Neurosecretory Dysfunction

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The clinical evaluation of infants, children, and adolescents with growth disorders may include provocative tests of GH secretion and 24-h profiles of spontaneous GH release; however, there is currently no gold standard laboratory test for the diagnosis of GH deficiency (121,122). A blunted GH response to known GH secretogogues may help to identify subjects suspected to be GH-deficient in the clinical setting of growth retardation (<3rd percentile), diminished growth velocity, and delayed bone maturation (bone age); however, no single stimulation test provides adequate specificity. As a result, a minimum of two provocative tests of GH secretion are required to make the diagnosis of GHD.

It had been suspected that a subset of children with clinical features of GHD (diminished growth velocity, delayed bone age) might have abnormalities of GH secretion despite a normal response to provocative GH testing. Subjects with growth retardation who demonstrate biochemical abnormalities in GH secretion, including variable GH peak response to provocative stimuli and abnormalities in spontaneous GH secretion, are at risk for GH neurosecretory dysfunction (GHND), a treatable cause of growth retardation (Fig. 4) (123,124). Newer statistical models have been suggested that make use of 24-h spontaneous GH secretion and IGF-I levels to improve specificity in identifying subjects with disorders of GH secretion (125).

We recently analyzed data collected from 300 24-h studies of spontaneous GH secretion (20-min sampling) in 272 children over a 7-yr period. Control subjects were defined as having a growth velocity standard deviation score (SDS) of > -1.0 and height SDS of > -3.0 of the mean for chronologic age without a recognizable syndrome, cranial irradiation, precocious puberty, or obesity. Subjects were further categorized by diagnosis for comparison, including chronic disease states, chronic renal failure, Noonan syndrome, obesity (BMI >95th percentile for age), precocious puberty, cranial or craniospinal irradiation, and Turner syndrome (Fig. 5) (48,126).

The mean 24-h (0800-0800) and 12-h (2000-0800) GH concentrations in control subjects was 3.8 ± 2.1 ^g/L (SD) and 5.6 ± 3.4 ^g/L, respectively, using a standard polyclonal radioimmunoassay for GH. Data analyzed by Cluster analysis identified preservation of GH pulsatile secretion and uniformity of GH pulse frequency in all subgroups except for obese subjects. Total spontaneous GH secretion increased in a linear fashion with increasing body mass index in children until the index reached 20-25 and has been confirmed by others (52). Mean 24-h GH concentration correlated positively with the peak GH response to provocation (arginine, insulin, l-DOPA, clonidine) (r = +0.52; p < 0.001, n = 245) and GHRH (r = +0.35; p < 0.001, n = 119) (48,126; B. Bercu, unpublished data).

Significant decreases in mean 24-h GH and mean GH peak amplitude were noted in the cranial irradiation and obese subsets; serum IGF-I remained normal in obese subjects, but were decreased in the cranial irradiation and Turner syndrome subjects. A subset of 36 growth retarded, non-GH deficient children demonstrated reduction in mean 24-h GH concentration (4.1 ± 1.9 ^g/L; p = 0.02), but without significant changes in mean GH peak amplitude (48,126).

Thus, spontaneous GH secretory profiles are a biochemical representation of a series of complex events with significant clinical utility. This large experience reported here demonstrates two things: diminished GH peak amplitude and frequency in obese subjects, whereas cranial irradiation subjects demonstrate decreased GH pulse amplitude; and short, slowly growing, non-GH deficient children have alterations in their spontaneous GH secretory profile relative to controls (48,126).

Abnormal elevation of serum prolactin has been demonstrated in subjects with classical GH deficiency (blunted peak GH response to two or more provocative stimuli and reduced 24-h spontaneous GH secretion), suggesting a disturbance in the normal dopaminergic inhibitory pathways on prolactin secretion (127). Pooled 24-h prolactin samples (equal aliquots from each 20 min sample combined between 0800-0800) and 8-h daytime

Fig. 4. Representative 24-h GH secretory patterns in GH-deficient, GH neurosecretory dysfunction (GHND), and control subjects. Control subjects in the left and right lower panels are Tanner stage I and IV, respectively. Note that a child with classic GH deficiency (right upper panel) had three pulses higher than 10 ng/mL and two above 20 ng/mL. This child had a mean endogenous 24-h GH concentration less than that of two other children with GHND. By definition, the patients with GHND had two or more normal GH provocative tests (peak >10 ng/mL), unlike classic GH-deficient children (two or more GH provocative tests <10 ng/mL). The GHND children had a linear growth response to exogenous GH similar to the classic GH-deficient children. Reproduced with permission from ref. 123.

Fig. 4. Representative 24-h GH secretory patterns in GH-deficient, GH neurosecretory dysfunction (GHND), and control subjects. Control subjects in the left and right lower panels are Tanner stage I and IV, respectively. Note that a child with classic GH deficiency (right upper panel) had three pulses higher than 10 ng/mL and two above 20 ng/mL. This child had a mean endogenous 24-h GH concentration less than that of two other children with GHND. By definition, the patients with GHND had two or more normal GH provocative tests (peak >10 ng/mL), unlike classic GH-deficient children (two or more GH provocative tests <10 ng/mL). The GHND children had a linear growth response to exogenous GH similar to the classic GH-deficient children. Reproduced with permission from ref. 123.

pools (0800-1600) were higher in classical GH deficient subjects when compared to control and GH neurosecretory dysfunction subjects and demonstrate a bimodal distribution in the GH deficient group, suggesting variability in the anatomic level of abnormality (i.e., hypothalamic vs pituitary) affecting GH secretion (48,126; B. Bercu, unpublished data).

Fig. 5. Mean 24-h GH concentrations in a variety of conditions associated with growth retardation. (CONT, controls; CDZ, chronic disease, including asthma, coeliac disease, and thalassemia; CRF, chronic renal failure; NS, Noonan syndrome; OB, obesity; PP, precocious puberty; RAD, CNS irradiation; TS, Turner syndrome). Reprinted with permission from ref. 141.

Fig. 5. Mean 24-h GH concentrations in a variety of conditions associated with growth retardation. (CONT, controls; CDZ, chronic disease, including asthma, coeliac disease, and thalassemia; CRF, chronic renal failure; NS, Noonan syndrome; OB, obesity; PP, precocious puberty; RAD, CNS irradiation; TS, Turner syndrome). Reprinted with permission from ref. 141.

A critical step in the evaluation of growth disorders is the documentation of individual growth velocity, clinically the most useful biologic marker of GH secretion. Thirty-eight children with growth retardation underwent provocative GH testing along with 24-h sampling of spontaneous GH secretion. Children were further divided into three distinct groups based on their GH secretory dynamics and pretreatment height velocity (preHV). Regardless of the individual GH test results, 88% of the children with pretreatment height velocity <2 cm/yr, 94% of subjects with a preHV >2 cm/yr but <4 cm/yr, and 79% of those with a preHV >4 cm/yr had an increase in height velocity of 2 cm/yr or greater while receiving exogenous recombinant hGH. A significant negative correlation between pre and post GH-therapy growth velocity (r = -0.67; p < 0.001) supports the conclusion that growth velocity is the more sensitive marker of future response to exogenous growth hormone therapy rather than individual GH secretory status (48,126,128).

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