Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men.

Serum GH concentrations are increased in fasted or malnourished human subjects. We investigated the dynamic mechanisms underlying this phenomenon in nine normal men by analyzing serum GH concentrations measured in blood obtained at 5-min intervals over 24 h on a control (fed) day and on the second day of a fast with a multiple-parameter deconvolution method to simultaneously resolve endogenous GH secretory and clearance rates. Two days of fasting induced a 5-fold increase in the 24-h endogenous GH production rate [78 +/- 12 vs. 371 +/- 57 micrograms/Lv (Lv, liter of distribution volume) or 0.24 +/- 0.038 vs. 1.1 +/- 0.16 mg/m2 (assuming a distribution volume of 7.9% body weight), P = 0.0001]. This enhanced GH production rate was accounted for by 2-fold increases in the number of GH secretory bursts per 24 h (14 +/- 2.3 vs. 32 +/- 2.4, P = 0.0006) and the mass of GH secreted per burst (6.3 +/- 1.2 vs. 11 +/- 1.6 micrograms/Lv, P = 0.002). The latter was a result of increased secretory-event amplitudes (maximal rates of GH release attained within a burst) with unchanged secretory burst durations. GH was secreted in complex volleys composed of multiple discrete secretory bursts. These secretory volleys were separated by shorter intervals of secretory quiescence in the fasted than fed state (respectively, 88 +/- 4.2 vs. 143 +/- 14 min, P = 0.0001). Similarly, within volleys of GH release, constituent individual secretory bursts occurred more frequently during the fast [every 33 +/- 0.64 (fasted) vs. every 44 +/- 2.0 min (fed), P = 0.0001]. The t1/2 of endogenous GH was not significantly altered by fasting [18 +/- 2.2 (fasted) vs. 20 +/- 1.5 min (fed), P = 0.47]. Serum insulin-like growth factor I concentrations were unchanged after 56 h of fasting. In conclusion, the present data suggest that starvation-induced enhancement of GH secretion is mediated by an increased frequency of GHRH release, and longer and more pronounced periods of somatostatin withdrawal.     

Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men

Mean plasma GH concentrations are controlled by the frequency, amplitude, and duration of underlying GH secretory bursts as well as by the half-life of endogenous GH. We investigated the specific mechanisms that subserve the clinically recognized negative effects of age and adiposity on mean serum GH concentrations. To this end, 21 healthy men, aged 21-71 yr, who were of nearly normal body weight underwent blood sampling at 10-min intervals for 24 h. Deconvolution analysis was used to estimate specific features of GH secretion and clearance. Compared to younger men, the older tertile of men had significant reductions in 1) GH secretory burst frequency, 2) the half-life of endogenous GH, and 3) the daily GH secretory rate, but not 4) GH secretory burst half-duration, amplitude, or mass. Linear regression analysis disclosed that age was a major negative statistical determinant of GH secretory burst frequency (r = -0.80; P = 0.005) and endogenous GH half-life (r = -0.70; P = 0.024). Body mass index, an indicator of relative obesity, was a significant negative correlate of GH half-life (P = 0.045) and GH secretory burst amplitude (P = 0.031). Age and body mass index each correlated negatively with the daily GH secretion rate (P = 0.0031 and P = 0.027, respectively), and together accounted for more than 60% of the variability in 24-h GH production rates (r = -0.78; P = 0.00056). On the average, for a normal body mass index, each decade of increasing age attenuated the GH production rate by 14% and the GH half-life by 6%. Conversely, each unit increase in body mass index, at a given age, reduced the daily GH secretion rate by 6%. We conclude that age and relative adiposity are distinct and specific correlates of individual attributes of GH secretion and clearance in men.     

Sleep, awakenings, and insulin-like growth factor-I modulate the growth hormone (GH) secretory response to GH-releasing hormone.

To delineate possible factors influencing the magnitude of the GH response to GH-releasing hormone (GHRH), eight young healthy men participated in seven 16-h studies involving saline infusions or injections of 0.3 micrograms/kg GHRH at various times of day and stages of sleep. GH responses were quantified by deconvolution, a procedure allowing for secretory rates to be estimated from peripheral levels. While the plasma responses were monophasic, deconvolution revealed that the secretory response to GHRH generally included several distinct bursts in rapid succession. The intersubject variability of GH responses was very wide, but for a given subject, the response was quite reproducible (mean +/- SEM coefficient of variation, 21 +/- 3%). When GHRH was given during the waking period, the magnitude of the response was directly related to the amount of spontaneous GH secretion, negatively correlated with circulating levels of insulin-like growth factor-I (IGF-I) and was not influenced by time of day. When GHRH was given during slow wave sleep, the magnitude of the response was enhanced. When GHRH was given during rapid eye movement sleep, the response was similar to that observed during wake. Awakenings during sleep consistently inhibited the secretory response to GHRH, and resumption of sleep was associated with a reappearance of the secretory process. Thus, in normal men of similar age and body weight, the GH response to GHRH is dependent on the sleep or wake condition, circulating levels of IGF-I, and, possibly, genetic and lifestyle factors.     

Luteinizing hormone (LH) secretory burst duration is independent from LH, prolactin, or gonadal steroid plasma levels in amenorrheic women

The possible presence of LH pulsatile secretion has been studied in patients with hypothalamic amenorrhea [LH plasma levels, less than 3 (n = 35) or greater than 3 IU/L (n = 18)], amenorrhea associated with hyperandrogenemia (n = 31), or hyperprolactinemia (n = 10). Patients were sampled every 10 min for 4 h, and LH plasma concentrations were determined by the use of an immunofluorimetric assay. The program Detect was used for both pulse detection and data deconvolution, i.e. for instantaneous secretory rate computation, on LH time series. The presence of episodic LH secretion was observed in all patients, and LH pulse frequency ranged between 3.5 +/- 0.3 and 3.8 +/- 0.2 peaks/4 h among the four groups. LH pulse amplitude was significantly reduced in patients affected by hypothalamic amenorrhea with LH plasma levels lower than 3 IU/L (0.7 +/- 0.1 IU/L; P less than 0.01) and significantly increased in patients with hyperandrogenic amenorrhea (6.8 +/- 0.3 IU/L; P less than 0.01) compared to levels in the other groups under study. Instantaneous secretory rate computation permitted the optimal resolution of the secretory events and demonstrated that the duration of gonadotrope secretory bursts ranged from 22.8 +/- 1.4 to 26.8 +/- 2.3 min in amenorrheic patients and did not depend on LH, PRL, or sex steroid plasma levels. In conclusion, the present study shows the presence of significant LH pulsatile release in amenorrheic patients, suggesting that in amenorrheic, as in normally cycling, women the secretory bursts from the gonadotropes have the same duration, despite the plasma LH, PRL, or steroid hormone levels.     

Activation of somatostatin-receptor subtype-2/-5 suppresses the mass, frequency, and irregularity of growth hormone (GH)-releasing peptide-2-stimulated GH secretion in men

Somatostatin antagonizes the stimulatory actions of GHRH and GH-releasing peptides (GHRPs). However, precisely how the inhibitory susceptibilities of the two secretagogues differ is not clear. One interpretative difficulty is that native somatostatin activates six different receptor subtypes. The present study adopts the complementary strategy of enforcing feedback inhibition via the preferential somatostatin receptor subtype 2 and 5 (SSTR-2/-5) agonist, octreotide. We postulated that putative SSTR-2/-5 agonism would unmask secretagogue-selective interactions in the control of GH secretory burst mass, frequency, and/or regularity. To this end, 10 healthy men each underwent eight randomly ordered, separate-day, fasting morning infusion sessions. Interventions comprised sc administration of octreotide (1 microg/kg), followed by bolus iv injection of saline, GHRH (1 microg/kg), GHRP-2 (1 microg/kg), or both peptides. Compared with placebo, the SSTR-2/-5 agonist reduced fasting GH concentrations from 0.27 +/- 0.07 to 0.12 +/- 0.02 microg/liter (P = 0.020), GH secretory burst mass from 2.7 +/- 0.65 to 0.55 +/- 0.11 microg/liter (P = 0.013), and basal GH secretion from 0.24 +/- 0.043 to 0.11 +/- 0.015 microg/liter.100 min (P = 0.0063). The foregoing outcomes were selective, because octreotide did not alter GH secretory burst frequency (3.1 +/- 0.5 vs. 3.3 +/- 0.21 events/3 h) or the regularity of the GH release process (approximate entropy, 0.58 +/- 0.048 vs. 0.68 +/- 0.064). In the GHRP-2-stimulated setting, presumptive SSTR-2/-5 agonism suppressed all three GH secretory burst masses, from 28 +/- 3.2 to 18 +/- 2.0 (P = 0.045); GH pulse frequency, from 3.3 +/- 0.30 to 2.0 +/- 0.18 (P = 0.0025); and the irregularity (approximate entropy) of GH release, from 0.648 +/- 0.049 to 0.433 +/- 0.047 (P < 0.01). In contrast, in the GHRH and combined GHRH/GHRP-2-stimulated contexts, octreotide decreased only GH secretory burst mass (P = 0.047). In summary, the present data indicate that GH secretory burst mass, frequency, and orderliness are subject to interactive control by at least SSTR-2/-5-dependent feedback and GHRP-dependent feedforward signals.     

The somatostatin analog octreotide inhibits the secretion of growth hormone (GH)-releasing hormone, thyrotropin, and GH in man

The effects of the somatostatin analog octreotide on plasma GH, TSH, and immunoreactive GH-releasing hormone (IR-GHRH) were studied in 10 normal men. After morning sc administration of 50 or 100 micrograms octreotide or placebo, plasma GH, TSH and GHRH were measured frequently for 6 h. Plasma GH or IR-GHRH concentrations did not change after placebo injection, but plasma TSH levels gradually decreased, in conformity with a circadian rhythm during the morning. The mean plasma GH levels after sc injection of 50 or 100 micrograms octreotide declined, and no spontaneous GH pulses occurred for 5 h. Plasma TSH decreased rapidly after both doses of octreotide and was significantly lower than the level after placebo treatment from 90-315 min (P less than 0.05) and 60-360 min (P less than 0.05 or P less than 0.01), respectively. Plasma IR-GHRH levels also were significantly lower from 30-360 min (P less than 0.05) in the group given 100 micrograms octreotide compared with the value in the placebo group. We conclude that octreotide inhibits not only GH and TSH secretion from the pituitary, but also GHRH release from the hypothalamus and/or peripheral tissues. These findings suggest that somatostatin controls GH secretion not only by suppressing pituitary secretion of GH but also by suppressing GHRH release from the hypothalamus.     

A study of the growth-promoting and metabolic effects of growth hormone (GH) in a patient with the "growth without GH" syndrome.

The paradox of normal or even excessive growth despite a proven lack of GH is a well-known but still unexplained phenomenon that has been described in some patients following resection of a craniopharyngioma or other suprasellar tumours. However, the consequences of GH deficiency on other metabolic aspects of GH action in this syndrome have not been adequately investigated. The aim of this study was to examine whether a dissociation might exist between the growth-promoting and metabolic effects of GH. We studied a 7.1 year old boy who, after removal of a suprasellar craniopharyngioma, developed panhypopituitarism with mild hyperprolactinaemia. Despite the presence of severe GH deficiency associated with persistently low IGF-I and IGFBP-3 levels, the patient grew spontaneously at an accelerated rate for a prepubertal boy, achieving a height velocity of 9.0 cm during the first and 8.5 cm during the second post-operative year. However, other metabolic parameters of GH activity were adversely affected by the lack of GH. The maximum tubular reabsorption rate for phosphate over glomerular filtration rate ratio (2.8) was persistently low and normalized during a 4 day course of hGH administration (4.2) together with the normalization of IGF-I (from 34 microg/l to 294 microg/l), suggesting that GH-dependent renal phosphate handling is impaired in this syndrome. In addition, bone age was delayed by 1.7 years consistently with delayed skeletal maturation, whereas skinfold thickness and the waist to hip ratio were increased in comparison with normative data, suggesting increased adipose tissue mass with central fat distribution, a phenotype characteristic of GH deficiency. In conclusion, our case study suggests that, in the "growth without GH" syndrome, the excessive growth is independent of GH and dissociated from other GH-dependent metabolic effects, which are decreased.     

Time mode of growth hormone (GH) entry into the bloodstream and steady-state plasma GH concentrations, rather than sex, estradiol, or menstrual cycle stage, primarily determine the GH elimination rate in healthy young women and men.

We have investigated whether a reduced MCR of GH in women will account for their higher serum GH concentrations premenopausally compared with those in men. To this end, we directly compared the half-life (t 1/2) of GH and its volume of distribution (Vo) in 13 young men and 6 comparably aged women, each evaluated at three stages of the normal menstrual cycle (viz. the early follicular, late follicular, and midluteal phases). To estimate nonequilibrium GH kinetics, each subject received octreotide pretreatment to suppress endogenous GH release and then 3 randomly ordered iv bolus doses of recombinant human GH (1, 2, and 4 microg/kg). The resultant peak serum GH concentrations were 18 +/- 4, 36+/-8, and 70+/-9 microg/L in six women and 17+/-2, 30+/-4, and 84+/-25 microg/L in six men (P = NS, gender contrast). Corresponding Vo values were 66+/-1, 71+/-1, and 60+/-1 mL/kg in women and 69+/-1, 78+/-1, and 73+/-1 mL/kg in men (P = NS). Matching monoexponential GH t1/2 values were 7.6+/-0.3, 8.2+/-0.4, and 8.8+/-0.7 min in women and 9.8+/-0.8, 10+/-1, and 9.5+/-1 min in men (average 1.7 min longer in men). Regression analysis disclosed no relationship between serum estradiol concentrations and peak serum GH levels, GH t 1/2, or Vo. GH t 1/2 values were also invariant of menstrual cycle stage, e.g. t 1/2 values of 8.1+/-0.5, 9.1+/-1.0, and 8.1+/-0.4 min for the early follicular, late follicular, and midluteal phases, respectively. Corresponding normalized MCRs were 319+/-39 (early follicular), 340+/-48 (late follicular), and 340+/-71 (midluteal) L/m2 x day in women and 336+/-50 L/m2 x day in men (P = NS). In parallel equilibrium infusion studies in men, we administered GH by constant iv infusions for 240 min during octreotide suppression. At doses of 0.5, 1.5, and 4.5 microg/kg x min, steady state GH t 1/2 values were 9+/-1, 12+/-1, and 15+/-1 min (at respective steady state serum GH concentrations of 0.5+/-0.05, 2.1+/-0.2, and 7.5+/-0.5 microg/L). In a third analysis in the same volunteers, stopping the constant iv infusions revealed t 1/2 values of GH decay from equilibrium of 26+/-5 and 23+/-2.3 min for the two higher GH infusion rates. In a fourth paradigm, endogenous GH t 1/2 values, as assessed in the same individuals by deconvolution analysis of overnight (10-min sampled) serum GH concentration profiles, averaged 18+/-1.3 min. This value was intermediate between that of poststeady state decay and iv bolus elimination of GH. In summary, the foregoing clinical experiments in healthy men and women indicate that 1) the nonequilibrium GH t 1/2, (body surface area-normalized) Vo, and MCR are independent of GH dose, sex, menstrual cycle stage, and serum estradiol concentrations; 2) the GH t 1/2 calculated after iv bolus injection is significantly (50%) shorter than that assessed during or after steady-state GH infusions or endogenously (overnight) by deconvolution analysis; and 3) the descending rank order of GH t 1/2 values in healthy volunteers is approximately: decay from steady state (23+/-2.3 min) > endogenously secreted GH (18+/-1.3 min) > during equilibrium infusion (15+/-1 min) > after bolus infusion (9.8+/-0.8 min). We thus conclude that for any given body surface area, the elimination properties of GH in men and women reflect predominantly the time mode of hormone entry into the circulation, rather than gender, menstrual cycle stage, or prevailing serum estradiol concentration. Accordingly, differences in serum GH concentrations in premenopausal women compared to those in young men and across the normal menstrual cycle reflect commensurate differences in pituitary GH secretion rates.     

High-affinity growth hormone (GH)-binding protein (GHBP), body fat mass, and insulin-like growth factor-binding protein-3 predict the GHBP response to GH therapy in adult GH deficiency syndrome

The study objective was to investigate which baseline factors can accurately predict plasma high-affinity growth hormone (GH)-binding protein (GHBP) levels after GH replacement therapy in patients with GH deficiency (GHD). The study group consisted of 36 GHD patients (22 men and 14 women; mean age, 43.1 years; (range, 21 to 60) known to have adult-onset GHD for many years (range, 4 to 22). They were randomly divided into a GH-treated group (n = 19) and a placebo group (n = 17). Body composition (assessed by bioelectrical impendance analysis [BIA]), plasma GHBP (fast protein liquid chromatography [FPLC] size-exclusion gel chromatography), insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 ([IGFBP-3] radioimmunoassays) were measured before and after 6 months. A stepwise multiple linear regression analysis with the plasma GHBP level after 6 months as the dependent variable was used to unravel significant explanatory (or predictor) variables. In contrast to placebo therapy, GH replacement therapy increased the mean plasma levels of IGF-I and IGFBP-3 to the normal range, whereas a small but statistically significant increase in plasma GHBP was observed. The combination of baseline plasma GHBP, body fat mass, and IGFBP-3 predicts posttreatment GHBP levels accurately (adjusted R2 = .97), indicating that baseline variables such as age, gender, fat-free mass, and IGF-I have no contribution. Furthermore, reliability analysis showed that the observed and predicted values for GHBP fit a strict parallel model. These findings indicate that the variations in body fat mass and IGFBP-3 among adult GHD subjects explain the reported variable response of GHBP to GH replacement therapy.     

Studies on the response of growth hormone (GH) secretion to GH-releasing hormone, thyrotropin-releasing hormone, gonadotropin-releasing hormone, and somatostatin in acromegaly

The plasma GH response to GH-releasing hormone (GHRH), TRH, or GnRH administration was examined in 25 acromegalic patients. Plasma GH levels increased in 21 patients after GHRH, in 19 after TRH, and in 4 after GnRH. The four GHRH nonresponders had had acromegaly longer than had the GHRH responders. No specific combination of GH responsiveness to these 3 releasing hormones was found among the patients. Infusion of 1 mg GHRH for 150 min gradually increased plasma GH levels, with some fluctuations, from the beginning to the end of infusion in normal subjects and in 7 patients who were GHRH responders, but a bolus injection of 100 micrograms GHRH at the end of the infusion did not further elevate plasma GH levels. These results suggest that desensitization to GHRH occurred in the normal subjects and acromegalic patients. However, in 5 acromegalic patients who responded to both GHRH and TRH, a bolus injection of 500 micrograms TRH given at the end of the 150-min infusion of 1 mg GHRH evoked a further plasma GH rise. In 5 normal subjects and 2 patients who were responders to GHRH but not TRH, a bolus injection of 500 micrograms TRH did not cause plasma GH elevation at the end of 150-min infusion of 1 mg GHRH. These results imply that TRH and GnRH stimulate GH secretion from the adenoma cells in vivo through receptors different from those for GHRH. In vitro studies using cultured pituitary adenoma cells from 2 patients revealed that the responses of GH secretion to GHRH were similar to those in vivo. These data, therefore, suggest that the responsiveness of GH secretion to stimuli is determined by the specificity of the receptors on adenoma cells. The action of somatostatin-28 was more potent than that of somatostatin-14 in the suppression of GH secretion from adenoma cells.     

Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency

To assess the effects of long-term continuous GH treatment on body composition, blood pressure (BP), and lipid metabolism in children with short stature born small for gestational age (SGA), body mass index (BMI), skinfold thickness measurements, systemic BP measurements, and levels of blood lipids were evaluated in 79 children with a baseline age of 3-11 yr with short stature (height SD-score, < -1.88) born SGA (birth length SD-score, < -1.88). Twenty-two of the 79 children were GH deficient (GHD). All children participated in a randomized, double-blind, dose-response multicenter GH trial. Four- and 6-yr data were compared between two GH dosage groups (3 vs. 6 IU/m2 body surface/day). Untreated children with short stature born SGA are lean (mean BMI SD-score, -1.3; mean SD-score skinfolds, -0.8), have a higher systolic BP (SD-score, 0.7) but normal diastolic BP (SD-score, -0.1), and normal lipids (total cholesterol, 4.7 mmol/L; low-density lipoprotein, 2.9 mmol/L; high-density lipoprotein, 1.3 mmol/L) compared with healthy peers. During long-term continuous GH treatment, the BMI normalized without overall changes in sc fat compared with age-matched references, whereas the BP SD-score and the atherogenic index decreased significantly. Although the mean 6-yr increase in height SD-score was significantly higher in the children receiving GH treatment with 6 IU/m2 x day (2.7) than in those receiving treatment with 3 IU/m2 day (2.2), no differences in the changes in BMI, skinfold measurements, BP, and lipids were found between the GH dosage groups. The pretreatment SD-scores for BMI, skinfold, and BP, as well as the lipid levels, were not significantly different between GHD and non-GHD children, but after 6 yr of GH treatment the skinfold SD-score and BP SD-score had decreased significantly more in the GHD than in the non-GHD children. Our data indicate that GH treatment has at least up to 6 yr positive instead of negative effects on body composition, BP, and lipid metabolism. In view of the reported higher risk of cardiovascular diseases in later life in children born SGA, further research into adulthood remains warranted.     

Morphological studies on mixed growth hormone (GH)- and prolactin (PRL)-secreting human pituitary adenomas. Coexistence of GH and PRL in the same secretory granule

A morphological study was carried out on five mixed GH- and PRL-secreting pituitary adenomas, surgically removed from acromegalic patients with hyperprolactinemia, in order to verify whether the two hormones were contained in the same cell or in different cells. Double labeling with the protein A-gold immunotechnique was used to visualize the ultrastructural localization of the two hormones on ultrathin sections of the tumors. By means of this high resolution technique we found in all adenomas the presence of numerous (from 50-80% of the whole cell population) mammosomatotrophs, i.e. cells containing simultaneously PRL and GH. The occurrence of cells producing only GH (in four tumors) or only PRL (in one tumor) was also observed. In mixed cells GH and PRL were segregated in the same mixed granule. In one tumor granules positive only for GH together with mixed granules were found in the same cell. Immunofluorescence studies, at the light microscopic level, allowed us to clearly identify mammosomatotrophs only in two tumors. Double labeling using the gold immunotechnique appears therefore to be the most suitable experimental approach to detect the existence of mixed cells in plurihormonal adenomas. Our results support the idea that the frequency of mixed adenomas with mixed cells may be higher than that believed previously. The simultaneous presence of two hormones in the same secretory granule could explain why, in patients having mixed tumors, factors able to stimulate or inhibit the release of one hormone can also stimulate or inhibit the secretion of the other.     

Effect of growth hormone (GH) and/or testosterone replacement on the prostate in GH-deficient adult patients

The prostate is a target organ of the GH and IGF-I axis because prostate hypertrophy is found in acromegaly, reduced prostate size is found in GH deficiency (GHD) patients, and additionally, IGF-I is reported to be a positive predictor factor of prostate cancer. To investigate whether GH replacement therapy in adult patients with GHD has adverse effects on the prostate, we studied the effect of 12-month GH or GH plus testosterone replacement on prostate pathophysiology in 24 adult patients with GHD (11 euandrogenemic and 13 hypoandrogenemic), compared with 24 age-matched healthy controls. At study entry, GHD patients had lower prostate volume than controls (19.4 +/- 1.7 vs. 24.9 +/- 1.7 ml; P = 0.03). After 12 months of treatment, all hypoandrogenemic patients achieved normal testosterone levels, and prostate volume increased in the patients to the same level as controls (25.0 +/- 1.9 ml). The percentage increase in prostate volume was greater in hypoandrogenemic patients receiving both GH and testosterone replacement (51 +/- 11%) than in those receiving GH replacement alone (15 +/- 3%; P < 0.0009). At baseline, prostate volume was similar in GHD patients below or above 60 yr of age (16.8 +/- 1.3 vs. 23 +/- 3.6 ml; P = 0.08), whereas after treatment it was higher in the latter patients (21.8 +/- 1.2 vs. 29.5 +/- 3.9 ml; P = 0.04). Prostate-specific antigen (PSA) and free PSA did not change, whereas PSA density was significantly reduced after treatment in hypoandrogenemic patients; there was also no change in calcifications, cysts, or nodules. In conclusion, GH replacement restores prostate size to normal in both young and elderly patients, with no increase in prostate abnormalities. Because the simultaneous treatment with GH and testosterone induces an increase of prostate size by 50% of baseline on average, care is suggested in elderly patients with prostate hyperplasia to avoid any risk of prostate symptoms. In these cases, GH replacement might be performed sequentially to reduce the hypertrophic effect of combining GH and testosterone.     

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.     

Plasma growth hormone (GH) responses to corticotropin-releasing hormone in patients with acromegaly--the effect of dexamethasone pretreatment and the comparison with GH responses to thyrotropin-releasing hormone, gonadotropin-releasing hormone and GH-releasing hormone.

It has been reported that paradoxical GH responses to corticotropin-releasing hormone (CRH) occur in only few patients with acromegaly. However, we have observed such responses in 7 of 14 active acromegalic patients. Therefore, we have studied the GH responses to thyrotropin-releasing hormone (TRH) (500 micrograms, iv), gonadotropin-releasing hormone (LHRH) (100 micrograms, iv) and GH-releasing hormone (GHRH) (100 micrograms, iv) in these patients to examine the relationships between the GH responses to CRH and the responses to these hypothalamic hormones. Further, these patients received human CRH (1-41) NH2 (100 micrograms, iv) with or without dexamethasone (Dex) pretreatment (1 mg/100 ml saline, iv, from -30 to +30 min) to study the mechanism of CRH-induced GH secretion, and a perifusion experiment was performed using adenoma tissue obtained at surgery from one patient (10(-7) M CRH and TRH were added) to elucidate whether CRH acts directly at the pituitary level. Aberrant GH responses induced by CRH were found in 7 of 14 (50%) acromegalic patients (TRH responders: 10/13, 77%; LHRH responders: 2/9, 22%; GHRH responders: 10/12, 83%). In these patients, percent GH increment induced by CRH ranged from 81 to 144% (Mean +/- SE, 118 +/- 8%), and the GH peak (19 +/- 3 min) appeared as early as after TRH (23 +/- 4 min, N = 10).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval--a General Clinical Research Center study

Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21-34 yr) and 8 older (aged 62-72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (+/- SEM) serum PRL concentration was significantly reduced at 4.3 +/- 0.78 microg/L in older men compared with 9.5 +/- 1.2 microg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = +0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 +/- 0.23 (older) vs. 3.9 +/- 0.57 microg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 +/- 0.00027 (older) vs. 0.00065 +/- 0.0002 microg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 +/- 5.3% in young and 99 +/- 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging. Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic) input to lactotrophs in older men. Given the multiple roles of PRL reported in experimental animals (e.g. on the one hand to support immune function and adrenal androgen biosynthesis and on the other hand to activate intraprostatic growth factors), we suggest that the nocturnal relative hypoprolactinemia observed in healthy aging men may have both adaptive and maladaptive clinical implications to target tissues.     

Expression,regulation and biological actions of growth hormone (GH) and ghrelin in the immune system

Immune and neuroendocrine systems have bidirectional communications. Growth hormone (GH) and an orexigenic hormone ghrelin are expressed in various immune cells such as T lymphocytes, B lymphocytes, monocytes and neutrophils. These immune cells also bear receptors for hormones: growth hormone receptor (GHR) for GH and growth hormone secretagogue receptor (GHS-R) for ghrelin. The expression of GH in immune cells is stimulated by ghrelin as in anterior pituitary cells, whereas the regulation of GH secretion in the immune system by other peptides seems to be different from that in the anterior pituitary gland. Cytokines and mitogens enhance GH secretion from immune cells. GH has several biological actions in the immune system: enhancing thymopoiesis and T cell development, modulating cytokine production, enhancing B cell development and antibody production, priming neutrophils and monocytes for superoxide anion secretion, enhancing neutrophil adhesion and monocyte migration and anti-apoptotic action. Biological actions of ghrelin include attenuation of septic shock and anti-inflammatory actions, modulating phagocytosis, and enhancing thymopoiesis. The effect of ghrelin may be direct or through GH production, and that of GH may be direct or through insulin like growth factor-I (IGF-I) production. Elucidation of the roles of GH and ghrelin in the immune system may shed light on the treatment and prevention of immunological disorders such as AIDS and organ damages due to obesity/ageing-related chronic inflammation.     

The metabolic clearance, distribution, and degradation of dimeric and monomeric growth hormone (GH): implications for the pattern of circulating GH forms

The ratio of oligomeric (big) to monomeric (little) human (h)GH forms in plasma exceeds that in the pituitary gland severalfold. To investigate whether delayed metabolic clearance of oligomers could explain this discrepancy, we measured MCR, distribution volumes, and degradation rates of radio-labeled hGH22K dimer, hGH20K dimer, hGH22K monomer, and hGH20K monomer in the rat. Hormones were injected as a bolus, and disappearance from plasma was followed by immunoprecipitation and trichloroacetic acid precipitation. MCRs of the dimers were significantly lower than those of the corresponding monomers (5-fold in the case of hGH22K, and 2-fold in the case of hGH20K). Both dimers were also degraded at slower rates than the monomers. Distribution volumes for the dimers, although somewhat smaller, were not statistically different from those for the monomers and were consistent with distribution in the extracellular space. We conclude that hGH dimers are relatively protected from degradation and hence cleared more slowly from the blood than hGH monomers. This may lead to their accumulation in the circulation relative to their monomeric counterparts, which may explain their high proportion in plasma as compared to pituitary.     

Impact of two or three daily subcutaneous injections of hexarelin, a synthetic growth hormone (GH) secretagogue, on 24-h GH, prolactin, adrenocorticotropin and cortisol secretion in humans

OBJECTIVE: To extend the insights on the action of GH secretagogues (GHS) on pituitary function, we studied the impact of intermittent daily s.c. administration of a peptidyl GHS, hexarelin (HEX), on 24-h GH, PRL, ACTH and cortisol release in healthy volunteers. DESIGN: We investigated the impact of two or three times daily s.c. administration of a short-acting peptidyl GHS, the hexapeptide HEX (1.5 microg/kg) on 24-h GH, PRL, ACTH and cortisol secretion (sampling every 20 min) in six normal young men. To monitor possible down-regulation, the effect of 1 microg/kg i.v. HEX at the end of each 24-h sampling period was studied. METHODS: Multi-parameter deconvolution analysis was used to quantitate pulsatile GH, PRL, ACTH and cortisol secretion and estimate the corresponding hormone half-lives. Complementary to deconvolution analysis, approximate entropy was used as a scale- and model-independent statistic to quantify the serial orderliness or pattern regularity of hormone measurements. RESULTS: Mean and integrated (24-h) serum GH concentrations were increased from baseline values to the same extent by two and three HEX injections. Both HEX schedules equally increased GH secretory burst mass (but not burst frequency), mean daily GH production rate, GH half-life and irregularity of GH release patterns. No change occurred in the secretion of IGF-I, PRL, ACTH and cortisol. Intravenous HEX at the end of each spontaneous 24-h profile induced a significant rise in GH, PRL, ACTH and cortisol. Prior HEX administration blunted the GH response, abolished that of ACTH and cortisol and did not modify the PRL increase. CONCLUSIONS: The study showed that two or three daily s.c. injections of HEX augmented 24-h GH secretion equally, amplifying selectively GH secretory pulse mass without altering lactotroph and corticotroph secretion. IGF-I levels were not modified by these 1-day HEX treatment schedules.     

Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men.

The present clinical study implements a novel interventional strategy of short-term profound and selective blockade of GH receptors to reduce plasma insulin-like growth factor I (IGF-I) concentrations reversibly in healthy eumetabolic adults. Thereby, we examine the feedback role of systemic IGF-I on GH secretion without introducing the complex metabolic disarray that can otherwise accompany secondary IGF-I deprivation. To this end, we sampled blood at 10-min intervals for 10 h overnight in 8 men (aged 19-46 yr) and 4 women (aged 19-39 yr) to quantitate endogenous GH secretion and half-life 72 h after the prospective, randomly ordered, double blind, and within-subject cross-over administration of pegvisomant (1 mg/kg) or saline (0.5 mL) sc. Pegvisomant is an oligopegylated recombinant human GH peptide mutated to antagonize GH receptor-dependent signaling. Statistical analyses of paired plasma IGF-I concentrations and deconvolution-based quantitation of pulsatile GH secretion revealed that GH receptor blockade 1) suppressed fasting total IGF-I concentrations by 31%, viz. from (mean +/- SEM) 276 +/- 42 (placebo) to 190 +/- 20 microg/L (pegvisomant; P = 0.006) 84 h after drug injection; 2) increased the 10-h mean serum GH concentration by 71% from 1.4 +/- 0.33 (placebo) to 2.4 +/- 0.58 (pegvisomant; P = 0.024); 3) augmented the amplitude of underlying GH secretory bursts by 2.1-fold (i.e. from 0.13 +/- 0.032 to 0.27 +/- 0.076 microg/L.min; P = 0.0088); and 4) elevated the basal/nonpulsatile rate of GH secretion by 2.5-fold (from 2.3 +/- 0.77 to 5.07 +/- 1.8 microg/L.10 h; P = 0.022). The rise in the amplitude of GH secretory bursts correlated with the fall in plasma IGF-I concentrations (r = 0.603; P = 0.038). In contrast, IGF-I depletion did not alter GH secretory pulse frequency, half-duration, interpulse interval, percentage of pulsatile GH release, or half-life of endogenous GH. In summary, selective short-term reduction of systemic IGF-I concentrations in healthy eumetabolic adults drives GH secretion via the specific bipartite neuroregulatory mechanism of amplified GH secretory burst amplitude and elevated basal/nonpulsatile GH release. Endogenous GH half-life and frequency-related features of pulsatile GH secretion are not measurably affected, thus identifying a highly distinctive mode of IGF-I feedback-dependent control of GH output. As the increment in GH secretory burst amplitude correlated with the decrement in plasma IGF-I concentrations, we infer that variations in circulating IGF-I availability within the adult midphysiological range can influence pulsatile and basal GH production by way of negative feedback. Based on data in experimental animals, we speculate that the negative feedback actions of systemic IGF-I on GH secretion are mediated via increased hypothalamic somatostatin release, decreased GHRH (or GH-releasing peptide) secretion, and/or suppressed pituitary GH biosynthesis.