Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)" , where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme -CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome" , peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway" , through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21-and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.
Purpose Most adrenal incidentalomas (AIs) are nonfunctioning adenomas (NFAs), but up to 30% may secrete cortisol autonomously without clinical evidence of Cushing syndrome (CS), which nevertheless may increase cardiovascular mortality. This subclinical hypercortisolism (SCH) is confirmed by cortisol resistance to a dexamethasone suppression test (DST). Cyclic cortisol secretion occurs in classic CS but was not reported in SCH. Objective Investigate cyclic cortisol production/autonomy in AIs using sequential DSTs. Methods A total of 251 patients with AI underwent 487 DSTs over 12 years; patients with at least three DSTs were selected. DSTs were validated by measuring serum dexamethasone. Cyclic SCH was defined when at least two abnormal and two normal DSTs were documented. Results A total of 44 patients had three or more DSTs during follow-up: 9 of 44 patients (20.4%) had all negative test results (post-DST cortisol ≤1.8 μg/dL) and were classified as NFA; another nine patients had all positive results (cortisol >1.8 μg/dL) and were classified as sustained SCH. The remaining 26 (59.2%) had discordant responses: 8 of 44 (18.3%) had at least two positive and two negative tests, matching the criterion for cyclic SCH, whereas 18 of 44 (40.9%) had only one discordant test and were classified as possibly cyclic SCH. Eleven of 20 (55%) patients initially classified as NFA did not maintain their cortisol pattern. Conclusions Extended follow-up with repeated DSTs uncovered an unusual subset of AIs with cyclic SCH. Recurring production of cortisol may affect determination of AI subtypes if based on just one DST. Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk.
Este é um guia que abrange os principais aspectos da fisiologia e da abordagem diagnóstica e terapêutica dos pacientes com doenças adrenais e hipertensão endócrina. Ao longo dos 29 capítulos, os autores adotam uma linguagem objetiva e que lança mão de fluxogramas, quadros e tabelas para maior absorção dos temas, todos eles em relação direta com as glândulas adrenais. Trazendo conhecimento e atualização científica de modo prático, o livro é mais um produto que a Sociedade Brasileira de Endocrinologia e Metabologia oferece a profissionais de saúde de todo o Brasil.
High blood pressure (BP) is not restricted to adults; children and adolescents may also be affected, albeit less frequently. Aside from unfavorable environmental factors, such as obesity and sedentary life leading to early-onset essential hypertension (HT), several secondary causes must be investigated in the occasional hypertensive child/adolescent. Endocrine causes are relevant and multiple, related to the pituitary, thyroid, parathyroid, gonads, insulin, and others, but generally are associated with adrenal disease. This common scenario has several vital components, such as aldosterone, deoxycorticosterone (DOC), cortisol, or catecholamines, but there are also monogenic disorders involving the kidney tubule that cause inappropriate salt retention and HT that simulate adrenal disease. Finally, a blood vessel disease was recently described that may also participate in this vast spectrum of pediatric hypertensive disease. This review will shed some light on the diagnosis and management of conditions, focusing on the most prevalent adrenal (or adrenal-like) disturbances causing HT.
Introduction: Ectopic ACTH production is a very unusual cause of Cushing Syndrome (CS). When it occurs, lung cancer is the main cause. Very rarely, this ectopic source of ACTH can arise from a Pheochromocytoma (Pheo). A recent literature review identified less than 100 cases described. We present a case of 28 years old woman who was referred for adrenalectomy for CS with notorious adrenal mass. However, during the investigation, ectopic ACTH due a Pheo was identified. Case Report: A 28-year-old woman required emergency care for ecchymosis and asymptomatic hypertension (BP: 230x130mmHg). Hyperpigmentation of the skin was evident on physical examination. Severe hypokalemia (K: 2.5mEq/liter) was detected. She denied taking any medication and was unaware of any previous illness. She always had normal BP measurements as well as laboratory tests. No family history of adrenal disease or secondary hypertension causes. During hospitalization, the hypothesis of CS was made and confirmed after: cortisol after 1mg dexamethasone: 44.5mcg/dl (<1.8mcg/dl) and 24h urinary free cortisol: 6228 mcg/dl (28-213mcg/dl). Concomitantly, a CT scan of the abdomen exhibited a left adrenal mass (3.1x2.8x3.5cm) of uncertain etiology and ACTH: 352pg/ml (<46pg/ml). Additionally, the patient presented hyperglycemia during hospitalization. After confirmation of the ACTH dependent CS, pituitary MRI was performed with normal results and a chest CT scan ruled out lung masses. As there was still no etiological confirmation and due to clinical deterioration, it was decided to start Ketoconazole 200mg/day, rising until 600mg and spironolactone with doses up to 250mg/day with a significant improvement in hypokalemia, decreased cortisol levels and optimal BP control. Due to the extremely high levels of ACTH and indeterminate adrenal mass, the hypothesis of ACTH ectopic due Pheo was postulated. Patient underwent abdomen MRI with left adrenal mass with hypersignal at T2 and urinary metanephrines levels: 6132mcg/24h (<289mcg/24h), urinary normetanephrines: 1808mcg/24h (<732mcg/24h). Once the diagnosis was elucidated, she received preoperative preparation with alpha blocker (Doxazosin) and underwent adrenalectomy without complications. After discharge, she received prednisone 10mg/day. The patient presented normalization of BP levels, as well as glycemic control with a slight improvement in skin hyperpigmentation. The pathology department confirmed Pheo and an ACTH expression was observed in immunohistochemistry. A genetic panel for Pheo is running with no results so far. Conclusion: Despite an extremely rare cause of CS, the ectopic production of ACTH by a Pheo has extremely high mortality rates, especially when not diagnosed or managed correctly. The clinicians must always remain alert and suspect this syndrome when the patient has a confirmed ACTH dependent CS associated with adrenal masses.
Background: The nuclear peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, distribution and function. Heterogeneous mutations of PPAR-γ can cause loss of gene function or reduce its expression leading to a clinical variety of phenotypes that characterize type 3 familial partial lipodystrophy syndrome. The most common features of this syndrome are abnormal body fat accumulation, muscle hypertrophy, insulin resistance, hypertriglyceridemia, polycystic ovary syndrome and hepatic steatosis. Case report: A 32-year-old-woman was referred to the Endocrinology Division of PUC-SP for treatment of a severe hypertriglyceridemia diagnosed 4 years ago with recurrent episodes of acute pancreatitis and eruptive xanthomas since then. Also, diabetes mellitus (DM) was diagnosed 1 year ago with poor glycemic control. Her sister also had severe hypertriglyceridemia, recurrent episodes of acute pancreatitis and died in 2016. No DM was reported in her family. On physical examination, we found the presence of lipodystrophy, acanthosis nigricans on the neck and eruptive xanthomas on trunk, upper limbs, and thighs. BMI=24.9kg/m2; waist circumference=96cm. Abdominal CT scan revealed splenomegaly and fatty liver disease. Genetic sequencing showed a heterozygous (autosomal dominant inheritance) in the PPAR-γ of a Chr3 variant: 12.416.957 T> C (or alternatively c.1073T> C - ENST000002287820), promoting the substitution of leucine in codon 358 by proline (p.Leu358Pro). Conclusion: The substitution of the amino acid leucine in codon 358 for proline is highly conserved in several species, and computer programs for predicting in silico of pathogenicity, suggesting that this new heterozygous mutation in the PPAR-γ gene is probably related to the type 3 familial partial lipodystrophy syndrome. Disclosure P. V. Wanderley: None. J. C. Dias: None. M. W. Vieira: None. G. Garcia: None. I. T. Filho: None. R. F. Chamma: None. L. S. Gugoni: None. R. B. Giorgi: None. C. R. G. Barcellos: None.
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