Evaluating and Managing Precocious Puberty and PCOS Good Morning and thank you to Drs Kelly and Jacobson for inviting me to give this presentation today. 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 Describe the role of insulin in steroidogenesis Identify when to refer to a specialist

Definitions Adrenarche (Pubarche) Gonadarche (Puberty) PCOS 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 For PCOS the higher androgens lead to Virilization, Hirsutism, Amenorrhea and often Infertility

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.

Steroidogenesis Role of Leptin Role of Insulin 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 Most obese people have high leptin levels, this then increases androgen production In addition, insulin resistance, seen in many overweight children and a precursor to DM2 can increase androgen production from both adrenal glands and ovaries

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

Xenobiotics Endocrine disruptors Mimic natural hormone binding phthalates BPA phyto-estrogens soy lavender oil tea tree oil Phthalate (ooooh!) exposure in pregnant women may come from a variety of sources, most of which contain fragrances. A coalition of environmental and public health groups compiled a study of commonly used cosmetics and listed which of them had high levels of phthalates, “including nine of 14 deodorants, all 17 fragrances tested, six of seven hair gels, four of seven mousses, 14 of 18 hair sprays, and two of nine hand and body lotions, in concentrations ranging from trace amounts to nearly three percent of the product formulation.” Phthalates are banned in cosmetics in the European Union, which may be why many of these companies also produce similar products that are phthalate free. Some examples from the full study (pdf) include: “Unilever make hair sprays with (Salon Selectives and Aqua Net) and without phthalates (Thermasilk and Suave). L’Oreal markets Jet Set nail polish without DBP but puts the phthalate in its Maybelline brand. Procter & Gamble sells Secret Sheer Dry deodorant with phthalates and Secret Platinum Protection Ambition Scent without phthalates. Louis Vuitton has taken phthalates out of its Urban Decay nail polish but still has these dangerous chemicals in Christian Dior nail polish and the fragrance Poison.” Not only are these ingredients legal to put in cosmetics in the United States, but not one of the products with them has anything in the ingredient list to let a consumer make an educated choice. You have to check a study such as this to know. Most phthlates are grouped in under the listing “fragrance”.

Xenobiotics Tea tree oil Linalool phthalates Lavendula acetate                                                                Tea tree oil Linalool It is easy to see how similar in structure tea tree oil and the two major components of lavender oil are to estrogen itself. Probably OK to use if you are making estrogen on your own…likely TOO much if prepubertal child. & can trigger pubertal changes. phthalates Lavendula acetate

Xenobiotics Bisphenol A Triclocarban                                                                Bisphenol A TCC is similar in chemical structure to BPA and is (chemically speaking) a polychlorinated diphenyl urea Triclocarban

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

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

Case Presentation

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

Case Presentation

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

Xenobiotics Avoid phthalates Diethyl phthalates are “scent enhancers” 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

Premature Adrenarche Fetal programming girls with low birth weight (-1.5SD) predisposed to insulin resistance rapid pubertal progression early-normal menarche The typical growth pattern of IUGR/LBW girls especially those with good catch-up growth is to have an exaggerated adrenarche, develop hyperinsulinemia prepubertally and then have a rapid progression through puberty with early-normal onset of menarche and high-risk of PCOS/syndrome X Ibanez, L. JCEM 1993;76:1599

Premature Adrenarche History and Physical Exam Laboratory Evaluations 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

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.

Case Presentation

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.

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 Dr Ibanez has studied growth and early pubertal development in girls with h/o lower birth weight (not always SGA)…find same fetal programming with higher rates of PA. 38 girls studied randomized to metofromin or NO metformin therapy (due to effects of insulin on steroidogenesis) In the third year of the study, the girls received double the metformin dose 0/19 had menarche yet 5/19 untreated group had menarche Ibanez, L. JCEM 91:2888-2891, 2006.

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

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.

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

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” What’s unusual about her history?

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 What’s unusual about her history?

Case

Polycystic Ovarian Syndrome Virilization Hirsutism Amenorrhea/Oligomenorrhea Infertility

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

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

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

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

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

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

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

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

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

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

Growth Case

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

Case

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