Transcript Case Conference

Case Conference
Lorena Muñiz, MD
December 2, 2009
13 mo girl with pubic hair
Incidental finding on PE at WCC
Pubic hair for 3 months
No axillary hair
No breast development
No vaginal discharge/bleeding
PMH
Birth: NSVD, FT, no complications
PMH: none
PSHx: none
Imm: UTD
Developmentally appropriate
Growth paramenters wnl
FH: + mom with similar history of pubic
hair as an infant
Physical Exam
Gen: WD, WN
HEENT: NC/AT, PERRL, TMi, MMM, no
dismorphic features, OP clear
Neck: supple, no masses
Lungs: CTA B/L
CV: RRR, no M
Abd: BS+ soft, no HSM, no masses
GU: + hair in labia majora, no clitoromegaly
Laboratory results
LH: <0.2
FSH: 2.9
DHEA-S <15
Testosterone total <4
Estrogen total
17 OH pregnenolone
CMP wnl
US pelvic
XR bone age pending
Premature Pubarche
Outline
Definitions
Normal Puberty
Premature Puberty: Central precocious
puberty / Precocious pseudopuberty
Premature adrenarche
Premature pubarche
Pubic hair of infancy
Definitions
Puberty : stage of development during which secondary
sexual characteristics appear, transition from the
sexually immature to the sexually mature stage.
Premature puberty: before the age of 8 years in girls and
9 years in boys.
Pubarche: appearance of sexual hair. In girls usually
appears first on the labia majora, and it gradually
spreads upwards onto the mons; in some girls, begins in
the axilla.
Premature pubarche: isolated appearance of sexual hair
before the age of 8 years in girls and 9 years in boys.
Thelarche: breast development, first sign of puberty in
girls.
Premature thelarche: isolated appearance of breast
development, usually in girls younger than 3 years;
Adrenarche: maturational increase in adrenal androgen
production, begins at about 6 years of age in girls and 7
in boys. Change in the pattern of adrenal secretory
response to corticotropin (ACTH), disproportionate rise
of 17-hydroxypregnenolone and
dehydroepiandrosterone (DHEA) relative to cortisol;
response primarily occurs in the zona reticularis of the
adrenal cortex.
Premature adrenarche: is the most common cause of
premature pubarche. The term applied to otherwise
unexplained premature pubarche in association with a
plasma steroid pattern indicative of adrenarche.
Premature puberty
Appearance of physical and hormonal signs of pubertal
development at an earlier age than is considered normal.
Early growth spurt initially can cause tall stature, but
rapid bone maturation can cause linear growth to cease
too early and can result in short adult stature. Early
appearance of breasts or menses in girls and increased
libido in boys can cause emotional distress.
Central precocious puberty is gonadotropin-dependent,
early maturation of the entire hypothalamic-pituitarygonadal axis, with full spectrum of physical and
hormonal changes.
Precocious pseudopuberty is much less common and
refers to conditions in which increased production of sex
steroids is gonadotropin-independent.
Causes of precocious
pseudopuberty
Congenital adrenal hyperplasia
Tumors that secrete human chorionic gonadotropin
(HCG)
Tumors of the adrenal gland, ovary, or testis
Male-limited precocious puberty
McCune-Albright syndrome
Aromatase excess syndromes
Exposure to exogenous sex steroid hormones.
Pathophysiology of central
precocious puberty
The onset of puberty is caused by the secretion
of high-amplitude pulses of gonadotropinreleasing hormone (GnRH) by the
hypothalamus.
Hypothesized mechanisms that suppress onset
of puberty include (1) the HPG axis, which is
highly sensitive to feedback inhibition by small
amounts of sex steroids, and (2) central neural
pathways that suppress the release of GnRH
pulses.
High-amplitude pulses of GnRH cause pulsatile
increases in the pituitary gonadotropin-luteinizing
hormone (LH) and follicle-stimulating hormone (FSH).
Increased LH levels stimulate production of sex steroids
by testicular Leydig cells or ovarian granulosa cells.
Pubertal levels of androgens or estrogens cause the
physical changes of puberty, including penile
enlargement and sexual hair in boys and breast
development in girls.
These levels also mediate the pubertal growth spurt.
Increased FSH levels cause enlargement of the gonads
in both sexes and eventually promote follicular
maturation in girls and spermatogenesis in boys.
CNS abnormalities associated with
precocious puberty
Tumors (astrocytomas, gliomas, germ cell tumors
secreting human chorionic gonadotropin)
Hypothalamic hamartomas
Acquired CNS injury caused by inflammation, surgery,
trauma, radiation therapy, or abscess
Congenital anomalies (eg, hydrocephalus, arachnoid
cysts, suprasellar cysts)
Laboratory Studies
Testosterone levels in boys.
Estradiol less reliable in girls.
Adrenal androgens usually elevated in boys and girls.
DHEA-S, is the preferred steroid to measure because its levels are
much higher and vary much less during the day.
17-OH serum progesterone study if congenital adrenal hyperplasia is
suspected. If a random level is wnl, the diagnosis can be excluded; if
elevated, ACTH stimulation test provides the greatest diagnostic
accuracy.
Random LH is now the best screening test for central precocious
puberty.
Stimulation with gonadotropin-releasing hormone.
Imaging Studies
Radiography: hand and wrist to determine bone
age.
 If bone age is within one year of chronological
age, puberty has not started.
 If bone age is advanced by 2 years or more,
puberty likely has been present for a year or
more or is progressing more rapidly.
Head MRI: tumor or a hamartoma
Pelvic ultrasonography: ovarian tumor or cyst
Treatment
Surgical Care
CNS tumor other than a hamartoma
Radiation therapy if surgical resection is incomplete.
Medication: Gonadotropin-releasing hormone analog
Continuous administration of LHRH and GnRH agonists
provides negative feedback and results in decreased
levels of LH and FSH 2-4 wk after initiating treatment.
Premature adrenarche
DHEA-S is the best marker for the presence of
adrenarche. >40 µg/dl, is above normal for 1 to 5 yo and
above average for 6 to 8 yo, no greater than normal for
early puberty.
Above-average DHEA level; other androgen levels are
normal or minimally elevated.
Plasma steroid responses to ACTH parallel these
changes, with rises of 17-hydroxypregnenolone and
DHEA predominating.
Serum testosterone and androstenedione concentrations
in the upper end of the normal prepubertal range, as
high as 40 and 75 ng/dL.
Exaggerated adrenarche
Clinically extreme type of premature adrenarche.
Suspected in children with premature adrenarche who
have clinical features that suggest an atypical degree of
androgen excess or insulin resistance.
DHEA-S or androstenedione level is over the level
typical for adrenarche or elevated for age, or baseline
plasma androgens or the response to ACTH of 17hydroxypregnenolone is above that of early pubertal
girls.
Slightly advanced onset of true puberty.
Etiology of premature adrenarche
Traditional hypothesis: early variant of normal
development.
Proposed mechanism: process caused by premature
development of the adrenal zona reticularis.
Girls with premature adrenarche appear to be at
increased risk for developing polycystic ovary syndrome,
obesity, metabolic syndrome, insulin resistance.
Premature adrenarche may be an early manifestation of
the steroidogenic dysregulation that will cause persistent
functional hyperandrogenism of the adrenal glands and
ovaries.
Management of premature
adrenarche
No specific endocrine treatment is required, since this is
a benign condition.
Informe that the condition is a variation of normal due to
sensitivity of the hair follicles to normal trace amounts of
male hormone in children, and/or a normal incomplete
form of early puberty.
Evaluate for type 2 diabetes
Re-evaluate 6 to 12 months later for evidence of
virilization.
Counseling about a diet and exercise program
15 to 20 % risk of developing PCOS.
Idiopathic premature pubarche
Premature pubarche without evidence of adrenal
androgen hypersecretion or true sexual precocity.
DHEA-S and other androgens in the normal range for 1
to 5 yo children.
Serum adrenal androgen responses to ACTH in the
normal range for 1 to 5 yo children.
Presumably reflects increased sensitivity of the
pilosebaceous unit to normal adrenarchal androgen
concentrations. May be due to increased androgen
receptor gene activity.
Evaluation of premature pubarche
History and physical examination: height, amount of
sexual hair.
Bone age: single most important laboratory test.
Hormonal measurements: testosterone,
androstenedione and DHEA-S.
ACTH stimulation test: to exclude congenital adrenal
hyperplasia and other virilizing disorders.
Serum 17-hydroxyprogesterone: >1000 ng/dL (30
nmol/L) compatible with 21-hydroxylase deficiency.
Dexamethasone androgen-suppression test: 1.0 mg/m2
in 3 to 4 doses for 4 days, then measure serum cortisol,
DHEA-S, and androgens.

In premature adrenarche, serum DHEA-S falls by
>75%, serum cortisol to<1.0 mcg/dL (28 nmol/L), and
serum androgens to prepubertal concentrations.

In patients with virilizing tumors, one or more
androgen levels remains above these benchmarks in
the presence of normal cortisol suppression.

In endogenous Cushing's syndrome, none suppress
normally.
Pubic hair of infancy
Isolated pubic hair during first 12 months.
Average age 5 months
Etiology remains unknown
Transient, undefined phenomenon
Premature adrenarche forerunner of adult diseases:
PCOS, hyperinsulinism, dyslipidemia, early
cardiovascular disease.
Differential diagnosis includes premature adrenarche
and pathologic hyperandrogenism: precocious puberty,
classic or nonclassic CAH, virilization tumors, exogenous
exposure.
QUESTIONS?
The parents of a 6-year-old boy are concerned because
he has been developing pubic hair over the past 6
months. On physical examination, you note a recent
growth spurt, Sexual Maturity Rating 3 pubic hair, a
penis that is 8 cm in length and androgenized, and
testes that are 5 mL in volume. Other findings are
normal. His bone age is 7 years. You order
measurements of serum testosterone, 17hydroxyprogesterone, dehydroepiandrosterone,
luteinizing hormone, and follicle-stimulating hormone.
Of the following, the MOST important additional test is
measurement of serum
a. adrenocorticotropic hormone
b. estradiol
c. free testosterone
d. human chorionic gonadotropin
e. prolactin