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Lecture 9: Growth and metabolism - Yvonne Hodgson

These notes accompany the lectures for PHY2032.

Learning Outcomes:
After completion of this lecture and reading of the textbooks you should be able to:

List the major hormones that control growth


Describe the actions of growth hormone on growth
List other hormones and the ways in which they affect growth
Give examples of how short stature can arise

Reading Texts:
Vanders Human Physiology by Eric Widmaier, Hershel Raff & Kevin Strang, 13th Edition, Chapter
11, p 340-345
The Endocrine system at a glance by Ben Greenstein and Diana Wood, 24-27
Boron & Boulpaep, Chapter 48, p1028-1043

Introduction
Growth involves an increase in stature until the epiphyses of the long bones fuse and growth ceases.
The highest growth rates occur during fetal life and just after birth. Post natal growth spurts occur in
boys and girls at 1.5-3 years of age, 4.0-8.0 years of age and during puberty. Growth rate is affected
by genetics, socioeconomic and nutritional factors and chronic disease. Endocrine factors involved in
growth include: Growth hormone and Insulin-like growth factors, Thyroid hormones, Sex steroids
(particularly in the pubertal growth spurt) and glucocorticoids. Growth is an important index of
physical and mental health and of the quality of a child's psychosocial environment. Chronic
problems in any of these decrease growth rate.

Growth Hormone
Growth hormone (GH) is a 191 aa polypeptide secreted by somatotrophs in the anterior pituitary
gland. Growth hormone circulates free in plasma with a half-life of 10-20 minutes, but a significant
fraction (~40%) is bound to a protein (GHBP), thereby increasing its half-life and providing a reservoir
of hormone. GH is secreted in a pulsatile and diurnal pattern as shown below. Peak GH levels occur
during sleep (see data shown below). Seventy percent of total daily GH is secreted during sleep.
Ironically this pulsatile, diurnal pattern of secretion results in slow growth over months and years.
The pulsatile secretion underlies the prominent role of the CNS in the regulation of GH secretion.
The pattern of bursts of CNS activity depends on the sleep-wake pattern, not on the light-dark
pattern. Exercise, stress, high protein meal and fasting can also cause a rise in GH secretion.

Baumann G P Endocrine Reviews 2012;33:155-186

Growth Hormone

Growth hormone concentrations are very high in mid-fetal life (up to 150 ng/ml), The levels in cord
blood are about 30 ng/ml and in children they are 5-10 ng/ml. The levels are lower in adults (25ng/nl) and very low in old age.

Regulation of Growth Hormone Secretion


GH secretion is regulated by the hypothalamus and pituitary gland and by negative feedback
mechanisms. The hypothalamus secretes growth hormone releasing hormone (GHRH), a 43 amino
acid peptide which stimulates the release of GH. It also secretes somatostatin, a 14 amino acid
peptide which inhibits GH secretion. The regulation by the hypothalamus is mainly stimulatory
because section of the pituitary stalk leads to a decline in GH secretion.

The above diagram is a stylised representation of how growth hormone (GH) secretion is controlled.
It is necessarily simple, and refinements on the schema pictured here can be made. It is, however, a
good starting point for understanding. The hypothalamus releases two substances (GHRH Growth
Hormone Releasing Hormone) and Somatostatin (SS) that stimulate, and inhibit, respectively, the

secretion of GH. GHRH is also sometimes known as GRF (Growth Hormone Releasing Factor), and SS
is sometimes known as SRIF (Somatotrophin (GH) Release Inhibiting Factor). When GH is released it
can act via short feedback loops to inhibit its own release directly at the pituitary, or by inhibiting the
release of GHRH.
GH also acts at the liver (an end-organ for GH) to stimulate the secretion of Insulin-like Growth
Factor-1 (IGF-1). IGF-1 mediates many of the actions of GH (more about that later). IGF-1 feeds
back at the pituitary to inhibit GH secretion, and at the hypothalamus to stimulate SS secretion, and
in so doing, increase the inhibition of GH secretion. These factors interact to maintain GH secretion
under a tight control.

HYPOTHALAMIC/STOMACH CONTROL OF SECRETION


As alluded to above, this is a simple representation of the control of GH secretion. Over the last
several years it has become apparent that a peptide made by the stomach most probably plays an
important role in GH secretion. This peptide is known as Ghrelin, and is made by the stomach when
it is full (eg just after eating). It seems to act at both the hypothalamus and pituitary gland to
stimulate GH secretion. It may also be an important peptide in the control of appetite. You will
learn more about this peptide later in the unit.

Regulation of secretion of Growth Hormone


The secretion of GH is pulsatile and episodic and follows a circadian pattern. Pulsatile means that
the secretion occurs in distinct bursts. This is not all that surprising for a peptide hormone that is
stored in secretory granules and released in response to specific stimulators from the hypothalamus.
Episodic means that pulses tend to occur close together with periods of relative increased activity,
and periods of quiescence. Secretion is stimulated by, sleep, exercise, stress and fasting (and
hypoglycaemia). Secretion is inhibited by somatostatin, postprandial hyperglycaemia, elevated free
fatty acids, elevated IGF-1 (negative feedback) and in aging.

Effects of exercise on GH secretion:

Left: 30 second exercise sprints with different


periods of recovery. A . 60 mins no second
pulse, B. 240 mins GH pulse was lower and
shorter in duration, C. 24 hours
Below: Mean serum growth hormone (GH)
concentrations during blood sampling at 10-min
intervals over 24 hr on C, control; SEB,
sequential exercise bouts and DEB, delayed
exercise bouts. Average of 3 separate measures
4 weeks apart.

Kanaley J A et al. J Appl Physiol 1997;83:1756


Stokes K et al. J Appl Physiol 2005;99:1254-1261
Effects of sleep and delaying sleep on GH secretion (from Takahasi
et al. J Clin Invest 1968;47:2079

Normal Sleep
Conclusions:
1. Growth hormone
secretion is raise during
sleep.
2. GH levels are unrelated
to those of glucose, insulin
or cortisol.
3. Peak cortisol secretion is
seen just before awakening

Delayed sleep
Conclusion:
1. Delayed sleep resulted in
lower peaks of GH
2. There was no effect on
the pattern of cortisol
secretion

Interrupted sleep
Conclusions:
1. Growth hormone
secretion is interrupted if
sleep is interrupted.
2. The second peak is
always lower in magnitude
than the first peak
3. Cortisol levels were
raised for a prolonged
period

Regulation of GH is achieved by negative


feedback involving IGF-I and GH at the level of
the hypothalamus and pituitary gland. GH has
insulin like and anti-insulin like actions. GH acts
on receptors present on the cell membrane of
target cells. The intracellular mechanism of
action involves the tyrosine kinase JAK2 signal
transduction system. GH continues to be
secreted even after the epiphyseal plates of the
long bones have fused and is an important
regulator of muscle mass and body composition,
having anabolic (insulin-like) actions in muscle.

The acute effects (minutes to hours) of Growth Hormone (GH) involve diabetogenic actions, i.e.
actions that oppose those of insulin. These actions include i) stimulation of lipolysis in adipose
tissue, ii) inhibition of glucose uptake by muscle and iii) stimulation of gluconeogenesis by
hepatocytes.

The
effects of daily injections of GH treatment in rats.
Guyton & Hall, 10th ed, chapter 75, Figure 75-5
The long term effects of GH involve insulin like actions, namely actions that promote growth in
tissues. These actions occur via IGFs (insulin-like growth factors) which are synthesised by various
tissues such as the liver, kidney, muscle, cartilage and bone and stimulated by GH.
The actions of GH are exerted mainly via the stimulation of the liver to produce and secrete insulin
like growth factor 1 (IGF-1). IGF-1 acts on osteoblasts to increase bone growth. IGF-1 also increases
Ca++ retention, muscle mass via hypertrophy of sarcomeres and increased protein synthesis. An
over secretion of GH prior to puberty leads to the disease of gigantism. If an over secretion occurs
after puberty it leads to the development of acromegaly. An under secretion of GH prior to puberty
leads to short stature. Recombinant DNA hGH is used to treat these children
An over secretion of GH (larger pulses, see graph below) in adult life leads to the disease of
Acromegaly. GH stimulates bone growth, but because the epiphyseal plates have fused in adults,
bone growth occurs in all bones except for the long bones. This leads to an increase in the size of
the hands, feet, jaw and skull. A common cause of Acromegaly is a tumour of the pituitary gland.
The data and photos shown below illustrate the change in secretion of GH and the physical changes
seen in a patient with Acromegaly.

Growth hormone excess


causes increased amounts
of extracellular matrix,
resulting in widening of
the gaps between teeth.
This is said to be a
common sign in athletes
abusing GH. Note the
enlarged hands of the
person with GH excess.
Acromegaly also leads to
an increased size of the
heart which can lead to
heart failure

Giantism - Carpal Tunnel Syndrome


This man initially presented with Carpal Tunnel
Syndrome and was later diagnosed with GH excess and
gigantism

Gigantism is sometimes associated with a delay


in the development of secondary sexual
characteristics. The patients are sometimes
said to look eunuchoid

Laron Dwarfism insensitivity to Growth


hormone caused by a mutation in the Growth
hormone receptor

Dwarfism -Idiopathic GH Deficiency

Hypopituitarism is a partial or complete insufficiency of


pituitary hormone secretion that may derive from
pituitary or hypothalamic disease. The onset can be at
any time of life.
The left photograph shows an untreated 21-month-old
girl with congenital hypopituitarism. The right panel
depicts the same child aged 29 months, following 8
months of growth hormone therapy

Normal growth
Growth involves the processes of hyperplasia, an increase in the number of cells, and hypertrophy,
an increase in the size of individual cells and of organs. Hyperplasia in the CNS is complete by 1 year
of age. Bone, muscle and fat cells continue to divide til later in childhood and some tissues, such as
skin, GIT and liver retain the ability to divide throughout life.
Linear growth is related to parental height and genetics. The control of linear growth (height)
depends upon multiple hormones. These include GH, IGF-1, IGF-2, insulin, T3, cortisol, androgens
and estrogens. GH & IGF-1 are the major determinants of growth. However, deficiencies in the
other hormones affect normal growth of the musculoskeletal system and other tissues.
Every species follows a pattern of development and
growth. Organs grow at different rates. Linear growth
equates to height and is assessed relative to standardised
growth curves. The growth in height of Australian
children is shown in the two panels below. These charts
show percentiles. The 97th percentile show the height at
which 97% of the population falls at or below. The 3rd
percentile shows the height at which only 3% of the
population falls on or below. Taller stature in boys is
accounted for by the later age for closure of the
epiphyseal plate.

Normal growth is affected by genetic, socioeconomic and nutritional factors and chronic disease.
There is good correlation between parental height and offspring height. Poor hygiene, poverty and
malnutrition adversely affect growth.

Skeletal Growth
Skeletal development is a reflection of physiological
maturation. Linear growth of the long bones continues until
hormonal influences at puberty cause the closure of the
epiphyseal plate. Bone growth occurs at the epiphyseal plate.
Oteoblasts turn cartilaginous tissue at this edge into bone.
Calcium and phosphate are essential nutrients for normal
bone growth (Ca10(PO4)6(OH)2. .
Bone age can be determined by radiography and comparison
of the shapes and stage of fusion of bone epiphyses. Wrist,
knee and foot are epiphyseal closure are commonly used.
Growth Hormone stimulates long bone growth at the
epiphyseal cartilages, stimulating deposition of new cartilage
and increasing osteoblast activity.
Vander: Figure 11-26.

Other hormonal influences - thyroid hormones, sex steroids, cortisol


Because growth is a difficult area to research, especially in humans where an experiment on growth,
even if ethical would take 10-20years, most of our knowledge about growth has come from
researching abnormal growth. The exact mechanism by which growth is regulated by various factors

is still not completely understood. However, it is know that a number of different hormones play a
significant role in the growth of an individual.
Thyroid hormones: Thyroid hormones are known to play an important role in growth and
development. In humans hypothyroidism before puberty leads to growth retardation (dwarfism) and
mental retardation (cretinism). Growth retardation occurs if the thyroid deficiency occurs before
the epiphyseal plates in the long bones have fused. Hormone replacement with thyroid hormone
can reverse this loss in height with catch up growth if given before the fusion of the epiphyseal
plates. Hormone replacement will not reverse the detrimental effects on mental development.
Sex steroids: Androgen or estrogen excess before the pubertal growth spurt accelerates bone
growth. However, the sex steroid also accelerate the rate at which the bones mature, shortening
the time before the epiphyseal plates close leading to short stature. The sex steroids narrow the
window of growth of the long bones thereby diminishing long bone growth. Excessive sex steroid
can arise from endogenous sources such as early maturation of the hypothalamus-pituitary-gonadal
axis, or tumours that secrete androgens or estrogens.
Glucocorticoids: An excess of glucocorticoids inhibits growth. The chronic use of synthetic
glucocorticoids to treat illnesses (eg asthma) can and do arrest growth. The specific biochemical
mechanism for this is unclear. Administration of GH does not return growth to normal indicating
that glucocorticoids acts via different mechanisms. Excess glucocorticoids impair tissue anabolism
and causes tissue wasting in bone and muscle.
Insulin: Insulin is an important growth factor in utero, stimulating the growth of the fetus (diabetic
mothers). Insulin has anabolic actions in some tissues (liver, muscle and adipose tissue). Insulin
deficiency produces catabolic effects such as muscle wasting.
The graph on the right demonstrates the
synergistic effects of insulin and growth
hormone on body weight (growth) in rats.
Because insulin is required for protein
synthesis it is as essential for growth as
Growth Hormone.
Thyroid hormone is also necessary for normal
growth, though it does not itself stimulate
growth, in the absence of Growth Hormone.
Without thyroid hormone, cells do not
develop and function properly, especially in
the brain.

Fig 78-6 Guyton Medical Physiology

Summary:
In summary we have looked at how growth is measured in humans and the hormones that play a
role in the control of growth. We have looked closely at the regulation of the secretion of Growth
hormone and its actions on tissues. The secretion or Growth hormone is controlled by sleep and
affected by exercise. Growth hormone has acute, diabetogenic effects which result directly from the
action of GH on its receptors in target cells. The long term growth promoting effects of GH occur via
the action of IGF-I on its receptors in tissues. We have looked at the role played by other hormones,
namely thyroid hormone, cortisol, insulin and the sex steroids. We have looked at how short stature
can arise from a deficiency of GH and thyroid hormones.