53 Endocrine Homeostasis and Integration of Systems
Hormones have a wide range of effects and modulate many different body processes. The key processes that will be examined in this section are hormonal regulation of the excretory system, the reproductive system, metabolism, blood calcium concentrations, growth, and the stress response.
We will see how hormones help the body to maintain homeostasis, by integrating different organ systems.
Hormonal Regulation of Fluid Balance
Maintaining a proper water balance in the body is important to avoid dehydration or excess water. The water concentration of the body is monitored by osmoreceptors in the hypothalamus, which detect the concentration of electrolytes in the blood. The concentration of electrolytes in the blood rises when there is water loss due to excessive perspiration, inadequate water intake, or low blood volume due to blood loss. An increase in blood electrolyte levels results in a neural signal being sent from the osmoreceptors to the hypothalamus. The hypothalamus produces antidiuretic hormone (ADH), which is transported to, and released from, the posterior pituitary. It is also known as vasopressin. The target cells for ADH are the distal tubule cells in the kidneys, which are stimulated to absorb more water from urine, resulting in an increase in the water level of blood and making urine which is more concentrated.
Chronic underproduction of ADH results in diabetes insipidus. If the posterior pituitary does not release enough ADH, water cannot be retained by the kidneys and is eliminated in the urine. This causes increased thirst, but water taken in is lost again, and water must be continually consumed. If the condition is not severe, dehydration may not occur, but severe cases can lead to electrolyte imbalances due to dehydration.
Another hormone responsible for maintaining electrolyte concentrations in extracellular fluids is aldosterone, a steroid hormone that is produced by the adrenal cortex. In contrast to ADH, which promotes the reabsorption of water to maintain proper water balance, aldosterone maintains proper water balance by enhancing Na+ reabsorption from extracellular fluids. Because it affects the concentrations of minerals, Na+, aldosterone is referred to as a mineralocorticoid. Aldosterone release is stimulated by a decrease in blood sodium levels, blood volume, or blood pressure, or an increase in blood potassium levels. Aldosterone targets the renal tubules of the kidneys, where it causes the reabsorption of Na+ from urine and the secretion of K+ into the urine. It also prevents the loss of Na+ from sweat, saliva, and gastric juice. The reabsorption of Na+ also results in the osmotic reabsorption of water, which alters blood volume and blood pressure.
Aldosterone production can be stimulated by low blood pressure, which triggers a sequence of chemical releases. When blood pressure drops, cells in the juxtaglomerular apparatus of the kidney detect this and release renin. Renin circulates in the blood and reacts with a protein produced by the liver called angiotensinogen. When angiotensinogen is cleaved by renin, it produces angiotensin I, which is then converted into angiotensin II. Angiotensin II impacts water and Na+ reabsorption and causes the release of aldosterone by the adrenal cortex with a similar effect; ultimately these increase blood pressure. Angiotensin II also causes an increase in ADH and increased thirst, which both help to increase fluids and raise blood pressure.
Hormonal Regulation of the Reproductive System
Regulation of the reproductive system is a process that requires the action of hormones from the pituitary gland, the adrenal cortex, and the gonads. During puberty in both males and females, the hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. These hormones regulate the gonads (testes in males and ovaries in females) and therefore are called gonadotropins. In both males and females, FSH stimulates gamete production, and LH stimulates production of hormones by the gonads. An increase in gonad hormone levels inhibits GnRH production through a negative feedback loop.
Regulation of the Male Reproductive System
In males, FSH and LH regulates the maturation of sperm cells. FSH stimulates the support cells in the testes called Sertoli (sustentacular) cells. These cells nourish and regulate the maturation of the sperm and produce androgen binding protein (ABP). ABP keeps the level of testosterone high within the testes, relative to the plasma levels. FSH production is inhibited by the hormone inhibin, which is also released by the Sertoli cells in the testes. LH stimulates production of the sex hormones (androgens) by the interstitial or Leydig cells of the testes and therefore is also called interstitial cell-stimulating hormone (ICSH).
The most important androgen in males is testosterone. Testosterone promotes the production and maturation of sperm and determines secondary sex characteristics. The adrenal cortex of both males and females also produces small amounts of testosterone, although the role of this additional hormone production in males is not well understood.
Regulation of the Female Reproductive System
In females, FSH stimulates development of support cells around the egg, which develop into structures called follicles. LH regulates the development and release of the egg from the follicle. Follicle cells initially produce the hormone estrogen that has effects on the hypothalamus and anterior pituitary, as well as the uterus. LH stimulates the egg to mature within the growing follicle. As estrogen levels rise, it triggers the anterior pituitary to release a surge of LH that stimulates ovulation. The follicle cells remaining in the ovary become the corpus luteum and now produce both estrogen and progesterone as well as inhibin, all of which inhibit the anterior pituitary.
Estrogen and progesterone are steroid hormones that prepare the body for pregnancy. Estrogen produces secondary sex characteristics in females, while both estrogen and progesterone together regulate the uterine menstrual cycle.
Regulation of Childbirth
In addition to producing FSH and LH, the anterior pituitary also produces the hormone prolactin (PRL). In females, prolactin stimulates the production of milk by the mammary glands following childbirth. Prolactin levels are regulated by the hypothalamic hormones prolactin-releasing hormone (PRH) and prolactin-inhibiting hormone (PIH), the latter of which is now known to be dopamine. Usually prolactin production is inhibited, but PRH, estrogen and infant suckling stimulation remove the inhibition. Males can produce small amounts of prolactin and its role in other aspects of reproduction and immunity are not well understood but are being investigated in humans.
The posterior pituitary releases the hormone oxytocin, which stimulates contractions during childbirth. The uterine smooth muscles are not very sensitive to oxytocin until late in pregnancy when the number of oxytocin receptors in the uterus peaks. Stretching of tissues in the uterus and vagina stimulates oxytocin release in childbirth. Contractions increase in intensity as blood levels of oxytocin rise until the birth is complete. Oxytocin also stimulates the contraction of myoepithelial cells around the milk-producing cells of the mammary glands. As these cells contract, milk is forced from the secretory alveoli into milk ducts and is ejected from the breasts in a milk let-down reflex. Oxytocin release is stimulated by the suckling of an infant, which triggers the synthesis of oxytocin in the hypothalamus and its release into circulation at the posterior pituitary.
Hormonal Regulation of Metabolism
Blood glucose levels vary widely over the course of a day as periods of food consumption alternate with periods of fasting. Insulin and glucagon are the two hormones that are primarily responsible for maintaining homeostasis of blood glucose levels. Additional regulation is mediated by the thyroid hormones.
Regulation of Blood Glucose Levels by Insulin and Glucagon
Cells of the body require nutrients in order to function, and they obtain these nutrients through feeding. In order to manage nutrient intake, storing excess and utilizing stores when necessary, the body uses hormones to modulate energy metabolism. Insulin is produced by the beta cells of the pancreas, which are stimulated to release insulin as blood glucose levels rise, for example, after a meal is consumed. Insulin lowers blood glucose levels by enhancing glucose uptake by most body target cells, which utilize glucose for ATP production; muscle cells are a good example. It also stimulates the liver to convert glucose to glycogen, which is then stored by cells for later use. Increased glucose uptake occurs through an insulin-mediated increase in the number of glucose transporter proteins in cell membranes, which remove glucose from circulation by facilitated diffusion. As insulin binds to its target cell, it triggers the cell to incorporate transport proteins into its membrane. This allows glucose to enter the cell, where it can be used as an energy source. However, this does not always occur in all body cells, as some cells in the kidneys and brain have been shown to regularly access glucose without the use of insulin. Insulin also stimulates the conversion of glucose to fat in adipocytes and the synthesis of proteins. The actions of insulin which cause blood glucose concentrations to fall, called a hypoglycemic effect, inhibit further insulin release from beta cells through a negative feedback loop.
Decreased insulin production or reduced sensitivity of cells to insulin can lead to a condition called diabetes mellitus. This prevents glucose from being absorbed by cells, causing high levels of glucose in the blood, or hyperglycemia. High blood glucose levels make it difficult for the kidneys to reabsorb all the filtered glucose, resulting in glucose being lost in urine. High glucose levels also result in less water being reabsorbed by the kidneys because the water is retained in the urine to osmotically balance the high levels of excess glucose. This causes increased urination, which may result in dehydration. Over time, high blood glucose levels can cause nerve damage to the eyes and peripheral body tissues, as well as damage to the kidneys and cardiovascular system. On the other hand, over-secretion of insulin can lead to low blood glucose levels, or hypoglycemia. This causes insufficient glucose availability to cells, often leading to muscle weakness, and can sometimes cause unconsciousness or death if left untreated.
When blood glucose levels decline below normal levels, for example, between meals or when glucose is utilized rapidly during exercise, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon raises blood glucose levels, called a hyperglycemic effect, by stimulating the breakdown of glycogen to glucose in skeletal muscle cells and liver cells in a process called glycogenolysis (glycogen-splitting). Glucose can then be utilized as energy by muscle cells and released into circulation by the liver cells. Glucagon also stimulates absorption of amino acids from the blood by the liver, which then converts them to glucose. This process of glucose synthesis is called gluconeogenesis (new glucose formation). Glucagon also stimulates adipose cells to release fatty acids into the blood. Collectively, these glucagon-mediated actions result in an increase in blood glucose levels to normal homeostatic levels. Rising blood glucose levels inhibit further glucagon release by the pancreas. In this way, insulin and glucagon work together to maintain glucose homeostasis.
Regulation of Blood Glucose Levels by Thyroid Hormones
The basal metabolic rate, which is the amount of calories required by the body at rest, is determined by two hormones produced by the thyroid gland: thyroxine, also known as tetraiodothyronine or T4, and triiodothyronine, also know as T3. Dietary iodine is needed to synthesize these hormones. These hormones affect nearly every cell in the body except for the adult brain, uterus, testes, and spleen. They cross the plasma membrane of target cells and bind to receptors on the mitochondria, resulting in increased ATP production. In the nucleus, T3 and T4 activate genes involved in energy production and glucose oxidation. This results in increased rates of metabolism and body heat production, which is known as the hormone’s calorigenic effect.
Disorders can arise from both the underproduction and overproduction of thyroid hormones. Hypothyroidism, under activity of the thyroid hormones, can cause a low metabolic rate, leading to weight gain, sensitivity to cold, and reduced mental activity, among other symptoms. In children, hypothyroidism can cause cretinism, which causes mental retardation and growth defects. Hyperthyroidism, the over-activity of thyroid hormones, can lead to an increased metabolic rate, causing weight loss, excess heat production, sweating, and an increased heart rate. Graves’ disease is one such hyperthyroid condition. In the absence of iodine, thyroid hormones are not produced, colloid storage increases, and thyroid enlargement (goiter) occurs.
Hormonal Control of Blood Calcium Levels
Regulation of blood calcium concentration is important for proper muscle contractions and release of neurotransmitters. Calcium also affects voltage-gated plasma membrane ion channels, affecting nerve impulses and other cell physiology. If plasma calcium levels are too high, membrane permeability to sodium decreases and membranes become less responsive. If plasma calcium levels are too low, membrane permeability to sodium increases and convulsions or muscle spasms can result.
Blood calcium levels are regulated by parathyroid hormone (PTH), which is produced by the parathyroid glands. PTH is released in response to low blood Ca2+ levels. PTH increases Ca2+ levels by targeting the skeleton, the kidneys, and the intestine. In the skeleton, PTH stimulates osteoclasts, causing bone to be broken down and releasing Ca2+ from bone into the blood. PTH also inhibits osteoblasts, reducing Ca2+ deposition in bone. In the kidneys and intestines, PTH stimulates the reabsorption of Ca2+. While PTH acts directly on the kidneys to increase Ca2+ reabsorption, its effects on the intestine are indirect. PTH triggers the formation of calcitriol, an active form of vitamin D, which acts on the intestines to increase absorption of dietary calcium. PTH release is inhibited by rising blood calcium levels.
The hormone calcitonin is produced by the parafollicular or C cells of the thyroid and has the opposite effect on blood calcium levels as PTH. Calcitonin decreases blood calcium levels by inhibiting osteoclasts, stimulating osteoblasts, and stimulating calcium excretion by the kidneys. This results in calcium being added to the bones to promote structural integrity. Calcitonin appears to play a major plasma calcium homeostasis role only in children, and in pregnant women to reduce maternal bone loss. Its role in adults is not well understood and it may be more important in regulating bone remodeling than blood plasma homeostasis.
Hormonal Regulation of Growth
Hormonal regulation is required for the growth and replication of most cells in the body. Growth hormone (GH) produced by the anterior pituitary accelerates the rate of protein synthesis, particularly in skeletal muscle and bones. Growth hormone has direct and indirect mechanisms of action. One direct action is the stimulation of fat breakdown (lipolysis) and release into the blood by adipocytes. This results in a switch by most tissues from utilizing glucose as an energy source to utilizing fatty acids. This process is called a glucose-sparing effect. Another direct action occurs in the liver, where GH stimulates glycogen breakdown, and subsequent release of glucose into the blood. Blood glucose levels increase as most tissues are metabolizing fatty acids instead of glucose. The GH-mediated increase in blood glucose levels is called a diabetogenic effect because it is similar to the high blood glucose levels seen in diabetes mellitus.
The indirect mechanism of GH action is mediated by somatomedins or insulin-like growth factors (IGFs), which are a family of growth-promoting proteins produced by the liver. IGFs stimulate the uptake of amino acids from the blood, allowing the formation of new proteins, particularly in skeletal muscle cells, cartilage cells, and other target cells. GH levels are regulated by two hormones produced by the hypothalamus. GH release is stimulated by growth hormone-releasing hormone (GHRH) and is inhibited by growth hormone-inhibiting hormone (GHIH), also called somatostatin. Both of these are produced by the hypothalamus and delivered to the anterior pituitary by the hypophyseal portal vein.
Over-secretion of growth hormone can lead to gigantism in children, causing excessive growth. In adults, excessive GH can lead to acromegaly, a condition in which bones still capable of growth in the face, hands, and feet enlarge. Under-production of GH in adults does not appear to cause any abnormalities, but in children it can result in pituitary dwarfism, in which growth is proportionally reduced.
Hormonal Regulation of Stress
When a threat or danger is perceived, the body responds by releasing hormones that will ready it for the fight-or-flight response. The effects of this response are familiar to anyone who has been in a stressful situation: increased heart rate, dry mouth, butterflies in your stomach and sweating. This is what we call a short-term stress. When one is under stress for more than several hours (or chronically), it translates into long term stress.
The sympathetic nervous system regulates the stress response via the hypothalamus. Stressful stimuli cause the hypothalamus to signal the adrenal medulla via nerve impulses, which mediates short-term stress responses, and to the adrenal cortex, via the hormone adrenocorticotropic hormone (ACTH), which mediates long-term stress response.
Short-Term Stress Response
Upon stimulation, the adrenal medulla releases the hormones epinephrine (also known as adrenaline) and norepinephrine (also known as noradrenaline), collectively referred to as the catecholamines. The release of these hormones into the blood provides the body with a burst of energy that is needed to respond to a stressful situation. Epinephrine and norepinephrine increase blood glucose levels by stimulating the liver and skeletal muscles to break down glycogen and by stimulating glucose release by liver cells. These hormones also increase oxygen availability to cells by increasing the heart rate and dilating the bronchioles. In addition, they increase the blood supply to essential organs such as the heart, brain, and skeletal muscles by stimulating specific blood vessels to relax or by constricting other vessels to divert blood away from nonessential organs such as the skin, digestive system, and kidneys.
Long-Term Stress Response
In a long-term stress response, the hypothalamus triggers the release of ACTH from the anterior pituitary. The adrenal cortex is stimulated by ACTH to release steroid hormones called corticosteroids. The two main corticosteroids are glucocorticoids, such as cortisol, and mineralocorticoids, such as aldosterone. The glucocorticoids primarily affect glucose metabolism by stimulating glucose synthesis. They also stimulate the redistribution of fat stored in adipose tissue for use in meeting long-term energy requirements. Glucocorticoids also have anti-inflammatory properties through inhibition of the immune system. For example, cortisone is used as an anti-inflammatory medication; however, it cannot be used long term as it increases susceptibility to disease due to its immune-suppressing effects as well as changes to blood pressure and constant heart stimulation.
Mineralocorticoids function to regulate ion and water balance of the body. The hormone aldosterone stimulates the reabsorption of water and sodium ions in the kidney, which results in increased blood pressure and volume.
Hypersecretion of glucocorticoids, unrelated to a normal stress response, can be caused by a condition known as Cushing’s disease. This can cause the accumulation of adipose tissue in the face and neck and excessive glucose in the blood. Hyposecretion of the corticosteroids, independent of the normal stress response, is often the result of Addison’s disease, which may result in low blood sugar levels and low electrolyte levels.
Disruption and Dysfunction of Homeostasis
Tumors
Endocrine glands tightly regulate hormone synthesis and release to maintain homeostasis in the body. Although they are rare, tumors in endocrine glands do occur, disrupting normal hormone synthesis. These cancers, called neuroendocrine tumors or NETs, affect cells of the endocrine and nervous system that control hormone synthesis.
Tumors of endocrine glands can produce symptoms that are similar to those caused by hypersecretion of hormones in endocrine disorders. For example, tumors of the adrenal glands that result in the excess production of steroid hormones produce symptoms of Cushing’s disease, which includes the accumulation of adipose tissue in the face and neck and excessive glucose in the blood.
Tumors of the pancreas that affect beta cells are called insulinomas, and those that affect alpha cells are called glucagonomas. Beta cell tumors result in the production of excess amounts of the hormone insulin, which results in hypoglycemia. Alpha cell tumors result in the production of excess amounts of the hormone glucagon, which results in hyperglycemia and symptoms similar to those seen in diabetes.
Tumors of the pituitary gland fall into two groups: secreting and non-secreting tumors. Secreting tumors cause the secretion of excess amounts of pituitary hormones. Symptoms of secreting pituitary tumors are related to the function of the hormone that is affected. For example, growth hormone-producing tumors can lead to gigantism and acromegaly.
Medullary thyroid cancer (MTC) is a cancer of the parafollicular cells of the thyroid gland. The parafollicular cells produce the hormone calcitonin, which plays a role in calcium regulation and bone formation. Unlike in other cancers, the increased levels of calcitonin produced by MTC in adults are not harmful. Increased blood calcitonin levels are used to diagnose MTC.
Many secretory NETs can be tentatively diagnosed by measuring blood hormone levels to identify hormones that are present in excess. Treatment of these tumors can include surgery to remove the tumor or affected endocrine gland and chemotherapy.
Osteoporosis
Osteoporosis is a disease of the skeletal system characterized by a decrease in bone density and deterioration of bone tissue. The mechanism of disease onset is an imbalance between bone formation and bone resorption, with bone resorption occurring at a greater rate than bone formation. Hormone levels play a vital role in maintaining a balance in bone turnover. Osteoporosis affects primarily the elderly and is three times more common in women than in men. This may be related to lower peak bone mass in women and to hormonal changes that occur during menopause. Low estrogen levels increase the rate of bone turnover, which alters the balance between bone formation and bone resorption. The decrease in estrogen that occurs during menopause appears to be the primary cause of osteoporosis in women over 50 years of age.
The elderly also have decreased levels of the hormone calcitriol, which is the active form of vitamin D3. Vitamin D helps maintain calcium balance in the skeleton by stimulating calcium absorption in the intestines and by maintaining calcium and phosphate levels for bone formation. Vitamin D also helps to maintain homeostatic levels of parathyroid hormone (PTH). Decreased vitamin D levels are associated with increased PTH levels, which result in increased bone turnover and bone loss.
Decreased dietary intake of calcium in the elderly is also associated with osteoporosis. In addition to the decreased availability of calcium for bone formation, low blood calcium levels stimulate the parathyroid glands to synthesize more PTH. PTH stimulates the release of calcium from bones to maintain blood calcium levels, resulting in increased bone loss.
Osteoporosis can be prevented by maintaining a lifestyle that includes exercise and proper nutrition. It can be treated using the hormone calcitonin, which is normally produced by the parafollicular cells of the thyroid gland. Calcitonin functions to lower blood calcium levels and promotes bone formation. Calcium and vitamin D supplements have also been shown to reduce the incidence of osteoporosis.
