Social, educational and vocational outcomes in patients with childhood-onset and young-adult-onset growth hormone deficiency.

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: A total of 2952 adult patients diagnosed with hypothalamic pituitary conditions before the age of 25 were divided into two groups: childhood-onset [<16 years (CO)] (n = 1782) and young-adult-onset [16 to <25 years (YAO)] (n = 1170). A total of 1617 adult patients diagnosed with a nonfunctioning pituitary adenoma at the age of 25 or older formed the adult-onset control group (AO). MEASUREMENTS: KIMS Patient Life Situation Form which provided information on social, educational and vocational outcomes. RESULTS: Compared with the AO control group, CO and YAO patients were between 4·5 and 8·0 times more likely to live with their parents in adulthood; CO and YAO patients were also less likely to live in partnership and to have children. The impact on educational and vocational outcomes was less marked than on social outcomes with no significant differences compared with the AO control group. Educational and vocational outcomes showed the lowest level in male and female CO and YAO patients who had been previously diagnosed with a brain tumour. CONCLUSIONS: Social outcomes were more affected than educational and vocational outcomes. Although CO patients are more adversely affected, YAO patients were also failing to achieve social milestones. This has consequences for the delivery of endocrine care in both paediatric and adult services.

Coping strategies have a strong impact on quality of life, depression, and embitterment in patients with Cushing's disease.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Diagnosis and management of acromegaly: the patient's perspective.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001, respectively]. In 48.5 % of patients, acromegaly was diagnosed by an endocrinologist (men: 45.1 %; women: 52.4 %). Overall disease duration from symptom onset until last surgery was 5.5 (SD 6.85) years, with no sex differences. A change in employment status was the most commonly reported event after diagnosis and a quarter of the patients stated that the illness had changed their lives. CONCLUSIONS: Our findings confirm the urgent need to increase awareness of the clinical manifestation of acromegaly to facilitate an earlier diagnosis of the disease and to provide diagnostic equality across the sexes.

GH deficiency after traumatic brain injury: improvement in quality of life with GH therapy: analysis of the KIMS database.

OBJECTIVE: Prevalence 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/METHODS: Pfizer 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. RESULTS: TBI patients compared with NFPA patients were younger, diagnosed with GHD 2.4 years later after primary disease onset (P<0.0001), had a higher incidence of isolated GHD, higher GH peak, a more favourable metabolic profile and worse QoL, were shorter by 0.9 cm (1.8 cm when corrected for age and gender; P=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. CONCLUSION: Compared with NFPA, TBI patients presented biochemically with less severe hypopituitarism and worse QoL scores. GHR achieved clinically relevant, long-term benefit in QoL.

Long-term treatment with pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY.

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.

Pregnancy in acromegaly patients treated with pegvisomant.

To summarize all available data on pregnancy outcome of acromegaly patients exposed to the growth hormone receptor antagonist pegvisomant (PEGV) during pregnancy as present in the Pfizer's Global Safety Database. Pfizer's Global Safety Database contains adverse event data obtained from the following sources: spontaneous reports, health authorities, Pfizer-sponsored post-marketing surveillance program (ACROSTUDY), customer engagement programs, and clinical studies, reported regardless of outcome. The safety database was searched up to 10th March 2014. From the 35 pregnancy cases, 27 involved maternal [mean age (range) 33.3 years (23-41) and 8 paternal (33.7 years (32-38)] PEGV exposure. Two female patients were reported with two pregnancy cases each. Fetal outcome was normal in 14 (4 paternal) of the 18 reported as live birth, while 4 cases (1 paternal) did not specify the birth outcome. At conception, PEGV mean dose (range) was 15.3 mg/d (4.3-30). In 3 cases of maternal exposure of the 18 cases reporting live birth, PEGV was continued throughout the pregnancy in a dose of 12.1 mg/d (10-15). In 5 cases (all maternal) an elective termination of the pregnancy was performed with no reported fetal abnormalities, 2 cases (maternal) reported a non-PEGV-related spontaneous abortion and in 1 maternal case an ectopic pregnancy occurred. In 9 cases (3 paternal), the fetal outcome was not reported. Three women reported gestational diabetes; one woman continued PEGV treatment during pregnancy. Although the number of reported pregnancies with exposure to PEGV is very small, the presented data reflect the largest series of data available to date and do not suggest adverse consequences of PEGV on pregnancy outcome. Nevertheless, it should be stressed that PEGV should not be used during pregnancy unless absolutely necessary.

The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients.

OBJECTIVE: Quality 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 METHODS: This 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. RESULTS: At 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. CONCLUSION: Adult 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.

Effects of long-term growth hormone replacement in adults with growth hormone deficiency following cure of acromegaly: a KIMS analysis.

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.

Primary treatment regimen and diabetes insipidus as predictors of health outcomes in adults with childhood-onset craniopharyngioma.

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.

The cost-effectiveness of growth hormone replacement therapy (Genotropin®) in hypopituitary adults in Sweden.

BACKGROUND: To evaluate the cost-effectiveness of growth hormone (GH) treatment (Genotropin®) 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®. All costs and treatment effects were discounted at 3%. Costs were expressed in Euro (1€ = 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 €15,975 and €20,241 for men and women, respectively. Including indirect cost resulted in lower cost per QALY gained: €11,173 and €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 €55,371 (SEK 500,000 - the informal Swedish cost-effectiveness threshold) per QALY threshold.

Clinical characteristics and effects of GH replacement therapy in adults with childhood-onset craniopharyngioma compared with those in adults with other causes of childhood-onset hypothalamic-pituitary dysfunction.

OBJECTIVE: Adults 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 METHODS: Retrospective 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. RESULTS: Compared with COH and COE patients, more COCP patients underwent surgery, had greater abnormalities of body composition and higher prevalence of pituitary hormone deficits (all P<0.001), but comparable fasting glucose, HbA1c, total cholesterol and LDL-cholesterol levels, marital status, parenthood, living arrangements, education, employment and annual sick-leave days. After 1 and 5 years of GH replacement therapy, similar changes were evident with regard to body composition, fasting glucose and HbA1c levels, QoL, and the level of and satisfaction with physical activity across the three groups. CONCLUSIONS: Adults 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.

Response to GH treatment in adult GH deficiency is predicted by gender, age, and IGF1 SDS but not by stimulated GH-peak.

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.

Magnetic resonance imaging of CNS in 15,043 children with GH deficiency in KIGS (Pfizer International Growth Database).

OBJECTIVES: Neuroimaging 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 METHODS: Results 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)). RESULTS: Abnormal 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. CONCLUSIONS: GHD 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.

Prevalence of diabetes mellitus in 6050 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis.

OBJECTIVE: GH 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 METHODS: Associations 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 <0.05 were considered statistically significant. RESULTS: PP 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. CONCLUSIONS: GHD 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.

Overall and cause-specific mortality in GH-deficient adults on GH replacement.

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.

Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY.

CONTEXT: Pegvisomant is a GH receptor antagonist. The ACROSTUDY is a global safety surveillance study of long-term treatment of acromegaly with pegvisomant. OBJECTIVE: The objective of the study was to monitor long-term safety and treatment outcomes. DESIGN: ACROSTUDY is open to all patients with acromegaly who are treated with pegvisomant. We report an interim analysis of data captured from 1288 subjects enrolled before a database freeze of December 31, 2009. SETTING: This was a global noninterventional surveillance study. MAIN OUTCOME MEASURE(S): Long-term monitoring of safety, including central magnetic resonance imaging (MRI) reading and treatment outcomes, was measured. RESULTS: Subjects (n = 1288) were treated with pegvisomant for a mean of 3.7 yr and followed up in ACROSTUDY for a mean of 2.1 yr. A total of 1147 adverse events (AE) were recorded in 477 subjects (37%), among which 192 AE in 124 subjects (9.6%) were considered to be related to pegvisomant. Serious AE were recorded in 159 subjects (12.3%), whereas pegvisomant-related Serious AE were recorded in 26 subjects (2%). No deaths (15 subjects; 1.2%) were attributed to pegvisomant use. The incidence of increase in pituitary tumor size in the subset with confirmed MRI increases on central reading represented 3.2% of the overall cohort with at least two available MRI (n = 936). Injection-site reactions were reported in 28 cases (2.2%). In 30 patients (2.5%), an elevated aspartate aminotransferase or alanine aminotransferase of more than 3 times the upper level of normality was reported. There were no reports of liver failure. After 5 yr of pegvisomant treatment, 63.2% of subjects had normal IGF-I levels at a mean dose of 18 mg/d. CONCLUSIONS: Data entered and evaluated in ACROSTUDY indicate that pegvisomant is an effective and safe medical treatment in patients with acromegaly. The reported low incidence of pituitary tumor size increase, liver enzyme elevations, and lipodystrophy at the injection site are reassuring.

Comorbidity and cardiovascular risk factors in adult GH deficiency following treatment for Cushing's disease or non-functioning pituitary adenomas during childhood.

OBJECTIVE: Cushing'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 METHODS: This 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. RESULTS: The 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 (P<0.001). Eighty-nine per cent of patients with CO-CD had height SDS lower than 0 compared with 61% of patients with CO-NFPA (P=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. CONCLUSION: Adult 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.

The metabolic consequences of thyroxine replacement in adult hypopituitary patients.

The metabolic consequences of thyroxine replacement in patients with central hypothyroidism (CH) need to be evaluated. The aim was to examine the outcome of thyroxine replacement in CH. Adult hypopituitary patients (n = 1595) with and without CH from KIMS (Pfizer International Metabolic Database) were studied before and after 2 years of GH replacement. CH patients (CH, n = 1080) were compared with TSH sufficient patients (TSHsuff n = 515) as one group and divided by thyroxine dose/kg/day into tertiles (CHlow-mid-high). Anthropometry, fasting glucose, glycosylated haemoglobin (HbA1c), blood pressure, lipids, IGF-I SDS, quality of life and morbidity were studied. Analyses were standardized for gender, age, number and types of pituitary insufficiencies, stimulated GH peak, age at GH deficiency onset, aetiologies and, when appropriate, for weight and GH dose. At baseline, TSHsuff patients did not differ from CH or CHmid in any outcome. CHlow (≤ 1.18 µg thyroxine/kg/day) had increased weight, BMI and larger waist circumference (WC), CHhigh (≥ 1.58 µg thyroxine/kg/day) had lower weight, BMI, WC and IGF-I than TSHsuff and compared to their predicted weights, BMIs and WCs. For every 0.1 µg/kg/day increase of thyroxine dose, body weight decreased 1.0 kg, BMI 0.3 kg/m(2), and WC 0.65 cm. The GH sensitivity of the CH group was higher (0.76 ± 0.56 SDS/mg GH) than that of TSHsuff patients (0.58 ± 0.64 SDS/mg GH), P < 0.001. The middle thyroxine dose (1.19-1.57 µg/kg/day) seems to be the most physiological. This is equivalent to 70, 100, 125 µg thyroxine/day for hypopituitary patients of 50, 70 or 90 kg weight, respectively.

Prevalence and characteristics of the metabolic syndrome in 2479 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis.

OBJECTIVE: An 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. Design In 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). METHODS: The 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. RESULTS: MetS 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. CONCLUSIONS: MetS 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.