Neurosecretory Dysfunction Research Articles

High resolution CT scanning of the pituitary gland in growth disorders.

We have performed 217 GEC 8800 CT scans of the hypothalamus and pituitary glands of 202 children with disorders of growth and development. Pituitary morphological abnormalities were common. Intrapituitary low density lesions were found in 17% of the whole series and in 58% of children with tall stature. Seventy-seven children with idiopathic growth hormone deficiency could be divided on the basis of pituitary morphology seen on CT scan into pituitary aplasia (n = 11) and pituitary hypoplasia (n = 53). Patients with pituitary aplasia had an absent adenohypophysis which probably dated from early intrauterine life and therefore could not be related to birth trauma. We have found a high incidence of evolving endocrinopathy in children with pituitary insufficiency: thus, if a short child is investigated the initial endocrine findings need to be repeated as the pattern of pituitary insufficiency changes with time. An evolving endocrinopathy starting in later childhood is suggestive of the presence of a cerebral tumour. Children with subnormal growth velocities and a normal growth hormone response to pharmacological tests have a wide spectrum of pituitary morphological abnormalities which may be associated with growth hormone neurosecretory dysfunction.

Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion.

GH secretion was studied in 73 children with classical GH deficiency or GH neurosecretory dysfunction (GHND), intrinsic short stature, or normal stature. The GH-deficient group was defined by a peak GH secretory response below 10 ng/ml to all provocative tests (arginine, L-dopa, insulin hypoglycemia, and clonidine). GHND was defined by a mean serum 24-h GH concentration below 3 ng/ml, with a normal response (greater than or equal to 10 ng/ml) to provocative testing. Twenty-one GH-deficient children, 21 children with GHND, and 18 short control children underwent provocative GH testing and a 24-h study with GH sampling every 20 min. A group of 13 normal stature control children also underwent 24-h GH sampling. The mean stimulated peak serum GH level [4.7 +/- 0.6 (+/- SEM) ng/ml] in the GH-deficient group was significantly below that in the GHND (19.5 +/- 1.7 ng/ml) and short control groups (24.0 +/- 3.5 ng/ml; P less than 0.01). The mean 24-h serum GH concentration was reduced in GH-deficient (1.5 +/- 0.2 ng/ml) and GHND (2.0 +/- 0.1 ng/ml) children compared to those in short (5.6 +/- 0.5 ng/ml) and normal stature (5.8 +/- 0.8 ng/ml) control children (P less than 0.01). Peak GH concentrations after provocative testing correlated poorly with 24-h mean concentrations in GH-deficient, GHND, and short control children (r = 0.38, 0.23, and 0.41, respectively; P = NS for all groups). Mean serum GH concentrations from blood sampling intervals of 12 h (day/night; 0800-2000/2000-0800 h, respectively) or even 6 h (day; 0900-1500 h) were statistically different in GHND or GH-deficient groups compared to those in control children; however, there was significantly more overlap for individual children using the 6- and 12-h daytime intervals than for the 24-h data. Plasma somatomedin-C/insulin-like growth factor I correlated with mean 24-h GH concentration endogenous secretion (r = 0.7; P less than 0.001). These data suggest that provocative GH testing frequently does not correlate with endogenous GH secretion.

Growth Hormone (GH) Response to GH-Releasing Hormone in Children with Subnormal Integrated Concentrations of GH*

We determined the GH responses to human GH-releasing hormone-40 (GHRH) in poorly growing children who had either normal or deficient GH secretion, as measured by pharmacological stimulation and integrated concentration of GH (IC-GH). Ten patients had both normal pharmacologically stimulated GH and IC-GH (GH-normal), 15 patients had normal pharmacologically stimulated GH but deficient IC-GH [GH neurosecretory dysfunction (GHND)], and the remaining 7 patients had both subnormal stimulated GH and IC-GH [GH deficiency (GHD)]. The mean peak plasma GH response to GHRH was 11.7 +/- 8.5 (+/- SD) ng/ml in GHD patients, significantly lower than the responses of both the GHND (49.2 +/- 39.2 ng/ml; P less than 0.0001) and GH-normal (51.8 +/- 44 ng/ml; P less than 0.0001) groups. The range of peak GH responses to GHRH in GHD patients overlapped the lower end of the range of responses in the GHND and GH-normal patients. Three GH-normal and eight GHND patients had greatly enhanced GH responses to GHRH (greater than 50 ng/ml); no GHD patients had a response over 24.2 ng/ml. There was no difference between the GH responses of male and female patients within groups to GHRH. There was a significant correlation between the log of the peak GH response to GHRH and the log of the maximal GH response to standard pharmacological stimuli (r = 0.51; P less than 0.005). Because of the variability of GH responses to GHRH encountered among the patients, the response to GHRH cannot be used as a test for identifying patients with inadequate spontaneous GH secretion. The IC-GH is the only method that can identify children with GHND.

926 LONG TERM ENDOCRINE SEQUELAE IN MEDULLOBLASTOMA PATIENTS

Over 50% of pts. with medulloblastoma who receive conventional therapy with craniospinal irradiation will be alive and free of disease five yrs. from diagnosis. Endocrine evaluation was performed in 22 pts. aged 2½-23½ yrs. at time of diagnosis, status post treatment for medulloblastoma. Evaluations were performed 2 mos. to 6 3/4 yrs. after diagnosis. The pts. received either 12 mos. of chemotherapy and/or radiation therapy. The mean radiation dose to the neuraxis and hypothalamus was 3600 rads. Three pts. had completed their growth prior to onset of disease. Post-treatment, decreased growth rates were observed in 13 pts. Only 3 of 10 pts. tested had deficient GH response to stimulation. Elevated TSH levels were noted in 15 pts. with abnormal TSH responses to TRH in 13 of 13 tested. Compensated thyroidal hypothyroidismwas observed in 13 pts., 1 patient each had thyroidal hypothyroidism, or hypothalamic hypothyroidism. We conclude that an abnormal growth rate associated with a normal GH response to standard stimuli, postulated to be caused by growth hormone neurosecretory dysfunction, and compensated hypothyroidism are frequent complications of therapy for medulloblastoma. Further, standard provocative tests of GH reserve are inadequate to define neurosecretory growth dysfunction; a trial of GH treatment may be indicated in children with poor growth rates. In addition, treatment with thyroid hormone of patients with compensated hypothyroidism should be considered. These therapies may allow achievement of normal growth and development and thus, decrease survivor's morbidity.

434 ENHANCED RESPONSE TO hpGRH-40 IN GROWTH HORMONE NEUROSECRETORY DYSFUNCTION

In growth hormone neurosecretory dysfunction (GHND), poor growth is due to low 24-h integrated concentration of GH (IC-GH) even though the response to paired pharmacologic stimulation (PS) of GH is normal. We compared the GH response to 1 μg/kg hpGRH-40 of 8 GHND children, 4 children with subnormal GH responses to paired PS tests and subnormal IC-GH (GHD), and 3 short children with normal PS and normal IC-GH (NORMAL SHORT). The peak GH response to hpGRH-40, PS stimulation and IC-GH of the 3 groups is presented as mean±lSD in ng/ml: The response to hpGRH-40 of GHND children was significantly higher than the other groups. Conclusion: 1/GHND children have an increased reserve of releasable GH. 2/GHND lack the neurologic GRH releasing mechanism to maintain adequate spontaneous GH release. 3/The increased response of GHND to hpGRH-40 may be of diagnostic value.

Growth hormone neurosecretory dysfunction. A treatable cause of short stature

Growth hormone neurosecretory dysfunction. A treatable cause of short stature

Growth Hormone Neurosecretory Dysfunction

Pulsatile growth hormone (GH) secretion was assessed in a subgroup of short children to determine whether they had GH secretory abnormalities, and these results were compared with those of normal and GH-deficient children. This subgroup of children was defined as having GH neurosecretory dysfunction and met the following criteria: height, less than first percentile; growth velocity, 4 cm/yr or less; bone age, two or more years behind chronological age, normal findings from provocative GH tests (peak, greater than or equal to 10 ng/mL), low somatomedin-C level, and abnormal 24-hour GH secretory patterns. When compared with controls, both children with GH neurosecretory dysfunction and GH-deficient patients had a significant decrease in parameters relating to the total GH secretion during the 24-hour period. As with GH-deficient children, the group with GH neurosecretory dysfunction more than doubled their growth velocity after replacement therapy with exogenous human GH during the first year of treatment. As a result of these detailed studies on pulsatile GH secretion, we suggest that there is a spectrum of GH secretory abnormalities from absolute deficiency to an intermittent irregularity in GH secretion.