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Open access

Balachandran Kumarendran, Dana Sumilo, Michael W O’Reilly, Konstantinos A Toulis, Krishna M Gokhale, Chandrika N Wijeyaratne, Arri Coomarasamy, Wiebke Arlt, Abd A Tahrani and Krishnarajah Nirantharakumar

Objective

Obesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs without PCOS and to examine the role of obesity in the observed findings.

Design

Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK.

Methods

76 978 women with PCOS and 143 077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models.

Results

Median patient age was 30 (IQR: 25–35) years; median follow-up was 3.5 (IQR: 1.4–7.1) years. We found 298 OSA cases in PCOS women vs 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10 000 person years, respectively. Women with PCOS were at increased risk of developing OSA (adjusted HR = 2.26, 95% CI: 1.89–2.69, P < 0.001), with similar HRs for normal weight, overweight and obese PCOS women.

Conclusions

Women with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.

Open access

Guodong Xu, Dingyun You, Liping Wong, Donghui Duan, Fanqian Kong, Xiaohong Zhang, Jinshun Zhao, Wenhua Xing, Liyuan Han and Li Li

Objective

Previous studies have shown sex-specific differences in all-cause and CHD mortality in type 2 diabetes. We performed a systematic review and meta-analysis to provide a global picture of the estimated influence of type 2 diabetes on the risk of all-cause and CHD mortality in women vs men.

Methods

We systematically searched PubMed, EMBASE and Web of Science for studies published from their starting dates to Aug 7, 2018. The sex-specific hazard ratios (HRs) and their pooled ratio (women vs men) of all-cause and CHD mortality associated with type 2 diabetes were obtained through an inverse variance-weighted random-effects meta-analysis. Subgroup analyses were used to explore the potential sources of heterogeneity.

Results

The 35 analyzed prospective cohort studies included 2 314 292 individuals, among whom 254 038 all-cause deaths occurred. The pooled women vs men ratio of the HRs for all-cause and CHD mortality were 1.17 (95% CI: 1.12–1.23, I 2 = 81.6%) and 1.97 (95% CI: 1.49–2.61, I 2 = 86.4%), respectively. The pooled estimate of the HR for all-cause mortality was approximately 1.30 in articles in which the duration of follow-up was longer than 10 years and 1.10 in articles in which the duration of follow-up was less than 10 years. The pooled HRs for all-cause mortality in patients with type 2 diabetes was 2.33 (95% CI: 2.02–2.69) in women and 1.91 (95% CI: 1.72–2.12) in men, compared with their healthy counterparts.

Conclusions

The effect of diabetes on all-cause and CHD mortality is approximately 17 and 97% greater, respectively, for women than for men.

Open access

Jan Idkowiak, Yasir S Elhassan, Pascoe Mannion, Karen Smith, Rachel Webster, Vrinda Saraff, Timothy G Barrett, Nicholas J Shaw, Nils Krone, Renuka P Dias, Melanie Kershaw, Jeremy M Kirk, Wolfgang Högler, Ruth E Krone, Michael W O’Reilly and Wiebke Arlt

Objective

Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess.

Design

Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years.

Methods

Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review.

Results

In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione.

Conclusions

Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.

Open access

Ingibjörg H Jonsdottir and Anna Sjörs Dahlman

Burnout has several different definitions, and attempts have been made to discriminate between burnout as a psychological construct and burnout as a clinical entity. A large body of research has focused on elucidating the biological link between stress exposure and burnout and/or finding a clinically usable biomarker for burnout. The objective of this narrative review is to summarize the main endocrine and immune findings in relation to burnout. The literature has primarily focused on dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. However, albeit the large body of studies, it cannot be concluded that clear effects are seen on HPA axis function in people with burnout. The HPA axis and anabolic acute reactivity to stress might be affected in clinical burnout. Plausible, effects of chronic stress might rather be seen when measuring responses to acute stress rather than resting state hormonal levels. Studies on other hormones, including thyroid hormones, prolactin and growth hormone in burnout subjects are inconclusive. It is important to note that this field is faced with many methodological challenges, one being the diurnal and pulsatile nature of many of the hormones of interest, including cortisol, which is not always considered. Another challenge is the heterogeneity regarding definitions and measurements of stress and burnout. Existing studies on burnout and immune function are heterogeneous regarding the results and no firm conclusion can be made if clinically relevant immune changes are present in burnout subjects. An overall conclusion is that existing research cannot confirm any homogenous reliable endocrinological or immunological changes related to burnout.

Open access

Fabrice Bonneville, Louis-David Rivière, Stephan Petersenn, John S Bevan, Aude Houchard, Caroline Sert, Philippe J Caron and the PRIMARYS Study Group

Objective

Pituitary adenoma MRI T2 signal intensity associates with tumor characteristics including responsiveness to somatostatin analogs (SSAs). These analyses determined whether baseline T2 signal intensity predicts response to primary medical treatment with long-acting SSA.

Design

Post hoc analyses of the prospective multicenter, open-label, single-arm PRIMARYS study in which patients with treatment-naïve GH-secreting pituitary macroadenomas received fixed-dose lanreotide autogel (120 mg) every 4 weeks for 48 weeks.

Methods

Associations were investigated between adenoma T2-signal hypo/iso/hyperintensity and treatment responses at week 48/last visit: hormonal control (GH ≤2.5 μg/L and IGF-1 normalization); tumor response (tumor volume reduction (TVR) ≥20%); separate GH/IGF-1 control and change from baseline in GH/IGF-1 and tumor volume.

Results

Adenomas were hypointense at baseline in 50/85 (59%) patients using visual assessment. Of these, 40% achieved hormonal control and 76% achieved a tumor response. Significant univariate associations arose for hypo- vs isointensity with tumor response and achievement of GH ≤2.5 μg/L, but not IGF-1 normalization or overall hormonal control. In multivariate analysis, tumor response was six times more likely for hypo- vs iso-intense tumors (= 6.15; 95% CI: 1.36–27.88). In univariate change-from-baseline analyses, hypo- vs isointensity was associated with greater TVR and IGF-1 reduction but not change in GH. In multivariate analysis, IGF-1 decreased by an estimated additional 65 μg/L (P = 0.0026)) for hypo- vs isointense.

Conclusions

Patients with hypointense vs isointense GH-secreting macroadenomas had greater reductions in IGF-1 following primary treatment with lanreotide autogel and were more likely to achieve tumor response. Assessment of T2 signal intensity at baseline may help to predict long-term responses to primary treatment with SSAs.

Open access

Aliya A Khan, Christian A Koch, Stan Van Uum, Jean Patrice Baillargeon, Jens Bollerslev, Maria Luisa Brandi, Claudio Marcocci, Lars Rejnmark, Rene Rizzoli, M Zakarea Shrayyef, Rajesh Thakker, Bulent O Yildiz and Bart Clarke

Purpose: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults.

Methods: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords ‘hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy’. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism.

Results: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults.

Main conclusions: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.

Open access

Hongbo Yang, Kemin Yan, Xu Yuping, Qi Zhang, Linjie Wang, Fengying Gong, Huijuan Zhu, Weibo Xia and Hui Pan

Context

Adult growth hormone deficiency (AGHD) is characterized by low bone density and increased risk of fracture. Bone microarchitecture is insufficiently evaluated in patients with childhood-onset AGHD (CO AGHD).

Objective

To assess volumetric bone density (vBMD) and bone microarchitecture in CO AGHD in early adulthood after cessation of recombinant growth hormone (rhGH) treatment.

Design and subjects

Case–control study in a major academic medical center in Beijing, including 20 young male adults with CO AGHD and 30 age- and weight-matched non-athletic healthy men. High-resolution peripheral quantitative computerized tomography (HR-pQCT) of distal radius and tibia was performed.

Outcomes

The main outcomes were vBMD and morphometry parameters from HR-pQCT.

Results

Compared with healthy controls, CO AGHD group had significantly decreased insulin-like growth factor 1 (IGF-1) level and IGF-1 SDS (P < 0.001). β-CTX and alkaline phosphatase levels in CO AGHD group were significantly increased (P < 0.001). CO AGHD group had significantly decreased total vBMD, cortical vBMD, trabecular vBMD, cortical area, cortical thickness as well as trabecular thickness and trabecular bone volume fraction of both tibia and radius (P < 0.001). CO AGHD patients had an 8.4 kg decrease in grip strength and a significant decrease in creatinine levels (P = 0.001). At both tibia and radius, by finite element analysis, bone stiffness and failure load of the CO AGHD patients were significantly decreased (P < 0.001). After adjusting for age, BMI and serum levels of testosterone and free thyroxin, serum IGF-1 level was a positive predictor for total vBMD, cortical vBMD, cortical area, trabecular vBMD, bone stiffness and failure load of both tibia and distal radius in all subjects.

Conclusions

Young adult male patients with childhood-onset adult growth hormone deficiency who are no longer receiving growth hormone replacement have prominently impaired volumetric bone density and bone microarchitecture and lower estimated bone strength.

Open access

S R Ali, J Bryce, M Cools, M Korbonits, J G Beun, D Taruscio, T Danne, M Dattani, O M Dekkers, A Linglart, I Netchine, A Nordenstrom, A Patocs, L Persani, N Reisch, A Smyth, Z Sumnik, W E Visser, O Hiort, A M Pereira, S F Ahmed and on behalf of Endo-ERN

Objective

To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions.

Methods

Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%.

Results

Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%.

Conclusion

Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.

Open access

René Klinkby Støving

Anorexia nervosa is a syndrome, that is collections of symptoms, which is not defined by its etiology. The severe cases are intractable. The syndrome is associated with multiple, profound endocrine alterations which may be adaptive, reactive or etiologic. Adaptive changes potentially may be inappropriate in clinical settings such as inpatient intensive re-nutrition or in a setting with somatic comorbidity. Electrolyte levels must be closely monitored during the refeeding process, and the need for weight gain must be balanced against potentially fatal refeeding complications. An important focus of clinical research should be to identify biomarkers associated with different stages of weight loss and re-nutrition combined with psychometric data. Besides well-established peripheral endocrine actions, several hormones also are released directly to different brain areas, where they may exert behavioral and psychogenic actions that could offer therapeutic targets. We need reliable biomarkers for predicting outcome and to ensure safe re-nutrition, however, first of all we need them to explore the metabolism in anorexia nervosa to open new avenues with therapeutic targets. A breakthrough in our understanding and treatment of this whimsical disease remains. Considering this, the aim of the present review is to provide an updated overview of the many endocrine changes in a clinical perspective.

Open access

L Audí, S F Ahmed, N Krone, M Cools, K McElreavey, P M Holterhus, A Greenfield, A Bashamboo, O Hiort, S A Wudy, R McGowan and the EU COST Action

The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 ‘DSDnet’ was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV) or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case.