An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade.

The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.

Cushing's clips.

Together with Sir William Macewen (1848-1924) and Sir Victor Horsley (1857-1916), Harvey Cushing (1869-1939) is recognised as one of the triumvirate of founders of the speciality of neuosurgery.

Cushing's syndrome from bedside to bench and back: a historical perspective.

This article focuses on the development of Cushing's syndrome as a clinical entity, a process that has moved from bedside to bench and back again.

"Osler's phenomenon": misdiagnosing Cushing's syndrome.

The clinical manifestations of Cushing's syndrome can be quite variable and are frequently mistaken, with consequent delayed diagnosis and significant morbidity and mortality. Harvey Cushing described the typical signs and symptoms of Cushing's syndrome but unfortunately attributed the features to myxoedema. The first typical description of a patient with Cushing's syndrome was probably made by Sir William Osler in 1898. Thus delay or misdiagnosis with consequent high morbidity and mortality exemplifies the history of Cushing's syndrome. Four cases of Cushing's syndrome are described that were associated with deteriorating morbidity because of the considerable delay from first presentation to a secondary care physician to eventual diagnosis. The clinical diagnosis was delayed in all the four patients, although they had symptoms and signs that were missed by a number of primary and secondary care physicians. Trans-sphenoidal surgery resulted in biochemical cure as well as improvement in the accompanying co-morbidity. Although still rare, the prevalence of Cushing's syndrome is increasing. Increasing clinical awareness and the use of appropriate screening tests should facilitate earlier diagnosis with reduced morbidity and mortality. Although the syndrome is named after Harvey Cushing, Sir William Osler was probably the first to describe it. Therefore, in deference to Osler's contribution to Cushing's syndrome and the work of Harvey Cushing, it is suggested that to the list of the other eponymous conditions of Osler-Weber-Rendu and Osler's nodes, should be added the delay or misdiagnosis of Cushing's syndrome-"Osler's phenomenon".

Cushing's case XLV: Minnie G.

A 23-year-old patient who was examined in 1910 by Harvey Cushing triggered his lifelong interest in the syndrome that bears his name. "Minnie G.," as she became historically known, presented with a "...syndrome of painful obesity, hypertrichosis, and amenorrhea with overdevelopment of secondary sexual characteristics accompanying a low grade of hydrocephalus and increased cerebral tension." This case stimulated Harvey Cushing's inquisitive mind and sparked an interest that 20 years later culminated in his seminal report, "The basophil adenomas of the pituitary gland and their clinical manifestations (pituitary basophilism)." In this classic work, Cushing reported in detail the cases of two patients encountered from his own practice and 10 similar cases collected from the literature. Minnie G. was the first case that Cushing reported. The clinical course of that case is briefly reviewed in this article.

Cushing's syndrome: historical aspects.

A brief overview of the most important steps leading to our present knowledge of hypercorticism is given. The adrenals were described in 1563 and the pituitary had been known since Antiquity. Until Addison's description of adrenal insufficiency in 1855 virtually nothing was known of their function. Cushing in 1912 described his famous patient with hypercorticism but assumed it to be a polyglandular disorder. For almost 40 years the etiology was disputed, though Bauer early had postulated that hypercorticism ultimately reflected adrenal hyperfunction, either primarily or secondarily. Though Krause, Schloffer, Cushing, Hirsch and others early in the 20th century had introduced pituitary surgery, it was not until 1933 that the first patient with Cushing's disease had neurosurgery performed. This therapy did not gain wide acceptance until Gidot & Thibaut and Hardy pioneered transsphenoidal surgery. Adrenal surgery was for many years the treatment of hypercorticism but prior to the availability of glucocorticosteroids substitution an extremely perilous undertaking.

How to learn from patients: Fuller Albright's exploration of adrenal function.

Fuller Albright (1900-1969) was acknowledged as the preeminent clinical and investigative endocrinologist of his day by many of his contemporaries, but his many achievements are all but unknown to the present generation of physicians. This article describes how he used his clinical knowledge and a few tools--the measurement of urinary 17-ketosteroid excretion and the administration of methyltestosterone--to elucidate the major hormonal functions of the adrenal cortex and to clarify the pathophysiology of the Cushing syndrome. In addition, in a tour de force of clinical reasoning, he predicted, 5 years before the event, the discovery of a hormone that would reverse the endocrinologic abnormalities of congenital adrenal hyperplasia. Fittingly, he and pioneer pediatric endocrinologist Lawson Wilkins were the first to treat this disease successfully with cortisone.

The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism.

The case of Harvey Cushing's historical patient, Minnie G, is now closed. Recent investigation has succeeded in identifying her, locating her death certificate, and finding her family. Information learned about the patient's personality is consistent with Cushing's assertion that her syndrome, although ameliorated, was persistent. The cause of her Cushing's syndrome remains unknown.