Linkage between growth retardation and pituitary cell morphology in a dystrophin-deficient pig model of Duchenne muscular dystrophy.

OBJECTIVE: Human patients with Duchenne muscular dystrophy (DMD) commonly exhibit a short stature, but the pathogenesis of this growth retardation is not completely understood. Due to the suspected involvement of the growth hormone/insulin-like growth factor 1 (GH/IGF1) system, controversial therapeutic approaches have been developed, including both GH- administration, as well as GH-inhibition. In the present study, we examined relevant histomorphological and ultrastructural features of adenohypophyseal GH-producing somatotroph cells in a porcine DMD model. METHODS: The numbers and volumes of immunohistochemically labelled somatotroph cells were determined in consecutive semi-thin sections of plastic resin embedded adenohypophyseal tissue samples using unbiased state-of-the-art quantitative stereological analysis methods. RESULTS: DMD pigs displayed a significant growth retardation, accounting for a 55% reduction of body weight, accompanied by a significant 50% reduction of the number of somatotroph cells, as compared to controls. However, the mean volumes of somatotroph cells and the volume of GH-granules per cell were not altered. Western blot analyses of the adenohypophyseal protein samples showed no differences in the relative adenohypophyseal GH-abundance between DMD pigs and controls. CONCLUSION: The findings of this study do not provide evidence for involvement of somatotroph cells in the pathogenesis of growth retardation of DMD pigs. These results are in contrast with previous findings in other dystrophin-deficient animal models, such as the golden retriever model of Duchenne muscular dystrophy, where increased mean somatotroph cell volumes and elevated volumes of intracellular GH-granules were reported and associated with DMD-related growth retardation. Possible reasons for the differences of somatotroph morphology observed in different DMD models are discussed.

Initial free cortisol dynamics following blunt multiple trauma and traumatic brain injury: A clinical study.

OBJECTIVE: To determine free and total cortisol serum concentrations in the first 24 h after trauma and to evaluate the influence of traumatic brain injury (TBI) on their dynamics. METHODS: This prospective cohort study enrolled patients who had experienced multiple trauma and were admitted to a level 1 trauma centre. The patients were divided in two groups based on the presence of TBI according to clinical and radiological findings. Blood was collected initially as well as at 12 h and 24 h after the traumatic injury. Total cortisol, corticosteroid binding globulin (CBG) and free cortisol levels were determined. RESULTS: The study analysed data from 49 patients (36 males and 13 females) with a mean ± SD age of 45.0 ± 16.0 years. Of these, 36 presented with TBI and 13 had multiple injuries without TBI. Patients with TBI showed significantly lower concentrations of total cortisol and free cortisol compared with patients without TBI. Repeated measures analysis revealed different concentration dynamics in patients with TBI, with no increase in cortisol after trauma. CONCLUSION: Multiple trauma patients with TBI are at risk of acute impaired cortisol secretion and show an attenuated stress response as early as 12 h after injury.

Obese adolescents exhibit a constant ratio of GH isoforms after whole body vibration and maximal voluntary contractions.

BACKGROUND: Growth hormone (GH) is a heterogeneous protein composed of several molecular isoforms, the most abundant ones being the 22 kDa- and 20 kDa-GH. Exercise-induced secretion of GH isoforms has been extensively investigated in normal-weight individuals due to antidoping purposes, particularly recombinant human GH (rhGH) abuse. On the other hand, the evaluation of exercise-induced responses in GH isoforms has never been performed in obese subjects. METHODS: The acute effects of whole body vibration (WBV) or maximal voluntary contraction (MVC) alone and the combination of MVC with WBV (MVC + WBV) on circulating levels of 22 kDa- and 20 kDa-GH were evaluated in 8 obese male adolescents [mean age ± SD: 17.1 ± 3.3 yrs.; weight: 107.4 ± 17.8 kg; body mass index (BMI): 36.5 ± 6.6 kg/m2; BMI standard deviation score (SDS): 3.1 ± 0.6]. RESULTS: MVC (alone or combined with WBV) significantly stimulated 22 kDa- and 20 kDa-GH secretion, while WBV alone was ineffective. In particular, 22 kDa- and 20 kDa-GH peaks were significantly higher after MVC + WBV and MVC than WBV. In addition, 22 kDa-GH (but not 20 kDa-GH) peak was significantly higher after MVC + WBV than MVC. Importantly, the ratio of circulating levels of 22 kDa- to 20 kDa-GH was constant throughout the time window of evaluation after exercise and similar among the three different protocols of exercise. CONCLUSIONS: The results of the present study confirm the ability of MVC, alone and in combination with WBV, to stimulate both 22 kDa- and 20 kDa-GH secretion in obese patients, these responses being related to the exercise workload. Since the ratio of 22 kDa- to 20 kDa-GH is constant after exercise and independent from the protocols of exercise as in normal-weight subjects, hyposomatotropism in obesity does not seem to depend on an unbalance of circulating GH isoforms. Since the present study was carried out in a small cohort of obese sedentary adolescents, these preliminary results should be confirmed in further future studies enrolling overweight/obese subjects with a wider age range.

Left-Sided Living Kidney Donation Leads to Transiently Reduced Adrenocortical Responsiveness.

Living kidney donation is safe and established, but can lead to long-term complications such as chronic fatigue. Since the adrenal vein is usually transected during left-sided donor nephrectomy-which is not necessary on the right-we hypothesized that venous congestion might lead to an impairment of adrenal function, offering a possible explanation. In this prospective open label, monocentric cohort study, adrenal function was compared in left- and right-sided living kidney donors. The primary endpoint was plasma cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation. Secondary endpoints included plasma renin and ACTH concentration as well as adrenal volume in response to donor nephrectomy. A total of 30 healthy donors-20 left- and 10 right-sided donations-were included. On postoperative day 1, response to low-dose ACTH stimulation was intact, but significantly lower after left-sided donor nephrectomy. After 28 days, adrenal responsiveness to ACTH stimulation did not differ any longer. Magnetic resonance imaging volumetry showed no significant adrenal volume change over 4 weeks, neither after left- nor after right-sided nephrectomy. In conclusion, left-sided living kidney donation entails a transiently reduced adrenocortical responsiveness, which returns to baseline after 28 days.

The Clinical Value of Salivary Aldosterone in Diagnosis and Follow-Up of Primary Aldosteronism.

Primary aldosteronism (PA), the most common form of secondary hypertension, causes relevant morbidity. The value of salivary measurements of aldosterone in clinical routine in PA so far has not been assessed. First, we analyzed salivary and plasma aldosterone concentrations of 42 patients with PA and 37 hypertensive controls (HC) during a sodium infusion test prospectively. Second, morning salivary and plasma aldosterone concentrations as well as diurnal saliva aldosterone profiles were analyzed in 115 patients treated for PA (46 adrenalectomy, 56 spironolactone, 13 eplerenone). Salivary aldosterone was substantially elevated in PA patients compared to HC at baseline (106±119 vs. 40±21 ng/l, p=0.01), and after 4-h sodium infusion test (60±36 vs. 23±14, p=0.01). Positive correlation between salivary and plasma aldosterone levels was evident, with exception of concentrations in or below the lower normal range. Applying a salivary aldosterone cutoff of 51.2 ng/l, found by ROC curve analysis, rendered a sensitivity of 81% and a specificity of 73% for PA. The diurnal rhythm of aldosterone was preserved in untreated PA patients, but concentrations were higher in the context of PA, and normalized after surgery (118±57 vs. 31±18 ng/l, p<0.01). Taken together, salivary aldosterone measurements correlate with plasma levels, allowing simple and cost effective assessments of aldosterone secretion in an outpatient setting. Nevertheless, as this method alone cannot replace other plasma parameters, and as aldosterone profiling would not alter diagnostic or treatment strategies, salivary aldosterone measurements in routine practice are of limited clinical value.

GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Unaltered ratio of circulating levels of growth hormone/GH isoforms in adults with Prader-Willi syndrome after GHRH plus arginine administration.

Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms, the most abundant being 22 kDa- and 20 kDa-GH. The availability of analytical methods to measure these GH isoforms might represent a valuable diagnostic tool to investigate GH hyposecretory states, including Prader-Willi syndrome (PWS), one of the most common causes of syndromic obesity. The aim of the present study was to measure circulating levels of 22 kDa- and 20 kDa-GH in PWS adults (n=14; M/F: 5/9; genotype DEL15/UPD15: 12/2; age: 19.0±3.7 years; BMI: 29.9±8.7 kg/m2) after combined GH releasing hormone (GHRH) plus arginine (ARG) administration. The results were analysed subdividing the study population in obese vs. nonobese (6/8) and GH deficient vs. nonGH deficient (GHD) (6/8) subjects, according to appropriate BMI-related diagnostic cut-off limits of GH peak response to the provocative test. Circulating levels of 22 kDa-GH were measured by a chemiluminescent method based on a detection monoclonal antibody targeting an epitope in the loop connecting helix 1 and 2 of GH, which is missing in 20 kDa-GH; the 20 kDa-GH was measured using a time resolved fluorescence assay based on two monoclonal antibodies with no cross-reactivity to 22-kDa GH. GHRH plus ARG significantly stimulated the secretions of 22 kDa- and 20 kDa-GH in nonobese (at 30, 45, 60 and 90 min and at 45, 60, 90 and 120 min vs. 0 min, p<0.05, with GH peaks of 15.8±10.3 ng/ml and 2.7±1.2 ng/ml, respectively) and in nonGHD PWS (at 30, 45 and 60 min and at 45, 60 and 90 min vs 0 min, p<0.05, with GH peaks of 12.5±9.0 ng/ml and 2.0±1.8 ng/ml, respectively). No significant GHRH plus ARG-induced changes in 22 kDa- and 20 kDa-GH were observed in obese or GHD PWS patients, the only exception being the increase of 22 kDa-GH (p<0.05) 60 min after the stimulus administration in GHD group (with GH peaks of 6.9±4.7 ng/ml and 0.8±0.6 ng/ml in obese subjects and 8.5±6.0 ng/ml and 1.2±1.0 ng/ml in GHD subjects for 22 kDa- and 20 kDa-GH, respectively). The GH responses for both isoforms were significantly higher in nonobese than in obese PWS patients (at 45 and 60 min for 22 kDa-GH and at 45, 60, 90 and 120 min for 20 kDa-GH, p<0.05), while no differences were detected between GHD vs. nonGHD groups. As previously reported in healthy subjects, the ratios of circulating levels of 22 kDa- to 20 kDa-GH remained constant after GHRH plus ARG both in obese/non-obese and GHD/non-GHD groups, thus suggesting the preservation of a normal balance in GH isoforms in PWS.

Mind over hormones: sex differences in associations of well-being with IGF-I, IGFBP-3 and physical activity in the KORA-Age study.

OBJECTIVES: A ssociations between well-being, serum levels of insulin-like growth factor 1 (IGF-I), and its primary binding protein IGFBP-3, were examined in an epidemiologic study. The influence of physical activity on the effect of hormones on well-being was considered. METHODS: Cross-sectional data from participants of the KORA-Age study (n=985, age 64-93) was analyzed in sex-specific multivariable regressions of well-being (World Health Organization (WHO) -5) or ill-being (geriatric depression scale (GDS) -15). Models were adjusted for age, physical activity, sleep, BMI, smoking, and cognition. Adjusted WHO-5 means demonstrated the interaction between hormone quintiles with physical activity. RESULTS: Full models indicated that increased IGFBP-3 positively associated with well-being in women (ß estimate=0.14, standard error (SE)=0.06) and less so in men (ß=0.11, SE=0.07). IGF-I associated positively with depression (ß=0.11, SE=0.06) and negatively with well-being (ß=-0.11, SE=0.06) in women. Similar but not statistically discernable effects were observed in men. Adjusted mean WHO-5 scores illustrated the positive effect of physical activity and IGFBP-3 on well-being in women only. CONCLUSIONS: Opposite and independent associations of IGF-I and IGFBP-3 on well-being observed in women suggests neuroprotective effects of IGFBP-3 in age.

Food intake regulating hormones in adult craniopharyngioma patients.

INTRODUCTION: Patients with craniopharyngioma (CP) have disturbances of the hypothalamic-pituitary axis and serious comorbidities such as obesity. We hypothesized that the secretion of hormones regulating the nutritional status is altered in adult patients with CP compared with patients with non-functioning pituitary adenoma (NFPA). METHODS: WE INCLUDED 40 CP (50% MALES, MEAN AGE: 49.6±14.3 years) and 40 NFPA (72.5% males, mean age: 63.4±9.8 years) patients. We measured glucose, insulin, leptin, total ghrelin, peptide-YY (PYY) and cholecystokinin (CCK) during oral glucose tolerance test (OGTT). Fat mass (FM) was determined by dual X-ray absorptiometry. RESULTS: Gender distribution was not significantly different, but CP patients were significantly younger (P<0.001). CP patients had significantly higher BMI and FM than NFPA patients (BMI 32±8 vs 28±4 kg/m(2), P=0.009 and FM 37±9 vs 33±9%, P=0.02). Fasting glucose level (84±12 vs 78±11 mg/dl, P=0.03), leptin (27.9±34.2 vs 11.9±11.6 µg/l, P=0.008) and leptin levels corrected for percentage FM (0.66±0.67 vs 0.32±0.25 µg/l%, P=0.005) were significantly higher in CP than in NFPA patients, whereas ghrelin was significantly lower (131±129 vs 191±119 ng/l, P=0.035). Insulin, PYY and CCK did not differ significantly between groups. After glucose load, leptin decreased significantly in CP patients (P=0.019). In both groups, ghrelin decreased significantly during OGTT (both P<0.001). The percentage decline was significantly smaller for CP. PYY and CCK increased equally after glucose in both groups. CONCLUSION: Our patients with CP have more metabolic complications than our patients with NFPA. The levels of leptin and ghrelin at fasting status and after glucose seem to be altered in CP, whereas changes in insulin, PYY and CCK do not seem to be responsible for the metabolic changes in these patients.

Novel use of endogenous GH-measurement directly after transsphenoidal microsurgery in acromegaly treated with pegvisomant.

OBJECTIVE: The GH receptor antagonist pegvisomant is increasingly used as therapy in acromegaly. Pituitary surgery might be indicated on pegvisomant treatment, due to side effects, adenoma growth or intention to cure after primary treatment. This study was initiated to clarify if, and when, GH measurement could be useful postoperatively with an assay specific for endogenous GH that does not cross-react with pegvisomant. METHODS: This study was designed as a prospective study in 2006 with the German Pituitary Working Group. Only 2 cases with potentially resectable adenomas from the German Pegvisomant Observational Study (GPOS) had been operated. Now with a post-operative follow-up of more than 5 years in these 2 cases, the usefulness of immediate pre-operative GH measurement shortly after pegvisomant treatment was evaluated. RESULTS: In both patients a steep decline of endogenous GH after transnasal microsurgery could be proven by using the special GH assay after near radical or radical removal, of the GH secreting adenomas respectively. Conventional GH assays showed no effect. GH half-life was more than 20 min in the patient with a small invasive residual adenoma and less than 20 min in the cured patient. Endogenous GH-levels declined to less than 1 ng/ml in the days after surgery in the patient with long-term cure. CONCLUSION: Measurement of endogenous GH in this special subgroup of patients under pegvisomant therapy can be used to decide upon early reoperation. Thus the beneficial effect of pegvisomant on acromegalic symptoms can be kept without interfering with post-operative monitoring of GH levels.

Hypertension and depressed symptomatology: a cluster related to the activation of the renin-angiotensin-aldosterone system (RAAS). Findings from population based KORA F4 study.

CONTEXT: Preliminary evidence points to aldosterone being not only prominently involved in the systemic regulation of the blood pressure but also to play a role in the pathophysiology of depression. OBJECTIVE: We evaluated whether the combination of hypertension and depressed symptomatology is useful to screen for individuals suffering an activation of the renin-angiotensin-aldosterone system (RAAS). DESIGN: We conducted a cross-sectional analysis in participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study conducted between 2006 and 2008 in Southern Germany. A total of 1805 participants of the F4 study were included in the study. METHODS: The association between aldosterone and renin levels and the different combinations of hypertension and depressed symptomatology was examined in four different models of multiple linear regression adjusted for age, sex, creatinine levels, potassium levels, body mass index (BMI) and behavioural risk factors. RESULTS: Individuals suffering both, depressed symptomatology and hypertension exhibited highly significantly increased aldosterone levels (p<0.001) and slightly, not significantly increased renin levels (p=0.08) compared to individuals with no depressed symptomatology and no hypertension. No significant activation of the RAAS was seen in only depressed or only hypertensive individuals. CONCLUSIONS: The finding of highly significantly increased aldosterone levels and increased renin levels in individuals suffering both, depressed symptomatology and hypertension provides further evidence for the involvement of the RAAS in the pathogenesis of depressed symptomatology. These findings have important implications for future research concerning the pathophysiological pathways that link depression and cardiovascular disease.

Assay characteristics influence the aldosterone to renin ratio as a screening tool for primary aldosteronism: results of the German Conn's registry.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. The aldosterone to renin ratio (ARR) is the gold standard for screening, but variability between biochemical methods used remains of concern. The aim of the study was to analyze center-specific features of biochemical diagnostic strategies prior to the 2008 consensus within the German Conn's Registry. The study was designed as a retrospective study in 5 tertiary care hospitals. Patients analyzed for PA between 1990 and 2006 were studied. Characteristics of the assays used to determine ARR during establishing the diagnosis of PA were analyzed in the retrospective part of the German Conn's Registry. Eighty-six out of 484 documented ARR values had to be excluded from further evaluations because the laboratory or the assays were unknown. In the remaining 398 patients ARR was determined using 10 different assay combinations in the centers (aldosterone plus plasma renin activity or concentration). Considerable differences were seen between the mean concentrations for aldosterone (p<0.0001), renin concentration (p<0.001), and renin activity (p=0.009) for the different assays. The differences between the absolute concentrations measured by the different assays also had significant impact upon the resulting mean ratios. If published cutoff values are applied, the use of different commercial assays to determine the ARR in clinical routine results in major differences in positive screening rates. This heterogeneity affects sensitivity and specificity of screening for PA. Our data emphasize the importance of standardized screening procedures, which must include standardization of biochemical methods.

Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.

CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 µg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies.

OBJECTIVE: The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects. METHODS: Data were obtained from the first follow-ups of the population-based study of health in Pomerania (SHIP; n=1392) and the cooperative health research in the region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies.Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC. RESULTS: The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects. CONCLUSIONS: A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients.

Association of IGF-I and the IGF-I/IGFBP-3 ratio with plasma aldosterone levels in the general population.

Several studies in patients with acromegaly or growth hormone (GH) deficiency suggest a stimulatory effect of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis on the renin-angiotensin-aldosterone system (RAAS). We analyzed the association of serum IGF-I with plasma aldosterone and the aldosterone-to-renin ratio in a large sample from the general population. In addition to serum IGF-I levels, we also considered the IGF-I-to-IGF binding protein (IGFBP)-3 ratio. A total of 1 504 men and 1 566 women aged 25-88 were selected from the first follow-up of the population-based Study of Health in Pomerania. Plasma aldosterone and renin concentrations, as well as serum IGF-I and IGFBP-3 levels were determined with immunoassays. Analyses of variance and linear regression analyses were performed. We found positive associations between serum IGF-I or the IGF-I/IGFBP-3 ratio with plasma aldosterone in women but not in men. Plasma aldosterone levels increased by 2.91 ng/l per IGF-I standard deviation (SD) and by 2.17 ng/l per IGF-I/IGFBP-3 SD. The associations remained significant after exclusion of subjects taking RAAS-altering medication and of subjects with serum IGF-I levels and aldosterone-to-renin ratios outside the reference range. We conclude that, serum IGF-I and the IGF-I/IGFBP-3 ratio are associated with plasma aldosterone levels in women but not in men from the general population.

Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial.

CONTEXT: With adequate dose titration, pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients. OBJECTIVE: The aim of the study was to investigate the efficacy of cabergoline monotherapy and pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial. MAIN OUTCOME MEASURE: We measured the change in serum IGF-I. RESULTS: After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monotherapy did not significantly reduce IGF-I (454 ± 219 baseline vs. 389 ± 192 ng/ml cabergoline), although two patients did normalize IGF-I. The addition of 10 mg pegvisomant daily for 12 wk significantly reduced IGF-I (389 ± 192 ng/ml cabergoline vs. 229 ± 101 ng/ml combination), and 68% achieved a normal IGF-I. Twelve weeks after cabergoline withdrawal, while continuing to receive pegvisomant 10 mg, only 26% of patients maintained an IGF-I within the reference range (229 ± 101 ng/ml combination vs. 305 ± 177 ng/ml pegvisomant). There were no significant changes in liver transaminases or glucose metabolism throughout the study. CONCLUSION: These data suggest that combination treatment with cabergoline and pegvisomant is more effective at reducing IGF-I levels than either cabergoline or pegvisomant monotherapy.

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.

To live alone and to be depressed, an alarming combination for the renin-angiotensin-aldosterone-system (RAAS).

INTRODUCTION: The renin-angiotensin-aldosterone-system (RAAS) is one of the most important systems involved in the pathogenesis of cardiovascular diseases. Its role in stress response has been generally neglected, although the progression of cardiovascular disease is considerably increased in the presence of stress and especially in the presence of depression risk. With the present analysis we aimed to evaluate whether the activity of the RAAS correlates with depressive symptomatology and with chronic stress. Moreover, we aimed to analyse whether stress response is altered in the presence of depressed symptomatology. We chose "living alone" to be our paradigm of chronic stress. METHODS AND RESULTS: Aldosterone and renin levels were assessed in 1743 (829 men, 914 women) from the population-based KORA study (Cooperative Health Research in the Region of Augsburg). The relationship between aldosterone, renin levels and the different combinations of living alone and depressive symptomatology was examined in three different multiple linear regression models adjusted for age, sex, creatinine levels, potassium levels, body mass index (BMI) and bio-behavioural factors. Neither "living alone" nor depressive symptomatology alone were associated with an activation of the RAAS, but the combination of living alone and depressive symptomatology yielded a highly significant increase in the aldosterone (p<0.01) and renin level (p=0.03). CONCLUSION: Our findings show that depressive symptomatology is associated with a hyper-responsiveness to chronic stress. Under the condition of chronic stress depressed individuals have an activated RAAS. Activation of the RAAS might explain the known increased risk of negative cardiovascular disease outcomes in this group.

A case of an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage.

BACKGROUND: The competitive GH receptor antagonist pegvisomant is reported to normalise IGF-1 levels in up to 97 % of acromegalic patients at a maximum dosage of 40 mg/d. Description of Case: We present an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage. The 60-year-old male patient presenting with typical clinical signs of acromegaly has underwent multiple transsphenoidal surgeries and pituitary irradiation, while currently available pharmacological therapies for acromegaly have been exhausted. RESULTS: Biochemical control of the disease could only be achieved until uptitration of pegvisomant to 60 mg/d which was tolerated well. CONCLUSIONS: The current treatment algorithm for acromegaly should be modified to treat cases of persistent and uncontrolled disease.