SECTION 10  Endocrine and Metabolic Disorders
42 
Disorders of Puberty
Peter M. Wolfgram
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
Terminology
Various terms are used to discuss puberty (Table 42.1). Bone age refers
to the degree of epiphyseal calcification, width, and proximity to adja-
cent 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.
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 termi-
nate 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 secre-
tion of FSH and LH is also required for follicle growth, ovulation, and
maintenance of the corpus luteum. In males, FSH regulates spermato-
genesis by Sertoli cells within the seminiferous tubules, and LH acti-
vates Leydig cells to produce testosterone. Androgens cause development
of male internal and external reproductive organs and secondary
774
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 developmen-
tal 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 cm3, decreasing to
2.7 cm3 by 12 months and to 1.7 cm3 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. Ele-
vated LH levels after birth stimulate Leydig cell production of testos-
terone 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