Chemical Coordination and Integration

Your body is coordinated by two systems working side by side. The neural system sends electrical signals along neurons. It is fast, it is precise, and it can only speak to the cells that its nerve endings actually reach. Its effects also stop almost as soon as the signalling stops. That is perfect for pulling your hand away from a hot vessel, but useless for a job that has to run for years, such as growing taller, or for a job that has to be done in every tissue at once, such as keeping blood glucose steady between meals.

For those jobs the body uses a second control system, the endocrine system, which signals with chemicals instead of electricity. Its messages are slower to start, but they spread everywhere and they last far longer. Neural and chemical control are not rivals; they work together, and the joint between them sits in the brain itself, in the hypothalamus.

Endocrine glands are ductless glands. An exocrine gland, such as a salivary gland, a sweat gland or the enzyme-making part of the pancreas, empties its product into a duct that carries it to a body surface or into a cavity. An endocrine gland has no duct at all. It releases its product straight into the blood flowing through it, and the blood then carries that product to every corner of the body. This is why a hormone reaches all cells but changes only some of them: only cells that carry the matching receptor can read the message.

A hormone is a non-nutrient chemical that acts as an intercellular messenger and is produced in trace amounts. Each part of that description matters. Non-nutrient means the hormone is not fuel and not building material; it carries information only. Intercellular messenger means it is made in one cell and acts on a different cell. Trace amounts means the blood carries an extremely small quantity, so a small change in how much a gland secretes can produce a large change in the body.

The organised endocrine glands in humans are the hypothalamus, pituitary, pineal, thyroid, parathyroid, thymus, adrenal and pancreas, together with the gonads, which are the testis in males and the ovary in females. Besides these, several organs whose main work is something else also release hormones: the heart, the kidney and the lining of the gastrointestinal tract. So the endocrine system is not simply a set of glands; it is glands plus hormone-secreting cells scattered inside other organs.

Chemically, hormones fall into four groups: peptide, polypeptide and protein hormones, such as insulin, glucagon and the hypothalamic and pituitary hormones; steroids, such as cortisol, testosterone, estradiol and progesterone; iodothyronines, which are the thyroid hormones; and amino acid derivatives, such as epinephrine. Do not treat this as a list to be memorised for its own sake. The chemical nature of a hormone decides whether it can cross the fatty plasma membrane, and that in turn decides where its receptor sits and how quickly it acts, which is the subject of the last section of this chapter.

The hypothalamus is the basal part of the diencephalon, in the forebrain. Inside it are clusters of nerve cells called nuclei, and these are neurosecretory: they are neurons, but instead of only passing a signal to the next neuron they manufacture and release hormones. Hypothalamic hormones come in two opposite kinds. Releasing hormones order the pituitary to secrete, and inhibiting hormones order it to stop. Gonadotrophin releasing hormone, GnRH, makes the pituitary release gonadotrophins; somatostatin stops the pituitary releasing growth hormone.

These hormones do not travel all the way round the body to reach the pituitary. A short special set of blood vessels called a portal circulation runs down the stalk that joins the two organs and delivers hypothalamic blood straight to the anterior pituitary. A portal system is simply a stretch of circulation in which blood passes through capillaries twice before returning to the heart, and here it means the hypothalamic message arrives concentrated and undiluted.

The pituitary gland sits in a bony hollow of the skull called the sella turcica and hangs from the hypothalamus by that stalk. Anatomically it has two divisions, the adenohypophysis and the neurohypophysis. The adenohypophysis itself has two parts, the pars distalis and the pars intermedia. The pars distalis is what everyone calls the anterior pituitary, and it manufactures six hormones: growth hormone (GH), prolactin (PRL), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), luteinising hormone (LH) and follicle stimulating hormone (FSH). The pars intermedia secretes only one hormone, melanocyte stimulating hormone (MSH), and in human beings this part is almost completely merged with the pars distalis. The neurohypophysis, also called the pars nervosa or the posterior pituitary, differs in an important way: it manufactures nothing at all. Oxytocin and vasopressin are made by hypothalamic neurons; those neurons send their long axons down into the posterior pituitary, and the two hormones are stored there and released from there into the blood.

Taking the anterior pituitary hormones one at a time. Growth hormone drives the growth of the body as a whole. Over-secretion of it during the growing years produces abnormal growth of the body, called gigantism, and low secretion produces stunted growth, called pituitary dwarfism. Prolactin causes the growth of the mammary glands and the formation of milk in them. TSH makes the thyroid gland synthesise and secrete thyroid hormones. ACTH makes the adrenal cortex synthesise and secrete the steroid hormones called glucocorticoids. LH and FSH are together called gonadotrophins because both act on the gonads. In males, LH acts on the Leydig cells of the testis and stimulates them to synthesise and secrete androgens, while FSH acts on the Sertoli cells inside the seminiferous tubules and, together with androgens, keeps sperm formation going. In females, FSH stimulates the growth and development of the ovarian follicles, and LH triggers the ovulation of a fully mature follicle and then maintains the corpus luteum left behind. MSH acts on the melanocytes of the skin and regulates skin pigmentation.

Now the two posterior pituitary hormones. Oxytocin acts on smooth muscle. It produces the vigorous contractions of the uterus at the time of childbirth, and it squeezes milk out of the mammary gland. Notice the clean division of labour with prolactin: prolactin makes the milk, oxytocin ejects it. Vasopressin acts mainly on the kidney, where it promotes the reabsorption of water and electrolytes by the distal tubules and so cuts down the amount of water lost in urine. Because it opposes diuresis it is also called antidiuretic hormone, ADH, and when it is deficient the body passes large volumes of dilute urine, a condition called diabetes insipidus. That is a water-handling problem and has nothing to do with the blood glucose problem of diabetes mellitus.

Because the pituitary controls so many other glands it is often called the master gland, but the title is only half deserved. The hypothalamus stands above it and decides when the pituitary secretes at all.

The pineal gland lies on the dorsal side of the forebrain. It secretes melatonin, whose main task is to regulate the twenty-four hour rhythm of the body, called the diurnal rhythm. That includes the sleep and wake cycle and the daily rise and fall of body temperature. Melatonin also influences the pigmentation of the skin, metabolism, the menstrual cycle and the defence capability of the body.

The thyroid gland is made of two lobes, one lying on each side of the trachea, connected across the front by a thin flap of connective tissue called the isthmus. Its tissue is built of closed sacs called follicles, held together by stroma. The follicular cells make two iodine-containing hormones: tetraiodothyronine, also called thyroxine (T₄), which carries four iodine atoms, and triiodothyronine (T₃), which carries three. Iodine is not the raw material out of which these hormones are built; it is added on to an amino acid framework, and the number of iodine atoms added is exactly what the two names count. Iodine in the diet is therefore not optional. Without enough of it the gland cannot make these hormones at a normal rate.

Iodine deficiency causes hypothyroidism, and the gland enlarges as it struggles to keep up. That enlargement is goitre, seen as a swelling at the front of the neck. If hypothyroidism occurs in a pregnant mother, the developing baby is affected: growth is stunted, a condition called cretinism, along with mental retardation, low intelligence quotient, abnormal skin and deaf-mutism. In adult women, hypothyroidism can make the menstrual cycle irregular. The opposite state, hyperthyroidism, which may follow cancer of the thyroid gland or the development of nodules in it, also disturbs body physiology.

What the thyroid hormones actually do is best held in mind as four jobs. They regulate the basal metabolic rate, the rate at which the body uses fuel at rest. They support the process of red blood cell formation. They control the metabolism of carbohydrates, proteins and fats. And they influence the maintenance of water and electrolyte balance.

The thyroid gland also secretes a protein hormone called thyrocalcitonin (TCT). This one contains no iodine and has an entirely different job: it regulates blood calcium by lowering it.

Attached to the back surface of the thyroid are four tiny parathyroid glands, one pair embedded in each of the two thyroid lobes. They secrete parathyroid hormone (PTH), a peptide hormone, and what controls its secretion is the level of calcium ions circulating in the blood. PTH raises blood calcium by three routes at once. It acts on bone and stimulates bone resorption, the dissolving away of bone mineral, which releases calcium into the blood. It makes the renal tubules reabsorb more calcium from the filtrate instead of allowing it to leave in the urine. And it increases the absorption of calcium from digested food. PTH is therefore a hypercalcemic hormone, and it works as the exact counterweight to thyrocalcitonin. Between them these two hormones hold blood calcium inside a narrow range.

The thymus is a lobed organ lying between the two lungs, behind the sternum, on the ventral side of the aorta. It secretes peptide hormones called thymosins. Thymosins drive the differentiation of T-lymphocytes, the cells that provide cell-mediated immunity, and they also promote the production of antibodies, which provide humoral immunity. The thymus is large in children and degenerates as a person grows old. With less thymus tissue there are fewer thymosins, and this is one reason the immune response of elderly people becomes weak.

There is one pair of adrenal glands, one sitting at the anterior, or upper, part of each kidney. Each gland is really two organs packed inside one covering, built from two different tissues with different hormones. The adrenal medulla is the tissue in the centre, and the adrenal cortex is the tissue that surrounds it on the outside. Fixing this arrangement in words prevents the most common slip in this chapter: medulla inside, cortex outside.

The medulla secretes adrenaline, also called epinephrine, and noradrenaline, also called norepinephrine. Together these two are called catecholamines. They are secreted rapidly whenever the body meets stress of any kind, or an emergency, which is why they are known as the emergency hormones or the hormones of fight or flight. Their effects fit that description exactly. They increase alertness, widen the pupils, raise the hairs of the skin, an effect called piloerection, and bring on sweating. They increase the heart rate and the strength of each heart contraction, and they increase the rate of respiration. They stimulate the breakdown of glycogen, so the concentration of glucose in the blood rises and fuel becomes available at once. They also stimulate the breakdown of lipids and of proteins.

The cortex is arranged in three layers. Counting from the outside inwards they are the zona glomerulosa, the zona fasciculata and the zona reticularis. The hormones of the cortex are called corticoids, and they fall into two main functional groups plus a small extra one.

Glucocorticoids are the corticoids concerned with carbohydrate metabolism, and in humans the main one is cortisol. Glucocorticoids stimulate gluconeogenesis, which is the making of glucose from non-carbohydrate sources; lipolysis, the breakdown of fats; and proteolysis, the breakdown of proteins. At the same time they hold back the uptake and use of amino acids by cells. Cortisol has several duties beyond metabolism. It helps maintain the working of the cardiovascular system and of the kidneys, it produces anti-inflammatory reactions and suppresses the immune response, and it stimulates the production of red blood cells.

Mineralocorticoids are the corticoids concerned with the balance of water and electrolytes, and in humans the main one is aldosterone. Aldosterone acts chiefly on the renal tubules, where it stimulates the reabsorption of sodium ions and water and the excretion of potassium ions and phosphate ions. Through this one action it helps to maintain the balance of electrolytes, the volume of body fluid, the osmotic pressure of the blood, and blood pressure.

The cortex also secretes small amounts of androgenic steroids. These play a part in the growth of axillary hair, pubic hair and facial hair during puberty.

A useful way to hold the whole gland together is to see its two halves as two speeds of one stress response. The medulla answers within seconds and prepares the body for immediate physical action. The cortex answers over minutes and hours, keeping fuel supplied and salt and water conserved for as long as the stress lasts.

The pancreas is a composite gland: it is exocrine and endocrine at the same time. The exocrine part pours digestive juice into a duct. The endocrine part is a set of small islands of tissue scattered through the organ, called the Islets of Langerhans. A normal human pancreas contains roughly one to two million islets, and together they make up only about one to two per cent of the whole pancreatic tissue, a tiny fraction of the organ doing a job the body cannot live without. Two kinds of cell matter here: the alpha cells, which secrete glucagon, and the beta cells, which secrete insulin.

Glucagon is a peptide hormone that acts mainly on the liver cells, the hepatocytes. It stimulates glycogenolysis, the breakdown of stored glycogen into glucose, so blood glucose rises. It also stimulates gluconeogenesis, and it reduces the uptake and use of glucose by cells. Glucagon is therefore a hyperglycemic hormone: it pushes blood glucose up when a meal is long past.

Insulin is also a peptide hormone, and it acts mainly on hepatocytes and on fat cells, the adipocytes. It enhances the uptake and utilisation of glucose by these cells, so glucose moves rapidly out of the blood and into them and the blood glucose level falls. Insulin also stimulates glycogenesis, the conversion of glucose into glycogen for storage. Insulin is therefore a hypoglycemic hormone. Glucagon and insulin are the two halves of one control loop working in opposite directions: glucagon is called on when blood glucose is falling, insulin when it is rising, and between them the level is held steady whether or not a meal has just been eaten.

When blood glucose stays high for a long time the result is diabetes mellitus, a complex disorder in which glucose is lost through the urine and compounds called ketone bodies are formed. Insulin therapy is the standard means of managing it.

The testes are a pair of organs lying in the scrotal sac, outside the abdomen. A testis does two jobs at once: it is the primary sex organ, producing sperms, and it is an endocrine gland. It is built of seminiferous tubules and, filling the spaces between them, interstitial or stromal tissue. The Leydig cells, also called interstitial cells, sit in those intertubular spaces and produce a group of hormones called androgens, mainly testosterone. Androgens regulate the development, maturation and functions of the male accessory sex organs, which are the epididymis, vas deferens, seminal vesicles, prostate gland and urethra. They stimulate muscular growth, the growth of facial and axillary hair, aggressiveness and the low pitch of the voice. They play a major stimulatory role in spermatogenesis. They act on the central neural system and influence male sexual behaviour. And they produce anabolic, that is synthetic, effects on protein and carbohydrate metabolism.

The ovaries are a pair of organs located in the abdomen. The ovary is the primary female sex organ. It produces one ovum during each menstrual cycle, and it also produces two groups of steroid hormones, estrogen and progesterone. The ovary is composed of ovarian follicles and stromal tissue. Estrogen is synthesised and secreted mainly by the growing ovarian follicles. After ovulation the ruptured follicle is converted into a structure called the corpus luteum, and this secretes mainly progesterone. Keep the two sources apart: follicle before ovulation for estrogen, corpus luteum after ovulation for progesterone.

Estrogens produce wide-ranging actions. They stimulate the growth and activities of the female secondary sex organs, the development of growing ovarian follicles, and the appearance of the female secondary sex characters, such as the high pitch of the voice. They cause the mammary glands to develop, and they regulate female sexual behaviour. Progesterone supports pregnancy. It also acts on the mammary glands, where it stimulates the formation of alveoli, the sac-like structures that store milk, and the secretion of milk.

Not every hormone comes from a gland whose only job is to make hormones. Three organs in the body are known for entirely different work and quietly act as endocrine tissue as well.

Begin with the heart. The wall of the atria secretes a peptide hormone called atrial natriuretic factor (ANF), and its job is to bring blood pressure down. When blood pressure is increased, ANF is secreted, and it causes dilation of the blood vessels. A wider vessel offers less resistance to the flow of blood, so the pressure falls. It is useful to see ANF as the opposite number of aldosterone and vasopressin: those two conserve salt and water and so tend to push blood pressure up, while ANF works to bring it down.

Next the kidney. The juxtaglomerular cells of the kidney produce a peptide hormone called erythropoietin, which stimulates erythropoiesis, the formation of red blood cells. There is a neat logic to placing this sensor in the kidney. The kidney receives a very large share of the blood pumped by the heart, so it is well placed to notice when the delivery of oxygen is falling; when it does, it sends out a chemical order for more oxygen carriers to be built.

Now the gastrointestinal tract. Endocrine cells present in the lining of different parts of the gut secrete four major peptide hormones. Gastrin acts on the gastric glands, the secretory glands of the stomach wall, and stimulates the secretion of hydrochloric acid and of pepsinogen, the inactive form of a protein-splitting enzyme. Secretin acts on the exocrine pancreas and stimulates the secretion of water and bicarbonate ions. Cholecystokinin, abbreviated CCK, acts on both the pancreas and the gall bladder, stimulating the secretion of pancreatic enzymes from the pancreas and of bile from the gall bladder. Gastric inhibitory peptide, abbreviated GIP, works in the reverse direction: it inhibits gastric secretion and gastric motility.

Notice the pattern in that group. Three of the four switch a secretion on and the fourth switches secretion off, and each is released from a region of the gut that needs an organ further along to get ready in advance. This is chemical coordination in its simplest form, one tissue releasing a message into the blood so that another organ prepares before the material reaches it. It also shows why the endocrine system had to evolve at all: nerves could not have reached every one of these scattered cells.

Beyond these named hormones, many tissues that are not endocrine glands secrete chemicals called growth factors. These are essential for the normal growth of tissues and for their repair and regeneration after damage. Their existence is a reminder that describing the endocrine system as a list of ten glands is a convenient teaching simplification. Chemical messengers are produced all over the body.

Blood carries every hormone to every tissue, and yet a hormone changes only a few of them. The reason is the receptor. A hormone produces its effect only on tissues that possess a specific protein, called a hormone receptor, able to bind it. Each receptor is specific to one hormone only, so receptors are said to be specific, and a tissue that carries the receptor for a hormone is called the target tissue of that hormone. When binding happens, a hormone-receptor complex is formed, and it is this complex, not the free hormone, that sets off change inside the cell. Those biochemical changes alter the metabolism of the target tissue, and the sum of them is the physiological effect we can observe.

Receptors sit in one of two places. Membrane-bound receptors are present on the cell membrane of the target cell, with the hormone-binding part facing outwards. Intracellular receptors are present inside the target cell, and most of these are nuclear receptors, found in the nucleus.

Which hormone uses which kind? The answer follows from chemistry rather than from a list to be crammed. The plasma membrane is made of lipid, so a fat-soluble molecule can pass straight through it while a water-soluble one cannot. Protein and peptide hormones such as insulin, glucagon and the pituitary hormones are water-soluble and large, so they stay outside and use membrane-bound receptors. Steroid hormones such as cortisol, testosterone and progesterone are lipid-soluble and pass through the membrane to intracellular receptors. The iodothyronines, which are the thyroid hormones, also use intracellular receptors. Two traps are worth marking here. Thyroid hormone is built from an amino acid, yet it behaves like a steroid and works through an intracellular receptor. Epinephrine is also built from an amino acid, but it is water-soluble and works through a membrane-bound receptor. Do not decide the receptor from the raw material of the hormone; decide it from solubility.

Hormones that interact with membrane-bound receptors normally do not enter the target cell at all. The hormone waits outside and is called the first messenger. Its binding changes the shape of the receptor protein, and that change causes a small molecule to be generated or released inside the cell. This inner molecule is the second messenger, and the common ones are cyclic AMP (cAMP), inositol triphosphate (IP₃) and calcium ions (Ca²⁺). The second messenger then switches on enzymes already present in the cytoplasm, and those enzymes regulate the metabolism of the cell.

Two features of this route deserve understanding rather than memorising. First, it is fast, because nothing new has to be manufactured. The enzymes already exist and only have to be turned on, so the response appears within seconds to minutes. Second, it amplifies the signal. One hormone molecule bound outside can cause many second messenger molecules to appear inside, and each of those can activate many enzyme molecules. This is exactly how a hormone present in trace amounts manages to produce a large effect.

Hormones that interact with intracellular receptors work in a completely different way. The hormone enters the cell, binds its receptor, and the hormone-receptor complex interacts with the genome, regulating gene expression or chromosome function. New messenger RNA is transcribed and new proteins are synthesised. Because a protein has to be built before anything visible happens, this route is slow to start, taking hours rather than seconds, but its effects last much longer. That suits the hormones which control growth, development and long-term metabolism.

In both routes the ending is the same. The cumulative biochemical actions inside target cells add up to the physiological and developmental effects that we measure from outside, which is why a single hormone deficiency can change the whole appearance and working of a body.