Increased neck soft tissue mass and worsening of obstructive sleep apnea after growth hormone treatment in men with abdominal obesity.

BACKGROUND: Risk factors for obstructive sleep apnea (OSA) are male gender, obesity and abnormalities in neck soft tissue mass. OSA is associated with both growth hormone (GH) excess and severe GH deficiency in adults. Adults with abdominal obesity have markedly suppressed GH secretion. AIM: To study the effect of GH treatment on OSA in abdominally obese men with impaired glucose tolerance. PATIENTS AND METHODS: Forty men with abdominal obesity and glucose intolerance were randomized in a prospective, 12-month double-blind trial to receive either GH or placebo. The treatment groups had similar BMI and waist circumference. Overnight polysomnography and computed tomography to assess muscle and fat distribution in the neck and abdomen were performed at baseline and after 12 months. RESULTS: GH treatment increased insulin-like growth-factor-1i from (mean [SD]) 168 (72) to 292 (117) microg/L, the apnea-hypopnea index from (n/h) 31 (20) to 43 (25) and oxygen-desaturation index from (n/h) 18 (14) to 29 (21) (p = 0.0001, 0.001, 0.002). Neck transverse diameter, circumference and total cross-sectional area (p = 0.007, 0.01, 0.02) increased, while abdominal visceral adipose tissue (p = 0.007) was reduced. No between-group differences in total sleep time, REM sleep, NREM sleep, and time spent in supine position were found. The Epworth sleepiness scale score was unchanged. CONCLUSIONS: GH treatment increased the severity of OSA in abdominally obese men. The possible mechanism appears to be reflected by the GH-induced increase of measures of neck volume. The present results, to some extent, argue against that low GH/IGF-I activity is a primary cause of OSA in abdominally obese men.

Models to predict changes in serum IGF1 and body composition in response to GH replacement therapy in GH-deficient adults.

OBJECTIVE: Clinical response to GH therapy in GH-deficient (GHD) adults varies widely. Good predictors of treatment response are lacking. The aim of the study was to develop mathematical models to predict changes in serum IGF1 and body composition (BC) in response to GH therapy in GHD adults. DESIGN AND METHODS: One hundred and sixty-seven GHD patients (103 men, median age 50 years) were studied before and after 12 months of GH treatment. GH dose was tailored according to serum IGF1 concentrations. Good responders (GR) and poor responders (PR) to GH therapy were defined as patients with a response >60th and <40th percentile respectively, for changes in serum IGF1 levels (adjusted for GH cumulative dose) and in BC (lean body mass (LBM) and body fat determined using dual-energy X-ray absorptiometry). A logistic regression model was used to predict the probability of being a GR or PR. RESULTS: In the IGF1 prediction model, men (odds ratio (OR) 5.62: 95% confidence interval 2.59-12.18) and patients with higher insulin levels (OR 1.06: 1.00-1.12) were more likely to be GR. The accuracy of the prediction model was 70%. In the BC model, men (OR 10.72: 1.36-84.18) and GHD patients with lower LBM (OR 0.82: 0.73-0.92) and greater height (OR 1.23: 1.08-1.40) at baseline were more likely to be GR. The accuracy of the prediction model was 80%. CONCLUSION: Accurate mathematical models to predict GH responsiveness in GHD adults were developed using gender, body height, baseline LBM, and serum insulin levels as the major clinical predictors.

Influence of the exon 3-deleted/full-length growth hormone (GH) receptor polymorphism on the response to GH replacement therapy in adults with severe GH deficiency.

CONTEXT: There is considerable individual variation in the clinical response to GH replacement therapy in GH deficient (GHD) adults. Useful predictors of treatment response are lacking. OBJECTIVE: The aim of the study was to assess the influence of the exon 3-deleted (d3-GHR) and full-length (fl-GHR) GH receptor isoforms on the response to GH replacement therapy in adults with severe GHD. DESIGN AND PATIENTS: A total of 124 adult GHD patients (79 men; median age, 50 yr) were studied before and after 12 months of GH therapy. GHD patients were divided into those bearing fl/fl alleles (group 1) and those bearing at least one d3-GHR allele (group 2), and the genotype was related to the effects of GH therapy on IGF-I levels and total body fat (BF). INTERVENTION: GH dose was individually titrated to obtain normal serum IGF-I levels. MAIN OUTCOME MEASURES: GHR genotype was determined by PCR amplification, IGF-I levels by immunoassay, and BF by a four-compartment model. RESULTS: Seventy-two (58%) patients had fl/fl genotype and were classified as group 1, whereas 52 (42%) had at least one d3-GHR allele and were classified as group 2 (40 were heterozygous and 12 were homozygous). At baseline, there were no significant differences in the study groups. Changes in IGF-I and BF after 12 months of GH treatment did not differ significantly between the two genotype groups. CONCLUSION: The presence of d3-GHR allele did not influence the response to GH replacement therapy in our cohort of adults with severe GHD.

The reduction in visceral fat mass in response to growth hormone is more marked in men than in oestrogen-deficient women.

CONTEXT: Women with severe growth hormone (GH) deficiency have a less marked response to GH replacement than men. This has mostly been attributed to the attenuating effects of oestrogen replacement therapy. OBJECTIVE: To study gender related differences in the response to GH treatment in men and postmenopausal women. METHODS: Fifteen men and 15 age- and BMI-matched women with abdominal obesity (mean age: 58; range 51-64 years) were treated for one year with similar doses (0.47 vs. 0.51 mg/day) of GH. All women were postmenopausal not receiving oestrogen treatment. Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp and body composition by computed tomography (CT) scans and from total body potassium, K(40). RESULTS: Men and women were comparable at baseline in terms of waist circumference, IGF-1 and lipid levels. After one year of GH treatment, there was a 18% reduction in visceral adipose tissue (VAT) in men and a 5% reduction in women (P=0.0001 men vs. women). Although the magnitude of the difference was small, men increased more in thigh muscle mass (P<0.0001 vs. women). A reduction in thigh intermuscular adipose tissue (IMAT) and diastolic blood pressure was seen only in men (both p<0.05 vs. baseline). A decrease in LDL cholesterol, and an increase in serum insulin, was observed only in women (both p<0.05 vs. baseline). CONCLUSION: Low dose GH treatment reduced VAT more markedly in men as compared with women. As all women were postmenopausal and oestrogen-deficient, this gender difference in responsiveness was not due to an antagonistic effect of oestrogen on peripheral GH action.

Body composition during GH replacement in adults - methodological variations with respect to gender.

OBJECTIVE: Men with growth hormone deficiency (GHD) may be more sensitive to GH treatment than women in terms of changes in body composition. We have studied whether age, body-mass index (BMI) and the different types of methodology used to assess body composition may explain these differences. DESIGN: Forty-four men and forty-four women with GHD, closely matched for age and BMI, were studied before and after 6 months of GH replacement. The dose of GH was individually adjusted. Body composition was assessed by measurements of potassium-40, total body nitrogen (TBN), tritiated water dilution, dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA). Four- and five-compartment models for body composition were also calculated. RESULTS: The total daily dose of GH was similar in men and women at 6 months. Serum insulin-like growth factor-I (IGF-I) was higher in men than women at baseline and after 6 months of treatment (P = 0.01, paired t-test). The increment was, however, similar. In women, GH treatment reduced body weight and increased TBN. In both men and women, total body water and body cell mass increased, while total body fat (BF) mass decreased. At baseline, mean total BF varied considerably depending on the methodology used, with the highest value obtained from DXA. The changes in BF were, however, less dependent on the methodology, but DXA and BIA demonstrated the largest inconsistency between men and women. CONCLUSIONS: These results suggest that gender differences in body composition in response to GH treatment are small, if adjustments are made for baseline factors such as age, BMI and dose of GH. Different methods of body composition measurements produce different results, but changes in response to GH administration are less inconsistent.

GH effect on enzyme activity of 11betaHSD in abdominal obesity is dependent on treatment duration.

OBJECTIVE: In the past years the interaction of GH and 11beta hydroxysteroid dehydrogenase (11betaHSD) in the pathogenesis of central obesity has been suggested. DESIGN: We studied the effects of 9 months of GH treatment on 11betaHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48-66 years, in a randomised, double-blind, placebo-controlled trial. METHODS: Urinary steroid profile was used to estimate 11betaHSD type 1 and 2 (11betaHSD1 and 11betaHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic-hyperinsulinaemic glucose clamp was used to assess insulin sensitivity. RESULTS: In the GH-treated group the 11betaHSD1 activity decreased transiently after 6 weeks (P < 0.01) whereas 11betaHSD2 increased after 9 months of treatment (P < 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11betaHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11betaHSD1 and 11betaHSD 2 and changes in GDR. DISCUSSION: The study demonstrates that short- and long-term GH treatment has different effects on 11betaHSD1 and 11betaHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11betaHSD.