The Interrelationship between Insulin-Like Growth Factor 1, Apolipoprotein E ε4, Lifestyle Factors, and the Aging Body and Brain.

Aging is associated with a decrease in body and brain function and with a decline in insulin-like growth factor 1 levels. The observed associations between alterations in insulin-like growth factor 1 levels and cognitive functioning and Mild Cognitive Impairment suggest that altered insulin-like growth factor 1 signaling may accompany Alzheimer's disease or is involved in the pathogenesis of the disease. Recent animal research has suggested a possible association between insulin-like growth factor 1 levels and the Apolipoprotein E ε4 allele, a genetic predisposition to Alzheimer's disease. It is therefore hypothesized that a reduction in insulin-like growth factor 1 signaling may moderate the vulnerability to Alzheimer's disease of human Apolipoprotein E ε4 carriers. We address the impact of age-related decline of insulin-like growth factor 1 levels on physical and brain function in healthy aging and Alzheimer's disease and discuss the links between insulin-like growth factor 1 and the Apolipoprotein E ε4 polymorphism. Furthermore, we discuss lifestyle interventions that may increase insulin-like growth factor 1 serum levels, including physical activity and adherence to a protein rich diet and the possible benefits to the physical fitness and cognitive functioning of the aging population.

Ranking Self-reported Gastrointestinal Side Effects of Pharmacotherapy in Sarcoidosis.

BACKGROUND: Clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. So far, no curative treatment exists; the disease can only be suppressed. All treatment options cause side effects affecting quality of life. The aim of this study was to establish and rank the prevalence of self-reported gastrointestinal side effects of drugs used in the treatment of sarcoidosis. METHODS: A cross-sectional web-based anonymous survey about complaints and side effects was conducted among sarcoidosis patients in the Netherlands, United Kingdom, and United States of America. RESULTS: Of the participants, 70% were being treated with one or more drugs. The most important reported side effect was weight gain, associated with increased appetite among prednisone users (as monotherapy as well as in combination with other drugs). Methotrexate (MTX) users especially experienced nausea, with monotherapy as well as combination therapy. Vomiting and weight loss were most prominent among azathioprine and mycophenolate mofetil (MMF) users, whereas diarrhoea was frequently mentioned by MMF and MTX users. The reported side effects of hydroxychloroquine were generally rather mild. CONCLUSION: The current study ranked the gastrointestinal side effects associated with pharmacotherapy in sarcoidosis patients. Pharmacotherapy does have multiple gastrointestinal side effects. The strongest association between a reported side effect and drug use was that of weight gain associated with increased appetite among prednisone users. It would therefore be useful for future research to look further into dietary interventions to counter these side effects and reduce their burden.

Self-reported Gastrointestinal Side Effects of Antifibrotic Drugs in Dutch Idiopathic Pulmonary Fibrosis patients.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is an inexorably progressive disease, which has a great impact on patients' lives. Pirfenidone and nintedanib are approved and recommended antifibrotic drugs for patients with IPF. The aim of this study was to evaluate self-reported gastrointestinal side effects of antifibrotic drugs in 176 Dutch IPF patients. METHODS: A cross-sectional web-based anonymous survey about complaints and side effects was conducted among IPF patients in the Netherlands. Logistic regression was used to quantify whether pirfenidone and nintedanib caused complaints of nausea, vomiting, diarrhoea, appetite loss, weight loss or loss of taste or smell perception. RESULTS: The questionnaire was completed by 176 IPF patients, 71 of whom used pirfenidone and 85 nintedanib, while 20 patients did not use any antifibrotic drugs. Nintedanib users reported complaints of diarrhoea, vomiting, weight loss and loss of appetite (p < 0.01). Nausea was a significant adverse reaction (p < 0.05). Pirfenidone caused increased appetite loss (p < 0.01) and the risk of weight loss (p < 0.05). The increase in loss of appetite and weight loss did not differ significantly between the two drugs. CONCLUSION: The current study showed that nintedanib causes a significant increase in diarrhoea, vomiting, weight loss and loss of appetite, while pirfenidone led to loss of appetite. Our results suggest new avenues regarding dietary recommendations for IPF patients.

Sarcoidosis and Work Participation: The Need to Develop a Disease-Specific Core Set for Assessment of Work Ability.

OBJECTIVE: Sarcoidosis, an inflammatory multi-organ disease with a wide variety of clinical manifestations, affecting people of working age. Patients suffer from a broad spectrum of physical symptoms of varying severity that impact function including cognitive impairment and disabling fatigue. The Dutch Sarcoidosis Society identified a knowledge gap in various facets related to work ability. The aim of this study was to assess sarcoidosis patients' perceived problems related to work performance, employer, and disability evaluations. METHODS: A cross-sectional web-based anonymous survey was conducted among Dutch sarcoidosis patients recruited through sarcoidosis patient societies and outpatient sarcoidosis clinics. This investigation queried work performance, employer support, and disability evaluations. RESULTS: The study sample included 755 patients of whom 43% (n = 328) had undergone disability evaluation and were significantly more likely to experience extrapulmonary symptoms, severe fatigue, reduced exercise capacity along with memory problems and concentration problems with higher mean FAS and SFNSL-scores. Of these 328, 37% (n = 121) perceived they had not been listened to or taken seriously at assessments, and 38% (n = 124) disagreed with the outcome of disability assessments by benefits authorities; 75% (n = 93) appealed or requested re-assessment. DISCUSSION: A better understanding of sarcoidosis-related impact on work ability and quantification of disease burden is needed. Education for medical examiners and employers on sarcoidosis may improve quality of assessments and work accommodations. Development of guidelines for benefit authorities, which consider the broad impact of sarcoidosis beyond that of reduced pulmonary function, including extra-pulmonary assessment like fatigue, cognitive difficulties, as well as other organ involvement are needed.

Correction to: The Burden of Sarcoidosis Symptoms from a Patient Perspective.

The original version of this article unfortunately contained a mistake in coauthor's given name. The abbreviated given name "M.D." for coauthor M.D.P. Elfferich's name has been inadvertently deleted during the production process.

The Burden of Sarcoidosis Symptoms from a Patient Perspective.

PURPOSE: The clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. Hence, sarcoidosis patients may suffer from a great variety of symptoms. The aim of this study was to compare the self-reported burden of sarcoidosis patients in Denmark, Germany and the Netherlands, especially the prevalence of fatigue and small fiber neuropathy (SFN)-related symptoms, as well as differences in treatment strategies. METHODS: A cross-sectional web-based anonymous survey about complaints was conducted among sarcoidosis patients. Patients were invited to take part through the sarcoidosis patient societies as well as through outpatient sarcoidosis clinics in these countries. RESULTS: The questionnaire was completed by 1072 sarcoidosis patients (152 Danish, 532 German and 388 Dutch). Almost all patients reported having sarcoidosis-associated symptoms (organ-related as well as non-specific, non-organ related). Fatigue was reported by almost all respondents (90%), followed by pulmonary symptoms (72.4%). More than 50% of the respondents were being treated with prednisone, which was comparable in all three countries. In contrast, second- and third-line treatment differed substantially between Denmark, Germany and the Netherlands. CONCLUSION: Sarcoidosis patients in Denmark, Germany and the Netherlands present with similar self-reported symptoms, organ-related as well as non-specific, non-organ related. Fatigue (90%) and symptoms associated with SFN (86%) were highly prevalent in all three countries.

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.

OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

The relationship between serum IGF-1, handgrip strength, physical performance and falls in elderly men and women.

OBJECTIVE: Human aging is accompanied by a decrease in growth hormone secretion and serum insulin-like growth factor (IGF)-1 levels. Also, loss of muscle mass and strength and impairment of physical performance, ending in a state of frailty, are seen in elderly. We aimed to investigate whether handgrip strength, physical performance and recurrent falls are related to serum IGF-1 levels in community-dwelling elderly. DESIGN: Observational cohort study (cross-sectional and prospective). METHODS: We studied the association between IGF-1 and handgrip strength, physical performance and falls in participants of the Longitudinal Aging Study Amsterdam. A total of 1292 participants were included (633 men, 659 women). Serum IGF-1 levels were divided into quartiles (IGF-1-Q1 to IGF-1-Q4). Data on falls were collected prospectively for a period of 3 years. All analyses were stratified for age and physical activity and adjusted for relevant confounders. RESULTS: Men with a low physical activity score in IGF-1-Q1 and IGF-1-Q2 of the younger age group had a lower handgrip strength compared to IGF-1-Q4. In younger more active males in IGF-1-Q2 physical performance was worse. Recurrent fallers were less prevalent in older, low active males with low IGF-1 levels. In females, recurrent fallers were more prevalent in older, more active females in IGF-1-Q2. IGF-1 quartile may predict changes in handgrip strength and physical performance in men and women. CONCLUSIONS: Our results indicate that lower IGF-1 levels are associated with lower handgrip strength and worse physical performance, but less recurrent fallers especially in men. Associations were often more robust in IGF-1-Q2. Future studies on this topic are desirable.

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors.

PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

The disturbed redox-balance in pulmonary fibrosis is modulated by the plant flavonoid quercetin.

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed pulmonary redox balance associated with inflammation. To restore this balance, antioxidants are often suggested as therapy for IPF but previous clinical trials with these compounds and their precursors have not been successful in the clinic. The exogenous antioxidant quercetin, which has a versatile antioxidant profile and is effective in restoring a disturbed redox balance, might be a better candidate. The aim of this study was to evaluate the protective effect of quercetin on oxidative and inflammatory markers in IPF. Here, we demonstrate that IPF patients have a significantly reduced endogenous antioxidant defense, shown by a reduced total antioxidant capacity and lowered glutathione and uric acid levels compared to healthy controls. This confirms that the redox balance is disturbed in IPF. Ex vivo incubation with quercetin in blood of both IPF patients and healthy controls reduces LPS-induced production of the pro-inflammatory cytokines IL-8 and TNFα. This anti-inflammatory effect was more pronounced in the blood of the patients. Our pro-fibrotic in vitro model, consisting of bleomycin-triggered BEAS-2B cells, shows that quercetin boosts the antioxidant response, by increasing Nrf2 activity, and decreases pro-inflammatory cytokine production in a concentration-dependent manner. Collectively, our findings implicate that IPF patients may benefit from the use of quercetin to restore the disturbed redox balance and reduce inflammation.

Acute and short-term effects of caloric restriction on metabolic profile and brain activation in obese, postmenopausal women.

OBJECTIVE: Early anthropometric and metabolic changes during a caloric-restricted diet in obese postmenopausal women and correlations between these factors with activity in brain areas involved in processing of visual food related stimuli were investigated. SUBJECTS AND METHODS: An 8-week prospective intervention study of 18 healthy postmenopausal women, with a body mass index of 30-35 kg m-2. The first 2 weeks subjects were on an isocaloric diet and 4 weeks on a 1000 kcal restricted diet followed by 2 weeks on an isocaloric diet. Anthropometric and laboratory analyses were performed weekly during the isocaloric diet and three times a week during the caloric-restricted diet. Functional magnetic resonance imaging scans were obtained before and after the caloric restriction in four separate sessions (fasting or sated). Generalized Estimating Equations analysis was used for data analysis. RESULTS: A mean weight loss of 4.2±0.5 kg (4.8%) and a 4.2±0.4 cm decline in waist circumference were achieved. In the first week of caloric restriction, triglyceride, leptin, resistin and adiponectin levels as well as systolic blood pressure decreased and insulin-like growth factor-binding protein 1 levels increased. During and after weight loss, a significant increase in ghrelin levels was observed. Before weight loss, increased activation of the right amygdala was seen in response to food stimuli, and free fatty acids and glucose correlated with activity in various areas involved in food reward processing. After weight loss, fasting ghrelin and sated leptin levels correlated with activity in these areas. CONCLUSIONS: Already in the first week of caloric restriction in obese postmenopausal women, various favourable metabolic changes occur before clinically relevant weight loss is achieved. Activity in the amygdala region and correlations of metabolic factors with activity in brain areas involved in food reward processing differ substantially before and after weight loss.

Fractures in pituitary adenoma patients from the Dutch National Registry of Growth Hormone Treatment in Adults.

PURPOSE: The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing's disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA). METHODS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated. RESULTS: At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy. CONCLUSIONS: During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms.

Risk of vertebral and non-vertebral fractures in patients with sarcoidosis: a population-based cohort.

UNLABELLED: In this retrospective cohort study using the Clinical Practice Research Datalink (CPRD), patients with sarcoidosis have an increased risk of clinical vertebral fractures and when on recent treatment with oral glucocorticoids, also an increased risk of any fractures and osteoporotic fractures. INTRODUCTION: Sarcoidosis is a chronic inflammatory disease, in which fragility fractures have been reported despite normal BMD. The aim of this study was to assess whether patients with sarcoidosis have an increased risk of clinical fractures compared to the general population. METHODS: A retrospective cohort study was conducted using the CPRD. All patients with a CPRD code for sarcoidosis between January 1987 and September 2012 were included. Cox proportional hazards models were used to derive adjusted relative risks (RRs) of fractures in all sarcoidosis patients compared to matched controls, and within the sarcoidosis group according to use and dose of systemic glucocorticoids. RESULTS: Five thousand seven hundred twenty-two sarcoidosis patients (mean age 48.0 years, 51 % females, mean follow-up 6.7 years) were identified. Compared to 28,704 matched controls, the risk of any fracture was not different in patients with sarcoidosis. However, the risk of clinical vertebral fractures was significantly increased (adj RR 1.77; 95 % CI 1.06-2.96) and the risk of non-vertebral fractures was decreased although marginally significant (adj RR 0.87; 95 % CI 0.77-0.99). Compared to sarcoidosis patients not taking glucocorticoids, recent use of systemic glucocorticoids was associated with an increased risk of any fracture (adj RR 1.50; 95 % CI 1.20-1.89) and of an osteoporotic fracture (adj RR 1.47; 95 % CI 1.07-2.02). CONCLUSIONS: Patients with sarcoidosis have an increased risk of clinical vertebral fractures, and when using glucocorticoid therapy, an increased risk of any fractures and osteoporotic fractures. In contrast, the risk of non-vertebral fractures maybe decreased. Further investigation is needed to understand the underlying mechanisms of these contrasting effects on fracture risk.

Oestrogens are Not Related to Emotional Processing: a Study of Regional Brain Activity in Female-to-Male Transsexuals Under Gonadal Suppression.

Although the prevailing opinion is that emotional processes are influenced by sex hormones, the literature is still inconclusive. The aim of the current study was to examine the effects of gonadal suppression on brain activity during affective picture processing. Twenty-one female-to-male (FtM) transsexuals and 19 control women were recruited and underwent functional magnetic resonance imaging scanning while rating emotional pictures adapted from the International Affective Picture System. The gonadal hormone production of the FtMs was suppressed for 8 weeks, the control group did not receive any treatment before scanning. Under gonadal suppression, FtMs showed less brain activation in the superior temporal lobe compared with female controls during perception of positive affective pictures. Regression analysis showed that during processing of positive affective images, brain activity within the right superior temporal lobe was not correlated with levels of estradiol, luteinizing hormone, and follicle-stimulating hormone. In the absence of associations with hormonal levels, the difference in activation in the superior temporal lobe during positive emotional stimuli between FtMs and control women may be attributed to a priori differences between the 2 groups. Future studies should clarify if these differences are a result of atypical sexual differentiation of the brain in FtMs.

Gender-Specific Associations of Serum Insulin-Like Growth Factor-1 With Bone Health and Fractures in Older Persons.

CONTEXT: IGF-1 plays a role in bone metabolism. Although IGF-1 and bone mass both decrease with advancing age, their relationship in older individuals remains to be elucidated. OBJECTIVE: The objective was to investigate associations of serum IGF-1 cross-sectionally with quantitative ultrasound and bone mineral density (BMD), and longitudinally with 3-year change in BMD and 10-year fracture risk in older individuals. DESIGN, SETTING, AND PATIENTS: The study included 627 men and 656 women aged ≥ 65 years from the Longitudinal Aging Study Amsterdam, an ongoing, population-based cohort study. MAIN OUTCOME MEASURES: Main outcome measures included baseline serum IGF-1 concentration; baseline quantitative ultrasound of the heel, including broadband ultrasound attenuation and speed of sound; BMD measured at several body sites at baseline and after 3 years; and prospective fracture incidence over 10 years. Associations were adjusted for relevant confounders. RESULTS: Women, but not men, in the lowest quintile of IGF-1 concentration had lower broadband ultrasound attenuation (B = -4.53; P = .03) and a greater 3-year decrease in total hip BMD (B = -0.02; P = .05), than women in the highest quintile of IGF-1. Moreover, compared to women in the highest quintile of IGF-1, women in the combined lowest four quintiles of IGF-1 had an increased 10-year fracture risk (hazard ratio = 1.98; P = .05). CONCLUSIONS: Associations of lower IGF-1 with lower BUA, greater 3-year decrease in BMD, and increased 10-year fracture risk were only observed in women, not in men. These results support previous findings of gender differences in the relationship between IGF-1 and bone in older individuals.

Tumor Recurrence or Regrowth in Adults With Nonfunctioning Pituitary Adenomas Using GH Replacement Therapy.

CONTEXT: GH replacement therapy (GH-RT) is a widely accepted treatment in GH-deficient adults with nonfunctioning pituitary adenoma (NFPAs). However, some concerns have been raised about the safety of GH-RT because of its potentially stimulating effect on tumor growth. OBJECTIVE: The aim of this study was to evaluate tumor progression in NFPA patients using GH-RT. DESIGN, SETTING, AND PATIENTS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severely GH-deficient adults (1998-2009), all NFPA patients with ≥ 30 days of GH-RT were selected (n = 783). Data were retrospectively collected from the start of GH-RT in adulthood (baseline). MAIN OUTCOME MEASURE: Tumor progression, including tumor recurrence after complete remission at baseline and regrowth of residual tumor. RESULTS: Tumor progression developed in 12.1% of the patients after a median (range) time of 2.2 (0.1-14.9) years. Prior radiotherapy decreased tumor progression risk compared to no radiotherapy (hazard ratio = 0.16; 95% confidence interval, 0.09-0.26). Analysis in 577 patients with available baseline imaging data showed that residual tumor at baseline increased tumor progression risk compared to no residual tumor (hazard ratio = 4.5; 95% confidence interval, 2.4-8.2). CONCLUSIONS: The findings in this large study were in line with those reported in literature and provide further evidence that GH-RT does not appear to increase tumor progression risk in NFPA patients. Although only long-term randomized controlled trials will be able to draw firm conclusions, our data support the current view that GH-RT is safe in NFPA patients.

Serum insulin-like growth factor 1 and late-life depression: a population-based study.

OBJECTIVE: Serum insulin-like growth factor 1 (IGF-1) concentration decreases, while the prevalence of depressive symptoms increases with advancing age. Although basic research indicates a link between low IGF-1 concentration and depression, this has scarcely been investigated in humans. This study investigates whether lower IGF-1 concentrations are associated with prevalent and incident late-life depression over a 3-year period. METHODS: The study included 1188 participants, aged ≥ 65 years, from the Longitudinal Aging Study Amsterdam (LASA), an ongoing, population-based cohort study. Depression was assessed at baseline and after three years using the Center for Epidemiological Studies-Depression Scale (CES-D) and the Diagnostic Interview Schedule (DIS), and categorized into minor depression and major depression (MDD). Serum IGF-1 concentration was determined at baseline. Associations were adjusted for relevant confounders. RESULTS: Serum IGF-1 concentrations were within the normal range (mean 13.9 nmol/l, standard deviation 5.3 nmol/l). At baseline, in men, as compared to high concentrations, mid concentrations decreased the probability of prevalent minor depression (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.15-0.82). In women, as compared to high concentrations, low concentrations tended to increase the probability of prevalent MDD (OR = 2.66, 95% CI = 0.89-7.89). At three-year follow-up, in men, no significant prospective associations were detected. In women, as compared to high concentrations, mid concentrations decreased the probability of incident minor depression (OR = 0.43, 95% CI = 0.19-0.95). CONCLUSIONS: Several associations, which differed across the genders, were observed between IGF-1 and depression. Cross-sectional findings were not supported by longitudinal findings, which suggest that IGF-1 may not play an important predictive role in the development of depression in older persons over time. However, a more acute role of IGF-1 in current depression, as indicated by the cross-sectional results, may be possible. Further studies are needed to elucidate the complex relation between IGF-1 and late-life depression.

Cerebrovascular events, secondary intracranial tumors, and mortality after radiotherapy for nonfunctioning pituitary adenomas: a subanalysis from the Dutch National Registry of Growth Hormone Treatment in Adults.

CONTEXT: Radiotherapy is frequently administered as adjuvant treatment in patients with clinically nonfunctioning pituitary adenomas (NFPAs). However, concerns have been raised about potential long-term side effects, including cerebrovascular events (CVEs) and secondary intracranial tumors. OBJECTIVE: The aim of this study was to analyze the risk of CVEs, secondary intracranial tumors, and mortality in irradiated (IRR) NFPA patients, compared with NFPA patients who were not irradiated (non-IRR). DESIGN, SETTING, AND PATIENTS: The study cohort included 806 patients with a NFPA from the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide long-term surveillance study in severe GH-deficient adult patients. IRR patients (n = 456) were compared with non-IRR patients (n = 350). MAIN OUTCOME MEASURES: CVEs, secondary intracranial tumors, and mortality were measured. RESULTS: Sixty-nine subjects developed a CVE. In men, but not in women, the incidence of a CVE was significantly higher in IRR patients than in non-IRR patients (hazard ratio 2.99, 95% confidence interval 1.31-6.79). A secondary intracranial tumor developed in five IRR patients and two non-IRR patients. After adjustment for age, radiotherapy was not associated with mortality. CONCLUSIONS: The incidence of secondary intracranial tumors and mortality did not differ between IRR and non-IRR patients. However, a CVE was found significantly more frequently in IRR men but not in women. Further research into the long-term effects of cranial radiotherapy seems mandatory. The potential risks of radiotherapy have to be taken into account when radiotherapy is considered in NFPA patients, and long-term follow-up is recommended.