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Objective Hypopituitarism diagnosed in childhood, adolescence and young adulthood has the potential to affect growth and somatic development. Less is known about the impact of such a diagnosis on other aspects of development. Design An analysis of the KIMS Database (Pfizer International Metabolic Database) was performed to explore social, educational and vocational outcomes of adult patients diagnosed in childhood, adolescence and young adulthood compared with adult-onset controls. Patients 2952 adult patients diagnosed with hypothalamic pituitary conditions before the age of 25 were divided into 2 group: childhood-onset [

Quality of life (QoL) and psychosocial well-being are substantially impaired in patients with Cushing’s disease (CD), not only at the acute illness stage but also after therapy; however, the reason for these impairments remains unclear. In this cross-sectional, patient-reported outcome study, we conducted a postal survey on psychosocial impairment and coping strategies in patients after surgical treatment of CD in three large tertiary referral centers. In total, 176 patients with CD completed a compilation of self-assessment inventories pertaining to depression (Hospital Anxiety and Depression Scale, HADS), QoL (Short Form SF-36, Tuebingen CD; Tuebingen CD-25), coping style (Freiburg questionnaire on coping with illness, FKV-LIS), and embitterment (Bern Embitterment Inventory), on average 6.8 ± 6.66 years after surgery. Regression analyses were performed to identify predictors of psychosocial impairment. At the time of the study, 21.8 % of patients suffered from anxiety, 18.7 % experienced an above-average feeling of embitterment, and 13.1 % suffered from depression. Maladaptive coping styles (FKV-LIS subscales depressive coping and minimizing importance) emerged as robust and strong predictors of psychosocial impairment in all inventories; while age, sex, and hydrocortisone intake failed to explain the variance in these measures. Similar to several studies in non-pituitary patient cohorts (e.g., patients with multiple sclerosis or lower back pain), our results indicate that psychosocial impairment in CD is significantly influenced by how the patient deals with the illness. Therefore, psychological training of positive coping styles could be a helpful complementary therapy in the overall treatment strategy of CD.

PurposeTo explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.MethodsPatients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5yrs of PEGV treatment.ResultsAmong 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.058.7mg/dl at baseline, 116.4 +/- 44.8mg/dl at year 1 and 120.0 +/- 44.3mg/dl at yr 4. Mean HbA1c was 6.6 +/- 1.2 % at yr 1 vs. 7.0 +/- 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n=109), mean blood glucose decreased by 20.2mg/dl at yr 4, mean HbA1c was 7.0 +/- 1.5% at baseline vs. 6.8 +/- 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs.Conclusions p id=Par4 Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

Objective: To evaluate use of pegvisomant, a growth hormone (GH) receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites). Methods: A descriptive analysis of safety, magnetic resonance imaging (MRI) reading, and treatment outcomes in 710 subjects who received at least 1 pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY. Results: Subjects received a mean of 5.4 years of pegvisomant and were followed in ACROSTUDY for a mean of 3.8 years. A total of 1,255 adverse events (AEs) were reported in 345 subjects (48.6%). Serious AEs (SAEs) were reported in 133 (18.7%) subjects, including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least 1 liver function test (LFT) reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases >3 times the upper limit of normal (ULN). No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, insulin-like growth factor 1 (IGF-1) level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy. Conclusions: ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective for patients with acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit-risk of pegvisomant therapy.

ObjectiveQuality of life (QoL) is impaired in hypopituitary patients and patients with primary adrenal insufficiency. The aim of this study was to analyse the impact of glucocorticoid (GC) replacement on QoL. The main hypothesis was that ACTH-insufficient patients experience a dose-dependent deterioration in QoL.Design, patients and methodsThis was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Data from 2737 adult GH-deficient (GHD) hypopituitary patients were eligible for analysis. Thirty-six per cent were ACTH sufficient and 64% ACTH insufficient receiving a mean±s.d. hydrocortisone equivalent (HCeq) dose of 22.3±8.7 mg (median 20.0). QoL at baseline and 1 year after commencement of GH replacement was assessed by the QoL-assessment of GHD in adults.ResultsAt baseline, no significant difference in QoL was observed between ACTH-sufficient and -insufficient patients. Increasing HCeq dose was associated with worse QoL. Patients on HCeq ≤10 mg had the best and patients receiving ≥25 mg demonstrated the poorest QoL. At 1 year of GH replacement, the improvement in QoL did not differ between ACTH-sufficient and -insufficient patients, and no association was observed between HCeq dose and QoL improvement.ConclusionAdult hypopituitary patients with untreated GHD receiving GC replacement have similar QoL as ACTH-sufficient patients. Among ACTH-insufficient patients, there is a dose-dependent association between increasing dose and impaired QoL. This association may be explained by supraphysiological GC exposure although it remains plausible that clinicians may have increased GC doses in order to address otherwise unexplained QoL deficits.

SummaryObjective Growth hormone (GH) replacement may increase bone mineral density (BMD) in GH-deficient (GHD) adults. The goal of this study was to identify predictors of BMD response to GH replacement in GH naive adults. Design and measurements This was a retrospective analysis of data extracted from KIMS (Pfizer International Metabolic Database), an international pharmacoepidemiological survey of adult GHD patients from 31 countries. Patients A total of 231 GH naive adults were identified (115 women and 116 men) who had BMD measured on the same densitometer in the lumbar spine (LS) and/or femoral neck (FN) both at baseline and after 4 years of GH replacement. Results After 4 years, there was a median (10th, 90th percentile) 4·6% (−5·2%, 12·2%) increase in LS BMD over baseline (P = 0·0001). There was a positive correlation between per cent change in LS BMD and age at the onset of pituitary disease (r = 0·25, P = 0·001). There was no change in FN BMD over baseline [0·0% (−7·3%, 8·5%)]. On multivariate analysis, older age at the onset of pituitary disease predicted a greater increase in LS BMD on GH replacement (r = 0·55, P

ObjectiveGH deficiency (GHD) in adults is characterized by a tendency toward obesity and an adverse body composition with visceral fat deposit and may thus predispose to the development of type 2 diabetes mellitus. The aim of this study was to assess the observed prevalence proportion (PP) and observed PP over expected PP ratio (standardized prevalence proportion ratio, SPR) of diabetes according to International Diabetes Federation criteria in a large cohort of GH-untreated adult-onset GHD patients.Design and methodsAssociations between baseline variables and diabetes prevalence in 6050 GHD patients from KIMS (Pfizer International Metabolic Database) were studied and robust Poisson-regression analyses were performed. Comparisons between baseline status and HbA1c categories in the nondiabetic patients were done with covariance analysis. P values ResultsPP was 9.3% compared with the expected 8.2%. SPR was 1.13 (95% confidence intervals (95% CIs), 1.04–1.23), which was significantly increased in females (1.23; 95% CI, 1.09–1.38%) but not in males (SPR 1.04; 95% CI, 0.92–1.17%). PP increased significantly by age, familial diabetes, country selection, BMI, waist circumference, number of pituitary deficiencies, and GHD etiology. SPR decreased significantly by age and increased significantly by BMI, waist circumference, and IGF1 SDS. Multiple regression model showed that the most important impact on SPR was from age and BMI. HbA1c values of 6.0–6.5% were found in 9.5% of nondiabetic patients and were associated with higher BMI and waist circumference.ConclusionsGHD is associated with an increased prevalence of diabetes, largely to be explained by the adverse body composition. These data urge toward early initiation of lifestyle modification measures.

Objective: Benefits of replacement therapy in growth hormone deficiency (GHD) are well documented in younger and middle-aged patients. The aim of our investigation was to prove the benefit of GH replacement for patients older than 60 years especially in terms of health-related quality of life (HRQoL) of age as well. Design: Data of 743 consecutively recruited patients (394 men, 349 women) with GHD aged 20 - 49 (n = 606) and 60 - 69 (n = 137) years enrolled from KIMS Germany (Pfizer International Metabolic Database) were compared. Treatment effects over the 12 months dose-finding and the subsequent phase up to three years were analysed using mixed models. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI) at baseline and at last visit were studied. HRQoL was assessed using the Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). Results: For both age groups and genders the IGF-I level and standardized IGF-I increased over the dose-finding phase. In women, the overall QoL-AGHDA score at the baseline examination was 8.7 (95% CI: 7.7 - 9.7) and decreased to 6.3 (95% CI: 5.1 - 7.6) at the end of the dose-finding phase (p Conclusion: We could show positive effects of GH replacement on HRQoL in patients older than 60 years of age. Therefore, GH replacement should be considered in elderly GHD adults without difference compared to younger age groups.

ObjectiveHypopituitarism 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.DesignIn KIMS (Pfizer International Metabolic Database) 13 983 GH-deficient patients with 69 056 patient-years of follow-up were available.MethodsThis 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 PResultsAll-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).ConclusionsGH-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.

ObjectiveCushing's disease (CD) and non-functioning pituitary adenoma (NFPA) are rare in paediatric patients. The aim of this study was to describe long-term consequences in adults with GH deficiency (GHD) treated for CD or NFPA during childhood.Design, patients and methodsThis was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Background characteristics, anthropometry and comorbidity were studied in 47 patients diagnosed with childhood-onset (CO)-CD and 62 patients with CO-NFPA. Data from 100 ACTH-sufficient patients with CO-idiopathic hypopituitarism (CO-Idio) were used for comparison. Cardiovascular risk profile was analysed at baseline and at 1 year on GH treatment in a subgroup of patients (17 CO-CD, 24 CO-NFPA and 55 CO-Idio) not receiving GH treatment at study entry.ResultsThe median age at diagnosis of pituitary tumour was 14.0 years (range 10–17) in patients with CO-CD and 13.7 years (range 8–17) in CO-NFPA. In addition to GHD, 41% of patients with CO-CD had three or four other pituitary hormone deficiencies compared with 78% of patients with CO-NFPA (PP=0.002). Hypertension was more common in CO-CD compared with CO-Idio (23 vs 9%,P=0.018). At 1 year on GH treatment, total- and low-density lipoprotein-cholesterol decreased significantly in CO-CD but not in CO-NFPA.ConclusionAdult patients with GHD following treatment for paediatric CD and NFPA have long-term adverse consequences. Despite more severe hypopituitarism in CO-NFPA, patients with CO-CD have more frequently compromised final stature.

OBJECTIVE Growth hormone (GH) deficiency is associated with insulin resistance and diabetes. The aim of the current study was to determine incidence of diabetes during GH replacement therapy (GHRT) and the effect of GHRT on fasting plasma glucose concentrations and HbA1c in adult patients with GH deficiency. RESEARCH DESIGN AND METHODS A total of 5,143 GH-deficient patients (male 49.9%; mean age ± SD, 49 ± 13 years; BMI 29.1 ± 5.9 kg/m2) were analyzed. Mean observation period was 3.9 years (range 0.01–13). Total number of patient-years was 20,106. Observed number of cases (O) was compared with expected number of cases (E). Reference rates were from Sweden, three additional European regions, and one U.S. region. RESULTS Patients who developed diabetes (n = 523) were older; had higher BMI, waist circumference, triglyceride concentrations, and blood pressure; and had lower HDL-cholesterol concentrations (P < 0.0001) than those who did not develop diabetes. Diabetes incidence was 2.6 per 100 patient-years, equal in both sexes, and significantly increased compared with the Swedish reference (O/E = 6.02; P < 0.0001) as well as with the four other populations (O/E = 2.11–5.22). O/E increased with BMI and decreased with duration of GHRT (P < 0.0001). There was no significant association with GH dose (P = 0.74) or IGF-I SDS (P = 0.47). In subjects not developing diabetes, plasma glucose concentrations increased from 84.4 ± 0.9 mg/dL to 89.5 ± 0.8 mg/dL (0.70 mg/dL/year) and HbA1c increased from 4.74 ± 0.04% to 5.09 ± 0.13% (0.036%/year) after 6 years of GHRT. CONCLUSIONS Diabetes incidence appears to be increased in GH-deficient patients receiving GHRT and exhibiting an adverse risk profile at baseline. Therefore, glucose homeostasis parameters should be monitored carefully in these patients.

Context: The prevalence of obesity is increased in hypopituitarism. In the general population, body mass index (BMI) and waist circumference increase with advancing age. It remains uncertain whether age-related changes in pituitary function contribute to the changes in body composition associated with advancing years.Objective: Our objective was to study the relationship between pituitary function, body composition, and age in a large cohort of patients with hypopituitarism and a matched reference population.Design, Setting, and Participants: A total of 3632 GH-deficient adults with hypopituitarism, adequately replaced with all pituitary hormones except for GH, from the prospective KIMS database (Pfizer International Metabolic Database) were included in present analysis. A random sample of the general population (3427 subjects) was used as reference. Patients and controls were grouped by gender in five age cohorts of 10 yr from 28 yr onward.Main Outcome Measures: Differences in BMI and waist circumference were evaluated.Results: Patients had a significantly higher BMI and waist circumference than controls, with larger differences at younger age. With advancing age, an increase in BMI and waist circumference was seen in controls but was virtually absent in the patients with adult-onset GH deficiency and hypopituitarism.Conclusion: Patients with hypopituitarism have more excess body fat than age-matched controls, especially in the youngest age groups. The normal increase in fat mass with advancing age is not seen in adult-onset GH-deficient hypopituitarism, suggesting a potential role for the normal pituitary gland as an age-dependent regulator of body composition in adult life. (J Clin Endocrinol Metab 95: 3664-3674, 2010)

ObjectivePatients in remission from Cushing's disease (CD) have many clinical features that are difficult to distinguish from those of concomitant GH deficiency (GHD). In this study, we evaluated the features of GHD in a large cohort of controlled CD patients, and assessed the effect of GH treatment.Design and methodsData were obtained from KIMS, the Pfizer International Metabolic Database. A retrospective cross-sectional comparison of background characteristics in unmatched cohorts of patients with CD (n=684, 74% women) and nonfunctioning pituitary adenoma (NFPA;n=2990, 39% women) was conducted. In addition, a longitudinal evaluation of 3 years of GH replacement in a subset of patients with controlled CD (n=322) and NFPA (n=748) matched for age and gender was performed.ResultsThe cross-sectional study showed a significant delay in GHD diagnosis in the CD group, who had a higher prevalence of hypertension, fractures, and diabetes mellitus. In the longitudinal, matched study, the CD group had a better metabolic profile but a poorer quality of life (QoL) at baseline, which was assessed with the disease-specific questionnaire QoL-assessment of GHD in adults. After 3 years of GH treatment (mean dose at 3 years 0.39 mg/day in CD and 0.37 mg/day in NFPA), total and low-density lipoprotein cholesterol decreased, while glucose and HbAlc increased. Improvement in QoL was observed, which was greater in the CD group (−6 CD group versus −5 NFPA group,PConclusionIn untreated GHD, co-morbidities, including impairment of QoL, were more prevalent in controlled CD. Overall, both the groups responded similarly to GH replacement, suggesting that patients with GHD due to CD benefit from GH to the same extent as those with GHD due to NFPA.

Objectives To examine quality of life (QoL) measured by a utility-weighted index in GH-deficient adults on GH replacement and analyse the impact of demographic and clinical characteristics on changes in utilities during treatment. Design Utilities for items in the QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDAutility) were estimated based on data obtained from the general population in England and Wales (E&W). These estimates were used to calculate QoL changes in GH-treated patients and compare these with normative population values. Patients A total of 894 KIMS patients (53% women) from E&W were followed for 1 to 6 years. Measurements QoL-AGHDAutility at baseline and at the last reported visit, total QoL-AGHDAutility gain and QoL-AGHDAutility gain per year of follow-up. Results QoL-AGHDAutility in patients before GH treatment differed from the expected population values [0·67 (SD 0·174) vs. 0·85 (SD 0·038), P < 0·0001], constituting a mean deficit of –0·19 (SD 0·168). There was a difference in the mean QoL-AGHDAutility deficit for men [–0·16 (SD 0·170)] and women [–0·21 (SD 0·162)] (P < 0·001). The main improvement occurred during the first year of treatment [reduction of a deficit to –0·07 (SD 0·163) (P < 0·001) in the total cohort]; however, patients’ utilities remained lower than those recorded for the general population during subsequent follow-up (P < 0·001). Despite an observed impact of age, primary aetiology, disease onset and comorbidities on QoL-AGHDAutility, all patients showed a similar beneficial response to treatment. Conclusions QoL-AGHDAutility efficiently monitors treatment effects in patients with GHD. The study confirmed the QoL-AGHDAutility deficit before treatment and a similar QoL-AGHDAutility gain observed after commencement of GH replacement in all patients.

Early diagnosis is a success factor for the prevention of long-term comorbidity and premature death in patients with acromegaly, but large-scale data on the diagnostic process and disease management are scarce. Therefore, we aimed to evaluate the diagnostic process, implementation of treatment and changes in life situation in patients with acromegaly, focusing on sex-specific differences. Non-interventional patient-reported outcome study. 165 patients with clinically and biochemically proven acromegaly were questioned about the diagnostic process and utilization of health care by means of a self-developed standardized postal survey including questions on acromegaly symptoms experienced before diagnosis, number and specialty of consulted doctors, time to diagnosis and aftercare. The diagnostic process took 2.9 (SD 4.53) years, during which 3.4 (SD 2.99) physicians were consulted. Women waited longer [4.1 (SD 5.53) years] than men [1.6 (SD 2.69) years; p = 0.001] for the correct diagnosis, and consulted more doctors in the process [4.0 (SD 2.99) vs. 2.7 (SD 2.84) doctors, p

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.

ObjectivePrevalence of GH deficiency (GHD) caused by traumatic brain injury (TBI) is highly variable. Short-term studies show improvement in quality of life (QoL) during GH replacement (GHR), but long-term data are lacking. The aim of this study was to analyse the clinical characteristics of post-traumatic hypopituitarism and the QoL effects of long-term GHR.Design/methodsPfizer International Metabolic Database patients with GHD caused by TBI and by non-functioning pituitary adenoma (NFPA) were compared regarding: clinical characteristics at baseline and 1-year of GHR, and QoL response up to 8-years of GHR (QoL-AGHDA total scores and dimensions) in relationship with country-specific norms.ResultsTBI patients compared with NFPA patients were younger, diagnosed with GHD 2.4 years later after primary disease onset (PP=0.004) and received higher GH dose (mean difference: 0.04 mg/day P=0.006). In TBI patients, 1-year improvement in QoL was greater than in NFPA (change in QoL-AGHDA score 5.0 vs 3.5, respectively, P=0.04) and was sustained over 8 years. In TBI patients, socialisation normalised after 1 year of GHR, self-confidence and tenseness after 6 years and no normalisation of tiredness and memory was observed.ConclusionCompared with NFPA, TBI patients presented biochemically with less severe hypopituitarism and worse QoL scores. GHR achieved clinically relevant, long-term benefit in QoL.

Context:GH deficiency (GHD) may occur in adults with cured acromegaly (acroGHD).Objective:Our objective was to examine the effectiveness and safety of GH replacement in acroGHD.Design:This study was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database).Setting:Data were extracted from a pharmaco-epidemiological survey of >16 000 GHD adults from 31 countries.Patients:The effectiveness population included 115 adults with acroGHD and 142 age-, gender-, and body mass index-matched GHD adults with nonfunctioning pituitary adenoma (NFPA) followed up to 5 years on GH. The safety population included 164 adults with acroGHD and 2469 with NFPA, all GH-replaced. Both acroGHD and NFPA were compared with several cohorts from the general population (including the World Health Organization Global Burden of Disease).Outcome Measures:Outcome measures included quality of life (QoL-AGHDA), lipids, serious adverse events, and additional safety endpoints.Results:Median GH dose was 0.3 mg/d in acroGHD and NFPA at 5 years. There were comparable improvements in QoL-AGHDA and total and low-density lipoprotein cholesterol in acroGHD and NFPA. High-density lipoprotein cholesterol increased only in acroGHD. Cardiovascular mortality was increased in acroGHD vs NFPA (standardized mortality ratio = 3.03, P = .02). All-cause mortality was similar in acroGHD (ratio between observed/expected cases [95% confidence interval] = 1.32 [0.70–2.25]) and lower in NFPA [observed/expected = 0.58 [0.48–0.70]) in comparison with the general population. There was no difference in incidence of all cancers, benign or malignant brain tumors, or diabetes mellitus between acroGHD and NFPA.Conclusions:GH replacement has comparable effects on quality of life and lipids in acroGHD and NFPA. Further investigation is needed to examine whether the increased cardiovascular mortality may be attributed to the history of previous GH excess in acroGHD.

Context: Craniopharyngiomas are often associated with significant morbidity due to their location and treatment effects. Little is known of the effects of primary treatment regimen and diabetes insipidus (DI), a clinical surrogate of hypothalamic obesity, on health outcomes in adults with childhood-onset craniopharyngioma (COCP). Objective: The objective of the study was to examine health outcomes of adults with COCP based on primary treatment regimens and the presence of DI. Design: This study included a retrospective KIMS (Pfizer International Metabolic Database) data analysis of 180 adults with COCP according to the primary treatment regimen [one surgery (1Surg) vs complex treatment regimen (CTrR) of more than 1Surg and/or radiotherapy] and the presence of DI. Results: The majority of COCP patients underwent transcranial surgery (77%) without receiving radiotherapy (84%). Compared with the 1Surg group, more CTrR patients developed visual field defects and ophthalmoplegia (all P < .01). Compared with patients without DI, those with DI had higher rates of anterior pituitary hormone deficits, body mass index, and fat mass (all P < .01). By contrast, fasting glucose, hemoglobin A1c, lipid panel, and quality of life were comparable among 1Surg vs CTrR patients, and patients with vs without DI. Regardless of primary treatment received, the presence of DI in either group was associated with higher rates of anterior pituitary hormone deficits and obesity. Conclusion: CTrR and DI predicted health outcomes differently. CTrR predisposed to the development of visual dysfunction, whereas DI was associated with higher rates of anterior pituitary dysfunction and weight gain. Higher body mass index and fat mass in patients with DI further implicate the role of hypothalamic damage as an important causal factor of obesity in these patients.

ObjectiveAdults with childhood-onset (CO) craniopharyngioma (COCP) have poor quality of life (QoL) and clinical outcomes, but few studies have compared these patients with adults with other causes of CO hypothalamic–pituitary dysfunction. In this study, we compared baseline clinical characteristics and patient-reported outcomes before starting GH replacement therapy in adults with GH deficiency (GHD) due to COCP with those of adults either with CO idiopathic/congenital hypopituitarism (COH) or with CO extrasellar (COE) tumours, and evaluated the 1- and 5-year effects of GH replacement therapy.Subjects and methodsRetrospective analysis of the data recorded in KIMS (Pfizer International Metabolic Database) was carried out. Patients with COCP, COH and COE tumours were evaluated at baseline, and after 1 and 5 years of therapy.ResultsCompared with COH and COE patients, more COCP patients underwent surgery, had greater abnormalities of body composition and higher prevalence of pituitary hormone deficits (allPConclusionsAdults with untreated COCP with GHD at baseline demonstrated more co-morbidities including greater abnormalities of body composition, pituitary hormone deficits and visual field defects. Overall, adults with COCP, COH and COE tumours responded comparably to short- and long-term GH replacement therapy, suggesting that patients with GHD due to COCP benefited from GH replacement therapy to a similar degree as those with other causes of CO hypothalamic–pituitary dysfunction did.

ObjectiveWe 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 measurementsThe 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.ResultsLower 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.ConclusionOur 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.

BACKGROUND: To evaluate the cost-effectiveness of growth hormone (GH) treatment (Genotropin(R)) compared with no GH treatment in adults with GH deficiency in a Swedish societal setting. METHODS: A Markov-type cost-utility simulation model was constructed and used to simulate, for men and women, morbidity and mortality for GH-treated and -untreated individuals over a 20-year period. The calculations were performed using current available prices concerning morbidity-related healthcare costs and costs for Genotropin(R). All costs and treatment effects were discounted at 3%. Costs were expressed in Euro (1[euro sign] = 9.03 SEK). GH-treated Swedish patients (n = 434) were identified from the KIMS database (Pfizer International Metabolic Database) and untreated patients (n = 2135) from the Swedish Cancer Registry and the Hospital Discharge Registry. RESULTS: The results are reported as incremental cost per quality-adjusted life year (QALY) gained, including both direct and indirect costs for GH-treated versus untreated patients. The weighted sum of all subgroup incremental cost per QALY was [euro sign]15,975 and [euro sign]20,241 for men and women, respectively. Including indirect cost resulted in lower cost per QALY gained: [euro sign]11,173 and [euro sign]10,753 for men and women, respectively. Key drivers of the results were improvement in quality of life, increased survival, and intervention cost. CONCLUSIONS: The incremental cost per QALY gained is moderate when compared with informal thresholds applied in Sweden. The simulations suggest that GH-treatment is cost-effective for both men and women at the [euro sign]55,371 (SEK 500,000 -- the informal Swedish cost-effectiveness threshold) per QALY threshold.

ObjectivesNeuroimaging has become an essential part of the diagnostic process in children with GH deficiency (GHD). The aim of the study was to document the frequency of neuroanatomical abnormalities in a very large cohort of children with GHD and to relate these findings to patient clinical characteristics.Design and methodsResults of magnetic resonance imaging (MRI) were reported in 15 043 of 43 725 children with non-acquired GHD (idiopathic, neurosecretory dysfunction (NSD) and known congenital cause) who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011. Clinical characteristics of patients before GH treatment with normal MRI (idiopathic GHD (IGHD) and NSD) were compared with those of patients with abnormal pituitaries (hypoplasia, empty sella (ES), HME (hypoplastic anterior pituitary, missing pituitary stalk and ectopic posterior pituitary)).ResultsAbnormal MRIs were found in 4032 (26.8%) children, within which ES (n=1178 (7.8%)) and HME (n=1019 (6.8%)) were the most frequent findings. In 2361 children diagnosed as IGHD or NSD before MRI examination, anatomical abnormalities ((pituitary hypoplasia:n=974); (HME:n=459)) were documented. Patients with anatomical abnormalities had more severe characteristics of GHD: normal MRI < pituitary hypoplasia < ES < HME.ConclusionsGHD is associated with a great variety of neuroanatomical abnormalities as identified by MRI. The investigation and evaluation of MRI need to be conducted in a structured mode. There is an association between anatomical and functional abnormalities of the pituitary.

ObjectiveChildhood-onset GH deficiency (COGHD) is associated with low bone mineral density (BMD). Adults with persistent COGHD may be at risk for insufficient bone accrual or bone loss during adulthood. The purpose of this study was to identify BMD predictors and to characterize the effects of GH replacement on BMD in COGHD adults with persistent GHD.DesignRetrospective analysis of the KIMS database.MethodsVariables predicting standardized BMD (sBMD) were identified. The effect of GH replacement (3 years) on BMD was examined.ResultsThree hundred and fourteen COGHD adults (148 women, 166 men; 62 non-naïve, 178 semi-naïve, and 74 true naïve, depending on length and timing of previous GH replacement), who had BMD measured in lumbar spine (LS) and femoral neck (FN) at study entry.In semi-naïve subjects, a longer gap in GH replacement between childhood and adulthood was predictive of lower sBMD in the FN (r=−0.18, P=0.038). TSH deficiency predicted lower sBMD in the LS (r=−0.16, P=0.052). In true naïve patients, a longer gap between onset of pituitary disease and study entry (r=−0.35, P=0.012), and female gender (r=−0.27, P=0.043) independently predicted lower sBMD in the FN. There were no differences in BMD increases between non-naïve, semi-naïve, and true naïve subjects on GH replacement.ConclusionsIn semi-naïve subjects a longer interval off GH replacement was associated with lower sBMD in the FN. Among true naïve patients, a longer gap between the onset of pituitary disease and GH replacement, and female gender predicted lower sBMD in the FN.

OBJECTIVE Growth hormone (GH) deficiency is associated with insulin resistance and diabetes. The aim of the current study was to determine incidence of diabetes during GH replacement therapy (GHRT) and the effect of GHRT on fasting plasma glucose concentrations and HbA1c in adult patients with GH deficiency. RESEARCH DESIGN AND METHODS A total of 5,143 GH-deficient patients (male 49.9%; mean age ± SD, 49 ± 13 years; BMI 29.1 ± 5.9 kg/m2) were analyzed. Mean observation period was 3.9 years (range 0.01–13). Total number of patient-years was 20,106. Observed number of cases (O) was compared with expected number of cases (E). Reference rates were from Sweden, three additional European regions, and one U.S. region. RESULTS Patients who developed diabetes (n = 523) were older; had higher BMI, waist circumference, triglyceride concentrations, and blood pressure; and had lower HDL-cholesterol concentrations (P < 0.0001) than those who did not develop diabetes. Diabetes incidence was 2.6 per 100 patient-years, equal in both sexes, and significantly increased compared with the Swedish reference (O/E = 6.02; P < 0.0001) as well as with the four other populations (O/E = 2.11–5.22). O/E increased with BMI and decreased with duration of GHRT (P < 0.0001). There was no significant association with GH dose (P = 0.74) or IGF-I SDS (P = 0.47). In subjects not developing diabetes, plasma glucose concentrations increased from 84.4 ± 0.9 mg/dL to 89.5 ± 0.8 mg/dL (0.70 mg/dL/year) and HbA1c increased from 4.74 ± 0.04% to 5.09 ± 0.13% (0.036%/year) after 6 years of GHRT. CONCLUSIONS Diabetes incidence appears to be increased in GH-deficient patients receiving GHRT and exhibiting an adverse risk profile at baseline. Therefore, glucose homeostasis parameters should be monitored carefully in these patients.

ObjectiveAn increased risk of cardiovascular morbidity and mortality in adult GH deficiency (GHD) may be related to hypopituitarism but also to the presence of the metabolic syndrome (MetS). Our objective was to investigate the characteristics and prevalence of MetS as well as its comorbidities in adult GHD.DesignIn KIMS (Pfizer International Metabolic Database) 2479 patients with severe adult-onset GHD, naïve to GH replacement, with complete information on all MetS components were found. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP) and the International Diabetes Foundation (IDF).MethodsThe prevalence of MetS was calculated and compared with previously published data from the normal population. Associations were assessed between background variables, baseline variables, comorbidities, and MetS.ResultsMetS was present in 43.1% (NCEP) and in 49.1% (IDF) of patients, clearly higher than data from the normal population (20–30%). MetS prevalence was related to age, GHD duration, and body mass index (BMI), but not to GHD severity, extent of hypopituitarism, or etiology of pituitary disease. Adjusted for age, gender, and BMI, patients with MetS had a higher prevalence ratio for diabetes mellitus: 4.65 (95% confidence interval (CI): 3.29–6.58), for cardiovascular morbidity: 1.91 (95% CI: 1.33–2.75), and for cerebrovascular morbidity: 1.77 (95% CI: 1.09–2.87) than patients without MetS.ConclusionsMetS is highly prevalent in GHD and is associated with a higher prevalence ratio for comorbidities. The presence of MetS in GHD may therefore contribute to the increased risk of cardiovascular morbidity and mortality found in these patients.

OBJECTIVE: This study reports on the Brazilian Portuguese adaptation of the QoL-AGHDA (Quality of Life Assessment of Growth Hormone Deficiency in Adults) for use in adult growth hormone deficient (GHD) patients. MATERIALS AND METHODS: The translation process adopted the dual panel methodology. The questionnaire was tested through field-test interviews (16 GHD patients). In the final stage, data from 120 GHD patients (81 included in a test-retest analysis) were analyzed for internal consistency, test-retest reliability, convergent validity and validity among known groups. RESULTS: The translation panels were successful and the draft version was amended to improve the wording as a result of the field-test interviews. Cronbach's alpha was 0.90 and test-retest reliability 0.88. QoL-AGHDA scores had the expected pattern of association with NHP scale scores and QoL-AGHDA was able to differentiate significantly between patients based on patient-reported general health (p < 0.01) and QoL (p < 0.01). CONCLUSIONS: The adaptation of the QoL-AGHDA for a Brazilian population was successful and the adapted questionnaire was shown to be reliable and valid.

Context: The association between IGFs and cancer in adults with GH deficiency (GHD) receiving GH replacement requires investigation. Objective: The objective was to examine the association between IGF-I, IGF-binding protein 2 (IGFBP-2), and IGFBP-3 sd scores (SDSs) in GH-deficient adults receiving GH therapy and the occurrence of de novo malignancies. Design: Serum IGF-I, IGFBP-2, and IGFBP-3 levels in GH-deficient patients who developed a malignancy since receiving GH were compared with patients with idiopathic GHD but without malignancy. Measurements were related to age-, sex-, and body mass index-specific SDS reference regions. Setting: The setting included the KIMS (the Pfizer International Metabolic Database). Patients: One hundred patients with de novo malignancy during GH therapy were compared with 325 patients with idiopathic GHD without malignancy. Intervention(s): Serum samples were obtained as close as possible to the diagnosis of malignancy, or after approximately 2 yr of GH replacement in KIMS. Main Outcome Measures: Associations between relative risk (RR) of malignancy and IGF-I, IGFBP-2, and IGFBP-3 SDSs were assessed in multiple log-linear Poisson working regression models, controlling for age, sex, onset of GHD, and GH naivety at KIMS entry. Results: No association between IGF-I SDSs and RR was observed (P = 0.48). Increasing IGFBP-2 and IGFBP-3 SDSs were associated with increasing RRs [18% per unit IGFBP-2 SDSs (95% confidence interval, 7–30%; P = 0.0006), 13% per unit IGFBP-3 SDS (2–26%; P = 0.01)]. Conclusions: IGF-I levels targeted to within normal age-related reference ranges during GH replacement were not associated with the occurrence of malignancies. Higher IGFBP-2 and/or IGFBP-3 SDSs may be associated with increased cancer risk.

Context: Little is known about the impact of childhood-onset GH deficiency (GHD), in particular the duration of GH cessation during the transition phase, on adult phenotype. Objective: We investigated the association between the manifestations and management of GHD during childhood/adolescence and the clinical features of GHD in adulthood. Design/Setting/Patients/Intervention: Patients with reconfirmed childhood-onset GHD who resumed GH treatment as adults were identified from two sequential databases (n = 313). The cohort was followed up longitudinally from GH start in childhood to reinitiation of treatment in adulthood and 1 yr beyond. Analyses were performed in the total cohort and in subgroups of patients with idiopathic GHD (IGHD) and non-IGHD. The cohorts were stratified based on duration of GH cessation (short, ≤2 yr; long, >2 yr). Main Outcome Measures: Regimen of pediatric GH administration, duration of GH interruption, IGF-I sd score, lipid concentrations, and quality of life were measured. Results: Mean duration of GH interruption was 4.4 yr. IGF-I sd score in adulthood was related to severity of childhood GHD. In non-IGHD patients, a longer duration of GH interruption was associated with a worse lipid profile (P < 0.0001). Non-IGHD patients who gained more height during childhood GH treatment reported better quality of life than those who gained less height (P < 0.05). Conclusions: Pediatricians should tailor GH treatment, not only for its beneficial effect on growth but also for future health in adulthood. In adults with reconfirmed GHD, particularly those with non-IGHD, early recommencement of GH should be considered.

Context Pegvisomant (Somavert, Pfizer Inc.) is the first and only available GH receptor antagonist. ACROSTUDY is an international surveillance study that offers inclusion in a web-based registry to all patients with acromegaly treated with pegvisomant; it aims at monitoring long-term safety and efficacy of this compound. Patients and methods This report summarizes the main baseline characteristics of this particular population of patients. In February 2009, over 300 centres in 10 countries had contributed 792 patients. A gradual increase in cumulative patient recruitment was observed since the launching of ACROSTUDY in 2004: from 116 patients in 2005, it steeply increased to 792 at the latest data freeze in February 2009. At the time of enrolment, 91.8% of patients were already treated with pegvisomant but baseline was considered at the time of pegvisomant start. IGF1 concentrations were measured at local laboratories. Results Of all patients, 80% were reported to have had surgery and 33% to have received radiation therapy. Of the 792 patients, 14% had received no prior medical treatment before pegvisomant start, 65.9% had received somatostatin analogues and 18.6% dopamine agonists. Interestingly, 66.7% had received only pegvisomant at study start, while it was taken in association with dopamine agonists in 5.7%, with somatostatin analogues in 23.4% and with both types of agents in 3.8%. Mean IGF1 at baseline was 522 ng/ml. Conclusion Analysis of the baseline features of these patients treated with pegvisomant and reported in the ACROSTUDY database underscores the severity of the disease in this subset of the population of patients with acromegaly previously unresponsive to several medical, surgical or radiation treatment approaches.

Quality of life (QoL) has emerged as an important construct that has found numerous applications across healthcare-related fields, ranging from research and clinical evaluation of treatment effects to pharmacoeconomic evaluations and global healthcare policy. Impairment of QoL is one of the key clinical characteristics in adult GHD and has been extensively studied in the Pfizer International Metabolic Database (KIMS). We provide summarized evidence on GH treatment effects for both clinical and health economic applications based on the KIMS data. The primary focus is on those aspects of QoL research that cannot be investigated in the traditional clinical trial setting, such as specific patient subgroups, cross-country comparisons and long-term follow-up. First, the impact of age, gender, disease onset, primary aetiology, extent of hypopituitarism, previous radiotherapy and obesity on QoL before and during long-term GH replacement is discussed. Secondly, the studies on QoL in relation to country-specific normative values are reviewed. Finally, health economic data derived from KIMS including both burden of disease and utility assessment are evaluated. We conclude that the wide spectrum of analyses performed on the KIMS data allows for practical application of the results not only to research and clinical practice but also to health policy and global medical decision making.

ObjectiveTo analyse 12-month response to GH treatment in a single-country cohort of hypopituitary adult patients with GH deficiency (GHD) in regards to health-related quality of life (HRQoL) and insulin-like growth factor-1 (IGF-1) compared with values from general population sample. Moreover, association between the response in HRQoL and the IGF-1 values in patients and in the background population was investigated.DesignHRQoL was assessed by quality of life assessment of GH deficiency in adults (QoL-AGHDA) in 651 patients retrieved from the German KIMS (Pfizer International Metabolic Database) before and after 12 months of GH replacement and in a sample drawn from a cross-sectional study in Germany (n=2734). IGF-1 was measured in KIMS patients and in the population-based study with the same assay technique.ResultsIn KIMS patients, mean QoL-AGHDA scores before GH replacement were 9.2±6.8 (8.7±6.8) in women (men) and in the general population sample 4.5±5.3 (4.3±5.0) in women (men). Mean differences in QoL-AGHDA scores were statistically significant for all age categories (PConclusionsThis study confirms an improvement in HRQoL and an increase of IGF-1 SDS in GH-replaced adults, which approximated the values of general population. However, there was no association between IGF-1 values and HRQoL assessment as one of the important treatment outcomes.

The concept of health-related quality of life (HrQoL) reflects the subjective perception of health and includes aspects of well-being and functioning in physical, emotional, mental and social life domains. Nowadays, HrQoL has become a relevant treatment outcome from epidemiological and clinical perspectives and is also broadly employed in health economic analyses. To assess HrQoL generic as well as condition-specific instruments are used. The former are applicable to a wide range of health conditions and aim at measuring HrQoL across different conditions. The latter focus on capturing the impact of a specific disease. Although HrQoL research in adults is now well-advanced, there are still open questions regarding how to assess HrQoL in pediatric conditions, such as short stature. Eight generic (one chronic-generic) and seven condition-specific (one treatment-specific) instruments used in HrQoL research in short stature of youth are described. Additionally, this mini review identifies a need for further research and indicates potential directions.

ObjectiveGH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL.Design and methodsAdult GHD subjects from the Pfizer International Metabolic Database were grouped according to BMI (n=291 with BMI 2, n=372 with BMI 25–30 kg/m2, n=279 with BMI >30 kg/m2), WG (n=508 with normal WG, n=434 with increased WG) and FM (n=357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-I concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment.ResultsAt baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups.ConclusionsVariables of obesity adversely affect the already unfavourable lipid profile in GHD subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.

Research on the health-related quality of life (HrQoL) impact of short stature and its treatment in children and adolescents has developed recently. Based on a PubMed literature search, studies addressing this issue were identified and considerable methodological problems mainly related to the HrQoL instruments used and conflicting results are discussed in this mini review. Additionally, this mini review identifies a need for further research and indicates potential directions.

ObjectiveThe impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy.Design and methodsData from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement.ResultsGHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement.ConclusionThe adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

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.

Objective: The aim of the present study was to clarify the relationship between GH deficiency (GHD) and some cardiovascular risk factors and to analyse the effect of GH replacement therapy in a large number of patients over a prolonged period of time. Design: Data for analysis were retrieved from KIMS (Pfizer International Metabolic Database). Serum concentrations of total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides were obtained from 2589 patients at baseline and from 1206 patients after 1 and 2 years of GH replacement therapy. Body mass index (BMI), waist and hip, resting blood pressure and body composition were also measured. Results: At baseline, the unfavourable effects of GHD were most obvious in the lipid profile demonstrating elevated mean total and LDL-cholesterol, in the increased waist circumference and the elevated BMI. The cholesterol concentration, BMI and body composition were significantly adversely affected by a number of factors, including age, sex and the use of anti-epileptic drugs. The therapeutic effect of GH was essentially uniform across the whole population. GH replacement reduced significantly the mean total and LDL-cholesterol, the waist circumference and the fat mass and was maintained during 2 years. Conclusions: This analysis of a large number of patients confirmed that GHD adults present with an increased cardiovascular risk. The sustained improvement of the adverse lipid profile and body composition suggests that GH replacement therapy may reduce the risk of cardiovascular disease and the premature mortality seen in hypopituitary patients with untreated GHD.

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: To test the hypothesis whether the effects of GH replacement therapy in adults could be affected by prior pituitary irradiation, the baseline characteristics and response to GH were evaluated in adults with severe GH deficiency (GHD), who had received or not irradiation for the treatment of pituitary adenoma or craniopharyngioma. Design: Data from 447 patients, who had received radiotherapy (427 in addition to surgery), and 630 patients, who were operated on but not irradiated for their tumour, were retrieved from Pfizer International Metabolic Database (KIMS) and compared at baseline and 1 and 2 years following the onset of GH replacement. Results: Irradiated and non-irradiated patients exhibited the expected phenotype of GHD at baseline. However, irradiated patients had a greater impairment in the quality of life (QoL), a higher fat mass, lower high-density lipoprotein cholesterol levels and a lower bone mineral content (BMC) than non-irradiated patients. Treatment with GH induced similar changes in both groups. After 1 year of GH replacement, there was an increase in serum IGF-I and fat-free mass, a reduction in fat mass and an improvement in QoL, all changes being equivalent in irradiated and non-irradiated patients. The lipid profile also improved with the irradiated patients showing a better response. These beneficial effects were maintained and the BMC also increased in both groups by the second year of treatment. Conclusions: This analysis shows that prior irradiation for pituitary adenoma or craniopharyngioma does not compromise the beneficial effects of GH replacement therapy.

What form of estrogen to prescribe a young hypopituitary woman with gonadal failure remains an open question despite evidence that oral estrogen therapy induces GH resistance and an increase in fat mass.Using an international surveillance study of hypopituitary patients, we examined two questions: 1) What estrogen is prescribed to young women of fertile years with hypopituitarism? 2) Is there a difference in body composition or IGF-I levels dependent on the type of estrogen prescribed?Six hundred twenty-eight GH-deficient women, aged 18-50 yr, were identified. Three hundred thirteen had normal gonadal function, and 315 were receiving estrogen therapy; of these 14% were using transdermal estradiol, and 86% were taking an oral estrogen preparation (38% oral estradiol, 18% conjugated estrogens, and 30% ethinyl estradiol in the oral contraceptive). There was no difference in weight, waist/hip ratio, or body composition between the women taking different estrogen therapies. However, if the oral estrogen groups were combined, they showed less change in waist and hip measurement and had a greater waist/hip ratio after 1 yr of GH treatment compared with patients with normal gonadal function (0.85 vs. 0.83; P = 0.022). Patients taking ethinyl estradiol had lower age-adjusted IGF-I sd scores and required almost twice the GH dose to achieve an IGF-I sd score that remained lower than patients with normal gonadal function and patients receiving transdermal estradiol.1) The majority of women of fertile years with hypo-pituitarism take oral estrogen replacement therapy. 2) Waist/hip ratio was greater in women taking oral estrogens, and there is indirect evidence that oral estrogens reduce the action of GH on fat mass. 3) Patients using the oral contraceptive had lower IGF-I levels and required twice the GH dose compared with patients receiving transdermal estradiol.

Objective: Sheehan’s syndrome occurs as a result of ischaemic pituitary necrosis due to severe postpartum haemorrhage. It is one of the most important causes of hypopituitarism, and hence growth hormone deficiency (GHD), in developing countries. However, little is known about the effects of growth hormone (GH) replacement therapy in patients with Sheehan’s syndrome. Design: The demographic background characteristics of 91 GH-deficient patients with Sheehan’s syndrome (mean age ± s.d., 46.3 ± 9.4 years) were compared with those of a group of 156 GH-deficient women (mean age ± s.d., 51.5 ± 13.1 years) with a non-functional pituitary adenoma (NFPA). The baseline characteristics and the effects of 2 years of GH replacement therapy were also studied in the 91 patients with Sheehan’s syndrome and an age-matched group of 100 women with NFPA (mean age ± s.d. 44.5 ± 10.2 years). Results: All patients were enrolled in KIMS (Pfizer International Metabolic Database). Patients with Sheehan’s syndrome were significantly younger at pituitary disorder onset, diagnosis of GHD and at entry into KIMS than patients with NFPA (P < 0.01), and had significantly lower insulin-like growth factor I levels (P < 0.001). At baseline, quality of life (QoL) was significantly (P < 0.05) reduced in patients with Sheehan’s syndrome compared with those with NFPA (P < 0.001). With regard to treatment effects, lean body mass increased significantly (P < 0.05), QoL improved significantly (P < 0.05) and total and low-density lipoprotein-cholesterol decreased significantly (P < 0.05) in patients with Sheehan’s syndrome after 1 year of GH replacement therapy. Similar significant changes in QoL and lipid profiles occurred in patients with NFPA after 2 years of GH replacement. Blood pressure remained unchanged in patients with Sheehan’s syndrome, but decreased significantly (P < 0.01) in the group with NFPA after 1 year, before returning to pretreatment levels at 2 years. Conclusions: In conclusion, patients with Sheehan’s syndrome have more severe GHD compared with individuals with NFPA. GH replacement therapy in patients with Sheehan’s syndrome may have beneficial effects on QoL, body composition and lipid profile.

Background: Craniopharyngioma is a parasellar tumour that, although benign, tends to behave aggressively. It can occur at any age but most commonly presents in childhood or adolescence. Objectives: To investigate the frequency and severity of problems associated with craniopharyngioma, using the large international database (KIMS) for adult patients with GH deficiency (GHD), and to assess the differences between the adult onset (AO, aged 18 or above) disease and adults with childhood onset (CO) craniopharyngioma. Design: Inclusion criteria were: an established diagnosis of craniopharyngioma, severe GHD and no recent GH treatment. These criteria were fulfilled by 393 (184 female, 209 male) patients; 241 had AO (mean age 28.7±8.7 years) and 152 had CO disease (age 42.0±12.3 years). Disease history, clinical features and anthropometric data were recorded at the time of enrolment in the database, and body composition, serum IGF-I, serum lipids and quality of life (QoL) were assessed. Results: Peak age at onset of craniopharyngioma was 15–20 years. Ninety percent of patients had been treated surgically. CO patients were shorter than AO patients and had much lower IGF-I standard deviation scores (SDS). The majority had hypopituitarism and over 60% had diabetes insipidus. Body mass index (BMI) was higher in AO males (30.2±5.5) than in CO males (28.5±7.5); waist circumference was also greater. Obesity was more common in AO patients (51.8% vs 39.1%). Body composition did not differ between groups. Cholesterol and triglycerides were higher in AO than in CO patients, but high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol did not differ. Quality of life, assessed by Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Nottingham Health Profile, was markedly reduced in all groups with no significant differences between them; the QoL-AGHDA score correlated with age at onset of both craniopharyngioma and GHD, and also with BMI in AO patients. Conclusions: These data emphasise the generally poor state of health of patients treated for craniopharyngioma, with respect to endocrine and metabolic function, and also the markedly reduced quality of life. In addition to GHD, most patients have evidence of hypothalamic damage with associated obesity, diabetes insipidus and hypopituitarism. Adults with CO craniopharyngioma were shorter, had lower IGF-I, lower BMI, less obesity and slightly lower blood lipid levels than patients with AO craniopharyngioma.

In epidemiological studies, hypopituitary adults show increased mortality compared with population controls. Patients with hypopituitarism caused by a craniopharyngioma (CP) and/or its treatment have a higher mortality than patients with other etiologies, such as a nonfunctioning pituitary adenoma (NFPA). To analyze this difference, we used the KIMS database (Pfizer International Metabolic Database) comparing CP and NFPA patients in terms of baseline characteristics and responses to GH replacement.Baseline characteristics were studied in 351 CP patients (189 men and 162 women; mean age, 42.5 yr) and compared with 370 NFPA patients, matched for age and sex (185 men and 185 women; mean age, 42.5 yr). The effects of 2 yr of GH replacement were analyzed in a subgroup of 183 CP and 209 NFPA patients.At baseline, both CP and NFPA patients had characteristic features of GH deficiency, with low serum IGF-I, increased body fat, dyslipidemia, and reduced quality of life. Male CP patients were significantly more obese (30.0 vs. 28.2 kg/m2; P = 0.0003) compared with NFPA patients, had a higher waist/hip ratio (P = 0.004), higher triglycerides (P = 0.003), and lower high-density lipoprotein cholesterol (P = 0.03). Similar, but much smaller, differences were seen in female CP compared with NFPA patients, only reaching significance for waist/hip ratio (P = 0.05) and triglycerides (P = 0.0004). CP patients had more often undergone surgery by the transcranial route (68.8% vs. 30.9%; P0.0001), and panhypopituitarism was more prevalent in CP than in NFPA patients (58.7% vs. 19.8%; P0.0001). The incidence of previous fractures, hypertension, coronary heart disease, claudication, and diabetes mellitus was high, but not different, between CP and NFPA patients. After 2 yr of GH replacement therapy, similar significant improvements were evident in both groups in fat-free mass, total and low-density lipoprotein cholesterol, and Quality-of-Life-Assessment in GH Deficient Adults score compared with baseline. In contrast to NFPA patients, CP patients had no significant decrease in body fat with GH therapy.In the KIMS database, patients with CP have more often undergone surgery by the transcranial route than patients with NFPA, have a higher prevalence of pituitary deficiencies, are more obese (predominantly males), and have more dyslipidemia. This could provide an explanation, at least in part, for the higher mortality rate in CP patients observed in epidemiological studies. CP patients respond equally well to GH therapy in fat-free mass, lipids, and quality of life, but are less likely to lose body fat. We assume that this difference in response merely reflects the stronger tendency of CP patients to accumulate fat over time.

Extreme degrees of obesity may occur in association with hypothalamic tumors, usually after surgical intervention. This phenomenon has been reported to occur in as many as 25–75% of children undergoing extensive surgical extirpation of craniopharyngiomas (Cranio). Because less is known about the auxology of children with Cranio with milder alterations in growth, we undertook a 3-yr longitudinal analysis, using the KIGS database (Pfizer International Growth Database), to study their growth patterns and evolution of weight. We compared the effect of GH therapy on height, weight, and body mass index (BMI) in 199 prepubertal children with diagnosed Cranio treated by surgery and/or radiotherapy to two other groups of children with other causes of organic GH deficiency (OGHD): one with postsurgical and/or postirradiated OGHD (OGHD + S/I; n = 92) and the other with OGHD not due to Cranio and not having undergone either surgery or irradiation (OGHD − S/I; n = 85). At the start of GH therapy, 1) mean chronological (P < 0.0001) and bone (P = 0.0002) ages were youngest in OGHD − S/I and oldest in OGHD + S/I; 2) the mean height sd score (SDS) was lowest in OGHD − S/I and comparably higher in the other two groups (P < 0.0001); 3) mean weight and BMI SDS were greatest in Cranio and least in OGHD − S/I (both P < 0.0001); and 4) the mean initial GH dose prescribed was highest in OGHD − S/I and comparable in the other two groups (P < 0.0001). After 3 yr of GH therapy, 1) mean bone age remained youngest in OGHD − S/I and oldest in OGHD + S/I (P < 0.0001); 2) mean height SDS was highest in Cranio and comparably lower in the other two groups (P = 0.0159); 3) mean weight and BMI SDS remained greatest in Cranio and least in OGHD − S/I (P < 0.0001 and P = 0.0003, respectively); and 4) the mean GH dose remained highest in the OGHD − S/I group and least in the Cranio group (P = 0.0082). There were statistically significant increases within each group between the start of treatment and after 3 yr of GH therapy in height and weight, but not in BMI SDS. Lastly, after 3 yr of GH treatment, children in the Cranio group continued to have disproportionately heavier weight and higher BMI (with the greatest values in those with lower stimulated peak GH concentrations) compared with members of the other two groups, with no salutary effect of GH treatment on weight SDS and a mild improvement in BMI SDS. After S/I treatment, children with Cranio are disproportionately prone to varying degrees of weight gain compared with children with other forms of OGHD. In the present cohort of prepubertal children with Cranio, GH therapy induced excellent linear growth, but failed to have an ameliorative effect on weight gain and had only a slight beneficial effect on BMI gain. Because affected children may have resultant significant long-term medical morbidity and diminished quality of life, it is critical that the mechanism of this phenomenon be determined to devise helpful preventive or therapeutic interventions.

GH replacement (GHR) is well established, and has been widely accepted to be safe in patients with a wide spectrum of pituitary pathologies. However, GHR in patients with treated germ cell tumours (GCTs) remains controversial, and its use has been cautioned (1, 2). Anecdotal experience from our centre and elsewhere (1–3) suggests that vigilant monitoring is mandatory in treated GCTs who are GH replaced. There are no published studies of long-term outcome and recurrence rates after GHR in treated GCTs. We have therefore surveyed our long-term experience with GHR in 18 adult patients with previously treated GCTs and a global experience of 142 patients from the KIMS database (Pfizer International Metabolic Database) in this diagnostic category in order to determine whether GHR plays a role in tumour relapse. This is a longitudinal observational study reporting a single centre experience and global experience using the KIMS database. The study groups comprised 18 consecutive patients with GCT treated at St Bartholomew’s Hospital, London (SBH) (median duration of follow-up from diagnosis of GCT 13 years (range 0.5–44)) and 142 patients with GCT enrolled in the KIMS database (median duration of follow-up 14.8 years (0.7–36.4)). The relapse rates pre-GHR and during GHR and relapse-free survival were evaluated. The characteristic and treatments of SBH and KIMS patients are shown in Table 1. In the SBH cohort, there were three relapses prior to GHR. All three patients had a histological diagnosis of non-germinomatous GCT (NGGCT), and had been treated with chemotherapy and/or surgery as primary treatment; radiotherapy was subsequently used after first relapse of disease; none of the patients received radiotherapy or craniospinal irradiation (CSI) as initial treatment. Four patients, two with germinomatous GCT (GGCT) and two with NGGCT, relapsed after GHR. Of the patients demonstrating a first relapse, only one had been treated previously with CSI. One patient relapsed prior to GHR, and was retreated successfully with external beam radiotherapy to the primary site of disease together with chemotherapy, but subsequently also relapsed after GHR. The estimated relapse rates were 240 and 323 per 10-000 patient-years, pre-GHR and during GHR respectively. The relative risk (RR) of relapsing after GHR was 1.34 (95% confidence interval (95% CI): 0.23–7.83; PZ0.73). Five instances of relapse were reported during KIMS follow-up. Of interest, two of these patients had never been treated with GHR (true nao ¨ve) before KIMS entry. The most relevant comparison of relapse rate during versus prior to GHR is for true nao ¨ve patients. This group had a RR of relapse during KIMS of 3.40 (95% CI: 0.26–101.4; PZ0.36). For the semi- and non-nao ¨ve patients (previously treated with GH within 6 months or !6 months before KIMS entry), the RR of relapse during KIMS was statistically similar to the true nao ¨ve group, or 2.62 (95% CI: 0.45–15.3; PZ0.27). RR for nao ¨ve versus semi- or non-nao ¨ve patients (including pre KIMS experience) was 1.36 (95% CI: 0.28–5.46; PZ0.65), indicating similar reported relapse rates between true nao ¨ve and those not true nao ¨ve. For all KIMS patients, the estimated relapse rates were 26.6 and 77.2 per 10-000 patient-years, pre-KIMS and during KIMS entry respectively. The RR of relapse during KIMS for all patients was 2.90 (95% CI: 0.73–12.13; PZ0.13). Our results do not support the hypothesis that GHR increases the recurrence of GCT. In view of the relative rarity of intracranial GCT, we elected to utilise longitudinal follow-up and calculation of relapse frequency expressed per patient years. Despite the variation in treatment modalities, there appeared to be similar relapse rate before and after exposure to GHR in the SBH cohort. Of particular interest, most relapses were NGGCT, which is well known to have a higher risk of relapse. Furthermore, the risk of relapse is also enhanced with the lack of use of radiotherapy as primary treatment. In general patients with NGGCT and those not treated with CSI appeared to have a worse relapsefree survival but no statistical significance was observed. The data from the KIMS do not provide evidence for an association between GHR and relapse. The KIMS relapse rate appears to be lower pre-KIMS than during KIMS, but the difference was not statistically significant. The disparity in recurrence frequency between the SBH and