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^ 23 The control of growth






Fig. 23.8 The lifetime pattern of GH secretion.

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.

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.

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 to 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.

GH-deficient children may be treated by injections of human GH and will usually achieve significant catch-up growth and an acceptable adult height (Fig. 23-9). Unlike other hormones such



Fig. 23.9 The pattern of growth in a girl with isolated pituitary GH deficiency, treated with three periods of exogenous GH administration. Note the 'catch-up' growth seen during rhe treatment periods. The downward-poinring arrows represent the end of each period of treatment. The range of heights for normal girls is indicated by the shaded area.

23.5 The role of other hormones in the process of growth

511


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 post-mortem. Unfortunately a few of the children treated in this way have since become ill or died from the degenerative brain disease Creutzfeldt—Jakob disease (CJD). In recent years recombinant 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.

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 overreaction to GH by its target tissues rather than an excess of GH itself. This is extremely rare.

In adulthood, GH-secreting pituitary tumors are much more common and result in a condition called acromegaly. After epiphy­seal fusion, no further increase in bone length can occur. Instead, in response to the raised levels of plasma GH, the bones start to thicken. This gives the patient a characteristic appearance, with large hands, feet, and jaws, and coarsening of the facial features. There is also overgrowth of soft tissues and the patient may become diabetic as a result of the anti-insulin-like metabolic effects of GH. They are also at increased risk from cardiovascular disease and neoplasias, due to effects of GH on the heart and colon.

Summary

  1. The anterior pituitary peptide growth hormone (GH) has a dominant
    effect on postnatal growth. GH secretion rises during early infancy
    and shows a further peak during puberty. It is under hypothalamic
    control and shows pulsatile release. Moreover, GH secretion is
    stimulated by exercise, stress, fasting, and during non-REM sleep.

  2. GH exerts both metabolic and growth-promoting effects. It directly
    stimulates the formation of cartilage by chondrocytes and enhances
    the rate of uptake and incorporation of amino acids into protein.

  3. GH exerts a number of indirect effects through IGFs (insulin-like
    growth factors). IGFs stimulate the clonal expansion of chondrocytes
    and the formation of the organic bone matrix.

  4. GH deficiency during childhood results in pituitary dwarfism. It may
    be treated by injections of genetically engineered human GH.
    Pituitary gigantism results from hypersecretion of GH before the age
    of puberty. It is very rare but hypersecretion of GH in adulthood is
    more common, resulting in acromegaly in which there are metabolic
    disturbances, thickening of bones, and overgrowth of soft tissues.

^ 23.5 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. 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 influence growth and development indirectly through their general metabolic actions or their actions on the physiology of bone. The growth-promoting actions of most of these have been discussed in the relevant sections of Chapter 12 so only a brief resume will be given here.

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 rhe fetus and very young child and 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.

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.

Corticosteroids

Hormones of the adrenal cortex, principally Cortisol, appear to have an inhibitory acrion on growth if presenr in excess of normal concentrations. Such a situation may develop patho­logically, for example in Cushing's syndrome, or as a result of therapeutic administration of steroids to treat asthma, rheuma­toid arthritis, kidney disease, or severe eczema. In these cases, the rate at which the skeleton matures is increased so that the potential for further growth is reduced.

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

^ 512

23 The control of growth


back again at the end of puberty. Although diabetic children whose disease is well controlled by injected insulin and a suit­able diet will grow normally, even small imbalances of plasma insulin and glucose levels can result in stunting and retardation of growth.

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 (see Section 12.6). Calcitriol (l^S-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.

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. 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.

Parathyroid hormone 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 in pregnancy.

Sex steroids and the adolescent growth spurt

The growth velocity curves shown in Fig. 23.2 illustrate the timing of the growth spurt which is evident in both girls and boys at puberty. The growth spurt may be divided into three stages. These are the age at 'take-off (i.e. the age at which growth velocity is at a minimum), 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. Boys are, therefore 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 the height gained during the spurt.

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

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

Summary

  1. Many hormones in addition to GH are involved in the regulation of
    growth. Thyroxine is required for growth from the early fetal period
    onwards and plays an important part in maturation of the CNS.
    Excessive secretion (or therapeutic administration) of corticosteroids
    can inhibit normal growth and maturation of the skeleton in chil­
    dren. Small imbalances in insulin secretion and plasma glucose seem
    also to interfere with normal development.

  2. Calcitriol (an active metabolite of vitamin D) stimulates the intes­
    tinal uptake of calcium and seems to be essential for normal growth,
    calcification, and remodeling of the skeleton. Parathyroid hormone
    stimulates the activity of the osteoblasts and is important for the
    normal growth of bone.

  3. The cooperative action of the gonadal steroids and pituitary GH
    underlie the growth spurt of puberty. Both estradiol and testosterone
    stimulate the secretion of GH, which in turn increases the rate of
    long-bone growth. The male and female sex steroids also exert specific
    effects which give rise to the secondary sex characteristics and the dif­
    ferences in musculoskeletal morphology between men and women.

^ 23.6 Growth of cells, tissues, and organs

All biological tissues are made up of cells which continually renew their constituents through metabolism (Chapter 3). In terms of overall growth characteristics, however, tissues may be divided into three categories. In the first are nerve and muscle which manufacture no new cells once the growth period 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 gastrointestinal epithelium, whose cells are con-

^ 23.6 Growth of cells, tissues, and organs

513


tinually dying and being replaced by new cells. Tissues such as these have a special germinative zone wherein new cells are man­ufactured. 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. 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 content of its constituent cells increases (hypertrophy);

  3. the amount of substance between the cells increases.

In nonregenerating tissue, growth occurs in three phases. At first the tissue increases its size through cell division and an increase in cell numbers. For further details of the stages of mitotic division see Chapters 3- 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, at around 18 weeks of gestation in the case of the cerebral cortex.

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 cells are 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 short­lived 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. By contrast, atrophy (loss of tissue mass) can result from the loss of normal stimulation. Muscles that lose their nerve supply will waste, while loss of thyroid-stimulating hormone will lead to atrophy of the thyroid gland.

Alterations in cell differentiation: carcinogenesis

The body consists of cells that are organized into populations, which are 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. Liver cells, for example, 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. Neoplasms are composed of two types of tissue, parenchymal tissue which represents the functional component of the organ

from which it derives, 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, which usually grow slowly and do not metastasize (spread to distant sites to seed secondary tumors). Malignant neoplasms, however, are poorly differentiated, grow rapidly, and readily metastasize via the blood or lymph. Cancer cells consume large amounts of nutrients, leading to the characteristic weight loss and tissue wasting that often contribute to death. Cancers can arise from almost any cell type 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.

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, while proto-oncogenes, benign forms of oncogenes, have been discovered in normal cells. These 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.

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.

Summary

  1. Tissues are either nonregenerating (such as nerve), or regenerating.
    The latter include those which are in a continual state of renewal
    (skin, blood cells, etc.) and those, like liver, which can regenerate in
    response to tissue loss or damage.

  2. Organs increase in size by cell division, by an increase in cell size, and
    by an increase in volume of intercellular material. In nonregenerating
    tissues, cell division stops when the tissue has reached an appropriate
    size.

  3. Under normal conditions, differentiated ceils adjust their rate of
    proliferation to requirements in response to a variety of signals.
    Failure to do so results in the formation of a benign or malignant
    neoplasm. Malignant neoplasms are poorly differentiated, grow
    rapidly, and metastasize.

  4. A cell may be transformed into a cancer cell when its DNA undergoes
    mutation and the expression of certain genes is altered. Specific cancer-
    promoting genes and tumor-suppressor genes have been discovered.

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