Growth hormone deficiency laboratory findings: Difference between revisions
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* Subnormal GH secretion in response to at least two provocative stimuli | * Subnormal GH secretion in response to at least two provocative stimuli | ||
GH secretion is pulsatile and its secretion is regulated by two hypothalamic factors; growth hormone releasing hormone and somatostatin. [33] | |||
measurement of a random serum GH level is not helpful | |||
insulin-like growth factor I (IGF-I) | |||
insulin-like growth factor binding protein-3 (IGFBP-3) levels | |||
GH stimulation tests. | |||
Their concentrations often reflect the integrated concentration of secreted GH. | |||
They are stable during the day and not pulsatile like growth hormone. [34] | |||
Despite relatively good correlations with groups of patients between GH secretion and IGF-I concentrations [35-38], there remain substantial problems in assessing GH status by measurement of IGF-I in individual patients [39,40]: | |||
Serum IGF-I levels may be low in conditions other than GHD, such as growth hormone insensitivity (GHI), hypothyroidism [41], diabetes [42], renal failure [41,43], and cancer [44]. | |||
IGFBP-3 is the major serum carrier protein for IGF-I [45-47] and the most GH dependent [48]. | |||
Interpretation | |||
●'''Moderately or severely reduced''' IGF-I and IGFBP-3 '''with''' delayed bone age: | |||
•In most cases, the possibility of GHD should be explored by provocative GH testing, if other causes of low IGF-1 and IGFBP-3, such as poor nutrition, have been excluded. | |||
•If the growth failure is severe, bone age is significantly delayed, and IGF-I and IGFBP-3 are definitively low (eg, <-2 SD), it is reasonable to make the diagnosis of GHD without performing GH stimulation testing, especially in the setting of known hypothalamic-pituitary disease and/or its treatment (eg, brain surgery and/or radiation) | |||
●'''Clearly normal''' IGF-1 and IGFBP-3 (SD ≥0); ie, in the upper half of the normal range) – GHD is extremely unlikely, and no further testing is required. | |||
'''GH stimulation tests''' | |||
Provocative GH testing is indicated for | |||
most patients to confirm a diagnosis of GHD. Because this testing has limitations, the results should not be used as the sole diagnostic criterion, and should be interpreted in the context of auxological findings, bone age, and IGF-1 and IGFBP-3 concentrations. | |||
Provocative GH testing is '''not''' necessary for selected patients in whom other clinical criteria are sufficient to make the diagnosis of GHD, including those with the following conditions: | |||
●Pituitary abnormality (secondary to a congenital anomaly, tumor, or irradiation), and a known deficiency of at least one other pituitary hormone, as well as auxological criteria [51]. | |||
●Newborn with a congenital pituitary abnormality (ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk) or known deficiency of a pituitary hormone, along with hypoglycemia, at which time a simultaneous serum GH concentration is <5 mcg/L [51]. | |||
●Infant or young child with extreme short stature (eg, height <-3 SD), normal nutrition, significantly reduced IGF-I (eg, <-2 SD) and IGFBP-3 and delayed bone age. This is the classic presentation of congenital and severe GHD, and most experts agree that provocative testing is not required to make the diagnosis. | |||
Provocative testing also is not necessary for short children with a normal bone age and height velocity, or for those with clearly normal levels of IGF-1 and IGFBP-3. These findings are sufficient to exclude GHD without provocative testing. | |||
'''Limitations''' (table 1) [7]: | |||
●The tests are non-physiological. | |||
●The interpretation of the test results depends upon age and sex hormone concentrations [52]. Children with constitutional delay of growth and puberty may have low GH results on provocative testing in the absence of true GHD (ie, false-positive results). Administration of sex steroids for a few days prior to the provocative GH testing (known as "priming") reduces the chance of a false-positive result, as discussed below. | |||
●Adiposity (as measured by the body mass index [BMI]) also influences GH response to the stimulation test, such that obese children show diminished GH responses to all stimuli [51,53,54]. | |||
●The tests rely upon GH assays of variable accuracy. | |||
●The tests are expensive, uncomfortable and carry some risks. | |||
●Test reproducibility has not been adequately documented. | |||
●The ability of the tests to discriminate between normal short children and children with partial GHD is limited. | |||
Because of these limitations, it is clear that there is no real "gold standard" for the diagnosis of GHD [32]. Nonetheless, GH stimulation tests are a valuable diagnostic tool when combined with auxological data and measurements of IGF-1 and IGFBP-3. The peak GH response to provocative testing is also a useful predictor of response during the first year of treatment with GH [55,56]. | |||
The stimulation tests are performed after an overnight fast. | |||
After the pharmacologic stimulus, serum samples are collected at intervals designed to capture the peak GH level; the expected time to this peak varies with the stimulus administered. | |||
most pediatric endocrinologists defined a "normal" response by a serum GH concentration of >10 mcg/L, but a cutoff of 7.5 mcg/L is often used for modern assays. | |||
Specific considerations for the measurement of human GH have been reviewed in detail [59]. | |||
There is general consensus that two different stimuli should be used for most patients [51]. In a patient with known pathology of the central nervous system, other pituitary hormone defects, or a genetic defect, one test is sufficient to establish the diagnosis [32,60]. Pharmacologic stimuli include L-dopa [61], clonidine [62], propranolol [61], glucagon [63], arginine [64], and insulin-induced hypoglycemia [65-67]. The last three tests have the highest specificity, but are still subject to false-positive results. Thus, the stimulants that are most commonly used clinically are: | |||
●Clonidine — Clonidine stimulates GH by several mechanisms, including the stimulation of GHRH via alpha-adrenergic pathways. It is administered at a dose of 5 mcg/kg (maximum 250 mcg), and serum GH is measured at 0, 30, 60 and 90 minutes; peak GH secretion typically occurs about one hour after the stimulus is given [60]. Clonidine may cause modest hypotension and hypoglycemia, so patients should be monitored for these problems during the test. Estimates of this test's sensitivity and specificity vary considerably [68,69]. | |||
●Arginine — An intravenous infusion of 0.5 g/kg body weight (to a maximum of 40 g) is given over 30 minutes, and serum GH is measured at 0, 30, 60, 90, and 120 minutes [60]. The maximum GH peak is expected at about 60 minutes. There are no side effects from this test, but overdoses have been described. GH secretion can be enhanced (and therefore false-positive results reduced) by adding a dose of L-Dopa orally just prior to the administration of arginine [60]. However, L-Dopa is not available in the United States. L-Dopa also can be used alone, but is a relatively weak stimulant of GH release. | |||
●Glucagon — Administration of glucagon causes transient hyperglycemia, which in turn stimulates endogenous insulin secretion followed by controlled hypoglycemia, and consequent GH secretion [60,70]. It is less risky than insulin-induced hypoglycemia (described below), and is a good choice for infants and young children. Glucagon is administered subcutaneously at a dose of 0.03 mg/kg (maximum 1 mg), and serum samples are drawn at intervals between one and three hours after the stimulus. Peak GH secretion occurs between two and three hours after glucagon administration; side effects are mild and transient, and include nausea, vomiting, sweating, or headaches. | |||
●Insulin-induced hypoglycemia — Insulin-induced hypoglycemia is a potent stimulant of GH release, and is therefore among the most specific tests for GHD. However, this test is less commonly used in children because of safety concerns [32] | |||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Laboratory Findings
In children,
- Low levels of IGF1, IGF2, IGF binding protein 3
- Subnormal frequency and amplitude of GH secretory peaks when sampled over several hours
- Subnormal GH secretion in response to at least two provocative stimuli
- Increased IGF1 levels after a few days of GH treatment
In adults,
- Higher cholesterol levels
- Low IGF1 level
- Subnormal frequency and amplitude of GH secretory peaks when tracked over several hours
- Subnormal GH secretion in response to at least two provocative stimuli
GH secretion is pulsatile and its secretion is regulated by two hypothalamic factors; growth hormone releasing hormone and somatostatin. [33]
measurement of a random serum GH level is not helpful
insulin-like growth factor I (IGF-I)
insulin-like growth factor binding protein-3 (IGFBP-3) levels
GH stimulation tests.
Their concentrations often reflect the integrated concentration of secreted GH.
They are stable during the day and not pulsatile like growth hormone. [34]
Despite relatively good correlations with groups of patients between GH secretion and IGF-I concentrations [35-38], there remain substantial problems in assessing GH status by measurement of IGF-I in individual patients [39,40]:
Serum IGF-I levels may be low in conditions other than GHD, such as growth hormone insensitivity (GHI), hypothyroidism [41], diabetes [42], renal failure [41,43], and cancer [44].
IGFBP-3 is the major serum carrier protein for IGF-I [45-47] and the most GH dependent [48].
Interpretation
●Moderately or severely reduced IGF-I and IGFBP-3 with delayed bone age:
•In most cases, the possibility of GHD should be explored by provocative GH testing, if other causes of low IGF-1 and IGFBP-3, such as poor nutrition, have been excluded.
•If the growth failure is severe, bone age is significantly delayed, and IGF-I and IGFBP-3 are definitively low (eg, <-2 SD), it is reasonable to make the diagnosis of GHD without performing GH stimulation testing, especially in the setting of known hypothalamic-pituitary disease and/or its treatment (eg, brain surgery and/or radiation)
●Clearly normal IGF-1 and IGFBP-3 (SD ≥0); ie, in the upper half of the normal range) – GHD is extremely unlikely, and no further testing is required.
GH stimulation tests
Provocative GH testing is indicated for
most patients to confirm a diagnosis of GHD. Because this testing has limitations, the results should not be used as the sole diagnostic criterion, and should be interpreted in the context of auxological findings, bone age, and IGF-1 and IGFBP-3 concentrations.
Provocative GH testing is not necessary for selected patients in whom other clinical criteria are sufficient to make the diagnosis of GHD, including those with the following conditions:
●Pituitary abnormality (secondary to a congenital anomaly, tumor, or irradiation), and a known deficiency of at least one other pituitary hormone, as well as auxological criteria [51].
●Newborn with a congenital pituitary abnormality (ectopic posterior pituitary and pituitary hypoplasia with abnormal stalk) or known deficiency of a pituitary hormone, along with hypoglycemia, at which time a simultaneous serum GH concentration is <5 mcg/L [51].
●Infant or young child with extreme short stature (eg, height <-3 SD), normal nutrition, significantly reduced IGF-I (eg, <-2 SD) and IGFBP-3 and delayed bone age. This is the classic presentation of congenital and severe GHD, and most experts agree that provocative testing is not required to make the diagnosis.
Provocative testing also is not necessary for short children with a normal bone age and height velocity, or for those with clearly normal levels of IGF-1 and IGFBP-3. These findings are sufficient to exclude GHD without provocative testing.
Limitations (table 1) [7]:
●The tests are non-physiological.
●The interpretation of the test results depends upon age and sex hormone concentrations [52]. Children with constitutional delay of growth and puberty may have low GH results on provocative testing in the absence of true GHD (ie, false-positive results). Administration of sex steroids for a few days prior to the provocative GH testing (known as "priming") reduces the chance of a false-positive result, as discussed below.
●Adiposity (as measured by the body mass index [BMI]) also influences GH response to the stimulation test, such that obese children show diminished GH responses to all stimuli [51,53,54].
●The tests rely upon GH assays of variable accuracy.
●The tests are expensive, uncomfortable and carry some risks.
●Test reproducibility has not been adequately documented.
●The ability of the tests to discriminate between normal short children and children with partial GHD is limited.
Because of these limitations, it is clear that there is no real "gold standard" for the diagnosis of GHD [32]. Nonetheless, GH stimulation tests are a valuable diagnostic tool when combined with auxological data and measurements of IGF-1 and IGFBP-3. The peak GH response to provocative testing is also a useful predictor of response during the first year of treatment with GH [55,56].
The stimulation tests are performed after an overnight fast.
After the pharmacologic stimulus, serum samples are collected at intervals designed to capture the peak GH level; the expected time to this peak varies with the stimulus administered.
most pediatric endocrinologists defined a "normal" response by a serum GH concentration of >10 mcg/L, but a cutoff of 7.5 mcg/L is often used for modern assays.
Specific considerations for the measurement of human GH have been reviewed in detail [59].
There is general consensus that two different stimuli should be used for most patients [51]. In a patient with known pathology of the central nervous system, other pituitary hormone defects, or a genetic defect, one test is sufficient to establish the diagnosis [32,60]. Pharmacologic stimuli include L-dopa [61], clonidine [62], propranolol [61], glucagon [63], arginine [64], and insulin-induced hypoglycemia [65-67]. The last three tests have the highest specificity, but are still subject to false-positive results. Thus, the stimulants that are most commonly used clinically are:
●Clonidine — Clonidine stimulates GH by several mechanisms, including the stimulation of GHRH via alpha-adrenergic pathways. It is administered at a dose of 5 mcg/kg (maximum 250 mcg), and serum GH is measured at 0, 30, 60 and 90 minutes; peak GH secretion typically occurs about one hour after the stimulus is given [60]. Clonidine may cause modest hypotension and hypoglycemia, so patients should be monitored for these problems during the test. Estimates of this test's sensitivity and specificity vary considerably [68,69].
●Arginine — An intravenous infusion of 0.5 g/kg body weight (to a maximum of 40 g) is given over 30 minutes, and serum GH is measured at 0, 30, 60, 90, and 120 minutes [60]. The maximum GH peak is expected at about 60 minutes. There are no side effects from this test, but overdoses have been described. GH secretion can be enhanced (and therefore false-positive results reduced) by adding a dose of L-Dopa orally just prior to the administration of arginine [60]. However, L-Dopa is not available in the United States. L-Dopa also can be used alone, but is a relatively weak stimulant of GH release.
●Glucagon — Administration of glucagon causes transient hyperglycemia, which in turn stimulates endogenous insulin secretion followed by controlled hypoglycemia, and consequent GH secretion [60,70]. It is less risky than insulin-induced hypoglycemia (described below), and is a good choice for infants and young children. Glucagon is administered subcutaneously at a dose of 0.03 mg/kg (maximum 1 mg), and serum samples are drawn at intervals between one and three hours after the stimulus. Peak GH secretion occurs between two and three hours after glucagon administration; side effects are mild and transient, and include nausea, vomiting, sweating, or headaches.
●Insulin-induced hypoglycemia — Insulin-induced hypoglycemia is a potent stimulant of GH release, and is therefore among the most specific tests for GHD. However, this test is less commonly used in children because of safety concerns [32]