Puberty and Gonadal Disorders

Puberty and Gonadal Disorders

Leslie P. Plotnick

Dominique N. Long

Because the range of normal onset and progression of puberty is broad and is different in boys and girls, pediatricians must have a solid grasp of normal pubertal events to assess when a child falls outside the normal range and needs evaluation or treatment.

Puberty is initiated by changes in the sensitive negative feedback system that exists among the gonads, hypothalamus, and pituitary in the prepubertal child. Puberty involves an increase in gonadal steroid production (i.e., gonadarche) and an increase in adrenal steroid production (i.e., adrenarche).

In most girls, puberty begins between 8 and 13 years of age and is completed, on average, in 4.2 years (range, 1.5 to 6.0 years). In 90% of girls, breast development (thelarche) is the first sign of puberty. The time from onset of breast buds to menarche is 2.3±1.0 years.

A 1997 cross-sectional study conducted by Herman-Giddens et al. showed that a substantial portion of girls have pubertal changes at age 7 years. The changes occurred earlier in black than in white girls. In 2002, Wu et al. reported data from the Third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988 and 1994, showing that, on average, black girls enter puberty first, followed by Mexican American and then white girls. Including current body mass index (BMI) did not modify the relationship between race/ethnicity and pubertal status, with the exception of attainment of menarche. Higher BMI led to earlier age at the onset of menarche. Sun et al. also reported data from NHANES III in 2002 finding little statistical difference between sexual development in non-Hispanic white girls and Mexican American girls. Using NHANES III, Sun et al. and Wu et al. both found the median age for onset of breast development was 9.48, 10.38, and 9.80 in non-Hispanic black girls, non-Hispanic white girls, and Mexican American girls, respectively. Similarly, the median age for onset of pubic hair in girls was 9.5, 10.5, and 10.3, respectively.

Chumlea et al. used NHANES III data in 2003 to show that the median age for attainment of menarche is 12.43 years, which is not significantly different from that reported for U.S. girls in 1973. Again, non-Hispanic black girls had a significantly earlier age of onset of menarche than did non-Hispanic white and Mexican American girls (12.06 years, 12.55 years, and 12.25 years, respectively).

In the vast majority of boys, puberty begins between 9 and 14 years of age and is completed, on average, in 3.5 years (range 2.0 to 4.5 years). In most boys, testicular enlargement (length greater than 2.5 cm) is the first sign of puberty. Sun et al. reported data from NHANES III showing the median age of genital development in boys to be 9.2 years, 10 years, and 10.3 years for non-Hispanic black boys, non-Hispanic white boys, and Mexican-American boys, respectively.

Classically, if a girl shows signs of pubertal maturation before she is 8 years of age or a boy shows signs of puberty before he is 9 years of age, the child should be evaluated for precocious puberty. The 1997 data by Herman-Giddens et al. were interpreted as lowering the age for evaluation to 6 years for black girls and 7 years for white girls. These recommendations are controversial, although detailed etiologic evaluations in 6to 8-year-old girls usually are not revealing of pathology. Each child must be considered individually, including past medical history, tempo of puberty, and physical examination. Conversely, if no signs of pubertal development occur by 13 years of age in girls or by 14 years of age in boys, the child should be evaluated for pubertal delay. Timing and progression of puberty is important. Pubertal changes that progress too rapidly or arrest in progression require evaluation.


Pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is regulated by the hypothalamic factor gonadotropin-releasing hormone (GnRH; also called LH-releasing hormone or factor). The hypothalamic secretion of this peptide is controlled by various neurotransmitters, which can be influenced by higher signals such as visual and
olfactory stimuli and stress. GnRH is secreted in pulses, the frequency of which is important for pituitary secretion of LH and FSH. At the onset of puberty, an increase in GnRH, LH, and FSH pulsatile secretion occurs. LH and FSH become more responsive to GnRH, and an increase in GnRH receptors occurs in the pituitary.

LH and FSH stimulate the testes to produce testosterone and the ovaries to produce estrogen and stimulate ovulation. The gonadal sex steroids feed back centrally. The feedback usually is negative, except that positive feedback of estrogens is needed to produce the LH surge required for ovulation.


Causes of precocious or inappropriate sexual development are listed in Box 374.1. Evaluating a child for sexual precocity requires obtaining a careful medical and family history. Does the child have any history of central nervous system (CNS) disorder? Previous growth measurements are valuable. What is the child’s growth pattern? Is there evidence of acceleration of linear growth? When did the various pubertal changes begin? How fast have these changes progressed? When did the parents and sibling have pubertal changes? Is there a family history of early sexual development? Questions regarding exposure to any exogenous source of sex steroids must be asked. Creams and pills can contain sex steroids, especially estrogens, and oral contraceptives are found readily in many homes. Are any athletes in the home taking anabolic steroids or is anyone in the family using topical androgen preparations?

The physical examination should include a careful examination of the fundi (looking for papilledema). The child’s skin should be inspected for signs of oiliness or acne (androgen effect) and café au lait spots (McCune-Albright). The thyroid should be palpated. The presence of axillary hair and odor, the amount of breast tissue, and whether the nipples and areolae are enlarging should be evaluated. The abdomen should be palpated for masses. The amount, location, and character of pubic hair should be noted.

In girls, the clitoris, labia, and vaginal orifice should be examined carefully. Is there evidence of maturation of the labia minora? Does the vaginal mucosa look red and shiny (prepubertal) or pink and dull (estrogenized)? Is the clitoris of normal size? Are vaginal secretions evident on the genitalia or on the child’s underwear?

In boys, the stretched length and width of the penis should be evaluated (this may require pushing down on a suprapubic fat pad). Careful palpation and measurement of the testes are key. Are the testes prepubertal in length (less than 2.5 cm), or are they enlarging? Is there a difference in size and consistency of the two testes, suggesting a unilateral mass? Transillumination of the testes may be helpful, especially if discrepancies in size exist. Is the scrotum thinning, or does is look thick and nonvascular (i.e., prepubertal)? Are the results of the neurologic examination normal?


True or central precocious puberty is caused by early maturation of hypothalamic GnRH secretion. In many cases, no definable CNS abnormality can be found, and the problem falls into the idiopathic category, which occurs more frequently in girls than in boys. In idiopathic precocious puberty, although the onset is at an early age, the pattern and timing of progression of pubertal events are normal.

A search for an underlying CNS abnormality should be made by imaging of the CNS with computed tomography (CT) or magnetic resonance imaging (MRI). CNS tumors, especially hypothalamic hamartomas, are known causes of central precocious puberty. Hypothalamic hamartomas contain GnRH neurons that function independently of CNS inhibition. Neurofibromas, gliomas, and other tumors have been found with some frequency. Other CNS lesions also are associated with precocious puberty, such as hydrocephalus, posttrauma, and postinfectious encephalitis or meningitis.

Children with central precocious puberty have accelerated linear growth, advanced bone ages, and pubertal levels of LH, FSH, and the sex steroids estradiol and testosterone. Because levels of LH and FSH fluctuate, single samples may be inadequate to make the diagnosis but are most helpful if drawn at 8 AM. An alternative includes drawing multiple samples taken at 20-minute intervals for 1 or more hours. Most reliable is a GnRH stimulation test with levels of LH and FSH determined at regular intervals, which often can help clarify the diagnosis. Newer, highly sensitive gonadotropin assays may allow
establishing the diagnosis of central puberty by a single basal LH measurement or by a single LH measurement 40 minutes after a subcutaneous GnRH injection. In boys, the finding of bilateral pubertal-sized testes almost always indicates central precocious puberty. This point is extremely important in the physical examination because it determines the diagnostic workup.

The discovery that the pulse frequency of endogenous GnRH is important for pituitary secretion of LH and FSH has had a major effect on designing treatments for blocking release of LH and FSH. GnRH agonists that provide consistent, not fluctuating, GnRH levels lower LH and FSH levels. Long-acting GnRH analogues have been successful in inhibiting pituitary release of LH and FSH and in stopping the progression of puberty. In many cases, secondary sex characteristics have regressed.

Treatment with GnRH analogues produces a prepubertal hormonal state, and growth acceleration, bone age advancement, and the progression of secondary sex characteristics cease. The first GnRH analogue to treat precocious puberty was approved by the Food and Drug Administration in the early 1990s, with others following. Most GnRH analogues are given as monthly intramuscular injections. Other preparations may be given as a depot intramuscular injection every 3 months, as well as daily subcutaneous injections.

The decision to treat should depend on several factors. First, the age of the child and his or her adjustment to the pubertal changes must be considered. A 2-year-old child is in need of treatment, but a 7-year-old child psychologically may handle the changes well. The rapidity of pubertal progression, as well as chronologic age, must be considered. In the older child with precocious puberty, the major issues in deciding whether to treat are the magnitude of bone age advancement and the rapidity of its progression, the degree of compromise of adult stature, and the decrease in predicted adult height.

Any form of pituitary gonadotropin-independent precocious sex hormone exposure causes accelerated linear growth and advanced bone age. If the bone age is advanced enough after the pathologic cause is removed, the child may experience spontaneous gonadotropin-dependent puberty. This puberty, although precocious for the chronologic age, is not precocious for bone age. This situation typically is seen in a boy in whom the diagnosis of congenital adrenal hyperplasia was made late and treatment with glucocorticoids was begun at an advanced bone age. In this situation, treatment with a GnRH analogue may be indicated.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Puberty and Gonadal Disorders
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