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-pituitary- gonadal 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 gonadotropin- releasing 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 (, gliomas, germ cell tumors secreting human chorionic gonadotropin) Tumors (astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin)astrocytomas 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 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. 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 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. 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 17- hydroxypregnenolone 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 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 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. 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, 17- hydroxyprogesterone, 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 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, 17- hydroxyprogesterone, 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