Background: The diagnosis of GH deficiency in adults is established by provocative testing of
GH secretion. The insulin tolerance test (ITT) is widely regarded as the gold standard test
for diagnosing adult GH deficiency despite concerns about its practicality, safety,
reproducibility, and its contraindications in elderly adults, adults with seizures and
patients with ischemic heart disease. The glucagon stimulation test (GST) has been proposed
as the alternative to the ITT for the following reasons: 1) availability; 2) low cost and 3)
safety. This test has been validated in the past as a reliable test in assessing the GH
reserve in both adults and children. In addition, a number of studies have also shown that
the GST is capable of stimulating not only GH but also ACTH release. However, the accuracy
and reliability of the GST in assessing the hypothalamic-pituitary-adrenal (HPA) axis and GH
reserve in obese and diabetic patients are still lacking.
Pegvisomant (PV) (Somavert®) is a GH receptor antagonist and is currently licensed by the FDA
for the treatment of acromegaly. Physiological studies have demonstrated that acute high dose
administration of PV can enhance endogenous GH stimulation. These data was more recently
utilized by Radetti et al. to prime the L-DOPA test in assessing its reliability in the
diagnostic work up of GH deficiency in short children. Using a PV dose of 1 mg/kg to prime
the L-DOPA test in 21 short children, these investigators demonstrated an improvement in the
reliability of the L-DOPA stimulation test in diagnosing GH deficiency with 10 out of the 18
(56%) children that initially failed the L-DOPA test successfully passed the L-DOPA test
following PV-priming. These investigators postulate that PV-priming unmasked potentially
false diagnoses of GH deficiency by exploiting the acute IGF-lowering effect and reducing the
negative feedback of GH on the hypothalamus.
We therefore propose this proof-of-concept pilot study to investigate the potential of acute
GH receptor blockade using PV to reduce false positive rates in adults undergoing GH testing
with the GST. In addition, we plan to investigate the effects of PV on IGF-I bioactivity, as
measured by the IGF-I kinase receptor activation (KIRA) assay (30).
Subjects: Ten subjects with suspected pituitary disease will be invited to participate in the
study. Subjects will be screened for eligibility before enrollment into the study.
Intervention: After completing the GST, eligible subjects will be randomized to undergo
either the PV-GST or the ITT. Subjects who are randomized to undergo the PV-GST first will
then undergo the ITT, and vice versa, 4-6 weeks later. For the PV-GST, a blood test for serum
IGF-I and IGF-I KIRA level will be measured and the patient will then receive PV at a dose of
1 mg/kg injected subcutaneously. The patient will then return in 3 days' time to undergo the
GST. For this part of the test, subjects will receive glucagon administered intramuscularly
at a dose of 1 mg if subject weighs 90 kg or less and 1.5 mg if subject weighs more than 90
kg.
Measurements: Blood samples for the measurement of glucose, IGF-I, IGF-I KIRA, GH and
cortisol will be performed at various time-points for the GST, PV-GST and ITT
Specific Aims:
Primary aims: 1) To investigate the potential of acute GH receptor blockade priming with PV
to glucagon (PV-GST test) on the characteristics of peak GH and cortisol levels; 2) To
ascertain cut-point levels for GH and cortisol with the PV-GST in comparison to the ITT in
defining GH and cortisol deficiency.
Secondary aims: 1) Correlation between peak GH and cortisol levels induced by the PV-GST and
BMI; 2) Correlation between peak GH and cortisol levels induced by the PV-GST and fasting
blood glucose levels; 3) Effects of PV on IGF-I bioactivity as determined by the IGF-I KIRA.