m. jennifer abuzzahab,md 1 june 2012 evaluating and managing precocious puberty and pcos

M. Jennifer Abuzzahab,MD1 June 2012

Evaluating and Managing Precocious

Puberty and PCOS

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 developmentDescribe the role of insulin in steroidogenesisIdentify when to refer to a specialist

Definitions

Adrenarche (Pubarche)Pubic or axillary hairPremature adrenarche (<8yo girls, <9yo boys)

Gonadarche (Puberty)LH/FSH activation of gonadsGender specific sex-steroid production

PCOSOvarian HyperandrogenismIncreased testosterone production (females)Can not occur until after onset of puberty

Precocious Puberty

BMI 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.

Steroidogenesis

Role of LeptinEnhances 17,20 Lyase activityIncreases androstenedioneIncreases DHEA-S

Role of InsulinIncreases ACTH-mediated steroidogenesisCo-gonadotrophic effect on theca cellLink between premature adrenarche and PCOS

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

Xenobiotics

phthalates

Tea tree oil Linalool

Lavendula acetate

Xenobiotics

Bisphenol A

Triclocarban

BPA Estrogen mimeticMice fed high BPA become obese

PhthalatesHigher levels found in obese men/womenLinked to insulin resistance

Insecticides/herbicides/antifungals and many antibacterial soaps

EstrogenicPotentiate steroid effects at receptor level

Xenobiotics

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

Choose plastics 1,2,4 or 5Use stainless steel or glass bottlesConsider alternatives to canned foods

FreshFrozenGlass

Avoid microwaving in plastic

Xenobiotics

Avoid phthalatesVinyl toysVinyl shower curtainsGlitter body products

Diethyl phthalates are “scent enhancers”

Certain air-freshenersLook for fragrance free personal care products, detergents, cleansers

Xenobiotics

Premature Adrenarche

Fetal programminggirls with low birth weight (-1.5SD) predisposed to insulin resistancerapid pubertal progressionearly-normal menarche

Ibanez, L. JCEM 1993;76:1599

Premature AdrenarcheHistory and Physical Exam

Birth historyTanner staging

Laboratory Evaluations17-OHP, Androstenedione, DHEA-S, consider TestosteroneLH/FSHConsider Estradiol

Radiologic EvaluationBone Age1-2 year advance expected

Case Presentation

nearly 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 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 advancedAdrenal precursors normalBreast tissue from peripheral conversion to EstroneFollowing clinically as slightly higher risk for true central precocious puberty.

Premature Adrenarche

Metformin treatment for girls with LBW and PALess insulin resistanceLess androgen excessLess atherogenic lipid profileAltered body composition

BMI 19.5 vs 20.3Fat 13.1kg vs 16.1kgLean 25.8kg vs 24.8kg

Menarche one year later in treated group

Ibanez, L. JCEM 91:2888-2891, 2006.

Premature 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

Insulin Resistance

PseudoacromegalyBlunted pubertal growth spurtPremature AdrenarchePubertal delay in malesPCOS

M De Simone. Int J Obes Relat Metab Disord. 1995 Dec;19(12):851-7M 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”

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

Polycystic Ovarian Syndrome

Virilization Hirsutism Amenorrhea/Oligomenorrhea Infertility

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


Diet and Activity HistoryLaboratory Evaluations

Free TestosteroneSex Hormone Binding GlobulinAdrenal Precursors

Androstenedione17 OH ProgesteroneDHEAS

Two hour post-prandial glucose and insulin


TreatmentDiet and ExerciseOral Contraceptives

low androgenic progesterone (desogestrel) low-estrogen pills not sufficient to supress Testosterone production

SpironolactoneMetformin


Oral contraceptivesChose low bio-available progesterone

DesogenOrtho-cyclen

Increases 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


Ovarian steroidogenesis

LH

FSH

Thecal Cell

Granulosa Cell

Cholesterol

Pregnenolone Progesterone

17OH-Progesterone

Androstenedione

Testosterone

Estrone

Estradiol

InhibinInsulinIGF-1

++-

--

+

+

Biguanides (Metformin)Reduces free testosterone levelsInduces normal ovulatory cycles in 91% of women with PCOSMust consider need for contraception in adolescent population

Gluek, et al. Metabolism, 48(4),1999. 511


Biguanides (Metformin)Decreases hepatic glucose outputIncreases hepatic and muscle sensitivity to insulinStart low, 250mg with dinner

slow increase to goal 1500-2000mg may change to XR

Side effects: anorexia, weight loss, abdominal pain, diarrheaRisk of lactic acidosis, Vit B12 deficiencyCheck 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

Conclusions

Normal timing and cadence of pubertal development

AdrenarchePubertyMenarche 2-21/2 years after breast development

Steroidogenesis altered by obesityLeptinInsulinAromatase in adipocytes

Identify when to refer to a specialistPuberty before 8yo (girls), 9yo (boys)BA more than 2 years advanced

m. jennifer abuzzahab,md 1 june 2012 evaluating and managing precocious puberty and pcos

Documents

pcos slide

specialist slide

growth case slide

role of insulin

fasting insulin

free testosterone levels

oh progesterone dheas

shbg decreases fsh