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PHYSIOLOGY OF GROWTH

Growth is a complex phenomenon that is affected not only by growth hormone and somatomedins

but also by thyroid hormones, androgens, estrogens, glucocorticoids, and insulin. It is also

affected, of course, by genetic factors, and it depends on adequate nutrition. It is normally

accompanied by an orderly sequence of maturational changes, and it involves accretion of protein

and increase in length and size, not just an increase in weight, which may be due to the formation

of fat or retention of salt and water.

Role of Nutrition

The food supply is the most important extrinsic factor affecting growth. The diet must be adequate

not only in protein content but also in essential vitamins and minerals (see Chapter 17: Energy

Balance, Metabolism, & Nutrition) and in calories, so that ingested protein is not burned for

energy. However, the age at which a dietary deficiency occurs appears to be an importantconsideration. For example, once the pubertal growth spurt has commenced, considerable linear

growth continues even if caloric intake is reduced. Injury and disease stunt growth because they

increase protein catabolism.

Growth Periods

Patterns of growth vary somewhat from species to species. Rats continue to grow, although at a

declining rate, throughout life. In humans, two periods of rapid growth occur (Figure 2211); the

first in infancy and the second in late puberty just before growth stops. The first period of

accelerated growth is partly a continuation of the fetal growth period. The second growth spurt, at

the time of puberty, is due to growth hormone, androgens, and estrogens, and the subsequent

cessation of growth is due in large part to closure of the epiphyses by estrogens (see Chapter 23:

The Gonads: Development & Function of the Reproductive System). Since girls mature earlier

than boys, this growth spurt appears earlier in girls. Of course, in both sexes the rate of growth of

individual tissues varies (Figure 2212).

Figure 2211.

Rate of growth in boys and girls from birth to age 20.


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Figure 2212.

Growth of different tissues at various ages as a percentage of size at age 20. The curves are composites

that include data for both boys and girls.

It is interesting that at least during infancy, growth is not a continuous process but is episodic or

saltatory. Increases in length of human infants of 0.52.5 cm in a few days are separated by

periods of 263 days during which no measurable growth can be detected. The cause of the

episodic growth is unknown.

Hormonal Effects

The contributions of hormones to growth after birth are shown diagrammatically in Figure 2213.

In laboratory animals and in humans, growth in utero is independent of fetal growth hormone.

Figure 2213.

Relative importance of hormones in human growth at various ages. (Courtesy of DA Fisher.)


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Plasma growth hormone is elevated in newborns. Subsequently, average resting levels fall but the

spikes of growth hormone secretion are larger, especially during puberty, so the mean plasma

level over 24 hours is increased; it is 24 ng/mL in normal adults but 58 ng/mL in children. One

of the factors stimulating IGFI secretion is growth hormone, and plasma IGF-I levels rise during

childhood, reaching a peak at 1317 years of age. In contrast, IGF-II levels are constant

throughout postnatal growth.

The growth spurt that occurs at the time of puberty (Figure 2211) is due in part to the protein

anabolic effect of androgens, and the secretion of adrenal androgens increases at this time in both

sexes. However, it is also due to an interaction among sex steroids, growth hormone, and IGF-I.

Treatment with estrogens and androgens increases the growth hormone responses to stimuli such

as insulin and arginine. Sex steroids also increase plasma IGF-I but fail to produce this increase in

individuals with growth hormone deficiency. Thus, it appears that the sex hormones produce an

increase in the amplitude of the spikes in growth hormone secretion that increases IGF-I

secretion, and this in turn causes growth.

Although androgens and estrogens initially stimulate growth, estrogens ultimately terminategrowth by causing the epiphyses to fuse to the long bones (epiphysial closure). Once the

epiphyses have closed, linear growth ceases (see Chapter 21: Hormonal Control of Calcium

Metabolism & the Physiology of Bone). This is why patients with sexual precocity are apt to be

dwarfed. On the other hand, men who were castrated before puberty tend to be tall because their

estrogen production is decreased and their epiphyses remain open so that some growth continues

past the normal age of puberty.

When growth hormone is administered to hypophysectomized animals, the animals do not grow as

rapidly as they do when treated with growth hormone plus thyroid hormones. Thyroid hormones

alone have no effect on growth in this situation. Their action is therefore permissive to that of

growth hormone, possibly via potentiation of the actions of somatomedins. Thyroid hormones alsoappear to be necessary for a completely normal rate of growth hormone secretion; basal growth

hormone levels are normal in hypothyroidism, but the response to hypoglycemia is frequently

subnormal in hypothyroid children. Thyroid hormones have widespread effects on the ossification

of cartilage, the growth of teeth, the contours of the face, and the proportions of the body. Cretins

are therefore dwarfed and have infantile features (Figure 2214). Patients who are dwarfed

because of panhypopituitarism have features consistent with their chronologic age until puberty,

but since they do not mature sexually, they have juvenile features in adulthood.

Figure 2214. Normal and abnormal growth. Hypothyroid dwarfs (cretins) retain their infantile proportions, whereas

dwarfs of the constitutional type and, to a lesser extent, of the hypopituitary type have proportionscharacteristic of their chronologic age. (Reproduced, with permission, from Wilkins L: The Diagnosis and


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Treatment of Endocrine Disorders in Childhood and Adolescence,3rd ed. Thomas, 1966.)

The effect of insulin on growth is discussed in Chapter 19: Endocrine Functions of the Pancreas &

Regulation of Carbohydrate Metabolism. Diabetic animals fail to grow, and insulin causes growth

in hypophysectomized animals. However, the growth is appreciable only when large amounts ofcarbohydrate and protein are supplied with the insulin.

Adrenocortical hormones other than androgens exert a permissive action on growth in the sense

that adrenalectomized animals fail to grow unless their blood pressures and circulations are

maintained by replacement therapy. On the other hand, glucocorticoids are potent inhibitors of

growth because of their direct action on cells, and treatment of children with pharmacologic doses

of steroids slows or stops growth for as long as the treatment is continued.

Catch-Up Growth

Following illness or starvation in children, A period of catch-up growth(Figure 22

15) takesplace during which the growth rate is greater than normal. The accelerated growth usually

continues until the previous growth curve is reached, then slows to normal. The mechanisms that

bring about and control catch-up growth are unknown.

Figure 2215.

Growth curve for a normal boy who had an illness beginning at age 5 and ending at age 7. Catch-up


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growth eventually returned his height to his previous normal growth curve. (Modified from Boersma B,

Wit JM: Catch-up growth. Endocr Rev 1997;18:646.)

Dwarfism

Short stature can be due to GRH deficiency, growth hormone deficiency, deficient secretion of

IGF-I, or other causes. Isolated growth hormone deficiency is often due to GRH deficiency, and in

these instances, the growth hormone response to GRH is normal. However, some patients with

isolated growth hormone deficiency have abnormalities of their growth hormone secreting cells.

In another group of dwarfed children, the plasma growth hormone concentration is normal or

elevated but their growth hormone receptors are unresponsive as a result of loss-of-function

mutations of the gene for the receptors. The resulting condition is known as growth hormone

insensitivityor Laron dwarfism. Plasma IGF-I is markedly reduced, along with IGFBP 3 (see

above), which is also growth hormone-dependent.

African pygmies have normal plasma growth hormone levels and a modest reduction in the

plasma level of growth hormone-binding protein. Their plasma IGF-I concentration fails to

increase at the time of puberty. However, they experience less growth than nonpygmy controls

throughout the prepubertal period. Thus, the explanation for the short stature of pygmies is still

unsettled.

As noted above, short stature is characteristic of cretinism and occurs in patients with precocious

puberty. It is also part of the syndrome of gonadal dysgenesis seen in patients who have an XO

chromosomal pattern instead of an XX or XY pattern (see Chapter 23: The Gonads: Development

& Function of the Reproductive System). Various bone and metabolic diseases also cause stunted

growth, and in many cases there is no known cause ("constitutional delayed growth"). Chronic

abuse and neglect can also cause dwarfism in children. This condition is known as psychosocial

dwarfismor the Kaspar Hauser syndrome,named for the patient with the first reported case.

Achondroplasia,the most common form of dwarfism in humans, is characterized by short limbs

with a normal trunk. It is an autosomal dominant condition caused by a mutation in the gene that

codes for fibroblast growth factor receptor 3 (FGFR3).This member of the fibroblast growth

receptor family is normally expressed in cartilage and the brain.

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