The negative feedback loop is the primary mode of communication among endocrine glands. It involves a hormone acting on target organs to bring about a change in the levels of a specific component, which then inhibits the secretion of the hormone. This negative feedback loop ensures stability by maintaining a normal range for physiological parameters such as blood glucose levels. However, there are also instances of positive feedback loops in endocrine regulation. These positive feedback loops create instability as a hormone increases the levels of a specific component, which in turn stimulates further secretion of the hormone. Positive feedback loops are responsible for processes like the rupture of a follicle through the ovarian wall or the expulsion of a fetus from the uterus.

Within the endocrine system, there are two basic configurations of negative feedback loops. The first is the response-driven feedback loop, observed in endocrine glands that regulate blood glucose levels (pancreatic islet cells), blood calcium and phosphate levels (parathyroid glands, kidneys), blood osmolarity and volume (hypothalamus/posterior pituitary gland), and blood sodium, potassium, and hydrogen ion levels (zona glomerulosa of the adrenal cortex and atrial cells). In this configuration, a change in the extracellular parameter (e.g., an increase in blood glucose level) stimulates or inhibits the secretion of a hormone (e.g., insulin secretion increases). The altered hormone levels then directly regulate the physiological characteristics of target organs, resulting in changes that regulate the specific parameter in question (e.g., decreased hepatic gluconeogenesis, increased glucose uptake by muscle). The change in the parameter (e.g., decreased blood glucose level) subsequently inhibits the secretion of the hormone (e.g., insulin secretion decreases).

The second configuration is the endocrine axis-driven feedback loop, which is organized into endocrine axes comprising the hypothalamus, pituitary gland, and peripheral endocrine glands. This three-tiered configuration involves hypothalamic neuroendocrine neurons secreting releasing hormones in the first tier. These releasing hormones stimulate the production and secretion of tropic hormones from the pituitary gland in the second tier. Tropic hormones, in turn, stimulate the production and secretion of hormones from peripheral endocrine glands in the third tier. The hormones produced peripherally, such as thyroid hormone, cortisol, sex steroids, and IGF-1, have pleiotropic actions on multiple cell types. However, in endocrine axis-driven feedback loops, the primary feedback loop involves the inhibition of pituitary tropic hormones and hypothalamic releasing hormones by the peripherally produced hormone. Unlike the response-driven feedback loop, the physiological responses to the peripherally produced hormone play a minor role in regulating feedback within endocrine axis-driven feedback loops.

From a clinical perspective, endocrine diseases are classified as primary, secondary, or tertiary diseases. Primary diseases involve lesions in the peripheral endocrine gland, secondary diseases involve lesions in the anterior pituitary gland, and tertiary diseases involve lesions in the hypothalamus.
The predominant mode of a closed feedback loop among endocrine glands is negative feedback. In a negative feedback loop, a hormone acts on one or more target organs to induce a change (either a decrease or increase) in circulating levels of a specific component, and the change in this component then inhibits secretion of the hormone. Negative feedback loops confer stability by keeping a physiological parameter (e.g., blood glucose level) within a normal range. There are also a few examples of positive feedback
CHAPTER 38 Introduction to the Endocrine System 687 • Fig. 38.1 Glands of the endocrine system.
in endocrine regulation. A closed positive feedback loop, in which a hormone increases levels of a specific component and this component stimulates secretion of the hormone, confers instability. Under the control of positive feedback loops, something has got to give; for example, positive feedback loops control processes that lead to rupture of a follicle through the ovarian wall or expulsion of a fetus from the uterus.
There are two basic configurations of negative feedback loops within the endocrine system: a physiological response–driven feedback loop (referred to simply as a response-driven feedback loop) and an endocrine axis–driven feedback loop (
Fig. 38.2).
The response-driven feedback loop is observed in endocrine glands that control blood glucose levels (pancreatic islet cells), blood Ca++ and Pi levels (parathyroid glands, kidneys), blood osmolarity and volume (hypothalamus/posterior pituitary gland), and blood Na+ , K+ , and H+ levels (zona glomerulosa of the adrenal cortex and atrial cells). In the response-driven configuration, secretion of a hormone is stimulated or inhibited by a change in the level of a specific extracellular parameter (e.g., an increase in blood glucose level stimulates insulin secretion). Alterations in hormone levels lead to changes in the physiological characteristics of target organs (e.g., decreased hepatic gluconeogenesis, increased uptake of glucose by muscle) that directly regulate the parameter (in this case, blood glucose level) in question. The change in the parameter (decreased blood glucose level) then inhibits further secretion of the hormone (i.e., insulin secretion drops as blood glucose level falls).
Much of the endocrine system is organized into endocrine axes; each axis consists of the hypothalamus, the pituitary gland, and the peripheral endocrine glands (see
Fig. 38.2 ). Thus the endocrine axis–driven feedback loop involves a three-tiered configuration. The first tier is represented by hypothalamic neuroendocrine neurons that secrete releasing hormones. Releasing hormones stimulate (or, in a few cases, inhibit) the production and secretion of tropic hormones from the pituitary gland (second tier). Tropic hormones stimulate the production and secretion of hormones from peripheral endocrine glands (third tier). The peripherally produced hormones—namely, thyroid hormone, cortisol, sex steroids, and IGF-1—typically have pleiotropic actions (e.g., multiple phenotypic effects) on numerous cell types. However, in endocrine axis–driven feedback, the primary feedback loop involves feedback inhibition of pituitary tropic hormones and hypothalamic releasing hormones by the peripherally produced hormone. In contrast to response-driven feedback, the physiological responses to the peripherally produced hormone play only a minor role in regulation of feedback within endocrine axis–driven feedback loops. From a clinical perspective, endocrine diseases are described as primary, secondary, or tertiary diseases (e.g., secondary hyperthyroidism, tertiary hypogonadism). Primary disease is a lesion in the peripheral endocrine gland; secondary disease is a lesion in the anterior pituitary gland; and tertiary disease is a lesion in the hypothalamus.