Classic and current concepts in adrenal steroidogenesis: a reappraisal

ABSTRACT 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.

Actualización en el manejo clínico de la hipertensión hiporreninémica / Update in the clinical management of low renin hypertension

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.

Molecular Mechanisms of Primary Aldosteronism

Primary aldosteronism (PA) results from excess production of mineralocorticoid hormone aldosterone by the adrenal cortex. It is normally caused either by unilateral aldosterone-producing adenoma (APA) or by bilateral aldosterone excess as a result of bilateral adrenal hyperplasia. PA is the most common cause of secondary hypertension and associated morbidity and mortality. While most cases of PA are sporadic, an important insight into this debilitating disease has been derived through investigating the familial forms of the disease that affect only a minor fraction of PA patients. The advent of gene expression profiling has shed light on the genes and intracellular signaling pathways that may play a role in the pathogenesis of these tumors. The genetic basis for several forms of familial PA has been uncovered in recent years although the list is likely to expand. Recently, the work from several laboratories provided evidence for the involvement of mammalian target of rapamycin pathway and inflammatory cytokines in APAs; however, their mechanism of action in tumor development and pathophysiology remains to be understood.

Addison Disease: Early Detection and Treatment Principles.

Primary adrenal insufficiency, or Addison disease, has many causes, the most common of which is autoimmune adrenalitis. Autoimmune adrenalitis results from destruction of the adrenal cortex, which leads to deficiencies in glucocorticoids, mineralocorticoids, and adrenal androgens. In the United States and Western Europe, the estimated prevalence of Addison disease is one in 20,000 persons; therefore, a high clinical suspicion is needed to avoid misdiagnosing a life-threatening adrenal crisis (i.e., shock, hypotension, and volume depletion). The clinical manifestations before an adrenal crisis are subtle and can include hyperpigmentation, fatigue, anorexia, orthostasis, nausea, muscle and joint pain, and salt craving. Cortisol levels decrease and adrenocorticotropic hormone levels increase. When clinically suspected, patients should undergo a cosyntropin stimulation test to confirm the diagnosis. Treatment of primary adrenal insufficiency requires replacement of mineralocorticoids and glucocorticoids. During times of stress (e.g., illness, invasive surgical procedures), stress-dose glucocorticoids are required because destruction of the adrenal glands prevents an adequate physiologic response. Management of primary adrenal insufficiency or autoimmune adrenalitis requires vigilance for concomitant autoimmune diseases; up to 50% of patients develop another autoimmune disorder during their lifetime.

Secondary Hypertension Caused by Endocrine Disorders Except Primary Aldosteronism and Pheochromocytoma / 대한내과학회지

Secondary hypertension can account for 15% of hypertension cases. The causes of secondary hypertension mostly come from renal diseases, such as renal parenchymal or renovascular disease, and endocrine diseases. The importance of diagnosing secondary hypertension lies in the fact that it may convert an incurable disease into a potentially curable disease. Even if the underlying disease may not be curable, being able to offer disease specific treatments may often make blood pressure control much easier. The causes of endocrine hypertension include primary aldosteronism, pheochromocytoma, Cushing's syndrome, acromegaly, hyper- or hypothyroidism, hyperparathyroidism and other mineralocorticoid hypertension (e.g. apparent mineralocorticoid excess syndrome, Liddle's syndrome). Primary aldosteronsim, pheochromocytoma, and Cushing's syndrome are among the common causes of endocrine hypertension. The first step in evaluating a patient with suspected endocrine-related hypertension is to exclude other secondary causes, particularly renal disorders. An accurate diagnosis of endocrine hypertension provides the clinician a unique treatment opportunity. This topic review will summarize rare causes of endocrine hypertension except primary aldosteronism and pheochromocytoma.

Hipoadrenocortiiismo primario canino: reporte de caso / Canine priary hyypoadrenocorticism: case report

Un canino macho Cocker Spaniel de 6 meses de edad fue presentado a la Clínica para Pequeños Animales de la Universidad Nacional de Colombia, con historia de vómito y diarrea de una semana de duración. El paciente presentaba hiperkalemia, y los electrocardiogramas realizados fueron compatibles con este hallazgo. El diagnóstico de hipoadrenocorticismo primario fue confirmado mediante la realización de una prueba de estimulación con ACTH. Posteriormente a la muerte súbita del paciente, el examen microscópico de las glándulas adrenales reveló cambios histológicos compatibles con la enfermedad de Addison. El hipoadrenocorticismo primario es un desorden endocrino poco común que afecta principalmente pacientes caninos; está caracterizado por la destrucción inmunomediada de las cortezas adrenales, lo cual conduce a deficiencia de glucocorticoides, mineralocorticoides y hormonas sexuales adrenales. La historia de los pacientes afectados es variable y los signos clínicos son usualmente inespecíficos; las pruebas de laboratorio, por lo general, revelan hiperkalemia e hiponatremia, resultantes de la pérdida de la secreción de aldosterona. La historia, el examen clínico, la ecografía abdominal y los hallazgos de laboratorio pueden indicar enfermedad de Addison, sin embargo, la prueba de estimulación con hormona adrenocorticotrópica (ACTH) es considerada como la prueba de oro para el diagnóstico definitivo de la entidad. La enfermedad de Addison no tiene cura, pero puede ser manejada con terapia médica para reemplazar las deficiencias de mineralocorticoides y glucocorticoides.

Six month old, male Cocker Spaniel was presented to the Small Animal Clinic at the Universidad Nacional de Colombia with a one week history of vomiting and diarrhea. The patient was hyperkalemic and the electrocardiogram results were consistent with this finding. The diagnosis of primary hypoadrenocorticism was confirmed by performing an ACTH stimulation test. Following the patient’s sudden death, micros copic examination of the adrenal glands revealed histologic changes consistent with Addison`s disease. Primary hypoadrenocorticism is an uncommon endocrine disorder that primarily affects canine patients. The disorder is caracterized by the immune-mediated destruction of the adrenal cortices, resulting in mineralocorticoid, glucocorticoid and adrenal sex hormone deficiencies. Patient history is variable and clinical signs are often nonspecific; laboratory testing commonly reveals hyperkalemia and hyponatremia resulting from lack of aldosterone secretion. Clinical history, physical exam, abdominal ultrasound and laboratory findings may indicate Addison disease, however, the adrenocorticotrophic hormone (ACTH) stimulation test is considered to be the gold standard for definitive diagnosis of primary hypoadrenocortisism. Addison disease is not curable but can be managed with pharmaceutical therapy that replaces the mineralocorticoids and glucocorticoids deficiency.

Historia de los glucocorticoides / History of glucocorticoids

En este artículo hacemos una completa revisión de la Historia de los corticoides desde Thomas Addison quien describió las características de la enfermedad que lleva su nombre, pasando por Edward Kendall quien fue el primero en sintetizar el compuesto E o cortisona, Philipe Hench y su grupo quienes hicieron la aplicación clínica de los glucorticoides en una paciente con artritis reumatoide, hasta llegar a Meyer Hermann con los conceptos actuales sobre ciclo circadioano. Es una historia fascinante que nos permite conocer en detalle todos los pasos que llevaron al descubrimiento de los corticoides y su aplicación clínica en diferentes enfermedades como la artritris reumatoide y el lupus eritematoso sistémico.

In this paper we do a complete review of the history of steroids from Thomas Addison, who described the characteristics of the disease that bears his name, through Edward Kendall who was the first to synthesize the compound E or cortisone, Philipe Hench and his group who made the clinical application of glucocorticoids in a patient with rheumatoid arthritis, up to Hermann Meyer with current concept on circadian rhytms. It is a fascinating story that lets us know in detail all the steps that led to the discovery of steroids and its clinical application in various diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Corticoides: 60 años después, una asignatura pendiente / Corticoids: 60 Years Later a Pending Subject

El objetivo de este artículo es hacer una breve recopilación de la fisiología del eje hipotálamo-hipofisiario-suprarrenal, para comprender el papelde los corticoides exógenos como herramientas terapéuticas en innumerables patologías,que, utilizados de manera inapropiada, pueden causar efectos deletéreos importantes. La historia de los corticoides empezó hace 164 años, en 1843, cuando Thomas Addison describió los síntomas de la insuficiencia suprarrenal. Casi 100 años después, el 21 de septiembre de 1948, marcó un hito en la historia de la medicina, cuando, en la Clínica Mayo, el Dr. Hench inyectó 100 g de cortisona por primera vez en un paciente con artritis reumatoidea. En 1950, Hench, Kendall y Reichstein recibieron el Premio Nobel de Medicina y Fisiología. En la corteza de las glándulas suprarrenales se sintetizan, a partir del colesterol, tres hormonas diferentes con diversos efectos sobre la homeostasis. Los glucocorticoides sintéticos se clasifican por su potencia antiinflamatoria, vida media y efecto mineralocorticoide; operan en casi todas las células por medio de mecanismos de acción genómicos y no genómicos, lo que genera diferentes respuestas, de ahí su amplio efecto terapéutico en esclerosis múltiple, rechazo de trasplantes, enfermedades respiratorias, como asma y Epoc, entre otras.

The objective of this article is to make a brief compilation of the physiology of the hypothalamic-pituitary-adrenal axis in order to understand the role of the exogenous corticoids as therapeutic tools in innumerable pathologies, but when used inappropriately, it can produce important deleterious effects. The history of the corticoids began 164 years ago in 1843 when Thomas Addison described the symptoms of the adrenal gland insufficiency. On September 21st 1948, almost one hundred years after, Dr. Hench injected cortisone for the first time in a patient with arthritis. In 1950 Hench, Kendall and Reichstein received the Nobel Prize in Medicine and Physiology. In the cortex of the adrenal glands, three different hormones are synthesized from cholesterol, and these hormones produce diverse effects on the homeostasis of the body. The synthetic glucocorticoids are classified by their anti-inflammatory power, half life, and mineralocorticoid effect; they operate in almost every cell through genomic and non genomic mechanisms of action producing different responses. This is the reason of their wide therapeutic effect in respiratory diseases like asthma and COPD, multiple sclerosis, rejection of transplants, among others.