Disorders of Puberty




Puberty is defined by both biologic and social standards. Puberty is the time when there is an increase in sex steroid production, resulting in physical changes such as breast development in girls and testicular enlargement in boys, as well as maturation of processes required for future fertility. Puberty, also known as adolescence, is the time when children make the transition to adult patterns of behavior, which involve maturity, responsibility, and sexuality.


Normal Pubertal Development


(See Nelson Textbook of Pediatrics, p. 2655.)


Terminology


Various terms are used to discuss puberty ( Table 42.1 ). Bone age refers to the degree of epiphyseal calcification, width, and proximity to adjacent metaphyses and is a marker of physical maturity that normally corresponds to chronologic age. Dental age generally correlates with bone age. Bone age is usually determined from a radiograph of the left hand and wrist, with comparison to gender-appropriate standards in Greulich and Pyle’s bone age atlas. In infants and toddlers, a more accurate assessment of bone age can be determined from a radiograph of the hemiskeleton, with primary attention to epiphyses of the long bones. Delayed or advanced bone age occurs in many conditions; bone age is strongly influenced by sex steroid production. The timing of the onset of puberty is usually more closely linked to the bone age than to the chronologic age when the 2 are significantly discordant. Regardless of chronologic age, linear growth ceases when the bone age reaches 15 years in females and 18 years in males.



TABLE 42.1







Puberty Terminology



  • Gonadarche: maturation of the gonads under the control of the hypothalamus (GnRH) and pituitary gland (FSH and LH)



  • Thelarche: presence of breast development in girls



  • Gynecomastia: presence of breast development in boys



  • Adrenarche or development of androgen-regulated pubarche: secondary sexual characteristics, including pubic hair, axillary hair, apocrine (underarm) odor, and acne, in both sexes



  • Menarche: time of the first menstrual period



  • Spermarche: time when a boy is first able to produce sperm



Anatomy


Puberty is controlled by the production of gonadotropin-releasing hormone (GnRH) in the anterior hypothalamus. GnRH-containing cell bodies project axons to the median eminence, where they terminate on the hypothalamic portal vessels. This system is referred to as the GnRH pulse generator . After GnRH reaches the anterior pituitary gland via the portal vasculature, it stimulates the production of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the gonadotroph cells. In females, both FSH and LH are required for estrogen production by ovarian granulosa cells. The regulated secretion of FSH and LH is also required for follicle growth, ovulation, and maintenance of the corpus luteum. In males, FSH regulates spermatogenesis by Sertoli cells within the seminiferous tubules, and LH activates Leydig cells to produce testosterone. Androgens cause development of male internal and external reproductive organs and secondary sexual characteristics in both sexes by binding to receptor proteins in the cells of target tissues. Sex steroids also exert a negative feedback effect on the pituitary gland and hypothalamus.


Physiology


Perinatal Period and Infancy


Maternal estrogens stimulate breast development in both male and female fetuses. Maternal estrogens also stimulate uterine developmental and endometrial growth; at birth, withdrawal of the high levels of maternal estrogen and placental progesterone causes the infant endometrium to regress or even slough and manifests as vaginal bleeding.


At birth, levels of LH and FSH in both sexes rise markedly and remain elevated for several months. In the girl, FSH stimulates ovarian granulosa cells to produce 17β-estradiol sufficient to maintain prenatal breast development for up to 8 months of life. Estrogen-induced vaginal cornification is generally evident as abundant vaginal discharge at birth and is maintained as long as estrogens are produced. Ovarian size from birth to 3 months ranges from 0.7-3.6 cm 3 , decreasing to 2.7 cm 3 by 12 months and to 1.7 cm 3 by 24 months; this size persists until the onset of puberty. Ultrasound studies of the ovaries in normal infants show many microcysts.


Male breast development regresses rather quickly after birth. Elevated LH levels after birth stimulate Leydig cell production of testosterone for 6-12 months, leading to further genital development. Penis length increases from 3-5 cm in the full-term newborn to 4.5-6 cm by 2-3 years.


Childhood


By 2 years of age, serum gonadotropin levels decrease, and thus serum sex steroid levels also decrease, frequently to levels undetectable by conventional assays.


Beginning approximately at ages 6-7 years in females and 7-8 years in males, adrenal androgen production begins to increase and can be detected by the presence of increasing concentrations of the weak adrenal androgen dehydroepiandrosterone (DHEA) and its sulfated derivative, DHEA sulfate (DHEAS). Despite these serum levels, there is initially no secondary sexual (pubic or axillary) hair development.


Adolescence


Beginning on average at about 10.5 years in females and 11.5 years in males, there is the return of activity of the hypothalamic GnRH pulse generator, leading to increased serum levels of FSH and LH. The trigger mechanism for this resurgence is unknown, but it may be linked to attainment of a critical body mass or fat mass. Leptin, a hormone produced by fat cells, may be the connection between weight (fat mass) and pubertal events. In early puberty, the activity of the hypothalamic GnRH pulse generator is mostly evident overnight (sleep-entrained), with pulses increasing in number and amplitude and eventually occurring every 60-90 minutes. Over time, this process begins to occur during the daytime; there is always greater gonadotropin secretion at night. Because of the longer half-life of sex steroids, serum levels of estradiol and testosterone show little, if any, diurnal variation. Testosterone levels may be slightly higher in the morning with advancing puberty. There is central sensitivity to the negative feedback effects of sex steroids, leading to significant elevations of gonadotropins when sex steroid production is impaired. The function of the hypothalamic GnRH pulse generator can be accelerated in the setting of obesity, and LH and FSH secretion can revert to the prepubertal pattern in the setting of significant weight loss, as occurs in females with anorexia nervosa.


Usually within 6 months of the onset of this heightened GnRH pulse generator activity in females, there is also increasing production of androgens by the adrenal glands, the major source of androgens in females. In males, the testes are the main source of androgens, although male adrenarche also begins about 6 months after gonadarche.


Sex Steroid Effects


(See Nelson Textbook of Pediatrics, p. 2735.)


In response to FSH, both testes and ovaries enlarge, starting gonadarche. Ovarian granulosa cells produce 17β-estradiol, which causes estrogen effects that generally occur in a fixed order ( Table 42.2 ). Growth increase is one of the early effects of estrogen. Growth is stimulated by estrogen-stimulated increased production of growth hormone and insulin-like growth factor 1. Estrogens along with growth hormone and thyroid hormones increase bone mineralization and growth.



TABLE 42.2

Estrogen Effects








  • Vaginal and urethral cornification



  • Breast development, often asymmetric



  • Linear growth



  • Fat development



  • Uterine development



  • Menarche: 2-2.5 yr after breast buds



In response to LH, testicular Leydig cells produce testosterone, which is converted to dihydrotestosterone, leading to androgen effects that generally occur in the same order ( Table 42.3 ).



TABLE 42.3

Androgen Effects








  • Psychologic changes



  • Skin and hair oils, sweat odors



  • Areolar growth and pigment



  • Sexual skin pigment and folding



  • Phallic growth



  • Voice change



  • Sexual hair growth



  • Hairline recession



  • Statural growth



  • Muscle mass/strength



Note that growth is not stimulated early in puberty by rising testosterone; in fact, during the phase when testosterone levels are beginning to rise, growth is usually slowed perceptibly from a prepubertal height velocity of perhaps 5 cm/yr to a velocity as slow as 4 cm/yr for 12-18 months. As levels of testosterone increase closer to 400 ng/dL and testis volume increases to between 10 and 12 cm 3 , males make the transition to rapid growth. Rapid growth for males thus occurs for about 2 years in middle puberty, and slower growth continues for 2-3 more years.


Benign adolescent gynecomastia occurs in as many as 40-60% of normal males; enough estrogen relative to the amount of testosterone is produced so that breast development occurs. Gynecomastia usually starts in early to middle puberty (peak age, 13 years), before adult male concentrations of testosterone are achieved. It typically starts on one side and resolves within 2 years. Gynecomastia is more common in obese males, although true breast tissue in this setting is often difficult to distinguish from fat tissue (lipomastia).


Chronology of Puberty


Females


Females begin puberty at an average age of 10.5 years (range, 8-13 years; mean ± 2.5 standard deviations [SD]). There are data suggesting that female puberty begins at an earlier age and that African-American females begin puberty about 1 year earlier than white females, but this is not universally accepted. In 85% of females, the first clinically detectable sign of puberty is breast development (thelarche), although ovarian enlargement, which is not clinically detectable in a strict sense, occurs first. Breast buds appear as small nodules either directly underneath the nipples or slightly off center, causing the areolae and nipples to be pushed out and sometimes cause minor, transient discomfort as the skin around the nipple is stretched. Breast development may be unilateral and asymmetric in its earliest stages. Pubic hair usually begins to develop within the next 6 months; in approximately 15% of females, pubic hair precedes breast development. Such discordance has no clinical significance. The female adolescent growth spurt commences near the onset of thelarche, generally spanning a 2-year period between the ages of 11 and 13 years. Axillary hair generally begins, on average, between 12 and 13 years. Menarche, a rather late event in female puberty, occurs on average between 12.2 and 12.8 years, typically 2-2.5 years following thelarche. Menarche is often preceded by a whitish, non–foul-smelling vaginal discharge (physiologic leukorrhea) for up to 6 months. At the time of menarche, an adolescent female has reached 96.5% of her adult height potential. However, more linear growth may remain in clinical situations in which menarche occurs at a younger bone age than is typical for the average adolescent female. Menstrual cycles for the 1st 2 years after menarche are often anovulatory and irregular in frequency.


Males


Males begin puberty at an average age of 11.5 years (range, 9-14 years; mean ± 2.5 SD). The 1st clinically detectable sign of puberty is testicular enlargement, a fact generally unknown to patients and their parents. From birth to the start of puberty, male testicular volumes range between 1 and 2 mL as determined by the use of an orchidometer (a series of ellipsoid models of varying volumes). Stretched penile length (measured with a rigid tape measure on the dorsum of the penis from the pubic symphysis to the tip of the nonerect penis without considering any foreskin tissue) averages about 3.5 cm (range, 2.8-4.2 cm) at birth and grows by an average of 2.5 cm until the start of puberty. The onset of male puberty is considered to have begun when at least 1 of the 2 testicles reaches 4 mL in volume. It takes approximately 5-6 years for the testicles to reach the average adult volume of 18 mL. Approximately 75-80% of the adult testicle consists of seminiferous tubules; testosterone-producing Leydig cells make up the remainder.


Within 6 months after the start of testicular enlargement, pubic hair can be found; pubic hair precedes testicular enlargement in approximately 15%. The presence of pubic hair is incorrectly considered the 1st evidence of puberty in boys by both patients and parents. Pubic hair is followed by the development of axillary hair at approximately 14 years of age. During this time, penile enlargement also occurs, reaching a mean adult length of 12.4 ± 1.6 cm at 20 years of age. The male adolescent growth spurt typically occurs between the ages of 13 and 15 years, commencing when the testicular volumes reach 12 mL. By age 15 years, a male has attained 98% of his final adult height. The ability of adolescent boys to produce sperm, as evidenced by detection of spermatozoa in urine samples, begins between 13.5 and 15 years.


Clinical Staging of Puberty


Standardized staging of pubertal development in both sexes allows for comparison between children, as well as longitudinal monitoring of individual children.


Breast development in females, genitalia in males, and pubic hair in both sexes are scored according to 5-stage systems originally devised by James M. Tanner and referred to as Tanner stages 1-5. Axillary hair in both sexes is rated by a 3-stage system referred to as stages 1-3. Puberty itself is not staged because different components of puberty may occur at different stages.


Females


For breast development, Tanner stage 1 refers to no breast development; Tanner stage 2, to the presence of just breast buds (1 or 2); Tanner stage 3, to the beginning of formation of the peripheral mound with elevation of the breast; Tanner stage 4, to a further increase in breast size, with the formation of the so-called “double contour,” in which the areola and papilla are both raised off the surface of the whole breast; and Tanner stage 5, to adult size, with a return to the single contour in which the surface of the areola is again flush with that of the breast. It may be difficult to differentiate between Tanner stages 3 and 5 because the only difference between these 2 stages is breast size (determined mostly by fat content). Thus, small breasts, especially in an older adolescent female, should not necessarily be construed as Tanner stage 3, especially if she has already menstruated, which typically occurs when the breasts have reached Tanner stage 4 and/or if women in the family typically have small breasts.


Males


For external genitalia, Tanner stage 1 refers to the prepubertal state (testes < 4 mL in volume); Tanner stage 2, to slight enlargement of the testes and scrotum; Tanner stage 3, to lengthening of the penis and further enlargement of the testes and scrotum; Tanner stage 4, to continued penile growth in both length and width with development of the glans; and Tanner stage 5, to adult appearance. An alternative, simplified, and equally accurate approach involves only sizing of the testicles, whereby 4 mL represents the start of puberty, 12 mL correlates with the start of the growth spurt, and 18 mL is the average adult size. In some cases, the appearance of pubic hair does not occur until the testicular volumes reach 12-15 mL. Testicular volumes may differ at all stages between sides but not usually by more than one size on a standard orchidometer. It is important not to confuse a hydrocele with an enlarged testis.


Females and Males


Tanner staging of pubic hair is similar in both sexes. Tanner stage 1 is defined by having no pubic hair. Tanner stage 2 is characterized by the presence of a few, countable strands of curly, coarse, pigmented hair either in the mons area or perilabially along the midline in females or at the base of the penis and/or on the scrotum in males. Lighter, peach fuzz–like hair (lanugo) in the pubic region is not pubic hair. On occasion, especially in individuals from ethnic populations from Mediterranean countries or Northern India, there may be an extension of coarse body hair (hypertrichosis) to the pubic region that can be difficult to discern from pubic hair. Tanner stage 3 refers to the presence of coarser, darker, and curlier hairs, the number of which is no longer countable, which have spread more laterally. Tanner stage 4 refers to a thick, fully triangular pattern of hair growth, without spread to the thighs. Finally, Tanner stage 5 refers to the adult pattern in which there is spread of hair to the medial thighs. The designation Tanner stage 6 is used to describe hair growing up the linea alba, referring to the so-called male escutcheon.


Axillary hair is the simplest component of puberty to quantify. Stage 1 refers to the absence of any hair. Stage 2 refers to a countable number of curly, coarse, pigmented strands in at least 1 armpit. Stage 3 refers to the adult complement, which is merely more hair than is present in stage 2. For the individual with shaved axillae, it is safe to assume either stage 2 or stage 3 hair is present.


Family Patterns


The timing of puberty is affected by familial patterns; both parents’ histories are important in assessing the child with early or late puberty. The following information is useful for establishing the parental effect:




  • Age of their mother’s menarche



  • Age their father began shaving on a daily basis



  • Age when their parents stopped growing





Precocious Puberty


(See Nelson Textbook of Pediatrics, p. 2657.)


Definition


The onset of puberty, at least in females, may be occurring earlier than in the past; therefore, the definition of precocious puberty has been modified to refer to the appearance of any feature of puberty before 7 years of age in African-American females (and perhaps even before 6 years), before 8 years of age in white females (and perhaps even before 7 years), and before 9 years of age in males (regardless of race). If this conservative definition is applied, it remains important to consider pathologic causes in children who present with signs of puberty in the age range between the new and former definitions. The family pattern must also be considered; an early onset of puberty is frequently familial.


Normal Variants


Idiopathic Isolated Premature Thelarche


This common condition is the development of breast tissue in females before 8 years of age in white children and 7 years of age in African-American children, with no other manifestations of puberty ( Fig. 42.1 ). Elevated serum estrogen levels for age have been difficult to demonstrate, although higher levels than in age-matched normal females have been measured by an ultrasensitive estradiol assay. Development of breast tissue commonly begins between 2 and 3 years of age; it may be present from birth. The observed tissue may be asymmetric, unilateral, or bilateral. When asymmetric or unilateral, parents are typically concerned about the possibility of malignancy, an extremely rare occurrence in childhood. The early breast tissue frequently regresses without intervention, but it may persist. If it persists, the degree of development does not usually exceed Tanner stage 3. The bone age, if determined, is not frequently advanced, and there is no associated growth spurt. If these simple clinical criteria are met, no hormonal studies or additional radiologic procedures are necessary.




FIGURE 42.1


Two-year-old twin sisters with idiopathic isolated premature thelarche manifested by isolated breast development to Tanner stage 3.


Physiologic breast enlargement also occurs in neonates from placental transfer of estrogens. Most marked in the 1st weeks of life, it usually regresses by 1-2 months.


Idiopathic Isolated Precocious Adrenarche


This common, normal variant is characterized by the development of pubic hair, axillary hair and odor, and/or a small amount of acne in white females before the age of 8 years, in African-American females before the age of 7 years, and in males before the age of 9 years. It appears to result from early production of adrenal androgens. Precocious adrenarche occurs much more commonly in females than in males and develops most often in obese and/or African-American females and in brain-injured children. There is no associated evidence of virilization (no growth spurt, no significant advancement of bone age, no increase in muscle bulk, no voice deepening, and no temporal hair recession). In females, there is no associated clitoromegaly and no evidence of estrogen-mediated components of puberty; in males, there is no phallic or testicular enlargement. If a child presents at a very young age, it is generally presumed that an organic cause (such as congenital adrenal hyperplasia) will be found. However, in infant males with isolated scrotal hair, typically no cause is found, and the hair subsequently falls out. In most cases of idiopathic precocious adrenarche (benign premature adrenarche), serum levels of DHEA and/or DHEAS are consistent with the reference range of Tanner staging of the hair growth, and the 8:00 a . m . 17-hydroxyprogesterone level is normal. If these criteria are met, no additional laboratory studies are indicated. This pubertal variant was considered benign and self-limited, but data suggest that at least in females with associated low birth weight, it may suggest an increased risk for polycystic ovary disease .


Isosexual Central Precocious Puberty


Central sexual precocity results from activation of the hypothalamic-pituitary-gonadal axis at an earlier-than-normal age ( Fig. 42.2 ). Isosexual development refers to pubertal changes appropriate for the sex of the child, such as breast budding in females and testicular enlargement in males. This is to be distinguished from contrasexual development, in which the pubertal features in females are mediated by male hormones (clitoromegaly) and those in males are mediated by female hormones (breast development).




FIGURE 42.2


A 3-year-old girl (left) with isosexual central precocious puberty characterized by both breast and pubic hair development, and tall stature, contrasted to a normal 5-year-old prepubertal girl (right).


Causes of isosexual precocious puberty are listed in Tables 42.4 and 42.5 . The majority of cases in females, who are at least 10-fold more likely to be affected than males, are idiopathic, whereas only a small percentage of affected males have no definable cause. Ovarian size, as seen on a sonogram, is generally a reflection of ovarian estrogen production. In true central puberty, pituitary gonadotropins cause both ovaries to increase in size.



TABLE 42.4

Classification of Sexual Precocity



































True Precocious Puberty or Complete Isosexual Precocity (GnRH-Dependent Sexual Precocity or Premature Activation of the Hypothalamic GnRH Pulse Generator)



  • Idiopathic true precocious puberty



  • CNS tumors



  • Optic glioma associated with neurofibromatosis type 1



  • Hypothalamic astrocytoma



  • Other CNS disorders



  • Developmental abnormalities including hypothalamic hamartoma of the tuber cinereum



  • Encephalitis



  • Static encephalopathy



  • Brain abscess



  • Sarcoid or tubercular granuloma



  • Head trauma



  • Hydrocephalus



  • Arachnoid cyst



  • Myelomeningocele



  • Vascular lesion



  • Cranial irradiation



  • True precocious puberty after late treatment of congenital virilizing adrenal hyperplasia or other previous chronic exposure to sex steroids



  • True precocious puberty due to gain-of-function mutations:




    • in the KISS1R/GRP54 genes



    • in the KISS1 gene


Incomplete Isosexual Precocity (Hypothalamic GnRH-Independent)
Males



  • Gonadotropin-secreting tumors



  • hCG-secreting CNS tumors (e.g., chorioepitheliomas, germinoma, teratoma)



  • hCG-secreting tumors located outside the CNS (hepatoma, teratoma, choriocarcinoma)



  • Increased androgen secretion by adrenal gland or testis



  • Congenital adrenal hyperplasia (CYP21 and CYP11B1 deficiencies)



  • Virilizing adrenal neoplasm



  • Leydig cell adenoma



  • Familial testotoxicosis (sex-limited autosomal dominant pituitary gonadotropin-independent precocious Leydig cell and germ cell maturation)



  • Cortisol resistance syndrome

Females



  • Ovarian cyst



  • Estrogen-secreting ovarian or adrenal neoplasm



  • Peutz–Jeghers syndrome

Both Sexes



  • McCune–Albright syndrome



  • Hypothyroidism



  • Iatrogenic or exogenous sexual precocity (including inadvertent exposure to estrogens in food, drugs, or cosmetics)

Variations of Pubertal Development



  • Premature thelarche



  • Premature isolated menarche



  • Premature adrenarche



  • Adolescent gynecomastia in boys



  • Macroorchidism

Contrasexual Precocity
Feminization in Males



  • Adrenal neoplasm



  • Chorioepithelioma



  • CYP11B1 deficiency



  • Late-onset adrenal hyperplasia



  • Testicular neoplasm (Peutz–Jeghers syndrome)



  • Increased extraglandular conversion of circulating adrenal androgens to estrogen



  • Iatrogenic (exposure to estrogens)

Virilization in Females



  • Congenital adrenal hyperplasia



  • CYP21 deficiency



  • CYP11B1 deficiency



  • 3β-HSD deficiency



  • Virilizing adrenal neoplasm (Cushing syndrome)



  • Virilizing ovarian neoplasm (e.g., arrhenoblastoma)



  • Iatrogenic (exposure to androgens)



  • Cortisol resistance syndrome



  • Aromatase deficiency


CNS, central nervous system; CYP11B1, 11-hydroxylase; CYP21, 21-hydroxylase; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; 3β-HSD, 3β-hydroxysteroid dehydrogenase 4,5-isomerase; KISS1R/GPR54 , kisspeptin/G protein–coupled receptor 54.

Modified from Grumbach MM. True or central precocious puberty. In: Kreiger DT, Bardin CW, eds. Current Therapy in Endocrinology and Metabolism, 1985-1986. Toronto, Canada: BC Decker; 1985:4-8.


TABLE 42.5

Differential Diagnosis of Sexual Precocity






























































































































Disorder Plasma Gonadotropins LH Response to GnRH Serum Sex Steroid Concentration Gonadal Size Miscellaneous
Gonadotropin Dependent
True precocious puberty Prominent LH pulses (premature reactivation of GnRH pulse generator) Pubertal LH response initially during sleep Pubertal values of testosterone or estradiol Normal pubertal testicular enlargement or ovarian and uterine enlargement MRI of brain to rule out CNS tumor or other abnormality; skeletal survey for McCune–Albright syndrome (by US)
Incomplete Sexual Precocity (Pituitary Gonadotropin Independent)
Males
Chorionic gonadotropin-secreting tumor in males High hCG, low LH Prepubertal LH response Pubertal value of testosterone Slight-to-moderate uniform enlargement of testes Hepatomegaly suggests hepatoblastoma; CT scan of brain if chorionic gonadotropin-secreting CNS tumor suspected
Leydig cell tumor in males Suppressed No LH response Very high testosterone Irregular, asymmetric enlargement of testes
Familial testotoxicosis Suppressed No LH response Pubertal values of testosterone Testes symmetric and > 2.5 cm but smaller than expected for pubertal development; spermatogenesis occurs Familial; probably sex-limited, autosomal dominant trait
Virilizing congenital adrenal hyperplasia Prepubertal Prepubertal LH response Elevated 17-OHP in CYP21 deficiency or elevated 11-deoxycortisol in CYP11B1 deficiency Testes prepubertal Autosomal recessive; may be congenital or late-onset form, may have salt loss in CYP21 deficiency or hypertension in CYP11B1 deficiency
Virilizing adrenal tumor Prepubertal Prepubertal LH response High DHEAS and androstenedione values Testes prepubertal CT, MRI, or US of abdomen
Premature adrenarche Prepubertal Prepubertal LH response Prepubertal testosterone, DHEAS, or urinary 17-ketosteroid values appropriate for pubic hair stage 2 Testes prepubertal Onset usually after 6 yr of age; more frequent in CNS-injured children
Females
Granulosa cell tumor (follicular cysts may present similarly) Suppressed Prepubertal LH response Very high estradiol Ovarian enlargement on physical examination, CT, or US Tumor often palpable on physical examination
Follicular cyst Suppressed Prepubertal LH response Prepubertal to very high estradiol Ovarian enlargement on physical examination, CT, or US Single or recurrent episodes of menses and/or breast development; exclude McCune–Albright syndrome
Feminizing adrenal tumor Suppressed Prepubertal LH response High estradiol and DHEAS values Ovaries prepubertal Unilateral adrenal mass
Premature thelarche Prepubertal Prepubertal LH, pubertal Prepubertal or early estradiol response Ovaries prepubertal Onset usually before 3 yr of age
Premature adrenarche Prepubertal Prepubertal LH response Prepubertal estradiol; DHEAS or urinary 17-ketosteroid values appropriate for pubic hair stage 2 Ovaries prepubertal Onset usually after 6 yr of age; more frequent in brain-injured children
Late-onset virilizing congenital adrenal hyperplasia Prepubertal Prepubertal LH response Elevated 17-OHP in basal or corticotrophin- stimulated state Ovaries prepubertal Autosomal recessive
In Both Sexes
McCune–Albright syndrome Suppressed Suppressed Sex steroid pubertal or higher Ovarian enlargement (visible on US); slight testicular enlargement Skeletal survey for polyostotic fibrous dysplasia and skin examination for café-au-lait spots
Primary hypothyroidism LH prepubertal; FSH may be slightly elevated Prepubertal FSH may be increased Estradiol may be pubertal Testicular enlargement; ovaries cystic TSH and prolactin elevated; T 4 low

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