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 Investigation of supra-physiological doses of pegvisomant revealed unexpected and previously unpublished findings; despite two to four fold increases in dose, six of the nine patients failed to achieve target subnormal IGF-I levels.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.