Testosterone blunts feedback inhibition of growth hormone secretion by experimentally elevated insulin-like growth factor-I concentrations

The present study tests the hypothesis that a high dose of testosterone (Te) drives GH and IGF-I production, in part, by blunting autonegative feedback by the end-product peptide. To this end, we infused saline or recombinant human IGF-I (10 microg/kg.h iv for 6 h) in seven healthy men ages 51-72 yr after administration of placebo (Pl) and Te in randomized order. GH release was quantitated fasting before and after injection of GHRH (1 microg/kg). Statistical analyses disclosed that Te vs. Pl: 1) increased the mean concentration of GH from 0.15 +/- 0.045 to 0.48 +/- 0.11 microg/liter (P = 0.007) and IGF-I from 108 +/- 5.0 to 124 +/- 4.1 (P = 0.047) without altering GHRH-induced GH release; 2) elevated the GH nadir from 0.13 +/- 0.03 to 0.23 +/- 0.06 microg/liter (P < 0.05) in the control session and from 0.06 +/- 0.02 to 0.14 +/- 0.04 microg/liter (P = 0.038) during IGF-I infusion; 3) augmented GHRH-stimulated GH release from 3.0 +/- 0.56 (Pl) to 3.7 +/- 0.52 microg/liter (Te) (P < 0.05) during IGF-I infusion; and 4) did not influence estimated IGF-I kinetics. In summary, supplementation of a high dose of Te in middle-aged and older men attenuates IGF-I feedback-dependent inhibition of nadir and peak GH secretion. Both effects of Te differ from those reported recently for estradiol in postmenopausal women. Accordingly, we postulate that Te and estrogen modulate IGF-I negative feedback differentially.     

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.     

Supplemental growth hormone increases the tumor cytotoxic activity of natural killer cells in healthy adults with normal growth hormone secretion

Using double-blind, placebo-controlled procedures, the effects of methionyl-human growth hormone (met-hGH) on the tumor cytotoxic activity of natural killer (NK) cells were studied in seven healthy adults using a repeated measures experiment. Subjects were assigned at random to either a placebo (bacteriostatic water) treatment condition or a met-hGH (16.0 mg/wk of Protropin) treatment condition, then crossed-over to the alternative treatment. Treatments were delivered on alternate days (3 d/wk) for 6 weeks. Without bias from the met-hGH treatment, there was no evidence for GH hyposecretion as measured by the peak circulating GH response to exercise stimulation (14.1 +/- 3.1 ng/mL) or insulin-like growth factor (IGF-I) levels (0.82 +/- 0.09 U/mL). When compared with placebo, met-hGH induced a significant overall increase in the percent specific lysis (%SL) of K562 tumor target cells (placebo 22.2 +/- 1.7 v met-hGH 28.5 +/- 2.1 %SL; P = .008). NK activity was increased within the first week of treatment and this level was maintained throughout the remaining period of supplementation. There was a trend (P = .057) for the met-hGH-induced percent change in NK activity (NK%) to be inversely related to placebo IGF-I levels (r = -.761), while there were significant positive correlations between NK% and the met-hGH-induced percent changes in IGF-I (r = .727; P = .035), the fat-free mass (FFM)/fat mass (FM) ratio derived by hydrodensitometry (r = .792; P = .012), and the endogenous GH response to exercise (r = .469; P = .034).(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-term suppression of elevated growth hormone concentrations following insulin-like growth factor 1 administration in young adults with type 1 diabetes does not alter glomerular filtration or albumin excretion rates

OBJECTIVE: Young adults with type 1 diabetes mellitus (T1DM) have increased glomerular filtration rate (GFR), which may mediate progressive renal disease and microalbuminuria. This may be secondary to low concentrations of insulin-like growth factor (IGF)-I and GH hypersecretion. We tested the hypothesis that restoration of circulating IGF-I concentrations in young adults with T1DM might suppress GH secretion, GFR and urinary albumin excretion. DESIGN: In a randomized double blind crossover study six young adults with T1DM (three men, 19-24 years) received 7 days treatment with rhIGF-I/insulin-like growth factor binding protein (IGFBP)-3 complex (SomatoKine) 0.4 mg/kg/day and placebo. Subjects underwent overnight insulin infusion for euglycaemia, followed by determination of GFR and albumin excretion rate. RESULTS: Following IGF-I/IGFBP-3 complex, overnight insulin requirements (0.15 vs placebo 0.21 mU/kg/min, P < 0.04), plasma insulin (77 vs placebo 152 pmol/l, P < 0.01) and mean overnight GH (2.6 vs placebo 4.8 mU/l, P < 0.04) fell. IGF-I (492 vs placebo 218 ng/ml, P < 0.01) and IGFBP-3 (4.5 vs placebo 3.9 microg/ml, P < 0.05) increased. GFR did not change (145.5 (23.9) ml/min/1.73 m(2) post-IGF-I/IGFBP-3 complex vs 152.2 (19.8) post placebo). Albumin excretion rate did not change 9.5 (5.5-16.6)mg/24 h pre- vs 11.5 (9.9-20.2) post-IGF-I/IGFBP-3 complex and 10.7 (8.1-21.2) pre- vs 11.5 (8.7-29.9) post placebo. Plasma creatinine levels were lower following IGF-I/IGFBP-3 complex (mean +/- SD, 56.2 +/- 16.8 micromol/l) vs placebo (61.5, 45.0, P < 0.02). CONCLUSIONS: Seven days treatment with IGF-I/IGFBP-3 complex enhanced overnight insulin sensitivity and reduced GH levels, but there was no effect on glomerular hyperfiltration or albumin excretion rates.     

Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy

OBJECTIVE: Testosterone supplementation increases GH and IGF-I concentrations in healthy older men via unknown mechanisms. We examine the hypotheses that (i) testosterone amplifies stimulation of GH secretion by GH-releasing peptide (GHRP)-2 or GH-releasing hormone (GHRH) infused with l-arginine to limit somatostatin outflow (i.e. upregulates each agonistic pathway), (ii) testosterone augments the effect of both peptidyl secretagogues infused together (i.e. reduces opposition by hypothalamic somatostatin) and (iii) abdominal visceral fat (AVF) mass is a negative determinant of specific secretagogue-stimulated GH secretion. DESIGN: Randomized double-blind crossover design of placebo versus testosterone administration in healthy older men. METHODS: Deconvolution analysis was used to estimate basal GH secretion and the mass (integral) and waveform (time-shape) of GH secretory bursts. RESULTS: Statistical contrasts revealed that administration of testosterone compared with placebo in seven men aged 60-77 years increased fasting concentrations of GH (P < 0.01) and IGF-I (P = 0.003), and basal (P < 0.005) and pulsatile (P < 0.01) GH secretion. Testosterone did not alter the absolute value or rank order of secretagogue efficacy: l-arginine/GHRP-2 (23-fold effect over saline) = GHRH/GHRP-2 (20-fold) > l-arginine/GHRH (7.5-fold). Waveform reconstruction indicated that each stimulus pair accelerated initial GH secretion within a burst (P < 0.01). Regression analysis disclosed a significant inverse association between GH secretory-burst mass and computer tomography-estimated AVF following stimulation with l-arginine/GHRH after testosterone supplementation (R(2) = 0.54, P = 0.015). CONCLUSION: Supraphysiological testosterone concentrations augment GH and IGF-I production in the elderly male without altering maximal somatotrope responses to single and combined GHRH and GHRP-2 drive, thus predicting multifactorial mechanisms of testosterone upregulation.     

Quantitation of urinary somatomedin-C and growth hormone in preterm and fullterm infants and normal children

Urinary GH and somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) excretion were measured in 12-h urine collections obtained from 43 infants (27 stable preterm infants and 16 healthy fullterm infants) and 31 normal children, aged 3-17 yr. Urinary Sm-C/IGF-I was excreted as the free hormone, since no binding of radiolabeled Sm-C/IGF-I to any urine protein with a mol wt similar to those described for plasma Sm-C/IGF-I-binding proteins was found. The preterm infants excreted significantly more urinary GH [13.5 +/- 2.1 (+/- SE) ng/kg.12 h] than either the fullterm infants (5.3 +/- 1.6 ng/kg.12h) or the children (0.27 +/- 0.02 ng/kg.12 h; P less than 0.01). The mean urinary Sm-C/IGF-I excretion in the preterm infants (98.9 +/- 7.5 mU/kg.12 h) was comparable to that in fullterm infants (87.6 +/- 9.7 mU/kg.12 h); both groups excreted significantly more urinary Sm-C/IGF-I than children (28.4 +/- 2.1 mU/kg.12 h; P less than 0.01). The group differences were similar when the results were expressed in terms of creatinine excretion. Urinary GH excretion correlated positively with urinary Sm-C/IGF-I excretion (r = 0.68). The higher output of these peptides in rapidly growing infants and their positive correlation in urine provide additional support for the Sm hypothesis.     

Quantitation of urinary somatomedin-C in children with normal and abnormal growth

The renal excretion of radioimmunoassayable somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) was measured in 12-h overnight urine samples obtained from 88 subjects, aged 3-19 yr. The participants included 34 healthy children (group 1), 29 children with idiopathic growth failure and normal GH stimulation tests (group 2), and 25 GH-deficient subjects (group 3). The mean (+/- SEM) urinary Sm-C/IGF-I excretion in group 1 (28.4 +/- 2.1 mU/kg) was significantly greater than that in group 2 (8.1 +/- 1.6 mU/kg) or group 3 (8.6 +/- 1.3 mU/kg). Twenty-two of the 29 subjects in group 2 had urinary Sm-C/IGF-I values less than 8 mU/kg. After the administration of biosynthetic GH to 12 GH-deficient subjects, urinary Sm-C/IGF-I excretion rose from 10.3 +/- 2.3 to 21.4 +/- 4.2 mU/kg within 12 h (P less than 0.05), indicating that renal excretion of Sm-C/IGF-I is GH dependent. One woman with acromegaly had markedly elevated urinary Sm-C/IGF-I excretion (420 mU/kg). The authenticity of urinary Sm-C/IGF-I was confirmed by high pressure liquid chromatography (HPLC). Assay of serial dilutions of urinary Sm-C/IGF-I demonstrated a direct proportionality between concentration and dilution. Although it is not possible to identify whether urinary Sm-C/IGF-I reflects local or generalized synthesis of the peptide, we hypothesize that quantitation of Sm-C/IGF-I in timed urine collections will yield additional information about GH production and action in children with normal and abnormal growth.     

Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu

To test the clinical hypothesis that an estrogen-enriched milieu enhances GHRH action, we administered placebo (Pl) and estradiol-17 beta (E(2)) orally for 23 d to six postmenopausal women in a prospectively randomized, double-masked, within-subject crossover design with 6 wk intervening. The GHRH stimulation protocol entailed consecutive i.v. infusion of L-arginine and a single i.v. pulse of saline or one of five randomly ordered doses of recombinant human GHRH-1,44-amide (0.03, 0.1, 0.3, 1.0, or 3.0 microg/kg) in a total of 12 separate morning, fasting sessions. GH secretion was monitored by sampling blood every 10 min for 6 h; chemiluminescence assay of GH concentrations; deconvolution analysis of stimulated GH release; and nonlinear dose-response reconstruction. Supplementation with E(2), compared with Pl: 1) increased (mean +/- SEM) E(2) concentrations from 18 +/- 3 (Pl) to 164 +/- 12 pg/ml (to convert to picomoles per liter, multiply by 3.57) (P < 0.001); 2) decreased IGF-I concentrations from 181 +/- 14 to 120 +/- 11 microg/liter (P < 0.01); 3) elevated mean GH concentrations from 0.27 +/- 0.06 to 0.59 +/- 0.08 microg/liter (P = 0.014); 4) potentiated GH secretion stimulated by L-arginine alone by 1.43-fold (P = 0.012); 5) reduced the ED(50) of GHRH from 0.27 +/- 0.02 to 0.13 +/- 0.01 microg/kg (P < 0.01), denoting enhanced GHRH potency; and 6) heightened the maximal slope of the dose-response function from 1.1 +/- 0.1 to 1.4 +/- 0.05 [( microg/liter) ( microg/kg)(-1)] (P < 0.05), signifying augmented pituitary sensitivity. The foregoing facilitative mechanisms were specific because E(2) replacement did alter maximal L-arginine/GHRH-induced GH secretion, indicating unchanged secretagogue efficacy. In conclusion, inasmuch as E(2) also attenuates inhibition of GH secretion by infused somatostatin and potentiates stimulation of GH secretion by GH-releasing peptide-2, we postulate that estrogenic steroids drive pulsatile GH production in part via mechanisms that include all three of GHRH, somatostatin, and putatively GH-releasing peptide/ghrelin signaling.     

Demonstration of insulin-like growth factor I in human urine

Immunoreactive and receptor-reactive insulin-like growth factor I (IGF-I) was demonstrated in human urine. Thirty percent of the IGF-I immunoreactivity in urine was free, and the remainder was a high mol wt form (approximately 43K). Urinary IGF-I was quantitated by RIA after extraction with octadecylsilyl silica cartridges (Sep-Pak C18 cartridge), a method that measures only free IGF-I. The mean urinary immunoreactive IGF-I levels in normal adults (n = 8) and patients with acromegaly (n = 10) or hypopituitarism (n = 9) were 72 +/- 7 (+/- SEM), 225 +/- 34, and 19 +/- 4 pg/mg creatinine, respectively; these mean values were significantly different from one another. The results indicate that IGF-I is present in human urine and that the quantity in urine is altered in patients with GH excess and deficiency.     

Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement

OBJECTIVE: GH dose requirement is lower in ACTH replete compared with ACTH deficient hypopituitary patients suggesting that adrenal androgens may augment IGF-I generation for a given GH dose. This study aimed to determine the effect of dehydroepiandrosterone (DHEA) administration on GH dose requirements in hypopituitary adults. DESIGN: A double blind placebo controlled trial was conducted adding 50 mg DHEA to the standard replacement of hypopituitary patients, including GH, over an initial 6 months, followed by an open phase study of 6 months DHEA replacement and a final 2 month washout phase after DHEA withdrawal. The dose of GH was adjusted to achieve a constant serum IGF-I. PATIENTS: Thirty female and 21 male hypopituitary patients were enrolled. Data from 26 women and 18 men were analysed after patient withdrawal. MEASUREMENTS: The primary outcome objective was the GH dose required to achieve a stable serum IGF-I. Secondary outcome measures were lipoprotein profiles, insulin, insulin sensitivity, IGFBP-3, waist/hip ratio and indices of bone remodelling. RESULTS: DHEA replacement in female patients lead to a 14.6 +/- 20% reduction in the dose of GH for a constant serum IGF-I (P < 0.05, 95% CI: 1.8, 32.7). This was maintained for 12 months and there was a significant fall in serum IGF-I two months after withdrawal of DHEA. There was no change in the male group. CONCLUSIONS: DHEA replacement may reduce GH dose requirements in female hypopituitary patients.     

Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women

The present study tests the mechanistic postulate that estrogen confers resistance to negative feedback by systemic IGF-I. To this end, eight postmenopausal women received a constant iv infusion of recombinant human (rh)IGF-I (10 micro g/kg.h x 6 h) and saline in randomized order on the 10th day of supplementation with oral estradiol (E(2)) and placebo (Pl). GH secretion was quantitated by 10-min blood sampling, immunochemiluminometry assay, and deconvolution analysis. Administration of E(2) compared with Pl followed by saline infusion: 1) stimulated pulsatile GH secretion ( micro g/liter.6 h), viz., 12 +/- 3.3 (Pl) and 18 +/- 4.6 (E(2)) (mean +/- SEM, paired comparison, P < 0.05); 2) halved the time latency (min) to achieve peak GH secretion after GHRH injection, 24 +/- 2.2 (Pl) and 12 +/- 2.1 (E(2)) (P < 0.01); and 3) did not alter the mass of GH secreted ( micro g/liter) in response to a maximally effective dose of GHRH, 30 +/- 7.2 (Pl) and 37 +/- 11 (E(2)). Exposure to E(2) compared with Pl followed by rhIGF-I infusion: 1) accelerated the rate of decline of GH concentrations by 3.3-fold, viz., absolute slope ( micro g/liter.1000 min), 3.8 (range, 2.5-5.0) (Pl) and 12 (range, 10-14) (E(2)) (P < 0.001); 2) augmented the algebraic decrement in GH concentrations ( micro g/liter) enforced by rhIGF-I infusion, 0.73 +/- 0.21 (Pl) and 1.6 +/- 0.25 (E(2)) (P < 0.01); 3) halved the time delay (min) to peak GHRH-induced GH secretion, 20 +/- 1.2 (Pl) vs. 10 +/- 1.3 (E(2)) min (P < 0.01). In contradistinction, E(2) did not alter: 1) the capability of rhIGF-I to suppress GHRH-stimulated GH secretory burst mass significantly, viz., by 50 +/- 8% (Pl) and 52 +/- 14% (E(2)) (P < 0.05 each vs. saline); 2) the hourly rate of rise of infused (total) IGF-I concentrations; and 3) total and ultrafiltratably free IGF-I concentrations ( micro g/liter) attained at the end of the two rhIGF-I infusions. In summary, compared with Pl, E(2) supplementation in postmenopausal women: 1) amplifies endogenously driven GH secretory-burst mass; 2) initiates rapid onset of GHRH-stimulated GH release; and 3) potentiates IGF-I-dependent suppression of unstimulated GH concentrations. Based upon companion modeling data, we postulate that E(2) facilitates the upstroke and IGF-I enforces the downstroke of high-amplitude GH secretory bursts in estrogen-replete individuals.     

Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy

OBJECTIVE: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. METHODS: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. RESULTS: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P = 0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 mumol/mmol creatinine (P = 0.027) and 65 nmol/mmol creatinine (P = 0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. CONCLUSION: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.     

Acute effects of growth hormone on vascular function in human subjects

GH is involved in the long-term regulation of peripheral vascular resistance and vascular reactivity. We determined whether GH plays a role in the acute regulation of vascular function in humans. The acute vascular effects of GH were studied in eight healthy subjects according to a double-blind, placebo-controlled design. Forearm blood flow (FBF), vascular resistance, and nitric oxide (NO) production were monitored during a 4-h infusion of GH into the brachial artery at a rate chosen to raise local GH to stress levels (approximately 40 ng/ml). During GH infusion, FBF rose 75% (P < 0.05), whereas forearm vascular resistance decreased comparably (P < 0.05). These changes were paralleled by augmented forearm release of NO (P < 0.02). GH heightened the response of FBF to the endothelium-dependent vasodilator acetylcholine (Ach; P < 0.02). With the highest Ach dose, FBF reached 30.4 +/- 4.2 and 16.9 +/- 3.1 ml/dl x min in the GH and placebo studies, respectively (P < 0.005). The slopes of the dose-response curves also differed markedly (0.45 +/- 0.07 and 0.25 +/- 0.05 ml/dl x min/ microg in the GH and placebo studies, respectively; P < 0.01). GH caused an upward shift of the FBF response to the endothelium-independent vasodilator sodium nitroprusside (P < 0.01), but did not affect the slope of the dose-response curve. GH infusion did not cause any appreciable increment in the venous IGF-I concentration in the test arm. In conclusion, GH acutely lowers peripheral vascular resistance and stimulates endothelial function. These effects are mediated by activation of the NO pathway and appear to be independent of IGF-I.     

Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement

CONTEXT: Patients with panhypopituitarism have impaired quality of life (QoL) despite GH replacement. They are profoundly androgen deficient, and dehydroepiandrosterone (DHEA) has been shown to have a beneficial effect on well-being and mood in patients with adrenal failure and possibly in hypopituitarism. OBJECTIVE: Our objective was to determine the effect of DHEA administration on mood in hypopituitary adults on established GH replacement with a constant serum IGF-I. DESIGN: A double-blind, placebo-controlled trial was conducted over an initial 6 months followed by an open phase of 6 months of DHEA. SETTING: The study was conducted at a tertiary referral endocrinology unit. PATIENTS: Thirty female and 21 male hypopituitary patients enrolled. Data from 26 females and 18 males were analyzed after patient withdrawal. INTERVENTIONS: DHEA (50 mg) was added to maintenance replacement including GH. MAIN OUTCOME MEASURES: The primary outcome objective was the effect on QoL and libido assessed by QoL assessment in GH deficiency in adults, Short Form 36, General Health Questionnaire, EuroQol, and sexual self-efficacy scale. RESULTS: Patients had impaired QoL at baseline compared with the age-matched British population. Females showed improvement in QoL assessment in GH deficiency in adults score (-2.9 +/- 2.8 DHEA vs.-0.53 +/- 3 placebo; P < 0.05), in Short Form 36 social functioning (14.6 +/- 23.1 DHEA vs.-4.7 +/- 25 placebo; P = 0.047), and general health perception (9.6 +/- 14.2 DHEA vs.-1.2 +/- 11.6 placebo; P = 0.036) after 6 months of DHEA. Men showed improvement in self-esteem (-1.3 +/- 1.7 DHEA vs. 0.5 +/- 1.5 placebo; P = 0.03) and depression (-1.6 +/- 2.2 DHEA vs. 1.2 +/- 2.4 placebo, P = 0.02) domains of the General Health Questionnaire after 6 months of DHEA. CONCLUSIONS: DHEA replacement leads to modest improvement in psychological well-being in female and minor psychological improvement in male hypopituitary patients on GH replacement.     

The effect of growth hormone (GH) therapy on urinary pyridinoline cross-links in GH-deficient adults

OBJECTIVE: The aim was to study the effect of growth hormone (GH) on new markers of bone resorption (fasting urinary excretion of pyridinium cross-links (pyridinoline and deoxypyridinoline)) in GH-deficient adults. DESIGN: Randomized, double-blind, placebo-controlled cross-over study. The treatment periods (GH 2 IU/m2 subcutaneously, or placebo daily for 4 months) were separated by a 4-month washout period. PATIENTS: Twenty GH-deficient adults (aged 18-39). MEASUREMENTS: Blood and fasting urine samples were collected at the end of each 4-month treatment period. Plasma bone Gla protein was measured by radioimmunoassay and urine pyridinoline and deoxypyridinoline were measured by spectrofluorometry after high performance liquid chromatography and corrected for urinary creatinine. RESULTS: GH increased fasting urinary excretion of pyridinoline (287 +/- 123%, P less than 0.001) and deoxypyridinoline (313 +/- 140%, P less than 0.001). The GH-induced increment in these parameters correlated with the increase seen in plasma bone Gla protein (r = 0.83-0.86, P less than 0.001). CONCLUSION: Four months of GH substitution in GH-deficient adults increases bone resorption as well as bone formation. The effect on bone mass has yet to be assessed.     

Changes in free rather than total insulin-like growth factor-I enhance insulin sensitivity and suppress endogenous peak growth hormone (GH) release following short-term low-dose GH administration in young healthy adults

High-dose GH administration is commonly associated with impaired insulin sensitivity (S(I)) in humans. Paradoxically we have shown that low-dose GH (1.7 microg/kg.d) administration enhances beta-cell function in young healthy adults. In the present double-blind, placebo-controlled, cross-over study, we explored the physiological effects of this low GH dose on glucose metabolism in 12 young healthy adults (seven males, 19-29 yr). At pretreatment and after each 14-d treatment block, overnight metabolic profiles were assessed followed by a hyperinsulinemic euglycemic clamp, whereas fasting blood samples were collected weekly.In subjects treated with GH first (group A, n = 6), GH treatment increased total IGF-I (P < 0.05) and IGF binding protein-3 (P < 0.01) after 7 d, but these levels subsequently returned to pretreatment levels after 14 d. In contrast, free IGF-I increased (P < 0.05), and overnight GH pulse peak amplitude decreased (P < 0.01) after 14 d. In subjects treated with placebo first (group B, n = 6), all biochemical parameters were unchanged after placebo treatment, whereas the changes in free and total IGF-I were similar to those of group A after GH treatment. Combined clamp data from both groups A and B (n = 12) showed that 14-d GH treatment decreased overnight plasma insulin levels (P < 0.02) and hepatic glucose appearance (P < 0.05) and increased S(I) (P < 0.01). Of note, the GH-induced changes in S(I) positively correlated with the changes in free IGF-I (r = 0.72, P < 0.01).In conclusion, low-dose GH administration enhanced S(I) and suppressed endogenous peak GH release, and we hypothesize that these effects are the direct result of increased serum levels of free IGF-I.     

The effect of long-term pharmacological antilipolysis on substrate metabolism in growth hormone (GH)-substituted GH-deficient adults

The lipolytic properties of GH are essential for the acute effects on glucose metabolism and insulin sensitivity, whereas its more long-term impact on substrate metabolism is uncertain. The aim of the study was to evaluate the influence of pharmacological antilipolysis on substrate metabolism during constant and continued GH exposure. Seven adult GH-deficient (GHD) patients were studied twice in a double-blind randomized order: 1) after 4 wk of acipimox treatment (250 mg, orally, three times daily) and 2) after 4 wk of placebo treatment. Daily GH replacement was continued throughout both study periods. At the end of each period glucose and lipid oxidation rates were assessed by indirect calorimetry, and the protein oxidation rate was estimated by urinary excretion of urea. Endogenous glucose production and whole body protein metabolism were assessed by isotope dilution techniques using tritiated glucose and stable phenylalanine and tyrosine isotopes, respectively. GH and IGF-I levels were not different between periods, whereas FFA and glycerol levels were distinctly suppressed after 4 wk of pharmacological antilipolysis [FFA, 256 +/- 63 (acipimox) vs. 596 +/- 69 (placebo) micromol/liter; P = 0.001]. Likewise, plasma levels of total and low density lipoprotein cholesterol as well as triglycerides were significantly reduced after acipimox. Despite this, lipid oxidation rates were identical at the end of the two treatment periods [589 +/- 106 (acipimox) vs. 626 +/- 111 (placebo) kcal/24 h; P = 0.698]. The total and oxidative rates of glucose as well as protein oxidation and urea excretion were identical at the end of the two treatment periods (P > 0.05). Phenylalanine flux, a measure of protein turnover, was increased [34.62 +/- 1.83 (acipimox) vs. 33.15 +/- 1.61 (placebo) micromol/kg.h; P = 0.049] as was phenylalanine incorporation into protein, a measure of protein synthesis [30.79 +/- 1.67 (acipimox) vs. 28.97 +/- 1.51 (placebo) micromol/kg.h; P = 0.035]. The following conclusions were reached: 1) prolonged antilipolysis by means of acipimox stimulates protein turnover without affecting net protein balance; and 2) acipimox in combination with constant GH exposure results in sustained suppression of circulating levels of FFA, glycerol, and triglycerides without a reduction in the rate of lipid oxidation. The site and origin of lipid fuels for oxidation during suppression of lipolysis remain to be determined.     

Continuation of growth hormone (GH) replacement in GH-deficient patients during transition from childhood to adulthood: a two-year placebo-controlled study

Previous studies have demonstrated beneficial effects of GH replacement, in adults with GH deficiency (GHD), on body composition, physical fitness, and quality of life. These studies, however, concern patients with adult-onset GHD or childhood-onset (CO) patients enrolled several years after withdrawal of initial therapy. So far, the effects of continuation of GH-administration in patients with CO-GHD have not been examined. We studied a group of nineteen young adults (13 males + 6 females; 16-26 yr old; mean age, 20.2 +/- 0.65 yr) with CO-GHD, in a randomized, parallel, double-blind, placebo-controlled trial for 1 yr, followed by an open phase with GH for 1 yr. All patients received GH therapy at the start of study, and trial medication (GH/placebo) was given in a similar dose. Patients randomized to continued GH treatment exhibited no significant changes in any parameters tested, but intra- and interindividual variations in insulin-like growth factor (IGF)-I levels could suggest compliance problems. Discontinuation of GH for 1 yr resulted in a decrease in serum IGF-I, from 422.0 +/- 56.8 to 147.8 +/- 33.4 microg/L, in the placebo group (P = 0.003). After discontinuation of GH for 1 yr, an increase in total body fat (TBF, kg), measured by dual-energy x-ray absorptiometry scan, was seen [placebo: 22.7 +/- 2.7 to 26.5 +/- 2.5 (P = 0.01); GH: 16.2 +/- 2.1 to 17.2 +/- 2.1 (not significant)]. Resumption of GH after placebo was followed by increments in serum IGF-I (microg/L) [from 147.8 +/- 33.4 to 452 +/- 76 (P = 0.001)] and IGF-binding protein 3, as well as in fasting glucose (mmol/L) [4.9 +/- 0.2 vs. 5.3 +/- 0.2 (P = 0.03)]. After resumption of GH lean body mass (kg) increased [52.4 +/- 4.9 vs. 60.7 +/- 5.6 (P = 0.006)]. Likewise, resumption of GH therapy increased thigh muscle volume and thigh muscle/fat ratio, as assessed by computed tomography [muscle volume (cm2/10 mm): 118.2 +/- 11.7 vs. 130.0 +/- 10.9 (P = 0.002); muscle/fat ratio: 1.33 +/- 0.24 vs. 1.69 +/- 0.36 (P = 0.02)]. In conclusion, discontinuation of GH treatment in GHD patients, during the transition from childhood to adulthood, induces significant and potentially unfavorable changes in IGF-I and body composition, both of which are reversed after resumption of GH treatment. By contrast, continuation of GH therapy results in unaltered IGF-I and body composition. We recommend continuation of GH therapy in these patients, to be undertaken in collaboration between pediatricians and adult endocrinologists.     

Impact of estradiol supplementation on dual peptidyl drive of GH secretion in postmenopausal women

As an indirect probe of estrogen-regulated hypothalamic somatostatin restraint, the present study monitors the ability of short-term oral E2 supplementation to modulate GH secretion during combined continuous stimulation by recombinant human GHRH [GHRH-(1-44)-amide] and the potent and selective synthetic GH-releasing peptide, GHRP-2. According to a simplified tripeptidyl model of GH neuroregulation, the effects of estrogen in this dual secretagogue paradigm should mirror alterations in endogenous somatostatinergic signaling. To this end, seven healthy postmenopausal women underwent frequent (10-min) blood sampling for 24 h during simultaneous i.v. infusion of GHRH and GHRP-2 each at a rate of 1 microg/kg x h on d 10 of randomly ordered placebo or 17beta-estradiol (E2) (1 mg orally twice daily) replacement. Serum GH concentrations (n = 280/subject) were assayed by chemiluminescence. The resultant GH time series was evaluated by deconvolution analysis, the approximate entropy statistic, and cosine regression to quantitate pulsatile, entropic (feedback-sensitive), and 24-h rhythmic GH release, respectively. Statistical comparisons revealed that E2 repletion increased the mean (+/- SEM) serum E2 concentration to 222 +/- 26 pg/ml from 16 +/- 1.7 pg/ml during placebo (P < 0.001) and suppressed the serum LH by 48% (P = 0.0033), serum FSH by 64% (P < 0.001), and serum IGF-I by 44% (P = 0.021). Double peptidyl secretagogue stimulation elevated mean 24-h serum GH concentrations to 8.1 +/- 1.0 microg/liter (placebo) and 7.7 +/- 0.89 microg/liter (E2; P = NS) and evoked prominently pulsatile patterns of GH secretion. No primary measure of pulsatile or basal GH release was altered by the disparate sex steroid milieu, i.e. GH secretory burst amplitudes of 0.62 +/- 0.93 (placebo) and 0.72 +/- 0.16 (E2) microg/liter x min, GH pulse frequencies of 27 +/- 1.8 (placebo) and 23 +/- 1.9 (E2) events/24 h, GH half-lives of 12 +/- 0.74 (placebo) and 15 +/- 4.5 (E2) min, and basal (nonpulsatile) GH secretion 70 +/- 22 (placebo) and 57 +/- 18 (E2) ng/liter x min. The approximate entropy (ApEn) of serial GH release [1.297 +/- 0.061 (placebo) and 1.323 +/- 0.06 (E2)] and the mesor (cosine mean), amplitude, and acrophase (time of the maximum) of 24-h rhythmic GH secretion were likewise invariant of estrogen supplementation. Estimated statistical power exceeded 90% for detecting significant (P < 0.05) within-subject changes exceeding 30-50% in the mean serum GH concentration, GH ApEn, or GH mesor. In contrast, ApEn analysis of the evolution of successive GH secretory burst-mass values over 24 h disclosed that E2 replacement disrupts the serial regularity of pulsatile GH output (elevates the ApEn ratio) during combined GHRH/GHRP-2 stimulation (P = 0.004). In summary, short-term elevation of serum E2 concentrations in postmenopausal individuals into the midfollicular phase range observed in young women does not significantly alter 24-h basal, pulsatile, entropic, or nyctohemeral GH secretion monitored under continuous combined drive by GHRH and GHRP-2. As E2 repletion without enforced GHRH/GHRP-2 stimulation augments each of the foregoing regulated facets of GH release, we infer that one or both of the infused peptidyl secretagogues may itself participate in E2's short-term amplification of GH secretion in postmenopausal individuals. Estrogen's disruption of the orderliness of sequential GH pulse-mass values during fixed GHRH/GHRP-2 feedforward would be consistent with a subtle reduction in the release and/or actions of hypothalamic somatostatin or an (unexpected) direct pituitary action of the sex steroid. Whether comparable dynamics mediate the effects of endogenous estrogen on the GH axis in premenopausal women or pubertal girls is not known.     

One year growth hormone replacement therapy does not alter colonic epithelial cell proliferation in growth hormone deficient adults

OBJECTIVE: Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo-controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate. PATIENTS AND DESIGN: Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n = 5), high dose GH therapy (2 U daily, n = 5) or placebo (n = 6) during 6 months. Thereafter, all patients were treated with 2 U of GH daily during a 6-months open extension period. MEASUREMENTS: Plasma Insulin-like growth hormone I (IGF-I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5-bromo-2'-deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period. RESULTS: IGF-I rose from 8.9 +/- 6.7 to 34.6 +/- 20.0 nmol/l after 6 months in 8 GH treated patients (P < 0.01 from baseline; P < 0.01 from change with placebo). In the extension study, plasma IGF-I was also increased in the patients who previously received placebo (P < 0.02, n = 5). LI was evaluable in 14 biopsies at baseline, in 16 after 6 months and in 14 after 12 months. Overall crypt LI did not change in 8 GH treated patients after 6 months (P > 0.40 from baseline; P > 0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9, P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS: Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.