Synergistic cortisol suppression by ketoconazole–osilodrostat combination therapy

Summary Here, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Learning points Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome. Ketoconazole and osilodrostat appear to act in a synergistic manner. This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Considering the current cost of newly-released drugs, such a strategy could lower the financial costs for patients and/or society.

Clinical course and management of pembrolizumab-associated isolated adrenocorticotrophic hormone deficiency: a new case and literature review

Hypophysitis is rarely reported in patients receiving pembrolizumab-only immunotherapies. Since the clinical presentation is usually as isolated adrenocorticotrophic hormone (ACTH) deficiency, patients may be misjudged as having clinical symptoms due to cancer or chemotherapy. A 49-year-old male with laryngeal cancer applied to our clinic just after the tenth cycle of his pembrolizumab treatment, with weakness and nausea/vomiting. Serum morning cortisol and ACTH were 0.47 mcg/dl and 10.1 pg/ml, respectively; the remaining anterior pituitary hormone levels were normal. Pituitary MRI revealed mild glandular enlargement and loss of posterior pituitary bright-spot. All symptoms and signs improved with low-dose prednisolone. This is the second reported case of pembolizumab-associated isolated ACTH deficiency having abnormal pituitary MRI findings as we have reviewed all reported cases in the literature.

Canine endogenous adrenocorticotrophic hormone preanalytical stability after sample shipping in dry ice or recyclable ice bars

ABSTRACT: Endogenous adrenocorticotrophic hormone (eACTH) measurement is useful in hypercortisolism and hypoadrenocorticism investigation; however, since the hormone is highly unstable, blood samples require proper processing and storage, as well as shipping is often a step limiting since few laboratories offer this assay in Brazil. The aim of this note was to compare overnight dog´s eACTH preanalytical stability when frozen samples were shipped in dry ice (DI), or with recyclable ice bars (RIB). A total of 56 paired samples for eACTH measurement were analyzed. Blood samples were properly handled, plasma aliquots transferred into plastic microtubes, and stored at -80ºC. The fifty-six paired samples were overnight shipped in two thermic isolated boxes with DI or involved by RIB. Despite there was a high correlation between results from both shipping methods (r Spearman = 0.958, P<0.001), the Wilcoxon matched-pairs rank test showed that the shipping method may influence results (P<0.001). However, this difference does not affect results interpretation. By this way, when DI shipping was not possible, RIB shipping may represent a risk to eACTH preanalytical stability.

The classic triad of triple A (Allgrove) syndrome

A 42-year-old patient was admitted with slowly progressive gait disturbance over a period of ten years. The patient complained of regurgitation and fatigue since childhood. Clinical examination revealed nasal voice, distal amyotrophic motor deficit with pyramidal signs, mild intellectual disability, increased skin pigmentation, and reduced body weight (BMI: 16.6 kg/m2). Schirmer test revealed bilateral alacrima and barium swallow confirmed achalasia cardia. Cortisol level was undetectable, while adrenocorticotrophic hormone was elevated.

THU0465 SERUM LEVEL OF ADRENOCORTICOTROPHIC HORMONE IS A CONTRIBUTING HORMONE OF METABOLIC SYNDROME IN NEWLY DIAGNOSED FIBROMYALGIA

Background:Evidence of components of metabolic syndrome including. Obesity dyslipidemia, abnormal glucose tolerance rate and hypertension are associated with fibromyalgia. Adrenocorticotrophic hormone (ACTH) is reported to be significantly higher in fibromyalgia patients, and it causes obesity, high blood pressure.Objectives:This study aimed to assess the serum level of ACTH as a contributing as well as a discriminator hormone in newly diagnosed fibromyalgia women presented with variable components of metabolic syndrome.Methods:This cross-sectional study comprised 100 women with newly diagnosis fibromyalgia and 30 apparent healthy women served as control from Kurdistan region-Iraq. Clinical data including the score of fibromyalgia impact questionnaire-revised (FIQR), tender point, body mass index, waist circumference, blood pressure and fasting serum levels of glucose and lipid profile, and ACTH level. The score of metabolic syndrome was calculated using the formula:Results:Compared to the controls, the Fibromyalgia women displayed significantly higher values of waist circumference (88.9 ± 5.7cm versus 87.1 ± 2.7cm, p=0.019), systolic blood pressure (136.1 ±13.5mmHg versus 131.4 ± 7.1, p=0.014), metabolic syndrome score (3.10 ±0.25 versus 3.03±0.19, p=0.039), and serum ACTH levels (16.66 ± 3.23pg/ml versus 14.42 ± 2.18pg/ml. p<0.001). Serum ACTH levels significantly and inversely correlated with the total score of the FIQR (r = - 0.320. p=0.001) and number of tender points (r= - 0.374, p<0.001). Metabolic syndrome score is significantly and inversely correlated with the total FIQR score (r = - 0.296, p=0.003). Multivariable regression analysis using showed that serum level of ACTH is a significant (p= predictor of 19.7% of fibromyalgia patients (Figure 1), and it is a significant (p=0.007) discriminator of tender points as the area under the curve is 0.325(95%C.I.: 0.212-0.438) (Figure 2).Figure 1.Multivariable regression analysis withposthocANOVA test showed significant correlations between serum level adrenocorticotrophic hormone as a dependent variable with the score s of fibromyalgia impact questionnaire and metabolic syndrome, and the number of tender points. R=0.443, F=7.777, P<0.001, prediction 19.7%),Figure 2.serum level of ACTH (cutoff level ≥14.5pg/ml, sensitivity=72%, specificity=50%) as a discriminator of the tender points (AUC95% C.I: 0.325[0.212-0.438], p=0.007), score of fibromyalgia symptoms (AUC95% C.I: 0.474[0.313-0.581], p=0.409), and metabolic syndrome score (AUC95% C.I: 0.546[0.423-0.668], p=0.480)Conclusion:Fibromyalgia women responded to the stress of pain by increasing the serum level of ACTH which effectively improves the clinical feature of fibromyalgia symptoms, but at the same time elevates the score of metabolic syndrome. Therefore, assessment of serum level of ACTH can serve as a predictor and discriminator of fibromyalgia comorbidity.References:[1]Acosta-Manzano P, Segura-Jiménez V, Estévez-López F, Álvarez-Gallardo IC, Soriano-Maldonado A, Borges-Cosic M, Gavilán-Carrera B, Delgado-Fernández M, Aparicio VA. Do women with fibromyalgia present higher cardiovascular disease risk profile than healthy women? The al-Ándalus project. Clin Exp Rheumatol. 2017; 35 Suppl 105(3):61-67.[2]Marwan S.M. Al-Nimer, Talar A.M. Mohammad, Avin M.A. Maroof. Dysfunction of anterior pituitary gland in women patients with recent fibromyalgia: A cross-sectional observational study. Electron J Gen Med 2018;15(4):em58[3]Soldatovic I, Vukovic R, Culafic D, Gajic M, Dimitrijevic-Sreckovic V. siMS score: simple method for quantifying metabolic syndrome. PLoS One. 2016; 11(1):e0146143Disclosure of Interests: :None declared

Stress Effector Systems

Three interacting peripheral stress effector systems are activated during exposure of humans and other animals to acute as well as chronic stressors. They include the sympathetic-adrenal medullary (SAM) system, the hypothalamic-pituitary-adrenocortical (HPA) axis, and the innate immune system. The SAM system includes the release of norepinephrine from sympathetic nerve terminals and epinephrine from the adrenal medulla. Plasma levels of norepinephrine and epinephrine have been utilized as an index of SAM activity under basal conditions and following exposure to stress. The HPA axis involves release of corticotropin-releasing factor from neurons in the paraventricular nucleus of the hypothalamus, which stimulates adrenocorticotrophic hormone (ACTH) release from the anterior pituitary, followed by cortisol or corticosterone release from the adrenal cortex. The HPA axis is regulated in part by a system of negative feedback loops. The chemical messengers of the innate immune system include proinflammatory (IL-1β‎, IL-6, and TNF-α‎) and anti-inflammatory cytokines (IL-4 and IL-10).