PCOS and Your Fertility. Jim Toner, MD, PhD Atlanta Center for Reproductive Medicine

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1 PCOS and Your Fertility Jim Toner, MD, PhD Atlanta Center for Reproductive Medicine

2 PCOS

3 Consequences Androgen excess Acne, oily skin Unwanted hair, male pattern baldness Insulin excess Diabetes, heart disease, high blood pressure Anovulation Infertility Miscarriage Endometrial cancer

4 Causes and consequences bad Genetics Medicines to control high Body Mass poor Diet low Exercise Insulin Androgens Ovary Skin Metabolism Inflammation

6 Cellular disorder

7 Excess insulin secretion in PCO

8 Fertility Goals Having a healthy child safely Getting pregnant Ensure ovulation Bypass hostile cervical mucus Staying pregnant Reducing miscarriage risk Safe pregnancy Reducing risks to mom Reducing risks to child

9 Goal #1: Ovulation First line: Improved diet Aerobic activity Inositol Metformin If insufficient: Clomiphene or letrozole Dexamethasone In vitro fertilization

10 Dietary Goals INCREASE: Complex carbohydrates Monosaturated fats Fiber Omega-3 fatty acids DECREASE: Total caloric intake Saturated fats Sugars

11 Dietary recommendations Low Glycemic Index food: Produces greater weight loss Induces less insulin resistance Low GI Medium GI High GI most fruit and vegetables (but not potato), basmati rice, oats, All-bran sucrose, Mars bar corn flakes, baked potato, jasmine rice, white bread, white rice (Chinese/Japanese) Roberts SB et al., Am Coll Nutr. 21:140S, 2002 Spieth LE et al., Arch Ped Adol. 154:947, 2000 Jenkins DJ et al., Curr Opin Clin Nutr Metab Care. 6:165, 2005

12 Exercise Muscle cells metabolize 80% of glucose Aerobic exercise: 3 to 4 sessions of min / wk Burns kcal 40% improvement in insulin sensitivity that lasts 2 days. DeFronzo et al., Diabetes 36:1379, Seagal et al., J Appl Physiol 71:2502,1991.

13 Medicines for PCOS Inositol Metformin Clomiphene Letrozole Dexamethasone Gonadotropins (FSH, LH)

14 Inositol 2 types, normally present in our bodies Myo-inositol has direct ovarian effects Precursor of inositol triphosphate, a second messenger of insulin, FSH and TSH D-chiro-inositol acts outside the ovarian primarily Normally converted by insulin epimerase into myo-inositol Normally present in 40:1 ratio Myo-inositol Facilitates glucose uptake and FSH action D-Chiro-inositol Facilitates glucose uptake and glycogen synthesis

16 Daily dosing + Myo-inositol = 2,000 mg D-chiro-inositol = 50 mg

17 Metformin effects Decreases insulin secretion levels & LH Increased SHBG Decreases androgens Total T ß 38% Free T ß 58% Androstenedione ß 58% Reduction in weight Improved ovulation rates Improved pregnancy rates Reduced miscarriage rates Nestler J. N Engl J Med 1996;335:617 Hass DA. Fertil Steril 2003;79:469. Macial GA, Fertil Steril 2004;81(2):355 Legro RS. N Engl J Med 2007:356:551

18 Metformin action

19 Metformin Acts to reduce glucose production in liver Increase dose slowly to minimize GI side effects Target dose: 750 to 2,500 mg daily Extended release can be taken once daily with dinner

20 Sufficient? Track menstrual periods If occurring at intervals between 21 and 35 days, likely ovulating Can use OPKs (ovulation predictor kits) to verify: Ensure going from negative to positive Usually occurs 2 weeks before period begins If sufficient, no need to add other medications Time intercourse to day of and after LH surge on OPK

21 Clomiphene versus letrozole clomiphene letrozole

22 Advantages of letrozole over clomiphene More pregnancies in PCO and overweight patients Fewer side effects Headaches, hot flashes, mood effects Less impact on cervical mucus Shorter half life Fewer cysts Gone before implantation, so lower risk of affecting fetal development

23 Role of dexamethasone If clomiphene and letrozole alone fail Reduces androgen levels, allowing for better ovarian response Dose: 0.5 to 2.0 mg daily each morning from days 3 to ovulation

24 Dexamethasone can help dexamethasone 0.5 mg with clomiphene Ovulation PREG Clomiphene CC + Dex Daley et. al., F&S, 1984; 41:844-9 Isaac JD, F&S, 1997; 641-3

25 Cycle management for conception letrozole or clomiphene Ultrasound to verify response (-) (-) (+) Ovul IUI intercourse Progesterone to verify ovulation dexamethasone metformin ER inositol

26 Goal 2: staying pregnant Control diabetes pre-conceptually Hemoglobin A1c < 8% Insulin resistance associated with more miscarriages Inositol and/or metformin

27 Reducing miscarriages in PCO Group Design Metformin Miscarriage rate ref PCO retrospective N=99 preg Yes 9% JCEM 87:524-9, No 42% PCO Prospective N=32 preg Yes 10% F&S 75:46-52, No 73%

28 Goal 3: Safe pregnancy Strive for optimal weight before conception Improve cardiovascular health before conception Close monitoring of pregnancy

29 Risks of being overweight To mom: High blood pressure / pre-eclampsia Diabetes C-section To child: Miscarriage Premature delivery Stillbirths Fetal macrosomia

30 Summary Diet, exercise has many benefits If overweight, a 5% loss can lead to spontaneous ovulation To improve metabolic function: inositol metformin To induce ovulation: letrozole or metformin IVF (but not FSH / IUI)

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