Pro- and anti-inflammatory macrophages express a sub-type specific purinergic receptor profile.

Extracellular nucleotides act as danger signals that orchestrate inflammation by purinergic receptor activation. The expression pattern of different purinergic receptors may correlate with a pro- or anti-inflammatory phenotype. Macrophages function as pro-inflammatory M1 macrophages (M1) or anti-inflammatory M2 macrophages (M2). The present study found that murine bone marrow-derived macrophages express a unique purinergic receptor profile during in vitro polarization. As assessed by real-time polymerase chain reaction (PCR), Gαs-coupled P1 receptors A2A and A2B are upregulated in M1 and M2 compared to M0, but A2A 15 times higher in M1. The ionotropic P2 receptor P2X5 is selectively upregulated in M1- and M2-polarized macrophages. P2X7 is temporarily expressed in M1 macrophages. Metabotropic P2Y receptors showed a distinct expression profile in M1 and M2-polarized macrophages: Gαq coupled P2Y1 and P2Y6 are exclusively upregulated in M2, whereas Gαi P2Y13 and P2Y14 are overexpressed in M1. This consequently leads to functional differences between M1 and M2 in response to adenosine di-phosphate stimulation (ADP): In contrast to M1, M2 showed increased cytoplasmatic calcium after ADP stimulation. In the present study we show that bone marrow-derived macrophages express a unique repertoire of purinergic receptors. We show for the first time that the repertoire of purinergic receptors is highly flexible and quickly adapts upon pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.

Influence of disease control with pegvisomant on sleep apnoea and tongue volume in patients with active acromegaly.

OBJECTIVES: Sleep apnoea has been consistently reported to occur in acromegaly. In uncontrolled patients, the severity of sleep apnoea influences physical activity in the daytime. We investigated the influence of disease activity on tongue volume and sleep apnoea treated with the GH receptor antagonist pegvisomant in poorly controlled patients with acromegaly under octreotide. DESIGN AND METHODS: A total of 12 patients with active acromegaly (six females; six males; mean age 57+/-15 years; body mass index 29.4+/-4.2 kg/m(2); mean+/-S.D.) were treated with pegvisomant (13.5+/-5.0 mg/die) for 6 months. Tongue volume was examined by magnetic resonance imaging, and sleep apnoea was characterized by polysomnography before and after 6 months of treatment with pegvisomant. The mandibular length was determined by lateral X-ray films. RESULTS: IGF1 levels decreased after 6 months in all patients (407+/-114 to 199+/-23 microg/l; P=0.0001). The tongue volume decreased (105+/-33 to 83+/-33 ml; P=0.007) as well as the apnoea-hypnoea index (23+/-22 to 18+/-18/h; P=0.0066). The mandibular length correlated with the initial tongue volume (r(2)=0.6072, P=0.0028). CONCLUSION: In conclusion, successful treatment with pegvisomant can decrease tongue volume, which has benefits for coexisting sleep disordered breathing.

From isolated GH deficiency to multiple pituitary hormone deficiency: an evolving continuum - a KIMS analysis.

OBJECTIVE: To describe baseline clinical presentation, treatment effects and evolution of isolated GH deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) in adult-onset (AO) GHD. DESIGN: Observational prospective study. METHODS: Baseline characteristics were recorded in 4110 patients with organic AO-GHD, who were GH naïve prior to entry into the Pfizer International Metabolic Database (KIMS; 283 (7%) IGHD, 3827 MPHD). The effect of GH replacement after 2 years was assessed in those with available follow-up data (133 IGHD, 2207 MPHD), and development of new deficiencies in those with available data on concomitant medication (165 IGHD, 3006 MPHD). RESULTS: IGHD and MPHD patients had similar baseline clinical presentation, and both groups responded similarly to 2 years of GH therapy, with favourable changes in lipid profile and improved quality of life. New deficiencies were observed in 35% of IGHD patients, which was similar to MPHD patients with one additional deficit other than GH. New deficiencies most often presented within the first year but were observed up to 6 years after GH commencement. Conversion of IGHD into MPHD was not predicted by aetiology, baseline characteristics, surgery or radiotherapy, whereas in MPHD additional deficits were predicted by age (P<0.001) and pituitary disease duration (P<0.01). CONCLUSION: Both AO-IGHD and -MPHD patients have similar baseline clinical presentation and respond equally well to 2 years of GH replacement. Hypopituitarism in adults seems to be a dynamic condition where new deficiencies can appear years after the initial diagnosis, and careful endocrine follow-up of all hypopituitary patients, including those with IGHD, is warranted.

The German ACROSTUDY: past and present.

Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible. As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging. Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients. In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.

Pituitary tumor size in acromegaly during pegvisomant treatment: experience from MR re-evaluations of the German Pegvisomant Observational Study.

In treatment-resistant patients with acromegaly, pharmacotherapy with pegvisomant (Somavert) is a highly effective option. However, safety concerns have been raised related to a potential increase in tumor size during long-term pegvisomant treatment. Therefore, neuroradiological monitoring of tumor extension and volume was performed in the German Pegvisomant Observational Study, which covers 87% of patients treated with pegvisomant in Germany. As of 15 July 2007, a total of 307 patients (156 males and 151 females) had been included in the study and were on pegvisomant therapy for an average of 86.7 weeks. Median and mean doses of pegvisomant were 15 and 16.6 mg/day respectively. Out of these 307 patients, 18 were reported to have tumor-size increases as adverse events. From these 18 patients, all available serial magnetic resonance images were collected. Identical or similar sequences were chosen and the region of interest was magnified and compared across time after the best possible fit had been achieved by size and gray-scale correction. All available images were carefully re-evaluated according to this method. In 10 out of the 18 patients, there was no evidence of tumor-size increase, when the pre-treatment scans were compared with the most recent follow-up investigations. In two out of the remaining eight patients, there was a rebound effect observed after withdrawal of somatostatin analog treatment, but no further progression. In another three out of the eight patients, tumor-size increase had already been documented before pegvisomant treatment was commenced, during preceding somatostatin analog treatment and continued therapy. In the last three patients, tumor progression after the start of pegvisomant treatment was confirmed. All three patients had undergone pituitary surgery as primary treatment, but had not been pre-treated with radiotherapy. In all three cases, the tumor increase was not considered clinically significant and the investigators decided to continue pegvisomant treatment. In conclusion, in this large group of pegvisomant-treated patients, tumor progression was rare. It was reported in between 2 and 3% of patients treated, and did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. In over one-half of patients, reports of tumor increase could not be confirmed by re-evaluation. This was mostly due to non-identical gantry projections. Misjudgements mainly occurred when only images from two individual investigations, rather than the entire series of scans, were compared. Thus, we recommend a careful serial evaluation of all available images to avoid misinterpretations and erroneous alerts. As from this presently largest database of acromegalic patients treated with pegvisomant, tumor-growth rate appears not to be different from patients on other treatment modalities. Although these data are reassuring with regard to the concern of somatotroph adenoma growth under peripheral GH receptor blockade, further study is required.

Diagnosing neuroendocrine dysfunction in patients after aneurysmal subarachnoid hemorrhage in clinical practice - does basal hormone screening make sense?

Recent studies indicate that neuroendocrine dysfunction is a more frequent sequel of aneurysmal subarachnoid hemorrhage (SAH), than has so far been recognized. However, from the available data it remains unclear whether certain subgroups of SAH patients carry a higher risk to sustain endocrine sequelae due to the hemorrhage than others and should be specifically followed up in terms of hormone assessment. To investigate whether a basal hormone screening is a practical method in clinical routine to single out patients in whom endocrine function testing is warranted, we established a screening protocol, based on the findings from a cohort of 40 SAH patients (study group) who had all been investigated by basal hormone para meters as well as standardized endocrinological function testing, within the framework of a previously published clinical study. We then applied this protocol to 45 newly investigated SAH-patients (screening group). According to the thus established protocol, 20 of the 45 screened patients (44.4 %) were recommended further investigations, 12 of whom agreed to undergo dynamic endocrine function testing. Altogether, the percentage of test-confirmed neuroendocrine dysfunction was only 13.3 % (6/ 45) in the screening group as compared to 55 % in the study group. Low IGF-I (2 SD below normal) did not serve to predict growth hormone deficiency, whereas low 9 am serum cortisol was of limited value to single out ACTH-deficiency in SAH-patients. In summary we conclude that basal hormone screening is not sufficient to identify SAH patients with impaired hypothalamo-pituitary function, at least not in the context of clinical routine practice.

High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels.

OBJECTIVE: The estimated prevalence of acromegaly is 40-125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known how many subjects with increased IGF-1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF-1 levels. DESIGN: A cross-sectional, epidemiological study (the DETECT study). Patients A total of 6773 unselected adult primary care patients were included. MEASUREMENTS: We measured IGF-1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF-1 levels (> 2 age-dependent SDS). RESULTS: Of 125 patients with elevated IGF-1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients. CONCLUSIONS: Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.

Predictors of anterior pituitary insufficiency after traumatic brain injury.

BACKGROUND: Several studies have reported a high prevalence of hypopituitarism after traumatic brain injury (TBI). Risk stratification is a prerequisite for cost-effective hormonal screening of these patients. However, it is still unclear which risk factors predispose patients to develop anterior hypopituitarism after TBI. OBJECTIVE: To assess clinical and radiological risk factors for post-traumatic hypopituitarism. PATIENTS AND METHODS: Seventy-eight consecutive patients (52 men, 26 women; mean age 36.0 years, range 18-65 years) with mild, moderate or severe TBI were studied. Endocrine and clinical parameters were assessed 3 and 12 months after TBI. RESULTS: We found diffuse axonal injury, basal skull fracture and older age to be major risk factors of post-traumatic hypopituitarism. CONCLUSIONS: We have defined specific risk factors for the development of post-traumatic hypopituitarism that are consistent with pathophysiological considerations. These findings might help to identify at-risk patients.

Differential T4 degradation pathways in young patients with preterminal and terminal renal failure.

INTRODUCTION: The aim of this study is to analyze thyroid hormone parameters in large homogenous patient cohorts with preterminal (stage 4) and terminal (stage 5) renal failure in an area of low iodine intake. PATIENTS AND METHODS: Thyroid parameters were measured in healthy controls (n=48), patients with preterminal renal failure (n=48) and patients with terminal renal failure undergoing hemodialysis (n=288). All patients were assessed by measurement of TSH, T4, T3, fT4, rT3, Tg and TPO-antibodies. RESULTS: There was a significant decrease of T4 and fT4 from healthy controls to patients with preterminal renal failure and to patients with terminal renal failure. T3 showed a decrease from healthy controls to patients with preterminal renal failure and to patients with terminal renal failure (1.54+/-0.06 microg/l VS. 1.05+/-0.05 microg/l VS. 1.09+/-0.23 microg/l, p<0.001 VS. controls). rT3 was significantly decreased in patients with terminal renal failure (0.24+/-0.01 microg/l VS. 0.25+/-0.02 microg/l VS. 0.16+/-0.01 microg/l, p<0.001). The rT3/T3 ratio was significantly elevated in patients with preterminal renal failure (p<0.01). TSH concentrations were in the normal range in all groups. CONCLUSION: Our data suggest different T4 degradation pathways in patients with preterminal and terminal renal failure.

Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study.

OBJECTIVE: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. DESIGN: GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection. METHODS: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. RESULTS: IGF-I levels decreased from 1.75+/-0.91-fold the upper limit of normal at baseline to 1.05+/- 0.62 at the 6-month visit, 0.96+/-0.60 at the 12-month visit, and to 0.89+/-0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8+/-35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4+/-45.9 to 101.5+/- 42.8 mg/dl after 6 months (P<0.01) and to 100.6+/-33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. CONCLUSIONS: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.

Effects of growth hormone treatment on B-type natriuretic peptide as a marker of heart failure in adults with growth hormone deficiency.

OBJECTIVE: Patients with growth hormone deficiency (GHD) have abnormalities of cardiac structure and function. Growth hormone replacement (GHR) therapy can induce an increase in cardiac mass and improvement in left ventricular ejection fraction. B-type natriuretic peptide (BNP) levels have been successfully used to identify patients with heart failure and they correlate with both disease severity and prognosis. DESIGN: To investigate the effect of growth hormone replacement on BNP and inflammatory cardiovascular risk factors in adults with GHD we determined NT-proBNP and high sensitive C-reactive protein (CrP) before, 6 and 12 months after GHR. PATIENTS: Thirty adults (14 males, 16 females) with GHD mean age: 41.7+/-14.5 years (range: 17.2 to 75.4 years) were recruited from the German KIMS cohort (Pfizer's International Metabolic Database). RESULTS: During 12 months of GHR, a significant increase of IGF-1 (85.4+/-72.1 VS. 172.0+/-98 mug/dl; p=0.0001; IGF-1 SDS mean+/-SD: -3.85+/-3.09 VS. -0.92+/-1.82) was detectable. Mean baseline NT-proBNP was 112+/-130 pg/ml (range: 7 to 562). Twelve patients had normal BNP, whereas 18 revealed NT-proBNP values corresponding to those of patients with heart failure NYHA classification I (n=10), NYHA II (n=6) and NYHA III (n=2), respectively. Baseline BNP levels correlated significantly (p=0.044) with increased baseline CrP values. After 12 months of GHR, a significant decrease (p=0.001) in NT-proBNP levels mean: 68+/-81 pg/ml (range: 5 to 395) was detectable, associated with an improvement in NYHA performance status in 10 of the 18 with increased baseline NT-proBNP. CONCLUSIONS: Based on our study, approximately two-thirds of patients with GHD have increased NT-proBNP levels which may be useful as screening/diagnostic laboratory parameter for heart failure in such patients. GHR therapy decreases BNP levels in most patients with GHD.

Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active hepatitis.

OBJECTIVE: The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy. DESIGN AND METHODS: Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transaminases was reported spontaneously and the other patients were treated in a clinical study. RESULTS: Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3 +/- 19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes. CONCLUSIONS: Liver function tests should be regularly followed on pegvisomant treatment. Biliary complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.

Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury.

OBJECTIVE: Cross-sectional studies report a high prevalence of hypopituitarism after traumatic brain injury (TBI); however, no longitudinal studies on time of manifestation and reversibility exist. This study was conducted to assess hypopituitarism 3 and 12 months after TBI. DESIGN: This was a prospective, longitudinal, diagnostic study. METHODS: Seventy-eight patients (52 men, 26 women, mean age 36.0 years) with TBI grades I-III and 38 healthy subjects (25 men, 13 women, mean age 36.4 years) as a control group for the GHRH + arginine test were studied. The prevalence of hypopituitarism was assessed 3 and 12 months after TBI by GHRH + arginine test, short adrenocorticotropic hormone (ACTH) test, and basal hormone measurements in patients. RESULTS: After 3 months, 56% of all patients had impairments of at least one pituitary axis with axes being affected as follows: gonadotropic 32%, corticotropic 19%, somatotropic 9% and thyrotropic 8%. After 12 months, fewer patients were affected, but in some cases new impairments occurred; 36% still had impairments. The axes were affected as follows after 12 months: gonadotropic 21%, somatotropic 10%, corticotropic 9% and thyrotropic 3%. CONCLUSIONS: Hypopituitarism occurs often in the post-acute phase after TBI and may normalize later, but may also develop after the post-acute phase of TBI.

Effects of a combination of rhGH and metformin on adiponectin levels in patients with metabolic syndrome.

Adiponectin is a recently discovered adipocytokine that correlates negatively with body mass index and body fat. In patients with GH deficiency, treatment with recombinant human growth hormone (rhGH) reduces body fat mass and thus may also have a favorable effect in patients with metabolic syndrome, and would also be expected to increase adiponectin levels. However, due to its diabetogenic effect, rhGH treatment also bears an increased risk for the development of type 2 diabetes mellitus. We conducted a 18-month randomized, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (MGH) in 14 obese men (7 MGH; 7 Metformin+Placebo, 54 +/- 2 years, BMI 33.0 +/- 1.2 kg/m(2)) with mildly elevated fasting plasma glucose (FPG) at screening (6.1-8.0 mmol/l). All patients received metformin (850 mg twice daily) for treatment of type 2 diabetes mellitus/impaired glucose tolerance, either alone or in combination with rhGH (daily dose 9.5 mug/kg body weight). Glucose disposal rate (GDR) was measured using the euglycemic hyperinsulinemic clamp technique, and body composition was measured by DEXA at 0 and 18 months. After 18 months, the mean adiponectin concentration increased by 32 +/- 11 % (p = 0.018) in the MGH group and did not change in the MP group (- 10 +/- 13 %; p = n. s.). The difference in relative changes in adiponectin levels between the two groups after 18 months was statistically significant (p = 0.026). Improvement in insulin sensitivity (GDR) correlated positively with adiponectin levels (r = 0.73; p = 0.004). In conclusion, the additional administration of rhGH increased adiponectin levels in patients with metabolic syndrome, indicating its potential role in adiponectin-associated insulin sensitivity alterations.

Insulin sensitivity and coronary vasoreactivity: insulin sensitivity relates to adenosine-stimulated coronary flow response in human subjects.

OBJECTIVE: Diabetes is associated with coronary microvasculature abnormalities and impaired coronary flow reserve (CFR). CFR is the ratio of coronary flow under maximal vasodilation to basal flow and is a measure for coronary vasoreactivity. Insulin resistance is the central defect in the development of type 2 diabetes, preceding its onset by 10-20 years. Thus, the relationship between insulin sensitivity and CFR in nondiabetic subjects is particularly interesting. The aim of the study was to investigate this relationship. DESIGN: Cross-sectional study. PATIENTS: The study population consisted of 18 nondiabetic subjects without coronary artery stenosis on coronary angiography. We excluded patients with structural heart disease or with conditions affecting CFR or insulin sensitivity such as low density lipoprotein (LDL)-cholesterol > or = 4.14 mmol/l, smoking, hypertension or obesity with a body mass index (BMI) > 28 kg/m(2). MEASUREMENTS AND RESULTS: CFR was 3.1 +/- 0.8 (range 1.7-4.8), as assessed by intracoronary Doppler measurements in the left anterior descending coronary arteries after adenosine stimulation. Intravascular ultrasound revealed zero to moderate coronary atherosclerotic changes. Whole-body insulin sensitivity (M-value) was 7.5 +/- 2.9 mg/kg/min (range 2.2-12.6), as assessed by the hyperinsulinaemic-euglycaemic clamp test. Subjects with low CFR (< 3.0) had a significantly lower M-value than subjects with normal CFR (> 3.0) (6.0 +/- 2.5 vs. 9.0 +/- 2.5 mg/kg/min, P = 0.021). Univariate linear regression demonstrated a strong correlation between CFR and M-value (r = 0.76, P < 0.001). In multiple regression analysis, the significant association of CFR with M-value was independent of potential confounders (sex, age, BMI, LDL-cholesterol and plaque burden on intravascular ultrasound). Bootstrap analysis corroborated this finding. CONCLUSIONS: Whole-body insulin sensitivity relates to coronary vasoreactivity. Across a wide range of both insulin sensitivity and coronary flow reserve from markedly abnormal to normal values, an increase in insulin sensitivity appears to be associated with an increase in coronary flow reserve. Insulin resistance is therefore associated with coronary microvasculature abnormalities in nondiabetics.

Effects of a combination of recombinant human growth hormone with metformin on glucose metabolism and body composition in patients with metabolic syndrome.

Abdominal obesity and insulin resistance are central findings in metabolic syndrome. Since treatment with recombinant human growth hormone (rhGH) can reduce body fat mass in patients with organic GH deficiency, rhGH therapy may also have favourable effects on patients with metabolic syndrome. However, due to the highly increased risk for type 2 diabetes in these patients, strategies are needed to reduce the antagonistic effect of rhGH against insulin. We conducted a 18-month randomised, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (Met) in patients with metabolic syndrome. 25 obese men (55 +/- 6 years, BMI 33.4 +/- 2.9 kg/m (2)) with mildly elevated fasting plasma glucose (FPG) levels at screening (6.1-8.0 mmol/l) were included. All patients received metformin (850 mg twice daily) either alone or in combination with rhGH (daily dose 9.5 microg/kg body weight). An oGTT was performed at baseline, after 6 weeks, and after 3, 6, 12, and 18 months of therapy. Glucose disposal rate (GDR) was measured by euglycemic hyperinsulinemic clamp at 0 and 18 months and body composition was measured by DEXA every 6 months. In the Met + GH group, IGF-I increased from 146 +/- 56 microg/l to 373 +/- 111 microg/l (mean +/- SD) after 3 months and remained stable after that. BMI did not change significantly in either group during the study. Total body fat decreased by -4.3 +/- 5.4 kg in the Met + GH group and by -2.7 +/- 2.9 kg in the Met + Placebo group (differences between the two groups: p = n. s.). Waist circumference decreased in both groups (Met + GH: 118 +/- 8 cm at baseline, 112 +/- 10 cm after 18 months; Met + Placebo: 114 +/- 7 cm vs. 109 +/- 8 cm; differences between the two groups: p = 0.096). In the Met + GH group, FPG increased significantly after 6 months (5.9 +/- 0.7 vs. 6.7 +/- 0.4 mmol/l; p = 0.005), but subsequently decreased to baseline levels (18 months: 5.8 +/- 0.2 mmol/l). FPG remained stable in the Met + Placebo group until 12 months had elapsed, and then slightly decreased (baseline: 6.2 +/- 0.3, 18 months: 5.5 +/- 0.6 mmol/l, p = 0.02). No significant changes were seen in either group regarding glucose and insulin AUC during oGTT or HbA (1c) levels. GDR at 18 months increased by 20 +/- 39% in Met + GH-group and decreased by -11 +/- 25% in the Met + Placebo group (differences between the two groups: p = 0.07). In conclusion, treatment of patients with metabolic syndrome and elevated FPG levels did not cause sustained negative effects on glucose metabolism or insulin sensitivity if given in combination with metformin. However, since our data did not show significant differences between the two treatment groups with respect to body composition or lipid metabolism, future studies including larger numbers of patients will have to clarify whether the positive effects of rhGH on cardiovascular risk factors that have been shown in patients with GH deficiency are also present in patients with metabolic syndrome, and are additive to the effects of metformin.

Effects of acute prolactin manipulation on sexual drive and function in males.

The neuroendocrine response to sexual activity in humans is characterized by a pronounced orgasm-dependent increase of plasma levels of prolactin. In contrast to the well-known inhibitory effects of chronic hyperprolactinemia on sexual drive and function, the impact of acute prolactin alterations on human sexual physiology is unknown. Therefore, this study was designed to investigate the effects of acute manipulation of plasma prolactin on sexual behavior. Ten healthy males participated in a single-blind, placebo-controlled, balanced cross-over design. Prolactin levels were pharmacologically increased to high levels (protirelin, 50 micro g i.v.) or reduced to low physiological concentrations (cabergoline, 0.5 mg p.o.). Sexual arousal and orgasm were then induced by an erotic film and masturbation. In addition to continuous neuroendocrine and cardiovascular recordings, the quality and intensity of the acute sexual drive, arousal, orgasm and refractory period were assessed by extensive psychometric measures. Administration of cabergoline decreased prolactin levels and significantly enhanced all parameters of sexual drive (P<0.05), function (P<0.01) and positive perception of the refractory period (P<0.01). Administration of protirelin increased prolactin concentrations and produced small, but not significant reductions of sexual parameters. The sexual effects observed from cabergoline were completely abrogated by coadministration of protirelin. Although different pharmacological sites of action of prolactin-altering drugs have to be considered, these data demonstrate that acute changes in prolactin plasma levels may be one factor modulating sexual drive and function. Therefore, besides a neuroendocrine reproductive reflex, a post-orgasmic prolactin increase may represent one factor modulating central nervous system centers controlling sexual drive and behavior. These findings may offer a new pharmacological approach for the treatment of sexual disorders.

Myocardial perfusion abnormalities in patients with active acromegaly.

Cardiomyopathy is often seen in patients with a long history of acromegaly. In order to screen for perfusion abnormalities, patients with active acromegaly without evidence for coronary heart disease were examined by single photon emission computed tomography (SPECT). The study included a group of 11 strictly selected patients with active acromegaly (7 males and 4 females; age 51 +/- 12 y [mean +/- S.D.]) with elevated age-adjusted IGF-I levels (IGF-I 569 +/- 193 micro g/l; GH 31.2 +/- 56.3 micro g/l) compared to an age- and sex-matched non-acromegalic control group with comparable muscle mass index of the left ventricle (126 +/- 41 active vs. 122 +/- 33 g/m 2 control group) and body mass index (26.6 +/- 2.7 vs. 27.0 +/- 5.0 kg/m 2). To address this issue, myocardial perfusion was investigated by single photon emission computed tomography (SPECT) using a triple head gamma-camera. 70 MBq 201TlCl was injected, and post-stress (from bicycle ergometer) images were obtained. Images were interpreted quantitatively by bull's eye polary map (16 regions of the left ventricle) and were compared to the control group. In the patients with active acromegaly, the mean nuclide uptake of the 16 regions of the left ventricle after bicycle stress examination was lower than in the control group (82.99 +/- 2.85 active vs 85.48 +/- 1.29 control group, p < 0.01). Non-homogeneity of nuclide uptake was defined as the standard deviations of the 16 regions and was higher in patients with active acromegaly (11.11 +/- 2.35 active vs. 8.77 +/- 1.39 control group, p < 0.01). In conclusion, myocardial perfusion is impaired in patients with active acromegaly, thus representing an early stage of cardiac involvement in acromegaly that may be directly mediated by growth hormone excess.

Glucose and lipid metabolism in young lean normotensive males with the G protein beta3 825T-allele.

The 825T-allele of the C825T polymorphism in GNB3, the gene for the G protein beta3 subunit, has been reported to be associated with essential hypertension and obesity. Expression of Gbeta3s, the gene product of GNB3 associated with the GNB3 825T-allele, causes increased signal transduction which may contribute to pathogenetic mechanisms ultimately resulting in hypertension and obesity. Given the known involvement of heterotrimeric G proteins in insulin secretion and insulin action on the cellular level, we analysed insulin sensitivity in each 15 young lean normotensive males with TC- and CC-genotypes, respectively. Blood glucose and serum insulin samples were taken during a standard oral glucose tolerance test. Insulin-stimulated glucose disposal was analysed by euglycemic-hyperinsulinemic clamp. Both groups did not differ with regard to the time-courses for glucose or insulin concentrations in the oral glucose tolerance test. Furthermore, insulin-stimulated glucose disposal was virtually independent of genotype. The TC-genotype is not associated with a primary defect in insulin secretion or sensitivity suggesting that obesity and hypertension in carriers of 825T do not likely result from primary alterations in glucose and insulin homeostasis. However, GNB3 825T-associated obesity may predispose to insulin resistance, an issue which remains to be investigated. Furthermore, fasting cholesterol was significantly higher in TC compared to CC genotype (4.71 versus 3.96 mmol/l; p = 0.007) suggesting that enhanced G protein signalling might be associated with alterations of cholesterol metabolism.