Alternatively, it is proposed that the high levels of ACTH, β-lipotropin, and γ-lipotropin, which contain weak MSH function, can act on the melanocortin 1 receptor. A variant of Cushings disease can be caused by ectopic, i.e. extra pituitary, ACTH production from, for example, a small-cell lung cancer.When Cushings syndrome is caused by an increase of cortisol at the level of the adrenal glands (via an adenoma or hyperplasia), negative feedback ultimately reduces ACTH production in the pituitary. In these cases, ACTH levels remain low and no hyperpigmentation develops. Causes
Cushings syndrome may result from any cause of increased glucocorticoid levels, whether due to medication or internal processes. Some sources however do not consider the glucocorticoid medication-induced condition as "Cushings syndrome" proper, instead using the term "Cushingoid" to describe the medications side effects which mimic the endogenous condition.Cushings disease is a specific type of Cushings syndrome caused by a pituitary tumor leading to excessive production of ACTH (adrenocorticotropic hormone). Excessive ACTH stimulates the adrenal cortex to produce high levels of cortisol, producing the disease state. While all Cushings disease gives Cushings syndrome, not all Cushings syndrome is due to Cushings disease. Several possible causes of Cushings syndrome are known. Exogenous
The most common cause of Cushings syndrome is the use of prescribed glucocorticoids to treat other diseases (iatrogenic Cushings syndrome). Glucocorticoids are used in treatment of a variety of disorders, including asthma and rheumatoid arthritis, and also used for immunosuppression after organ transplants.
Finally, rare cases of CRH-secreting tumors (without ACTH secretion) have been reported, which stimulates pituitary ACTH production. Pseudo-Cushings syndrome
Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone, leading to pseudo-Cushings syndrome. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated. However, the total free cortisol, which is the active hormone in the body, as measured by a 24-hour urine collection for urinary free cortisol, is normal. Pathophysiology
The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on CRH in the hypothalamus, which decreases the amount of ACTH released from the anterior pituitary gland.Strictly, Cushings syndrome refers to excess cortisol of any etiology (as syndrome means a group of symptoms). One of the causes of Cushings syndrome is a cortisol-secreting adenoma in the cortex of the adrenal gland (primary hypercortisolism/hypercorticism).