One hundred years have passed since Harvey Williams Cushing presented the first patient with the syndrome that bears his name. In patients with Cushing's syndrome (CS), body composition and lipid, carbohydrate and protein metabolism are dramatically affected and psychopathology and cognitive dysfunction are frequently observed. Untreated patients with CS have a grave prognosis with an estimated 5-year survival of only 50%. Remission can be achieved by surgery, radiotherapy and sometimes with medical therapy. Recent data indicate that the adverse metabolic consequences of CS are present for years after successful treatment. In addition, recent studies have demonstrated that health-related quality of life and cognitive function are impaired in patients with CS in long-term remission. The focus of specialised care should therefore be not only on the diagnostic work-up and the early postoperative management but also on the long-term follow-up. In this paper, we review the long-term consequences in patients with CS in remission with focus on the neuropsychological effects and discuss the importance of these findings for long-term management. We also discuss three different phases in the postoperative management of surgically-treated patients with CS, each phase distinguished by specific challenges: the immediate postoperative phase, the glucocorticoid dose tapering phase and the long-term management. The focus of the long-term specialised care should be to identify cognitive impairments and psychiatric disorders, evaluate cardiovascular risk, follow pituitary function and detect possible recurrence of CS.
Oskar Ragnarsson and Gudmundur Johannsson
Daniel S Olsson, Ing-Liss Bryngelsson and Oskar Ragnarsson
Increased mortality rates are found in women and young adults with non-functioning pituitary adenomas (NFPAs). This nationwide study aimed to investigate the burden of comorbidities in patients with NFPA and to examine whether gender influences the outcome.
NFPA patients were identified and followed-up from National Registries in Sweden. It was a nationwide, population-based study.
Standardised incidence ratios (SIRs) for comorbidities with 95% confidence intervals (CI). Comorbidities were analysed in all patients, both patients with and without hypopituitarism.
Included in the analysis were 2795 patients (1502 men, 1293 women), diagnosed with NFPA between 1987 and 2011. Hypopituitarism was reported in 1500 patients (54%). Mean patient-years at risk per patient was 7 (range 0–25). Both men (SIR 2.2, 95% CI: 1.8–2.5; P<0.001) and women (2.9, 2.4–3.6; P<0.001) had a higher incidence of type 2 diabetes mellitus (T2DM) than the general population, with women having a higher incidence compared with men (P=0.02). The incidence of myocardial infarction was increased in women (1.7, 1.3–2.1; P<0.001), but not in men. Both men (1.3, 1.1–1.6; P=0.006) and women (2.3; 1.9–2.8; P<0.001) had an increased incidence of cerebral infarction, with women having a higher incidence than men (P<0.001). The incidence of sepsis was increased for both genders. The incidence of fractures was increased in women (1.8, 1.5–1.8; P<0.001), but not for men.
This nationwide study shows excessive morbidity due to T2DM, cerebral infarction and sepsis in all NFPA patients. Women had higher incidence of T2DM, myocardial infarction, cerebral infarction and fracture in comparison to both the general population and to men.
Casper Hammarstrand, Oskar Ragnarsson, Olivia Bengtsson, Ing-Liss Bryngelsson, Gudmundur Johannsson and Daniel S Olsson
Patients with hypopituitarism have an increased mortality. The aim of this study was to investigate comorbidities including cerebral infarction, type 2 diabetes mellitus (T2DM) and malignant tumors in patients with non-functioning pituitary adenomas (NFPA) with and without growth hormone replacement therapy (GHRT).
Observational cohort study in patients with NFPA within the western region of Sweden. Subjects were identified through the National Patient Registry and followed between 1987 and 2014. Patient records were reviewed and standardized incidence ratios (SIRs) with 95% CIs for comorbidities were calculated.
In total, 426 patients were included, 206 with GHRT and 219 without. Median (range) follow-up time for patients with and without GHRT was 12.2 (0–24) and 8.2 (0–27) years, respectively. Mean ± s.d. BMI was 28.5 ± 4.5 and 26.5 ± 4.4 for patients with and without GHRT, respectively (P < 0.001). Incidence of cerebral infarction was increased (SIR: 1.39; 95% CI: 1.03–1.84; P = 0.032), with no difference between patients with and without GHRT. SIR for T2DM in patients not receiving GHRT was increased (1.65; 1.06–2.46; P = 0.018), whereas the incidence in patients receiving GHRT was not (0.99; 0.55–1.63; P = 0.99). The incidence of malignant tumors was not increased, either in patients with or without GHRT.
The incidence of cerebral infarction is increased in patients with NFPA irrespective of GHRT. Patients without GHRT had an increased risk of T2DM, whereas patients with GHRT had a normal incidence of T2DM, despite having higher BMI. Incidence of malignant tumors was not increased. Thus, long-term GHRT seems to be safe regarding risk of comorbidities.
Daniela Esposito, Oskar Ragnarsson, Daniel Granfeldt, Tom Marlow, Gudmundur Johannsson and Daniel S Olsson
New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated.
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.
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).
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).
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.
Axel Tjörnstrand, Kerstin Gunnarsson, Max Evert, Erik Holmberg, Oskar Ragnarsson, Thord Rosén and Helena Filipsson Nyström
The number of studies on the incidence of pituitary adenomas (PAs) is limited. The aim of this study was to evaluate the standardised incidence rate (SIR) of PAs in western Sweden.
Design, subjects and methods
Data from adult patients diagnosed with PAs in 2001–2011, living in the Västra Götaland County, were collected from the Swedish Pituitary Registry (SPR). In addition, medical records on all patients diagnosed with PAs at the six hospitals in the region were reviewed. In total, 592 patients were included in the study.
Age-SIR, given as rate/100 000 inhabitants (95% CI), was calculated using the WHO 2000 standard population as a reference.
The total SIR for PAs was 3.9/100 000 (3.6–4.3); 3.3/100 000 (2.9–3.7) for men and 4.7/100 000 (4.1–5.3) for women. In men, SIR increased with age, while in women SIR peaked at 25–34 years, mainly due to prolactinomas. Non-functioning PA (NFPA) was the most common PA (54%, 1.8/100 000 (1.6–2.0)) followed by prolactinomas (32%, 1.6/100 000 (1.3–1.9)), acromegaly (9%, 0.35/100 000 (0.25–0.45)), Cushing's disease (4%, 0.18/100 000 (0.11–0.25)) and TSH-producing PA (0.7%, 0.03/100 000 (0.00–0.05)). The proportion of macroadenomas for NFPA was 82%, prolactinomas 37%, GH-producing PA 77%, ACTH-producing PA 28% and TSH-producing PA 100%. The lifetime risk for PAs was 0.27% (0.24–0.31) in men and 0.29% (0.26–0.33) in women.
This study provides a reliable estimate on the overall incidence of PAs and confirms an increased incidence of PAs compared with studies conducted in the pre-magnetic resonance imaging era. The lower proportion of prolactinomas compared with previous studies is probably explained by the different criteria used.
Oskar Ragnarsson, Peter Berglund, Derek N Eder, Henrik Zetterberg, Max A Hietala, Kaj Blennow and Gudmundur Johannsson
Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission.
A cross-sectional, single-center study.
Twelve women previously treated for CS and six healthy subjects.
Neurodegenerative CSF markers: total tau, hyperphosphorylated tau, amyloid beta peptides, soluble amyloid precursor protein alpha and beta, neurofilament light proteins, glial fibrillary acidic protein, and monocyte chemoattractant protein 1; and inflammatory CSF markers: interferon gamma, interleukin (IL) 1B, IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, and tumor necrosis factor alpha.
The mean age (mean±s.d.) was similar in patients with CS in remission (44.9±14 years) and healthy subjects (42.3±15.7 years; P=0.726). No differences were observed in the concentrations of any neurodegenerative biomarkers between the patients and healthy subjects. Nor were the concentrations of inflammatory biomarkers different between the groups.
The pattern of neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission does not differ from that of the healthy subjects. The underlying mechanisms of the cognitive deficits in patients with CS in remission are different from those observed in patients with neurodegenerative disorders and remain to be explained.
Oskar Ragnarsson, Morton G Burt, Ken K Y Ho and Gudmundur Johannsson
Long-term pharmacological glucocorticoid (GC) therapy leads to skeletal muscle atrophy and weakness. The objective of this study was to investigate whether short-term treatment with GH and testosterone (T) can increase lean mass without major impairment of glucose homoeostasis in patients on GC therapy.
Design, materials and methods
This was a prospective, open-label, randomised, crossover study. Twelve men (age 74±6 years) on chronic GC treatment participated. The effects of 2 weeks' treatment with GH, testosterone and the combination of both on lean body mass (LBM), appendicular skeletal muscle mass (ASMM), extracellular water (ECW), body cell mass (BCM) and plasma glucose concentrations were investigated.
LBM increased significantly after GH (Δ1.7±1.4 kg; P=0.007) and GH+testosterone (Δ2.4±1.1 kg; P=0.003), but not testosterone alone. ASMM increased after all three treatment periods; by 1.0±0.8 kg after GH (P=0.005), 1.7±0.4 kg after GH+testosterone (P=0.002) and 0.8±1.0 kg after testosterone (P=0.018). The increase in ASMM was larger with combined treatment than either GH or testosterone alone (P<0.05). ECW increased significantly after GH+testosterone by 1.5±2.6 l (P=0.038) but not after GH or testosterone alone. BCM increased slightly after single and combined treatments, but the changes were not significant. Fasting glucose increased significantly after GH (Δ0.4±0.4 mmol/l, P=0.006) while both fasting (Δ0.2±0.3 mmol/l, P=0.045) and post glucose-load (Δ1.8±2.3 mmol/l, P=0.023) plasma glucose concentrations increased after GH+testosterone.
GH and testosterone induce favourable and additive body compositional changes in men on chronic, low-dose GC treatment. In the doses used, combination therapy increases fasting and postprandial glucose concentration.
Oskar Ragnarsson, Anders F Mattsson, John P Monson, Helena Filipsson Nyström, Ann-Charlotte Åkerblad, Maria Kołtowska-Häggström and Gudmundur Johannsson
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.
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.
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.
Oskar Ragnarsson, Camilla A M Glad, Ragnhildur Bergthorsdottir, Erik G Almqvist, Eva Ekerstad, Håkan Widell, Bo Wängberg and Gudmundur Johannsson
Adverse body compositional features and low bone mineral density (BMD) are the characteristic of patients with active Cushing's syndrome (CS). The aim of this study was to evaluate body composition and BMD in women with CS in long-term remission and the influence of polymorphisms in genes affecting glucocorticoid (GC) sensitivity on these end-points.
Design, patients and methods
This was a cross-sectional, case–controlled study, including 50 women previously treated for CS and 50 age and gender-matched controls. Median (interquartile range) remission time was 13 (5–19) years. Body composition and BMD were measured with dual-energy X-ray absorptiometry. Five polymorphisms in four genes associated with GC sensitivity were analysed using TaqMan or Sequenom single-nucleotide polymorphism genotyping.
Patients with CS in remission had increased abdominal fat mass (P<0.01), whereas BMD was not significantly different at any site between patients and controls. In patients, the NR3C1 Bcl1 polymorphism was associated with reduced total (P<0.05) and femur neck BMD (P<0.05). The polymorphism rs1045642 in the ABCB1 gene was associated with increased abdominal fat mass (P<0.05) and decreased appendicular skeletal muscle mass (P<0.05). GC replacement was associated with reduced total BMD (P<0.01), BMD at lumbar spine (P<0.05) and increased abdominal fat (P<0.01).
Ongoing GC replacement therapy together with polymorphisms in two genes related with GC sensitivity is associated with abdominal obesity and adverse skeletal health in patients with CS in long-term remission.
Casper Hammarstrand, Oskar Ragnarsson, Tobias Hallén, Eva Andersson, Thomas Skoglund, Anna G Nilsson, Gudmundur Johannsson and Daniel S Olsson
Patients with secondary adrenal insufficiency (AI) have an excess mortality. The objective was to investigate the impact of the daily glucocorticoid replacement dose on mortality in patients with hypopituitarism due to non-functioning pituitary adenoma (NFPA).
Patients with NFPA were followed between years 1997 and 2014 and cross-referenced with the National Swedish Death Register. Standardized mortality ratio (SMR) was calculated with the general population as reference and Cox-regression was used to analyse the mortality.
The analysis included 392 patients (140 women) with NFPA. Mean ± s.d. age at diagnosis was 58.7 ± 14.6 years and mean follow-up was 12.7 ± 7.2 years. AI was present in 193 patients, receiving a mean daily hydrocortisone equivalent (HCeq) dose of 20 ± 6 mg. SMR (95% confidence interval (CI)) for patients with AI was similar to that for patients without, 0.88 (0.68–1.12) and 0.87 (0.63–1.18) respectively. SMR was higher for patients with a daily HCeq dose of >20 mg (1.42 (0.88–2.17)) than that in patients with a daily HCeq dose of 20 mg (0.71 (0.49–0.99)), P = 0.017. In a Cox-regression analysis, a daily HCeq dose of >20 mg was independently associated with a higher mortality (HR: 1.88 (1.06–3.33)). Patients with daily HCeq doses of ≤20 mg had a mortality risk comparable to patients without glucocorticoid replacement and to the general population.
Patients with NFPA and AI receiving more than 20 mg HCeq per day have an increased mortality. Our data also show that mortality in patients substituted with 20 mg HCeq per day or less is not increased.