Pathophysiology
Summary
Cushing's syndrome results from excessive glucocorticoid excretion, which has multi-systemic effects. Exogenous glucocorticoids suppress adrenocorticotropic hormone (ACTH) through negative feedback, causing adrenal atrophy. Clinically, abnormal fat deposits manifest as central obesity, moon facies, and buffalo hump. Glucocorticoids induce hyperglycemia via gluconeogenesis and insulin resistance, potentially leading to type 2 diabetes.
Glucocorticoids also contribute to hypertension by increasing sodium reabsorption and catecholamine sensitivity, leading to vasoconstriction. Spironolactone, a mineralocorticoid receptor antagonist, can be useful for treating hypertension in these cases. Additionally, glucocorticoids cause skin changes like purple striae, muscle weakness, and osteoporosis by altering collagen, muscle, and calcium metabolism, respectively. The immune system is impaired, leading to increased infections, impaired wound healing, and increased neutrophil count.
Psychiatric symptoms such as depression, anxiety, & mood swings are common. Reproductive health is impacted via glucocorticoid inhibition of GnRH release, causing dysmenorrhea.
Cushing's disease is a form of Cushing's syndrome caused by an ACTH-secreting pituitary adenoma, leading to elevated ACTH and cortisol levels as well as bilateral adrenal hyperplasia. ACTH and MSH are both cleaved from POMC, resulting in excessive MSH and hyperpigmentation. ACTH-stimulation of the zona reticularis leads to hyperandrogenism, manifesting as hirsutism & acne in women.
In contrast, a cortisol-secreting adrenal tumor, either an adenoma or carcinoma, results in ACTH-independent Cushing's syndrome. This leads to decreased ACTH and adrenal atrophy in the zona fasciculata. Another ACTH-dependent form is due to an ectopic ACTH-secreting tumor, commonly found in lung cancers, causing similar adrenal changes as Cushing's disease.
Diagnosis often utilizes 24-hour urine free cortisol and late-night salivary cortisol tests. Pharmacological tests include the low and high dose dexamethasone tests; the former suppresses physiological hypercortisolism, while the latter can inhibit ACTH secretion in pituitary adenomas but is ineffective against ectopic ACTH-secreting tumors
Treatment for endogenous Cushing's syndrome is usually surgical tumor removal. In inoperable cases, drugs like ketoconazole, metyrapone, and mitotane can be used. Extreme cases may necessitate bilateral adrenalectomy, risking Nelson syndrome, a sudden drop in cortisol follow bilateral adrenalectomy leading to increased ACTH secretion, enlargement of the pituitary adenoma, and symptoms like headache, visual disturbances, & hyperpigmentation.
Lesson Outline
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FAQs
Exogenous glucocorticoids lead to decreased levels of adrenocorticotropic hormone (ACTH) through a negative feedback mechanism acting on the anterior pituitary gland. When the body detects the presence of these external hormones, it signals the pituitary gland to reduce ACTH secretion, as it interprets the hormone levels as sufficient. This ultimately leads to reduced stimulation of the adrenal glands.
Excessive glucocorticoids in Cushing's syndrome result in a variety of physical symptoms. These include central obesity due to insulin resistance and hyperglycemia, facial rounding known as "moon facies," and a fat deposit on the upper back and neck called a "buffalo hump." Additionally, patients may experience purple stretch marks, known as striae, and muscle weakness. The specific symptoms can vary depending on whether the syndrome is caused by endogenous or exogenous factors.
Excessive glucocorticoids can elevate blood glucose levels by promoting gluconeogenesis in the liver and causing insulin resistance. This can eventually lead to type 2 diabetes. Additionally, these hormones have some mineralocorticoid activity, which increases sodium reabsorption and fluid retention, contributing to hypertension. They also heighten cardiovascular sensitivity to catecholamines like epinephrine and norepinephrine, causing more significant vasoconstriction and further elevating blood pressure.
Endogenous Cushing's syndrome can arise from several sources. Cushing's disease is caused by an ACTH-secreting pituitary adenoma, leading to elevated ACTH and cortisol levels. Another cause is a cortisol-secreting adrenal tumor, which results in decreased ACTH due to negative feedback on the anterior pituitary, known as ACTH-independent Cushing's syndrome. Ectopic ACTH production, often from lung tumors, can also lead to endogenous Cushing's syndrome by causing elevated ACTH and cortisol levels.
Diagnosis of hypercortisolism in Cushing's syndrome can involve a 24-hour urine free cortisol test or a late-night salivary cortisol test. Dexamethasone suppression tests, both low and high dose, can also be used to evaluate the body's hormonal response. For treatment, surgical removal of the tumor is often the first-line option. If surgery is not feasible or effective, medications such as ketoconazole, mifepristone, metyrapone, and mitotane may be used. Bilateral adrenalectomy is a last-resort option, requiring lifelong glucocorticoid and mineralocorticoid replacement therapy.
