Reduced Growth Hormone Secretion Research Articles

Impact of long-term naltrexone treatment on growth hormone and insulin secretion in hyperandrogenic and normal obese patients

The growth hormone (GH) response to stimulation tests is impaired in obesity. Moreover, obese patients exhibit a “paradoxical” increase of GH to GH-releasing hormone (GHRH) stimulation after food ingestion; this paradoxical response is reversed by naloxone infusion. On the other hand, β-endorphin seems to exert profound effects on insulin release. Recent studies also demonstrated an impairment of GH response to several stimuli in polycystic ovary syndrome (PCOS), a condition associated with obesity, hyperinsulinism, and insulin resistance. Chronic inhibition of opioid tone by the opioid antagonist naltrexone (NTX) is able to reduce the insulin response to an oral glucose tolerance test (OGTT) in hyperinsulinemic PCOS patients. Since insulin and GH may reciprocally influence their secretion and the opioid system may have a role in the pathogenesis of hyperinsulinemia and reduced GH secretion, we have explored the involvement of these neuroendocrine mechanisms in essential obesity and in obesity associated with hyperandrogenism by a long-term treatment with an opiate antagonist. We tested seven obese patients affected by PCOS, seven matched women with essential obesity (EO), and five non-obese control subjects. All patients, in the follicular phase, underwent an OGTT (75 g) and basal hormone assay. Two days later, patients were subjected to a GHRH test. The patients then had 4 weeks of treatment with NTX 50 mg/d. Following continuation of the treatment, OGTT and GHRH tests were repeated. Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) plasma concentrations were also determined in the basal condition before and after NTX treatment. NTX treatment reduced fasting insulin levels in patients with EO ( P < .05) and restored a normal GH response to GHRH without affecting IGF-1 and IGFBP-3 levels. In PCOS subjects, NTX reduced the insulin response to a glucose load and failed to modify the blunted GH response to GHRH. Our data suggest a significant difference in opioid system function in PCOS and EO subjects, indicating a particular form of obesity in PCOS. The opiate antagonist treatment in EO may act through the reduction of negative insulin feedback on GH secretion. In PCOS patients, the failure to improve GH secretion in obese hyperandrogenized patients may be related to a high opioidergic tone or to the inhibitory predominance of other neurotransmitters.

Relationship between protein kinase C and adenylyl cyclase activity in the regulation of growth hormone secretion by human pituitary somatotrophinomas.

To determine the potential role of protein kinase C (PKC) and its relationship to adenylyl cyclase activity in controlling growth hormone (GH) secretion by human pituitary somatotrophinomas. Twenty-eight somatotrophinomas were placed into cell culture, and the in vitro effects of the PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) and the PKC inhibitor staurosporine on basal and GH-releasing hormone (GHRH)-stimulated GH secretion were examined. In addition, the influence of chronic exposure of cultured somatotrophinoma cells to TPA on the rate of inositol 1,4,5-trisphosphate production was determined. Each tumor was assessed for the presence of gsp oncogenes, and thus constitutive adenylyl cyclase activity, by direct sequence analysis of polymerase chain reaction-generated deoxyribonucleic acid. GH secretory responses of tumors with and without these oncogenes were compared. TPA consistently stimulated GH secretion by cultured somatotrophinoma cells. There was no difference in response between somatotrophinomas with and without gsp oncogenes, and the effects did not correlate with the variable stimulation exerted by GHRH. Tumors in which GHRH had no significant effect nevertheless responded to TPA. In combination, TPA and GHRH exerted additive stimulation. TPA treatment of cultured somatotrophinoma cells eventually resulted in suppression of inositol 1,4,5-trisphosphate production, probably reflecting down-regulation of membrane phosphatidylinositol hydrolysis, a second messenger system that also generates the endogenous PKC activator diacylglycerol. GHRH had no effect on phosphatidylinositol hydrolysis. In contrast to the effects of TPA, the PKC inhibitor staurosporine tended to reduce GH secretion, although this effect was not observed in all tumors examined. As with TPA, the effects of staurosporine did not correlate with presence or absence of gsp oncogenes. Furthermore, staurosporine did not reduce the stimulatory effects exerted by GHRH on GH secretion. These results demonstrate a role for the phosphatidylinositol-PKC second messenger cascade in controlling GH secretion by human pituitary somatotrophinomas. The results also show that the system operates relatively independent of intracellular adenylyl cyclase and, thus, protein kinase A.

Treatment options for acromegaly

Treatment options for acromegaly include surgical removal of the adenoma, radiotherapy, or pharmacological reduction of growth hormone (GH) levels by dopamine agonists or somatostatin analogs. Whether such treatment can truly cure acromegaly is debatable. A problem with evaluating efficacy of treatment is the lack of consensus of what constitutes a cure. Despite modern neurosurgical techniques for resecting GH-secreting pituitary adenomas, more than 50% of patients may have persistent GH hypersecretion; radiotherapy may take years to produce an effect. There is thus interest in pharmacological relief of symptoms and reduction in GH secretion. We report on eight patients with a biochemical diagnosis of acromegaly (failure of suppression of GH levels to < 2.5 μg/L following a glucose tolerance test [GTT]). The use of Sandostatin-LAR ® (Sandoz Pharma Ltd, Basel, Switzerland) in doses of 20 to 30 mg intramuscularly at 4 week intervals produced consistent and therapeutic serum octreotide concentrations, suppressed GH secretion to 5 μg/L in all eight subjects, lowered insulin-like growth factor-1 (IGF-1) levels in all and normalized values in seven of eight, improved or led to disappearance of symptoms and signs, and was not associated with an increase in adverse events as compared with subcutaneous treatment.

Insulin-like growth factors (IGFs) and IGF-I treatment in the adolescent with insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) during adolescence is associated with complex derangements of the growth hormone (GH)/insulin-like growth factor (IGF) axis. Despite GH hypersecretion, IGF-I levels and IGF bioactivity are reduced. The diabetogenic effects of GH are well established, and GH hypersecretion has been implicated in the deterioration in glycemic control during adolescence and in the development of microangiopathy. Insulin deficiency or reduced portal delivery of insulin plays a central role in the development of these abnormalities, and although continuous subcutaneous insulin delivery may improve plasma IGF-I levels, it does not necessarily suppress GH levels. Recombinant IGF-I has been proposed as an adjunct to conventional insulin therapy, as restoring circulating IGF-I levels might lead to GH suppression. Placebo-controlled studies have shown a consistent reduction in GH secretion and related improvements in insulin sensitivity following a single subcutaneous IGF-I injection (40 μg/kg). Repeated daily subcutaneous IGF-I administration for 1 month resulted in a sustained increase in IGF-I levels, as well as a reduction in GH secretion and insulin requirements. There was no increase in hypoglycemia or other adverse effects. Recombinant IGF-I used in conjunction with insulin may therefore provide an additional approach to the management of IDDM during adolescence, allowing correction of abnormalities in the GH/IGF axis and leading to improved control and, hence, reduced risk of long-term complications. However, this hypothesis needs to be rigorously tested in long-term placebo-controlled studies.

Hypothalamic Mediation of Reduced GH Secretion in Diabetic Rats: Evidence for Reduced Cholinergic Inhibition of Somatostatin Release

The Goto-Kakizaki (GK) rat is a new model of diabetes mellitus and in this study we have characterized the diabetic and growth hormone (GH) secretory status of male GK rats at 6 and 16 weeks of age. We have also investigated the role of endogenous somatostatin (SS) and cholinergic manipulation on the GH responses to GH-releasing hormone (GHRH). GK rats were non-obese with significant fasting hyperglycaemia, hyperinsulinaemia and absent insulin responses to IV glucose. The GH response to GHRH was reduced at 16 weeks compared with normal, age-matched Wistar rats but no differences were observed at 6 weeks. Pretreatment of older rats (16 weeks) with anti-somatostatin antibodies (SS-Ab) significantly increased GH responses to GHRH in both normal and GK groups. Cholinergic augmentation with pyridostigmine (PD) reversed the blunted GH responses to GHRH in older GK rats but had no effect in the normal or young (6 weeks) GK rats. These results indicate that SS release mediates the blunted GH response to GHRH in GK rats and that reduced hypothalamic cholinergic signalling to the somatostatinergic neurone may mediate the increase in SS release. This view is supported by the results from in vitro studies in which cholinergic muscarinic blockade with pirenzepine (PIR) caused dose-related stimulation of SS release from normal rat hypothalami but was without effect on GK rat hypothalami. The cause of this alteration in hypothalamic function is, at present, unknown.

Reduced growth hormone secretion with maintained periodicity following cranial irradiation in children with acute lymphoblastic leukaemia.

Low dose cranial irradiation in children with acute lymphoblastic leukaemia (ALL) has been reported to reduce GH secretion in puberty. A recent study also reported a disturbed periodicity of GH secretion during puberty. We have focused on the different stages of puberty in studying these two parameters of GH secretion and have also compared the effects of 18 vs 24 Gy radiation dose. Thirty-four children previously treated for ALL were compared with a control group of 208 healthy normally growing children. GH secretion was measured as 24-hour profiles. In children treated for ALL, GH secretion rate and GH peak amplitude were below the median values for controls, both before puberty and during all stages of puberty. The difference between patients and controls was most pronounced in late puberty. Radiation with 18 or 24 Gy gave similar results. However, time sequence analysis showed a similar periodicity of GH secretion in both patient and control groups before, as well as during, puberty. Thus, before puberty a broad range of cycles per 24 hours was seen. These synchronized during puberty to a predominant GH peak frequency of one every 3-4 hours. After low dose cranial irradiation with 18 or 24 Gy, the total amount of GH secreted is reduced both before and during puberty. We could not confirm previous findings of impaired periodicity of GH secretion in these children.

Growth retardation and reduced growth hormone secretion in a boy with achalasia

Growth retardation and reduced growth hormone secretion in a boy with achalasia

Effects of stimulated growth hormone secretion on age-related changes in plasma cholesterol and hepatic low density lipoprotein messenger RNA concentrations

Growth hormone (GH) secretion declines during aging. Since GH alters plasma cholesterol (PC) concentrations, it was of interest to determine how GH secretagogues affect age-related hypercholesterolemia. Fischer 344 rats (3 and 14 months old) were co-administered (s.c.) GH releasing hormone (3 μg/kg; GHRH) and GH releasing hexapeptide (100 μg/kg; GHRP) for 120 consecutive days. Aging was associated with a progressive increase in PC, which was reduced in rats administered GHRH and GHRP compared to those administered vehicle, i.e. changes in PC during the study were 26.5 ± 1.2 mg/dl vs. 40.1 ± 0.9 mg/dl ( P < 0.05) in the younger rats and 17.6 ± 2.3 mg/dl vs. 31.6 ± 5.3 mg/dl ( P < 0.05) in the older rats, respectively. The lower concentrations of PC in GH secretagogue-treated older rats were associated with higher mean concentrations of hepatic LDL receptor mRNA (1.27 ± 0.4 vs. 0.4 ± 0.1; P < 0.05) but not cholesterol 7-α hydroxylase mRNA. Although GH secretagogue treatment was also associated with lower plasma cholesterol in the younger rats, it was not accompanied by quantitative changes in mean group concentrations of hepatic LDL receptor mRNA. Instead, daily administration of GHRH and GHRP in the younger rats correlated with a significant reciprocal relationship ( P < 0.05) between PC and hepatic LDL receptor mRNA for individual group members. The results of this study suggest that reduced GH secretion during aging contributes, at least in part, to a progressive increase in plasma cholesterol that can be partially prevented with GH secretagogues. Furthermore, the effects on PC may result from GH-mediated, qualitative and quantitative changes in hepatic LDL receptor mRNA that increase receptor-mediated cholesterol clearance.

Subnormal concentrations in the feminine profile of circulating growth hormone enhance expression of female-specific CYP2C12

When newborn female rats were treated with monosodium glutamate, 4 mg/g body weight, on days 1 and 3 of life, circulating growth hormone concentrations were permanently reduced 75–85% in adulthood, whereas the feminine secretory profile characterized by frequent growth hormone pulses, separated by short-lived, measurable troughs, persisted. Associated with this reduction in growth hormone secretion was a mild obesity and a slight depression in peripubertal body weight. In contrast, expression of growth hormone-dependent, female-specific CYP2C12 was increased by almost 100% when measured at both its protein and mRNA levels. In agreement, this supraphysiological expression of CYP2C12 was reflected at a pharmacologic level by a simultaneous elevation in in vitro and in vivo hexobarbital metabolism. When growth hormone secretion was pulsatile (i.e. masculine) or was eliminated from the circulation (i.e. hypophysectomy), hepatic CYP2C12 protein and mRNA were undetectable. The present findings suggest that the normal levels of plasma growth hormone found in female rats are not necessarily optimum for the expression of female-specific CYP2C12.

Sleep-related growth hormone secretion is persistently suppressed in women with recurrent depression: A preliminary longitudinal analysis

Growth hormone secretion was monitored during sleep in a group of 43 women with recurrent major depression who were participating in a 3-year maintenance therapy program. Patients were studied before acute treatment, after complete remission, and at 3-month intervals during maintenance treatment and the data generated were compared to those obtained in a control group of 14 age-matched healthy women studied once under identical conditions. When compared to the control group, the depressed patients secreted significantly less growth hormone before treatment. This reduction in growth hormone secretion, which was confined to the first half of the sleep period, persisted across the length of the maintenance study regardless of whether the subjects completed three years of therapy or experienced a recurrence.

Triiodothyronine reduces growth hormone secretion and pituitary growth hormone mRNA in the chicken, in vivo and in vitro.

The influence of triiodothyronine (T3) on growth hormone (GH) mRNA and GH secretion has been examined in the chicken. Initially T3 treatment in the diet for three days did not alter plasma concentrations of GH. Plasma concentrations of GH were depressed with seven and 14 days of T3 treatment (1 or 5 ppm in the diet). There was a concomitant decline in pituitary GH mRNA with T3 treatment. Pituitary GH content was reduced with 14 but not seven days of T3 treatment. No effect of T3 was observed on the percentage by somatotroph cells in the anterior pituitary gland by fluorescence flow cytometry analysis. While exposure of pituitary cells in vitro from young chickens to GHRF for 2 hr increased GH mRNA, no effect was observed with T3. The presence of T3, for 48 hr in vitro, tended to reduce GH mRNA in adenohypophyseal cells from young chickens and decreased GH mRNA with anterior pituitary cells from adult chicks. It is concluded that T3 chronic administration of T3 depresses circulating concentrations of GH, at least in part, by decreasing GH mRNA and hence GH synthesis.

Potential Therapeutic Applications of Growth Hormone in Adults

Potential therapeutic applications of recombinant human growth hormone (GH) in adults are under investigation in various clinical situations. Patients with GH deficiency represent the more natural indication of replacement therapy with GH; clinical trials have demonstrated a potent metabolic effect with changes in body composition, and improvement in quality of life and physical performances. This treatment is well tolerated since the adverse effects related to fluid retention could be suppressed by dose reduction. In aging, reduction in GH secretion is considered partly responsible for some symptoms and GH treatment can be considered as replacement therapy. In short- and long-term treatments, the effects on body composition and subjective well-being are similar to those obtained in younger GH-deficient adults. In catabolic conditions, nitrogen sparing is demonstrated in most patients. The effect of GH treatment on final outcome is at present unknown.

Sustained High Insulin-Like Growth Factor-Binding Protein 3 Levels after Suppression of Gonadal Steroids in Central Idiopathic Precocious Puberty

The direct role of sex steroids in pubertal bone growth may be an increased growth hormone (GH) receptor-coupled GH action. We previously reported that suppression of sex steroids by a gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate) increases the activity of serum growth hormone-binding protein (GHBP), identical to the extracellular domain of GH receptor, in central idiopathic precocious puberty (CIPP). Since insulin-like growth factor (IGF) -binding protein 3 (IGFBP-3) is a GH-dependent IGF binding protein, we measured IGFBP-3 and GHBP before and after treatment with the GnRH agonist in eight children with CIPP. IGFBP-3 and GHBP were measured by radioimmunoassay and immunoprecipitation.The treatment suppressed gonadal function. The initial IGFBP-3 level was high. After the treatment, IGFBP-3 remained at this level despite a reduction in GH secretion. There was a significant positive correlation between IGFBP-3 level and GHBP activity (r=0.63, p<0.01).The high IGFBP-3 level in a patient with CIPP is presumed to result from increased GH secretion, similar to the GH-dependent increase in IGF-I. Although we can not explain the sustained increase in IGFBP-3 after gonadal suppression, the high IGFBP-3 level may interfere with the growth promoting effect of IGF-I.

Reduced Growth Hormone Secretion in Turner Syndrome: Is Body Weight a Key Factor?

The age-related decline in spontaneous growth hormone (GH) secretion has been suggested to cause growth failure in girls with Turner syndrome (TS). We studied 23 girls (mean age +/- SD: 11.1 +/- 2.7 years) diagnosed to have TS by karyotype analysis. The control group consisted of 18 prepubertal age-matched subjects (10.7 +/- 2.5 years) with growth retardation due to familial short stature and/or constitutional growth delay. In addition, 18 children (10.9 +/- 3.3 years) diagnosed to have GH deficiency by two different provocative tests were chosen as a further comparison group. Spontaneous 12-hour nocturnal GH secretion was assessed by RIA at 30-min intervals. Plasma insulin-like growth factor 1 (IGF-1) levels were determined by RIA after acid-ethanol extraction. Girls with TS had a percentage of ideal body weight significantly higher than controls (p < 0.0001) and showed spontaneous GH secretion significantly lower than controls (mean +/- SD: 3.2 +/- 1.6 in TS vs. 5.5 +/- 1.3 microgram/l in controls; p < 0.0001) but higher than GH-deficient patients (1.3 +/- 0.8 microgram/l; p < 0.0001). No significant difference was found in IGF-1 levels between TS patients and controls, whereas GH-deficient children showed IGF-1 levels significantly lower than those of TS patients (p < 0.0005). As expected, GH concentrations correlated with bone age in controls (r = 0.51, p < 0.05), whereas no relationship was seen in TS. interestingly, in TS, GH levels were negatively related to the percentage of ideal body weight (r = -0.43, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function

The growth hormone-releasing hormone receptor (GHRHR) is a member of the family of G protein-coupled receptors that is expressed on pituitary somatotrope cells and mediates the actions of GHRH in stimulating growth hormone (GH) synthesis and secretion. We report that the Ghrhr gene is located in the middle of mouse chromosome 6 in the same region as the little mutation. Mice homozygous for this mutation have reduced GH secretion and a dwarf phenotype. A missense mutation was identified in the extracellular domain of the little GHRHR that disrupts receptor function, suggesting that the growth deficit in these mice results from a defect in the GHRHR. Similar alterations in GHRHR might explain some isolated GH deficiencies in humans.

Evidence for a Role for Insulin and Growth Hormone in Overnight Regulation of 3-Hydroxybutyrate in Normal and Diabetic Adolescents

To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. We studied overnight changes in plasma ketones--3-hydroxybutyrate and acetoacetate--in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 +/- 5 microM), reaching a peak at 0200 (103 +/- 16 microM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = -0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.

Effect of prolonged hyperglycemia on growth hormone levels and insulin sensitivity in insulin-dependent diabetes mellitus

The aim of the present study was to characterize the effect of a hyperglycemic period (44 hours) on the levels of insulin-antagonistic hormones and insulin sensitivity in seven subjects with well-controlled insulin-dependent diabetes mellitus (IDDM). Hyperglycemia (∼15 mmol · L −1) was induced by a glucose infusion while the degree of insulinization was similar to that of the period with near normoglycemia (∼6.9 mmol · L −1). Insulin sensitivity was measured with hyperinsulinemic euglycemic clamps performed 4 hours before and after the periods of normoglycemia (control) and hyperglycemia. d-[3- 3H]glucose was infused in the second clamp in each study to evaluate glucose production and utilization. Since growth hormone (GH) levels frequently are elevated during poor diabetic control, diurnal GH secretion was measured in blood samples continuously drawn for 24 hours during the euglycemic and hyperglycemic periods. Levels of epinephrine, norepinephrine, cortisol, and nonesterified free fatty acids (NEFA) were similar during the control and hyperglycemic periods and during the clamps. GH levels were also similar, but an abnormal diurnal secretion pattern was present with increased numbers of daytime peaks. Hyperglycemia did not reduce GH secretion in IDDM. Hyperglycemia for 44 hours induced insulin resistance (32% reduction of glucose infusion rate, P < .02). In the control study, a 21% reduction ( P = .064, NS) of the glucose disposal rate (R d) was seen, suggesting that the hospitalization period per se may also reduce insulin sensitivity. In conclusion, a period of hyperglycemia leads to insulin resistance in IDDM patients. This insulin resistance cannot be attributable to increased levels of insulin-antagonistic hormones, although an abnormal secretion pattern for GH was found. Thus, hyperglycemia per se seems to be an important reason for the insulin resistance in IDDM.

Growth hormone secretion is differently affected in genetically obese male and female rats.

Growth hormone (GH) secretion is markedly blunted in obesity. Reportedly, genetically obese Zucker rats show a reduced GH secretion due to an impaired function of hypothalamic neurons producing the GH-releasing hormone (GHRH). The aim of this work was: (1) to compare the in vitro GH responsiveness to GHRH in genetically obese female versus male Zucker rats and, (2) to evaluate the function of hypothalamic GHRH and somatostatin and of pituitary receptors for these neurohormones as assessed by the effectiveness of GHRH and somatostatin on adenylate cyclase (AC) activity. Baseline GH secretion of pituitaries obtained from male and female obese rats was not different and similar to that present in lean counterparts. Stimulation with 10(-7) M GHRH elicited a significantly lower GH secretion from the pituitaries of obese male rats but induced a similar GH secretion from the pituitaries of lean and obese female rats. In these pituitaries, GH concentration was similar in obese versus lean male and female rats [corrected]. A sex-related difference was also evidenced when plasma concentrations of somatomedin C (IGF-I) were evaluated. Obese male rats had lower IGF-I concentrations than lean counterparts, while this was not the case for obese versus lean female rats. Evaluation of AC activity following GHRH disclosed a lower activation in obese than in lean male rats, whereas in the females the enzyme activation was higher in obese than in lean animals. Conversely, the inhibitory effect of somatostatin on forskolin-stimulated AC was similar in pituitary membranes of obese and lean rats of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulated growth hormone (GH) secretion in children with delays in pubertal development before and after the onset of puberty: relationship with peripheral plasma GH-releasing hormone and somatostatin levels.

A reduced GH secretion has often been shown in prepubertal children with delays in pubertal development. In order to study the mechanism underlying this finding, we evaluated peripheral circulating levels of GH, GHRH, and somatostatin (SRIH) before and after the onset of sexual development in a group of eight late maturing children (six boys, two girls), comparing the results with those obtained in two groups of five prepubertal and four pubertal short children with familial short stature. GH was measured by a two-site immunoradiometric assay. Both GHRH and SRIH were assayed by specific RIAs after an acetone-petrolether extraction from plasma. Our data showed a significant increase (P less than 0.001) in GH, GHRH, and SRIH levels (peak vs. basal values) in response to L-dopa administration in all groups. In pubertal children with delays in pubertal development GH and GHRH peak values (15.8 +/- 2.2 micrograms/L and 120 +/- 18 pg/mL, respectively) were significantly greater (P less than 0.001) than in the same subjects before puberty (8.2 +/- 0.9 micrograms/L and 79 +/- 9 pg/mL, respectively), whereas SRIH peak values did not significantly change (41 +/- 6 vs. 41 +/- 5 pg/mL; P = NS). Furthermore, prepubertal subjects with delays in pubertal development showed GH and GHRH peak values lower (P less than 0.001) than those of prepubertal subjects with FSS (13.3 +/- 1.8 micrograms/L and 120 +/- 13 pg/mL, respectively), whereas no statistical difference was present between the two groups of subjects after pubertal development (18.2 +/- 2.9 micrograms/L and 128 +/- 11 pg/mL, respectively). In conclusion, these findings support the assumption that in late maturing subjects during prepubertal period the decreased GH secretion may be ascribed to a reduced GHRH secretion, reversible with the onset of puberty, without change in circulating SRIH levels.

Effect of diabetes on in vivo and in vitro hypothalamic somatostatin release.

In order to better understand the mechanisms underlying the reduction in growth hormone (GH) secretion in diabetic rats, we studied hypothalamic somatostatin secretion both in vivo (into hypophysial portal blood) and in vitro (from hypothalamic fragments) 5, 9 and 30 days after induction of diabetes. Experimental diabetes was induced by an intraperitoneal injection of streptozotocin (STZ) at a dose of 65 mg/kg. Basal plasma GH was significantly reduced in diabetic rats at all stages. Somatostatin levels in hypophysial portal blood was unaffected in 5-day STZ-diabetic rats and significantly increased 9 days after STZ administration. Chronic insulin replacement therapy in diabetic animals partly normalized somatostatin levels as well as plasma GH and glucose levels. A good correlation was observed between in vivo and in vitro experiments. Indeed, somatostatin release from hypothalamic fragments did not change 5 days after STZ-induced diabetes and significantly increased 9 and 30 days after STZ administration. The in vitro increase in hypothalamic somatostatin secretion was observed in 10 as well as in 33 mM glucose concentration in the incubation medium. In the same experiment, the in vitro hypothalamic corticotropin-releasing factor secretion was lowered 5 and 9 days after diabetes induction. We conclude that hypothalamic somatostatin release increases in diabetic rats. These changes may contribute to the reduction in GH secretion in these animals. However, since these changes occur after the onset of plasma GH decrease, a factor(s) other(s) than somatostatin may play a causal role in the reduction in GH secretion.