Docstoc

Motility of the Gastrointestinal Tract

Document Sample
Motility of the Gastrointestinal Tract Powered By Docstoc
					Chapter 41: General Principles of Endocrine Physiology

Genetic diseases causing deficient or abnormal synthesis of peptide or protein hormones are rare and
usually involve the hormone gene itself (e.g., insulin). In the case of thyroid or steroid hormones, the
product of the mutant gene is usually an enzyme that catalyzes one of the many separate reactions in
the biosynthetic sequence for the affected hormone (e.g., adrenal steroid hydroxylases).


Individuals undergoing major medical or surgical stress demonstrate a pattern of hormonal release
(e.g., cortisol, catecholamines, glucagon) that stimulates the mobilization of fuels such as glucose or
free fatty acids and augments their delivery to the heart and musculature. In contrast, growth and
reproductive processes are suppressed. Hormones also modulate immune responses to stress.


Certain individuals susceptible to autoimmune diseases develop antibodies to some of their own
hormone receptors. When such antibodies react with the receptor molecules, they may simply block
access of the hormone to the receptor and cause biological deficiency (e.g., hypothyroidism caused by
chronic autoimmune thyroiditis). Alternatively, the antibody-receptor combination mimics the hormone-
receptor interaction and causes hyperfunction of the gland (e.g., hyperthyroidism caused by Graves'
disease). These conditions are described in Chapter 46.


Although rare, diseases caused by mutant genes for receptors or G proteins have provided much
insight into the mechanisms of hormone action. For example, the reduced activity of a mutant α
subunit of a stimulatory G protein leads to diminished cAMP levels, resulting in deficient action of
parathyroid hormone and then hypocalcemia (see Chapter 44). Another mutant G protein, which is
constitutively overactive, is associated with continuous hypersecretion of growth hormone, or
acromegaly (see Chapter 45). Loss of function mutant nuclear receptors for thyroid hormone leads to
hypothyroidism caused by the inability of thyroid target cells to respond normally to the hormone (see
Chapter 46). Mutant plasma membrane receptors for insulin cause diabetes mellitus (see Chapter 43).


Obesity is a good example of a condition in which sensitivity to a hormone, insulin, is considerably
diminished. In type 2 diabetes (non-insulin-dependent diabetes), both sensitivity and maximal
responsiveness to insulin are reduced, factors that play a major role in causing high plasma glucose
levels. A mutation in one of the calpain genes is associated with diabetes in some populations.


Chapter 42: Whole-Body Metabolism

The condition known as ketosis occurs when fasting is prolonged beyond the usual overnight period or
when carbohydrate intake is low and keto acids accumulate. It develops to an extreme degree in
diabetes mellitus when the hormone insulin is deficient.


Normal humans can vary their fuel mix and RQ from 0.7 to 1.0 without difficulty. Patients with poor
pulmonary function who cannot excrete CO2 efficiently benefit from a low RQ. They are therefore given
a higher proportion of fat calories as an energy source so that the least amount of CO 2 is produced for
the quantity of O2 used.


When liver disease causes severe hepatic insufficiency (e.g., alcoholic hepatitis, cirrhosis), energy
metabolism can be markedly distorted. An inability to store glucose as glycogen leads to hypoglycemia
during fasting. Inability to take up lactate produced by peripheral anaerobic glycolysis can cause high
plasma levels of lactic acid and serious metabolic acidosis.
When the plasma glucose level falls below 60 mg/dL, as may occur with an overdose of insulin taken
by a patient with diabetes, the uptake of the sugar and use of O2 by the brain decrease in parallel.
Central nervous system function becomes progressively impaired, leading to convulsions, coma, and
even death.


A deficiency of protein intake is a worldwide problem. When people are chronically deprived of both
protein and calories, marked loss of muscle mass and adipose tissue results. When calories are
sufficient but protein is deficient over relatively short periods, a syndrome known as kwashiorkor
occurs. This is characterized by low plasma albumin levels, edema caused by low plasma oncotic
pressure, fragile hair, depressed immune function, deficiency of lymphocytes, reduced wound healing,
increased infections, and fatty infiltration of the liver.


The typical fat intake previously cited is now deemed excessive for good health, particularly because it
promotes atherosclerosis. In this common condition, plaques laden with lipid form in the walls of the
arteries and are often the sites of thrombosis, which obstructs the flow of blood and causes necrosis
of vital tissue such as heart muscle or cerebral cortex. Current nutritional recommendations are for
the intake of fat not to exceed 30% and of saturated fat (usually animal fat) not to exceed 10% of total
calories. The intake of monounsaturated fat should modestly exceed that of polyunsaturated fat.
Cholesterol intake should be less than 600 mg/day and reduced to below 300 mg/day if the plasma
cholesterol level is elevated.


Genetic abnormalities in apoprotein and lipid receptor particles account for a substantial number of
dyslipidemias. The premature development of coronary artery disease is often the consequence. For
example, mutant apoprotein E molecules cause familial forms of hyperlipidemia, which is
characterized by elevations of both triglyceride and cholesterol levels caused by the accumulation of
IDL and remnant particles. An excessive apoprotein B-100 content of VLDL and LDL particles
characterizes familial combined hyperlipidemia, in which cholesterol and often triglyceride levels are
high. In familial hypercholesterolemia, mutant LDL receptors prevent the normal cellular uptake of
cholesterol; this diminished uptake results in extremely high plasma cholesterol concentrations (>700
mg/dL) in homozygotes, visible and palpable deposits of cholesterol in skin and tendons, and even
coronary thrombosis in children.


Circumstances such as accidental isolation in areas totally lacking in food sources evoke these
adaptations to prolonged fasting. As long as sufficient water is available to prevent dehydration, the
adipose stores of a normal human (≈10 kg) can sustain the reduced basal energy needs and greatly
limited physical activity (≈1400 kcal/day) for up to 60 days. Likewise, the mobilizable protein stores
(≈6 kg) can supply the diminished requirements for glucose oxidation. However, the loss of protein
leads to progressive muscle weakness, apathy, organ dysfunction, and ultimately death.


Several muscle diseases resulting from defects in energy generation are caused by a deficiency of an
enzyme in the pathway from glycogen to pyruvate and lactate. An example is McArdle's disease, or
muscle phosphorylase deficiency. Such patients experience pain and weakness after exercise. The
defect in glycogen mobilization is evidenced by a failure of lactate levels to increase in the antecubital
vein after brief forearm muscle anaerobic exercise during which the arterial inflow and blood-borne
oxygen are excluded by a cuff.


Genetic defects in the oxidation of fatty acids lead to reduced exercise capacity and muscle pain or
even progressive muscle weakness. Cardiac muscle dysfunction may occur. Deficiencies of carnitine
or the enzyme carnitine palmityltransferase impair the transfer of fatty acids from the cytoplasm into
the mitochondria. Deficiencies of beta oxidation enzymes cause even more severe consequences in
infants, who cannot tolerate even short fasts because an overdependence on glucose for fuel leads to
hypoglycemia.


Pharmacological ligands for PPARα are fibric acid derivatives that are used to lower serum
triglycerides in patients with dyslipidemias. Glucose metabolism is enhanced and responsiveness to
the hormone insulin is increased by thiazolidinedione drugs, which activate PPARγ. These drugs are
used to lower plasma glucose concentration in patients with type 2 diabetes.


Humans who suffer damage to the hypothalamus from neoplasms or infiltrative disorders, such as
sarcoidosis, sometimes gain large amounts of weight, which they maintain. Conversely, in the
hypothalamic dysfunction of anorexia nervosa, weight is maintained at low, even life-threatening levels.


The pathological accumulation of energy stores as fat (i.e., obesity) is a major health problem growing
to epidemic proportions in many countries with an excess of calories available and a declining need
for exercise in essential life activities. A body weight 20% above desirable or a body mass index (BMI)
of 25 to 27 increases the risk of diabetes, hypertension, and cardiovascular disease; a body weight
40% to 50% above the desirable level or a BMI above 30 increases the risk of death.

The accumulation of fat in abdominal and particularly visceral depots confers especially high risk.




Studies of leptin in obese humans suggest that absolute leptin deficiency is an extremely rare cause
of obesity. In obese humans, the plasma leptin levels and leptin messenger RNA levels in adipose
cells are usually increased and correlate with fat mass. Hence, the peripheral signal indicating that
energy stores are too large is usually being generated, but it is not being received or acted on normally
in the hypothalamus. However, only rarely has a mutant leptin receptor been found as a cause for
obesity. Thus, human obesity is likely to result from defects in the generation of a leptin second-
messenger or effector mechanism within the leptin target cells or in effector cell pathways farther
"downstream." Rare cases of obesity are caused by mutations in the genes encoding
proopiomelanocortin (POMC) and melanocortin 4 receptor (MC4R) in the satiety limb of leptin action
(Figure 42-6). Whether partial resistance to leptin action can be overcome by sufficient exogenous
leptin therapy is still under study. The present therapy for fighting obesity-dieting, disciplined exercise,
behavior modification, and drugs that may act favorably at some point in the complex system that sets
energy stores-is palliative but not curative. Gastric reduction or bypass surgery gives the best long-
term results in people with BMI above 35 and associated medical conditions such as diabetes and
hypertension. Its popularity is growing despite surgical complications and a low but definite mortality
rate.
Chapter 43: Hormones of the Pancreatic Islets

Type 1 diabetes mellitus results from the complete destruction of β cells and the ultimate loss of all
insulin. However, in rare instances, much milder diabetes mellitus is caused by genetic abnormalities
in insulin synthesis and secretion; such abnormalities include mutant genes encoding glucokinase,
IPF-1, and insulin. In addition, inactivating mutations of the K + channel SUR1 subunit can cause
neonatal diabetes; hyperactive mutants of SUR1 cause continuous insulin secretion and hypoglycemia.


Type 2 diabetes mellitus is the most common form of the disease. One important factor in this type of
diabetes is an early subtle disturbance in the pattern of insulin secretion. This is characterized by
altered cyclicity, diminished pulse frequency, and delayed response to rising glucose levels. Eventually,
glucose is no longer recognized as a stimulus. The primary cause of such β-cell dysfunction remains
unknown.


The hypersecretion of insulin by a β-cell tumor causes hypoglycemia. Hypoglycemia produces central
nervous system dysfunction that ranges from mild difficulty in concentrating to severe behavioral
disturbances, psychosis, convulsions, and coma. Symptoms are typically worse in the fasting state and
are countered by overeating carbohydrates, often with resulting weight gain. The diagnosis is
established by demonstrating inappropriately high levels of plasma insulin and C peptide when the
plasma glucose concentration is low.


Virtually complete loss of insulin and its actions causes the striking manifestations of type 1 diabetes
mellitus. During a period of weeks, hyperglycemia develops to a point exceeding the renal threshold of
glucose (see Chapter 37). Large amounts of glucose are lost in the urine; the high urinary glucose
concentration creates a continuous osmotic diuresis (polyuria), leading to thirst and dehydration. This
drain of carbohydrate calories along with catabolic losses of adipose triglyceride stores and lean body
mass causes weight loss despite increased food intake (polyphagia). Uninhibited lipolysis leads to high
plasma levels of free fatty acids, the stimulation of ketogenesis, and very high plasma levels of β-
hydroxybutyrate and acetoacetate. The plasma level of HCO3- and the pH fall, and a profound
metabolic acidosis ensues (see Chapter 40). Coma and death follow unless treatment with insulin,
intravenous fluids, and electrolytes is provided.


When insulin is administered to patients in diabetic ketoacidosis, increased transport into cells can
cause profound drops in plasma phosphate, potassium, and magnesium levels. Potassium always,
phosphate occasionally, and magnesium rarely must be given intravenously to prevent the serious or
even fatal consequences of hypokalemia, hypophosphatemia, or hypomagnesemia.


In rare instances, deletions as well as missense and nonsense mutations in the insulin receptor gene
cause receptor malfunction and marked resistance to the action of insulin. In affected infants, this can
lead to diabetes mellitus, profound disorders of growth, and death. Impaired insulin action (as well as
inadequate insulin secretion) is also a major factor, producing hyperglycemia in the common type 2
diabetes mellitus. Because most of these patients are obese and seldom exhibit increased
ketogenesis, insulin resistance may be greater in muscle than in adipose tissue.


Prolonged fasting and sustained exercise, circumstances that require glucose mobilization, increase
glucagon secretion. Under stressful conditions, such as major infection or surgery, glucagon secretion
is often greatly augmented. This probably occurs through sympathetic nervous system stimulation of
the α cells via α-adrenergic receptors.


In type 1 diabetes, the loss of α cell responsiveness to a drop in the plasma glucose level (i.e.,
functional glucagon deficiency) often develops. Patients with such a condition become increasingly
vulnerable to the risk of severe hypoglycemia if too large a dose of insulin is administered or if a meal
is missed. If hypoglycemia severe enough to impair consciousness occurs, glucagon can be injected to
raise plasma glucose levels and restore function of the central nervous system.


In diabetic ketoacidosis (see previous section), high plasma glucagon levels provide important
contributions to the overproduction of the keto acids. The suppression of glucagon secretion by insulin
administration helps restore normal keto acid levels and pH.


Because of the array of its actions, GLP-1 has potential for treatment of diabetes, especially type 2. It
lowers plasma glucose in patients, but its very short half-life limits its usefulness. Synthesis of GLP-1
analogues resistant to dipeptidyl peptidase action and the administration of inhibitors of the peptidase
are currently being explored to enhance the therapeutic effectiveness of GLP-1.


Chapter 44: Endocrine Regulation of the Metabolism of Calcium and
Phosphate

When the [Ca++] drops below normal, neuromuscular irritability develops. This is manifested by
numbness and paresthesias ("pins and needles" sensation) and by tetanic contractions of muscles in
the hands and feet (carpopedal spasm) and, most dangerously, in the larynx, where airway obstruction
can result. Epileptic seizures may also occur. When the [Ca++] is excessive, depressed
neurotransmission can cause impaired mentation or consciousness, muscle weakness, and
decreased gastrointestinal motility. Individuals who hyperventilate to the point of severe respiratory
alkalosis can lower the Ca++ level enough (without changing the total concentration) to produce the
sensory symptoms described.
These control mechanisms are clinically important when Ca++ conservation is needed, such as in aged
people, whose Ca++ intakes typically fall, causing an increase in the danger of osteoporosis. These
mechanisms protect the mother from hypocalcemia and bone loss during pregnancy, when Ca ++
stores are drained by the fetus. In contrast, these mechanisms also act to protect against lethal
hypercalcemia (e.g., hypercalcemia that can occur when metastatic cancer causes the rapid
destruction of bone).


Rare clinical syndromes of genetic origin have helped to establish the critical importance of the Ca++
receptor. Inactivating mutations in the extracellular portion of the Ca ++ receptor reduce the affinity of
the receptor for Ca++. They reset the system so that hypercalcemia is maintained with inappropriately
low urine excretion. By contrast, hyperactivating mutations in the transmembrane domain of the
receptor enhance the signal generated by Ca++. This results in maintenance of hypocalcemia by
inappropriately high urinary Ca++ excretion caused by impaired tubular reabsorption of Ca++.


Women have a smaller bone mass than men do, and during the perimenopausal period, they lose
bone rapidly as ovarian function declines. This is caused by estrogen deficiency, but lifelong Ca ++
intakes that are only marginally adequate also contribute. The resultant osteoporosis leads to
fractures of the spine and wrist. Later in life, senescent osteoporosis leads to hip fractures in both
genders.


Vitamin D deficiency can occur in several ways. If individuals who live in sunny climates (e.g., India)
and are dependent on vitamin D synthesis move to cloudy countries (e.g., England), they may become
deficient in vitamin D if they do not alter their dietary habits or ingest supplementary vitamin D. In
urban centers overcast with smog, black infants who are breast-fed are also at risk because less
effective UV radiation reaches sites of vitamin D synthesis. When a subject's exposure to sunlight is
inadequate, deficiency also results from gastrointestinal diseases that cause malabsorption of fats,
such as pancreatic insufficiency. Liver disease leads to diminished rates of 25-hydroxylation and
hence to deficient vitamin D action. A common cause of deficient vitamin D action is kidney failure, in
which the production of the most active metabolite, 1,25-(OH)2-D, is almost totally lost.


The skeletal manifestations of vitamin D deficiency vary with the stage of life. In children, the growth
centers are preferentially affected, and the failure of normal bone mineralization leads to abnormal
epiphyses (Figure 44-5), bowing of the extremities, and collapse of the chest wall-a disease called
rickets. In adults, bone pain, vertebral collapse, and fractures along stress lines occur. Plasma Ca++
and Pi levels are decreased, whereas the alkaline phosphatase concentration is increased. Therapy
with vitamin D or the appropriate metabolite is curative.


In diseases characterized by the formation of granulomas (i.e., sarcoidosis or tuberculosis), the
component macrophages may synthesize excessive amounts of 1,25-(OH)2-D. This can result in
hypercalcemia and hypercalciuria.

Interest in vitamin D or analogues as anticancer agents has been awakened by its antiproliferative
and prodifferentiation actions. Vitamin D blocks the cell cycle at the G 1/S phase by regulating cyclin-
dependent kinases and also induces programmed cell death (apoptosis). 1,25-(OH)2-D suppresses
epidermal growth factor and insulin-like growth factor receptors in some common cancer cell lines.


Prolonged excess secretion of PTH occurs in primary hyperparathyroidism, usually because of a benign
neoplasm in one parathyroid gland. The plasma [Ca++] is high (with attendant symptoms, as previously
described), and the [Pi] is often low. The increased renal excretion of Ca ++ can cause kidney stones.
Modest loss of cortical bone may result. In hyperparathyroidism secondary to kidney failure, both 1,25-
(OH)2-D and [Ca++] decrease, and the parathyroid glands enlarge. Massive bone resorption by
osteoclasts can result, with attendant pain, fractures, and deformities. Cure of hyperparathyroidism
requires removal of the excess parathyroid tissue.


CT is used therapeutically to block bone resorption in situations in which the resorption rate is high
(e.g., Paget's disease). The hormone is also used to treat osteoporosis.


Chapter 45: Hypothalamus and Pituitary Gland

Just above the pituitary gland and sella turcica lies the crossing of the optic nerves as they course
from the retina to the cerebral cortex. Any upward tumorous growth of the pituitary out of the sella
turcica can compress the optic nerves and cause a characteristic loss of visual fields and visual acuity.
This anatomy can be well visualized by magnetic resonance imaging (Figure 45-2).


In women who are infertile because of hypothalamic dysfunction, ovulatory menstrual cycles can be
restored only if the appropriate hypothalamic releasing hormone is administered in pulses of the
correct size and frequency throughout the day. If the releasing hormone is administered continuously,
the necessary anterior pituitary response is ultimately lost because of the down-regulation of the
releasing hormone receptor. The same phenomenon is observed with regard to spermatogenesis in
men.


A deficiency of ADH caused by disease or traumatic destruction of the ADH neurons, a condition
known as central diabetes insipidus, has dramatic consequences. Urine volume can reach 500 to
1000 mL/hr, with osmolalities as low as 50 mOsm/kg. This forces frequent urination and requires the
individual to drink equally large volumes of water to prevent collapse from volume depletion and
hyperosmolality. Impairment of thirst or consciousness can therefore lead to death from dehydration.
Treatment with ADH or longer acting synthetic analogues provides rapid relief.


A clinical syndrome of primary secretion of excess ADH in amounts inappropriate to the plasma
osmolality occurs in a variety of settings. These include psychiatric or cerebral disease and pulmonary
disease or tumor; it also occurs after major surgery and use of psychotropic drugs. Due to water
retention, the plasma osmolality is low and can reach a point at which the patient becomes obtunded
or has seizures. The restriction of water intake or the inhibition of ADH action is required to correct this
situation, known as the syndrome of inappropriate ADH secretion (SIADH).


There is controversial evidence regarding the function of maternal OCT in normal labor in humans, but
the sustained contractions produced by OCT may be important in reducing blood loss from the uterus
after the delivery of the conceptus. OCT in large doses is often used therapeutically to induce labor or
to stop excessive postpartum bleeding.


Mutations of Pit-1 cause hypoplasia of the anterior pituitary gland with deficient secretion of thyroid-
stimulating hormone, growth hormone, and prolactin.


Children who cannot secrete GH or respond to its actions grow at a reduced rate and are delayed in
skeletal and sexual maturation. They are short in stature and modestly obese (Figure 45-10). In some
short children, deficiency is easily established because of the failure of plasma GH to rise acutely with
any stimulus. In others, a fairly specific loss of nocturnal peaks or a diminution of total daily integrated
secretion is used as evidence for a more subtle GH deficiency that justifies replacement therapy. GH
secretion is reduced by a deficiency of thyroid hormone or by an excess of cortisol. In both conditions,
the growth and maturation of children are also impaired.


GH, via IGFs, is a hormone with overall anabolic action (see Chapter 42). When it is administered to
GH-deficient children or adults, it decreases plasma amino acid levels and urea production because
the amino acids are shunted toward protein synthesis and away from oxidative degradation (see
Chapter 42). The total body nitrogen balance, along with the related balances of the intracellular
minerals K+ and Pi, becomes positive. Lean body mass increases, whereas fat mass decreases. Bone
formation is enhanced. The resting metabolic rate, exercise capacity, and sense of well-being all
increase. These changes suggest that GH is essential to optimal health, even in adults. The decrease
in GH with aging is likely to play a role in the changes of senescence, particularly in the declining lean
body mass.


Sustained hypersecretion of GH from a slow-growing somatotroph tumor produces a unique syndrome
called acromegaly, which reflects all these actions. In adults, the accumulation of excess soft tissue
and the widening of bones lead to coarser features (Figure 45-12) and spadelike digits. Thick skin,
enlarged muscles such as that in the tongue, and decreased subcutaneous fat are seen. Glomerular
filtration and cardiac output are increased. Glucose intolerance or frank diabetes occurs in some
individuals. Life expectancy is reduced via accelerated atherosclerosis. The diagnosis is confirmed by
elevated plasma GH levels, which do not decrease when suppressive amounts of glucose are given,
and by elevated IGF levels. If surgery is not curative, somatostatin analogues are effective treatment.


Although the exact role of PRL in normal human reproduction is uncertain, an excess of PRL from a
pituitary tumor has major consequences. Because the secretion of pituitary gonadotropins is
suppressed, ovulation and menstruation are prevented in women, and spermatogenesis is blocked in
men. Nonpregnant women secrete milk, and men may have breast enlargement. Surgical removal of
the tumor and treatment with dopamine agonists reverse these effects.


Chapter 46: Thyroid Gland

Iodide is not plentiful in the environment, and deficiency of I - is a major cause of hypothyroidism in
such varied areas of the world as China and the Peruvian Andes. This tragic form of endemic cretinism
(see later) can easily be prevented by public health programs that add I - to table salt or that provide
yearly injections of a slowly absorbed I- preparation. The Environmental Protection Agency has also
raised concerns about contamination of food or water with ClO4- and a potential hazard of
hypothyroidism. The NIS gene is repressed by I-. Mutations of NIS cause hypothyroidism and goiter
(thyroid enlargement).


Any step in the sequence from I- trapping to thyroglobulin proteolysis may be defective in congenital
biosynthetic disorders, and these defects result in thyroid hormone deficiency (hypothyroidism).
Mutant NIS and pendrin molecules have already been identified as causes of hypothyroidism. A group
of drugs known as thiouracils block the enzyme peroxidase and are useful in treating states of thyroid
hyperfunction. A large excess of I- itself, its competitive anion ClO4-, or Li+ (widely used in the treatment
of manic-depressive disorders) also inhibits T4 synthesis. Iodide is sometimes used to treat
hyperthyroidism for short periods until more definitive therapy takes hold.


The trophic effects of TSH are commonly expressed pathophysiologically. A genetic biosynthetic defect,
an acquired impairment of thyroid hormone synthesis caused by inflammation or drugs, and I -
deficiency all increase TSH secretion via negative feedback. Chronic stimulation of the thyroid gland by
TSH hypersecretion may then produce a spectacular enlargement of the gland, known as a goiter
(Figure 46-1, A).


Individuals with long-standing deficiencies of thyroid hormone from thyroid gland disease have high
plasma TSH levels as well as enlarged pituitary glands that contain increased numbers of thyrotroph
cells and an elevated TSH content. Conversely, a pathological excess of thyroid hormone causes very
low plasma TSH levels and atrophy of the thyrotroph cells. Abnormalities of the TSH receptor lead to
hyperthyroidism and goiter when the mutant is hyperactive and to hypothyroidism when the mutant is
inactive.


The replacement of thyroid hormone in deficient individuals is almost always carried out with the
prohormone, T4, and not with the more active metabolite, T3. This is done to mimic the physiological
situation. The biochemical targets are a normal level of T4 and a reduction to normal (via negative
feedback) of TSH levels if they are elevated, as in primary hypothyroidism.


Acute hepatic disease, pregnancy, or estrogen therapy raises serum TBG levels. In severe chronic
hepatic disease (such as cirrhosis) or kidney disease (such as the nephrotic syndrome), serum TBG
levels fall because of either reduced synthesis or loss of TBG in the urine. Any resultant changes in
free T4 levels are transient because negative feedback alters TSH secretion and thyroid gland
secretion so that free T4 levels can be restored to normal.


The critical importance of the T3 receptor is clinically illustrated by individuals whose hypothyroidism is
caused by resistance to thyroid hormone. These patients have either mutant receptors that are unable
to transduce the hormone signal efficiently or a single allele for a mutant receptor that blocks T 3
binding to the normal receptor. If the receptor dysfunction is generalized, the individual is hypothyroid.
If the dysfunction is only in the hypothalamic-pituitary part of the axis and T3 is not properly recognized,
deficient negative feedback may lead to excessive TSH secretion and T4 production with resultant
hyperthyroidism.


Hyperthyroidism presents a striking clinical picture because of the described effects. The increase in
metabolic rate leads to weight loss, which is characteristically accompanied by an increased intake of
food. The excessive generation of heat causes discomfort in warm environments, fever if the condition
is severe, excessive sweating, thirst, and increased ventilation. Muscle weakness, atrophy, and even
osteoporosis can result from increased protein degradation. The increase in β-adrenergic responsivity
is manifested by tremor, nervousness, insomnia, and an anxious stare. The heart rate is rapid, atrial
fibrillation may occur, and a high-cardiac output form of heart failure may develop in extreme cases.
The use of β-adrenergic antagonists ameliorates the sympathetic nervous system manifestations.


The clinical effects of hypothyroidism (Figure 46-7) may be severe, especially in a newborn, in whom
the condition is known as cretinism. The central nervous system manifestations can include mental
retardation and delayed developmental milestones such as sitting, standing, and walking. Lethargy,
growth retardation, skeletal immaturity, and poor school performance occur. In children and adults,
the decreased metabolic rate causes intolerance of cold, decreased sweating, dry skin, low cardiac
output, and weight gain. The weight gain results from both excess adipose tissue and edema fluid that
accumulates in association with ground substance mucopolysaccharides (Figure 46-8). All these
abnormalities vanish with thyroid hormone replacement (except any signs resulting from irreversible
central nervous system damage).
Chapter 47: Adrenal Cortex

The discovery and synthesis of cortisol were medical landmarks. Cortisol was lifesaving for patients
whose adrenal glands were destroyed by disease, and it dramatically reversed their debilitation.
Cortisol also has potent antiinflammatory and antiimmune effects that are used to treat diseases in
which autoimmunity plays an important pathogenetic role and to prevent rejection of organ
transplants.


Genetic defects in cortisol biosynthesis have important and varied consequences for infants. A defect
in either the 21- or 11-hydroxylase enzyme gene (see steps D and E in Figure 47-3) leads to
overproduction of androgenic steroids from 17-hydroxyprogesterone and 17-hydroxypregnenolone, the
accumulated precursors. This causes masculinization of female fetuses in utero and early secondary
sexual changes in male infants and young boys. A severe deficiency of 21-hydroxylase activity may
also cause manifestations of cortisol (glucocorticoid) and aldosterone (mineralocorticoid) deficiency.
Deficiency of 11-hydroxylase leads to overproduction of the mineralocorticoid 11-deoxycorticosterone
(Figure 47-3), which causes hypertension and hypokalemia.




Given in large doses for long periods, synthetic glucocorticoids profoundly suppress the function of the
CRH neurons, the corticotroph cells, and consequently the cells of the zona fasciculata and zona
reticularis. The ACTH-dependent adrenal cortex atrophies. After such therapy is withdrawn, full
recovery of the inactivated hypothalamic-anterior pituitary-adrenal axis can take up to 1 year. During
this time, patients must be protected against deficient responses to stress by receiving supplemental
cortisol.


Extra cortisol is secreted in patients with serious medical illnesses (such as sepsis) or major fractures,
those undergoing surgery or electroconvulsive therapy, and those experiencing hypoglycemia. In
patients in intensive care units, plasma cortisol levels are elevated twofold to fivefold; there is an
increased risk of mortality in patients with the highest levels.


The clinical expression of the negative nitrogen balance that results from prolonged cortisol excess
(Cushing's syndrome) is striking (Figure 47-7). Skin becomes so thin from loss of connective tissue
that the capillaries show through, and because of fragile walls, they rupture spontaneously, causing
bruises. Muscle weakness and atrophy are prominent. Osteoporosis results in atraumatic fractures
and bone necrosis.


Cortisol has a profound influence on the complex set of reactions evoked by trauma, chemical irritants,
foreign proteins, and infection. The overriding effect is to inhibit many important steps in the response
to tissue injury.

Cortisol impedes the ability of tissues either to eliminate immediately noxious substances and
invaders or to wall them off from the rest of the body. Thus, long-term treatment with pharmacological
doses of any glucocorticoid increases a patient's susceptibility to opportunistic infections, allows their
dissemination, and masks them. Normal wound healing after injury may also be prevented.


The therapeutic use of glucocorticoids represents a two-edged sword. Glucocorticoids are dramatically
beneficial when inflammatory reactions are so severe that they are functionally disabling or life-
threatening (e.g., during a severe asthma attack) or when the rejection of transplanted organs, such
as a kidney or heart, must be prevented. However, their adverse effects-vulnerability to serious
infection, diabetes, osteoporosis, and psychiatric disorders-require physicians to PRESCRIBE
GLUCOCORTICOIDS CAUTIOUSLY AND ONLY WHEN NO SAFER FORM OF TREATMENT EXISTS.

This injunction does not apply to the use of replacement doses of cortisol in patients who lack
adrenocortical function (Addison's disease). Cortisol deficiency leads to anorexia, weight loss, fatigue,
poor tolerance of stress, fever, hypoglycemia, and, in women, loss of sexual hair. The loss of negative
feedback causes hypersecretion of ACTH and darkening of the skin through its melanocyte-stimulating
activity. Suitable cortisol replacement therapy can reverse these findings without adverse effects.


Therefore, β-adrenergic blocking agents (e.g., propranolol) used in the treatment of hypertension or
angina, inhibitors of prostaglandin synthesis (e.g., indomethacin) used in the treatment of
inflammatory conditions, and angiotensin-converting enzyme inhibitors (e.g., captopril) used in the
treatment of hypertension or congestive heart failure can all depress aldosterone secretion and
elevate plasma K+ levels (see later section).


The net clinical effect of primary hyperaldosteronism is modest fluid retention without detectable
edema. Hypertension, hypokalemia, and metabolic alkalosis are the dominant signs. This situation can
be ameliorated by the administration of aldosterone antagonists (e.g., spironolactone). In contrast,
aldosterone deficiency leads to natriuresis, dehydration, hypotension, hyperkalemia, modest
hyponatremia, and hyperchloremic acidosis. These findings are also present in Addison's disease,
which is caused by adrenocortical destruction and loss of the zona glomerulosa.
Chapter 48: Adrenal Medulla

The catecholamine hormones are diabetogenic. They contribute materially to the development of
hyperglycemia and ketonemia in diabetic ketoacidosis, particularly when an intercurrent stress has
provoked this metabolic emergency.


The activity of the sympathetic nervous system tends to be decreased in obese individuals. This
characteristic favors storage of energy as fat when dietary calories are plentiful.


In severe or prolonged states of shock, the compensatory hypersecretion of catecholamines can
eventually contribute to fatal ischemic kidney and hepatic failure and to lactic acidosis (see Chapter
26). The catecholamine response to exercise may also be disadvantageous in patients who have
coronary artery disease and who cannot adequately increase myocardial blood flow. β-Adrenergic
antagonists are used to good therapeutic advantage in this situation; by decreasing heart rate, cardiac
contractility, and systolic blood pressure, these drugs improve the balance between myocardial work
and O2 supply and prevent angina pectoris (chest pain).


During acute asthma attacks, constriction of the bronchioles increases airway resistance (see Chapter
32) and causes wheezing and hypoxia. Synthetic β-adrenergic agonists of epinephrine, administered
through inhalers, relax the bronchioles and provide critical relief to patients in respiratory distress.


Pathological hypersecretion of epinephrine and norepinephrine from a tumor of the chromaffin cells
(pheochromocytoma) results in a distinct and dangerous syndrome. Bursts of catecholamine release
can cause sudden tachycardia, extreme anxiety with a sense of impending death, cold perspiration,
skin pallor resulting from vasoconstriction, blurred vision, headache, and chest pain. The blood
pressure may rise greatly and cause stroke or heart failure. In addition to such episodes, chronic
catecholamine excess may produce weight loss (as a result of the increased metabolic rate) and
hyperglycemia. Prompt surgical removal of the tumor is mandatory.


Chapter 49: Overview of Reproductive Function

Prolonged stimulation by GnRH causes the down-regulation of its receptor, consequent desensitization
of the gonadotroph to GnRH, and resulting profound inhibition of gonadotropin secretion. Long-acting
GnRH superagonists are commonly used therapeutically when gonadotropin secretion and androgen
or estrogen production by the gonad must be suppressed. Such situations include carcinoma of the
prostate in men and endometriosis in women. In participants of in vitro fertilization programs, it may
be easier to produce ova at a specified time with an external program of FSH and LH administration
(see Chapter 51) if endogenous secretion of these hormones is eliminated.


Negative feedback forms the basis for the use of current contraceptive drugs by women. Combinations
of relatively small doses of estrogens and synthetic progestational agents, given orally, decrease the
secretion of pituitary gonadotropins to levels below those needed to produce a mature ovum monthly.
The cessation of oral contraceptives is generally followed by rapid reinstitution of fertility. Analogous
administration of androgens for this purpose has not yet been successfully formulated for safe and
effective use as a male contraceptive.
Clinical endocrine testing often fails to distinguish between a late onset of normal puberty and a
disorder of the hypothalamus that prevents the increased secretion of LH and FSH. Because failure to
show physical signs of puberty by the age of 13 or 14 years (see Chapters 50 and 51) is
psychologically distressing to the child, treatment with sufficient testosterone or estradiol to induce
such changes and a growth spurt may be warranted. Such hormonal support can be withdrawn after
an appropriate period to determine whether normal puberty has finally begun.


Chapter 50: Male Reproduction

Inability to ejaculate, or impotence, is a common problem. It may be caused by structural and
functional disorders, including neuropathies and spinal cord lesions, or by psychogenic complications.
Direct self-injection of α-adrenergic antagonists or appropriate prostaglandins into the cavernosa at
the base of the penis generates erections that last 1 to 3 hours. Drugs that inhibit cGMP
phosphodiesterase increase cGMP and facilitate erection under conditions of sexual stimulation.


Approximately 10% of otherwise normal males are completely or relatively infertile, often because of
inadequate spermatogenesis, for which no current therapy is reliably effective. The ejaculate may
contain no sperm (azoospermia), an inadequate number (<10,000,000/mL) of sperm (oligospermia),
a high percentage of sperm with reduced mobility, or a high percentage of sperm with immature or
abnormal morphological characteristics. With azoospermia, the serum FSH level is elevated secondary
to loss of negative feedback by inhibin, which is deficient. However, in other situations, routine
measurements of plasma gonadotropin and testosterone levels may be normal, yet testicular biopsy
specimens may show spermatogenic arrest at various stages from spermatogonia to spermatids, with
few normal-appearing spermatozoa, or failure of Sertoli cells to form properly functioning junctional
complexes with germ cells. It is not clear whether the timing, frequency, or amplitude of FSH/LH
pulses may still be abnormal, whether paracrine hormonal effects may be defective, or whether the Y
chromosome genes that program spermatogenesis are ineffective mutants.


The mitogenic effects of androgens (and specifically of DHT) on the prostate gland are of great clinical
importance. The conditions known as benign prostatic hypertrophy and prostate cancer are common
after the age of 50 years. Benign prostatic hypertrophy interferes with bladder function, and it can
even cause renal failure by obstruction. The presence of prostate cancer is suggested by an elevated
serum level of prostate-specific antigen. Growth of prostate cancer is at least partly androgen
dependent, and removal of androgen action is a mainstay of treatment. Methods include excision of
the testes, markedly reducing LH and hence testosterone secretion with long-acting GnRH agonists
that down-regulate their receptors, and inhibiting testosterone and DHT actions with a receptor
blocker or with estrogens.


Chapter 51: Female Reproduction

Extraordinary coordination between the various elements of the female hypothalamic-pituitary-ovarian
axis is required for ovulation and conception. This creates numerous possibilities for failure, and
infertility arising from dysfunction of this system is common. Disease or conditions that disrupt GnRH
release or impair the gonadotrophic responsiveness prevent the necessary initial FSH pattern to
recruit a dominant follicle, and they may result in complete loss of menses (amenorrhea). A dominant
follicle may produce enough estrogen for uterine bleeding to occur (see later section) but not enough
to induce a midcycle peak of LH; this causes anovulatory cycles. On the other hand, an elevated ratio
of LH to FSH in the follicular phase is associated with excessive theca cell production of androgens
and the formation of numerous atretic and cystic follicles; this constitutes the polycystic ovary
syndrome. Even if ovulation occurs, an inadequate luteal phase, either too short or substandard in
progesterone production, may lead to poor preparation of the reproductive tract for either fertilization
or implantation.
Various manipulative medical therapies are available for female infertility, in contrast to the situation
in men. For example, the drug clomiphene is an estrogen antagonist that blocks the estrogen receptor
in the hypothalamus. By simulating estrogen deficiency and the absence of negative feedback,
clomiphene produces an increase in GnRH and gonadotropin secretion in women with a hypothalamic
origin of infertility. Alternatively, endogenous pituitary function can be suppressed with a long-acting
GnRH superagonist, and ovulation can be induced by carefully timed doses of exogenous FSH and LH
or by pulses of native GnRH.


The close coordination between the emergence of a single dominant follicle and the ovulatory signal it
recruits makes multiple pregnancies unlikely in humans. For example, the natural rate of occurrence
of dizygotic twins is less than 1% of live births. This is further emphasized by the much higher rate
(15%) of multiple ova produced during cycles in which follicular development and ovulation are
produced artificially "from above" by superimposed profiles of stimulation with exogenous FSH and LH.
Multiple pregnancies are also more common (5%) when endogenous FSH and LH are released in
response to clomiphene administered on the fifth day of the cycle to infertile women.


Well-known examples of anovulation or even complete loss of menses occur in women with anorexia
nervosa, in ballet dancers, and in marathon runners. The ovarian dysfunction can be so serious that it
causes profound estrogen deficiency with consequent osteoporosis.


The importance of understanding the estrogen receptors has been greatly heightened by the discovery
of selective estrogen receptor modulators, such as raloxifene and tamoxifen. These pharmaceutically
produced nonsteroidal estrogen receptor ligands have varied estrogen receptor profiles. Tamoxifen
antagonizes the action of estrogens on the breast but mimics the action of estrogens on the uterine
endometrium. It is an excellent chemotherapeutic agent for breast cancer, but it can rarely also
produce endometrial cancer of the uterus. Raloxifene has beneficial agonist effects on bone and
serum lipids but not on breast or endometrium. It is therefore safe for treatment of osteoporosis, but
its antagonist effects on the brain produce, as a side effect, the hot flashes associated with estrogen
deficiency.


he manifestations of ovarian insufficiency, most particularly estradiol deficiency, depend on the stage
of female life. Intrauterine estradiol deficiency-even caused by complete absence of the ovaries-does
not prevent expression of the basic feminine phenotype (see Chapter 49), although the external
genitalia may appear somewhat undersized. During puberty, estrogen deficiency causes a lack of
breast development and menses. The uterus and ovaries remain infantile in size. In an XX individual,
instead of a growth spurt, there is slow but prolonged growth until the epiphyses close late.

In women whose reproductive function is terminated early by disease and in postmenopausal women,
estrogen deficiency causes thinning of the vaginal epithelium, loss of its secretions, and discomfort
during intercourse. A decrease in breast mass and thinning of the skin also occur. Vascular flushing
and emotional lability are disturbing symptoms. Of great importance is a sharp increase in the
incidence of coronary artery disease. In women with relatively low bone mass caused by other factors,
such as poor intake of calcium earlier in life, accelerated further bone loss from estrogen deficiency
causes osteoporosis, with fractures of the wrist, spine, and hips. Hip fractures become a common and
major source of morbidity after the age of Page 80 years. Short-term estrogen replacement can be
safely provided to alleviate symptoms such as hot flashes. The benefit (prevent osteoporosis) to risk
(breast cancer) ratio of long-term estrogen replacement and the effect on cardiovascular outcomes
are still being debated.
Implantation is even more susceptible to mishap than conception is. Approximately 70% of all
conceptions result in miscarriage. The majority occur within 14 days and are unrecognized by the
woman, who may only have a slightly delayed menstrual period. Miscarriages later in the first trimester
may still reflect suboptimal maternal-fetal attachment but are also caused by fetal anomalies.


The insulin resistance of pregnancy, when it is added to an underlying vulnerability to diabetes,
produces gestational diabetes in 4% of pregnancies. Hyperglycemia appears around week 24 to 28 of
gestation, and this occurrence may have serious consequences for the fetus. Maternal hyperglycemia
is transmitted to the fetus and stimulates fetal hyperinsulinemia; this causes heavier babies that are
more difficult to deliver and a tendency toward hypoglycemia in the newborn infant. Immature lungs
that lack surfactant can cause respiratory distress, and sudden death caused by heart muscle
abnormalities may occur in utero, even near term.