The endocrinology of growth failure.

Growth during infancy, childhood, and adolescence is a complex process controlled by many factors, including hormones, nutrition, and genetics. Maternal size, nourishment, and weight gain during pregnancy certainly affect the size of an infant at birth. In general, the size of the mother is proportional to the size of the baby at birth. Hormones that strongly affect growth include growth hormone (GH), thyroid hormone, glucocorticoids, and insulin. During puberty, the sex hormones play an important role in the adolescent growth spurt.

GH is secreted by the anterior pituitary gland. Its release is stimulated by growth-hormone-releasing hormone (GHRH), which is secreted by the hypothalamus. This release is suppressed by somatostatin, also secreted by the hypothalamus. Thus the balance between GHRH and somatostatin secretion control GH secretion. Hypothyroidism can induce functional (or reversible) GH deficiency.

GH has direct effects on metabolism such as the induction of insulin resistance to elevate blood glucose and the release of free fatty acids by adipose tissue. GH's growth-promoting effect results from its ability to release insulin-like growth factor-I (IGF-I), which is produced by the liver and circulates systemically. Possibly even more important to growth is the local production of IGF-I by body tissues in response to GH. During the adolescent growth spurt at puberty, IGF-I levels rise and then decline after puberty.

Measuring short stature

Short stature in children is a common problem addressed by the pediatric endocrinologist. Although the term "short stature" is a relative definition, that diagnosis is usually made when the child's height is less than the 3rd to 5th percentile for the child's age group. After a 3- to 6-month period of observation, the child with short stature can be characterized according to what is called height velocity. Height velocity is the rate of gaining height per a unit of time, which is usually expressed as the number of centimeters of increase in height per year. For example, if a child grows 2 cm in 4 months, his or her height velocity is expressed as 6 cm/yr. If the growth rate is normal (e.g., [greater than] 4-5 cm/year), endocrine causes of short stature can generally be excluded.

The differential diagnosis of short stature with normal height velocity (and therefore nonendocrine in etiology) includes: (1) familial short stature, (2) genetic short stature, (3) primordial short stature, and (4) constitutional delay in growth and adolescence. Primordial short stature is short stature present from birth and persisting during childhood. Constitutional delay in growth and adolescence is delayed onset of puberty and is also known as delayed maturation (often called a late bloomer).

General screening procedures

To exclude various forms of subtle chronic disease, general laboratory screening is optional in children with short stature and normal height velocity but is absolutely required in children with low height velocities (see Table 1). When the child's height velocity is below normal, however, a variety of serious diseases may be present including (1) chronic disease, (2) psychosocial short stature, (3) Turner syndrome, and (4) endocrine disorders. In addition to the tests outlined in Table 1, thyroid function [e.g., either thyroxine ([T.sub.4]) plus [T.sub.3]-resin uptake or T-uptake, or free [T.sub.4] and thyroid stimulating hormone (TSH)] should also be measured in children with short stature and low height velocities. A normal height velocity essentially excludes hypothyroidism; thus, measuring thyroid function in children with normal height velocities is not indicated unless there are other clinical suggestions of possible hypothyroidism.

Chronic conditions that sometimes produce short stature include cyanotic congenital heart disease, cystic fibrosis, chronic inflammatory bowel disease, and cerebral palsy. Psychosocial short stature results from insufficient caloric intake and/or the absence of a psychologically nurturing environment.

Clinical features of Turner syndrome in girls include short stature, edema of the hands and feet at birth, bicuspid aortic valve, webbed neck, hyperconvex nails, a shield-like chest, horseshoe kidneys, and streak (or undifferentiated) gonads. Because of streak gonads, estrogenization at the time of puberty usually does not occur. In these girls, follicular stimulating hormone (FSH) levels can be greatly elevated because of gonadal failure. Turner syndrome occurs in girls that exhibit absence (45X) or deletion of the short arm of the X chromosome. If Turner syndrome is suspected, a karyotype is indicated.

Endocrine disorders

After the previously mentioned causes of short stature with low height velocity are excluded, endocrine disorders must next be considered. The first system to investigate is the hypothalamic-pituitary-thyroid gland axis. Hypothyroidism, either isolated or combined with GH deficiency, is one of the most common endocrine causes of low height velocity and must be excluded before patients can be evaluated for GH deficiency. This is because GH deficiency can develop secondary to hypothyroidism; and after treatment of the hypothyroidism, the GH deficiency resolves. Because either central or primary hypothyroidism can cause growth failure, both TSH and [T.sub.4] should be measured. Thyroxine is best assessed by measurement of free (unbound) [T.sub.4]. Alternatively, total [T.sub.4] can be measured along with [T.sub.3] resin uptake or T-uptake to calculate a free thyroxine index.

Primary hypothyroidism. If TSH is elevated and the free [T.sub.4] is low, the patient has primary hypothyroidism. Primary hypothyroidism is thyroid hypofunction where the gland fails to produce adequate amounts of the thyroid hormones [T.sub.4] and [T.sub.3]. If TSH is elevated but free [T.sub.4] is normal, the patient has subclinical hypothyroidism that may manifest as a decline in growth rate.

If primary hypothyroidism is diagnosed, the most common etiology during childhood is Hashimoto thyroiditis; and therefore, these children should be tested for thyroid microsomal (or thyroperoxidase) autoantibodies and thyroglobulin autoantibodies. Other causes of primary hypothyroidism include thyroid hypoplasia or ectopia with hypoplasia (e.g., lingual thyroid), iodine deficiency or excess, inborn errors in thyroid hormone biosynthesis, thyroidectomy, irradiation, and ingestion of antithyroid drugs.

Central hypothyroidism. Central hypothyroidism is hypothyroidism that results from a deficiency in either thyrotropin-releasing hormone (TRH) or thyrotropin (also called thyroid stimulating hormone, or TSR). Both secondary and tertiary hypothyroidism are forms of central hypothyroidism. TSH deficiency is referred to as secondary hypothyroidism, whereas TRH deficiency is referred to as tertiary hypothyroidism. If central hypothyroidism is present (normal or low TSH and low free [T.sub.4]), hypopituitarism or panhypopituitarism may be present. In this case, computed axial tomography (CAT or CT scan) or magnetic resonance imaging (MRI) should be performed to check for organic lesions. Computed tomographic scans take multiple, computerized X-ray images that allow radiologists to produce cross-sectional images of the body, including the head and central nervous system. In this way, the hypothalamus and pituitary gland can be visualized. In an analogous approach (however, without the use of X-rays), MRI exams can also create cross-sectional images to determine if there are structural changes (e.g., tumor, malformation, infarction) in the hypothalamus, pituitary gland, or surrounding bony or vascular structures.

Structural abnormalities. Prolactin, a hormone secreted by the anterior pituitary gland, should also be measured because hyperprolactinemia serves as a marker for the loss of hypothalamic dopamine secretion or interruption in the hypothalamic-pituitary portal system. Isolated deficiency of TSH as a cause of hypothyroidism is very rare. Conditions such as craniopharyngioma, hamartoma, and teratoma can damage the hypothalamus and/or pituitary leading to hypopituitarism.

None of the aforementioned tumors are malignant. Craniopharyngioma is the most common pediatric tumor to produce hypopituitarism as well as damage the hypothalamus. Cranjopharyngioma results from aberrant growth of remnants of the Rathke pouch, a structure in the roof of the embryonic mouth that forms the anterior pituitary gland. Hamartomas are composed of normal cellular and tissue elements that are disorganized and lack normal histologic form or function and produce a mass. In contrast to hamartomas, which are composed of cells and tissues intrinsic to the affected organ, teratomas are germ cell tumors that include cells and tissues that can develop into structures not intrinsic to the affected organ. For example, a teratoma of the central nervous system can include the development of teeth or hair within such tumors.

TSH deficiency is often present concurrently with GH deficiency. In addition to TSH and GH deficiencies, other potential anterior pituitary hormone deficiencies include adrenocorticootropic hormone (ACTH) deficiency, which causes cortisol deficiency, and gonadotropin [luteinizing hormone (LH), FSH] deficiency, which causes absent, delayed, or interrupted puberty. Damage to the hypothalamus, the hypothalamic-pituitary portal system, or the posterior pituitary can produce diabetes insipidus from antidiuretic hormone (ADH) deficiency.

If an operable lesion is identified, there is no reason to examine the hypothalamic-pituitary growth hormone axis before surgery. This is because surgery can damage the hypothalamus, hypothalamic-pituitary portal system, and/or pituitary gland; and patients who were not GH deficient preoperatively can become GH deficient postoperatively. Testing for GH deficiency preoperatively is an additional test that is not routinely necessary; but because untreated glucocorticoid deficiency (from ACTH deficiency) can be life- threatening, the hypothalamic-pituitaryadrenal gland axis should be evaluated preoperatively to determine if glucocorticoid replacement is indicated. This can be done by performing an insulin-tolerance test (ITT), for example.

The pituitary gland is suspended from the ventral portion of the brain stem by the pituitary stalk. The pituitary gland is encased anteriorly, ventrally, and posteriorly in a bony cup called the sella turcica. If the CT/MRI does not show a lesion or shows only an empty sella (normal sella turcica lacking a normally sized pituitary), the workup of hypopituitarism should proceed to evaluate GH and ACTH secrenon. If puberty is disrupted or delayed, gonadotropin secretion after administration of gonadotropin-releasing hormone (GnRH) can also be studied. If polyuria and/or polydipsia are present suggesting ADH deficiency, a water deprivation test for diabetes insipidus should be performed.

GH deficiency

As mentioned previously, hypothyroidism must always be excluded or treated before GH testing is carried out because hypothyroidism can induce reversible GH deficiency. If an organic lesion is excluded by CT/MRI in the child with central hypothyroidism, GH testing can be pursued, provided the hypothyroidism is first treated for 6 to 12 weeks. Isolated, idiopathic TSH deficiency is rare.

If an organic lesion is identified and treated surgically, there are 2 approaches to GH testing. In one approach, height velocity is measured in the child 6 to 9 months after surgery. If height velocity is low, GH testing is performed, and if it is normal, the physician simply continues to monitor height velocity. In the other approach, GH testing is performed several months after surgery. Both approaches allow postoperative healing and resolution of swelling. If postoperative GH deficiency is diagnosed and the height velocity is low, GH treatment should be initiated. The replacement dose for [T.sub.4] in children is 100 ug/[M.sup.2]/day of Nal-thyroxine. Evaluation of GH secretion is described below.

GH screening tests. In the absence of hypothyroidism or in the case of low height velocity in children with adequately treated hypothyroidism (e.g., normal free [T.sub.4] or free [T.sub.4] index), GH testing should be carried out. Random measurements of GH are usually uninformative because basal GH levels are normally low and do not differentiate patients who are GH deficient from those who are not.

Therefore, to diagnose GH deficiency, stimulated GH measurements must be assessed. This GH screening test is obtained by first using physiologic stimulants such as exercise (approximately 20 minutes) or sleep, or pharmacologic stimulants such as clonidine (5 [micro]g/kg orally). Then, GH is measured at defined time intervals after each stimulus. When using exercise as a stimulant, GH is measured at 20 minutes when the exercise is completed, and at 40 minutes. When using sleep, measure GH 60 minutes after the patient falls asleep; and when using clonidine, measure GH 90 minutes after administration. These screening tests are minimally invasive, require only 1-[micro]g specimens, and are usually relatively inexpensive compared with definitive GH testing. All GH testing should be performed after an overnight fast.

Another approach to screening for GH deficiency is to measure IGF- 1 (somatomedin-C) or insulin-like growth factor binding protein-3 (IGFBP-3) concentrations. In GH deficiency, both IGF-l and IGFBP-3 levels are expected to be suppressed because GH stimulates the synthesis and secretion of both proteins. However, other factors control IGF-1 secretion (such as thyroid hormone status, nutrition, stress, sex steroids); thus, a low IGF-1 level is not diagnostic for GH deficiency and does not preclude the need to perform definitive testing for GH deficiency. Because IGF-1 is the major growth factor stimulated by GH, IGF-l measurements are likely to be more informative than IGFBP-3 measurements. There is no clear advantage to measuring both IGF-1 and IGFBP-3. Because these analytes' concentrations do not vary diurnally, they can be measured on random specimens. However, the reference ranges for IGF-1 and IGFBP-3 must be adjusted for pubertal stage because both IGF-1 and IGFBP-3 levels rise with puberty and then dec line after puberty.

To decrease the likelihood of a falsely abnormal GH test, various pretreatments can be used both for GH screening and definitive GH testing (see Table 2). These pretreatments (with an overnight fast) prime the patient to produce a maximal GH response after stimulation. Androgens can be given to boys as intramuscular testosterone enanthate in oil, while estrogen pretreatment can be given to boys or girls. Estrogens can cause malaise or nausea. Beta-blockage will intensify the effects of fasting, which will increase the likelihood of a vigorous GH response in a child not deficient in GH.

Definitive testing. Definitive GH testing requires that an indwelling heparinized catheter be placed both to administer intravenous stimulants (e.g., arginine HCl or insulin) and to draw multiple, timed specimens for GH measurement. Various approaches to definitive GH testing are outlined in Table 3. Because only 80% of the healthy population will display a normal GH response to a single GH stimulus, 2 definitive tests are required to establish the diagnosis of GH deficiency in children. Using 2 definitive tests, approximately 95% of the normal population will exhibit a peak GH of 7-10 ng/mL. The cutoff that a laboratory uses to define GH deficiency (e.g., a peak GH [less than] 7-10 ng/mL) depends on the GH immunoassay kit used and the clinician's experience. The laboratory and the pediatric endocrinologist should work together to establish this cutoff. The GH cutoff also applies to the measurement of GH during screening tests.

GH deficiency diagnoses

If GH is elevated and IGF-1 is low, growth hormone resistance (GHR) must be considered. This condition can result from defects in the GH receptor generation of second messengers in GH target tissues (e.g., the liver, where large amounts of IGF-1 are produced). GHR is termed Laron dwarfism after its first description by Dr. Zvi Laron. Since its original description, a large number of people in a remote region of Ecuador have also been described with GHR.

Adults can also display GH deficiency. Adult GH deficiency is approved by the Food and Drug Administration as an indication for the use of GH replacement. In adults, a normal stimulated GH response is generally considered to be approximately 5 ng/mL. Growth hormone deficiency is present in adults when one of the following conditions is met:

* 1 abnormal definitive GH test plus evidence of at lease 1 other pituitary hormone deficiency

* 1 abnormal definitive GH test plus a previous diagnosis of GH deficiency in childhood

* 2 abnormal definitive GH tests when there are no other pituitary hormone deficiencies and there is no previous diagnosis of GH deficiency in childhood

Making the correct diagnosis is critical to avoiding inappropriate therapy. FDA-approved indications for GH therapy include: (1) proven GH deficiency in children, (2) Turner syndrome, (3) short stature in children with chronic renal insufficiency, (4) proven GH deficiency in adults, and (5) acquired immunodeficiency syndrome (AIDS) with wasting. GH deficiency is treated by daily subcutaneous injections of recombinant DNA-produced GH, which is very expensive (approximately $20,000 per year).

When GH deficiency is diagnosed, a CT or MRI search for a central nervous system lesion must be pursued if it was not already performed. Of similar importance, other anterior and posterior pituitary hormone deficiencies should be sought in a child with GH deficiency. The thyroid status should already be known from previous testing. The hypothalamic-pituitary-adreno-cortical glucocorticoid axis can be studied during the insulin tolerance test. Cortisol secretion is normally elicited by hypoglycemia. If the peak cortisol is [less than] 18-20 [micro]g/dL and the change in cortisol over baseline is [less than] 7 [micro]g/dL glucocorticoid deficiency is present. The absolute cortisol level is a better indicator of glucocorticoid status than the cortisol change over baseline. For example, if the cortisol rose from 2 [micro]g/dL to 9 [micro]g/dL the change over baseline would be normal; yet the peak cortisol would be deficient, consistent with glucocorticoid deficiency.

If the pituitary stalk or hypothalamus is damaged, diabetes insipidus or hyperprolactinemia may be present. In patients with diabetes insipidus, if access to water is restricted or the patient's thirst center is damaged, hypovolemia and hypernatremia can result. Prolactin is the only anterior pituitary hormone that is regulated solely by suppression. Hyperprolactinemia can cause galactorrhea, delayed puberty, or infertility and loss of libido in sexually mature individuals. Disruption in the magnitude or timing of gonadotropin releasing hormone (GnRH) secretion or gonadotropin secretion (LH and FSH) can prevent or halt the development of normal puberty as noted previously.

Other causes of GH deficiency

If hypothyroidism and GH deficiency have been excluded as endocrine causes of short stature with low height velocity, Gushing syndrome should next be considered. The decision to pursue a biochemical workup for Gushing syndrome depends on the physician's suspicion for this condition. Factors that suggest Gushing syndrome include centripetal obesity, moon facies, buffalo hump, bluish stria, hypertension, diabetes mellitus, and osteoporosis. Children with exogenous obesity are generally tall for their age and may display advanced bony maturation and pubertal features. In exogenous obesity, the biologic time table for puberty appears to be accelerated. On the other hand, children with Gushing syndrome are typically short because excess glucocorticoid interferes with linear growth.

The 2 recommended screening tests for Cushing syndrome are the overnight dexamethasone suppression test and the measurement of 24-hour urinary free cortisol excretion. It is not necessary to perform both tests. In the overnight dexamethasone suppression test, 1 mg of dexamethasone in adults (maximum 8 tug) or 0.3 mg/[M.sup.2] in children is administered at 10 pm. After an overnight fast, a sample is drawn at 8 am and tested for cortisol. Suppression of cortisol in the 8 am sample to [less then] 5 [micro]g/dL excludes Gushing syndrome. If the cortisol is between 5.0 and 9.9 [micro]g/dL, the result is inconclusive, and further testing is required. The alternate screening test can be performed or formal suppression testing can be pursued (see below) at the physician's discretion. If the result from the 8 am cortisol test is equal to greater than 10 [micro]g/dL, the response is frankly abnormal, suggesting Cushing syndrome. Urinary free cortisol measurements provide an integrated assessment of cortisol dynamics. Because children tested for Cushing syndrome are frequently obese, the reference range for urinary free cortisol excretion must consider either body weight or body surface area (e.g., normal maximum urinary free cortisol 25-75 [micro]g/[M.sup.2]/24 hours). Formal suppression testing involves the low-dose-high-dose dexamethasone suppression test. Several other endocrine disorders can cause short stature such as isolated diabetes insipidus and poorly controlled diabetes mellitus. If the clinical history and physical examination suggest any of these conditions, a further workup should be pursued.

In summary, because serious illness can underlie short stature in children, short stature requires careful evaluation. If the height velocity is low, the likelihood of serious illness is further increased. Chronic disease must be excluded by careful review of the history and physical examination. Laboratory analyses outlined in Table 1 should be the minimal screening requirements plus assessment of thyroid hormone status (ideally, TSH plus free [T.sub.4]) when height velocity is low. In girls, if there is a clinical suspicion of Turner syndrome, FSH can be measured near the time of puberty. However, even with a normal FSH, if the index of suspicion for Turner syndrome is considerable, a karyotype should be performed. The nutritional status of the child and his or her interaction with caregivers should be assessed when considering the possibility of psychosocial short stature. These children can display acquired, reversible deficiencies in thyroid hormone or GH secretion, and thus indiscriminate GH testing ca n lead to inappropriate conclusions. Hypothyroidism should always be treated before GH testing is pursued. When endocrine disorders are considered as possible causes of short stature, a step-wise workup is required as outlined above.

William E. Winter, MD, is Professor of Pathology, Laboratory Medicine and Immunology, Pediatrics, and Molecular Genetics and Microbiology; Medical Director and Section Chief, Clinical Chemistry. Nancy S. Hardt, MD, is Associate Professor of Pathology, Immunology and Laboratory Medicine, and Obstetrics and Gynecology. Both authors are affiliated with the University of Florida College of Medicine, Department of Pathology, Laboratory Medicine, and Immunology, Gainesville, FL.

Suggested reading

Demers LM. Pituitary function. In: Tietz Textbook of Clinical Chemistry. Burtis CA, Ashwood ER, eda. Philadelphia: WB Saunders; 1999: 1470-1495.

Rosenfield RG. Disorders of growth hormone and insulin-like growth factor secretion and action. In: Pediatric Endorinology. Sperling MA, ed. Philadelphia: WB Saunders; 1996:117-169.

Reiter EO, Rosenfeld RG. Normal and aberrant growth. In: Williams Textbook of Endocrinology. Wilson JD, Foster DW, Kronenberg HM, Larsen PR, ads. Philadelphia: WB Saunders; 1998: 1427-1507.

            Tests used to screen for occult disease in children
                            with short stature
Tests                              Information value
Hematocrit/hemoglobin              General screen for chronic disease
Electrolytes                       Fluid and electrolyte balance; renal
                                   and adrenal
([Na.sup.+], [K.sup.+], [Cl.sup.-] function
[CO.sub.2])
Glucose                            Excludes diabetes mellitus
BUN, creatinine, urinalysis        Evaluation of renal function
Total protein, albumin             Measures synthetic ability of the
                                   liver and/or
                                   nutrition; increased globulins can
                                   suggest chronic
                                   inflammatory, autoimmune or infectious
                                   diseases
Total bilirubin                    Assesses detoxifying ability of liver
ALT, AST                           Assesses hepatocyte membrane
                                   health/intactness
Alkaline phosphatase               Assesses bone and vitamin D
                                   metabolism;
[Ca.sup.2+], [[PO.sub.4].sup.3-]   alkaline phosphatase also assesses
                                   biliary tract
                     Pharmacologic priming strategies
                         in growth hormone testing
Category     Agent
Estrogens    Ethinyl estradiol
             Premarin
             Diethylstilbestrol (DES)
Androgen     Testosterone
Beta-blocker Propranolol
Category     Dose(s)
Estrogens    Body weight: [less than]50 lbs: 20 [micro]g/dose
             18,12,1 hour before test
             Body weight: [greater than]50 lbs: 50 [micro]g/dose
             18,12,1 hour before test or 100 [micro]g/day x 3 days
             Body weight: [less than] 30 lbs: 2.5 mg b.i.d. x 3 days
             Body weight: [greater than] 30 lbs: 5 mg b.i.d. x 3 days
             5 mg/day x 3 days
Androgen     50 mg intramuscular 2 or 3 weeks before testing
Beta-blocker 0.75 mg/kg po (max 40 mg) 2 hrs before testing, or
             Body weight: [less than]: 20 mg 2 hrs before testing
             Body weight: [greater than] 20 kg: 40 mg 2 hrs before testing
              Stimuli used to elicit growth harmone secretion
GH stimulus            Dose
Arginine HCI           0.5 gm/kg, max 30 gm
                       (10% solution IV over 30 min)
Insulin tolerance test 0.1 U/kg (0.05 to 0.15)
                       IV push insulin
Arginine-insulin       Arginine: begin at
tolerance test         time zero, give insulin
                       at +60 mon.
Glucagon               0.1 mg/kg IM, max 1 mg
L-dopa                 500 mg/[M.sup.2] (15 mg/kg)
                       max 500 mg (or)
                       [less than]15 kg:125 mg1
                       5-30 kg: 250 mg
                       [greater than]30 kg: 500 mg
Clonidine              0.15 mg/[M.sup.2]
                       [less than]30 lbs: 0.05 mg
                       [greater than or equal to]30
                       lbs: 0.1 mg (0.1 mg/tab)
GH stimulus            GH sampling [*] (minutes)
Arginine HCI           0, [plus or minus]15, 30, 60, 90,
                       [plus or minus]120
Insulin tolerance test 0, 10, 20, [plus or minus]30, 40, 60,
                       [plus or minus]75, [plus or minus]90,
                       [plus or minus]120
Arginine-insulin       0, 30, 60, 70, 80, 100, [plus or minus]240
tolerance test
Glucagon               0, 30, 60, 90, 120, 150, 180, [plus or
                       minus]240 (maximum response 2-3 hours)
L-dopa                 0, 40, 60, 90, 120
Clonidine              0, 30, 60, 90
(*.)Various experts differ on the interval of GH
measurements; [plus or minus] = optional time point.