CONFIGURATION OF FEEDBACK LOOPS WITHIN THE ENDOCRINE SYSTEM

The predominant mode of a closed feedback loop among endocrine glands is negative feedback. In a negative-feedback loop, “hormone A” acts on one or more target organs to induce a change (either a decrease or increase) in circulating levels of “component B,” and the change in component B then inhibits secretion of hormone A. Negative-feedback loops confer stability by keeping a physiological parameter (e.g., blood glucose) within a normal range. There are also a few examples of positive feedback in endocrine regulation. A positive closed feedback loop, in which hormone X increases levels of component Y and component Y stimulates secretion of hormone X, 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 “response-driven feedback”) and an endocrine axis–driven feedback loop (Fig. 37-2). The response-driven feedback loop is observed in endocrine glands that control blood glucose levels (pancreatic islets), blood Ca⁺⁺ and P_i levels (parathyroid glands, kidney), blood osmolarity and volume (hypothalamus/posterior pituitary), and blood Na⁺, K⁺, and H⁺ (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 stimulates insulin secretion). Altered hormone levels lead to changes in the physiology of target organs (e.g., decreased hepatic gluconeogenesis, increased uptake of glucose by muscle) that directly regulate the parameter (i.e., blood glucose) in question. The change in the parameter (i.e., decreased blood glucose) then inhibits further secretion of the hormone (i.e., insulin secretion drops as blood glucose falls).

Figure 37-2 Physiological response–driven and endocrine axis–driven negative-feedback loops.

Much of the endocrine system is organized into endocrine axes, with each axis consisting of the hypothalamus and the pituitary and peripheral endocrine glands (Fig. 37-2). 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-I, 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.

An important aspect of the endocrine axes is the ability of descending and ascending neuronal signals to modulate release of the hypothalamic releasing hormones and thereby control the activity of the axis. A major neuronal input to releasing hormone–secreting neurons comes from another region of the hypothalamus called the suprachiasmatic nucleus (SCN). SCN neurons impose a daily rhythm, called a circadian rhythm, on the secretion of hypothalamic releasing hormones and the endocrine axes that they control (Fig. 37-3). SCN neurons represent an intrinsic circadian clock, as evidenced by the fact that they demonstrate a spontaneous peak of electrical activity at the same time every 24 to 25 hours. The 24- to 25-hour cycle can be “entrained” by the normal environmental light-dark cycle created by the earth’s rotation such that the periodicity of the clock appears to be environmentally controlled (Fig. 37-4). Neural input is generated from specialized light-sensitive retinal cells that are distinct from rods and cones and from signals to the SCN via the retinohypothalamic tract. Under constant conditions of light or dark, however, the SCN clock becomes “free running” and slightly drifts away from a 24-hour cycle each day.

Figure 37-3 A circadian pacemaker directs numerous endocrine and body functions, each with its own daily profile. The nighttime rise in plasma melatonin may mediate certain other circadian patterns.

(Data from Schwartz WJ: Adv Intern Med 38:81, 1994.)

Figure 37-4 Origin of circadian rhythms in endocrine gland secretion, metabolic processes, and behavioral activity.

(Modified from Turek FW: Recent Prog Horm Res 49:43, 1994.)

The pineal gland forms a neuroendocrine link between the SCN and various physiological processes that require circadian control. This tiny gland, close to the hypothalamus, synthesizes the hormone melatonin from the neurotransmitter serotonin, of which tryptophan is the precursor. The rate-limiting enzyme for melatonin synthesis is N-acetyltransferase. The amount and activity of this enzyme in the pineal gland vary markedly in a cyclic fashion, which accounts for the cycling of melatonin secretion and its plasma levels. Synthesis of melatonin is inhibited by light and markedly stimulated by darkness (Fig. 37-4). Thus, melatonin may transmit the information that nighttime has arrived, and body functions are regulated accordingly. Melatonin feedback to the SCN at dawn or dusk may also help evoke day-night entrainment of the SCN 24- to 25-hour clock. Melatonin has numerous other actions, including induction of sleep.

Another important input to hypothalamic neurons and the pituitary gland is stress, either as systemic stress (e.g., hemorrhage, inflammation) or as processive stress (e.g., fear, anxiety). Major medical or surgical stress overrides the circadian clock and causes a pattern of persistent and exaggerated hormone release and metabolism that mobilizes endogenous fuels, such as glucose and free fatty acids, and augments their delivery to critical organs. By contrast, growth and reproductive processes are suppressed. Additionally, cytokines released during inflammatory or immune responses, or both, directly regulate the release of hypothalamic releasing hormones and pituitary hormones.