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Endocrine Control of Growth
- One of the major functions of the endocrine system is to control growth.
- At least a dozen hormones directly or indirectly have important functions in stimulating or inhibiting growth.
- This complex process is also influenced by genetics and a variety of environmental factors, including nutrition, and provides an illustration of the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition.
- The growth process involves cell division and net protein synthesis throughout the body, but a person’s height is determined specifically by bone growth, particularly of the vertebral column and legs.
- We first provide an overview of bone and the growth process before describing the roles of hormones in determining growth rates.
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11.17 Bone Growth
- Bone is a living, metabolically active tissue consisting of a protein (collagen) matrix upon which calcium salts, particularly calcium phosphates, are deposited.
- A growing long bone is divided, for descriptive purposes, into the ends, or epiphyses, and the remainder, the shaft.
- The portion of each epiphysis in contact with the shaft is a plate of actively proliferating cartilage (connective tissue composed of collagen and other fibrous proteins) called the epiphyseal growth plate.
- Osteoblasts, the bone-forming cells at the shaft edge of the epiphyseal growth plate, convert the cartilaginous tissue at this edge to bone, while cells called chondrocytes simultaneously lay down new cartilage in the interior of the plate.
- In this manner, the epiphyseal growth plate widens and is gradually pushed away from the center of the bony shaft as the shaft lengthens.
- Linear growth of the shaft can continue as long as the epiphyseal growth plates exist but ceases when the growth plates themselves are converted to bone as a result of other hormonal influences toward the end of puberty.
- This is known as epiphyseal closure and occurs at different times in different bones.
- Thus, a person’s bone age can be determined by taking an x-ray of bones
- and determining which ones have undergone epiphyseal closure.
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Bone growth over the years
- Figure 11.28 Relative growth in brain, total-body height (a measure of long-bone and vertebral growth), and reproductive organs. Note that brain growth is nearly complete by age 5, whereas maximal height (maximal bone lengthening) and reproductive-organ size are not reached until the late teens.
- As shown in Figure 11.28, children manifest two periods of rapid increase in height, the first during the first 2 years of life and the second during puberty.
- Note that increase in height is not necessarily correlated with the rates of growth of specific organs.
- The pubertal growth spurt lasts several years in both sexes, but growth during this period is greater in boys.
- In addition, boys grow more before puberty because they begin puberty approximately 2 years later than girls.
- These factors account for the differences in average height between men and women.
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11.18 Environmental factors influencing growth
- Adequate nutrition and good health are the primary environmental factors influencing growth.
- Lack of sufficient amounts of protein, fatty acids, vitamins, or minerals interferes with growth.
- The growth-inhibiting effects of malnutrition can be seen at any time of development but are most profound when they occur early in life.
- For this reason, maternal malnutrition may cause growth retardation in the fetus.
- Because low birth weight is strongly associated with increased infant mortality, prenatal malnutrition causes increased numbers of prenatal and early postnatal deaths.
- Moreover, irreversible stunting of brain development may be caused by prenatal malnutrition.
- During infancy and childhood, too, malnutrition can interfere with both intellectual development and total-body growth.
- Following a temporary period of stunted growth due to malnutrition or illness, and given proper nutrition and recovery from illness, a child can manifest a remarkable growth spurt called catch-up growth that brings the child to within the range of normal heights expected for his or her age.
- The mechanisms that account for this accelerated growth are unknown, but recent evidence suggests that it may be related to the rate of stem cell differentiation within the growth plates.
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11.19 Hormonal Influences on Growth
- The hormones most important to human growth are growth hormone, insulin-like growth factors 1 and 2, T3, insulin, testosterone, and estradiol, all of which exert widespread effects.
- In addition to all these hormones, a large group of peptide growth factors exert effects, most of them acting in a paracrine or autocrine manner to stimulate differentiation and/or cell division of certain cell types.
- Molecules that stimulate cell division are called mitogens.
- The various hormones and growth factors do not all stimulate growth at the same periods of life.
- For example, fetal growth is less dependent on growth hormone, thyroid hormone, and the sex steroids than are the growth periods that occur during childhood and adolescence.
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Growth Hormone and Insulin-Like Growth Factors
- Growth hormone, secreted by the anterior pituitary gland, has little effect on fetal growth but is the most important hormone for growth after the age of 1–2 years.
- Its major growth-promoting effect is stimulation of cell division in its many target tissues.
- Thus, growth hormone promotes bone lengthening by stimulating maturation and cell division of the chondrocytes in the epiphyseal plates, thereby continuously widening the plates and providing more cartilaginous material for bone formation.
- Importantly, growth hormone exerts most of its mitogenic effect not directly on cells but indirectly through the mediation of the mitogenic hormone IGF-1, whose synthesis and release by the liver are induced by growth hormone.
- Under the influence of growth hormone, IGF-1 is secreted by the liver, enters the blood, and functions as a hormone. In addition, growth hormone stimulates many other types of cells, including bone, to secrete IGF-1, where it functions as an autocrine or paracrine substance.
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Current concepts of how growth hormone and IGF-1 interact on the epiphyseal plates of bone
- (1) Growth hormone stimulates the chondrocyte precursor cells (prechondrocytes) and/or young differentiating chondrocytes in the epiphyseal plates to differentiate into chondrocytes.
- (2) During this differentiation, the cells begin both to secrete IGF-1 and to become responsive to IGF-1.
- (3) The IGF-1 then acts as an autocrine or paracrine substance (along with blood-borne IGF-1) to stimulate the differentiating chondrocytes to undergo cell division.
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The importance of IGF-1 in mediating the major growth promoting effect of growth hormone
- is illustrated by the fact that short stature can be caused not only by decreased growth hormone secretion but also by decreased production of IGF-1 or failure of the tissues to respond to IGF-1.
- For example, one rare form of short stature (called growth hormone–insensitivity syndrome) is due to a genetic mutation that causes a change in the growth hormone receptor such that it fails to respond to growth hormone (an example of hyporesponsiveness).
- The result is failure to produce IGF-1 in response to growth hormone, and a consequent decreased growth rate in a child.
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The secretion and activity of IGF-1 can be influenced by
- the nutritional status of the individual and by many hormones other
- than growth hormone.
- For example, malnutrition during childhood can inhibit the production of IGF-1 even if plasma growth hormone concentration is increased.
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Other growth hormone effects
- In addition to its specific growth-promoting effect on cell division via IGF-1, growth hormone directly stimulates protein synthesis in various tissues and organs, particularly muscle.
- It does this by increasing amino acid uptake and both the synthesis and activity of ribosomes.
- All of these events are essential for protein synthesis. This anabolic effect on protein metabolism facilitates the ability of tissues and organs to enlarge.
- Growth hormone also contributes to the control of energy homeostasis.
- It does this in part by facilitating the breakdown of triglycerides that are stored in adipose cells, which then release fatty acids into the blood. It also stimulates gluconeogenesis in the liver and inhibits the ability of insulin to promote glucose transport into cells.
- Growth hormone, therefore, tends to increase circulating energy sources.
- Not surprisingly, therefore, situations such as exercise, stress, or fasting, for which increased energy availability is beneficial, result in stimulation of growth hormone secretion into the blood.
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Control of growth hormone secretion
- The control system begins with two of the hormones secreted by the hypothalamus.
- Growth hormone secretion is stimulated by growth hormone–releasing hormone (GHRH) and inhibited by somatostatin (SST).
- As a result of changes in these two signals, which are usually out of phase with each other (i.e., one is high when the other is low), growth hormone secretion occurs in episodic bursts and manifests a striking daily rhythm.
- During most of the day, little or no growth hormone is secreted, although bursts may be elicited by certain stimuli, such as exercise.
- In contrast, 1 to 2 hours after a person falls asleep, one or more larger, prolonged bursts of secretion may occur.
- In addition to the hypothalamic controls, a variety of hormones—notably, the sex steroids, insulin, and thyroid hormones—influence the secretion of growth hormone.
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The net result of all these inputs on growth hormone
- The net result of all these inputs is that the secretion rate of growth hormone is highest during adolescence (the period of most rapid growth), next highest in children, and lowest in adults.
- The decreased growth hormone secretion associated with aging is responsible, in part, for the decrease in lean-body and bone mass, the expansion of adipose tissue, and the thinning of the skin that occur as people age.
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Treatment of children with short stature due to growth hormone deficiency.
- The availability of human growth hormone produced by recombinant DNA technology has greatly facilitated the treatment of children with short stature due to growth hormone deficiency.
- Controversial at present is the administration of growth hormone to short children who do not have growth hormone deficiency, to athletes in an attempt to increase muscle mass, and to elderly persons to reverse growth hormone–related aging changes.
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Administration of GH to an otherwise healthy individual
- Administration of GH to an otherwise healthy individual (such as an athlete) can lead to serious side effects.
- Abuse of GH in such situations can lead to symptoms similar to those of diabetes mellitus, as well as numerous other problems.
- The consequences of chronically increased growth hormone concentrations are dramatically illustrated in the disease called acromegaly.
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The role of GH in fetal growth
- As noted earlier, the role of GH in fetal growth, while still under investigation, appears not to be nearly as significant as at later stages of postnatal life.
- IGF-1, however, is required for normal fetal total-body growth and, specifically, for normal maturation of the fetal nervous system.
- The chief stimulus for IGF-1 secretion during prenatal life appears to be placental lactogen, a hormone released by cells of the placenta, which shares sequence similarity with growth hormone.
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insulin-like growth factor 2 (IGF-2)
- Finally, it should be noted that there is another messenger— insulin-like growth factor 2 (IGF-2), which is closely related to IGF-1.
- IGF-2, the secretion of which is independent of growth hormone, is also a crucial mitogen during the prenatal period.
- It continues to be secreted throughout life, but its postnatal function
- is not definitively known.
- Recent evidence suggests a link between IGF-2 concentrations and the maintenance of skeletal muscle mass and strength in elderly persons.
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Thyroid Hormone
- Thyroid hormone is essential for normal growth because it facilitates the synthesis of growth hormone.
- T3 also has direct actions on bone, where it stimulates chondrocyte differentiation, growth of new blood vessels in developing bone, and responsiveness of bone cells to other growth factors such as fibroblast growth factor.
- Consequently, infants and children with hypothyroidism have slower growth rates than would be predicted.
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Insulin
- The major actions of insulin are described in Chapter 16.
- Insulin is an anabolic hormone that promotes the transport of glucose and amino acids from the extracellular fluid into adipose tissue and skeletal and cardiac muscle cells.
- Insulin stimulates storage of fat and inhibits protein degradation.
- Thus, it is not surprising that adequate amounts of insulin are necessary for normal growth.
- Its inhibitory effect on protein degradation is particularly important with regard to growth.
- In addition to this general anabolic effect, however, insulin exerts direct growth-promoting effects on cell differentiation and cell division during fetal life and, possibly, during childhood.
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Sex steroids
- As Chapter 17 will explain, sex steroid secretion (testosterone in the male and estradiol in the female) begins to increase between the ages of 8 and 10 and reaches a plateau over the next 5 to 10 years.
- A normal pubertal growth spurt, which reflects growth of the long bones and vertebrae, requires this increased production of the sex steroids.
- The major growth-promoting effect of the sex steroids is to stimulate the secretion of growth hormone and IGF-1.
- Unlike growth hormone, however, the sex steroids not only stimulate bone growth but ultimately stop it by inducing epiphyseal closure.
- The dual effects of the sex steroids explain the pattern seen in adolescence—rapid lengthening of the bones culminating in complete cessation of growth for life.
- In addition to these dual effects on bone, testosterone exerts a direct anabolic effect on protein synthesis in many non-reproductive organs and tissues of the body.
- This accounts, at least in part, for the increased muscle mass of men in comparison to women.
- This effect of testosterone is also why athletes sometimes use androgens called anabolic steroids in an attempt to increase muscle mass and strength.
- These steroids include testosterone, synthetic androgens, and the hormones dehydroepiandrosterone (DHEA) and androstenedione.
- However, these steroids have multiple potential toxic side effects, such as liver damage, increased risk of prostate cancer, infertility, and changes in behavior and emotions. Moreover, in females, they can produce virilization [the development of male physical characteristics].
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Cortisol
- Cortisol, the major hormone the adrenal cortex secretes in response to stress, can have potent antigrowth effects under certain conditions.
- When present in high concentrations, it inhibits DNA synthesis and stimulates protein catabolism in many organs, and it inhibits bone growth.
- Moreover, it breaks down bone and inhibits the secretion of growth hormone and IGF-1.
- For all these reasons, in children, the increase in plasma cortisol that accompanies infections and other stressors is, at least in part, responsible for the decreased growth that occurs with chronic illness.
- One of the hallmarks of Cushing’s syndrome in children is a dramatic decrease in the rate of linear growth.
- Furthermore, the administration of pharmacological glucocorticoid therapy for asthma or other disorders may decrease linear growth in children in a dose-related way.
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