Acromegaly is a rare disease and thus challenging to accurately quantify epidemiologically. In this comprehensive literature review, we compare different approaches to studying acromegaly from an... Show moreAcromegaly is a rare disease and thus challenging to accurately quantify epidemiologically. In this comprehensive literature review, we compare different approaches to studying acromegaly from an epidemiological perspective and describe the temporal evolution of the disease pertaining to epidemiological variables, clinical presentation and mortality. We present updated epidemiological data from the population-based Danish cohort of patients with acromegaly (AcroDEN), along with meta-analyses of existing estimates from around the world.Based on this, we conclude that the incidence, prevalence and age at acromegaly diagnosis are all steadily increasing, but with considerable variation between studies. An increased number of incidental cases may contribute to the increase in incidence and age at diagnosis, respectively. The clinical features at presentation are trending toward a milder disease phenotype at diagnosis, and advances in therapeutic options have reduced the mortality of patients with acromegaly to a level similar to that of the general population. Moreover, the underlying cause of death has shifted from cardiovascular to malignant neoplastic diseases. Show less
In this thesis sex differences in migraine symptomatology and sex-specific aspects of migraine are assessed with a focus on differences between perimenstrual and non-perimenstrual migraine attacks.... Show moreIn this thesis sex differences in migraine symptomatology and sex-specific aspects of migraine are assessed with a focus on differences between perimenstrual and non-perimenstrual migraine attacks. Remarkably little is known about sex differences in the clinical presentation of migraine and female-specific aspects of migraine, despite obvious sex differences in prevalence. There is currently no female-specific approach or treatment that acts on sex hormones, although the relation to the menstrual cycle is indisputable. The first part of this thesis seeks to increase our understanding of menstrual migraine and includes recommendations to improve diagnostic criteria. The second part examines sex differences in the clinical presentation of a migraine attack, addresses possible clinical manifestations of sex hormones in men with migraine and offers practical guidelines for sex-specific treatment. Show less
The two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies... Show moreThe two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies based on the two-hit stress model have investigated early postnatal stress as the first hit with adult stress as the second hit. Adolescence, however, represents another highly sensitive developmental window during which exposure to stressful events may affect programming outcomes following exposure to stress in adulthood. Here, we discuss the programming effects of different types of stressors (social and nonsocial) occurring during adolescence (first hit) and how such stressors affect the responsiveness toward an additional stressor occurring during adulthood (second hit) in rodents. We then provide a comprehensive overview of the potential mechanisms underlying interindividual and sex differences in the resilience/susceptibility to developing stress-related disorders later in life when stress is experienced in two different life stages. Show less
Stroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics,... Show moreStroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics, lifestyle, and environment of the individual, among others. This is also known as precision prevention. An important example illustrating the need for precision prevention is the existence of sex differences in stroke occurrence. In practice, for predicting stroke risk, only traditional risk factors (such as smoking and hypertension) are included, and women-specific risk factors are not yet routinely included. As a result, women with an increased risk of stroke may be missed, which also prevents timely initiation of preventive treatments. In this thesis, I tried to lay the foundation for precision prevention of stroke in women.Part I discussed the pathophysiology underlying women-specific risk factors for stroke, and gender differences in the clinical presentation of stroke. I found that the mechanisms underlying the relationship between women-specific risk factors and stroke, in particular the relationship between migraine and cerebral infarctions, seem to be particularly significant in the childbearing phase of life.In Part II, I described how health data from the EHR can be used to develop prediction models for the risk of myocardial infarction or stroke specifically for women under 50 years of age, and found that women-specific risk factors can add value in the predictions. However, there is still a long way to go to actually implement these models in practice, such as testing them on new datasets, and complying with current laws and regulations for safe application. Show less
Complex Regional Pain Syndrome (CRPS) is a severely disabling pain syndrome. Patients report a poorer quality of life than patients with other chronic pain conditions, particularly in the physical... Show moreComplex Regional Pain Syndrome (CRPS) is a severely disabling pain syndrome. Patients report a poorer quality of life than patients with other chronic pain conditions, particularly in the physical domains (chapter 2). Sex differences are small, although male patients experience a higher psychological burden than female CRPS patients (chapter 3).Considering the pathophysiology CRPS, we could not reproduce previous MRI findings of altered brain function and structure in rest (Chapter 4). We did find increased salience detecting during the application of a painful stimulus with opposite activation of brain regions involved in reducing the affected burden of pain (chapter 5). Lastly, cortical motor activations during motor tasks differ from previously published results in patients with functional movement disorders (chapter 6). Show less
Aims A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they... Show moreAims A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. Methods and results An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. Conclusion The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP. Show less
Quaas, A.; Biesma, H.D.; Wagner, A.D.; Verheij, M.; Henegouwen, M.I.V.; Schoemig-Markiefka, B.; ... ; Grieken, N.C.T. van 2022
Objective: Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability ... Show moreObjective: Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability (MSI)-high and microsatellite stable (MSS) gastric cancer (GC). Design: We analysed MSI status by polymerase chain reaction (PCR) and/or mismatch repair (MMR) status by immunohistochemistry in a pooled analysis of individual patient data from one retrospective cohort from Cologne, and the randomised phase III clinical trials D1/D2 and CRITICS. All patients had resectable adenocarcinoma of the stomach and/or gastro-oesophageal junction. Patients were treated with either surgery only or perioperative chemo(radio) therapy. Results: MSI and/or MMR analyses on 1307 tumours resulted in 1192 (91.2%) MSS and/or MMR proficient (MMRP) [median age, 65 years; 759 males (63.7%); 619 treated with surgery only (51.9%)], and 115 (8.8%) MSI-high [median age, 69 years; 67 males (58.3%); 76 treated with surgery only (66.1%)] GC cases. Males had shorter overall survival (OS) than female MSI-high GC (5-year OS 34.7% vs. 69.7%; hazard ratio (HR) 2.68, 95%CI 1.60 to 4.49; p < 0.001). Females with MSI-high had longer OS than those with MSS/MMRP GC ( HR 0.61, 95%CI 0.41 to 0.92; p = 0.02). Males with MSI-high did not have longer OS than those with MSS/MMRP GC (HR 1.26, 95%CI 0.94 to 1.69; p = 0.12). Conclusions: MSI-high GC males had a significantly worse prognosis compared to their female counterparts in three independent cohorts. In addition, the favourable prognostic value of MSI was only seen in females and not in males. These observations emphasise the need to consider sex differences in prognosis and treatment effects in oncology. Show less
Galbally, M.; Watson, S.J.; Lappas, M.; Kloet, E.R. de; Wyrwoll, C.S.; Mark, P.J.; Lewis, A.J. 2022
In examining maternal depression, placental 11 beta-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders,... Show moreIn examining maternal depression, placental 11 beta-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders, it has become clear that sex differences may be important to consider. This study reports on data obtained from 209 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) recruited before 20 weeks of pregnancy. Maternal depressive disorders were diagnosed using the SCID-IV and maternal childhood trauma using the Childhood Trauma Questionnaire. Placental 11 beta-HSD2 mRNA was measured using qRT-PCR. For assessment of stressinduced cortisol reactivity, salivary cortisol samples were taken at 12 months of age. At 4 years of age, measurement of Childhood Emotional Disorders (depression and anxiety) was based on maternal report using the Preschool Age Psychiatric Assessment (PAPA) and internalizing symptoms using the Child Behavior Checklist (CBCL). Maternal depression in pregnancy and postpartum, and infant cortisol reactivity, was associated with internalizing symptoms for females only. For female offspring only, increased 12-month cortisol reactivity was also associated with increased emotional disorders at 4 years of age; however, there was no association with placental 11 beta-HSD2 mRNA expression. In females only, the combination of lower placental 11 beta-HSD2 mRNA expression and higher cortisol reactivity at 12 months of age predicted increased internalising problems. These findings suggest there may be sex differences in prenatal predictors and pathways for early childhood depression and anxiety symptoms and disorder. Show less
Women with severe aortic stenosis (AS) have better long-term prognosis after transcatheter aortic valve implantation (TAVI) compared to men. Whether this is caused by sex-related differences in... Show moreWomen with severe aortic stenosis (AS) have better long-term prognosis after transcatheter aortic valve implantation (TAVI) compared to men. Whether this is caused by sex-related differences in left ventricular (LV) reverse remodeling after TAVI is unknown. Patients with severe AS who underwent transfemoral TAVI between 2007 and 2018 were selected. LV dimensions, volumes, and ejection fraction (LVEF) were assessed by transthoracic echocardiography before TAVI and at 6 and 12 months follow-up after TAVI. LV reverse remodeling was defined as the percentual LV mass index (LVMi) reduction compared to baseline. The primary outcome was all-cause mortality. A total of 459 patients (80 +/- 8 years; 52% male) were included. At 6 and 12 months follow-up, both sexes showed significant reductions in LV volumes and LVMi accompanied by improvement in LVEF, without significant differences between the sexes over time. During a median follow-up of 2.8 [IQR 1.9-4.3] years, 181 (39%) patients died. Women showed better outcomes compared to men (log-rank p = 0.024). In addition, male sex was independently associated with all-cause mortality in multivariable Cox regression (HR 1.423, 95% CI 1.039-1.951, p = 0.028). No association was observed between the interaction of percentual LVMi reduction and sex with outcomes (p = 0.64). Men and women with severe AS had similar improvement in LVEF, and similar reductions in LV volumes and LVMi at 6 and 12 months after TAVI. Women showed better survival after TAVI as compared to men. The superior outcomes noted in women after TAVI are not associated with sex differences in LV reverse remodeling.[GRAPHICS]. Show less
With, R.R. de; Arita, V.A.; Nguyen, B.O.; Linz, D.; Cate, H. ten; Spronk, H.; ... ; Rienstra, M. 2022
Aims:The clinical risk profile of atrial fibrillation (AF) patients is different in men and women. Our aim was to identify sex differences in blood biomarkers in patients with paroxysmal AF.... Show moreAims:The clinical risk profile of atrial fibrillation (AF) patients is different in men and women. Our aim was to identify sex differences in blood biomarkers in patients with paroxysmal AF. Methods and results: Sex differences in 92 blood biomarkers were measured in 364 patients included in our discovery cohort, the identification of a risk profile to guide atrial fibrillation therapy (AF-RISK) study, assessed by multivariable logistic regression and enrichment pathway analysis. Findings were subsequently confirmed in 213 patients included in our validation cohort, the Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF (RACE V) study. In the discovery cohort, mean age was 59 +/- 12 years, 41% were women. CHA(2)DS(2)-VASc-score was 1.6 +/- 1.4. A total of 46% had hypertension, 10% diabetes, and 50% had heart failure, predominantly with preserved ejection fraction (47%). In women, activated leucocyte cell adhesion molecule (ALCAM) and fatty acid binding protein-4 (FABP-4) were higher. In men, matrix metalloproteinase-3 (MMP-3), C-C motif chemokine-16 (CCL-16), and myoglobin were higher. In the validation cohort, four out of five biomarkers could be confirmed: levels of ALCAM (P = 1.73 x 10(-4)) and FABP-4 (P = 2.46 x 10(-7)) and adhesion biological pathways [false discovery rate (FDR) = 1.23 x 10(-8)] were higher in women. In men, levels of MMP-3 (P = 4.31 x 10(-8)) and myoglobin (P = 2.10 x 10(-4)) and markers for extracellular matrix degradation biological pathways (FDR = 3.59 x 10(-9)) were higher. Conclusion: In women with paroxysmal AF, inflammatory biomarkers were more often higher, while in men with paroxysmal AF, biomarkers for vascular remodelling were higher. Our data support the clinical notion that pathophysiological mechanisms in women and men with AF may differ. Show less
The heart is innervated by the autonomic nervous system, which can be divided into sympathetic and parasympathetic parts. The balance between cardiac sympathetic and parasympathetic innervation is... Show moreThe heart is innervated by the autonomic nervous system, which can be divided into sympathetic and parasympathetic parts. The balance between cardiac sympathetic and parasympathetic innervation is critical for maintaining normal cardiac function. After myocardial infarction, sympathetic hyperinnervation has been discovered in patients as well as in animal models, which has raised growing awareness in relation to arrhythmogenesis. However the mechanism is not clear yet. In this thesis, we hypothesize a role for epicardium-derived cells (EPDCs) in this process. In addition, we aimed to study ganglia remodeling after myocardial infarction. We explored: i) the role of EPDCs in promoting cardiac sympathetic re-/hyperinnervation after cardiac damage in vitro, ii) the impact of sex of EPDCs on cardiac innervation, iii) the generation of inducible proliferative human EPDCs (iEPDCs), iv) neuronal remodeling of superior cervical ganglia after myocardial infarction and v) the molecular signature of SCG revealed by single nucleus RNA sequencing. Show less
Raafs, A.; Verdonschot, J.; Ferreira, J.P.; Wang, P.; Collier, T.; Henkens, M.; ... ; Heymans, S. 2021
Aims Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF... Show moreAims Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF sex-specifically are scarce. This study therefore aims to test the sex-specificity of 252 protein biomarkers for new-onset HF.Methods and results A matched case-control design in patients selected from cohorts within the HOMAGE consortium was used. Cases (new-onset HF, n = 562) and controls (n = 780) were matched for cohort (PREDICTOR, HEALTH-ABC, & PROSPER), follow-up time (defined as time from entry to incident HF), and age. Incident HF was defined as first hospitalization for HF. Targeted plasma proteins (n = 252) were measured using Proximity Extension Assay technology from O-link. To look for sex differences for new onset HF, we adjusted for cohort, age, and baseline clinical parameters. At baseline, women had a biomarker profile reflecting activated metabolism and immune responses. However, none of the biomarkers had a significant interaction with sex in predicting new onset HF, but four biomarkers had a trend towards sex-specificity (P < 0.013). E-selectin and interleukin 1 receptor antagonist were more female-specific, whereas IL17A and CHIT1 tended to be male sex-specific for incident HF.Conclusions The majority of biomarkers associated with incident HF did not significantly differ between women and men, despite clear differences in biomarkers at baseline. Show less
Hendriksen, L.C.; Linden, P.D. van der; Lagro-Janssen, A.L.M.; Bemt, P.M.L.A. van den; Siiskonen, S.J.; Teichert, M.; ... ; Visser, L.E. 2021
Background Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5-1.7 times more... Show moreBackground Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5-1.7 times more likely to develop ADRs. The main objective was to identify sex differences in the types and number of ADRs leading to hospital admission. Methods ADR-related hospital admissions between 2005 and 2017 were identified from the PHARMO Database Network using hospital discharge diagnoses. Patients aged >= 16 years with a drug possibly responsible for the ADR and dispensed within 3 months before admission were included. Age-adjusted odds ratios (OR) with 95% CIs for drug-ADR combinations for women versus men were calculated. Results A total of 18,469 ADR-related hospital admissions involving women (0.35% of all women admitted) and 14,678 admissions involving men (0.35% of all men admitted) were included. Most substantial differences were seen in ADRs due to anticoagulants and diuretics. Anticoagulants showed a lower risk of admission with persistent haematuria (ORadj 0.31; 95%CI 0.21, 0.45) haemoptysis (ORadj 0.47, 95%CI 0.30,0.74) and subdural haemorrhage (ORadj 0.61; 95%CI 0.42,0.88) in women than in men and a higher risk of rectal bleeding in women (ORadj 1.48; 95%CI 1.04,2.11). Also, there was a higher risk of admission in women using thiazide diuretics causing hypokalaemia (ORadj 3.03; 95%CI 1.58, 5.79) and hyponatraemia (ORadj 3.33, 95%CI 2.31, 4.81) than in men. Conclusions There are sex-related differences in the risk of hospital admission in specific drug-ADR combinations. The most substantial differences were due to anticoagulants and diuretics. Show less
Background Age-related decline in muscle strength, dynapenia, is linked to serious adverse health outcomes. Evidence on the determinants of muscle strength decline in the oldest old is lacking.... Show moreBackground Age-related decline in muscle strength, dynapenia, is linked to serious adverse health outcomes. Evidence on the determinants of muscle strength decline in the oldest old is lacking. Aims To identify clinical variables associated with handgrip strength and its change over a 4-year period in an oldest old cohort. Methods We included 555 participants from the Leiden 85-plus Study, a prospective population-based study of 85-year-old inhabitants of Leiden, the Netherlands. Handgrip strength was assessed at age 85 and 89 years. Anthropometry, mental status, functional performance, and biochemical variables were obtained at baselines. Significant univariates were included into multivariable regression models to extract the final predictive variables. Results Handgrip strength for men and women at age 85 years was 30.6 kg (SD 8.2) and 18.7 kg (SD, 5.5), respectively. In the cross-sectional analysis, body height and weight were positively associated with handgrip strength in both genders. Higher functional performance was associated with stronger handgrip strength in women. Mean absolute handgrip strength decline over 4 years was greater for men than women (- 6.1 kg (SD, 5.2) vs. - 3.4 kg (SD, 4.1),p < 0.001). Men with better baseline cognitive functioning had smaller decline in handgrip strength. Conclusions This study further strengthens evidence linking functional and cognitive performances to muscle strength in the oldest old. Future research is needed to ascertain causality and determine if these markers represent potential targets for intervention. Show less
Veen, K.M.; Mokhles, M.M.; Braun, J.; Versteegh, M.I.M.; Bogers, A.J.J.C.; Takkenberg, J.J.M.; Data Registry Comm Netherlands 2019
OBJECTIVES: This study aims to explore male-female differences in baseline and procedural characteristics, and outcomes of patients undergoing isolated or concomitant tricuspid valve (TV) surgery... Show moreOBJECTIVES: This study aims to explore male-female differences in baseline and procedural characteristics, and outcomes of patients undergoing isolated or concomitant tricuspid valve (TV) surgery.METHODS: All TV procedures registered between 2007 and 2016 in the database of the Netherlands Association for Cardio-Thoracic Surgery were analysed. Logistic regression analyses with interaction terms were used to determine whether sex was associated with hospital mortality.RESULTS: Five thousand five hundred and eighty-two patients underwent TV surgery [isolated: N = 685 (49% male), TVrepair : N = 5286 (50% male) and TVreplacement: N = 250 (46% male)]. In the TVrepair group, females were significantly older, had less prior percutaneous/surgical coronary interventions, less extracardiac arteriopathies, a lower prevalence of renal impairment, less endocarditis, a lower prevalence of preoperative critical condition, less recent myocardial infarction, less concomitant coronary artery bypass grafting (CABG) and, in case of concomitant mitral valve surgery, less concomitant mitral valve repair compared to males. In the TVreplacement group, females more often had a history of prior valve surgery and less prior CABG. Hospital mortality for males and females was 7.0% (N = 183) and 6.1% (N = 163), P = 0.241 in the TVrepair group and 2.6% (N = 3) and 8.8% (N = 12), P = 0.074 in the TVreplacement group. Sex was not associated with hospital mortality (odds ratio (OR) 1.14, 95% confidence interval (CI) 0.88-1.48; P = 0.322). Sex demonstrated a significant interaction with the parameter 'critical preoperative condition' (OR 0.44, 95% CI 0.22-0.90; P = 0.026).CONCLUSIONS: Substantial differences in patient and procedural characteristics existed between male and female patients undergoing TV surgery, although sex was not a derterminant for hospital mortality. Nevertheless, sex interacted with a critical preoperative condition, indicating the usefulness of separate risk factor models for males and females requiring TV surgery. Show less
Spoel, E. van der; Oei, N.; Cachucho, R.; Roelfsema, F.; Berbee, J.F.P.; Blauw, G.J.; ... ; Heemst, D. van 2019
Atrial fibrillation (AF) is the clinically most prevalent rhythm disorder with large impact on quality of life and increased risk for hospitalizations and mortality in both men and women. In recent... Show moreAtrial fibrillation (AF) is the clinically most prevalent rhythm disorder with large impact on quality of life and increased risk for hospitalizations and mortality in both men and women. In recent years, knowledge regarding epidemiology, risk factors, and patho-physiological mechanisms of AF has greatly increased. Sex differences have been identified in the prevalence, clinical presentation, associated comorbidities, and therapy outcomes of AF. Although it is known that age-related prevalence of AF is lower in women than in men, women have worse and often atypical symptoms and worse quality of life as well as a higher risk for adverse events such as stroke and death associated with AF. In this review, we evaluate what is known about sex differences in AF mechanisms-covering structural, electrophysiological, and hormonal factors-and underscore areas of knowledge gaps for future studies. Increasing our understanding of mechanisms accounting for these sex differences in AF is important both for prognostic purposes and the optimization of (targeted, mechanism-based, and sex-specific) therapeutic approaches. Show less
