Background: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. Objectives: We investigated whether AAS influence coagulation parameters associated with... Show moreBackground: Anabolic androgenic steroids (AAS) are thought to increase venous thromboembolism (VTE) risk. Objectives: We investigated whether AAS influence coagulation parameters associated with VTE by assessing their changes during and after AAS use. Methods: The HAARLEM study enrolled 100 male amateur athletes voluntarily starting an AAS cycle between 2015 and 2018. We measured procoagulant and anticoagulant protein levels, D-dimer levels, endogenous thrombin potential (ETP), and clot lysis time (CLT) at baseline and during 2 years of follow-up. Changes in coagulation during AAS cycle, 3 months after its discontinuation, and 1 year after its inclusion compared with baseline were estimated using linear mixed models. The associations between AAS dose and duration of use with these outcomes were studied through adjusted multivariable linear regression. Results: Participants used AAS for a median of 13 weeks (IQR: 10-23) with a median weekly dose of 901 mg (IQR: 634-1345 mg). Mean levels of multiple coagulation factors (F) increased during use compared with baseline, whereas FVIII and von Willebrand factor levels remained unchanged. Protein S and D-dimer showed the biggest increase (22% [95% CI: 15-29] and 1.3-fold [95% CI: 1.2-1.5], respectively). CLT was 8 minutes longer (95% CI: 5-10) and ETP was 165 nM*min (95% CI: -205 to -124) lower during the AAS cycle. A high weekly AAS dose and short cycle duration were associated with changes in protein S and ETP during use. All parameters returned to baseline values 3 months after discontinuation and remained similar after. Conclusion: During AAS use, procoagulant and anticoagulant protein levels increased in a reversible manner. The overall balance did not suggest a clear procoagulant state. Show less
Testosterone therapy is the cornerstone in the care of men with hypogonadism and transgender males. Gel and intramuscular injections are most frequently used and are registered and included in the... Show moreTestosterone therapy is the cornerstone in the care of men with hypogonadism and transgender males. Gel and intramuscular injections are most frequently used and are registered and included in the international guidelines. The specific preparation should be selected according to the patient's preference, cost, availability, and formulation-specific properties. As the majority of men with hypogonadism and transgender males require lifelong treatment with testosterone, it is important to utilize a regimen that is effective, safe, inexpensive, and convenient to use with optimal mimicking of the physiological situation. This systematic review reviews current literature on differences between the three most used testosterone preparations in adult men with hypogonadism and transgender males. Although it appeared hardly any comparative studies have been carried out, there are indications of differences between the preparations, for example, on the stability of testosterone levels, hematocrit, bone mineral density, and patient satisfaction. However, there are no studies on the effects of testosterone replacement on endpoints such as cardiovascular disease in relation to hematocrit or osteoporotic fractures in relation to bone mineral density. The effect of testosterone therapy on health-related quality of life is strongly underexposed in the reviewed studies, while this is a highly relevant outcome measure from a patient perspective. In conclusion, current recommendations on testosterone treatment appear to be based on data primarily from non-randomized clinical studies and observational studies. The availability of reliable comparative data between the different preparations will assist in the process of individual decision-making to choose the most suitable formula. Show less
Beekman, K.M.; Regenboog, M.; Nederveen, A.J.; Bravenboer, N.; Heijer, M. den; Bisschop, P.H.; ... ; Maas, M. 2022
Bone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific... Show moreBone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific variations and age- and gender-specific differences in BMAT and BMAT composition in healthy subjects. In this cross-sectional study, we included 40 healthy subjects (26 male: mean age 49 years, range 22-75 years; 14 female: mean age 50 years, range 29-71) and determined the bone marrow signal fat fraction and bone marrow unsaturation in the spine (C3-L5), pelvis, femora, and tibiae using chemical shift encoding-based water-fat imaging (WFI) with multiple gradient echoes (mGRE). Regions of interest covered the individual vertebral bodies, pelvis and proximal epimetaphysis, diaphysis, and distal epimetaphysis of the femur and tibia. The spinal fat fraction increased from cervical to lumbar vertebral bodies (mean fat fraction ( +/- SD or (IQR): cervical spine 0.37 +/- 0.1; thoracic spine 0.41 +/- 0.08. lumbar spine 0.46 +/- 0.01; p < 0.001). The femoral fat fraction increased from proximal to distal (proximal 0.78 +/- 0.09; diaphysis 0.86 (0.15); distal 0.93 +/- 0.02; p < 0.001), while within the tibia the fat fraction decreased from proximal to distal (proximal 0.92 +/- 0.01; diaphysis 0.91 (0.02); distal 0.90 +/- 0.01; p < 0.001). In female subjects, age was associated with fat fraction in the spine, pelvis, and proximal femur (rho = 0.88 p < 0.001; rho = 0.87 p < 0.001; rho = 0.63 p = 0.02; rho = 0.74 p = 0.002, respectively), while in male subjects age was only associated with spinal fat fraction (rho = 0.40 p = 0.04). Fat fraction and unsaturation were negatively associated within the spine (r = -0.40 p = 0.01), while in the extremities fat fraction and unsaturation were positively associated (distal femur: r = 0.42 p = 0.01; proximal tibia: r = 0.47, p = 0.002; distal tibia: r = 0.35 p = 0.03), both independent of age and gender. In conclusion, we confirm the distinct, age- and gender-dependent, distribution of BMAT throughout the human skeleton and we show that, contradicting previous animal studies, bone marrow unsaturation in human subjects is highest within the axial skeleton compared to the appendicular skeleton. Furthermore, we show that BMAT unsaturation was negatively correlated with BMAT within the spine, while in the appendicular skeleton, BMAT and BMAT unsaturation were positively associated. Show less
Background Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects.... Show moreBackground Vitamin D deficiency is frequently found in patients with chronic obstructive pulmonary disease (COPD). Vitamin D has antimicrobial, anti-inflammatory, and immunomodulatory effects. Therefore, supplementation may prevent COPD exacerbations, particularly in deficient patients. Objectives We aimed to assess the effect of vitamin D supplementation on exacerbation rate in vitamin D-deficient patients with COPD. Methods We performed a multicenter, double-blind, randomized controlled trial. COPD patients with >= 1 exacerbations in the preceding year and a vitamin D deficiency (15-50 nmol/L) were randomly allocated in a 1:1 ratio to receive either 16,800 International Units (IU) vitamin D-3 or placebo once a week during 1 y. Primary outcome of the study was exacerbation rate. Secondary outcomes included time to first and second exacerbations, time to first and second hospitalizations, use of antibiotics and corticosteroids, pulmonary function, maximal respiratory mouth pressure, physical performance, skeletal muscle strength, systemic inflammatory markers, nasal microbiota composition, and quality of life. Results The intention-to-treat population consisted of 155 participants. Mean +/- SD serum 25-hydroxyvitamin D [25(OH)D] concentration after 1 y was 112 +/- 34 nmol/L in the vitamin D group, compared with 42 +/- 17 nmol/L in the placebo group. Vitamin D supplementation did not affect exacerbation rate [incidence rate ratio (IRR): 0.90; 95% CI: 0.67, 1.21]. In a prespecified subgroup analysis in participants with 25(OH)D concentrations of 15-25 nmol/L (n = 31), no effect of vitamin D supplementation was found (IRR: 0.91; 95% CI: 0.43, 1.93). No relevant differences were found between the intervention and placebo groups in terms of secondary outcomes. Conclusions Vitamin D supplementation did not reduce exacerbation rate in COPD patients with a vitamin D deficiency. This trial was registered at clinicaltrials.gov as NCT02122627. Show less
Velzen, D. van; Wiepjes, C.; Nota, N.; Raalte, D. van; Mutsert, R. de; Simsek, S.; Heijer, M. den 2022
Context: In trans women receiving hormone therapy, body fat and insulin resistance increases, with opposite effects in trans men. These metabolic alterations may affect the risk of developing type... Show moreContext: In trans women receiving hormone therapy, body fat and insulin resistance increases, with opposite effects in trans men. These metabolic alterations may affect the risk of developing type 2 diabetes in trans women and trans men. Context: We aimed to compare the incidence of type 2 diabetes of adult trans women and trans men during hormone therapy with rates from their birth-assigned sex in the general population. Methods: Retrospective data from the Amsterdam Cohort of Gender Dysphoria with transgender individuals on hormone therapy between 1972 and 2018 were linked to a nationwide health data registry. Because no central registry of diabetes is available, the occurrence of diabetes was inferred from the first dispense of a glucose-lowering agent. Standardized incidence ratios (SIR) were computed for trans women and trans men in comparison with the same birth sex from the general population. Results: Compared with their birth-assigned sex in the general population, no difference in the incidence of type 2 diabetes mellitus was observed in trans women (N = 2585, 90 cases; SIR 0.94; 95% CI, 0.76-1.14) or trans men (N = 1514, 32 cases; SIR 1.40; 95% CI, 0.96-1.92). Conclusion: Despite studies reporting an increase in insulin resistance in feminizing hormone therapy and a decrease in insulin resistance in masculinizing hormone therapy, the incidence of diabetes in transgender individuals after initiation of hormone therapy was not different compared with the general population. Show less
Klaver, M.; Velzen, D. van; Blok, C. de; Nota, N.; Wiepjes, C.; Defreyne, J.; ... ; Mutsert, R. de 2022
Introduction: Excess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the... Show moreIntroduction: Excess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the ratio of visceral fat to total body fat (VAT/TBF) and their associations with changes in lipids and insulin resistance after 1 year of hormone therapy in trans persons. Methods: In 179 trans women and 162 trans men, changes in total body and visceral fat estimated with dual-energy X-ray absorptiometry before and after 1 year of hormone therapy were related to lipids and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] with linear regression analysis. Results: In trans women, total body fat increased by 4.0 kg (95% CI 3.4, 4.7), while the amount of visceral fat did not change (-2 grams; 95% CI -15, 11), albeit with a large range from -318 to 281, resulting in a decrease in the VAT/TBF ratio of 17% (95% CI 15, 19). In trans men, total body fat decreased with 2.8 kg (95% CI 2.2, 3.5), while the amount of visceral fat did not change (3 g; 95% CI -10, 16; range -372, 311), increasing the VAT/TBF ratio by 14% (95% CI 10, 17). In both groups, VAT/TBF was not associated with changes in blood lipids or HOMA-IR. Conclusions: Hormone therapy in trans women and trans men resulted in changes in VAT/TBF, mainly due to changes in total body fat and were unrelated to changes in cardiometabolic risk factors, which suggests that any unfavorable cardiometabolic effects of hormone therapy are not mediated by changes in visceral fat or VAT/TBF. Show less
Florijn, B.W.; Duijs, J.M.G.J.; Klaver, M.; Kuipers, E.N.; Kooijman, S.; Prins, J.; ... ; Zonneveld, A.J. van 2021
Endocrinology Objective: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol ... Show moreEndocrinology Objective: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. Methods: Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. Results: Estradiol in transwomen lowered plasma miR-224 and-452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). Conclusion: This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy. Show less
Objectives This study aimed to determine the effect of bariatric surgery-induced weight loss on bone marrow adipose tissue (BMAT) and bone mineral density (BMD) in postmenopausal, nondiabetic women... Show moreObjectives This study aimed to determine the effect of bariatric surgery-induced weight loss on bone marrow adipose tissue (BMAT) and bone mineral density (BMD) in postmenopausal, nondiabetic women.Methods A total of 14 postmenopausal, nondiabetic women with obesity who were scheduled for laparoscopic Roux-en-Y gastric bypass surgery (RYGB) were included in this study. Vertebral bone marrow fat signal fraction was determined by quantitative chemical shift magnetic resonance imaging, and vertebral volumetric BMD (vBMD) was determined by quantitative computed tomography before surgery and 3 and 12 months after surgery. Data were analyzed by linear mixed model.Results Body weight [mean (SD)] decreased after surgery from 108 (13) kg at baseline to 89 (12) kg at 3 months and 74 (11) kg at 12 months (P < 0.001). BMAT decreased after surgery from 51% (8%) at baseline to 50% (8%) at 3 months and 46% (7%) at 12 months (P = 0.004). vBMD decreased after surgery from 101 (26) mg/cm(3) at baseline to 94 (28) mg/cm(3) at 3 months (P = 0.003) and 94 (28) mg/cm(3) at 12 months (P = 0.035). Changes in BMAT and vBMD were not correlated (rho = -0.10 and P = 0.75). Calcium and vitamin D concentrations did not change after surgery.Conclusions RYGB decreases both BMAT (after 12 months) and vBMD (both after 3 months and 12 months) in postmenopausal, nondiabetic women. Changes in BMAT and vBMD were not correlated. These findings suggest that BMAT does not contribute to bone loss following RYGB. Show less
Scheres, L.J.J.; Selier, N.L.D.; Nota, N.M.; Diemen, J.J.K. van; Cannegieter, S.C.; Heijer, M. den 2021
Background The transgender population that uses gender-affirming hormone therapy (GAHT) is rapidly growing. The (side) effects of GAHT are largely unknown. We examined the effect of GAHT on... Show moreBackground The transgender population that uses gender-affirming hormone therapy (GAHT) is rapidly growing. The (side) effects of GAHT are largely unknown. We examined the effect of GAHT on coagulation parameters associated with venous thromboembolism (VTE) risk.Methods Factor (F)II, FIX, FXI, protein (p)C and free pS, fibrinogen, hematocrit, sex hormone-binding globulin, and normalized activated protein C ratio were measured in 98 transwomen (male sex at birth, female gender identity) and 100 transmen (female sex at birth, male gender identity) before and after 12 months of GAHT (oral or transdermal estradiol and anti-androgens in transwomen, transdermal or intramuscular testosterone in transmen). Mean paired differences in coagulation measurements were estimated with 95% confidence intervals (95% CI). Differences for route of administration and age were assessed with linear regression.Results After GAHT, transwomen had more procoagulant profiles with a mean increase in FIX: 9.6 IU/dL (95% CI 3.1-16.0) and FXI: 13.5 IU/dL (95% CI 9.5-17.5), and a decrease in pC: -7.7 IU/dL (95% CI -10.1 to -5.2). Changes in measures of coagulation were influenced by route of administration (oral vs. transdermal) and age. A higher sex-hormone binding globulin level after 12 months was associated with a lower activated protein C resistance. In transmen, changes were not procoagulant overall and were influenced by age. Differences for route of administration (transdermal vs. intramuscular) were small.Conclusions GAHT in transmen was not associated with apparent procoagulant changes, which provides some reassurance regarding VTE risk. In transwomen, GAHT resulted in procoagulant changes, which likely contributes to the observed increased VTE risk. Show less
Klaver, M.; Mutsert, R. de; Loos, M.A.T.C. van der; Wiepjes, C.M.; Twisk, J.W.R.; Heijer, M. den; ... ; Klink, D.T. 2020
BACKGROUND AND OBJECTIVES: The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate... Show moreBACKGROUND AND OBJECTIVES: The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in transgender adolescents at 22 years compared with peers.METHODS: Changes in BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a subsequent addition of sex hormones (17 years).RESULTS: In transwomen, changes in BMI (13.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (22 mmHg; 95% CI 27 to 3), DBP (110 mmHg; 95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI 20.2 to 0.2), HOMA-IR (10.6; 95% CI 20.6 to 1.9), and lipid values were similar or more favorable compared with peers. The same was true for transmen regarding changes in BMI (12.3; 95% CI 1.7 to 2.9), SBP (17 mmHg; 95% CI 3 to 10), DBP (17 mmHg; 95% CI 5 to 10), glucose (10.1 mmol/L; 95% CI 20.1 to 0.3), HOMA-IR (20.2; 95% CI 20.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in transmen, 2.2% in ciswomen, and 3.0% in cismen.CONCLUSIONS: Generally, endocrinological treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is more prevalent in transgender adolescents compared with peers, body weight management should be important during the medical trajectory. Show less
Beekman, K.M.; Zwaagstra, M.; Veldhuis-Vlug, A.G.; Essen, H.W. van; Heijer, M. den; Maas, M.; ... ; Bravenboer, N. 2019
Estrogen deficiency induces bone loss by increasing bone resorption, in part through upregulation of receptor activator of nuclear factor-kappa B ligand (RANKL). RANKL is secreted by osteoblasts... Show moreEstrogen deficiency induces bone loss by increasing bone resorption, in part through upregulation of receptor activator of nuclear factor-kappa B ligand (RANKL). RANKL is secreted by osteoblasts and osteocytes, but more recently bone marrow (pre)adipocytes have also been shown to express RANKL. Estrogen deficiency increases bone marrow adipose tissue (BMAT). The aim of this study was to determine the effect of ovariectomy (OVX) on RANKL protein expression by bone marrow adipocytes in C3H/HeJ mice. Fourteen-week-old female C3H/HeJ mice (n = 20) were randomized to sham surgery (Sham) or OVX. After 4 wk animals were euthanized. BMAT volume fraction (BMAT volume/marrow volume) was quantified by polyoxometalate-based contrast-enhanced nano-computed tomography. The percentage of RANKL-positive bone marrow adipocytes (RANKL-positive bone marrow adipocytes/total adipocytes) and the percentage of RANKL-positive osteoblasts covering the bone surface (bone surface covered in RANKL-positive osteoblasts/total bone surface) were quantified in the distal metaphysis of immunohistochemically stained sections of the left femur. The effects of OVX were analyzed by Student's t test or Mann-Whitney U test. RANKL was detected in osteoblasts, osteocytes, and bone marrow adipocytes. OVX significantly increased mean percentage of RANKL-positive bone marrow adipocytes [mean (SD): Sham 42 (18)%; OVX 64 (12)%; P = 0.029] as well as BMAT volume/marrow volume [median (interquartile range): Sham 1.4 (4.9)%; OVX 7.2 (7.3)%; P = 0.008] compared with Sham. We show that OVX increased both the percentage of RANKL-positive bone marrow adipocytes and the total BMAT volume fraction in C3H/HeJ mice. Therefore, RANKL produced by bone marrow adipocytes could be an important contributor to OVX-induced bone loss in C3H/HeJ mice. Show less
Boone, S.; Mook-Kanamori, D.; Rosendaal, F.; Heijer, M. den; Lamb, H.; Roos, A. de; ... ; Mutsert, R. de 2019
