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Controversial effects of weight reduction on gonadotropin secretion in obesity have been reported. As a result of pulsatility, single serum samples or frequent sampling studies are somewhat limited with regard to monitoring LH and FSH concentrations. We studied follicular phase nocturnal urinary (nu) LH and FSH secretion and glucose metabolism (150-min euglycemic hyperinsulinemic clamp) during 1 menstrual cycle/30-day period before and after weight reduction in 10 severely overweight infertility patients (age, 29 +/- 3.1 yr; body mass index, 37.1 +/- 3.3 kg/m2; +/-SEM). A 6-week very low calorie diet was followed by a 4-week normocaloric period. The urinary LH and FSH results reported represent samples taken 12 to 2 days before the LH surge, or 10 consecutive samples in the case of amenorrhea. We observed a decrease of 8% (P < 0.001) in percent body fat mass and a 5% (P < 0.005) reduction in waist to hip ratio. Mean nu-LH decreased by 45% [6.06 +/- 1.05 (+/-SEM) to 3.22 +/- 0.71 IU/L], whereas mean nu-FSH remained unchanged. Insulin-stimulated glucose uptake increased by 41% (P < 0.01), which was accounted for by a significant increase in nonoxidative glucose disposal (P = 0.003). Serum sex hormone-binding globulin concentrations increased by 39% (P < 0.01), and insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels increased by 46% (P < 0.05). Fasting serum insulin concentrations decreased by 38%, those of leptin by 37%, those of androstenedione by 32%, those of testosterone by 20% (all P < 0.01), and those of dehydroepiandrosterone sulfate by 13% (P < 0.05). The percent change in nu-LH correlated negatively with glucose uptake (r = -0.76; P < 0.01) and the increase in serum sex hormone-binding globulin (r = -0.85; P < 0.005) and positively with the percent change in waist to hip ratio (r = 0.79; P < 0.01). The absolute nu-LH levels after weight reduction correlated significantly with fasting insulin concentrations (r = 0.88; P < 0.001) and negatively with glucose uptake (r = -0.67; P < 0.05). No significant relationships were found between absolute levels or changes in nu-LH concentrations and leptin, IGF-I, IGFBP-3, or IGFBP-1 concentrations. Our findings suggest that weight reduction with a very low calorie diet results in a decrease in nu-LH concentrations, a reduction in the LH/FSH ratio, and FSH predominance favoring folliculogenesis. The decrease in LH concentrations is inversely related to the severity of insulin resistance. It is possible that the decrease in LH secretion with weight reduction is more dependent on the absolute levels of insulin sensitivity than on the degree of general adiposity.
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PMID:The decrease in luteinizing hormone secretion in response to weight reduction is inversely related to the severity of insulin resistance in overweight women. 1099 21

Circulating GH levels are reduced in obesity due to true reduction of the 24-h GH production rate. GH insufficiency in obesity might reflect neuroendocrine abnormalities and/or alterations in peripheral hormones and metabolic factors. The somatotroph response to provocative stimuli including GHRH is markedly blunted in obese patients. However, the somatotroph responsiveness to GHRH in obesity shows also peculiar refractoriness to the inhibitory effect of glucose load. In this present study we aimed at verifying the effect of low dose rhIGF-I (20 microgram/kg, sc, at 0 min) on the GH response to GHRH (1 microgram/kg, iv, at 180 min) in obesity. With this goal in mind, six obese women with abdominal adiposity [OB; age (mean +/- SEM), 32.3 +/- 4.4 yr; body mass index, 32.8 +/- 2.3 kg/m(2)] were studied. The effects of recombinant human insulin-like growth factor I (rhIGF-I) administration on circulating total IGF-I, insulin, and glucose levels were also evaluated. The results in OB were compared with those recorded in age-matched lean women (NW; age, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m(2)), in whom the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I levels in OB were similar to those in NW (199.7 +/- 33.3 vs. 274.4 +/- 25.3 microgram/L). The mean GH concentration over 3 h (from 0-180 min) in OB was lower than that in NW (0.9 +/- 0.4 vs. 2.6 +/- 0.8 microgram/L; P = NS). Administration of GHRH induced a GH response in OB lower than that in NW (area under the curve from 180-270 min, 576.5 +/- 137.5 vs. 1315.9 +/- 189.9 microgram/L.min; P < 0.02). Administration of rhIGF-I increased circulating IGF-I levels in both groups to the same percent extent (326.8 +/- 28.3 and 420.3 +/- 26.5 microgram/L in OB and NW, respectively). rhIGF-I administration inhibited the GH response to GHRH in OB (240.1 +/- 99.6 microgram/L; P < 0.05) as well as in NW (730.2 +/- 288.1 microgram/L; P < 0.05), although it failed to lower the mean GH concentration over 3 h in either OB or NW. After rhIGF-I the GH response to GHRH in OB was slight and was still lower (P < 0.05) than that in NW; in fact, the percent decreases were similar in both groups (44.21 +/- 14.06 and 48.21 +/- 13.95 microgram/L, in OB and NW, respectively). The mean insulin (107.1 +/- 21.9 and 36.8 +/- 7.2 pmol/L), but not glucose (4.0 +/- 0.3 and 4.1 +/- 0.1 mmol/L), levels calculated over 270 min, were higher (P = 0.005) in OB than in NW; rhIGF-I administration did not modify insulin and glucose levels in either group. Our study shows that the sc administration of a low rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese as well as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect of rhIGF-I is preserved in obesity.
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PMID:Effects of recombinant human insulin-like growth factor I administration on the growth hormone (gh) response to GH-releasing hormone in obesity. 1123 96

In normal subjects the main form of circulating insulin-like growth factor (IGF) is the 150-kDa complex. This complex is formed by the IGF peptide, the acid-stable IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS). Experimental and clinical data have demonstrated that ALS is primarily under the control of GH and plays a critical role in maintaining constant levels of circulating IGF-I. In this study we evaluated ALS, IGF-I, and IGFBP-1, -2, and -3 in 45 acromegalic patients in basal conditions and, in 37 of these, twice after surgical therapy compared with 100 age- and sex-matched control subjects to estimate their value as parameter of GH secretory state. The results demonstrated that in acromegaly before treatment all parameters (ALS, 523 +/- 26; IGF-I, 129 +/- 6; IGFBP-1, 0.7 +/- 0.1; IGFBP-3, 234 +/- 21; nmol/L; mean +/- SEM) but IGFBP-2 were significantly different (P<0.0001) from those in healthy subjects (ALS, 281 +/- 4; IGF-I, 22 +/- 1; IGFBP-1, 1.6 +/- 0.1; IGFBP-3, 91 +/- 3). IGF-I was more sensitive (100%) than ALS (89%), and both were more predictive of disease status than IGFBP-3, in that 27% of the patients had IGFBP-3 levels within the normal range. Considering the ALS/IGFBP-3 molar ratio, almost 55% of ALS circulated in a free form in active acromegaly. Before treatment, the IGF-I/IGFBPs (-1 + -2 + -3) molar ratio, which can be regarded as free, biologically active, IGF-I, was greatly increased (0.77 +/- 0.06; P<0.0001) compared with that in control subjects (0.23 +/- 0.01). After surgery, all 10 patients with controlled disease showed normalization of ALS (100% sensitivity), whereas 9 of them had normal IGFBP-3; reevaluation after varying lengths of time showed all these parameters within the normal range. In the 27 patients with active disease, IGF-I and ALS were more predictive of disease status (91% and 83% negative predictive values, respectively) than IGFBP-3 (53%). The basal ALS concentration correlated only with IGFBP-3 (r = 0.70; P<0.001). In postsurgery samples (first control) a statistically significant (P<0.001) correlation was found between mean GH values as well as minimum GH after oral glucose tolerance test and ALS (r = 0.72 and 0.83, respectively), IGF-I (r = 0.69 and 0.77), IGFBP-3 (r = 0.50 and 0.72), and IGFBP-2 (r = -0.36 and -0.63). Similarly, IGF-I, IGFBP-3, and ALS were positively correlated among themselves and negatively correlated with IGFBP-2 (P<0.001). In conclusion, in the diagnosis of acromegaly, the measurement of total IGF-I appears to be the most sensitive parameter among the subunits of the 150K complex, and IGFBP-3 the least sensitive. For ALS, this subunit is quite sensitive and appears to be a useful parameter in reassessment after surgical treatment.
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PMID:Diagnostic value of the acid-labile subunit in acromegaly: evaluation in comparison with insulin-like growth factor (IGF) I, and IGF-binding protein-1, -2, and -3. 1123 91

Limited proteolysis of insulin-like growth factor binding protein-3 (IGFBP-3) is a fundamental mechanism in the regulation of IGF-I bioavailability in the bloodstream. Its measurement by Western immunoblotting provides only semiquantitative estimation. We have developed a ligand immunofunctional assay (LIFA) for quantifying human (h) intact IGFBP-3 in biological fluids. IGFBP-bound IGFs are dissociated and separated by acid pH ultrafiltration, and a monoclonal antibody specific to the first 160 amino acids of IGFBP-3 is used to capture hIGFBP-3 in a solid-phase assay. The complex is then incubated with (125)I-IGF-I, which binds to intact IGFBP-3 but not to its proteolytic fragments. Binding specificity was demonstrated in competition experiments with unlabeled IGF. Nonspecific binding was 1.4%. The fragments comprising residues 1-160 and 1-95 of recombinant hIGFBP-3 [corresponding to the major proteolytic fragments of approximately 30 kDa and (glycosylated) 20 or (nonglycosylated) 16 kDa detected in serum by Western immunoblotting, respectively] fail to bind (125)I-IGF-I when complexed with the monoclonal antibody. Similarly, no binding of (125)I-IGF-I was obtained in the LIFA when applied to plasmas from pregnant women during the final 3 months of pregnancy, where the characteristic 42- to 39-kDa doublet of intact IGFBP-3 is undetectable. The standard curve was established using a pool of plasmas (EDTA) from healthy adults, for which standardization with glycosylated recombinant hIGFBP-3 yielded an intact IGFBP-3 content of 2 microg/mL. The dynamic range of the LIFA was 0.50-3.75 microL equivalent of the plasma pool in a total volume of 300 microL per assay tube, with a sensitivity threshold of approximately 1 ng intact IGFBP-3. Unknown plasma samples were studied at three concentrations. Intra- and interassay variations were 3.6% and 4%, respectively. In 31 healthy adults, the mean plasma concentration of intact IGFBP-3 was 2.24 +/- 0.08 (SEM) mg/L, and that of total IGFBP-3 measured by immunoradiometric assay was 3.27 +/- 0.14 mg/L. The calculated mean proportion of proteolysed IGFBP-3 was 29.4 +/- 1.9%. In these subjects, a close correlation was found between intact and total IGFBP-3 (r = 0.71, P = 0.0001). The LIFA for IGFBP-3, therefore, provides accurate and sensitive measurement of intact IGFBP-3, the form with the functional capacity to sequester IGF-I in the bloodstream by association with the acid-labile subunit in 140-kDa complexes. In combination with total IGFBP-3 and IGF-I assays, the LIFA opens new perspectives in investigating the regulation of IGFBP-3 proteolysis and IGF-I bioavailability in man.
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PMID:Measurement of intact insulin-like growth factor-binding protein-3 in human plasma using a ligand immunofunctional assay. 1160 May 91

The ligand immunofunctional assay for plasma insulin-like growth factor (IGF) binding protein (IGFBP)-3 developed in our laboratory provides for specific measurement of intact, as opposed to proteolyzed, IGFBP-3. IGFBP-bound IGFs are dissociated and separated by acid pH ultrafiltration; thereafter, intact and proteolyzed IGFBP-3 are captured by a monoclonal antibody in a solid-phase assay and incubated with (125)I-IGF-I, which detects the intact protein but not its proteolytic fragments. This assay was combined with assays for IGF-I (RIA of the ultrafiltrate) and total IGFBP-3 (immunoradiometric assay) to quantify the percentage of proteolyzed IGFBP-3 (percent proteolyzed IGFBP-3) and to calculate the IGF-I/intact IGFBP-3 ratio as an index of the fraction of exchangeable IGF-I bound to IGFBP-3. This fraction represents most of the IGF-I that is bioavailable. Because GH and insulin control the hepatic production and plasma concentrations of IGF-I and IGFBP-3, we set out to determine whether variations in the secretion of the two hormones are involved in the regulation of IGFBP-3 proteolysis. The study included adult populations of 36 healthy subjects, 23 hypopituitary patients untreated with GH, 43 acromegalics (13 untreated), 42 insulin-treated type 1 diabetics [insulin-dependent diabetes mellitus (IDDM)] patients, and 50 type 2 diabetics [non-IDDM (NIDDM)] patients, 22 of whom were insulin-treated and the remaining 28 treated with sulfonylurea and/or metformin). Unlike IGF-I and (to a lesser extent) total IGFBP-3 levels, which decline with age, percent proteolyzed IGFBP-3 seemed relatively stable. In healthy adults, the mean +/- SEM was 29.4 +/- 1.9 for subjects less than 45 yr old and was slightly (but not significantly) lower, 25.7 +/- 3, for those of more than 45 yr. There was no difference between male and female subjects. In GH-deficient patients, despite severely depressed IGF-I levels, percent proteolyzed IGFBP-3 and IGF-I/intact IGFBP-3 ratios were within the normal range. Among acromegalics, percent proteolyzed IGFBP-3 was elevated: 36.6 +/- 3.3 for patients of less than 45 yr, 33.3 +/- 3.2 for patients of more than 45 yr (P = 0.02 vs. healthy subjects). Consequently, the effects of excessive IGF-I synthesis are exacerbated by the enlarged exchangeable fraction of IGFBP-3-bound IGF-I. There was no significant difference in percent proteolyzed IGFBP-3 between GH-deficient patients before and after GH treatment or between treated and untreated acromegalics. In IDDM patients, the means for percent proteolyzed IGFBP-3 were higher than those in healthy adults: 36.7 +/- 3.7 (P = 0.03) and 31.3 +/- 3.3 for subjects of less than 45 and more than 45 yr, respectively. In NIDDM patients, all of whom were more than 45 yr old, the means were 35.2 +/- 2.5 (P = 0.02) for insulin-treated patients and 33 +/- 2.5 for the group treated orally. Among the diabetics, increased IGFBP-3 proteolysis resulted in an IGF-I/intact IGFBP-3 ratio that was normal for IDDM patients of less than 45 yr and above normal (P = 0.01) for the others. Percentage proteolyzed IGFBP-3 and the IGF-I/intact IGFBP-3 ratio were inversely related to body mass index in IDDM patients (r = -0.42, P = 0.008; and r = -0.31, P = 0.05, respectively) and to percentage glycosylated hemoglobin in all insulin-treated diabetics (r = -0.25, P = 0.05; and r = -0.33, P = 0.008, respectively). There was also an inverse relationship between IGF-I/intact IGFBP-3 ratios and IGFBP-1 levels in healthy adults (r = -0.39, P = 0.03) and orally treated NIDDM patients (r = -0.37, P = 0.05). Percentage proteolyzed IGFBP-3 was positively correlated to total IGFBP-3 in healthy adults (r = 0.65, P = 0.0001) and in all the groups of patients. It was negatively correlated to IGF-I/total IGFBP-3 in healthy subjects (r = -0.40, P = 0.02) and diabetics (r = -0.30, P = 0.005). This suggests an autoregulatory mechanism controlling the bioavailability of IGFBP-3-bound IGF-I in the 140-kDa complexes. In the pathological conditions studied here, regulation of IGF-I bioavailability by limited proteolysis of IGFBP-3 contributes toward an appropriate adaptation to insulin deficiency and/or resistance but not to disturbances of GH secretion.
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PMID:Use of the ligand immunofunctional assay for human insulin-like growth factor ((IGF) binding protein-3 (IGFBP-3) to analyze IGFBP-3 proteolysis and igf-i bioavailability in healthy adults, GH-deficient and acromegalic patients, and diabetics. 1134 89

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40 microg/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg x h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg x night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean +/- SEM:IGF-I, 401 +/- 22 ng/ml; placebo, 256 +/- 20 ng/ml (P = 0.0002); IGF-I, 0.108 +/- 0.006; placebo, 0.074 +/- 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 +/- 0.03; placebo, 0.23 +/- 0.03 U/kg x min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r = -0.34; P < 0.01). Yet despite reduced free insulin levels (8.5 +/- 1.5; placebo, 12.2 +/- 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 +/- 6.8; placebo, 82.2 +/- 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.
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PMID:The role of IGF-binding proteins in mediating the effects of recombinant human IGF-I on insulin requirements in type 1 diabetes mellitus. 1150 96

Adult hypopituitarism is known to be associated with reduced life expectancy related to excess vascular events, and endothelial dysfunction is present in patients with this condition. We studied the relationship between biophysical and biochemical markers of endothelial dysfunction, including E-selectin, intercellular cell adhesion molecule-1, von Willebrand factor, and thrombomodulin in 52 adult patients with hypopituitarism and severe GH deficiency (<2 ng/ml on provocative testing) compared with 54 age-, sex-, and smoking-matched normal controls. We also examined endothelium-dependent dilatation of the brachial artery to postischemic occlusion and carotid artery morphology (intima-media thickness) by high-resolution ultrasonography. The patients were stable on conventional hormone replacement therapy but not on GH therapy, and none of the subjects had a known risk factor for vascular disease. Levels of E-selectin [57 +/- 3 vs. 49 +/- 2 ng/ml (mean +/- SEM)] (P < 0.043), intercellular cell adhesion molecule-1 (308 +/- 11 vs. 266 +/- 10 ng/ml) (P < 0.001), thrombomodulin (49 +/- 3 vs. 35 +/- 2 ng/ml) (P < 0.001), and von Willebrand factor (132 +/- 7% vs. 105 +/- 5%) (P < 0.004) were significantly higher in patients than in controls. Brachial artery endothelium-dependent dilatation was significantly lower in patients than in controls [4.7% (0.00-9.77) vs. 10.5% (6.4-16.2) (median, interquartile range)] (P < 0.001). This difference in endothelium-dependent dilatation was more marked in female patients than in controls (P < 0.003), although it disappeared when estrogen-sufficient female patients were compared with controls (P = 0.31). However, the female patients who were not replaced with estrogen continued to show a striking difference compared with estrogen-deficient control females (P < 0.004). There was no difference in carotid intima-media thickness between patients of either sex and controls. On univariate analysis, brachial artery endothelium-dependent dilatation correlated inversely with intercellular cell adhesion molecule-1 (r = -0.225, P < 0.033). Intercellular cell adhesion molecule-1 correlated positively with E-selectin (r = 0.466, P < 0.0001) and negatively with IGF-I (r = -0.238, P < 0.016). E-selectin correlated with thrombomodulin (r = 0.215, P < 0.034) and von Willebrand factor (r = 0.218, P < 0.03) and negatively with IGF-I (r = -0.255, P < 009). Thrombomodulin correlated positively with von Willebrand factor (r = 0.422, P < 0.0001) and inversely with IGF-I (r = -0.266, P < 0.008). These correlations persisted after correction for age, sex, body mass index, and waist to hip ratio, with the exception of IGF-I, which now correlated with thrombomodulin only. These results confirm significant endothelial dysfunction in hypopituitarism and provide insight into the relationship of biochemical and biophysical markers of early atherosclerosis in hypopituitary GH-deficient adults. The negative correlation of IGF-I with some biochemical markers of endothelial dysfunction and the predictive nature of GH deficiency in stepwise regression analysis in this study supports the hypothesis that GH deficiency may play a role in these abnormalities. Future studies will determine whether GH treatment can reverse these abnormalities. Furthermore, the more significant endothelium-dependent dilatation abnormality in the female estrogen-deficient subjects compared with those who were estrogen replete suggests that estrogen replacement in these patients is a crucial element in protecting against vascular disease.
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PMID:Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency. 1154 53

Female gender confers resistance to GH autonegative feedback in the adult rat, thereby suggesting gonadal or estrogenic modulation of autoregulation of the somatotropic axis. Here we test the clinical hypothesis that short-term E2 replacement in ovariprival women reduces GH's repression of spontaneous, GHRH-, and GH-releasing peptide (GHRP)-stimulated GH secretion. To this end, we appraised GH autoinhibition in nine healthy postmenopausal volunteers during a prospective, randomly ordered supplementation with placebo vs. E [1 mg micronized 17 beta-E2 orally twice daily for 6-23 d]. The GH autofeedback paradigm consisted of a 6-min pulsed i.v. infusion of recombinant human GH (10 microg/kg square-wave injection) or saline (control) followed by i.v. bolus GHRH (1 microg/kg), GHRP-2 (1 microg/kg), or saline 2 h later. Blood was sampled every 10 min and serum GH concentrations were measured by chemiluminescence. Poststimulus GH release was quantitated by multiparameter deconvolution analysis using published biexponential kinetics and by the incremental peak serum GH concentration response (maximal poststimulus value minus prepeak nadir). Outcomes were analyzed on the logarithmic scale by mixed-effects ANOVA at a multiple-comparison type I error rate of 0.05. E2 supplementation increased the (mean +/- SEM) serum E2 concentration from 43 +/- 1.8 (control) to 121 +/- 4 pg/ml (E2) (158 +/- 6.6 to 440 +/- 15 pmol/liter; P < 0.001), lowered the 0800 h (preinfusion) serum IGF-I concentration from 127 +/- 7.7 to 73 +/- 3.6 microg/liter (P < 0.01), and amplified spontaneous pulsatile GH production from 7.5 +/- 1.1 to 13 +/- 2.3 microg/liter per 6 h (P = 0.020). In the absence of exogenously imposed GH autofeedback, E2 replacement enhanced the stimulatory effect of GHRP-2 on incremental peak GH release by 1.58-fold [95% confidence interval, 1.2- to 2.1-fold] (P = 0.0034) but did not alter the action of GHRH (0.83-fold [0.62- to 1.1-fold]). In the E2-deficient state, bolus GH infusion significantly inhibited subsequent spontaneous, GHRH-, and GHRP-induced incremental peak GH responses by, respectively, 33% (1-55%; P = 0.044 vs. saline), 79% (68-86%; P < 0.0001), and 54% (32-69%; P = 0.0002). E2 repletion failed to influence GH autofeedback on either spontaneous or GHRH-stimulated incremental peak GH output. In contrast, E2 replenishment augmented the GHRP-2-stimulated incremental peak GH response in the face of GH autoinhibition by 1.7-fold (1.2- to 2.5-fold; P = 0.009). Mechanistically, the latter effect of E2 mirrored its enhancement of GH-repressed/GHRP-2-stimulated GH secretory pulse mass, which rose by 1.5-fold (0.95- to 2.5-fold over placebo; P = 0.078). In summary, the present clinical investigation documents the ability of short-term oral E2 supplementation in postmenopausal women to selectively rescue GHRP-2 (but not spontaneous or GHRH)-stimulated GH secretion from autonegative feedback. The secretagogue specificity of E's relief of GH autoinhibition suggests that this sex steroid may enhance activity of the hypothalamopituitary GHRP-receptor/effector pathway.
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PMID:E2 supplementation selectively relieves GH's autonegative feedback on GH-releasing peptide-2-stimulated GH secretion. 1173 62

GH administration, either alone or combined with resistance exercise training (RT), has attracted interest as a means of increasing muscle mass and strength in the elderly. In the present study, 31 healthy, elderly men [age, 74 +/- 1 yr (mean +/- SEM)] were assigned to either RT [3 sessions/wk, 3-5 sets of 8-12 repetition maximum (RM)/session] + placebo (n = 8), RT + GH (n = 8), GH (n = 8), or placebo (n = 7) in a randomized, placebo-controlled, double-blinded (RT + placebo and RT + GH) or single-blinded (GH or placebo) design. Measurements of: 1) isokinetic quadriceps muscle strength; 2) quadriceps muscle power; 3) quadriceps muscle fiber type, size, and myosin heavy chain (MHC) composition; 4) quadriceps cross-sectional area (CSA) [nuclear magnetic resonance imaging (NMRI)]; 5) body composition (dual-energy x-ray absorptiometry scanning); and 6) GH-related serum markers were performed at baseline and after 12 wk. The final GH dose was 1.77 +/- 0.18 IU x d(-1) (approximately 7.2 +/- 0.8 microg x kg(-1) x d(-1)). GH alone had no effect on isokinetic quadriceps muscle strength, power, CSA, or fiber size. However, a substantial increase in MHC 2X isoform was observed with GH administration alone, and this may be regarded as a change into a more youthful MHC composition, possibly induced by the rejuvenating of systemic IGF-I levels. RT + placebo caused substantial increases in quadriceps isokinetic strength, power, and CSA; but these RT induced improvements were not further augmented by additional GH administration. In the RT + GH group, there was a significant decrease in MHC 1 and 2X isoforms, whereas MHC 2A increased. RT, therefore, seems to overrule the changes in MHC composition induced by GH administration alone. Changes in body composition confirmed previous reports of decreased fat mass, increased fat-free mass, and unchanged bone mineral content with GH administration. A high incidence of side effects was reported. Our results do not support a role for GH as a means of increasing muscle strength or mass, either alone or combined with RT, in healthy elderly men; although GH administration alone may induce changes in MHC composition.
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PMID:GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. 1183 79

The present clinical study compares the impact of low- and high-dose parenteral testosterone (T) supplementation on daily GH secretory patterns and serum IGF-I, IGFBP-1, and IGFBP-3 concentrations in healthy older (60-82 yr) and young (20-40 yr) men. To this end, we administered three consecutive weekly injections of randomly ordered saline and either a low (100 mg) or a high (200 mg) dose of testosterone enanthate im; namely, saline (n = 17, young and n = 16, older), a low dose (n = 8 young, n = 8 older) and a high dose (n = 9 young, and n = 8 older) of androgen. To monitor somatotropic-axis responses, blood was sampled every 10 min for 24 h for later chemiluminescence-based assay of serum GH, RIA of serum IGF-I, and immunoradiometric assay of serum IGFBP-1 and IGFBP-3 concentrations. Data were analyzed via a nested analysis of covariance statistical design. At baseline (saline injection), older, compared with young, men maintained: 1) similar serum total T, IGFBP-1, and IGFBP-3 but reduced IGF-I concentrations, namely, mean (+/- SEM) IGF-I 160 plus or minus 15 vs. 280 plus or minus 18 microg/liter, (P < 0.001); 2) reduced GH secretory burst mass (0.68 +/- 0.09 vs. 1.2 +/- 0.20 microg/liter, P = 0.031); 3) more disorderly GH release patterns (approximate entropy 0.501 +/- 0.058 vs. 0.288 +/- 0.021, P < 0.001); and 4) blunted 24-h rhythmic GH output (nyctohemeral amplitude 0.25 +/- 0.05 vs. 0.47 +/- 0.08 microg/liter, P = 0.025). Serum T concentrations (ng/dl) did not differ in the two age groups supplemented with either a low dose [550 +/- 50 (young) and 544 +/- 128 (older)] and high [1320 +/- 92 (young) and 1570 +/- 140 (older)] dose of T. The 100-mg dose of androgen exerted no detectable effect on GH secretion in either age cohort but increased the serum IGF-I concentration in young men by 20% (P = 0.00098). The 200-mg dose of T failed to alter daily GH production in young volunteers but in older men stimulated: 1) a 2.03-fold rise in the mean (24-h) serum GH concentration (P = 0.0053, compared with the response to saline); 2) a 1.20-fold increase in basal (nonpulsatile) GH production (P = 0.039); 3) a 2.15-fold amplification of GH secretory burst mass (P = 0.0020); 4) a 2.17-fold elevation of the Mesor of nyctohemeral GH output (P = 0.025); 5) a 1.79-fold enhancement in GH approximate entropy (P = 0.0003); and 6) a 40% increase in the fasting serum IGF-I concentration (P = 0.000005). Multivariate statistical analysis indicated that following high-dose T administration, the E2 increment significantly predicted the IGF-I increment in both age groups combined (P = 0.003); T dose positively forecast the serum total IGF-I concentration (P = 0.0031); and age and T dose jointly determined serum LH concentrations (P = 0.031). In summary, neither a physiological nor a pharmacological dose of T administered parenterally for 3 wk augments daily GH secretion in eugonadal young men. In contrast, a high dose of aromatizable androgen significantly amplifies 24-h basal, pulsatile, entropic, and nyctohemerally rhythmic GH production and elevates the serum IGF-I concentration in older men. The mechanistic basis for the foregoing age-related distinction in GH/IGF-I axis responsivity to T is not known.
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PMID:Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men. 1183 28


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