Table 2.

Accepted GH cut-offs for GH stimulation tests used in the United States and Europe to diagnose adult GHD.

Types of GH stimulation tests	GH cut-offs (μg/L)	Comments
ITT	<3.0–5.0	Requires close medical supervision throughout the test due to concerns for hypoglycemia (46)
		May be unpleasant and cautioned in some patients because of potential side effects (e.g. seizures or loss of consciousness resulting from neuroglycopenia) and contraindicated in the elderly and patients at risk for cardio/cerebrovascular disease (5)
		Patients with insulin resistance may fail to achieve adequate hypoglycemia because of underlying insulin resistance, requiring the use of higher insulin doses (0.15–0.2 IU/kg), thus increasing the risk of delayed hypoglycemia (47)
		Although the ITT demonstrates good sensitivity can be used to simultaneously test for secondary adrenal insufficiency (45), its reproducibility is a limitation (46)
Glucagon		Advantages include reproducibility, safety, and lack of influence by gender (51, 52)
BMI < 25 kg/m2	≤3.0	Disadvantages include the long duration of the test (3–4 h), intramuscular injection, and relatively common side effects that include nausea, vomiting, and headaches ranging from <10% to 34% (51, 53, 54)
BMI 25–30 kg/m2	≤1.0	Cautioned in the elderly, where severe symptomatic hypotension, hypoglycemia, and seizures have been reported (53, 54)
BMI ≥ 30 kg/m2	≤1.0
GH-releasing peptides 2 and 6	Ranges from 3.5 to 15.0 depending on which test	Advantages include not being affected by gender (68), safe, well tolerated, convenient, sensitive, reproducible (66, 67, 72), can be combined with GHRH (64, 65), can be used to simultaneously test for secondary adrenal insufficiency (75, 76, 77), and can be administered by several routes (e.g. intravenous, subcutaneous, intranasal, and oral) (64, 65, 71, 70, 73, 74, 73, 74, 75, 78, 79)
		Disadvantages include some tests that cannot discriminate with acceptable sensitivity and specificity between healthy children (66) and GH-deficient patients and limited accessibility (only accessible in Japan) (72)
Macimorelin	≤2.8	First oral GH secretagogue to be approved as a diagnostic test for adult GHD (80, 81)
		Approved for use as a diagnostic test in the United States (78) and Europe (79)
		Showed good discrimination comparable to GHRH plus arginine and ITT (77)
		Simple, highly reproducible, well-tolerated, and safe (76, 77)
		The United States Food and Drug Administration selected a low GH cut-off of 2.8 μg/L (78), but using a higher GH cut-off of 5.1 μg/L was still able to correctly identify all GH-deficient patients without misclassifying those that were GH-sufficient (76)
		Performance not dependent on age, BMI, or sex (76, 77)
Clonidine	≤6.8	Used more commonly in children, but not in adults (83, 84)
	≤0.4	Relatively short over 90 min (85)
		Side effects may be prolonged over several hours (81, 82)
l-dopa	<6.0	High incidence of side effects, hence rarely used (89)
		Lower sensitivity but similar specificity compared to the clonidine test (87)
Arginine	≤6.5 for children and adolescents and ≤0.4 for adults	Weak GH secretagogue, requiring very low GH cut-off (5)
		Side effects uncommon, but 5–10% of subjects reported paresthesias, dry mouth, and headache (81)
		Still used in children but no longer recommended for use in adults unless no other GH stimulation tests are available (5)
GHRH-arginine		Transient facial flushing may occur after administration of recombinant GHRH (99)
BMI < 25 kg/m2	<11.0	Recombinant GHRH is now not available in the United States, but still available and used in Europe (49)
BMI 25–30 kg/m2	<8.0
BMI ≥ 30 kg/m2	<4.0

BMI, body mass index; FDA, Food and Drug Administration; GH, growth hormone; GHD, growth hormone deficiency; GHRH, growth hormone-releasing hormone; ITT, insulin tolerance test.