Transcript Slides - mnaap

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
Describe the role of insulin in
steroidogenesis
Identify when to refer to a
specialist
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
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
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
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
Tea tree oil
Linalool
phthalates
Lavendula
acetate
Xenobiotics
Bisphenol A
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
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
Ibanez, L. JCEM 1993;76:1599
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
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
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”
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
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
Granulosa Cell
Estradiol
Inhibin
Insulin
IGF-1
Ovarian steroidogenesis
LH
+
Cholesterol
Pregnenolone
+
+
-
Progesterone
17OH-Progesterone
Androstenedione
Thecal Cell
Testosterone
FSH
- -
+
Estrone
Granulosa Cell
Estradiol
Inhibin
Insulin
IGF-1
Ovarian steroidogenesis
LH
+
Cholesterol
Pregnenolone
+
+
-
Progesterone
17OH-Progesterone
Androstenedione
Thecal Cell
Testosterone
FSH
- -
+
Estrone
Granulosa Cell
Estradiol
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