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I C van Nieuwpoort, M C Vlot, L A Schaap, P Lips and M L Drent

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.

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Andrea Osswald, Timo Deutschbein, Christina M Berr, Eva Plomer, Anne Mickisch, Katrin Ritzel, Jochen Schopohl, Felix Beuschlein, Martin Fassnacht, Stefanie Hahner and Martin Reincke

Objective

Aim of our study was to analyze long-term outcome of patients with the ectopic Cushing’s syndrome (ECS) compared to patients with Cushing’s disease (CD) regarding cardiovascular, metabolic, musculoskeletal and psychiatric comorbidities.

Design

Cross-sectional study in patients with ECS and CD in two German academic tertiary care centers.

Methods

Standardized clinical follow-up examination was performed including health-related quality of life (QoL) in 21 ECS patients in long-term remission (≥18 months since successful surgery). Fifty-nine patients with CD in remission served as controls.

Results

Time from first symptoms to diagnosis of Cushing’s syndrome (CS) was shorter in ECS than in CD (8.5 (IQR: 30.3) vs 25 (IQR: 39.0) months, P = 0.050). ECS patients had lower self-reported psychiatric morbidity compared to CD (19% vs 43%, P = 0.050) at follow-up. Moreover, female ECS patients reported favorable scores for QoL in the SF-36 questionnaire (mental health: 92 (IQR: 30) vs 64 (IQR: 32) in CD, P = 0.010) and a Cushing-specific QoL questionnaire (73 (IQR: 18) vs 59 (IQR: 36) in CD, P = 0.030). In a pooled analysis of ECS and CD patients, QoL correlated with time from first symptoms until diagnosis of CS, but not with urinary free cortisol levels or serum cortisol after dexamethasone at the time of diagnosis. Long-term outcomes regarding hypertension, metabolic parameters, bone mineral density and grip strength were comparable in ECS and CD.

Conclusions

Our data support the concept that time of exposure to glucocorticoid excess appears to be a better predictor than peak serum cortisol levels at the time of diagnosis regarding long-term psychiatric morbidity and QoL.

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Charlotte A Heinen, Zhi Zhang, Lars P Klieverik, Tim C de Wit, Edwin Poel, Maqsood Yaqub, Anita Boelen, Andries Kalsbeek, Peter H Bisschop, A S Paul van Trotsenburg, Hein J Verberne, Jan Booij and Eric Fliers

Objective

Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including β3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans.

Design

A randomized, placebo-controlled, double-blind, cross-over trial.

Methods

We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512).

Results

Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P = 0.066). MRglu showed a significant increase after TRH administration (P = 0.014). The increase in 18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations.

Conclusion

Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.

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Yun Shen, Peng Wang, Leishen Wang, Shuang Zhang, Huikun Liu, Weiqin Li, Nan Li, Wei Li, Junhong Leng, Jing Wang, Huiguang Tian, Cuilin Zhang, Jaakko Tuomilehto, Xilin Yang, Zhijie Yu and Gang Hu

Aims

To compare risks of early postpartum diabetes and prediabetes in Chinese women with and without gestational diabetes mellitus (GDM) during pregnancy.

Subjects and methods

Tianjin GDM observational study included 1263 women with a history of GDM and 705 women without GDM who participated in the urban GDM universal screening survey by using World Health Organization’s criteria. Postpartum diabetes and prediabetes were identified after a standard oral glucose tolerance test. Cox proportional hazards regression was used to assess risks of postpartum diabetes and prediabetes between women with and without GDM.

Results

During a mean follow-up of 3.53 years postpartum, 90 incident cases of diabetes and 599 incident cases of prediabetes were identified. Multivariable-adjusted hazard ratios among women with prior GDM, compared with those without it, were 76.1 (95% CI: 23.6–246) for diabetes and 25.4 (95% CI: 18.2–35.3) for prediabetes. When the mean follow-up extended to 4.40 years, 121 diabetes and 616 prediabetes cases were identified. Women with prior GDM had a 13.0-fold multivariable-adjusted risk (95% CI: 5.54-30.6) for diabetes and 2.15-fold risk (95% CI: 1.76-2.62) for prediabetes compared with women without GDM. The positive associations between GDM and the risks of postpartum diabetes and prediabetes were significant and persistent when stratified by younger and older than 30 years at delivery and normal weight and overweight participants.

Conclusions

The present study indicated that women with prior GDM had significantly increased risks for postpartum diabetes and prediabetes, with the highest risk at the first 3–4 years after delivery, compared with those without GDM.

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Vesna Salamun, Mojca Jensterle, Andrej Janez and Eda Vrtacnik Bokal

Objective

Glucagon-like peptide-1 (GLP-1) has been investigated in regulation of reproductive system in animal models. The potential impact of short-term preconception intervention with liraglutide on fertility potential in polycystic ovary syndrome (PCOS) has not been evaluated yet.

Design

A prospective randomized open-label study was conducted in 28 infertile obese PCOS patients (age: 31.07 ± 4.75, BMI: 36.7 ± 3.5 kg/m2, mean ± s.d.). They were assigned to metformin (MET) 1000 mg BID or to MET 1000 mg BID combined with low-dose liraglutide 1.2 mg QD s.c. (COMBI) for 12 weeks. Ovarian stimulation protocol was started after a 4-week medication-free period.

Methods

The in vitro fertilization pregnancy rate (PR) was defined as the number of clinical pregnancies confirmed by ultrasound visualization of the fetal cardiac activity, divided by the total number of cycles performed or embryo transfers (ET). The spontaneous PR was followed for 12 months.

Results

Patients in the MET group on average lost 7.0 ± 6.0 kg (P = 0.001) compared with 7.5 ± 3.9 kg in the COMBI group (P < 0.001) with no significant between-treatment difference (P = 0.246). The PR per ET was significantly higher in the COMBI (85.7%) compared with the MET (28.6%) group (P = 0.03). The cumulative PR in the time frame of 12 months was 69.2% in the COMBI group compared to 35.7% in the MET group.

Conclusions

Preconception intervention with low-dose liraglutide added to metformin is superior to metformin alone in increasing PRs per ET and cumulative PRs in infertile obese women with PCOS, despite comparable weight reduction in both groups. A potential impact of liraglutide on the reproductive system needs further exploration, in particular the GLP-1 impact on endometrial quality and receptivity.

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Tracy Ann Williams and Martin Reincke

The syndrome of primary aldosteronism (PA) is characterized by hypertension with excessive, autonomous aldosterone production and is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. The diagnostic workup of PA is a sequence of three phases comprising screening tests, confirmatory tests and the differentiation of unilateral from bilateral forms. The latter step is necessary to determine the optimal treatment approach of unilateral laparoscopic adrenalectomy (for patients with unilateral PA) or medical treatment with a mineralocorticoid receptor antagonist (for patients with bilateral PA). Since the publication of the revised Endocrine Society guideline 2016, a number of key studies have been published. They challenge the recommendations of the guideline in some areas and confirm current practice in others. Herein, we present the recent developments and current approaches to the medical management of PA.

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Ayrton Custodio Moreira, Sonir Rauber Antonini and Margaret de Castro

The circadian rhythm of glucocorticoids has long been recognised within the last 75 years. Since the beginning, researchers have sought to identify basic mechanisms underlying the origin and emergence of the corticosteroid circadian rhythmicity among mammals. Accordingly, Young, Hall and Rosbash, laureates of the 2017 Nobel Prize in Physiology or Medicine, as well as Takahashi’s group among others, have characterised the molecular cogwheels of the circadian system, describing interlocking transcription/translation feedback loops essential for normal circadian rhythms. Plasma glucocorticoid circadian variation depends on the expression of intrinsic clock genes within the anatomic components of the hypothalamic–pituitary–adrenal axis, which are organised in a hierarchical manner. This review presents a general overview of the glucocorticoid circadian clock mechanisms, highlighting the ontogeny of the pituitary–adrenal axis diurnal rhythmicity as well as the involvement of circadian rhythm abnormalities in the physiopathology and diagnosis of Cushing’s disease.

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F Bolfi, A F Neves, C L Boguszewski and V S Nunes-Nogueira

Objective

To compare the acromegaly mortality rates with those expected for the general population from studies published before and after 2008.

Methods

We performed a systematic review and included observational studies in which the number of deaths observed in acromegaly was compared with the expected mortality for the general population mortality observed/expected (O/E). The following electronic databases were used as our data sources: EMBASE, MEDLINE and LILACS. From the observed and expected deaths, we recalculated all standardized mortality ratios (SMR) and their respective confidence intervals (95% CI), which were plotted in a meta-analysis using the software RevMan 5.3.

Results

We identified 2303 references, and 26 studies fulfilled our eligibility criteria. From the 17 studies published before 2008, the mortality in acromegaly was increased, while from the nine studies published after 2008, the mortality was not different from the general population (SMR: 1.35, CI: 0.99–1.85). In six studies where somatostatin analogs (SAs) were used as adjuvant treatment, acromegaly mortality was not increased (SMR: 0.98, CI: 0.83–1.15), whereas in series including only patients treated with surgery and/or radiotherapy, mortality was significantly higher (SMR: 2.11; CI: 1.54–2.91). In studies published before and after 2008, the mortality was not increased in patients who achieved biochemical control, while it was higher in those with active disease. Cancer has become a leader cause of deaths in acromegaly patients in the last decade, period in which life expectancy improved.

Conclusion

Mortality in acromegaly is normalized with biochemical control and decreased in the last decade with the more frequent use of SAs as adjuvant therapy. Increased life expectancy has been associated with more deaths due to cancer.

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Ada S Cheung, Alistair J Tinson, Stefan V Milevski, Rudolf Hoermann, Jeffrey D Zajac and Mathis Grossmann

Objective

Hypogonadism from androgen deprivation therapy (ADT) for prostate cancer causes adverse body composition changes associated with insulin resistance and decreased quality of life (QoL). Our objective was to assess whether adverse body composition changes improve after cessation of ADT.

Design

Prospective case–control study in a tertiary referral hospital. Thirty-four men newly commencing ADT (cases, median age: 67.6 years (interquartile range: 64.6–72.0)) and 29 age-matched (70.6 years (65.3–72.9)) prostate cancer controls not on ADT were assessed 2 years after cessation of ADT (median: 4.4 years).

Methods

Serum testosterone, body composition, handgrip strength, frailty and QoL were measured. Using a mixed model, the mean adjusted differences (MADs (95% CI)) between groups from baseline to study end are reported.

Results

Twenty-seven cases and 19 controls completed the study. Median duration of ADT was 2.3 years (interquartile range: 1.8–3.1). Two years after cessation of ADT, total testosterone remained lower (MAD: −3.4 nmol/L (−6.3 to −0.5), P < 0.022), fat mass (2214 g (490–3933), P = 0.025) and insulin resistance (homeostasis model assessment of insulin resistance: 0.69 (0.31–1.07), P < 0.001) remained higher in cases, whereas lean mass (−1450 g (−2259 to −640), P < 0.001) and physical component of QoL remained lower than controls (−11.9 (−16.4 to −7.4), P < 0.001).

Conclusion

Two years after ADT cessation, metabolically adverse changes in body composition, increased insulin resistance and reduced QoL persisted. This may be related to incomplete testosterone recovery. Persisting adverse effects need to be considered in the risk to benefit assessment of ADT and proactive mitigation should continue after cessation of treatment.

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Lilian C Mendoza, Jürgen Harreiter, David Simmons, Gernot Desoye, J M Adelantado, Fabiola Juarez, Ana Chico, Roland Devlieger, Andre van Assche, Sander Galjaard, Peter Damm, Elisabeth R Mathiesen, Dorte M Jensen, Lise Lotte T Andersen, Mette Tanvig, Annunziata Lapolla, Maria G Dalfra, Alessandra Bertolotto, Urszula Mantaj, Ewa Wender-Ozegowska, Agnieszka Zawiejska, David Hill, Judith G Jelsma, Frank J Snoek, Mireille N M van Poppel, Christof Worda, Dagmar Bancher-Todesca, Alexandra Kautzky-Willer, Fidelma P Dunne, Rosa Corcoy and the DALI Core Investigator Group

Objective

Risk factors are widely used to identify women at risk for gestational diabetes mellitus (GDM) without clear distinction by pregnancy period or oral glucose tolerance test (OGTT) time points. We aimed to assess the clinical risk factors for Hyperglycemia in pregnancy (HiP) differentiating by these two aspects.

Design and methods

Nine hundred seventy-one overweight/obese pregnant women, enrolled in the DALI study for preventing GDM. OGTTs were performed at ≤19 + 6, 24–28 and 35–37 weeks (IADPSG/WHO2013 criteria). Women with GDM or overt diabetes at one time point did not proceed to further OGTTs. Potential independent variables included baseline maternal and current pregnancy characteristics. Statistical analysis: Multivariate logistic regression.

Results

Clinical characteristics independently associated with GDM/overt diabetes were at ≤19 + 6 weeks, previous abnormal glucose tolerance (odds ratio (OR): 3.11; 95% CI: 1.41–6.85), previous GDM (OR: 2.22; 95% CI: 1.20–4.11), neck circumference (NC) (OR: 1.58; 95% CI: 1.06–2.36 for the upper tertile), resting heart rate (RHR, OR: 1.99; 95% CI: 1.31–3.00 for the upper tertile) and recruitment site; at 24–28 weeks, previous stillbirth (OR: 2.92; 95% CI: 1.18-7.22), RHR (OR: 3.32; 95% CI: 1.70-6.49 for the upper tertile) and recruitment site; at 35–37 weeks, maternal height (OR: 0.41; 95% CI: 0.20–0.87 for upper tertile). Clinical characteristics independently associated with GDM/overt diabetes differed by OGTT time point (e.g. at ≤19 + 6 weeks, NC was associated with abnormal fasting but not postchallenge glucose).

Conclusion

In this population, most clinical characteristics associated with GDM/overt diabetes were non-modifiable and differed by pregnancy period and OGTT time point. The identified risk factors can help define the target population for future intervention trials.