Hormone Receptors.

Hormones exert their effects by recognizing their target tissues and attaching to receptor sites in a “lock-and-key” type of mechanism. Therefore a hormone will act only on cells that have a receptor specific for that hormone (Fig. 48-2).

Lipid-Soluble and Water-Soluble Hormones.

Hormones are classified by their chemical structure as either lipid soluble or water soluble. The differences in solubility become important in understanding how the hormone interacts with the target cell.

Lipid-soluble hormones are synthesized from cholesterol and are produced by the adrenal cortex, sex glands, and thyroid.² Lipid-soluble hormones (steroids, thyroid) are relatively small molecules that cross the target cell membrane by simple diffusion. Steroid and thyroid hormone receptors are located inside the cell (Fig. 48-3). Lipid-soluble hormones are bound to plasma proteins for transport in the blood. Although lipid-soluble hormones are inactive when bound to plasma proteins, they can be released when appropriate and immediately exert their action at the target tissue.

Water-soluble hormones (insulin, growth hormone [GH], and prolactin) have receptors on or in the cell membrane.³ Water-soluble hormones circulate freely in the blood to their target tissues, where they act. Water-soluble hormones are not dependent on plasma proteins for transport (see Fig. 48-3).

Regulation of Hormonal Secretion.

The regulation of endocrine activity is controlled by specific mechanisms of varying levels of complexity. These mechanisms stimulate or inhibit hormone synthesis and secretion and include feedback, nervous system control, and physiologic rhythms.

Simple Feedback.

Negative feedback relies on the blood level of a hormone or other chemical compound regulated by the hormone (e.g., glucose). It is the most common type of endocrine feedback system and results in the gland increasing or decreasing the release of a hormone. Negative feedback is similar to the functioning of a thermostat in which cold air in a room activates the thermostat to release heat, and hot air signals the thermostat to prevent more warm air from entering the room.

The pattern of insulin secretion is a physiologic example of negative feedback between glucose and insulin. Elevated blood glucose levels stimulate the secretion of insulin from the pancreas (see eFig. 48-1 available on the website for this chapter). As blood glucose levels decrease, the stimulus for insulin secretion also decreases. The homeostatic mechanism is considered negative feedback because it reverses the change in blood glucose level. Another example of negative feedback is the relationship between calcium and parathyroid hormone (PTH). Low blood levels of calcium stimulate the parathyroid gland to release PTH, which acts on bone, the intestine, and the kidneys to increase blood calcium levels. The increased blood calcium level then inhibits further PTH release (Fig. 48-4).

Positive feedback is also used to regulate hormone synthesis and release. The female ovarian hormone estradiol operates by this type of feedback. Increased levels of estradiol produced by the follicle during the menstrual cycle result in increased production and release of follicle-stimulating hormone (FSH) by the anterior pituitary. FSH causes further increases in estradiol until the death of the follicle. This results in a drop of FSH serum levels. Thus with this type of feedback, rising hormone levels cause another gland to release a hormone that then stimulates further release of the first hormone. A mechanism for shutting off release of the first hormone (e.g., follicle death) is required or it will continue to be released.

Rhythms.

A common physiologic rhythm is the circadian rhythm. This is an endogenous 24-hour rhythm that can be driven and altered by sleep-wake or dark-light 24-hour (diurnal) cycles. Hormone levels fluctuate predictably during these cycles. For example, cortisol rises early in the day, declines toward evening, and rises again toward the end of sleep to peak by morning (Fig. 48-5). GH, thyroid-stimulating hormone (TSH), and prolactin secretions peak during sleep.

The menstrual cycle is an example of a body rhythm that is longer than 24 hours (ultradian). These rhythms must be considered when interpreting laboratory results for hormone levels. (See diagnostic studies section in this chapter and Chapter 51.)

Anterior Pituitary.

The anterior lobe accounts for 80% of the gland by weight and is regulated by the hypothalamus through releasing and inhibiting hormones. These hypothalamic hormones reach the anterior pituitary through a network of capillaries known as the hypothalamus-hypophyseal portal system. The releasing and inhibiting hormones in turn affect the secretion of six hormones from the anterior pituitary (Fig. 48-6).

Several hormones secreted by the anterior pituitary are referred to as tropic hormones. These are hormones that control the secretion of hormones by other glands. Thyroid-stimulating hormone (TSH) stimulates the thyroid gland to secrete thyroid hormones. Adrenocorticotropic hormone (ACTH) stimulates the adrenal cortex to secrete corticosteroids. Follicle-stimulating hormone (FSH) stimulates secretion of estrogen and the development of ova in women and sperm in men. Luteinizing hormone (LH) stimulates ovulation in women and secretion of sex hormones in both men and women. In men LH is sometimes referred to as interstitial cell–stimulating hormone (ICSH).

Growth hormone (GH) affects the growth and development of all body tissues. It also has numerous biologic actions, including a role in protein, fat, and carbohydrate metabolism. Prolactin stimulates breast development necessary for lactation after childbirth. Prolactin is also referred to as a lactogenic hormone.

Posterior Pituitary.

The posterior pituitary is composed of nerve tissue and is essentially an extension of the hypothalamus. Communication between the hypothalamus and posterior pituitary occurs through nerve tracts known as the median eminence. The hormones secreted by the posterior pituitary, antidiuretic hormone (ADH) and oxytocin, are actually produced in the hypothalamus. These hormones travel down the nerve tracts from the hypothalamus to the posterior pituitary and are stored until their release is triggered by the appropriate stimuli (see Fig. 48-6).

The major physiologic role of ADH (also called arginine vasopressin) is regulation of fluid volume by stimulating reabsorption of water in the renal tubules. ADH is also a potent vasoconstrictor. ADH secretion is stimulated by plasma osmolality (a measure of solute concentration of circulating blood) and hypovolemia (Fig. 48-7). Plasma osmolality increases when there is a decrease in ECF or an increase in solute concentration. The increased plasma osmolality activates osmoreceptors, which are extremely sensitive, specialized neurons in the hypothalamus. These activated osmoreceptors stimulate ADH release. Volume receptors in large veins, heart atria, and carotid arteries that sense pressure changes also contribute to ADH control. When ADH is released, the renal tubules reabsorb water and the urine becomes more concentrated. When ADH release is inhibited, renal tubules do not reabsorb water, resulting in a more dilute urine excretion.

Oxytocin stimulates ejection of milk into mammary ducts during lactation and contraction of the uterus; it may also affect sperm motility. Oxytocin secretion is increased by stimulation of touch receptors in the nipples of lactating women and vaginal pressure receptors during childbirth.

Thyroxine and Triiodothyronine.

Thyroxine (T₄) accounts for 90% of thyroid hormone produced by the thyroid gland. However, triiodothyronine (T₃) is much more potent and has greater metabolic effects. About 20% of circulating T₃ is secreted directly by the thyroid gland, and the remainder is obtained by peripheral conversion of T₄. Iodine is necessary for the synthesis of both T₃ and T₄. These two hormones affect metabolic rate, caloric requirements, oxygen consumption, carbohydrate and lipid metabolism, growth and development, brain function, and other nervous system activities. More than 99% of thyroid hormones are bound to plasma proteins, especially thyroxine-binding globulin synthesized by the liver. Only the unbound “free” hormones are biologically active.

Thyroid hormone production and release is stimulated by TSH from the anterior pituitary gland. When circulating levels of thyroid hormone are low, the hypothalamus releases thyrotropin-releasing hormone (TRH), which in turn causes the anterior pituitary to release TSH. High circulating thyroid hormone levels inhibit the secretion of both TRH from the hypothalamus and TSH from the anterior pituitary gland.

Calcitonin.

Calcitonin is produced by C cells (parafollicular cells) of the thyroid gland in response to high circulating calcium levels. Calcitonin inhibits the transfer of calcium from bone to blood, increases calcium storage in bone, and increases renal excretion of calcium and phosphorus, thereby lowering serum calcium levels. Calcitonin and PTH regulate calcium balance.

Parathyroid Hormone.

The parathyroid glands secrete parathyroid hormone (PTH), also called parathormone. Its major role is to regulate the blood level of calcium. PTH acts on bone, the kidneys, and indirectly on the GI tract. PTH stimulates the transfer of calcium from the bone into the blood and inhibits bone formation, resulting in increased serum calcium and phosphate. In the kidney, PTH increases calcium reabsorption and phosphate excretion. In addition, PTH stimulates the renal conversion of vitamin D to its most active form (1,25-dihydroxyvitamin D₃). This active vitamin D promotes absorption of calcium and phosphorus by the GI tract, which ultimately increases bone mineralization. The secretion of PTH is directly regulated by a feedback system. When the serum calcium level is low, PTH secretion increases. When the serum calcium level rises, PTH secretion falls. In addition, high levels of active vitamin D inhibit PTH, and low levels of magnesium stimulate PTH secretion.

Adrenal Medulla.

The adrenal medulla is the inner part of the gland and consists of sympathetic postganglionic neurons. The medulla secretes the catecholamines epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Catecholamines are synthesized from the amino acid phenylalanine. Catecholamines, usually considered neurotransmitters, are hormones when secreted by the adrenal medulla because they are released into the circulation. They are an essential part of the body’s “fight or flight” response to stress (see Chapter 7).

Adrenal Cortex.

The adrenal cortex is the outer part of the adrenal gland. It secretes several steroid hormones, including glucocorticoids, mineralocorticoids, and androgens. Cholesterol is the precursor for steroid hormone synthesis. Glucocorticoids (e.g., cortisol) are named for their effects on glucose metabolism. Mineralocorticoids (e.g., aldosterone) are essential for the maintenance of fluid and electrolyte balance. The term corticosteroid refers to hormones synthesized by the adrenal cortex excluding androgens.

Glucagon.

Glucagon is synthesized and released from pancreatic α cells and the gut in response to low levels of blood glucose, protein ingestion, and exercise. Glucagon increases blood glucose by stimulating glycogenolysis, gluconeogenesis, and ketogenesis. Glucagon and insulin function in a reciprocal manner to maintain normal blood glucose levels. In the fasting state, hormones such as catecholamines, cortisol, and glucagon break down stored complex fuels (catabolism) to provide glucose as fuel for energy.

Insulin.

Insulin is the principal regulator of metabolism and storage of ingested carbohydrates, fats, and proteins. Insulin facilitates glucose transport across cell membranes in most tissues. However, the brain, nerves, lens of the eye, hepatocytes, erythrocytes, and cells in the intestinal mucosa and kidney tubules are not dependent on insulin for glucose uptake. An increased blood glucose level is the major stimulus for insulin synthesis and secretion. Other stimuli to insulin secretion are increased amino acid levels and vagal stimulation. Insulin secretion is usually inhibited by low blood glucose levels, glucagon, somatostatin, hypokalemia, and catecholamines.

A major effect of insulin on glucose metabolism occurs in the liver, where the hormone enhances glucose incorporation into glycogen and triglycerides by altering enzymatic activity and inhibiting gluconeogenesis. After a meal, insulin is responsible for the storage of nutrients (anabolism). Another major effect occurs in peripheral tissues, where insulin facilitates glucose transport into cells, transport of amino acids across muscle membranes and their synthesis into protein, and transport of triglycerides into adipose tissue.