Endocrine systems of vertebrates

Endocrine systems have been known only since the early twentieth century. The first known hormone was discovered around 1902 when William Bayliss and Ernest Starling discovered, in dogs, secretin, a hormone that stimulates pancreatic exocrine secretion in response to acid in the small intestine. Since that date, dozens of other hormones have been discovered, which control all aspects of growth, metabolism, and reproduction.

The endocrine system consists of glands that secrete chemical substances called hormones in response to specific signals. The hormones are secreted into the bloodstream, where they travel to specific target cells or tissues, which contain specific receptors that allow the hormones to bind, initiating the response. Classically, hormones were thought to belong to two very different groups, the polypeptide (small protein) hormones and the steroid (cholesterol-like) hormones. It is now known that hormones can be composed of several different kinds of molecules, including fats (prostaglandins) and even gases (nitric oxide). Protein-like hormones bind receptors found on external cell membranes to stimulate second messengers, such as cyclic adenosine monophosphate (cAMP), which activate enzymes and other cellular substances to produce a response. Steroid hormones enter target cells and bind intracellular receptors. The hormone-receptor complexes migrate to the nucleus and activate gene expression, which results in the response. This, like descriptions of many concepts in biology, is an oversimplification, and many hormones appear to work by a combination of the two mechanisms.

Endocrine Control Systems

The endocrine secretions are controlled by the nervous system through a complex chain of command. Receptors around the body monitor sensory signals and alert the brain, which then relays the information to specific cells in the median eminence of the hypothalamus. For example, temperature receptors in the skin detect cold and inform the brain of potential body cooling. The brain then relays the information to cells in the hypothalamus, which secrete a molecule called thyrotropin-releasing hormone into a blood vessel called the hypothalamo-hypophysial portal vessel. This blood vessel delivers the releasing hormone to the anterior pituitary gland, which in turn secretes a hormone called thyroid-stimulating hormone (TSH), or thyrotropin, into the blood. The TSH travels to the thyroid gland to stimulate the secretion of thyroid hormones, which stimulate metabolism in liver, muscle, and other cells. Heat produced as a by-product of metabolism warms the body. Some hormones are under dual control. Growth hormone (somatotropin) is stimulated by a releasing hormone called somatocrinin and inhibited by somatostatin. There are about seven anterior pituitary hormones that are controlled by similar mechanisms. Adrenocorticotropic hormone (ACTH) is controlled by corticotropin-releasing hormone. Melanocyte-stimulating hormone (MSH) and prolactin are under dual control by both releasing hormones and inhibiting hormones. The gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—are under the control of a single releasing hormone called gonadotropin-releasing hormone. All these control systems are subject to feedback loops, which usually involve negative feedback (for example, TSH secretion being inhibited by thyroid hormone), but positive feedback loops exist (estrogen feeding back positively to stimulate LH secretion).

Hormones Controlling Growth, Development, and Metabolism

The major control of growth is carried out by somatotropin (STH) from the anterior pituitary. STH does not act directly, however. Cells in the liver respond to STH to produce somatomedin, which stimulates bone growth and muscle production. Prolactin, a protein similar to STH, stimulates breast development in female mammals. In an interesting case of hormone evolution, thyroid hormone stimulates amphibian metamorphosis (tadpole to frog transition); however, in warm-blooded vertebrates, this same hormone has evolved to stimulate metabolism for the purpose of heat production in birds and mammals. Several hormones stimulate metabolism for different reasons. Epinephrine (adrenaline), in addition to elevating blood pressure, mobilizes glucose from glycogen in response to stress. Steroid hormones, also produced in the adrenal glands, stimulate the production of glucose from noncarbohydrate molecules (gluconeogenesis). The stimulus for this is prolonged stress, for example, starvation. These glucocorticoids, such as cortisol and corticosterone, evolved early and are very important in combating stresses resulting from migration among birds and even fish. The pancreatic hormones insulin and glucagon also impact energy metabolism. These two proteins regulate blood sugar, fat, and protein levels. After eating, insulin stimulates transport of these molecules into liver, fat, and muscle cells and then stimulates the incorporation of the simple molecules, such as glucose, amino acids, and fatty acids, into larger storage molecules, such as glycogen, protein, and fats. Glucagon has opposite actions. After a prolonged period without food intake, glucagon stimulates breakdown of complex molecules, such as glycogen and fats, into simple molecules, which are released into the blood and made available to metabolizing cells. These two hormones act independently of the pituitary and respond directly to blood-borne signals, such as glucose concentration. This regulation ensures a steady delivery of nutrients to metabolizing cells in animals who only eat intermittently.

Control of Water and Salt Balance

The state of hydration and salt levels in the body are of critical importance to vertebrate animals. Dehydration has obvious severe detrimental consequences. The salt composition of body fluids is equally important. For enzymes and other proteins, such as antibodies and even hormones to function properly, salt concentrations (ionic concentrations) must be maintained. For example, blood levels of sodium and potassium must be maintained at approximately 145 and 4 millimoles, respectively, in most vertebrates. These levels are lower in amphibians (100 and 2 millimoles). Water content of the body is controlled primarily by a posterior pituitary hormone called antidiuretic hormone (ADH). When the body becomes dehydrated, both concentration receptors and volume receptors in the brain trigger the secretion of ADH. This small peptide then stimulates thirst and water retention in the kidneys. In amphibians, it also stimulates water absorption by the skin and urinary bladder. A steroid hormone produced in the adrenal glands called aldosterone stimulates the kidney and large intestine to conserve sodium. The kidneys also excrete increased amounts of potassium in response to aldosterone. Aldosterone secretion is stimulated by angiotensin II. When blood sodium levels decrease, there is a consequent loss of water and, thus, body fluid volume. Pressure receptors in the kidneys trigger the release of renin, which initiates a complex series of enzymatic reactions in the blood, leading to the appearance of angiotensin II, which stimulates the secretion of aldosterone. When blood pressure increases, aldosterone secretion decreases, sodium excretion increases, and other hormones appear, which also help eliminate sodium. Pressure receptors in the heart cause that organ to secrete atrial natriuretic peptide (ANP). ANP inhibits sodium conservation in the kidneys. Increased pressure in blood vessels activates nitric oxide synthetase, which produces nitric oxide locally. Nitrous oxide increases the excretion of sodium by the kidneys.

Calcium and phosphate are also controlled by hormones. The parathyroid hormones respond directly to blood calcium concentrations. When calcium levels are low, parathyroid hormone (PTH) is secreted into the blood to stimulate three centers. In bone, PTH mobilizes calcium to elevate blood levels of this ion. Because mobilization of bone also elevates phosphate, which can be toxic at high concentrations, the kidneys become important. PTH stimulates the kidneys to increase calcium conservation and potassium excretion. PTH also stimulates uptake of calcium in the small intestine. Vitamin D enhances the action of PTH. Working antagonistically to PTH, calcitonin, produced in the thyroid gland, responds directly to high blood calcium to move this ion into bone.

Digestive Hormones

The digestion and assimilation of food are also controlled by hormones. In meat-eating animals, beginning in the stomach, stretch, and the presence of protein stimulate the secretion of gastrin into blood vessels in the wall of the stomach. This gastrin stimulates the secretion of hydrochloric acid into the lumen of the stomach to digest protein. When the partially digested food enters the small intestine for the completion of digestion and assimilation, a slightly alkaline pH is required. The walls of the small intestine detect the acidity and secrete another pair of hormones into blood vessels. Secretin travels to the pancreas and stimulates sodium bicarbonate secretion. The sodium bicarbonate travels through the common bile duct to the small intestine, where it neutralizes the acid. Gastric inhibitory polypeptide travels to the stomach to inhibit acid secretion and stomach contractions. Another peptide, cholecystokinin-pancreozymin (CCKPZ), responds to fats and proteins in the small intestine and is thus secreted into the blood. This hormone travels to the gallbladder, causing it to contract and release its bile through the common bile duct to aid digestion of fats in the small intestine. CCKPZ also stimulates secretion of a whole host of enzymes by the pancreas. These enzymes also move through the common bile duct to the small intestine to aid in the digestion of carbohydrates, fats, and protein. At least two other digestive hormones have been discovered that are not well understood at present. Motilin is secreted by the small intestine and stimulates stomach muscle contractions. Vasoactive intestinal polypeptide also is secreted by the small intestine, and it, in turn, stimulates sodium bicarbonate secretion by the walls of the small intestine. Both hormones are of obvious benefit, but key details of their function, such as what triggers their secretion, are not clearly understood. It is important to realize that all the hormones of the stomach and small intestine are secreted into the blood vessels in the walls of the organs, not into their lumens.

Reproductive Hormones

The two pituitary hormones that are involved in reproduction are called the gonadotropins, FSH and LH. These hormones are identical in males and females. The gonadal hormones differ between the two sexes. Females produce estrogens and progesterone in their ovaries. Males produce androgens (primarily testosterone) in the testes.

The mammalian menstrual cycle has two components. Both the ovarian cycle and the uterine cycle proceed simultaneously and last approximately four days in rats, sixteen days in sheep, and twenty-eight days in humans. The length and pattern of the cycle vary with species. For the sake of comparison, the human cycle is described here. The first five days of each cycle is called the menstrual period, and during this period, the built-up walls of the uterus (resulting from the previous cycle) are shed and discharged through the vagina. At this time, the concentrations of FSH and LH in the blood are about the same. From the close of the menstrual period until ovulation is the follicular cycle. FSH stimulates the ovaries to begin the growth and maturation of an egg-containing follicle. This follicle produces estrogen. Estrogen feeds back negatively on FSH, causing its levels in the blood to drop. At the same time, estrogen is feeding back positively on LH, causing its levels to rise.

At the midpoint of the ovarian cycle, LH peaks and causes the now-mature follicle to burst and eject an egg (ovum) into the oviduct. The ruptured follicle becomes a corpus luteum and continues to secrete estrogen, but also begins to secrete progesterone. Estrogen, and now Progesterone, stimulate the walls of the uterus to thicken and produce glandular tubes and blood vessels. This goes on for the final half of the cycle, which is called the follicular phase in the ovaries and the proliferative phase in the uterus. If fertilization of the ovum in the oviduct fails to occur during this period, a hormone, probably a prostaglandin, builds up in the corpus luteum, causing it to stop producing estrogen and progesterone. With the loss of these two steroids, the thickened wall of the uterus is shed, and the menses flows during the first five days of the next cycle.

Male reproductive endocrinology is much different. The first striking difference is that, although the pituitary hormones FSH and LH are the same, the patterns of secretion are different. Instead of the cyclic peaks found in females, males secrete constant levels of gonadotrophins. FSH stimulates sperm production and maturation in the seminiferous tubules of the testes. LH stimulates testosterone secretion by the interstitial cells of the testes. Testosterone helps FSH to stimulate sperm maturation. This androgen also stimulates such primary sex characteristics as penis and epididymal growth during puberty. The epididymis is a tubular structure that stores sperm in preparation for ejaculation. Testosterone also stimulates secondary sex characteristics, such as the deepening of the voice and development of muscle mass that manifest during puberty in humans.

Endocrine Disruption

While the harmful effects of environmental chemicals, known as endocrine disruptors (EDs), on humans are well-documented, the evidence of their negative impact on the animal kingdom is growing in the twenty-first century. Household pets, fish, wildlife, and cattle have all shown poor health outcomes linked to exposure to these environmental chemicals, mostly from wastewater or urban and agricultural runoff. In vertebrates, studies have linked EDs to impaired reproduction, sexual dysfunction, developmental malformations, and increased cancer risk, as well as adversely impacting the immune, nervous, and thyroid system function. EDs most heavily impact aquatic animals and urban wildlife. Some frogs have been subjected to chemical castration, and some fish are born unable to reproduce.

While the list is likely to grow, the U.S. Environmental Protection Agency (EPA) lists several EDs linked to negative animal outcomes, including organochlorine compounds, ethane (DDT) and its metabolite dichorodiphenyldichloroethylene (DDE), and polychlorinated biphenyls (PCBs).

Principal Terms

Feedback: In endocrinology, this usually refers to one hormone controlling the secretion of another that stimulates the first, usually in the form of negative feedback, in which the second hormone inhibits the first

Gland: A tissue composed of similar cells that produce a hormone

Hormone: A blood-borne chemical messenger

Receptor: A protein molecule on or in a cell that responds to the hormone by binding to it and initiating a series of events that compose the response

Target: Cells that contain hormone receptors

Bibliography

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Strauss, Jerome F., et al. Yen & Jaffe's Reproductive Endocrinology: Physiology Pathophysiology and Clinical Management. 9th ed., Elsevier, 2023.