Gender Dysphoria – Prevalence and Co-Morbidities in an Irish Adult Population

Introduction: Gender dysphoria (GD) is a condition in which there is a marked incongruence between an individual’s psychological perception of his/her sex and their biological phenotype. Gender identity disorder was officially renamed “gender dysphoria” in the DSM-V in 2013. The prevalence and demographics of GD vary according to geographical location and has not been well-documented in Ireland. Methods: We retrospectively reviewed medical records of 218 patients with suspected or confirmed GD referred to our endocrine service for consideration of hormonal therapy (HT) between 2005 and early 2014. We documented their demographics, clinical characteristics, and treatment during the study period. Results: The prevalence of GD in the Irish population was 1:10,154 male-to-female (MTF) and 1:27,668 female-to-male (FTM), similar to reported figures in Western Europe. 159 of the patients were MTF and 59 were FTM, accounting for 72.9% and 27.1% of the cohort, respectively. The rate of referral has increased year-on-year, with 55 patients referred in 2013 versus 6 in 2005. Mean ages were 32.6 years (MTF) and 32.2 years (FTM). 22 of the patients were married and 41 had children, with 2 others having pregnant partners. 37.6% were referred by a psychologist, with the remainder evenly divided between GPs and psychiatric services. There were low rates of coexistent medical illness although psychiatric conditions were more prevalent, depression being a factor in 34.4% of patients. 5.9% of patients did not attend a mental health professional. 74.3% are currently on HT, and 9.17% have had gender reassignment surgery (GRS). Regret following hormonal or surgical treatment was in line with other Western European countries (1.83%). Conclusion: The incidence of diagnosis and referral of GD in Ireland is increasing. This brings with it multiple social, health, and financial implications. Clear and accessible treatment pathways supported by mental health professionals is essential

Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus

Aims/hypothesis Glucagon-like peptide 1 (GLP-1) is a gut hormone used in the treatment of type 2 diabetes mellitus. There is emerging evidence that GLP-1 has anti-inflammatory activity in humans, with murine studies suggesting an effect on macrophage polarisation. We hypothesised that GLP-1 analogue therapy in individuals with type 2 diabetes mellitus would affect the inflammatory macrophage molecule soluble CD163 (sCD163) and adipocytokine profile. Methods We studied ten obese type 2 diabetes mellitus patients starting GLP-1 analogue therapy at a hospital-based diabetes service. We investigated levels of sCD163, TNF-α, IL-1β, IL-6, adiponectin and leptin by ELISA, before and after 8 weeks of GLP-1 analogue therapy. Results GLP-1 analogue therapy reduced levels of the inflammatory macrophage activation molecule sCD163 (220 ng/ml vs 171 ng/ml, p <0.001). This occurred independent of changes in body weight, fructosamine and HbA1c. GLP-1 analogue therapy was associated with a decrease in levels of the inflammatory cytokines TNF-α (264 vs 149 pg/ml, p <0.05), IL-1β (2,919 vs 748 pg/ml, p <0.05) and IL-6 (1,379 vs 461 pg/ml p <0.05) and an increase in levels of the anti-inflammatory adipokine adiponectin (4,480 vs 6,290 pg/ml, p <0.002). Conclusions/interpretation In individuals with type 2 diabetes mellitus, GLP-1 analogue therapy reduces the frequency of inflammatory macrophages. This effect is not dependent on the glycaemic or body weight effects of GLP-1

Invariant Natural Killer T Cell Deficiency and Functional Impairment in Sleep Apnea: Links to Cancer Comorbidity

Study Objectives: Emerging evidence links obstructive sleep apnea (OSA) with increased cancer incidence and mortality. Invariant natural killer T (iNKT) cells play an important role in cancer immunity. We hypothesized that patients with OSA have low number of circulating invariant natural killer T (iNKT) cells, which may also be functionally impaired. This study aims to evaluate the frequency of circulating iNKT cells in OSA. Design: We evaluated the frequency of circulating iNKT cells by flow cytometry in 33 snorers being assessed for possible OSA. Using iNKT cell lines, we also evaluated the effect of exposure to hypoxia over 24 hours on apoptosis, cytotoxicity, and cytokine production. Setting: Teaching hospital based sleep unit and research laboratory. Patients: Thirty-three snorers were evaluated: 9 with no OSA (apnea-hypopnea frequency [AHI] < 5/h), 12 with mild-moderate OSA (AHI 5–30) and 12 with severe OSA (AHI > 30). Measurements and Results: Patients with severe OSA had considerably fewer iNKT cells (0.18%) compared to patients with mild-moderate (0.24%) or no OSA (0.35%), P = 0.0026. The frequency of iNKT cells correlated negatively with apnea-hypopnea index (r = −0.58, P = 0.001), oxygen desaturation index (r = −0.58, P = 0.0003), and SpO2% < 90% (r = −0.5407, P = 0.005). The frequency of iNKT cells increased following 12 months of nCPAP therapy (P = 0.015). Hypoxia resulted in increased apoptosis (P = 0.016) and impaired cytotoxicity (P = 0.035). Conclusion: Patients with obstructive sleep apnea (OSA) have significantly reduced levels of circulating invariant natural killer T (iNKT) cells and hypoxia leads to impaired iNKT cell function. These observations may partly explain the increased cancer risk reported in patients with OSA

Tissue Specific Regulation of Glucocorticoids in Severe Obesity and the Response to Significant Weight Loss Following Bariatric Surgery (BARICORT)

Context: Tissue cortisol exposure is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 in vivo, acts as an oxoreductase converting inactive cortisone to active cortisol. We hypothesized that 11β-HSD1 activity is dysregulated in obesity and alters following bariatric surgery induced weight loss in different tissues. Methods: We recruited 21 patients prior to undergoing bariatric surgery and performed cortisol generation profiles (following oral cortisone administration), urinary corticosteroid metabolite analysis, adipose tissue microdialysis, and tissue gene expression before and after weight loss, following bariatric surgery. Archived tissue samples from 20 previous bariatric surgery patients were also used for tissue gene expression studies. Results: Gene expression showed a positive correlation with 11β-HSD1 and BMI in omental adipose tissue (OM) (r = +0.52, P = .0001) but not sc adipose tissue (r = +0.28, P = .17). 11β-HSD1 expression in liver negatively correlated with body mass index (BMI) (r = −0.37, P = .04). 11β-HSD1 expression in sc adipose tissue was significantly reduced after weight loss (0.41 ± 0.28 vs 0.17 ± 0.1 arbitrary units, P = .02). Following weight loss, serum cortisol generation increased during a cortisol generation profile (area under the curve 26 768 ± 16 880 vs 47 579 ± 16 086 nmol/L/minute, P ≤ .0001.) Urinary corticosteroid metabolites demonstrated a significant reduction in total cortisol metabolites after bariatric surgery (15 224 ± 6595 vs 8814 ± 4824 μg/24 h, P = .01). Microdialysis of sc adipose tissue showed a threefold reduction in cortisol/cortisone ratio after weight loss. Conclusions: This study highlights the differences in tissue specific regulation of cortisol metabolism in obesity and after weight loss. Following bariatric surgery hepatic 11β-HSD1 activity increases, sc adipose tissue 11β-HSD1 activity is reduced and total urinary cortisol metabolites are reduced indicating a possible reduction in hypothalamic pituitary adrenal axis drive. 11β-HSD1 expression correlates positively with BMI in omental adipose tissue and negatively within hepatic tissue. 11β-HSD1 expression is reduced in sc adipose tissue after weight loss

Altered Distribution and Increased IL-17 Production by Mucosal-Associated Invariant T Cells in Adult and Childhood Obesity

Mucosal-associated invariant T (MAIT) cells are innate MHC-unrestricted cells that regulate inflammatory responses through the rapid production of cytokines. In this article, we show that circulating MAIT cells are depleted in obese adults, and depletion is associated with diabetic status. Circulating MAIT cells more frequently produced IL-17 upon stimulation ex vivo, a cytokine implicated in insulin resistance. MAIT cells were enriched in adipose tissue (AT) compared with blood. AT MAIT cells, but not circulating MAIT cells, were capable of producing IL-10. In AT from obese subjects, MAIT cells were depleted, were less likely to produce IL-10, and more frequently produced IL-17. Finally, we show that IL-17+ MAIT cells are also increased in childhood obesity, and altered MAIT cell frequencies in obese children are positively associated with insulin resistance. These data indicate that MAIT cells are enriched in human AT and display an IL-17+ phenotype in both obese adults and children, correlating with levels of insulin resistance. The alterations in MAIT cells may be contributing to obesity-related sterile inflammation and insulin resistance