GH response to hypoglycemia and clonidine in the GH-releasing hormone resistance syndrome

Abstract

GH secretion by the pituitary is the result of the balance between the stimulatory effect of GHRH and the inhibitory effect of SS. Patients with mutations in GHRH receptor (GHRH-R) gene (GHRH-R) offer a unique model to study the mechanism of action of different GH secretion stimuli. In the past, we have demonstrated a small but significant GH response to a GH secretagogue (GHRP-2) in a homogenous cohort of patients with severe GH deficiency (GHD) due to a homozygous null mutation in GHRH-R (IVS1+1G-->A). Now, we sought to determine if we could detect a GH response to hypoglycemia (ITT: insulin tolerance test) or clonidine (CL) in these patients. Nine young GHD subjects underwent both ITT and CL tests, and 2 additional subjects underwent only CL test. There was a small but significant GH increase during ITT, but not during CL test. These results indicate that a minimal albeit significant GH response to ITT can occur despite complete lack of GHRH-R function.

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…This finding may have physiological implications, contributing to differences among these severe IGHD models despite similar degrees of IGF-I deficiency. Probably the difference of magnitude of these genetic IGHD models comes from the fact that the patients in our IGHD cohort are still able to secrete small but detectable amounts of GH (25,26) causing some residual effect. It is also possible that the timing of these two genes expression during fetal and postnatal development may have additional consequences.…”

“…GHD was further confirmed by abnormal GH responsiveness (with peak values less than 1 ng/mL) to clonidine (CL) and insulin tolerance test (ITT) (2,25). There was a small but significant GH increase during ITT, but not during CL test, showing that some response to hypoglycemia can occur despite complete lack of GHRHR function (25).…”

“…GHD was further confirmed by abnormal GH responsiveness (with peak values less than 1 ng/mL) to clonidine (CL) and insulin tolerance test (ITT) (2,25). There was a small but significant GH increase during ITT, but not during CL test, showing that some response to hypoglycemia can occur despite complete lack of GHRHR function (25). Similarly, we found a small but significant response to a GH secretagogue (GHRP-2) that acts on the ghrelin receptor, suggesting a GHRH-independent effect of this substance on the somatotroph cells, despite their hypoplasia (26).…”

“…This suggests in these three organs a possible compensatory overgrowth. The lower number of pregnancies may contribute to the reduced uterine size (25). Very recently, we studied the ocular axial length (AL) and its relationship with head circumference and stature.…”

“…These features have been published in 42 different publications (2,19,22,25,27,29,30,31,32,33,36,37,38,40,41,44,45,46,47,48,49,50,51,52,53,54,56,57,61,62,63,64,66,67,68,74,75,76,77,78,79,80). We have used this experiment of nature to discover 'usual laws of nature' as suggested by William Harvey, and to understand some aspects of more common conditions such as short stature, insulin resistance, diabetes, atherosclerosis, osteoporosis, cancer and ultimately longevity.…”