The document discusses the control of growth and development. It covers several topics: 1. Cells begin to specialize early in development into different tissue types like muscle and nerve cells. Growth involves an increase in body size through protein deposition while development causes changes in complexity and function. 2. Growth and development are influenced by genetic and environmental factors like nutrition. A child who is malnourished may not reach their full genetic height potential. 3. Growth occurs at the cellular, tissue, and whole body levels regulated by hormones like growth hormone. Patterns of growth are described for fetal life, childhood, and adolescence.

1. The control of growth

2. Introduction
• All biological tissues are made up of cells. Life
begins as a single cell, the fertilized egg, from which
all the diverse cell types of the body arise within a
few weeks.
• Very early in development, cells begin to specialize
and develop into particular types—liver cells,
nerve cells, epithelial cells, muscle cells, and so on.
• Each cell type has its appropriate place within the
organism. This development of specific and
distinctive features is known as differentiation.
• Differentiated cells maintain their specialized
character and pass it on to their progeny through
the process of mitosis

3. • Overall growth of the body involves an increase in size
and weight of the body tissues with the deposition of
additional protein, and is thus a measurable quantitative
change.
• In contrast, development occurs through a series of
coordinated qualitative changes that affect the complexity
and function of body tissues. Developmental change is
most rapid while an individual is young.
• Growth and development are complex processes that are
influenced by a number of different factors, both genetic
and environmental. It is believed that genetic factors set
both the basic guidelines for the overall height that may
be achieved (as indicated by the correlation of adult
height between parents and children) and the pattern and
timing of growth spurts.

4. • The major influence superimposed upon the
genetic makeup of an individual is probably
nutritional, although illness, trauma, and other
socio-economic factors such as smoking can also
modify the processes involved in growth.
• A child who has a diet that is inadequate with
regard to either its quality or quantity will be
unlikely to achieve his or her full genetic
potential in terms of adult height. Indeed,
improved nutrition is cited as one of the most
important factors in the increase in average
height that has been noted in Western societies
over the last century.

5. • Growth occurs at the level of individual cells,
in populations of cells (the tissues and
organs), and at the level of the whole body.
• The underlying processes are regulated by a
number of different hormones including
growth hormone, thyroid hormones, and the
sex steroids.

6. Patterns of growth during fetal life
• The period of prenatal growth is of great
importance to an individual's future well-being.
The development of sensitive ultrasound
techniques has meant that it is now possible to
monitor fetal size throughout pregnancy.
• Measurements of abdominal circumference,
femur length, and biparietal diameter (the
distance across the head measured from one ear
to the other) are commonly taken to assess the
increasing size of the fetus.

7. • A large number of factors may influence the rate of
fetal growth, but their relative importance remains
unclear.
• Genetic, endocrine, and environmental factors are
likely to be as important in fetal life as they are in
postnatal development, with the genetic
constitution setting the upper limits of fetal size and
the level of nourishment provided by the placenta
determining to what extent the genetic potential is
achieved.
• In turn, placental efficiency will be affected by
numerous maternal influences such as smoking,
medication, alcohol consumption, and nutritional
status.

9. Patterns of growth and development
during childhood and adolescence
• The rapid rate of growth seen in fetal life
continues into the postnatal period but
declines significantly through early childhood.
• There is further deceleration prior to the
growth spurt of puberty.

11. • The age at which the adolescent growth spurt
takes place varies considerably between
individuals. It occurs on average between 10.5
and 13 years in girls and between 12.5 and 15
years in boys.
• In general, the earlier the growth spurt occurs,
the shorter will be the final stature.
• During this period, there is considerable variation
in both stature and development between
individuals of the same chronological age.

12. • Most body measurements follow
approximately the growth curves described
for height.
• The skeleton and muscles grow in this manner,
as do many internal organs such as the liver,
spleen and kidneys.
• However, certain tissues do not conform to
this pattern and vary in their rate and timing
of growth.

13. • Examples include the reproductive organs
(which show a significant growth spurt during
puberty), the brain and skull, and the
lymphoid tissue.
• The brain, together with the skull, eyes, and
ears, develops earlier than any other part of
the body and thus has a characteristic
postnatal curve.

14. • The lymphoid tissue also shows a characteristic
pattern of growth. It reaches its maximum mass
before adolescence and then, probably under the
influence of the sex hormones, declines to its
adult value.
• In particular, the thymus gland, a well-developed
structure in children that plays a major role in the
early development of the immune system,
atrophies after puberty. It is no more than a
residual nodule of tissue in adults.

15. • Growth, even of the skeleton, does not cease
entirely at the end of the adolescent period.
Although there is no further increase in the length
of the limb bones, the vertebral column continues
to grow until the age of about 30 by the addition
of bone to the upper and lower surfaces of the
vertebrae. This gives rise to an additional height
increase of 3–5 mm in the post-adolescent
period. However, for practical purposes it can be
considered that the average boy stops growing at
around 17.5 years of age and the average girl at
around 15.5 years of age with a 2-year variability
range on either side.

17. The physiology of bone
• Bone is a specialized form of connective tissue that
is made durable by the deposition of mineral within
its infrastructure. In an adult, skeletal bone forms
one of the largest masses of tissue, weighing
10–12 kg.
• Far from being the inert supporting structure its
outward appearance might suggest, bone is a
dynamic tissue with a high rate of metabolic activity
which is continuously undergoing complex
structural alterations under the influence of
mechanical stresses and a variety of hormones.

18. • Four main functions are ascribed to bone:
1. to provide protection and structural support for the
body and an attachment for muscles, tendons, and
ligaments;
2. to allow movement by means of articulations (joints);
3. the homeostasis of mineral (calcium and phosphate);
4. to form blood cells from hematopoietic tissue in the
red bone marrow, which is found particularly in the
short,
5. flat, and irregular bones.

20. • Three major tissue components are found in
bone.
• About 30 per cent of total skeletal mass is made
up of osteoid, an organic matrix consisting largely
of collagen together with hyaluronic acid,
chondroitin sulfate, and a vitamin-K- dependent
protein called osteocalcin which is an important
calcium-binding molecule.
• The remainder consists of a mineral matrix of
calcium phosphate (hydroxyapatite) crystals and
bone cells including osteoblasts (bone-forming
cells), osteoclasts (bone-resorbing cells),
osteocytes (mature bone cells), and fibroblasts.

21. • The anatomical features of a typical long bone are
illustrated in Fig. 23.4.
• The central shaft is called the diaphysis while the
regions at either end of the bone are the
epiphyses. Between the diaphysis and epiphysis is
a region of bone known as the epiphyseal plate or
growth plate. Adjacent to this is the growing end
of the diaphysis, known as the metaphysis. During
growth, this region is made of cartilage, but once
growth is completed following puberty, the plate
becomes fully calcified and remains as the
epiphyseal line.

22. • Growth in length occurs by deposition of new
cartilage at the metaphysis and its subsequent
mineralization. The process by which bone
becomes mineralized is not fully understood.
• Calcium phosphate appears to become oriented
along the collagen molecules of the organic
matrix. Surface ions of the crystals are hydrated,
forming a layer through which exchange of
substances with the extracellular medium can
occur.
• The adult skeleton contains between 1 and 2 kg
of calcium (about 99 per cent of the body total)
and between 0.5 and 0.75 kg of phosphorus
(about 88 per cent of the body total).

23. • The surfaces of the bones are covered by periosteum,
which consists of an outer layer of tough fibrous
connective tissue and an inner layer of osteogenic
(‘bone-forming’) tissue. A central space runs
through the center of bones. This is the marrow (or
medullary) space, which is lined with osteogenic
tissue (the endo-steum).
• The marrow spaces of the long bones contain mainly
fatty yellow marrow that is not involved in
hematopoiesis under normal circumstances. Red
marrow containing hematopoietic tissue is found
within the small, flat, and irregular bones of the
skeleton, such as the sternum, ilium, and vertebrae. It
is here that blood cell production is carried out.

24. • Long bones are supplied by the nutrient artery, the
periosteal arteries, and the metaphyseal and epiphyseal
arteries. The nutrient artery branches from a systemic artery
and pierces the diaphysis before giving rise to ascending and
descending medullary arteries within the marrow cavity. In
turn, these give rise to arteries supplying the endosteum
and diaphysis. The periosteal blood supply takes the form of
a capillary network, while the metaphyseal and epiphyseal
vessels branch off from the nutrient artery.
• At rest, the arterial flow rate to the skeleton is around 12
per cent of the total cardiac output (2–3 ml per 100 mg
tissue per minute).
• The mechanisms that control skeletal circulation are poorly
understood, but it is known that blood flow is significantly
increased during inflammation and infection and following
fracture (see below). The blood flow to the red bone
marrow is increased during chronic hypoxia when red blood
cell production is enhanced in response to erythropoietin
secreted by the kidney.

25. • Bone is not uniformly solid but contains spaces
that provide channels for blood vessels and also
reduce the weight of the skeleton. Bone can be
classified as either compact (dense) or spongy
(trabecular, cancellous) according to the size and
distribution of the spaces.
• Compact bone forms the outer regions of all
bones, the diaphysis of long bones, and the
outer and inner regions of flat bones. It contains
few spaces and provides protection and support
especially for the long bones in which it helps to
reduce the stress of weight bearing.

26. • The functional units of compact bone are the
Haversian systems or osteons. These consist of a
central canal, which contains blood vessels,
lymphatics, and nerves, surrounded by concentric
rings of hard intercellular substance (lamellae)
between which are spaces (lacunae) containing
osteo-cytes (mature bone cells) (Fig. 23.5).
• Radiating from the lacunae are tiny canals
(canaliculi) that connect with adjacent lacunae to
form a branching network through which
nutrients and waste products can be transported
to and from the osteocytes.

27. • In contrast, spongy bone contains no true osteons
but consists of an irregular lattice of thin plates or
spicules of bone (trabeculae) between which are
large spaces filled with bone marrow. Lacunae
containing osteocytes lie within the trabeculae. The
osteocytes are nourished directly by blood
circulating through the marrow cavities from blood
vessels penetrating to the spongy bone from the
periosteum.
• Spongy bone makes up most of the mass of short,
flat, and irregular bones and is present within the
epiphyses of long bones and at the growth plates.
Figure 23.6 illustrates the different organization of
dense and spongy bone.

31. The bone cells
• Three major cell types are recognized in
histological sections of bone. These are
osteoblasts, osteocytes, and osteoclasts.
• The first two types originate from progenitor
cells within the osteogenic tissue of the bone.
Osteoclasts are believed to differentiate
separately from mono-nuclear phagocytic
cells.

32. • Osteoblasts are present on the surfaces of all
bones and line the internal marrow cavities.
• They contain numerous mitochondria and an
extensive Golgi apparatus associated with rapid
protein synthesis. They secrete the constituents
of the organic matrix of bone including collagen,
proteoglycans, and glyco-proteins.
• They are also important in the process of
mineralization (calcification) of this matrix.
• Osteoblasts possess specific receptors for
parathyroid hormone and calcitriol

33. • Osteocytes are mature bone cells derived
from osteoblasts that have become trapped in
lacunae (small spaces)
• within the matrix that they have secreted. As
described above, adjacent osteocytes are
linked by fine cytoplasmic
• processes that pass through tiny canals
(canaliculi) between lacunae

34. • This arrangement permits the exchange of calcium
from the interior to the exterior of bones and thence
into the extracellular fluid.
• This transfer is known as osteocytic osteolysis and
can be used to remove calcium from the most
recently formed mineral crystals when plasma
calcium levels fall.
• Osteoclasts are giant multinucleated cells that are
believed to arise from the fusion of several precursor
cells and therefore contain numerous mitochondria
and lysosomes.
• They are highly mobile cells that are responsible for
the resorption of bone during growth and skeletal
remodeling. They are abundant at or near the
surfaces of bone undergoing erosion.

35. • At their site of contact with the bone is a highly
folded ‘ruffled border’ of microvilli that
infiltrates the disintegrating bone surface.
• Bone dissolution is brought about by the actions
of collagenase, lysosomal enzymes, and acid
phosphatase. Calcium, phosphate, and the
constituents of the bone matrix are released into
the extracellular fluid as bone mass is reduced.
• The activity of the osteoclasts appears to be
controlled by a number of hormones, notably
parathyroid hormone, calcitonin, thyroxine,
estrogens, and the metabolites of vitamin D.

36. Bone development and growth (osteogenesis)
• At week 6 of gestation the fetal skeleton is constructed
entirely of fibrous membranes and hyaline cartilage.
• From this time, bone tissue begins to develop and
eventually replaces most of the existing structures.
Although this process of ossification begins early in
fetal life, it is not complete until the third decade of
adult life. The bones of the cranium, lower jaw, scapula,
pelvis, and the clavicles develop from fibrous
membranes by a process called intramembranous
ossification. In this process, new bone is formed on the
surface of existing bone.
• The bones of the rest of the skeleton grow in length as
hyaline cartilage templates are replaced by bone (a
process known as endochondral ossification).

37. Growth of bone length
• A long bone such as the radius in the forearm is laid
down first as a cartilage model. At the center of this
model, the so-called primary center of ossification,
the cartilage cells break down and bone appears.
This process begins early in fetal life and, shortly
before birth, secondary centers of ossification have
also developed, predominantly at the ends of the
bone or epiphyses. Smaller bones such as the
carpals and tarsals of the hands and feet develop
from a single ossification center.
• The areas of cartilage between the diaphysis and
the epiphyses are known as the growth plates.

38. • In the part of the growth plate immediately
under the epiphysis is a layer of stem cells or
chondroblasts. These give rise to clones of cells
(chondrocytes) arranged in columns extending
inwards from the epiphysis towards the
diaphysis.
• Several zones can be distinguished within the
columns of chondrocytes. The outer zone is one
of proliferation in which the cells are dividing
rapidly. Beneath this are layers in which the cells
mature, enlarge, and eventually degenerate The
innermost layer of cells is the region of
calcification. Here, the osteogenic cells
differentiate into osteoblasts and lay down bone.

39. • Thus, cartilage is produced at one end of the
epiphyseal plate, while at the other end it is
degenerating.
• Therefore growth in length is dependent upon the
proliferation of new cartilage cells. In humans, it
takes around 20 days for a cartilage cell to
complete the journey from the start of
proliferation to degeneration.
• Clearly, the bone marrow cavity must also increase
in size as the bone grows, and to ensure this,
osteoclasts erode bone within the diaphysis.

40. • At the end of the growth period, the growth plate thins
as it is gradually replaced by bone until it is eliminated
• altogether and the epiphysis and diaphysis are unified,
a process known as synostosis. Following this
‘fusion’ of the epiphyseal plate no further
increase in bone length is possible at this site. Although
growth in length of most bones is complete by the age
of 20, the clavicles do not ossify completely until the
third decade of life.
• The dates of ossification are fairly constant between
individuals but different between bones. This fact is
exploited in forensic science to determine the age of a
body according to which bones have, and which have
not, ossified.

41. Growth of bone diameter
• The growth in width of long bones is achieved by
appositional bone growth in which osteoblasts
beneath the periosteum of the bone form new
osteons on the external surface of the bone.
• Thus the bone becomes thicker and stronger. Rapid
ossification of this new tissue takes place to keep
pace with the growth in length of the bone. This
process is similar to the mechanism by which the
flat bones grow.

42. Bone healing following a fracture
• When bone is fractured its original structure and
strength are restored quite rapidly through the
formation of new bone tissue. Provided that the
edges of the fractured bone are repositioned and
the bone is immobilized by splinting, repair will
normally occur with no deformity of the skeleton.
There are three stages in the repair of a fractured
bone.
• The first stage occurs during the first 4 or 5 days
after injury and involves the removal of debris
resulting from the tissue damage.

43. • This includes bone and other tissue fragments as
well as blood clots formed by bleeding between the
bone ends and into surrounding muscle when the
periosteum is damaged.
• Phagocytic cells such as macrophages clear the area
and granulation tissue forms. This is a loosely gelled
protein-rich exudate that forms at any site of tissue
damage and which later becomes fibrosed and
organized into scar tissue.
• As it revascularizes from undamaged capillaries in
adjacent tissue, it takes on a pink granular
appearance.

44. • Osteoblasts within the endos-teum and periosteum
migrate to the site of damage to initiate the second
stage of healing.
• During this stage, which normally lasts for the next
3 weeks or so, osteoid is secreted by the osteoblasts
into the granulation tissue to form a mass between
the fractured bone to bridge the gap. This tissue
mass is also known as soft callus.
• The soft callus gradually becomes ossified to form a
region of woven bone (similar to cancellous bone),
also called hard callus.
• At this stage of healing there is normally some
degree of local swelling at the site of the fracture
caused by the hard callus deposit.

45. • During the final stage in the process of healing the
mass of hard callus is restructured to restore the
original architecture of the bone.
• This stage may take place over many months and
involves the actions of both osteoblasts and
osteoclasts.
• During this time, the periosteum also re-forms
and the bone is able to tolerate normal loads and
stresses.

48. Remodeling of bone
• Even after growth has ended, the skeleton is in a
continuous state of remodeling as it is renewed and
revitalized at the tissue level. Large volumes of bone
are removed and replaced, and bone architecture
continually changes as 5–7 per cent of bone mass is
recycled each week. Furthermore, following a break
to a bone, self-repair takes place remarkably quickly.
• Remodeling allows bone to adapt to external stresses,
adjusting its formation to increase strength when
necessary. Remodeling occurs in cycles of activity in
which resorption precedes formation.
• First, bone is eroded by the osteoclasts. This erosion is
followed by a period of intense osteoblastic activity in
which new bone is laid down to replace that which
has been resorbed.

49. • In general terms, bone is deposited in proportion
to the load it must bear. Therefore it follows that
in an immobilized person bone mass is rapidly
(though reversibly) lost—a process known as
disuse osteoporosis.
• Astronauts experiencing prolonged periods of
weightlessness in space have been shown to lose
up to 20 per cent of their bone mass in the
absence of properly planned exercise programs.

50. • Similarly, appropriate exercise during childhood
and adolescence is thought to enhance the
development of bone and result in a stronger
healthier skeleton in adult life, a factor that may
be particularly important in females.
• However, the exact mechanisms that control the
rate of deposition and loss of bone in response to
mechanical requirements remain largely unknown.

51. The role of growth hormone in the
control of growth
• Growth is the result of the multiple interactions
of circulating hormones, tissue responsiveness,
and the supply of nutrients and energy for
growing tissues.
• Many hormones are known to be involved in the
regulation of growth at different stages of life.
• Nevertheless, growth hormone is the hormone
that undoubtedly exerts a dominant effect on
normally coordinated growth.

52. • GH is a polypeptide derived from the pituitary
somatotrophs. It bears a marked structural similarity
to prolactin and human placental lactogen.
• The secretion of GH is controlled by hypothalamic
releasing hormones. Growth hormone releasing
hormone (GHRH) stimulates the output of GH while
somatostatin inhibits it. GH shows a marked irregular
pulsatile pattern of release which is influenced by a
number of physiological stimuli.
• For example, stress and exercise both stimulate GH
secretion, and there is a significant increase in the rate
of secretion during slow-wave (deep) sleep,
particularly in children. Both the pulsatile character
and the sleep-induced patterns of release are lost in
patients suffering from hypo- or hypersecretion of GH.

53. • Other hormones and products of metabolism
also influence the rate of GH secretion.
• For example, estrogens increase the sensitivity of
the pituitary to GHRH, an effect that contributes
to the earlier growth spurt seen in adolescent
girls compared with boys.
• GH secretion is decreased by the adrenal
glucocorticoid hormones and stimulated by
insulin.
• Oral glucose depresses GH release, while
secretion is promoted by low levels of plasma
glucose.

54. • In common with most endocrine systems, the
secretion of GH is under negative feedback control.
This is probably mediated both by GH itself (chiefly at
the level of the hypothalamus) and by the insulin-like
growth factors (IGFs) that are thought to act at both
pituitary and hypothalamic levels. GH interacts with
its target cells at the plasma membrane where it binds
to surface receptors.
• Synthesis of these receptors requires the presence of
GH itself, while an excess of GH causes down-
regulation of the receptors.
• The mechanisms of signal transduction have now
been clarified. GH activates membrane-bound
tyrosine kinases which phosphorylate a group of
proteins that activate gene transcription.

55. • The actions of GH can be divided into metabolic
and growth-promoting effects. The metabolic
actions of GH tend to oppose those of insulin and
are largely direct in nature. GH exerts its direct
actions on a variety of target tissues, principally
the liver, muscle and adipocytes.
• It depresses glucose metabolism (to spare
glucose for use by the central nervous system in
times of fasting or starvation). Furthermore, GH
stimulates lipolysis, which increases the
availability of fatty acids for oxidation, and
facilitates the uptake of amino acids into cells for
protein synthesis.

56. • The growth-promoting actions of GH embrace
both direct and indirect effects. GH seems to
exert a direct stimulatory effect on chondrocytes,
increasing the rate of differentiation of these cells
and therefore of cartilage formation.
• Many of the direct metabolic actions of GH, such
as the increase in uptake of amino acids and the
rate of protein synthesis, will also contribute to
the overall processes of growth and repair.

57. • The indirect actions of growth hormone are
mediated by a family of peptide hormone
intermediaries called insulin-like growth factors
(IGFs) formerly known as somatomedins.
• They have a molecular weight of around 7000
and are structurally related to proinsulin, the
precursor of insulin.
• The IGFs are synthesized in direct response to GH,
chiefly by the liver but also by other tissues
including cartilage and adipose tissue. Plasma
IGF-1 is increased by the administration of GH,
with a time lag of 12–18 hours, and is reduced
in individuals who lack GH.

58. • IGFs have plasma half-lives in excess of that of
GH because they are carried in the blood
bound to several proteins.
• The blood level of IGF-1 is low in infancy, rises
gradually until puberty, and then increases
more swiftly to reach a peak which coincides
with the peak height increase,after which it
falls to its adult (and prepubertal) value.

59. GH excess
• Although hypersecretion of GH may occur at any
stage of life, the incidence of pituitary gigantism
resulting from an excess of GH in childhood is
extremely rare.
• Tumors of the pituitary gland or overgrowth of the
GH-producing cells can occasionally cause vastly
excessive (though proportionate) growth.
• A further condition characterized by extreme tallness
is cerebral gigantism (Sotos′ syndrome) which
seems to be caused by an over-reaction to GH by its
target tissues rather than an excess of GH itself.
• This is extremely rare.

62. • The actions of the IGFs, as their name suggests,
tend to be insulin-like in character and account
principally for the growth-promoting effects of
GH. They act on cartilage, muscle, fat cells,
fibroblasts, and tumor cells.
• More specifically related to bone growth is the
action of IGFs (particularly IGF-1 and IGF-2) in
stimulating the clonal expansion of chondrocytes
and the formation and maturation of osteoblasts
in the growth plates of the long bones.

63. • All aspects of the functions of the chondrocytes
are stimulated, including the incorporation of the
amino acid proline into collagen and its
subsequent conversion to hydroxyproline.
• Furthermore, GH (via IGFs) stimulates the
incorporation of sulfate into chondroitin.
• Chondroitin sulfate and collagen together form
the tough inorganic matrix of cartilage. Growth
of soft tissue and the viscera is also attributed to
the indirect actions of GH via the IGFs.

64. The importance of GH in growth at different stages of
life
• Importance in the control of growth and GH receptors
do not appear until the final 2 months of gestation.
• The growth factors IGF-1 and IGF-2 appear to play a
dominant role in fetal growth.
• Following delivery, and in the early part of childhood,
GH secretion increases considerably, and during this
phase, overall growth and increase in stature seems to
depend almost entirely on the actions of GH itself and
of IGF-1. At puberty, there is a further significant rise in
GH secretion (probably associated with an increase in
the output of sex steroids) with a parallel increase in
IGF-1 output.
• This promotes the further growth of the long bones
and contributes to the adolescent growth spurt.

65. • During the final phases of puberty the sex
steroids cause the epiphyses to fuse, and
during subsequent adult life no further
increase in stature occurs.
• However, GH, may still play a part in the
remodeling of bone and in the repair and
maintenance of cartilage.

66. GH deficiency
• As the preceding discussion suggests, GH is needed
for normal growth between birth and adulthood.
Individuals who Lack GH (so-called pituitary dwarfs)
grow to a height of around 120–130 cm while
remaining of normal proportions.
• This is in contrast with the disproportionate growth
seen in achondroplasia, the congenital type of
dwarfism in which growth of the bones is impaired
due to defects in other local growth factors. A
further type of growth impairment caused by
defective GH receptors rather than a lack of the
hormone itself is known as Laron dwarfism.
• These individuals have the same physical
appearance as those who lack growth hormone.

67. • GH-deficient children can be treated by injections
of human GH.
• After treatment, they usually achieve significant
catch-up growth and reach an acceptable adult
height (Fig. 23.13). Unlike other hormones such as
insulin and ACTH, growth hormone is species
specific, i.e. animal GH is without effect in humans.
• From 1958 until 1985, the GH administered to
patients was extracted from the pituitary glands of
human cadavers at postmortem.
• Unfortunately a few of the children treated in this
way have since become ill or died from the
degenerative brain disease Creutzfeld- Jakob
Disease (CJD).

68. • In recent years recombin-ant DNA technology has
developed, and now human GH can be
manufactured and used to treat GH deficiency
without risk of CJD.
• Finally, short stature may be caused by a failure
to produce the IGFs in response to GH rather than
a simple lack of GH. In conditions of this kind, GH
treatment will be of no value but such children
can be treated with recombinant IGF- 1.

70. The role of other hormones in the process of
growth
• Although growth hormone undoubtedly plays a
pivotal role in the process of physical growth,
many other hormones are also important.
• Indeed, the number of hormones involved in the
normal growth and development of an individual
is indicated by the range of abnormalities of
hormone secretion that can result in disturbed
growth and abnormal development.

71. • Hormones of particular significance include
thyroxine and the sex steroids.
• A number of other hormones, including
insulin, the metabolites of vitamin D,
parathyroid hormone, calcitonin, and cortisol,
may indirectly influence growth and
development through their general metabolic
actions or their actions on the physiology of
bone.

72. Thyroid hormone
• Thyroxine is necessary for normal growth from early
fetal life onwards and for normal physiological
function in both children and adults.
• Its secretion begins at weeks 15–20 of gestation
and it seems to be essential for protein synthesis in
the brain of the fetus and very young children. It is
also required for the normal development of nerve
cells.
• As the brain matures, this action assumes less
importance. Children born with thyroid hormone
deficiency will be mentally handicapped unless
treated quickly—a condition known as cretinism.

73. • Children who develop thyroid hormone
deficiency at a later stage have increasingly
slowed bodily growth and delayed skeletal and
dental maturity, but do not suffer obvious brain
damage.
• Catch-up growth is achieved rapidly following
treatment with exogenous thyroxine. Thyroid
hormones appear to play a permissive rather
than a direct role in growth, allowing cells
(including the somatotrophs of the anterior
pituitary) to function normally.

74. Corticosteroids
• If present in excess of normal concentrations,
hormones of the adrenal cortex, principally
cortisol, appear to have an inhibitory action on
growth. Such a situation may develop
pathologically, for example in Cushing's syndrome
or following therapeutic administration of steroids
to treat asthma, rheumatoid arthritis, kidney
disease, or severe eczema.
• In such cases, the rate at which the skeleton
matures is increased so that the potential for
further growth is reduced.

75. Insulin
• Insulin is produced by the islets of Langerhans in the
pancreas. It has no particular significance as far as
growth is concerned except that it must be secreted in
normal concentrations for normal growth to take place.
The plasma level of insulin, both in the fasting state and
following a meal, rises during puberty and falls back
again at the end of puberty.
• Even small imbalances of plasma insulin and glucose
levels can result in stunting and retardation of growth.
• However, diabetic children whose disease is well
controlled by injected insulin and a suitable diet will
grow normally.

76. Vitamin D metabolites and parathyroid
hormone
• The hormones that regulate plasma mineral
levels have indirect effects on growth through
their actions on the development and
maintenance of the skeleton. Of particular
importance are the metabolites of vitamin D.
• Calcitriol (1,25-dihydroxycholecalciferol)
stimulates the intestinal uptake of calcium,
thereby helping to maintain normal plasma levels
of calcium. Calcitriol may also have a direct effect
on bone to stimulate mineralization.

77. • Vitamin D deficiency causes the disorder of skeletal
development known as rickets in children and
osteomalacia in adults.
• Both conditions are characterized by failure of the
matrix of bone (osteoid) to calcify. In children
whose bones are still growing there is a reduction in
the rate of remodeling, which results in swelling of
the growth regions of the bones, lack of ossification,
and a thickened growth plate of cartilage which is
soft and weak.
• The weight-bearing bones bend, leading to bow legs
or knock-knees as shown in Fig. 23.15.
• In osteomalacia, layers of osteoid are produced
which eventually cover practically the entire surface
of the skeleton. The main feature of the condition is
pain, and bones may show partial fractures.

79. • Parathyroid hormone (PTH) is important in whole-
body calcium and phosphate homeostasis. Normal
secretion of this hormone is needed for normal
bone formation. PTH is believed to bind to
osteoblasts (possibly under the permissive
influence of calcitriol) and to stimulate their activity.
• Calcitonin, secreted by parafollicular cells of the
thyroid gland, is hypocalcemic in its action,
encouraging the binding of calcium to bone.
Although its importance in adults is questioned, it is
possible that calcitonin contributes to the growth or
preservation of the skeleton during childhood and
possibly throughout pregnancy through an
inhibition of osteoclast activity.

80. Sex steroids and the adolescent growth spurt
• The growth spurt can be divided into three stages. These
are the age at ‘take-off’ (i.e. the age at which
growth velocity begins to increase), the period of peak
height velocity, and the time during which growth velocity
declines and finally ceases at epiphyseal fusion. In general,
boys begin their growth spurt 2 years later than girls.
• Therefore boys are taller at the time of ‘take-off’
and reach their peak height velocity 2 years later.
• During the growth spurt, boys increase their height by an
average of 28 cm and girls by 25 cm.
• The average 10 cm difference in height between boys and
girls is due more to the height difference at ‘take-
off’ than to the height gained during the spurt.

81. • Virtually every aspect of muscular and skeletal
growth is altered during puberty, and sex
differences are seen (e.g. in shoulder growth)
which result in accentuation of sexual
dimorphism (the differences between men
and women) in adulthood.

82. • The hormonal mechanisms that underlie the
growth spurt of puberty involve the cooperative
actions of pituitary growth hormone and the
gonadal steroids.
• At puberty, estradiol-17β from the ovaries and
testosterone from the testicular Leydig cells are
secreted in increasing amounts under the
influence of pituitary gonadotrophins.
• These steroids stimulate the secretion of GH,
which in turn stimulates growth of the long bones
resulting in an increase in height.
• Estradiol-17β is also responsible for the
development of the breasts, uterus, and vagina,
and for the growth of parts of the pelvis.

83. • Testosterone stimulates the development of male
secondary sexual characteristics and has a direct
action on the bones and muscles, which accounts
for the differences in lean body mass and skeletal
morphology seen between men and women.
• The increased secretion of sex steroids at puberty
is important in triggering the process of
epiphyseal fusion, limiting long-bone growth at
the end of puberty.

84. Growth of cells, tissues, and organs
• All biological tissues are made up of cells, which continually
renew their constituents through metabolism.
• In terms of overall growth characteristics, however, tissues
can be divided into three categories.
• In the first are nerve and muscle, which manufacture few, if
any, new cells once the period of growth is over.
• Once formed, the cells in these tissues last for most or all of
the individual's life. In the second category are tissues such
as skin, blood, and the GI epithelium whose cells are
continually dying and being replaced by new cells.
• Tissues such as these have a special germinative zone (e.g.
hematopoietic tissue in red bone marrow) wherein new
cells are born. In the third category, cells are relatively long
lived and stable, but new cells can be generated if the tissue
is damaged or when increased activity is required of it.

85. • This group of tissues with significant powers of
regeneration includes parts of the liver and
kidneys and most glands.
• An organ may enlarge in three ways:
1. the number of its constituent cells increases
(hyperplasia);
2. the size of its constituent cells increases
(hypertrophy);
3. The amount of substance between the cells
increases.

86. • In non-regenerating tissue, growth occurs in three
phases. First, the tissue increases its size through cell
division and an increase in cell numbers.
• During the second phase, the rate of cell division
falls but the cells increase in size as proteins
continue to be synthesized and enter the cytoplasm.
In the third phase, cell division stops almost
completely and the tissue expands only by
increasing cell size.
• The age at which the cells stop dividing depends
upon the individual tissue or organ.
• The neurons of the CNS are the first cells to stop
dividing, at around 18 weeks of gestation in the case
of the cerebral cortex.

87. • During early development, the overall number of cells in the
body is increasing. In general, more cells than are needed are
produced, and the excess is eliminated by pre-programmed
cell death known as apoptosis.
• Once adult size is reached, cell division is important mainly
for wound repair and the replacement of short-lived cells.
During young adulthood, cell numbers remain fairly constant.
• However, local changes in the rate of cell division are seen, for
example in anemia, when the bone marrow undergoes
hyperplasia, or accelerated growth, so that red blood cells are
produced at an increased rate. In contrast, atrophy (loss of
tissue mass) can result from the loss of normal stimulation.
• Muscles that lose their nerve supply will atrophy, while loss of
TSH, which normally exerts a trophic effect on the thyroid
gland, will similarly lead to atrophy of the thyroid tissue and a
reduction in thyroid hormone output.

88. Alterations in cell differentiation: carcinogenesis
• The body consists of cells that are organized into populations
that form the tissues and organs.
• Cells reproduce by cell division and are programmed to die.
The balance between cell proliferation and cell death within a
tissue determines its overall size.
• Under normal circumstances, it seems that differentiated cells
can continually sense their environment and adjust their rate
of proliferation to suit the prevailing requirements. For
example, liver cells increase their rate of proliferation in
response to loss of liver tissue caused by alcohol.
• However, when cells fail to obey the normal rules governing
their proliferation and multiply excessively, an abnormal mass
of rapidly dividing cells is formed. This is called a neoplasm
(new formation) and the process is called neoplasia.

89. • Neoplasms are composed of two types of
tissue: parenchymal tissue which represents the
functional component of the organ from which
it is derived, and stroma, or supporting tissue,
consisting of blood vessels, connective tissue,
and lymph structures.
• Neoplasms are classified as benign or malignant
according to their growth characteristics.
Benign neoplasms are well-defined local
structures that usually grow slowly and do not
metastasize (spread to distant sites to seed
secondary tumors).

90. • Malignant neoplasms, however, are poorly
differentiated, grow rapidly, and readily metastasize
via the blood or lymph.
• Cancer cells consume large amounts of nutrients, thus
depriving other cells of necessary metabolic fuels.
• This leads to the characteristic weight loss and tissue
wasting which often contribute to the death of cancer
patients. Cancers can arise from almost any cell type
except neurons, but the most common cancers
originate in the skin, lung, colon, breast, prostate
gland, and urinary bladder.
• About 20 per cent of all inhabitants of the prosperous
countries of the world die of cancer.

91. What are the factors that cause transformation of a normal cell
into a
cancer cell?
• It is well known that certain physical and chemical factors,
including irradiation, tobacco tars, and saccharine can act as
carcinogens. They do so by causing mutations—changes in
the DNA that alter the expression of certain genes.
• Cancer-causing genes (oncogenes) have been detected in
certain rapidly spreading tumors, and proto-oncogenes
(benign forms of oncogenes) have been discovered in
normal cells.
• Proto-oncogenes code for the proteins that are essential for
cell division, growth, and cellular adhesion, and it is believed
that they may be converted to oncogenes when fragile sites
within them are exposed to and damaged by carcinogens.
• As a result, dormant genes may be switched on that allow
cells to become invasive and to metastasize.
• These capabilities are possessed by embryonic cells and
cancer cells but not by differentiated adult cells.

92. • Recently, tumor-suppressor genes (anti-
oncogenes) have been discovered.
• They seem to protect cells against cancer by
influencing processes that inactivate
carcinogens, aid in the repair of DNA, or
enhance the ability of the immune system to
destroy cancer cells.