Hypothalamic Somatostatin Tone Research Articles

Adult growth hormone deficiency in patients with fibromyalgia.

Adult growth hormone (GH) deficiency is a well-described clinical syndrome with many features reminiscent of fibromyalgia. There is evidence that GH deficiency as defined in terms of a low insulin-like growth factor-1 (IGF-1) level occurs in approximately 30% of patients with fibromyalgia and is probably the cause of some morbidity. It seems most likely that impaired GH secretion in fibromyalgia is related to a physiologic dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) with a resulting increase in hypothalamic somatostatin tone. It is postulated that impaired GH secretion is secondary to chronic physical and psychological stressors. It appears that impaired GH secretion is more common than clinically significant GH deficiency with low IGF-1 levels. The severe GH deficiency that occurs in a subset of patients with fibromyalgia is of clinical relevance because it is a treatable disorder with demonstrated benefits to patients.

Back to basics: Early diagnosis and compliance improve final height outcome in congenital adrenal hyperplasia

Back to basics: Early diagnosis and compliance improve final height outcome in congenital adrenal hyperplasia

Glucocorticoids and growth

Glucocorticoids play a critical role in the regulation of the hypothalamic-somatotropic-insulin-like growth factor axis. These steroids enhance growth hormone gene transcription and increase growth hormone-releasing hormone receptor synthesis. However, glucocorticoid excess inhibits somatic growth. Evidence to date suggests that this is in part due to impaired growth hormone secretion observed during hypercortisolism as well as impaired actions of growth hormone at the peripheral level. This includes impaired spontaneous growth hormone secretion, suppressed growth hormone responses to a number of stimuli, including growth hormone-releasing hormone, and increased insulin-like growth factor inhibitors and binding proteins. The inhibitory effect of the glucocorticoids appears to be due to increased hypothalamic somatostatin tone and inhibition of insulin-like growth factor bioactivity.

Influence of thyroid hormones on the regulation of growth hormone secretion.

The effects of thyroid hormones on GH secretion and the mechanisms underlying their action are very similar in man and the laboratory animal. We feel that it is possible to organize the available data into a unique pathophysiological model explaining these complex interactions (Table 1). In summary, physiological levels of circulating thyroid hormones are necessary to maintain normal pituitary GH secretion owing to their direct stimulatory actions. When the serum concentrations of thyroid hormone increase above the normal range there is an increase in hypothalamic somatostatin tone, which in turn suppresses pituitary GH secretion and overrides any stimulatory effects. The suppression of GH secretion by thyroid hormones may be mediated at the hypothalamic level also by a decrease in GHRH release.

Hexarelin, a novel GHRP-6 analog, counteracts the inhibitory effect of hydrocortisone on growth hormone secretion in acromegaly.

Hexarelin (His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a GHRP-6 analog with the substitution of D-tryptophan with its 2-methyl derivative. The aim of our study was to ascertain whether hexarelin was able to counteract the glucocorticoid-mediated increase in hypothalamic somatostatin tone and consequent inhibition on serum GH levels in acromegalic patients. Ten patients (5 males, 5 females; age range 27-71 years; BMI range 23.3-35 kg/m2) with active acromegaly underwent: 1) hydrocortisone alone: a bolus iv injection of 100 mg hydrocortisone succinate in 2 mL saline, at time -60 followed by a 120 min iv infusion of 250 mg hydrocortisone succinate in 250 mL saline, from -60 to 60 min; 2) hexarelin+hydrocortisone: a bolus iv injection of hexarelin 100 micrograms, 60 min after initiation of a 2-hour hydrocortisone infusion; 3) hexarelin alone: a bolus iv injection of hexarelin at time 0, 60 min after initiation of a 2-hour saline infusion. The mean GH peak, expressed as percent change with respect to baseline level (mean of -75 and -60 minute samples), after hexarelin (1750 +/- 1157%) did not differ significantly with respect to that observed after hexarelin+hydrocortisone (1120 +/- 770%). After hydrocortisone alone the patients showed a mean decrease in GH levels as compared to baseline levels, of 47 +/- 7%. Our data show that the GH response to hexarelin in acromegaly is resistant to the inhibitor action of an acute and sustained elevation of serum cortisol levels. That hexarelin counteracts the glucocorticoid-mediated inhibition of GH secretion supports the hypothesis of an hexarelin-induced decrease in endogenous somatostatin tone.

Effect of pyridostigmine on the growth hormone response to growth hormone-releasing hormone in lean and obese type II diabetic patients

A suppressed growth hormone (GH) response to GH-releasing hormone (GHRH) in both lean and overweight type II diabetics has been reported. Pyridostigmine (PD), an acetylcholinesterase inhibitor, elicits GH secretion when administered alone and enhances the GH response to GHRH in normal subjects. The aim of our study was to evaluate the effect of PD on GHRH-stimulated GH secretion in both lean and obese type II diabetic patients. We studied 16 patients with type II diabetes mellitus (seven lean and nine obese). Eleven nondiabetic subjects (six lean and five obese) served as controls. Each subject underwent treatment with (1) 120 mg PD orally or (2) 2 tablets of placebo orally, 60 minutes before intravenous (IV) injection of 100 μg GHRH-(1–29)NH 2. We have found no significant differences in GH responses to GHRH between obese diabetics and obese controls. On the other hand, the absolute GH levels were significantly suppressed in lean type II diabetics compared with lean controls at 15 and 30 minutes after GHRH injection. Obese diabetic subjects had slightly but not significantly decreased GH responses to GHRH + PD compared with obese nondiabetic subjects (8.36 ± 1.62 v 14.4 ± 7.62 μg/L). Lean type II diabetics showed a blunted GH release after GHRH + PD compared with normal-weight healthy subjects (GH peaks, 15.77 ± 2.17 v 40 88 ± 6.17 μg/L, P < .05). PD enhanced significantly the GH response to GHRH in obese diabetics, obese controls, and non-obese controls ( P < .05), but not in non-obese type II diabetics. On the basis of our data, it can be hypothesized that chronic, as well as acute, hyperglycemia in the presence of normal or elevated circulating insulin levels may cause a decrease in pituitary GH secretion through an enhancement in hypothalamic somatostatin tone. Moreover, that this altered cholinergic/somatostatin-mediated GH regulation is observed in both lean and obese diabetics suggests that the defects in GH secretion observed in type II diabetes cannot be simply ascribed to the increased body weight.

The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly

To indirectly evaluate the hypothalamic somatostatin (SS) tone in patients with acromegaly, the effects of pyridostigmine (PD), a cholinesterase inhibitor which can inhibit hypothalamic SS secretion, on TRH-induced TSH secretion and the effects of SMS 201-995 on TSH or GH secretion were studied in acromegalic patients (31-69 yr, n = 10), normal young (21-24 yr, n = 7) and normal old male subjects (62-71 yr, n = 7). After pretreatment with PD (60 mg po, -30 min), normal young subjects showed significantly enhanced TSH responses to TRH (500 micrograms i.v., 0 min) compared to single administration of TRH, whereas normal old and acromegalic patients did not show such enhancement. Plasma TSH response to a single administration of TRH in acromegalic patients was significantly lower than that of normal young and old subjects. Although normal young and old subjects showed significantly enhanced GH responses to GHRH (100 micrograms i.v. at 0 min) after the pretreatment with PD (60 mg, -30 min), no such enhancement was observed in acromegalic patients. In contrast, the decrement in plasma TSH after SMS 201-995 administration was similar between normal subjects (5 young 5 old) and 7 acromegalic patients. Further, the maximal plasma GH decrement after administration was significantly greater in acromegalic patients than in the 5 normal young and 5 old subjects p < 0.01). In conclusion, hypothalamic SS tone does not appear to be elevated in acromegalic patients compared to normal young and probably old subjects.

Corticotropin-releasing hormone inhibition of paradoxical growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics

A paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) has been observed in type 1 diabetic patients and was hypothetically attributed to a reduced hypothalamic somatostatin tone. We have previously reported that corticotropin-releasing hormone (CRH) inhibits GH response to growth hormone-releasing hormone (GHRH) in normal subjects, possibly by an increased release of somatostatin. To study the effect of CRH on anomalous GH response to TRH, we tested with TRH (200 μg intravenously [IV]) and CRH (100 μg IV) + TRH (200 μg IV) 13 patients (six males and seven women) affected by insulin-dependent diabetes mellitus. A paradoxical GH response to TRH was observed in seven of 13 patients, one man and six women. In these subjects, the simultaneous administration of CRH and TRH significantly reduced the GH response to TRH, as assessed by both the maximal GH mean peak ± SE (2.18 ± 0.67 v 9.2 ± 1.26μg/L, P < 0.005) and the area under the curve (AUC) ± SE (187 ± 32 v 567 ± 35μg · min/L, P < .001). CRH had no effect on TRH-induced thyroid-stimulating hormone (TSH) release. Our data demonstrate that the paradoxical GH response to TRH in patients with type 1 diabetes mellitus is blocked by CRH administration. This CRH action may be due to an enhanced somatostatin release. Our data also show that exogenous CRH has no effect on TSH response to TRH, thus suggesting the existence of separate pathways in the neuroregulation of GH and TSH secretion.

Mechanism of impaired growth hormone secretion in patients with Cushing's disease.

The function of the growth hormone-releasing hormone (GHRH)-growth hormone (GH) axis in Cushing's disease was studied by monitoring (a) the GH responses to GHRH loading and L-dopa loading, (b) the GHRH response to L-dopa loading, and (c) the daytime profiles of plasma GH concentration. GH release following GHRH and L-dopa was blunted in patients as compared to that in age-matched control subjects. However, GHRH release following L-dopa was similar in patients and controls. The plasma GH levels in four patients measured every 20 min by a highly sensitive immunoradiometric assay for GH showed pulsatile GH secretion at low levels during the observation period. These results indicate that GHRH release from the hypothalamus is preserved in patients with Cushing's disease, and support the hypothesis that glucocorticoid inhibits GH secretion by altering the hypothalamic somatostatin tone.

Arginine normalizes the growth hormone (GH) response to GH-releasing hormone in adult patients receiving chronic daily immunosuppressive glucocorticoid therapy.

Glucocorticoids are thought to inhibit GH secretion through an enhancement of endogenous somatostatin tone. The aim of our study was to evaluate the effect of arginine, a secretagogue that increases GH secretion acting at the hypothalamic level, probably by decreasing somatostatin tone, on GH-releasing hormone (GHRH)-induced GH secretion in three male and five female adult patients with nonendocrine disease who were receiving daily immunosuppressive glucocorticoid therapy. Six normal subjects (four males and two females) served as controls. GHRH-induced GH secretion was evaluated after 30-min iv infusion of saline (100 mL) or arginine (30 g) in 100 mL saline. After saline administration, steroid-treated patients showed a blunted GH response to GHRH (GH peak, 8.7 +/- 2.4 micrograms/L) compared to that of normal subjects (GH peak, 23.8 +/- 3.9 micrograms/L). The GH responses to GHRH increased (P less than 0.05) after pretreatment with arginine compared to saline pretreatment in both normal subjects (GH peak, 36.6 +/- 4.0 micrograms/L) and steroid-treated patients (GH peak, 28.4 +/- 5.5 micrograms/L). The GH responses to GHRH plus arginine were not significantly different in steroid-treated and normal subjects. Thus, arginine is able to normalize the GH response to GHRH in patients receiving chronic glucocorticoid treatment. Our data are evidence that the stimulatory action of arginine and the inhibitory action of glucocorticoids on GH secretion are mediated by opposite effects on hypothalamic somatostatin tone.

Effect of galanin on growth hormone-releasing hormone-stimulated growth hormone secretion in adult patients with nonendocrine diseases on long-term daily glucocorticoid treatment

Glucocorticoids are thought to inhibit growth hormone (GH) secretion through an enhancement of endogenous somatostatin tone. The aim of our study was to evaluate the effect of galanin, a neuropeptide that stimulates GH secretion, on GH-releasing hormone (GHRH)-induced GH secretion in adult patients with nonendocrine diseases who were under daily immunosuppressive glucocorticoid therapy. Six normal subjects (four men, two women) and seven steroid-treated subjects (three men, four women) were studied. GHRH-induced GH secretion was evaluated during a 40-minute intravenous (IV) infusion of saline or porcine galanin (12.5 μg/min). During saline infusion, steroid-treated patients showed a blunted GH response to GHRH (GH peak, 8.1 ± 2.8 μg/L), as compared with normal subjects (GH peak, 23.8 ± 3.9 μg/L). During galanin infusion, the GH response to GHRH was significantly enhanced (GH peak, 46.6 ± 9.4 μg/L, P < .05), as compared with saline infusion in normal subjects. In contrast, galanin infusion did not enhance the GH response to GHRH (GH peak, 16.6 ± 6.5 μg/L), as compared with saline infusion in steroid-treated patients. The area under the GH-response curves was also significantly ( P < .05) lower in steroid-treated subjects, as compared with normal subjects. Thus, galanin failed to normalize or enhance the GH response to GHRH in patients treated long-term with glucocorticoids. It can be hypothesized that galanin does not elicit GH secretion by decreasing hypothalamic somatostatin tone.

Effect of arginine on the GHRH-stimulated GH secretion in patients with hyperthyroidism.

Patients with hyperthyroidism have reduced GH responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of arginine on GH secretion has been suggested to depend on a decrease in hypothalamic somatostatin tone. The aim of our study was to evaluate the effects of arginine on the GH-releasing hormone (GHRH)-stimulated GH secretion in patients with hyperthyroidism. Six hyperthyroid patients with recent diagnosis of Graves' disease [mean age +/- SEM, 39.2 +/- 1.4 years; body mass index (BMI) 22 +/- 0.4 kg/m2] and 6 healthy nonobese volunteers (4 males, 2 females; mean age +/- SEM, 35 +/- 3.5 years) underwent two experimental trials at no less than 7-day intervals: GHRH (100 micrograms, i.v.)-induced GH secretion was evaluated after 30 min i.v. infusion of saline (100 ml) or arginine (30 g) in 100 ml of saline. Hyperthyroid patients showed blunted GH peaks after GHRH (13.2 +/- 2.9 micrograms/l) as compared with normal subjects (23.8 +/- 3.9 micrograms/l, p < 0.05). GH peaks after GHRH were only slightly enhanced by arginine in hyperthyroid subjects (17.6 +/- 2.9 micrograms/l), whereas, in normal subjects, the enhancement was clear cut (36.6 +/- 4.4 micrograms/l; p < 0.05). GH values after arginine + GHRH were still lower in hyperthyroid patients with respect to normal subjects. Our data demonstrate that arginine enhances but does not normalize the GH response to GHRH in patients with hyperthyroidism when compared with normal subjects. We hypothesize that hyperthyroxinemia may decrease GH secretion, both increasing somatostatin tone and acting directly at the pituitary level.

Effects of pyridostigmine on spontaneous and growth hormone‐releasing hormone stimulated growth hormone secretion in children on daily glucocorticoid therapy after liver transplantation

We aimed to investigate both nocturnal spontaneous and morning growth hormone (GH)-releasing hormone (GHRH)-induced GH secretion in children on daily glucocorticoid treatment after liver transplantation and to evaluate the effect of pyridostigmine (an acetylcholinesterase inhibitor thought to reduce hypothalamic somatostatin tone) on GH secretion in these patients. We performed a randomized, single-blind, cross-over study. We studied three male and three female juvenile patients, within a year of orthotopic liver transplantation and under immunosuppressive glucocorticoid therapy (mean dose +/- SEM, 5.92 +/- 0.63 mg/day) and five normal children (four males, one female). Both nocturnal spontaneous and morning GHRH-induced GH secretion were evaluated after administration of placebo, 1 tablet p.o., or pyridostigmine, 2 mg/kg p.o. Spontaneous GH. Placebo: in liver transplanted children nocturnal GH secretion (mean GH level 10.8 +/- 2.0 mU/l) was not significantly different with respect to normal children (mean GH level 12.8 +/- 1.2 mU/l); pyridostigmine: nocturnal GH secretion was significantly increased as compared to placebo in subjects with liver transplantation but not in normal children. GHRH test. Placebo: liver transplanted patients showed a blunted GH response to GHRH with respect to normal children; pyridostigmine: the GH responses to GHRH (P less than 0.05) increased as compared to placebo and did not differ significantly in the two groups. Our data suggest a steroid-mediated increase in hypothalamic somatostatin tone in liver transplanted children.

Impaired Growth Hormone (GH) Response to Pyridostigmine in Type 1 Diabetic Patients with Exaggerated GH-Releasing Hormone-Stimulated GH Secretion*

In the present study we investigated the effects of the acetylcholinesterase inhibitor pyridostigmine (PD), which is hypothesized to decrease hypothalamic somatostatin tone, alone and in association with GH-releasing hormone (GHRH) on GH secretion in 18 type 1 diabetic patients and 12 normal subjects using a randomized double blind placebo-controlled protocol. All subjects received either 120 mg oral PD or placebo 60 min before iv injection of either human GHRH-(1-29) NH2 (100 micrograms) or sterile water (2 mL). In normal subjects both PD alone and GHRH alone caused a significant increase in GH. PD and GHRH acted in a synergistic fashion when combined. In diabetic patients the GH response to GHRH was variable. To segregate the responses, the ratio between the GH increase after GHRH plus PD and after GHRH alone was calculated for each subject. In 10 diabetic patients (group A) the ratio was lower than 2 SD (P less than 0.05) from the mean response of normal subjects. These patients showed an exaggerated GH increase after GHRH and a lower GH increase after PD with respect to normal subjects. Eight diabetic patients (group B) showed a ratio similar to that in normal subjects and similar GH responses to the stimuli. No significant differences were found between groups A and B with respect to age, body mass index, and blood glucose levels. Duration of diabetes was longer and basal GH levels were higher in group A. Hemoglobin-A1c was higher in group A, but of only borderline statistical significance (P = 0.052). Our data demonstrate that in diabetic patients with exaggerated GH responses to GHRH an increase in cholinergic tone does not affect GH secretion. These data suggest that in some type 1 diabetic patients an altered somatostatinergic control of GH secretion may contribute to their abnormal GH response to GHRH.

Glucocorticoids: Potent Inhibitors and Stimulators of Growth Hormone Secretion*

Excessive glucocorticoid concentrations are well recognized inhibitors of linear growth, due in part to their suppression of GH secretion. The mechanism of this inhibition has been unclear, especially since glucocorticoids enhance the in vitro GH response of pituitary cells to GH-releasing hormone (GHRH). We investigated the possibility that hypothalamic somatostatin might be mediating these dichotomous observations by using passive immunization techniques. The GH response to GHRH was significantly blunted in rats pretreated with the synthetic glucocorticoid, dexamethasone, compared to that in normal animals. In marked contrast, the immunoneutralization of somatostatin resulted in a significantly enhanced GH response to GHRH in dexamethasone-treated animals. These results suggest that the previously described inhibitory action of glucocorticoids on GH secretion in vivo are mediated via altered hypothalamic somatostatin tone.

Effects of Inhibition of Norepinephrine Synthesis on Spontaneous and Growth Hormone-Releasing Hormone-Induced GH Secretion in Cynomolgus Macaques: Evidence for Increased Hypothalamic Somatostatin Tone

To define the role of noradrenergic regulation of growth hormone (GH) secretion in a primate species, spontaneous and GH-releasing hormone (GHRH) stimulated GH secretion was studied in 6 chronically catheterized adult male cynomolgus monkeys before and after inhibition of norepinephrine synthesis. Blood samples were obtained at 15-min intervals during an 8-hour period to characterize the pattern of GH secretion, and the GH response to GHRH, 10 micrograms/kg i.v., was determined. These measurements were repeated 2 weeks later, 2 h after the intravenous administration of 12.5 mg/kg of the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDTC), which has been shown to be an effective norepinephrine synthesis inhibitor in the rat. Spontaneous and stimulated GH secretory patterns before and after DDTC administration were compared. Both the frequency and the amplitude of spontaneous GH pulses were markedly reduced by DDTC [3.8 +/- 0.4 before vs. 1.8 +/- 0.4 peaks/8 h after DDTC (p less than 0.005) and 5.5 +/- 0.7 vs. 2.0 +/- 0.6 ng/ml (p less than 0.01)]. Areas under the curve were also reduced by DDTC treatment [10.8 +/- 1.0 vs. 5.7 +/- 1.1 ng.h/ml (p less than 0.01)], and DDTC administration diminished the peak GH responses to GHRH [12 +/- 6 vs. 4 +/- 2 ng/ml (p less than 0.05)]. These results are consistent with the belief that DDTC is a potent inhibitor of spontaneous and GHRH-induced GH secretion. The action of DDTC could be mediated by a reduction in GHRH due to reduced norepinephrine synthesis, by an increase in somatostatin release through a dopaminergic stimulus, or by a direct dopaminergic effect on somatotrophs.