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Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of 'one size fits all', and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects' genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

Purpose: The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing's disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA)., Methods: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated., Results: At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy., Conclusions: During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms.

Aim: The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non-adherence through circumventing the relatively complex temporal dosing scheme., Methods: Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil., Results: Formulation 2 had a higher maximum concentration (Cmax ) for testosterone, 8.06 ng ml(-1) (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng ml(-1)  h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml(-1) (95% CI 4.63, 6.69) and 5.12 ng ml(-1)  h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng ml(-1) (95% CI 126, 220) and a lower AUC, 476 ng ml(-1)  h (95% CI 401, 551) than formulation 1, 268 ng ml(-1) (95% CI 188, 348) and 577 ng ml(-1)  h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10)., Conclusions: The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing., What Is Already Known About This Subject: Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking. The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD. In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues., What This Study Adds: A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart. This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies., (© 2016 The British Pharmacological Society.)

Context: GH replacement therapy (GH-RT) is a widely accepted treatment in GH-deficient adults with nonfunctioning pituitary adenoma (NFPAs). However, some concerns have been raised about the safety of GH-RT because of its potentially stimulating effect on tumor growth., Objective: The aim of this study was to evaluate tumor progression in NFPA patients using GH-RT., Design, Setting, and Patients: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severely GH-deficient adults (1998-2009), all NFPA patients with ≥ 30 days of GH-RT were selected (n = 783). Data were retrospectively collected from the start of GH-RT in adulthood (baseline)., Main Outcome Measure: Tumor progression, including tumor recurrence after complete remission at baseline and regrowth of residual tumor., Results: Tumor progression developed in 12.1% of the patients after a median (range) time of 2.2 (0.1-14.9) years. Prior radiotherapy decreased tumor progression risk compared to no radiotherapy (hazard ratio = 0.16; 95% confidence interval, 0.09-0.26). Analysis in 577 patients with available baseline imaging data showed that residual tumor at baseline increased tumor progression risk compared to no residual tumor (hazard ratio = 4.5; 95% confidence interval, 2.4-8.2)., Conclusions: The findings in this large study were in line with those reported in literature and provide further evidence that GH-RT does not appear to increase tumor progression risk in NFPA patients. Although only long-term randomized controlled trials will be able to draw firm conclusions, our data support the current view that GH-RT is safe in NFPA patients.

Context: Radiotherapy is frequently administered as adjuvant treatment in patients with clinically nonfunctioning pituitary adenomas (NFPAs). However, concerns have been raised about potential long-term side effects, including cerebrovascular events (CVEs) and secondary intracranial tumors., Objective: The aim of this study was to analyze the risk of CVEs, secondary intracranial tumors, and mortality in irradiated (IRR) NFPA patients, compared with NFPA patients who were not irradiated (non-IRR)., Design, Setting, and Patients: The study cohort included 806 patients with a NFPA from the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide long-term surveillance study in severe GH-deficient adult patients. IRR patients (n = 456) were compared with non-IRR patients (n = 350)., Main Outcome Measures: CVEs, secondary intracranial tumors, and mortality were measured., Results: Sixty-nine subjects developed a CVE. In men, but not in women, the incidence of a CVE was significantly higher in IRR patients than in non-IRR patients (hazard ratio 2.99, 95% confidence interval 1.31-6.79). A secondary intracranial tumor developed in five IRR patients and two non-IRR patients. After adjustment for age, radiotherapy was not associated with mortality., Conclusions: The incidence of secondary intracranial tumors and mortality did not differ between IRR and non-IRR patients. However, a CVE was found significantly more frequently in IRR men but not in women. Further research into the long-term effects of cranial radiotherapy seems mandatory. The potential risks of radiotherapy have to be taken into account when radiotherapy is considered in NFPA patients, and long-term follow-up is recommended.

Objective: The effect of GH deficiency (GHD) on the metabolic profile of acromegaly patients is unclear in patients previously treated for acromegaly, as are the efficacy and safety of GH treatment in this particular group. The aim of the study is to describe the characteristics of patients with severe GHD who were previously treated for acromegaly, and to investigate the effects of long-term GH treatment on cardiovascular risk factors and morbidity, compared with patients who were treated for a nonfunctioning pituitary adenoma (NFPA)., Design: A nationwide surveillance study., Methods: Sixty-five patients from the Dutch National Registry of Growth Hormone Treatment in Adults with previous acromegaly were compared with 778 patients with previous NFPA. Cardiovascular indices, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity were investigated., Results: GHD patients with previous acromegaly had an unfavorable metabolic profile comparable with or more than GHD patients with previous NFPA. GH treatment led to improvement of the lipid profile in both groups, also after excluding patients using lipid-lowering medication. In patients with previous acromegaly, HbA1c levels increased more than in patients with previous NFPA (estimate 0.03, 95% CI 0.002-0.06, P=0.04). The risk for developing cardiovascular diseases was not different between the groups., Conclusions: The patients with GHD after previous acromegaly have an unfavorable metabolic profile comparable with patients with GHD after previous NFPA. In both groups, the lipid profile improves during GH treatment. Changes in glucose metabolism should be monitored closely. GH treatment in patients with GHD previously treated for acromegaly had no deleterious effect on cardiovascular morbidity., (© 2014 European Society of Endocrinology.)

Objective: Isolated GH deficiency (IGHD) could provide a model to investigate the influence of GH deficiency per se and the effect of GH replacement therapy without the influence from other pituitary hormone deficiencies or their treatment. The aim of this study is to address the questions about differences between IGHD and multiple pituitary hormone deficiencies (MPHDs) in clinical presentation and in responsiveness to GH treatment., Design: A nationwide surveillance study was carried out to describe the difference in the clinical presentation and responsiveness to GH treatment of patients with IGHD and MPHDs., Methods: The Dutch National Registry of GH Treatment in Adults was founded in 1998 to gain more insight into long-term efficacy and safety of GH therapy. Out of 2891 enrolled patients, 266 patients with IGHD at the start of GH treatment were identified and compared with 310 patients with MPHDs. Cardiovascular indices will be investigated at baseline and during long-term follow-up, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity., Results: Patients with IGHD and MPHDs were demonstrated to be different entities at clinical presentation. Metabolically, patients with MPHDs had a larger waist circumference, lower HDL cholesterol level, and higher triglyceride level. The effect of GH treatment was comparable between patient groups. GH seems to protect against rising lipid levels and blood pressure, even after excluding patients using corresponding concomitant medication. The risk for cardiovascular disease or diabetes mellitus during follow-up was not different between patients with IGHD and MPHDs., Conclusions: Patients with IGHD had a less impaired metabolic profile than patients with MPHDs at baseline. Influence of other pituitary hormone replacement therapies on the effect of GH treatment is not demonstrated., (© 2014 European Society of Endocrinology.)

Decreases in GH secretion with age may contribute to cognitive changes associated with aging. We evaluated the relation between GH secretion and cognition in elderly males by assessing correlations between GH secretion and performance on cognitive tests in conjunction with recording of event-related potentials (ERPs) to assess underlying neurophysiological mechanisms. GH secretion of 17 elderly male participants was assessed by a GHRH-GHRP-6 test. Standardized neuropsychological tests were used to assess cognitive function. EEG/ERPs were recorded to assess on-line electrocortical correlates of sensory-cortical processing and selective attention. GH secretion was significantly correlated with target detections and speed of responding in the selection-potential task. Furthermore, GH peak was significantly correlated with the performance letter-digit span test. The present data confirm that cognitive performance in elderly males is associated with GH secretion, with respect to target detection and speed of responding in conditions of selective attention, short-term memory, and basic processing speed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The objective of this study was to investigate the relation between growth hormone (GH) and attentional electro-cortical responses to task-relevant stimuli (N2b), target detections, speed of responding, P300 latencies, and performance on neuropsychological tests in 19 patients who received external beam radiation therapy for brain tumors in adulthood. In addition, we studied the association between IGF-I and activation of the motor cortex responses (lateralized readiness potential, LRP). Brain function was assessed using event-related potentials (ERPs) during a go/no go selective-attention task, including N2b, P300 and selective motor preparation as reflected in the LRP. Correlations were calculated between peak GH levels after a standardized growth hormone-releasing hormone (GHRH)-arginine test, plasma IGF-I, and cognitive functions. We separately studied four patients who were diagnosed with GHD according to the GHRH-arginine test. Performance on WAIS digit span backward and the Rey-Osterrieth complex figure test correlated positively with GH peak. GHD patients performed worse than non-GHD patients on Stroop interference, trail making B/A attentional shifting and Rey-Osterrieth complex figure test. At trend-level significance, trails A performance was better in patients with lower GH levels and higher radiation doses, and GHD participants detected fewer targets in the go/no go selective attention task. N2b was not significantly altered by GH status. Furthermore, plasma IGF-I was positively correlated with the sum of digit span forward and backward. No relations with P300 were observed. In this study only 21% (4/19) of the patients who received fractionated radiotherapy for a non-endocrine brain tumor were diagnosed with GHD. GHD in these patients was associated with impaired interference control, attentional shifting, and visual long-term memory. The results for interference control and attentional shifting suggest an additional effect of the radiation history., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Context: Adults with GH deficiency (GHD) have a decreased life expectancy. The effect of GH treatment on mortality remains to be established., Objective: This nationwide cohort study investigates the effect of GH treatment on all-cause and cause-specific mortality and analyzes patient characteristics influencing mortality in GHD adults., Design, Setting, and Patients: Patients in the Dutch National Registry of Growth Hormone Treatment in Adults were retrospectively monitored (1985-2009) and subdivided into treatment (n = 2229), primary (untreated, n = 109), and secondary control (partly treated, n = 356) groups., Main Outcome Measures: Standardized mortality ratios (SMR) were calculated for all-cause, malignancy, and cardiovascular disease (CVD) mortality. Expected mortality was obtained from cause, sex, calendar year, and age-specific death rates from national death and population counts., Results: In the treatment group, 95 patients died compared to 74.6 expected [SMR 1.27 (95% confidence interval, 1.04-1.56)]. Mortality was higher in women than in men. After exclusion of high-risk patients, the SMR for CVD mortality remained increased in women. Mortality due to malignancies was not elevated. In the control groups mortality was not different from the background population. Univariate analyses demonstrated sex, GHD onset, age, and underlying diagnosis as influencing factors., Conclusions: GHD men receiving GH treatment have a mortality rate not different from the background population. In women, after exclusion of high-risk patients, mortality was not different from the background population except for CVD. Mortality due to malignancies was not elevated in adults receiving GH treatment. Next to gender, the heterogeneous etiology is of influence on mortality in GHD adults with GH treatment.

Objective: The Dutch National Registry of GH Treatment in Adults was established in 1998 as an initiative of the Ministry of Health. The main goals were to gain more insight into long-term efficacy, safety, and costs of GH therapy (GHT) in adult GH-deficient (GHD) patients in The Netherlands., Methods: Baseline patient characteristics and diagnostic test procedures were evaluated., Results: Until January 2009 in roughly 10 years, 2891 patients (1475 men and 1416 women, mean age 43.5±16.5 years) were registered. GHD was of childhood-onset (CO) in over 20% of the patients and of isolated in 11%. The most common causes of GHD were pituitary tumors and/or their treatment, craniopharyngiomas, and idiopathic GHD. In 85% of the patients, a GH stimulation test was performed, in the majority an insulin tolerance test (ITT) (49%) or a combined GHRH-arginine test (25%). In 12% of the patients, IGF1 levels were ≤-2 s.d. combined with two or more additional pituitary hormone deficits, and in 2%, it concerned patients with CO-GHD continuing GHT in adulthood. Over the years, the test of first choice shifted from ITT toward GHRH-arginine test., Conclusion: Nearly, 2900 patients were included in the nationwide surveillance database of the Dutch National Registry of GH Treatment in Adults until January 2009. Baseline patient characteristics are comparable to that reported previously. In 85% of these patients, the diagnosis of GHD was established by provocative testing, particularly an ITT or a combined GHRH-arginine test, with an evident increase in the percentage of GHRH-arginine tests being performed in the last years.

Objective: Effect of genetic screening on outcome in multiple endocrine neoplasia type 1 (MEN1) remains unclear. Expression of MEN1 is described using currently available diagnostic techniques. Manifestations and outcome are compared in patients diagnosed because of clinical expression with those diagnosed by genetic screening., Design: Retrospective cohort study. Patients are divided into two groups: patients with a (i) clinical MEN1 diagnosis and (ii) MEN1 diagnosis by genetic screening., Patients and Measurements: Demographic and clinical data were collected on MEN1 patients treated in the UMCU up to 1 January 2008. Results of mutation analysis were obtained from the Department of Medical Genetics., Results: A total of 74 patients was included (median follow-up 5.5 year); 78% had hyperparathyroidism, 46% a pancreatic neuro-endocrine tumour (NET), 38% a pituitary abnormality, 8% a NET of other origin and 16% an adrenal adenoma at the end of follow-up. Of the patients 18% had no manifestation. All five MEN1-related tumours were seen as first manifestation. Compared with patients identified by genetic screening, patients with a clinical MEN1 diagnosis had significantly more manifestations at diagnosis (P < 0.001) and at end of follow-up (P = 0.002). Eleven of 30 patients with a genetic MEN1 diagnosis (mean age at diagnosis 30.0 years) already had manifestations at diagnosis. No malignancy or death was seen in genetically diagnosed patients., Conclusions: MEN1 is a syndrome with high morbidity. Genetic diagnosis is associated with less morbidity at diagnosis and at follow-up. Early genetic diagnosis might therefore lead to improvement of long-term outcome.

Objective: To assess whether methylprednisolone (MP) pulse therapy is efficacious in the treatment of moderately severe Graves' orbitopathy (GO)., Design: Prospective, placebo (PL)-controlled, double-blind, randomized study., Methods: Fifteen previously untreated patients with active, moderately severe GO participated in the study; 6 patients received MP and 9 patients a PL. Moderately severe disease was defined using the NOSPECS classification of clinical signs of GO . Activity was measured with the clinical activity score (CAS). A dose of 500 mg MP or only solvent was administered intravenously, over three consecutive days, in four cycles at 4 weekly intervals (6 g of MP in total). Qualitatively, a successful treatment outcome was defined as an improvement in one major and/or two minor criteria in the worst eye at week 48. The major criteria were: improvement in diplopia grade; improvement in eye movement; a decrease in CAS of three points. The minor criteria were: decrease of eyelid retraction; decrease of proptosis; improvement in grade of soft tissue swelling; a decrease in CAS of two points., Results: The qualitative treatment outcome was successful at the end of the trial in five out of six (83%) patients receiving MP and in one out of nine (11%) patients given the PL (relative risk=7.5; (95% confidence interval 1.1-49.3), P=0.005). The treatment was well tolerated., Conclusions: In spite of the small number of patients, a significant difference in outcome was observed between MP- and PL-treated patients. We conclude that MP pulse therapy appears to be an effective treatment for active, moderately severe GO.

No experimental data exist on the thyroid toxicity of nitrate among humans. We aimed to show that no significant antithyroid effect could be observed after exposure to a three times the acceptable daily intake of nitrate in humans. In a randomized controlled non-inferiority trial, 10 volunteers received 15 mg/kg sodium nitrate during 28 days whereas 10 control participants received distilled water. We performed 5- and 24-h measurements of thyroidal (131)I uptake (RAIU) before and at the end of the exposure period. Thyroid hormone plasma concentrations of T3, rT3, T4, TSH were also measured prior to and after exposure. Differences in RAIU between the intervention and the control groups at 4 weeks were 3.4% (95% confidence interval -0.5 to 7.3, and 4.8% (95% confidence interval -1.4 to 11.0, respectively, for the 5- and 24-h RAIU measurement. Plasma concentrations of thyroid hormones stayed normal. In conclusion, no significant effects on thyroidal (131)I uptake and thyroid hormones plasma concentrations were observed after sub-chronic exposition to 15 mg/kg sodium nitrate among humans.

Objective: To determine whether impaired quality of life (QoL) in adults with GH deficiency (GHD) is reversible with long-term GH therapy and whether the responses in QoL dimensions differ from each other., Methods: QoL was measured by the Quality of Life-Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) in general population samples in England & Wales, The Netherlands, Spain and Sweden (n = 892, 1038, 868 and 1682 respectively) and compared with corresponding patients' data from KIMS (Pfizer International Metabolic Database) (n = 758, 247, 197 and 484 respectively) for 4-6 years a follow-up. The subsets of patients from England and Wales, and Sweden with longitudinal data for 5 years' follow-up were also analysed. The change of the total QoL-AGHDA scores and responses within dimensions were evaluated. Subanalyses were performed to identify any specificity in response pattern for gender, age, disease-onset and aetiology., Results: Irrespective of the degree of impairment, overall QoL improved dramatically in the first 12 months, with steady progress thereafter towards the country-specific population mean. Problems with memory and tiredness were the most serious burden for untreated patients, followed by tenseness, self-confidence and problems with socialising. With treatment, these improved in the reverse order, normalising for the latter three., Conclusions: Long-term GH replacement results in sustained improvements towards the normative country-specific values in overall QoL and in most impaired dimensions. The lasting improvement and almost identical pattern of response in each patient subgroup and independent of the level of QoL impairment support the hypothesis that GHD may cause these patients' psychological problems.

Objective: This study set out to determine the change in quality of life (QoL) and healthcare utilization during 2 years of growth hormone (GH) replacement therapy in adults with GH deficiency. Data were compared from three European countries., Design: Analysis was made from KIMS, the Pfizer International Metabolic Database on adult GH deficiency., Methods: QoL and healthcare utilization were measured at baseline and after 1 and 2 years of GH replacement in patient cohorts from Sweden (n = 302), The Netherlands (n = 103) and Germany (n = 98). QoL was assessed by the QoL-Assessment in Growth Hormone Deficient Adults (QoL-AGHDA) questionnaire, and the KIMS Patient Life Situation Form was used to evaluate healthcare utilization., Results: QoL improved significantly (P < 0.0001) and comparably in all three cohorts. The improvement was seen during the first year of treatment and QoL remained improved during the second year. The number of days in hospital was reduced by 83% (P < 0.0001) during GH replacement. There were no country-specific differences either at baseline or during follow-up. The same was true for the number of days of sick leave (reduction of 63%; P = 0.0004). Significant reductions were recorded in the number of doctor visits in each of the three cohorts after 2 years of GH replacement (P < 0.05)., Conclusions: This study provides a detailed comparative analysis of GH replacement therapy in GHD patients in three European countries. Despite some differences in treatment strategies, the beneficial effects on QoL, patient-reported outcomes and healthcare utilization are essentially similar in the healthcare environment of Western European countries.

Objective: Obesity is characterized by low basal levels of growth hormone (GH) and impeded GH release. However, the main problem arises in the diagnosis of GH deficiency in adults, as all accepted cut-offs in the diagnostic tests of GH reserve are no longer valid in obese subjects. In this work, the role of obesity in the GH response elicited by the GHRH + GHRP-6 test was assessed in a large population of obese and nonobese subjects., Patients: GHRH + GHRP-6-induced GH peaks were evaluated in 542 subjects. One hundred and five were healthy obese, 50 were morbid obese, and 261 were nonobese (both normal weight and overweight). One hundred and seventy-six GH-deficient patients (obese and nonobese) were also studied., Results: A regression analysis of the 366 subjects with normal pituitary function indicated that adiposity had a negative effect on the elicited GH peak (r = -0.503, P < 0.0001). A receiver operating characteristic (ROC) curve analysis showed that in subjects with a BMI < or =35, the currently accepted cut-offs of the GHRH + GHRP-6 test (GH peaks > or =20 microg/l: normal secretion; GH peaks < or =10 microg/l: GH deficiency), were fully operative. However, in subjects with a BMI > 35, normality was indicated by GH peaks > or =15 microg/l and GH deficiency by peaks < or =5 microg/l (1 microg/l = 2.6 mU/l)., Conclusions: This study confirms: (a) that the combined provocative test is adequate to separate normal and GH-deficient subjects; (b) the negative effect of obesity on GH secretion; (c) that obesity accounts for 25% of the reduction of GH release; and (d) that present cut-off values are applicable to normal weight, overweight and grade I obesity subjects, whereas in obese subjects with a BMI exceeding 35, all the normative limits of the GHRH-GHRP +6 test must be reduced by 5 microg/l.

Background: Ample evidence from animal research indicates that the gonadal steroid hormone testosterone has fear-reducing properties. Human data on this topic, however, are scarce and far less unequivocal. The present study therefore aimed to scrutinize anxiolytic effects of a single dose of testosterone, using a direct physiological index of fear in humans., Methods: Twenty healthy female participants were tested in a double-blind, placebo-controlled crossover design involving sublingual administration of a single dose of testosterone. Four hours after intake, we assessed effects on baseline startle and fear-potentiated startle in a verbal threat-of-shock paradigm., Results: In accordance with predictions, testosterone administration resulted in reduced fear-potentiated startle, without affecting baseline startle., Conclusions: This study provides direct evidence that a single dose of testosterone reduces fear in humans. The relationship of this effect to previous research on anxiolytic effects of benzodiazepines, as well as possible mechanisms of action, is discussed.

Aim: Needle-free administration of recombinant human growth hormone (rhGH) is effective in the treatment of growth hormone deficiency (GHD) in children, but has not been studied in adult patients. Therefore, we evaluated the efficacy of needle-free administration of rhGH in adults with GHD., Methods: Insulin-like growth factor-I (IGF-I) concentrations were compared in newly diagnosed patients with GHD (n = 21) and in patients previously treated by subcutaneous injection of rhGH (switchers, n = 34), at baseline, 12 months and 24 months., Results: In the new patients, IGF-I standard deviation scores (SDS) increased from - 1.82 +/- 0.46 to + 0.75 +/- 0.33 at 12 months and to + 0.65 +/- 0.41 at 24 months (P < or = 0.001 vs. baseline). In switchers, IGF-I SDS remained unchanged with values of + 0.98 +/- 0.32 at baseline, + 0.87 +/- 0.23 at 12 months and + 0.73 +/- 0.29 at 24 months (P = 0.696 vs. baseline). In new patients, the rhGH dose was 0.46 +/- 0.03 mg day(-1) at 12 months and 0.47 +/- 0.03 mg day(-1) at 24 months. In switchers, the rhGH dose was 0.53 +/- 0.04 mg day(-1) at baseline (s.c. injection), 0.52 +/- 0.03 mg day(-1) at 12 months and 0.48 +/- 0.03 mg day(-1) at 24 months (NS between the different time points). There was no difference in the dose of rhGH at 12 and 24 months between the two groups. Side-effects were generally minor and consisted of local tissue reactions., Conclusion: Administration of rhGH by needle-free, transdermal injection is effective in maintaining IGF-I concentrations in the normal range for age in adults with GHD, and is as effective as traditional subcutaneous injection of rhGH.

Objective: Untreated GH-deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short-term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF-I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and adiponectin] in adults with severe GH deficiency., Patients and Methods: In this 12-month open, prospective study, 25 GH-deficient adults were randomized to receive either a fixed LGH (0.10 mg/day, n = 13) or SGH (mean dose 0.48 mg/day, n = 12), and eight age- and body mass index (BMI)-matched GH-deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual-energy X-ray absorptiometry, were performed at baseline and at month 12., Results: The LGH decreased fasting glucose levels (P < 0.01) and enhanced insulin sensitivity (P < 0.02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0.05), CRP (P < 0.05) and IL-6 (P < 0.05) levels, and increased NEFA levels (P < 0.05). No changes were observed with the untreated controls., Conclusion: Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.

Increasing evidence suggests that the steroid hormone testosterone (T) enhances libido and decreases depression. Even a single administration of T (0.5 mg sublingually) in healthy young women is sufficient to enhance physiological sexual responsiveness. Such physiological evidence is not yet available for the link between T and depression. Recent research has revealed that lowered functional connectivity in a specific cortico-cortical pathway may be a sensitive physiological index for depression. This pathway, comprised of the left prefrontal and right parietal cortex, has been named a cortical depression circuit. In the present study, a single dose of T was administered to healthy young women to investigate the effects on the functional connectivity in this cortico-cortical depression circuit. It was hypothesized that administration of T would lead to an increase of functional connectivity. In a double-blind placebo-controlled, crossover design, fourteen healthy females received (sublingually) a single dose of 0.5 mg T or placebo in a randomly assigned fashion. Three hours after drug administration the functional coupling between the left prefrontal and right parietal cortex was established by measuring the interhemispheric electroencephalogram (EEG) coherence for the different frequency bands. Compared to placebo, T administration significantly increased the functional connectivity in the sigma (1-3 Hz) frequency range between the left prefrontal and right parietal cortex. Reductions in interhemispheric coherence in the sigma frequency range have been observed in clinically depressed patients. Thus the present findings may provide a first insight into the neurobiological mechanism by which T decreases depression. The fact that only a single dose of T was able to induce the effect in healthy female subjects suggests that the mechanism is highly sensitive. A feasible application of T treatment in the struggle against depression is discussed.

Cognitive deficits have been reported in adults with childhood-onset growth hormone (GH) deficiency. We evaluated cognitive deficits simultaneously with parameters for neuronal integrity using (1)H magnetic resonance spectroscopy (MRS) in a cross-sectional design. We studied 11 adults (mean age 24.5 years) with childhood-onset GH deficiency, which persisted after reaching final height. All subjects were evaluated after interruption of GH supplementation for at least 3 months. We performed neuropsychological assessment (NPA) using tests evaluating memory, mental processing speed, reading ability and executive functioning. MRS was used to assess brain N-acetylaspartate (NAA)/choline ratios. Data were compared with an age-, sex- and education-matched control group (n=9, mean age 27.3 years). NPA demonstrated attenuated performance of the patients in the delayed verbal memory recall score (P<0.05) and the trail making A test (P<0.05), a measure of planning of behavior, processing speed and attention. Other neuropsychological tests were not affected. NAA/choline ratios were significantly reduced (P<0.01) in GH deficient subjects. Specific cognitive defects indicating affected memory and attention were found in patients with childhood-onset GH deficiency. These defects occur simultaneously with reduced neuronal integrity.

Objective and Design: Ageing and obesity result in decreased activity of the GH/IGF-I axis and concomitant impaired GH responses to secretory stimuli. We therefore determined the validity of the GH cut-off value of 15.0 microg/l in the GH-releasing hormone (GHRH)/GH releasing peptide-6 (GHRP-6) test for the diagnosis of GH deficiency in elderly or severely obese men., Methods: We performed a combined GHRH/GHRP-6 test in ten elderly men (mean age 74 years; mean body mass index (BMI) 24.6 kg/m(2)), nine obese men (mean age 47 years; mean BMI 40.6 kg/m(2)) and seven healthy male controls (mean age 51 years, mean BMI 24.3 kg/m(2)). After assessment of fasting plasma GH, IGF-I and IGF-binding protein-3 (IGFBP-3), GHRH (100 microg) and GHRP-6 (93 microg) were given intravenously as a bolus injection. Repeated GH measurements were performed for two hours., Results: Both peak GH levels and areas under the curve (AUC) were significantly lower in the obese than in the controls (peak 13.2 vs 53.4 microg/l, P = 0.001; AUC 707 vs 3250 microg/l x 120 min; P = 0.001). Mean GH response in the elderly was lower than in the controls (peak 35.0 microg/l; AUC 2274 microg/l x 120 min), but this was not statistically significant. In contrast, GH peak levels in seven obese men remained below the cut-off level of 15.0 microg/l associated with severe GH deficiency. All others had GH peak levels exceeding this threshold. IGFBP-3 levels were significantly lower in the elderly than in the controls (1.35 vs 2.05 mg/l, P = 0.001). Baseline GH or IGF-I did not differ significantly between groups., Conclusions: GH responses following GHRH/GHRP-6 administration were significantly reduced in severely obese men, but were not significantly reduced in elderly men, despite a negative trend. Our data indicate that the cut-off GH level of 15.0 microg/l after GHRH + GHRP-6 administration for the diagnosis of severe GH deficiency cannot be used in severely obese men.

Elevated levels of the stress hormone cortisol are associated with increased episodic memory for emotional events. Elevated levels of cortisol are also seen in anxiety and depression disorders. Because it is well documented how both depression and anxiety are related to valence-specific biases in attention and memory, the present study sought to establish relations between basal cortisol levels and episodic memory for neutral, positive and negative stimuli. Thirty-nine healthy young women performed an immediate recall and long-term (20 min) version of a task measuring spatial memory for neutral, happy and fearful faces. The sample as a whole showed a valence-specific better performance for happy faces than for neutral faces in the immediate recall condition, and a better performance for all emotional faces in the long-term condition. Salivary cortisol measures were found to be related to better memory for emotional faces in the long-term condition. This relation to cortisol was not valence-specific and is similar to effects predicted by a model on long-term consolidation and the influence of cortisol in this process.

This study was designed to investigate the central neuroendocrine mechanisms by which exercise (EX) stimulates growth hormone (GH) release as a function of age. Twelve male subjects, six in their early-to-mid twenties and six in their late sixties or seventies, received a strong GH stimulus either as incremental EX until volitional exhaustion or by administration of GHRH alone or Hex alone two hours after a presumed maximal GH response to combined administration of GHRH plus hexarelin (Hex). Total GH availability was calculated as area under the curve (AUC) over time periods 0 - 120 and 120 - 240 min. The mean AUC in micro g/l x 120 min to GHRH+Hex in the younger group was approximately twice that in the older group (11,260, range 3,947 - 19,007 vs. 5,366, range 2,262 - 8,654). In younger males, the mean AUC to EX (509, range 0 - 1,151) was larger than to GHRH (119, range 0 - 543), but less than that to Hex (919, range 0 - 1,892). In the older group, GH responses to EX and GHRH were abolished (mean AUC: 112, range 0 - 285, and 156, range 30 - 493), respectively) in contrast to the response to Hex (1,077, range 189 - 1,780). These data indicate that maximal GH stimulation by GHRH+Hex results in greater desensitization of GHRH compared to Hex, irrespective of age. We postulate that the abolished responsiveness of GH to EX in older group is due to insufficient disinhibition of hypothalamic somatostatin activity and desensitization of GHRH, while the preserved activity of a central Hex-related pathway is not involved. The GH response to EX in younger males is due to complete inhibition of somatostatin activity and stimulation of a central Hex-related pathway in spite of GHRH desensitization. We conclude that a central Hex-related pathway is the primary factor for EX-induced GH release only in younger males.

In the present report assumed relationships between hypercortisolism, depression and cortico-cortical cross-talk in Cushing's syndrome were investigated. Electroencephalographic (EEG) recordings and depression ratings from three patients diagnosed with mild, moderate and severe hypercortisolism were obtained. Reductions in cortico-cortical cross-talk as quantified by EEG coherence together with increases in depression were observed in the moderate and severe as compared to the mild hypercorticolism state. These findings provide preliminary evidence for the hypothesis that loss of cortico-cortical cross-talk might be linked to hypercortisolism and the severity of depressive symptoms.

Previous research has documented correlations between endogenous testosterone levels and visuospatial cognitive function. Some causal relations have also been established in treatment designs in which testosterone was administered to elderly subjects for a number of weeks. Particularly, one study reported a selective effect of a single administration of testosterone on some aspects of spatial memory in 15 women. The present study tested the hypothesis whether a single administration of 0.5 mg of sublingual testosterone would improve visuospatial ability in healthy young women on a test that has consistently been associated with male superiority. Twenty-six women participated in a double-blind placebo-controlled cross-over trial of single administration of testosterone and placebo. Subjects were tested in the same phase of the menstrual-cycle. Four to five hours after both administrations, subjects completed a standardized measure of visuospatial ability (3-D Mental Rotations Test). Visuospatial ability improved significantly after testosterone administration compared to placebo, after controlling for learning effects due to repeated testing. Testosterone is suggested to be causally related to visuospatial ability in young women.

Cardiomyopathy is a major cause of death in overt acromegaly. Recent progress in research has increasingly revealed the molecular mechanisms concerning growth hormone and insulin-like growth factor in the development of heart failure. In this article, we propose mechanisms according to which heart failure occurs, and we aim to extrapolate this knowledge to more general processes involved in heart failure.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) receptors can be found in several areas of the brain. GH receptors are mainly found in the choroid plexus, thalamus, hypothalamus, pituitary, putamen, and hippocampus, whereas IGF-1 receptors are mainly concentrated in the hippocampus and parahippocampal areas. In early life, GH and IGF-1 have an important role in the development and differentiation of the central nervous system. In the more developed central nervous system, GH and IGF-1 are thought to have a variety of functions such as a neuroprotective function, an appetite increasing function, various cognitive functions, and perhaps a blood flow-regulating function. In GH-deficient children and adults, improvement of cognitive functions was observed after the administration of GH. Furthermore, specific cognitive functions in healthy older subjects may improve after increasing GH or IGF-1 levels.

In the present study, a systematic comparison of sex differences for several tests of spatial memory was conducted. Clear evidence for more accurate male performance was obtained for precise metric positional information in a wayfinding task and in an object location memory task. In contrast, no sex difference characterized topological information processing (object-to-position assignment). Together, these findings provide further insight in the specificity of sex differences in spatial memory and in the functional architecture of spatial memory. Implications for the relevant evolutionary basis are discussed.

Background: The diagnosis of growth hormone deficiency (GHD) relies on provocative tests of GH reserve. The aim in these tests is to obtain an objective, biochemical-based, measure of gland function, but clinicians and researchers rely on the GH peak, as a surrogate of the 24-hour pituitary secretion. However, on a mathematical basis the area under the secretory curve (AUC) should be more valid for this evaluation., Objectives: To validate which variable provided by a provocative test of GH secretion is mathematically more robust for supporting the clinical diagnosis. Adult normal subjects and GHD patients were challenged with the combined stimulus GHRH + GHRP-6. The diagnostic efficacy of the GH peak, and the AUC were compared by the receiver operating characteristic (ROC) curve methodology., Patients and Methods: 146 patients with GH deficiency due to organic pituitary disease and 184 healthy subjects were administered GHRH 1 microg/Kg iv, plus GHRP-6 1 microg/Kg iv, and GH was determined. Four variables were studied: (a) the GH peak; (b) the "standard" AUC, (c) the "stimulated" AUC and (d) the basal value, used as internal control., Results: Under ROC curve analysis, the basal variable was devoid of diagnostic capability, while the other variables performed strikingly well, the ROC curve area for the GH peak was 0.9997; and for the AUC 0.9993, with no statistical differences., Conclusions: The variables provided by measuring the GH peak and the area under the curve were similarly effective for diagnosis, although on clinical grounds, the peak was more convenient as needed no calculation. If results for other test were similar the time-honored method of measuring the GH peak could be considered mathematically validated.

Reduced levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are associated with deteriorated cognitive performance in senescence. Little work has been done on the effect of GH and IGF-1 on a crucial aspect of cognition, selective attention. This study investigated the effect of GH/IGF-1 on performance and brain potentials (EEG) during a selective-attention task in patients with low levels of GH and IGF-1 (childhood-onset growth hormone deficiency) compared to healthy controls. Detection of occasional visual target patterns was impaired in patients. This was paralleled by a reduction in an attention-related brain potential, which has been associated previously with anterior cingulate cortex functioning.

Heightened cortisol levels due to stress or acute administration seem to enhance memory for emotional material, independently of emotional valence. An arousal-driven neurobiological mechanism involving the amygdala has been proposed. The relation between pre-task salivary measures of cortisol (by convention named 'basal levels') and emotionally modulated memory has not been investigated yet. Given the association between higher basal levels of cortisol and indices of low mood, valence-specific effects on emotionally modulated memory could be expected (e.g. mood-congruent or stimulus-specific forms of processing). This study was designed to investigate the relationship between basal levels of salivary cortisol, self-reported mood and spatial memory for neutral, happy and angry facial expressions in healthy young volunteers (N=31). Memory performance was indexed using a modified version of a computerized object-relocation task, using emotional facial expressions as stimuli. Results showed a significant relation between cortisol and depressive mood. More importantly, both the levels of cortisol and depressive mood were inversely related to the memory performance for the happy facial expressions, while a similar relationship between cortisol and memory performance on angry faces neared significance. An explanation in terms of the down-regulation of social behavior by elevated basal cortisol levels is postulated.

Unlabelled: GROWTH HORMONE AND ATHEROSCLEROSIS: Adult-onset growth hormone (GH) deficiency is associated with an increase in cardiovascular morbidity and mortality., Mechanisms: Other than classical risk factors, such as dyslipidemia, a direct interaction between the activity of the GH/IGF-1 axis and the endothelium also plays a part. It is possible that the modulating effect of IGF-1 on nitric oxide (NO) synthesis is also important, together with the anabolic effect on the myocardiocytes. Substitution of recombinant GH induces rapid reduction in the atherosclerotic plaques, suggesting a direct effect of the GH/IGF axis on the atherosclerotic process. In addition to the acquired GH deficiency, as in non-substituted patients following hypophysectomy, attention has recently been focused on the relative GH deficiency as is seen in obesity and in the course of ageing. PERSPECTIVES FOR CARDIOVASCULAR ENDOCRINOLOGY: Therapeutic intervention in the GH/IGF axis might influence the atherosclerotic process. Study of the GH/IGF axis activity and of its correlation with atherosclerosis opens new perspectives in the understanding of the role of this axis in cardiovascular diseases.

The aim of this study was to investigate the involvement of endogenous growth hormone-releasing hormone (GHRH) in the growth hormone (GH) release during strenuous exercise (EX). Eight healthy male subjects (age: 22.1 +/- 0.8 yr, body mass index: 22.2 +/- 0.9 kg/m 2, .VO 2 max: 52.2 +/- 0.5 ml/min/kg [mean +/- SEM]) were exposed to incremental EX until volitional exhaustion (cycle ergometry), and in random order to a maximally stimulating bolus injection of 100 microg GHRH, or to combined administration of 100 microg GHRH and EX (GHRH+EX). Serial blood samples in the fasted state were taken immediately before the start of each trial, and at appropriate intervals over 2 h. Total GH availability was calculated as area under the response curve (AUC), corrected for differences in baseline values. The results showed that peak serum GH levels to GHRH alone and EX alone were not significantly different: 41.5 +/- 9.0 microg/l and 64.1 +/- 8.1(mean +/- SEM). Peak GH level to GHRH+EX was 156.1 +/- 19.9 microg/l, which was significantly greater than to either stimulus alone (p < 0.02) or additively (105.6 +/- 17.1 microg/l, p < 0.02). AUC's to GHRH alone and EX alone were not significantly different (3242 +/- 839 vs. 2472 +/- 408 microg/l x 120 min). AUC to GHRH+EX (7807 +/- 1221 microg/l x 120 min) was greater than to either stimulus alone (p < 0.02) or additively (5714 +/- 1247 microg/l x 120 min, p < 0.02). This indicates a potentiating (synergistic) effect between GHRH and EX. We postulate that GH responses to strenuous EX are only partially due to maximal GHRH activation. Next to complete inhibition of hypothalamic somatostatin activity, which is achieved by strenuous exercise, activation of endogenous GH-releasing peptides, such as Ghrelin, must be operative.

The development of recombinant human thyrotropin (rhTSH) has given clinicians new options for diagnostic follow-up and treatment of patients with differentiated thyroid cancer (DTC). This paper evaluates the tumour dosimetry and response following -iodine-131 treatment of metastatic thyroid cancer patients after rhTSH stimulation instead of classical hormone withdrawal-induced hypothyroidism. Nineteen consecutive (131)I treatments in 16 patients were performed after rhTSH stimulation. All patients had undergone a near-total thyroidectomy followed by an ablative dosage of (131)I. They all suffered from metastatic or recurrent disease showing tumoral (131)I uptake on previous post-treatment scintigraphy. Dosimetric calculations were performed using (131)I tumour uptake measurements from post-treatment (131)I scintigrams and tumour volume estimations from radiological images. Response was assessed by comparing pre-treatment serum thyroglobulin (Tg) level with the Tg level 3 months post treatment. In 18 out of 19 treatments, uptake of (131)I in metastatic or recurrent lesions was seen. The median tumour radiation dose was 26.3 Gy (range 1.3-368 Gy), and the median effective half-life was 2.7 days (range 0.5-6.5 days). Eleven of 19 treatments (10/16 patients) were evaluable for response after 3 months. (131)I therapy with rhTSH resulted in a biochemical partial response in 3/11 or 27% of treatments (two patients), biochemical stable disease in 2/11 or 18% of treatments and biochemical progressive disease in 6/11 or 55% of treatments. Our study showed that although tumour doses in DTC patients treated with (131)I after rhTSH were highly variable, 45% of treatments led to disease stabilisation or partial remission when using rhTSH in conjunction with (131)I therapy, without serious side-effects and with minimal impact on quality of life. RhTSH is therefore adequately satisfactory as an adjuvant tool in therapeutic settings and is especially suitable in advanced recurrent or metastatic DTC patients who may be intolerant to TSH stimulation by levothyroxine withdrawal.

Increased cardiovascular mortality due to premature atherosclerosis is a clinical feature in the adult-onset GH deficiency (AGHD) syndrome. Inflammation is a key feature in atherogenesis and may be triggered by postprandial lipoprotein remnants. We hypothesized that increased postprandial lipoprotein remnant levels in AGHD may be associated with an inflammatory response. In this case-control study, 10 AGHD patients [6 males and 4 females; age, 48 +/- 9 yr; body mass index (BMI), 26.9 +/- 2.6 kg/m(2)] and 10 healthy control subjects (matched for age, BMI, gender, baseline lipid levels, and apolipoprotein E genotype) were included. They all ingested an oral fat load. Fasting and postprandial levels of plasma remnant-like particle-cholesterol (RLP-C; 0.31 +/- 0.13 mmol/liter and 4.14 +/- 1.37 mmol/liter.h in GHD; 0.18 +/- 0.06 mmol/liter and 2.56 +/- 1.02 mmol/liter.h in controls, respectively) were significantly increased in AGHD patients compared with control subjects. The median inflammatory cytokines, IL-6 and TNF-alpha, were higher in the fasting [3.9 (range, 3.1-11.9) pg/ml and 6.8 (range, 2.5-27.6) pg/ml, respectively] and postprandial [151.7 (range, 87.0-294.3) pg/ml.24 h and 289.9 (range, 87.5-617.6) pg/ml.24 h, respectively] states in AGHD than in controls [fasting, 0.9 (range, 0.2-5.2) pg/ml and 2.8 (range, 2.5-5.7) pg/ml; and postprandial, 54.5 (range, 11.50-126.5) pg/ml.24 h and 118.3 (range, 81.2-243.1) pg/ml.24 h, respectively]. In addition, postprandial profile of RLP-C and IL-6 in AGHD and in the total group were significantly associated (r(2) = 0.44, P < 0.05; and r(2) = 0.38, P < 0.01, respectively). In conclusion, the increased postprandial RLP-C level in GHD is associated with an inflammatory response that may result in increased susceptibility for premature atherosclerosis.

Objective: Reduction of plasma free fatty acids leads to enhanced GH response after stimulation by GH-releasing hormone (GHRH). We studied the clinical usefulness of combined administration of acipimox and GHRH for the diagnosis of GH deficiency., Design: We evaluated 35 patients [mean age 53.0 years; mean body mass index (BMI) 26.7 kg/m2] after pituitary surgery. We compared GH responses after acipimox and GHRH with the GH response during an insulin tolerance test (ITT) and, in a subgroup of 12 patients, with the GHRH/arginine test. The acipimox/GHRH test was additionally performed in 21 control subjects (mean age 53.8 years; mean BMI 24.7 kg/m2)., Results: In the patients, the mean (+/- SEM) peak GH was almost four-fold higher after acipimox/GHRH (6.94 +/- 1.07 microg/l, range 0.46-23.1; P < 0.001) and after GHRH/arginine (8.32 +/- 1.23 microg/l, range 1.1-49.2; P < 0.001) than after ITT (1.84 +/- 0.46 microg/l, range 0.01-11.9). According to the ITT, 29 patients were severely GH deficient (peak GH < 3.0 microg/l). Peak GH levels after acipimox/GHRH in controls ranged from 7.5 to 78.4 microg/l (mean 29.3 +/- 3.5). GH peak values during the acipimox/GHRH test were significantly correlated with values from the ITT (r = 0.63, P < 0.01) and GHRH/arginine test (r = 0.87, P < 0.001). Areas under the curve were also correlated. According to generally accepted cut-off peak GH levels for the ITT and GHRH/arginine test, a GH peak exceeding 11.2 micro g/l excludes severe GH deficiency after acipimox/GHRH. Our control data indicate that the cut-off level is lower at older age., Conclusions: The acipimox/GHRH test leads to GH responses similar to those of the GHRH/arginine test, and to higher peak GH values if compared with the ITT. The acipimox/GHRH test is a potential additional tool to detect GH deficiency in patients with pituitary disease, in particular in patients with a perturbation of fatty acid metabolism.

Background: The diagnosis of GH deficiency in adults is based on the provocative testing of GH secretion. When testing a patient with suspected GH deficiency, clinicians assess the whole secretory curve and select the GH peak as an index of secretory capability. This procedure is time consuming and the determination of GH in several samples is necessary. The combined administration of growth hormone releasing hormone (GHRH) plus growth hormone releasing peptide-6 (GHRP-6) is an effective test of GH secretion, and it has been unambiguously demonstrated that the elicited GH peak is capable of segregating normal GH secretion subjects from GH deficient patients on an individual basis. The GHRH + GHRP-6 test biochemically classifies patients into three groups; those with a stimulated GH peak >/= 20 micro g/l are considered normal and those with peaks at

The aim of this study was to investigate whether growth hormone (GH) release during strenuous exercise (EX) is due to complete inhibition of hypothalamic somatostatin (SS) activity. Eight healthy male subjects (age, 22.1 +/- 2.2 years; body mass index [BMI], 22.2 +/- 2.5 kg/m(2); maximum oxygen consumption [Vo(2)max], 52.2 +/- 1.5 mL/min/kg [mean +/- SD]) were exposed to strenuous EX on a cycle ergometer, with and without administration of pyridostigmine (PD), and to administration of PD alone. PD is an acetylcholine-esterase inhibitor that stimulates GH secretion by suppressing hypothalamic SS secretion and unmasking endogenous GH-releasing hormone (GHRH) tone. Serial blood samples in the fasted state were taken immediately before the start of each trial, and at appropriate intervals over 2 hours. GH responses were calculated as area under the response curve (AUC) by trapezoidal integration. The mean peak serum GH level to PD alone was 18.3 microg/L (range, 0.3 to 40.9), which was significantly lower than to EX alone: 64.1 microg/L (range, 30.5 to 90.5), and to the combined administration of PD and EX (PD+EX): 79.8 microg/L (range, 37.7 to 98.2) (P <.05). The arithmetic sum of the individual peak levels of 82.4 microg/L was not different from the mean peak level to PD+EX: 79.8 microg/L. AUC (mean +/- SEM) to PD alone (1,721 +/- 358 microg/L x 180 min) was not significantly different from that to EX alone (2,472 +/- 408 microg/L x 120 min), but was significantly lower than that to PD+EX: 3,526 +/- 752 (P <.05). Although the latter AUC was 6% smaller than the AUC obtained by arithmetic addition (3,747 +/- 706), this difference was not statistically significant. In conclusion, the additive effect between PD and EX indicates that PD and EX act independently in evoking GH responses to strenuous EX. Therefore, GH responses to strenuous EX are only partially due to complete inhibition of hypothalamic SS. Additional potentiating factors, such as activation of endogenous GHRH and ghrelin must be operative., (Copyright 2002, Elsevier Science (USA). All rights reserved.)