Secretion of hormones is regulated by a system of sensing elements that can detect the need for both increased and decreased secretion. The particular sensing network, feedback elements, and network of control responses are unique for each hormone.
Hormonal pathways maintain homeostasis, and adjustments in secretion usually result in changes that will help maintain the status quo. In addition, secretion and activity of a particular hormone may be adjusted upward or downward in response to challenges such as chronic stress, disease, or change in nutritional status.
The concept of negative feedback and its relationship to the control of hormonal pathways is important in understanding pathway regulation and evaluation of endocrine function tests. For example, insulin is released in response to an increase in the concentration of glucose bathing the beta cells in the pancreatic islets of Langerhans. One of insulin’s actions is to lower glucose concentrations in extracellular fluid by enhancing its uptake in target tissues. This decline in glucose leads to decreases in insulin secretion.
In patients suspected of having an insulin-secreting tumor (insulinoma Functional Islet Cell Tumors in Small Animals Islet cell tumors are the most common cause of hypoglycemia in older dogs. Clinical signs vary but often consist of weakness, ataxia, collapse and seizures. Diagnosis is by documenting hypoglycemia... read more ), the feedback relationship between insulin and glucose is lost. The finding of a low blood glucose concentration (hypoglycemia) together with an increased insulin concentration demonstrates inappropriate feedback, which is characteristic of such a tumor.
Understanding negative feedback is central to understanding a common disorder in dogs: hyperadrenocorticism (Cushing syndrome Cushing Syndrome (Hyperadrenocorticism) Cushing syndrome refers to any cause of elevated cortisol concentrations. Pituitary-dependent hyperadrenocorticism (PDH; Cushing disease) is the most common form of hyperadrenocorticism and... read more ; see Endocrine Diseases in Animals Endocrine Diseases in Animals Endocrine diseases are common in animals. They are more frequently diagnosed and treated in companion animals (dogs or cats) than in large animal species. Clinical signs and treatments vary... read more for additional discussion). In healthy dogs, corticotroph cells in the pituitary release ACTH into circulation, which in turn stimulates the release of cortisol from the adrenals.
In addition to its myriad biological effects on most tissues in the body, cortisol feeds back on corticotrophs to decrease ACTH secretion. This decrease, in turn, temporarily lowers cortisol secretion.
In pituitary-dependent hyperadrenocorticism (Cushing disease Cushing Disease (Pituitary-dependent Hyperadrenocorticism) in Animals Cushing disease is hyperadrenocorticism caused by an ACTH-secreting tumor of the pituitary gland. Clinical signs include polyuria, polydipsia, alopecia, and muscle weakness. A low-dose dexamethasone... read more )—the most common form of hyperadrenocorticism in dogs—corticotroph cells form a small (often micro-sized) adenoma in the pituitary that secretes excess ACTH. Over time, this increased ACTH results in bilateral adrenal enlargement and increased cortisol secretion, which mediates the development of characteristic clinical signs of the disease.
By an unknown mechanism, the corticotroph adenoma develops a relative (or in some cases total) resistance to the negative feedback effect of cortisol (this characteristic of the disease is central to the ability of dexamethasone suppression tests to diagnose it). Thus, the body is affected by a sustained elevation in cortisol concentrations.
Functional adrenocortical tumor is a much rarer cause of hyperadrenocorticism. In these cases, dogs develop a benign or malignant tumor in one adrenal cortex. These tumors autonomously secrete excess cortisol, resulting in clinical signs of hyperadrenocorticism and, in addition, a high amount of negative feedback to the otherwise normal corticotrophs.
The negative feedback suppresses ACTH secretion, often resulting in very low concentrations of the hormone in circulation. Low ACTH, in turn, leads to atrophy of the nonaffected adrenal cortex (the contralateral gland). However, some reports indicate that the contralateral adrenal is not always noticeably atrophied when evaluated by ultrasonography.
Secretory patterns of hormones vary tremendously. Compared to the patterns of steroid hormone secretion, those of thyroid hormone secretion tend to vary less, showing only moderate daily or weekly variation. In contrast, blood concentrations of the adrenal steroid cortisol show much more fluctuation, with occasional bursts of secretion followed by periods of low activity (low blood concentrations) occurring throughout the day.