Normal Growth

Growth is influenced by many factors including overall health, heredity, gender, and environmental factors such as nutrition. Growth is rapid during the first year of life and then slows between 1 and 2 years of age (Table 9-1). After 2 years of age, linear growth continues to decline slowly, averaging a growth rate of approximately 2.0 inches (5 cm) per year until it reaches a nadir just before the initiation of the pubertal growth spurt. This nadir has been referred to as the “prepubertal dip” or the “prepubertal deceleration.” The “pubertal growth spurt” occurs during puberty. There are noticeable differences in the growth pattern of girls and boys during puberty. Girls generally start puberty at a younger chronologic age than boys and their pubertal growth spurt happens at an earlier pubertal stage. The pubertal growth spurt is also shorter in duration and displays a lower peak growth velocity in girls compared with boys. This sexual dimorphism is responsible for the differences in adult mature height between males and females. The average mature height of males is 13 cm greater than that of females.

Table 9-1 Normal Growth Rates in Children

Because stature varies among healthy children, incremental growth rate is one of the most important elements used to assess health in a child. Subnormal growth velocity can indicate endocrine and nonendocrine disorders. The most critical tool to evaluate normal and pathologic growth is the growth chart. In May of 2000, the Centers for Disease Control and Prevention (CDC) released updated growth charts based on a broad population sample combining many different growth studies (Fig. 9-1, A–D). These charts are readily available (http://www.cdc.gov/growthcharts). The charts not only define the 3rd and 97th percentiles for height and weight, but also characterize standards for head circumference and body mass index (BMI) defined as weight (kg)/height² (m). In contrast to adults for whom specific BMI values are used to define overweight and obesity, age- and gender-specific BMI values are used to classify children as over- or underweight. Health care professionals can use established percentile cutoff points to identify underweight and overweight children (Table 9-2).

Figure 9-1 A-D, Growth charts from the Centers for Disease Control. A, Stature-for-age and weight-for-age percentiles (3rd to 97th) for boys 2 to 20 years of age. B, Stature-for-age and weight-for-age percentiles for girls 2 to 20 years of age. C, Body mass index-for-age percentiles for boys 2 to 20 years of age. D, Body mass index-for-age percentiles for girls 2 to 20 years of age.

(Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion [2000]. Available online at http://www.cdc.gov/growthcharts.)

Table 9-2 Body Mass Index Cutoff Points

Although it can be normal for a child to change percentiles between birth and 18 months of age, after this age children usually follow their growth curves fairly closely. When a child crosses percentiles in a relatively short period of time, he or she should be carefully evaluated through a detailed investigation regarding the etiology of the abnormal growth pattern. Between 4 years and adolescence, a growth rate below 4 to 5 cm per year for girls and boys is abnormal and should be assessed. Adolescence is the only time during which the rapid growth of the infant is recapitulated. For girls, a sharp increase in growth velocity is the harbinger of puberty.

Short stature with normal body proportions and decreased growth velocity can be due to endocrine as well as nonendocrine disorders. Endocrine causes of short stature include growth hormone (GH) deficiency, GH resistance (GH receptor mutations or defects in insulin-like growth factor I [IGF-I] action), and hypothyroidism. Exogenous pharmacologic steroid therapy often leads to growth deceleration. Nonendocrine causes include chronic illness (e.g., renal tubular acidosis, celiac disease, or inflammatory bowel disease), genetic disorders, and undernutrition. One common cause of short stature in children is familial or genetic short stature. The genetic growth potential of a child is heavily influenced by the growth achieved by both parents and their relatives. The heritability of height has been estimated to be 0.7 to 0.8, rising to as much as 0.9 between identical twins. Common endocrine and nonendocrine causes of short stature are listed in Tables 9-3 and 9-4.

Table 9-3 Selected Nonendocrine Causes of Short Stature

Table 9-4 Endocrine Causes of Impaired Growth and Short Stature

Calculation of the target height provides an estimate of a child’s genetic potential. The target height, also referred to as mid-parental height (MPH), is the midpoint between the heights of parents, correcting for the 13-cm difference between male and female adult mature heights. For boys, the MPH is the midpoint between the father’s height and the corrected mother’s height (i.e., mother’s height plus 13 cm). This can be easily calculated by adding 6.5 cm (2.5 inches) to the mean of the parents’ heights. For girls, the MPH is the midpoint between the mother’s height and the corrected father’s height (i.e., father’s height minus 13 cm). This can be easily calculated by subtracting 6.5 cm (2.5 inches) from the mean of the parents’ heights. Ideally, this calculation should be based on measured parental heights, given that reported heights are frequently overestimated. The standard deviation of the target has been calculated as 5 cm in boys and 4.5 cm in girls. Therefore, the target height range is MPH ± 10 cm in boys and MPH ± 9 cm in girls. This information should be obtained during the initial evaluation, especially for children with concerns of tall or short stature. As an example, calculation of the MPH of a boy whose father’s height is 179 cm and mother’s height is 160 cm, would be as follows: 179 + 160 divided by 2 plus 6.5 cm. This is 176 cm. The target height range would be 166 to 186 cm.

Radiographic determination of epiphyseal maturation, or bone age, is often helpful in evaluating children with short stature. By convention, a radiograph of the left hand is compared with established standard radiographs to determine the bone age or skeletal age. Before 24 months of life, epiphyseal development is better estimated by radiographic examination of the hemiskeleton. Children who have familial or genetically determined short stature generally have a bone age equivalent to their chronologic age. The term “constitutional delay of growth” refers to children who have later onset of puberty. Typically, the bone age of children with constitutional delay is delayed, being more consistent with the children’s height age rather than chronologic age.

Children with constitutional delay typically have a period of decreased linear growth within the first 3 years of life. In this variation of normal growth and pubertal development, the rate of linear growth velocity and weight gain slow temporarily, often resulting in downward crossing of growth percentiles. By 2 or 3 years of age, linear growth resumes at a normal rate. Subsequently, children may grow either along the lower growth percentiles or beneath the curve but parallel to it for the remainder of their prepubertal years (Fig. 9-2). A family history of “late bloomers” or delayed puberty is common.

Figure 9-2 Growth curve of a child with constitutional growth delay. Note the typical pattern of growth deceleration followed by a normal growth rate.

Genetic syndromes (such as Turner, Noonan, and Down syndromes) are examples of chromosomal abnormalities associated with short stature. Congenital disorders of bone mineralization and bone growth, such as the chondrodystrophies, represent an important cause of disproportionate short stature. When evaluating a child with a suspected chondrodystrophy, body proportions should be measured. A simple method of determining proportions consists of measuring the lower segment (symphysis pubis to floor) and subtracting this value from the total height to determine the upper segment and then calculating the upper segment–to–lower segment ratio. This ratio, along with the arm span–to-height ratio, is used to document whether the spine or limbs are more severely shortened. Arm span is usually equal to standing height. However, in children with achondroplasia, the long bones are disproportionately shortened. Sitting height (another way of calculating the length of the upper segment), determined with a special sitting stadiometer, is generally normal whereas the standing height is short. During adolescence, hypogonadism is often associated with increased limb length. For the child with short stature and subnormal linear growth velocity, the evaluation should be comprehensive with consideration of endocrine and nonendocrine disorders.

Pubertal Development

Puberty is the process through which reproductive competence is achieved and is initiated by reactivation of the hypothalamic–pituitary–gonadal axis (gonadarche). In humans and several nonhuman primates, adrenal pubertal maturation, indicated by increased adrenal dehydroepiandrosterone sulfate (DHEAS) secretion, occurs in close temporal proximity to gonadarche. Clinical studies have demonstrated that gonadarche and adrenarche are regulated through different molecular mechanisms.

The pattern of timing of pubertal events for boys and girls is generally predictable (Fig. 9-3). For both boys and girls, mean ages for the onset of puberty vary among different ethnic groups and represent the combined influences of genetic and environmental factors. In boys, puberty, first evidenced by testicular enlargement, usually begins between 9 and 14 years of age. In girls, puberty, evidenced by breast development, usually begins between 8 and 12 years of age. Among white girls, the mean age of onset of breast development and pubic hair growth occurs at approximately years of age, with menarche occurring at approximately years of age. African-American females tend to enter puberty at an earlier age. For girls, increased BMI may be associated with premature adrenarche and earlier pubertal onset. Large-scale population studies have identified a secular trend for slightly earlier (by 2.5 to 4 months) ages at menarche, suggesting changes in the timing of the onset of puberty. Boys with rapid weight gain during childhood tend to have a later onset of puberty. The physiologic basis for this intriguing discordant effect of obesity on pubertal timing in boys versus girls is unexplained. These shifts, however, have generally not altered clinical practice guidelines regarding evaluation of “off-time” puberty.

Figure 9-3 Schematic representation of the onset of male and female puberty.

(Modified from Johnson TR, Moore WM, Jeffries JE: Children are different: development physiology, ed 2, Columbus, Ohio, 1978, Ross Laboratories, Division of Abbott Laboratories, pp. 26-29. Used with permission of Ross Products Division, Abbott Laboratories, Inc., Columbus, Ohio 43215.)

Tanner Staging

To describe the onset and progression of pubertal changes (Fig. 9-4), boys and girls are rated on five-point scales. Boys are rated for both genital development and pubic hair growth, and girls are rated for breast development and pubic hair growth. In general, for healthy children, Tanner stages of puberty for genital development and pubic hair growth are congruent. Differences in pubertal staging may be useful to formulate the differential diagnosis for children with “off-time” puberty. Attention should be paid to the Tanner staging of genital and pubic hair development especially for the child with “off-time” puberty. Inconsistent staging assists with the initial differential diagnosis.

Figure 9-4 A-C, Schematic drawings of male and female Tanner stages show male genital development (A), pubic hair development (B), and breast development (C).

(Modified from Johnson TR, Moore WM, Jefferies JE: Children are different: development physiology, ed 2, Columbus, Ohio, 1978, Ross Laboratories, Division of Abbot Laboratories, pp. 26-29. Used with permission of Ross Products Division, Abbott Laboratories, Inc., Columbus, Ohio 43215.)

The stages for male genital development are as follows (Fig. 9-4, A):

Stage I (Preadolescent)—The testes, scrotal sac, and penis have a size and proportion similar to those seen in early childhood

Stage II—There is enlargement of the scrotum and testes and a change in the texture of the scrotal skin. The scrotal skin may also be reddened.

Stage III—Further growth of the penis has occurred, initially in length with some increase in circumference. There is also increased growth of the testes and scrotum.

Stage IV—The penis is significantly enlarged in length and circumference, with further development of the glans penis. The testes and scrotum continue to enlarge, and there is distinct darkening of the scrotal skin.

Stage V—The genitalia are adult in size and shape.

The stages in male pubic hair development are as follows (Fig. 9-4, B):

Stage I (Preadolescent)—Vellus hair appears over the pubes with a degree of development similar to that over the abdominal wall. There is no androgen-sensitive pubic hair.

Stage II—There is sparse development of long pigmented downy hair, which is only slightly curled or straight. The hair is seen chiefly at the base of the penis.

Stage III—The pubic hair is considerably darker, coarser, and curlier. The distribution of hair has now spread over the junction of the pubes.

Stage IV—The hair distribution is now adult in type but still is considerably less than that seen in adults. There is no spread to the medial surface of the thighs.

Stage V—Hair distribution is adult in quantity and type and is described as an inverse triangle. There can be spread to the medial surface of the thighs.

The stages in female breast development are as follows (Fig. 9-4, C):

Stage I (Preadolescent)—Only the papilla is elevated above the level of the chest wall.

Stage II (Breast budding)—Elevation of the breasts and papillae may occur as small mounds along with some increased diameter of the areolae.

Stage III—The breasts and areolae continue to enlarge, although they show no separation of contour.

Stage IV—The areolae and papillae elevate above the level of the breasts and form secondary mounds with further development of the overall breast tissue.

Stage V—Mature female breasts have developed. The papillae may extend slightly above the contour of the breast as the result of recession of the areolae.

Pubic hair growth in females is staged as follows (Fig. 9-4, B):

Stage I (Preadolescent)—Vellus hair develops over the pubes. There is no sexual hair.

Stage II—Sparse, long, pigmented, downy hair, which is straight or only slightly curled, appears mainly along the labia.

Stage III—Considerably darker, coarser, and curlier sexual hair appears. The hair has now spread sparsely over the junction of the pubes.

Stage IV—The hair distribution is adult in type but decreased in total quantity. There is no spread to the medial surface of the thighs.

Stage V—Hair is adult in quantity and type and appears in an inverse triangle of the classically feminine type. There is spread to the medial surface of the thighs, but not above the base of the inverse triangle.

The Hypothalamus and the Pituitary Gland

The hypothalamus is derived from neuroectodermal tissue of the diencephalon and surrounds the inferior aspect of the third ventricle. Its basilar portion consists of the median eminence and pituitary stalk, which provide the common route for hypothalamic factors to reach the pituitary gland. Various regions in the hypothalamus secrete small peptide hormones that use this pathway to regulate pituitary hormone secretion. The neurohypophysis, consisting of unmyelinated axons and axon terminals, extends from the median eminence to the posterior pituitary gland.

The pituitary gland develops as a fusion of cells of different embryonic origins. There is an upgrowth of ectodermal cells from the roof of the primitive pharynx (known as Rathke pouch), and a downgrowth of neural tissue cells from the hypothalamus. These two distinct areas form the anterior lobe (the adenohypophysis) and the posterior lobe (the neurohypophysis), respectively.

Both congenital and acquired abnormalities of pituitary function occur. Structural abnormalities of the central nervous system (CNS), such as septo-optic dysplasia (Fig. 9-5, A and B) and holoprosencephaly (Fig. 9-5, C), can interfere with pituitary function. Craniopharyngiomas and CNS tumors can be associated with acquired hypopituitarism (Fig. 9-6). Additional causes of acquired hypopituitarism include radiation therapy to treat CNS tumors, granulomatous infiltration, and traumatic interruption of the pituitary stalk.

Figure 9-5 A-C, Congenital abnormalities of the CNS commonly associated with hypothalamic–pituitary dysfunction. A, Pale optic discs noted on funduscopic examination indicative of optic nerve hypoplasia, which can be associated with septo-optic dysplasia. B, Magnetic resonance image showing optic nerve hypoplasia. C, Holoprosencephaly.

(A, Courtesy D. Hiles, MD, Pittsburgh, Pa.)

Figure 9-6 Craniopharyngioma. Heterogeneous, densely enhancing suprasellar mass extending from the pituitary fossa into the hypothalamus and third ventricle.

Anterior Pituitary

The anterior pituitary, with its diverse cell types and hormonal secretory patterns, controls many important biologic processes. It contains cells that secrete three types of hormones: (1) corticotrophin-related peptide hormones, (2) glycoprotein hormones, and (3) somatomammotropins. These compounds have great biologic potency with tight regulation of hormone secretion governed by positive and negative feedback signals. Anterior pituitary hormone deficiencies cause subsequent hypofunction in the output of secondary endocrine glands, with substantial consequences for growth and development.

Children with midline defects have a higher incidence of hypopituitarism when compared with normal children. The child seen in Figure 9-7 has a single central incisor, an example of a midline abnormality associated with GH deficiency. Thus, specific alterations in physical appearance should alert physicians to a possible abnormality in anterior pituitary development potentially associated with secondary hormone deficiencies (e.g., thyroid-stimulating hormone [TSH] deficiency affecting thyroid function). The molecular etiologies for autosomal recessive, autosomal dominant, and X-linked disorders affecting anterior pituitary development and function have been elucidated.

Figure 9-7 Central maxillary incisor. The presence of a single central maxillary incisor should alert the clinician to investigate the possibility of growth hormone (GH) deficiency.

(Courtesy P. Lee, MD, Hershey, Pa.)

Growth Hormone

GH influences linear growth and modulates several complex metabolic processes. GH secretion is regulated by the relative balance between the levels of GH-releasing hormone (GHRH) and somatostatin (Fig. 9-8). Both GHRH and somatostatin are secreted by the hypothalamus. The GH receptor is a single transmembrane protein. After the binding of GH to its receptor, a second GH receptor dimerizes with the first receptor to initiate the signal transduction process. GH generates direct effects via the GH receptor signal transduction pathway and secondary effects by promoting an increase in IGF-I and insulin-like growth factor-binding protein-3 (IGF-BP3).

Figure 9-8 Feedback regulation of growth hormone (GH) at the level of the hypothalamus, pituitary, and target organs. GHRF, growth hormone-releasing factor.

In children with hypopituitarism due to growth hormone deficiency, GH treatment markedly improves growth velocity. GH stimulates an increase in lean body mass, as well as a marked increase in the size of the heart, pancreas, liver, and kidneys. It has positive effects on carbohydrate, fat, and protein metabolism and causes a decrease in body fat. GH inhibits carbohydrate uptake by muscle. This diabetogenic effect of GH action is a known complication of GH hypersecretion. Typically, children with GH deficiency have normal birth weights and normal growth patterns during the first year of life, after which time their growth velocities decelerate. As seen in Figure 9-9, GH-deficient children have a characteristic “kewpie” doll appearance. They are often described as being “cherubic” because of their short stature, excess subcutaneous fat, retarded body proportion changes, and high-pitched voices. Infants with hypopituitarism may present in the early neonatal period with hypoglycemia or prolonged jaundice. On physical examination, male infants with hypopituitarism may have small penises due to concomitant luteinizing hormone (LH) deficiency.

Figure 9-9 Growth hormone deficiency. The normal old boy (right) is in the 50th percentile for height. The short 3-year-old girl (left) has GH deficiency.

The pulsatile nature of GH secretion necessitates provocative stimulation tests to diagnose GH deficiency. Thus, measurements of random GH concentrations are not helpful in the evaluation of short stature. IGF-I concentrations may be low in children with GH deficiency. Because IGF-I concentrations also reflect nutritional status, IGF-I concentrations may be low in children with inadequate caloric intake.

Excessive GH secretion is uncommon in children. If GH excess begins during childhood, gigantism with increased growth velocity ensues. After closure of the epiphyses, soft tissue growth of the hands and feet and coarsening of facial features are typically the first clinical manifestations of acromegaly. Random GH, IGF-I, and IGF-BP3 concentrations are usually elevated in gigantism/acromegaly.

Adrenocorticotropic Hormone

The corticotropin-related peptide hormones consist of adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), and γ- and β-lipotropins (γ-LPH, β-LPH). These hormones are derived from a common precursor molecule, pro-opiomelanocortin. Within the subunit structure of β-LPH are the important neuroendocrine molecules α-, β-, and γ-endorphin and enkephalin. After posttranslational processing from this large precursor molecule, the secretion of ACTH is regulated by the level of corticotropin-releasing hormone (CRH), which is secreted by the hypothalamus. Cortisol secreted from the adrenal gland also influences ACTH secretion by negative feedback (Fig. 9-10). Prolonged pharmacologic glucocorticoid therapy suppresses the hypothalamic–pituitary–adrenal axis, with the potential for adrenal insufficiency as well as a significant impact on growth and development.

Figure 9-10 Feedback regulation of adrenocorticotropic hormone (ACTH) at the level of the hypothalamus, pituitary, and adrenal glands. CRF, corticotropin-releasing factor.

Gonadotropins

The glycoprotein hormones include follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Each of these hormones is composed of two dissimilar peptide subunits. The α chain is identical for both hormones. However, the β chain is unique and confers specificity to each hormone. These hormones also contain significant amounts of carbohydrate and sialic acid residues along with their basic amino acid structures.

Secretion of LH and FSH is regulated by the pulsatile gonadotropin-releasing hormone (GnRH) secretion. Neurons in the hypothalamus secrete GnRH in pulses that vary in amplitude and frequency during childhood and puberty. Various neurotransmitters are involved in controlling GnRH-secreting neurons and thus modulate the GnRH pulses. Kisspeptin, which acts via its receptor GPR54 (also known as KISS1-R), has been identified as a major stimulus for GnRH and LH release. Translational studies have identified several other genes that are involved in controlling the onset of puberty. In addition to kisspeptin and its receptor, other genes include neurokinin B, its cognate receptor (TACR3), PROK2, and its receptor (PROKR2).

After active secretion in late gestation and in the early neonatal period, the GnRH pulse generator becomes quiescent until the onset of puberty, which is characterized by the resumption of increased GnRH secretion. Increased nocturnal LH secretion marks the reactivation of the GnRH pulse generator and the onset of puberty. In primary gonadal failure, the deficiency of sex steroids interferes with negative feedback inhibition, resulting in elevated gonadotropin secretion during infancy, puberty, and adulthood.

The primary actions of FSH and LH affect gonadal function. LH binds to the LH receptor on Leydig cells to stimulate testosterone synthesis and secretion. In the testes, FSH supports Sertoli cell development and spermatogenesis (Fig. 9-11). The ovary is characterized by a two-cell model for steroidogenesis. LH stimulates ovarian theca cells to synthesize androstenedione, which serves as the precursor for estradiol synthesis. Subsequently, in the ovarian granulosa cells, FSH increases expression of aromatase, the enzyme that converts androgens to estrogens. The negative feedback effect of sex steroids on LH and FSH production is dramatically emphasized in postmenopausal women and in individuals with gonadal failure, in whom marked elevations of these hormones occur. Inhibin B is produced by the gonads and inhibits FSH release.

Figure 9-11 Feedback regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at the level of the hypothalamus, pituitary, and gonads. GnRH, gonadotropin-releasing hormone.

Gonadotropin secretion, especially in females, is influenced by metabolic state and by the degree of adiposity. Very athletic and lean girls experience delayed puberty with low gonadotropin levels; girls with eating disorders of the restrictive type experience amenorrhea with suppressed gonadotropins. Pubertal development may be slow among boys who restrict food intake to maintain a low weight for wrestling. Leptin, a hormone produced by the adipose tissue, exerts a significant effect on the hypothalamus and is a major link between energy balance and gonadotropin secretion.

Thyroid-stimulating Hormone

Thyroid-stimulating hormone (TSH) is the third glycoprotein hormone; its α subunit is identical to the α subunits of LH and FSH. Its specificity lies in its β subunit. TSH stimulates many aspects of thyroid function. Its major role is to promote the synthesis and secretion of thyroid hormone. Mediated by the TSH receptor, TSH increases the size of the thyroid cells, vascularity of the gland, iodide uptake, thyroglobulin synthesis, and thyroid hormone secretion. The rate of TSH secretion appears to be determined by the level of circulating thyroid hormone and by the hypothalamic hormone, thyrotropin-releasing hormone (TRH), as seen in Figure 9-12. Negative feedback of TSH secretion by circulating thyroid hormone occurs mainly at the pituitary level.

Figure 9-12 Feedback regulation of thyroid-stimulating hormone (TSH) at the level of the hypothalamus, pituitary, and thyroid gland. TRH, thyrotropin-releasing hormone.

Prolactin

Prolactin (PRL) acts directly on its target organs and does not require an intermediary secondary endocrine gland. The major known function of PRL in humans is the initiation and maintenance of lactation. In contrast to other anterior pituitary hormones, PRL is regulated by tonic inhibition by dopamine secreted by the hypothalamus. Congenital or acquired interruption of the hypothalamic–pituitary stalk may be accompanied by elevated prolactin concentrations reflecting decreased inhibition due to impaired hypothalamic–pituitary communication. Galactorrhea may be a clinical manifestation of hyperprolactinemia. Hyperprolactinemia can be observed with pituitary adenomas or secondary to medications such as neuroleptics, antipsychotics, estrogens, and antihypertensive medications. When hyperprolactinemia is secondary to medications, the prolactin concentrations are generally less than 75 ng/mL.

Posterior Pituitary

Vasopressin and oxytocin are two evolutionarily related peptides, each composed of nine amino acids. These hormones are synthesized in the hypothalamus and stored in the posterior pituitary gland. Expression of vasopressin and oxytocin genes occurs in the hypothalamic paraventricular and supraoptic nuclei. On magnetic resonance T₁-weighted images, the posterior pituitary has a characteristic high signal intensity. The presence of this high signal intensity adjacent to the median eminence with absence of the normal pituitary bright spot within the sella on T₁-weighted images is evidence of an ectopic posterior pituitary. An ectopic posterior pituitary is often associated with anterior pituitary hormone deficiencies, but typically these patients do not have diabetes insipidus (Fig. 9-13).

Figure 9-13 Ectopic pituitary. Note the absent normal posterior pituitary bright spot (arrow) within the sella on magnetic resonance imaging. Instead, the bright spot is located in the median eminence.

Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone (ADH), is a hormone important in water balance. It is synthesized and carried via axonal transport to the posterior pituitary, its primary site of storage. It is then released into the systemic circulation. AVP acts primarily on the kidneys at V2 receptors to aid in the reabsorption of water by affecting water permeability in the collecting duct of the kidney. At high concentrations, it also causes constriction of the arterioles through its action at V1 receptors, thereby leading to an increase in blood pressure. V3 receptors in the pituitary contribute to ACTH release by potentiating the action of CRH. Osmoreceptors in the hypothalamus detect an increase in osmotic pressure in the blood, leading to increased AVP secretion and increased thirst. The combination of increased AVP secretion leading to increased renal reabsorption of free water and increased oral fluid intake will decrease osmolality. Other factors that increase AVP secretion include pain, trauma, nausea, and vomiting.

Head trauma, brain tumors, encephalitis, pneumonia, and some drugs are associated with overproduction of AVP. This can lead to inappropriate water retention and hyponatremia, known as the syndrome of inappropriate ADH secretion (SIADH). The symptoms of SIADH include headache, apathy, nausea, vomiting, and impaired consciousness. Underproduction of AVP results in central diabetes insipidus (DI). DI can result from pituitary tumors; head trauma; infiltrative disease processes such as Langerhans cell histiocytosis, sarcoidosis, hemochromatosis, and autoimmune hypophysitis; or from any surgery that damages the pituitary gland and hypothalamus. Familial central DI, inherited in both recessive and dominant patterns, is rare and has its onset in infancy. Wolfram syndrome is an autosomal dominant form of central DI often associated with diabetes mellitus, optic atrophy, and deafness (DIDMOAD).

Nephrogenic DI is characterized by failure of the kidney tubules to respond to ADH. Genetic causes of nephrogenic DI include X-linked forms due to mutations in the V2 receptor gene and autosomal forms due to mutations in the aquaporin-2 gene. Acquired nephrogenic DI can be caused by drugs such as lithium. Psychogenic water drinking, hypercalcemia, hypokalemia, sickle cell anemia, and polycystic kidney disease can also impair renal concentrating ability.

Oxytocin secretion occurs in response to nervous stimulation of the hypothalamus. This hormone causes contraction of the smooth muscle of the uterus and also of the myoepithelial cells lining the duct of the mammary gland. Although some oxytocin is found in males, its function is unclear.

The Thyroid Gland

The thyroid gland is situated in the neck or, in rare cases, at the base of the tongue or in the mediastinum. The gland originates in the floor of the primitive pharynx, near the base of the tongue, approximately 24 days after fertilization, forming initially the thyroid diverticulum. During the elongation of the embryo, the developing thyroid gland moves down anteriorly to the hyoid bone and laryngeal cartilages along a narrow tube, the thyroglossal duct. When reaching its final position anterior to the trachea, the thyroid divides into right and left portions called the thyroid lobes connected by a thin layer of thyroid tissue, the isthmus, which lies ventrally to the second and third tracheal rings. The thyroglossal duct degenerates and disappears. On occasion, the lower portion of the thyroglossal duct fills up with thyroid tissue forming the pyramidal lobe. On occasion, the atrophy of the thyroglossal duct is not complete, leading to the presence of fluid-filled thyroglossal duct cysts, which appear clinically as tense, painless, and movable swellings at any point along the course of the thyroglossal duct. The thyroid gland synthesizes thyroxine (T₄) and triiodothyronine (T₃); this process is dependent on the availability of iodine. Most circulating T₄ and T₃ is transported by thyroid-binding globulin (TBG), albumin, and transthyretin. The free hormone is the active moiety. T₄ and T₃ are metabolized by inner ring deiodination to reverse T₃ and diiodothyronine (T₂), respectively.

Inherited disorders affecting TBG concentration or acquired alterations in availability of binding sites may confound interpretation of thyroid hormone function studies. The gene encoding TBG is mapped to the X chromosome. Both X-linked dominant and X-linked recessive inheritance have been reported for TBG excess and TBG deficiency; such patients are typically euthyroid.

Both overactivity and underactivity of the thyroid gland may be associated with a goiter. However, the clinical features typical of hyperthyroidism and hypothyroidism are dramatically different. The medical history and examination of the thyroid gland provide important information when evaluating a suspected abnormality in thyroid function.

As seen in Figure 9-14, the thyroid gland usually is best palpated with the examiner behind the patient. After identification of the cricothyroid cartilage, the second and third fingers are moved laterally along the trachea just medial to the sternocleidomastoid muscles. Two distinct lobes are palpable; the right lobe is usually greater in size than the left lobe. When a goiter is present, these lobes may be quite easily identified (Fig. 9-15). The texture of the gland varies with hyperthyroidism and hypothyroidism, the former usually being soft and fleshy, and the latter usually firm or bosselated. Nodules can also be palpated and may be indicative of an adenoma or carcinoma. Because the thyroid is directly supported by the trachea, having the patient swallow will elevate and depress a palpable gland along with the trachea during the swallowing motion.

Figure 9-14 Examination of the thyroid gland. The thyroid gland is best palpated with the examiner behind the patient.