Polycystic Ovarian Syndrome (PCOS) in the Adolescent: Where we've been and where are we going Paola Palma Sisto, MD Pediatric Endocrinology Children’s Hospital of Wisconsin Department of Pediatrics Medical College of Wisconsin September 26, 2017

Disclosure Nothing to disclose

Agenda History Diagnosis (2017) Case Assessment Management Future of PCOS

History Vallisneri (1721) Chereau and Rokitansky (1844) Tait (1879) First to describe infertile woman with “shiny large ovaries” Chereau and Rokitansky (1844) Tait (1879) Bulius and Kretschmar (1897) Von Kahlden (1902) McGlinn (1915) Stein and Leventhal (1935) Szydlarska et al. Adv Clin Exp Med (2017)

History Stein and Leventhal 7 women with menstrual irregularities, hirsutism, enlarged ovaries with many small follicles Ovarian wedge resection – resumed menses and allowed for pregnancy >65% Szydlarska et al. Adv Clin Exp Med (2017)

Names Polcystic ovaries disorder A syndrome of polycystic ovaries Functional ovary androgenism Hyperandrogenic chronic anovulation Polycystic ovarian syndrome Ovarian dysmetabolic syndrome Sclerotic polycystic ovary syndrome Polycystic ovary syndrome Szydlarska et al. Adv Clin Exp Med (2017)

Pathophysiology

Infants and childhood: Anti-Muellerian hormone (AMH) Hyperresponsive glucose release Insulin excess Increases steroidogenesis in ovary Reduced liver production of SHBG increased free testosterone

Genetics Of PCOS

Diagnosis 1960’s Elevated LH, testosterone, and urinary 17-ketosteroids Elevated LH/FSH ratio Bilateral cystic ovaries Szydlarska et al. Adv Clin Exp Med (2017)

Diagnosis NIH (1991) Unexplained hyperandrogenic anovulation Criteria Clinical or biochemical excess androgens Rare ovulations Exclusion of other disorders Franks et al. J Clin Endocrinol Metab (1991)

Diagnosis Rotterdam Criteria (2004) 2 out of 3 necessary Anovulation or rare ovulation Clinical and/or biochemical hyperandrogenism Polycystic ovaries on US (after exclusion of other causes) Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Hum Reprod.(2004)

Diagnosis Androgen Excess-PCOS Society consensus criteria (2006) Clinical and/or biochemical hyperandrogenism Ovarian dysfunction and/or polycystic ovaries on US (after exclusion of other causes) Azziz et al. J Clin Endocrinol Metab (2006)

Diagnosis Obesity and insulin resistance Intrinsic to condition Exacerbate PCOS symptoms Not included in diagnostic criteria

Diagnosis in Adolescence Controversial Diagnostic criteria (acne, irregular menses, PCO) normal pubertal events Hyperandrogenemia Disease VS lack of regulated hypothalamic-pituitary-ovarian axis during typical peripubertal anovulatory cycles Witchel et al. Horm Res Paediatr (2015)

Consensus meeting (2015) Pediatrics specialists and Androgen Excess-PCOS Society Criteria for defining PCOS in adolescence Witchel et al. Horm Res Paediatr (2015)

Consensus meeting (2015) Hyperandrogenism (clinical) Excess coarse sexual hair presenting in male-like pattern Moderate-severe inflammatory acne And/or menstrual irregularities Rare-alopecia Witchel et al. Horm Res Paediatr (2015)

Consensus meeting (2015) Hyperandrogenism (biochemical) Assay determines normal range Persistent elevation of serum total and/or free testosterone levels Elevated testosterone in presence of asymptomatic patient NOT considered evidence for hyperandrogenism Witchel et al. Horm Res Paediatr (2015)

Consensus meeting (2015) Oligo-anovulation Menstrual intervals <20 days or >45 days for 2 or more years after menarche Menstrual interval >90 days Lack of onset of menses by 15 years or by >2 years after thelarche Witchel et al. Horm Res Paediatr (2015)

Consensus meeting (2015) Polycystic ovaries by US Limited data Ovarian volume > 12 cubic cm Mulifollicular NORMAL in adolescence NOT a criteria DEFER imaging to make diagnosis Witchel et al. Horm Res Paediatr (2015)

Cases 15 year old Caucasian female 12 year old African American female Breast bud age 9, pubic hair age 10, menarche age 12 Increasing acne, excess facial hair, weight gain (BMI increased from 60th percentile to 85th), menses every 3-4 months Mother with irregular menses, acne, and overweight Breast bud age 9, pubic hair age 8, menarche age 10 Facial acne, sideburns, lower back hair, elevated BMI (consistently >90th percentile since age 8), menses <6 in 1 year Mother with regular menses and obese, facial hair

15 yr old… Questions Thoughts

12 yr old… Questions Thoughts

Physical Findings 15 yr old… 12 yr old… Hirsutism: chin, moustache, sideburns, lower back, linea alba (FG 22) Acne: forehead and upper back No clitoromegaly No acanthosis nigricans Normal thyroid, no galactorrhea Hirsutism: chin, sideburns, lower back (FG 10) Acne: forehead No clitoromegaly Acanthosis nigricans cervical neck Normal thyroid, no galactorrhea

Differential Diagnosis (Hyperandrogenism/Irregular menses) Congenital Adrenal Hyperplasia 21 hydroxylase deficiency (nonclassic) Cushing’s Syndrome McCune Albright Syndrome Glucocorticoid resistance Ovarian androgen secreting tumors Thyroid dysfunction Hyperprolactinemia Adrenal tumors

Assessment: History will direct testing 17-OH progesterone Morning levels >200 ng/dl-- consider CAH Total testosterone Free testosterone SHBG Androstenedione DHEAS Consider.. TSH LH,FSH Prolactin ACTH stimulation testing for CAH Bone age (younger age)

Assessment: Obesity Metabolic workup directed by history (patient and family) and physical exam Fasting: Glucose BUN/creatinine LFTs Lipids ?insulin/c-peptide ?HbA1c

PCOS and mental health Study in adult women from multiple countries including US 2.8 times more likely to report anxiety symptoms vs control 3.5 times more likely to report depressive symptoms vs control Blay et al. Neuropsychiatric Disease and Treatment(2016)

Management Lifestyle Metformin OCP Anti-androgen (spironolactone) Co-morbidities

Management Lifestyle – weight loss reduces insulin resistance reduced androgens Metformin OCP Anti-androgen (spironolactone) Co-morbidities

Management Lifestyle Metformin – improves insulin resistance/reduces androgen production/free testosterone OCP Anti-androgen (spironolactone) Co-morbidities

Management Lifestyle Metformin OCP – puts the ovary “to rest” preventing chronic androgen exposure; protective to reproductive organs Anti-androgen (spironolactone) Co-morbidities

Management Lifestyle Metformin OCP Anti-androgen (spironolactone) – reduces the sensitivity of the hair follicle to testosterone Co-morbidities

Management Lifestyle Metformin OCP Anti-androgen (spironolactone) Co-morbidities – hypertension, hyperlipidemia, acne/hair management

Future Prediction and prevention Epigenetics

EPIGENETICS MODEL PCOS Heritability is high 50% risk of PCOS if mother has it 75% identical twin 35% sister Epigenetic factors Post conception exposure Androgens Endocrine disruptors If in germ cells can be transferred transgenerationally Obesity and PCOS Link to SGA and future insulin resistance

Support for Patients Androgen Excess and PCOS Society (ae-society.org) PCOS Awareness Association (pcosaa.org)

RESOURCES Pedsendo.org

Summary 6-15% women diagnosed with PCOS Complex condition arising from genetic and epigenetic influences, intra and extrauterine environmental factors, exacerbated by insulin resistance Diagnosis in the adolescent needs to take into account the associated risk factors Lifestyle is the mainstay of therapy, support with metformin and OCP, +/- anti androgen to improve symptoms and quality of life

Questions?? Thank you…