18. HORMONE ACTIVITY

18. HORMONE ACTIVITY

The Role of Hormone Receptors

• Although a given hormone travels throughout the body in the blood, it affects only specific target cells. 
• Hormones, like neuro-transmitters, influence their target cells by chemically binding to specific protein receptors. 
• Only the target cells for a given hormone have receptors that bind and recognize that hormone. 

For example, 

• thyroid-stimulating hormone (TSH) binds to receptors on cells of the thyroid gland, 
• but it does not bind to cells of the ovaries because ovarian cells do not have TSH receptors.

• Receptors, like other cellular proteins, are constantly being synthesized and broken down. 
• Generally, a target cell has 2000 to 100,000 receptors for a particular hormone. 

• If a hormone is present in excess, the number of target-cell receptors may decrease—an effect called down-regulation. 

For example, 

• when certain cells of the testes are exposed to a high concentration of luteinizing hormone (LH), the number of LH receptors decreases. 
• Down-regulation makes a target cell less sensitive to a hormone. 

• In contrast, when a hormone is deficient, the number of receptors may increase. This phenomenon, known as upregulation,
• makes a target cell more sensitive to a hormone.

CLINICAL CONNECTION 

Blocking Hormone Receptors

• Synthetic hormones that block the receptors for some naturally occurring hormones are available as drugs.

 For example, 


RU486 (mifepristone), which is used to induce abortion, 

• binds to the receptors for progesterone (a female sex hormone) 
• and prevents progesterone from exerting its normal effect, in this case preparing the lining of the uterus for implantation. 

When RU486 is given to a pregnant woman, 

• the uterine conditions needed for nurturing an embryo are not maintained, 
• embryonic development stops, 
• and the embryo is sloughed off along the the uterine lining.

 This example illustrates an important endocrine principle:

•  If a hormone is prevented from interacting with its receptors the hormone cannot perform its normal functions. 

Circulating and Local Hormones

• Most endocrine hormones are circulating hormones
• —they pass from the secretory cells that make them into interstitial fluid and then into the blood. 

• Other hormones, termed local hormones, act locally on neighboring cells or on the same cell that secreted them without first entering the bloodstream. 

• Local hormones that act on neighboring cells are called paracrines (para- beside or near), 
• and those that act on the same cell that secreted them are called autocrines (auto- self ). 

One example of a local hormone is 

• interleukin 2 (IL-2), 
• which is released by helper T cells (a type of white blood cell) during immune responses . 
• IL-2 helps activate other nearby immune cells, a paracrine effect. 
• But it also acts as an autocrine by stimulating the same cell that released it to proliferate. 
• This action generates more helper T cells that can secrete even more IL-2 and thus strengthen the immune response.

 Another example of a local hormone is 

• the gas nitric oxide (NO), 
• which is released by endothelial cells lining blood vessels. 
• NO causes relaxation of nearby smooth muscle fibers in blood vessels, which in turn causes vasodilation (increase in  blood vessel diameter). 
• The effects of such vasodilation range from a lowering of blood pressure to erection of the penis in males. 
• The drug Viagra® (sildenafil) enhances the effects stimulated by nitric oxide in the penis.

• Local hormones usually are inactivated quickly; 
• circulating hormones may linger in the blood and exert their effects for a few minutes or occasionally for a few hours. 

• In time, circulating hormones are inactivated by the liver and excreted by the kidneys. 
• In cases of kidney or liver failure, excessive levels of hormones may build up in the blood.

Chemical Classes of Hormones

• Chemically, hormones can be divided into two broad classes:

1. those that are soluble in lipids, 
2. and those that are soluble in water.

• This chemical classification is also useful functionally because the two classes exert their effects differently.

A. Lipid-soluble Hormones

The lipid-soluble hormones include 

• steroid hormones, 
• thyroid hormones, and 
• nitric oxide.

1. Steroid hormones 

• are derived from cholesterol. 
• Each steroid hormone is unique due to the presence of different chemical groups attached at various sites on the four rings at the core of its structure. 
• These small differences allow for a large diversity of functions.

2. Two thyroid hormones (T3 and T4) 

• are synthesized by attaching iodine to the amino acid tyrosine. 
• The benzene ring of tyrosine plus the attached iodines make T3 and T4 very lipid soluble.

3. The gas nitric oxide (NO)

•  is both a hormone and a neurotransmitter. 
• Its synthesis is catalyzed by the enzyme nitric oxide synthase.

B. Water-soluble Hormones

• The water-soluble hormones include 
• amine hormones, 
• peptide and protein hormones, and 
• eicosanoid hormones.

1. Amine hormones 

• are synthesized by decarboxylating (removing a molecule of CO2) and otherwise modifying certain amino acids. 
• They are called amines because they retain an amino group (9NH3 ). 
• The catecholamines—epinephrine, norepinephrine, and dopamine—are synthesized by modifying the amino acid tyrosine. 
• Histamine is synthesized from the amino acid histidine by mast cells and platelets. 
• Serotonin and melatonin are derived from tryptophan.

2. Peptide hormones and protein hormones 

• are amino acid polymers. 
• The smaller peptide hormones consist of chains of 3 to 49 amino acids; 
• the larger protein hormones include 50 to 200 amino acids. 

Examples of peptide hormones are

• antidiuretic hormone and oxytocin; 

protein hormones include

• human growth hormone and insulin. 

• Several of the protein -hormones, such as thyroid-stimulating hormone, have attached carbohydrate groups 
• and thus are glycoprotein hormones.

3. The eicosanoid hormones ( eicos- twenty forms; -oid resembling) 

• are derived from arachidonic acid, a 20-carbon fatty acid. 
• The two major types of eicosanoids are 

1. prostaglandins and
2.  leukotrienes. 

• The eicosanoids are important local hormones,
•  and they may act as circulating hormones-

Hormone Transport in the Blood

• Most water-soluble hormone molecules circulate in the watery blood plasma in a “free” form (not attached to other molecules),
• but most lipid-soluble hormone molecules are bound to transport proteins. 
• The transport proteins, which are synthesized by cells in the liver, have three functions:

1. They make lipid-soluble hormones temporarily watersoluble,

• thus increasing their solubility in blood.

2. They retard passage of small hormone molecules through the filtering mechanism in the kidneys, 

• thus slowing the rate of hormone loss in the urine.

3. They provide a ready reserve of hormone, 

• already present in the bloodstream.

• In general, 0.1–10% of the molecules of a lipid-soluble hormone are not bound to a transport protein. 
• This free fraction diffuses out of capillaries, 
• binds to receptors,
•  and triggers responses. 

• As free hormone molecules leave the blood and bind to their receptors, transport proteins release new ones to replenish the free fraction.

 CLINICAL CONNECTION 

Administering Hormones

• Both steroid hormones and thyroid hormones are effective when taken by mouth. 
• They are not split apart during digestion 
• and easily cross the intestinal lining because they are lipid-soluble. 

• By contrast, peptide and protein hormones, such as insulin, are not effective oral medications because digestive enzymes destroy them by breaking their peptide bonds. 
• This is why people who need insulin must take it by injection.

MECHANISMS OF HORMONE ACTION

• The response to a hormone depends on both the hormone and the target cell. 
• Various target cells respond differently to the same hormone. 

Insulin, for example,

•  stimulates synthesis of glycogen in liver cells 
• and synthesis of triglycerides in adipose cells.

• The response to a hormone is not always the synthesis of new molecules, as is the case for insulin. 

Other hormonal effects include 

• changing the permeability of the plasma membrane, 
• stimulating transport of a substance into or out of the target cells, 
• altering the rate of specific metabolic reactions, 
• or causing contraction of smooth muscle or cardiac muscle. 

• In part, these varied effects of hormones are possible because a single hormone can set in motion several different cellular responses.

• However, a hormone must first “announce its arrival” to a target cell by binding to its receptors. 
• The receptors for lipid-soluble hormones are located inside target cells. 
• The receptors for water-soluble hormones are part of the plasma membrane of target cells.

Action of Lipid-soluble Hormones

•  lipid-soluble hormones, including steroid hormones and thyroid hormones, bind to receptors within target cells. 

Their mechanism of action is as follows 

1. A free lipid-soluble hormone molecule 

• diffuses from the blood, 
• through interstitial fluid, 
• and through the lipid bilayer of the plasma membrane into a cell.

2. If the cell is a target cell, 

• the hormone binds to and activates receptors located within the cytosol or nucleus. 
• The activated receptor–hormone complex then alters gene expression: 
• It turns specific genes of the nuclear DNA on or off.

3. As the DNA is transcribed, 

• new messenger RNA (mRNA) forms, 
• leaves the nucleus, 
• and enters the cytosol. 
• There, it directs synthesis of a new protein, often an enzyme, on the ribosomes.

4 The new proteins 

• alter the cell’s activity
•  and cause the responses typical of that hormone.

Action of Water-soluble Hormones

• Because amine, peptide, protein, and eicosanoid hormones are not lipid-soluble, they cannot diffuse through the lipid bilayer of the plasma membrane and bind to receptors inside target cells.
• Instead, water-soluble hormones bind to receptors that protrude from the target cell surface. 
• The receptors are integral transmembrane proteins in the plasma membrane. 

• When a watersoluble hormone binds to its receptor at the outer surface of the plasma membrane,  
• it acts as the first messenger. 
• The first messenger (the hormone) then causes production of a second messenger inside the cell, where specific hormone-stimulated responses take place.
•  One common second messenger is cyclic AMP (cAMP). 
• Neurotransmitters, 
• neuropeptides, 
• and several sensory transduction mechanisms (for example, vision; ) also act via second-messenger systems. 

The action of a typical water-soluble hormone occurs as follows :

1. A water-soluble hormone (the first messenger) diffuses from the blood through interstitial fluid

•  and then binds to its receptor at the exterior surface of a target cell’s plasma membrane. 
• The hormone–receptor complex activates a membrane protein called a G protein. 
• The activated G protein in turn activates adenylate cyclase.

2. Adenylate cyclase 

• converts ATP into cyclic AMP (cAMP).
• Because the enzyme’s active site is on the inner surface of the plasma membrane, this reaction occurs in the cytosol of the cell.

3 Cyclic AMP (the second messenger) 

• activates one or more protein kinases, which may be free in the cytosol or bound to the plasma membrane. 
• A protein kinase is an enzyme that phosphorylates (adds a phosphate group to) other cellular proteins (such as enzymes). 
• The donor of the phosphate group is ATP, which is converted to ADP.

4. Activated protein kinases 

• phosphorylate one or more cellular proteins. 
• Phosphorylation activates some of these proteins and inactivates others, rather like turning a switch on or off.

5. Phosphorylated proteins 

• in turn cause reactions that produce physiological responses. 
• Different protein kinases exist within different target cells and within different organelles of the same target cell. 

 Thus, 

• one protein kinase might trigger glycogen synthesis,
•  a second might cause the breakdown of triglyceride, 
• a third may promote protein synthesis, and so forth. 

• As noted in step 4 , phosphorylation by a protein kinase can also inhibit certain proteins.

 For example,

• some of the kinases unleashed when epinephrine binds to liver cells inactivate an enzyme needed for glycogen synthesis.

6 After a brief period, 

• an enzyme called phosphodiesterase inactivates cAMP. 
• Thus, the cell’s response is turned off unless new hormone molecules continue to bind to their receptors in the plasma membrane.
• The binding of a hormone to its receptor activates many G-protein molecules, 
• which in turn activate molecules of adenylate cyclase (as noted in step ●1 ). 

• Unless they are further stimulated by the binding of more hormone molecules to receptors, 
• G proteins slowly inactivate, 
• thus decreasing theactivity of adenylate cyclase 
• and helping to stop the hormone response. 

• G proteins are a common feature of most secondmessenger systems.

• Many hormones exert at least some of their physiological effects through the increased synthesis of cAMP. 

Examples include

• antidiuretic hormone (ADH), 
• thyroid-stimulating hormone (TSH), 
• adrenocorticotropic hormone (ACTH), 
• glucagon, 
• epinephrine,
• and hypothalamic–releasing hormones. 

• In other cases, such as growth hormone–inhibiting hormone (GHIH), the level of cyclic AMP decreases in response to the binding of a hormone to its receptor. 

Besides cAMP, other second messengers include 

• calcium ions (Ca2+ ), 
• cGMP (cyclic guanosine monophosphate, a cyclic nucleotide similar to cAMP), 
• inositol trisphosphate (IP3), and
•  diacylglycerol (DAG). 

• A given hormone may use different second messengers in different target cells.

• Hormones that bind to plasma membrane receptors can induce their effects at very low concentrations because they initiate a cascade or chain reaction,
•  each step of which multiplies or amplifies the initial effect. 

For example, 

• the binding of a single molecule of epinephrine to its receptor on a liver cell may activate a hundred or so G proteins, each of which activates an adenylate cyclase molecule. 
• If each adenylate cyclase produces even 1000 cAMP, then 100,000 of these second messengers will be liberated inside the cell. 
• Each cAMP may activate a protein kinase, 
• which in turn can act on hundreds or thousands of substrate molecules. 

• Some of the kinases phosphorylate
•  and activate a key enzyme needed for glycogen breakdown. 
• The end result of the binding of a single molecule of epinephrine to its receptor is the breakdown of millions of glycogen molecules into glucose monomers.

Hormone Interactions

• The responsiveness of a target cell to a hormone depends on

(1) the hormone’s concentration, 
(2) the abundance of the target cell’s hormone receptors, and
(3) influences exerted by other hormones. 

• A target cell responds more vigorously when the level of a hormone rises or when it has more receptors (up-regulation). 

• In addition, the actions of some hormones on target cells require a simultaneous or recent exposure to a second hormone. 
• In such cases, the second hormone is said to have a permissive effect. 

For example, 

• epinephrine alone only weakly stimulates lipolysis (the breakdown of triglycerides),
• but when small amounts of thyroid hormones (T3 and T4) are present, the same amount of epinephrine stimulates lipolysis much more powerfully. 

• Sometimes the permissive hormone increases the number of receptors for the other hormone, and 
• sometimes it promotes the synthesis of an enzyme required for the expression of the other hormone’s effects.

• When the effect of two hormones acting together is greater or more extensive than the effect of each hormone acting alone, the two hormones are said to have a synergistic effect. 

For example, 

• normal development of oocytes in the ovaries requires both follicle-stimulating hormone from the anterior pituitary and estrogens from the ovaries. 
• Neither hormone alone is sufficient.

• When one hormone opposes the actions of another hormone, the two hormones are said to have antagonistic effects. 

An example of an antagonistic pair of hormones is 

• insulin, which promotes synthesis of glycogen by liver cells, and 
• glucagon, which stimulates breakdown of glycogen in the liver.

18. ENDOCRINE GLANDS AND EXOCRINE GLANDS

18. ENDOCRINE GLANDS AND EXOCRINE GLANDS

• the body contains two kinds of glands: 

1. exocrine glands and 
2. endocrine glands. 

Exocrine glands (exo- outside) 

• secrete their products into ducts that carry the secretions into body cavities, into the lumen of an organ, or to the outer surface of the body. 
• Exocrine glands include 

1. sudoriferous (sweat), 
2. sebaceous (oil), 
3. mucous, and 
4. digestive glands.

Endocrine glands (endo- within) 

• secrete their products (hormones) into the interstitial fluid surrounding the secretory cells rather than into ducts. 
• From the interstitial fluid, hormones diffuse into blood capillaries and blood carries them to target cells throughout the body. 
• Because most hormones are required in very small amounts, circulating levels typically are low.

The endocrine glands include 

1. the pituitary,
2.  thyroid, 
3. parathyroid,
4. adrenal, and 
5. pineal glands 

•  In addition, several organs and tissues are not exclusively classified as endocrine glands but contain cells that secrete hormones. 
• These include the

1.  hypothalamus, 
2. thymus, 
3. pancreas, 
4. ovaries, 
5. testes,
6. kidneys, 
7. stomach, 
8. liver, 
9. small intestine, 
10. skin, 
11. heart, 
12. adipose tissue, and 
13. placenta. 

• Taken together, all endocrine glands and hormone-secreting cells constitute the endocrine system. 
• The science of the structure and function of the endocrine glands-and the diagnosis and treatment of disorders of the endocrine system is endocrinology ( endo- within; -crino to secrete; -logy study of).

18. COMPARISON OF CONTROL BY THE NERVOUS AND ENDOCRINE SYSTEMS

18. COMPARISON OF CONTROL BY THE NERVOUS AND ENDOCRINE SYSTEMS

• The nervous and endocrine systems act together to coordinate functions of all body systems. 

•  the nervous system acts through nerve impulses (action potentials) conducted along axons of neurons. 
• At synapses, nerve impulses trigger the release of mediator (messenger) molecules called neurotransmitters. 

• The endocrine system also controls body activities by releasing mediators, called hormones,
• but the means of control of the two systems are very different.

• A hormone (hormon to excite or get moving) is a mediator molecule that is released in one part of the body 
• but regulates the activity of cells in other parts of the body. 
• Most hormones enter interstitial fluid and then the bloodstream. 
• The circulating blood delivers hormones to cells throughout the body. 

• Both neurotransmitters and hormones exert their effects by binding to receptors on or in their “target” cells. 

• Several mediators act as both neurotransmitters and hormones.
• One familiar example is norepinephrine, which is released as 
• a neurotransmitter by sympathetic postganglionic neurons and 
• as a hormone by chromaffin cells of the adrenal medullae.

• Responses of the endocrine system often are slower than responses of the nervous system; 
• although some hormones act within seconds, most take several minutes or more to cause a response. 

• The effects of nervous system activation are generally briefer than those of the endocrine system. 

• The nervous system acts on specific muscles and glands.

•  The influence of the endocrine system is much broader; 
• it helps regulate virtually all types of body cells.

• We will also have several opportunities to see how the nervous and endocrine systems function together as an interlocking “super- system.”

 For example, 

• certain parts of the nervous system stimulate or inhibit the release of hormones by the endocrine system.

Comparison of Control by the Nervous and Endocrine Systems
CHARACTERISTIC	NERVOUS                  SYSTEM	ENDOCRINE            SYSTEM
Mediator molecules	Neurotransmitters released locally in response to nerve impulses.	Hormones delivered to tissues throughout the body by the blood.
Site of mediator action	Close to site of release, at a synapse; binds to receptors in postsynaptic membrane.	Far from site of release (usually);  binds to receptors on or in target cells.
Types of target cells	Muscle (smooth, cardiac, and skeletal) cells,  gland cells, other neurons.	Cells throughout the body.
Time to onset of action	Typically within milliseconds (thousandths of a second).	Seconds to hours or days.
Duration of action	Generally briefer (milliseconds).	Generally longer (seconds to days).

18. THE ENDOCRINE SYSTEM AND HOMEOSTASIS

18. THE ENDOCRINE SYSTEM

18. THE ENDOCRINE SYSTEM AND HOMEOSTASIS

• Circulating or local hormones of the endocrine system contribute to homeostasis by regulating the activity and growth of target cells in your body. 
• Hormones also regulate our metabolism.

• As girls and boys enter puberty, they start to develop striking differences in physical appearance and behavior. 
• Perhaps no other period in life so dramatically shows the impact of the endocrine system in directing development and regulating body functions. 

In girls,

• estrogens promote accumulation of adipose tissue in the breasts and hips,
•  sculpting a feminine shape. 

At the same time or a little later, 

• increasing levels of testosterone in boys begin to help build muscle mass and enlarge the vocal cords, producing a lowerpitched voice.

•  These changes are just a few examples of the powerful influence of endocrine secretions. 
• Less dramatically, perhaps, multitudes of hormones help maintain homeostasis on a daily basis. 
• They regulate the activity of smooth muscle, cardiac muscle, and some glands; 
• alter metabolism;
• spur growth and development; 
• influence reproductive processes; 
• and participate in circadian (daily) rhythms established by the suprachiasmatic nucleus of the hypothalamus.

6. BONE’S ROLE IN CALCIUM HOMEOSTASIS

6. BONE’S ROLE IN CALCIUM HOMEOSTASIS

• Bone is the body’s major calcium reservoir, storing 99% of total body calcium. 

• One way to maintain the level of calcium in the blood 

1. is to control the rates of calcium resorption from bone into blood and of calcium deposition from blood into bone. 

•  Both nerve and muscle cells depend on a stable level of calcium ions (Ca²⁺ ) in extracellular fluid to function properly. 
• Blood clotting also requires Ca²⁺. 
• Also, many enzymes require Ca²⁺ as a cofactor (an additional substance needed for an enzymatic reaction to occur). 
• For this reason, the blood plasma level of Ca²⁺  is very closely regulated between 9 and 11 mg/100 mL. 

Even small changes in Ca²⁺ concentration outside this range may prove fatal—

• the heart may stop (cardiac arrest) if the concentration goes too high,
•  or breathing may cease (respiratory arrest) if the level falls too low. 

The role of bone in calcium homeostasis is to help “buffer” the blood Ca²⁺ level, 

• releasing Ca²⁺ into blood plasma (using osteoclasts) when the level decreases, 
• and absorbing Ca²⁺ (using osteoblasts) when the level rises.

1. Parathyroid hormone (PTH)

• Ca²⁺ exchange is regulated by hormones, the most important of which is parathyroid hormone (PTH) secreted by the parathyroid glands . 
• This hormone increases blood Ca²⁺ level.

• PTH secretion operates via a negative feedback system .
•  If some stimulus causes the blood Ca²⁺ level to decrease, parathyroid gland cells (receptors) detect this change and increase their production of a molecule known as cyclic adenosine monophosphate (cyclic AMP). 
• The gene for PTH within the nucleus of a parathyroid gland cell (the control center) detects the intracellular increase in cyclic AMP (the input). 
• As a result, PTH synthesis speeds up, and more PTH (the output) is released into the blood. 
• The presence of higher levels of PTH increases the number and activity of osteoclasts (effectors), which step up the pace of bone resorption.
• The resulting release of  Ca²⁺  from bone into blood returns the blood Ca²⁺ level to normal.

• PTH also acts on the kidneys (effectors) to decrease loss of Ca²⁺ in the urine, so more is retained in the blood. 
• And PTH stimulates formation of calcitriol (the active form of vitamin D), a hormone that promotes absorption of calcium from foods in the gastrointestinal tract into the blood. 
• Both of these actions also help elevate blood Ca²⁺level.

2. Calcitonin (CT)

• Another hormone works to decrease blood Ca²⁺ level. 
• When blood  Ca²⁺ rises above normal, parafollicular cells in the thyroid gland secrete calcitonin (CT). 
• CT inhibits activity of osteoclasts, speeds blood Ca²⁺ uptake by bone, and accelerates Ca²⁺ deposition into bones. 

• The net result is that CT promotes- bone formation and decreases blood Ca²⁺ level. 
• Despite these effects, the role of CT in normal calcium homeostasis is uncertain because it can be completely absent without causing- symptoms. 

• Nevertheless, calcitonin harvested from salmon ( Miacalcin®) is an effective drug for treating osteoporosis because it slows bone resorption.

EXERCISE AND BONE TISSUE

• Within limits, bone tissue has the ability to alter its strength in response to changes in mechanical stress. 
• When placed under stress, bone tissue becomes stronger through increased deposition of mineral salts and production of collagen fibers by osteoblasts. 
• Without mechanical stress, bone does not remodel normally because bone resorption occurs more quickly than bone formation.

• The main mechanical stresses on bone are those that result from 

1. the pull of skeletal muscles and 
2. the pull of gravity. 

• If a person is bedridden or has a fractured bone in a cast, the strength of the unstressed bones diminishes because of the loss of bone minerals and decreased numbers of collagen fibers. 
• Astronauts subjected to the microgravity of space also lose bone mass. 
• In both cases, bone loss can be dramatic—as much as 1% per week.

•  In contrast, the bones of athletes, which are repetitively and highly stressed, become notably thicker and stronger than those of astronauts or nonathletes. 
• Weight-bearing activities, such as walking or moderate weight lifting, help build and retain bone mass. 
• Adolescents and young adults should engage in regular weight-bearing exercise prior to the closure of the epiphyseal -plates to help build total mass prior to its inevitable reduction with aging. 
• However, people of all ages can and should strengthen their bones by engaging in weight-bearing exercise.

AGING AND BONE TISSUE-

• From birth through adolescence, more bone tissue is produced than is lost during bone remodeling. 
• In young adults the rates of bone deposition and resorption are about the same. 
• As the level of sex hormones diminishes during middle age, especially in women after menopause, a decrease in bone mass occurs because bone resorption by osteoclasts outpaces bone deposition by osteoblasts. 

• In old age, loss of bone through resorption occurs more rapidly than bone gain. 
• Because women’s bones generally are smaller and less massive than men’s bones to begin with, loss of bone mass in old age typically has a greater adverse effect in females. 
• These factors contribute to the higher incidence of osteoporosis in females.

• There are two principal effects of aging on bone tissue: 

1. loss of bone mass and
2.  brittleness. 

1. Loss of bone mass results from -

• demineralization , the loss of calcium and other minerals from bone extracellular matrix. 
• This loss usually begins after age 30 in females, -
• accelerates greatly around age 45 as levels of estrogens decrease, 
• and continues until as much as 30% of the calcium in bones is lost by age 70.

• Once bone loss begins in females, about 8% of bone mass is lost every 10 years.

•  In males, calcium loss typically does not begin until after age 60, 
• and about 3% of bone mass is lost every 10 years. 

• The loss of calcium from bones is one of the problems in osteoporosis 

2. The second principal effect of aging on the skeletal system, brittleness, 

• results from a decreased rate of protein synthesis.
• the organic part of bone extracellular matrix, mainly collagen fibers, gives bone its tensile strength. 
• The loss of tensile strength causes the bones to become very brittle and susceptible to fracture. 

• In some elderly people, collagen fiber synthesis slows, in part, due to diminished production of human growth hormone. 
• In addition to increasing the susceptibility to fractures, loss of bone mass also leads to deformity, pain, loss of height, and loss of teeth.

Factors That Influence Bone Metabolism
FACTOR	COMMENT
MINERALS
Calcium and phosphorus	Make bone extracellular matrix hard
Magnesium	Helps form bone extracellular matrix.
Fluoride	Helps strengthen bone extracellular matrix.
Manganese	Activates enzymes involved in synthesis of bone extracellular matrix.
VITAMINS
Vitamin A	Needed for the activity of osteoblasts during remodeling of bone; deficiency stunts bone growth; toxic in high doses.
Vitamin C	Needed for synthesis of collagen, the main bone protein; deficiency leads to decreased collagen production, which slows down bone growth and delays repair of broken bones.
Vitamin D Active form (calcitriol)	is produced by the kidneys; helps build bone by increasing absorption of calcium from gastrointestinal tract into blood; deficiency causes faulty calcification and slows down bone growth; may reduce the risk of osteoporosis but is toxic if taken in high doses.
Vitamins K and B12 .	Needed for synthesis of bone proteins; deficiency leads to abnormal protein production in bone extracellular matrix and decreased bone density
HORMONES
Human growth hormone (hGH)	Secreted by the anterior lobe of the pituitary gland; promotes general growth of all body tissues, including bone, mainly by stimulating production of insulinlike growth factors.
Insulinlike growth factors (IGFs) .	Secreted by the liver, bones, and other tissues upon stimulation by human growth hormone; promotes normal bone growth by stimulating osteoblasts and by increasing the synthesis of proteins needed to build new bone
Thyroid hormones  (thyroxine and triiodothyronine)	Secreted by thyroid gland; promote normal bone growth by stimulating osteoblasts.
Insulin	Secreted by the pancreas; promotes normal bone growth by increasing the synthesis of bone proteins.
Sex hormones (estrogens and testosterone)	Secreted by the ovaries in women (estrogens) and by the testes in men (testosterone); stimulate osteoblasts and promote the sudden “growth spurt” that occurs during the teenage years; shut down growth at the epiphyseal plates around age 18–21, causing lengthwise growth of bone to end; contribute to bone remodeling during adulthood by slowing bone resorption by osteoclasts and promoting bone deposition by osteoblasts
Parathyroid hormone (PTH)	Secreted by the parathyroid glands; promotes bone resorption by osteoclasts; enhances recovery of calcium ions from urine; promotes formation of the active form of vitamin D (calcitriol).
Calcitonin (CT)	Secreted by the thyroid gland; inhibits bone resorption by osteoclast
EXERCISE
	Weight-bearing activities stimulate osteoblasts and, consequently, help build thicker, stronger bones and retard loss of bone mass that occurs as people age.
AGING
	As the level of sex hormones diminishes during middle age to older adultood, especially in women after menopause, bone resorption by osteoclasts outpaces bone deposition by osteoblasts, which leads to a decrease in bone mass and an increased risk of osteoporosis