GH-releasing Hormone Test Research Articles

Baseline IGFBP - 3 as the Key Element to Predict Growth Response to Growth Hormone and IGF - 1 Therapy in Subjects with Non - GH Deficient Short Stature and IGF - 1 Deficiency.

BackgroundShort stature in children represents a heterogeneous group with different etiologies. Primary Insulin like growth factor 1 (IGF - 1) deficiency in short stature can present with normal or elevated growth hormone (GH) production. Currently there is no model that can reliably predict response to recombinant (r)GH therapy and/or rIGF - 1 therapy in children with non - GH deficient short stature.HypothesisBaseline Insulin like growth factor binding protein 3 (IGFBP - 3) along with ∆ IGF - 1 in the first 3 months of GH therapy level can be a marker of growth response to the rGH and/or rIGF - 1 therapy in children with non - growth hormone deficiency short stature.ObjectivesTo study the relationship between baseline IGFBP - 3 and IGF - 1 levels and the response to rGH and rIGF - 1 therapy in children with short stature, normal GH secretion and low IGF - 1 SDS.Methods43 children, age 9.07 ± 2.75 years with height -2.72 ± 0.7 SD and baseline IGF - 1 of -2.76 ± 0.58 SD, who passed the growth hormone releasing hormone (GHRH) stimulation test were included in a retrospective chart review. They were treated with rGH therapy with a mean dose of 0.46 ± 0.1 mg/kg/week. Growth velocity (GV), IGF - 1 and IGFBP - 3 levels were done at 3 and 6 months of therapy. Subjects with poor response to rGH after 6 months of therapy were switched to rIGF - 1 therapy at 0.24 mg/kg/day for the next 6 months. Subjects were divided according to their growth rate into responders to rGH (N = 23); non - responders to rGH, responders to rIGF - 1 (N = 14) and non - responders to rGH and rIGF-1 (N = 6).ResultsThere was no correlation between GV and peak GH level at GHRH test. Growth velocity positively correlated with ΔIGF - 1 SD among subjects treated with rGH therapy. Height SD positively correlated with IGFBP - 3 SD. Baseline IGFBP - 3 also inversely correlated with GH peak during GHRH test.ConclusionsIn subjects with short stature and low IGF - 1 level, baseline IGFBP - 3 levels can predict the growth response to rGH and/or rIGF - 1 therapy.

Evaluation of growth hormone response to GHRH plus arginine test in children with idiopathic short stature: role of peak time.

To describe the course of growth hormone response to growth hormone releasing hormone (GHRH) plus arginine provocative test in children with idiopathic short stature (ISS) and to evaluate the role of peak time. A retrospective study was performed analyzing 344 GHRH plus arginine provocative tests performed in children and adolescents with short stature. Serum GH levels were measured at four-time points (T0', T30', T45' and T60') and GH peak was defined as the maximum value at any time point. Mean (T30'-T60') GH value and area under the curve (AUC) were calculated. When analyzing the time of peak at the provocative test, the most frequent peak time was T45' (53.8%) in the ISS group, with no differences in gender, age, and pubertal stage. Analyzing GHD subjects, the most frequent time of peak was T30 (50%). Analyzing the whole population, the GH T0' levels were significantly lower in subjects with the GH peak at T45' than those with the GH peak at T30' (1.7±2.0 vs. 3.2±4.0, p<0.001). In subjects with GH peak at T45', the value of GH peak, AUC and mean GH were significantly higher than in those with GH peak at T30' and T60'. A direct correlation was found between the value of GH peak and growth velocity SDS (r=0.127, p=0.04) and a negative one between GH peak and GH level at T0' (r=-0.111, p=0.04), even when adjusted for gender, age, pubertal stage and BMI Z score. The time peak at 45min seems to be associated with a better response to the test considering GH peak, mean and AUC. Patients with a GH peak at 30min more probably could have a derangement in GH secretion showing worst growth pattern and/or a GH deficiency and should be carefully observed.

The usefulness of the GHRH stimulation test in the diagnostics of growth hormone deficiency in children.

Stimulation tests form the basis for the diagnostic process in growth hormone deficiency (GHD). One of these tests uses the GH releasing hormone (GHRH). This provides the potential to differentiate patients with pituitary dysfunction from patients with hypothalamus abnormalities. However, the routine use of the GHRH test is still being debated. The aim of this study was to assess the diagnostic usefulness of the GHRH test in the diagnostics of GHD. The study group consisted of 20 prepubertal children with GHD. In all the children, one of the performed stimulation tests was the GHRH test. The results showed that the mean peak concentration of GH in the GHRH test was 14.7 ± 11.3 ng/mL. In eight children the MRI showed pituitary hypoplasia, in one patient pituitary hypoplasia and pituitary stalk agenesis, and in one patient septo-optic dysplasia. All patients with pituitary malformations, except for one patient with a hypoplastic pituitary gland, presented GH levels < 10 ng/mL in the GHRH test. The sensitivity of the GHRH test in the diagnostics of GHD was 45%. The high correlation between the GHRH test and anatomical changes in the pituitary provides this test with a high predictive value. In individual clinical cases, knowledge about the level of damage in the hypothalamic-pituitary area can determine diagnostic and therapeutic procedures.

Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: Possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion.

Longitudinal neuroendocrine changes assessed by dexamethasone/CRH and growth hormone releasing hormone tests in psychotic depression

Although psychotic depression has been reported to exhibit a greater degree of dysregulation of hypothalamic-pituitary-adrenocortical (HPA) function than non-psychotic depression, little is known concerning hypothalamic-pituitary-somatotropic (HPS) function in psychotic depression and how neuroendocrine function changes after treatment. To investigate the longitudinal changes in HPA and HPS system function in psychotic depression, we performed repeated dexamethasone/corticotropin releasing hormone (DEX/CRH) tests and growth hormone (GH) releasing hormone (GHRH) tests in inpatients with major depressive disorder. The psychotic depression group exhibited greater elevation of ACTH responses to the DEX/CRH test and stronger decreases in GH responses to the GHRH test than the non-psychotic depression group at admission. At discharge, the neuroendocrine responses to the DEX/CRH test of the psychotic depression group were still stronger than those of the non-psychotic depression group, though there were no significant differences in severity of depression between the groups. There were significant longitudinal changes in neuroendocrine responses to the DEX/CRH test between admission and discharge. The psychotic depression group exhibited increased GH responses to GHRH at discharge compared with those at admission, whereas no significant longitudinal change in GH response was found in the non-psychotic depression group. Consequently, there were no significant differences in GH responses to GHRH between the psychotic and non-psychotic depression groups at discharge. The results of GHRH test showed no significant relationships with severity of depression except psychotic features and the results of the DEX/CRH test. Our findings suggest that the HPS axis may be associated with psychotic features rather than general severity of depression. Further longitudinal studies are needed to clarify the role of HPS function in psychotic depression and whether sustained dysregulation of HPA function in psychotic depression is associated with a poor outcome after discharge.

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.

Relationships of DEX/CRH and GHRH test results to the outcome of depression – Preliminary results suggest the GHRH test may predict relapse after discharge

To explore and compare hypothalamic–pituitary–somatotropic (HPS) axis function and hypothalamic–pituitary–adrenocortical (HPA) axis function in depression, the dexamethasone (DEX)/CRH test and growth hormone releasing hormone (GHRH) test were prospectively performed on patients with depression at the time of admission and discharge. The patients who relapsed within six months after discharge exhibited significantly lower growth hormone (GH) responses to GHRH at the time of discharge than those who did not relapse. There were no significant correlations between GH response to GHRH and the results of DEX/CRH tests after controlling for age, sex, and body mass index. The findings of this study suggest that results of the GHRH test may be a predictor of future relapse in patients with depression.

Administration of Arginine plus Growth Hormone Releasing Hormone to Evaluate Growth Hormone (GH) Secretory Status in Children with GH Deficiency

Diagnosis of growth hormone deficiency (GHD) in childhood is usually based on growth hormone (GH) response to at least two provocative stimuli. The aim of this study was to determine whether sequential administration of arginine (Arg) plus GH releasing hormone (GHRH) could be a useful tool in evaluating GHD in children. Thirty patients with short stature (mean age 9.0 years) with decreased growth rate were tested for GHD with Arg and the insulin tolerance test (ITT). Patients with confirmed GHD (peak GH <8 ng/ml) were subsequently tested with Arg + GHRH. Maximum GH stimulation for Arg and ITT was 6.3 (1.0-7.8) and 6.7 (0.5-7.7) ng/ml, respectively. Peak GH for the Arg + GHRH test was 36.3 (4.3-84.5) ng/ml and significantly different from the other provocative tests. Peak GH values for the three tests were not significantly correlated between tests or with clinical parameters. There were no significant differences in Arg + GHRH results between children with or without abnormal hypothalamic-pituitary MRI scans. Arg + GHRH gave higher GH levels than insulin or Arg alone. Because of the different causes of childhood GHD (hypothalamic and/or pituitary dysfunction), the Arg + GHRH test is unsuitable .for evaluating GHD and deciding whether GH replacement therapy is indicated.

Growth hormone outgrows growth.

Growth hormone (GH) replacement has been offered to GH-deficient (GHD) children for approximately 40 years whereas it has only been a licensed indication for the treatment of GHD adults since 1996. Nonetheless, the advent of GH replacement for adult GHD patients (Jorgensen et al., 1989; Salomon et al., 1989) has proved informative about the overall management of the GHD child and teenager; equally, the longstanding experience of the paediatric endocrinologist with GH replacement has provided some guidance about potential pitfalls in the diagnosis and management of the adult GHD patient. It is the knowledge exchange at this professional interface that forms the focus of this article.

The Reduced Release of GH by GHRH in 8 Subjects Aged 65–69 Years Is Augmented Considerably by Rivastigmine, a Drug for Alzheimer’s Disease

Background: The growth hormone (GH) secretion declines by 14% with each decade of adult life. Several attempts have been made to reverse the manifestations of the senile GH deficiency, termed somatopause, but GH substitution treatment in old age has not yet developed an established regimen. Cholinesterase inhibitors like pyridostigmine are able to elicit GH secretion when administered alone and to enhance the GH response to growth hormone releasing hormone (GHRH), but its clinical use is limited due to the strong peripheral cholinergic side effects. Objective: The aims of our experiments were to find out whether the GH response to GHRH can be augmented by rivastigmine, a new orally applicable and well-tolerated selective inhibitor of cerebral acetylchoinesterase. Methods: Eight healthy volunteers (age range 65–69 years) were studied. After an overnight fast, GHRH tests were done: 1 µg/kg GHRH was injected as an intravenous bolus. Blood samples for an immunoradiometric GH assay were taken at the time of GHRH injection (time 0) and after 15, 30, 45, 60, and 120 min. First, the baseline experiment was done: it consisted of two subsequent GHRH tests which were carried out within an interval of 120 min. Four weeks later the rivastigmine experiment was done identically, but 60 min before performing the second GHRH test, rivastigmine (4.5 mg) was administered orally. The GH secretory responses were expressed as areas under the curve (AUC; median, interquartile range), Wilcoxon’s signed-rank test was used for statistical comparisons. Results: Baseline experiment: The GH AUC of the first GHRH test was 1,040 (range 420–1,250) ng/ml/h. The repeated GHRH stimulation after 120 min (second GHRH test) showed a 13-fold decrease to 80 (range 60–130) ng/ml/h. Rivastigmine experiment: The GH AUC of the first GHRH test was 950 (range 540–1,430) ng/ml/h and, therefore, similar to that of the baseline experiment. 60 min after ingestion of the single oral dose of rivastigmine (4.5 mg), the following GHRH stimulation (second GHRH test) nearly doubled the GH AUC to 1,580 (range 860–3,330) ng/ml/h. Comparing the ΔGH AUC values (ΔGH AUC = GH AUC of the first GHRH test minus GH AUC of the second GHRH test), baseline experiment versus rivastigmine experiment, there was a 20-fold (p = 0.018) increase in GH AUC after rivastigmine pretreatment. Conclusions: Rivastigmine is a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. Future investigations are necessary to find out whether rivastigmine can restore the senile decline of the circadian GH secretion in the long term and, therefore, has new implications for patient treatment.

The hypothalamus–pituitary function after pituitary stereotactic radiosurgery: evaluation of growth hormone deficiency

Radiation therapy to the pituitary gland means a considerable risk of developing hypopituitarism. The aim of the study was to investigate the growth hormone releasing hormone (GHRH)-growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis after treatment with stereotactic radiosurgery to the pituitary because of Cushing's disease. Inpatient ward in university clinic. Eleven adult patients (eight women, three men), 20-65 years of age were studied 2.5-11.3 years after stereotactic radiosurgery (isocentre dose 50-100 Gy lesion-1) and compared with healthy controls. Spontaneous GH secretion was evaluated as 12-h night GH profiles. Stimulated GH responses were evaluated in seven of 11 patients using arginine-insulin and GHRH tests. Serum IGF-I levels were measured in fasting serum morning samples. All patients except one displayed blunted nocturnal GH profiles. After arginine-insulin challenge, six of seven patients displayed low GH release. GH response was higher after GHRH injection compared with both the response to arginine-insulin and to the maximum GH levels in the nocturnal profiles. Seven patients had an IGF-I standard deviation score (SDS) within the normal range for age. Serum IGF-I values were correlated to mean GH values in the 12-h night profile (r = 0.67, P < 0.05) and both these variables were negatively correlated to time elapse since last radiation treatment (r = -0.64, P < 0.05 and r = -0.78, P < 0.05, respectively). Our patients with Cushing's disease evaluated several years after stereotactic radiosurgery as the primary and only treatment, demonstrated severely blunted spontaneous GH secretion and GH response to arginine-insulin. A disturbed regulation at the hypothalamic level was suggested as mechanism for this. Noteworthy is that serum IGF-I values correlated to the mean values of the 12-h GH profile.

Effect of the opioid blockade on the feeding-induced growth hormone response to growth hormone-releasing hormone in women with polycystic ovary syndrome

Objective: To investigate the effect of naloxone, an opioid receptor antagonist, on the release of growth hormone (GH) induced by the growth hormone-releasing hormone (GHRH) in normal-weight and obese women with PCOS in relation to feeding. Design: Prospective clinical study. Setting: Academic research center. Patient(s): Seventeen women with PCOS (10 who were normal weight and 7 who were obese) and 14 control women (7 who were normal weight and 7 who were obese). Intervention(s): A GHRH test (50 μg i.v.) and, on a different day, a GHRH test during a naloxone infusion (1.6 mg/h) during fasting. The same tests were repeated after a standard meal. Main Outcome Measure(s): GH response to GHRH (expressed as the area under the curve [AUC]) in different experimental conditions. Result(s): All normal-weight women showed a significantly higher AUC-GH compared with obese women in the fasting state. Normal-weight controls had a decrease in GH response to GHRH after feeding, and naloxone did not reverse the decrease. In obese controls, feeding increased the GH response but naloxone induced a decrease in the AUC. In fasting, normal-weight women with PCOS, naloxone significantly decreased the AUC-GH; in these patients, food intake induced an inhibition of GH response to GHRH, reversed by naloxone infusion. In obese PCOS patients, GH levels did not increase significantly after GHRH stimulation, either in the fasting state or after a meal, and naloxone did not affect these responses. Conclusion(s): Factors other than obesity and insulin may be involved in disruption of GH secretion in women with PCOS.

Growth hormone deficiency in pituitary disease: relationship to depression, apathy and somatic complaints.

Adults with GH deficiency (GHD) have been reported to suffer from increased levels of depression and apathy, which are thought to contribute to the reduced quality of life observed in these patients when compared with healthy controls. Recent studies, however, cast doubt on the attribution of these impairments to GHD as opposed to an unspecific stress response to the chronic medical condition. To further clarify this relationship, we used psychometric tests to quantify depression, apathy and typical psychosomatic complaints in patients with different types of pituitary disease and compared the results with measurements of the patients' widely varying GH status. In 98 patients, serum IGF-I was measured and at least one provocative test of the somatotrope pituitary axis was performed (GH-releasing hormone test (GHRHT) and/or insulin tolerance test (ITT)). All patients completed a set of well-established psychometric instruments (Beck Depression Inventory (BDI), Apathy Evaluation Scale (AS) and List of Somatic Complaints (LSC)). In addition, AS was administered in an informant report version for completion by a close relative or friend to verify the validity of the patient's self assessment. No relationship between measures of GHD (IGF-I, GHRHT and ITT) and psychometrically measured depression, apathy or psychosomatic well-being was found. A highly significant linear correlation between scores of all psychometric instruments (BDI, AS and LSC) was found. The absence of any relationship between the severity of GHD and the level of depression/apathy/psychosomatic complaints suggests that these impairments are not specific symptoms of GHD. The reported improvement of these symptoms under GH substitution therapy might thus be interpreted as a secondary effect of somatic effects of GH substitution. Consequently, indication for GH substitution therapy should not be based on psychological impairments alone without the presence of somatic symptoms of GHD.

Factors Influencing the Growth Hormone Response to Growth Hormone-Releasing Hormone in Children with Idiopathic Growth Hormone Deficiency

Objective: To evaluate the factors influencing the growth hormone (GH) response to GH-releasing hormone (GHRH) test in idiopathic GH deficiency. Methods: 28 patients aged 4.9 ± 0.7 years with certain GH deficiency were given GHRH (2 µg/kg). Results: The GH peak after GHRH was correlated negatively with age at evaluation (r = –0.37, p < 0.05) and body mass index (r = –0.44, p = 0.02), and positively with anterior pituitary height (r = 0.47, p = 0.02), GH peak after non-GHRH stimulation (r = 0.78, p < 0.0001) and spontaneous GH peak (r = 0.82, p = 0.007). It was lower in the patients aged >5 years than in the youngest (p = 0.04), but it was similar in the patients with and without features suggesting a hypothalamic origin. Conclusion: The GH response to GHRH test cannot be used to differentiate between hypothalamic and pituitary forms of idiopathic GH deficiency, probably because the GH response decreases after the first 5 years of life, whatever the origin of the deficiency.

Somatotropic axis dysfunction in critically ill patients: altered response to growth hormone-releasing hormone

The aim of this study was to investigate the pituitary‘s capacity to release growth hormone (GH) in critically ill patients by stimulation with GH-releasing hormone (GHRH). Thirty-two patients with severe sepsis and 20 critically ill, nonseptic patients after major surgery were studied in the setting of a surgical intensive care unit. Nine healthy individuals without clinical signs of disturbance of the somatotropic hypothalamic-pituitary axis were included for comparison. The pituitary‘s capacity to release GH was tested with an intravenous bolus injection of 1μg per kg body weight GHRH (Ferring, Kiel, Germany). The median basal plasma GH level was comparable in all groups studied. In contrast, the median peak plasma GH level was significantly lower in critically ill, nonseptic patients after major surgery (5.1, range 1.3–131.0ng/ml, n=20) compared to healthy individuals (23.2, range 12.8–35.2 ng/ml, n=9) (p ;0.01). However, the median peak plasma GH level in patients with severe sepsis (15.3, range 1.6–111.5ng/ml, n=32) was not significantly different compared to healthy individuals (23.2, range 12.8–35.2ng/ml, n=9) (p>>;0.05). The median plasma insulin-like growth factor-I (IGF-I) level was significantly decreased in patients with severe sepsis (32.0, range 32.0–150.0ng/ml, n=32) and in critically, ill, nonseptic patients after major surgery (50.0, range 32.0–144.0ng/ml, n=20) compared to healthy individuals (229.0, range 129.0–503.0ng/ml, n=9) (p ;0.001). No significant difference was found between patients after major surgery and patients with severe sepsis. In conclusion, a low level of circulating IGF-I was associated with the pituitary‘s low capacity to release GH in critically ill, nonseptic patients after major surgery, whereas patients with severe sepsis had a widespread range of pituitary capacity to release GH associated with low IGF-I levels. The pathophysiological basis for not secreting stored GH during critical illness is at present unclear. The treatment with high doses of human GH has been shown to attenuate the catabolic response to injury, surgery and sepsis, whereas in patients with severe sepsis GH administration bypasses its pituitary storage and may trigger a hyperinflammatory response. However, critically ill nonseptic patients after major surgery may profit from GH treatment since they possess a low pituitary capacity to release GH. Thus, performing a GHRH test might facilitate the decision for treatment with human GH.

Effect of feeding on growth hormone response to growth hormone-releasing hormone in polycystic ovarian syndrome: relation with body weight and hyperinsulinism.

The plasma growth hormone (GH) response to direct stimulation with growth hormone-releasing hormone (GHRH) before and after a standard meal was investigated in 14 polycystic ovarian syndrome (PCOS) subjects. Data were compared with those obtained from 14 healthy normovulatory matched patients. All women underwent an oral glucose tolerance test (OGTT) (75 g) and basal plasma hormone concentrations were evaluated. On a different day all subjects had a GHRH test (50 microg GHRH) both before and after lunch randomly. In obese PCOS subjects the GH response to GHRH was blunted after a meal, while in obese control patients there was an enhanced response of GH to GHRH after a meal. Normal control subjects showed an inhibition of the GH response after feeding and lean PCOS subjects showed a trend toward an augmented GHRH related secretion after a meal significantly higher than normal controls (P < 0.05) but not significantly higher than the pre-prandial response. In conclusion, the data indicate in PCOS a derangement of GH secretion related to food ingestion; in particular obese PCOS patients did not exhibit any change of GH response after a meal compared with the paradoxical response observed in obese controls. Several other factors beyond body mass index and hyperinsulinism could be involved in these pathophysiological events.

Persistence of anomalies in the growth hormone-releasing hormone-stimulated growth hormone response in diabetic-uremic patients after combined kidney-pancreas transplantation.

Increased circulating growth hormone (GH) levels and aberrant response to different stimuli characterize both type 1 diabetes mellitus and chronic uremia and are associated with severe retinal, kidney and heart complications. Combined kidney and pancreas transplantation is a therapy that restores the endogenous, closed-loop, insulin secretion in diabetes and cure uremia. To evaluate if combined transplantation can restore a normal secretion and response of GH to growth hormone releasing hormone (GH-RH), we studied four groups of subjects: (1) seven type 1 diabetic patients with end-stage renal failure who had received pancreas and kidney transplantation (KPTx); (2) six diabetic uremic subjects, candidates for combined transplantation (IDDUP); (3) nine patients with chronic uveitis on immunosuppressive therapy comparable to pancreas recipients, six of whom treated only with prednisone (UVEST), while three (4) were treated with both prednisone and cyclosporin (UVESTCY). All subjects underwent a GH-RH test (50 microg intravenously, i.v., at 13:00 h). Serum insulin levels were significantly higher in IDDUP compared to UVEST (P=0.05) both at baseline and post GH-RH stimulus, while were similar to KPTx (P=0.2) and UVESTCY (P=0.7). In contrast, plasma free fatty acids were similar in all groups. In IDDUP baseline plasma glycerol was higher than in KPTx (P=0.04) and UVEST (P=0.02) and similar to UVESTCY (P=0.36); glycerol concentration did not change after GH-RH (P=0.08). Before and after GH-RH, serum GH levels tended to be higher in IDDUP (P=0.5) and KPTx (P=0.2) compared to UVEST and UVESTCY. Our results indicate that: 1) kidney-pancreas transplantation does not normalize the GH response to GH-RH; 2) GH abnormalities are not due either to the chronic immunosuppressive therapy or to the insulin effect on GH release; 3) GH abnormalities are probably secondary to functional and/or organic complications of the hypothalamus and/or pituitary as a sequela of diabetes mellitus.

Diagnosis of Growth Hormone (GH) Deficiency in Adults with Hypothalamic-Pituitary Disorders: Comparison of Test Results Using Pyridostigmine Plus GH-Releasing Hormone (GHRH), Clonidine Plus GHRH, and Insulin-Induced Hypoglycemia as GH Secretagogues1

The insulin tolerance test (ITT) is widely accepted as the method of choice to evaluate GH secretion capacity in adults with hypothalamic-pituitary disorders. However, the test is not suitable in the elderly or in patients with cardiovascular disease or seizure disorders. In recent years alternatives to the ITT have been introduced. The purpose of the present study was to investigate the diagnostic outcome with the ITT, the pyridostigmine plus GHRH (PD + GHRH) test, the clonidine plus GHRH (CLO+GHRH) test, and insulin-like growth factor I (IGF-I) in an unselected group of patients with hypothalamic-pituitary disease. An evaluation of the reproducibility of the different stimulation tests was included in the study. Based on repeated testing with the various GH stimulation tests in healthy adult males and females, the lower limits of normality for the ITT, the PD+GHRH test, and the CLO+GHRH test were 3.92, 12.8, and 19.0, microg/L, respectively. A consecutive group of 26 unselected patients with hypothalamic-pituitary disorders, 13 males and 13 females (median age, 44 ys), were tested twice with all stimulation tests, except that only 10 patients were tested once with the CLO+GHRH test due to side-effects related to clonidine. The peak GH responses between test 1 and test 2 correlated significantly in both the ITT and the PD + GHRH test (P < 0.02), and no significant difference was observed in the median peak response to repeated testing. In addition, no sex difference was observed. The coefficients of variation (CV) were 96% (ITT) and 45% (PD + GHRH), but in the majority of patients low values were repeatedly low. The peak GH response was significantly higher during the PD+GHRH test than during the ITT (P = 0.008). In the 10 patients tested with the PD+GHRH and CLO+GHRH tests there was no significant difference in the peak GH response (P = 0.398). When the test specific cut-off values were used, no significant difference in diagnostic outcome was observed between the various tests (P > 0.3). In contrast, the diagnosis obtained with IGF-I differed significantly from all GH stimulation tests (P < 0.03). Twenty (77%) and 22 (85%) patients were diagnosed to be GH deficient with the ITT and the PD+GHRH test, respectively. Of the 14 patients with multiple pituitary failure (>2 hormones affected), GH deficiency was present in more than 90% regardless of the type of stimulation test used. The IGF-I levels were only subnormal in 42% of the patients and did not correlate with the peak GH responses in any of the stimulation tests (P > 0.05). Except for 1 patient all patients with subnormal IGF-I were GH deficient in all stimulation tests. It is concluded that in patients with hypothalamic-pituitary disease and a normal IGF-I level 2 stimulation tests should be performed to establish a diagnosis of GH deficiency. In patients with a subnormal IGF-I value a single GH stimulation test should be sufficient to confirm the presence of GH deficiency.

Growth Hormone Response to a Growth Hormone-Releasing Hormone Stimulation Test in a Population-Based Study following Cranial Irradiation of Childhood Brain Tumors

Children with brain tumors are at high risk of developing growth hormone deficiency (GHD) after cranial irradiation (CI) if the hypothalamus/pituitary (HP) axis falls within the fields of irradiation. The biological effective dose (BED) of irradiation to the HP region was determined, since BED gives a means of expressing the biological effect of various irradiation treatment schedules in a uniform way. Hypothalamic versus pituitary damage as cause of GHD was distinguished in 62 patients by comparing the growth hormone (GH) peak response to an insulin tolerance test (ITT)/arginine stimulation test and the GH response to a growth hormone-releasing hormone (GHRH) stimulation test. Peak GH response to a GHRH test was significantly higher (median 7.3 mU/l; range: 0.5–79.0 mU/l) than that of an ITT/arginine test (median 4.7 mU/l; range: 0.01–75.0 mU/l) (p = 0.017). Peak GH after a GHRH test was significantly inversely correlated to follow-up time (r_s = –0.46, p < 0.0001) and to BED (R_s = –0.28, p = 0.03), and both were found to be of significance in a multivariante regression analysis. We speculate that a significant number of patients developed hypothalamic radiation-induced damage to the GHRH secreting neurons, and secondary to this the pituitary gland developed decreased responsiveness to GHRH following CI in childhood.