Clinical Endocrinology

Muraleedharan, Vakkat; Hugh Jones, T.

2014 Clinical Endocrinology

doi: 10.1111/cen.12503pmid: 25041142

Epidemiological studies have found that men with low or low normal endogenous testosterone are at an increased risk of mortality than those with higher levels. Cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone. Cancer and respiratory deaths in some of the studies are also significantly more prevalent. Disease‐specific studies have identified that there are higher mortality rates in men with cardiovascular, respiratory and renal diseases, type 2 diabetes and cancer with low testosterone. Obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease and inflammatory disorders are all associated with an increased prevalence of testosterone deficiency. Two major questions that arise from these findings are (1) is testosterone deficiency directly involved in the pathogenesis of these conditions and/or a contributory factor impairing the body's natural defences or is it merely a biomarker of ill health and the severity of underlying disease process? (2) Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival? This review will discuss the current state of knowledge and discuss whether or not there are any answers to either of these questions. There is convincing evidence that low testosterone is a biomarker for disease severity and mortality. Testosterone deficiency is associated with adverse effects on certain cardiovascular risk factors that when combined could potentially promote atherosclerosis. The issue of whether or not testosterone replacement therapy improves outcomes is controversial. Two retrospective studies in men with diagnosed hypogonadism with or without type 2 diabetes have reported significantly improved survival.

Dijk, P.R.; Logtenberg, S.J.J.; Gans, R.O.B.; Bilo, H.J.G.; Kleefstra, N.

2014 Clinical Endocrinology

doi: 10.1111/cen.12546pmid: 25041605

Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed.

Davenport, Emily; Lennard, Tom

2014 Clinical Endocrinology

doi: 10.1111/cen.12488pmid: 24802156

Rapid onset or acute hypercortisolism is a rare critical illness requiring emergency management. The majority of patients will have underlying malignancy with surgery an obvious choice in the minority with resectable disease. For those with unresectable disease, medical management alone has been the traditional approach. However, this often proves inadequate raising interest in the role of surgery as palliation in this setting. Patient selection, timing of surgery and optimal surgical technique are areas of current controversy with little literature available to provide answers. Decisions regarding management of patients with acute hypercortisolism are complex, and these patients are best managed in a subspecialized setting.

Mermejo, Livia M.; Leal, Leticia F.; Colli, Leandro M.; Fragoso, Maria C.B.V.; Latronico, Ana C.; Tone, Luiz G.; Scrideli, Carlos A.; Tucci, Silvio; Martinelli, Carlos E.; Yunes, Jose A.; Mastellaro, Maria J.; Seidinger, Ana L.; Brandalise, Silvia R.; Moreira, Ayrton C.; Ramalho, Leandra N.; Antonini, Sonir R.; Castro, Margaret

2014 Clinical Endocrinology

doi: 10.1111/cen.12462pmid: 24717047

Summary Context The role of planar cell polarity (Wnt/PCP) and calcium‐dependent (Wnt/Ca) noncanonical Wnt pathways in adrenocortical tumours (ACTs) is unknown. Objectives To investigate the gene expression of Wnt/PCP and Wnt/Ca pathways and its association with TP53 p.R337H and CTNNB1 mutations in paediatric and adult ACTs and to correlate these findings with clinical outcome. Patients Expression of noncanonical Wnt‐related genes was evaluated in 91 ACTs (66 children and 25 adults) by qPCR and the expression of beta‐catenin, P53 and protein effectors of Wnt/Ca (NFAT) and Wnt/PCP (JNK) by immunohistochemistry. TP53 and CTNNB1 genes were sequenced. Results TP53 p.R337H mutation frequency was higher in children (86% vs 28%), while CTNNB1 mutation was higher in adults (32% vs 6%). Mortality was higher in adults harbouring TP53 p.R337H and in children with CTNNB1 mutations. Overexpression of WNT5A, Wnt/Ca ligand, was observed in children and adults. Overexpression of MAPK8 and underexpression of PRICKLE, Wnt/PCP mediators, were observed in paediatric but not in adult cases. Cytoplasmic/nuclear beta‐catenin and P53 accumulation was observed in the majority of paediatric and adult ACTs as well as NFAT and JNK. Overexpression of MAPK8 and underexpression of PRICKLE were associated with mortality in children, while overexpression of WNT5A and underexpression of PRICKLE were associated with mortality in adults. Conclusions In our study, TP53 p.R337H and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. We demonstrate, for the first time, the activation of Wnt/PCP and Wnt/Ca noncanonical pathway genes, and their association with poor outcome in children and adults, suggesting their putative involvement in ACTs aggressiveness.

Kluger, Nicolas; Matikainen, Niina; Sintonen, Harri; Ranki, Annamari; Roine, Risto P.; Schalin‐Jäntti, Camilla

2014 Clinical Endocrinology

doi: 10.1111/cen.12484pmid: 24801591

Summary Objective Patients with Addison's disease (AD) on conventional replacement therapy have impaired health‐related quality of life (HRQoL). It is possible that lower hydrocortisone (HC) doses recommended by current guidelines could restore HRQoL. We compared HRQoL in AD patients treated according to current HC recommendations to that of the age‐ and gender‐standardized general population. Subjects, design and measurement We assessed HRQoL in a cross‐sectional setting with the 15D instrument in a Finnish AD cohort (n = 107) and compared the results with those of a large sample of general population (n = 5671). We examined possible predictors of HRQoL in AD. Within the patient group, HRQoL was also assessed by SF‐36. Results Mean HC dose was 22 mg/d, corresponding to 12 ± 4 mg/m2. HRQoL was impaired in AD compared with the general population (15D score; 0·853 vs 0·918, P < 0·001). Within single 15D dimensions, discomfort and symptoms, vitality and sexual activity were most affected. Stepwise regression analysis demonstrated that Patient's Association membership (P = 0·02), female gender (P < 0·01), presence of other autoimmune or inflammatory comorbidity (P < 0·02), lower education (P < 0·02) and longer disease duration (P < 0·05) independently predicted impaired HRQoL, whereas replacement regimens, autoimmune‐related comorbidities, total number of comorbidities or level of healthcare follow‐up did not. In AD, HRQoL was impaired also as assessed by SF‐36. Conclusions HRQoL is significantly impaired in AD compared with the general population despite use of recommended HC doses. Patient's Association membership was the most significant predictor of impaired HRQoL. This finding should be explored in more detail in the future.

Shetty, Sahana; Kapoor, Nitin; Naik, Dukhabandhu; Asha, Hesarghatta S; Thomas, Nihal; Paul, Thomas V

2014 Clinical Endocrinology

doi: 10.1111/cen.12495pmid: 24821494

Summary Background and Objectives Recently, the Indian Council of Medical Research (ICMR) has published normative data for bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) scanning. However, the impact this has had on the diagnosis of osteoporosis when compared to currently used Caucasian databases has not been analysed. Hence, this study was undertaken to look at agreement between the Hologic Database (HD) based on BMD normative data in Caucasians and the ICMR database (ICMRD) in defining osteoporosis in subjects with or without hip fracture. Materials and Methods It is a cross ‐sectional study of 2976 subjects (men 341, women 2757) (mean age ± SD = 62·2 ± 7·2 years), including 316 subjects with low impact hip fracture: 2199 were from the hospital database, and 461 were healthy postmenopausal women from the community who underwent (DXA) scanning between January 2010 and March 2013. Recalculated T scores from ICMRD were used for the diagnosis of osteoporosis and compared with HD. Results An almost perfect agreement existed between the two databases for the diagnosis of osteoporosis at the hip (κ −0·82, P < 0·0001) in all subjects, and a moderate relationship existed in those with hip fracture (κ −0·65, P < 0·0001). Seventy‐three of 316 hip fracture subjects (23·5%) defined as osteoporosis according to HD were classified as osteopenia according to ICMRD. Conclusion The threshold of hip BMDT score for treating osteoporosis may have to be redefined if the ICMR reference database is used. Initiation of treatment in these subjects must be based on multiple fracture risk factor assessment in addition to looking at BMD. Further studies with a larger sample size of subjects with fracture are needed to validate our findings.

Kahal, H.; Abouda, G.; Rigby, A. S.; Coady, A. M.; Kilpatrick, E. S.; Atkin, S. L.

2014 Clinical Endocrinology

doi: 10.1111/cen.12369pmid: 24256515

Summary Introduction Nonalcoholic fatty liver disease (NAFLD) has been linked to polycystic ovary syndrome (PCOS) and carries an increased risk of liver cirrhosis. Procollagen type 3 amino‐terminal peptide (PIIINP) is an independent predictor of liver cirrhosis. Objective To assess whether 6‐month treatment with GLP‐1 analogue, liraglutide, improves markers of liver fibrosis. Design A case–control study comparing women with PCOS to age‐ and weight‐matched controls. PCOS was diagnosed according to the Rotterdam criteria. All participants underwent liver function tests and liver ultrasound scan to assess for fatty infiltration. Serum marker for liver fibrosis, PIIINP, was measured at baseline and after 6‐month treatment with liraglutide 1·8 mg od. Results Nineteen women with PCOS and 17 controls were recruited, age 32·8 ± 7·2 vs 33·5 ± 6·7 years and weight 100·9 ± 16·7 vs 99·3 ± 14·7 kg, respectively. At baseline, the PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nm (P = 0·01), HOMA‐IR 5·1 ± 2·6 vs 3·5 ± 1·3 (P = 0·03), AST 22·4 ± 5·2 vs 18·8 ± 3·4 u/l (P = 0·04), PIIINP 4·4 ± 0·8 vs 3·5 ± 0·8 ug/ml (P = 0·01) and NAFLD seven (35%) vs none (P = 0·005), respectively. Twenty‐five (69%) participants completed the study (13 PCOS, 12 controls). Following treatment, weight was reduced by 3·0 ± 4·2 kg (P = 0·01) and 3·8 ± 3·4 kg (P = 0·001), respectively. Similarly, HOMA‐IR, hsCRP, triglycerides and urinary isoprostane significantly reduced in both groups. PIIINP significantly reduced the in PCOS group 4·4 ± 0·8 vs 3·7 ± 0·9 ug/ml (P < 0·01), but not in controls 3·5 ± 0·8 vs 3·2 ± 0·7 ug/ml (P = 0·08). Conclusions Treatment with liraglutide, and/or associated weight loss, significantly reduced PIIINP levels in obese women with PCOS. This may be an additional beneficial factor when considering the use of liraglutide in women with PCOS, obesity and NAFLD.

Orlik, Bartłomiej; Madej, Paweł; Owczarek, Aleksander; Skałba, Piotr; Chudek, Jerzy; Olszanecka‐Glinianowicz, Magdalena

2014 Clinical Endocrinology

doi: 10.1111/cen.12381pmid: 24392647

Summary Objective It is suggested that disturbed adipokines release plays a role in PCOS pathogenesis. The aim of this study was to assess plasma levels of omentin and adiponectin as well as the omentin to adiponectin ratio, as markers of adipose tissue dysfunction in relation to hormonal or metabolic changes in PCOS. Study Design, Patients and Measurements A cross‐sectional study involved 87 PCOS (48 obese) and 72 non‐PCOS women (41 obese). Anthropometric parameters and body composition were determined, and serum glucose, hormones, omentin‐1 and adiponectin levels were measured. Results The adiponectin level was similar in PCOS and non‐PCOS groups, but, in both, was significantly lower in obese compared with normal weight subgroups, while the omentin‐1 level was significantly lower in the PCOS compared with the non‐PCOS group, and not related to body mass. The adiponectin to omentin‐1 ratio (AOR) was significantly higher in the PCOS than non‐PCOS group. Moreover, AOR was significantly higher in the normal weight than in obese subgroups in both PCOS and non‐PCOS groups. Multiple regression analyses revealed that AOR variability is explained by oestradiol level and all anthropometric parameters as well as FAI, but not LH to FSH and HOMA‐IR values. Conclusions Our results suggest secondary to insulin resistance and hyperandrogenism impairment of hormonal stroma adipose tissue function in PCOS, independent of nutritional status. Contrarily, the adipocyte hormonal dysfunction is primarily dependent on excessive fat accumulation. It seems that the AOR may be useful in the assessment of adipose tissue dysfunction not only in PCOS.

Lee, Chee‐Tin Christine; Harris, Stewart B.; Retnakaran, Ravi; Gerstein, Hertzel C.; Perkins, Bruce A.; Zinman, Bernard; Hanley, Anthony J.

2014 Clinical Endocrinology

doi: 10.1111/cen.12390pmid: 24372524

Summary Background Higher white blood cell count (WBC) is associated with incident type 2 diabetes; however, little is known about the potential relationship of WBC subtypes with metabolic abnormalities underlying diabetes. Design Cross‐sectional analysis. Participants Six hundred and fifty‐six nondiabetic participants in the Prospective Metabolism and Islet Cell Evaluation cohort. Measurements Granulocytes (basophils, neutrophils and eosinophils), lymphocytes and monocytes were measured in fasting blood samples. Neutrophil lymphocyte ratio (NLR) is the ratio of neutrophil to lymphocyte. Insulin resistance was measured by insulin sensitivity index (ISOGTT) and homeostasis model assessment of insulin resistance (HOMA‐IR). Beta‐cell dysfunction was measured by insulinogenic index (IGI) divided by HOMA‐IR (IGI/IR) and Insulin Secretion Sensitivity Index‐2 (ISSI‐2). Results All WBC subtypes were inversely associated with ISOGTT (β = −0·12 (−0·15, −0·083) for granulocytes, β = −0·23 (−0·31, −0·15) for lymphocytes, β = −0·67 (−1·00, −0·34) for monocytes) and positively associated with HOMA‐IR (β = 0·11 (0·074, 0·15) for granulocytes, β = 0·22 (0·14, 0·30) for lymphocytes, β = 0·64 (0·33, 0·97) for monocytes). Granulocytes and lymphocytes were inversely associated with IGI/IR (β = −0·10 (−0·15, −0·047), β = −0·23 (−0·35, −0·11), respectively) and ISSI‐2 (β = −0·048 (−0·074, −0·022), β = −0·14 (−0·19, −0·089), respectively). BMI attenuated the associations of monocytes with IGI/IR and ISSI‐2, and those of NLR with ISOGTT and HOMA‐IR. NLR was not associated with IGI/IR and ISSI‐2. Conclusions All WBC subtypes were independently associated with insulin resistance, whereas granulocytes and lymphocytes, but not monocytes, were associated with β‐cell dysfunction. NLR was not associated with β‐cell dysfunction, and its association with insulin resistance was confounded by obesity.

Rigamonti, A. E.; Bini, S.; Grugni, G.; Agosti, F.; De Col, A.; Mallone, M.; Cella, S. G.; Sartorio, A.

2014 Clinical Endocrinology

doi: 10.1111/cen.12395pmid: 24372155

Summary Objective The effect of eating rate on the release of anorexigenic gut peptides in Prader‐Willi syndrome (PWS), a neurogenetic disorder clinically characterized by hyperphagia and excessive obesity, has not been investigated so far. Design and Patients Postprandial PYY and GLP‐1 levels to fast (5 min) and slow (30 min) ice cream consumption were measured in PWS adult patients and age‐matched patients with simple obesity and normal‐weighted subjects. Visual analog scales (VASs) were used to evaluate the subjective feelings of hunger and satiety. Results Fast ice cream consumption stimulated GLP‐1 release in normal subjects, a greater increase being observed with slow feeding. Fast or slow feeding did not change circulating levels of GLP‐1 in obese patients, while, unexpectedly, fast feeding (but not slow feeding) stimulated GLP‐1 release in PWS patients. Plasma PYY concentrations increased in all groups, irrespective of the eating rate. Slow feeding was more effective in stimulating PYY release in normal subjects, while fast feeding was more effective in PWS patients. Slow feeding evoked a lower hunger and higher satiety compared with fast feeding in normal subjects, this finding being not evident in obese patients. Unexpectedly, fast feeding evoked a lower hunger and higher satiety in PWS patients in comparison with slow feeding. Conclusions Fast feeding leads to higher concentrations of anorexigenic gut peptides and favours satiety in PWS adult patients, this pattern being not evident in age‐matched patients with simple obesity, thus suggesting the existence of a different pathophysiological substrate in these two clinical conditions.