Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Effects of testosterone therapy on constructs related to aggression in transgender men: A systematic review.

BACKGROUND: Transgender men are assigned female sex at birth, but identify as men. The anabolic and androgenic sex hormone testosterone has been positively associated with aggression. Therefore, transgender men are warned of increasing aggression when initiating testosterone therapy. AIM: To explore the literature regarding the effects of testosterone therapy on aggression-related constructs in transgender men. METHODS: Following PRISMA-guidelines, PsycINFO, MEDLINE®, EMBASE, and PubMed® were searched in November 2019. Risk of bias was analyzed using the Newcastle-Ottawa-Scale, and result-synthesis was grouped by aggression-outcome. RESULTS: Seven prospective cohort studies investigating aggression-dimensions pre- and post-testosterone therapy, reporting on data from 664 transgender men, were eligible. The studies had moderate to high risk of bias due to non-randomization, lack of appropriate control groups, and reliance on self-report. The behavioral tendency to react aggressively increased in three studies out of four (at three months follow-up), whereas only one study out of five found angry emotions to increase (at seven months follow-up). In contrast, one out of three studies reported a decrease in hostility after initiation of testosterone therapy. The remaining studies found no change in aggressive behavior, anger or hostility during hormone therapy. DISCUSSION AND CONCLUSION: Four out of seven studies reported an increase in aggression-related constructs, while one study reported a decrease. In all studies reporting changes, the follow-up period was less than 12 months, indicating that gender-affirming testosterone therapy could have a short-term impact on aggression-related constructs. However, the available studies carried a risk of bias, which indicates a need for further research.

Whole-body oxidative stress reduction during testosterone therapy in aging men: A randomized placebo-controlled trial.

BACKGROUND: Testosterone replacement therapy in aging men increases lean body mass and decreases whole-body fat. The safety of testosterone replacement therapy concerning cardiovascular disease is unresolved and assessment of whole-body oxidative stress may contribute to future decision making. OBJECTIVES: To determine whole-body oxidative stress during testosterone replacement therapy and placebo in aging men and evaluate if a change in oxidative stress was mediated by changed body composition. MATERIALS AND METHODS: This was a double-blinded, randomized, placebo-controlled study for 24 weeks in 38 men aged 60-78 years with bioavailable testosterone <7.3 nmol/L and waist circumference ≥94 cm who were randomized to testosterone replacement therapy (testosterone gel) (N = 20) or placebo (N = 18). At baseline and after 24 weeks, whole-body oxidative stress was assessed by oxidized derivatives of nucleic acids, 8-oxoguanosine and 8-oxo-2'-deoxyguanosine in 24-h urine samples by ultra-performance liquid chromatography tandem mass spectrometry. Lean body mass and whole-body fat were measured by dual X-ray absorptiometry. Subcutaneous and visceral adipose tissue were estimated by magnetic resonance imaging. Testosterone replacement therapy versus placebo was compared by Mann-Whitney tests on ∆-values (24-0 weeks). RESULTS: Baseline age was 67 (64-72) years (median [interquartile range]), body mass index 29.8 (26.6-33.3) kg/m2 , waist 107 (99-117) cm, and bioavailable testosterone 4.7 (3.7-5.9) nmol/L. During testosterone replacement therapy, 8-oxoguanosine in 24-h urine samples decreased from 21.6 (19.8; 27.7) nm to 15.0 (12.2; 18.8) nm (p = 0.038 vs. placebo), lean body mass increased (p < 0.01) and whole-body fat (p = 0.02) and subcutaneous adipose tissue (p < 0.01) decreased. 8-Oxoguanosine in 24-h urine samples was inversely associated with Δ-lean body mass (ρ = -0.38, p = 0.03), which remained significant after adjusting for Δ-total testosterone. 8-Oxo-2'-deoxyguanosine in 24-h urine samples was unchanged (p = 0.06) during testosterone replacement therapy and Δ-8-oxo-2'-deoxyguanosine in 24-h urine samples was associated with Δ-whole-body fat (kg) (ρ = 0.47, p < 0.01). Δ-Values of oxidative stress biomarkers were not associated with Δ-fasting insulin or Δ-homeostatic model assessment of insulin resistance. DISCUSSION: Oxidative stress decreased during testosterone replacement therapy compared to placebo, which could be mediated by changed body composition. CONCLUSION: Whole-body oxidative stress decreased during 24 weeks of testosterone replacement therapy in aging men.

Muscle function following testosterone replacement in men on opioid therapy for chronic non-cancer pain: A randomized controlled trial.

BACKGROUND: Chronic pain and opioid treatment are associated with increased risk of male hypogonadism and subsequently decreased muscle function. A diagnosis of hypogonadism is based on the presence of low total testosterone and associated symptoms. The effect of testosterone replacement therapy on muscle function in men with chronic pain and low total testosterone remains to be investigated. OBJECTIVES: To investigate the effects of testosterone replacement therapy on muscle function and gait performance in men treated with opioids for chronic non-cancer pain. MATERIALS AND METHODS: A double-blind, placebo-controlled study. Forty-one men (>18 years) with opioid-treated chronic pain and serum total testosterone < 12 nmol/L were randomized to 24 weeks testosterone replacement therapy (testosterone undecanoate injection three times/6 months, n  = 20) or placebo injections (n  = 21). Muscle function was measured as leg press maximal voluntary contraction, leg extension power using the Nottingham power rig and handgrip strength using a handheld dynameter. Gait performance was measured at usual and maximal gait speed on a 10-m track. Body composition (lean body mass and fat mass) was determined by dual-energy X-ray absorptiometry. Mann-Whitney tests were performed on ∆-values (24-0 weeks) between testosterone replacement therapy and placebo. RESULTS: At baseline, median (interquartile range) age was 55 ± 13 years and BMI was 30.7 ± 5.2 kg/m2 . ∆-muscle function and ∆-gait performance were similar between testosterone replacement therapy and placebo. Median ∆-leg press maximal voluntary contraction was 174.2 ± 406.7 Newton, following testosterone replacement therapy, and 7.6 ± 419.1 Newton, after placebo, p = 0.091. ∆-lean body mass was significantly higher following testosterone replacement therapy compared to placebo, 3.6 ± 2.7 versus 0.1 ± 3.5 kg, respectively (p < 0.001). DISCUSSION: Testosterone replacement therapy, compared to placebo, did not improve muscle function or gait performance despite increased lean body mass. Changes in body composition did not infer any changes in muscle function. CONCLUSION: 24 weeks testosterone replacement therapy in opioid-treated men with pain-related male hypogonadism did not improve muscle function.

Testosterone replacement therapy of opioid-induced male hypogonadism improved body composition but not pain perception: a double-blind, randomized, and placebo-controlled trial.

BACKGROUND: Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear. PURPOSE: To measure changes in body composition, pain perception, quality of life, and adrenal function after TRT or placebo in opioid-treated men with chronic non-malignant pain. METHODS: Double-blind, placebo-controlled study in 41 men (>18 years) with total testosterone <12 nmol/L were randomized to 24 weeks TRT (Testosterone undecanoate injection three times/6 months, n = 20) or placebo (placebo-injections, n = 21). OUTCOMES: Body composition (lean body mass and fat mass assessed by DXA), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life (SF36), and adrenocorticotrophic hormone (ACTH) test. Data were presented as median (quartiles). Mann-Whitney tests were performed on delta values (24-0 weeks) between TRT and placebo. RESULTS: The median age was 55 years (46; 59) and total testosterone before intervention was 6.8 (5.0; 9.3) nmol/L. TRT was associated with change of testosterone levels: 12.3 (7.0; 19.9) nmol/L (P < 0.001 vs placebo), increased lean body mass: 3.6 (2.3; 5.0) kg vs 0.1 kg (-2.1; 1.5) during TRT vs placebo and decreased total fat mass: -1.2 (-3.1; 0.7) kg vs 1.2 kg (-0.9; 2.5) kg, both P < 0.003. Changed pain perception, SF36, and ACTH-stimulated cortisol levels were non-significantly changed during TRT compared with placebo. CONCLUSIONS: Six months of TRT improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.

The imprinted gene Delta like non-canonical notch ligand 1 (Dlk1) associates with obesity and triggers insulin resistance through inhibition of skeletal muscle glucose uptake.

BACKGROUND: The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial. METHODS: Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1+/+ and Dlk1-/- mice included DXA scanning, glucose tolerance tests (GTTs), blood measurements, and skeletal muscle glucose uptake studies by positron emission tomography (PET), histology, qRT-PCR, and in vitro cell studies. FINDINGS: Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1-/- mice, the increase in fat percentage and adipocyte size induced by HFD is attenuated, and these animals are protected against insulin resistance. These Dlk1 effects seem independent of gluconeogenesis, but at least partly relies on increased in vivo glucose uptake in skeletal muscles by Dlk1 regulating the major glucose transporter Glut4 in vivo as well as in two independent cell lines. INTERPRETATION: Thus, instead of an adipogenic inhibitor, Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. FUND: The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Danish National Research Council (#09-073648), The Lundbeck Foundation, University of Southern Denmark, and Dep. Of Clinical Biochemistry and Pharmacology/Odense University Hospital, the Swedish Research Council, the Swedish Diabetes Foundation, the Strategic Research Program in Diabetes at Karolinska Institute and an EFSD/Lilly grant.