A Physiologic Approach to Diagnosis of the Cushing Syndrome

A Physiologic Approach to Diagnosis of the Cushing Syndrome

Hershel Raff, PhD; and
James W. Findling, MD

From St. Luke's Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE

Co-sponsored by the American College of Physicians and the American Physiological Society

Physiology in Medicine: Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD, Associate Editor; William J. Koopman, MD, Associate Editor

Annals of Internal Medicine: Paul Epstein, MD, Series Editor

Clinical Principles*

General

Obesity
Hypertension

Metabolic

Diabetes mellitus or impaired glucose tolerance
Hyperlipidemia
Nephrolithiasis
Polyuria

Skin

Plethora
Hirsutism
Striae
Acne
Bruising

Musculoskeletal

Osteopenia or osteoporosis
Proximal myopathy

Neuropsychiatric

Depression
Cognitive impairment
Emotional lability
Euphoria
Psychosis

Gonadal dysfunction

Oligomenorrhea or amenorrhea
Impotence, decreased libido

Immune suppression (susceptible to opportunistic infection)

*Notice that many of the features of the Cushing syndrome resemble those of the metabolic syndrome (e.g., obesity, hypertension, impaired glucose tolerance, hyperlipidemia, hirsutism, acne, and gonadal dysfunction).

Pathophysiologic Principles

The hypothalamic–pituitary–adrenal axis
Control of adrenal function and growth
Hypothalamic control of pituitary function
Glucocortcoid-negative feedback
Circadian rhythm
The stress response
Posttranslational processing of proopiomelanocortin to adrenocorticotropic hormone
Cortisol plasma binding, metabolism, and excretion
Glucocorticoid action
11β-hydroxysteroid dehydrogenase type 1 and 11β-hydroxysteroid dehydrogenase type 2

The relationship among obesity, impaired glucose tolerance or diabetes, hypertension, and gonadal dysfunction was initially recognized in two clinical syndromes described early in the 20th century. In 1932, Harvey Cushing reported these findings as well as other featu•res of endogenous hypercortisolism in patients with small basophilic pituitary adenomas (1). A decade earlier, two French physicians, Drs. Archard and Thiers, described a similar phenotype in the syndrome that is now recognized as the syndrome of insulin resistance (the metabolic syndrome) and the polycystic ovary syndrome (2).

Recently, increasing evidence has shown that the Cushing syndrome is a reversible cause of the metabolic syndrome (3) and that it may be more common than previously thought. Some patients with incidentally discovered adrenocortical tumors have …

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