Negative Feedback Regulation of Hormone Release in the Hypothalamic-Pituitary Axis

Negative Feedback

One distinctive feature of hormones whose secretion is regulated through the hypothalamus and pituitary is that they regulate their own secretion through negative feedback inhibition. What this means is that a hormone from a peripheral gland, for example, cortisol, binds to its receptor on cells in the hypothalamus and adenohypophysis, and has the effect of inhibiting secretion of tropic hormones: in this case, CRH (corticotropin releasing hormone) and ACTH (adrenocorticotropic hormone). Less CRH secretion leads to less ACTH secretion, which leads to less stimulation of cortisol secretion by cells of the zona fasciculata of the adrenal cortex.

The usefulness of negative feedback inhibition is that it results in "hormonal homeostasis", that is the maintenance of hormone levels within a particular appropriate physiological range. Consider a case where one adrenal gland is damaged. This will cause decreased secretion of cortisol. There will be a decrease the degree of negative feedback inhibition on the hypothalamus and anterior pituitary. The release from negative feedback inhibition means that more CRH and ACTH will be secreted. More ACTH will stimulate the remaining adrenal tissue to grow and to secrete more cortisol. This will have the effect of bringing cortisol back up towards its normal daily level of secretion.

Disorders of Secretion

An important place to consider negative feedback inhibition is in evaluating disorders of secretion. In order to accurately determine the cause of abnormal hormone secretion, one needs to look not only at the hormone in question, but also the tropic hormone from the anterior pituitary that regulates its secretion. This is illustrated in the table for disorders of cortisol secretion.

Cushing's syndrome is the name given to hypersecretion of cortisol (or hypercortisolism). Cushing's syndrome frequently causes a very characteristic type of central obesity. Hypercortisolism also causes insulin resistance (which can lead to the development of type 2 diabetes mellitus), excessive bone resorption (which can lead to osteoporosis), and hypertension.

When Cushing's syndrome is due to a tumor in the adrenal cortex, increased negative feedback inhibition has the effect of decreasing secretion of tropic hormones. Therefore, the level of ACTH will be low.

Alternatively, Cushing's syndrome might result because of hypersecretion of ACTH. In fact, Cushing's syndrome is more commonly caused by a pituitary adenoma (a pituitary tumor), than by an adrenal tumor. Cushing's syndrome caused by a pituitary adenoma is known as Cushing's disease. In Cushing's disease, both ACTH and cortisol levels will be high.

Hyposecretion of cortisol is known as adrenal insufficiency. Primary adrenal insufficiency is the term for the disorder when the problem originates in the adrenal gland. If there is generalized damage to the adrenal cortex, there will also be hyposecretion of aldosterone, the steroid hormone that regulates Na⁺ and K⁺ balance in the extracellular fluid. Adrenal insufficiency involving hyposecretion of both cortisol and aldosterone is known as Addison's disease. In primary adrenal insufficiency, there is a release of the pituitary from negative feedback inhibition, and consequently, ACTH levels are high.

Secondary adrenal insufficiency (or hypopituitary adrenal insufficiency) describes the situation where abnormally low ACTH levels lead to hyposecretion of cortisol. Interestingly, this can occur after the end of high dose glucocorticoid therapy (glucocorticoid is the name for a molecule that is a glucocorticoid receptor agonist; the glucocorticoid receptor is the receptor for cortisol). Glucocorticoids are used therapeutically to treat inflammation and autoimmune diseases.

The diagram at left illustrates how glucocorticoids cause hypopituitary adrenal insufficiency. Chronic high levels of glucocorticoids lead to a supression of ACTH secretion that can sometimes persist for several months after glucocorticoid treatment stops. When the glucocorticoid therapy is discontinued, the result is hypocortisolism. Long-term suppression of the ACTH-secreting cells can be avoided by alternate-day dosing of glucocorticoids. Another strategy to avoid hypopituitary adrenal insufficiency is to gradually reduce the dosage of glucocorticoids before ending therapy.