Sex steroids, growth hormone, leptin and the pubertal growth spurt
Alan D. Rogol, M.D., Ph.D
Professor of Clinical Pediatrics
Riley Hospital for Children
University of Virginia
A normal rate for the linear growth of a child is a strong statement for the good general
health of that child. On a population basis just knowing the mid-arm circumference of a
large cohort of children denotes similar information concerning the nutritional status of
the children (and the gross national product of the nation). Growth during childhood is
characterized by a relatively constant rate averaging 5-6 cm/yr and 2.5 kg/yr for both
boys and girls after the fourth year of life . Normal growth during childhood is
primarily dependent on adequate nutrition, an adequate psychosocial environment, and
absence of disease. From the hormonal point of view one must have adequate levels of
thyroid hormone and sufficient levels of insulin-like growth factor I (IGF-I) as the stable
pharmacodynamic marker of growth hormone (GH) function. The hypothalamic-
pituitary-gonadal (HPG) axis operates at a very low activity until late childhood  when
early (re)activation occurs well before the outward signs of pubertal development—
testicular enlargement in boys and glandular breast tissue in girls.
Linear growth progresses at a virtually constant rate until very late childhood when there
may be a slight decrease before the inflection to an increase (“take off”), when height
velocity accelerates . Some, but certainly not all, children show a minor growth spurt
(Mid-growth spurt) in stature and weight during late childhood. Adrenal androgens
(adrenarche) may be responsible for this “mini”-spurt which may be missed if very
infrequent measurements are obtained.
Most healthy children are measured approximately yearly at this age and the usual
growth chart represent “smoothed” growth data. Linear growth is actually a saltatory
(episodic with stepwise jumps) at least as noted by daily measurements over time in both
newborns and adolescents (4-6]
The Hypothalamic-Pituitary-Gonadal (HPG) Axis
Pulsatile gonadotropin-releasing hormone (GnRH) secretion (as detected by pulsatile LH
release) is present at all ages, but particularly prominent just after birth (mini-puberty)
and during adolescent development [2, 7]. The relatively robust secretion of LH and
gonadal steroid hormones in the first few months of life is damped, likely by an alteration
in the hypothalamic feedback system for gonadal steroids on GnRH secretion. During the
vast majority of the rest of childhood the small, but now measurable concentrations of
sex steroids (by modern chromatography/mass spectrometry methods) are able to restrain
the GnRH neurons from making very much peptide product. Very likely the first
alteration is a change in feedback sensitivity so that these same levels of gonadal steroids
are no longer capable of inhibiting GnRH secretion. Thus, GnRH is secreted in greater
amounts at first only at night, likely coincident with the first episode of deep sleep. Since
the gonadotropes are capable of responding to GnRH, LH is secreted and coaxes the
testis or ovary to produce testosterone or estradiol. The increase in the concentrations of
the gonadal steroids is once again able to inhibit GnRH secretion for the rest of the night
and during the entire day. This process continues with decreasing levels of sensitivity at
the hypothalamus and then more LH secretion during the night and finally during the day
. The system comes into a steady state with secretion of both LH (and FSH) and
gonadal steroid hormones during the night and day with an imbalance favoring the
nighttime until at least late mid-puberty. Gonadal steroid hormone levels promote the
development and growth of the secondary sexual characteristics and the changes in body
composition (see below) characteristic of pubertal development.
During childhood GH secretion patterns are very much alike for boys and girls with a
marked night/day rhythm favoring early nighttime (after the first episode of deep sleep).
GH secretion is thus maximal during the early hours of sleep. Additional bursts of GH
release occur throughout the rest of the night/day, but with smaller amplitude. There is
virtually no GH circulating between secretory episodes, although levels can be measured
using very sensitive immunoassays. However, the effector for many, but not all, of GH
actions is circulating IGF-I produced under the direction of this pattern of GH secretion.
Exercise, food intake, and emotional factors can modify the pattern of GH release. After
an individual peak one has an absolute and then a relative refractory period before the
next burst of GH secretion.
Puberty is hearalded by a dramatic activation of the GH/IGF-I axis. The rise in mean 24-
hr GH levels results from an increase in the amplitude of the secretory burst and in the
mass of the GH release per burst rather than in the number of secretory events . The
differential increase between boys and girls during pubertal development follows the
pattern of change in height velocity noting that that is biologically anchored rather than
being related to one’s chronological age. Girls show a significant increase in GH
secretory dynamics (GH and IGF-I levels) beginning at Tanner breast stage 2, with the
highest circulating levels at Tanner breast stage 3/4. In boys the increases of GH and
IGF-I concentrations occur later during pubertal development, peaking at Tanner genital
stage 4. After full sexual development (but before the adult body composition is attained)
the levels of GH and IGF-I fall to those of the young adult.
Leptin and central peptide hormones
The fat-derived hormone, leptin, and its receptor are likely involved in at least two
aspects of pubertal development—sexual development itself and the alterations in body
composition including bone. Normosmic idiopathic hypogonadotropic hypogonadism is
clearly linked to defects in the leptin (LEP) or the leptin receptor (LEPR) genes [9, 10].
The linkage of the leptin signaling system to normal pubertal development has yet to be
proven. It is possible that common variants in LEP or LEPR may contribute to the
variation of pubertal development (timing and/or tempo) within the normal population of
The onset of puberty is almost certainly polygenic. At least one major upstream regulator
of GnRH release is the kisspeptin/GPR54 system . Kisspeptin from some arcuate and
periventricular (hypothalamic) nuclei interacts with its cognate receptor, GPR54 on the
cell membranes of GnRH neurons. In some mammals kisspeptin levels increase during
pubertal development. In the prepubertal macacque repetitive administration of an
intravenous infusion of kisspeptin-10 (2 µg in 1 mL as a pulse of 1 min duration onece
every hour for 48 h) was able to induce GnRH release as measured by circulating levels
of LH. This was consistent with advancing the start of puberty. This response was
abrogated by concomitant treatment with a GnRH antagonist. These findings are
consistent with the concept that in primates the transition from the juvenile (prepubertal)
period (attenuated GnRH release) to the pubertal state is controlled by a process that
includes KISS-1 gene product activating the GPR54 on hypothalamic GnRH neurons
In the human the activity of the kisspeptin/GPR54 system is likely activated during
puberty, since inactivating mutations of either the ligand or the receptor are associated
with delayed pubertal development  and activating mutations with central precocious
puberty . Although upstream regulators of the kisspeptin/GPR54 system have yet to
be convincingly demonstrated, recently IGF-I has been proposed as a positive regulator
of KISS-I gene expression in the anteroventral periventricular (AVPV) nucleus of the
prepubertal female rat. This was true whether the IGF-I was delivered into the third
ventricle or systemically through the jugular vein. The specificity of the effect was
clarified when it was noted that the IGF-I receptor antagonist, JB-1 blocked the IGF-I-
induced increase in KISS-1 gene expression . It is clear from these animal studies
that the kisspeptin/GP54R system is necessary for pubertal development (tonic GnRH
release); however, it may very well be that other aspects of HPG axis physiology, such
as positive feedback of estradiol on the hypothalamus and pituitary to release the surge of
LH, are not .
Leptin/LEPR may be one of the conduits linking pubertal development with central
energy regulation (homeostasis). The center for this intergration is likely the arcuate
nucleus (infundibular in the human) for it integrates neural, metabolic and humoral
signals from all parts of the body. It is likely that the “sum” of these inputs is a signal to
control appetite as well as energy stores [17, 18]. The central melanocortin system, as
defined by MC3R and MC4R on distinct subsets of neurons within the arcuate nucleus, is
the primary sensor for the whole body energy homeostasis. The orexigenic peptides
neural peptide Y (NPY) and agouti-related protein (AgRP) are secreted from cells within
the arcuate nucleus. The latter (AgRP) is a potent MC3R and MC4R antagonist. Since the
proopiomelanocortin (POMC) neurons acting on MC3R and MC4R decrease food intake,
the NPY and AgRP neurons act as part of the orexigenic pathway by silencing the POMC
system (Fig 1).
Taken together the reciprocal activity of the two potent systems, NPY and AgRP
(orexigenic) and POMC (anorexic) can control energy homeostasis at puberty (and other
stages of development) to sense whether pubertal development should advance, as well as
to fine tune alterations in body composition and likely the regional distribution of body
fat. In the excess energy state POMC neurons are activated and release melanocortins that
activate MCR4, suppressing food intake and perhaps increasing energy expenditure.
Concurrently, activity within the AgRP/NPY system is suppressed. That has the effect of
removing inhibitory activity of α-MSH on MC4R. The opposite occurs during times of
energy deficit—the activity of the anorexigenic POMC neurons is decreased and the
activity of the orexigenic NPY/AgRP system is increased. The “goal” is to bring the
organism back to energy homeostasis. The previously noted LEP and LEPR system is
intimately involved with receptors on NPY/AgRP neurons that have the reciprocal
relationship with POMC neurons. (Fig. 1).
We  and others  have observed a very close relationship between subcutaneous
fat and serum LEP levels with those with higher degrees of fatness (and LEP levels)
perhaps entering puberty earlier , at least in girls. Bandini and co-workers [Bandini,
22] took this concept one step further using as a biological anchor the age at menarche
and noting the body compositional and hormonal relationships over time both before and
after menarche. At menarche the girls averaged 24.6% body fat (bioelectrical impedance,
not a criterion method). Leptin levels rose from 8.4 ng/mL at menarche to approximately
12 ng/mL after menarche as the percent body fat increased to approximately 27. One
cannot determine causation from these data; however, the change in leptin concentration
closely paralleled the change in percent body fat. Thus, there are associated changes in
both adolescent development, the hormones of the hypothalamic-pituitary-gonadal and
GH/IGF-I axes and the central neuroendocrine regulation of energy homeostasis through
the reciprocal activation of the NPY/AgRP and POMC neuronal systems. There are many
too many unknowns to identify the primary driver for the onset and progression of
pubertal development. Suffice it to say that there are extensive connections among the
regulators of central energy homeostasis, including the control of appetite and body
composition as well as the timing and tempo of pubertal development. These are the
familiar HPG and GH/IGF-I axes.
Linear Growth and Adolescent Development
Although virtually all growth curves for adolescent have the same appearance, variation
in the timing and tempo of pubertal development may be detected from several
parameters that provide useful information about the adolescent growth spurt and provide
an indicator of sexual maturation . The two primary parameters are takeoff, or
initiation of the spurt (often after a slight deceleration or “dip” in height velocity) and
peak height velocity. The age, size and rate of growth at takeoff and peak height velocity
can be derived from the growth curves, either graphically or mathematically by curve
fitting. The age at peak height velocity is an indicator of somatic maturity, specifically
related to the timing of pubertal development. The peak height velocity (cm/yr) itself
provides an estimate of the tempo. Estimates of these parameters of the adolescent growth
spurt for mainly European are shown in Table 1. Since these are for individuals and not
populations of adolescents, the range is quite broad, for these normal populations.
Similarly broad ranges apply to the development of the secondary sexual characteristics.
Body Composition and Adolescent Development
Body composition may be described with a series of methods from two, three and four
compartment models to molecular and anatomic ones . All are approximations that
indirectly estimate body composition, some with very large sets of assumptions. The
major issue at puberty is the changing state of hydration of the fat-free mass, the largest
source of metabolically active tissue. Methods that use a fixed value (rather than an
experimentally determined one) may lead to significant systematic errors in that
determination, and thus in the appropriate basal energy expenditure as part of the
calculation of energy homeostasis.
During the prepubertal years the male-female differences in body composition are quite
modest. Children of both genders have relative decreases in body fat between 1 and 6
years of age. Girls then begin to increase in fatness again whereas the boys primarily gain
lean body mass as they gain weight . The marked differences in the regional
distribution of fat mass emerge at puberty with boys losing relative fat mass in
comparison with the marked gain in lean body mass. For girls the gain in lean body mass
is more modest that that of fat mass with a predominance on the trunk compared to
peripheral sites . In girls there are epidemiological data to indicate that BMI z-score
at 36 months, the rate of change of BMI between 36 months and grade 1 in school (~age
6 years) are associated with earlier pubertal development . From a population
perspective the data suggest that the increasing rate of obesity may result in an earlier
average age on onset of pubertal development. It should be noted that often those girls
who begin pubertal development at an earlier age have a slower tempo of sexual
development and do not have menarche much earlier than those girls starting with breast
development at an average age 
The marked changes in body composition , including alterations in the relative
proportions of water, muscle, fat and bone are characteristic of pubertal maturation and
the result of not only the hypothalamic-pituitary-gonadal axis (male-female differences),
but also the GH/IGF-I and hypothalamic-pituitary-adrenal axes and the relevant upstream
(hypothalamic) hormones.  The end points are the increases in lean body, fat, and
bone mineralization attained within the third decade attainment of the adult body
composition several years after reaching adult height). Differential growth of the
shoulders and hips and differences in lean tissue accrual highlights the sexually
dimorphic alterations in body composition during pubertal development. The net effect of
all of these factors is that the young adult female has ~25% body fate and the male ~13%.
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