Studies of GH Receptor Signalling and Antagonism in the setting of Growth Hormone Deficiency and Acromegaly.
Abstract
Conditions of GH excess and deficiency cause significant morbidity and mortality.
Treatments for both situations have evolved considerably in recent years, but
heterogeneity in therapeutic responses remains poorly understood. An improved
understanding of the role of the growth hormone receptor’ (GHR) has the potential
to advance future clinical management. Deletion of exon 3 in the GH receptor (d3-
GHR) has been linked to enhanced rhGH responsiveness in children; the effect in
adults with GH deficiency and acromegaly in adults is less well understood.
Pegvisomant, a GHR antagonist is a highly effective treatment for acromegaly but
monitoring of treatment is limited by the potential imprecision of IGF-I as the sole
marker of response.
The aim of this work was two-fold; to investigate the effect of the d3-GHR in
determining an individual’s response to GH in GH deficiency and acromegaly and to
investigate the effect of supraphysiological doses of pegvisomant on IGF-I and the
physiological markers of GH activity in patients with acromegaly.
194 GHD patients and 79 acromegaly patients were genotyped for d3-GHR and
results correlated with clinical and biochemical response to GH. Homozygosity for
d3-GHR confers a marginal increase in GH responsiveness in GH deficiency and
acromegaly but without significant clinical effects. Both d3 alleles are required to
achieve this response; given that only 10% of the population are d3 homozygotes,
d3-GHR does not explain heterogeneity in GH responsiveness.
Investigation of supra-physiological doses of pegvisomant revealed unexpected and
previously unpublished findings; despite two to four fold increases in dose, six of the
nine patients failed to achieve target subnormal IGF-I levels. The absence of a significant role for d3-GHR in determining GH response and the
unexpected difficulty in causing GH deficiency with high dose GH receptor
antagonism highlights the need for further study of the GHR in determining an
individual’s response to GH.
Authors
Moyes, VeronicaCollections
- Theses [3706]