OBJECTIVE:We studied whether the severity of GH deficiency (GHD) defined as i) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, and glucagon), ii) number of additional pituitary deficits, or iii) baseline IGF1 SDS could impact the response to GH treatment. We further explored whether iv) IGF1 SDS after 24 months of GH replacement or v) ΔIGF1 SDS from baseline to 24 months was related to the phenotypic response to GH treatment. DESIGN, PATIENTS, AND MEASUREMENTS: The patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into three groups of approximately equal size (tertiles) according to the stimulated GH-peak values and baseline IGF1 SDS and were studied at baseline, 12, and 24 months of GH therapy.RESULTS:Lower baseline IGF1 SDS predicted better response in weight, BMI, total cholesterol, and triglycerides, while IGF1 SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol, and improved quality of life (QoL). Age-correlated negatively with the response in body weight, BMI, waist, IGF1 SDS, and total and LDL-cholesterol. Response in weight and BMI was greater in men than in women, whereas women showed greater improvement in QoL than men. Patients with more severe GHD as assessed by lower GH-peaks and more pituitary hormone deficiencies had a greater increase in IGF1 SDS. The increase in IGF1 SDS was associated with a reduction in waist/hip ratio and an increase in weight, BMI, and triglycerides. There was no correlation with other lipids, blood pressure, or glucose.CONCLUSION:Our findings indicate that baseline and 24 months, IGF1 and its degree of increase during GH replacement were more important than stimulated peak GH to predict the phenotypic response.

OBJECTIVETo determine whether insulin tolerance tests (ITTs), arginine stimulation tests (ASTs), and glucagon stimulation tests (GST) identify patients who have similar clinical features of growth hormone (GH) deficiency when a diagnostic GH threshold of 3 μg/L is used.METHODSData were obtained from the KIMS database (Pfizer International Metabolic Database). Comparisons were made between patients who underwent ITT, AST, or GST for GH peak, body mass index, lipids, waist circumference, waist-to-hip ratio, and quality of life.RESULTSA total of 5453 tests were available from 4867 patients registered in the database (ITT = 3111, AST = 1390, GST = 952). Significant (P<.001) intraindividual correlations were observed between the GH peaks for ITT vs AST (r = 0.655), ITT vs GST (r = 0.445), and AST vs GST (r = 0.632). GH peaks in response to all tests were negatively correlated to the number of additional pituitary hormone deficiencies and positively correlated to the insulinlike growth factor 1 standard deviation score. Body mass index had a negative influence on all 3 tests. Most clinical variables did not differ between the groups when comparing GH-deficient patients according to the diagnostic test used. The only exceptions that showed any difference were body mass index (slightly higher in the AST and GST groups), triglyceride levels (increased in the GST group), and insulinlike growth factor 1 (standard deviation score) (lower in the ITT and AST groups than in the GST group). Waist circumference was greater and quality of life was worse in the GST group than in the other groups.CONCLUSIONSThe ITT, AST, and GST produce similar GH peaks, are influenced by similar clinical factors, and identify patients with similar features of GH deficiency at a diagnostic threshold of 3 μg/L.

OBJECTIVE:Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients.DESIGN:In KIMS (Pfizer International Metabolic Database) 13,983 GH-deficient patients with 69,056 patient-years of follow-up were available.METHODS:This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05.RESULTS:All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044).CONCLUSIONS:GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

Clinical studies have demonstrated that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. This study aimed to assess the prevalence and associated factors of post-traumatic hypopituitarism in a large national registry of patients with TBI and SAH. Data were collected from 14 centers in Germany and Austria treating patients for TBI or SAH and performing endocrine assessments. Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. A total of 1242 patients (825 TBI, age 43.5±19.7 years; 417 SAH, age 49.7±11.8 years) were included. We studied the prevalence of hypopituitarism reported based on different definitions of laboratory values and stimulation tests. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. The prevalence of hypopituitarism in the chronic phase (at least 5 months after the event) by laboratory values, physician diagnoses, and stimulation tests, was 35%, 36%, and 70%, respectively. Hypopituitarism was less common in the acute phase. According to the frequency of endocrine dysfunction, pituitary hormone secretion was impaired in the following sequence: ACTH, LH/FSH, GH, and TSH. TBI patients with abnormal stimulation tests had suffered from more severe TBI than patients with normal stimulation tests. In conclusion, our data confirm that hypopituitarism is a common complication of TBI and SAH. It is possible that patients with a higher likelihood of hypopituitarism were selected for endocrine stimulation tests.

Objective This study aimed at investigating how symptoms and perceived health changes in acromegalic patients during pegvisomant treatment in respect to IGF-1 levels and disease characteristics.Design/patients Retrospective, multicentre cohort study in 131 acromegalic patients within the German Pegvisomant Observational Study (GPOS).Measurements Outcome measure was the change of perceived health evaluated by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) between baseline and after 1 year of pegvisomant therapy. Predictors were change in IGF-1 levels, maximal pegvisomant dosage, adverse events and comorbidities.Results Perspiration, soft tissue swelling and perceived health improved after 1 year of pegvisomant therapy while other symptoms such as headache, fatigue and joint pain remained largely unchanged over time. The highest mean IGF-1/upper limit of normal (ULN) values before pegvisomant therapy were found in those patients with a reported amelioration in perspiration and soft tissue swelling after 1 year of pegvisomant treatment. The highest mean decrease of IGF-1/ULN was found in those patients with reported amelioration of numbness and tingling of limbs. Other factors such as decrease in fasting glucose may play a role as independent predictor for some symptoms such as the improvement of headache, perspiration and perceived health, while other factors such as maximal pegvisomant dosage, occurrence of adverse events, tumour growth, or liver enzyme elevation did not play a predictive role.Conclusions Patients' symptoms and perceived health are in part an independent construct, not merely reflecting IGF-1 status or biochemical control. Subjective measures should therefore be regularly documented in acromegalic patients as a patient-oriented indicator for treatment success.

Objective: We aimed at investigating the association of age-dependent IGF-I SDS with diabetes, dyslipidemia, hypertension, and heart diseases, in a large patient sample.Background: IGF-I has been suggested to be associated with several diseases and a prognostic marker for the development of cardiovascular diseases and risk factors. The findings, though, have been inconsistent possibly due to the methodological factors.Methods: We studied 6773 consecutive primary care patients, aged 18+ years, in a cross-sectional, epidemiological study in primary care, Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment study. All patients underwent a standardized clinical diagnostic and laboratory assessment. IGF-I levels were measured with an automated chemiluminescence assay system. We calculated the odds ratios (OR) for diseases in quintiles of IGF-I, and additionally analyzed the association of age-dependent IGF-I SDS with these conditions.Results: After multiple adjustments for confounders, we found increased ORs for coronary artery disease in patients with high IGF-I. Women, but not men, with low IGF-I also showed increased ORs for coronary artery disease. Dyslipidemia was positively associated with IGF-I. Type 2 diabetes showed a curvilinear association with IGF-I SDS.Conclusions: The findings suggest the existence of multiple and complex interactions between IGF-I and several health conditions. The complex nature of disease- and subgroup-specific associations along with the methodological factors can be held responsible for divergent findings in previous studies.

Within the last years, it has been established that neuroendocrine dysfunction is a frequent sequel of traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH). However, epidemiological data on the prevalence and incidence of hypopituitarism after TBI and SAH in the general population do not exist. Moreover, very little is known about risk factors and clinical characteristics of pituitary impairment after brain damage.

Objective Patients who have sustained aneurysmal subarachnoid haemorrhage (SAH) often suffer persistent impairments in their quality of life (QoL) and psychological disturbances despite a good neurological outcome. In the light of the high prevalence of partial hypopituitarism in SAH survivors demonstrated in recent investigations, we aimed to determine whether neuroendocrine dysfunction has an impact on QoL and neurobehavioural symptoms in these patients.Design/patients QoL, depression and psychological distress were assessed in 40 SAH survivors who had undergone endocrine function testing at least 1 year after the haemorrhage.Measurements QoL was assessed using the Nottingham Health Profile (NHP), the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Short Form-36 questionnaire (SF-36). The Beck Depression Inventory (BDI) and the Impact of Event Scale (IES) were used to evaluate depression and symptoms of current subjective distress in response to the SAH as a stressful life event, respectively.Results In a stepwise multiple regression analysis, basal cortisol level was included as the first and often only predictor for several QoL domains assessing psychological aspects of well-being and depression whereas physical aspects of QoL were predicted primarily by neurological recovery from the SAH. Severe GH deficiency (GHD) was the first predictor for the criterion NHP subscale 'Energy' and highest stimulated ACTH level in the insulin tolerance test (ITT) was the first predictor for disturbed sleep as assessed with the NHP subscale 'Sleep'.Conclusion Our results provide preliminary data that neuroendocrine disturbances contribute to disturbed QoL, depression and sleeping disturbances in SAH patients.

Context: The diagnosis of GH deficiency ( GHD) in adults is based on provocative tests of GH release, all influenced by clinical factors. It is unknown whether the amount of residual GH reserve under the cutoff value has any physiological implication.Objectives: We used a large pharmacoepidemiological database of adult GHD (KIMS) and tested the impact of confounding factors on GH release of no greater than 3 mu g/liter after an insulin tolerance test ( ITT) and evaluated its potential physiological role.Design, Settings, and Patients: A total of 1098 patients fulfilled the criteria of having a GH peak of no greater than 3 mu g/liter during ITT as well as documented IGF-I levels.Outcomes: The impact of underlying hypothalamic-pituitary disease, age, gender, body weight, as well as treatment modalities such as irradiation on peak GH level to ITT was evaluated, and the correlations between GH peak and targets of GH action were analyzed.Results: The GH response to ITT was regulated by gender, age, and the number of additional pituitary deficiencies. In a multivariate evaluation, the extent of hypothalamic-pituitary dysfunction was the most important single predictor of GH peak in ITT. GH peaks in ITT were positively related to IGF-I levels and high-density lipoprotein-cholesterol, as well as inversely to triglycerides.Conclusions: Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.