1. 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

2. Disclosure
Nothing to disclose

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

4. 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)

5. 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)

6. 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)

7. Pathophysiology

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

9. Genetics Of
PCOS

10. 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)

11. 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)

12. 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)

13. 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)

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

15. 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)

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

17. 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)

18. 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)

19. 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)

20. 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)

21. 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

22. 15 yr old…
Questions
Thoughts

23. 12 yr old…
Questions
Thoughts

25. 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

26. 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

27. 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)

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

29. 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)

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

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

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

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

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

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

36. Future
Prediction and prevention
Epigenetics

37. 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

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

40. RESOURCES
Pedsendo.org

41. 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

44. Questions??
Thank you…