Effect of Pegvisomant on GH/IGF-I Relationship in GHD
Effect of Pegvisomant on GH/IGF-I Relationship in GHD
Approximately 50% of middle-aged patients with severe AGHD have a normal age-related serum
 IGF-I. It remains unclear if in these individuals serum IGF-I is GH dependent or independent.
 This study compared the relationship between GH and serum IGF-I in two cohorts of male
 patients with severe AGHD; one with normal and the other with subnormal age-related serum
 IGF-I values. The GH receptor antagonist - pegvisomant was be used to specifically inhibit GH
 action and the changes in markers of the GH axis, such as serum IGF-I, IGFBP-3, GH and GHBP
 were measured.
There is an increasing reliance on serum insulin-like factor-I (IGF-I) in the management of
 disturbances of the growth hormone (GH) axis. IGF-I is predominantly, but not exclusively,
 regulated by GH secreted from the pituitary, with the majority of circulating IGF-I being
 hepatic in origin.

 In parallel with the age-related decline in GH secretion, circulating levels of IGF-I fall
 with age (1). For a given GH level women have lower serum IGF-I levels than men, indicative
 of a relative GH resistance (1,2). Nutrition-related factors are known to affect GH, IGF-I
 and their relationship. Obesity is associated with low GH production, but increased GH
 sensitivity resulting in relatively high IGF-I for given GH (3-6). Deprivation of important
 nutrients during fasting is known to stimulate GH, whilst reducing IGF-I (7-9). In vitro
 studies demonstrated complex role of insulin in IGF-I generation. Insulin stimulates hepatic
 IGF-I production directly by increasing IGF-I mRNA synthesis and indirectly by enhancing the
 effect of GH (10,11). By decreasing insulin-like growth factor 1 and 2 (IGFBP1-2), insulin
 may also affect bioavailability of IGF-I (12-13).

 In acromegaly, IGF-I is an important marker for diagnosis and monitoring of disease activity.
 If patients are treated with a GH receptor antagonist, IGF-I becomes the only useful
 biochemical marker for monitoring disease activity.

 GH deficiency in adults is associated with increased morbidity (14-16). In patients with
 pituitary disease there has been great progress in the recognition and treatment of this
 disorder. There is increasing awareness of GH deficiency, not only as a complication of the
 long-recognised causes of hypopituitarism, but also in the setting of traumatic brain injury
 and subarachnoid haemorrhage (17). The phenotype of severe adult GHD has been described but
 many of the features lack specificity and biochemical confirmation of the diagnosis is
 necessary. The Port Stevens consensus on severe adult GHD relies on the measurement of
 stimulated GH secretion for confirmation of the diagnosis with a peak GH of <3 µg/L, in one
 or two stimulation tests, depending on the number of other pituitary hormone deficiencies
 (18) GH replacement therapy relies on measurement of serum IGF-I for dose titration, with the
 biochemical goal being of placing circulating IGF-I within age- and gender-related reference
 range, preferably between 0 and +1 SDS (19). The Port Stephens consensus recognises the
 apparent paradox that approximately 50% of middle-aged patients diagnosed with severe GHD by
 a peak stimulated GH levels of <3 µg/L have a pre-treatment IGF-I within the reference range.
 In untreated severe GHD of adult onset and predominately in men, serum IGF-I may even be in
 the upper half of reference range. In other words, before treatment these patients already
 have an IGF-I that would be regarded as satisfactory response to GH replacement therapy.
 Prima facia, it is difficult to reconcile a serum IGF-I within the reference range and a
 diagnosis of GHD. Inevitably, it poses the question if factors other than GH are regulating
 circulating IGF-I levels in such patients.

 Pegvisomant is a GH analogue that binds to, but does not activate the GH receptor and has
 been shown to normalise IGF-I in up to 97% of patients with acromegaly (20). We used
 pegvisomant to study the relationship between GH and IGF-I in patients with severe adult GHD
 and investigate whether IGF-I in such patients, is particularly GH-dependent.
Inclusion Criteria:

 -  Over 18 years of age

 -  Confirmed severe AGHD

 -  GH response <9 mU/l (preferably <4) to insulin-induced hypoglycaemia or glucagon
 stimulation test plus (These tests will have taken place as part of routine
 management).

 -  Full, stable pituitary replacement therapy

 -  Willing to provide informed consent

 Exclusion Criteria:

 -  Unwilling to provide written consent

 -  Current GH therapy

 -  Pharmacological doses of glucocorticoids

 -  Any acute illness