10/24/2014 Conflict of Interest PCOS across the Lifespan: An Update on Treatment • Financial conflict – none Strategies • Research conflict – Funded research: • Ferring Pharmaceutical • Nora Therapeutics • Off –label drug use Marcelle I. Cedars, M.D. – none University of California – San Francisco PCOS: Overview PCOS across the lifespan � Characterized by oligo-ovulation, hirsutism, polycystic ovaries Young Adult Reproductive Age Post Reproductive � 5-10% Reproductive age females � Pathogenesis unclear: - Androgen Diagnosis Fertility - Insulin - Pituitary Management of Symptoms: Cycle Control Hirsutism � Familial clustering: genetic etiology ? Metabolic Alterations 1
10/24/2014 Young Adult PCOS: Diagnosis Rotterdam Criteria Must have at least 2 out of 3: Making the PCOS Diagnosis 1. Oligo- or anovulation 2. Clinical and/or laboratory evidence of hyperandrogenism 3. Polycystic ovaries Exclusion of other etiologies PCOS Diagnosis: Anovulation PCOS Diagnosis: Hyperandrogenism Anovulation Clinical Evidence Lab Evidence Oligo-anovulation • Hirsutism Total Testosterone 1. Less than 8 periods/year • Acne Free Testosterone 2. Variable bleeding pattern • Male pattern DHEA-S 3. Amenorrhea rare alopecia 4. Unopposed estrogen increases risk 2
10/24/2014 PCOS Diagnosis: Ovary Controversy: Follicle Number • Specificity concerns: Ovary Criteria: Follicle cut off of 12 is too low • 12 or more follicles measuring 2-9 mm in • Relevance concerns: diameter Follicle count does not • Increased ovarian associate with metabolic volume (>10cm 3 ) abnormalities Rotterdam Criteria for Polycystic Controversy: Follicle Number Ovary Syndrome (PCOS) • Specificity concerns: Percentage Meeting Rotterdam Criteria, by Age 70 Follicle cut off of 12 is too 62.5 60 AFC >12 in one ovary low Percentage 50 40 34.48 • Relevance concerns: 30 24.69 Follicle count does not 20 6.82 associate with metabolic 10 abnormalities 0 25-30 31-35 36-40 41-45 (n= 48) (n = 88) (n = 84) (n = 45) Age group Modified from Johnstone 2010 3
10/24/2014 Metabolic Impact of Isolated PCO Young Adult -> Reproductive Age • Cycle control and uterine protection • Hirsutism • Acne Johnstone 2010 Management: Uterine Protection Mechanism of OCP ocp o Protect the uterus • Unopposed estrogen = Estrogen o Increase SHBG risk of hyperplasia Pituitary o Inhibit of LH secretion adrenal liver o Inhibit adrenal DHEAS • Options for protection: androgen secretion SHBG LH . Progestin 1. Cyclical Progestin Estrogen 2. Combined contraceptive uterus ovary Testosterone 3. Mirena IUD 4
10/24/2014 Management: Hyperandrogenism Hirsutism Mechanical Removal Pharamacologic Androgenic Alopecia Acne Hirsutism � Oral � Laser Contraceptives � Electrolysis � Spironolactone � Flutamide � Finasteride � Vaniqua Mechanism of OCP Summary: Hirsutism ocp o Protect the uterus Estrogen o Increase SHBG Direct Removal Pituitary o Inhibit of LH secretion adrenal liver Oral Contraceptive o Inhibit adrenal DHEAS androgen secretion SHBG LH . Progestin 6 months Second Agent: Spironolactone uterus ovary Testosterone 5
10/24/2014 Androgenetic Alopecia : Reproductive Age: Fertility Differential Diagnosis: Importance of • Weight Loss and Lifestyle History/Physical Change - Telogen Effluvium - Alopecia Areata • Clomid • Metformin Treatment: • FDA Approved option: Rogaine • Letrozole • Oral contraceptive and Spironolactone 50 mg per day • Drilling • Gonadotropins Lifestyle Changes Lifestyle Change 87 women • 40 women with PCOS/anovulatory 67 patients completed program - obese infertility •Mean change in BMI -3.7 - 79 % PCOS • 27% spontaneous conception Patient choice…. • 53% conceived with assistance •Increased self esteem •Decreased anxiety/depression Structured Hypocaloric Exercise Diet 6 month group 24 weeks 3 sessions/wk program High Protein 20 patients dropped out week - regular exercise 800 kcal deficit •No changes in BMI - gradual dietary •No conceptions changes • C l Palomba et al Human Reproduction 2008 a r k Clark et al Human Reproduction 1995 e t 6
10/24/2014 Exercise vs. Diet: Results Lifestyle Exercise Diet • Lifestyle interventions may increase ovulations and chance of pregnancy Age 26.8 25.8 NS BMI 33.1 33.2 NS • Weight reduction may reduce Dropout 15% 35% 0.14 pregnancy complications % Ovulatory 65% 25% 0.01 Pregnancy Rate 35% 10% 0.06 • Lifestyle interventions should be considered first line Palomba et al Human Reproduction 2008 Ovulation Induction: Mechanism Clomiphene Citrate (Clomid) Clomid • Synthetic Antiestrogen Pituitary Gland FSH • Convenient LH E2 • Inexpensive • Long-standing first choice for ovulation induction in Letrozole women with PCOS Metformin Improve insulin sensitivity Weight Loss 7
10/24/2014 Clomid: What are the chances for conception? How many women will ovulate with Clomid? • 160 patients • Normogonadotropic anovulation • Successful response to clomid • Normal SA • BMI >18.5 Imani, B. et al. J Clin Endocrinol Metab 1999;84:1617-1622 Imani, B. et al. J Clin Endocrinol Metab 1998;83:2361-2365 Reproductive Medicine Network Metformin for ovulation • Multicenter • Biguanide Insulin Sensitizer • Double blind • Category B • 626 women with • Not FDA approved PCOS Randomized Both Metformin Clomiphene Legro et al. NEJM 2007; 35:551-66 8
10/24/2014 Live Birth Prediction Chart Results of RMN PPCOS Trial P<.001 60% 50% P<.001 40% P<.001 30% Predictors of success: 20% •Low hirsutism score 10% •Lower BMI •Younger age 0% OVULATION Conception Livebirth Pregnancy loss •Shorter duration of Metformin Clomid Both infertility Legro et al. NEJM 2007; 35:551-66 Rausch M E et al. JCEM 2009;94:3458-3466 PCOSMIC: Met/Clomid in BMI <32 and >32 Metformin as Pre-Treatment: Results • Randomized double blind trial in New Zealand • BMI >32 (n=65): placebo vs.metformin • BMI < 32 (n=106) CC vs. Met vs. CC/MET Pregnancy rate: • Six month treatment period Metformin 52.6% Live Birth Rates Placebo: 40.4% 50% 43% 36% 40% 29% 30% 16% Effect more Obese Non-Obese 20% 6% 10% pronounced 0% in obese Placebo Metformin Clomid Metformin Clomid + women Met BMI <32 BMI >32 Johnson et al 2010 Hum. Reprod. 25 (7): 1675-1683. Morin-Papunen L et al. JCEM 2012;97:1492-1500 9
10/24/2014 Clomiphene citrate vs. Aromatase Inhibitors Letrozole Legro RS, NEJM 2014 Post-reproductive Summary: Fertility PCOS and Insulin Resistance • The first line treatment for ovulation induction remains lifestyle. 90 • Letrozole superior to Clomiphene citrate 80 70 • Metformin may add benefit as pre-treatment Insulin Resistance (min -1/nmol/ml) 60 • Gonadotropins are second line treatment 50 40 • IVF third line treatment or if over-stimulation 30 cannot avoided 20 10 0 Lean Lean PCOS Obese Obese PCOS Adapted from Dunaif A, et al. JCEM 81: 942-947, 1996 10
10/24/2014 Insulin and the Pathophysiology of Prevalence of IGT or Diabetes PCOS Cardiovascular Insulin disease Hyperglycemia 80% Resistance Diabetes 60% Chicago n=122 Hyperinsulinemia Penn State n=144 40% Fatty Liver Mt Sinai n=110 20% Rezulin Collab Group n=408 Decreased SHBG 0% ovary IGF NGT IGT Type 2 RECEPTOR DM Increased Free Androgen Legro, et al. JCEM 1999; 84: 165-169 Androgen Clinical Hyperandrogenism Azziz et al. JCEM 2001; 86: 1626-1632 production Anovulation Ehrmann et al. Diabetes Care 1999; 22:141-146 Prevalence of IGT and Diabetes IGT Across the Lifespan PCOS versus National population • Adolescents have impaired glucose 40% tolerance 30% and TYPE 2 diabetes 7.4% Percent • Prevalence of Type 2 diabetes in 20% perimenopausal women with history of PCOS is four fold higher compared to controls (32% vs 8%) 0% PCOS Lean PCOS NHANES IGT 30% 10% 1.6% T2DM 8% 0% 2.2% Palmert, MR et al JCEM 2002; 87:1017 11
10/24/2014 Metabolic Syndrome Meta-Analysis of BMI Matched Studies 368 Non-diabetic PCOS patients (Ages18-41) 80% • No Metabolic 80% 66% syndrome in Women with BMI <27 (n=52) 60% 33% 32% 40% • Women with BMI > 30 21% 20% had 13X chance of Odds Ratio (95% CI) in women with PCOS compared to 5% Metabolic syndrome BMI controls 0% � Impaired glucose tolerance: OR: 2.54 (1.44, 4.47) � Diabetes: OR: 4.00 (1.97, 8.10) Ehrmann et al. J Clin Endocrinol Metab. 2006 Jan;91(1):48-53. Moran L J et al. Hum. Reprod. Update 2010;16:347-363 PCOS Phenotypes The Impact of BMI on IGT Impaired Glucose Metabolism by BMI 80% Percent with IGT or T2DM Oligo or Hyperandrogenism Anovulation 60% 40% 20% Polycystic 0% Ovaries 15-20 20-25 25-30 30-35 35-40 40-45 45-50 IGT or T2DM 9% 7% 42% 53% 40% 55% 44% Adapted from Legro, et al. JCEM 1999; 84: 165-169 12
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