AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

recombinant human growth hormone, rhGH, growth hormone-releasing hormone, GHRH, somatotropin-releasing factor, SRF, somatomedin deficiency , pituitary adenylate cyclase activating polypeptide, PACAP, pituitary-specific transcription factor-1, Pit-1, prophet of Pit-1, PROP1, HESX1, insulinlike growth factor, IGF, insulinlike growth factor-1, IGF-1, IGF deficiency, insulinlike growth factor deficiency, insulinlike growth factor binding protein, IGFBP, thyroid-stimulating hormone, thyroid hormone, sex steroids

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Remarkable research over the past 4 decades has advanced our knowledge of the physiology of the growth hormone (GH) axis.

Human pituitary-derived growth hormone

More than 40 years have elapsed since human pituitary-derived growth hormone (pit-hGH) was purified and the first patient, a 17-year-old male adolescent with growth hormone deficiency (GHD), was treated successfully with pit-hGH. For many years, pituitary glands harvested from human cadavers provided the only practical source of GH with which to treat GHD. Worldwide, more than 27,000 children with GHD received pit-hGH from the 1950s to the mid 1980s.

Pit-hGH was a suboptimal therapy for 3 reasons.

1. The shortage of pit-hGH limited its use and the dosages administered.
2. The biopotency of preparations varied. Strict diagnostic criteria for GHD were used to address these problems (eg, peak plasma immunoreactive GH levels of more than 3.5-5 ng/mL after provocative stimuli).
3. Treatment was often interrupted. The mean age for starting treatment with pit-hGH was often 12-13 years (late in childhood), and severe growth failure (height Z score -4 to -6) was required. As a result, pit-hGH therapy was often discontinued when girls attained a height of 60 inches and when boys attained a height of 65 inches.

Nonetheless, pit-hGH had dramatic effects. Among patients with isolated GHD, final height standard deviation scores increased to approximately -2 in boys and -2.5 to -3 in girls. For children with multiple pituitary-hormone deficiencies, height standard deviation scores increased to between -1 and -2.

The number of patients with GHD who were treated with pit-hGH increased from approximately 150 to more than 3000 by 1985. However, in 1985, studies indicated that pit-hGH was the likely source of contaminated material (prions) responsible for Creutzfeldt-Jakob disease (a slowly developing, progressive, fatal neurologic disorder) in 3 young men. As a consequence, production and distribution of pit-hGH for therapy was discontinued.

Recombinant human growth hormone

The commercial introduction of recombinant human growth hormone (rhGH) in 1985 dramatically changed the field of therapy for GH. Since then, rhGH has been administered to more than 50,000 children worldwide, making it one of the most extensively studied therapies in the pediatric pharmacopoeia.

US Food and Drug Administration–approved indications for the administration of rhGH in children include treatment of the following conditions:

• Growth failure associated with GHD (approved in 1985)
• Chronic renal failure (approved in 1993)
• Turner syndrome (approved in 1996-1997)
• Prader-Willi syndrome (approved in 2000)
• Small size for gestational age, with failure to catch up (approved in 2001)
• Idiopathic short stature (approved in 2003)

Achievement of final adult height consistent with a child's genetic potential remains the primary therapeutic endpoint for rhGH therapy in the pediatric population. In addition to its effects on bone mass, GH regulates muscle mass, muscular strength, body composition, lipid and carbohydrate metabolism, and cardiac function. Patients with GHD typically have hyperlipidemia, increased body fat, premature atherosclerotic plaques, delayed bone maturation, and impaired cardiac function.

At present, GHD in adults is recognized as a distinct clinical syndrome that encompasses reduced psychological well-being and specific metabolic abnormalities. Such abnormalities, including hypertension, central obesity, insulin resistance, dyslipidemia, and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased rates of cardiovascular morbidity and mortality reinforce the close association between the syndromes.

Replacement of GH in adults with GHD markedly reduces central obesity and substantially reduced total cholesterol levels, but it has produced little change in other risk factors, particularly, insulin resistance and dyslipidemia. For these patients, concerns are the persistent insulin resistance and dyslipidemia, together with the elevated plasma insulin and lipoprotein(a) levels observed with GH replacement. Long-term follow-up data are required to assess the effect of GH replacement on cardiovascular morbidity and mortality in adults with GHD.

The large commercial supply of rhGH fuels research and debate over the proper indications for this potent and expensive therapy. Few disagree that many patients with childhood-onset GHD require continuous GH replacement therapy into adulthood. However, the diagnostic criteria for GHD in patients of any age remain controversial. This ambiguity stems from the wide variability in current tools used to diagnose GHD, as discussed below (see Workup).

Clinicians and researchers alike will continue to grapple with these dilemmas in the foreseeable future. However, commercial interests and patient advocates will pressure the medical community to expand the accepted indications for rhGH. Therefore, it is incumbent on the clinician and the clinical researcher to examine published data critically and to educate individual patients and their families about the risk-benefit ratio of rhGH therapy for them.

Pathophysiology

Anatomy

Most of the pituitary gland is dedicated to synthesizing and secreting GH from somatotrophs of the adenohypophysis (anterior pituitary). The adenohypophysis derives from the Rathke pouch, a diverticulum of the primitive oral cavity. The adenohypophysis consists of 3 lobes, namely, the pars distalis, the pars intermedia (which is vestigial in humans), and the pars tuberalis. The pars distalis is the largest lobe and contains most of the somatotrophs. The pituitary gland lies within the sella turcica, covered superiorly by the diaphragma sellae and the optic chiasm.

Growth hormone

The hypothalamus communicates with the anterior pituitary gland by releasing of hypothalamic peptides, which are subsequently transported in the hypophyseal portal circulation (ie, the blood supply and communication between the hypothalamus and the adenohypophysis). GH is secreted in a pulsatile pattern as a single-chain, 191-amino acid, 22-kDa protein.

Two specific hypothalamic peptides play major regulatory roles in GH secretion: growth hormone-releasing hormone (GHRH) and somatotropin-releasing factor. Amplitudes and frequencies for release of GHRH and somatotropin-releasing factor, as well as GH, differ between boys and girls and may partially account for differences in the phenotypes between the sexes.

Several neurotransmitters and neuropeptides also control GH secretion by directly acting on somatotrophs or by indirectly acting by means of hypothalamic pathways. These neurotransmitters include pituitary adenylate cyclase activating polypeptide (PACAP), galanin, pituitary-specific transcription factor-1 (Pit-1), prophet of Pit-1 (PROP1), HESX1, serotonin, histamine, norepinephrine, dopamine, acetylcholine, gamma-aminobutyric acid, thyrotropin-releasing hormone, vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, and corticotropin-releasing hormone.

Insulinlike growth factors

Insulinlike growth factors (IGFs) are a family of peptides that partially depend on GH and that mediate many of its anabolic and mitogenic actions.

Two theories exist regarding the relationship between GH and IGFs: the somatomedin hypothesis and the dual-effector hypothesis. According to the somatomedin hypothesis, IGF mediates all of the anabolic actions of GH. Although this theory is partially correct, GH also has a variety of other independent metabolic actions, such as enhancement of lipolysis, stimulation of amino acid transport in the diaphragm and the heart, and enhancement of hepatic protein synthesis. The attempt to resolve this discrepancy lies in the dual-effector model. According to this theory, GH stimulates precursor cells to differentiate and secrete IGF, which, in turn, exerts mitogenic and stimulatory effects.

Insulinlike growth factor binding proteins

Six high-affinity insulinlike growth factor binding proteins (IGFBPs) bind IGFs in the circulation and tissues, regulating IGF bioavailability to the IGF receptors. Under most conditions, IGFBPs appear to inhibit the action of IGFs by competing with IGF receptors for IGF peptides. However, under specific conditions, several IGFBPs can enhance IGF actions or exert IGF-independent actions.

Relative concentrations of the IGFBPs vary among biologic fluids. IGFBP-3 is the most abundant IGFBP species in human serum and circulates as part of a ternary complex consisting of IGFBP-3, an IGF molecule, and a glycoprotein called the acid-labile subunit. IGFBP-3 is the only IGFBP that clearly demonstrates GH dependence. Therefore, IGFBP-3 is a clinically useful tool for the diagnosis of GHD and the follow-up care of patients.

Sex steroids

Androgens and estrogens substantially contribute to growth during the adolescent growth spurt. Children with GHD lack the normal growth spurt despite adequate amounts of exogenous or endogenous gonadal steroids. The relationship among the sex steroids, GH, and skeletal maturation is not clearly understood. However, GH secretion is lower in frequency and higher in amplitude among males than in among females.

Androgen and estrogen receptors have been identified in the hypothalamus and are suspected to play an important regulatory role in the release of somatostatin, the hypothalamic hormone that inhibits GH secretion. Somatostatin regulation is believed to direct the frequency and amplitude of GH secretion. Therefore, it may be one of the sources of the differences between male and female individuals.

Thyroid hormone

Thyroid hormone is essential for postnatal growth. Growth failure, which may be profound, is the most common and prominent manifestation of hypothyroidism. The interrelationships between the thyroid and the pituitary-GH-IGF axis are complex and not yet fully defined. Hypotheses include a direct effect of thyroid hormone on the growth of epiphyseal cartilage and a permissive effect on GH secretion. Proof of the permissive effect on GH secretion derives from studies revealing that spontaneous GH secretion is decreased and that the response to provocative GH testing is blunted in patients with hypothyroidism (see Workup).

In addition, growth velocity is markedly decreased among rhGH-treated patients with GHD and hypothyroidism until thyroid hormone replacement is begun. Downregulation of GH receptors and decreased production of IGF-1 and IGFBP-3 have been reported in the hypothyroid state. An unexplained relationship exists between the treatment of patients with GHD by using rhGH and the development and unmasking of hypothyroidism.

Frequency

United States

The prevalence is 1 case per 3480 children or adolescents aged 4-15 years.

International

No strong data about the international prevalence of hyposomatotropism are available.

Mortality/Morbidity

Morbidity

Sequelae of hyposomatotropism include the following:

• Behavioral and educational difficulties
• Peripheral vascular disease and reduced myocardial function
• Lean body mass, reduced muscular strength, and reduced exercise capacity
• Reduced thermoregulation
• Abnormal metabolism of thyroid hormone
• Impaired psychosocial well-being
• Decreased bone mineral content

Mortality

The overall crude mortality rate for patients with tumor-related, trauma-related, or iatrogenic GHD is 2.7%.

Clinicians must be cognizant of the increased incidence of mortality among patients with multiple pituitary hormone insufficiency secondary to adrenal crisis.

Race

A racial ascertainment bias may exist. Demographic and diagnostic features of GHD in children in the United States reveal that African American children with idiopathic GHD are shorter than Caucasian children are at the time of diagnosis. The low overall representation of African American children in the population with GHD (6.0%) compared with their representation in the at-risk population (12.9%) also suggests an ascertainment bias between the races.

Sex

A male ascertainment bias may exist. The predominance of GHD diagnosed in boys in the United States and the observation that girls with idiopathic GHD are comparatively shorter than boys at the time of diagnosis suggest a sex-based ascertainment bias.

Age

The age of patients with GHD is depends on the etiology of the disease (see Causes).

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Congenital disease
• • Infants with congenital GHD were typically born with a length and weight between the 5th and 10th percentiles for their gestational age. A family history of short stature or parental consanguinity may suggest a genetic etiology.
  • Newborns with congenital hypopituitarism (defined as deficiencies of all anterior pituitary hormones) often present with midline craniofacial abnormalities (eg, single central maxillary incisor, cleft lip or palate, optic hypoplasia), hypoglycemia, blindness, micropenis, and hyperbilirubinemia.
  • Hypoglycemia can be profound and clinically resembles congenital hyperinsulinism in patients with GHD or, especially, hypopituitarism. Hypoglycemia results from the lack of counterregulatory hormones important for glucose homeostasis; these include GH, corticotropin, and thyroid-stimulating hormone. Although not usually considered a source for hypoglycemia, thyroid hormone may stimulate gluconeogenesis and increase insulin clearance. This mechanism could account for the hyperinsulinemic hypoglycemia observed in a small number of patients with congenital hypothyroidism.
  • The combination of microcephalus, cryptorchidism, and hypoplasia of the scrotum can occur with coexistent GHD and gonadotropin deficiencies. Testosterone bioactivity plays an essential role in the differentiation and development of the male genitalia. During the first trimester, GH modulates fetal testosterone production, perhaps by regulating placental chorionic gonadotropins. During the second and third trimesters, testosterone production appears to be independent of GH and relies on fetal pituitary gonadotropins.
  • Liver disease has been associated with neonatal hypopituitarism. Hypothyroidism is a well-recognized cause of neonatal jaundice, typically an indirect hyperbilirubinemia. The current theory regarding conjugated hyperbilirubinemia is based on the relationship of GH to bile acid synthesis. GH stimulates the synthesis of bile acids, which are major determinants for the induction of canalicular bile secretion. Cholestasis associated with congenital hypopituitarism resolves with hormonal replacement.
  • Neonatal hypoglycemia, persistent cholestatic jaundice, or hypogonadism in a male patient should immediately suggest the possibility of GHD. Neonatal hypopituitarism is potentially fatal if untreated.
• Acquired disease
• • Acquired GHD can have multiple sources (see Causes).
  • By the age of 6-12 months, infants with GHD clearly demonstrate an abnormally low growth velocity. Skeletal proportions remain normal, but skeletal age is delayed, often to less than 60% of the infant's chronologic age. Delay in dental eruption may precede this finding. Characteristic facies in patients with GHD result from retarded growth of the facial bones. Closure of the fontanelles is often delayed and results in frontal bossing and hydrocephalus. The nasal bridge may be markedly underdeveloped, and the orbits may be shallow; these alterations result in disproportionate cephalofacial relationships.
  • The weight-to-height ratio tends to be increased, just as the ratio of fat to lean muscle is elevated the absence of the effect of GH on the peripheral tissues. Decreased development of lean muscle results in poor muscular tone during infancy and early childhood; this sometimes leads to gross motor delays. Hair growth is sparse, and nails are thin and grow slowly. Laryngeal hypoplasia results in continuation of the prepubescent voice in boys with GHD.
  • Puberty may be delayed by 3-7 years despite normal gonadotropin release. This is likely related to the delay in skeletal age. For reasons that remain incompletely understood, skeletal development must be of a certain age (at least 9 y for girls and 10 y for boys) for puberty to ensue. Despite this delay, sexual function and fertility are normal in people with GHD. Although micropenis may occur during infancy in the congenital form of GHD, the penis is normal for the person's body size during adulthood.

Physical

Findings in patients with congenital or acquired hyposomatotropism are summarized below.

• Congenital disease
• • Normal length at birth
  • Midline defects
  • Cleft lip
  • Cleft palate
  • Blindness
  • Single central maxillary incisor
  • Hypogonadotropic hypogonadism
  • Jaundice
  • Icterus
  • Hepatosplenomegaly
  • Hypoglycemia
  • Shaking
  • Irritability
  • Lethargy
  • Hypotonia
  • Diaphoresis
  • Tachycardia
  • Pallor
  • Seizures
• Acquired disease
• • Short stature
  • Characteristic facies
  • • Frontal bossing
    • Flattened nasal bridge
    • Forehead prominence
• Other findings
• • Delayed dental eruption and exfoliation
  • Delayed bone age
  • Increased weight-to-height ratio
  • Poor muscle tone (motor delay may result)
  • Laryngeal hypoplasia
  • Poor hair and nail growth
  • Delayed puberty
  • Normal genitalia
  • Normal skeletal proportions

Causes

Hypothalamic regulatory peptides

Decreased or abnormal production of any of the regulatory peptides discussed above, or their respective receptors, may result in GHD.

Genetic abnormalities of GH production

A great deal has been learned about the genetic causes of hypopituitarism. By 1979, many families with isolated GHD or diminished production of GH and 1 or more additional pituitary hormones had been described. The development of a complementary DNA probe for the pit-hGH gene permitted scientists to recognize GH gene deletions in 1981 and placental GH and chorionic somatotropin gene deletions in 1982. The power of polymerase chain reaction (PCR) amplification and DNA sequencing subsequently revealed mutations and small deletions affecting GH in other families with isolated GHD.

The path to understanding the mechanisms that underlie multiple pituitary hormone deficiency was less straightforward than that regarding single genetic defects. Solutions emerged with the discovery of transcriptional activation factors that direct embryonic development of the anterior pituitary. This story began with the discovery in 1988 of a homeobox protein, called Pit-1, that binds to sequences in the promoter for the GH gene. The story continued with the recognition of many other pituitary and hypothalamic factors that orchestrated pituitary development. Three main transcriptional factors have been implicated as causes of multiple pituitary hormone deficiency in humans. In chronologic order of their association with human disease, they are Pit-1, PROP1, and HESX1.

The PIT1 gene, located on chromosome 3, is a member of a large family of transcription factor genes responsible for the development and function of somatotrophs and of other neuroendocrine cells of the adenohypophysis. At least 7 point mutations of the PIT1 gene have been associated with hypopituitarism in Dutch, American, Japanese, and Tunisian families.

In 1992, Tatsumi et al described the first human example of pituitary hormone deficiency due to a PIT1 mutation.¹ Two sisters born to parents who were second cousins had profound neonatal hypothyroidism without elevated levels of thyroid-stimulating hormone. One died from aspiration pneumonia at the age of 2 months. The surviving sister also had deficiencies of GH and prolactin. Multiple recessive and dominant types of PIT1 mutations have been recognized over the years. Sporadic cases have also been reported.

The first examples of PROP1 mutations in humans with pituitary hormone deficiencies were reported in early 1998. In humans, the hormonal phenotype involves deficiencies of luteinizing hormone, follicle-stimulating hormone, prolactin, thyroid-stimulating hormone, and GH. Mutations recognized to date involve the paired-like DNA-binding domain encoded by exons 2 and 3 and demonstrate autosomal recessive inheritance.

The HESX1 gene plays an important role in the development of the optic nerves and the anterior pituitary gland. The human gene is located on chromosome 3p21.2. Dattani et al (1998) identified the first human patients with a mutation in HESX1 after 135 patients with pituitary disorders were screened.²

Developmental malformations

Developmental malformations commonly associated with GHD include anencephaly, holoprosencephaly, and septooptic dysplasia (de Morsier syndrome). Septooptic dysplasia, in its complete form, combines hypothalamic insufficiency with hypoplasia (or absence) of the optic chiasm, optic nerves, septum pellucidum, and corpus callosum. Consider this diagnosis in any child with growth failure and impaired vision, especially in one with accompanying nystagmus. HESX1 mutations have been associated with septooptic dysplasia.

Trauma, infections, tumors, and cranial irradiation

Trauma, infections, sarcoidosis, tumors, and cranial irradiation of the hypothalamus, pituitary stalk, or anterior pituitary may also result in isolated GHD or anterior hypopituitarism. GHD is most commonly associated with breech delivery, prolonged labor, placental abruption, and other complicated deliveries. Hypothalamic tumors or pituitary tumors (eg, craniopharyngioma, glioma) are major causes of hypothalamic-pituitary insufficiency.

In rare cases, metastasis from extracranial carcinomas (eg, histiocytosis, germ cell tumor) lead to hypopituitarism.

Craniopharyngiomas and histiocytosis X are major etiologies of pituitary insufficiency. Craniopharyngiomas arise from remnants of the Rathke pouch, which is a diverticulum arising from the roof of the embryologic oral cavity and which gives rise to the anterior pituitary.

Most patients present in mid childhood with symptoms of increased intracranial pressure, such as headaches, vomiting, visual field deficits, and oculomotor abnormalities. Short stature often coexists, but this is usually not the first complaint. Most children with craniopharyngiomas have growth failure at the time of presentation. Because of this association, any child in whom GHD is diagnosed should undergo MRI to exclude a brain tumor before the start of GH therapy.

Irradiation-induced hypothalamic-pituitary dysfunction is dose related. Low-dose irradiation usually results in isolated GHD, whereas high doses most often result in multiple hormonal deficiencies. One study group reported that 2-5 years after irradiation, 100% of children receiving doses of at least 3000 cGy to the hypothalamic-pituitary axis over 3 weeks had subnormal GH responses to provocative testing. Hypothalamic irradiation also damages the growth plate cartilage and is associated with an increased incidence of precocious puberty (advanced bone age and premature epiphyseal fusion); both of these processes compound the effect on linear growth.

Developmental abnormalities of the pituitary

Congenital absence or hypoplasia of the pituitary has also been identified. Common findings on MRI include an ectopic neurohypophysis, an absent infundibulum, a small adenohypophysis, and absence of the usual high signal intensity (bright spot) in the posterior pituitary as seen on T1-weighted MRIs.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Primary growth disorders

Osteochondrodysplasias - Group of disorders characterized by intrinsic abnormalities of cartilage and/or bone
Chromosomal abnormalities - Aberrations of autosomes and sex chromosomes
Intrauterine growth retardation - Infections, syndromes, placental abnormalities, and maternal disorders
Genetic short stature
Constitutional delay of growth and maturation

Secondary growth disorders

Chronic diseases - GI, renal, cardiovascular, and autoimmune
Endocrine disorders - Hypothyroidism, Cushing syndrome, pseudohypoparathyroidism, GH insensitivity, and IGF deficiency
Rickets

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

The diagnosis of GHD remains controversial. The Growth Hormone Research Society recently convened an international workshop of acknowledged authorities to address this issue. The diagnosis of GHD is a multifaceted process requiring comprehensive clinical and auxologic assessment combined with biochemical testing of the GH-IGF axis and radiologic evaluation. Biochemical testing of the GH-IGF axis includes radioimmunoassays (RIAs) of GH, IGF, and IGFBPs.

RIA for GH

Many RIAs are available to measure GH levels, and all offer limited accuracy. Repeated measurements may vary by as much as 3-fold, even when the tests are conducted in laboratories with personnel experienced in the procedures. This variation is observed because several molecular forms of GH exist in the serum and because polyclonal (instead of monoclonal) antibodies are used. To improve standardization, use of a 22-kDa rhGH GH-reference preparation with an assigned potency of 3 IU/mg has been recommended. When assay data are reported, a clear statement of the method should be included. Today, the optimal assay measures the 22-kDa hGH species by using a monoclonal antibody.

Serum GH concentrations remain constitutively elevated from the newborn period to as late as 6 months of age. Therefore, a serum GH level of less than 20 ng/mL in infants younger than 6 months suggests GHD. However, a random hGH level is not diagnostic in patients older than 6 months because hGH is intermittently secreted in brief nocturnal pulses (of 10-15 minutes during deep sleep) beyond early infancy. GHD cannot be diagnosed on the basis of a single random serum GH concentration at any age.

RIA for IGF

Specific RIAs distinguish IGF-1 and IGF-2. Serum IGF-1 concentrations are depend on GH and vary with the patient's age, nutritional status, and sexual maturation. In children younger than 8 years, serum IGF-1 levels may be indistinguishable from levels measured in children with GHD. Concentrations of serum IGF-2 vary less than IGF-1 levels do at a given age; however, serum IGF-2 is less GH dependent than IGF-1.

Rosenfeld and colleagues evaluated the effectiveness of using IGF-1 and IGF-2 RIAs to identify children with GHD.³ When performed alone, assays for both produced false-positive and false-negative results. However, combined assays helped in correctly identifying 96% of children with GHD. Only 0.5% of healthy children had serum concentrations of both IGF-1 and IGF-2 that were below the reference ranges for their age and sex.

Total serum IGF-1 levels represent the combined quantity of unbound IGF-1 (free IGF-1) plus IGF-1 bound to IGFBP-3. Free IGF-1 is postulated to be the bioactive fraction, but it accounts for only a small fraction of the total amount.

Hasegawa and colleagues (1996) developed an immunoradiometric assay for free IGF-1 in plasma and reported the relationship of free IGF-1 to GH-secretory status.⁴ Low serum levels of free IGF-1 assayed by using this method were highly correlated highly complete GHD but not partial GHD. Despite their reduced diagnostic usefulness in patients with partial GHD, free IGF-1 levels may prove useful for assessing compliance with or the effectiveness of rhGH therapy.

RIA for IGFBPs

To diagnose GHD, assaying the serum IGFBP-3 concentration may be superior to measuring the free IGF-1 concentration for at least 2 reasons. First, IGFBP-3 levels vary less with nutritional status than free IGF-1 values do. Second, serum IGFBP-3 levels, even in young children, are typically more than 500 mg/mL; therefore, the detection of low levels is feasible.

Imaging Studies

Radiography

Radiography to assess skeletal maturation, similar to an examination of growth and development, is a useful diagnostic tool to determine a patient's GH secretory status. Anteroposterior radiographs of the left hand and wrist (knee or ankle in children <1 y) are used to evaluate the progress of epiphyseal ossification by comparing the results to age- and sex-matched reference ranges.

Crude estimates of skeletal maturation can also be obtained by assessing dental eruption. Primary teeth begin to erupt at approximately 6 months of age, and exfoliation starts at 6-12 years.

Height predictions rely on the observation that the greater the delay in bone age relative to chronologic age, the longer the time before epiphyseal fusion occurs and, thus, final height is achieved. The method of height prediction is based on formulas Bayley and Pinneau (1952) developed using information from Greulich and Pyle's classic radiographic atlas.⁵ Tanner and colleagues (1975) and Roche and colleagues (1971) subsequently refined these predictions by linking skeletal maturation to a rating of sexual maturity.^{6, 7}

Each system is useful for estimating the range of a patient's likely adult height to within 2 inches above or below the predicted value. A major limitation of current methods for predicting height is that the standards Greulich and Pyle established are based on calculations from a few Caucasian children who lived in 2 affluent suburbs in the United States during the 1940s. Normal skeletal maturation varies with ethnicity and is likely to vary with socioeconomic status. Moreover, most industrialized countries are home to a heterogeneous population. A modern reappraisal of these radiographic standards is overdue.

Magnetic resonance imaging

A lateral skull image may provide evidence of enlargement or distortion of the sella turcica, as well as suprasellar calcification, which indicates a craniopharyngioma. As a result of the high false-negative rate of skull findings with plain radiography, MRI is the procedure of choice to exclude intracranial masses or developmental abnormalities arising from pituitary anlagen. Before rhGH therapy is started, patients with GHD should undergo MRI of the brain to exclude the possibility of an organic lesion.

Contemporary MRI techniques can be overly sensitive, with MRIs depicting clinically insignificant signal intensity in the hypothalamus or pituitary gland. Most of these lesions require only clinical evaluation (eg, ophthalmologic examination, growth surveillance). A thickened pituitary stalk or asymmetric elevation of the pituitary contour warrants further evaluation.

Other Tests

Regarding clinical and auxologic assessment, history taking and physical examination are the most useful diagnostic tools because the diagnosis of GHD rests on clinical judgment. The foundation for the diagnosis of GHD is careful, serial documentation of the patient's height and a determination of height velocity.

In the absence of other evidence of pit-hGH secretory dysfunction, testing for GH secretion is typically unnecessary.

Procedures

Diagnostic criteria for hyposomatotropism and provocative testing

Random testing of serum GH concentrations is of no use in establishing the diagnosis of GHD. Provocative GH testing is not the current criteria standard. Current diagnostic criteria include the following:

• Growth-velocity Z score below -2.0, evidence of certain genetic mutations (eg, GH1 deletion; IGF1 deletion; mutations involving SHOX, PIT1, PROP1, Turner syndrome, and Prader-Willi syndrome)
• Predicted adult height (Bayley-Pinneau value more than 1.5 standard deviations below the calculated midparental target height)
• Serum-free or total IGF-1 Z score below -2.0 (ie, more than 2 standard deviations below the mean for the patient's age, sex, and Tanner stage)

Provocative GH testing is criticized for several reasons, including the following:

• None of the tests reproduces the physiologic secretory pattern of GH because they involve the use of pharmacologic stimuli to indirectly assess physiologic GH production.
• Individual clinicians assign what are essentially arbitrary definitions for subnormal responses (ie, cutoffs for peak serum GH values) to provocation.
• The reproducibility of provocative tests and GH RIAs is limited. Many pediatric endocrinologists apply other clinical criteria (eg, growth velocity Z score below -2) and do not perform provocative GH tests to diagnose GHD.

Despite limitations, provocative GH tests remain helpful ways to measure GH reserve. Pediatric endocrinologists use physiologic stimuli (eg, strenuous exercise, fasting, deep sleep) and pharmacologic stimuli (eg, clonidine, levodopa-propranolol, glucagon, arginine, insulin) to provoke GH secretion. In euthyroid children, all of the tests must be performed after overnight fasting.

To improve diagnostic sensitivity and specificity, at least 2 provocative tests are performed. Immediately before and during the earliest phases of puberty, GH production is often indistinguishable in unaffected children and in children with GHD. Serum GH concentrations typically rise during puberty. Many investigators suggest that children approaching puberty should be given gonadal steroids to prime the GHRH-GH axis before testing.

Specific provocative tests are described below.

Insulin tolerance test

Insulin-induced hypoglycemia is the most potent stimulus for GH secretion and the most dangerous tool for provocative GH testing in patients who may have GH deficiency. Insulin tolerance testing makes advantage of the hormonal counterregulatory response to hypoglycemia. In patients without GHD, plasma concentrations of glucagon, epinephrine, norepinephrine, cortisol, corticotropin, and GH are elevated in response to acute hypoglycemia.

To perform the test, patients fast for 8 hours. Then, lispro insulin 0.1 U/kg of body weight is administered rapidly as an intravenous bolus. Serial blood samples are subsequently obtained to measure GH, cortisol, and glucose concentrations at 0, 15, 30, 60, 75, 90, and 120 minutes. With each sample, the blood glucose level is simultaneously determined by using a bedside glucometer to document an appropriate reduction and to ensure safety. Performance of the test is considered adequate when the blood glucose level decreases below 50% of its baseline value.

Adverse effects expected during the procedure include symptoms secondary to hypoglycemia, such as lethargy, shaking, confusion, headache, abdominal pain, nausea, vomiting, syncope, and seizure activity. The test must be performed under the watchful eye of the physician who can begin prompt resuscitation with glucose and/or glucagon as soon as the diagnostic samples have been obtained. To date, the insulin tolerance test is the only provocative test associated with fatalities; therefore, personnel must be trained and conduct the test judiciously.

Clonidine stimulation test

Clonidine acts centrally to stimulate alpha-adrenergic receptors, which are involved in regulating GH release. Serum GH levels are obtained at baseline and at 60 and 90 minutes after the oral administration of clonidine 0.1 mg/kg. Clonidine may induce hypotension during the test. Therefore, warn parents that they may experience lethargy and/or depression for 24 hours after clonidine is administered.

Levodopa-propranolol HCl test

Levodopa is a dopamine receptor agonist. Dopamine is involved in the stimulation of GH secretion. In the converse, beta-adrenergic control negatively regulates GH release.

Propranolol is a beta-blocker used to hinder inhibitory input affecting GH release while levodopa simultaneously stimulates GH release by means of the dopaminergic pathway. Propranolol 0.75-1 mg/kg is orally administered before levodopa. The dosage of levodopa for levodopa-propranolol HCl testing varies with weight so that children weighing less than 15 kg receive 125 mg, children weighing 10-30 kg receive 250 mg, and children weighing less than 30 kg receive 500 mg.

Blood samples for GH testing are drawn at 0, 60, and 90 minutes after the administration of levodopa. Adverse effects include nausea and, in rare cases, emesis. In addition, the patient's heart rate may decrease because of the use of propranolol. Closely monitor his or her vital signs, and ensure that appropriate resuscitative measures are available.

Arginine HCl test

Arginine appears to exert a direct depolarizing action on somatropic neurons, increasing GH secretion. After an overnight fast, patients are given 10% arginine HCl in 0.9% NaCl 0.5 g/kg (not to exceed 30 g) as a constant intravenous infusion over 30 minutes. Blood samples for GH testing are obtained at 0, 15, 30, 45, and 60 minutes after the infusion of arginine is begun. Arginine has historically been used as a primer before insulin is administered during insulin tolerance testing.

Glucagon test

Glucagon increases peripheral glucose concentrations by means of glycogenolysis and gluconeogenesis. Because glucagon is rapidly metabolized, an abrupt reduction in serum glucose concentration ensues and triggers the release of counterregulatory hormones.

After fasting overnight, patients receive an intramuscular injection of glucagon 0.03 mg/kg (not to exceed 1 mg). Some clinicians advocate the concomitant use of propranolol to inhibit the catecholaminergic response to hypoglycemia. Serum GH concentrations are determined at 0, 30, 60, 90, 120, 150, and 180 minutes after glucagon administration. Nausea and, occasionally, emesis may occur.

Expected results

Most clinicians use a peak serum GH concentration of more than 10 ng/mL (30 IU) to exclude GHD in children.

New models for diagnosis

Basal, oscillating, and pulsatile GH inputs and the wide range of intrasubject and intersubject variance in GH pharmacokinetics negate the assumption of a uniform relationship between GH secretion and serum GH concentration. Because of this, peak GH concentration is an oversimplified outcome of GH testing. Bright and colleagues (1999) postulated that serum GH concentrations reflect multiple components of GH input and that a composite pharmacokinetic model that accounts for pulsatile (infused), basal, and oscillatory components is required to accurately estimate each individual's pharmacokinetic parameters.⁸ Ongoing research may aid in applying these complex mathematic models to daily practice.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Replacement dosages of rhGH

For patients with GHD, effective replacement dosages of rhGH are 0.175-0.75 mg/kg/wk, and therapy should be individualized. Dividing the weekly dose into 6 or 7 daily subcutaneous injections is more effective than dividing the total dose into 3 doses administered on alternate days.

Height outcome

In the authors' personal experience in treating patients with GHD starting at younger than 4 years, the patient's final height may exceed the target height.

The patient's final height is best correlated with his or her pretreatment chronologic age. It is also related to the height standard deviation score and to the child's predicted adult height, duration of therapy, and birth length. In many studies, the final height was closely correlated with the height standard deviation score, the patient's age at onset of puberty, weight, and serum concentrations of GH binding protein (indicators of GH receptor mass).

Early recognition of GHD is essential for an optimal outcome in terms of height.

Patterns of growth during childhood

Growth during childhood follows predictable patterns.

• Before birth - Prenatal growth averages 1.2-1.5 cm each week.
• Infancy and childhood - Growth velocity increases to 15 cm (approximately 6 inches) per year over the first 2 years and then slows to 6 cm (approximately 2 inches) per year until puberty.
• Puberty - A second peak in growth velocity occurs during puberty. This peak occurs earlier but is lower in magnitude and is shorter in girls than in boys.

  Characteristics of the Pubertal Peak of Growth Velocity in Girls and Boys

  Characteristic	Girls	Boys
  Mean age at peak height velocity, y	11.5	13
  Magnitude, cm/y	8.5	9.5
  Duration, y	5	6

In children who are receiving rhGH therapy, growth velocity usually exceeds reference values in the first few years. Therefore, suspect partial GH resistance or noncompliance if suboptimal growth velocity is observed at the beginning of rhGH therapy.

Treatment principles

• Monitor patients with visits every 3 months.
• Conduct physical examination.
• • Perform funduscopy to exclude pseudotumor cerebri.
  • Pubertal staging should be performed during each visit because gonadal steroids have a notable effect on skeletal maturation.
  • Monitor patients by measuring their height in centimeters and weight in kilograms.
• Obtain interim histories.
• Monitor medical therapy.
• • Adjust drug dosages by weight, and monitor patients for adverse effects of therapy (see Medication).
  • For patients whose condition does not respond well to weight-based therapy, some clinicians advocate titrating dosages according to IGF-1 levels. The goal is to maintain an IGF-1 value in the upper quartile for the child's age and sex.
• Bone age can be used to determine the remaining growth potential for patients with GHD who are approaching their final height. Bone ages have no proven role in monitoring GH therapy.

Surgical Care

• Brain tumors and/or secondary hydrocephalus indicate a need for consultation with a neurosurgeon.
• A pediatric surgeon may be consulted to address cleft lip repair, cleft palate repair, and/or cosmetic reconstruction of the facies in a patient with long-standing GHD.

Consultations

Consultations with the specialists listed below may aid in the care of patients with hyposomatotropism.

• Neurosurgeon
• Plastic surgeon
• Radiation oncologist
• Neurooncologist
• Psychologist
• Nutritionist

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

GH extracted from cadaveric pituitary glands was used to treat hypopituitarism in children for more than 30 years until 1985, when rhGH became commercially available. Cadaveric hGH was effective. However, complications associated with its use were an inadequate supply, variable biopotencies, and the transmission of Creutzfeldt-Jakob disease.

rhGH and novel treatment modalities

Widespread production of rhGH has increased worldwide use of rhGH. Dosing of rhGH remains arbitrary to some degree.

• In the United States, the customary starting dosage is 0.3 mg/kg/wk given subcutaneously divided in 7 nightly injections.
• In Japan and in many European countries, the customary dosage is approximately 0.025 mg/kg/d or 0.15 mg/kg/wk (50% of the US dose).

With respect to nomenclature and conversion,

3 IU of rhGH = 1 mg of rhGH.

In children who have completely GH deficient, rhGH typically accelerates linear growth to 10-12 cm/y during the first year of therapy and to 7-9 cm/y in the second and third years.

Several novel treatment modalities for GHD have emerged:

• Oral GH secretagogs
• Growth hormone-releasing hormone
• Oral liquid formulations of rhGH
• Depot GH (administered once or twice a month)

Evaluation of most of these modalities remains incomplete at this time. Depot rhGH had been approved for use in GHD but was subsequently removed from the market. Data from clinical trials reported to date suggest that the depot form is less effective for stimulating growth than the daily form. This result was also found with clinical use.

Children with GHD have dramatic and clearly distinguishable responses to rhGH treatment compared with children given placebo. Data regarding the potential benefits of high doses are still being collected. The dose response of rhGH is nonlinear.

A double-blind, placebo-controlled, crossover trial of rhGH therapy in adults with GHD suggested sex-related differences in GH responsiveness. An identical dose of rhGH per body surface area was administered to men and women. With treatment, men had less basal body fat, as well as higher basal levels of serum IGF-1, greater basal lean body mass, enhanced lowering of cholesterol levels, and more increases in markers of bone metabolism than did the women. These sex-related differences in the response to rhGH treatment resemble differences found in children.

Of interest, boys have a linear dose-response curve, with maximal effects observed with dosages of 0.1 mg/kg/d, whereas girls have a bell-shaped dose-response curve, with maximal effect at 0.05 mg/kg/d. This evidence suggests that estrogen and testosterone play a role in regulating the secretion and action of GH. As a result, optimal dosing strategies for the treatment of GHD may differ in boys and girls.

The dosage of rhGH may be a valuable parameter for optimizing the response to therapy. In patients who are receiving GH replacement, serum IGF-1 and IGFBP-3 concentrations should be monitored carefully, for 2 reasons:

1. IGF-1 and IGFBP-3 are direct biomarkers of tissue responsiveness to rhGH therapy. The standard of practice in adults with GHD is titrating the dosage of rhGH to maintain serum growth-factor levels within an age-appropriate reference range; this approach may become standard practice in pediatric patients. Some have proposed mathematical prediction models that can be used to predict the growth response to a specific dosage and to guide the pediatric endocrinologist in modifying therapy when a patient's observed growth falls short of the predicted outcome.
2. Monitoring of growth factors is useful for evaluating compliance and for assessing risk. Results of several studies have linked high serum IGF-1 levels to an increased risk of cancer in otherwise healthy patients. Although the data did not indicate a causal relationship, further consideration of this issue is warranted, as is monitoring of IGF-1 and IGFBP-3 levels during rhGH therapy. Individually defined treatment is the goal in patients with GHD. The ability to adjust rhGH dosing on the basis of clinical and biochemical information provides an ideal strategy.

GnRH agonists

Gonadal steroids are important mediators of bone development. When normal or precocious puberty limits the response to GH, delaying puberty with an analog of luteinizing hormone-releasing hormone may be appropriate. However, this strategy in pubertal patients has not led to documented enhancements in final heights.

Nevertheless, the younger the age of pubertal onset, the lower the patient's final height. As a result, leuprolide has been used in patients with fast-tempo puberty or in those in whom GHD was diagnosed late. In a recent multicenter trial in pubertal children (predominantly boys) with GHD, high-dose rhGH 0.7 mg/kg/wk increased near-final heights, without a change in the safety profile. Both of these therapeutic strategies require further study.

GHRH ghrelin is a synthetic form of an identified endogenous ligand for the GH-secretagogue receptor. Ghrelin is involved in a novel system for regulating GH release. It is an acylated peptide with a molecular weight of 3300 Da. Intravenously administered ghrelin stimulated GH release in primary pituitary cell cultures and serum GH in rats. Furthermore, ghrelin strongly stimulates GH release in humans. These characteristics make this peptide a possible therapeutic tool for the future.

Drug Category: rhGHs

These agents are used to treat GHD, chronic renal failure, Turner syndrome, Prader-Willi syndrome, AIDS-wasting syndrome, small size for gestational age with failure to catch up, idiopathic short stature, and short gut syndrome.

Drug Category: IGFs

These agents are indicated for long-term treatment of severe primary IGF deficiency.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Complications

• rhGH has a well-established profile of adverse effects in the pediatric population.
• • rhGH reduces insulin sensitivity, resulting in hyperglycemia among patients who are predisposed to develop insulin resistance.
  • Slipped capital femoral epiphysis occurs more frequently in patients with renal or endocrine disorders or in patients undergoing rapid growth than in the general population.
• Scoliosis may progress in patients with rapid growth secondary to rhGH therapy.
• Intracranial hypertension with papilledema, visual changes, headaches, nausea, and/or vomiting have been reported in a small number of patients treated with rhGH. The symptoms usually occurred within the first 8 weeks of initiating rhGH therapy.
• Funduscopic examination is recommended at start of rhGH therapy and at each follow-up visit.
• Peripheral edema and prepubertal gynecomastia have been associated with rhGH therapy.
• With the exception of slipped capital femoral epiphysis, most adverse effects associated with rhGH therapy resolve after the dosage is reduced or after therapy ends.

Prognosis

• The prognosis depends on the underlying etiology of GHD.

Patient Education

• Offer psychological support to patients and families.
• Discuss the possibility of a delayed onset of puberty.
• Discuss the importance of complying with daily injections.
• Discuss our current understanding of the metabolic actions of GH with patients.
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Growth Hormone Deficiency, Growth Hormone Deficiency in Children, Growth Failure in Children, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to evaluate children with GHD for cranial neoplasm before the start of rhGH therapy
• Failure to immediately search for pseudotumor cerebri in children who develop symptoms or signs of increased intracranial pressure during rhGH therapy
• Failure to exercise caution with diagnostic insulin tolerance testing (the only provocative test associated with fatalities to date)
• Failure to warn parents regarding potential lethargy and/or depression in the 24 hours after an administration of clonidine for diagnostic testing
• Failure to test the corticotropin-cortisol axis during provocative testing (Adrenal crisis and, possibly, death may result.)

Special Concerns

Potential need to discontinue rhGH therapy

Therapy with rhGH may need to be discontinued in patients who have acute critical conditions or illnesses, such as open heart or abdominal surgery, multiple accidental trauma, or respiratory failure. The safety of continuing rhGH treatment has not been established in patients receiving replacement doses for approved indications who concurrently develop these critical illnesses.

In a study of adults without GHD who were hospitalized for critical illness, supplemental rhGH therapy may have been associated with a significant increase in mortality rates.

Jeschke et al (2000) performed a prospective, randomized, placebo-controlled study in pediatric patients hospitalized for severe burns.⁹ The mortality risk did not increase with rhGH therapy.

Potential association between rhGH therapy and leukemia

Watanabe and colleagues (1993) reported an increased frequency of leukemia in Japanese children who were treated with rhGH.¹⁰ Several investigators subsequently examined the potential relationship between rhGH therapy and leukemia.

Children with GHD have more risk factors that predispose them to develop leukemia than do children in the general population. These factors include the following:

• Previous episodes of cancer
• Treatment with modalities such as irradiation and chemotherapy
• Comorbid conditions, such as, Down, Bloom, or Fanconi syndrome

Examination of large databases reveals that the incidence of leukemia is not elevated among rhGH-treated patients without these additional risk factors. In addition, no current evidence suggests that the risk of leukemia or brain-tumor recurrence rises in patients receiving long-term rhGH treatment.

Patients with cancer in remission who require rhGH should be evaluate carefully. The pediatric endocrinologist and the oncologist should assess the appropriateness of rhGH therapy on an individual basis.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors thank Gloria Matthews, Nora Eblen, and Debra Tate of the Division of Pediatric Endocrinology, University of Texas Health Science Center at San Antonio, for their administrative assistance. This work was supported in part by National Institutes of Health (NIH) grant K08 DK02876.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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