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M. Jennifer Abuzzahab,MD 1 June 2012

Evaluating and Managing Precocious Puberty and PCOS. M. Jennifer Abuzzahab,MD 1 June 2012. Disclosures. I have no relevant financial relationships to disclose. I will be discussing off label use of medications. Objectives. Recognize the normal timing and cadence of pubertal development

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M. Jennifer Abuzzahab,MD 1 June 2012

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  1. Evaluating and Managing Precocious Puberty and PCOS M. Jennifer Abuzzahab,MD 1 June 2012

  2. Disclosures • I have no relevant financial relationships to disclose. • I will be discussing off label use of medications.

  3. Objectives Recognize the normal timing and cadence of pubertal development Describe the role of insulin in steroidogenesis Identify when to refer to a specialist

  4. Definitions Adrenarche (Pubarche) Pubic or axillary hair Premature adrenarche (<8yo girls, <9yo boys) Gonadarche (Puberty) LH/FSH activation of gonads Gender specific sex-steroid production PCOS Ovarian Hyperandrogenism Increased testosterone production (females) Can not occur until after onset of puberty

  5. Precocious Puberty • BMI major consideration in evaluation of puberty prior to age 8 • Breast development can be seen in girls as young as 7 depending on ethnicity and BMI • Pubic hair prior to 8y in girls and 10y in boys is premature IF BMI is <85% Rosenfield RL, Pediatrics 2009 ;123(1):84-88.

  6. Steroidogenesis • Role of Leptin • Enhances 17,20 Lyase activity • Increases androstenedione • Increases DHEA-S • Role of Insulin • Increases ACTH-mediated steroidogenesis • Co-gonadotrophic effect on theca cell • Link between premature adrenarche and PCOS

  7. Case • 7 4/12 yo boy referred for early pubertal development • adult type body odor for two years, pubic hair development for 6-8 months • diet recall shows excessive portions at every meal and breakfast both at home and school • family history for type 2 Diabetes Mellitus in multiple family members • PE remarkable for height above mid parental target, obesity, Tanner 2 pubic hair, scrotal thinning, 2 cc testes, apocrine secretions but no axillary hair • lab tests: Bone age 9 years, adrenal precursors slightly elevated, testosterone & LH/FSH prepubertal • diet and exercise regimen started, attempt to get whole family involved

  8. Xenobiotics • Endocrine disruptors • Mimic natural hormone binding • phthalates • BPA • phyto-estrogens • soy • lavender oil • tea tree oil

  9. Xenobiotics Tea tree oil Linalool phthalates Lavendula acetate

  10. Xenobiotics Bisphenol A Triclocarban

  11. Xenobiotics • BPA • Estrogen mimetic • Mice fed high BPA become obese • Phthalates • Higher levels found in obese men/women • Linked to insulin resistance • Insecticides/herbicides/antifungals and many antibacterial soaps • Estrogenic • Potentiate steroid effects at receptor level

  12. Case Presentation • 3-11/12 yo girl with 6 months of breast development • Term infant, 7# 10oz • No known exposures • Rapid height gain over past year, without significant change in weight • PE: Tanner 3 breast, Tanner 1 pubic hair

  13. Case Presentation

  14. Case Presentation • Bone Age advanced at 5y9m • Estradiol <15ng/dL • GnRH stimulation testing revealed no rise in LH/FSH or estrogen • pelvic ultrasound revealed prepubertal ovaries, no cysts, uterine enlargement • Endocrine RN noted glitter “all over” patient at time of stim test

  15. Case Presentation

  16. Xenobiotics • Choose plastics 1,2,4 or 5 • Use stainless steel or glass bottles • Consider alternatives to canned foods • Fresh • Frozen • Glass • Avoid microwaving in plastic

  17. Xenobiotics • Avoid phthalates • Vinyl toys • Vinyl shower curtains • Glitter body products • Diethyl phthalates are “scent enhancers” • Certain air-fresheners • Look for fragrance free personal care products, detergents, cleansers

  18. Premature Adrenarche Fetal programming • girls with low birth weight (-1.5SD) • predisposed to insulin resistance • rapid pubertal progression • early-normal menarche Ibanez, L. JCEM 1993;76:1599

  19. Premature Adrenarche History and Physical Exam Birth history Tanner staging Laboratory Evaluations 17-OHP, Androstenedione, DHEA-S, consider Testosterone LH/FSH Consider Estradiol Radiologic Evaluation Bone Age 1-2 year advance expected

  20. Case Presentation • nearly 5 yo girl with BO for 2 years, breasts for 1-2 months • attends preschool, keeps up with her peers. • Mood swings and some flirtatious behavior over the past 6 months. • Term infant 7#,4 oz (AGA), adopted at 11 days of age. • no hormone or body building supplement exposures • Ht 118.4 cm (+2.2 SD), Wt 25.4 kg (+2 SD), BMI 18.1 (95%), T2 breasts (flat disks of acinar tissue) with T3 contour, T1 pubic hair (fine, dark hairs across mons pubis), prepubertal labia. no axillary hair, very light apocrine secretions.

  21. Case Presentation

  22. Case Presentation • AGA infant, not at higher risk for precocious puberty, type 2 DM or PCOS. • BA only 1.5 years advanced • Adrenal precursors normal • Breast tissue from peripheral conversion to Estrone • Following clinically as slightly higher risk for true central precocious puberty.

  23. Premature Adrenarche Metformin treatment for girls with LBW and PA • Less insulin resistance • Less androgen excess • Less atherogenic lipid profile • Altered body composition • BMI 19.5 vs 20.3 • Fat 13.1kg vs 16.1kg • Lean 25.8kg vs 24.8kg • Menarche one year later in treated group Ibanez, L. JCEM 91:2888-2891, 2006.

  24. Premature Adrenarche Metformin therapy may be indicated for girls with LBW and premature adrenarche • Prevents earlier steps in the cascade from LBW infant to early puberty and menarche, obese BMI and IR/PCOS • Normalizes pubertal progression and growth in this population • May attenuate the activity of the GnRH pulse generator and enhance gonadal feedback on LH secretion • Insulin has effects far beyond glucose metabolism

  25. Insulin Resistance • Pseudoacromegaly • Blunted pubertal growth spurt • Premature Adrenarche • Pubertal delay in males • PCOS M De Simone. Int J Obes Relat Metab Disord. 1995 Dec;19(12):851-7 M Vignolo. Eur J Pediatr. 1999 Apr; 147(3):242-4.

  26. Insulin Resistance Mantazoros CS, Flier JS, Adv Endo Metab 1995;6:193

  27. Case • 13-9/12yo girl • menarche at age 10 • Irregular menses and increased acne for one year • Significant weight gain over past two years • Strong family history for type 2 diabetes • Many female family members with “thyroid condition”

  28. Case • PE: obesity, acanthosis nigricans, T5 breast, T5 pubic hair in male estucheon, moderate acne face/chest, prominent sideburns • Adrenal precursors normal • freeTestosterone elevated at 7.6 • total testosterone 65 • Estradiol 72 • LH/FSH normal

  29. Case

  30. Polycystic Ovarian Syndrome • Virilization • Hirsutism • Amenorrhea/Oligomenorrhea • Infertility

  31. Polycystic Ovarian Syndrome Adolescent females • Need not have cysts • Need not have LH > FSH • Must be differentiated from Adrenal Disease • Exaggerated Adrenarche is a harbinger of PCOS after menarche

  32. Polycystic Ovarian Syndrome • Diet and Activity History • Laboratory Evaluations • Free Testosterone • Sex Hormone Binding Globulin • Adrenal Precursors • Androstenedione • 17 OH Progesterone • DHEAS • Two hour post-prandial glucose and insulin

  33. Polycystic Ovarian Syndrome Treatment • Diet and Exercise • Oral Contraceptives • low androgenic progesterone (desogestrel) • low-estrogen pills not sufficient to supress Testosterone production • Spironolactone • Metformin

  34. Polycystic Ovarian Syndrome Oral contraceptives • Chose low bio-available progesterone • Desogen • Ortho-cyclen • Increases estrogen and SHBG • Decreases FSH and LH by negative feedback • Decreases all steroid production by the ovary • Idiosyncratic elevation of cholesterol in 5% of women on OCP • New “low” estrogen products not sufficient for teens or PCOS

  35. Ovarian steroidogenesis LH + Cholesterol + • Pregnenolone Progesterone + - 17OH-Progesterone Androstenedione Thecal Cell Testosterone FSH + - - Estrone Estradiol Granulosa Cell Inhibin Insulin IGF-1

  36. Ovarian steroidogenesis LH + Cholesterol + • Pregnenolone Progesterone + - 17OH-Progesterone Androstenedione Thecal Cell Testosterone FSH + - - Estrone Estradiol Granulosa Cell Inhibin Insulin IGF-1

  37. Ovarian steroidogenesis LH + Cholesterol + • Pregnenolone Progesterone + - 17OH-Progesterone Androstenedione Thecal Cell Testosterone FSH + - - Estrone Estradiol Granulosa Cell Inhibin Insulin IGF-1

  38. Polycystic Ovarian Syndrome Biguanides (Metformin) • Reduces free testosterone levels • Induces normal ovulatory cycles in 91% of women with PCOS • Must consider need for contraception in adolescent population Gluek, et al. Metabolism, 48(4),1999. 511

  39. Polycystic Ovarian Syndrome Biguanides (Metformin) • Decreases hepatic glucose output • Increases hepatic and muscle sensitivity to insulin • Start low, 250mg with dinner • slow increase to goal 1500-2000mg • may change to XR • Side effects: anorexia, weight loss, abdominal pain, diarrhea • Risk of lactic acidosis, Vit B12 deficiency • Check renal panel, start MVI

  40. Growth Case • 14 4/12 yo girl referred for irregular periods • Breast development at 11, menarche at 13 • Irregular periods: cycles 21- 45d, 3-9d menses • rapid weight gain over past year (20#) • skips breakfast, otherwise reasonable diet • Birth history: term infant 5# 8 ounces • FHX: type 2 DM mgm, pgm, HTN pgf • BMI 26.2 (90%), light mustache, mild acanthosis nigricans • Laboratory evaluations • adrenal precursors normal • free testosterone 3.7% (0.8-1.4) • SHBG 0.1 (1 - 3) • fasting insulin 12, glucose 64 • cholesterol 160

  41. Growth Case

  42. Case 15 1/2 yo Hmong girl concerned about excessive acne skips breakfast, very light lunch, concentrates calories at the end of the day sedentary lifestyle: “lots of homework”, babysitting breast development at 10 y, no menarche BMI 33 Acanthosis Nigricans, acne, skin tags, hirsute, mild clitoromegaly (2.2 cm x 0.8 cm) testosterone elevated, adrenal normal, glucose 211, insulin 296

  43. Case

  44. Conclusions Normal timing and cadence of pubertal development Adrenarche Puberty Menarche 2-21/2 years after breast development Steroidogenesis altered by obesity Leptin Insulin Aromatase in adipocytes Identify when to refer to a specialist Puberty before 8yo (girls), 9yo (boys) BA more than 2 years advanced

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