Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport.

GH abuse by elite athletes is currently undetectable. To define suitable markers of GH doping, we assessed the effects of acute exercise, GH administration, and GH withdrawal on the GH/insulin-like growth factor (IGF) axis in athletic adult males. Acute endurance-type exercise increased serum GH, GH-binding protein (GHBP), total IGF-I, IGF-binding protein (IGFBP)-3, and acid-labile subunit (ALS), each peaking at the end of exercise. IGFBP-1 increased after exercise was completed. Free IGF-I did not change with exercise. Recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum total IGF-I, IGFBP-3, and ALS, exaggerating the responses to exercise. IGFBP-2 and IGFBP-1 were trivially suppressed. After GH withdrawal, the GH response to identical exercise was suppressed. Total IGF-I, IGFBP-3, and ALS returned to baseline over 3-4 days. In summary, 1) acute exercise transiently increased all components of the IGF-I ternary complex, possibly due to mobilization of preformed intact complexes; 2) GH pretreatment augmented the exercise-induced changes in ternary complexes; 3) postexercise IGFBP-1 increments may protect against delayed onset hypoglycemia; 4) serum total IGF-I, IGFBP-3, and ALS may be suitable markers of GH abuse; and 5) differences in disappearance times altered the sensitivity of each marker for detecting GH abuse.     

Changes in non-22-kilodalton (kDa) isoforms of growth hormone (GH) after administration of 22-kDa recombinant human GH in trained adult males

GH is being used by elite athletes to enhance sporting performance. To examine the hypothesis that exogenous 22-kDa recombinant human GH (rhGH) administration could be detected through suppression of non-22-kDa isoforms of GH, we studied seventeen aerobically trained males (age, 26.9 +/- 1.5 yr) randomized to rhGH or placebo treatment (0.15 IU/kg/day for 1 week). Subjects were studied at rest and in response to exercise (cycle-ergometry at 65% of maximal work capacity for 20 min). Serum was assayed for total GH (Pharmacia IRMA and pituitary GH), 22-kDa GH (2 different 2-site monoclonal immunoassays), non-22-kDa GH (22-kDa GH-exclusion assay), 20-kDa GH, and immunofunctional GH. In the study, 3 h after the last dose of rhGH, total and 22-kDa GH concentrations were elevated, reflecting exogenous 22-kDa GH. Non-22-kDa and 20-kDa GH levels were suppressed. Regression of non-22-kDa or 20-kDa GH against total or 22-kDa GH produced clear separation of treatment groups. In identical exercise studies repeated between 24 and 96 h after cessation of treatment, the magnitude of the responses of all GH isoforms was suppressed (P < 0.01), but the relative proportions were similar to those before treatment. We conclude: 1) supraphysiological doses of rhGH in trained adult males suppressed exercise-stimulated endogenous circulating isoforms of GH for up to 4 days; 2) the clearest separation of treatment groups required the simultaneous presence of high exogenous 22-kDa GH and suppressed 20-kDa or non-22-kDa GH concentrations; and 3) these methods may prove useful in detecting rhGH abuse in athletes.     

The response of molecular isoforms of growth hormone to acute exercise in trained adult males

Circulating GH consists of multiple molecular isoforms, all derived from the one gene in nonpregnant humans. To assess the effect of a potent stimulus to pituitary secretion on GH isoforms, we studied 17 aerobically trained males (age, 26.9 +/- 1.5 yr) in a randomized, repeat measures study of rest vs. exercise. Exercise consisted of continuous cycle ergometry at approximately 80% of predetermined maximal oxygen uptake for 20 min. Serum was assayed for total, pituitary, 22-kDa, recombinant, non-22-kDa, 20-kDa, and immunofunctional GH. All isoforms increased during, peaked at the end, and declined after exercise. At peak exercise, 22-kDa GH was the predominant isoform. After exercise, the ratios of non-22 kDa/total GH and 20-kDa GH/total GH increased and those of recombinant/pituitary GH decreased. The disappearance half-times for pituitary GH and 20-kDa GH were significantly longer than those for all other isoforms. We conclude that 1) all molecular isoforms of GH measured increased with and peaked at the end of acute exercise, with 22-kDa GH constituting the major isoform in serum during exercise; and 2) the proportion of non-22-kDa isoforms increased after exercise due in part to slower disappearance rates of 20-kDa and perhaps other non-22-kDa GH isoforms. It remains to be determined whether the various biological actions of different GH isoforms impact on postexercise homeostasis.     

Long-term effects of growth hormone (GH) on bone mineral status and bone turnover markers in patients with isolated GH deficiency and multiple pituitary hormone deficiency

OBJECTIVE: This study was designed to assess the long-term effects of growth hormone (GH) replacement therapy on bone mass and bone turnover markers in children with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD). MATERIALS AND METHODS: Fifty children (35 IGHD, 15 MPHD) receiving GH replacement therapy were enrolled in the study. The patients were followed for 38.6 +/- 15.7 months (1-5 years). Bone mineral density (BMD) of the lumbar region and bone turnover markers [PTH, osteocalcin, bone-specific alkaline phosphatase (boneALP), and the carboxyterminal propeptide of type-1 collagen (CPP-I)] were assessed annually. RESULTS: The height standard deviation score (SDS) of patients with IGHD and MPHD at diagnosis was statistically significant (P = 0.012), and the change in height SDS during 3 years (Deltaheight SDS(3 years)) was statistically similar between these two groups (P = 0.651). The BMD z-scores of the two groups were comparable at the start of GH therapy (P = 0.083), and then increased in both groups similarly during 5 years of GH replacement therapy (F = 0.349, P = 0.567). When the BMD z-scores during 5 years of GH therapy were analysed in the IGHD and MPHD groups separately, it was found that the BMD z-score increased significantly in IGHD (P < 0.001) but the increase was not significant in MPHD (P = 0.140). Multiple regression analysis showed that the change in BMD z-score during 3 years of GH therapy (DeltaBMD z-score(3 years)) was predicted by the BMD z-score and height SDS at the start of GH therapy and by Deltaheight SDS(3 years) in the IGHD group (t = -2.582, P = 0.02; t = 2.322, P = 0.034 and t = 2.908, P = 0.01, respectively). Age and BMD z-score and height SDS at diagnosis were found to have predictive values for the DeltaBMD z-score(3 years) (t = -3.652, P = 0.022; t = -4.073, P = 0.015 and t = 3.389, P = 0.028, respectively) in the MPHD group. The changes in boneALP, osteocalcin, CPP-1 and PTH levels during the therapy were statistically similar between the IGHD and MPHD groups. CONCLUSION: BMD increased during GH therapy in the IGHD and MPHD groups. GH had a positive effect on bone mass in the short as well as the long term. Early diagnosis and treatment could improve peak bone mass in patients with MPHD. The time and dose of sex steroids for pubertal induction and progression, which mimics physiological secretion, might also contribute to bone accretion in patients with MPHD.     

Short and long-term effects of growth hormone treatment on bone turnover and bone mineral content in adult growth hormone-deficient males*

OBJECTIVE In view of the fact that GH-deficient adults present with pronounced osteopaenia and can be considered at risk for osteoporotic fractures, we wanted to investigate the effects of biosynthetic GH replacement therapy (0.25 IU/kg/week) on biochemical indices of bone turnover and on bone mineral content (BMC) in a group of GH-deficient adult males. DESIGN We performed a 6-month randomized, double-blind, placebo-controlled study, followed by 12–24 months of GH treatment in all patients. PATIENTS Twenty adult males with GH deficiency of childhood onset were studied. MEASUREMENTS We measured serum IGF-I, serum phosphate, biochemical indices of bone turnover (serum alkaline phosphatase activity, serum osteocalcin, serum carboxyterminal propeptide of type-I procollagen, fasting urinary hydroxyproline/creatinine and calcium/creatinine ratios) and bone mineral content, measured at the forearm and the lumbar spine by single and dual-photon absorptiometry respectively. RESULTS After 3 and 6 months of GH administration, the serum levels of alkaline phosphatase, osteocalcin and carboxyterminal propeptide of type-I procollagen, and the fasting urinary hydroxyproline/creatinine ratio were significantly increased compared to placebo-treated patients (P<0.01 to P<0.001). During the open study phase, the values for these indices of bone turnover remained elevated above pretreatment levels (P<0 01 to P<0 001 at 12 months), a downward trend becoming apparent after about one year of GH treatment. BMC values showed an initial decline after 3 months of GH treatment (most likely due to an expansion of the remodelling space), followed by a significant and progressive increase above pretreatment values, reaching 7–8% for total BMC at the lumbar spine (L2-L4) and 9–9% for total BMC at the forearm, after 30 months of GH administration. CONCLUSIONS The data of our study show that administration of substitutive doses of growth hormone to GH-deficient adult males activates bone turnover for a period of at least one year and suggests that this may have a beneficial effect on bone mass in these patients.     

Responses of growth hormone (GH) and somatomedin-C to GH-releasing hormone in healthy aging men

Although controversy exists regarding the effects of aging on GH secretory responses to indirect stimulation, in the only prior study of GH-releasing hormone (GHRH)-mediated GH secretion decreased GH responsivity occurred in healthy men after age 40 yr. We measured serum GH before and up to 180 min after and somatomedin-C (SM-C) levels before and 24 h after single morning bolus iv injections of GHRH-(1-44)-NH2 (1 microgram/kg) in 50 healthy fasted men, aged 21-86 yr, from the Baltimore Longitudinal Study of Aging. Only subjects with a body mass index (BMI; kilograms per m2) between 20.0 and 29.0 were studied. Basal serum GH levels were undetectable (less than 0.7 ng/ml) in all but 2 men. Neither the frequency of GH responses (P greater than 0.8), the magnitude of response (P greater than 0.2), nor the timing (P greater than 0.05) of the peak GH responses to GHRH were significantly altered with age. Although BMI values did not vary significantly with age in our study group, there was a significant negative correlation (r = -0.37; P less than 0.01) of peak GH with BMI. Regression analysis revealed a slight but significant increase in the level of fasting blood sugar with age, but no significant correlation between fasting blood sugar and peak GH levels. Serum levels of SM-C were significantly lower in older men both before (P less than 0.001) and 24 h after (P less than 0.02) GHRH injection. Repeated measures analysis of variance revealed significant (P less than 0.001) responses of SM-C to endogenous GH elevations produced by GHRH at all ages, but no age-dependent alterations in the magnitudes of these responses (P greater than 0.7). Our findings suggest that increasing age in adult men has little effect on the secretory responsiveness of pituitary somatotropes to GHRH. However, the finding of lower serum levels of SM-C with intact SM-C responsivity to endogenous GH is compatible with prior observations of an age-related decrease in the total daily spontaneous secretion of GH.     

Childhood-onset growth hormone (GH) deficiency in adult life

Over the last decade GH replacement therapy for adults has progressed in status from research study to a mainstream clinical indication. An area ripe for further research, however, is the difference between adults who developed GHD before and after completion of growth and puberty. That differences exist, not only in aetiology, but also in phenotype and response to GH therapy is clear. However, whether these differences are intrinsic to the timing of onset of GHD, or related to secondary factors including the method of assessment or dose of GH employed is uncertain. This chapter discusses the current state of knowledge in this area and poses further questions, not only for the researcher attempting to understand the mechanisms underlying these differences, but also for the physician seeking to ameliorate the impact of GHD in patients who acquired GHD in childhood.     

Biochemical markers of bone turnover in tibia fracture patients randomly assigned to growth hormone (GH) or placebo injections: Implications for detection of GH abuse

Context

It has been argued that increased levels of bone remodelling markers are not suitable indicators of GH abuse, as bone injuries per se increase the expression levels of these markers.

Objective

To investigate the impact of a recovering tibia fracture on circulating bone markers in subjects receiving placebo or GH treatment.

Design and setting

A randomised, double-blind, placebo-controlled trial of up to 16 weeks GH treatment, followed by a 16-week washout.

Participants and intervention

Subjects (406 adult males and females) with a tibia fracture were randomly allocated within three days after surgery, to either placebo or GH treatment (15, 30 or 60 μg/kg daily) until fracture healing or 16 weeks after treatment initiation.

Main outcome measures

IGF-I, serum C-terminal telopeptide of type I collagen (CTX), osteocalcin (OST) and bone-specific alkaline phosphatase (BAP) were measured during and after treatment.

Results

Dose-dependent increases were observed in groups receiving GH, and mean levels in the highest GH dose group peaked at eight (IGF-I, CTX) or 12 weeks (OST) after treatment initiation. Statistically significant differences between GH treatment and placebo were seen for IGF-I, CTX and OST in all GH dose groups throughout the treatment period, and persisted until eight (CTX) or 12 (OST) weeks after cessation of treatment.

Conclusion

IGF-I, CTX and OST are suitable candidate markers of prolonged, illicit administration of GH. Furthermore, CTX and OST have potentials to serve as markers also after cessation of GH administration.     

Effect of withdrawal of somatostatin and growth hormone (GH)-releasing factor on GH release in vitro

The secretion of GH, in vivo, is pulsatile. We have proposed that the timing of the episodic bursts of GH secretion is set by somatostatin (SRIF) withdrawal, while the magnitude of the bursts is set by the amount of GH-releasing factor (GRF) impinging on the somatotrophs, before and during SRIF withdrawal. We have now used an in vitro model of perifused rat pars distalis cells to further examine the interaction between GRF and SRIF on the magnitude of the burst of GH release that follows SRIF withdrawal. We first characterized the GH response, with time, to constant perifusion with GRF. The initial burst, followed by a rapid decrease in GH release induced by constant perifusion is due to a loss of GRF bioactivity in the perifusion medium and not to a decreasing responsiveness of the somatotrophs. This was followed by studies on the interaction between GRF and SRIF. The burst of GH release after cessation of perifusion with SRIF (10(-9) M) plus GRF (10(-10) M) can be blocked by the administration of SRIF during the burst. Also, the magnitude of the burst is proportional to the concentration of GRF preceding the withdrawal of SRIF. It is likely that similar relations apply in vivo, where SRIF withdrawal sets the timing and duration of the episodic burst of GH release, while GRF sets the magnitude.     

Repetitive growth hormone-releasing hormone administration restores the attenuated growth hormone (GH) response to GH-releasing hormone testing in normal aging

The plasma GH response to human pituitary GH (hpGH)-releasing hormone-40 (hpGHRH-40; 1 microgram/kg BW) was significantly lower in seven healthy aged men (age range, 65-78 yr) than in seven healthy young men (age range, 18-31 yr) 30, 60, and 90 min after acute hpGHRH-40 administration (P less than 0.0001, by Student's unpaired t test). To verify whether a priming regimen might be able to reverse the reduced GH response to GHRH, elderly subjects underwent repetitive administration of hpGHRH-40 and placebo in a double blind design (100 micrograms hpGHRH-40 or volume-matched saline iv as a single morning dose, every 2 days for 12 days). After the hpGHRH-40-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 after placebo treatment. These findings suggest that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response.     

Efficacy of a long-acting growth hormone (GH) preparation in patients with adult GH deficiency

CONTEXT: Treatment of adult GH deficiency (AGHD) with daily injections of GH results in decreased adipose mass, increased lean body mass (LBM), increased bone mineral density, and improved quality of life. OBJECTIVE: This study seeks to determine whether a depot preparation of GH given every 14 d would lead to comparable decreases in trunk adipose tissue as daily GH. DESIGN: This open-label, randomized study compares subjects receiving depot GH, daily GH, or no therapy. SETTING: The study was performed at 23 university or local referral endocrine centers. PATIENTS OR OTHER PARTICIPANTS: One hundred thirty-five adults with AGHD syndrome participated in the study. INTERVENTION: Subjects were randomized to receive depot GH (n = 51), daily GH (n = 53), or no treatment (n = 31) for 32 wk. The dose of GH was titrated so that IGF-I was less than or equal to +2 SD of the age-adjusted normal range. MAIN OUTCOME MEASURE: Trunk adipose tissue was the main outcome measure as measured by dual energy x-ray absorptiometry. RESULTS: The percentage of the trunk region that is fat increased by 0.4 in the no treatment group, but decreased by 3.2 (P = 0.001 vs. untreated) in the GH depot group and by 2.5 (P < 0.004 vs. untreated) in the daily GH group. Visceral adipose tissue area decreased by 9.1% in the GH depot group and by 6.8% in the daily GH group. LBM and high-density lipoprotein increased in both treatment groups. Side effect profiles were similar. Three subjects receiving GH experienced serious episodes of adrenal insufficiency. CONCLUSIONS: GH diminishes trunk and visceral adipose tissue and increases LBM in AGHD. A depot form of GH that is administered every 14 d is as safe and effective as daily GH injections.     

Effect of withdrawal of somatostatin plus growth hormone (GH)-releasing hormone as a stimulus of GH secretion in Cushing's syndrome

OBJECTIVE: Somatostatin (SS) may not merely be inhibitory to GH secretion but, under appropriate temporal conditions, may act in a paradoxically positive manner to sensitize somatotroph responsiveness to GHRH. SS infusion withdrawal (SSIW) produces a rebound GH rise in humans and increases GHRH-induced GH release. Theoretically SSIW leaves the somatotroph cell in a situation of low endogenous SS. In Cushing's syndrome, GH secretion appears blunted to all stimuli. The mechanisms by which glucocorticoids impair GH secretion in Cushing's syndrome are unknown. There are no data evaluating GH responsiveness to SSIW plus GHRH in Cushing's syndrome patients. The aim of the present study was to evaluate the GH response to SSIW plus GHRH in a group of Cushing's syndrome patients, in order to further understand the deranged GH secretory mechanisms in Cushing's syndrome. PATIENTS AND MEASUREMENTS: Eight female patients with Cushing's syndrome were studied. As a control group, eight normal subjects of similar age and sex were studied. Three tests were done. On one day, SS intravenous (i.v.) infusion (500 micro g for 0-90 min) was performed followed by placebo i.v. bolus at min 90 after SS withdrawal (SSIW). On another day, SS i.v. infusion (500 micro g for 0-90 min) was performed followed by GHRH (100 micro g) i.v. bolus at min 90 after SS withdrawal. On a third day, slow infusion of 150 mmol/l NaCl administration was performed followed by GHRH (100 micro g) i.v. bolus at min 90 after the start of the infusion. Blood samples were taken at appropriate intervals for determination of GH. RESULTS: GHRH-induced GH secretion in normal subjects showed a mean peak of 15.4 +/- 2.1 micro g/l (conversion factor: 1 micro g/l = 1.2 mUI/l). Normal control subjects had a mean peak of 3.3 +/- 1.6 micro g/l after SSIW-induced GH secretion. When GHRH was administered after SSIW there was increased GH secretion with a mean peak of 23.7 +/- 4.2 micro g/l significantly greater than the response after SSIW alone (P < 0.05) and GHRH alone (P < 0.05). The patients with Cushing's syndrome had a blunted GH response after GHRH administration with a mean peak of 1.4 +/- 0.4. After SSIW, Cushing's syndrome patients had a mean peak of 1.0 +/- 0.5 micro g/l. When GHRH was administered after SSIW there was a similar GH response with a mean peak of 1.7 +/- 0.6 micro g/l, not statistically different than the response after SSIW alone (P = ns) and GHRH alone (P = ns). When we compare the response of normal subjects and Cushing's syndrome patients, after SSIW plus GHRH, it was decreased in Cushing's syndrome patients (P < 0.05), with a mean GH peak of 23.7 +/- 4.2 micro g/l and 1.7 +/- 0.6 micro g/l for normal subjects and Cushing's syndrome patients, respectively. CONCLUSIONS: This study has demonstrated a significantly blunted peak GH response to somatostatin infusion withdrawal plus GHRH in Cushing's syndrome patients. In this theoretical situation of decreased somatostatinergic tone there is persistence of GH hyposecretion in Cushing's syndrome, suggesting the existence of a pituitary defect responsible for the decreased GH secretion in Cushing's syndrome.     

Plasma growth hormone (GH) responses to single and repetitive subcutaneous administration of GH releasing factor (hpGRF-44) in normal and GH deficient children

Synthetic human pancreatic GRF (hpGRF-44) was administered sc to 8 normal children with short stature and 11 patients with GH deficiency. After a dose of 100-200 micrograms hpGRF-44, mean plasma GH levels reached a peak at 15 min of 27.2 +/- 6.4 (+/- SE) ng/ml in normal children. However the responses were variable and peak plasma GH varied from 10.1 to 56.5 ng/ml. Eight of 11 patients with idiopathic GH deficiency did not respond to sc administration of 100-300 micrograms hpGRF-44. However, a plasma GH increase of more than 5 ng/ml occurred in 2 patients and to twice the basal level in 1 patient. Their GH values were 14.3, 5.2 and 3.4 ng/ml, respectively. After repetitive administration of hpGRF-44 (200 micrograms, twice a day) sc for 5 consecutive days, 2 of 8 patients restored their responsiveness, but the remaining patients did not show GH rise in response to both sc and iv bolus administration of hpGRF-44. Repetitive hpGRF-44 administrations for 5 days had no effect on somatomedin-C production.     

Oral administration of growth hormone (GH)-releasing peptide stimulates GH secretion in normal men.

Intravenous infusions of the synthetic hexapeptide GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2; GHRP) specifically stimulate GH release in man. To determine whether orally administered GHRP stimulates GH secretion, 10 normal men received oral doses of placebo, 30, 100, and 300 micrograms/kg GHRP, and an iv injection of 1.0 micrograms/kg GHRP at weekly intervals in a single blind, randomized design. Serum GH concentrations were measured in blood samples obtained at 5-min intervals for 1 h (0700-0800 h) before and 4 h (0800-1200 h) after each dose. Mean (+/- SE) peak GH concentrations were 4.0 +/- 1.5, 5.2 +/- 1.6, 9.2 +/- 3.3, 18 +/- 3.7, and 26 +/- 5.6 micrograms/L for placebo; 30, 100, and 300 micrograms/kg oral GHRP; and 1 micrograms/kg iv GHRP, respectively; mean 4-h (0800-1200 h) integrated GH concentrations were 312 +/- 109, 406 +/- 159, 698 +/- 284, 1264 +/- 303, and 1443 +/- 298 min.micrograms/L, respectively. To analyze changes in the pulsatile pattern and amount of GH secretion after the administration of GHRP, a waveform-independent deconvolution method was used to estimate GH secretion rates. Variable increases in GH secretion after placebo and GHRP treatments were observed. Despite this variability, weighted least squares linear regression revealed that increasing doses of oral GHRP progressively stimulated GH secretion (P less than 0.005); similar relationships were observed for the peak GH concentration and 4-h integrated GH concentrations. The GH responses to oral GHRP (300 micrograms/kg) and iv GHRP (1 microgram/kg) were significantly greater than that to placebo (P less than 0.05) and were comparable in magnitude. Pairwise comparisons revealed that increases in GH concentrations and secretion rates after the 30 and 100 micrograms/kg oral doses of GHRP were not significantly different from those after placebo. The increase in GH secretion after GHRP treatment was accounted for entirely by an increase in the amplitude of GH secretory events, as no significant increase in the number of GH secretory pulses was observed. The onset and duration of action of GHRP were analyzed by a proportional hazards general linear regression model. Intravenous GHRP had a more rapid onset of action than all doses of oral GHRP (P less than 0.02). Increasing doses of oral GHRP resulted in earlier GH responses (P = 0.006). However, the duration of the GH response was similar for iv GHRP and all doses of oral GHRP, averaging 120-150 min.(ABSTRACT TRUNCATED AT 400 WORDS)     

Serum leptin response to the acute and chronic administration of growth hormone (GH) to elderly subjects with GH deficiency

In human studies, the principal determinant of serum leptin concentrations is fat mass (FM), but lean mass (LM) also has a significant negative influence. GH treatment in GH deficiency (GHD) alters body composition, increasing LM and decreasing FM, and thus would be expected to alter leptin concentrations. We have therefore examined the acute and chronic effects of GH on serum leptin in 12 elderly GHD subjects (ages 62-85 yr; 3 women and 9 men). FM (kilograms) and LM (kilograms) were determined by dual energy x-ray absortiometry. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured by specific immunoassays. Leptin, insulin, and IGFBP-1 concentrations were log10 transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). All other data are presented as the mean +/- SD. In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations. In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin. High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.     

Chronic administration of growth hormone (GH) to adult chickens exerts marked effects on circulating concentrations of insulin-like growth factor-I (IGF-I), IGF binding proteins, hepatic GH regulated gene I, and hepatic GH receptor mRNA

In young birds, growth hormone (GH) administration has been found to have only a small or even no effect on circulating concentrations of insulin-like growth factor-I (IGF-I). This is in obvious contrast to the situation in mammals. The present study examines the effect of continuous administration of GH in adult male chickens. Plasma concentrations of IGF-I were markedly elevated (2.5–3.0-fold,p<0.001) in GH-treated chickens. There were also some transient increases in the circulating levels of IGF binding proteins. Adult chickens showed other manifestations of increased responsiveness to GH, including elevated hepatic expression of GH-regulated gene-I (mRNA) with GH treatment (p<0.05), and a tendency (p<0.08) for decreased GH-receptor mRNA. In contrast to the changes in circulating concentrations of GH and IGF-I with GH treatment, no changes in plasma concentrations of thyroid hormones, reproductive hormones, glucose, or nonesterified fatty acids were evident.     

The effects of acute and chronic growth hormone (GH) administration on GH secretion in patients with idiopathic GH deficiency

The effect of acute and chronic administration of GH on plasma GH responses to GHRH were studied in patients with idiopathic GH deficiency (GHD). Nine untreated GHD patients, 1 untreated patient with postoperative craniopharyngioma, and 7 normal short children were given synthetic human GHRH-44 (100 micrograms, iv) injection before and 2 days after being given a single dose of 4 IU biosynthetic methionyl human GH (mGH), im. Twelve GHD patients, who had been treated with 0.31-0.48 IU/kg.week pituitary-derived hGH (pdGH), im, for 8-79 months, were given GHRH 2 and 14 days after a final injection of 4 IU pdGH. Three other GHD patients were given GHRH before and after 2 yr of pdGH therapy (0.35-0.39 IU/kg.week). The GHRH-induced GH response (max delta GH) was significantly inhibited after mGH administration in the 9 untreated GHD patients [2.7 +/- 0.3 (+/- SE) vs. 4.7 +/- 0.6 micrograms/L; P less than 0.01]. The patient with secondary GH deficiency also had a marked reduction in her peak plasma GH value after mGH administration (from 32.0 to 11.7 micrograms/L). Similarly, the mean max delta GH response in the 7 normal short children was significantly inhibited by prior mGH injection (max delta GH, 12.7 +/- 2.0 vs. 28.8 +/- 4.8 micrograms/L; P less than 0.01). In the 12 treated GHD patients the GHRH-induced GH response on the 2nd day after discontinuation of pdGH therapy was significantly lower than that on the 14th day (max delta GH, 3.4 +/- 1.2 vs. 6.9 +/- 1.6 micrograms/L; P less than 0.02). In the 3 GHD patients who were studied before and after 2 yrs of pdGH therapy, the plasma GH responses were similar. In each group, plasma somatomedin-C levels on the second day after GH administration were slightly but not significantly higher than those before or 14 days after the administration. The GH responses to GHRH given on 2 occasions at 7- to 14-day intervals in individuals not receiving GH were similar in both 9 normal children and 10 GHD patients. These results indicate that acute GH administration inhibits somatotroph function in GHD patients, but chronic GH therapy does not cause irreversible damage to the somatotrophs. The acute inhibition of GHRH-induced GH release after GH administration is more likely due to direct and indirect pituitary inhibition by somatomedin-C and/or somatostatin than decreased GHRH secretion.