Normal Cortisol Research Articles

ODP058 Topiramate causing elevation of urinary cortisol assay

Abstract 69-year-old female with pituitary adenoma status-post transsphenoidal resection 6 years prior and isolated growth hormone deficiency [on somatropin 0.2 mg daily], migraines [on topiramate 25 mg daily], left lipid-rich adrenal incidentaloma, primary hypothyroidism [on levothyroxine 75 mcg daily], and secondary hyperparathyroidism from vitamin-D deficiency [on ergocalciferol 50000 IU weekly] and hydrochlorothiazide 25 mg daily presented for follow-up. Physical exam: afebrile, blood pressure hypertensive at 163/71 mmHg, heart rate 91 beats per minute, respiratory rate 18 breaths per minute, saturating 100% on room air and patient weighed 105 kg. Patient appeared obese but did not exhibit cervicodorsal fat pads, abdominal striae, or other cushingoid features. Neck was supple and did not demonstrate palpable nodules or lymphadenopathy. Labs ordered at clinic visit demonstrated normal TSH 1.28 with normal free T4 1.21, elevated PTH 232 with corrected calcium 9.7 (on hydrochlorothiazide) and normal vitamin-D, 25 level 43, normal ACTH 21, and normal IGF-1 level 75. Given adrenal incidentaloma and prior pituitary adenoma, the integrity of the hypothalamus-pituitary-adrenal axis was also tested. A subsequent 8: 00 a. m. cortisol was insufficiently suppressed at 5.2 after 1 mg dexamethasone suppression test which raised concern for hypercortisolism from pituitary adenoma or adrenal adenoma. Accordingly, ACTH as well as DHEA-S and 24 hour urine cortisol as well as midnight salivary cortisol level was ordered to assess pituitary versus adrenal origin, respectively. Interestingly, while midnight salivary cortisol was found to be normal at less than 50, the 24 hour urine cortisol measurement was elevated at 878 despite otherwise normal cortisol findings. ACTH and DHEA-S levels are still pending. Plan was made to check two additional midnight cortisol levels and await ACTH and DHEA-S levels. In an effort to explain the urinary cortisol elevation, the patient's medications were reviewed and subsequent literature search revealed that topiramate may interfere with urinary cortisol measurement by causing a dose-dependent increase in the measured urinary cortisol, presumably due to its action on the kidney during renal excretion. Patient had been on topiramate for approximately 6 months prior to this assay. Presentation: No date and time listed

ODP068 A Case Report of Nivolumab Associated Hypercalcemia

Abstract Introduction Nivolumab is a human immunoglobulin G4 (IgG4) antibody which binds to programmed cell death receptor-1 (PD-1) and blocks the binding of PD-1 to either the PD-ligand 1 (PD-L1) or PD-L2 expressed on the surface of cancer cells. It has been approved for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma etc. Various endocrine immune-related adverse events including thyroiditis, hyper- and hypothyroidism, hypophysitis and type 1 diabetes has been described. We report a case of Nivolumab associated hypercalcemia. Case presentation 67-year-old female with history of CKD stage 3 with secondary hyperparathyroidism, melanoma of right ankle was admitted after one month of receiving the first dose of Nivolumab for her melanoma. She had altered mentation with elevated corrected calcium of 15.94(8.4-10.2) mg/dl. Prior calcium levels were in low to normal range, eGFR was 13, creatinine elevated at 3.4 (0.57-1.11) mg/dl, PTH 84 (10-65) pg/ml, 25 OH vitamin D 54 (30-74) ng/ml, Phosphorus normal, Magnesium normal, 1,25-OH vitamin D was elevated at 103(18-72) pg/ml, PTHrp normal, normal SPEP, normal TSH, no history of fractures, normal DXA, no history of kidney stones, not on any calcium supplements, not on thiazide or lithium. Chest x ray and NM full body PET CT did not show any evidence of granulomatous disease except for recurrence and metastasis of melanoma in right thigh, calf, and ankle. No family history of kidney stones or hypercalcemia. Patient was treated with IV fluids and Calcitonin. Her calcium quickly improved to 9.9 within 48 hours. Within 3 weeks of discharge, she was readmitted for elevated calcium of 14.4 mg/dl, creatinine 2.29 mg/dl, eGFR 21, PTH 96 pg/ml, Mg 1.8 (1.6-2.6) mg/dl. She was treated with IV fluids and calcitonin and calcium normalized within 48 hours. Parathyroid scan did not show any parathyroid adenoma. She was started on prednisone for possible Nivolumab associated immune adverse reaction. She was also briefly treated with cinacalcet which was discontinued. Prednisone was tapered and then stopped over the course of 6 weeks. Calcium remains normal. PTH remains slightly elevated which is thought to be due to secondary hyperparathyroidism from CKD. Normal cortisol level. Discussion This is likely a case of Nivolumab associated hypercalcemia given the onset soon after immunotherapy initiation and improvement with glucocorticoid therapy. Immunotherapy was not resumed after the first dose due to recurrent severe hypercalcemia. The patient is currently under surveillance for melanoma. Calcium level remains normal. Although it is rare, a few cases of Nivolumab associated hypercalcemia have been reported previously. Exact mechanism is not known but it has been speculated that macrophage activation by Nivolumab can cause increased level of 25(OH) D-hydroxylase with increased conversion of 25-OH vitamin D to 1,25-OH vitamin D resulting in calcitriol mediated hypercalcemia. Presentation: No date and time listed

PSUN42 New-Onset Rheumatoid Arthritis After Surgical Treatment of Cushing Syndrome

Abstract Background Cushing syndrome (CS) is a rare endocrinopathy resulting from prolonged exposure to endogenous or exogenous glucocorticoids. CS can be subclinical or can present with an array of overt signs and symptoms. The goal of treatment in CS is to reestablish normal cortisol levels in the body by eliminating the source of excess cortisol. Autoimmune diseases are often treated successfully with exogenous glucocorticoids. There are several case reports/series in the literature describing patients who developed autoimmune diseases, or experienced recrudescence of otherwise quiescent autoimmune processes, after the withdrawal of glucocorticoids. Such diseases include rheumatoid arthritis, Graves disease, Hashimoto's thyroiditis, systemic lupus erythematosus, psoriasis, and myasthenia gravis. Below we share a case of rheumatoid arthritis that presented after unilateral adrenalectomy for CS. Clinical case A 55 year old female with a history of Graves disease status post radioactive iodine ablation many years ago with post-ablative hypothyroidism was found to have a left adrenal mass on CT in 2016. An MRI in February 2021 showed interval growth from 3.8×2.9×3.6cm to 5.1×3.5×4.8cm. ACTH was suppressed to <1.5 pg/mL (7.2-63.3 pg/mL), 24 hour urine free cortisol was elevated to 256 ug/24hr (10-34 ug/24hr), midnight salivary cortisol was elevated to 219 ng/dL then 430 ng/dL on repeat (n<100 ng/dL), and AM cortisol was 13.7 ug/dL (6.0-18.4 ug/dL) after 1mg overnight dexamethasone administration. This biochemical testing was supportive of the diagnosis of ACTH-independent adrenal CS. Our patient underwent successful left adrenalectomy in March 2021 and was started on hydrocortisone postoperatively given long-standing suppression of her hypothalamic-pituitary-adrenal axis. Within three months, she developed muscle aches and pain in bilateral hands, ankles and feet with stiffness and swelling. These symptoms worsened with glucocorticoid taper. She was found to have a rheumatoid factor of 32 IU/mL (0-13 IU/mL) and was diagnosed with rheumatoid arthritis, for which she was started on hydroxychloroquine and briefly switched from hydrocortisone to prednisone. She has since been tapered off steroids with resolution of adrenal insufficiency. Her rheumatoid arthritis symptoms remain adequately controlled on hydroxychloroquine. Conclusions While it is known that withdrawal of exogenous chronic steroids can result in exacerbation of pre-existing autoimmune disease, the emergence of new autoimmune disease upon withdrawal of endogenous steroid production after treatment of pituitary ACTH-dependent or adrenal ACTH-independent CS is extremely rare. Of special interest, our patient described above had a history of Graves disease years before her CS diagnosis was made, suggesting an underlying proclivity towards autoimmunity. Further study may reveal the need for higher vigilance in postoperative monitoring in patients with preexisting autoimmune conditions. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

GNAS mutation is an unusual cause of primary adrenal insufficiency: a case report

BackgroundPrimary adrenal insufficiency in children has non-specific and extensive clinical features, so the diagnosis of its etiology is complex and challenging. Although congenital adrenal hyperplasia is the most common cause, more and more other genetic causes have been identified. GNAS mutation is easily overlooked as a rare cause of primary adrenal insufficiency. Here we firstly report a neonatal case of primary adrenal insufficiency caused by GNAS mutation.Case presentationA boy was diagnosed with congenital hypothyroidism 10 days post-partum and treated immediately. He also had persistent hyperkalaemia and hyponatraemia with elevated adrenocorticotropic hormone. At 70 days after birth, he was transferred to our hospital on suspicion of congenital adrenal hyperplasia. Physical examination found no other abnormalities except for growth retardation. Laboratory examination revealed increased aldosterone and normal cortisol, 17-hydroxyprogesterone, and androstenedione levels. Abnormally elevated parathyroid hormone was accompanied by normal blood calcium. Genetic assessment found a de novo, heterozygous c.432 + 1G > A variant in GNAS.ConclusionsWe report this case to highlight that GNAS mutation is an unusual cause of primary adrenal insufficiency. The combination of primary hypothyroidism and /or pseudohypoparathyroidism will provide diagnostic clues to this condition.

Unilateral or bilateral adrenalectomy in PPNAD: six cases from a single family followed up over 40 years

The most frequent endocrine Carney complex manifestation is a bilateral primary pigmented nodular adrenocortical disease and bilateral adrenalectomy (BA) is therefore its main treatment. In this study, a 40 years follow-up of six members of the same family with heterozygous PRKAR1A germline mutation, is reported over two generations. The first cases, two sisters with severe hyperandrogenism and Cushing syndrome (CS) diagnosed in 1972 at age 14 and 25, were successfully treated with unilateral adrenalectomy (UA). Their two brothers were then diagnosed, one with a CS-related severe osteoporosis treated with BA and the other with CS treated with UA. The second generation was diagnosed with CS signs at 7 and 21 years of age and were treated with BA and UA respectively. Out of the four patients treated with UA, the only event possibly related to CS was spontaneous episode of pulmonary embolism, 30 years after surgery. Hormonal evaluation revealed either eucortisolism in one patient or partial adrenal deficiency in two and mild hypercortisolism in one patient. For the two patients with BA, one of them accidentally died. The second one, surprisingly, recovered progressively normal cortisol secretion and circadian variation. Steroid substitution was stopped 6 years after her surgery and we demonstrated by iodocholesterol scintigraphy the presence of bilateral adrenal remnants. In conclusion, our results of long term evolution of PPNAD patients show that UA in this subset of patients could be considered to treat CS.

Real sweating in a virtual stress environment: Investigation of the stress reactivity in people with primary focal hyperhidrosis.

BackgroundHyperhidrosis (excessive sweating, OMIM %114110) is a complex disorder with multifactorial causes. Emotional strains and social stress increase symptoms and lead to a vicious circle. Previously, we showed significantly higher depression scores, and normal cortisol awakening responses in patients with primary focal hyperhidrosis (PFH). Stress reactivity in response to a (virtual) Trier Social Stress Test (TSST-VR) has not been studied so far. Therefore, we measured sweat secretion, salivary cortisol and alpha amylase (sAA) concentrations, and subjective stress ratings in affected and non-affected subjects in response to a TSST-VR.MethodIn this pilot study, we conducted TSST-VRs and performed general linear models with repeated measurements for salivary cortisol and sAA levels, heart rate, axillary sweat and subjective stress ratings for two groups (diagnosed PFH (n = 11), healthy controls (n = 16)).ResultsPFH patients showed significantly heightened sweat secretion over time compared to controls (p = 0.006), with highest quantities during the TSST-VR. In both groups, sweating (p < 0.001), maximum cortisol levels (p = 0.002), feelings of stress (p < 0.001), and heart rate (p < 0.001) but not sAA (p = 0.068) increased significantly in response to the TSST-VR. However, no differences were detected in subjective ratings, cortisol concentrations and heart rate between PFH patients and controls (pall > 0.131).ConclusionPatients with diagnosed PFH showed stress-induced higher sweat secretion compared to healthy controls but did not differ in the stress reactivity with regard to endocrine or subjective markers. This pilot study is in need of replication to elucidate the role of the sympathetic nervous system as a potential pathway involved in the stress-induced emotional sweating of PFH patients.

Hair cortisol in polycystic ovary syndrome

The aim of the study was to evaluate adrenal axis hyperactivation measuring hair cortisol levels, and its influence on the relationship among metabolic parameters, inflammation markers and androgens in adult women with PCOS. 44 women (18–34 years) with PCOS diagnosis and a control group of 49 healthy women (19–35 years) were included. In both gropus body mass index (BMI) was calculated and waist circumference (WC) was measured. Hair cortisol, total serum testosterone (TT), serum cortisol, 25 OH vitamin D (25OHD), insulin, high sensitivity C-reactive protein (hsCRP), triglycerides (TG), HDL cholesterol (HDL), glucose and leptin were measured. Bioavailable testosterone (bioT) was calculated. Hair cortisol concentration was higher and significantly different in PCOS patients compared to the control group (130 vs 63 pg/mg of hair, p < 0.001). Subsequently, patients with PCOS were divided into two groups according to hair cortisol levels: group 1 with normal hair cortisol concentration and group 2 with levels above the upper limit of the reference values (128 pg/mg of hair). In group 2, TT significantly correlated with 25OHD, hsCRP, TG/HDL index, BMI, WC, insulin and HOMA (p < 0.05); bioT correlated with hsCRP and leptin (p < 0.05). Finally, 25OHD was inversely correlated with leptin and with TG/HDL index (p < 0.05). High hair cortisol concentration in patients with PCOS confirmed hyperactivation of the HPA axis. The associations observed were only found in patients with PCOS with high hair cortisol levels (> 128 pg/mg of hair), showing a possible effect of HPA axis in these associations.

Antenatal glucocorticosteroids treatment: mechanisms of child healths programming

Synthetic glucocorticoids are widely used in pregnancies at risk of preterm delivery and in pregnant women at risk of having a child with severe 21-hydroxylase deficiency. The positive effects of reducing mortality in preterm and virilisation in girls with congenital adrenal hyperplasia are now unquestionable. The adrenogenital syndrome responding to 21-hydroxylase deficiency is a common, potential fatal disease. Its incidence calculated on the basis of neonatal screening data makes 1 case for 14000 live newborns among the worldwide population, 1 for 9638 – In Russia. DEX passes through the placenta and decreases fetal ACTH production thereby suppressing the fetal production of androgens. The prenatal treatment does not preclude from a life-long treatment in future and it is not prevention of a salt-losing syndrome at the postnatal period, and dexamethasone safety in relation to cognitive development of children prenatally treated with dexamethasone is still up for debate. Adding to the concern is the fact that the doses of DEX that the fetus is exposed to are estimated to be 60 times the normal fetal cortisol level. The glucocorticoid and the mineralocorticoid receptors are highly expressed in the hippocampus, amygdala, and prefrontal cortex. These areas, important for executive functioning, emotional regulation, and memory, are vulnerable to high doses of GCs. Most experimental data from animal have shown that prenatal exposure to synthetic glucocorticoids programs the foetal HPA and may lead to altered susceptibility to metabolic and cardiovascular disease i.e. metabolic syndrome, high blood pressure. Prenatal glucocorticoid exposure also leads to modification of HPAassociated behaviours and cognition.

Pharmacokinetic Modeling of Hydrocortisone by Including Protein Binding to Corticosteroid-Binding Globulin.

Background: Patients with adrenal insufficiency are treated with oral hydrocortisone (HC) to compensate for the loss of endogenous cortisol production. Intrinsic imperfections of cortisol replacement strategies in mimicking normal cortisol secretion are the underlying cause of the increased morbidity and mortality of patients suffering from secondary adrenal insufficiency (SAI). To improve oral hydrocortisone substitution therapy, a better understanding of its pharmacokinetics (PK) is necessary. The previous PK model did not include protein binding. It is known that protein binding can impact hydrocortisone pharmacokinetics. The aim of this study is to describe HC pharmacokinetics including the protein-binding state using Edsim++ (Mediware, Prague) pharmacokinetic modeling software, paving the way for an in-silico tool suitable for drug delivery design. Methods: A total of 46 patients with SAI participated in a randomized double-blind crossover study Patients randomly received a low dose of HC (0.2–0.3 mg/kg body weight/day) for 10 weeks, followed by a high dose (0.4–0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. Plasma samples were obtained and analyzed for free and total hydrocortisone. Single compartment population pharmacokinetic analysis was performed using an extended Werumeus-Buning model built in Edsim++. This model includes a mathematical approach for estimating free cortisol by Nguyen et al., taking the protein binding of HC to albumin and hydrocortisone-binding globulin (CBG, transcortin) into consideration, as well as different states of CBG which affect binding kinetics to HC. The goodness of fit for observed versus predicted values was calculated. Results and conclusions: Nguyen’s formula for free cortisol estimation was successfully implemented in a pharmacokinetic model. The model shows high Spearman’s correlation for observed versus predicted hydrocortisone concentrations. Significantly higher correlations (Spearman’s r, 0.901 vs. 0.836) between total and free hydrocortisone AUC24 (area-under the curve over 24 h) are found when comparing new and old models. This new model was used to simulate the plasma concentration–time behavior of a more suitable hydrocortisone formulation.

Long-term results from the Phase III LINC 4 study: Osilodrostat maintained normal mean urinary free cortisol in patients with Cushing's disease, with a favourable safety profile

Long-term results from the Phase III LINC 4 study: Osilodrostat maintained normal mean urinary free cortisol in patients with Cushing's disease, with a favourable safety profile

Isolated ACTH deficiency with unusual clinical presentation and normal morning cortisol levels

Isolated ACTH deficiency with unusual clinical presentation and normal morning cortisol levels

The diagnosis and management of Cushing's syndrome in pregnancy.

Endogenous Cushing's syndrome (CS) is rarely encountered during pregnancy. Clinical and biochemical changes in healthy pregnancy overlap with those seen in pregnancy complicated by CS; the diagnosis is therefore challenging and can be delayed. During normal gestation, adrenocorticotrophic hormone, corticotrophin‐releasing hormone, cortisol, and urinary free cortisol levels rise. Dexamethasone administration fails to fully suppress cortisol in pregnant women without CS. Localisation may be hindered by non‐suppressed adrenocorticotrophic hormone levels in a large proportion of those with adrenal CS; smaller corticotroph adenomas may go undetected as a result of a lack of contrast administration or the presence of pituitary hyperplasia; and inferior petrosal sinus sampling is not recommended given the risk of radiation and thrombosis. Yet, diagnosis is essential; active disease is associated with multiple insults to both maternal and foetal health, and those cured may normalise the risk of maternal–foetal complications. The published literature consists mostly of case reports or small case series affected by publication bias, heterogeneous definitions of maternal or foetal outcomes or lack of detail on severity of hypercortisolism. Consequently, conclusive recommendations, or a standardised management approach for all, cannot be made. Management is highly individualised: the decision for surgery, medical control of hypercortisolism or adoption of a conservative approach is dependent on the timing of diagnosis (respective to stage of gestation), the ability to localise the tumour, severity of CS, pre‐existing maternal comorbidity, and, ultimately, patient choice. Close communication is a necessity with the patient placed at the centre of all decisions, with risks, benefits, and uncertainties around any investigation and management carefully discussed. Care should be delivered by an experienced, multidisciplinary team, with the resources and expertise available to manage such a rare and challenging condition during pregnancy.

Abstract #1139960: Pseudo-adrenal insufficiency caused by repeated hypoglycemia in an Insulinoma patient

Usual adrenal response to hypoglycemia is increase in serum cortisol production. It is considered as stress response to hypoglycemia and mediates rise in serum glucose levels through several different mechanisms. Here we describe a case of inappropriately normal serum Cortisol levels in a patient with repeated hypoglycemia emanating from Insulinoma.

A novel device for serial venous blood sampling in a canine model

Diagnostic serial venous blood sampling has the potential to introduce stress-related artifactual elements into the analytical results. We have evaluated the use of a wearable automated serial blood sampling device in a canine model that obviates a need for multiple manual venipuncture. Efficacy in measuring cortisol levels during prolonged serial blood sampling is described. Automated serial blood sampling from the jugular vein was performed in two Beagle dogs. Over two separate 22-h periods, serial blood samples were withdrawn for routine cell counting and blood chemistries from each animal, whilst animal behavior along with durability of catheter placement and tolerability by the vascular system were assessed.During the study, no behavioral changes attributed to the serial blood sampling device were seen and no stress-related deviations from normal blood cell counts and cortisol levels were detected. Minor erythema was eident at the sites of catheter placement, which was consistent with the presence of an indwelling catheter. The wearable, serial blood sampling device performed well and was tolerated by the animals without stress-related changes in blood analysis or behavioral observation. This study has demonstrated the potential significant benefit of the Fluispotter® device for serial blood sampling in veterinary and clinical settings. The samples collected are free from stress-related signatures in blood chemistry otherwise common to serial blood sampling protocols requiring repeated venipuncture. This device has valuable implications for use in routine preclinical pharmacology and toxicology studies.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside.

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Characterisation of the onset and severity of adrenal and thyroid dysfunction associated with CTLA4-related hypophysitis.

The use of the CTLA4 inhibitor, ipilimumab, has proven efficacious in the treatment of melanoma, renal carcinoma and non-small cell lung cancer; however, it is associated with frequent immune-related adverse events (irAE). Ipilimumab-induced hypophysitis (IIH) is a well-recognised and not infrequent endocrine irAE. To investigate the timing of onset and severity of adrenal and thyroid hormone dysfunction around the development of IIH in patients treated for melanoma. Aretrospective review of hormone levels in consecutive adult patients treated with ipilimumab (3 mg/kg) for advanced melanoma as monotherapy or in combination with a PD-1 inhibitor. Of 189 patients, 24 (13%; 13 males; 60.5 ± 12.2 years) presented with IIH at a median of 16.1 (range: 6.7-160) weeks after commencing treatment, occurring in 14 (58%) after the fourth infusion. At the presentation of IIH, corticotroph deficiency was characterised by an acute and severe decrease in cortisol levels to ≤83 nmol/L (≤3 μg/dL) in all patients, often only days after a previously recorded normal cortisol level. Free thyroxine (fT4) levels were observed to decline from 12 weeks prior to the onset of cortisol insufficiency, with the recovery of thyroid hormone levels by 12 weeks after the presentation of IIH. A median fall in fT4 level of 20% was observed at a median of 3 weeks (IQR: 1.5-6 weeks) prior to the diagnosis of IIH. IIH is characterised by an acute severe decline in cortisol levels to ≤83 nmol/L at presentation. A fall in fT4 can herald the development of ACTH deficiency and can be a valuable early indicator of IIH.

Effects of tubastatin A on adrenocorticotropic hormone synthesis and proliferation of AtT-20 corticotroph tumor cells.

Cushing's disease is an endocrine disorder characterized by hypercortisolism, mainly caused by autonomous production of ACTH from pituitary adenomas. Autonomous ACTH secretion results in excess cortisol production from the adrenal glands, and corticotroph adenoma cells disrupt the normal cortisol feedback mechanism. Pan-histone deacetylase (HDAC) inhibitors inhibit cell proliferation and ACTH production in AtT-20 corticotroph tumor cells. A selective HDAC6 inhibitor has been known to exert antitumor effects and reduce adverse effects related to the inhibition of other HDACs. The current study demonstrated that the potent and selective HDAC6 inhibitor tubastatin A has inhibitory effects on proopiomelanocortin (Pomc) and pituitary tumor-transforming gene 1 (Pttg1) mRNA expression, involved in cell proliferation. The phosphorylated Akt/Akt protein levels were increased after treatment with tubastatin A. Therefore, the proliferation of corticotroph cells may be regulated through the Akt-Pttg1 pathway. Dexamethasone treatment also decreased the Pomc mRNA level. Combined tubastatin A and dexamethasone treatment showed additive effects on the Pomc mRNA level. Thus, tubastatin A may have applications in the treatment of Cushing's disease.

Adrenal function during long‐term ACTH therapy for patients with developmental and epileptic encephalopathy

Some patients with developmental and epileptic encephalopathy (DEE) respond to adrenocorticotropic hormone (ACTH) therapy but relapse soon after. While long‐term ACTH therapy (LT‐ACTH) has been attempted for these patients, no previous studies have carefully assessed adrenal function during LT‐ACTH. We evaluated the effectiveness of LT‐ACTH, as well as adverse effects (AE), including their adrenal function in three DEE patients. Patients underwent a corticotropin‐releasing hormone (CRH) stimulation test during LT‐ACTH, and those with peak serum cortisol below 15 μg/dL were considered to be at high risk of adrenal insufficiency (AI). Two of three responded, and their life‐threatening seizures with postgeneralized electroencephalogram (EEG) suppression decreased. Although no individuals had serious AE, CRH stimulation test revealed relatively weak responses, without reaching normal cortisol peak level (18 μg/dL). Hydrocortisone replacement during stress was prepared in a case with lower cortisol peak than our cutoff level. LT‐ACTH could be a promising treatment option for cases of DEE that relapse soon after effective ACTH treatment. The longer duration and larger cumulative dosage in LT‐ACTH than in conventional ACTH could increase the relative risk of AI. Careful evaluation with pediatric endocrinologists, including hormonal stimulation tests, might be useful for continuing this treatment safely.

УРОВЕНЬ КОРТИЗОЛА У ПОТЕНЦИАЛЬНЫХ ДОНОРОВ ОРГАНОВ

Currently, the need for the administration of corticosteroids to restore the normal adrenal function in patients with brain death (BD) in order to condition the functional systems before organ harvesting remains unclear. Objectives. To analyze the level of cortisol in potential donors with brain death before harvesting their organs and tissues for transplantation. Material and methods. A prospective pilot study included 60 patients with brain death. The average age of a patient with brain death was 53.5 (48.5; 58.5) years, males - 32 (53.3%) years, females - 28 (46.7%) years. The causes of brain death were: intracerebral hemorrhage - in 30 (50%) patients, traumatic brain injury - in 10 (16.7%) patients, subarachnoid hemorrhage - in 7 (11.7%) patients, cerebral infarction - in 13 (21.6%) patients. The level of cortisol in the blood was determined by the method of radioimmune assay using a set of reagents UP «PP IBC NAS of Belarus» ( Minsk, Republic of Belarus). Results. The cortisol level in patients with BD was 422.8 (216.7; 687.1) nmol/L. The level of cortisol was lower than the reference values in 11 (18.3%) patients with BD, and higher - in 12 (20%) patients. There were no differences between the groups in terms of cortisol level in the following parameters: arterial blood pressure, heart rate, frequency of vasopressors use, dose of vasopressors, time from the patient’s admission to the moment of BD diagnosis, time of observation of a potential donor between two examinations of the council, the number of organs being harvested for transplantation. Conclusions. In potential donors with brain death with low cortisol level, the indices of arterial blood pressure and the doses of injected vasopressors did not statistically significantly differ from those in donors with normal and elevated cortisol level.

Feminizing adrenocortical adenoma in a girl from a resource-limited setting: a case report

BackgroundAn adrenocortical tumor is a rare tumor in pediatrics, which can be functional or nonfunctional. Functional tumors present with virilization, feminization, or hypercortisolism. Feminizing adrenal tumors, though rare in pediatrics, need to be excluded in any child presenting with features of feminization. Case presentationWe report a case of a 4-year-old Sudanese girl who presented with gradually progressive bilateral breast enlargement and accelerated growth since the age of 6 months. The family had sought medical advice several times in numerous health facilities without much gain. Investigations showed pubertal luteinizing hormone levels, high estradiol E2, and dehydroepiandrosterone sulfate, with normal early morning cortisol level. Abdominal ultrasound revealed a right-sided hypoechoic suprarenal mass. Abdominal computed tomography scan showed a right adrenal mass. The diagnosis of feminizing adrenal neoplasm was confirmed and right adrenalectomy was done. Histopathological examination of the resected adrenal gland showed adrenocortical adenoma. The patient was started on gonadotrophin-releasing hormone agonist for secondary central precocious puberty.ConclusionAdrenocortical tumors, though rare in pediatrics, are a documented cause of precocious puberty; biochemical and imaging screening protocol should be adopted for patients with precocious puberty, even in a resource-limited setting, for early detection and treatment.