Presentation on theme: "Evaluating and Managing Precocious Puberty"— Presentation transcript:
1Evaluating and Managing Precocious Puberty and PCOSGood Morning and thank you to Drs Kelly and Jacobson for inviting me to give this presentation today.M. Jennifer Abuzzahab,MD1 June 2012
2Disclosures I have no relevant financial relationships to disclose. I will be discussing off label use of medications.
3ObjectivesRecognize the normal timing and cadence of pubertal developmentDescribe the role of insulin in steroidogenesisIdentify when to refer to a specialist
4Definitions Adrenarche (Pubarche) Gonadarche (Puberty) PCOS Pubic or axillary hairPremature adrenarche (<8yo girls, <9yo boys)Gonadarche (Puberty)LH/FSH activation of gonadsGender specific sex-steroid productionPCOSOvarian HyperandrogenismIncreased testosterone production (females)Can not occur until after onset of pubertyFor PCOS the higher androgens lead to Virilization, Hirsutism, Amenorrhea and often Infertility
5Precocious PubertyBMI major consideration in evaluation of puberty prior to age 8Breast development can be seen in girls as young as 7 depending on ethnicity and BMIPubic hair prior to 8y in girls and 10y in boys is premature IF BMI is <85%Rosenfield RL, Pediatrics 2009 ;123(1):84-88.
6Steroidogenesis Role of Leptin Role of Insulin Enhances 17,20 Lyase activityIncreases androstenedioneIncreases DHEA-SRole of InsulinIncreases ACTH-mediated steroidogenesisCo-gonadotrophic effect on theca cellLink between premature adrenarche and PCOSMost obese people have high leptin levels, this then increases androgen productionIn addition, insulin resistance, seen in many overweight children and a precursor to DM2 can increase androgen production from both adrenal glands and ovaries
7Case 7 4/12 yo boy referred for early pubertal development adult type body odor for two years, pubic hair development for 6-8 monthsdiet recall shows excessive portions at every meal and breakfast both at home and schoolfamily history for type 2 Diabetes Mellitus in multiple family membersPE remarkable for height above mid parental target, obesity, Tanner 2 pubic hair, scrotal thinning, 2 cc testes, apocrine secretions but no axillary hairlab tests: Bone age 9 years, adrenal precursors slightly elevated, testosterone & LH/FSH prepubertaldiet and exercise regimen started, attempt to get whole family involved
8Xenobiotics Endocrine disruptors Mimic natural hormone binding phthalatesBPAphyto-estrogenssoylavender oiltea tree oilPhthalate (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”.
9Xenobiotics Tea tree oil Linalool phthalates Lavendula acetate Tea tree oilLinaloolIt 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.phthalatesLavendula acetate
10Xenobiotics Bisphenol A Triclocarban Bisphenol ATCC is similar in chemical structure to BPA and is (chemically speaking) a polychlorinated diphenyl ureaTriclocarban
11Xenobiotics BPA Estrogen mimetic Mice fed high BPA become obese PhthalatesHigher levels found in obese men/womenLinked to insulin resistanceInsecticides/herbicides/antifungals and many antibacterial soapsEstrogenicPotentiate steroid effects at receptor level
12Case Presentation 3-11/12 yo girl with 6 months of breast development Term infant, 7# 10ozNo known exposuresRapid height gain over past year, without significant change in weightPE: Tanner 3 breast, Tanner 1 pubic hair
14Case Presentation Bone Age advanced at 5y9m Estradiol <15ng/dL GnRH stimulation testing revealed no rise in LH/FSH or estrogenpelvic ultrasound revealed prepubertal ovaries, no cysts, uterine enlargementEndocrine RN noted glitter “all over” patient at time of stim test
16Xenobiotics Choose plastics 1,2,4 or 5 Use stainless steel or glass bottlesConsider alternatives to canned foodsFreshFrozenGlassAvoid microwaving in plastic
17Xenobiotics Avoid phthalates Diethyl phthalates are “scent enhancers” Vinyl toysVinyl shower curtainsGlitter body productsDiethyl phthalates are “scent enhancers”Certain air-freshenersLook for fragrance free personal care products, detergents, cleansers
18Premature Adrenarche Fetal programming girls with low birth weight (-1.5SD)predisposed to insulin resistancerapid pubertal progressionearly-normal menarcheThe 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 XIbanez, L. JCEM 1993;76:1599
19Premature Adrenarche History and Physical Exam Laboratory Evaluations Birth historyTanner stagingLaboratory Evaluations17-OHP, Androstenedione, DHEA-S, consider TestosteroneLH/FSHConsider EstradiolRadiologic EvaluationBone Age1-2 year advance expected
20Case Presentationnearly 5 yo girl with BO for 2 years, breasts for 1-2 monthsattends 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 exposuresHt 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.
22Case PresentationAGA infant, not at higher risk for precocious puberty, type 2 DM or PCOS.BA only 1.5 years advancedAdrenal precursors normalBreast tissue from peripheral conversion to EstroneFollowing clinically as slightly higher risk for true central precocious puberty.
23Premature Adrenarche Metformin treatment for girls with LBW and PA Less insulin resistanceLess androgen excessLess atherogenic lipid profileAltered body compositionBMI 19.5 vs 20.3Fat 13.1kg vs 16.1kgLean 25.8kg vs 24.8kgMenarche one year later in treated groupDr 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 menarcheIbanez, L. JCEM 91: , 2006.
24Premature AdrenarcheMetformin therapy may be indicated for girls with LBW and premature adrenarchePrevents earlier steps in the cascade from LBW infant to early puberty and menarche, obese BMI and IR/PCOSNormalizes pubertal progression and growth in this populationMay attenuate the activity of the GnRH pulse generator and enhance gonadal feedback on LH secretionInsulin has effects far beyond glucose metabolism
25Insulin Resistance Pseudoacromegaly Blunted pubertal growth spurt Premature AdrenarchePubertal delay in malesPCOSM De Simone. Int J Obes Relat Metab Disord Dec;19(12):851-7M Vignolo. Eur J Pediatr Apr; 147(3):242-4.
27Case 13-9/12yo girl menarche at age 10 Irregular menses and increased acne for one yearSignificant weight gain over past two yearsStrong family history for type 2 diabetesMany female family members with “thyroid condition”What’s unusual about her history?
28CasePE: obesity, acanthosis nigricans, T5 breast, T5 pubic hair in male estucheon, moderate acne face/chest, prominent sideburnsAdrenal precursors normalfreeTestosterone elevated at 7.6total testosterone 65Estradiol 72LH/FSH normalWhat’s unusual about her history?
31Polycystic Ovarian Syndrome Adolescent femalesNeed not have cystsNeed not have LH > FSHMust be differentiated from Adrenal DiseaseExaggerated Adrenarche is a harbinger of PCOS after menarche
32Polycystic Ovarian Syndrome Diet and Activity HistoryLaboratory EvaluationsFree TestosteroneSex Hormone Binding GlobulinAdrenal PrecursorsAndrostenedione17 OH ProgesteroneDHEASTwo hour post-prandial glucose and insulin
33Polycystic Ovarian Syndrome TreatmentDiet and ExerciseOral Contraceptiveslow androgenic progesterone (desogestrel)low-estrogen pills not sufficient to supress Testosterone productionSpironolactoneMetformin
34Polycystic Ovarian Syndrome Oral contraceptivesChose low bio-available progesteroneDesogenOrtho-cyclenIncreases estrogen and SHBGDecreases FSH and LH by negative feedbackDecreases all steroid production by the ovaryIdiosyncratic elevation of cholesterol in 5% of women on OCPNew “low” estrogen products not sufficient for teens or PCOS
38Polycystic Ovarian Syndrome Biguanides (Metformin)Reduces free testosterone levelsInduces normal ovulatory cycles in 91% of women with PCOSMust consider need for contraception in adolescent populationGluek, et al. Metabolism, 48(4),
39Polycystic Ovarian Syndrome Biguanides (Metformin)Decreases hepatic glucose outputIncreases hepatic and muscle sensitivity to insulinStart low, 250mg with dinnerslow increase to goal mgmay change to XRSide effects: anorexia, weight loss, abdominal pain, diarrheaRisk of lactic acidosis, Vit B12 deficiencyCheck renal panel, start MVI
40Growth Case 14 4/12 yo girl referred for irregular periods Breast development at 11, menarche at 13Irregular periods: cycles d, 3-9d mensesrapid weight gain over past year (20#)skips breakfast, otherwise reasonable dietBirth history: term infant 5# 8 ouncesFHX: type 2 DM mgm, pgm, HTN pgfBMI 26.2 (90%), light mustache, mild acanthosis nigricansLaboratory evaluationsadrenal precursors normalfree testosterone 3.7% ( )SHBG 0.1 (1 - 3)fasting insulin 12, glucose 64cholesterol 160
42Case 15 1/2 yo Hmong girl concerned about excessive acne skips breakfast, very light lunch, concentrates calories at the end of the daysedentary lifestyle: “lots of homework”, babysittingbreast development at 10 y, no menarcheBMI 33Acanthosis Nigricans, acne, skin tags, hirsute, mild clitoromegaly (2.2 cm x 0.8 cm)testosterone elevated, adrenal normal, glucose 211, insulin 296
44Conclusions Normal timing and cadence of pubertal development AdrenarchePubertyMenarche 2-21/2 years after breast developmentSteroidogenesis altered by obesityLeptinInsulinAromatase in adipocytesIdentify when to refer to a specialistPuberty before 8yo (girls), 9yo (boys)BA more than 2 years advanced