Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

Obesity measures, metabolic health and their association with 15-year all-cause and cardiovascular mortality in the SAMINOR 1 Survey: a population-based cohort study.

BACKGROUND: The mortality of metabolic-obesity phenotypes has been thoroughly studied, but it is not known if or how the association between mortality and body mass index (BMI), waist circumference or a body shape index (ABSI) differ in strata of cardiometabolic health status. METHODS: We linked data on 12,815 men and women aged 36-79 years from the SAMINOR 1 Survey with mortality data from the Norwegian Cause of Death Registry. We defined metabolically healthy and unhealthy as having zero and ≥ 1, respectively, of the following: MetS, pre-existing diabetes or cardiovascular disease (CVD), or prescribed drugs for high blood pressure, hyperglycaemia or dyslipidaemia. We defined general and abdominal obesity as BMI ≥ 30 kg/m2 and waist circumference ≥ 88 cm (women) or 102 cm (men), respectively, and cross-classified these categories with metabolic status to create metabolically healthy non-obese and obese (MHNO and MHO) and metabolically unhealthy non-obese and obese (MUNO and MUO) phenotypes. We used Cox regression to estimate the hazard ratio (HR) for all-cause and CVD mortality for 1) the four phenotypes and 2) BMI, waist circumference and ABSI fitted with restricted cubic splines. We adjusted for age and lifestyle, and tested for interactions with sex and metabolic status (only continuous measures). RESULTS: The MHO phenotype was present in 7.8% of women and 5.8% of men. During a median follow-up of 15.3/15.2 years, 596/938 women/men had died, respectively. The MUNO and MUO groups had higher mortality than the MHNO group. Sex and phenotypes interacted with respect to CVD mortality: relative to the MHNO group, the MHO group had an adjusted HR (95% confidence interval) for CVD mortality of 1.05 (0.38-2.88) in women and 2.92 (1.71-5.01) in men. We found curvilinear associations between BMI/waist circumference and all-cause mortality irrespective of metabolic status. Corresponding relationships with CVD mortality were linear and the slope differed by sex and metabolic status. ABSI was linearly and positively associated with all-cause and CVD mortality in men. CONCLUSION: The relationships between BMI, waist circumference or ABSI and mortality differed by sex, metabolic status and cause of death. Poor metabolic health substantially increases mortality regardless of obesity status.

GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility.

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).

A man in his sixties with dyspnoea and oedema. / Mann i 60-årene med tungpustethet og ødemer.

BACKGROUND/CASE PRESENTATION: A man in his sixties with chronic obstructive pulmonary disease was hospitalised due to oedema and dyspnoea during the previous weeks. He was hypertensive, with 10 kg weight gain, generalised oedema, proximal myopathy and moon face. The assessment was consistent with ectopic ACTH-dependent Cushing's syndrome. A 15 mm lung tumour was detected on CT, with inconclusive cytological examination, and negative FDG/PET CT and octreotide scintigraphy. He developed necrotising pancreatitis and a duodenal perforation, which were surgically treated. His cortisol levels and Cushingoid appearance normalised after surgery, and it was concluded that his hypercortisolism was part of a physiological response. He remained clinically in habitual shape until two years later, when he again developed Cushingoid stigmata. A new octreotide scintigraphy was negative, but FDG/PET CT revealed increased FDG uptake in the lung lesion. Before a lung biopsy was performed, the patient developed necrotising pancreatitis. He was treated conservatively and died in respiratory failure. Autopsy revealed a NET in the lung and necrotising pancreatitis. INTERPRETATION: The case demonstrates diagnostic challenges in the assessment of ectopic ACTH-dependent cyclic Cushing's syndrome. Is also suggests that pancreatitis could be triggered by hypercortisolism.

Change in prevalence and severity of metabolic syndrome in the Sami and non-Sami population in rural Northern Norway using a repeated cross-sectional population-based study design: the SAMINOR Study.

OBJECTIVE: To examine the change in both the prevalence and severity of metabolic syndrome (MetS) in the Sami and non-Sami in Northern Norway due to a lack of knowledge regarding the development of MetS in this population. DESIGN: Repeated cross-sectional study. SETTING: The study is based on data from the SAMINOR 1 Survey (2003-2004, n=6550) and the SAMINOR 2 Clinical Survey (2012-2014, n=6004), conducted in 10 municipalities in Northern Norway. PARTICIPANTS: Men and women aged 40-79 years were invited. We excluded participants not handing in the questionnaire and with missing information concerning ethnicity questions or MetS risk factors resulting in a final sample of 6308 (36.0% Sami) subjects in SAMINOR 1 and 5866 (40.9% Sami) subjects in SAMINOR 2. OUTCOME MEASURES: MetS prevalence was determined using the harmonised Adult Treatment Panel III (ATP-III) criteria, and severity was assessed with the MetS severity Z-score. Generalised estimating equations with an interaction term (survey × ethnicity) were used to compare prevalence and severity between the two surveys while accounting for partly repeated measurements. RESULTS: The overall, age-standardised ATP-III-MetS prevalence was 31.2% (95% CI: 29.8 to 32.6) in SAMINOR 1 and 35.6% (95% CI: 34.0 to 37.3) in SAMINOR 2. Both the ATP-III-MetS prevalence and the mean MetS severity Z-score increased between the surveys in all subgroups, except the ATP-III-MetS prevalence in non-Sami women, which remained stable. Over time, Sami men showed a slightly larger increase in MetS severity than non-Sami men (p<0.001): the score increased by 0.20 (95% CI: 0.14 to 0.25) and 0.06 (95% CI: 0.01 to 0.10) in Sami and non-Sami men, respectively. Abdominal obesity increased markedly between the surveys in all subgroups. CONCLUSION: The prevalence and severity of MetS increased over time in rural Northern Norway. Abdominal obesity appeared to drive the increase in ATP-III-MetS prevalence. Sami men had a slightly larger increase in severity than non-Sami.

Estimated 8-year cumulative incidence of diabetes mellitus among Sami and non-Sami inhabitants of Northern Norway - The SAMINOR Study.

BACKGROUND: The aim of the study was to estimate and compare the 8-year cumulative incidence of diabetes mellitus (DM) among Sami and non-Sami inhabitants of rural districts in Northern Norway. METHODS: Longitudinal study based on linkage of two cross-sectional surveys, the SAMINOR 1 Survey (2003-2004) and the SAMINOR 2 Clinical Survey (2012-2014). Ten municipalities in rural Northern Norway were included in the study. DM-free participants aged 30 and 36-71 years in SAMINOR 1 were followed from 2 years after SAMINOR 1 to attendance in SAMINOR 2. The average follow-up time was 8.1 years. Of 5875 subjects who had participated in SAMINOR 1 and could potentially be followed to SAMINOR 2, 3303 were included in the final analysis. Self-reported DM and/or HbA1c ≥ 6.5% were used to identify incident cases of DM. RESULTS: At baseline, body mass index (BMI) and waist-to-height ratio (WHtR) were higher among Sami than among their non-Sami counterparts. After 8 years of follow-up, 201 incident cases of DM were identified (6.1% both Sami and non-Sami subjects). No statistically significant difference was observed in the cumulative incidence of DM between the Sami and non-Sami. CONCLUSIONS: No statistically significant difference in the 8-year cumulative incidence of DM among Sami and non-Sami was observed, although Sami men and women had higher baseline BMI and WHtR.

Vitamin D supplementation has no effect on cognitive performance after four months in mid-aged and older subjects.

BACKGROUND: Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with impaired cognitive function, but the effect of vitamin D supplementation on cognitive function is uncertain. METHODS: 422 subjects were included in a randomized controlled trial with vitamin D (cholecalciferol) 100,000 IU given as a bolus dose followed by 20,000 IU per week versus placebo for four months. Cognitive function was evaluated with verbal recall test, coding test and tapping test. RESULTS: 374 subjects (mean age 52 years, 198 males) had complete cognitive tests both at baseline and at end of study. Mean baseline serum 25(OH)D level was 34 nmol/L. At baseline there were no significant associations between serum 25(OH)D and the three separate cognitive tests. At the end of the study mean serum 25(OH)D levels were 89 nmol/L and 31 nmol/L in the vitamin D and placebo groups, respectively. At the end of the study, there were no statistically significant differences between the two groups regarding change in the cognitive test scores. Nor did sub-group analyses based on gender, age, baseline serum 25(OH)D and cognitive test scores reveal significant differences between the two groups at the end of the study. CONCLUSIONS: Vitamin D supplementation did not improve cognitive function during a four months intervention in mid-aged and older subjects. TRIAL REGISTRATION: ClinicalTrials.govNCT02750293.

The prevalence of diabetes mellitus among Sami and non-Sami inhabitants of Northern Norway - the SAMINOR 1 Survey (2003-2004) and the SAMINOR 2 Clinical Survey (2012-2014).

INTRODUCTION: This study aimed to compare the prevalence of diabetes mellitus (DM) between Sami and non-Sami inhabitants of Northern Norway participating in the SAMINOR 1 Survey and the SAMINOR 2 Clinical Survey, and to track DM prevalence over time. METHODS: SAMINOR 1 (2003-2004) and SAMINOR 2 (2012-2014) are cross-sectional, population-based studies that each recruited Sami and non-Sami inhabitants. The data used in this article were restricted to participants aged 40-79 years in 10 municipalities in Northern Norway. Participants completed self-administered questionnaires and underwent clinical examination and blood sampling. Both questionnaire information and non-fasting/random plasma glucose levels were used to ascertain DM. The study included 6288 and 5765 participants with complete data on DM and outcomes, ie 54.6% and 46.3% of the invited samples, respectively. RESULTS: No difference in the prevalence of DM between Sami and non-Sami participants was observed, in either survey. Women had a statistically significantly lower DM prevalence than men in SAMINOR 2. Mean waist-to-height ratio and waist circumference increased substantially in both sexes; mean body mass index increased only slightly in men and remained unchanged in women. The total, age-standardized DM prevalence in SAMINOR 1 and 2 was 10.0% (95% confidence interval (CI) 9.2-10.7) and 11.2% (95%CI 10.4-12.0), respectively, and the proportion of self-reported (ie known) DM increased from 49.2% to 73.0%. In almost the same time span (2004-2015), the use of oral glucose-lowering agents increased. CONCLUSION: Overall, no ethnic difference was observed in DM prevalence. Overall DM prevalence was high, but did not change significantly from SAMINOR 1 to SAMINOR 2. The percentage of known versus unknown cases of DM increased, as did the prescription of medication for DM between 2004 and 2015.

Prevalence of pre-diabetes and type 2 diabetes mellitus among Sami and non-Sami men and women in Northern Norway - The SAMINOR 2 Clinical Survey.

The aim of this study was to determine and compare the prevalence of pre-diabetes and type 2 diabetes mellitus (T2DM) among Sami and non-Sami men and women of rural districts in Northern Norway. The SAMINOR 2 Clinical Survey is a cross-sectional population-based study performed in 2012-2014 in 10 municipalities of Northern Norway. A total of 12,455 Sami and non-Sami inhabitants aged 40-79 years were invited to participate and 5878 were included in the analyses. Participants with self-reported T2DM and/or a glycated haemoglobin (HbA1c) result ≥6.5% were categorised as having T2DM. Those with 5.7%≤HbA1c<6.5% were categorised as pre-diabetics. In men, the total age-standardised prevalence of pre-diabetes (37.9% vs 31.4%) and T2DM (10.8% vs 9.5%) were higher in Sami compared with non-Sami; the ethnic difference was statistically significant for both pre-diabetes (OR 1.42, p < 0.001) and T2DM (OR 1.31, p = 0.042). In women, pre-diabetes (36.4% vs 33.5%) and T2DM (8.6% vs 7.0%) were also more common in Sami than non-Sami; the differences in both pre-diabetes (OR 1.20, p = 0.025) and T2DM (OR 1.38, p = 0.021) were also statistically significant. The observed ethnic difference in the waist-to-height ratio (WHtR) was a plausible explanation for the ethnic difference in the prevalence of pre-diabetes and T2DM.

Associations between serum levels of calcium, parathyroid hormone and future risk of venous thromboembolism: the Tromsø study.

OBJECTIVE: The relationship between serum levels of calcium, parathyroid hormone (PTH) and risk of venous thromboembolism (VTE) has not been addressed in population-based cohorts. We investigated the associations between serum levels of calcium and PTH, with future risk of VTE in a general adult population. DESIGN: Population-based cohort. METHODS: A total of 27 712 subjects (25-87 years) who participated in Tromsø 4 (1994-1995) and Tromsø 5 (2001-2002) surveys were included in the study, and total calcium and PTH were measured in 27 685 and 8547 subjects respectively. Incident VTE was recorded through December 31, 2012. Cox-regression models with calcium and PTH as time-varying exposures were used to calculate hazard ratios (HR) of VTE by quartiles of calcium and PTH. Quartiles of calcium and PTH were also combined to assess the effect of discordants of both PTH and calcium (e.g. highest and lowest quartiles of both calcium and PTH) on VTE risk using the middle two quartiles as reference. RESULTS: There were 712 VTEs during 15.0 years of median follow-up. Serum levels of calcium and PTH were not associated with risk of VTE. However, subjects with discordant high serum levels of both calcium and PTH (calcium ≥2.45 mmol/L and PTH ≥4.0 pmol/L) had increased risk of VTE compared to those in subjects with normal calcium and PTH (multivariable HR: 1.78, 95% CI: 1.12-2.84). CONCLUSIONS: Serum levels of calcium and PTH separately were not associated with future risk of VTE, but subjects with high levels of both calcium and PTH had increased risk of VTE compared to those in subjects with normal levels.

Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation.

BACKGROUND: Few studies have assessed bone health in lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Therefore, we aimed to assess bone mineral density (BMD) at six different skeletal sites and to investigate associations between clinical factors and BMD in these survivors. MATERIAL AND METHODS: Eligible lymphoma survivors were aged ≥18 years at diagnosis and at HDT-ASCT given between 1987 and 2008. Participants responded to questionnaires, blood samples were drawn, and a dual energy X-ray absorptiometry (DXA) was performed. Mean Z-score was applied for assessment of BMD in relation to age. Prevalence of Z-scores ≥-1, between -1 and -2, and ≤-2 is reported for each measurement site and for the lumbar spine, femoral neck, and hip in combination. Likewise, T-scores were applied to assess the prevalence of normal BMD (≥-1), osteopenia (between -1 and -2.5), and osteoporosis (≤-2.5). RESULTS: We included 228 lymphoma survivors, of whom 62% were males. The median age at survey was 56 years, and median observation time from HDT-ASCT was eight years. Among males, Z-scores were lower at the left femoral neck and higher at the ultra-distal (UD) radius and whole body compared to the Lunar reference database. In females, Z-scores were lower at UD radius and one-third (33%) radius and higher at the whole body. Using a classification based on Z-scores at the lumbar spine, femoral neck, and hip in combination, 25% of males and 16% of females had Z-scores <-1 and >-2, while 8% and 6% had Z-scores ≤-2. According to T-scores, 35% of males and 41% of females had osteopenia, while 8% and 13% had osteoporosis, respectively. CONCLUSION: BMD was close to normal for age in this population of long-term lymphoma survivors treated with HDT-ASCT.

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma.

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant syndrome caused by activating germline mutations in the RET (REarranged during Transfection) proto-oncogene. MEN 2A has a strong (>95%) and age-dependent (5-25 years) clinical penetrance of medullary thyroid carcinoma (MTC). Several major studies have analyzed the predictive and prognostic factors for MEN 2A to find indicators that predict the optimal timing of prophylactic thyroidectomy. The aims of this study were to describe all known RET positive MEN 2A patients diagnosed in Norway and to evaluate the clinical course of MTC, as well as its predictive and prognostic factors. METHODS: This nationwide retrospective cohort study included data for 65 (14 index and 51 screening patients) out of a total of 67 MEN 2A patients with the RET gene mutation who were diagnosed in Norway since 1974. Data were collected by reviewing patient files. The variables analyzed were genotype, phenotype, preoperative basal calcitonin, age at thyroid surgery, central lymph node dissection and nodal status at primary surgery, number of surgical procedures, and biochemical cure. Of the 65 patients, 60 had undergone thyroid surgery. The median follow-up period was 9.9 years. The patients were divided into pre-RET-and RET-era, which included patients who had thyroid surgery before January 1, 1994, and after, respectively. RESULTS: In index and screening patients, MTC was found, respectively, in 100% and 45% of cases, central lymph node dissection at primary surgery was done for 64% and 52% of patients, and the median total number of surgical procedures was two (range 1-6) and one (range 1-4). At primary surgery, all patients (n = 13) with lymph node metastases had preoperative basal calcitonin levels ≥68 pg/mL, and all patients (n = 17) without central lymph node dissection and preoperative basal calcitonin <40 pg/mL were biochemically cured. Multivariate analysis showed that preoperative basal calcitonin was a significant predictive factor for MTC superior to age at thyroid surgery when analyzing the entire period (p = 0.009) and the RET-era separately (p = 0.021). Prognostic factors for biochemical cure were preoperative basal calcitonin, central lymph node dissection, and nodal status at primary surgery (p = 0.037, p = 0.002, and p = 0.005) when analyzing the entire period, but only nodal status at primary surgery when the RET-era was considered separately (p = 0.006). CONCLUSIONS: Preoperative basal calcitonin alone can serve as an indicator for optimal timing and the extent of thyroid surgery for MEN 2A patients that could be considered safe. The results are consistent with previously reported data.

Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects.

BACKGROUND: In observational studies vitamin D deficiency is associated with increased risk of infections, whereas the effect of vitamin D supplementation in randomized controlled trials is non-conclusive. METHODS: Five hundred and eleven subjects with prediabetes were randomized to vitamin D3 (20,000 IU per week) versus placebo for five years. Every sixth month, a questionnaire on respiratory tract infections (RTI) (common cold, bronchitis, influenza) and urinary tract infection (UTI) was filled in. RESULTS: Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/L. Two hundred and fifty-six subjects received vitamin D and 255 placebo. One hundred and sixteen subjects in the vitamin D and 111 in the placebo group completed the five-year study. Eighteen subjects in the vitamin D group and 34 subjects in the placebo group reported UTI during the study (p < 0.02), whereas no significant differences were seen for RTI. The effect on UTI was most pronounced in males. The effect of vitamin D on UTI was unrelated to baseline serum 25(OH)D level. CONCLUSION: Supplementation with vitamin D might prevent UTI, but confirmatory studies are needed.

A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.

CONTEXT: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. OBJECTIVE: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016). PATIENTS: All known Norwegian patients with APS1. RESULTS: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. CONCLUSIONS: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

Epidemiology and Health-Related Quality of Life in Hypoparathyroidism in Norway.

OBJECTIVE: The epidemiology of hypoparathyroidism (HP) is largely unknown. We aimed to determine prevalence, etiologies, health related quality of life (HRQOL) and treatment pattern of HP. METHODS: Patients with HP and 22q11 deletion syndrome (DiGeorge syndrome) were identified in electronic hospital registries. All identified patients were invited to participate in a survey. Among patients who responded, HRQOL was determined by Short Form 36 and Hospital Anxiety and Depression scale. Autoantibodies were measured and candidate genes (CaSR, AIRE, GATA3, and 22q11-deletion) were sequenced for classification of etiology. RESULTS: We identified 522 patients (511 alive) and estimated overall prevalence at 102 per million divided among postsurgical HP (64 per million), nonsurgical HP (30 per million), and pseudo-HP (8 per million). Nonsurgical HP comprised autosomal dominant hypocalcemia (21%), autoimmune polyendocrine syndrome type 1 (17%), DiGeorge/22q11 deletion syndrome (15%), idiopathic HP (44%), and others (4%). Among the 283 respondents (median age, 53 years [range, 9-89], 75% females), seven formerly classified as idiopathic were reclassified after genetic and immunological analyses, whereas 26 (37% of nonsurgical HP) remained idiopathic. Most were treated with vitamin D (94%) and calcium (70%), and 10 received PTH. HP patients scored significantly worse than the normative population on Short Form 36 and Hospital Anxiety and Depression scale; patients with postsurgical scored worse than those with nonsurgical HP and pseudo-HP, especially on physical health. CONCLUSIONS: We found higher prevalence of nonsurgical HP in Norway than reported elsewhere. Genetic testing and autoimmunity screening of idiopathic HP identified a specific cause in 21%. Further research is necessary to unravel the causes of idiopathic HP and to improve the reduced HRQOL reported by HP patients.

Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes.

CONTEXT: Vitamin D deficiency is associated with insulin resistance and risk of future diabetes. OBJECTIVE: The objective of the study was to test whether supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes mellitus (T2DM). DESIGN: This was a randomized controlled trial performed in 2008 through 2015. SETTING: The study was conducted at the clinical research unit at a teaching hospital. PATIENTS: Five hundred eleven subjects (mean age 62 y, 314 males) with prediabetes diagnosed with an oral glucose tolerance test as part of the Tromsø Study 2007­2008 were included. A total of 256 were randomized to vitamin D and 255 to placebo. Twenty-nine subjects in the vitamin D and 24 in the placebo group withdrew because of adverse events. INTERVENTIONS: Interventions included vitamin D (cholecalciferol) 20 000 IU/wk vs placebo for 5 years. Annual oral glucose tolerance tests were performed. MAIN OUTCOME MEASURE: Progression to T2DM was the main outcome measure. Secondary outcomes were change in glucose levels, insulin resistance, serum lipids, and blood pressure. RESULTS: The mean baseline serum 25-hydroxyvitamin D level was 60 nmol/L (24 ng/mL). One hundred three in the vitamin D and 112 in the placebo group developed T2DM (hazard risk 0.90; 95% confidence interval 0.69­1.18, Cox regression, P = .45, intention to treat analysis). No consistent significant effects on the other outcomes were seen. Subgroup analyses in subjects with low baseline 25-hydroxyvitamin D yielded similar results. No serious side effects related to the intervention were recorded. CONCLUSIONS: In subjects without vitamin D deficiency, vitamin D supplementation is unlikely to prevent progression from prediabetes to diabetes. Very large studies with inclusion of vitamin D-deficient subjects will probably be needed to show such a putative effect. This study tested if supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes (T2DM).

Thyroid function, as assessed by TSH, and future risk of venous thromboembolism: the Tromsø study.

OBJECTIVE: The relationship between thyroid function and the risk of venous thromboembolism (VTE) has not been addressed in population-based cohorts. We investigated the association between TSH levels and the risk of VTE in a general adult population. DESIGN: Population-based cohort study. METHODS: TSH was measured in 11 962 subjects aged 25-89 years who participated in Tromsø 4-6 starting in 1994-1995. Incident VTE events were recorded through 31st December 2010. Cox's regression models with TSH as a time-varying covariate were used to calculate hazard ratios (HRs) of VTE by TSH categories (low TSH: <0.05  mU/l; moderately reduced TSH: 0.05-0.19  mU/l; normal TSH: 0.20-4.00  mU/l; moderately elevated TSH: 4.01-5.00  mU/l; and high TSH: >5.00 mU/l) and within the normal range of TSH, modeling TSH as a continuous variable. RESULTS: There were 289 VTEs during 8.2 years of median follow-up. Subjects with low (prevalence: 0.22%) and high (3.01%) TSH had slightly higher risk estimates for VTE than did subjects with normal TSH (multivariable HRs: 2.16, 95% CI 0.69-6.76 and 1.55, 95% CI 0.87-2.77 respectively), but the CIs were wide. Moreover, there was no association between TSH within the normal range and VTE (HR per 1 mU/l increase: 0.95, 95% CI 0.82-1.11). CONCLUSION: Serum levels of TSH within the normal range were not associated with a risk of VTE, whereas low and high TSH levels were rare and associated with a moderately higher risk of VTE. The present findings suggest that only a minor proportion of the VTE risk in the population can be attributed to thyroid dysfunction.

No effect of high-dose vitamin D supplementation on glycemic status or cardiovascular risk factors in subjects with prediabetes.

OBJECTIVE: In observational studies, low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and other risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We present 1-year data from an ongoing 5-year trial in 511 individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) randomly assigned to 20,000 IU/week vitamin D3 or placebo. An oral glucose tolerance test was performed at baseline and after 1 year. RESULTS: Mean baseline serum 25(OH)D was 59.9 nmol/L and 61.1 nmol/L in the vitamin D and placebo groups, respectively, and increased by 45.8 nmol/L and 3.4 nmol/L, respectively. With adjustment for baseline concentrations, no differences in measures of glucose metabolism, insulin secretion or sensitivity, blood pressure, or hs-CRP were found after 1 year. There was a slight, but significant decrease in total and LDL cholesterol in the vitamin D group compared with the placebo group, but as there was also a decrease in HDL cholesterol, the change in the total/HDL cholesterol ratio did not differ significantly. Only analyzing subjects with 25(OH)D <50 nmol/L did not change the results. CONCLUSIONS: This study shows that vitamin D supplementation does not improve glycemic indices, blood pressure, or lipid status in subjects with IFG and/or IGT.

The phosphodiesterase 8B gene rs4704397 is associated with thyroid function, risk of myocardial infarction, and body height: the Tromsø study.

OBJECTIVE: High serum thyrotropin (TSH) levels predict cardiovascular disease (CVD). Recently several single nucleotide polymorphisms (SNPs) associated with TSH levels have been identified, one of them being the rs4704397 SNP in the phosphodiesterase 8B (PDE8B) gene. If the relation between thyroid function and CVD is causal, one could also expect rs4704397 genotypes to predict CVD and possibly health in general. METHODS: DNA was prepared and genotyping performed for rs4704397 in subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer, or death, as well as a randomly selected control group. Similarly, genotyping was performed in subjects who had participated in clinical trials where serum TSH, free T4 (fT4), and free T3 (fT3) were measured. RESULTS: From the Tromsø Study, 8938 subjects without thyroid disease or thyroid medication were successfully genotyped for rs4704397. Among these, 2098 were registered with MI, 1025 with T2DM, 2748 with cancer, and 3592 had died. The minor homozygote genotype (A:A) had a median serum TSH level that was 0.29 mIU/L higher than in the major homozygote genotype (G:G). The A:A genotype had a significantly increased risk of MI as compared to the G:G genotype (1.14 [1.00-1.29], hazard ratio [confidence interval], Cox regression with adjustment for age, sex, and body mass index). No significant associations were seen with the other endpoints or CVD risk factors. Furthermore, subjects with the G:G genotype were significantly taller than subjects with the A:A genotype (mean difference 1.5 cm). In 584 subjects with serum TSH, fT4, and fT3 measurements, the subjects with the A:A genotype had significantly higher serum TSH and nonsignificantly lower serum fT3 (mean difference 0.15 pmol/L) levels than subjects with the G:G genotype. CONCLUSION: rs4704397 is associated with thyroid function, risk of MI, and body height. However, confirmation in other cohorts is needed before firm conclusions can be drawn.