Interpretation of Abnormal Dexamethasone Suppression Test is Enhanced With Use of Synchronous Free Cortisol Assessment

Context Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding Objective We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders, and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic work up. Design and Setting Cross-sectional study conducted in a tertiary medical center Participants Adult volunteers without adrenal disorders (n=168; 47 women on oral contraceptive therapy (OCP), 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n=196; 16 women on OCP) Measurements Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). Main Outcome Measures Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. Results Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared to post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95%CI 81.7-91.7); all false positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false positive results (21.1% vs 4.9%, p=0.02). Conclusions Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

Short-term transport stress and supplementation alter immune function in aged horses

Long-distance transport is associated with stress-related changes in equine immune function, and shipping-associated illnesses are often reported. Horses are frequently transported short distances, yet the effects of short-term transport on immune function remain largely unknown. Twelve horses, aged 15–30 yr, were assigned to either the control (n = 6) or treatment (n = 6) groups; treatment horses received a daily antioxidant supplement 3 weeks before and after transport. All horses were transported for approximately 1.5–2 hr on Day 0. Blood was collected via jugular venipuncture at 15-min pre- and post-transport and on Days –21, 1, 3, 7, 14, and 21. Body temperature, heart rate, body weight, total cortisol, and gene expression of IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12α, IL-17α, SAA1, and TNFα in whole blood were measured. Peripheral blood mononuclear cells were isolated, stimulated with PMA/ionomycin, and stained for IFNγ and TNFα before analysis via flow cytometry. Statistical analyses were performed with significance set at P < 0.05 (SAS 9.4). Transport and supplementation did not appear to affect body weight, heart rate, IL-4, IL-8, IL-12α, IL-17α, change (Δ) in the % and mean fluorescence intensity (MFI) of IFNγ+ lymphocytes after stimulation, or Δ in the % and MFI of TNFα+ lymphocytes after stimulation. Supplementation decreased IL-1β and SAA1 expression. Transport increased total cortisol concentration, body temperature, and IL-2, IL-6, and IL-10 expression but decreased IL-1β, TNFα, and IFNγ expression. Short-term transportation affected physiological, endocrine, and immune responses; supplementation may ameliorate inflammation in aged horses. Immune responses were most altered at 15-min post-transport and typically recovered by Day 1, suggesting that horses may be vulnerable to disease during and almost immediately after short-term transport.

CBG Montevideo: a clinically novel SERPINA6 mutation leading to haploinsufficiency of corticosteroid-binding globulin

Corticosteroid-binding globulin (CBG) is the main transport protein for cortisol, binding up to 90% in a 1:1 ratio. CBG provides transport of cortisol within the circulation and targeted cortisol tissue delivery. Here we describe the clinically novel “CBG Montevideo” a SERPINA6 pathogenic variant that results in a 50% reduction in plasma CBG levels. This was associated with low serum total cortisol and clinical features of hypoglycaemia, exercise intolerance, chronic fatigue and hypotension in the proband, a 7-year-old boy, and his affected mother. Previous reports of nine human CBG genetic variants affecting either CBG concentrations or reduced CBG-cortisol binding properties have outlined symptoms consistent with attenuated features of hypocortisolism, fatigue and hypotension. Here, however, the presence of hypoglycaemia, despite normal circulating free cortisol, suggests a specific role for CBG in effecting glucocorticoid function, perhaps involving cortisol-mediated hepatic glucose homeostasis and cortisol-brain communication.

Maternal Total Cortisol Levels in Early Pregnancy Depends on Fetal Sexual Dimorphism. But Finally No Association With Birth Weight

Enhanced maternal cortisol levels may have a negative impact on fetal development with a higher risk for diseases later in life, e.g. premature cardiovascular disease and type 2 diabetes. Prior studies do assume even a sex specific impact. Currently, it is unknown whether sexual dimorphism in the fetus could display a different maternal cortisol level that is associated with intra uterine growth. In the present study (performed in the Amsterdam Born Children and their Development (ABCD) –cohort), we evaluated in 3049 pregnant women (in early pregnancy) whether fetal sex is related to the level of maternal serum total cortisol and whether this contributes to fetal growth. Maternal serum total cortisol levels increased along early pregnancy from on average 390±22 nmol/L (at 5th week of pregnancy) to 589±15 nmol/L (at 20th week of pregnancy). The presence of a female fetus was associated with higher maternal total cortisol level in a distinctive time interval along early pregnancy; before 11th week of pregnancy, no difference, and from the 12th week of pregnancy a difference of 15 (SE:7) nmol/L between mothers carrying a male vs female fetus was found and that difference increased to 45 (22) nmol/L at 20th week of pregnancy (p-for-interaction=0.05). Maternal serum total cortisol levels were negatively associated with maternal age, pBMI, smoking and parity, the last one also increasing with pregnancy duration. After adjusting for these factors, the association between fetal sex and maternal cortisol remained Maternal serum total cortisol levels were significantly associated with birth weight, standardized for pregnancy duration (ß -.22; SE:0.06; P &lt; 0.001). Girls had a significantly lower birth weight (-132 SE:16 gram) compared to males, however, maternal cortisol did not alter the association between fetal sex and birth weight to a relevant degree indicating no mediation by maternal cortisol. In early pregnancy, the maternal total cortisol levels are related to fetal sex. However this difference in maternal total cortisol level was finally not related to birth weight.

An Oral Contraceptive Containing Estetrol 15 MG and Drospirenone 3 MG Has Limited Effects on Endocrine and Metabolic Parameters

Background: Most combined oral contraceptives (COCs) contain ethinylestradiol (EE), an estrogen component known to increase the risk of venous thromboembolic events. Previous phase 2 trials have shown that Estetrol (E4), a naturally-occurring estrogen produced by the human fetal liver, in combination with Drospirenone (DRSP), inhibits ovulation and is associated with favorable vaginal bleeding, safety and tolerability profiles and high user satisfaction. When administered in doses up to 10 mg for less than 3 months, E4 either alone or in combination with DRSP showed limited effects on liver function as well as on metabolic and endocrine parameters. However, the impact of E4 15 mg/DRSP 3 mg, the selected dose for pregnancy prevention (hereafter referred to as E4/DRSP), on metabolic and endocrine parameters was never investigated. Methods: A randomized, open-label, controlled, three-arm parallel study was conducted in 101 healthy volunteers aged 18-50 years with a body mass index between 18.0 and 30.0 kg/m2. Of the randomized individuals, 98 subjects received either E4/DRSP (n=38), EE 30 µg/levonorgestrel (LNG) 150 µg (n=29) or EE 20 µg/DRSP 3 mg (n=31) COCs for six consecutive treatment cycles of 28 days. Endocrine and metabolic parameters were measured at baseline, cycle 3 and cycle 6. Results: FSH and LH decreased with both EE/LNG (-84% and -92%, respectively) and EE/DRSP (-64% and -90%, respectively), whereas E4/DRSP slightly increased FSH (31%) and had minor effect on LH (-8%). Total cortisol increased by more than 100% during treatment with EE/LNG (109%) and EE/DRSP (107%), while E4/DRSP only slightly increased total cortisol (26%). The effects of E4/DRSP, EE/LNG and EE/DRSP on other endocrine parameters including androstenedione (-31%, -49% and -40%) and free testosterone (-50%, -50% and -71%) were similar. Liver proteins, except CRP, increased from baseline in all treatment groups. The increase in angiotensinogen, CBG, and TBG levels was significantly lower for E4/DRSP (75%, 40% and 17%) in comparison with EE/LNG (170%, 152% and 37%) and EE/DRSP (207%, 140% and 70%). SHBG substantially increased for EE/DRSP (251%), while EE/LNG and E4/DRSP had limited effects on SHBG (74% and 55%, respectively). Triglycerides changed to a lesser extent for E4/DRSP (24%) compared to EE/DRSP (66%); EE/LNG increased triglycerides levels by 28%. Moreover, E4/DRSP had minimal impact on lipid parameters including HDL (4%), Apolipoprotein A1 (5%) and Apolipoprotein B (4%) compared to baseline, and no effects on carbohydrate metabolism. Conclusion: These data confirm that E4/DRSP has limited effects on liver proteins, lipid and carbohydrate metabolism, cortisol, and gonadotropins. The effect on other endocrine parameters, including suppression of ovarian steroids, was typical for a COC. In conclusion, combining E4 15 mg with DRSP 3 mg resulted in a different and potentially favorable metabolic profile.

Comparison of hypothalamo-pituitary-adrenal function in treatment resistant unipolar and bipolar depression

Altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in patients with treatment-resistant depression, although studies have often conflated patients with unipolar and bipolar depression. This is problematic given that the two groups often present with opposed neurovegetative symptom patterns. The aim of this study was to test, for the first time, whether post-awakening cortisol, a highly reliable, naturalistic measure of HPA functioning, could distinguish patients with clearly defined treatment-resistant unipolar (TRUD) and bipolar depression (TRBD). A total of 37 patients with TRUD, 17 patients with TRBD, and 47 healthy controls were recruited. Areas under the curve (AUC) with respect to the ground (g) and increase (i) of post-awakening cortisol concentrations (awakening, +15, +30, +45, +60, +90 min) were measured over two days. Patients with TRUD had higher total cortisol production in the morning hours compared to controls (AUCg, p = 0.01), while they did not differ in terms of the awakening response (AUCi, p = 0.28). By contrast, subjects with TRBD had lower total cortisol when compared to controls by trend (AUCg, p = 0.07), while they did not differ in the awakening response (AUCi, p = 0.15). A direct comparison of TRUD and TRBD revealed differences in the AUCg (p = 0.003) and AUCi (p = 0.03). This finding of comparatively elevated HPA axis activity in the morning in TRUD and attenuated HPA axis activity in TRBD attests to a fundamental biological distinction between unipolar and bipolar depression. It has implications for the understanding and treatment of bipolar depression and in differentiating the two types of depression.

Expression of Glucocorticoid Receptors in the Early Period After the Return of Spontaneous Circulation Among Patients Who Experienced Cardiac Arrest : A Retrospective Observational Study

Background: Rapid changes in glucocorticoid (GC) levels and adrenal insufficiency are related to the development of post-cardiac arrest syndrome. However, changes in glucocorticoid receptors (GR) have not been studied. Hence, this study aimed to investigate the association of early changes in GR and prognosis and immune response in patients who experienced cardiac arrest (CA). Methods: In this observational single-center case-control study, we enrolled patients who were in the early period of return of spontaneous circulation after CA and were admitted to the emergency department of the Beijing Chaoyang Hospital between October 2018 and October 2019. Age- and sex-matched healthy individuals were recruited for the control group after a physical examination.GR expression and cell counts of circulatory T and B lymphocytes, natural killer, and regulatory T (Treg) cells were assessed. Plasma total cortisol and adrenocorticotrophic hormone (ACTH) levels were tested. Since the data for total cortisol and ACTH levels had a skewed distribution, we compared our results with the natural logarithmic conversion values after adding 1 (ln [total cortisol+ 1], ln [ACTH+ 1]). Measurement data with a skewed distribution are expressed as medians (25th and 75th percentiles). The Mann–Whitney U test was used to compare variables between groups. The qualitative parameters in the 2 × 2 contingency table were used for analysis.Results: Overall, 85 patients who experienced CA and 40 healthy individuals were enrolled. All cell counts were lower and plasma total cortisol levels were higher (P<0.001) in patients who experienced CA than those in the healthy control group. GR expression in Treg cells and CD3+CD4+ T lymphocytes was not significantly different, but the mean fluorescence intensity and GR expression in other cells were lower in patients who experienced CA (P<0.05) than those in the healthy control group. ACTH levels did not show any difference. There were no significant differences between survivors and non-survivors. Conclusion: Our findings provide insights into GC sensitivity and immunosuppressive status in these patients, and a new perspective for GC targeted treatment.