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Hypopituitarism in children typically results in abnormally slow growth and short stature with normal proportions. It is usually due to a pituitary tumor but may be idiopathic. Diagnosis involves measurement of growth hormone (GH) levels at baseline and in response to pharmacologic stimuli. Treatment usually involves removal of the causative tumor and GH replacement.
Hypopituitarism in children may be generalized, involving deficiency of several pituitary hormones, but it is usually first expressed clinically as short stature resulting from deficiency of GH. Isolated deficiency of GH may also occur.
Hypopituitarism in children is usually due to a pituitary tumor (most commonly a craniopharyngioma) or is idiopathic. The combination of lytic lesions of the bone or skull and diabetes insipidus suggests Langerhans' cell histiocytosis (see Histiocytic Syndromes: Langerhans' Cell Histiocytosis). Hypothalamic or pituitary hormone deficiency as well as isolated GH deficiency may occur in patients with midline defects, such as cleft palate or septo-optic dysplasia, which involves absence of the septum pellucidum, optic nerve atrophy, and hypopituitarism. GH deficiency, either alone or in patients with other abnormalities, is hereditary in about 5% of cases.
Therapeutic radiation of the CNS for various cancers causes slowing of linear growth, which can often be linked to resulting GH deficiency. Radiation of the spine, either prophylactic or therapeutic, may further impair the growth potential of the vertebrae and further jeopardize height gain.
Symptoms and Signs
In a child with hypopituitarism, height is below the 3rd percentile, and growth velocity is < 6 cm/yr before age 4 yr, < 5 cm/yr from age 4 to 8 yr, and < 4 cm/yr before puberty. Skeletal maturation, assessed by bone age determination, is > 2 yr behind chronologic age.
Although of small stature, a child with hypopituitarism retains normal proportionality between upper and lower body segments. The child fails to begin pubertal development. However, a child with isolated GH deficiency secondary to hypopituitarism may undergo delayed pubertal development.
Growth data for height and weight should be plotted on a growth chart (auxologic assessment) for all children. (See the standard growth charts available from the Centers for Disease Control and Prevention for more information.) 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. Evaluating the pituitary gland and sella turcica with CT or MRI is indicated to rule out calcifications and tumors; the sella turcica is abnormally small in 10 to 20% of patients.
Diagnosis
In mid to late childhood, IGF-1 levels, which reflect GH activity, are measured because GH levels are highly variable and difficult to interpret. Normal IGF-1 levels help exclude GH deficiency. However, IGF-1 levels are low in conditions other than GH deficiency, such as psychosocial deprivation, undernutrition, and hypothyroidism. Because IGF-1 levels are normally low in infancy and early childhood, they do not allow reliable discrimination between normal and subnormal in these age groups. In these children, levels of IGFBP-3 (the major carrier of IGF peptides) are measured. IGFBP-3 is less affected by undernutrition than is IGF-1.
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), assessment of GH levels requires provocative testing. However, provocative testing is nonphysiologic, subject to laboratory error, and poorly reproducible, and interpretation of data relies on arbitrary definitions of “normal” that vary by age and sex.
The insulin tolerance test may be the most effective provocative test for stimulating GH release. Less dangerous, but also less reliable, are tests using arginine infusion (500 mg/kg IV given over 30 min), levodopa (10 mg/kg to children; 500 mg po to adults), sleep, or 20 min of vigorous exercise. Generally, any GH level > 10 ng/mL or any response of > 5 ng/mL after a stimulus is sufficient to rule out GH deficiency. Increases in GH of < 5 ng/mL or to levels < 10 ng/mL are difficult to interpret.
What constitutes a normal response, however, is arbitrary, and all provocative tests of GH secretion occasionally produce misleading results. Because no single test is 100% effective in eliciting GH release, a 2nd provocative test should be done if the first is abnormal. GH levels generally peak 30 to 90 min after administration of insulin or the onset of arginine infusion, 30 to 120 min after levodopa, 60 to 120 min after the onset of sleep, and after 20 min of vigorous exercise. Because GH responses are generally abnormal in patients with diminished thyroid or adrenal function, testing should be conducted in these patients only after adequate hormone replacement therapy.
The value of exogenous growth hormone–releasing hormone (GHRH) alone in evaluating GH secretion is not established. In normal people, a dose of 1 μg/kg GHRH IV administered over 15 to 30 sec results in maximal but variable release of GH, typically reaching a peak about 60 min after GHRH injection. The variability in pituitary responsiveness to GHRH is consistent with the hypothesis that intermittent secretion of somatostatin, which opposes GHRH, is responsible for modulating pituitary GH output. Presumably, absent or diminished increases in GH in response to GHRH identify patients with GH deficiency, but whether the pattern of response distinguishes primary hypothalamic disease from pituitary disease is unclear. In children with GH deficiency presumably secondary to GHRH deficiency, highly variable GH responses to GHRH occur. The combination of arginine and GHRH improves the sensitivity for diagnosing GH 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 h indicate abnormally low 12- or 24-h integrated GH secretion.
If diminished GH release is confirmed, secretion of other pituitary hormones and (if abnormal) hormones of their target peripheral endocrine glands also must be evaluated.
Treatment
Recombinant GH is indicated for all children with short stature who have documented GH deficiency. Dosing is usually from 0.03 to 0.05 mg/kg sc once/day. With therapy, height velocity often increases to 10 to 12 cm/yr in the first year and, although it increases more slowly thereafter, remains above pretreatment rates. Therapy is continued until an acceptable height is reached or growth rate falls below 2.5 cm/yr.
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 yr after treatment (see Prion Diseases: Creutzfeldt-Jakob Disease (CJD)). Pituitary-extracted GH was last used in the 1980s.
It is controversial whether short children with clinical features of GH deficiency but with normal GH secretion and normal IGF-1 levels should be treated with GH. Many experts recommend a trial of GH therapy for 6 to 12 mo, continuing GH only if there is a doubling of or an increase of 3 cm/yr 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.”
Cortisol and thyroid hormone should be replaced throughout childhood, adolescence, and adulthood in patients with short stature due to pituitary dwarfism when circulating levels of these hormones are low (see Thyroid Disorders: Treatment and see also Adrenal Disorders: Treatment). When puberty fails to occur normally, treatment with gonadal sex steroids is indicated (see Endocrine Disorders in Children: Treatment).
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 yr after the successful completion of anticancer therapy.
Last full review/revision February 2007 by Ian M. Chapman, MBBS, PhD
Content last modified February 2012
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