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Open access

D A Dart, K Ashelford and W G Jiang

Advanced prostate cancer is often treated with AR antagonists which target the androgen receptor (AR) on which the growth of the tumour depends. Prostate cancer often develops AR-antagonist resistance via a plethora of mechanisms, many of which are as yet unknown, but it is thought that AR upregulation or AR ligand-binding site mutations, may be responsible. Here we describe the production of cell lines based on LNCaP and VCaP, with acquired resistance to the clinically relevant AR antagonists, bicalutamide and enzalutamide. In these resistant cells, we observed, via RNA-seq, that new variants in the 3′UTR of the AR mRNA were detectable and that the levels were increased both with AR-antagonist treatment and with hormonal starvation. Around 20% of AR transcripts showed a 3 kb deletion within the 6.7 kb 3′UTR sequence. Actinomycin D and luciferase fusion studies indicated that this shorter mRNA variant was inherently more stable in anti-androgen-resistant cell lines. Of additional interest was that the AR UTR variant could be detected in the sera of prostate cancer patients in a cohort of serum samples collected from patients of Gleason grades 6–10, with an increasing level correlated to increasing grade. We hypothesise that the shorter AR UTR variant is a survival adaptation to low hormone levels and/or AR-antagonist treatment in these cells, where a more stable mRNA may allow higher levels of AR expression under these conditions.

Open access

Ling Zhou, Zhexin Ni, Wen Cheng, Jin Yu, Shuai Sun, Dongxia Zhai, Chaoqin Yu and Zailong Cai

Polycystic ovary syndrome (PCOS) is a chronic endocrine and metabolic disease. Gut microbiota is closely related to many chronic diseases. In this study, we conducted a cross-sectional study and recruited 30 obese (OG) and 30 non-obese (NG) women with PCOS, 30 healthy women (NC) and 11 healthy but obese women (OC) as controls to investigate the characteristic gut microbiota and its metabolic functions in obese and non-obese patients with PCOS. The blood and non-menstrual faecal samples of all the participants were collected and analysed. As a result, the Hirsutism score, LH/FSH and serum T level in NG and OG both increased significantly compared with their controls (P < 0.05). High-throughput 16S rRNA gene sequencing revealed that the abundance and diversity of the gut microbiota changed in patients with PCOS. The linear discriminant analysis (LDA) indicated that Lactococcus was the characteristic gut microbiota in NG, while Coprococcus_2 in OG. Correlation heatmap analysis revealed that the sex hormones and insulin levels in human serum were closely related to the changes in the gut microbiota of NG and OG. Functional prediction analysis demonstrated that the citrate cycle pathway enriched both in NG and OG, and other 12 gut bacterial metabolic pathways enriched in NG. This study highlighted significant differences in the gut microbiota and predictive functions of obese and non-obese women with PCOS, thereby providing insights into the role and function of the gut microbiota that may contribute to the occurrence and development of PCOS in obese and non-obese women.

Open access

Bettina Winzeler, Michelle Steinmetz, Julie Refardt, Nicole Cesana-Nigro, Milica Popovic, Wiebke Fenske and Mirjam Christ-Crain

Objective

The syndrome of inappropriate antidiuresis (SIAD) is a common condition in hospitalized patients. It is crucial to establish the cause of SIAD, especially in order to exclude underlying malignancy. As malignant SIAD may be due to a paraneoplastic synthesis of arginine vasopressin, we hypothesized that its stable surrogate marker copeptin can be used as a diagnostic tool to differentiate between malignant and non-malignant SIAD.

Methods

Prospective observational study. We analyzed data from 146 SIAD patients of two different cohorts from Switzerland and Germany. Patients were included while presenting at the emergency department and underwent a standardized diagnostic assessment including the measurement of copeptin levels.

Results

Thirty-nine patients (median age: 63 years, 51% female) were diagnosed with cancer-related SIAD and 107 (median age: 73 years, 68% female) with non-malignant SIAD. Serum sodium levels were higher in cancer-related versus non-malignant SIAD: median (IQR) 124 mmol/l (120; 127) versus 120 mmol/l (117; 123) (P<0.001). Median (IQR) copeptin levels of patients with cancer-related SIAD were 11.1 pmol/l (5.2; 37.1) and 10.5 pmol/l (5.2; 25.2) with non-malignant SIAD (P = 0.38). Among different cancer entities, patients suffering from small-cell lung cancer showed the highest copeptin values, but overall no significant difference in copeptin levels between cancer types was observed (P = 0.46).

Conclusions

Copeptin levels are similar in cancer-related and non-malignant SIAD. Therefore, Copeptin does not seem to be suitable as a marker of malignant disease in SIAD.

Open access

L E Zijlstra, D M van Velzen, S Simsek, S P Mooijaart, M van Buren, D J Stott, I Ford, J W Jukema and S Trompet

Objective

Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate whether kidney function modifies the association of subclinical thyroid dysfunction and the risk of cardiovascular outcomes.

Methods

In total, 5804 patients were included in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). For the current analysis, 426 were excluded because of overt thyroid disease at baseline or 6 months, 266 because of inconsistent thyroid function at baseline and 6 months, 294 because of medication use that could influence thyroid function, and 16 because of missing kidney or thyroid values. Participants with normal fT4 were classified, based on TSH both at inclusion and 6 months, into three groups: subclinical hypothyroidism (TSH >4.5 mIU/L); euthyroidism (TSH = 0.45–4.5 mIU/L); and subclinical hyperthyroidism (TSH <0.45 mIU/L). Strata of kidney function were made based on estimated glomerular filtration rate into three clinically relevant groups: <45, 45–60, and >60 mL/min/1.73 m2. The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke.

Results

Mean age was 75.3 years, and 49.0% patients were male. Mean follow-up was 3.2 years. Of all participants, 109 subjects (2.2%) had subclinical hypothyroidism, 4573 (94.0%) had euthyroidism, and 182 (3.7%) subclinical hyperthyroidism. For patients with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, primary outcome occurred in 9 (8.3%), 712 (15.6%), and 23 (12.6%) patients, respectively. No statistically significant relationship was found between subclinical thyroid dysfunction and primary endpoint with adjusted hazard ratios of 0.51 (0.24–1.07) comparing subclinical hyperthyroidism and 0.90 (0.58–1.39) comparing subclinical hypothyroidism with euthyroidism. Neither was this relationship present in any of the strata of kidney function, nor did kidney function interact with subclinical thyroid dysfunction in the association with primary endpoint (P interaction = 0.602 for subclinical hyperthyroidism and 0.388 for subclinical hypothyroidism).

Conclusions

In this secondary analysis from PROSPER, we found no evidence that the potential association between thyroid hormones and cardiovascular disease is modified by kidney function in older patients with subclinical thyroid dysfunction.

Open access

Simon Chang, Christian Fynbo Christiansen, Anders Bojesen, Svend Juul, Anna-Marie B Münster and Claus H Gravholt

Objectives

Klinefelter syndrome (KS), 47,XXY, can be viewed as a disease model for investigating the risk of thrombosis in male hypogonadism and the subsequent risk related to testosterone treatment. We describe rates of thrombotic risk factors, thrombosis and thrombosis mortality in KS and the association with testosterone treatment.

Methods

National registry-based matched cohort study with follow-up from 1995 to 2016 set in Denmark. For the study, 1155 men with KS were each matched by year and month of birth to 100 men from the background population. First thrombotic events and thrombosis mortality was evaluated by event rates and hazard ratios (HRs) and by applying testosterone treatment as a time-dependent covariate.

Results

The KS cohort had higher incidence of venous thromboembolism relative to the comparison cohort (HR, 3.95; 95% CI, 2.83–5.52). Total thrombotic deaths were increased in KS (HR, 1.76; 95% CI, 1.18–2.62), and all-cause mortality was increased in KS following arterial thrombosis (HR 1.73; 95% CI 1.22–2.47). Only 48.7% of men with KS redeemed prescriptions for testosterone. Untreated men with KS were on average born 12 years before those treated, and the majority of untreated men with KS with available biochemistry were hypogonadal. Testosterone treatment in KS was associated with a non-significant decrease in venous thromboembolism and thrombotic deaths.

Conclusion

Thrombosis and thrombotic deaths are increased in KS. Only half of the men with KS ever received testosterone treatment, despite overt hypogonadism in the non-treated. Testosterone treatment in Klinefelter syndrome was insignificantly associated with lower incidence rates of venous thrombosis and thrombotic deaths.

Open access

Mojca Jensterle, Nika Aleksandra Kravos, Simona Ferjan, Katja Goricar, Vita Dolzan and Andrej Janez

Objective

Long-term efficacy of metformin in polycystic ovarian syndrome (PCOS) apart from in those with impaired glucose tolerance or diabetes remains unproven. We aimed to evaluate the impact of metformin in overweight-obese patients with PCOS and normal baseline glycemic homeostasis.

Methods

A 10-year longitudinal follow-up of a retrospective cohort comprising 159 patients with PCOS defined by Rotterdam criteria, BMI ≥25 kg/m2 and normal initial glucose homeostasis (age 28.4 ± 6.4 years, BMI 34.9 ± 6.6 kg/m2) that had been receiving metformin 1000 mg BID. Collection data contained 6085 time-points including anthropometric, hormonal and metabolic parameters.

Results

After the first year body mass (BM) decreased for 3.9 ± 6.8 kg (P < 0.001) and remained stable during the following 3 years. Menstrual frequency (MF) increased to 3.0 ± 3.9 bleeds/year (P < 0.001) after first year to over 11 bleeds/year in the following years. The total testosterone and androstenedione decreased to 15.4 ± 47.9% and 11.3 ± 46.4% within first year, with further decrease in total testosterone and androstenedione to 37.8 ± 61.8 and 24.8 ± 40.5% at the fifth year of the follow-up. The total conversion rate to prediabetes and diabetes was extremely low throughout observation period. Less than 25% of patients continued with metformin for more than 5 years with further dropout to only 6% on metformin therapy at the tenth year of follow-up.

Conclusions

Long-term metformin treatment of overweight-obese women with PCOS and normal baseline glycemic homeostasis resulted in reduction and stabilization of BM, improvements of MF and androgen profile and low conversion rate to diabetes.

Open access

Anne M Drewes, Maria E Møller, Rasmus Hertzum-Larsen, Gerda Engholm and Hans H Storm

Introduction

Cancer registry data in the USA indicated that women diagnosed with breast cancer before the age of 40 were at increased risk of a new primary tumour within the brain and women aged 50 years or above were at lower risk than expected. Our aim was to investigate if similar results could be found in Danish population-based data, considering an explanatory role of hormonal status.

Methods

Our study cohort included all women diagnosed with breast cancer below the age of 60 between 1978 and 2013 in Denmark. A total of 47,920 women were followed up in the Danish Cancer Registry for primary brain cancer. Standardized incidence ratios (observed/expected cases (O/E)) were used to estimate the risk of getting a primary brain tumour in the breast cancer cohort.

Results

Data indicated an increased tendency of brain cancer following breast cancer at ages below 60 years (O/E = 1.24). For premenopausal women (age <49 at the diagnosis of breast cancer) the O/E was 1.25. Stratifying by time of breast cancer diagnosis, we observed an increased risk of being diagnosed with a brain tumour among women aged 49 years or younger at breast cancer diagnosis between 2004 and 2013.

Conclusion

The results indicate an increased tendency of developing a primary brain tumour in women with previous breast cancer history. Whereas the finding in premenopausal women is in line with the SEER data, the finding among postmenopausal is not. Primary brain tumours in breast cancer patients call for research in genetics and hormones to establish common risk factors.

Open access

Aleksandra Kukulska, Jolanta Krajewska, Zofia Kolosza, Ewa Paliczka-Cieslik, Aleksandra Kropinska, Agnieszka Pawlaczek, Zbigniew Puch, Kornelia Ficek, Teresa Lisik, Dorota Sygula, Zbigniew Wygoda, Jozef Roskosz, Jerzy Wydmanski and Barbara Jarzab

The value of postoperative radiotherapy in the treatment of medullary thyroid carcinoma (MTC) has not been unequivocally demonstrated. Therefore our study aimed to answer the question of whether adjuvant radiotherapy showed any impact on the risk of local recurrence and whether there were any differences in response to radiotherapy between hereditary and sporadic MTC.

Methods

A retrospective analysis involved 254 MTC patients, among them 73 patients with a hereditary disease. Two hundred and twenty-four patients, including 43 persons at a high risk of local relapse, underwent only initial surgery; 18 other patients were operated due to MTC recurrences, whereas the remaining 12 patients had cytoreductive procedure or were not amenable for surgery. Radiotherapy was carried out in 132 patients. One hundred and twenty patients underwent adjuvant radiotherapy, among them 102 patients after initial surgery. The median follow-up was 10 years (range 0.5–29 years).

Results

Local recurrence occurred in 107/254 patients, among them in 63 subjects after prior radiotherapy. The frequency of relapse showed significantly increasing trend toward higher MTC stages (P <0.001). More relapses occurred in patients with lymph node metastases present at MTC onset. Adjuvant radiotherapy was associated with a lower risk of nodal recurrence only in high-risk patients, particularly if lymph node metastases were present at MTC diagnosis. The differences between hereditary and sporadic subgroups were not significant.

Conclusions

Adjuvant radiotherapy has a limited importance in MTC treatment. It should be considered in high-risk MTC patients. The presence of RET mutation does not influence the response to radiation.

Open access

Mette H Viuff and Claus H Gravholt

In this commentary, we discuss the state of affairs concerning the clinical care of females with Turner syndrome (TS) in Germany. TS is a rare disease and new international guidelines describe an appropriate setup for optimal clinical care. Several countries have implemented a program with centralized adult Turner syndrome clinics, which are now found in France, Denmark, the Netherlands, Sweden, parts of England and possibly other countries, but hitherto not in Germany. Such an approach should ensure the availability of high quality multi-disciplinary care for all women with TS to be treated and to detect all the conditions that have been associated with TS, which typically appear at odd times during the lifetime of a female with TS. Care should be offered at no added cost for the patient, and treatment with relevant drugs should be available at reasonable cost for the individual patient. Currently, it is quite problematic that many female sex hormone preparations are not available at low cost in a number of countries. Additional problems include supply chain issue which lead to patients not being able to buy their usual drug for a certain period of time. We think it is timely that countries improve the care for individuals with rare conditions, such as TS.

Open access

E R Polina, F M Oliveira, R C Sbruzzi, D Crispim, L H Canani and K G Santos

Circulating microRNA-155 (miR-155) is associated with type 2 diabetes mellitus (T2DM) and the rs767649 polymorphism in the pre-MIR155 gene is associated with miR-155 expression. However, their relationship with diabetic retinopathy (DR) is still unknown. Therefore, the aim of this case-control study was to test the hypothesis that the rs767649 polymorphism in the pre-MIR155 gene is associated with DR in South Brazilians with T2DM. We also evaluated the association of plasma levels of miR-155 with DR and the rs767649 polymorphism in a subgroup of subjects. The rs767649 polymorphism was genotyped in 139 blood donors and 546 T2DM patients (244 had no DR, 161 had non-proliferative DR and 141 had proliferative DR). miR-155 expression was quantified in 20 blood donors and 60 T2DM patients (20 from each group). Among T2DM patients, the carriership of the A allele and the A allele were more frequent in subjects with DR than in those without it (P < 0.05), and the A allele was independently associated with an increased risk of DR (adjusted OR = 2.12, 95% CI = 1.12–4.01). The plasma levels of miR-155 were lower in T2DM patients than in blood donors (P < 0.001). However, the miR-155 levels did not differ according to the presence and severity of DR or according to rs767649 genotypes among T2DM patients. These findings support that the rs767649 polymorphism in the pre-MIR155 gene is associated with DR in T2DM and that the miR-155 plasma levels might be associated with T2DM. Additional studies are needed to further investigate their clinical significance in DR and T2DM.