Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency

OBJECTIVE: Reduction of growth hormone (GH) secretion in obesity probably reflects neuroendocrine and metabolic abnormalities. Even short-term fasting stimulates GH secretion and distinguishes normal from hypopituitary subjects with growth hormone deficiency (GHD). Marked weight loss improves GH secretion in obesity but the effect of fasting is controversial. We studied the effects of a 36 h fasting on the GH/IGF-I axis and metabolic parameters in obesity. SUBJECTS: We studied nine obese patients (OB; three male and six female; age, 29.2+/-4.8; range, 18-59 y; body mass index (BMI), 43.4+/-2.7 kg/m(2); WHR, 0.9+/-0.1). Fifteen normal subjects (NS; eight male and seven female 28.9+/-0.6, 25-35 y; 21.6+/-0.4 kg/m(2)) and 10 adult hypopituitary patients with severe GH deficiency (GHD; seven male and three female; 37.6+/-2.3, 29-50 y; 24.5+/-1.0 kg/m(2); GH peak<3 microg/l after ITT and/or<9 microg/l after GHRH+arginine) served as control groups. STUDY DESIGN: We studied the effects of 36 h fasting on 8 h diurnal mean GH, insulin and glucose concentrations (mGHc, mINSc and mGLUc; assay every 30 min from 8.00 am to 4.00 pm) as well as on IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and free fatty acid (FFA) levels. RESULTS: Before fasting, basal IGF-I and ALS levels in OB were similar to those in NS and both were higher (P<0.001) than those in GHD. IGFBP-3 levels in OB were lower (P<0.01) than in NS but higher (P<0.02) than in GHD. GHBP levels in OB and GHD were similar and both were higher (P<0.01) than in NS. Glucose levels were similar in all groups. FFA levels in OB were higher (P<0.01) than in NS but similar to those in GHD. IGFBP-1 in OB were lower (P<0.05) than in NS and GHD which, in turn, were similar. On the other hand, mINSc in OB was higher (P<0.01) than that in NS and GHD which, in turn, were similar. The mGHc in OB was similar to that in NS but only the latter was higher (P<0.05) than in GHD. The individual mGHc in the three groups overlapped. After fasting, IGF-I levels in GHD were unchanged while they decreased in OB (P=NS) as well as in NS (P<0.01). IGFBP-3 and ALS levels did not change. GHBP levels in OB and GHD were unchanged while they increased in NS (P<0.01). Glucose and FFA levels were reduced and increased, respectively, in all groups (P<0.02 and P<0.01). IGFBP-1 increased while mINSc decreased in all groups (P<0.02 and P<0.01); in OB they persisted lower and higher (P<0.01) respectively, than in NS and GHD. Fasting significantly increased mGHc in NS (P<0.001) but not in OB as well as in GHD. Individual mGHc in OB showed persistent overlap with GHD. CONCLUSIONS: Short-term fasting does not increase GH secretion in obesity and does not distinguish somatotroph function in obese from that in severe GHD adults. Short-term fasting in obesity has attenuated effects on insulin and IGFBP-1 secretion while it normally increases free fatty acids in spite of any change in GH secretion.     

Transmural atrial pacing in patients with postoperative congenital heart disease

INTRODUCTION: Some patients with postoperative congenital heart disease require permanent cardiac pacing, but the use of transvenous or epicardial pacing leads may be limited by type of cardiac malformation, venous connections, body size, or fibrosis. Transmural atrial pacing may provide an alternative in difficult patients, but to date has been described in only a few articles with small patient numbers, and data from lead performance are lacking. METHODS AND RESULTS: Records were reviewed in 18 consecutive patients (4 months to 21 years old) with postoperative congenital heart disease receiving transmural atrial pacing leads from July 1994 to December 1996. Implantation materials and techniques were described. Lead sensing and capture thresholds obtained acutely and during short-term follow-up (mean: 11.0 months) were evaluated, and comparisons were made between patients with postoperative Fontan anatomy and non-Fontan patients, and between patients receiving steroid-eluting and nonsteroid leads. Overall, the median acute sensing and capture thresholds of transmural leads were 4.1 m V and 0.7 V at 0.5 msec, respectively. Median follow-up thresholds were 2.8 m V and 0.8 V, respectively. Performance of leads in Fontan patients was similar to those in non-Fontan patients. Steroid-eluting leads had a chronic capture threshold of 0.6 V versus 0.9 V for nonsteroid leads (P = 0.038). CONCLUSION: Transmural atrial pacing leads were successfully implanted in patients with diverse ages and types of postoperative congenital heart disease. Lead performance was acceptable both acutely and during the first year of follow-up.     

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.     

Diagnosis and treatment of acromegaly complications

The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly. Fifty nine pituitary specialists (endocrinologists, neurosurgeons and cardiologists) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion. The impact of elevated GH levels on cardiovascular disease, hypertension, diabetes, sleep apnea, colon polyps, bone disease, reproductive disorders, and neuropsychologic complications were considered. Guidelines are proposed for effective management of these complications in the context of overall acromegaly control. When appropriate, requirements for prospective evidence-based studies and surveillance database development are enunciated. Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly.     

Development and psychometric properties of a disease-specific quality of life questionnaire for adult patients with growth hormone deficiency

BACKGROUND: Adults with growth hormone (GH) deficiency (GHD) may experience physical and psychological disturbances, which can affect their quality of life (QOL). OBJECTIVES: To develop and validate a disease-specific module from the previously published QOL measure Questions on Life Satisfaction Modules (QLS(M)): the QLS(M)-H that specifically addressed the needs of patients with hypopituitarism. A second aim was for the questionnaire to be applicable across different cultural backgrounds in order to evaluate the efficacy of therapy in large, international clinical trials, thus providing additional clinical endpoints for these studies. DESIGN: A preliminary German language version of the QLS(M)-H was developed from 26 semi-structured interviews of adults with GHD. The questionnaire was then independently translated into five other languages and applied in open, non-controlled, multicentre, longitudinal studies to patient (n=717) and normative populations (n=2700). METHODS: A revised, nine-item version of the questionnaire was developed, based on previously defined criteria, and was evaluated for reliability and validity. Sensitivity to detect changes after GH replacement was also assessed. RESULTS: The 16 items of the preliminary questionnaire were reduced to nine items on the basis of the correlation of items/factors from initial patient interviews. Psychometric analysis revealed the reliability of the nine-item scale. The Cronbach's alpha scores ranged from 0.81 to 0.89 and the test-retest correlations ranged from 0.76 to 0.88, all of which indicate reliability over time. Mean scores increased significantly during GH replacement therapy, with observed changes greater than those seen with the non-specific modules of the QLS(M), indicating the sensitivity of the scale. CONCLUSIONS: The QLS(M)-H questionnaire is concise, easy to complete, and can be effectively applied across different cultural backgrounds. Psychometric evaluation of the questionnaire reveals that it is a valid, reliable and sensitive tool useful for assessing impaired life satisfaction in adult patients with GHD and also for monitoring the efficacy of GH therapy.     

Motivation for and adherence to growth hormone replacement therapy in adults with hypopituitarism: the patients‘ perspective

Pituitary - While reasons for non-adherence in children requiring growth hormone (GH) replacement (GH-Rx) are well researched, few studies have investigated adherence in adult GH deficient...