Growth Hormone Deficiency

Growth hormone deficiency (GHD) is a rare disorder characterized by low secretion of growth hormone (GH) from the pituitary gland. Childhood-onset GHD (COGHD) is most commonly idiopathic and hypothalamic in origin; secondary causes of COGHD include genetic variants, brain structural defects, and acquired causes. COGHD is associated with delayed growth or growth deceleration and short stature. Adult-onset GHD (AOGHD) is most commonly caused by hypothalamic-pituitary tumors and their treatment; other causes include traumatic brain injury, subarachnoid hemorrhage, ischemic stroke, and central nervous system infections. AOGHD is associated with significant adverse metabolic abnormalities, reduced quality of life, and potentially, early mortality. In both adults and children, once GHD has been diagnosed, it can be treated with recombinant human growth hormone (rhGH). Retesting for GHD is especially important during the period between puberty and attainment of adult height and body composition (the transition period). Static tests for GH and insulin-like growth factor 1 (IGF-1) and stimulation tests are used in patients of all ages to establish the diagnosis and ensure appropriate treatment; IGF-1 and other tests are also used in monitoring.

Quick Answers for Clinicians

How do growth hormone levels change over the course of the day, and how does this affect laboratory testing?

Growth hormone (GH) is secreted by the anterior pituitary gland in a pulsatile fashion. Sleep naturally stimulates secretion, so GH levels increase at night. GH may also increase sporadically during the day, possibly as a result of meal consumption, and in response to hypoglycemia. Because of these diurnal variations, random single (static) GH and insulin-like growth factor 1 (IGF-1) measurements should not be used to diagnose GHD in most cases, and stimulation testing is required. See the Laboratory Testing section for more information.

What is the role of growth hormone testing in idiopathic short stature?

Idiopathic short stature (ISS) is a controversial diagnosis, and the distinction between ISS and growth hormone deficiency (GHD) is unclear. Furthermore, laboratory findings may be similar in mild GHD and ISS. If growth hormone (GH) treatment is initiated for ISS, it may be reasonable to titrate the dose of GH based on insulin-like growth factor 1 (IGF-1) levels. Careful monitoring of GH-treated ISS is required.

Indications for Testing

Children

Laboratory testing for GHD is appropriate in pediatric patients with:

Short stature (ie, stature ≥2 standard deviations below mean)
Severe growth deceleration
History of surgery or irradiation to the hypothalamus or pituitary gland
Radiologic evidence of structural hypothalamic-pituitary disease
History of traumatic brain injury
Neonatal signs of GHD (eg, hypoglycemia)

Patients Transitioning from Pediatric to Adult Care (Transition Patients)

Laboratory retesting for GHD is also appropriate to determine if GHD is persistent in patients transitioning from pediatric to adult care (ie, during the time that spans late puberty through establishment of adult height and bone and muscle composition) who have been off GH treatment for at least 1 month with:

Suspected hypothalamic GHD
Idiopathic isolated GHD (with or without a small pituitary gland or ectopic posterior pituitary)
Organic GHD with deficiency of two or fewer pituitary hormones in addition to GH

Testing for GHD is also appropriate in transition patients after radiation treatment.

Adults

Laboratory testing for GHD is appropriate in adult patients with:

Evidence or history of hypothalamic-pituitary disease (including hypothalamic-pituitary tumors)
Symptoms suggestive of GHD or pituitary dysfunction (eg, low lean body mass, increased body fat, dyslipidemia, cardiac dysfunction, low muscle strength, low exercise capacity, low bone mineral density, increased insulin resistance, decreased fibrinolysis, premature atherosclerosis)
History of traumatic brain injury, subarachnoid hemorrhage, ischemic stroke, or central nervous system infection

Laboratory Testing

Test Methods

Two types of tests, static and stimulation, are used in the diagnosis of GHD.

Static Tests

Static tests entail one-time measurement of a component of the GH axis. Due to the lack of harmonization between assays, use of the same assay throughout evaluation and diagnosis is recommended. Laboratory-specific and age-adjusted reference intervals are also recommended. Static tests are also useful in monitoring (see Treatment Monitoring).

Static Tests for GHD
Test	Uses	Limitations
IGF-1	Preferred initial test for GHD Concentrations are less variable than GH concentrations Low concentration in the absence of a catabolic condition (eg, diabetes) is strong evidence for GHD; stimulation testing is recommended	Low concentration is suggestive of GHD, but insufficient to diagnose GHD, and may be secondary to another condition (eg, uncontrolled diabetes, liver disease, or oral estrogen therapy) Normal concentration does not rule out GHD
GH	Aids in diagnosis of GH excess or deficiency disorders	Single, random GH result is nondiagnostic because GH is produced in a pulsatile fashion
IGFBP-3	Can be used in addition to GH concentration and IGF-1 testing to investigate suspected anterior hypopituitarism; concentrations reflect IGF-1 concentrations	Low concentration is suggestive of GHD, but insufficient to diagnose GHD
IGFBP-3, insulin-like growth factor binding protein 3 Sources: AACE, 2019; Grimberg, 2016; Molitch, 2011

Stimulation Tests

In most cases, standalone static testing is not sufficient for the diagnosis of GHD and should be followed up with stimulation tests. Stimulation tests (also referred to as provocative tests) entail administration of a drug, followed by repeat testing for GH over time to assess the body’s response. Stimulation tests are only recommended if there is reasonable clinical suspicion for GHD and there is the intent to treat with rhGH if the diagnosis is confirmed.

Stimulation Tests for GHD^a
Test	Description	Limitations	Peak GH Cutpoints
GST	Safe and accurate test for GHD if appropriate BMI-adjusted GH cutpoints are used	Diagnostic accuracy in patients with glucose intolerance is unknown Long duration, multiple blood draws, requires intramuscular administration May cause gastrointestinal side effects	Children: <5.0 ng/mL^b Transition patients and adults: ≤3.0 ng/mL if normal weight ≤3.0 ng/mL if overweight with high pretest probability of GHD ≤1.0 ng/mL if overweight with low pretest probability of GHD ≤1.0 ng/mL if obese
ITT	“Gold standard” test in adults	Safety concerns in certain patient populations Laborious May cause severe hypoglycemia Contraindicated in patients >60 yrs, patients with seizure disorders, and patients with cardio/cerebrovascular disease	Children: <5.0 ng/mL^b Transition patients and adults: ≤5.0 ng/mL
Macimorelin test	Suitable alternative when ITT is contraindicated; FDA approved for adult GHD in 2017	Intraindividual variability Appropriate reference values have not been determined for many populations (eg, patients with a BMI >40 kg/m²) Costly	Children: <5.0 ng/mL^b Transition patients and adults: ≤2.8 ng/mL
^aGHRH-arginine testing is currently unavailable in the United States. ^bFor children, some experts consider values of 5-8 ng/mL equivocal and only peak values of >8 ng/mL as truly normal. BMI, body mass index; FDA, U.S. Food and Drug Administration; GHRH, growth hormone-releasing hormone, GST, glucagon stimulation test; ITT, insulin tolerance test Sources: AACE, 2019; Molitch, 2011

Childhood-Onset Growth Hormone Deficiency

In addition to diagnosing COGHD in pediatric patients, laboratory testing is important in retesting for GHD in patients transitioning from pediatric to adult care, especially in cases of idiopathic GHD. Testing to confirm persistent GHD in transition patients should be performed at least 1 month after rhGH therapy has been discontinued. Care should be taken to minimize the amount of time a patient is off of rhGH therapy if GHD is confirmed.

Diagnosis

Static Testing

In pediatric and transition patients, static testing is sufficient to confirm persistent GHD if the patient has been off GH therapy for at least 1 month and has structural lesions with multiple hormone deficiencies or an established genetic cause of GHD. Static testing is also sufficient for diagnosis in children with all three of the following: auxologic criteria, at least one hypothalamic-pituitary defect (eg, a congenital malformation), and deficiency of at least one additional pituitary hormone. Finally, stimulation testing is not required for diagnosis in neonates with all three of the following: hypoglycemia, a serum GH ≤5 ng/mL, and either a deficiency in another pituitary hormone or an ectopic posterior pituitary and pituitary hypoplasia with an abnormal stalk.

Stimulation Testing

Stimulation testing may be appropriate for pediatric or transition patients if static testing is inconclusive. The decision to perform stimulation testing should be informed by individual patient characteristics such as degree of growth failure. BMI-adjusted reference intervals for stimulation tests have not been determined for pediatric patients. Sex steroid priming is recommended before stimulation testing in prepubertal boys older than 11 years and prepubertal girls older than 10 years with a prognosticated adult height within 2 standard deviations of the reference mean to distinguish between GHD and constitutional delay of growth and puberty.

Treatment Dosing

IGF-1-based dosing targets have yet to be established for pediatric patients; therefore, dosing based on body surface area or weight is recommended in this population.

Serum IGF-1 should be used to guide rhGH dosing in transition patients who are restarting therapy. The upper limit of the normal reference interval should not be exceeded.

Treatment Monitoring

In children treated with rhGH, routine cardiac testing, dual x-ray absorptiometry, and lipid profiles are not recommended. Serum IGF-1 testing is recommended to monitor adherence and response to treatment. Testing for adrenal and thyroid hormone deficiencies is recommended in patients whose GHD may be associated with multiple pituitary hormone deficiencies. Evaluation of glucose metabolism is recommended in patients at increased risk for diabetes.

Fasting lipids should be measured in transition patients who have discontinued rhGH at baseline, and every year thereafter. IGF-1 should be used in ongoing monitoring, which should be consistent with monitoring recommendations for adult patients.

Adult-Onset Growth Hormone Deficiency

Diagnosis

Static serum GH and IGF-1 levels are insufficient to diagnose AOGHD unless the patient has organic hypothalamic-pituitary disease with deficiency in at least three pituitary hormone axes, known genetic defects, or structural hypothalamic-pituitary defects. Stimulation testing should be performed only after all other pituitary hormone deficiencies have been treated and dosing is stable.

Two positive stimulation tests are suggested to make a diagnosis of idiopathic GHD in adults without suggestive clinical circumstances because there is a high false-positive rate for single stimulation tests. Patients with obesity will often appear to have a decreased response to stimulation tests despite a lack of true GHD deficiency; therefore, an IGF-1 test may be useful to support the diagnosis in this population.

Treatment Dosing

IGF-1 is the recommended test to guide rhGH dose determination in adults, although IGF-1 levels are only weakly correlated with clinical endpoints. Although there are insufficient data to determine the ideal target serum IGF-1 concentration, maintaining a target serum IGF-1 level within the age-adjusted, laboratory-specific reference range is recommended (depending on clinical circumstances and the patient’s pretreatment IGF-1 level). A 1-2 month retest interval for dose adjustment is recommended, as is use of the same assay that was used in the diagnosis of GHD.

Treatment Monitoring

In adults treated with rhGH, IGF-1 testing is recommended at 6-12 month intervals once a suitable maintenance dose has been achieved. Shorter intervals may be appropriate depending on the clinical circumstances (eg, in elderly patients or patients with diabetes mellitus).

GH may interact with other pituitary hormones, including the thyroid and glucocorticoid hormone axes. Monitoring of the thyroid axis should include free T4 because GH replacement is associated with reduced free T4 levels. Monitoring the adrenal axis and adrenal function is recommended. Hemoglobin A1c and cortisol or cosynotropin stimulation tests may be appropriate, depending on the clinical circumstances. Fasting lipids are recommended at 6-12 month intervals due to the increased risk of cardiovascular morbidity and mortality in adult patients with GHD.