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Insulin Resistance & Rush Hour

PCOS Findings Physical Obesity Hirsutism Acanthosis Abnormal menses Acne Waist to hip ratio Biochemical Androgen FreeTestosterone DHEAS 17OH progesterone Anti-mullerian hormone LH 2 hr Insulin/Glucose HgbA1c PAI-1 Lipids hs CRP TNFα, IL-6, adiponectin Ultrasound Necklace sign Ovarian volume Antral follicle count Doppler blood flow changes

PCOS: Multi-Factorial Treatment Approach Identify multidisciplinary team Eating plan & supplements Exercise plan Sleep hygiene Stress management Insulin-sensitizing medications Metformin GLP-1 receptor agonists Myoinositol:DCI Grassi A. PCOS:The Dietitian s Guide to PCOS. Luca Publishing, Haverford, PA 2013. Cheang KI, Huszar JM, Best AM, Sharma S, Essah PA, Nestler JE. Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Diab Vasc Dis Res. 2009 Apr;6(2):110-9. Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008 Jul;93(7):2670-8. Copyright 2014 PCOS Nutrition Center

PCOS Weight Loss Frequency of obesity in women with anovulation and PCO: 30%-75% Ehrmann. NEJM 325:1223; 2005 Six month weight-loss program for overweight anovulatory women Results of the Treatment group: Lost an average of 6.3 kg (13.9 lbs) Decreased fasting insulin and testosterone levels Increased SHBG concentrations 92% resumed ovulation (12/13) 85% became pregnant (11/13) Clark et al. Hum Reprod 10:2705; 1995

PCOS Dietary Goals Change your relationship with meal time & food Consume more foods rich in complex carbohydrates monounsaturated fat fiber with a ratio of omega-6 to omega-3 fatty acids Reduce Total caloric intake Saturated fat Cholesterol

PCOS Nutritional Supplements Myoinositol D-Chiro 40:1 NAC 600mg bid Cinnamon 600 mg bid Fish Oil 1,000 mg/day: Vitamin D3 Berberine Maitake Mushroom Extract Chlorogenic Acid Carbease: white kidney bean extract, coffee bean extract Garcinia Cambogia Ultra 3-in 1 Carb Blocker: chromium piccolinate, Fish Oil, white kidney bean extract, cinnamon, lipase, protease, black pepper extract Hlebowicz J,et al. Amer J Clin Nutr. 85(6):1552, 2007 Nestler J, et al. N Engl J Med. 340:1314, 1999 Oner G, et al. Eur J Obstet Gynecol Reprod Biol. 159(1):127, 2011 Fulghesu AM, et al. Fertil Steril. 77(6):1128 2002 Wehr E, et al. Eur J Endocrinol. 164(5):741, 2011

PCOS Exercise Sugar intake 10x over past 100 years As glycogen storage muscles become more insulin resistant, insulin levels rise Insulin = storage Once glycogen storage maxed, FFA stored as TG Peripheral muscle cells metabolize 80% of glucose Stored as glycogen High Intensity Interval Training Utilized during endurance cardio > 60 70% target rate & resistance training over 70% of weight max Little JP et al: Appl Physiol EPUB, 2011 Aerobic exercise 3-4x/wk 20-30 min/session Burns 100-200 kcal 40% improvement in insulin sensitivity lasting 48 hrs. DeFronzo RA, et al: Diabets 36:1379, 1987; Segal KR, et al: J Appl Physiol 71:2502, 1991

Burning Calories Muscle tissue is active tissue that burns calories and fat is inactive tissue that stores calories. 75 calories/day lb of muscle tissue. 3 calories a day per lb of fat Those trying to burn calories and lose body fat should increase muscle mass.

Strength Training Program 2-3 sets at 75% of max. weight load Muscle failure ~ 50 seconds or 8-10 reps 2 min break between sets 7 day rest after working each area Exercise large muscle groups first Add 5 lbs if reps > 15 Moderate to slow speed A longer period of muscle tension A higher level of muscle force A lower level of momentum A lower risk of tissue injury

Myoinositol versus Metformin Raffone E, et al, 2010 RCT 120 PCOS women MET vs MI+FA Results: Metformin: 50% restored ovulation 18% conceived 42 pts received MET+ FSH 37.5 IU/day 26% conceived Total pregnancy rate MET and MET+FSH: 36% Myoinositol: 65% restored spontaneous ovulation 30% conceived 38 pts received MYO+FSH 29% conceived Total pregnancy rate MYO and MYO+FSH 48%

Inositol vs Metformin in PCOS 128 women treated for 3 months Group A: myoinositol+d-chiroinositol Group B: metformin 1500mg Significantly better restoration of menses, pregnancy and weight loss in Group A 50 45 40 35 30 25 20 15 10 5 0 Menses Pregnancy Inositol Metformin Hamid A, et al Evidence Based Women s Health J. 5:3; 93-98, 2015. 12

GLP-1 Receptor Agonists & PCOS Prospective 12 week study. 40 obese women with PCOS, pretreated with metformin randomized to one of three groups: [1] metformin 1000 mg BID, [2] victoza 1.2 mg QD or [3]combined metformin 1000 mg BID and Victoza 1.2 mg QD Results: Combined group of metformin and Victoza significantly more weight loss, BMI and waist circumference decreases than other groups. Jensterle Sever etal. Eur J Endocrinol. 170(3): 451, 2014. Combination therapy was superior to Byetta or metformin monotherapy in improving menstrual cyclicity, ovulation rate, free androgen index, and insulin sensitivity and reducing weight and abdominal fat. Both Byetta arms were more effective in promoting weight loss than metformin alone. Elkind-Hirsch et al, J Clin Endocrinol Metab. 93(7):2670, 2008.

Letrozole vs Clomiphene for Infertility in PCOS 750 women received letrozole or clomiphene for 5 cycles Rotterdam PCOS criteria 18-40 years old Adequate sperm, 1 patent fallopian tube & nl uterine cavity Ovulation rate 61.7% vs 48.3% of cycles Live births 27.5% vs 19.1% L vs C 44% more likely with L No significant difference in preg loss rate Twins 3.4% vs 7.4% NS Clomiphene hot flashes Letrozole fatigue & dizziness Legro RS, et al: NEJM 371(2):119 2014

Metformin Who might benefit? 8 or fewer menses per year Hirsutism or elevated androgens Acanthosis nigricans History of gestational diabetes PCO appearing ovaries Family history of diabetes Fasting insulin over 10 miu/ml; 2 hour over 50 miu/ml Hypoglycemic response on 2hr IGTT Metabolic Syndrome

PCOS GRS Metformin Protocol Metformin 500 mg qd wk 1; bid wk 2; tid wk 3; followed by metformin 850 mg bid Take with full glass of water/milk at middle of meal Monitor BBT s, u-hcg if 16 day temp rise seen Re-evaluate @ 3 months Additional time Supplements: NAC, Cinnamon, Ovasitol Increased metformin to 1000mg bid Add GLP1 receptor agonist Letrozole/clomiphene Ovarian drilling Low dose injectables with oocyte cryopreservation IVF

PCOS Metformin & Ovulation 61 PCOS women with BMI >28 26 women received - Placebo 35 women received - Metformin 1500 mg/day 1 ovulated 14 ovulated P<0.001 1 14 28 35 Prog. >25 nmol/l Nestler et al. N Engl J Med 1998

PCOS Metformin & Clomiphene 25 women received - Placebo 2 ovulated 21 women received - Metformin 1500 mg/day 19 ovulated CC P<0.001 50 mg 1 5 10 18 Nestler et al. N Engl J Med 1998

Metformin Improves Pregnancy Rates OGTT offered to women with obesity, AN, GDM, FHX or CC failure 51 had hyperinsulinemia Group 1: Metformin alone (n=11), Met+CC (n=17), Group 2: CC alone (n=23) for 7.5 months average Ovulation (82% vs 78%) Pregnancy rates (63% vs 36%, NS) Pregnancy in women who ovulated appeared higher in metformin patients (75% vs 44%, p=0.054) Lavoie HB, et al. Abstract P2-426 Endocrine Society, 2001

Glucophage XR vs Clomiphene 626 infertile women with the polycystic ovary syndrome Pregnancy rate Clomiphene + placebo 22.5% Extended release metformin plus placebo 7.2% Clomiphene +metformin XR 26.8% Multiples 6%, 0%, 3% Synergistic effect of diet and exercise ignored Equivalency of Glucophage XR and metformin not proven Legro etal: N Engl J Med. 2007 Feb 8;356(6):551-66.

Metformin Reduces Pregnancy Loss in PCOS Retrospective study of PCOS women who became pregnant Group 1: received metformin during pregnancy (n=101) Group 2: control (n=31) Early loss rate 12.9% vs 41.9% (p=0.001) Prior SPAB: 15.7% vs 58.3% (p=0.005) Jakubowicz DJ, et al: abstract P2-427, Endocrine Society, 2001

PCOS Ovarian Drilling Spontaneous ovulation 60-95% Pregnancy 60-85% Requires surgery Adhesions formation 30% require ovulation meds Doesn t work in smokers

PCOS Stimulated Cycles Patients are often hyperresponders Reduced follicular vascularization in PCOS women Jarvela et al. Fert Steril 82:1358; 2004 Hyperinsulinema can result in higher E2/androstendione ratios and increased immature follicles Fulghesu et al. J Clin Endocrinol Metab 82:644; 1997 A major concern is Ovarian Hyperstimulation Syndrome (OHSS) How do you lower risk of OHSS? Insulin sensitizers Lower gonadotropin doses GnRH antagonist cycles Lupron trigger Coasting vs low dose hcg Embryo cryo with ET in an unstimulated cycle Hespan, Dostinex (cabergoline) at retrieval Delvigne & Roszenberg Hum Reprod Update 8:559; 2002

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