascular Dz = At risk

Whereas those with metabolic syndrome and/or type2 DM = High risk

http://www.pcoschallenge.org/symposium/2014-presentations/pcos-preventing-cardiovascular-disease-gregorry-pokrywka.pdf

The absence of the important cardiometabolic risk factor represented by obesity often misguides clinicians when lean PCOS patients are evaluated

Actually, IR even in lean women represents an important risk factor for glycometabolic and cardiovascular sequelae 

http://www.sciencedirect.com/science/article/pii/S001502821400315X

Research suggests that PCOS associated with long-term, low-grade inflammation polycystic ovaries to produce androgens

Inflammation is associated with hardened arteries major risk factor for heart attack & stroke.

? inflammation results from obesity and metabolic dysfunction or whether it’s an independent symptom of the disorder

Spontaneous Abortions- increased in high BMI/PCOS pts

Impaired Glucose Tolerance

Gestational Diabetes

HTN

Small for Gestational Age http://www.pcoschallenge.org/symposium/2014-

presentations/pcos-improving-feritliy-mark-perloe.pdf

Likely a Genetic & Environmental component

Genetic. Research has found subtle changes in insulin receptor gene which may alter its function in the ovaries. It is known that insulin is capable of stimulating the ovaries to produce testosterone which causes many of the symptoms of PCOS

Combination effect of pituitary lutenizing hormone (LH) & insulin on stimulating the ovary to produce excessive male hormone (androgens). Obesity magnifies this.

Intrinsic enzymatic abnormalities have been demonstrated in the ovaries as well as the adrenal glands

Part Two: Role of Insulin Resistance in PCOS

IR is a condition where cells do not adequately respond to insulin

IR appears to result from several defects in the relationships among insulin, its receptor, and the genome

IR increases with age and is aggravated by obesity IR is exacerbated at puberty and in pregnancy

http://www.pcospregnancy.net/insulin-resistance.htm

Stimulation of ovarian and adrenal androgen production

Stimulation of pituitary luteinizing hormone (LH) secretion

Inhibition of hepatic sex hormone binding globulin (SHBG) production, leading to a reduced total testosterone in men and increased free testosterone in women

Increased risk of miscarriage

Increased BP Low HDL, high TG Increased apolipoprotein B levels Small dense LDL cholesterol particles Increased fibrinogen levels Increased C reactive protein and other

inflammatory markers Increased thickening and pigmentation of

skin (acanthosis nigricans) Premature atherosclerosis

Can also lead to

Increased food cravings

Weight gain and/or difficulty losing weight

Diagnosing Insulin Resistance is tricky!!

Insulin levels vary throughout the day

Normal range is up to 18, however many experts feel any number over 8 is high

Test Interpretation Fasting insulin 8-14 mU/L mild IR(not very accurate test!) > 14-18 moderate –

severe

Fasting glucose/insulin < 4.5 (< 7.0 in adolescents)ratio

Oral glucose tolerance Normal: 2 hr < 140test Impaired: 2 hr 140-199

Diabetes: 2 hour glucose ≥200

HOMA (Homeostasis Model Assessment) < 2 = normal, 2.2 - 3 = moderate, > 3 = severe

Hyperinsulinaemic glucose clamp “gold standard” – but rarely used

Other clues of IR:Elevated LH/FSH ratioLow SHBGLow HDL and/or TGUpper-body obesity

Acanthosis nigricans BMI > 25 (or waist circumference > 35” in women)

Fam hx of type 2 diabetes or glucose intolerance Age > 40

Study: 72% of overweight/obese pts with PCOS were IR compared to 26% lean

Hypothesized that lean PCOS pts could be affected by an “intrinsic” form of IR whereas obese patients have a combined form of IR due in part to the syndrome itself and in part to the weight excess. In fact, lean PCOS patients could be considered to be a “unique model” to study the natural history of IR per se, because the IR occurs in the presence of normal glucose

http://www.sciencedirect.com/science/article/pii/S001502821400315X

10.3% of lean PCOS have IGT and 1.5% have diabetes. In long-term f/u, 16% of women who had been treated for PCOS 20–30 yrs. earlier had developed DM by menopause. The etiology of the insulin resistance is unclear, but suppression of the excess androgens does not alter the insulin resistance

Even in lean PCOS, a higher waist-to-hip ratio is seen in those with PCOS compared to those without PCOS. This is supported by the higher proportion of visceral adiposity measured by ultrasound in lean PCOS patients compared to weight-matched control subjects

Obese women with PCOS have greater insulin resistance than weight-matched control subjects or lean PCOS subjects http://clinical.diabetesjournals.org/content/21/4/154.full

Part Three : Diagnosing and Treating PCOS

Symptoms and physical exam

Hormonal testing

Ultrasound

Much controversy on what the proper diagnostic criteria are!

Using the Rotterdam criteria, a woman with 2 of the 3 cardinal features that characterize PCOS may have the condition:

Hyperandrogenism (androgen excess) based on:-sx: acne, excessive hirsutism or male-pattern hair loss -elevated circulating levels of androgens (usually

testosterone)

Ovulatory dysfunction – can be manifested as oligomenorrhea or infrequent menstruation

Small cysts on the ovaries as seen on ultrasound.

Legro BMC Medicine (2015) 13:64

http://womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html#j

Individualization is essential

Regulation of cycle Promote weight loss Correction of metabolic abnormalities

- Cholesterol, glucose, insulin resistance, blood sugar, HTNDecrease androgens - Skin, hairImprove FertilityImprove overall well-being

Traditional: the individual symptoms were treated

◦ BCP, anti-androgens, fertility treatments

More recent: targets insulin resistance as well as the individual symptoms

◦ Traditional treatments as above as well as weight loss/exercise and insulin sensitizing agents (ISA)

Lowers blood glucose Slows release of glucose from liver Decreases insulin resistance in muscle

Lowers androgen and insulin levels May lower LDL May aid in weight loss Off label usage in PCOS Helps overweight and normal weight

women achieve ovulation

Gastrointestinal intolerance in 30% (take with meal)

Contraindications:- Creatinine ≥1.4 mg/dL (for women)- Liver disease (or risk thereof: alcohol

abuse/binge drinking)- Other risks for lactic acidosis: pulmonary

disease, congestive heart failure

Dosages range from 500-1000 mg bid. Start slow!!

May need B12 supplement

Has been shown to restore regular menstruation in > 90% amenorrheic adolescents, restoring ovulation in 80%

More effective at restoring ovulation than clomiphene

Potentiates the effect of clomiphene Taken during the 1st trimester, reduces

miscarriage rate by 80%

However – not every women needs Metformin!

Benefits Include:

Increased regularity of menstrual cycles Decreased levels of androgens Improvement in lipid levels Decreased risk of diabetes Improves insulin sensitivity

Part Four: Lifestyle Counseling Tips

- exercise- nutrition- counseling session - practical tips

Weight training ? Card

io?

HIIT?

Movement ?

- Enhances both GLUT4-dependent and hypoxia-dependent glucose transport in skeletal muscle

- Increases skeletal muscle vascularization, mitochondrial neobiogenesis and eventually tissue mass

- Repartitions intracellular fat, thereby improving its utilization

- Fat mass loss

Physical Activity and Insulin Sensitivity The RISC Study Diabetes. 2008 Oct; 57(10):

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2551669/

 

Aerobic exercise increases insulin sensitivity (especially in skeletal muscle) from ~ 25-50% in all ages, gender, body weights

A systemic review of 20 studies found that supervised resistance training improved glycemic control and

insulin sensitivity in a wide variety of study groups

*however this review showed that RT compliance and glycemic control are generally less without supervision

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129661/#R278

HIIT demonstrates improved insulin sensitivity

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129661/#R278

RISC Study: activity has beneficial effects on insulin sensitivity

Total accumulated activity was the important factor rather than intensity of the activity. More movement during the day as well as from exercise, accumulated to exert a beneficial effect on insulin sensitivity

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129661/#R278

Increases insulin sensitivity

Decreases blood pressure

Raises HDL, decreases TG

Burns calories

Increases lean mass

Aids in stress management

Lowers fasting glucose

Anything is better than nothing Get a baseline and increase from there Ideally 3 aerobic and 2 weight training

sessions a week (but not many can do this!) Suggest some HIIT sessions in motivated fit

patients Increase everyday movement Consider activity tracker Beware of “over-exercisers”

In PCOS, women who self-reported 8 hours of sports activities per week had improvement in acne and menstrual irregularities

Exercise as the primary intervention without attendant weight loss (< 5% weight loss) improved insulin sensitivity and free testosterone index and induced ovulation in 9 of 18 obese PCOS patients Julie L. Sharpless, MD http://clinical.diabetesjournals.org/content/21/4/154.full

No one eating plan works for everyone

Realistic, livable eating plan

Long term healthy diet to decrease health risks

If overweight, lose 5-10% of body weight

Low glycemic seems to work best

•PMH•Symptoms (menstrual history, skin, hair, weight)

•Labs (full lipid profile, glucose, insulin, GTT)

•Meds (BCP, anti-androgen, insulin sensitizer, etc.)

• Family hx of PCOS, diabetes, heart

disease

Obtain medical history (including fam. hx), as well as labs, meds, supplements

Ask about symptoms Obtain weight, diet history Ask about “food/mood/energy level” link Provide education on PCOS Discuss exercise Address sleep, mood, sitting time Develop individually tailored meal plans Set realistic goals Maintain supportive demeanor Develop referral network

Hormonal imbalance

Explain insulin resistance

How food affects insulin & glucose levels

Importance of weight loss (even 5-10% of body weight

Role of exercise in lowering insulin levels

Lose weight if overweight

Exercise

Do not smoke

Low glycemic index diet

Medications (insulin sensitizing agents)

Do you feel tired soon after eating a highcarb meal and / or does this meal trigger sugar cravings?

Do meals higher in protein and fat make youfeel more energetic?

Do you feel very tired or irritable if you go for more than 4

hours without eating?

Do you constantly crave carbs?

Is your LDL cholesterol high? Are your triglycerides high?

Calorie control if weight management needed

Low glycemic

Ideally combine “healthy” carb + protein + fat at meals. Promotes satiety and may help prevent insulin spikes

Anti-inflammatory foods

Heart healthy diet

Consume adequate omega 3 fats (supplement if needed)

Magnesium rich foods

Adequate sleep

Stress management

Exercise: cardio & weight train & movement

Pay attention to how foods make you feel

Supplement if needed (Vit B12, Vit D, ? Omega 3, others?)

Endocrine disruptors BPA Phthalates (some) Pesticides Perchlorate Cosmetics, Fragrances ArsenicHormonesAntibiotics I don’t really address these – just food for thought!

Be Fruitful Victoria Maizes MD Integrative Healthcare Symposium, NYC

Inositol and PCOSInositol and PCOS

•Inositols are C6 sugar alcohols of cyclohexane

•There are 9 stereoisomers of inositol, including

myo-inositol and D-chiro-inositol

•Inositol is a component of the inositolphosphoglycans (IPGs) which are “secondary messengers” in insulin signaling

•Insulin resistance appears to be a main underlying metabolic derangement in PCOS, possibly due to a defect in IPG signaling

•Published studies confirm that inositol supplementation can improve insulin sensitivity, reduce serum levels of insulin, testosterone, and LH, and induce ovulation in women with PCOS

Myo-inositol and hormone, metabolic, and Myo-inositol and hormone, metabolic, and ovulation induction effects in women with PCOSovulation induction effects in women with PCOS

•Myo-inositol increased ovulation rates and improved metabolic factors. Gerli, 2007

•Myo-inositol decreased insulin and testosterone levels and improved metabolic factors. Costantino, 2009

•Myo-inositol improved insulin sensitivity and decreased LH and LH/FSH ratio. Artini, 2013

•Myo-inositol improves insulin resistance and hormonal parameters in non-obese women. Genazzani, 2014  

Myo-inositol and Egg Quality Myo-inositol and Egg Quality in Women with PCOSin Women with PCOS

•Myo-inositol decreased the number of days of stimulation, reduced E(2) levels at hGC administration, and decreased degenerated oocytes without compromising total number of oocytes retrieved. Papaleo, 2009

•Myo-inositol increased number of oocytes retrieved and embryos transferred, and improved embryo scores. Ciotta, 2011

•Myo-inositol, but not D-chiro-inositol, improved egg and embryo quality during ovarian stimulation. Unfer, 2011 -

•In women without PCOS, myo-inositol significantly reduced number of ooctyes retrieved, with no change in clinical pregnancy rate. Lisi, 2012

Myo-inositol + D-chiro-inositolMyo-inositol + D-chiro-inositol

•Research indicates that a combination of myo- and D-chiro-inositol, in the body’s physiological ratio of 40:1, is more beneficial than either alone.

• This combination improved metabolic parameters more than myo-inositol alone after 3 months of treatment in overweight women with PCOS. Nordio and Proietti, 2012

•This combination improved lipid profile in obese women with PCOS. Minozzi, 2013

•This combination (vs. D-chiro-inositol alone) improved egg and embryo quality, and pregnancy rates, in women with PCOS undergoing IVF. Colazingari, 2013

Inositol: Treatment considerationsInositol: Treatment considerations

•Inositol is safe and relatively inexpensive

•Reasonable evidence of benefit in PCOS, but may be counterproductive in non-PCOS patients

•Available from multiple sources online or in retail outlets

•Typical recommended daily dose: 2 grams, bid

•Typical treatment regimen of 3-6 months

•Myo-inositol vs. Metformin- in one study, women taking 4 g myo-inositol had higher pregnancy rates and percentage restored ovulation than women on 1500 mg Metformin (Raffone, 2010)

NAC is an antioxidant & amino acid

Derivative of the amino acid L-cysteine, an essential precursor used by the body to produce glutathione

Glutathione is an antioxidant produced by the body to help protect against free radical damage, and is a critical factor in supporting a healthy immune system.

NAC has also been found to reduce inflammation, heart disease and most recently, insulin

http://www.pcosnutrition.com/links/blogs/nac-and-pcos.html

Improved menstrual regularity but has not been shown to help improve fertility in women with PCOS.

NAC may help improve insulin resistance in women with PCOS who have high insulin levels and could be used with metformin or if metformin isn't an option.

NAC also seems to have a favorable effect of lowering cholesterol, TG and testosterone

http://www.pcosnutrition.com/links/blogs/nac-and-pcos.html

Systematic review and meta-analysis of randomized controlled clinical trials

8 studies with a total of 910 women with PCOS were randomized to NAC or other treatments/placebo. RESULTS:

NAC showed significant improvement in pregnancy and ovulation rate as compared to placebo

No significant difference in rates of the miscarriage, menstrual regulation, acne, hirsutism, and adverse events, or change in body mass index, testosterone, and insulin levels with NAC as compared to placebo.

More studies are needed

Obstet Gynecol Int. http://www.ncbi.nlm.nih.gov/pubmed/25653680 2015

 Combination of CoQ10 and clomiphene citrate in the treatment of clomiphene-citrate-resistant PCOS patients improves ovulation and clinical pregnancy rates.

It is an effective and safe option and can be considered before gonadotrophin therapy or laparosc

http://www.ncbi.nlm.nih.gov/pubmed/?term=Coenzyme+Q10+and+pcos opic ovarian drilling