Pituitary Growth Hormone Reserve Research Articles

Recruiting of somatotroph cells after combined somatostatin, GHRH and growth hormone (GH) secretagogue stimulation in a study of pituitary GH reserve in prepuberal female rats.

Diagnostic confirmation of growth hormone (GH) deficiency in children and adults is based on stimulation tests designed to assess the pituitary reserve by measuring the amount of GH released into the bloodstream; however, the results obtained by this means cannot provide any direct indication of the amount of GH actually produced by pituitary somatotroph cells. The present paper sought to test the hypothesis that release of GH following administration of specific stimuli does not accurately reflect the somatotroph cell response, and that the amount of GH released into the bloodstream may often be greater or smaller than the amount synthesized. GH release and changes in the proportion of somatotroph cells were charted in prepuberal female Wistar rats, following administration of several different GH stimuli: GHRH (1 microg/kg), GHRP-6 (1 microg/kg), GHRELIN (1 microg/kg) and combined GHRH-based treatments, with or without SRIH pretreatment (1 microg/kg) 90 minutes earlier. Peak serum GH values were recorded 15 minutes after administration of GHRH+GHRELIN and GHRH+GHRP-6; maximum stimulation in terms of an increased proportion of somatotroph cells occurred 15 minutes after combined adminstration of GHRH + GHRELIN. SRIH pretreatment (- 90 min) inhibited GH release, with a subsequent "escape" and lack of response to stimulation which lasted at least 30 minutes except following administration of GHRH. However, combined administration of GHRH+GHRELIN maintained stimulation of the somatotroph cell population. In conclusion, the results suggest that the enhanced GH release prompted by stimulation tests used to diagnose GH deficiency in prepuberal female rats does not fully reflect somatroph cell dynamics, and that not all the GH produced and stored by somatotroph cells is released into the bloodstream.

Traumatic brain injury as a relevant cause of growth hormone deficiency in adults: A KIMS-based study

Casanueva FF, Leal A, Koltowska-Häggström M, Jonsson P, Góth MI. Traumatic brain injury as a relevant cause of growth hormone deficiency in adults: a KIMS-based study. ObjectivesTo characterize further the clinical manifestations and the efficacy of growth hormone (GH) replacement therapy in patients with adult-onset growth hormone deficiency (GHD) reported in the KIMS (Pfizer’s international metabolic database) as caused by traumatic brain injury (TBI) and to compare them with nonirradiated patients whose GHD was due to a nonfunctioning pituitary adenoma (NFPA). DesignObservational study. SettingSubjects selected from the KIMS database. ParticipantsFifty-one patients with GHD resulting from TBI and 688 patients with GHD resulting from NFPA. Both groups were selected from the KIMS and had adult-onset GHD with GH replacement therapy only after KIMS entry and before and after KIMS entry. InterventionsNot applicable. Main outcome measuresAge, body mass index, age at disease onset, age at disease diagnosis, age at KIMS entry, final height, GH peak at testing, GH replacement dose, routine biochemical analysis, clinical manifestations of disease, and quality of life measurements. ResultsPatients with TBI were significantly younger at study entry and were younger both at pituitary disease onset and at GHD diagnosis, but they showed a significant delay in treatment. When comparing patients not treated with GH before entering in the KIMS, patients with TBI were significantly shorter (167.2±1.7cm) than those with NFPA (171.6±0.4cm) in final height. TBI patients had lower GH reserves than NFPA patients, and although the latter group experienced more positive changes, both groups benefited from GH replacement therapy. ConclusionsPatients with GHD due to TBI showed a significant reduction in height and a reduction in pituitary GH reserve and were diagnosed and treated with inappropriate delay.

Growth hormone response to growth hormone-releasing hormone varies with the hypothalamic-pituitary abnormalities

We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 +/- 4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI, Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30-09.00 h, as well as after infusion of GHRH (1-29) at escalating doses for 3h: 0.2 micrograms/kg at 09.00-10.00 h, 0.4 micrograms/kg at 10.00-11.00 h, 0.6 micrograms/kg at 11.00-12.00 h and an intravenous bolus of 2 micrograms/ kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1-29) was delayed (135-180 min) and extremely low (median 2mU/l). In group II it was delayed (135-180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185-210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75-120 min) but it declined rapidly (median 14.4 mU/l at 185-210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I (0.23 +/- 0.05 U/ml) than in groups II (0.39 +/- 0.13U/ ml, p < 0.01) and III (1.54 +/- 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1-29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1-29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group Ia patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained.

Growth hormone (GH) responses to the combined administration of GH-releasing hormone plus GH-releasing peptide 6 in adults with GH deficiency

In recent years the health problems of adults with growth hormone deficiency (GHD) and the benefits of GH replacement therapy have received considerable attention. However, the reliability of conventional GH tests in the assessment of pituitary GH reserve in this group of patients is still controversial. In this study, we assessed GH secretion after the combined administration of GH-releasing hormone (GHRH) (1 microgram/kg iv) and GH-releasing peptide 6 (GHRP-6, 1 microgram/kg iv) in adult patients diagnosed with GHD by conventional GH testing, and correlate this response with insulin-like growth factor I levels. Twenty-one subjects (13 male, 8 female) with long-standing diagnosis of GHD aged 21-54 years were studied. In 13 subjects GH responses to GHRH plus GHRP-6 were markedly reduced (peak GH response < 10 mU/l), whereas in the remaining eight the response was greater (range 11-100 mU/l). In conclusion, our data show that combined administration of GHRH plus GHRP-6 elicited a significant increase in plasma GH levels in about 40% of patients diagnosed with GHD by conventional GH testing.

Another look at co-treatment with growth hormone and human menopausal gonadotrophins in poor ovarian responders

The objective of this study was to evaluate whether a combined human growth hormone (HGH) and human menopausal gonadotrophin (HMG) treatment can improve ovulation induction in poor ovarian responders. Ten patients aged 28-43 years and requiring > 25 ampoules of HMG for ovulation were admitted to the study. Pituitary growth hormone reserve was evaluated by clonidine stimulation and insulin tolerance tests before commencement of treatment. The patients underwent one treatment cycle with D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp6-LHRH) and HMG and another cycle with D-Trp6-LHRH, HMG and HGH. Serum HGH, insulin-like growth factor (IGF)-I and oestradiol were measured throughout the two treatment cycles and follicular maturation was assessed by ultrasonographic studies. All patients tested showed no elevation of their serum HGH concentration during a clonidine test, but showed an adequate response during insulin tolerance tests. No significant difference was found in the number of HMG ampoules, duration of treatment, number of leading follicles, and serum oestradiol concentration between the two treatment cycles. Co-treatment with HGH and HMG did not improve ovarian performance in poor ovarian responders. No correlation was found between the results of HGH pituitary function tests and the ovarian response to gonadotrophins.

A new test for the diagnosis of growth hormone deficiency due to primary pituitary impairment: combined administration of pyridostigmine and growth hormone-releasing hormone

The diagnosis of growth hormone (GH) deficiency (GHD) is currently based on failure to increase plasma GH levels to an arbitrary cutoff point of 7 or 10 micrograms/l in response to two provocative stimuli. False negative responses to these tests, however, frequently occur thus reducing their diagnostic reliability. The aim of this study was to assess a combination of pyridostigmine (PD) and GH-releasing hormone (GHRH) (60 mg oral PD 60 min before 1 microgram/Kg GHRH iv) as a reliable test probing pituitary somatotropic function. In fact PD, an acetylcholinesterase inhibitor, strikingly potentiates GH response to GHRH likely by inhibiting somatostatin release. The combination PD + GHRH was tested in normal children and adolescents (NS, n = 27) and in a large group of short children classified as having familial short stature (FSS, n = 24), constitutional growth delay (CGD, n = 34) and GH deficiency (organic, oGHD, n = 6; idiopathic, iGHD, n = 10). In all groups results obtained by PD + GHRH were compared with those obtained by testing with GHRH, clonidine (CLON) and PD alone and by studying spontaneous nocturnal GH secretion over 8 hours. Assuming 7 micrograms/l as minimum normal GH peak, a positive response occurred in only 18/24, 11/12 and 12/13 NS for GHRH, CLON, and PD, respectively. In contrast even assuming a minimum normal GH peak as high as 20 micrograms/l, PD + GHRH induced a positive response in 27/27 NS all having a nocturnal GH mean concentration (MC) greater than or equal to 3 micrograms/l. Therefore PD + GHRH test gave no false negative responses and this was true not only in NS but even in all FSS and CGD having a GH MC greater than or equal to 3 micrograms/l. On the other hand, PD + GHRH induced a negative GH response in all oGHD and in 8/10 iGHD patients. In the remaining two iGHD patients, PD + GHRH demonstrated a normal pituitary GH reserve in spite of a GH MC less than 3 micrograms/l and low IGF-I level, thus pointing to a hypothalamic pathogenesis for the GHD. Considering FSS and CGD children having a GH MC less than 3 micrograms/l, PD + GHRH showed a primary pituitary GH deficiency in 3/12 CGD with low plasma IGF-I levels. In conclusion, in slowly growing children PD + GHRH test is the most reliable provocative test for the diagnosis of primary pituitary GH deficiency being capable to discriminate between an unequivocally normal and impaired somatotropic function.(ABSTRACT TRUNCATED AT 400 WORDS)

Correlation between pituitary growth hormone reserve and degree of growth failure in children with short stature.

The correlation between a releasable pituitary growth hormone (GH) pool and degree of growth failure was examined in 30 children with GH deficiency (group I) and 19 children with normal short stature (group II). Based on the responsiveness of GH to GH-releasing hormone (GHRH), group I, with low GH responses (below 7 ng/ml) to both insulin and arginine, was classified into three subgroups; Ia (peak value less than 10 ng/ml, n = 19), Ib (10-20 ng/ml, n = 5) and Ic (above 20 ng/ml, n = 6). Group II, with a GH response above 10 ng/ml to either insulin or arginine, was also divided into IIa (below 20 ng/ml, n = 5) and IIb (above 20 ng/ml, n = 14). Body length and growth velocity in Ia and Ib were significantly reduced vs Ic; bone age in Ia was retarded vs Ic; plasma somatomedin C (Sm-C) levels in Ia and Ib were decreased vs Ic, who had almost normal levels (0.90 +/- 0.55 U/ml). The incidence of other combined pituitary hormone deficiencies and previous perinatal distress was definitely high in Ia and Ib, but zero in Ic. In group II also, body length and growth velocity were significantly decreased in IIa vs IIb (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma GH responses to GHRH and other provocative stimuli in idiopathic GH deficiency with or without abnormal delivery.

Seventeen patients with idiopathic growth hormone deficiency (GHD) were divided into two groups: one has no perinatal abnormalities (group A, n = 7) and the other has perinatal abnormalities, i.e. breech delivery and asphyxia (group B, n = 10). To see whether there are any differences in hypothalamo-pituitary dysfunctions in the two groups, the pituitary growth hormone (GH) reserve was examined. After 100 micrograms of synthetic growth hormone releasing hormone (GHRH) injection, group A showed a much higher peak values compared to group B (mean +/- S.E.: 16.1 +/- 3.5 ng/ml vs. 3.6 +/- 0.7 ng/ml, p less than 0.01), although there were no differences in their baseline GH values. In addition, plasma GH responses to arginine and L-dopa, which were performed at the diagnosis of GHD, were also greater in group A than group B (mean peak value: arginine, 3.4 +/- 0.5 ng/ml vs 1.8 +/- 0.5 ng/ml, p less than 0.05; L-dopa, 3.2 +/- 0.7 ng/ml vs. 1.3 +/- 0.2 ng/ml, p less than 0.01). There were no significant differences in the bone ages in the two groups, but bone age to chronological age ratio and pubertal development were significantly lower in group B. High frequency of primipara was observed in group B (7/10) compared to group A (2/7). These results indicate that pituitary GH reserve is much impaired in GHD with abnormal delivery compared to that without abnormal delivery, probably depending on the irreversible hypothalamo-pituitary damages due to prolonged anoxic state during the delivery. Especially, such risks seems to be high when cases of breech presentation are delivered from primipara mothers.

Growth hormone response to growth hormone releasing hormone 1-40 in Turner's syndrome.

The response of growth hormone (GH) to acute administration of GH-releasing hormone 1-40 (GHRH) was evaluated in 12 patients with Turner's syndrome and in 12 prepubertal or early pubertal girls. In 7 of 12 patients GHRH induced a definite increase (greater than 10 ng/ml) of plasma GH levels. In 5 patients there was a poor GH rise after GHRH administration (less than 10 ng/ml). Overall, the mean GH response of patients was significantly lower than that of normal girls. Five out of 7 patients with a 45 X,O karyotype had a reduced GH rise after GHRH, while all patients with non X,O karyotype (mosaicism and/or 46 X,iX) had a normal GH response to GHRH. Although the cause of short stature in patients with Turner's syndrome is most likely multifactorial, a reduced pituitary GH reserve, as documented by the reduced GH response to GHRH in some of our patients, may contribute to the growth impairment in this disorder.

Long-term Efficacy of Deferoxamine Iron Chelation Therapy in Adults With Acquired Transfusional Iron Overload

Transfusional iron overload in adult patients with acquired anemias may result in widespread organ dysfunction. Long-term deferoxamine mesylate therapy was administered by continuous subcutaneous infusion to six such patients, who have been followed up for up to 66 months of therapy while continuing to be transfusion-dependent. During deferoxamine therapy, liver density by computed tomographic scan decreased in four of five patients, liver iron content decreased in two of three patients, and liver function normalized in two patients. Plasma cortisol response to insulin-induced hypoglycemia improved in three of five patients receiving therapy. Pituitary growth hormone reserve normalized in two patients and remained normal in the other three tested. One patient, treated concurrently with ascorbic acid, died suddenly. The other five patients have had no cardiac deterioration by noninvasive testing. We conclude that long-term deferoxamine iron chelation therapy is effective not only in retarding but, in some cases, even reversing organ damage caused by transfusional iron overload.

Plasma growth hormone response to human growth hormone releasing factor in rats administered with chlorpromazine and antiserum against somatostatin. Effects of hypo- and hyperthyroidism.

The effect of hypo- and hyperthyroidism on the plasma growth hormone (GH) response to synthetic human growth hormone releasing factor (GRF) was determined in conscious, freely moving rats pretreated with chlorpromazine and antiserum against somatostatin. Chlorpromazine plus somatostatin antiserum pretreated rats gave consistent response to GRF which was not observed in untreated rats. Chlorpromazine alone has no effect on GH secretion induced by GRF in rat pituitary monolayer culture. In rats made hypothyroid by thyroidectomy, both basal and peak plasma GH responses to a small (0.25 microgram/kg bw) and a moderate dose of GRF (1 microgram/kg bw) were significantly reduced as compared to controls. In rats made hyperthyroid by the administration of thyroxine, basal and peak plasma GH responses to a small but not to a moderate dose of GRF were significantly reduced as compared to controls. A reduced plasma GH response to a small dose of GRF was observed 8 days after the cessation of thyroxine administration. The pituitary GH reserve was markedly reduced in hypothyroid but not in hyperthyroid rats as compared to their respective controls. These results indicate that plasma GH response to GRF is reduced both in hypo- and hyperthyroidism. The mechanism involved in the phenomenon appears to be different between the two conditions.

Growth-hormone releasing factor and clonidine in children with constitutional growth delay. Evidence for defective pituitary growth hormone reserve.

Six male prepubertal children with constitutional growth delay (CGD), and a subnormal growth hormone (GH) response to insulin hypoglycemia, and four normal prepubertal children were given in different occasions 1 microgram/Kg iv synthetic hpGRF-40 or a single oral dose of 0.15 mg/m2 clonidine (Clon), an effective growth hormone (GH) secretagogue. In the normal children brisk and clear-cut GH rises were detected in plasma after hpGRF-40 (peak GH levels at 15-30 min) or clonidine (peak GH levels 60-90 min). In CGD children hpGRF-40 induced a biphasic response, e.g. a slight increase in plasma GH at 15 min followed by a delayed and erratic GH rise occurring 45-120 min post-injection. Also the GH response to Clon was sluggish and delayed and peak plasma GH levels were attained only 90-180 min post-drug administration. These data indicate that the CGD children of our study have a defect in the pituitary GH reserve.

The glucagon stimulation test: Effect on plasmagrowth hormone and on immunoreactive insulin, cortisol, and glucose in children

Plasma growth hormone (GH), immunoreactive insulin (IRI), cortisol, and glucose were studied before andafter the intramuscular injection of glucagon (0.1 mg. per kilogram) in 80 prepubertal children. Glucose, IRI, GH, and cortisol values rose after the injection of glucagon in normal children. Peak levels were observed at 30 minutes for glucose and IR1, at 120 minutes for GH, and at 180 minutes for cortisol. Blunted responses of GH were observed in some patients with hypothyroidism or celiac disease. Hypopituitary patients had a normal response of glucose and of IR1 but not of plasma GH; plasma cortisol levels incresed following glucagon administration in those patients who otherwise had normal corticotropin reserve. In 32 of 38 children without pituitary disease, GH responses were higher to glucagon than they were to induced hypoglycemia. It is concluded that the glucagon stimulation test is a safe, easy, and reliable test to study pituitary GH reserve in children. Plasma growth hormone (GH), immunoreactive insulin (IRI), cortisol, and glucose were studied before andafter the intramuscular injection of glucagon (0.1 mg. per kilogram) in 80 prepubertal children. Glucose, IRI, GH, and cortisol values rose after the injection of glucagon in normal children. Peak levels were observed at 30 minutes for glucose and IR1, at 120 minutes for GH, and at 180 minutes for cortisol. Blunted responses of GH were observed in some patients with hypothyroidism or celiac disease. Hypopituitary patients had a normal response of glucose and of IR1 but not of plasma GH; plasma cortisol levels incresed following glucagon administration in those patients who otherwise had normal corticotropin reserve. In 32 of 38 children without pituitary disease, GH responses were higher to glucagon than they were to induced hypoglycemia. It is concluded that the glucagon stimulation test is a safe, easy, and reliable test to study pituitary GH reserve in children.

The effect of arginine infusion on plasmagrowth hormone and insulin in children

The plasma growth hormone (GH) and insulin responses to the intravenousadministration of arginine (0.5 Gm. per kilogram) have been determined in 25 children with intact anterior pituitary function and in 17 children with hypopituitarism. Arginine increased the plasma GH concentrations in 21 of the 25 control subjects, but failed to do so in 4 boys. After pretreatment with diethylstilbestrol, two of these patients had increased GH concentrations in control specimens, while in the other two subjects the GH response to arginine improved. The GH concentration was low in control specimens and did not increase following the administration of arginine in 16 of 17 patients with hypopituitarism. A low normal GH response was recorded in one such patient. The mean plasma insulin responses of the two groups were similar. It is concluded that arginine-induced GH release is a reasonable screening test of pituitary GH reserve, but that abnormal responses or results that do not agree with one's clinical impression should be confirmed by other studies.

Comparison of insulin and 2-deoxy-D-glucose-induced glucopenia as stimulators of growth hormone secretion

Responses of plasma growth hormone after insulin-induced hypoglycemia and 2-deoxy-D-glucose (2-DG)-induced glucopenia were studied in 10 normal, 6 obese, 8 acromegalic, 6 addisonian, and 2 hypopituitary subjects. After insulin hypoglycemia, the mean increases of growth hormone above basal levels were: normal 27.6, addisonian 38.8, obese 2.3, active acromegalic 9.9, and inactive acromegalic subjects 3.1 mμg./ml. After 2-DG-induced glucopenia, the mean increases of growth hormone above basal levels were: normal 19.1, addisonian 25.6, obese 0.6, active acromegalic 6.5 and inactive acromegalic subjects 2.7 mμg./ml. No increase was noted with either stimulus in a hypopituitary subject. Both stimuli were effective in releasing growth hormone from the pituitary. The increase in growth hormone levels was higher and more consistent after insulin-induced hypoglycemia than after 2-DG-induced glucopenia. 2-DG, however, did produce a more sustained increase in growth hormone levels. In those subjects who have impaired insulin sensitivity, 2-DG—which acts by inducing cellular glucopenia—should be useful in evaluating pituitary growth hormone reserve.