Deterioration of male reproductive functions in hyperprolactinaemia

Since the early seventies, chronic hyperPRLaemia due to hypothalamic-pituitary disorders, drug abuse, hypothyroidism or other causes, has been recognized as a cause of reproductive dysfunctions in both women and men. Possible mechanisms by which PRL exerts its effects on male reproductive functions have been extensively studied during the last two decades, but the mode of PRL action on reproductive functions has not been clarified by these studies. Mter an introduction on the physiological significance of PRL in vertebrates and the possible molecular processes involved in PRL action (chapter I), experimental models are discussed to study the effects of hyperPRLaernia on male reproductive functions in the rat (chapter II). This animal was used in the experiments presented in this thesis, because of the resemblance between the effects of hyperPRLaernia observed in rats and humans. During the experiments, the transplantable PRL-secreting tumour 7315b was employed as an experimental model to induce high serum PRL levels (2000- 5000 ng/rnl), comparable to those found in humans with hyperPRLaernia-associated impotence. Preceding the presentation of the data obtained from the experiments discussed in this thesis (chapters IV, V, VI, VII and VIII), male reproductive dysfunctions during hyperPRLaernia in the rat are reviewed (chapter III). Subsequently, aims and questions which are dealt with in this thesis are described

Metformin:A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice

Self-tracking of physical activity in people with type 2 diabetes:a randomized controlled trial

The purpose of this study was to determine the efficacy of an online self-tracking program on physical activity, glycated hemoglobin, and other health measures in patients with type 2 diabetes. Seventy-two patients with type 2 diabetes were randomly assigned to an intervention or control group. All participants received usual care. The intervention group received an activity tracker (Fitbit Zip) connected to an online lifestyle program. Physical activity was analyzed in average steps per day from week 0 until 12. Health outcome measurements occurred in both groups at baseline and after 13 weeks. Results indicated that the intervention group significantly increased physical activity with 1.5 +/- 3 days per week of engagement in 30 minutes of moderate-vigorous physical activity versus no increase in the control group (P = .047). Intervention participants increased activity with 1255 +/- 1500 steps per day compared to their baseline (P <.010). No significant differences were found in glycated hemoglobin A1c, with the intervention group decreasing -0.28% +/- 1.03% and the control group showing -0.0% +/- 0.69% (P = .206). Responders (56%, increasing minimally 1000 steps/d) had significantly decreased glycated hemoglobin compared with nonresponders (-0.69% +/- 1.18% vs 0.22% +/- 0.47%, respectively; P = .007). To improve effectiveness of eHealth programs, additional strategies are needed

The Role of Self-Regulation in the Effect of Self-Tracking of Physical Activity and Weight on BMI

Self-tracking of health may have positive effects on lifestyle behavior and weight loss; however, not much is known about the role of psychological processes in this effect. The purpose of this study was to assess to what extent a change in self-regulation capabilities can explain weight loss after 4 and 12 months of self-tracking physical activity and weight. An explorative cohort study was conducted with measurements at baseline (T0), 4 months (T1), and 12 months (T2). Healthy adult volunteers (N = 80) were included and provided with a digital weight scale and an activity tracker. Personal characteristics as well as the intention to change weight and physical activity were measured at T0. Self-regulation capabilities (goal orientation, self-direction, decision making, and impulse control) were measured with the Self-Regulation Questionnaire at T0, T1, and T2, together with body weight. At T0, all four dimensions of self-regulation were negatively related to BMI (p <.01). At T1, weight significantly declined compared to T0 (− 2.0 kg/− 0.64 kg/m2, p <.001). At T2, this weight loss was maintained (− 1.8 kg/− 0.57 kg/m2, p <.01). At T1, intention to lose weight, self-weighing frequency, and an increase in goal orientation explained weight loss. At T2, an increase in decision making explained weight loss. Incremental self-regulation capabilities may explain weight loss after engaging in self-tracking of physical activity and weight. Future research should focus on exploring effective ways to further enhance self-regulation when using self-tracking technology and to assess the impact of different types of self-regulation stimuli on weight loss

Hepatitis in a patient with SLE: Is it autoimmune hepatitis?

In a patient with systemic lupus erythematosus (SLE), we considered the diagnosis of autoimmune hepatitis (AIH) in view of raised serum aminotransferases, hypergammaglobulinaemia, antinuclear antibodies (titre 1:10240), seronegative of markers for viral hepatitis and absence of recent hepatotoxic drug usage. The diagnosis of AIH was supported by using the scoring system, recently developed by the International Autoimmune Hepatitis Group and the excellent response to treatment with prednisone. Liver histology, however, showed no characteristic features of AIH. The relevance of liver histology and scoring for AIH in SLE with hepatic involvement is discussed

Pregnancy Outcomes:Effects of Metformin (POEM) study: a protocol for a long-term, multicentre, open-label, randomised controlled trial in gestational diabetes mellitus

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy with health risks for mother and child during pregnancy, delivery and further lifetime, possibly leading to type 2 diabetes mellitus (T2DM). Current treatment is focused on reducing hyperglycaemia, by dietary and lifestyle intervention and, if glycaemic targets are not reached, insulin. Metformin is an oral blood glucose lowering drug and considered safe during pregnancy. It improves insulin sensitivity and has shown advantages, specifically regarding pregnancy-related outcomes and patient satisfaction, compared with insulin therapy. However, the role of metformin in addition to usual care is inconclusive and long-term outcome of metformin exposure in utero are lacking. The primary aim of this study is to investigate the early addition of metformin on pregnancy and long-term outcomes in GDM. METHODS AND ANALYSIS: The Pregnancy Outcomes: Effects of Metformin study is a multicentre, open-label, randomised, controlled trial. Participants include women with GDM, between 16 and 32 weeks of gestation, who are randomised to either usual care or metformin added to usual care, with insulin rescue in both groups. Metformin is given up to 1 year after delivery. The study consists of three phases (A-C): A-until 6 weeks after delivery; B-until 1 year after delivery; C-observational study until 20 years after delivery. During phase A, the primary outcome is a composite score consisting of: (1) pregnancy-related hypertension, (2) large for gestational age neonate, (3) preterm delivery, (4) instrumental delivery, (5) caesarean delivery, (6) birth trauma, (7) neonatal hypoglycaemia, (8) neonatal intensive care admission. During phase B and C the primary outcome is the incidence of T2DM and (weight) development in mother and child. ETHICS AND DISSEMINATION: The study was approved by the Central Committee on Research Involving Human Subjects in the Netherlands. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02947503

Metformin and high-sensitivity cardiac troponin I and T trajectories in type 2 diabetes patients: a post-hoc analysis of a randomized controlled trial

Background: Metformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo. Methods: This study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease. Results: This study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [− 8.4% (− 18.6, 3.2), p = 0.150, and − 4.6% (− 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [− 1.6% (− 2.9, − 0.2), p = 0.021] but not troponin I concentrations [− 1.5% (− 4.2, 1.2), p = 0.263]. Conclusions: In this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinically relevant effect on cardiac troponin I and cardiac troponin T levels when compared to placebo. Cardioprotective effects of the drug observed in clinical studies are not reflected by a reduction in these biomarkers of subclinical myocardial injury. Trial registration ClinicalTrials.gov identifier NCT00375388

How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study

Aims: Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT-2i CVOTs of a general T2D population. Methods: T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) by the total T2D population. Results: In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV-preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE-TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2-, 3- and 4-fold higher compared to the CANVAS (34%), EMPA-REG OUTCOME (21%) and VERTIS-CV (17%) trials, respectively. Conclusions: In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE-TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries