Severe Adult Growth Hormone Deficiency Clinical Trial
Official title:
A Study of the Relationship Between Serum Growth Hormone (GH) and Insulin-Like Growth Factor One (IGF-I) in Patients With Severe Adult Growth Hormone Deficiency (AGHD)
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.
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Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double-Blind