Excessive Cortisol Production Research Articles

The Role of Decreased Expression of Glucocorticoid Receptors in the Development of Itsenko-Cushing Syndrome

Background: Itsenko-Cushing syndrome is caused by unregulated excessive cortisol incretion by the adrenal cortex. The causes of increased stimulation of cortisol incretion by the adrenal cortex, leading to hyperplasia and tumors (adenoma and cancer) of the adrenal cortex, as well as to adenoma of the pituitary gland itself, remain unclear to date. Materials and Methods: 6 patients with adrenal Itsenko-Cushing syndrome with adrenal cortex adenoma were under observation. The age of the patients ranged from 24 to 87 years. The patients underwent removal of the adrenal gland on the affected side. The control group consisted of 6 individuals who underwent surgical treatment of varicocele and hernias of various localization. In patients of the main group and control group, with their consent, a small fragment of skin from the edge of the surgical wound was taken for examination, which were fixed in a 10% formalin solution. Results: The presence of adrenal Itsenko-Cushing syndrome in patients of the main group was confirmed by laboratory and instrumental studies, as well as characteristic clinical manifestations. The average Histochemical score of the expression of glucocorticoid receptors (GR) of the skin in patients of the main group with Itsenko-Cushing adrenal syndrome was 2.7 times less than the same value in the control group. Conclusions: A decrease in the formation or absence of glucocorticoid receptors (congenital or acquired) blocks the negative feedback of cortisol suppression of corticoliberin production by the hypothalamus and ACTH-pituitary gland. The resulting excessive incretion of corticoliberin becomes the main link in pathogenesis of pituitary adenoma formation, and an excessive incretion of ACTH leads to the formation of cortical hyperplasia and tumors (adenomas, cancers) of the adrenal cortex. Unregulated excessive cortisol production by hyperplastic adrenal tissues or benign/malignant adrenal tumors leads to overcoming resistance to glucocorticoids and, according to the principle of negative feedback, suppresses the production of corticoliberin by the hypothalamus and ACTH-pituitary gland. As a result, the pituitary form of Itsenko-Cushing syndrome turns into an adrenal form with an unregulated increase in cortisol levels and a decrease in ACTH levels. Transfusion of the mononuclear fraction of peripheral blood obtained from healthy donors, which allows the pluripotent stem cells contained in it to partially replace the altered cells of all tissues of patients, is a promising method of treating patients with Itsenko-Cushing syndrome due to a hereditary decrease in the expression of glucocorticoid receptors.

Hyperprogesteronism associated with adrenocortical tumours in two dogs

AbstractA 9‐year‐old, entire, female, soft‐coated Wheaten terrier and a 7‐year‐old, male, neutered greyhound were presented for clinical signs suggestive of hyperadrenocorticism (polyuria, polydipsia, and in the first case, polyphagia and weight gain). Adrenocorticotrophic hormone stimulation test and low‐dose dexamethasone suppression test ruled out excessive production of cortisol. Imaging (abdominal ultrasound and computed tomography) revealed an adrenal mass in both cases. Further hormonal testing revealed hyperprogesteronism. In the first case, surgical treatment was not considered due to vascular invasion of the mass, the patient was treated successfully with trilostane and was still stable 18 months later. In the second case, adrenalectomy was performed, and the clinical signs resolved, the dog was stable 10 months later. We report two clinical cases of progesterone‐secreting adrenocortical tumours and their management.

The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders.

Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer's and Parkinson's, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

SAT323 Management Of Severe Cushing’s Syndrome Due To Cortisol Secreting Adrenal Tumor In A Critically Ill Patient

Abstract Disclosure: H. Obeid: None. E.D. Buras: None. T. Else: None. Introduction: Severe Cushing’s syndrome is associated with multiple life threatening complications. Clinical Case: A 69 year-old man with Cushing’s syndrome was admitted to the hospital with septic shock due to bacteremia with necrotic left lower extremity infection. He required above knee amputation. His hospital course was complicated with invasive pulmonary Aspergillosis and ventilator associated pneumonia. He developed acute kidney injury that required dialysis, altered mental status, deep venous thrombosis bilateral pulmonary embolisms, bleeding duodenal ulcer and retroperitoneal hematoma. Prior to admission: Random cortisol was 31.7 mcg/dL (Normal: 4.8-19.5 mcg/dL), AM Cortisol following 1 mg oral dexamethasone was 47 mcg/dL (Normal: <1.8 mcg/dL), DHEA-s was 210 mcg/dL (normal: 33.6-249 mcg/dL) and 24 hour urine free cortisol was 622 mcg/day (Normal: <60 mcg/day). ACTH was undetectable. An FDG-PET scan showed a 6.5 centimeters hypermetabolic left adrenal mass with internal coarse calcifications but no evidence of metastasis. Etomidate drip, Metyrapone and Osilodrostat were tried to lower excess cortisol production. During admission while on Osilodrostat: Cortisol level: 20 mcg/dL (normal: 8-19 mcg/dL). Deoxycorticosterone: 53 ng/dL (Normal: 2-19 ng/dL). 11-Desoxycortisol: 580 ng/dL (Normal: 12-158 ng/dL). 17-alpha-hydroxyprogesterone: 45 ng/dL (Normal: 27-199 ng/dL). Surgery was considered, but adrenalectomy was deemed high risk and not pursued. Therefore, the patient underwent computed tomography (CT) cryoablation of the left adrenal gland. Labs following cryoablation: Cortisol: 7.7 mcg/dL. Deoxycorticosterone: 10 ng/dL. 11-Desoxycortisol: 34 ng/dL. 17-alpha-hydroxyprogesterone: 25 ng/dL. The procedure was complicated by T11/T12 intercostal artery injury leading to hemothorax. He was continued on physiologic doses of hydrocortisone. On follow up 4 weeks following discharge, he had complete resolution of hypercortisolism symptoms. A repeat whole body PET scan showed persistent FDG-avid neoplasm in left adrenal area, as well as metastasis in the liver and the duodenum. Conclusion: It is critical to control hypercortisolism in patients with Cushing’s syndrome. Several medications can be used. Surgical adrenalectomy remains the gold standard for treatment. CT-guided cryoablation of the adrenal tumor is a reasonable alternative when patient is not a surgical candidate. However, it is not a completely benign procedure as it can be associated with complications. Our treatment approach improved short term outcome for our patient, but did not provide long term benefit since he developed metastasis. Presentation: Saturday, June 17, 2023

Clinical, Radiological, and Histopathological Characteristics of a Patient with a Pituitary Tumor of the Corticotrophinoma Type — Case Report

Introduction. Cushing disease is a rare but severe endocrine disorder. It is caused by a pituitary tumor producing excessive amounts of adrenocorticotropic hormone (ACTH) which is subsequently responsible for excessive production of cortisol in the adrenal glands. Hypercortisolism manifests with many symptoms and disorders that affect numerous organs.
 Aim. To increase knowledge among nursing staff about the symptoms, causes, and treatment of patients with Cushing disease.
 Case Report. A 40-year-old patient with a history of infertility treatment was admitted to the Clinical Department of Neurosurgery of St. Raphael Hospital in Krakow due to a pituitary tumor. For 7 years the patient had been experiencing symptoms such as weight gain, excessive tiredness, and menstrual disorders. The MRI examination of the pituitary showed a tumor in the sella turcica with dimensions of 4.5×5.5×4.5 mm. The histopathological examination revealed corticotropic pituitary adenoma (positive for ACTH). The patient underwent surgery after which symptoms of hypercortisolism decreased and menstruation returned. The patient became pregnant and gave birth to a child.
 Discussion. A proper diagnosis in this patient’s case could protect her from development of many complications related to other organs, such as diabetes mellitus or hypertension.
 Conclusions. Cushing disease remains in some cases undiagnosed for many years. The patient is being referred to various specialists (ophthalmologist, gynecologist, rheumatologist) due to symptoms that are in fact complications of hypercortisolism. The case illustrates the importance of early recognition of the main symptoms of hypercortisolism. Such clinical skill would undeniably help to refer the patient to the appropriate specialist, i.e., an endocrinologist much earlier, and thus establish the correct diagnosis and implement appropriate treatment. (JNNN 2023;12(3):134–139)

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

Calcinosis cutánea en un perro con hipercortisolismo: Reporte de caso

Cutaneous calcinosis in dogs is a dermatological condition that involves the deposition of calcium salts in the animals' skin. Its etiology has not yet been fully established, but it is believed that genetic, nutritional and metabolic factors may play an important role in the development of the disease. It is divided into four subtypes, according to its pathogenesis: dystrophic; metastatic; idiopathic and iatrogenic, with dystrophic being the most common. Hypercortisolism, also known as Cushing's syndrome, is one of the main causes of cutaneous calcinosis in dogs. In this condition, there is excessive production of cortisol by the adrenal glands, leading to a series of metabolic, immune and inflammatory changes that contribute to the formation of calcium deposits in the skin. Symptoms can vary, but they usually manifest as the formation of hard, white subcutaneous nodules that may ulcerate or leak creamy material. Diagnosis is performed through clinical and laboratory examinations, such as cytology of the nodules, biopsy, and laboratory tests. Treatment aims to control the underlying disease and provide local care, but it is quite challenging as there is no specific established therapy. This study aimed to report the case of a dog diagnosed with hypercortisolism, presenting secondary cutaneous calcinosis.

Advances in Molecular Pathophysiology and Targeted Therapy for Cushing's Disease.

Cushing's disease is caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from corticotroph pituitary neuroendocrine tumors. As a result, excess cortisol production leads to the overt manifestation of the clinical features of Cushing's syndrome. Severe complications have been reported in patients with Cushing's disease, including hypertension, menstrual disorders, hyperglycemia, osteoporosis, atherosclerosis, infections, and mental disorders. Cushing's disease presents with a variety of clinical features, ranging from overt to subtle. In this review, we explain recent advances in molecular insights and targeted therapy for Cushing's disease. The pathophysiological characteristics of hormone production and pituitary tumor cells are also explained. Therapies to treat the tumor growth in the pituitary gland and the autonomous hypersecretion of ACTH are discussed. Drugs that target corticotroph pituitary neuroendocrine tumors have been effective, including cabergoline, a dopamine receptor type 2 agonist, and pasireotide, a multi-receptor-targeted somatostatin analog. Some of the drugs that target adrenal hormones have shown potential therapeutic benefits. Advances in potential novel therapies for Cushing's disease are also introduced.

An adrenal incidentaloma that had appeared to produce dehydroepiandrosterone-sulfate in excess before immunohistochemical study of the tumor.

Adrenal incidentaloma is a clinically unapparent adrenal mass more than one cm in diameter detected during imaging performed not for adrenal disease. A 34-year-old man was evaluated for AI with a diameter of 3.5 cm in the left adrenal. He was obese with body mass index of 33,9. Blood pressure was 110-120/90 mmHg. The general laboratory tests were unremarkable. An adrenal hormone screening set revealed that ACTH was 6.9 pg/mL, cortisol 14.9 μg/dL, renin activity 0.9 ng/mL/h, aldosterone 79.4 pg/mL, dehydroepiandrosterone-sulfate (DHEA-S) measured on two occasions 5,217 ng/mL and 6,477 ng/mL (gender- and age-adjusted reference values, 1,060-4,640 ng/mL). The levels of metanephrine and normetanephrine were normal. The tumor was thought to produce solely DHEA-S. The excised left adrenal tissue contained a tumor with a diameter of 26 mm and neighboring adrenal tissue. The tumor consisted mostly of acidophil cells without necrosis, capsular or vascular invasion, and mitosis. Immunohistochemical study revealed followings: the cells of the tumors were stained positive for 3β-hydroxysteroid dehydrogenase, and 17α-hydroxylase, and 11β-hydroxylase, weakly positive for DHEA sulphotransferase, and negative for aldosterone synthetase. The atrophy of neighboring tissue was presumably caused by excess cortisol production. Four months after surgery, the cortisol level was 11.2 μg/dL and DHEA-S level 1,462 ng/mL. The tumor is considered to be a cortisol-producing adenoma with modestly excessive DHEA-S production rather than isolated DHEA-S-producing adenoma. Immunohistochemical study of steroidogenic enzymes is a valuable addition to blood hormone measurement to clarify steroid production profile.

Secondary arterial hypertension and endogenous hypercortisolism in general medical practice

Arterial hypertension (AH) is a widespread syndrome in clinical practice. In most cases, the blood pressure increase is essential (primary) in nature. Meanwhile, many clinical situations require exclusion of secondary AH due medications and other substances, renal, endocrine, cardiovascular, neurological pathology. A special place in the structure of the endocrine AH is engaged in pathology caused by excessive production of cortisol. Despite its heterogeneous origin, endogenous hype rcortisolism (EH) has a certain similarity in clinical manifestations. The article describes two clinical cases of AH in 32-year-old women with different pathogenetic variants of endogenous hypercortisolism (EH). The presented medical histories are the basis for the discussion of features of the clinical and laboratory manifestations of EH, principles of the differential diagnos is and modern approaches to treatment. The aim of this publication is to draw attention of doctors of various specialties to early detection of EH, the timely elimination of which significantly improves the quality and increases the life expectancy of patients.

ODP340 NOVEL THERAPY OSILODROSTAT AS AN OPTION FOR RECURRENT CUSHING'S DISEASE

Abstract Introduction Cushing's Disease (CD) denotes a pathologic endogenous hypercortisolism secondary to excessive adrenocorticotropic hormone (ACTH) production. Cushing Disease is a rare condition with an estimated incidence of approximately 1.2-1.4 new cases / 1. 000. 000 per year. Although surgical intervention is the gold standard in the management of CD, many patients may present persistence or recurrence of disease despite surgical intervention, resulting in significant deterioration of their quality of life (QoL). For those in whom pituitary surgery is not an option or has not been curative, medical therapies have been developed. One of these newer treatments is the drug Osilodrostat, an inhibitor of the enzyme 11-beta-hydroxylase, responsible for the final step of cortisol biosynthesis in the adrenal glands. Case Discussion Case of a 21 year-old female patient with history of Cushing's Disease status post-transsphenoidal surgery (TSS) in 2017, obesity and oligomenorrhea who presented to our clinics showing signs and symptoms of hypercortisolism despite previously documented post-surgical remission in 2017. Patient reported recent development of acne, weight gain, round face, elevated blood pressure and mood changes. At the moment of evaluation, her most recent MRI showed post-surgical changes without a discrete lesion. Work-up was compatible with recurrence of Cushing's with an ACTH at 75pg/mL (nl, 10-60pg/mL), urinary free cortisol (UFC) at 1,122mcg/24h (nl, 4-50mcg/24h) and serum morning cortisol at 24. 0mcg/dL (nl, 5-20mcg/dL). In view of a negative MRI for a pituitary lesion, a Bilateral Inferior Petrosal Sinus Sampling (BIPSS) was performed. The BIPSS procedure revealed a pituitary source with a right pituitary lateralization suggestive of a right ACTH-producing tumor. The patient was consulted to Neurosurgery Service, but while waiting for repeat surgery, control of hypercortisolism was needed. The patient was started on Osilodrostat 2mg twice a day and was able to achieve normalization of UFC to 4mcg/24h, serum morning cortisol 5mcg/dL and late-night salivary cortisol (LNSC) of 30ng/dl (<90ng/dL) with significant improvement in her QoL, depression and clinical manifestations. The patient tolerated therapy well. Conclusion Cushing's Disease is a complex condition with potential serious complications if untreated. Even though TSS is the first line therapy, approximately 25% of patients show persistence of disease, and a similar proportion may experience recurrence. When surgery fails, medical treatment such as Osilodrostat, can temporarily suppress excessive cortisol production and ameliorate its clinical manifestations improving patients’ QoL while more definitive therapy is established. Presentation: No date and time listed

ODP303 Cushing's Syndrome Due to Ectopic Adrenocorticotropic Hormone-Secreting Metastatic Neuroendocrine Tumor

Abstract Introduction Cushing's syndrome (CS) due to ectopic ACTH secretion (EAS), is an infrequent form of ACTH-dependent CS. EAS results from unregulated ACTH secretion by neuroendocrine tumors (NETs) of various locations resulting in severe hypercortisolism. The progression of CS is usually precipitous. To improve outcomes, it is imperative to recognize early so that treatments of cortisol-induced comorbidities and targeted treatments can be initiated. Case Presentation A 74-year-old female presented to an outside hospital with fatigue, bilateral lower extremity edema and intractable hypokalemia. She was later transferred to our facility, where workup of CS was initiated. She underwent a 1mgdexamethasone suppression test (DST)which resulted in an unsuppressed 8amcortisol of 34.7 ug/dL (<2 ug/dL). This was followed by a 4mgDST, again resulting in an unsuppressed 8amcortisol of25.4 ug/dL. A 24-hour urine cortisol level was collected and resulted at 2,108.9 ug/d (<45 ug/d). ACTH level was elevated at 136 pg/ml (7.2-63.3 pg/ml). CT abdomen/pelvis identified liver lesions concerning for metastatic disease. PET DOTATATE revealed multiple liver lesions and a few pulmonary nodules. Biopsy of liver lesions demonstrated strongly positive staining of synaptophysin and chromogranin confirming NET, with a weak TTF-1 positivity suggestive of pulmonary origin. Lanreotide injections were initiated for tumor control and ketoconazole for treatment of persistent hypercortisolism. Despite titration of ketoconazole, symptoms and labs showed minimal improvement. Osilodrostat was then added as a third line and examethasone was initiated in a block and replace approach. The regimen of lanreotide, osilodrostat and ketoconazole improved her24-hoururine cortisol to 15 from 2,109 ug/24hr. Subsequently patient underwent trans-arterial chemoembolization (TACE) of the liver lesions with resolution of hypercortisolism. She is currently only on Lanreotide for tumor control. Discussion NET with ectopic ACTH production is rare. While primary tumor location was not definitively identified, multiple lung lesions and histopathology suggested primary lung tumor with hepatic metastases. 20-40% of all NETS originate in the chest. Patient management necessitates a multidisciplinary approach not only for the diagnosis and treatment of CS but also for the specific management of neuroendocrine tumors (NET). This case highlights a rare presentation of EAS, and aggressive treatment modalities needed to treat symptoms of excess cortisol production and tumor progression. Presentation: No date and time listed

Hyperadrenocorticism Treatment with High Dilution – Case Report

Background: Hyperadrenocorticism is a common endocrinopathy in dogs, associated to an excessive production or administration of cortisol. Aims: Report the evolution of homeopathic treatment in hyperadrenocorticism of a yorkshire male dog with 10 years old, analyzing with basal and post-acth stimulation cortisol values. Methodology: Homeopathic treatment was chosen, based on the principle of similitude and because it is efficient and less harmful for the patient using Ignatia amara associated to cortisol biotherapy to inhibit cortisol production and adrenal biotherapy to stimulate the gland response. The exposed information is consented by the tutor. Results: The dog was in convencional treatment with trilostane but didn’t response to the therapy, showing 5,41 μg/dL of basal result and 11,8 μg/dL of post-acth result and the symptoms were worst on 12/12/2021, presenting lethargic, panting, more evident alopecia and severe muscle weakness which the patient unable to stand. Therefore, the protocol was recommended for 3 months, included 3 globules of Ignatia amara 30cH orally, every 12 hours, 3 globules of cortisol biotherapy 30 cH and also of adrenal biotherapy 6 cH every 24 hours for 30 days. On 03/28/2022 the basal and post-acth stimulation results was 3,71 μg/dL e 5,79 μg/dL respectively and the patient was more active, the skin was better and even with difficulty it was moving and having more independence. Conclusion: Homeopathic treatment with high dilution proved to be effective, keeping the indices with the recommended range of post acth between 2.0 and 5.0, confirming an adequate therapeutic monitoring and symptomatic improvement.
 Keywords: Homeopathy, Biotherapy, Hyperadrenocorticism, Cortisol
 

Endogenous Cushing's syndrome during pregnancy.

Endogenous Cushing's syndrome (CS) is rare during pregnancy, probably because hypercortisolism induces anovulation and infertility. To date, slightly above 200 cases have been reported in the literature. The most frequent etiology of CS diagnosed during gestation is from primary adrenal causes, namely adrenal adenomas and an entity called pregnancy-induced CS. The latter can be secondary to the aberrant adrenal expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) in the adrenal lesions. Diagnosis of CS during pregnancy is extremely challenging, as a consequence of the physiologic hypercortisolism normally present during pregnancy. Assessment of excess cortisol production tests should be interpreted cautiously using adapted upper limits of normal criteria for pregnant patients and a high index of suspicion is required for diagnosis. Imaging is also limited due to high risk of radiation exposure with computed tomography and teratogenicity with contrast agents. The optimal treatment strategy is surgical resection of adrenal adenoma or pituitary adenoma, ideally before 24 weeks of gestation to reduce the risk of maternal and fetal complications. In mild cases, surgery can be postponed until after delivery and treatment should focus on controlling metabolic complications of hypercortisolism, such as hypertension and dysglycemia. Maternal and fetal outcomes of excess cortisol exposure, except fetal loss, are not readily improved by successful treatment of hypercortisolism.

Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk.

In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications. This study is a retrospective cross-sectional study. A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications. The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC. MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.

Association Between Cushing's Syndrome and Sleep Apnea: Results From the National Inpatient Sample.

BackgroundCushing’s syndrome is a metabolic disorder related to excess cortisol production. Patients with Cushing’s syndrome are at risk for the development of other comorbid medical conditions such as hypertension, diabetes, obesity, and obstructive sleep apnea. Obstructive sleep apnea has been well associated with endocrine disorders such as acromegaly and hypothyroidism. However, its causal association with Cushing’s syndrome is still unclear. We utilized a national database to study the prevalence of sleep apnea in Cushing’s syndrome.HypothesisWe hypothesized that patients with Cushing’s syndrome might have an increased prevalence of sleep apnea.MethodsPatients aged above 18 years from the NIS database between 2017 and 2018 with a diagnosis of Cushing’s syndrome and sleep apnea were extracted using the 10th revision of the International Classification of Diseases (ICD-10) codes, with code E24 representing Cushing’s syndrome and G47.3 representing sleep apnea. The prevalence of sleep apnea and other comorbid medical conditions were identified using the ICD-10 codes. Logistic regression analysis was performed to examine the association between Cushing’s syndrome and sleep apnea.ResultsCushing’s syndrome was prevalent in 0.037% (2,248 of 6,023,852) of all inpatient hospitalizations. Patients with Cushing’s syndrome were slightly younger (mean age: 54 ± 16 versus 58 ± 20) and more likely to be females (76%, 1,715 out of 2,248) and had higher rates of sleep apnea (21.9% versus 8.7%, p < 0.000) and obstructive sleep apnea (OSA) (18.6% versus 7.2%, p < 0.000) when compared to the general population. Cushing’s syndrome is independently associated with sleep apnea, with an unadjusted odds ratio (OR) of 2.94 (p < 0.01) and an adjusted odds ratio (aOR) of 1.79 after adjusting for demographics and other risk factors for sleep apnea and comorbid medical conditions (p < 0.01).ConclusionsCushing’s syndrome is associated with increased prevalence of sleep apnea and independent predictor of sleep apnea. Further prospective studies are recommended to validate the causal association. The high prevalence and coexistence of both these disorders validate screening for sleep apnea as part of routine workup in patients with Cushing’s syndrome and vice versa.

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.

Clinical Characteristics for the Improvement of Cushing's Syndrome Complicated With Cardiomyopathy After Treatment With a Literature Review.

Background: Endogenous Cushing's syndrome (CS), also called hypercortisolism, leads to a significant increase in mortality due to excessive cortisol production, which is mainly due to cardiovascular disease. CS complicated with cardiomyopathies, which is a rare and severe condition, has rarely been reported in the literature.Objective: To investigate the clinical characteristics of CS complicated with cardiomyopathies, we retrospectively reviewed the clinical manifestations, laboratory results, cardiac imaging results and prognosis to further understand the diagnosis, treatment, and management of these cases.Methods: The clinical data of patients diagnosed with CS complicated with cardiomyopathies obtained from discharge sheets from Peking Union Medical College Hospital from January 1986 to August 2021 were collected. Case reports of CS complicated with cardiomyopathies were retrieved from PubMed. In addition, Cushing's disease (CD) patients without cardiomyopathies were collected as controls to compare the clinical features.Results: A total of 19 cases of CS complicated with cardiomyopathies and cases of CD without cardiomyopathies (n = 242) were collected. The causes of CS included pituitary adenoma (n = 8, 42.11%), adrenal adenoma (n = 7, 36.84%), ectopic adrenocorticotropic hormone (ACTH) tumor (n = 2, 10.53%) and unclear causes (n = 2, 10.53%) in the CS complicated with cardiomyopathies group. The types of cardiomyopathies were dilated cardiomyopathies (n = 15, 78.94%) and hypertrophic cardiomyopathies (n = 4, 21.05%). The serum sodium concentration was significantly higher [145.50 (140.50–148.00) mmol/L vs. 141.00 (140.00–143.00) mmol/L], while the serum potassium concentration was significantly lower [2.70 (2.40–3.60) mmol/L] vs. 3.90 (3.50–4.20 mmol/L)] in the CS complicated with cardiomyopathies group compared to the CD patients without cardiomyopathies. There were no significant differences between the CS complicated with cardiomyopathies group and the CD patients without cardiomyopathies in the serum cortisol concentration and 24-h urine free cortisol, but a significant difference in the adrenocorticotropic hormone level [109.00 (91.78–170.30) pg/ml vs. 68.60 (47.85–110.00) pg/ml]. Twelve/16 (75.0%) patients showed significant improvement or even a complete healing of the heart structure and function after remission of hypercortisolemia after treatment with CS.Conclusions: CS complicated with cardiomyopathies is a very rare clinical entity, in which cortisol plays an important role and it can be greatly improved after remission of hypercortisolemia.

Metabolic profiling of serum from dogs with pituitary-dependent hyperadrenocorticism

Hyperadrenocorticism (HAC) is one of the most common endocrine diseases in dogs characterized by excessive cortisol production caused by an adrenocorticotropic hormone (ACTH)-secreting tumor, namely pituitary-dependent HAC (PDH) or cortisol-secreting adrenal tumor. Metabolomics presents the ability to identify small molecule metabolites. Thus, the use of metabolomics techniques in canine PDH can provide information about the pathophysiology and metabolic changes in this disease. This study aimed to identify and compare differences in serum metabolites between dogs with PDH and healthy dogs. The metabolomic profile of 20 dogs diagnosed with PDH was compared with 20 healthy dogs using liquid chromatography/mass spectrometry (LC/MS), and metabolite discrimination was performed using partial least squares-discriminant analysis (PLS-DA), the variable important in projection (VIP) and fold changes (FC) group-wise comparisons. The hypergeometric test identified the significantly altered pathways. A total of 21 metabolites were found to be significantly different between the two groups. The major alterations were found in arachidonic and decanoic acid, and phospholipids related to phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI). These metabolites are related to insulin resistance and other complications (i.e. hypertension). Our results indicate that PDH produces changes in serum metabolites of dogs, and the knowledge of these changes can aid to better understanding of pathophysiological processes involved and contribute to potentially detect new biomarkers for this disease.

Intratumoral steroid profiling of adrenal cortisol-producing adenomas by liquid chromatography- mass spectrometry

Endogenous Cushing syndrome (CS) is an endocrine disorder marked by excess cortisol production rendering patients susceptible to visceral obesity, dyslipidemia, hypertension, osteoporosis and diabetes mellitus. Adrenal CS is characterized by autonomous production of cortisol from cortisol-producing adenomas (CPA) via adrenocorticotropic hormone-independent mechanisms. A limited number of studies have quantified the steroid profiles in sera from patients with CS. To understand the intratumoral steroid biosynthesis, we quantified 19 steroids by mass spectrometry in optimal cutting temperature compound (OCT)-embedded 24 CPA tissue from patients with overt CS (OCS, n = 10) and mild autonomous cortisol excess (MACE, n = 14). Where available, normal CPA-adjacent adrenal tissue (AdjN) was also collected and used for comparison (n = 8). Immunohistochemistry (IHC) for CYP17A1 and HSD3B2, two steroidogenic enzymes required for cortisol synthesis, was performed on OCT sections to confirm the presence of tumor tissue and guided subsequent steroid extraction from the tumor. LC–MS/MS was used to quantify steroids extracted from CPA and AdjN. Our data indicated that CPA demonstrated increased concentrations of cortisol, cortisone, 11-deoxycortisol, corticosterone, progesterone, 17OH-progesterone and 16OH-progesterone as compared to AdjN (p < 0.05). Compared to OCS, MACE patient CPA tissue displayed higher concentrations of corticosterone, 18OH-corticosterone, 21-deoxycortisol, progesterone, and 17OH-progesterone (p < 0.05). These findings also demonstrate that OCT-embedded tissue can be used to define intra-tissue steroid profiles, which will have application for steroid-producing and steroid-responsive tumors.