Effect of Severe Growth Hormone (GH) Deficiency due to a Mutation in the GH-Releasing Hormone Receptor on Insulin-Like Growth Factors (IGFs), IGF-Binding Proteins, and Ternary Complex Formation Throughout Life1

Abstract

Measurement of the insulin-like growth factors (IGFs) and their binding proteins has become commonplace in the indirect assessment of the integrity of the GH axis. However, the relative effect of GH deficiency (GHD) on each component of the IGF axis and the merit of any one parameter as a diagnostic test have not been defined in a homogeneous population across all ages. We therefore measured IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3, and acid labile subunit (ALS) in 27 GHD subjects (aged 5-82 yr) from an extended kindred in Northeast Brazil with an identical GHRH receptor mutation and in 55 indigenous controls (aged 5-80 yr). The effect of GHD on the theoretical distribution of IGFs between the IGFBPs and the ternary complex was also examined. All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP-1 and IGFBP-2 concentrations, which did not differ. The most profound effects of GHD were on total IGF-I, IGF-I in the ternary complex, and ALS. The proportion of IGF-I associated with IGFBP-3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF-I/IGFBP-2 complexes. IGF-I in the ternary complex was determined principally by concentrations of ALS in GHD and IGFBP-3 in controls, implying that ALS has greater GH dependency. In the controls, IGF-II was associated primarily with IGFBP-3 and to a lesser extent with IGFBP-2, whereas in GHD the reverse was found. There was also a dramatic decline in the proportion of free ALS in GHD adults that was not evident in controls. As diagnostic tests, IGF-I in the ternary complex and total IGF-I provided the greatest separation between GHD and controls in childhood. Similarly, in older adults the best separation was achieved with IGF-I in the ternary complex, with free ALS being optimal in younger adults. Severe GHD not only reduces the amounts of IGFs, IGFBP-3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF-I in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.

The Auxological and Biochemical Continuum of Short Children Born Small for Gestational Age (SGA) or with Normal Birth Size (Idiopathic Short Stature)

“…This combination would suggest that cases of mild GH deficiency or resistance are rare, but that disorders at the level of GH signal transduction, causing a selective inhibition of IGF-I rather than of IGFBP-3, may be involved in short stature. Another explanation is that IGFBP-3 is less dependent on the biological action of GH than IGF-I [28–30]. …”

Endocrine consequences of brain irradiation

“…However, the severity of the hypopituitarism, as measured by the number of anterior pituitary hormone deficiencies that develop, depends upon the dose of radiation. Low doses of radiation used in the treatment of children with leukaemia (18)(19)(20)(21)(22)(23)(24) usually result in isolated GH deficiencies [5,9]; whereas, higher doses, such as those used to treat nasopharyngeal carcinoma (60 Gy), can cause multiple pituitary hormone deficiencies and may result in panhypopituitarism in a proportion of patients [2]. Radiation schedules used in different centres for similar conditions can vary in terms of total dose and fraction size used.…”

“…Studies have demonstrated discordance between the cortisol responses achieved during a standard synacthen (250 lg) test (SST) and either a low-dose (1 lg) synacthen test (LDST) or a metyrapone test; the response to the metyrapone test or LDST was diminished in patients who achieved a satisfactory peak during the SST [22][23][24]. It was suggested that cranial irradiation caused a subtle abnormality of the pituitary-adrenal axis, which may compromise patients in times of stress.…”

Quantitative measures of the vascular and neural components of the retina in adult individuals with congenital and untreated growth hormone deficiency

“…We have described a large cohort of individuals residing in Itabaianinha, in the Brazilian state of Sergipe, with severe short stature, but near normal ocular axial length [ 16 ], due to a congenital isolated GHD (IGHD), caused by the c.57 + 1G > A mutation in the GH releasing hormone receptor (GHRHR) gene ( GHRHR OMIM n.618157) [ 17 ]. These individuals otherwise normal pituitary function, and present extremely low serum GH levels throughout life and, in most cases, undetectable levels of serum IGF-I [ 18 ]. They also have visceral obesity [ 19 ], but with increased insulin sensitivity [ 20 ].…”