Growth hormone deficiency is the most common pituitary hormone deficiency in children and can be isolated or accompanied by deficiency of other pituitary hormones. Growth hormone deficiency typically results in abnormally slow growth and short stature. Diagnosis involves measurement of pituitary hormone levels and CT or MRI to detect structural pituitary anomalies or brain tumors. Treatment usually involves specific hormone replacement and removal of any causative tumor.
Patients with growth hormone deficiency associated with generalized hypopituitarism (panhypopituitarism) also have deficiency of one or more other pituitary hormones (eg, follicle-stimulating hormone [FSH], luteinizing hormone [LH], adrenocorticotropic hormone [ACTH], thyroid-stimulating hormone [TSH], antidiuretic hormone [ADH]). Hypopituitarism can be primary (a pituitary disorder) or secondary to interference with hypothalamic secretion of specific releasing hormones that control anterior pituitary hormone (GH, FSH, LH, ACTH, TSH) production.
Etiology of Growth Hormone Deficiency
Growth hormone (GH) deficiency can occur in isolation or in association with generalized hypopituitarism. In both instances, growth hormone deficiency may be acquired or congenital (including hereditary genetic causes). Rarely, GH is not deficient, but the GH receptors are abnormal (GH insensitivity).
Isolated growth hormone deficiency is estimated to occur in 1/4,000 to 1/10,000 children. It is usually idiopathic, but about 25% of patients have an identifiable etiology. Congenital causes include abnormalities of the GH-releasing hormone receptor and of the GH1 gene and certain central nervous system (CNS) malformations. Acquired causes include therapeutic radiation of the CNS (high-dose radiation can cause generalized hypopituitarism), meningitis, histiocytosis, and brain injury. Radiation of the spine, either prophylactic or therapeutic, may further impair the growth potential of the vertebrae and further jeopardize height gain.
Generalized hypopituitarism may have genetic causes, involving hereditary or sporadic mutations that affect cells of the pituitary. In such cases, there also may be anomalies of other organ systems, particularly midline defects, such as cleft palate or septo-optic dysplasia (which involves absence of the septum pellucidum, optic nerve atrophy, and hypopituitarism). Generalized hypopituitarism also can be acquired from many types of lesions that affect the hypothalamus (impairing secretion of releasing hormones) or pituitary; examples include tumors (eg, most commonly craniopharyngioma), infections (eg, tuberculosis, toxoplasmosis, meningitis), and infiltrative disorders. The combination of lytic lesions of the bones or skull and diabetes insipidus suggests Langerhans cell histiocytosis.
Symptoms and Signs of Growth Hormone Deficiency
Manifestations of growth hormone deficiency depend on the patient's age, the underlying etiology, and the specific hormone deficiencies.
Growth hormone deficiency itself typically manifests as growth failure, sometimes along with delay in tooth development. Height is below the 3rd percentile, and growth velocity is < 6 cm/year before age 4 years, < 5 cm/year from age 4 to 8 years, and < 4 cm/year before puberty. Although of small stature, a child with hypopituitarism retains normal proportionality between upper and lower body segments. Skeletal maturation, assessed by bone age determination, is > 2 years behind chronologic age.
Other abnormalities may be present, depending on the underlying defect, and the child may have delayed or absent pubertal development. Weight gain may be out of proportion to growth, resulting in relative obesity. Neonates who have congenital defects of the pituitary or hypothalamus may have hypoglycemia (which also can occur in older children), hyperbilirubinemia, midline defects (eg, cleft palate), or micropenis, as well as manifestations of other endocrine deficiencies.
Diagnosis of Growth Hormone Deficiency
Auxologic assessment (height and weight data recorded on a growth chart)
Imaging studies
Insulin-like growth factor 1 (IGF-1) levels and IGF binding protein type 3 (IGFBP-3) levels
Usually confirmation by provocative testing
Evaluation of other pituitary hormones and for other causes of poor growth
Current consensus guidelines for diagnosis of growth hormone deficiency require integration of growth criteria, medical history, laboratory testing, and imaging test results.
Growth is assessed; data for height and weight should be plotted on a growth chart (auxologic assessment) for all children. (For children 0 to 2 years, see World Health Organization [WHO] Growth Charts; for children 2 years and older, see Centers for Disease Control and Prevention [CDC] Growth Charts.)
Measurement of IGF-1 and IGFBP-3 levels begins the assessment of the GH/IGF-1 axis. IGF-1 reflects GH activity, and IGFBP-3 is the major carrier of IGF peptides. Levels of IGF-1 and IGFBP-3 are measured because GH levels are pulsatile, highly variable, and difficult to interpret.
IGF-1 levels vary by age and should be interpreted relative to bone age rather than to chronologic age. IGF-1 levels are lowest in infancy and early childhood (< 5 years) and thus do not reliably discriminate between normal and subnormal in these age groups. At puberty, IGF-1 levels rise and normal levels help exclude GH deficiency. Low IGF-1 levels in older children suggest GH deficiency; however, IGF-1 levels are low in conditions other than GH deficiency (eg, emotional deprivation, undernutrition, celiac disease, hypothyroidism) and these conditions must be excluded. However, IGFBP-3 levels, unlike IGF-1, are less affected by undernutrition and allow discrimination between normal and subnormal in younger children.
In children with low levels of IGF-1 and IGFBP-3, GH deficiency is usually confirmed by measuring GH levels. Because basal GH levels are typically low or undetectable (except after the onset of sleep), random GH levels are not useful and assessment of GH levels requires provocative testing. However, provocative testing is nonphysiologic, subject to laboratory variation, and poorly reproducible. Also, the definition of a normal response varies by age, sex, and testing center and is based on limited evidence. Treatment of GH deficiency should not be based solely on the results of provocative testing.
Imaging studies are done when growth is abnormal; bone age should be determined from an x-ray of the left hand (by convention). In GH deficiency, skeletal maturation is usually delayed to the same extent as height. With GH deficiency, evaluating the pituitary gland and hypothalamus with MRI is indicated to rule out calcifications, tumors, and structural anomalies.
Screening laboratory tests are done to look for other possible causes of poor growth, including
Hypothyroidism (eg, thyroid-stimulating hormone, thyroxine)
Renal disorders (eg, electrolytes, creatinine levels)
Inflammatory and immune conditions (eg, tissue transglutaminase antibodies, C-reactive protein)
Hematologic disorders (eg, complete blood count with differential)
Genetic testing for specific syndromes (eg, Turner syndrome) may be indicated by physical findings or if growth pattern differs significantly from family. If GH deficiency is highly suspected, additional tests of pituitary function are done (eg, ACTH, 8 AM serum cortisol level, LH, FSH, and prolactin levels).
Pearls & Pitfalls
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Provocative testing
Because GH responses are typically abnormal in patients with diminished thyroid or adrenal function, provocative testing should be done in these patients only after adequate hormone replacement therapy.
The insulin2
Because no single test is 100% effective in eliciting GH release (1), two GH provocation tests are done (typically on the same day). GH levels generally peak 30 to 90 minutes after administration of insulin
The GH response that is considered normal is somewhat arbitrary. Generally, any stimulated GH level > 10 ng/mL (> 10 mcg/L) is sufficient to rule out classic GH deficiency. GH deficiency may be considered for responses < 10 ng/mL (< 10 mcg/L; some centers use a lower cutoff, eg, 7 ng/mL [7 mcg/L]) to two pharmacologic stimuli, but results must be interpreted in the context of auxologic data. Because of the arbitrary nature of thresholds for normal results on provocative GH tests, children with otherwise unexplained short stature and normal provocative GH test results may be considered to have GH deficiency if they meet most of the following criteria:
Height > 2.25 standard deviations (SD) below the mean for age or > 2 SD below the midparental height percentile
Growth velocity < 25th percentile for bone age
Bone age > 2 SD below the mean for age
Low serum insulin-like growth factor 1 (IGF-1) and IGF binding protein type 3 (IGFBP-3) levels
Other clinical features suggesting growth hormone deficiency
Provocative testing may not detect subtle defects in the regulation of GH release. For example, in children with short stature secondary to GH secretory dysfunction, results of provocative testing for GH release are usually normal. However, serial measurements of GH levels over 12 to 24 hours indicate abnormally low 12- or 24-hour integrated GH secretion. However, this test is expensive and uncomfortable and thus is not the test of choice for GH deficiency.
If diminished GH release is confirmed, tests of secretion of other pituitary hormones and (if abnormal) hormones of their target peripheral endocrine glands along with pituitary imaging studies must be done if not done previously.
Provocative testing reference
1. Kamoun C, Hawkes CP, Grimberg A: Provocative growth hormone testing in children: How did we get here and where do we go now? J Pediatr Endocrinol Metab 34(6):679–696, 2021. doi: 10.1515/jpem-2021-0045
Treatment of Growth Hormone Deficiency
Recombinant GH supplements
Sometimes other pituitary hormone replacement
Recombinant GH is indicated for all children with short stature who have documented growth hormone deficiency. (See also the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society's 2016 guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents.) Documented growth hormone deficiency is based on auxologic, biochemical, and sometimes radiologic findings.
Adverse effects of GH therapy are few but include idiopathic intracranial hypertension (pseudotumor cerebri), slipped capital femoral epiphysis, and transient mild peripheral edema. Before the advent of recombinant GH, GH extracted from pituitary glands was used. This preparation rarely led to Creutzfeldt-Jakob disease 20 to 40 years after treatment. Pituitary-extracted GH was last used in the 1980s.
It is controversial whether short children without evidence of an endocrine, metabolic, or other disease that explains the short stature should be treated with GH. These children are considered to have idiopathic short stature (ISS). ISS is defined as height 2 standard deviations (SD) below the mean for age, normal height velocity (near or at lower limit of normal), no biochemical evidence of a growth-restricting condition, and normal GH stimulation testing that excludes classic GH deficiency. Recombinant GH can be used to treat children with ISS who have a height 2.25 SD below the mean for age and a predicted adult height below the normal range (ie, < 150 cm for females and < 160 cm for males). Guidelines recommend against the routine use of GH for every child with ISS, and the decision to treat should be made on a case-by-case basis. Treatment responses are highly variable. With 5 years of treatment, some children may have a mean increase of about 5 cm in adult height, whereas other children may have no increase in adult height. A greater response to GH treatment may be expected in children with ISS based on height response in first year of treatment, age at the start of treatment (better response if treatment is started before age 9 in girls and before age 10 in boys), and change in IGF-1 level from baseline. For children who are treated, many experts recommend a trial of GH therapy for 6 to 12 months, continuing GH only if there is a doubling of or an increase of 3 cm/year over the pretreatment height velocity. Others object to this approach because it is expensive, is experimental, may lead to adverse effects, labels otherwise healthy children as abnormal, and raises ethical and psychosocial concerns that feed into the bias of “heightism.”
When other pituitary hormone deficiencies accompany growth hormone deficiency, additional hormone replacement is required. Cortisol ( see Treatment) and thyroid hormone ( see Treatment see Treatment). When puberty does not occur normally, treatment with gonadal sex steroids is indicated ( see Delayed Puberty).
GH therapy in children with short stature due to therapeutic radiation of the pituitary gland for cancer carries a theoretic risk of causing cancer recurrence. However, studies have not shown a greater-than-expected incidence of new cancers or a greater recurrence rate. GH replacement can probably be safely instituted at least 1 year after the successful completion of anticancer therapy.
Key Points
Growth hormone (GH) deficiency can occur in isolation or in association with generalized hypopituitarism.
Causes include congenital (including genetic) disorders and a number of acquired disorders of the hypothalamus and/or pituitary.
GH deficiency causes short stature; numerous other manifestations may be present depending on the cause.
Diagnosis is based on a combination of clinical findings, imaging studies, and laboratory testing, usually including provocative tests of GH production.
Children with short stature and documented GH deficiency should receive recombinant GH; other manifestations of hypopituitarism are treated as needed.
More Information
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society: Guidelines for growth hormone and insulin-like growth factor-1 treatment in children and adolescents: Growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-1 deficiency (2016)
