Elevated incidence of sleep apnoea in acromegaly-correlation to disease activity.

PURPOSE: An elevated prevalence of sleep apnoea (SA) in patients with acromegaly has been suggested. METHODS: We performed polysomnographies in 52 patients with acromegaly (25 m, 27 f, age 51 years, range 19-82 years). Patients were defined having SA if they had more than five apnoeas or hypopnoeas per hour (respiratory disturbance index = RDI). The type of SA was divided into obstructive (OSA), central (CSA) or mixed (OSA+CSA). Seventeen patients had newly diagnosed disease, and 18 patients were treated with somatostatin analogues. RESULTS: Twenty-three patients had controlled disease activity (mean GH levels <1 µg/l during a 3-h profile and normalised IGF-1 levels). Twelve had active acromegaly despite medical treatment. Thirty patients (58%) had SA. Twenty-five of those had OSA, three had CSA, and two had mixed. Of the patients with active disease, 66% had SA, compared to 48% in the cured group. Significantly more patients with hypertension (n = 18) than without hypertension (n = 12, p = 0.041) had SA. Basal glucose was not significantly different between patients with (100 mg/dl, range 75-207 mg/dl) and without SA (92 mg/dl, range 74-120 mg/dl), but HbA1c was significantly higher in patients with SA (5.9% (4.9-9.0%) vs. 5.4% (4.3-6.1%), p = 0.001). A positive correlation between RDI and BMI (p = 0.04), RDI and age (p = 0.013) and RDI and disease activity (p = 0.014) was seen. No major correlation could be found between RDI and the duration of disease activity nor between RDI and GH levels. CONCLUSION: RDI correlates positively with disease activity but not with the duration of the disease. The parameters of the metabolic syndrome are positively associated to the degree of SA in acromegalic patients.

Effects on metabolic variables after 12-month treatment with a new once-a-week sustained-release recombinant growth hormone (GH: LB03002) in patients with GH deficiency.

INTRODUCTION: GH substitution in GH deficiency (GHD) must be subcutaneously administered daily. A new sustained-release formulation of GH (LB03002) has been developed, which has to be injected once a week. As a substudy to the phase III study, we performed this prospective study to evaluate the influence of LB03002 on metabolic variables and hormones. METHODS: Eleven patients with GHD [four women/seven men, 58 years (29-69 years)] without GH therapy were included in the study. Eight patients were treated with LB03002 for 12 months and three patients received placebo for 6 months followed by LB03002 for 6 months. A 3-h oral glucose tolerance test (OGTT) was performed at study entry and at study end. Additionally, IGF-I, cholesterol, LDL, HDL, triglycerides, leptin, ghrelin, HbA1c and C-peptide were measured. Body composition was evaluated by dual-energy X-ray absorptiometry (DXA), and waist/hip ratio (WHR) and waist/height (WHtR) ratio were measured by tape and scale. RESULTS: Multiple of upper limit of normal (xULN) of IGF-I (0·23 (0·09-0·4) vs 0·71 (0·4-1·04), P < 0·01), WHR (0·98 (0·86-1·04) vs 1·01 (0·86-1·05), P < 0·05) and ghrelin levels [119·8 ng/l (67·7-266·6) vs 137 ng/l (67-289·5), P < 0·05] were significantly higher, whereas fat mass (FM) [34·7% (20·4-49·2) vs 32·4% (16·7-48·5), P < 0·05] and leptin [11·2 µg/l (3·3-55·7) vs 7·05 µg/l (2·4-54·3), P < 0·05] were significantly lower at study end. Glucose, insulin, HOMA-IR, ISI, HOMA-ß, C-peptide and HbA1c during OGTT were not significantly different before and after GH substitution, neither were BMI, WHtR, bone mineral density and lipid variables. CONCLUSION: Substitution with LB03002 showed statistically significant reduction in FM, which reduces leptin levels and increases ghrelin levels but does not seem to influence glucose and lipid metabolism.

Cognitive function in acromegaly: description and brain volumetric correlates.

In acromegaly, we reported on increased rates of affective disorders such as dysthymia and depression, as well as structural brain changes. Objective of this study was to determine if cognitive impairments in patients with acromegaly exist and whether such impairments are associated with structural brain alterations defined by magnetic resonance imaging (MRI). In this cross-sectional study, 55 patients with biochemically confirmed acromegaly were enrolled. MRI data were compared with 87 control subjects. Main outcome measures were performance levels in 13 cognitive tests covering the domains of attention, memory and executive function, with performance below the cut-off level of the 16th percentile rated as impaired. In addition, individual global and hippocampal volume changes were defined for each patient in reference to a normative sample. We found that up to 33.3% of the patients were impaired in the attention, up to 24.1% in the memory, and up to 16.7% in the executive function domain. 67.3% of the patients failed to reach the cut-off level in at least one subtest. MRI demonstrated increased global, left and right hippocampal grey matter and white matter, particularly early in the disease course. Rather few positive than expected negative correlations could be established between the hippocampal grey matter gain and cognitive performance. Cognitive dysfunction, particularly attentional deficits, are common in acromegaly, rendering neuropsychological testing essential in the diagnostic work-up.

Influence of pegvisomant on serum ghrelin and leptin levels in acromegalic patients.

INTRODUCTION: Pegvisomant (peg) is a GH receptor antagonist. In de novo acromegalic patients with high GH levels, ghrelin and leptin levels are reduced, suggesting a direct GH-mediated effect. The aim of our study was to evaluate whether peg treatment in acromegalic patients may abolish the GH impact on ghrelin and leptin levels. METHODS: Ghrelin, leptin and endogenous GH were measured in ten peg-treated acromegalic patients (three females/seven males, 47 years (28-57)), ten patients with active (act) and ten patients with inactive disease (inact) as well as in ten gender-, age- and body mass index (BMI)-matched healthy volunteers (controls). Endogenous GH was measured using a special in-house assay without interference by peg; total ghrelin and leptin were determined using a commercial RIA and an immunofluorometric in-house assay respectively. RESULTS: Age and BMI did not differ significantly between groups. Endogenous GH was significantly higher in peg (6.3 µg/l (1.5-41)) and act (9.3 µg/l (1.7-70)) compared with controls (0.1 µg/l (0.1-3.1)) and inact (0.35 µg/l (0.1-2.0), P<0.001). Ghrelin was significantly higher in peg (232  ng/l (96-351)) compared with act (102 ng/l (33-232), P<0.01), whereas ghrelin was not significantly different between the other groups. Leptin was highest in controls (19 µg/l (4-57)) and lowest in act (6 µg/l (2-21)), but this difference did not reach significance. CONCLUSION: Treatment with peg seems to disrupt the feedback loop of ghrelin and GH, leading to elevated ghrelin levels. Furthermore, peg therapy appears not to have a strong impact on leptin levels, as acromegalic patients with and without peg treatment showed similar leptin levels.

The acute effect of a single application of cabergoline on endogenous GH levels in patients with acromegaly on pegvisomant treatment.

OBJECTIVE: Treatment with pegvisomant, an antagonist of growth hormone (GH) receptors, increases GH levels in a dose dependent manner. Cabergoline can suppress GH secretion in approximately 40% of acromegalic patients. However, the acute effects of cabergoline have not been studied in patients treated with pegvisomant. We performed this cross-sectional study to evaluate endogenous GH after an additional single cabergoline administration. DESIGN: 9 acromegalic patients on pegvisomant therapy were included. A 6h GH profile after pegvisomant alone (P) and a 9h profile in combination with oral cabergoline 0.5mg (PC) were performed. After 3 or 6h, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. The GH assay showed no interference with pegvisomant. RESULTS: Endogenous GH levels at baseline did not differ significantly between the profiles (P: 16.5 µg/l (range 3.2-36.6 µg/l), PC: 8.0 µg/l (1.6-48 µg/l), p>0.05). In both profiles, GH fluctuated before meal. GH decreased more pronounced in PC but this decrease was not statistically significant. After meal, a significant decline in endogenous GH levels from 16.4 µg/l (0.4-27.1 µg/l, 100%) to 8.1 µg/l (0.2-24.7 µg/l, 66%) appeared in P at 300 min (p<0.01). Also in PC a decline from 7.8 µg/l (1.1-29.6 µg/l, 100%) to 5.2 µg/l (0.4-23.9 µg/l, 75%) at 300 min was observed but it was not significant. CONCLUSION: Endogenous GH is not significantly decreased after a single oral cabergoline application during pegvisomant treatment in acromegaly.

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population.

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 +/- 5.9 vs. 27.3 +/- 5.8 kg/m(2); P = 0.020; waist circumference 100.9 +/- 16.8 vs. 94.8 +/- 15.5 cm; P = 0.031; hip circumference 110.7 +/- 9.9 vs. 105.0 +/- 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.

Endogenous estradiol may influence IGF-I levels in acromegalic women treated with pegvisomant.

We present the case of a 46-year-old woman with acromegaly currently being treated with the growth hormone (GH) receptor antagonist pegvisomant showing strongly fluctuating IGF-I levels. We prospectively measured estradiol, IGF-I, IGF-I binding protein, acid labile subunit, basal endogenous GH, binding protein and pegvisomant levels for 6 months every week. Estradiol levels showed a strongly negative correlation with IGF-I (r = -0.733, P < 0.001), and less so with ALS (r = -0.433, P < 0.05) and IGFBP3 (r = -0.590, P < 0.01). Estradiol was not significantly correlated with endogenous GH or pegvisomant levels. Likewise, IGF-I did not correlate with endogenous GH or pegvisomant levels. In our patient, endogenous estradiol levels have a significant influence on IGF-I levels. When female acromegalic patients on permanent pegvisomant treatment show fluctuating IGF-I levels, estradiol levels should be taken into consideration.

Influence of long-term growth hormone replacement on leptin and ghrelin in GH deficiency before and after glucose load.

INTRODUCTION: This cross-sectional study was performed to evaluate the effect of long-term GH substitution on leptin and ghrelin in GH deficiency (GHD). METHODS: Leptin and ghrelin were measured after glucose load for 3 h in 52 pat and 10 age- and BMI-matched healthy controls. 22 GHD pat were on GH substitution (GH-Sub) for a median of 10 yr (range 2-27 yr). 30 age- and BMI-matched GHD pat were not substituted for at least 2 yr (non-Sub). RESULTS: Basal leptin (8 microg/l (1-130) vs. 16 microg/l (3-89), p<0.05) and AUC of leptin (p<0.05) was significantly lower in GH-Sub compared to non-Sub. In the control group, leptin was higher compared to GH-Sub and similar to non-Sub (19 microg/l (4-57)). Ghrelin (baseline: non-Sub 113 ng/l (61-270), GH-Sub 145 ng/l (83-280), controls 131 ng/l (83-274)) were slightly but not significantly lower for non-Sub. After glucose load, a significant decrease in leptin appeared in both GHD groups, but not in the control group. Ghrelin decreased significantly in all groups. CONCLUSION: Lipolytic GH causes lower leptin in GH-Sub. The reason for similar ghrelin might be the compensating effect of acute GH suppression and stimulating low fat mass on ghrelin. Leptin regulation after glucose load is impaired in GHD, whereas ghrelin regulation seems to be not effected.

Macroscopic brain architecture changes and white matter pathology in acromegaly: a clinicoradiological study.

Although long-term exposure of the brain to increased GH/IGF-1 likely influences cerebral functions, no in vivo studies have been directed towards changes of the brain structure in acromegaly. Here, we used high resolution magnetic resonance images to compare volumes of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of forty-four patients with acromegaly to an age and gender matched, healthy control group (n = 44). In addition, white matter lesions (WMLs) were quantified and graded. Patients exhibited larger GM (+3.7% compared with controls, P = 0.018) and WM volumes (+5.1%, P = 0.035) at the expense of CSF. Differences of WML counts between patients and controls were subtle, however, showing more patients in the 21-40 lesions category (P = 0.044). In conclusion, this MRI study provides first evidence that acromegalic patients exhibit disturbances of the macroscopic brain tissue architecture. Furthermore, acromegalic patients may have an increased risk of neurovascular pathology, likely due to secondary metabolic and vascular comorbidities.

Serum leptin and ghrelin levels in active and inactive acromegalic patients during an oral glucose tolerance test.

OBJECTIVE: Elevated BMI, fat mass and food intake increases leptin whereas ghrelin is reduced. Ghrelin stimulates growth hormone (GH) secretion. This prospective cross-sectional study was performed to investigate the influence of GH excess on leptin and ghrelin levels at baseline and after glucose load in a large group of acromegalic patients. DESIGN/METHODS: Leptin, ghrelin, GH, glucose and insulin concentrations were measured during a 3 h OGTT in 17 active, 25 inactive patients without medication (inact) and 8 inactive patients treated successfully with somatostatin analogues (inact-SA). Leptin concentration was measured using an in-house immunofluorometric assay, total serum ghrelin by a commercially available radioimmunoassay. Leptin was corrected for BMI. RESULTS: During OGTT, no significant difference of baseline, nadir or AUC of leptin/BMI was seen between the groups (baseline leptin/BMI: act: 0.26 microgm(2)/lkg (0.06-0.87); inact: 0.34 microgm(2)/lkg (0.03-1.79); inact-SA: 0.29 microgm(2)/lkg (0.03-1.47). A slight but significant reduction of leptin/BMI occurred in all groups during OGTT (active p<0.001, inact p<0.001, inact-SA p<0.05). Inact had higher ghrelin levels (130 ng/L (69-292) compared to active (102 ng/L (27-232); p=n.s.). Inact-SA had significantly lower ghrelin levels (88 ng/L (72-113)) than inact (p<0.001). There was a significant decline of ghrelin during OGTT in all groups (active p<0.001, inact p<0.001, inact-SA p<0.05). CONCLUSIONS: GH only has a slight influence on leptin secretion. Ghrelin levels are lowered by GH and SA. Nevertheless, the physiological decreasing effect of glucose load on ghrelin secretion is preserved.

Personality in patients with pituitary adenomas is characterized by increased anxiety-related traits: comparison of 70 acromegalic patients with patients with non-functioning pituitary adenomas and age- and gender-matched controls.

OBJECTIVE: Although neuropsychiatric and morphological brain alterations in acromegalic patients have been described and a distinct disease personality is clinically suspected, this has never been systematically investigated. We examined whether patients with acromegaly showed an altered personality profile compared with patients with non-functioning pituitary adenomas and healthy controls. DESIGN AND METHODS: In this cross-sectional study, 70 acromegalic patients and 58 patients with non-functioning pituitary adenomas were compared with 140 mentally healthy population controls, matched for age and gender. Personality traits were measured by standardized personality questionnaires (Eysenck personality questionnaire-RK and tridimensional personality questionnaire). RESULTS: Compared with healthy controls, acromegalic patients described themselves as distinctly more harm avoidant and neurotic and presented themselves with high social conformity. On harm avoidant subscales, they reported more anticipatory worries and pessimism, higher fear of uncertainty, higher fatigability and asthenia. This personality pattern was not specific for acromegaly, but could similarly be observed in patients with non-functioning pituitary adenomas. However, specific for patients with GH-producing adenomas was an even more reduced novelty-seeking behaviour, especially in terms of lower impulsiveness, compared with patients with non-functioning pituitary adenomas. CONCLUSION: Patients with pituitary adenomas show a distinct pattern of increased anxiety-related personality traits compared with the general population, potentially as a result of the pituitary lesion and/or associated hormonal dysregulations and comorbidities. Acromegaly is additionally associated with reduced impulsivity and novelty-seeking behaviour, which might affect patients' management and their quality of life.

The effect of acute application of pegvisomant alone and in combination with octreotide on endogenous GH levels during a 6-h test in patients with acromegaly on constant pegvisomant treatment.

OBJECTIVE: Co-treatment with somatostatin analogues and growth hormone receptor antagonists in acromegaly might be a new treatment option abolishing the negative effects of monotherapy. Nevertheless, little is known about the acute effect of the combined treatment on endogenous GH and pegvisomant levels. DESIGN: Ten acromegalic patients on constant pegvisomant therapy were included. Two 6-h GH secretion profiles were performed once after pegvisomant alone (P), the other after an additional 100 microg octreotide sc injection (PO). After 180 min, all patients received a standardized light mixed meal. Endogenous serum GH and pegvisomant levels were measured by special in-house assays. In addition, insulin and glucose were measured. RESULTS: In the combined profile PO, a significant decrease of median endogenous GH was seen (p<0.01, median percentage decline 75.2%, range 23.7-88.2), which was not seen in profile P. Seven of 10 patients had a decline >70% and might be seen as responders. After meal, endogenous GH significantly decreased only in profile P (p<0.01). Pegvisomant levels did not differ significantly between profiles and did not change significantly during the tests. After meal, glucose levels rose higher and later and insulin levels lower and later in profile PO than in profile P. CONCLUSION: During pegvisomant treatment, endogenous GH can be reduced significantly by acute application of a somatostatin analogue. Therefore, in acromegalic patients on pegvisomant therapy GH regulation due to somatostatin analogues seems to be preserved.