Biomedical subjects

S Fisker

Publications and source records attributed to S Fisker.

At least 37 records · Page 2Linked to original sources

PubMed1999

Impact of gender and androgen status on IGF-I levels in normal and GH-deficient adults.

OBJECTIVE: The regulation of IGF-I levels is complex and not only dependent on GH status, as the diagnostic sensitivity of serum IGF-I levels for GH deficiency (GHD) in adults is low. Other GH-related parameters have so far not proven to be of additional diagnostic value in GHD adults. In the present study we evaluated the impact of gender and androgen status on IGF-I levels and the diagnostic value of IGF-I and GH-related parameters in a population of adult hypopituitary patients and age- and gender-matched healthy subjects. DESIGN: A cross-sectional study. SUBJECTS: Fifty-nine GHD patients (40 males, mean age 39.3+/-1.7 (s.e.m.) years, and 19 females, mean age 41.9+/-2.6 years) and 69 healthy subjects (42 males, mean age 36. 7+/-1.5 years, and 27 females, mean age 38.9+/-2.1 years). RESULTS: IGF-I levels were low in the GHD patients (91+/-7 vs 173+/-7 microgram/l, P<0.001), and lower in female patients than in male (68+/-10 vs 100+/-8 microgram/l, P=0.03). In the control group there was no gender-related difference in IGF-I levels (males: 178+/-8, females: 164+/-12 microgram/l, P=0.23). IGF-II and IGF-binding protein-3 (IGFBP-3) were also decreased in GHD without any gender-related differences. GH-binding protein (GHBP) levels were increased in the patient group. The diagnostic sensitivity (%) of IGF-I, IGF-I/GHBP, IGF-I/IGFBP-3, and of the combination of IGF-I plus IGF-II (both low or one normal and one low), was higher in female patients than in male (IGF-I: 57.8 vs 22.0, P<0.0001; IGF-I/GHBP: 84.2 vs 48.8, P=0. 002; IGF-I/IGFBP-3: 36.8 vs 7.3 P=0.001; IGF-I+IGF-II: 77.8 vs 52.6, P=0.01). Testosterone levels were reduced in the female patients compared with female controls (0.5+/-0.3 vs 2.1+/-0.2nmol/l, P<0.001). Forward regression analyses revealed that IGFBP-3 was a significant predictor of IGF-I levels in both patients and healthy subjects. In a combined analysis of both patients and controls, sex hormone-binding globulin (SHBG) level was the main contributor as an explanatory variable. Gender and prolactin also predicted IGF-I in patients, whereas SHBG and estradiol were significant predictors only in the control group. CONCLUSION: (i) Levels of IGF-I, and of IGF-I/IGFBP-3 and IGF-I/GHBP ratios are lower in females compared with male adult GHD patients. (ii) IGF-I/GHBP has a high diagnostic sensitivity of adult GHD, in particular in women. (iii) We hypothesize that the gender difference in IGF-I levels among adult GHD patients are causally related to the very low androgen levels observed among females.

Adult↗

PubMed1999

The role of nitric oxide in L-arginine-stimulated growth hormone release.

Nitric oxide (NO) exerts widespread and fundamental physiological effects. It is identical to the so-called endothelium-derived relaxing factor which regulates vascular tone. It has also been demonstrated to act as a neurotransmitter in both the peripheral and central nervous systems. NO is generated from L-arginine catalyzed by the NO synthases (NOS), of which two constitutive and one inducible form exist. NO stimulates the soluble guanylate cyclase which generates cyclic guanosine monophosphate (cGMP), that is believed to mediate the effects of NO. Recently, however, it has also been shown that NO is generated non-enzymatically from both L- and D-arginine by reaction with peroxide. The role of this pathway in the neuroregulation of growth hormone (GH) secretion has not yet been investigated. In rats, NO stimulates secretion of GH-releasing hormone (GHRH) and thus increases secretion of GH. However, it has also been observed that GHRH, in turn, increases production of NO in somatotroph cells, which subsequently blunts GH secretion. In humans, L-arginine stimulates pituitary GH release, but the mechanism is not fully clarified. Most studies suggest that an inhibition of somatostatin secretion is responsible for the effect. Infusion of low doses of the NOS inhibitor N(G)-nitro-L-arginine methyl ester have been shown not to change L-arginine-stimulated GH secretion. The effect of the NO donor molsidomine has also been found to have no influence on GH secretion. We investigated whether intravenous infusion of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) influenced L-arginine-stimulated GH secretion in healthy young men. All subjects were examined twice in random order. On both occasions L-arginine was infused intravenously. This treatment was accompanied by either: L-NMMA co-infused or a saline infusion. Plasma cGMP was unchanged and identical in the two treatment groups, and the urine cGMP/creatinine ratio increased identically during both examinations. GH secretion increased significantly during L-arginine infusion and was not influenced by co-infusion of L-NMMA. There is so far no evidence that L-arginine stimulates GH release via NO production. However, it remains to be elucidated whether the doses of different L-arginine inhibitors/NO donors used in the previous studies were insufficient.

Animals↗

PubMed1998

Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood.

BACKGROUND: Our aim was to evaluate endocrinological status 10-21 years after treatment for childhood acute lymphoblastic leukemia (ALL) with chemotherapy (C) and cranial irradiation (C + I) or only C, and to correlate the endocrine data with growth parameters. PROCEDURE: Of 30 patients (15 females and 15 males), 18 were treated with C + I and 12 were treated with C only. Height standard deviation score (HSDS) and body mass index standard deviation score (BMISDS) before treatment, at end of treatment, and at follow-up were calculated from height and weight registered from the charts. At follow-up examinations, provocative growth hormone (GH) tests (clonidine and insulin tolerance test) and an ACTH test were performed. Furthermore, blood samples for hormonal analysis, IGF-I, IGFBP-3, GHBP, and leptin were drawn. RESULTS: Eleven patients (9 treated with C + I and 2 treated with C) showed insufficient response to GH tests. Two patients had hypogonadism. HSDS and IGF-I were significantly lower and GHBP significantly higher in GH-deficient patients compared to the group with normal GH secretion at follow-up. BMISDS steadily increased from start of treatment until follow-up, independent of GH status at follow-up. BMISDS at follow-up was positively correlated with serum leptin (P < 0.001), and serum leptin was significantly higher in the cranial irradiated group as compared to the nonirradiated group. CONCLUSIONS: GH deficiency is frequently found at long-term follow-up in patients treated for childhood ALL. Other hormonal deficiencies are rare. HSDS at long-term follow-up is dependent on GH secretory status. Long-term endocrinological follow-up examinations in patients treated for childhood ALL are recommended, as hormonal replacement therapy may be indicated.

Adolescent↗

PubMed1998

Serum leptin levels and leptin expression in growth hormone (GH)-deficient and healthy adults: influence of GH treatment, gender, and fasting.

Growth hormone (GH) treatment is associated with a reduction in fat mass in healthy and GH-deficient (GHD) subjects. This is mainly mediated via a direct GH action on adipose cells and stimulation of lipolysis. Leptin is secreted from adipose tissue and may be involved in signaling information about adipose tissue stores to the brain. Hormonal regulation of leptin is still not fully elucidated, and in the present study, we investigated both the long-term (4-month) and short-term (28-hour) GH effects on serum leptin and leptin gene expression in subcutaneous adipose tissue. In GHD adults (n = 24), leptin correlated with most estimates of adiposity (r = .62 to .86), as previously found in healthy subjects. However, no correlation was observed with intraabdominal fat determined by computed tomographic (CT) scan (INTRA-CT). GH treatment for 4 months had no independent effect on either serum leptin or leptin gene expression. In a short-term study, we found that fasting gradually reduced leptin levels in both healthy men and GHD adults, with a maximum reduction of 58% to 60% (P < .01) after 31 hours. No independent effect of GH suppression or GH substitution on serum leptin was found during fasting. Adipose tissue leptin mRNA correlated with serum leptin (r = .51, P < .01) and the body mass index ([BMI] r = .55, P < .05). Serum leptin levels and gene expression were significantly higher in women compared with men (26.6 +/- 5.8 v 10.0 +/- 1.30 ng/mL, P < .05). However, in regression analysis accounting for the gender differences in subcutaneous femoral adipose tissue (FEM-CT), the difference in serum leptin disappeared, indicating that subcutaneous femoral fat or factors closely related to femoral fat (eg, sex hormones) may be causal factors for the gender difference in leptin.

Adipose Tissue↗

PubMed1998

Variability in growth hormone stimulation tests.

The diagnosis of growth hormone deficiency (GHD) in adulthood has become increasingly important because of the approved indication for growth hormone (GH) substitution therapy in such patients. While GH stimulation tests are superior to single measurements of other growth factors or spontaneous GH secretion in the diagnosis in adults, the reproducibility and specificity of GH stimulatory tests are often described to be low. This is also the case with the insulin tolerance test. Many external factors, such as fasting, physical activity, heat exposure and sleep, are known to influence GH secretion. The stimulatory or inhibitory effect of these factors on GH secretion might, therefore, influence the GH provocative test and contribute to the variability in response. Age and body composition are also known to influence GH secretion, and these factors must be considered when evaluating GH test responses. However, age-related cut-off levels for GHD have not been defined. Obesity is still a complicating factor in the diagnosis of GHD, even though some GH tests have been able to distinguish between obesity and true GHD. Based on these complicating factors, the parameters of GH stimulatory tests are recommended to be defined and standardized to optimize reproducibility and specificity. Furthermore, such tests should be performed only in patients with firm evidence of pituitary disease.

Adult↗

PubMed1998

Growth hormone (GH) substitution for one year normalizes elevated GH-binding protein levels in GH-deficient adults secondary to a reduction in body fat. A placebo-controlled trial.

The high affinity growth hormone binding protein (GHBP) in human serum derives from the extracellular domain of the GH receptor. It is well known that fat mass correlates positively to GHBP levels, but it is uncertain whether GH secretory status influences GHBP levels. Since body composition is known to change during GH substitution in adult GHD patients, we determined the relation between GHBP and body composition during GH substitution in GHD adults. Twenty-five GHD adults aged 45.0 +/- 1.8 years, were examined before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. A group of 27 healthy age- and gender-matched normal-weight adults provided reference data. The participants underwent anthropometric measurements [body mass index (BMI), waist/hip ratio (W/H)], computer-tomography (CT-scan) of femoral and abdominal regions, dual-energy X-ray absorptiometry (DEXA-scan), and bioimpedance (BIA), as well as blood sampling. At baseline, the GHBP levels were increased compared to controls (1.63 +/- 0.14 nmol/l vs 1.12 +/- 0.1 nmol/l, P = 0.01). During 12 months of GH substitution, GHBP levels decreased to the levels of the control subjects. GHBP correlated positively to indices of adiposity in GHD patients at baseline: intra-abdominal fat (r = 0.54, P = 0.005), subcutaneous abdominal fat (r = 0.59, P < 0.002), body fat (BIA) (r= 0.41, P= 0.044), BMI (r= 0.58, P = 0.002), and total body fat (DEXA scan) (r= 0.61, P < 0.001). After 12 months of GH substitution, different estimates of body fat were significantly decreased in the GH treated group, but the positive relationship between GHBP and these estimates of body fat was maintained. In multiple linear regression analyses, fasting insulin levels were also a significant determinant of GHBP levels. We conclude that GHBP levels are increased in GHD patients and decrease to normal levels during 12 months of GH substitution. Furthermore, GHBP is predominantly correlated to indices of adiposity also in GHD patients.

Adipose Tissue↗

PubMed1998

L-arginine and insulin-tolerance tests in the diagnosis of adult growth hormone deficiency: influence of confounding factors.

OBJECTIVE: In the attempt to define a GH stimulation test with high specificity and reproductibility, few studies have addressed the influence of potential interfering external factors on the test result. We therefore tested the influence of physical activity (admission to hospital on test morning) and mild heat exposure on the GH response to L-arginine stimulation test (Arg) and insulin-tolerance test (ITT). DESIGN: One Arg stimulation test and one ITT were performed in all subjects during standard conditions (overnight hospital stay, 10 hours fasting). In addition, each subject was randomized to undergo either two additional Arg tests, or two ITTs, performed under two different conditions: admission to hospital on the morning of the test and during standard conditions except for heat exposure before testing. The four tests were performed in random order. PATIENTS: Twenty-two patients (six women, 16 men) (mean age +/- SEM, 38.3 +/- 5.3 years and 36.1 +/- 2.7 years, respectively) presenting with pituitary disease and a group of healthy age and gender-matched normal subjects (six women, 13 men) (age 38.3 +/- 4.8 years and 35.7 +/- 2.4 years, respectively) participated. MEASUREMENTS: During the GH-stimulation tests serum GH, cortisol, blood glucose, and plasma glucagon were measured and compared in the three different test conditions. RESULTS: During standard conditions, peak GH response was higher in the ITT compared to the Arg test in the control group (23.4 +/- 3.6 mU/l vs 11.6 +/- 2.0 mU/l, P = 0.004), and the specificity of the ITT was higher (18/19 versus 13/19, P = 0.047). Minor heat exposure before the ITT (temperature rise 0.24 +/- 0.05 degrees C, range 0.0-0.5 degrees C) did not change the GH response in the healthy adults whereas admission to hospital on the morning of the test reduced the GH response significantly (P < 0.05). The lowest blood glucose did not change in the three situations and did not correlate with peak GH during the ITT. In the patients there were no significant differences between the GH response during different conditions. Plasma glucagon did not significantly differ between the different test conditions in the control group (P = 0.88), but there was a significant decrease in the glucagon response to the test performed after hospital admission on the test morning in the patients (P < 0.025). Serum cortisol response in the control group did not differ in the three situations. CONCLUSIONS: Since provocative GH responses are influenced by external factors, conditions should be standardized to optimize the reproductibility and specificity of the tests. Furthermore the higher specificity of the insulin-tolerance test as compared to the arginine stimulation test was confirmed.

Adult↗

PubMed1998

Determinants of serum insulin-like growth factor I in growth hormone deficient adults as compared to healthy subjects.

OBJECTIVE: Growth hormone status is an important determinant of serum IGF-I but it is well known that hypopituitary adults with pronounced GH-deficiency (GHDA) may exhibit normal IGF-I levels. To elucidate possible causes of this apparent paradox we compared the significance of putative IGF-I predictors in GHDA and normal subjects. DESIGN: A cross-sectional study. SUBJECTS: Twenty-seven GHDA (9 females, 18 males, mean +/- SE age 44 +/- 1 years) and 27 healthy control subjects (9 females, 18 males, mean +/- SE age 43 +/- 2 years). RESULTS: Serum IGF-I and IGFBP-3 were significantly lower in GHDAs, but a considerable overlap existed (IGF-I (microgram/l) 87 +/- 12 (GHDA) vs 177 +/- 10 (Control) (P < 0.001)). In both Controls and GHDA, IGF-I was higher in males than females (Control: 196 +/- 12 vs 138 +/- (P = 0.004); GHDA: 97 +/- 16 vs 56 +/- 11 (P = 0.05)). In GHDA, males on testosterone substitution had the highest IGF-I concentrations. The molar IGF-I:IGFBP-3 ratio was significantly lower in GHDAs (0.18 +/- 0.01 vs 0.23 +/- 0.02 (P = 0.002)). IGFBP-1 (microgram/l) was significantly elevated in GHDAs (6.28 +/- 1.11 vs 3.07 +/- 0.32 (P < 0.001)) despite comparable fasting insulin levels. Percentage total body fat (TBF, DEXA, waist/hip ratio, and intra-abdominal fat (CT) were all elevated in GHDAs. IGF-I correlated positively with lean body mass (DEXA) and negatively with TBF and IGFBP-1 in both groups. IGF-I correlated negatively with age in CON but not in GHDAs, whereas IGF-I correlated positively with IGFBP-3 only in GHDAs. Multiple regression analysis revealed that age and IGFBP-1 were the only significant predictors of IGF-I in CON, whereas IGFBP-3 and, to a lesser extent TBF, were the only independent predictors of IGF-I in GHDAs. Neither peak stimulated GH, nor physical fitness contributed in any equations in the two groups. CONCLUSIONS: 1) IGF-I levels are regulated by several variables in addition to GH status 2) age per se is an independent negative determinant in healthy subjects but not in GHDA 3) it is probable that some cases of paradoxically high IGF-I levels in GHDA are secondary to inappropriately elevated IGFBP-3 levels. 4) in mid-adulthood males have higher IGF-I levels than females and it is likely that testosterone directly stimulates IGF-I. The influence of gender and sex steroids must therefore be accounted for when comparing IGF-I levels between hypopituitary and healthy subjects.

Adult↗

PubMed1998

Influence of growth hormone binding protein on growth hormone estimation in different immunoassays.

Growth hormone (GH) quantitation in biological fluids varies depending on the assays employed, and factors which may interfere in the assays include the high affinity GH-binding protein (GHBP). To evaluate this potential effect on GH estimates, we studied the influence of adding increasing amounts of high affinity glycosylated GHBP to normal, acromegalic and GH-deficient sera, which were then processed in four different immunoassays. Two commercial immunometric assays, Delfia and Nichols (assays 1 and 2), and two RIAs, one using a polyethylene glycol (PEG) precipitation (assay 3) and one using wick-chromatography (assay 4) for separation of free and bound 125I-GH, were employed. In the Delfia assays, GH estimates of 11 sera decreased (p < 0.05) to 87.2 +/- 2.6%, 73.0 +/- 2.7% and 60.1 +/- 2.5% (mean +/- SEM) of basal GH estimates with the addition of GHBP in concentrations of 0.54, 2.14 and 6.42 nmol/l, respectively. In the Nichols assay, GH estimates were not significantly reduced (93.4 +/- 2.6%, 83.8 +/- 4.5% and 83.9 +/- 3.9%) with the applied GHBP concentrations. In assay 3 (RIA), the addition of GHBP increased GH estimates to 122 +/- 10.0% and 167 +/- 19.1% (both p < 0.05) with the addition of GHBP in concentrations of 2.14 and 6.42 nmol/l, respectively, whereas an increase in GHBP concentration of 0.54 nmol/l did not change the estimates from basal levels (99.0 +/- 4.8%, p > 0.05). In assay 4 (RIA), the addition of GHBP induced decreased GH estimates. With this varying influence of GHBP on GH estimates, binding protein interference should be taken into consideration when comparing GH estimates obtained with many currently utilized GH immunoassays. The present results demonstrate that GHBP levels within physiological range may interfere with the results of GH assays, giving either spuriously high or low values depending on the GH assay methodology.

Artifacts↗

PubMed1998

Increased pulsatile, but not basal, growth hormone secretion rates and plasma insulin-like growth factor I levels during the periovulatory interval in normal women.

The secretion of GH changes during the menstrual cycle, exhibiting high levels during the periovulatory phase (PO). Previous studies have not investigated whether this difference in GH status is due to increased secretion or reduced clearance of pituitary GH and amplified pulsatile vs. basal GH secretion. It is also unclear whether the PO phase is accompanied by changes in circulating insulin-like growth factor I (IGF-I). In this study we investigated the 24-h GH release patterns in the early follicular (EF) vs. the periovulatory menstrual phase in the same individuals. Ten young (aged 24-34 yr) healthy women with regular menses were studied with deconvolution analysis of GH profiles obtained by blood sampling every 20 min for 24 h, followed by an arginine stimulation test. A high sensitivity immunofluorometric GH assay was used. All women were studied in both the EF and PO phases in random order. There were no differences in the basal GH secretion rate or GH half-life during the two phases. The number of GH secretory bursts identified during the 24-h sampling period was significantly increased during the PO (13.3 +/- 0.5) compared to the EF (10.3 +/- 0.6) phase (P = 0.002); conversely, the mean interburst interval was shorter in the PO (107 +/- 5 min) than in the EF (134 +/- 8 min) phase (P = 0.004). There was no difference in GH pulse mass (P = 0.13) or amplitude (P = 0.21) between the two phases. The pulsatile GH production rate (milligrams per L/24 h) was significantly elevated during the PO (61 +/- 6) compared to that during the EF (37 +/- 8; P = 0.004). Increased total GH pulse area was confirmed by Cluster analysis (P = 0.027). Furthermore, the 24-h mean serum GH concentration was significantly increased in the PO (1.4 +/- 0.1 mg/L) vs. that in the EF (0.9 +/- 0.1 mg/L; P = 0.002). There was a positive correlation between estradiol (E2) and GH secretory pulse amplitude, frequency, and mean 24-h serum GH concentration in the PO cycle phase, indicating E2 to be a major statistical determinant of GH secretion. Serum GH increased significantly after arginine infusion in both phases (P < 0.001), whereas there was no difference between the two cycle phases (P = 0.20). Serum IGF-I levels were increased during the PO phase (253 +/- 20 mg/L) compared to those during the EF phase (210 +/- 16 mg/L; P = 0.03), whereas serum IGF-binding protein-3, IGF-II, and GH-binding protein were similar during the two phases. This study unequivocally documents elevated GH levels during the PO phase of the menstrual cycle, mediated by increased GH production rate and burst frequency. The concomitant increase in serum IGF-I suggests a central stimulation of the GH-IGF-I axis, which may be mediated by endogenous E2 levels.

Adult↗

PubMed1998

GH stimulation tests: evaluation of GH responses to heat test versus insulin-tolerance test.

OBJECTIVE: Heat exposure has been shown to stimulate GH release, but the specificity and the reproducibility have not been determined, and the test has not been compared with validated GH stimulation tests in adulthood. We therefore tested the specificity and the reproducibility of the heat exposure test in healthy subjects and compared the results with those obtained with the insulin-tolerance test (ITT). DESIGN: Ten healthy non-obese men, aged 31.3+/-4.80 years, underwent four GH stimulation tests in random order: two ITTs and two heat exposure tests. In the heat test, subjects were placed in a hot bath with water temperature at 40.3+/-0.11 degrees C for 45 min, resulting in an identical (P = 0.477) significant increase in tympanic temperature of 1.26+/-0.05 and 1.41+/-0.07 degrees C in the two tests. RESULTS: Peak GH response to the heat exposure test was less than the peak GH response to ITT (5.25+/-1.72 vs 15.5+/-3.17 microg/l, P = 0.006). Furthermore the specificity (arbitrary cut-off level = 3 microg/l) of the heat test was lower than of the ITT (8/17 vs 18/20, P = 0.006). The coefficient of variation did not differ between the two tests (heat test 0.31, ITT 0.36, P = 0.77). Peak GH values in the individual tests were highly correlated (heat, r = 0.908, P = 0.002; ITT, r = 0.815, P = 0.004). Reproducible increments in the circulating levels of stress hormones were observed during ITT. but these hormones remained largely unchanged during heat exposure. CONCLUSIONS: The heat exposure test is not a reliable GH stimulation test compared with the ITT in adults. This study documents that the ITT has a high specificity and reproducibility in the diagnosis of GH deficiency in adulthood. We propose that the heat exposure test is not used in the diagnosis of this condition in adulthood.

Adult↗

PubMed1997

Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year.

The gene product from the ob gene, leptin, has recently been characterized in humans. The circulating level of leptin is related to body mass index (BMI) and more closely to estimates of total body fat, whereas visceral fat has been reported to be of minor importance. However, it is unknown if leptin is directly regulated by hormones that influence substrate metabolism and body composition. We studied leptin in adult growth hormone (GH)-deficient (GHD) patients substituted with GH treatment for 12 months in a parallel double-blind, placebo-controlled study. Twenty-seven GHD adults aged 44.9 +/- 1.9 years underwent anthropometric measurements for determination of regional and total body fat (BMI, waist to hip ratio [WHR], computed tomographic [CT] scan, dual-energy x-ray absorptiometry [DEXA] scan, and bioimpedance analysis [BIA]) before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. The same measurements were performed in 42 healthy adults aged 39.1 +/- 1.7 years. The logarithm of serum leptin levels correlated positively with abdominal subcutaneous fat and total body fat (BIA and DEXA) in untreated GHD patients and healthy subjects. Fasting insulin did not correlate with leptin levels in either of the groups. After 12 months of GH administration, the body composition of GHD patients was significantly changed with respect to a marked decrease in body fat. The relations of leptin to the estimates of body fat were maintained, and leptin was furthermore related to BMI and fasting insulin. In multiple linear regression analyses, additional estimates of visceral adiposity (intraabdominal fat and maximal anterior-posterior diameter determined by CT scan) were significant determinants of leptin in the healthy subjects. The increase in fasting insulin levels during GH substitution correlated negatively with the reduction in leptin levels (r = -.823, P = .003). At baseline, leptin levels were increased in the patients compared with controls in both sexes (women, 21.8 +/- 3.3 v 11.3 +/- 1.4 ng/mL, P = .002; men, 8.1 +/- 1.2 v 4.7 +/- 0.7 ng/mL, P = .008). Leptin levels were similar in GHD patients treated for 12 months compared with healthy controls for both women and men (women, 15.9 +/- 2.3 and 11.3 +/- 1.4 ng/mL, P = .163; men, 7.1 +/- 2.8 and 4.7 +/- 0.7 ng/mL, P = .759). In healthy adults and in GHD patients, leptin levels were significantly higher in women than in men (11.3 +/- 1.4 v 4.7 +/- 0.7 ng/mL, P < .001; 21.8 +/- 3.3 v 8.1 +/- 1.2 ng/mL, P < .001). Gender remained a significant determinant of leptin levels in several models of multiple linear regression analysis also including age, estradiol levels, insulin, and estimates of body fat. We conclude that leptin is increased but not differently regulated in GHD patients compared with normal subjects, and that leptin levels are closely related to estimates of body fat. This relationship is maintained during a decrease in body fat due to GH substitution.

Absorptiometry, Photon↗

PubMed1997

Somatopause and adiposity.

Mobilization of lipids is the pivotal action of growth hormone (GH) in both children and adults. The temporal association between declining GH levels and accumulation of body fat with ageing is, therefore, interesting although the cause-effect relationship remains unknown. Recent cross-sectional data suggest that both stimulated and spontaneous GH release is predominantly predicted by the amount of abdominal fat in both men and women. The same study also shows that ageing is associated with an increased metabolic clearance rate and apparent distribution volume, both of which correlate positively with fat mass and negatively with age. Furthermore, the acute lipolytic response to a GH bolus is somewhat lower in older adults (and in women). It is, therefore, proposed that changes in life style and dietary habits, perhaps together with an age-determined reduced lipolytic responsiveness to GH, initiates fat accumulation. The increased fat mass, in turn, inhibits the release and promotes the clearance of GH thus establishing a vicious circle.

Adipose Tissue↗

PubMed1997

Abdominal fat determines growth hormone-binding protein levels in healthy nonobese adults.

The circulating high affinity GH-binding protein (GHBP), which derives from the extracellular domain of the hepatic GH receptor, correlates inversely to GH levels and directly to body mass index (BMI) in healthy adults. As GH secretion and adiposity are also interrelated, we tested the hypothesis that body composition more than GH, determines GHBP levels in healthy adults. Forty-two healthy adults [21 females and 21 males; mean age, 39.4 yr range, 27-59 yr); mean BMI, 23.9 kg/m2 (range, 18.9-34.7 kg/m2)], underwent anthropometric measurements (BMI, W/H ratio, computed tomography scan, dual energy x-ray absortiometry (DEXA) scan, and bioimpedance) in addition to two GH stimulation tests (arginine and clonidine) and a 24-h GH profile. By simple linear regression, serum GHBP correlated positively to several indices of adiposity: intraabdominal fat (r = 0.537; P = 0.001), sc abdominal fat (r = 0.680; P < 0.001), BMI (r = 0.483; P = 0.001), W/H ratio (r = 0.452; P = 0.003), total body fat (DEXA scanning; r = 0.503; P = 0.002), and body fat (bioimpedance; r = 0.354; P = 0.023). Lean body mass estimated by DEXA scan was negatively associated with GHBP (r = 0.541; P < 0.001). GHBP was inversely proportional to arginine-stimulated GH release (r = -0.346; P = 0.027) and negatively associated with several measures of spontaneous GH release as estimated by deconvolution analysis (GH mass, GH production rate, and mean GH; r = -0.371; P = 0.017, r = -0.393; P = 0.011, and r = -0.343; P = 0.028, respectively)). With multiple linear regression analyses, indices of adiposity were significant determinants of GHBP levels, whereas GH status did not contribute independently to the prediction of GHBP. Neither insulin-like growth factor I nor fasting insulin levels correlated to GHBP levels. In conclusion, GHBP levels in normal adults seem to be determined by abdominal fat mass rather than GH secretion.

Abdomen↗

PubMed1997

Body composition and physical fitness are major determinants of the growth hormone-insulin-like growth factor axis aberrations in adult Turner's syndrome, with important modulations by treatment with 17 beta-estradiol.

The objectives of this study were to 1) study the GH-insulin-like growth factor (IGF) axis in adult untreated Turner's syndrome compared to that in age-matched controls; 2) examine the effects of sex hormone substitution on this axis, 3) study the effects of route of administration of 17 beta-estradiol on the measured variables, and 4) examine the effects of sex steroids on hepatic function in Turner patients. Twenty-seven patients with Turner's syndrome were evaluated before and during sex hormone replacement, and an age-matched control group (n = 24) was evaluated once. Main outcome variables were GH and other measures of the GH-IGF axis, body composition, maximal oxygen uptake, sex hormone-binding globulin, and hepatic enzymes and proteins. The integrated 24-h GH concentration (IC-GH; micrograms per L/24 h) was reduced in women with Turner's syndrome (T) compared to controls [C; mean +/- SD, 18.3 +/- 12.0 (T) vs. 37.2 +/- 29.7 (C); P = 0.007]. However, multiple regression revealed that fat-free mass (FFM) and maximal oxygen uptake were significant explanatory variables (joint r = 0.77; P < 0.0005), accounting for 60% of the variance in the 24-h IC-GH. This association was also present in controls. After adjustment for these two variables, any difference in GH concentration between Turner patients and controls disappeared. Serum IGF-I and IGF-II were identical in Turner patients and controls despite the difference in 24-h IC-GH. The level of GH-binding protein (GHBP; nanomoles per L) was higher in Turner women [1.87 +/- 0.72 (T) vs. 1.22 +/- 0.33 (C); P = 0.0005]; after adjustment for FFM, the difference in GHBP levels disappeared between Turner patients and controls. During sex hormone treatment a significant increase was seen in the 24-h IC-GH (P = 0.02), FFM (percentage of weight; P < 0.0005) and maximal oxygen uptake (milliliters of O2 per kg/min; P = 0.02). Serum IGF-I was unchanged, whereas serum IGF-II (micrograms per L) decreased significantly [Turner, basal (TB), vs. Turner, treatment (TT), 860 +/- 135 vs. 823 +/- 150; P = 0.04]. Alanine aminotransferase (units per L), gamma-glutamyl transferase (units per L), and alkaline phosphatase (units per L) were significantly elevated during the basal study period, and all decreased during treatment [alanine amino-transferase, 55 +/- 55 (TB) vs. 30 +/- 20 (TT; P = 0.006); gamma-glutamyl transferase, 92 +/- 98 (TB) vs. 43 +/- 65 (TT; P = 0.003); alkaline phosphatase, 211 +/- 113 (TB) vs. 175 +/- 54 (TT); P = 0.06]. The route of administration of 17 beta-estradiol did not affect its actions. In conclusion, we found the GH-IGF axis in Turner's syndrome to be normal, with body composition and physical fitness exerting the same modifying effects on this axis as seen in the normal population. Sex hormone replacement in Turner's syndrome is associated with normalizing effects on the GH-IGF axis, body composition, physical fitness, and hepatic function. The lowering of hepatic enzymes is a surprising and hitherto undiscovered action of sex steroids. Finally, the route of administration of 17 beta-estradiol is of minor importance in Turner's syndrome.

Adult↗

PubMed1997

Growth hormone binding protein and growth hormone availability in acromegalic patients treated with long-acting octreotide (Sandostatin-LAR).

OBJECTIVE: In the medical treatment of acromegaly different factors are influential; among these the impact on growth hormone binding protein (GHBP) has not been clarified. DESIGN: Twenty acromegalic patients and nineteen age- and gender-matched normal subjects participated in this study. The patients were treated for 21 months with depot long-acting microsphere-enclosed octreotide (Sandostatin-LAR). Previously, all the patients were treated s.c. with octreotide t.i.d. After a 2-week wash-out period (baseline) the patients received the first i.m. injection of the long-acting octreotide. The first two injections were administered at 60-day intervals; thereafter the injections were at 28-day intervals. METHODS: The levels of GHBP, complexed GHBP, growth hormone (GH) and insulin-like growth factor-I (IGF-I) were determined in fasting serum samples. RESULTS: In the 2-week wash-out period GHBP levels decreased from 1.13 +/- 0.17 to 0.92 +/- 0.15 nmol/l (P < 0.05). During the 21-months treatment, GHBP increased again to 1.10 +/- 0.16 nmol/l. In the age- and gender-matched control group GHBP levels were significantly higher at all times (1.95 +/- 0.21 nmol/l. P(all) < 0.02). Mean levels of 8-h GH decreased from 12.6 +/- 2.58 microg/l at baseline to 1.97 +/- 0.20 microg/l after 21 months of treatment (P < 0.05). Mean 8-h GH levels were unchanged during long-acting octreotide treatment compared with levels during s.c. treatment (1.97 +/- 0.20 microg/l and 1.90 +/- 0.20 microg/l respectively). In fasting blood samples GH-complexed GHBP ranged from 13.8 +/- 2.4% (9 months) to 25.4 +/- 4.5% (baseline) of total GHBP. Serum IGF-I increased from 367 +/- 45 to 764 +/- 80 microg/l (P < 0.05) during the 2-week wash-out period and decreased to 290 +/- 35 microg/l (P < 0.05) after 21 months of treatment with long-acting octreotide. IGF-I levels after 21 months were significantly lower than during s.c. octreotide treatment (P < 0.05). CONCLUSION: Serum GHBP levels are similar during treatment with long-acting octreotide as compared with regular octreotide. Furthermore, significant changes in GHBP can occur within 2 weeks. Finally, in addition to the lowering effect on GH levels, the induced increase in GHBP levels may imply a further advantage in octreotide treatment of acromegaly. circulating GH bound to GHBP may less readily reach the tissues.

Acromegaly↗

PubMed1997

Increased circulating leptin concentrations in insulin-resistant first-degree relatives of patients with non-insulin-dependent diabetes mellitus: relationship to body composition and insulin sensitivity but not to family history of non-insulin-dependent diabetes mellitus.

OBJECTIVE: To explore a possible association between serum concentration of leptin, insulin sensitivity and non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: Forty first-degree relatives of NIDDM patients and 35 control subjects matched for age, gender and body mass index underwent a hyperinsulinaemic (insulin infusion rate 0.6 mU/kg per min) euglycaemic clamp combined with indirect calorimetry. Serum leptin was measured in fasting blood samples obtained before the clamp. RESULTS: All subjects had a normal oral glucose tolerance test. Insulin-stimulated glucose uptake (M) was decreased in the relatives compared with the control subjects (4.58 +/- 0.27 versus 6.06 +/- 0.25 mg/kg per min, P < 0.001). Conversely, serum leptin was increased in the relatives (9.6 x/divided by 1.1 versus 6.1 x/divided by 1.2 ng/ml (geometric mean x/divided by antilog S.E.M.), P < 0.05). A positive correlation was observed between circulating levels of leptin and percentage body fat (P < 0.001) and inverse correlations were found between leptin, M (P < 0.01), maximal aerobic capacity (VO2 max) (P < 0.01), and energy expenditure (P < or = 0.01) in both groups. In multiple linear regression analysis, percentage body fat, gender and M significantly determined the level of leptin (r2 = 0.71, P < 0.001) whereas family history of NIDDM and VO2 max did not. CONCLUSION: Serum leptin is increased in insulin-resistant offspring of NIDDM patients. The association between leptin, anthropometric measures and insulin sensitivity is, however, comparable with that of a control group. The increased concentrations of serum leptin in the relatives appear to be associated with the insulin resistance, but not with a family history of NIDDM.

Administration, Oral↗

PubMed1997

Effects of hyperinsulinaemia and hypoglycaemia on circulating leptin levels in healthy lean males.

Current knowledge of the regulatory mechanisms of leptin synthesis and release is limited. To elucidate the role of short-term hyperinsulinaemia and hypoglycaemia on circulating levels of leptin, 7 healthy lean men underwent a 360-min hyperinsulinaemic (insulin infusion rate: 1.5 mU/kg/min) clamp in two conditions: (i) during 360 min of euglycaemia and (ii) during 120 min of euglycaemia followed by 240 min of graded hypoglycaemia (nadir 2.9 +/- 0.1 mmol/l). During hyperinsulinaemic euglycaemia, serum leptin levels were initially stable and then rose gradually after 180 min to a peak value of 147 +/- 7% of baseline (ANOVA, p < 0.01). During the hypoglycaemic clamp, the leptin profile differed from that of euglycaemic conditions (p < 0.01) since the increase was postponed and reduced. In both clamp studies, leptin dynamics contrasted with the changes in a control study performed in 7 other men whose serum leptin fell significantly (p < 0.05) to 77 +/- 4% of baseline values during a 360-min fast (following overnight fasting). It is concluded that hyperinsulinaemia for more than 3 h increases circulating levels of leptin in lean males, whereas hyperinsulinaemia with concomitant hypoglycaemia leads to transient suppression. The exact nature of the underlying mechanisms, e.g. changes in levels of insulin, glucose, various substrates, glucose turnover and/or counterregulatory hormones, remains to be determined.

Adult↗