Morbidities and mortality among hospitalized patients with hypopituitarism: Prevalence, causes and management.

Hypopituitarism is a highly heterogeneous multisystem disorder that can have a major impact on long-term morbidity and mortality, but even more so during acute medical conditions requiring hospitalization. Recent studies suggest a significant in-hospital burden with prolonged length of stay, increased rate of intensive care unit (ICU) admission, and initiation of mechanical ventilation - all of which may lead to an increased risk of in-hospital mortality. On the one hand, patients with hypopituitarism are often burdened by metabolic complications, including obesity, hypertension, dyslipidemia, and hyperglycemia, which alone, or in combination, are known to significantly alter relevant physiological mechanisms, including metabolism, innate and adaptive immune responses, coagulation, and wound healing, thereby contributing to adverse in-hospital outcomes. On the other hand, depending on the extent and the number of pituitary hormone deficiencies, early recognition of hormone deficiencies and appropriate management and replacement strategy within a well-organized multidisciplinary team are even stronger determinants of short-term outcomes during acute hospitalization in this vulnerable patient population. This review aims to provide an up-to-date summary of recent advances in pathophysiologic understanding, clinical implications, and recommendations for optimized multidisciplinary management of hospitalized patients with hypopituitarism.

Incidence, mortality, and cardiovascular diseases in pituitary adenoma in Korea: a nationwide population-based study.

PURPOSE: Few nationally representative studies have evaluated the epidemiology of PA (pituitary adenoma). This South Korean study evaluated the incidence of different PA subtypes, cardiovascular disease (CVD), and related mortality. METHODS: This population-based study evaluated 31,898 patients with PA during 2005-2015. The incidence of PA, mortality, and CVD occurrence in PA cases were evaluated during a median follow-up of 5.3 years (range: 0-10 years). Cox regression analysis was used to evaluate the associations between CVD and mortality. RESULTS: The annual incidences (per 100,000 population) were 3.5 for non-functioning pituitary adenoma (NFPA), 1.6 for prolactinoma (PRL), 0.5 for growth hormone-secreting pituitary adenoma (GH), and 0.2 for adrenocorticotropic or thyroid-stimulating hormone-secreting pituitary adenoma (ACTH + TSH). The standardized mortality ratios were 1.9 for ACTH + TSH, 1.7 for NFPA with hypopituitarism, 1.4 for NFPA without hypopituitarism, 1.3 for GH, and 1.1 for PRL. During 2005-2015, the overall incidence of CVD among PA patients was 6.6% (2106 cases), and the standardized incidence ratios were 4.1 for hemorrhagic stroke, 3.0 for ischemic stroke, and 1.7 for acute myocardial infarction. The standardized incidence ratios for stroke were significantly higher in the ACTH + TSH and NFPA groups, which also had higher risks of CVD-related mortality, relative to the PRL and GH groups. CONCLUSION: South Korea had a relatively high incidence of NFPA. The incidence of stroke was highest for ACTH + TSH and NFPA, which was directly related to mortality during long-term follow-up. Patients with these types of PA should receive stroke prevention measures to reduce their risk of mortality.

Excess Mortality Among Hospitalized Patients With Hypopituitarism-A Population-Based, Matched-Cohort Study.

CONTEXT: Patients with hypopituitarism face excess mortality in the long-term outpatient setting. However, associations of pituitary dysfunction with outcomes in acutely hospitalized patients are lacking. OBJECTIVE: The objective of this work is to assess clinical outcomes of hospitalized patients with hypopituitarism with or without diabetes insipidus (DI). DESIGN, SETTING, AND PATIENTS: In this population-based, matched-cohort study from 2012 to 2017, hospitalized adult patients with a history of hypopituitarism were 1:1 propensity score-matched with a general medical inpatient cohort. MAIN OUTCOME MEASURES: The primary outcome was in-hospital mortality. Secondary outcomes included all-cause readmission rates within 30 days and 1 year, intensive care unit (ICU) admission rates, and length of hospital stay. RESULTS: After matching, 6764 cases were included in the study. In total, 3382 patients had hypopituitarism and of those 807 (24%) suffered from DI. All-cause in-hospital mortality occurred in 198 (5.9%) of patients with hypopituitarism and in 164 (4.9%) of matched controls (odds ratio [OR] 1.32, [95% CI, 1.06-1.65], P = .013). Increased mortality was primarily observed in patients with DI (OR 3.69 [95% CI, 2.44-5.58], P < .001). Patients with hypopituitarism had higher ICU admissions (OR 1.50 [95% CI, 1.30-1.74], P < .001), and faced a 2.4-day prolonged length of hospitalization (95% CI, 1.94-2.95, P < .001) compared to matched controls. Risk of 30-day (OR 1.31 [95% CI, 1.13-1.51], P < .001) and 1-year readmission (OR 1.29 [95% CI, 1.17-1.42], P < .001) was higher among patients with hypopituitarism as compared with medical controls. CONCLUSIONS: Patients with hypopituitarism are highly vulnerable once hospitalized for acute medical conditions with increased risk of mortality and adverse clinical outcomes. This was most pronounced among those with DI.

The implication of giant tumor size on surgical resection, oncological, and functional outcomes in craniopharyngioma.

OBJECTIVE: Implication of the tumor size on oncological and functional outcomes of craniopharyngioma is inconsistently reported. The aim of this study is to assess the postoperative outcome of giant craniopharyngiomas (> 4 cm in diameter) and to elucidate the impact of tumor size on various outcome parameters and survival. MATERIAL AND METHODS: Forty-four patients (children aged ≤ 18 years: 25; adults: 16) with giant craniopharyngioma, operated between January 2001 and December 2015, were included in this study. Various outcomes, progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Gross total resection (GTR) was achieved in 17 (39%) and subtotal resection (STR) in 27 (61%) patients. Eleven patients (25%) received radiotherapy (RT) after STR. Postoperatively, new cranial nerve and motor deficits were noted in 12 (27%) and 9 (20%) patients, respectively. Tumor recurrence following GTR and STR without adjuvant RT was diagnosed in 3 (17%), and 5 (38%) patients, respectively. Following STR with RT, one (9%) experienced recurrence. PFS at 5-, and 10- year following GTR, STR, and STR + RT was 80.8%, 45.4%, and 90%, respectively. At 5- and 10- year, OS was 86.5%, 77.9% and 100% following GTR, STR, and STR + RT, respectively. The rate of GTR was significantly lower in patients with giant tumors (39% vs. 62%; Chi-square test, p value 0.008). Postoperatively, neurological deficit (20%), hypopituitarism (95%) and hypothalamic dysfunction (26%) were significantly higher for giant craniopharyngiomas. Hazards of recurrence were not significant between giant and non-giant tumors (hazard ratio 1.86; 95% CI 0.94-3.68; p 0.07). There was no significant difference in OS between the patients with giant and non-giant tumors (log-rank test 2.1; p value 0.14). CONCLUSION: Tumor size should be considered as an important predictor of the postoperative functional outcome. Although the rate of GTR is less than that of small tumors, the recurrence rate, progression-free survival, and overall survival of the patients with giant tumor are comparable to non-giant tumors.

Long-term Effects of Growth Hormone Replacement Therapy in Childhood-onset Craniopharyngioma: Results of the German Craniopharyngioma Registry (HIT-Endo).

OBJECTIVE: Quality of survival, prognosis and long-term outcome are often severely impaired in childhood-onset craniopharyngioma patients (CP). Identification of risk factors for sequelae such as growth hormone (GH) deficiency is important for appropriate treatment and rehabilitation. DESIGN: In a cross-sectional study, 79 CP recruited in HIT-Endo before 2000 were analyzed according to GH substitution: a. CP never GH-treated (noGH); b. CP GH-treated only during childhood (pedGH); c. CP under GH, initiated at adulthood (adultGH); d. CP under GH during childhood and continued during adulthood (contGH). METHODS: Progression-free (PFS) and overall survival (OS), height, body mass index (BMI), psychosocial and neuropsychological status (EORTC QLQ-C30, MFI-20). RESULTS: OS and PFS rates were similar in all subgroups. ContGH and pedGH CP presented with increases in height (p=0.002; p=0.0001) during long-term follow-up when compared with baseline. In all subgroups except for pedGH, increases in BMI were observed when compared with BMI at diagnosis. For emotional functionality and physical fatigue, adultGH CP showed worse (p=0.037; p=0.034) response (mean: 61.4%; 12.5%) when compared with pedGH CP (mean: 83.5%; 7.7%). Observed differences were not related to irradiation and hypothalamic involvement. In terms of psychosocial status, no differences were observed between subgroups. CONCLUSIONS: We conclude that GH substitution was safe with regard to risk of tumor progression/relapse in CP. Growth was improved by GH, whereas the development of obesity was not influenced by GH substitution. However, early initiation of GH substitution after CP diagnosis might have beneficial effects on weight development and neuropsychological outcome.

Clinical study on microsurgical treatment for craniopharyngioma in a single consecutive institutional series of 335 patients.

OBJECTIVES: The optimal management of craniopharyngioma is still controversial. The aim of this study is to explore microsurgical outcomes of craniopharyngioma in 335 cases. PATIENTS AND METHODS: Clinical data of 335 consecutive patients with craniopharyngioma between March 2011 and March 2017 were retrospectively analyzed. RESULTS: Gross total resection (GTR) was achieved in 265 cases (79.1%), subtotal resection (STR) was obtained in 70 cases (20.9%). The GTR rate was 81.93% in pediatric group and 78.17% in adult group respectively, no significant difference regarding the GTR rate was found in adult group compared with in pediatric group (p > 0.05). However, there was a noticeable difference in the elevated hypothalamic obesity in children group compared with in adult group after operation (p < 0.05). Multivariate analysis indicated that the tumor recurrence and surgical times played a negative role in the resection extent, the odds ratio and 95% confidence interval of the tumor recurrence and surgical times is [0.306 (0.155-0.603), (p < 0.01)] and [2.135 (1.101-4.142), (p < 0.05)] respectively. There was significant difference on panhypopituitarism between GTR and STR group (p < 0.05). However, No significant difference regarding the postoperative visual dysfunction and indepent quality of life respectively between GTR and STR group was found (p > 0.05). Additionally, there were no statistically significant differences for recurrence-free curves between GTR and STR plus adjuvant radiotherapy (p > 0.05). CONCLUSIONS: Present findings demonstrated that tumor recurrence and surgical times contribute to negative total resection for craniopharyngioma. Postoperative precise adjuvant radiotherapy was considered in selected cases if pursuit of GTR was rather dangerous under disadvantageous removal factors.

Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study.

CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04-2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options.

Mortality in patients with non-functioning pituitary adenoma.

Non-functioning pituitary adenomas (NFA) are benign pituitary neoplasms not associated with clinical evidence of hormonal hypersecretion. A substantial number of patients with NFA have morbidities related to the tumor and possible recurrence(s), as well as to the treatments offered. Studies assessing the long-term mortality of patients with NFA are limited. Based on the published literature of the last two decades, overall, the standardized mortality ratios in this group suggest mortality higher than that of the general population with deaths attributed mainly to circulatory, respiratory and infectious causes. Women seem to have higher mortality ratios, and assessment of time trends suggests improvement over the years. There is no consensus on predictive factors of mortality but those most consistently identified are older age at diagnosis and high doses of glucocorticoid substitution therapy. Well designed and of adequate power studies are needed to establish the significance of factors compromising the survival of patients with NFA and to facilitate improvements in long-term prognosis.

Mortality in adults with hypopituitarism: a systematic review and meta-analysis.

PURPOSE: Hypopituitarism is a rare disorder with significant morbidity. To study the evidence on the association of premature mortality and hypopituitarism. METHODS: A comprehensive search of multiple databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was conducted through August, 2015. Eligible studies that evaluated patients with hypopituitarism and reported mortality estimates were selected following a predefined protocol. Reviewers, independently and in duplicate, extracted data and assessed the risk of bias. RESULTS: We included 12 studies (published 1996-2015) that reported on 23,515 patients. Compared to the general population, hypopituitarism was associated with an overall excess mortality (weighted SMR of 1.55; 95 % CI 1.14-2.11), I 2 = 97.8 %, P = 0.000. Risk factors for increased mortality included younger age at diagnosis, female gender, diagnosis of craniopharyngioma, radiation therapy, transcranial surgery, diabetes insipidus and hypogonadism. CONCLUSION: Hypopituitarism may be associated with premature mortality in adults. Risk is particularly higher in women and those diagnosed at a younger age.

Time trends of mortality in patients with non-functioning pituitary adenoma: a Swedish nationwide study.

PURPOSE: Patients with non-functioning pituitary adenomas (NFPA), especially women, have increased mortality. The aim of this study was to investigate whether mortality in NFPA patients has changed during the last two decades. METHODS: This was a nationwide population-based study including 2795 patients (1502 men, 1293 women) diagnosed with NFPA between 1997 and 2011. Patients were identified and followed in Swedish National Health Registries. Standardized mortality ratios (SMRs) with 95 % confidence intervals were calculated for three time periods at first NFPA diagnosis using the general population as reference. RESULTS: Mean (±SD) age at NFPA diagnosis was 58.9 ± 16.8 years. Mean (range) follow-up time was 8.3 (0-18) years, resulting in 20,517 patient-years at risk. Surgical treatment and radiotherapy were used in 53 and 5 %, respectively. The prevalence of hypopituitarism was 64 % during the first time period of diagnosis and then declined gradually during the study period (P value for trend <0.0001). The use of pituitary surgery and radiotherapy remained stable. In women, mortality was increased for patients diagnosed between 1997 and 2006 but not for those diagnosed between 2007 and 2011. The SMR in men remained stable throughout the study and did not differ from the general population. During the last time period, 2007-2011, the SMR between men and women did not differ. CONCLUSIONS: While mortality in men with NFPA remains normal and stable during the last two decades, mortality in women has declined. Decreasing prevalence of pituitary insufficiency may be a plausible explanation for this positive development.

Excess mortality associated with hypopituitarism in adults: a meta-analysis of observational studies.

CONTEXT: Several previous observational studies showed an association between hypopituitarism and excess mortality. Reports on reduction of standard mortality ratio (SMR) with GH replacement have been published recently. OBJECTIVE: This meta-analysis assessed studies reporting SMR to clarify mortality risk in hypopituitary adults and also the potential benefit conferred by GH replacement. DATA SOURCES: A literature search was performed in Medline, Embase, and Cochrane library up to March 31, 2014. ELIGIBILITY CRITERIA: Studies with or without GH replacement reporting SMR with 95% confidence intervals (95% CI) were included. DATA EXTRACTION AND ANALYSIS: Patient characteristics, SMR data, and treatment outcomes were independently assessed by two authors, and with consensus from third author, studies were selected for analysis. Meta-analysis was performed in all studies together, and those without and with GH replacement separately, using the statistical package metafor in R. RESULTS: Six studies reporting a total of 19 153 hypopituiatary adults with a follow-up duration of more than 99,000 person years were analyzed. Hypopituitarism was associated with an overall excess mortality (weighted SMR, 1.99; 95% CI, 1.21-2.76) in adults. Female hypopituitary adults showed higher SMR compared with males (2.53 vs 1.71). Onset of hypopituitarism at a younger age was associated with higher SMR. GH replacement improved the mortality risk in hypopituitary adults that is comparable to the background population (SMR with GH replacement, 1.15; 95% CI, 1.05-1.24 vs SMR without GH, 2.40; 95% CI, 1.46-3.34). GH replacement conferred lower mortality benefit in hypopituitary women compared with men (SMR, 1.57; 95% CI, 1.38-1.77 vs 0.95; 95% CI, 0.85-1.06). LIMITATIONS: There was a potential selection bias of benefit of GH replacement from a post-marketing data necessitating further evidence from long-term randomized controlled trials. CONCLUSIONS: Hypopituitarism may increase premature mortality in adults. Mortality benefit from GH replacement in hypopituitarism is less pronounced in women than men.

Fractionated stereotactic radiotherapy for large and invasive non-functioning pituitary adenomas: long-term clinical outcomes and volumetric MRI assessment of tumor response.

OBJECTIVE: We describe the use of fractionated stereotactic radiotherapy (FSRT) for the treatment of large, invasive, nonfunctioning pituitary adenomas (NFPAs). FSRT is frequently employed for the treatment of residual or recurrent pituitary adenomas. PATIENTS AND METHODS: Sixty-eight patients with a large residual or recurrent NFPAs were treated between April 2004 and December 2012, including 39 males and 29 females (median age 51 years). Visual defects were present in 34 patients, consisting of visual field defects (n=31) and/or reduced visual acuity (n=12). Forty-five patients had evidence of partial or total hypopituitarism before FSRT. For most of the patients, the treatment was delivered through 5-10 noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS: At a median follow-up of 75 months (range 12-120 months), the 5- and 10-year actuarial local control were 97 and 91%, respectively, and overall survival 97 and 93%, respectively. Forty-nine patients had a tumor reduction, 16 remained stable, and three progressed. The relative tumor volume reduction measured using three-dimensional (3D) magnetic resonance imaging (MRI) was 47%. The treatment was well tolerated with minimal acute toxicity. Eighteen patients developed partial or complete hypopituitarism. The actuarial incidence of new anterior pituitary deficits was 40% at 5 years and 72% at 10 years. No other radiation-induced complications occurred. CONCLUSIONS: Our results suggest that FSRT is an effective treatment for large or giant pituitary adenomas with low toxicity.

Long-term effects of treatment of pituitary adenomas.

Pituitary adenomas can be treated effectively in the vast majority of cases. After successful treatment for pituitary disease, many patients still report reduced quality of life in the presence of persistent morbidity and (slightly) increased mortality. At present, there is an increasing awareness that in many cases long-term remission of functioning or nonfunctioning adenomas does not equal cure. The causes are most probably multifactorial. Hypopituitarism, intrinsic imperfections of surgical or endocrine replacement therapy, but also persistent effects of treatment and of previous hormone excess on the central nervous system all affect long-term morbidity, general well-being, and mortality. This implies that treatment goals for patients with pituitary adenomas will shift from long-term cure to long-term care. Further research is therefore needed to get more insight into each of these factors of influence, such as the extent of reversibility of hormone excess syndromes on cardiovascular risk and behavior. The fact that coping strategies, despite long-term remission, are altered and illness perceptions are affected strongly suggests that long-term care should incorporate self-management interventions that might help to improve quality of life for patients.

Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma.

CONTEXT: Ipilimumab (Ipi) is approved by the Food and Drug Administration for the treatment of unresectable or metastatic melanoma. Little is known about Ipi-induced hypophysitis (IH), an important treatment complication. OBJECTIVE: The objectives of the study were as follows: 1) to examine the prevalence of IH, 2) to characterize the clinical course and treatment outcomes in IH, 3) to identify the risk factors for the development of IH, and 4) to determine optimal strategies for the management of IH. DESIGN: This was a retrospective review. SETTING: The study was conducted at a tertiary referral center. SUBJECTS: One hundred fifty-four adult patients with metastatic melanoma were evaluated at Massachusetts General Hospital and were treated with Ipi between March 2008 and December 2013. INTERVENTION(S): The intervention included treatment with Ipi. MAIN OUTCOME MEASURE(S): Pituitary magnetic resonance imaging, pituitary hormone assessment, and patient survival were measured. RESULTS: IH was diagnosed in 17 patients (11%). Male gender (P = .02) and older age (P = .005), but not the cumulative dose of Ipi, were risk factors for IH. All patients with IH had anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was persistent in most individuals (76%). Diffuse pituitary enlargement was observed exclusively in all cases of IH and, upon retrospective review of magnetic resonance imaging scans, this finding preceded the clinical diagnosis of hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40 d in seven of seven patients). Median survival in patients with IH was 19.4 vs 8.8 months (P = .05) in the remainder of the cohort. CONCLUSIONS: Male gender and older age are risk factors for IH. Pituitary enlargement is sensitive and specific for IH in the appropriate setting, can precede the clinical diagnosis, and resolves rapidly. Anterior pituitary function recovery is uncommon. The incidence of hypophysitis may positively predict survival in melanoma patients treated with Ipi.

Socioeconomic factors do not but GH treatment does affect mortality in adult-onset growth hormone deficiency.

CONTEXT: GH deficiency is associated with changes in body composition, increased cardiovascular risk markers, and reduced bone mineral density. There seem to be multiple causes of the reported increased morbidity and mortality. OBJECTIVE: The objective was to study the socioeconomic status in patients with adult-onset GH deficiency and its impact on mortality. DESIGN: This is a nationwide registry study in which the socioeconomic status in adult-onset GH deficient patients was identified in the Danish registries and compared with controls matched on age and gender. The socio-economic status included cohabitation, education, income, parenthood, convictions, and retirement. PATIENTS AND CONTROLS: All patients had adult-onset GH deficiency and were born between 1950 and 1980. Two-hundred seventy-six patients (53.6% men) and 25 717 controls were included. RESULTS: GH-treated patients had a reduced mortality in total and due to malignancy compared with untreated patients. This difference remained after adjustment for cohabitation and education. Compared with the background population, the incidence of cohabitation, parenthood, and convictions was significantly reduced in patients, whereas education was unaffected. Retirement was significantly increased. CONCLUSIONS: Mortality was increased in patients, especially among patients not treated with GH. In GH-treated patients, mortality was decreased in total and due to malignancy compared with untreated patients, even after adjustment for all possible measured confounders. The patients had an impaired socioeconomic profile on most parameters compared with controls. This study does not support the suggestion that GH replacement therapy causes increased mortality.

Updates in growth hormone treatment and mortality.

PURPOSE OF REVIEW: To review the literature with regard to mortality in patients with hypopituitarism with a focus on the role of growth hormone (GH) deficiency and therapy. RECENT FINDINGS: Mortality is increased in hypopituitarism, particularly in female patients. In recent years mortality rates appear to be trending downwards towards that of the general population. Recent studies from retrospective or postmarketing surveillance studies have suggested that patients who receive GH therapy may not have increased mortality. Recent studies regarding mortality in paediatric patients treated with GH are conflicting and this area needs further study. SUMMARY: There are several important limitations of available data regarding mortality in hypopituitarism and even more so in the impact of GH therapy, which need to be taken into account when interpreting the available data. The data regarding mortality in patients treated with GH as children is an area of much debate and will need further studies to clarify, given the conflicting reports in recent studies.

Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.

CONTEXT: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.