Case ConferenceCase Conference

Lorena Muñiz, MDLorena Muñiz, MDDecember 2, 2009December 2, 2009

13 mo girl with pubic hair13 mo girl with pubic hair

Incidental finding on PE at WCCIncidental finding on PE at WCC

Pubic hair for 3 monthsPubic hair for 3 months

No axillary hairNo axillary hair

No breast developmentNo breast development

No vaginal discharge/bleedingNo vaginal discharge/bleeding

PMHPMH

Birth: NSVD, FT, no complicationsBirth: NSVD, FT, no complicationsPMH: nonePMH: nonePSHx: nonePSHx: noneImm: UTDImm: UTDDevelopmentally appropriateDevelopmentally appropriateGrowth paramenters wnlGrowth paramenters wnlFH: + mom with similar history of pubic FH: + mom with similar history of pubic hair as an infanthair as an infant

Physical ExamPhysical Exam

Gen: WD, WNGen: WD, WN

HEENT: NC/AT, PERRL, TMi, MMM, no HEENT: NC/AT, PERRL, TMi, MMM, no dismorphic features, OP cleardismorphic features, OP clear

Neck: supple, no massesNeck: supple, no masses

Lungs: CTA B/LLungs: CTA B/L

CV: RRR, no MCV: RRR, no M

Abd: BS+ soft, no HSM, no massesAbd: BS+ soft, no HSM, no masses

GU: + hair in labia majora, no clitoromegalyGU: + hair in labia majora, no clitoromegaly

Laboratory resultsLaboratory results

LH: <0.2LH: <0.2FSH: 2.9FSH: 2.9DHEA-S <15DHEA-S <15Testosterone total <4Testosterone total <4Estrogen totalEstrogen total17 OH pregnenolone17 OH pregnenoloneCMP wnlCMP wnl

US pelvic US pelvic XR bone age pendingXR bone age pending

Premature PubarchePremature Pubarche

OutlineOutline

DefinitionsDefinitions

Normal PubertyNormal Puberty

Premature Puberty: Central precocious Premature Puberty: Central precocious puberty / Precocious pseudopuberty puberty / Precocious pseudopuberty

Premature adrenarchePremature adrenarche

Premature pubarchePremature pubarche

Pubic hair of infancyPubic hair of infancy

DefinitionsDefinitions

Puberty : stage of development during which secondary Puberty : stage of development during which secondary sexual characteristics appear, transition from the sexual characteristics appear, transition from the sexually immature to the sexually mature stage. sexually immature to the sexually mature stage.

Premature puberty: before the age of 8 years in girls and Premature puberty: before the age of 8 years in girls and 9 years in boys. 9 years in boys.

Pubarche: appearance of sexual hair. In girls usually Pubarche: appearance of sexual hair. In girls usually appears first on the labia majora, and it gradually appears first on the labia majora, and it gradually spreads upwards onto the mons; in some girls, begins in spreads upwards onto the mons; in some girls, begins in the axilla.the axilla.

Premature pubarche: isolated appearance of sexual hair Premature pubarche: isolated appearance of sexual hair before the age of 8 years in girls and 9 years in boys. before the age of 8 years in girls and 9 years in boys.

Thelarche: breast development, first sign of puberty in Thelarche: breast development, first sign of puberty in girls.girls.

Premature thelarche: isolated appearance of breast Premature thelarche: isolated appearance of breast development, usually in girls younger than 3 years; development, usually in girls younger than 3 years;

Adrenarche: maturational increase in adrenal androgen Adrenarche: maturational increase in adrenal androgen production, begins at about 6 years of age in girls and 7 production, begins at about 6 years of age in girls and 7 in boys. Change in the pattern of adrenal secretory in boys. Change in the pattern of adrenal secretory response to corticotropin (ACTH), disproportionate rise response to corticotropin (ACTH), disproportionate rise of 17-hydroxypregnenolone and dehydroepiandrosterone of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) relative to cortisol; response primarily occurs in (DHEA) relative to cortisol; response primarily occurs in the zona reticularis of the adrenal cortex. the zona reticularis of the adrenal cortex.

Premature adrenarche: is the most common cause of Premature adrenarche: is the most common cause of premature pubarche. The term applied to otherwise premature pubarche. The term applied to otherwise unexplained premature pubarche in association with a unexplained premature pubarche in association with a plasma steroid pattern indicative of adrenarche.plasma steroid pattern indicative of adrenarche.

Premature pubertyPremature pubertyAppearance of physical and hormonal signs of pubertal Appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal.development at an earlier age than is considered normal.

Early growth spurt initially can cause tall stature, but Early growth spurt initially can cause tall stature, but rapid bone maturation can cause linear growth to cease rapid bone maturation can cause linear growth to cease too early and can result in short adult stature. Early too early and can result in short adult stature. Early appearance of breasts or menses in girls and increased appearance of breasts or menses in girls and increased libido in boys can cause emotional distress.libido in boys can cause emotional distress.

Central precocious puberty is gonadotropin-dependent, Central precocious puberty is gonadotropin-dependent, early maturation of the entire hypothalamic-pituitary-early maturation of the entire hypothalamic-pituitary-gonadal axis, with full spectrum of physical and gonadal axis, with full spectrum of physical and hormonal changes.hormonal changes.

Precocious pseudopuberty is much less common and Precocious pseudopuberty is much less common and refers to conditions in which increased production of sex refers to conditions in which increased production of sex steroids is gonadotropin-independent.steroids is gonadotropin-independent.

Causes of precocious Causes of precocious pseudopubertypseudopuberty

Congenital adrenal hyperplasiaCongenital adrenal hyperplasia

Tumors that secrete human chorionic gonadotropin Tumors that secrete human chorionic gonadotropin (HCG)(HCG)

Tumors of the adrenal gland, ovary, or testisTumors of the adrenal gland, ovary, or testis

Male-limited precocious pubertyMale-limited precocious puberty

McCune-Albright syndromeMcCune-Albright syndrome

Aromatase excess syndromesAromatase excess syndromes

Exposure to exogenous sex steroid hormones.Exposure to exogenous sex steroid hormones.

Pathophysiology of central Pathophysiology of central precocious pubertyprecocious puberty

The onset of puberty is caused by the secretion The onset of puberty is caused by the secretion of high-amplitude pulses of gonadotropin-of high-amplitude pulses of gonadotropin-releasing hormone (GnRH) by the releasing hormone (GnRH) by the hypothalamus.hypothalamus.

Hypothesized mechanisms that suppress onset Hypothesized mechanisms that suppress onset of puberty include (1) the HPG axis, which is of puberty include (1) the HPG axis, which is highly sensitive to feedback inhibition by small highly sensitive to feedback inhibition by small amounts of sex steroids, and (2) central neural amounts of sex steroids, and (2) central neural pathways that suppress the release of GnRH pathways that suppress the release of GnRH pulses. pulses.

High-amplitude pulses of GnRH cause pulsatile High-amplitude pulses of GnRH cause pulsatile increases in the pituitary gonadotropin-luteinizing increases in the pituitary gonadotropin-luteinizing hormone (LH) and follicle-stimulating hormone (FSH). hormone (LH) and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex steroids Increased LH levels stimulate production of sex steroids by testicular Leydig cells or ovarian granulosa cells. by testicular Leydig cells or ovarian granulosa cells. Pubertal levels of androgens or estrogens cause the Pubertal levels of androgens or estrogens cause the physical changes of puberty, including penile physical changes of puberty, including penile enlargement and sexual hair in boys and breast enlargement and sexual hair in boys and breast development in girls. development in girls. These levels also mediate the pubertal growth spurt. These levels also mediate the pubertal growth spurt. Increased FSH levels cause enlargement of the gonads Increased FSH levels cause enlargement of the gonads in both sexes and eventually promote follicular in both sexes and eventually promote follicular maturation in girls and spermatogenesis in boys.maturation in girls and spermatogenesis in boys.

CNS abnormalities associated with CNS abnormalities associated with precocious pubertyprecocious puberty

Tumors (Tumors (astrocytomasastrocytomas, gliomas, germ cell tumors , gliomas, germ cell tumors secreting human chorionic gonadotropin)secreting human chorionic gonadotropin)

Hypothalamic hamartomas Hypothalamic hamartomas

Acquired CNS injury caused by inflammation, surgery, Acquired CNS injury caused by inflammation, surgery, trauma, radiation therapy, or abscess trauma, radiation therapy, or abscess

Congenital anomalies (eg, hydrocephalus, arachnoid Congenital anomalies (eg, hydrocephalus, arachnoid cysts, suprasellar cysts)cysts, suprasellar cysts)

Laboratory StudiesLaboratory StudiesTestosterone levels in boys.Testosterone levels in boys.

Estradiol less reliable in girls.Estradiol less reliable in girls.

Adrenal androgens usually elevated in boys and girls.Adrenal androgens usually elevated in boys and girls.

DHEA-S, is the preferred steroid to measure because its levels are DHEA-S, is the preferred steroid to measure because its levels are much higher and vary much less during the day. much higher and vary much less during the day.

17-OH serum progesterone study if congenital adrenal hyperplasia is 17-OH serum progesterone study if congenital adrenal hyperplasia is suspected. If a random level is wnl, the diagnosis can be excluded; if suspected. If a random level is wnl, the diagnosis can be excluded; if elevated, ACTH stimulation test provides the greatest diagnostic elevated, ACTH stimulation test provides the greatest diagnostic accuracy.accuracy.

Random LH is now the best screening test for central precocious Random LH is now the best screening test for central precocious puberty.puberty.

Stimulation with gonadotropin-releasing hormoneStimulation with gonadotropin-releasing hormone. .

Imaging StudiesImaging Studies

Radiography: hand and wrist to determine bone Radiography: hand and wrist to determine bone ageage. . If bone age is within one year of chronological If bone age is within one year of chronological

age, puberty has not started. age, puberty has not started. If bone age is advanced by 2 years or more, If bone age is advanced by 2 years or more,

puberty likely has been present for a year or puberty likely has been present for a year or more or is progressing more rapidly.more or is progressing more rapidly.

Head MRI: tumor or a hamartoma Head MRI: tumor or a hamartoma Pelvic ultrasonography: ovarian tumor or cystPelvic ultrasonography: ovarian tumor or cyst

TreatmentTreatment

Surgical CareSurgical Care

CNS tumor other than a hamartomaCNS tumor other than a hamartoma

Radiation therapy if surgical resection is incomplete. Radiation therapy if surgical resection is incomplete.

Medication: Gonadotropin-releasing hormone analogMedication: Gonadotropin-releasing hormone analog

Continuous administration of LHRH and GnRH agonists Continuous administration of LHRH and GnRH agonists provides negative feedback and results in decreased provides negative feedback and results in decreased levels of LH and FSH 2-4 wk after initiating treatment. levels of LH and FSH 2-4 wk after initiating treatment. 

Premature adrenarchePremature adrenarcheDHEA-S is the best marker for the presence of DHEA-S is the best marker for the presence of adrenarche. >40 µg/dl, is above normal for 1 to 5 yo and 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 above average for 6 to 8 yo, no greater than normal for early puberty. early puberty.

Above-average DHEA level; other androgen levels are Above-average DHEA level; other androgen levels are normal or minimally elevated. normal or minimally elevated.

Plasma steroid responses to ACTH parallel these Plasma steroid responses to ACTH parallel these changes, with rises of 17-hydroxypregnenolone and changes, with rises of 17-hydroxypregnenolone and DHEA predominating.DHEA predominating.

Serum testosterone and androstenedione concentrations Serum testosterone and androstenedione concentrations in the upper end of the normal prepubertal range, as in the upper end of the normal prepubertal range, as high as 40 and 75 ng/dL.high as 40 and 75 ng/dL.

Exaggerated adrenarcheExaggerated adrenarche

Clinically extreme type of premature adrenarche. Clinically extreme type of premature adrenarche.

Suspected in children with premature adrenarche who Suspected in children with premature adrenarche who have clinical features that suggest an atypical degree of have clinical features that suggest an atypical degree of androgen excess or insulin resistance. androgen excess or insulin resistance.

DHEA-S or androstenedione level is over the level DHEA-S or androstenedione level is over the level typical for adrenarche or elevated for age, or baseline typical for adrenarche or elevated for age, or baseline plasma androgens or the response to ACTH of 17-plasma androgens or the response to ACTH of 17-hydroxypregnenolone is above that of early pubertal hydroxypregnenolone is above that of early pubertal girls.girls.

Slightly advanced onset of true puberty.Slightly advanced onset of true puberty.

Etiology of premature adrenarcheEtiology of premature adrenarche

Traditional hypothesis: early variant of normal Traditional hypothesis: early variant of normal development.development.

Proposed mechanism: process caused by premature Proposed mechanism: process caused by premature development of the adrenal zona reticularis.development of the adrenal zona reticularis.

Girls with premature adrenarche appear to be at Girls with premature adrenarche appear to be at increased risk for developing polycystic ovary syndrome, increased risk for developing polycystic ovary syndrome, obesity, metabolic syndrome, insulin resistance. obesity, metabolic syndrome, insulin resistance.

Premature adrenarche may be an early manifestation of Premature adrenarche may be an early manifestation of the steroidogenic dysregulation that will cause persistent the steroidogenic dysregulation that will cause persistent functional hyperandrogenism of the adrenal glands and functional hyperandrogenism of the adrenal glands and ovaries. ovaries.

Management of premature Management of premature adrenarcheadrenarche

No specific endocrine treatment is required, since this is No specific endocrine treatment is required, since this is a benign condition.a benign condition.

Informe that the condition is a variation of normal due to Informe that the condition is a variation of normal due to sensitivity of the hair follicles to normal trace amounts of sensitivity of the hair follicles to normal trace amounts of male hormone in children, and/or a normal incomplete male hormone in children, and/or a normal incomplete form of early puberty.form of early puberty.

Evaluate for type 2 diabetes Evaluate for type 2 diabetes

Re-evaluate 6 to 12 months later for evidence of Re-evaluate 6 to 12 months later for evidence of virilization.virilization.

Counseling about a diet and exercise programCounseling about a diet and exercise program

15 to 20 % risk of developing PCOS. 15 to 20 % risk of developing PCOS.

Idiopathic premature pubarcheIdiopathic premature pubarche

Premature pubarche without evidence of adrenal Premature pubarche without evidence of adrenal androgen hypersecretion or true sexual precocity.androgen hypersecretion or true sexual precocity.

DHEA-S and other androgens in the normal range for 1 DHEA-S and other androgens in the normal range for 1 to 5 yo children.to 5 yo children.

Serum adrenal androgen responses to ACTH in the Serum adrenal androgen responses to ACTH in the normal range for 1 to 5 yo children.normal range for 1 to 5 yo children.

Presumably reflects increased sensitivity of the Presumably reflects increased sensitivity of the pilosebaceous unit to normal adrenarchal androgen pilosebaceous unit to normal adrenarchal androgen concentrations. May be due to increased androgen concentrations. May be due to increased androgen receptor gene activity. receptor gene activity.

Evaluation of premature pubarcheEvaluation of premature pubarche

History and physical examination: height, amount of History and physical examination: height, amount of sexual hair.sexual hair.

Bone age: single most important laboratory test. Bone age: single most important laboratory test.

Hormonal measurements: testosterone, Hormonal measurements: testosterone, androstenedione and DHEA-S. androstenedione and DHEA-S.

ACTH stimulation test: to exclude congenital adrenal ACTH stimulation test: to exclude congenital adrenal hyperplasia and other virilizing disorders. hyperplasia and other virilizing disorders.

Serum 17-hydroxyprogesterone: >1000 ng/dL (30 Serum 17-hydroxyprogesterone: >1000 ng/dL (30 nmol/L) compatible with 21-hydroxylase deficiency.nmol/L) compatible with 21-hydroxylase deficiency.

Dexamethasone androgen-suppression test: 1.0 mg/m2 Dexamethasone androgen-suppression test: 1.0 mg/m2 in 3 to 4 doses for 4 days, then measure serum cortisol, in 3 to 4 doses for 4 days, then measure serum cortisol, DHEA-S, and androgensDHEA-S, and androgens. . In premature adrenarche, serum DHEA-S falls by In premature adrenarche, serum DHEA-S falls by

>75%, serum cortisol to<1.0 mcg/dL (28 nmol/L), and >75%, serum cortisol to<1.0 mcg/dL (28 nmol/L), and serum androgens to prepubertal concentrations. serum androgens to prepubertal concentrations.

In patients with virilizing tumors, one or more In patients with virilizing tumors, one or more androgen levels remains above these benchmarks in androgen levels remains above these benchmarks in the presence of normal cortisol suppression. the presence of normal cortisol suppression.

In endogenous Cushing's syndrome, none suppress In endogenous Cushing's syndrome, none suppress normally.normally.

Pubic hair of infancyPubic hair of infancyIsolated pubic hair during first 12 months.Isolated pubic hair during first 12 months.

Average age 5 monthsAverage age 5 months

Etiology remains unknownEtiology remains unknown

Transient, undefined phenomenonTransient, undefined phenomenon

Premature adrenarche forerunner of adult diseases: Premature adrenarche forerunner of adult diseases: PCOS, hyperinsulinism, dyslipidemia, early PCOS, hyperinsulinism, dyslipidemia, early cardiovascular disease.cardiovascular disease.

Differential diagnosis includes premature adrenarche Differential diagnosis includes premature adrenarche and pathologic hyperandrogenism: precocious puberty, and pathologic hyperandrogenism: precocious puberty, classic or nonclassic CAH, virilization tumors, exogenous classic or nonclassic CAH, virilization tumors, exogenous exposure.exposure.

QUESTIONS?QUESTIONS?

The parents of a 6-year-old boy are concerned because The parents of a 6-year-old boy are concerned because he has been developing pubic hair over the past 6 he has been developing pubic hair over the past 6 months. On physical examination, you note a recent months. On physical examination, you note a recent growth spurt, Sexual Maturity Rating 3 pubic hair, a growth spurt, Sexual Maturity Rating 3 pubic hair, a penis that is 8 cm in length and androgenized, and penis that is 8 cm in length and androgenized, and testes that are 5 mL in volume. Other findings are testes that are 5 mL in volume. Other findings are normal. His bone age is 7 years. You order normal. His bone age is 7 years. You order measurements of serum testosterone, 17-measurements of serum testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone, hydroxyprogesterone, dehydroepiandrosterone, luteinizing hormone, and follicle-stimulating hormone.luteinizing hormone, and follicle-stimulating hormone.

Of the following, the MOST important additional test is Of the following, the MOST important additional test is measurement of serummeasurement of serum

a. adrenocorticotropic hormonea. adrenocorticotropic hormoneb. estradiolb. estradiolc. free testosteronec. free testosteroned. human chorionic gonadotropind. human chorionic gonadotropine. prolactine. prolactin