Diurnal Growth Hormone Research Articles

Circadian variation in the pharmacokinetics of steady state continuous subcutaneous infusion of growth hormone in adult growth hormone deficient patients

BackgroundPrevious studies in growth hormone (GH)-deficient (GHD) patients have indicated a possible diurnal variation in the pharmacokinetics (PK) of GH after subcutaneous (sc) GH administration. Thus, higher GH levels were observed during the night with continuous sc infusion, and increased GH bioavailability was reported following daily sc injections in the evening compared to morning. ObjectiveThe aim was to study whether diurnal variability in the PK of sc administered exogenous GH can be reproduced under standard conditions for all study participants, e.g. supine rest. Design and methodsEight male GHD patients (59.8±8years, body mass index 29.7±4.9kg/m2) received a continuous sc infusion of GH (3mg/24h) for 60h on two different occasions. Diurnal variation in PK of GH was studied during steady state in the last 24h of the infusion period. ResultsMedian GH levels were higher at night time (23:00h–07:00h) than during the day (10:00h–18:00h) for visit 1 [5.1 (4.5–7.2ng/ml/0.5h) vs. 4.6 (3.7–5.7ng/ml/0.5h); p<0.05], and reproducible results of diurnal GH variation were obtained during visit 2 [5.7 (4.6–7.4) ng/ml/0.5h vs. 4.6 (3.8–6.0) ng/ml/0.5h, p<0.05]. Reproducible results between days 1 and 2 were also obtained during 08:30h–20:30h and 20:30h–08:30h, respectively. ConclusionsPrevious findings of higher nocturnal GH levels were confirmed during steady state continuous sc GH infusion under standard conditions. The underlying mechanisms, e.g. whether GH absorption, distribution or elimination is primarily affected need to be further elucidated.

Changes in IGF-I, IGFBP-3 and ghrelin levels after adenotonsillectomy in children with sleep disordered breathing

Objective The aim of this study was to determine the changes in insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and ghrelin levels following adenotonsillectomy (T&A) in children with sleep disordered breathing (SDB). Methods Forty children (mean age 4.85 ± 2.15 years) clinically diagnosed with adenotonsillar hypertrophy (ATH) related SDB were enrolled. All children underwent T&A. Serum levels of IGF-I, IGFBP-3 and ghrelin were measured before and 6 months after T&A. Results Serum levels of IGF-I and IGFBP-3 were significantly higher after T&A ( p < 0.001). Serum ghrelin levels showed a significant decrease after T&A ( p < 0.001). Conclusion Children with ATH related SDB who underwent T&A showed significant increases in IGF-I and IGFBP-3 levels indicating an increase in diurnal growth hormone secretion as well as a significant decrese in ghrelin levels indicating an increased oral food intake in the postoperative period.

Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarction

OBJECTIVESWe investigated whether insulin-like growth factor-1 (IGF-1) is reduced in the early phase of acute myocardial infarction (AMI) and whether such a decrease might influence prognosis.BACKGROUNDInsulin-like growth factor-1 protects against insulin resistance and apoptosis. Although insulin resistance has been reported in AMI, IGF-1 levels have not been investigated.METHODSWe measured serum IGF-1 in 23 patients with AMI within 24 h of symptom onset and in 11 matched controls. In the first 12 patients and controls, we also measured fasting insulin, diurnal growth hormone (GH) and insulin sensitivity (assessed as glucose disappearance or T/2 after an insulin bolus), and repeated IGF-1, insulin and GH after one year. In all patients, 90-day cardiovascular death, recurrent ischemia, reinfarction, revascularization and late malignant arrhythmias were assessed.RESULTSThe AMI patients versus controls showed markedly reduced IGF-1 (115 ± 112 vs. 615 ± 300 ng/ml, p < 0.0001) and slower T/2 (−0.98 ± 1.5 vs. −2.57 ± 1.0 mg/dl/min, p = 0.01). Low IGF-1 often preceded the rise of myocardial necrosis markers. Patients with 90-day events (n = 12) versus those without had lower IGF-1 (47 ± 54 vs. 189 ± 110 ng/ml, p < 0.0001). Acute phase GH and insulin concentrations did not differ significantly from controls. After one year, the patients’ IGF-1 values had risen to 460 ± 242 ng/ml (p = 0.1 vs. controls, p < 0.0005 vs. acute phase), whereas GH levels were lower (0.2 ± 0.2 vs. 2.5 ± 2.3 ng/ml, p = 0.01) and insulin levels higher (12.5 ± 0.2 vs. 3.9 ± 2.6 μU/ml, p < 0.0001) compared with controls.CONCLUSIONSIn the early phase of AMI, serum IGF-1 levels are markedly reduced and may contribute to adverse outcomes. Reduced IGF-1 preceding the rise of myocardial necrosis markers suggests a possible pathogenetic role. A compensatory increase in IGF-1 appears to occur by one year.

Estimation of growth hormone secretion rate: impact of kinetic assumptions intrinsic to the analytical approach.

We compared four common mathematical techniques to determine daily endogenous growth hormone (GH) secretion rates from diurnal plasma GH concentration profiles in 24 women (16 upper- or lower-body obese and 8 normal-weight individuals). Two forms of deconvolution analysis and two techniques based on a priori determined GH clearance estimates were employed. Deconvolution analyses revealed significant differences in the 24-h GH secretion rate between normal-weight and upper-body obese women, whereas the other two techniques did not. Moreover, deconvolution analyses predicted that the reduction in mean plasma GH concentrations in upper-body obese women was accounted for by impaired GH secretion, whereas the other methods suggested that obesity increases GH metabolic clearance. Thus we infer that disparate conclusions concerning GH secretion can be drawn from the same primary data set. The different inferences likely reflect dissimilar kinetic assumptions and the particular limitations intrinsic to each analytical approach. Accordingly, we urge caution in the facile comparison of calculated GH secretion data in humans, especially when kinetic and secretion measurements are performed under different conditions. The most appropriate way to determine the GH secretion rate in humans must be balanced by the exact intent of the experiment and the acceptability of different assumptions in that context.

Gender Differences in Diurnal Growth Hormone and Epinephrine Values in Young Adults during Ambulation

In the present study, the impact of gender, oral contraceptives, and ambulation on serum growth hormone (GH) and urinary catecholamines was examined in healthy young adults. Twenty-one medical student volunteers--7 men, 7 women, and 7 women taking oral contraceptives--were investigated. Serum samples were drawn every second hour during a 24-h period. At 0800 the first morning, serum samples were drawn while subjects were in the ambulatory state; the next morning, serum samples were drawn at 0800 while the subjects were still resting in bed. During the daytime, GH concentrations were sevenfold higher in the women than in the men, a difference larger than described previously. During the night, there was no gender difference. In the morning, ambulatory GH concentrations were 28-fold higher in the women than in the men, whereas supine GH concentrations were only 4.6-fold higher in the women than in the men. Daytime urinary output of epinephrine was lower in the women than in the men, whereas there was no difference at night. Women using estrogen-containing oral contraceptives had lower epinephrine and higher GH values than women not taking oral contraceptives. In women, morning GH concentrations were higher in the ambulatory than in the resting state, whereas they were lower in the ambulatory state than in the resting state in men. The secretion of GH and epinephrine is gender-dependent and differs during the daytime in a reciprocal manner, with higher GH and lower epinephrine in women than in men. Oral contraceptives appear to further increase such differences. It seems likely that the data reflect a gender difference in the utilization of substrates for energy production.

The effect of diabetes mellitus on endocrine and reproductive function.

The adverse effects of diabetes on the circulatory, visual, renal, and peripheral nervous system are commonly recognized and have been extensively studied. The effects of decreased insulin secretion or resistance to insulin action on endocrine glands have not been as carefully documented. Both clinical and animal research have demonstrated that diabetes mellitus is commonly associated with altered thyroid, adrenal and gonadal function. Some of these changes are reversed with insulin replacement therapy, but endocrine function is not always restored to normal even with rigorous glycemic control. Patients with poorly controlled diabetes exhibit basal and stimulated growth hormone (GH) hypersecretion, while patients with good metabolic control still present with diurnal and exercise-induced GH hypersecretion. In contrast, diabetes suppresses GH secretion in the rat. It is unclear why GH secretion is altered, but clinical and experimental evidence exists for diabetes-associated changes in GH-releasing hormone and somatostatin release as well as for changes in the pituitary response to these hypothalamic hormones. The thyroid hormones, T3 and T4, are usually suppressed in both humans and experimental animals with diabetes. This effect of diabetes appears to involve changes in hypothalamic thyrotropin-releasing hormone (TRH) secretion as well as changes in pituitary thyrotropin (TSH) release and direct effects at the level of the thyroid gland. Adrenal cortical function is often enhanced in diabetes, most likely due to alterations in glucocorticoid feedback responses. There is much conflicting data on adrenal medullary function in diabetes; responses to stress and exercise, however, are often abnormal. Finally, male and female reproductive function is often disrupted in diabetes. Data from animal studies suggest that the major cause is altered hypothalamic LHRH secretion secondary to diabetes-induced changes in hypothalamic neurotransmitter metabolism.

EFFECT OF GLYCINE INGESTION AND ACUTE RESISTANCE EXERCISE ON GROWTH HORMONE RELEASE IN MALE WEIGHTLIFTERS 220

Previous research has shown an increase in growth hormone(GH) release following glycine infusion. The purpose of this study was to examine the effect of ingesting 12g of powdered glycine alone, and when combined with acute resistance exercise on GH release. 5 weight trained males (86.4kg,25yrs) participated in 3 randomly presented conditions separated by 5-8 days, with all sessions at the same time of day to minimize diurnal GH variations. Conditions were glycine alone (G), resistance exercise alone(RX), and glycine plus exercise(GRX). Blood from a forearm vein catheter was analyzed for GH(via RIA), hemoglobin, and hematocrit. Exercise consisted of 4 sets of 10 reps for the following exercises: squat, leg press, leg extension, leg curl, calf press, front lat pulldown, pulley rows, and dumbbell rows. Sets were separated by 1 minute rest. Blood was collected 15 minutes post-arrival (base), immediate post-ingestion (0)30,60,90,120 minutes post-ingestion. GH values are shown below (ng/ml). All values were corrected for plasma volume shifts. For RX and GRX conditions, the 30 and 60 samples were collected after the calf press and dumbbell rows, respectively. Table No differences were found between RX and GRX primarily due to a large subject intervariability. Some subjects showed a dramatic GH release with glycine alone and with exercise plus glycine ingestion, suggesting that a percentage of the population may be more sensitive to glycine ingestion.

Dynamic changes of growth hormone—binding protein concentrations in normal men and patients with acromegaly: Effects of short-term fasting

Plasma concentrations of growth hormone (GH) and GH-binding protein (GHBP) were measured at hourly intervals in five healthy men and five patients with acromegaly during the fed state and after a 5-day fast. GHBP concentrations (both total and complexed with endogenous GH) were analyzed by the ligand-mediated immunofunctional assay (LIFA). Total GHBP was similar in both groups during the fed state (104.4 ± 5.2 and 101.6 ± 10.3 pmol/L), did not exhibit a diurnal rhythm, and was unchanged by fasting (91.9 ± 5.4 and 109.9 ± 10.5 pmol/L, respectively). However, the GHBP GH complex concentration was significantly higher in acromegalics than in controls (41.0 ± 2.8 v 18.0 ± 2.2 pmol/L, respectively; P < .05), closely followed diurnal GH rhythm in normals, and was significantly correlated with mean 24-hour GH concentrations ( r = .86, P < .01). We conclude that plasma concentrations of GHBP are stable throughout the day and are unchanged either by short-term calorie deprivation or by chronic exposure to high levels of endogenous GH. In contrast, GHBP/GH complex concentrations are altered both acutely and chronically by ambient GH.

Continuous Versus Intermittent Subcutaneous Infusion of Octreotide in the Treatment of Acromegaly

This review evaluates the efficacy, tolerability, and safety of continuous subcutaneous infusion (CSI) relative to intermittent subcutaneous injection (ISI) of the somatostatin analog, octreotide in the treatment of acromegaly. Data was extracted from five clinical series using CSI octreotide in acromegaly, six reports comparing CSI to ISI, and three studies comparing pulsatile subcutaneous infusion (PSI) to ISI. Effects of each drug regimen on the control of growth hormone (GH), insulin-like growth factor (IGF-1), clinical symptomatology, pituitary tumor size, and adverse effects were evaluated. Normalization of serum GH or IGF-1 levels, as well as improvement in clinical symptoms was reported in the majority of the patients studied. Cases in which pituitary adenomas decreased in size were also documented during the study period. When the effects of CSI were compared with ISI, a more pronounced control of GH and IGF-1 was observed. In addition, diurnal GH fluctuation during CSI was significantly reduced relative to ISI in two reports. Moreover, in two patients, CSI achieved similar clinical and biochemical effects at lower doses than when the drug was given by ISI. Finally, adverse effects with CSI may be less severe than with ISI. Continuous subcutaneous infusion of octreotide produced biochemical improvement in 67 of the 88 patients reviewed. When compared with ISI, CSI induced more pronounced biochemical control, often with less fluctuation in GH and IGF-1 levels. Because of a lack of data, definite conclusions regarding the differences between regimens on clinical symptomatology and tolerability could not be discerned. A large prospective, long-term randomized crossover study is recommended to make these determinations.

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.

Criteria for recognition of the growth-inefficient child who may respond to treatment with growth hormone.

In this study three groups of short children composed of 104 subjects (61 boys, 43 girls) were evaluated for spontaneous secretion of growth hormone (GH). Group 1 consisted of 10 subjects (6 boys, 4 girls) with "classic" GH deficiency. Group 2 consisted of 31 subjects (17 boys, 14 girls) with "nonclassic" GH deficiency. Group 3 consisted of 63 subjects (38 boys, 25 girls) with short normal stature. Blood samples were drawn every 20 minutes over 24 hours, and the mean GH concentration, nocturnal GH concentration, diurnal GH concentration, pulse amplitude, and number of pulses with a GH peak above 5 micrograms/L were determined. The values for mean height, height velocity, bone age to chronological age ratio, somatomedin C concentration, GH concentration, nocturnal GH concentration, diurnal GH concentration, pulse amplitude, and number of pulses with a GH peak over 5 micrograms/L were significantly greater in group 3 than in group 2, and these same values, except for the mean diurnal GH concentration, were greater in group 2 than in group 1. The mean GH concentration correlated with the mean nocturnal GH concentration. Subjects in groups 1 and 2 were treated with GH for 1.23 +/- 0.53 years (mean +/- SD). All the group 1 subjects and 27 (87%) of the group 2 subjects responded with an increase in height velocity greater than 2 SDs per year of therapy. In conclusion, 87% of subjects with a normal GH response to provocative stimuli testing who had a mean height velocity of less than 4 cm/y, mean height lower than the third percentile, mean bone age to chronological age ratio of less than 0.8, and mean GH concentration less than 3 micrograms/L responded to GH therapy.

Insulin-like growth factor I in depressed patients and controls.

To explore the role of the somatomedin-mediated long-loop negative feed-back mechanism in altered growth hormone (GH) secretory dynamics associated with depression, plasma IGF-I concentrations were measured in 34 patients with a major depressive episode and matched healthy subjects. Compared with controls, depressed patients exhibited significantly increased plasma IGF-I concentrations. In the patient group plasma IGF-I concentrations were positively correlated with the maximum post-dexamethasone plasma cortisol concentrations. Our data suggest that increased plasma IGF-I concentration may reflect diurnal GH hypersecretion, contribute to deficient GH responses to dynamic challenges, and indicate an interrelationship between the hypothalamic-pituitary-somatotropic (HPS) and -adrenocortical (HPA) system regulation in depression.

Plasma growth hormone in acromegalic patients

Abstract. The effects of the selective α2-adrenoreceptor antagonist idazoxan on diurnal variations in plasma growth hormone levels were studied in acromegalic patients. Seven patients entered the study; six patients had been unsuccessfully treated with either pituitary adenotomy, bromocriptine or other drug therapy or a combination of the two procedures. Plasma growth hormone levels were measured at hourly intervals over a period of 24 h under control conditions and following 4 days treatment with either placebo or idazoxan (20 mg po, three times a day); the comparison of idazoxan with placebo was a double blind cross-over study. Except in one patient, the diurnal growth hormone plasma profiles were virtually superimposable under control conditions and following either placebo or idazoxan; each patient had a characteristic profile. Four patients had impressive nocturnal elevations ranging from about 40 to 200 per cent above average daytime levels. Only one had definite paradoxical early postprandial peaks. These observations are contrary to accepted views on growth hormone levels in acromegalic patients. The majority of our patients thus had profiles reminiscent of the normal diurnal plasma growth hormone pattern albeit at a higher level indicating some preserved central drive. The rather high prevalence in the present study of patients having relapses after adenomectomy may indicate that a selection had been made of cases with hypothalamic aetiology. Administration of the selective α2-adrenoreceptor antagonist idazoxan did not modify plasma growth hormone profiles in these patients.

Is there paradoxical growth hormone response to thyrotropin-releasing hormone in depression?

Several investigators have reported a paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in depressed patients, but other studies have failed to confirm this. In the present study, the GH response to TRH was studied in depressed patients and normal subjects. The rate of paradoxical GH response to TRH in depression was no different than that observed in control subjects. This was the case whether the data was examined using mean values or using frequency of abnormal responses. Patients with blunted thyrotropin (TSH) responses did not differ in GH release from patients with normal TSH response. A variety of factors may have contributed to the earlier reports of a positive GH response to TRH, including the definition of paradoxical GH release and the fact that depressed patients exhibit more frequent spontaneous diurnal GH release than do normal subjects.

Diurnal growth hormone responses to dextroamphetamine in normal young men and postmenopausal women

(1) D-amphetamine stimulates growth hormone (GH) secretion, probably through its catecholaminergic effects. (2) In normal post-menopausal women we found the GH response to dextroamphetamine to be small and significantly less than that seen in young normal men. (3) In post-menopausal women but not in young men, the GH response to amphetamine was significantly higher in the evening than in the morning. (4) The reduced GH responses to dextroamphetamine in postmenopausal women may be due to sex difference, hypoestrogenism, or to reduced brain catecholamines associated with age. (5) The diurnal variation of the GH response to d-amphetamine in post-menopausal women may reflect a diurnal variation in hypothalamic nor-adrenergic activity higher in the evening, which was not masked by a reciprocal variation in estradiol levels.

Growth hormone, insulin and sugar in the blood plasma of bulls. Interrelated diurnal variations.

Plasma growth hormone (GH) of eight young, sexually mature, pedigree bulls, observed at hourly intervals, varied during the day in a manner indicating intermittent secretion in peaks or bursts. The diurnal GH averages were about 10 ng/ml. GH averages for 2-3 h intervals showed minima following or during the periods of morning and afternoon feeding. A third minimum occurred between 10 and 12 p.m. Peak activity, estimated by the frequency of GH values greater than 10 ng/ml was significantly reduced during two of these low-GH-periods (afternoon and late night). The minima in GH followed after (morning) or coincided with (afternoon) maxima in plasma insulin (two materials, GH/insulin, 11 a. m.-10 p.m.: r=-0.31 and -3.34, P less than 0.01). This means that the two hormones behaved after food intake much in the same ways as in man in spite of the fact that plasma sugar decreased after feeding (GH/sugar, 11 a.m.-10 p.m.: r=0.27, two materials combined, P less than 0.001). The possibility of GH involvement in the hour-to-hour metabolic homoeostasis of the animals is discussed.

Diurnal growth hormone and glucose abnormalities in unstable diabetics: studies of ambulatory-fed subjects during continuous blood glucose analysis.

Blood glucose (BG) was monitored continuously and plasma growth hormone (hGH) was determined at hourly intervals in patients under standardized ambulatory-fed conditions (48-hr study periods after prolonged preparation for optimal therapy). BG regulatory stability was quantified on the basis of mean amplitude of glycemic excursions (MAGE, a measure of withinday BG variability), mean of daily differences of matched BG values on successive days (MODD, a measure of between-day BG variability), and mean BG (MBG, a measure of diurnal glycemia). Eight unstable diabetics, all with high BG parameters, also had high mean hourly hGH and peak hGH values compared with three stable diabetics and three normal subjects. While inadvertent hypoglycemic episodes and rcise-related and sleep-related hGH increases contributed to the higher hGH levels in the unstable diabetics, none of these events accounted for the observed differences. In this study, diabetic instability and sex were found to exert significant effects. At th...