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Chapter 14
The endocrine system consists of all body
structures that secrete hormones (Fig.
14.1,
Fig. 14.2). Hormones are substances that result from manufacturing processes in
cells, are secreted into the blood, and alter the activities of cells in other
parts of the body. Body materials with only one or two of these characteristics
are not hormones (e.g., CO2, lactic acid, oil from sebaceous glands,
blood-clotting materials). Many scientists now consider vitamin D a hormone
rather than a dietary nutrient because it can be manufactured in the body,
enters the blood, and increases intestinal calcium absorption.
Many endocrine system structures (e.g., heart, stomach) have
additional important functions. Usually, only endocrine structures that seem to
have hormone secretion as their primary function are called endocrine
glands (e.g., pituitary gland, thyroid gland, adrenal glands).
Main Functions for Homeostasis
Like the nervous system, the overall job of the endocrine
system is to regulate parts of the body and ensure that they contribute to
maintaining homeostasis. The main functions for homeostasis of this system are
similar to four of those performed by the nervous system: monitoring,
communicating, stimulating, and coordinating (Chap. 6). However, the endocrine
system performs these functions somewhat differently.
When an endocrine structure detects that a body condition is
changing or has strayed from homeostasis, it secretes a hormone, which
communicates information about the errant condition to other body cells. The
hormone also causes alterations in cell activities to stop the change from
occurring and bring the straying condition back into the homeostatic range.
Often the hormone alters functions in many types of cells in several ways and
therefore coordinates adaptive responses in various organs. For example, if the
concentration of calcium in the blood declines, the parathyroid gland detects
this change and secretes parathormone. The parathormone causes the blood
calcium level to rise back to normal through its effects on bones, the small
intestine, and the kidneys. The parathyroid gland then detects the rise in
blood calcium and diminishes parathormone secretion, preventing the calcium
concentration from rising too high. If calcium levels rise above a satisfactory
level, the thyroid gland secretes thyrocalcitonin, which lowers blood calcium
through its effects on bone matrix. Therefore, like the nervous system, the
endocrine system performs the first two steps in negative feedback systems and
contributes to the third by causing adaptive responses by parts of the body.
Negative feedback responses are not governed simply by turning hormone
secretions and the functions being controlled on and off as thermostats do in
systems operating heaters and air conditions. Negative feedback control by the
endocrine system can produce a continuous gradation and modulation in the rates
of hormone secretion and functional alterations.
Therefore, negative feedback responses in the endocrine system
operate more like a driver who maintains a proper and fairly steady speed on a
hilly highway by adjusting foot pressure on the accelerator and brake pedals of
a vehicle. Furthermore, like slightly excessive foot pressure on an accelerator
or a brake pedal, the amount of circulating hormone can become slightly too
high or low. Though a small error may cause no harm over a short period,
sustaining such a condition can result in substantial deviations in the
condition being regulated. Normally, negative feedback responses prevent such
occurrences. Finally, like an alert driver, the endocrine system is a highly
sensitive and rapidly responsive negative feedback system that can reverse
shifts in hormone levels quickly so that minimal fluctuations occur. There are
a few situations in which the endocrine system provides positive feedback
responses, which increase rather than decrease change. These situations involve
functions in the female reproductive system that cause ovulation by the ovary
and milk production by the breasts. These functions end during menopause.
Comparing Endocrine and Nervous Systems
Since the overall job and main functions of the endocrine
system are very similar to several functions performed by the nervous system,
why does the body have both systems? A comparison reveals that these systems
complement rather than duplicate each other.
The nervous system can cause adaptive responses such as the
blink of an eye with pinpoint accuracy and within a fraction of a second
because it uses nerve impulses and highly specialized and localized
connections. It is also able to provide remembering and thinking. However, the
nervous system can directly control only neurons, muscle contractions, and
secretions from a few glands (e.g., sweat glands, salivary glands).
Furthermore, this system has difficulty sustaining long-term control of
activities because neurotransmitters become depleted.
While minutes or hours may be required for an endocrine
structure to secrete enough hormone to cause an adaptive response, the hormone
may remain in the blood and cause the adaptive response to continue for many
hours. Additional hormone can be secreted gradually to continue long-term
responses for days, weeks, or months (e.g., growth, maturation). Furthermore,
hormones can directly control many body cells and functions that are not
influenced by neurotransmitters, including epidermis, bone, cartilage, and
blood cells. Representative functions include growth and gene activity. In
fact, every type of body cell has at least some of its functions regulated by
hormones.
Though the nervous and endocrine systems have exclusive
control of certain body activities, they share responsibility for regulating
others, such as GI tract functioning and blood pressure.
Coordination of the nervous and endocrine systems is
provided by three communication links. The hypothalamus and infundibulum at the
base of the brain provide one main link by which the brain can influence
hormone secretion by the pituitary gland ((Fig.
14.1,
Fig. 14.2).
The hypothalamus uses neurons to send hormones through the infundibulum
and into the blood in the posterior pituitary gland. In contrast, the
hypothalamus uses blood vessels in the infundibulum to send hormones to the
anterior pituitary gland. These hormones regulate the production of other
hormones by the anterior pituitary gland. Since the pituitary secretes many
hormones, some of which regulate the secretion of other hormones, influencing
the pituitary gland produces widespread effects on the endocrine system.
Production of most hormones by the hypothalamus is
controlled by negative feedback mechanisms. In addition, the production of
hormones destined for the anterior pituitary gland can be influenced by brain
activities involved in psychological states and emotional reactions.
The nervous system also uses certain sympathetic nerves to
stimulate epinephrine and norepinephrine secretion by the adrenal medulla
(inner part of the adrenal glands). Epinephrine and norepinephrine have similar
effects. Recall that many sympathetic nerves in other parts of the body release
norepinephrine as a neurotransmitter.
The third link between these systems is the circulatory
system, which delivers hormones to the brain. Some hormones significantly alter
brain function. Of course, altered brain function in turn can result in modified
hormone secretion.
The body has three ways to control hormone secretion. First,
it can be controlled by nervous impulses that result from internal or external
stimuli. For example, the secretion of norepinephrine can be controlled by
sympathetic nerve impulses initiated by fear. Second, secretion can be
controlled by other hormones. For example, the secretion of anterior pituitary
hormones is controlled by hormones from the hypothalamus.
Third, secretion can be controlled by the substance or
condition being regulated by a hormone. For example, it was noted earlier in
this chapter that the rate of parathormone secretion is controlled by calcium
in the blood, which in turn is regulated by parathormone. Control of hormone
secretion by a substance or condition acted on by the hormone is called substrate
control.
The concentration of a hormone in the blood is determined by
the balance between the rate at which the hormone is secreted and the rate at
which it is eliminated. Hormones are removed from the blood by being chemically
broken down, converted to other materials, or excreted. The liver and kidneys
are very active in these processes. Elimination of substantial amounts of some
hormones requires only minutes, while elimination of significant amounts of
others may require several hours.
Since hormones are secreted into the blood, which transports
them to virtually all parts of the body, each hormone contacts many cell types,
yet most hormones affect only certain cells and organs. The affected
structures, called the hormone's targets, respond because their
cells contain receptor molecules to which the hormone molecules bind. Receptors
for some hormones are on the target cell membranes, while receptors for others
are in the target cell cytoplasm.
Different targets exposed to the same amount of a particular
hormone respond to different degrees because they have fewer or more receptors
or because their receptors bind the hormone more weakly or strongly. In
addition, the strength of each target's response can be changed by modulating the
number or binding strength of its receptors. Finally, the effectiveness of a
hormone can be influenced by conditions in the target that affect its response
mechanism.
We have seen that hormone effectiveness can be influenced by
the rate of hormone secretion, the rate of hormone elimination, target
receptors, and conditions within the target cells. However, many other factors,
such as substances that bind hormones, changes in rhythms of secretion, and
interference by nerve impulses or other hormones, can influence the
effectiveness of a hormone.
With so many factors influencing hormonal effectiveness,
determining the rates of hormone secretion or measuring the concentrations of
hormones in the blood at any one time provides only a small portion of the
information needed to evaluate endocrine system performance and the ability of
the aging endocrine system to continue contributing effectively to homeostasis.
The endocrine system produces a prodigious number and
assortment of hormones that have myriad influences on various cell types and
parts of the body. There is significant information about the presence or
absence of age changes and the nature and effects of such changes for only a
few hormones. The following section contains additional information about these
few hormones.
Abnormal and disease conditions will be discussed only with
regard to insulin and glucagon because abnormalities and diseases of other
hormones are not common among the elderly. When such conditions arise, they
usually involve having an inadequate amount or an excess of a hormone.
Inadequacies are usually treated simply by administering more of the hormone or
stimulating its secretion. Excesses are often treated by destroying or removing
part or all of the structure secreting the hormone or administering other
hormones or medications that reduce the secretion or effects of the excess
hormone.
Finally, little mention will be made of changes in endocrine
structures. Usually, aging results in decreases in size, increases in fibrous
material or lipofuscin, and certain changes in the cells. Except for the thymus
gland and ovaries, these age changes do not seem to have a significant effect
on the ability of the endocrine structure to perform its functions. This
situation may exist because of the large reserve capacity in many endocrine
structures.
Source and
Control of Secretion
Growth hormone (GH)
secretion by the anterior pituitary gland is regulated primarily by hormones
from the hypothalamus using negative feedback mechanisms (Fig.
14.3). A decline in blood levels of GH results in increased GH secretion,
which causes an elevation in GH blood levels. GH secretion is also increased by
low blood levels of insulin-like
growth factor (IGF-1), also known as somatomedin C, and
by exercise. Conversely, elevations in GH result in decreased GH secretion and
a decline in GH blood levels. GH secretion is also slowed by high blood levels
of IGF-1. Other factors that influence GH secretion include brain neurons and
blood levels of glucose, fatty acids, and amino acids.
Growth hormone is secreted in short bursts (i.e., pulses).
The accumulation of GH from many large frequent pulses causes blood levels of
GH to rise. In young adults, GH secretion and blood levels rise during the
night. As secretion diminishes later during the night and GH is removed from
the blood, blood levels begin to decline. The blood level of GH reaches a
minimum during the following day. Since this cycle is repeated with each
succeeding night and day, it is called a circadian rhythm (diurnal
rhythm). Though GH blood levels follow a circadian rhythm, IGF-1 levels
remain steady.
The pattern of GH pulses plus the total blood level of GH
cause its effects. Growth hormone causes the liver and other target cells to
secrete IGF-1. The IGF-1 affects target cells and diffuse to neighboring cells,
producing the effects from GH. IGF-¼1 in the blood also promotes the effects
from GH. The local effects from IGF-1 may be more important than the effects
from IGF-1 in the blood.
The IGF-1 increases passage of amino acids into cells and
increases synthesis of proteins from those acids. These chemical changes result
in growth, especially of bone and muscle. Growth hormone also causes an
increased breakdown of fat to supply energy. The combination of these changes
increases the proportion of lean body mass, which consists mainly of the
skeletal and muscle systems and the skin, spleen, liver, kidneys and immune cells.
Finally, GH increases blood glucose levels and therefore is considered to
antagonize insulin.
Age changes in growth hormone have been studied mostly in
men. On the average, GH secretion and IGF-1 levels during the day remain unchanged.
During the night, there is less rise in GH pulses and blood levels and IGF-1
secretion. The declines in secretions begin for many men at age 30. These
age-related decreases have been called somatopause.
When the nighttime rise in GH secretion finally disappears,
the circadian rhythm in GH blood levels vanishes and these levels become steady
at all times. As a result, both the total amount of GH produced in each 24-hour
period and the blood level of IGF-1 decrease. IGF-1 levels in women are also
known to decrease with age.
Though many men show the age changes just described, decline
in the nighttime surge in GH blood levels shows considerable heterogeneity
among individuals. Some elderly men have nighttime surges that are
approximately equal to those found in young men. However, virtually no
individuals show substantial increases in GH or IGF-1 levels with advancing
age.
Decreasing GH and IGF-1 seem to contribute to a gradual
decrease in lean body mass. For example, decreased stimulation of bone and
muscle may contribute to the age-related decline in the thickness and strength
of bone matrix and muscles plus the age-related increase in body fat. The
increase in body fat may then reduce GH secretion, and a downward spiral of GH
secretion begins as body fat increases. Age changes in the skin and kidneys may
also be due in part to decreased GH secretion. The smoothing of the circadian
peaks in GH blood levels may contribute to changes in other circadian rhythms,
such as sleep patterns. Finally, the effects of lowered GH levels may be
amplified because there is an age-related decrease in the responsiveness of
cells to IGF-1.
Growth
Hormone Supplementation
Though GH production declines, target structures seem to
retain their ability to respond to it by producing IGF-1. For example, when
older men are injected with GH or artificial substances that stimulate GH
secretion, the levels of IGF-1 and lean body mass increase and body fat
decreases. Also, loss of matrix from some bones occurs more slowly or is
reversed; blood LDLs decline and HDLs increase; skin thickens; immune function
and mental functions improve. Recall that an increase in exercise produces almost
all these results, perhaps by stimulating GH secretion. However, unlike
exercise, injections of GH or GH stimulants cause undesirable increases in
blood pressure and blood glucose levels, and they may prevent normal circadian
rhythms. Questions remain about the desirability of GH-stimulated enlargement
of parts of the body such as the spleen, liver, and kidneys. Other potential
problems include heart disease; high blood pressure; arthritis; high blood
glucose levels and diabetes mellitus; and faster growth of cancers. The lack of
adequate information about the short-term and long-term effects of GH
administration argues against the routine use of GH supplementation to stop or
reverse GH-related age changes.
Source and
Control of Secretion
Antidiuretic hormone (ADH) is released by neurons that originate in the hypothalamus
and extend through the infundibulum to the posterior pituitary (Fig.
14.1,
Fig. 14.2). ADH secretion is stimulated by an increase in osmotic pressure or a
decrease in blood pressure. Conversely, it is inhibited by decreased osmotic
pressure, increased blood pressure, and alcohol.
Antidiuretic hormone provides a communication link in the
negative feedback mechanisms that maintain homeostatic levels of body osmotic
pressure and blood pressure. When more ADH is secreted, more water is allowed
to pass from the filtrate in the kidney collecting ducts back into the blood.
The reabsorbed water helps prevent increases in body osmotic pressure and, by
helping maintain a substantial blood volume, prevents lowering of blood
pressure. The constriction of blood vessels caused by ADH also helps sustain
adequate blood pressure.
Conversely, a decrease in ADH secretion causes more water to
escape in the urine, increasing body osmotic pressure or lowering blood volume
and blood pressure.
Though there is wide variation among individuals, aging
results in an average increase in blood levels of ADH, particularly when body
osmotic pressures are high. Since the extra ADH stimulates more water
reabsorption by the kidneys, this age-related increase seems to compensate
partially for the corresponding decline in the ability of the kidneys to retain
water when needed. The ability to increase ADH secretion in response to low
blood pressure seems to remain intact or decrease slightly. There is no
apparent age change in the ability to decrease ADH secretion to eliminate more
water in the urine. Therefore, the contributions to homeostasis made by ADH do
not decline significantly, and one of them seems to improve in many
individuals.
Source and
Control of Secretion
Melatonin
is secreted by the pineal gland (Fig.
14.1). Its secretion seems to be controlled by alterations in brain
impulses caused by light detected by the eyes. Since an increase in light
exposure inhibits melatonin secretion, blood levels follow a circadian rhythm,
with low levels during the day and high levels at night. Secretion is also
influenced by the qualities of light, including time of exposure, light
intensity, and wavelengths (colors). Melatonin is also produced by the retina,
where it seems to have an antioxidant effect.
Melatonin seems to inhibit sexual maturation until the
teenage years. Its circadian rhythm regulates circadian rhythms, including
sleep and body temperature. Also, oscillations in melatonin seem to affect
psychological parameters such as mood and depression. Therefore, adverse
effects from alterations in circadian secretion may occur in people who receive
little exposure to natural light, who are exposed to different wavelengths of light
(e.g., fluorescent light), or who receive exposure to artificial light very
different from the natural schedule of daylight.
Melatonin travels easily to all body parts. It is a powerful
antioxidant. Also, it stimulates production enzymes that remove *FRs, and it
promotes the formation and effectiveness of other antioxidant substances. It
seems to have a major role in protecting the brain and other body parts (e.g.,
lungs) from *FR damage.
Aging is accompanied by a decrease in the amplitude of the
circadian rhythm of melatonin, which results from a decrease in the maximum
blood levels attained at night. This leveling in rhythm may influence
age-related changes in circadian rhythms such as sleep patterns and hormone
secretion (e.g., GH, testosterone).
Using melatonin supplements has become popular. Melatonin is
inexpensive, easy to obtain and can be taken orally. Though it is a hormone,
its sale and use are not regulated like most other hormones. Melatonin is used
commonly to reduce the effects from "jet lag" and to help establish
or reestablish circadian rhythms. Some people take melatonin to slow, stop, or
reverse age changes because it is an antioxidant, caloric restriction helps
sustain melatonin levels as it increases ML and XL, and melatonin supplements
increase ML in animals. Hazards from melatonin supplementation include
disruption of circadian rhythms, unbalancing other hormones, and overdosing or
toxicity from the unregulated production and testing of melatonin supplements.
Source and
Control of Secretion
Most of the hormone-producing cells of the thyroid gland
secrete two related thyroid hormones: thyroxine (T4)
and triiodothyronine (T3). Target cells convert some T4
to T3 and then release the T3 back into the blood.
Thyroid hormone secretion is controlled primarily by a
negative feedback mechanism that acts through the hypothalamus and anterior pituitary
gland. Low blood levels of thyroid hormone result in increased thyroid
production, and vice versa. However, thyroid hormone secretion can be
influenced by other factors. For example, a low metabolic rate stimulates
thyroid hormone secretion. By contrast, high blood levels of somatostatin,
glucocorticoids, and sex steroids (e.g., testosterone, estrogen) inhibit
secretion.
Effects
Though T3 is more powerful than T4,
both cause a general increase in the metabolic rate by increasing the rates of many
chemical reactions in most cells. Only certain cells in the brain, spleen,
testes, uterus, and thyroid gland are unaffected by thyroid hormones. The
general increase in metabolic rate increases heat production, which assists in
maintaining normal body temperature. Regulating the metabolic rate also assures
that each organ will grow, repair itself, and perform its functions at a proper
rate.
Age Changes
As age increases, average thyroid hormone blood levels
decline slightly, though they remain in the normal range. In addition, there is
a decrease in the T3/T4 ratio. These changes may be
compensatory because they prevent the development of excessively high metabolic
rates in certain cells (e.g., muscle) as lean body mass declines. Therefore,
aging does not alter the ability of thyroid hormones to provide proper
regulation of their target tissues.
There is an age-related increase in damage to the thyroid
gland by the immune system, which occurs usually in women. The result is in
adequate thyroid hormone production, which affects as many as 10 percent of
elderly women. Some diagnostic procedures and therapies that use iodine also
damage the thyroid gland. The treatment is thyroid hormone supplementation.
Excess thyroid production is rare in the elderly. It can result from Grave's
disease, excess iodine intake, or thyroid nodules. These conditions are treated
easily by removing part or all of the thyroid gland or reducing iodine intake.
(thyrocalcitonin)
Sources and
Control of Secretion
Though most thyroid gland cells secrete thyroid hormones,
others secrete calcitonin (thyrocalcitonin). Calcitonin secretion
is controlled by blood calcium levels, using a simple negative feedback
mechanism that does not involve the hypothalamus or pituitary gland but instead
uses substrate control. High blood levels of calcium stimulate calcitonin
secretion, which causes blood calcium levels to decline by stimulating removal
of calcium from the blood. The resulting lower blood calcium levels then reduce
calcitonin secretion and allow parathormone to raise blood calcium levels. When
blood calcium rises, calcitonin secretion increases again. As a result,
homeostasis of blood calcium is maintained.
Effects
Calcitonin decreases blood calcium by stimulating
osteoblasts to incorporate blood calcium into bone matrix, inhibiting
osteoclasts from removing calcium from bone matrix, and allowing the kidneys to
release more calcium in the urine.
Age Changes
Calcitonin levels may decrease with age, increasing the risk
of osteoporosis in some individuals. Furthermore, the possible decrease in the
effectiveness of calcitonin which may be caused by decreases in estrogen, may
play an additional role in the development of osteoporosis in women (see Sex
Hormones in Women, below).
Sources and
Control of Secretion
Parathormone
is produced by the parathyroid gland, which consists of several clusters of
cells on the back of the thyroid gland (Fig. 14.1). The secretion of
parathormone is controlled by a negative feedback system similar to the one
regulating calcitonin secretion. However, unlike calcitonin, parathormone secretion
is stimulated by low blood calcium and inhibited by high blood calcium.
Effects
Parathormone raises blood calcium levels by causing several
alterations in target cell activities. It stimulates the removal of calcium
from bone matrix; reduces the release of calcium by the kidneys into the urine;
stimulates directly the absorption of calcium by the small intestine; and
stimulates the activation of vitamin D by the kidneys. The increase in active
vitamin D aids the absorption of calcium by the small intestine.
Note that parathormone directly antagonizes the effects of
calcitonin. Maintenance of blood calcium homeostasis depends on providing a
proper balance between these two hormones, proper functioning of their target
structures, and adequate supplies of active vitamin D and dietary calcium.
Besides building and maintaining bone matrix, homeostasis of blood calcium is
important for cell and muscle movements, nervous impulse transmission, blood
clotting, and regulation of cell activities.
Age Changes
During aging, the parathyroid gland retains the ability to
increase or decrease the secretion of parathormone in response to changes in blood
calcium levels. Blood levels of active parathormone either do not change or
increase slightly. Paradoxically, blood calcium levels decline, though they
remain satisfactory. This decline may result from decreases in dietary calcium
intake and vitamin D levels.
Individuals with increased parathormone levels may be at
greater risk for both rapid loss of bone matrix and osteoporosis. In addition,
as noted for calcitonin, the drop in estrogen levels in postmenopausal women
may have adverse effects on the ability of the parathyroid gland and
parathormone to regulate blood calcium and to help maintain bone matrix.
Source and
Control of Secretion
Thymosin
is a group of several related hormones produced by the thymus gland
(Fig.
14.1). The mechanisms controlling thymosin secretion and blood levels are
not understood, though secretion and blood levels of thymosin seem to be
positively correlated with the size of the thymus. As the thymus increases in
size during childhood, thymosin secretion and blood levels rise. Later, the
increase in sex steroid hormones that accompanies puberty causes the thymus to
stop growing. At about age 20 the thymus begins to shrink, and thymosin
production and blood levels begin to decline slowly. After age 30, thymosin
secretion and blood levels decrease more quickly as shrinkage of the thymus
continues. By age 60, secretion stops and thymosin levels reach zero.
Effects
Thymosin is necessary for the maturation of lymphocytes,
which are specialized white blood cells. Lymphocytes constitute a major part of
the immune system, whose overall function is defense. This system identifies,
destroys, and eliminates many types of undesirable materials, microbes, and
viruses that may either enter the body or be produced within it.
Age Changes
As thymosin decreases with age, fewer immature lymphocytes
are able to mature and become functional defense cells. Therefore, the ability
of the immune system to protect the body declines. The consequences include an
increased susceptibility to infection and an increased risk of cancer.
Source and
Control of Secretion
Cholecystokinin (CCK)
is secreted by the inner lining of the first section of the small intestine
(duodenum). Its secretion is stimulated by dietary fat that enters the small
intestine from the stomach.
Effects
Cholecystokinin stimulates contraction of the gallbladder,
causes relaxation of the muscular valve that controls the passage of bile and
pancreatic digestive juices from the common bile duct into the duodenum, and
stimulates the pancreas to secrete digestive juices. Recall that both bile and
enzymes in pancreatic juice are essential for the proper digestion and
absorption of fat.
Age Changes
Aging is accompanied by an increase in the length of time during
which rapid CCK secretion occurs after fat enters the duodenum. Therefore, the
total amount of CCK produced increases and blood levels of CCK remain elevated
longer. These changes seem to compensate for an age-related decrease in the
sensitivity of the gallbladder to CCK. The overall result is no age change in
the rate of gallbladder emptying or the total amount of bile ejected from the
gallbladder. This compensatory mechanism helps sustain normal digestion and
absorption of fat.
Source and
Control of Secretion
Glucocorticoids
are a mixture of more than 12 steroid hormones secreted by selected cells in
the adrenal cortex, the outer region of the adrenal glands
(Fig.
14.1). The main glucocorticoid is cortisol.
Glucocorticoid secretion is controlled by a negative
feedback system that resembles the mechanism controlling thyroid hormone
secretion. Activities in the hypothalamus and other brain areas cause a
circadian rhythm in glucocorticoid secretion and blood levels. Peak secretion
is at about the time of awakening in the morning, and slowest secretion occurs
at approximately midnight.
Effects
Glucocorticoids have many types of target cells and produce
a variety of responses, including increases in glucose production and release
by the liver, leading to an increase in the blood glucose level; fat breakdown
to supply energy for cells; breakdown of proteins to supply free amino acids;
and vasoconstriction to increase blood pressure. Glucocorticoid secretion
increases in times of stress because these four responses help the body
overcome threats to homeostasis. Glucocorticoids also inhibit the inflammatory
response and therefore reduce the accompanying pain, itching, and/or swelling.
This effect has led to the widespread use of several forms of glucocorticoidlike
medications (e.g., cortisone, hydrocortisone, prednisone) to treat many
physical injuries, skin disorders, and chronic inflammatory diseases (e.g.,
arthritis).
Besides these responses, glucocorticoids cause five
undesirable effects. These effects are suppression of cartilage and bone
formation; stimulation of bone demineralization; promotion of GI tract bleeding
and ulcer formation; damage to memory centers in the brain (i.e., hippocampus);
and inhibition of portions of the immune response. The last effect increases
susceptibility to infection when a person experiences severe stress.
When glucocorticoidlike steroids (corticosteroids) are
administered therapeutically to reduce inflammation, their blood levels often
rise above those established by internal negative feedback controls. This
situation increases the number of unwanted effects. Older persons are
especially susceptible to higher risks of glucose intolerance and diabetes
mellitus, high blood pressure, osteoporosis, and infections. These risks can be
reduced by using minimal doses, administering alternative forms of
corticosteroids, or simultaneously instituting other medications or diet
modifications to counteract the side effects. Alternatively, using nonsteroidal
anti-inflammatory drugs (NSAIDs) can reduce these risks. However, NSAIDs
promote certain problems, including ulcer formation in the GI tract and kidney
malfunction.
Age Changes
In healthy adults, aging causes no change in blood levels of
glucocorticoids or the circadian rhythm of those levels. Therefore, aging seems
to have no adverse effect on the contribution of glucocorticoids to
homeostasis. However, there is a small age-related decrease in the sensitivity
of the negative feedback mechanisms that control glucocorticoid levels. This
change may lead to abnormally high levels in elderly individuals with disorders
(e.g., Alzheimer's disease, depression) that reduce the effectiveness of the
glucocorticoid control mechanism even further.
(aldosterone)
Source and
Control of Secretion
Like glucocorticoids, mineralocorticoids are a mixture of
steroid hormones from the adrenal cortex. In humans, aldosterone is essentially
the only mineralocorticoid that affects body functions.
Aldosterone secretion is controlled by four negative
feedback mechanisms that operate through the kidney. These mechanisms help
maintain homeostasis by regulating blood pressure, osmotic pressure, and blood
levels of sodium and potassium.
In the most influential of these mechanisms, aldosterone
secretion increases when the kidney secretes renin in response to
low blood pressure, high osmotic pressure, or adverse changes in sodium
concentrations. Aldosterone increases sodium and water reabsorption and
retention by the kidneys, causing an increase in blood pressure and adjustments
to osmotic pressure and sodium concentrations. Conversely, high blood pressure,
low osmotic pressure, and the opposite changes in sodium concentration can
suppress renin secretion and aldosterone production, allowing more sodium and
water to leave in the urine. This lowers blood pressure, raises osmotic pressure,
and corrects sodium concentrations.
Aldosterone secretion is regulated secondarily by the
effects of blood levels of sodium and potassium on the adrenal cortex, by a
hormone (atrial natriuretic factor) secreted by the heart when blood volume is
high, and by a hormone (ACTH) secreted by the anterior pituitary gland during
stress. In each case, the adjustment in aldosterone secretion helps maintain
proper blood pressure, osmotic pressure, and blood levels of sodium and
potassium.
Effects
Aldosterone and other mineralocorticoids cause these
adaptive responses by stimulating the kidney tubules to reabsorb sodium and
water and secrete potassium and/or acids (hydrogen ions).
Age Changes
Though aldosterone secretion decreases with aging, blood
levels remain steady under ideal body conditions because the decline in
secretion is accompanied by a compensatory decrease in elimination. However,
aging is accompanied by a decrease in the ability to raise aldosterone
secretion and blood levels when needed, leading to a decrease in aldosterone
reserve capacity.
These changes are not due to age changes in the adrenal
cortex, which largely retains the ability to increase aldosterone levels when
needed. The age-related decrease in aldosterone reserve capacity is due
primarily to the declining ability of the kidneys to secrete renin when needed.
Aging is also accompanied by a declining ability to increase aldosterone
secretion during stress. There is an age-related decrease in kidney sensitivity
to aldosterone.
Because of the interrelationships between aldosterone
secretion and kidney functioning, there is age-related decrease in the ability
to maintain normal conditions when faced with adverse conditions such as low
blood pressure, dehydration, and disease. Body conditions that are likely to
become abnormal include blood pressure; osmotic pressure; concentrations of
sodium and potassium; and acid/base balance
Sources and
Control of Secretion
DHEA (dehydroepiandrosterone) is a steroid hormone produced by the adrenal cortex. DHEA
is converted to DHEAS, testosterone, estrogen, and other steroids plus unknown
substances.
Effects
The functions of DHEA and DHEAS are unknown. Levels of DHEA
and DHEAS in rats, mice, and most other research animals are very low and do
not show age-related changes like those found in humans. Therefore, research on
DHEA and its possible effects in humans is limited.
Age Changes
Between conception and birth of a child, the child's blood
levels of DHEA rise to almost adult levels, dropping to almost zero as birth
approaches. During childhood, DHEA levels rise until age 20, after which they
gradually decline throughout life. DHEAS levels show a similar pattern.
Like melatonin, using DHEA supplements has become popular.
DHEA is inexpensive, easy to obtain and can be taken orally. Though it is a
hormone, its sale and use are not regulated like most other hormones. People
take melatonin to slow, stop, or reverse age changes. Some reports suggest it
can slow, stop, or reverse aging and age-related diseases in the circulatory
system, nervous system, muscle system, skeletal system, and immune system and
cancer growth. However, research reports reveal contradictory results depending
upon many variables (e.g., age, sex, other hormone levels, dosages, animals
used).
Hazards from DHEA and DHEAS supplementation include
increasing certain age changes and age-related diseases, unbalancing other
hormones, promoting cancers, and unpredictable effects from the unregulated
production and testing of DHEA and DHEAS supplements.
Sources and
Control of Secretion
Testosterone
is the main sex steroid in men. Nearly all testosterone is secreted by the interstitial
cells (Leydig's cells), which lie between the seminiferous tubules in
the testes (Fig.
14.1). The small amount of testosterone secreted by the adrenal cortex does
not play a significant role in men unless the testes are removed. Another sex
hormone, inhibin, is secreted by the sustentacular cells in the seminiferous
tubules.
Secretion of testosterone and inhibin is stimulated by
hormones from the anterior pituitary gland. Luteinizing hormone (LH)
stimulates the interstitial cells to secrete testosterone. Because of this
action, LH is also called interstitial cell-stimulating hormone (ICSH).
Follicle-stimulating hormone (FSH) stimulates inhibin secretion.
The secretion of all these hormones is controlled primarily by negative
feedback mechanisms similar to those which regulate the secretion of thyroid
hormones and glucocorticoids. Testosterone secretion can also be influenced by
brain activities such as those involved in emotional reactions.
Besides stimulating inhibin secretion, FSH stimulates the sustentacular
cells to manufacture a protein called androgen-binding protein (ABP),
which helps testosterone stimulate sperm production by binding testosterone and
concentrating it in the seminiferous tubules.
Testosterone secretion in young men occurs in a circadian
rhythm. The blood level reaches its peak value during the night or early
morning. Testosterone secretion and blood levels then decline during the day,
reaching a minimum value by evening.
Much of the testosterone that passes out of the testes binds
to molecules in the blood called sex hormone-binding globulin (SHBG).
Testosterone that is bound to SHBG is inactive, d only free testosterone
molecules significantly alter target cell activities.
Testosterone can be converted to other sex steroids. The
main alternative form is dihydrotestosterone (DHT). Though the
testes produce some DHT, approximately 80 percent of DHT in the blood results
from the conversion of testosterone to DHT by target tissues. For example, the
prostate gland releases DHT back into the blood. Some target cells respond to
testosterone (e.g., skeletal muscle), while others respond to DHT (e.g., most
reproductive system structures). A small amount of testosterone is converted to
the hormone estrogen by certain brain regions and fat tissue.
Effects
Testosterone and DHT stimulate numerous responses in men, including
(1) sperm production, (2) development and maintenance of all reproductive
structures, (3) development and maintenance of male secondary sex
characteristics such as deep voice, beard, thick body hair, and little fat on
the hips and thighs, (4) interest in sexual activity (libido), (5) involuntary
nocturnal erections during sleep, (6) thickening and strengthening of bones and
muscles, and (7) a high basal metabolic rate (BMR).
Age Changes
On the average, aging is accompanied by a gradual decrease
in blood testosterone levels that becomes evident after age 40 in many men.
However, there is great variability in age changes in testosterone, and some
older men have levels equal to or greater than the normal values for young
adult men. There is also an average decrease in the proportion of free (active)
testosterone. Furthermore, there is a gradual decline in the early morning peak
levels, which tends to flatten the circadian rhythm, and the peaks and valleys
in daily testosterone levels occur up to 2 hours later. The effects of aging on
DHT levels remain controversial.
Causes of
Age Changes Age-related changes in testosterone seem to result from
several age changes. These include decreasing effects of LH on interstitial
cells; decreasing numbers of interstitial cells; decreasing reserve capacity
for LH and FSH secretion; and changing rhythms of LH secretion. However, the
age-related increase in blood levels of LH that occurs in many aging men may
help compensate for these changes. The increase may also explain why less than
10 percent of older men have blood testosterone levels low enough to be
considered clinically abnormal.
Other age-related factors that may reduce testosterone
levels include aging of the brain; adverse changes in the circulatory system;
poor nutrition; obesity; alcohol consumption; medications;
institutionalization; other specific diseases; and poor general health status.
Other Factors Affecting Testosterone and DHT Besides age-related
changes in testosterone levels, men are subject to age-related changes in the
effectiveness of testosterone and DHT. First, the effectiveness of testosterone
is reduced by the decrease in the proportion of free testosterone. Second, the
effectiveness is reduced by an age-related decrease in the number of
testosterone receptors in most target cells. In contrast, the prostate gland
has an age-related increase in testosterone binding, which may contribute to
benign prostatic hypertrophy. Third, the effectiveness of both testosterone and
DHT is reduced by the age-related increase in estrogen, which results from
increased conversion of testosterone and other hormones to estrogen by fat
tissue. The increase in estrogen also may be partially responsible for the
age-related increase in the incidence of benign prostatic hypertrophy.
Effects of Changes in Sex Hormones The age-related
changes that affect testosterone and DHT in healthy men result in most age
changes in the male reproductive system. However, testosterone levels remain
adequate to sustain enough reproductive system functioning to achieve
reproductive success and sexual satisfaction throughout life. Except in very
old men, lower testosterone levels are not correlated with a decreased
frequency of sexual activity. Furthermore, the age-related increase in blood
levels of FSH and the resulting increase in stimulation of the sustentacular
cells may be a compensatory factor. It may contribute to the lifelong ability
to produce adequate numbers of functional sperm cells.
Using testosterone supplementation can benefit men who have
a severe testosterone deficiency. Such cases are unusual. Men who have normal
levels of testosterone and who take testosterone supplements receive little
benefit while increasing their risks from atherosclerosis, benign prostatic
hypertrophy, and possibly from prostate cancer.
Other alterations associated with age-related changes in
testosterone and DHT and their effectiveness include reductions in body hair
and in secretion by apocrine sweat glands and sebaceous glands. Finally,
declining testosterone activity seems to be a main factor in the more rapid
loss of bone matrix and the increased incidence of type II osteoporosis in
older men, particularly men over age 65.
Sources and
Control of Secretion
Young adult women produce two main sex steroids: estrogen
and progesterone. There are two main forms of estrogen: estriol
and estrone. Estriol, which constitutes approximately 60 percent
of total estrogen, is more powerful than estrone.
Before menopause, almost all estrogen and progesterone come
from follicle cells, which surround the developing egg cells in
the ovaries (Fig.
14.1). Follicle cells also secrete inhibin. Stroma cells,
which surround each group of follicle cells, secrete some testosteronelike
hormone. Almost all of this hormone is converted to estrogen by the follicle
cells. In addition, small amounts of estrogen, testosterone, and
androstenedione are produced by the adrenal cortex, but these secretions do not
play a significant role in women unless the ovaries are removed or menopause
occurs.
Secretion of estrogen, progesterone, and inhibin by the
ovaries is controlled by mechanisms that result in dramatic and rhythmic
increases and decreases in hormone levels. These hormone cycles are accompanied
by cycles of development and degeneration of follicles, egg cells, and the
uterine lining.
The negative feedback mechanisms that control the secretion
of estrogen, progesterone, and inhibin are similar to those which regulate
testosterone and inhibin in men. However, in women a positive feedback
mechanism becomes operative for a few days at about the middle of each cycle.
This mechanism results in high LH levels, which cause ovulation. The high blood
levels of estrogen and progesterone that also occur then produce a negative
feedback effect again, resulting in decreasing LH and FSH levels; degeneration
of the follicle; diminishing estrogen and progesterone levels; destruction of
the uterine lining; and finally, menstruation. These changes lead to the next
cycle.
Sex hormone secretion can be influenced by various brain
activities; this may result in irregular cycles or the cessation of cycles.
Effects
The main effects of estrogen include (1) developing and
maintaining reproductive system structures, including the breasts but not the
ovaries, (2) developing and maintaining female secondary sex characteristics
(e.g., fat deposits on the hips and thighs, female pattern of hair
distribution), (3) maintaining low blood levels of LDLs and high levels of
HDLs, and (4) increasing and maintaining bone matrix. Estrogen seems to affect
bone matrix in several ways. These ways include directly stimulating
osteoblasts; increasing the secretion or effectiveness of calcitonin;
inhibiting the effects of parathormone on bone cells; and inhibiting the
production and effects of IL-6. IL-6 stimulates osteoclast activity and bone
removal.
Progesterone stimulates the development of glandular tissues
in the uterine lining and breasts. These functions become important only if a
woman becomes pregnant or nurses her child. Finally, as in men, testosterone
stimulates interest in sexual activity.
Age Changes
Before Menopause At about age 45 the length of each male cycle
begins to shorten because the time between the end of one cycle and ovulation
in the next cycle decreases. Since this phase of the cycle produces much
estrogen, its shortening results in a decline in estrogen secretion, and
estrogen levels fall. These levels become so low that an increasing number of
cycles do not produce a positive feedback effect, and ovulation does not occur.
These changes seem to be caused initially by a decrease in the responsiveness
of the ovaries to FSH and LH.
Because of these changes, there is less progesterone
production, less development of the uterine lining, and an increasing number of
cycles with little or no menstrual flow. Since menstrual flow is the most
noticeable indicator of female cycles, the occasional absence of menstrual flow
when it is expected indicates that the cycles are becoming irregular. By age 50
to 51 progesterone is essentially absent, menstrual flow happens less than once
each year, ovarian and menstrual cycles (uterine cycles) have ended, and
menopause has occurred.
After Menopause When menopause occurs, estrogen secretion by
the ovaries and blood estrogen levels decline quickly. During the four years
after menopause estrogen secretion by the ovaries dwindles to zero. Blood
estrogen levels do not reach zero, however, because small amounts of estrogen
are produced by conversion of testosterone and androstenedione to estrogen and
by the adrenal cortex. In spite of this estrogen production, blood estrogen
levels usually drop to slightly below the lowest levels that were present
during premenopausal hormone cycles. Furthermore, postmenopausal estrogen
levels may be less than 5 percent of those present during midcycle estrogen
peaks before menopause. The low estrogen levels reached within a few years
after menopause do not fluctuate cyclically.
As with testosterone levels in older men, estrogen levels
among postmenopausal women show considerable variation. Obese women generally
have higher levels because fat tissue converts much androstenedione to estrogen.
In extreme cases these elevated estrogen levels may equal or exceed average
levels in premenopausal women. However, the estrogen in postmenopausal women is
not as potent as that in premenopausal women because most postmenopausal
estrogen is estrone rather than estriol.
Testosterone secretion from both the ovaries and the adrenal
glands in postmenopausal women declines slightly, resulting in a small decrease
in the already low blood levels. This testosterone has a greater impact,
however, because the ratio of testosterone to estrogen increases.
Up to the time of menopause slow age changes in sex hormones
result in gradually shorter and increasingly irregular menstrual cycles.
Temporary Effects As menopause occurs, ovarian sex hormone
levels plummet, causing many menopausal women to experience temporary signs and
symptoms that are often considered part of menopause. Among these common
phenomena, hot flashes involve sudden dilation of skin blood
vessels in the head and neck, which often spreads downward over other regions.
Affected women may feel a sense of pressure in the head, followed by sensations
of heat or burning in areas where vessel dilation is occurring. The affected
areas appear flushed, and profuse sweating may occur. Hot flashes seem to be
caused by low estrogen levels.
These flashes usually last approximately four minutes but
may last from a few seconds to over 30 minutes. It is difficult to estimate the
incidence among menopausal women because of the extreme individual variations
in the intensity of hot flashes. Hot flashes in some women are barely
noticeable, while other women may be briefly disabled or may be awakened by
very intense flashes.
In approximately 85 percent of menopausal women who
experience hot flashes, the flashes occur for more than a year after menopause.
They continue to occur for up to five years in 25 to 50 percent of the women
who experience them after menopause.
Other consequences of altered sex hormone levels during and
shortly after menopause may include depression, anxiety, irritability,
nervousness, fatigue, and impaired memory and ability to concentrate. Some of
these psychological changes may result from sleep disturbances caused by low
estrogen levels or nocturnal hot flashes. All these undesirable features
usually subside. These and other effects from menopause vary greatly among
different cultures.
Permanent Effects Since hot flashes and the psychological
alterations accompanying menopause are almost always temporary, they do not
seem to fit the definition of age changes. Other changes caused primarily by
the paucity of estrogen after menopause are permanent unless estrogen levels
are raised, and many of these changes intensify into very old age. They include
shrinkage and decreased functioning of all reproductive system structures;
alterations in secondary sex characteristics (e.g., shrinkage of the breasts,
increase in visible facial hair, decrease in axillary and pubic hair);
increases in LDLs and decreases in HDLs; and more rapid loss of bone matrix.
The changes resulting from plunging estrogen levels and
menopause are diverse. As for the reproductive system, the loss of childbearing
ability is considered by some people to be a negative effect which can lead
menopausal women into depression or other psychological disturbances. Others
view the loss of childbearing ability as a positive outcome because it
eliminates concerns about unwanted pregnancies. As a result, some women have an
increase in sexual activity. Other consequences of reproductive system changes
that follow menopause are discussed in Chap. 13.
Alterations in secondary sex characteristics after menopause
are often considered cosmetically undesirable. Other changes in the skin
include decreased secretion by apocrine sweat glands and sebaceous glands and
an increased incidence of skin abnormalities. The changes in blood lipoproteins
raise the risk of developing atherosclerosis and its complications (e.g., heart
attacks, strokes). Shrinkage of the urethra promotes urinary stress
incontinence. Finally, the rapid loss of bone matrix is a main risk factor for
type I osteoporosis.
Since many target structures retain much of their
responsiveness to estrogen, many postmenopausal changes can be slowed, stopped,
or reversed by administering estrogenlike substances. This type of treatment is
often called estrogen replacement therapy (ERT).
Benefits In many women ERT reduces or eliminates hot
flashes. It also restores low LDL levels and high HDL levels, lowering the risk
of atherosclerosis, and it seems to maintain cognitive functions and reduce the
risk of getting Alzheimer's disease. To be most effective against osteoporosis,
ERT should begin within six months after menopause, before significant bone
loss has occurred. Furthermore, prevention of osteoporosis may require ERT for
10 or more years after menopause because stopping ERT allows the rate of bone
resorption to increase to pretreatment levels. Postmenopausal prevention of
osteoporosis may also require measures such as exercise, calcium supplements,
and vitamin D supplements.
Risks Estrogen replacement therapy is especially
recommended for women who have an early menopause and those at high risk for
developing osteoporosis. Because ERT increases the risks of certain disorders
(e.g., thrombus formation, breast cancer, gallbladder disease, endometrial cancer),
it is not recommended for women with risk factors for certain conditions. These
conditions include breast cancer or other reproductive system cancers;
circulatory abnormalities such as high blood pressure, thrombus formation, and
varicose veins; liver or gallbladder disease; or endometriosis. Women who are
heavy smokers or are obese are also poor candidates for ERT.
The risks from ERT can be greatly reduced in several ways.
These include using small doses of estrogen; administering estrogen by injection
rather than orally; administering estrogen in cycles that mimic natural cycles;
and administering low levels of certain progesteronelike substances
(progestins). Cyclic administration of estrogen, especially when supplemented
with progestins, often results in continued uterine cycles and periodic
menstrual flow, which is usually less than premenopausal menstrual flow.
However, no egg cells are produced and pregnancy is impossible.
In conclusion, ERT can relieve several serious consequences
of low estrogen levels in postmenopausal women. Though ERT increases certain
risks somewhat, it greatly reduces others. Therefore, the net effect in many
women is an increase in the quality of life and life expectancy.
Alternatives For some women, the risks from estrogen supplementation are
too high when compared with the possible benefits. Scientists have found
artificial compounds that promote some beneficial effects from estrogen
supplements (e.g., reduce risk of atherosclerosis, reduce bone thinning) while
not increasing certain risks from estrogen supplements (e.g., blood clots,
cancers). Examples include tamoxifen and raloxifene. Other alternatives to
traditional estrogen supplement therapy are being developed and evaluated.
These alternatives include using different methods of estrogen administration
(e.g., skin patches, vaginal creams); minimizing other risk factors (e.g., high
fat diet); increasing alternative beneficial practices (e.g., improved diet;
exercise; vitamin and calcium supplements; exercise; foods containing natural
estrogens; herbal remedies).
Sources and
Control of Secretion
Cells in the pancreas that secrete hormones are located in
pinhead-sized clusters called islets of Langerhans, which are
scattered throughout the pancreas (Fig.
14.1). Some islet cells secrete insulin, and others secrete glucagon.
The secretion of both insulin and glucagon is regulated
primarily by negative feedback mechanisms involving substrate control by blood
glucose. High blood glucose levels stimulate insulin secretion and inhibit
glucagon secretion, leading to a decline in blood glucose. Conversely, low
blood glucose levels inhibit insulin secretion and stimulate glucagon
secretion, leading to a rise in blood glucose. These mechanisms help maintain homeostasis
of blood glucose.
Effects
Insulin The principal target structures of insulin
are muscle, liver, and fat cells. Insulin helps provide energy for these cells
while simultaneously reducing blood glucose levels by stimulating entry of
glucose into the cells; the breakdown of glucose for energy; storage of glucose
as glycogen; and storage of glucose as fat. The first three processes occur
primarily in muscle and liver cells, while liver and fat cells carry out most
of the fourth. These three target cell types obtain and use blood glucose only
if adequate insulin is supplied. Body cells other than muscle, liver, and fat
cells can use glucose without the presence of insulin. Of all the glucose
removed from the blood because of insulin, approximately 75 percent enters
muscle cells. Insulin also stimulates both the passage of amino acids into
cells and the synthesis of proteins from amino acids.
Glucagon Unlike insulin, glucagon causes blood glucose
levels rise by stimulating liver cells to produce and release glucose. The
glucose is produced from glycogen in the liver, amino acids in the blood and
liver, and fats in the liver and fat cells.
Combined Effects The antagonistic effects of insulin and glucagon make up the
body's main mechanism for providing proper and fairly stable blood glucose
levels. Insulin is essentially the only control signal that causes a decrease
in blood glucose. By contrast, though glucagon is the main control signal that
causes an increase in blood glucose, sympathetic nerves and other hormones
(e.g., growth hormone, epinephrine, glucocorticoids) can also cause such an
increase.
Maintaining blood glucose homeostasis is important for two
reasons. First, preventing low glucose levels assures that all body cells
receive enough glucose to obtain energy and building materials. Second,
avoiding high levels helps prevent many problems associated with the
disease diabetes mellitus
(see Diabetes Mellitus, below). The effects of insulin on amino acids and
protein synthesis are also helpful to the body because they assist in the
formation and replacement of parts of the body and secretions that contain
protein.
The blood glucose level is often expressed as glucose per
100 ml (per deciliter) of blood plasma in a sample taken at least 2 hours after
eating. The result, called the fasting plasma glucose (FPG)
value, is normally 80 to 115 mg/dl. Glucose levels may fluctuate irregularly
within this range because of changes in body activity, sympathetic nerve
impulses, and hormone levels.
The ability of the body to reverse a dramatic rise in blood
glucose and restore glucose homeostasis is called its glucose tolerance.
For example, soon after a person has ingested large quantity of sugar, the
blood glucose level may exceed 200 mg/dl. If that person has good glucose
tolerance, blood glucose is brought down below 140 mg/dl within 2 hours of
ingesting the sugars, and glucose levels stabilize at 80 to 115 mg/dl soon
afterward.
Glucose tolerance can be tested by an oral glucose
tolerance test (OGTT). In this procedure, blood glucose levels are
measured during the 2-hour period after ingesting a large amount (75 grams) of
glucose.
As age increases, the pancreas retains the ability to
quickly increase blood insulin levels and glucagon levels and maintain them
within the normal range for young adults. Furthermore, aging causes no
significant changes in the ability of insulin and glucagon to regulate blood
glucose levels. Because of the continued effectiveness of insulin and glucagon
in regulating glucose levels, aging causes no important change in FPG values or
glucose tolerance.
Although aging has essentially no effect on the ability of
the pancreas to regulate insulin levels, there is an average age-related
increase in blood insulin levels. This is not an age change but is associated
with reductions in physical activity and *VO2 max and increases in
body fat. Elevated insulin levels are closely associated with increased
abdominal body fat near the waist, which is common (increased waist/hip ratio),
in aging men.
The age-related increase in blood insulin seems to result
from a decrease in target cell responsiveness to insulin, which is called insulin
resistance. Because of insulin resistance, the target cells (muscle,
liver, and fat cells) remove little blood glucose even when blood glucose and
insulin levels are high. Since blood glucose remains high, the pancreas
secretes additional insulin, further elevating insulin levels. Insulin levels
are increased until they are high enough to stimulate the somewhat unresponsive
target cells to remove some blood glucose and lower blood glucose levels.
In individuals with insulin resistance, once insulin levels
become high, they stay high because more insulin is needed to counter the
effects of glucagon. (Recall that the blood levels and the effectiveness of
glucagon do not change with advancing age.) By themselves, small increases in
insulin resistance and insulin levels do not cause problems, but they can be
warning signs that more substantial changes in insulin may occur. Therefore, it
is advisable to monitor these changes and take steps to prevent or reverse
them.
Restoring Insulin Levels and Target Sensitivity Elderly people with
an age-related increase in insulin resistance can regain much insulin
sensitivity and reduce high blood insulin levels through a program that
combines vigorous exercise and weight loss. Although improvements in insulin sensitivity
occur within a few days of starting such a program, regular exercise must be
continued because exercise-induced gains in insulin sensitivity begin to
decline within three days of ending the program. If the program is not
reinstated, the original low levels of insulin sensitivity are reached within
several days to 2 weeks.
Blood Glucose Levels Individuals who have normal FPG values and
take almost 2 hours during an OGTT to reduce blood glucose to less than 140
mg/dl are considered to have normal glucose regulation but decreased
glucose tolerance. Individuals who have FPG values below 140 mg/dl and
whose blood glucose levels at the end of an OGTT are 140 to 200 mg/dl have an
abnormal condition called impaired glucose tolerance (IGT).
Individuals with FPG values greater than 115 mg/dl have an abnormal condition
called hyperglycemia. finally, individuals with FPG values below
80 mg/dl have an abnormal condition called hypoglycemia.
The proportion of people with decreased glucose tolerance
rises rapidly after age 45. Since glucose tolerance depends on the action of
insulin, the decrease in glucose tolerance usually occurs in those who also
have insulin resistance and increased insulin levels. Like age-related changes
in insulin, decreased glucose tolerance is probably not an age change.
Small decreases in glucose tolerance do not constitute a
problem, though they may warn of impending difficulties with glucose
regulation. Monitoring, preventing, and reversing decreases in glucose
tolerance may be appropriate.
Decreased glucose tolerance in older people can be improved
by the same techniques that improve high insulin levels and low insulin
sensitivity (see above). Decreased glucose tolerance often worsens and becomes
impaired glucose tolerance (IGT). Other than abnormally high OGTT values,
individuals with IGT have no signs or symptoms of the disorder. This allows
problems from IGT to develop insidiously.
Impaired glucose tolerance develops in up to 40 percent of
those over age 60. Among these individuals, approximately 30 percent will
improve with no medical intervention and their glucose tolerance will enter the
normal range. Another 50 percent will continue to have only IGT and its risks.
The remaining 20 percent will develop diabetes mellitus.
Impaired glucose tolerance can be caused by the same factors
that cause insulin resistance and decreased glucose tolerance and by other
factors that contribute to diabetes mellitus (see below). However, IGT can be
prevented or reversed by methods used in connection with decreased glucose
tolerance and diabetes mellitus. Such actions are highly advisable because of
the complications that result from continued IGT and the subsequent development
of diabetes mellitus. For example, elderly individuals who continue to have IGT
are at high risk for developing atherosclerosis and its related disorders.
Diabetes mellitus (DM)
is a group of diseases characterized by chronic hyperglycemia, poor glucose
tolerance, and usually other abnormalities in metabolism. Diabetics have FPG
values above 140 mg/dl (above 126 mg/dl according to the American Diabetes
Association) and final OGTT values above 200 mg/dl . High glucose levels, which
may exceed 800 mg/dl, persist because of inadequate insulin production or high
insulin resistance. As a result, muscle, liver, and fat cells cannot lower
blood glucose adequately and the effect of glucagon, which raises blood
glucose, remains unchecked.
There are four types of DM. Individuals with type I,
or insulin-dependent diabetes mellitus (IDDM) cannot survive less
they receive insulin therapy. This type of DM is also frequently called juvenile-onset
diabetes mellitus because most cases develop before age 20 and very few
develop after age 30. A third name is ketosis-prone diabetes mellitus
because these patients usually develop high blood levels of ketoacids. Many
individuals who develop IDDM as children or young adults receive adequate
treatment and survive long enough to enter the elderly population.
Victims of type II, or non-insulin-dependent
diabetes mellitus (NIDDM) have low insulin levels or high insulin
resistance but do not require insulin therapy to survive. However, insulin
treatment may be of significant help in more severe cases. NIDDM is frequently
called maturity-onset diabetes mellitus because most cases
develop after age 40. It is also called non-ketosis-prone diabetes mellitus
because few cases involve high ketoacid levels. NIDDM may advance to become
IDDM.
Another type of DM is called secondary diabetes
mellitus because it develops as a complication from another abnormality
or disease, such as alcoholism, pancreatitis, excess growth hormone, or excess
glucocorticoids. The fourth type is gestational diabetes, which
occurs in some women during pregnancy because high sex hormone levels reduce
the effectiveness of insulin. We will consider only IDDM and NIDDM in detail
because no cases of gestational diabetes occur among older people and because
most cases of secondary diabetes, though differing in cause, have the same
effects as NIDDM.
Diabetes mellitus ranks as the eighth leading chronic
condition among both people over age 45 and those over age 65. Its incidence
nearly doubles between ages 45 and 65. Because of its many complications, DM is
among the most common factors causing older people to visit a physician, and it
is the sixth or seventh leading cause of death among people over age 65.
NIDDM is the most common type of DM among the elderly. It is
estimated that 10 percent of all people over age 56 have NIDDM. Furthermore,
the incidence increases with age, and NIDDM is present in approximately 20
percent of those age 65 to 74 years and approximately 40 percent of those over
age 85.
IDDM seems to be caused by autoimmune reactions against insulin-producing
cells in the pancreas. Virtually no insulin can be produced because essentially
all the insulin-producing cells are destroyed.
NIDDM has a strong tendency to run in families, certain
ethnic groups, and blacks. Therefore, it seems to rely heavily on genetic
predispositions that interact with other factors. One important factor is
obesity; another is eating large quantities of carbohydrates. These factors are
important because they are associated with high insulin resistance. The significance
of high insulin resistance becomes evident when one realizes that though some
people with NIDDM produce little insulin, many have normal or high insulin
levels but high insulin resistance. Finally, contrary to previous beliefs,
aging makes little or no contribution to the development of NIDDM.
Main Effects
and Complications
The most important effect of diabetes mellitus is the
maintenance of abnormally high blood glucose levels. The glucose causes several
alterations, each of which contributes to one or more of the complications of
DM. The development and consequences of most of the complications mentioned
below are described in greater detail in Chaps. 3-10, 12, 13, and 15 on the
body systems in which these complications appear.
For some photos of the effects and complications from
diabetes, go to sections of Preserved
Specimen Photos and to Microscope Slides.
For Internet images of the effects and complications from diabetes, search the Images
section of http://www.google.com/ for
specific items (e.g., diabetic cataract, diabetic retinopathy, diabetic
gangrene, diabetic kidney). For diseases, I highly recommend searching WebPath:
The Internet Pathology Laboratory , the excellent complete version of which
can be purchased on a CD.
Excess Glucose One outcome of high blood glucose levels is
excess conversion of glucose to a sugar-like molecule (i.e., sugar alcohol)
called sorbitol, which accumulates in certain areas. Within the eye, sorbitol
causes cataracts in the lens and initiates diabetic retinopathy. These
conditions are, respectively, the leading eye disease and the leading cause of
blindness among the elderly. Within nerves, sorbitol causes degeneration of
neurons and the Schwann cells that surround them, resulting in deterioration of
sensory and motor neuron functioning and leading to diminished reflex response,
conscious sensation, and voluntary muscle control. Effects include reduced
sweating, increased traumatic injury, gangrene of the feet, abnormal GI tract
peristalsis, and fecal and urinary incontinence.
A second outcome of high blood glucose levels is the
formation of glucose cross-links between protein molecules both inside and
outside cells. No enzymes are needed to initiate this process, which is called
nonenzymatic glycosylation. Furthermore, once started, the process continues
even if glucose levels return to normal. Since the cross-links formed by
glucose are strong and permanent, the movement of protein molecules and the
passage of materials between proteins, such as collagen fibers, are restricted.
Harmful consequences of nonenzymatic glycosylation in the circulatory system
adversely affect all parts of the body. The most frequent serious complications
of circulatory system changes are heart attacks, strokes, and gangrene of the
feet and legs. Non-enzymatic glycosylation promotes free radical formation, and
it can also lead to degeneration and failure of the kidneys.
A third effect of high blood glucose levels is high osmotic
pressure. A high concentration of glucose in the blood causes some dehydration
of cells because water moves from the cells into the blood, causing the cells
to malfunction. The situation is compounded because the extra glucose prevents
the collecting ducts in the kidneys from reabsorbing enough water, leading to
excess water loss in urine.
The consequences of altered kidney functioning caused by
high blood glucose levels are revealed by three classic signs and symptoms of
diabetes mellitus: an increase in urine production (polyuria),
the presence of glucose in the urine (glycosuria), and an
increase in appetite and eating (polyphagia). An abnormally high
loss of water in the urine tends to lower blood pressure while further
increasing blood osmotic pressure and cell dehydration. This is indicated by the
fourth classical sign and symptom of DM: increased thirst and drinking (polydipsia).
Finally, as more water leaves the body and dehydration worsens, additional
minerals (e.g., sodium, potassium) are lost and mineral deficiencies develop.
Outcomes may include circulatory failure, brain malfunction, coma, and death.
Two other effects of high blood glucose levels include; (a)
increased risk of infection. This occurs because the glucose provides abundant
nutrients for microbes, encouraging their rapid proliferation, and because the
glucose inhibits defense functions by WBCs; (b) reduced oxygen carrying
capacity by RBCs, because hemoglobin is distorted when glucose binds to it.
Ketoacidosis In all cases of IDDM and some cases of
NIDDM, insulin levels are so low that very little glucose enters liver, muscle,
and fat cells. These cells then attempt to obtain energy from the breakdown of
fats and amino acids. However, this requires the use of some glucose because
glucose provides the substance that channels fatty acid fragments and amino
acid fragments into the Krebs cycle. With inadequate insulin to assist the
entry and use of glucose, the fragments from the fat and amino acids cannot be
broken down but are converted into substances called ketoacids (ketones).
Ketoacids enter and accumulate in the blood, producing a condition called ketoacidosis.
The resulting disturbance in acid/base balance causes cells to malfunction,
especially in the brain.
Excess ketones leave the body in exhaled breath and in the
urine (ketonuria). The ketones are noticed as a sweet fruity
aroma, which indicates the presence of ketoacidosis. When ketoacids are
eliminated in the urine, they carry minerals (e.g., sodium, potassium, zinc,
magnesium) out of the body, causing increased mineral deficiencies.
There are no preventive measures for IDDM. However, the
development over a period of weeks of polyuria, polydipsia, and polyphagia,
which are usually accompanied by rapid weight loss, is a clear warning sign
that this disease has developed. The intensity of these conditions forces
affected individuals to seek medical attention. Failure to obtain treatment
results in serious acute illness and death.
NIDDM develops subtly and insidiously over a period of
years. The classic warning signs and symptoms may not be apparent or may
develop gradually and be ignored or attributed to other conditions. Therefore,
the first indication of NIDDM to be noticed is often a complication it causes,
such as eye diseases, heart attack, stroke, and foot infections. At this stage
many other complications are also well established. Therefore, early prevention
of NIDDM by avoiding modifiable risk factors is very important, especially for
blacks and anyone with close relatives who have NIDDM.
Perhaps the most important modifiable risk factor for NIDDM
is having an abundance of body fat, particularly when it reaches the level of
obesity. Obesity accompanied by a diet high in carbohydrates creates an
especially high risk of developing NIDDM. Furthermore, the greater the amount
of body fat, obesity, and carbohydrate intake, the greater the risk. Therefore,
one of the best ways to prevent NIDDM is to maintain a desirable body weight
and avoid excess body fat. The other important modifiable risk factor for NIDDM
is having a low level of physical activity. Exercise reduces the risk of NIDDM
by helping to increase insulin sensitivity, improve glucose tolerance, and
prevent obesity by increasing energy use and influencing appetite (Chap. 8).
The goals for treating DM include maintaining homeostasis of
blood glucose levels and avoiding ketoacidosis. One key to achieving these
goals is dietary regulation. Careful planning includes controlling the times
food is consumed; the amounts of sugar, fiber, and other carbohydrates
consumed; and the total intake of kilocalories.
A second aspect of these treatment plans is regulating the amount
of physical activity. Exercise tends to lower glucose levels by causing cells
to consume glucose and glycogen and to have increased insulin sensitivity.
Sedentary periods have the opposite effects. Exercise that is accompanied by
reductions in body fat can cure some cases of NIDDM. However, exercise programs
must be tailored to individual needs to maximize the benefits while minimizing
the adverse effects.
Treatment plans may include the administration of insulin or
medications that stimulate insulin production. Various types, doses, and
schedules of insulin administration are used in different individuals.
Furthermore, the administration of insulin and other medications is adjusted
frequently to compensate for fluctuations in diet, exercise, and other aspects
of daily living.
In spite of all efforts at planning, numerous factors
militate against maintaining glucose homeostasis and preventing ketoacidosis at
all times. These factors include an inability to adequately regulate diet and
exercise; age changes; the presence of abnormal conditions or diseases; other
medications; physical and mental limitations and disabilities; and a host of
social, psychological, and economic factors. Furthermore, the number and
severity of these factors and the complexity of interactions among them
increase with age. Therefore, it is likely that an elderly person with diabetes
mellitus will develop at least some complications. However, the adverse effects
can be minimized by regularly checking for complications and promptly treating
any that appear.
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Copyright 2020: Augustine G. DiGiovanna, Ph.D.,
Salisbury University, Maryland
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