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1. Chapter 555
Physiology of Puberty
Luigi Garibaldi and Wassim Chemaitilly
Between early childhood and approximately 8-9 yr of age (pre-
pubertal stage), the hypothalamic-pituitary-gonadal axis is
dormant, as reflected by undetectable serum concentrations of
luteinizing hormone (LH) and sex hormones (estradiol in girls,
testosterone in boys). One to 3 yr before the onset of clinically
evident puberty, low serum levels of LH during sleep become
demonstrable (peripubertal period). This sleep-entrained LH
secretion occurs in a pulsatile fashion and reflects endogenous
episodic discharge of hypothalamic gonadotropin-releasing
hormone (GnRH). Nocturnal pulses of LH continue to increase
in amplitude and, to a lesser extent, in frequency as clinical
puberty approaches. This pulsatile secretion of gonadotropins is
responsible for enlargement and maturation of the gonads and
the secretion of sex hormones. The appearance of the secondary
sex characteristics in early puberty is the visible culmination of
the sustained, active interaction occurring among hypothalamus,
pituitary, and gonads in the peripubertal period. By mid-puberty,
LH pulses become evident even during the daytime and occur at
about 90- to 120-min intervals. A second critical event occurs in
middle or late adolescence in girls, in whom cyclicity and ovula-
tion occur. A positive feedback mechanism develops whereby
increasing levels of estrogen in midcycle cause a distinct increase
of LH.
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2. The increasing secretion of hypothalamic GnRH in a pulsatile
fashion thus underlies the onset of pubertal development. The
resulting “GnRH pulse generator” is regulated by multiple neu-
rotransmitters, including glutamic acid and kisspeptin (both
stimulatory) and γ-aminobutyric acid and pre-proenkephalin
(both inhibitory). GnRH secretion is also regulated by factors
produced by the glial cells, such as transforming growth factor β
(TGF-β). The role of GnRH is fundamental; its pulsed adminis-
tration can reproduce pubertal development in sexually immature
or gonadotropin-deficient animals and humans. Mutations of the
GPR54 gene (a G protein–coupled receptor gene whose ligand is
kisspeptin) cause an autosomal recessive form of hypogonado-
tropic hypogonadism. Defects of this receptor-ligand system do
not affect GnRH neuronal migration, in contrast to the X-linked
hypogonadotropic hypogonadism of Kallmann syndrome; rather
they impair the activity of GnRH-secreting neurons in the hypo-
thalamus. Conversely, TGF-β signaling has been associated with
the occurrence of central precocious puberty in patients with
hypothalamic hamartoma.
The interpretation of the hormonal changes of puberty is
complex. Issues in interpreting gonadotropin (LH and follicle
stimulating hormone [FSH]) measurements include the presence
of multiple isoforms, immunoassay-related variability, and prob-
lems inherent to their pulsatile secretion, which mandates serial
sampling in plasma or urine. Important sex differences exist in
the maturation of the hypothalamus and pituitary gland, and
serum LH concentrations increase earlier in the course of the
pubertal process in boys than in girls. Adrenocortical androgens
also have a role in sexual maturation. Serum levels of dehydro-
epiandrosterone (DHEA) and its sulfate (DHEAS) begin to
increase at approximately 6-8 yr of age, before any increase in
LH or sex hormones and before the earliest physical changes of
puberty are apparent; this process has been called adrenarche.
DHEAS is the most abundant adrenal C-19 steroid in the blood,
and its serum concentration remains fairly stable over 24 hr. A
single measurement of this hormone is commonly used as a
marker of adrenal androgen secretion. Although adrenarche typi-
cally antedates the onset of gonadal activity (gonadarche) by a
few years, the 2 processes do not seem to be causally related,
because adrenarche and gonadarche are dissociated in conditions
such as central precocious puberty and adrenocortical failure.
The effects of gonadal steroids (testosterone in boys, estradiol
in girls) on bone growth and osseous maturation are critical. Both
aromatase deficiency and estrogen receptor defects result in
delayed epiphyseal fusion and tall stature in affected boys. These
observations suggest that estrogens, rather than androgens, are
responsible for the process of bone maturation that ultimately
leads to epiphyseal fusion and cessation of growth. Estrogens also
mediate the increased production of growth hormone, which,
along with a direct effect of sex steroids on bone growth, is
responsible for the pubertal growth spurt.
The age of onset of puberty varies and is more closely corre-
lated with osseous maturation than with chronological age
(Chapter 12). In girls, the breast bud (thelarche) is usually the
first sign of puberty (10-11 yr), followed by the appearance of
pubic hair (pubarche) 6-12 mo later. The interval to the onset of
menstrual activity (menarche) is usually 2-2.5 yr but may be as
long as 6 yr. In the United States, at least 1 sign of puberty is
present in approximately 95% of girls by 12 yr of age and in
99% of girls by 13 yr of age. Peak height velocity occurs early
(at breast stage II-III, typically between 11 and 12 yr of age) in
girls and always precedes menarche. The mean age of menarche
is about 12.75 yr. There are, however, wide variations in the
sequence of changes involving growth spurt, breast bud, pubic
hair, and maturation of the internal and external genitalia.
In boys, growth of the testes (≥4 mL in volume or 2.5 cm in
longest diameter) and thinning of the scrotum are the first signs
of puberty (11-12 yr). These are followed by pigmentation of the
scrotum and growth of the penis (Chapter 12) and by pubarche.
Appearance of axillary hair usually occurs in mid-puberty. In
boys, unlike in girls, acceleration of growth begins after puberty
is well under way and is maximal at genital stage IV-V (typically
between 13 and 14 yr of age). In boys, the growth spurt occurs
approximately 2 yr later than in girls, and growth can continue
beyond 18 yr of age.
Genetic and environmental factors affect the onset of puberty.
Despite the debate raised by population-based studies in the USA
suggesting a secular trend for slightly earlier (by 2.5 to 4 months)
ages at menarche, the latter has generally been considered stable
over the last 30-40 yr. This period of relative stability follows a
significant decrease over the previous century, a result of major
changes in nutritional and health conditions. African American
girls may be more advanced in development of secondary sex
characteristics for age than Caucasian girls. A positive correlation
between the degree of adiposity and early pubertal development
in girls has been reported. Conversely, ballet dancers, gymnasts,
and other female athletes in whom leanness and strenuous physi-
cal activity have coexisted from early childhood often exhibit a
marked delay in puberty or menarche, and they often have oli-
gomenorrhea or amenorrhea as adults (Chapter 682). Pubertal
delay is also prevalent in boys who are physically very active.
These observations support the thesis that the energy balance is
closely related to the activity of the GnRH pulse generator and
the mechanisms initiating and sustaining puberty, perhaps via
hormonal signals, which can include adipokines.
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1886.e8 n Part XXVI The Endocrine System