The Association of Cortisol Excretion with Weight and Metabolic Parameters in Nondiabetic Patients with Morbid Obesity

<b><i>Introduction:</i></b> Cortisol is involved in the regulation of gluconeogenesis and glucose utilization. In morbid obesity (MO), the association of cortisol excretion with metabolic parameters is not well-characterized. In our study, we evaluated cortisol excretion in nondiabetic subjects with MO and its effect on glucose metabolism. <b><i>Methods:</i></b> We included 1,249 nondiabetic patients with MO (79.8% females, mean BMI 44.9 ± 6.5 kg/m², mean age 38 ± 11 years). Anthropometric data and cardiovascular risk factors were assessed, and an oral glucose tolerance test for calculation of insulin resistance was performed. Cortisol excretion was assessed on 2 consecutive days (24 h urine specimens). <b><i>Results:</i></b> Regarding cortisol excretion, patients were divided into 3 tertiles (urinary cortisol ≤51.6, &#x3e;51.6 and &#x3c;117.6, and ≥117.6 μg/24 h, respectively). Patients in the highest tertile were younger (<i>p</i> = 0.003), more obese (BMI: <i>p</i> = 0.040), had lower diastolic blood pressure ([DBP]; <i>p</i> = 0.012), lower total (<i>p</i> = 0.032) and LDL cholesterol (<i>p</i> = 0.021), fasting (<i>p</i> = 0.049) and 2-h glycemia (<i>p</i> = 0.028), 2-h insulinemia (<i>p</i> = 0.020), and HbA1c (<i>p</i> &#x3c; 0.001), and a higher estimated glomerular filtration rate (eGFR) (<i>p</i> &#x3c; 0.001). The glucose (<i>p</i> &#x3c; 0.001) and insulin (<i>p</i> = 0.011) area under the curve (AUC) were also lower. Urinary cortisol excretion adjusted for age, sex, and eGFR was positively correlated with body weight (BW, beta = 0.076, <i>p</i> = 0.004) and overall glucose tolerance (oral disposition index, beta = 0.090, <i>p</i> = 0.011), and negatively with HbA1c (beta = −0.179, <i>p</i> &#x3c; 0.001), 2-h glycemia (beta = −0.075, <i>p</i> = 0.032), AUC glucose (beta = −0.103, <i>p</i> = 0.002), and DBP (beta = −0.139, <i>p</i> &#x3c; 0.001). HbA1c, BW, and DBP remained significant after multivariable analysis. <b><i>Discussion/Conclusion:</i></b> Despite being more obese, patients with higher cortisol excretion have a more favorable metabolic profile. These results deserve further attention regarding the respective mechanisms.

Abstract P251: Out-of-clinic Cortisol Secretion Is Increased In Masked Uncontrolled Hypertension

Introduction: Masked uncontrolled hypertension (MUCH) in treated patients is defined as controlled office BP but uncontrolled out-of-clinic ambulatory BP (ABP). In contrast, patients with true controlled hypertensive (CHTN) have controlled BP by both office BP and out-of-clinic ABP. Previously, we have shown that patients with MUCH have increased out-of-clinic catecholamines/metanephrines (indicative of SNS activity) and aldosterone levels (indicative of RAAS activity). The current study tested the hypothesis that MUCH patients have higher cortisol levels (corticotropin-glucocorticoid axis) compared to patients with true CHTN. Methods: 222 patients with controlled office BP at ≥3 clinic visits were recruited. Patients taking glucocorticoid-containing medications were excluded. All patients were evaluated by automated office BP. Out-of-clinic ABP monitoring and 24-hour-urinary cortisol, cortisone, aldosterone, catecholamines and metanephrines levels were also measured. 115 patients had MUCH and remaining 75 patients had true CHTN. Results: MUCH patients had significantly higher out-of-clinic levels of 24-hour-urinary cortisol, catecholamines, metanephrines and aldosterone compared to true CHTN. Further, in correlation matrix analysis higher urinary cortisol was associated with higher catecholamines, metanephrines and aldosterone in MUCH patients.BP. Conclusions: Patients with MUCH had higher out-of-clinic urinary cortisol levels compared to patients with true CHTN. These findings suggest that patients with MUCH have higher out-of-clinic cortisol, aldosterone secretion and SNS tone that may contribute to their higher out-of-clinic BP.

Detection of Urinary Exosomal HSD11B2 mRNA Expression: A Useful Novel Tool for the Diagnostic Approach of Dysfunctional 11β-HSD2-Related Hypertension

ObjectiveApparent mineralocorticoid excess (AME) is an autosomal recessive disorder caused by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme deficiency, traditionally assessed by measuring either the urinary cortisol metabolites ratio (tetrahydrocortisol+allotetrahydrocortisol/tetrahydrocortisone, THF+5αTHF/THE) or the urinary cortisol/cortisone (F/E) ratio. Exosomal mRNA is an emerging diagnostic tool due to its stability in body fluids and its biological regulatory function. It is unknown whether urinary exosomal HSD11B2 mRNA is related to steroid ratio or the HSD11B2 662 C&gt;G genotype (corresponding to a 221 A&gt;G substitution) in patients with AME and essential hypertension (EH).Aim of the StudyTo detect and quantify HSD11B2 mRNA from urinary exosomes in samples from family members affected by AME and EH, and to evaluate the relationship between exosomal HSD11B2 mRNA, steroid ratio, 662C&gt;G genotype, and hypertension.MethodsIn this observational case–control study, urinary steroid ratios and biochemical parameters were measured. Urinary exosomes were extracted from urine and exosomal HSD11B2 mRNA was quantified by Droplet Digital PCR (ddPCR). B2M (β-2 microglobulin) gene was selected as the reference housekeeping gene.ResultsAmong family members affected by AME, exosomal urinary HSD11B2 mRNA expression was strictly related to genotypes. The two homozygous mutant probands showed the highest HSD11B2 mRNA levels (median 169, range 118–220 copies/µl) that progressively decreased in 221 AG heterozygous with hypertension (108, range 92–124 copies/µl), 221 AG heterozygous normotensives (23.35, range 8–38.7 copies/µl), and wild-type 221 AA subjects (5.5, range 4.5–14 copies/µl). Heterozygous hypertensive subjects had more HSD11B2 mRNA than heterozygous normotensive subjects. The F/E urinary ratio correlated with HSD11B2 mRNA copy number (p &lt; 0.05); HSD11B2 mRNA strongly decreased while THF+5αTHF/THE increased in the two probands after therapy. In the AME family, HSD11B2 copy number correlated with both F/E and THF+5αTHF/THE ratios, whereas in EH patients, a high F/E ratio reflected a reduced HSD11B2 mRNA expression.ConclusionsHSD11B2 mRNA is detectable and quantifiable in urinary exosomes; its expression varies according to the 662 C&gt;G genotype with the highest levels in homozygous mutant subjects. The HSD11B2 mRNA overexpression in AME could be due to a compensatory mechanism of the enzyme impairment. Exosomal mRNA is a useful tool to investigate HSD11B2 dysregulation in hypertension.

Early maternal loss leads to short- but not long-term effects on diurnal cortisol slopes in wild chimpanzees

The biological embedding model (BEM) suggests that fitness costs of maternal loss arise when early-life experience embeds long-term alterations to hypothalamic-pituitary-adrenal (HPA) axis activity. Alternatively, the adaptive calibration model (ACM) regards physiological changes during ontogeny as short-term adaptations. Both models have been tested in humans but rarely in wild, long-lived animals. We assessed whether, as in humans, maternal loss had short- and long-term impacts on orphan wild chimpanzee urinary cortisol levels and diurnal urinary cortisol slopes, both indicative of HPA axis functioning. Immature chimpanzees recently orphaned and/or orphaned early in life had diurnal cortisol slopes reflecting heightened activation of the HPA axis. However, these effects appeared short-term, with no consistent differences between orphan and non-orphan cortisol profiles in mature males, suggesting stronger support for the ACM than the BEM in wild chimpanzees. Compensatory mechanisms, such as adoption, may buffer against certain physiological effects of maternal loss in this species.

Adrenocorticotropic Hormone-independent Cushing Syndrome with Right Adrenal Adenoma and HIV Infection: A Case Report

Background: Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS) with right adrenal adenoma combined with HIV infection has rarely been reported. Case presentation: A 39-year-old Chinese male patient with HIV infection was admitted to our hospital due to increased blood pressure in the previous 2 years and weight gain in the previous 6 months. Endocrinological examinations showed that blood cortisol (8 a.m.) was 22.23 µg/dl, the level of ACTH (8 a.m.) was less than 1pg/ml and twenty-four-hour urinary cortisol was 1429 µg/24h. ACTH-independent CS was diagnosed based on low ACTH levels (<1.00 pg/ml), a lack of cortisol circadian rhythms and unsuppressed cortisol levels by dexamethasone. The ultrasonography and multislice spiral computed tomography scan revealed a right adrenal mass. Due to the HIV status of the patient, we measured the count of CD4+ T helper cells. Laparoscopic right adrenal resection was performed after the CD4+ T helper cell count was > 200 cells/µl. Subsequent immunohistochemical staining confirmed right adrenal adenoma. Results: The postoperative recovery was good, and wound healing was possible. After surgical treatment, endocrinological examinations indicated that the level of ACTH increased and the levels of serum cortisol and twenty-four-hour urinary cortisol decreased, which indicated that CS was controlled. CD4/CD8 was 0.47 at reexamination, and the patient's immunity was improved. Conclusion: Due to the potential side effects of steroid drugs, clinicians should use these medications with caution and closely monitor the development of adrenal deficiency.

Paediatric reference range for overnight urinary cortisol corrected for creatinine

Objectives Systemic activity of inhaled corticosteroids (ICS) may be assessed via urinary cortisol measurement. Overnight urinary free cortisol corrected for creatinine (OUFCC) has been extensively reported in adult studies. However, a paediatric mass spectrometric (MS) reference range for OUFCC is not established. MS methods for OUFCC avoid cross-reactivity with other steroid hormones and are thus preferable to immunoassays. The aim of the present study was to define an MS OUFCC normative range in children. Methods This was a cross-sectional study of healthy pre-pubertal children from 5 to 11 years. Children collected urine from 10 pm or bedtime, whichever was earlier, until 8 am. Urinary free cortisol was measured via a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay (Acquity UPLC with Xevo TQ-S Mass Spectrometer [Waters]) with in-house reagents. Urinary creatinine was measured using a commercial assay (Roche). Results Complete urine collections were obtained from 72 males and 70 females, mean age (SD) 8.6 (1.9) (range 5.0–11.8) years. The OUFCC 95% prediction interval was 1.7–19.8 nmol/mmol. Geometric mean OUFCC was 5.7; range 1.1–24.8 nmol/mmol. Conclusions The obtained normative LC-MS/MS OUFCC reference data facilitate the use of mass spectrometry OUFCC assays in assessment of systemic activity of endogenous and exogenous corticosteroids in children.

Primary Macronodular Adrenal Hyperplasia Associated With Autosomal Dominant ARMC5 Mutation

Background: Primary macronodular adrenal hyperplasia (PMAH) is an uncommon cause of Cushing’s syndrome. In some cases, this is an inherited disorder due to a mutation in the armadillo repeat-containing 5 (ARMC5) gene. Clinical Case: A 43-year-old African American woman presented to clinic with weight gain, worsening type 2 diabetes mellitus, and symptomatic hypertensive cardiomyopathy. Physical exam was significant for central obesity, bilateral supraclavicular fat pads, acanthosis nigricans and wide striae over the abdomen. Her serum cortisol was 13.8 mcg/dL after 1 mg of dexamethasone (n&lt;1.8 mcg/dL), urinary cortisol was 180 mcg in 24 hours (n=3.5–45 mcg/24h) and two midnight salivary cortisol tests were 227 and 118 ng/dL (n&lt;100 ng/dL). Her ACTH was 2.4 pg/mL (n=7.2–63.3 pg/mL). Computed tomography (CT) of the abdomen showed nodularity, diffuse thickening and low-density (&lt;10 Hounsfield units) of the bilateral adrenal glands. She underwent bilateral adrenalectomy for a diagnosis of PMAH. Pathology showed nodular adrenocortical hyperplasia; the right and left adrenal glands measured 75 grams and 68 grams, respectively. She was started on hydrocortisone and fludrocortisone postoperatively. Over the following two years, she had a 68-pound weight loss, an 86% reduction in her daily insulin requirement and a 10% improvement in her left ventricular ejection fraction. Approximately two years later, the patient’s brother was referred for bilateral macronodular hyperplasia incidentally discovered on a CT of the abdomen. He had a history of hypertension and type 2 diabetes mellitus with cushingoid features on exam. His serum cortisol was 20.7 mcg/dL after 1 mg of dexamethasone, urinary cortisol was 65.1 mcg in 24 hours, two midnight salivary cortisol tests were 232 and 404 ng/dL and ACTH was 2.0 pg/mL. Upon obtaining further family history, the patients reported clinical features of Cushing’s syndrome in their paternal grandmother but denied features in either parent. The second patient had genetic testing which showed a mutation in the ARMC5 gene, c.1777C&gt;T, p.R593W, a mutation previously described. Due to clinical signs of Cushing’s syndrome, he underwent bilateral adrenalectomy in which pathology showed right and left nodular adrenocortical hyperplasia measuring 110 and 73 grams, respectively. He is doing well postoperatively. The patients recently reported their aunt was diagnosed with PMAH and mild Cushing’s syndrome. She had a unilateral adrenalectomy of the larger adrenal gland and is doing well postoperatively. Conclusion: In some cases, Cushing’s syndrome is an inherited disorder. Autosomal dominant mutations in the ARMC5 gene are occasionally seen in PMAH, which causes less than 2% of endogenous Cushing’s syndrome. For all patients diagnosed with PMAH, clinicians should consider screening their family members with a dexamethasone suppression test.

A Mass in Disguise: A Rare Case of High-Attenuation Adrenal Myelolipoma

Background: Adrenal incidentalomas are common, and imaging studies play a large role in reaching the diagnosis in many cases. Adrenal myelolipomas are classically diagnosed by CT as a hypodense well circumscribed heterogenous mass with low attenuation. Clinical Case: A 51-year-old man with history of resistant hypertension presented with neck pain after a motor vehicle crash. After a cervical X-ray revealed an odontoid fracture, a whole body CT was obtained. The CT incidentally identified a massive heterogeneous left adrenal mass measuring 22.3 × 15.5 × 20.6 cm, with multiple attenuation measurements ranging from 20 to 53 Hounsfield units (HU). The patient’s physical examination and hormonal assessment were both unrevealing, with normal catecholamine, androgen, and an unremarkable renin aldosterone ratio. Inpatient urinary cortisol levels were elevated, however a repeat urinary cortisol as an outpatient weeks after repair of the odontoid fracture showed normal levels, suggesting physiologic stress response. Positron emission tomography showed a metabolically inactive adrenal mass without metastatic diseases. The patient eventually underwent a left adrenalectomy, and pathology revealed a myelolipoma measuring 24.2 × 20.5 × 8.3 cm. Imaging characteristics for adrenal incidentalomas are considered useful diagnostic information according to most clinical guidelines. Lesions with high HU are typically pheochromocytomas, adrenocortical carcinoma, metastatic disease, or lipid poor adenomas. Myelolipomas are identified on CT by their characteristically low HU (often -30). In this case of a massive myelolipoma with high HU, the unique imaging characteristics posed a diagnostic challenge. The patient’s history of resistant hypertension combined with the high HU led to the patient undergoing extensive testing for a functional mass or cancer. Conclusion: This is a rare case of a massive myelolipoma with low attenuation. The role of imaging studies in the diagnosis of adrenal incidentalomas is not definitive, and detailed exam along with hormonal assessment may be warranted in atypical cases. Providers should consider myelolipoma in the differential diagnosis of a large adrenal mass with a negative hormonal evaluation even in the setting of high HU.