Download - M. Jennifer Abuzzahab,MD 1 June 2012
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.
ObjectivesRecognize the normal timing and cadence of pubertal developmentDescribe the role of insulin in steroidogenesisIdentify when to refer to a specialist
DefinitionsAdrenarche (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 Leptin
Enhances 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 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 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 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.
Premature AdrenarcheMetformin treatment for girls with LBW and PA
Less 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 groupIbanez, 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
Case
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
Polycystic Ovarian Syndrome
Diet and Activity HistoryLaboratory Evaluations
Free TestosteroneSex Hormone Binding GlobulinAdrenal Precursors
Androstenedione17 OH ProgesteroneDHEAS
Two hour post-prandial glucose and insulin
Polycystic Ovarian Syndrome
TreatmentDiet and ExerciseOral Contraceptives
low androgenic progesterone (desogestrel) low-estrogen pills not sufficient to supress Testosterone production
SpironolactoneMetformin
Polycystic Ovarian Syndrome
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
Polycystic Ovarian Syndrome
Ovarian steroidogenesis
LH
FSH
Thecal Cell
Granulosa Cell
Cholesterol
Pregnenolone Progesterone
17OH-Progesterone
Androstenedione
Testosterone
Estrone
Estradiol
InhibinInsulinIGF-1
++-
--
+
+
Ovarian steroidogenesis
LH
FSH
Thecal Cell
Granulosa Cell
Cholesterol
Pregnenolone Progesterone
17OH-Progesterone
Androstenedione
Testosterone
Estrone
Estradiol
InhibinInsulinIGF-1
++-
--
+
+
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
Polycystic Ovarian Syndrome
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
Polycystic Ovarian Syndrome
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
ConclusionsNormal 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