anatomy and biochemistry of hormones

1. CHAP=74(ENDOCR
INOLOGY)

2. OBJECTIVES
Recognize various forms of intercellular communication
and describe ways in which chemical messengers
(including second messengers) affect cellular physiology.
Classification , synthesis, transport and mechanism of
action of hormones

3. COORDINATION OF BODY FUNCTIONS
BY CHEMICAL MESSENGERS
Cells communicate with one another via chemical messengers.
Neurotransmitters
Endocrine hormones
Neuroendocrine hormones
Paracrines
Autocrines
Cytokines

4. COORDINATION OF BODY
FUNCTIONS BY CHEMICAL
MESSENGERS
Endocrine hormones
are released by glands or specialized cells into the
circulating blood and influence the function of target cells
at another location in the body.
Paracrines are secreted by cells into the extracellular fluid
and affect neighboring target cells of a different type.
Autocrines are secreted by cells into the extracellular fluid
and affect the function of the same cells that produced
them.
Cytokines are peptides secreted by cells into the
extracellular fluid and can function as autocrines,
paracrines, or endocrine hormones. Examples of cytokines
include the interleukins and other lymphokines that are
secreted by helper cells and act on other cells of the
immune system

5. ENDOCRINE AND
NEUROENDOCRINE
HORMONE SYSTEMS
neuroendocrine hormone systems
the adrenal medullae
POSTERIOR PITUITARY GLAND secrete their hormones
primarily in response to neural stimuli.
The neuroendocrine cells, located in the hypothalamus,
have axons that terminate in the posterior pituitary gland
and median eminence and secrete several neurohormones,
including antidiuretic hormone (ADH),
oxytocin,
hypophysiotropic hormones, which control the secretion of
anterior pituitary hormones.

6. THE ENDOCRINE HORMONES
are carried by the circulatory system to cells throughout
the body, including the nervous system in some cases
where they bind with receptors and initiate many cell
reactions.
Some endocrine hormones affect many different types of
cells of the body;
for example, growth hormone (from the anterior
pituitary gland) causes growth in most parts of the body,
thyroxine (from the thyroid gland) increases the rate of
many chemical reactions in almost all the body's cells.

7. AFFECT MAINLY SPECIFIC
TARGET TISSUE
Other hormones affect mainly specific target tissues
because these tissues have abundant receptors for the
hormone.
Adreno corticotropic hormone (ACTH) from the anterior
pituitary gland specifically stimulates the adrenal cortex,
Adreno cortical hormones
ovarian hormones have their main effects on the female
sex organs and the secondary sexual characteristics of
the female body.

8. Cytokines
are peptides secreted by cells into the
extracellular fluid and can function as
autocrines, paracrines, or endocrine
hormones.
The widespread distribution of cellular
sources for cytokines may be a feature
that differentiates them from hormones.
all nucleated cells, but especially
endo/epithelial cells and
resident macrophages (many near the
interface with the external environment)
are potent producers of IL-1, IL-6,
and TNF-α.[5]
In contrast, classic hormones, such as
insulin, are secreted from discrete glands

9. Examples of cytokines include the interleukins and other
lymphokines that are secreted by helper cells and act on
other cells of the immune system.
Cytokine hormones (e.g., leptin) produced by adipocytes
are sometimes called adipokines

10. RECEPTORS FOR CHEMICAL
MESSENGERS
The recognition of chemical messengers by cells typically
begins by interaction with a receptor at that cell.
There have been over 20 families of receptors for
chemical messengers.
These proteins are not static components of the cell, but
their numbers increase and decrease in response to
various stimuli, and their properties change with changes
in physiological conditions.

11. When a hormone or neurotransmitter is
present in excess, the number of active
receptors generally decreases (down-
regulation),
whereas in the presence of a deficiency of the
chemical messenger, there is an increase in
the number of active receptors (up-
regulation).
In its actions on the adrenal cortex,
angiotensin II is an exception; it increases
rather than decreases the number of its
receptors in the adrenal.

12. Down regulation can occur by
Receptor-mediated endocytosis;
ligands bind to their receptors, and the ligand–receptor
complexes move laterally in the membrane to coated pits, where
they are taken into the cell by endocytosis (internalization).
Some receptors are recycled after internalization, whereas others
are replaced by de novo synthesis in the cell.

13. Another type of down-regulation is desensitization, in
which receptors are chemically modified in ways that
make them less responsive.

14. MECHANISMS BY WHICH
CHEMICAL MESSENGERS
ACTReceptor–ligand interaction is transduced into secondary
responses within the cell that can be divided into four broad
categories:
(1) ion channel activation,
(2) G-protein activation,
(3) activation of enzyme activity within the cell,
(4) direct activation of transcription.

15. Many ligands in the ECF bind to receptors on the surface of cells
and trigger the release of intracellular mediators such as cAMP,
IP3, and DAG that initiate changes in cell function.
Consequently, the extracellular ligands are called "first
messengers" and the intracellular mediators are called "second
messengers."

16. Second messengers bring about many short-term
changes in cell function by altering enzyme function,
triggering exocytosis, and so on, but they also can lead
to the alteration of transcription of various genes.

17. The cell signaling pathway provides
amplification of the primary signal and
distribution of the signal to appropriate
targets within the cell.
Extensive cell signaling pathways also
provide opportunities for feedback and
regulation that can fine tune the signal
for the correct physiological response
by the cell.

18. CHEMICAL CLASSIFICATION
OF HORMONES1. Polypeptides and proteins.
Polypeptide hormones generally contain less than 100 amino
acids; an example is antidiuretic hormone.
Protein hormones are polypeptides with more than 100 amino
acids; growth hormone is an example
the anterior and posterior pituitary gland, the pancreas (insulin
and glucagon), the parathyroid gland (parathyroid hormone),

19. CHEMICAL CLASSIFICATION
OF HORMONES
2. Steroids.
These are lipids derived from cholesterol. They include the
hormones testosterone, estradiol, progesterone,and
cortisol
.
3.Derivatives of the amino acid tyrosine Amines These
are hormones derived from the amino acids tyrosine and
tryptophan. They include the hormones secreted by the

20. Glycoproteins.
These molecules consist of a long polypeptide (containing
more than 100 amino acids) bound to one or more
carbohydrate groups. Examples are follicle-stimulating
hormone (FSH) and luteinizing hormone (LH).

21. SYNTHESIS OF HORMONES

22. STEROID HORMONES
Steroid Hormones Are Usually Synthesized from
Cholesterol and Are Not Stored
Much of the cholesterol in steroid-producing cells comes
from the plasma, but there is also de novo synthesis of
cholesterol in steroid-producing cells. Because the
steroids are highly lipid soluble, once they are
synthesized, they simply diffuse across the cell
membrane and enter the interstitial fluid and then the
blood.

23. Amine Hormones
Are Derived from Tyrosine
The two groups of hormones derived from tyrosine, the thyroid
and the adrenal medullary hormones, are formed by the actions
of enzymes in the cytoplasmic compartments of the glandular
cells.

24. Transport of Hormones in the
Blood
Water-soluble hormones (peptides and catecholamines) are
dissolved in the plasma and transported from their sites of
synthesis to target tissues, where they diffuse out of the
capillaries, into the interstitial fluid, and ultimately to target
cells.
Steroid and thyroid hormones, in contrast, circulate in the blood
mainly bound to plasma proteins. Usually less than 10 percent of
steroid or thyroid hormones in the plasma exist free in solution.
For example, more than 99 percent of the thyroxine in the blood
is bound to plasma proteins.

25. Protein-bound hormones cannot easily diffuse across the
capillaries and gain access to their target cells and are therefore
biologically inactive until they dissociate from plasma proteins.
The relatively large amounts of hormones bound to proteins
serve as reservoirs, replenishing the concentration of free
hormones when they are bound to target receptors or lost from
the circulation. Binding of hormones to plasma proteins greatly
slows their clearance from the plasma.

26. FEEDBACK CONTROL OF
HORMONE SECRETION
Negative feedback
Positive feedback

28. MECHANISM OF ACTION OF
DIFFERENT HORMONES

29. THE LOCATIONS FOR THE
DIFFERENT TYPES OF
HORMONE RECEPTORS ARE
GENERALLY THE FOLLOWING
: In or on the surface of the cell membrane.
The membrane receptors are specific mostly
for the protein, peptide, and catecholamine
hormones.
In the cell cytoplasm. The primary receptors
for the different steroid hormones are found
mainly in the cytoplasm.
In the cell nucleus. The receptors for the
thyroid hormones are found in the nucleus
and are believed to be located in direct
association with one or more of the
chromosomes

30. G proteins the most common
second messenger system for
Protein Hormones

32. Activation of alpha component can lead to:
Opening specific ion channels through the postsynaptic cell
membrane.
Activation of cyclic adenosine monophosphate (cAMP) or cyclic
guanosine monophosphate (cGMP) in the neuronal cell.
Activation of one or more intracellular enzymes.
Activation of gene transcription.

34. Calcium-Calmodulin Second Messenger System
Another second messenger system operates in response to the
entry of calcium into the cells. Calcium entry may be initiated by
(1) changes in membrane potential that open calcium channels
or
(2) a hormone interacting with membrane receptors that open
calcium channels.

35. On entering a cell, calcium ions bind with the protein
calmodulin. This protein has four calcium sites.
Activation of calmodulin-dependent protein kinases causes, via
phosphorylation, activation or inhibition of proteins involved in
the cell's response to the hormone.
For example, one specific function of calmodulin is to activate
myosin light chain kinase, which acts directly on the myosin of
smooth muscle to cause smooth muscle contraction.

36. The normal calcium ion concentration in most cells of the body
is 10-8 to 10-7 mol/L, which is not enough to activate the
calmodulin system. But when the calcium ion concentration rises
to 10-6 to 10-5 mol/L, enough binding occurs to cause all the
intracellular actions of calmodulin.
It is interesting that troponin C is similar to calmodulin in both
function and protein structure.

38. ENZYME-LINKED HORMONE
RECEPTORS
Some receptors, when activated, function directly as enzymes or
are closely associated with enzymes that they activate. These
enzyme-linked receptors are proteins that pass through the
membrane only once, in contrast to the seven-transmembrane G
protein-coupled receptors.
Enzyme-linked receptors have their hormone-binding site on
the outside of the cell membrane and their catalytic or enzyme-
binding site on the inside. When the hormone binds to the
extracellular part of the receptor, an enzyme immediately inside
the cell membrane is activated (or occasionally inactivated).

39. One example of an enzyme-linked receptor is the leptin receptor
Leptin is a hormone secreted by fat cells regulating appetite
energy balance
leptin receptor (cytokine receptors) that do not themselves
contain enzymatic activity but signal through associated
enzymes.
In the case of the leptin receptor, one of the signaling pathways
occurs through
a tyrosine kinase of the janus kinase (JAK) family, JAK2.

40. The leptin receptor exists as a dimer (i.e., in two parts),
and binding of leptin to the extracellular part of the receptor
alters its conformation,
enabling phosphorylation and
activation of the intracellular associated JAK2 molecules.
The activated JAK2 molecules then phosphorylate other tyrosine
residues within the leptin receptor-JAK2 complex to mediate
intracellular signaling.

42. The intracellular signals include phosphorylation of signal
transducer and activator of transcription (STAT) proteins, which
activates transcription by leptin target genes to initiate protein
synthesis.
Phosphorylation of JAK2 also leads to activation of other
intracellular enzyme pathways such as mitogen-activated
protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K).
Some of the effects of leptin occur rapidly as a result of
activation of these intracellular enzymes, whereas other actions
occur more slowly and require synthesis of new proteins.

43. P
leptin receptor
Leptin
receptor
JAK2
Activation of
enzymes
STAT 3
Physiological
effects
GENE
ACTIVATION
translation

44. Two factors can increase or decrease the concentration of a
hormone in the blood.
One of these is the rate of hormone secretion into the blood.
The second is the rate of removal of the hormone from the
blood, which is called the metabolic clearance rate.
This is usually expressed in terms of the number of milliliters of
plasma cleared of the hormone per minute.
To calculate this clearance rate, one measures
(1) the rate of disappearance of the hormone from the plasma
(e.g., nanograms per minute) and
(2) the plasma concentration of the hormone (e.g., nanograms
per milliliter of plasma).

45. A purified solution of the hormone to be measured is tagged
with a radioactive substance.
Then the radioactive hormone is infused at a constant rate into
the blood stream until the radioactive concentration in the
plasma becomes steady. At this time, the rate of disappearance
of the radioactive hormone from the plasma equals the rate at
which it is infused, which gives one the rate of disappearance.
At the same time, the plasma concentration of the radioactive
hormone is measured using a standard radioactive counting
procedure. Then, using the formula just cited, the metabolic
clearance rate is calculated.

46. Hormones are "cleared" from the plasma in several ways,
including
(1) metabolic destruction by the tissues,
(2) binding with the tissues,
(3) excretion by the liver into the bile, and
(4) excretion by the kidneys into the urine.
For certain hormones, a decreased metabolic clearance rate may
cause an excessively high concentration of the hormone in the
circulating body fluids. For instance, this occurs for several of
the steroid hormones when the liver is diseased because these
hormones are conjugated mainly in the liver and then "cleared"
into the bile.

47. Hormones are sometimes degraded at their target cells by
enzymatic processes that cause endocytosis of the cell
membrane hormone-receptor complex*
Most of the peptide hormones and catecholamines are water
soluble and circulate freely in the blood. They are usually
degraded by enzymes in the blood and tissues and rapidly
excreted by the kidneys and liver. For example, the half-life of
angiotensin II circulating in the blood is less than a minute.

48. Hormones that are bound to plasma proteins are cleared from
the blood at much slower rates and may remain in the
circulation for several hours or even days.
The half-life of adrenal steroids in the circulation, for example,
ranges between 20 and 100 minutes, whereas the half-life of the
protein-bound thyroid hormones may be as long as 1 to 6 days.

49. MEASUREMENT OF
HORMONE CONCENTRATIONS
IN THE BLOOD
Most hormones are present in the blood in extremely
minute quantities; some concentrations are as low as one
billionth of a milligram (1 picogram) per milliliter.

50. Radioimmunoassay
1)an antibody that is highly specific for the hormone to be
measured is produced
2)Second, a small quantity of this antibody is mixed with a
quantity of fluid from the animal containing the hormone to be
measured and
3)mixed simultaneously with an appropriate amount of purified
standard hormone that has been tagged with a radioactive
isotope. However, one specific condition must be met:
There must be too little antibody to bind completely both the
radioactively tagged hormone and the hormone in the fluid to be
assayed.*

52. In the process of competing, the quantity of each of the two
hormones, the natural and the radioactive, that binds is
proportional to its concentration in the assay fluid.
Third, after binding has reached equilibrium, the antibody-
hormone complex is separated from the remainder of the
solution, and the quantity of radioactive hormone bound in this
complex is measured by radioactive counting techniques.

53. If a large amount of radioactive hormone has bound with the
antibody, it is clear that there was only a small amount of natural
hormone to compete with the radioactive hormone, and
therefore the concentration of the natural hormone in the
assayed fluid was small.
Conversely, if only a small amount of radioactive hormone has
bound, it is clear that there was a large amount of natural
hormone to compete for the binding sites.

54. Fourth, to make the assay highly quantitative, the
radioimmunoassay procedure is also performed for "standard"
solutions of untagged hormone at several concentration levels.
Then a "standard curve" is plotted,
By comparing the radioactive counts recorded from the
"unknown" assay procedures with the standard curve, one can
determine within an error of 10 to 15 percent the concentration
of the hormone in the "unknown" assayed fluid. As little as
billionths or even trillionths of a gram of hormone can often be
assayed in this way.

55. ELISA

56. Enzyme-linked immunosorbent assays (ELISAs) can be used to
measure almost any protein, including hormones. This test
combines the specificity of antibodies with the sensitivity of
simple enzyme assays.
Each well is coated with an antibody (AB1) that is specific for the
hormone being assayed. Samples or standards are added to each
of the wells, followed by a second antibody (AB2) that is also
specific for the hormone but binds to a different site of the
hormone molecule.
A third antibody (AB3) that is added recognizes AB2 and is
coupled to an enzyme that converts a suitable substrate to a
product that can be easily detected by colorimetric or
fluorescent optical methods.

57. Because each molecule of enzyme catalyzes the formation of
many thousands of product molecules, even small amounts of
hormone molecules can be detected.
In contrast to competitive radioimmunoassay methods, ELISA
methods use excess antibodies so that all hormone molecules
are captured in antibody-hormone complexes.
Therefore, the amount of hormone present in the sample or in
the standard is proportional to the amount of product formed.

61. The ELISA method has become widely used in clinical laboratories
because
(1) it does not employ radioactive isotopes,
(2) much of the assay can be automated using 96-well plates,
and
(3) it has proved to be a cost-effective and accurate method for
assessing hormone levels.

62. PITUITARY HORMONES
AND THEIR CONTROL BY
THE HYPOTHALAMUS

64. also called the hypophysis,
is a small gland-about 1 centimeter in diameter and 0.5 to 1
gram in weight-that lies in the sella turcica, a bony cavity at the
base of the brain, and is connected to the hypothalamus by the
pituitary (or hypophysial) stalk.
Physiologically, the pituitary gland is divisible into two distinct
portions: the anterior pituitary, also known as the
adenohypophysis, and the posterior pituitary, also known as the
neurohypophysis. Between these is a small, relatively avascular
zone called the pars intermedia*

65. Embryologically:
anterior pituitary from Rathke's pouch, which is an embryonic
invagination of the pharyngeal epithelium
the posterior pituitary from a neural tissue outgrowth from the
hypothalamus.
anterior pituitary has epithelioid nature cells, and the posterior
pituitary has large numbers of glial-type cells.

67. Five hormones from anterior pituitary
Growth hormone
Adrenocorticotropin (corticotropin)
Thyroid-stimulating hormone (thyrotropin
Prolactin
Two separate gonadotropic hormones,
 follicle-stimulating hormone
 luteinizing hormone

68. The two hormones secreted by the posterior pituitary play other
roles.
Antidiuretic hormone (also called vasopressin) controls the rate
of water excretion into the urine, thus helping to control the
concentration of water in the body fluids.
Oxytocin helps express milk from the glands of the breast to the
nipples during suckling and helps in the delivery of the baby at
the end of gestation.

70. FIVE CELL TYPES CAN BE
DIFFERENTIATED
Somatotropes-human growth hormone (hGH)
Corticotropes-adrenocorticotropin (ACTH)
Thyrotropes-thyroid-stimulating hormone (TSH)
Gonadotropes-gonadotropic hormones, which include
both luteinizing hormone (LH) and follicle-stimulating
hormone (FSH)
Lactotropes-prolactin (PRL)

71. About 30 to 40 percent of the
anterior pituitary cells are
somatotropes that secrete
growth hormone,
and about 20 percent are
corticotropes that secrete
ACTH.
Each of the other cell types
accounts for only 3 to 5 percent
of the total.
Somatotropes stain strongly
with acid dyes and are therefore

72. POSTERIOR PITUITARY
HORMONES
The bodies of the cells that secrete the posterior
pituitary hormones are not located in the pituitary gland
itself but are large neurons, called magnocellular
neurons, located in the supraoptic and paraventricular
nuclei of the hypothalamus.
The hormones are then transported in the axoplasm of
the neurons' nerve fibers passing from the hypothalamus
to the posterior pituitary gland.

73. HYPOTHALAMUS CONTROLS
PITUITARY SECRETION

75. GROWTH HORMONE

76. PLASMA LEVELS, BINDING, &
METABOLISMApproximately 50% of the circulating pool of growth hormone
activity is in the bound form.
The basal plasma growth hormone level in adult humans is
normally less than 3 ng/mL. This represents both the protein-
bound and free forms.
Growth hormone is metabolized rapidly, probably at least in part
in the liver. The half-life of circulating growth hormone in
humans is 6–20 min, and the daily growth hormone output has
been calculated to be 0.2–1.0 mg/d in adults.

77. The growth hormone receptor is protein with a large
extracellular portion, a transmembrane domain, and a large
cytoplasmic portion. Growth hormone has two domains that can
bind to its receptor, and when it binds to one receptor, the
second binding site attracts another, producing a homodimer,
Dimerization is essential for receptor activation.

78. GROWTH HORMONE PROMOTES
GROWTH OF MANY BODY TISSUES
Growth hormone, also called somatotropic hormone or
somatotropin,
is a small protein molecule that contains 191 amino acids in a
single chain and has a molecular weight of 22,005.
It causes growth of almost all tissues of the body that are
capable of growing.
It promotes increased sizes of the cells and increased mitosis,
with development of greater numbers of cells and specific
differentiation of certain types of cells such as bone growth cells
and early muscle cells.

80. EFFECT OF GROWTH
HORMONE

81. METABOLIC EFFECTS
1) increased rate of protein synthesis in most cells of the
body;
(2) increased mobilization of fatty acids from adipose
tissue, increased free fatty acids in the blood, and
increased use of fatty acids for energy; and
(3) decreased rate of glucose utilization throughout the
body.

82. GROWTH HORMONE PROMOTES
PROTEIN DEPOSITION IN TISSUES
Enhancement of Amino Acid Transport Through the Cell
Membranes
Enhancement of RNA Translation to Cause Protein Synthesis by
the Ribosomes
Increased Nuclear Transcription of DNA to Form RNA (24-48hrs)
Decreased Catabolism of Protein and Amino Acids
In summary Growth hormone enhances almost all facets of
amino acid uptake and protein synthesis by cells, while at the
same time reducing the breakdown of proteins.

83. GROWTH HORMONE ENHANCES FAT
UTILIZATION FOR ENERGY
release of fatty acids from adipose tissue and increased
concentration of fatty acids in the body fluids.
enhances the conversion of fatty acids to acetyl coenzyme A
(acetyl-CoA) and its subsequent utilization for energy.*
Growth hormone's ability to promote fat utilization, together
with its protein anabolic effect, causes an increase in lean body
mass.

84. Anabolic hormone
Increased lean body mass
Protein Sparer
Inhibit glucose utilization

85. “Ketogenic” Effect of
Excessive Growth Hormone
Under the influence of excessive
amounts of growth hormone, fat
mobilization from adipose tissue
sometimes becomes so great that
large quantities of acetoacetic acid
are formed by the liver and released
into the body fluids, thus causing
ketosis.
This excessive mobilization of fat
from the adipose tissue also
frequently causes a fatty liver.

86. GROWTH HORMONE
DECREASES
CARBOHYDRATE UTILIZATION
Growth hormone causes multiple effects that influence
carbohydrate metabolism, including
(1) decreased glucose uptake in tissues such as skeletal
muscle and fat,
(2) increased glucose production by the liver, and
(3) increased insulin secretion.

87. Growth hormone-induced "insulin
resistance"
GH attenuates insulin's actions to
stimulate the uptake and utilization of
glucose in skeletal muscle and adipose
tissue and to inhibit gluconeogenesis
(glucose production) by the liver;
this leads to increased blood glucose
concentration and a compensatory
increase in insulin secretion.
For these reasons, growth hormone's
effects are called diabetogenic.

88. PROBABLE CAUSE OF
INSULIN RESISTANCE
Growth hormone-induced increases in blood
concentrations of fatty acids likely contribute to
impairment of insulin's actions on tissue glucose
utilization.
Experimental studies indicate that raising blood levels of
fatty acids above normal rapidly decreases the sensitivity
of the liver and skeletal muscle to insulin's effects on
carbohydrate metabolism.

89. NECESSITY OF INSULIN AND
CARBOHYDRATE FOR THE
GROWTH-PROMOTING ACTION OF
GROWTH HORMONE
Adequate insulin activity and adequate availability of
carbohydrates are necessary for growth hormone to be
effective.
Part of this requirement for carbohydrates and insulin is
to provide the energy needed for the metabolism of
growth, but there seem to be other effects as well.
Especially important is insulin's ability to enhance the
transport of some amino acids into cells, in the same
way that it stimulates glucose transport.

90. GROWTH HORMONE STIMULATES
CARTILAGE AND BONE GROWTH
Increases growth of the skeletal frame.
This results from multiple effects of growth hormone on bone,
including
 (1) increased deposition of protein by the chondrocytic and osteogenic cells
that cause bone growth,
 (2) increased rate of reproduction of these cells, and
 (3) a specific effect of converting chondrocytes into osteogenic cells, thus
causing deposition of new bone.

91. TWO PRINCIPAL MECHANISMS OF
BONE GROWTH
First, the long bones grow in length at the epiphyseal cartilages,
where the epiphyses at the ends of the bone are separated from
the shaft.
This growth first causes deposition of new cartilage, followed by
its conversion into new bone, thus elongating the shaft and
pushing the epiphyses farther and farther apart.
At the same time, the epiphyseal cartilage itself is progressively
used up, so by late adolescence, no additional epiphyseal
cartilage remains to provide for further long bone growth.
At this time, bony fusion occurs between the shaft and the
epiphysis at each end, so no further lengthening of the long
bone can occur.

92. Osteoblasts in the bone periosteum and in some bone cavities
deposit new bone on the surfaces of older bone and osteoclasts
in the bone remove old bone.
Growth hormone strongly
stimulates osteoblasts. Therefore, the
bones can continue to become thicker throughout life under the
influence of growth hormone; this is especially true for the
membranous bones.
e.g, the jaw bones, skull bones.

93. "SOMATOMEDINS" (ALSO
CALLED "INSULIN-LIKE GROWTH
FACTORS")
Produced from liver under the effect of GH
have the potent effect of increasing all aspects of bone
growth.
Many of the somatomedin effects on growth are similar
to the effects of insulin on growth. Therefore, the
somatomedins are also called insulin-like growth factors
(IGFs).

94. TYPES OF SOMATOMEDINS
At least four somatomedins have been isolated, but by
far the most important of these is somatomedin C (also
called insulin-like growth factor-1, or IGF-I).
The molecular weight of somatomedin C is about 7500,
and its concentration in the plasma closely follows the
rate of growth hormone secretion.

95. SHORT DURATION OF ACTION
OF GROWTH HORMONE BUT
PROLONGED ACTION OF
SOMATOMEDIN C
Most of the growth results from the effect of
somatomedins rather then GH
Growth hormone attaches only weakly to the plasma
proteins in the blood and is released to the tissues
rapidly, having a half-time in the blood of less than 20
minutes.
By contrast, somatomedin C attaches strongly to a carrier
protein in the blood, with a half-time of about 20 hours.

98. The pygmies of Africa have a congenital inability to
synthesize significant amounts of somatomedin C.
. plasma concentration of growth hormone is either
normal or high, they have diminished amounts of
somatomedin C in the plasma;
this apparently accounts for the small stature of these
people. Some other dwarfs (e.g., the Lévi-Lorain dwarf)
also have this problem.

100. REGULATION OF GH

102. GROWTH HORMONE IS SECRETED IN A
PULSATILE PATTERN, INCREASING AND
DECREASING.

104. Under acute conditions, hypoglycemia is a far more potent
stimulator of growth hormone secretion than is an acute
decrease in protein intake.
Conversely, in chronic conditions, growth hormone secretion
seems to correlate more with the degree of cellular protein
depletion than with the degree of glucose insufficiency.
For instance, the extremely high levels of growth hormone that
occur during starvation are closely related to the amount of
protein depletion.

105. GH=NG/ML
5-20 years 6
20-40 years 3
40-70 years 1.6

106. ROLE OF THE HYPOTHALAMUS, GHRH AND GHIH IN
THE CONTROL OF GROWTH HORMONE SECRETION
Both of these are polypeptides;
GHRH is composed of 44 amino acids, and GHIH(somatostatin) is
composed of 14 amino acids.
GHRH secreted from ventromedial nucleus; this is sensitive to
blood glucose concentration, causing satiety in hyperglycemic
states and hunger in hypoglycemic states.

107. MECHANISM OF ACTION OF
GHRHGHRH acts through (cAMP). This has both short-term and long-
term effects.
The short-term effect is to increase calcium ion transport into
the cell; within minutes release of the hormone into the blood.
The long-term effect is to increase transcription in the nucleus
by the genes to stimulate the synthesis of new growth hormone.

108. ABNORMALITIES OF GROWTH
HORMONE SECRETION
Panhypopituitarism
This term means decreased secretion of all the anterior
pituitary hormones.
The decrease in secretion may be congenital (present
from birth), or it may occur suddenly or slowly at any
time during life, most often resulting from a pituitary
tumor that destroys the pituitary gland.

109. Most instances of dwarfism result from generalized deficiency of
anterior pituitary secretion (panhypopituitarism) during
childhood.
In general, all the physical parts of the body develop in
appropriate proportion to one another, but the rate of
development is greatly decreased.

110. TYPES OF DWARFISM
1) Pan hypopitutrism
2) Levi Lorain dwarfism
3) Kasper Hauser dwarfism
4) Achondroplasia

111. 1) PAN HYPOPITUTRISM
A person with panhypopituitary dwarfism does not pass
through puberty and never secretes sufficient quantities
of gonadotropic hormones to develop adult sexual
functions.
In one third of such dwarfs, however, only growth
hormone is deficient; these persons do mature sexually
and occasionally reproduce.

112. LÉVI-LORAIN DWARF
In this type of dwarfism the
rate of growth hormone
secretion is normal or high,
but there is a hereditary
inability to form
somatomedin C.

113. Kaspar Hauser Dwarf
Chronic abuse and neglect can
also cause dwarfism in children,
independent of malnutrition.
This condition is known as
psychosocial dwarfism or the
Kaspar Hauser syndrome,
named for the patient with the
first reported case.

114. ACHONDROPLASIA
most common form of dwarfism in humans, is
characterized by short limbs with a normal trunk.
It is an autosomal dominant condition caused by a
mutation in the gene that codes for fibroblast growth
factor receptor 3 (FGFR3).
This member of the fibroblast growth receptor family is
normally expressed in cartilage and the brain.

116. TREATMENT WITH HUMAN GROWTH
HORMONE
Growth hormones from different species of
animals are sufficiently different.
Human growth hormone can now be
synthesized by Escherichia coli bacteria as a
result of successful application of
recombinant DNA technology.
Dwarfs who have pure growth hormone
deficiency can be completely cured if treated
early in life.
Human growth hormone may also prove to be
beneficial in other metabolic disorders
because of its widespread metabolic
functions.

117. PANHYPOPITUITARISM IN THE
ADULTPanhypopituitarism first occurring in adulthood frequently
results from one of three common abnormalities.
Two tumorous conditions, craniopharyngiomas or chromophobe
tumors, may compress the pituitary gland until the functioning
anterior pituitary cells are totally or almost totally destroyed.
The third cause is thrombosis of the pituitary blood vessels. This
abnormality occasionally occurs when a new mother develops
circulatory shock after the birth of her baby.

118. SHEEHAN SYNDROME
• Postpartum Hammorhage
• Decreased blood supply
• shock
• ischemia
• Infarction of pituitary gland

119. The general effects of adult panhypopituitarism are due to
(1) hypothyroidism,
(2) depressed production of glucocorticoids by the adrenal
glands, and
(3) suppressed secretion of the gonadotropic hormones so that
sexual functions are lost.

120. S/S
lethargic person (from lack of thyroid hormones)
who is gaining weight (because of lack of fat mobilization by
growth, adrenocorticotropic, adrenocortical, and thyroid
hormones), low BMR and has lost all sexual functions.
Except for the abnormal sexual functions, the patient can usually
be treated satisfactorily by administering adrenocortical and
thyroid hormones.

121. INVESTIGATIONS
Routine
CBC
R/E Urine
Lipid profile
BSL
Serum electrolytes
Specific
CT Scan
MRI
Hormonal assay

122. EXCESS OF GH
Gigantism
Acromegaly

123. GIGANTISM(ALAM CHANNA)
Acidophilic tumors.
All body tissues grow rapidly,
including the bones.
If the condition occurs before
adolescence, before the epiphyses
of the long bones have become
fused with the shafts, height
increases so that the person
becomes a giant-up to 8 feet tall.
.

124. The giant has
hyperglycemia,
and the beta cells of the islets of Langerhans in the
pancreas are prone to degenerate because they become
overactive owing to the hyperglycemia.
10 percent of giants, full-
blown diabetes mellitus
eventually develops

125. GIGANTISM
In most giants, panhypopituitarism eventually develops if they
remain untreated because the gigantism is usually caused by a
tumor of the pituitary gland that grows until the gland itself is
destroyed.
This eventual general deficiency of pituitary hormones usually
causes death in early adulthood. However, once gigantism is
diagnosed, further effects can often be blocked by microsurgical
removal of the tumor or by irradiation of the pituitary gland.

126. ACROMEGALY
If an acidophilic tumor occurs after puberty the condition is
known as acromegaly.
Enlargement is especially marked in the bones of:
the hands and feet
and in the membranous bones e.g the cranium, nose, bosses on
the forehead, supraorbital ridges, lower jawbone, and portions
of the vertebrae, because their growth does not cease at
adolescence.

127. ACROMEGALY
the lower jaw protrudes forward, sometimes as much as half an
inch,
the forehead slants forward because of excess development of
the supraorbital ridges,
the nose increases to as much as twice normal size,
the feet require size 14 or larger shoes,

128. the fingers become extremely thickened so that the
hands are almost twice normal size.
changes in the vertebrae ordinarily cause a hunched
back, which is known clinically as kyphosis.
many soft tissue organs, such as the tongue, the liver,
and especially the kidneys, become greatly enlarged

129. Carpel tunnel syndrome:
due to hypertrophy of soft tissues, median nerve compression
results.
Pituitary Diabetes:

135. POSSIBLE ROLE OF DECREASED GROWTH
HORMONE SECRETION IN CAUSING
CHANGES ASSOCIATED WITH AGING
In people who have lost the ability to secrete growth hormone,
some features of the aging process accelerate.*
The physical and physiological effects are increased wrinkling of
the skin, diminished rates of function of some of the organs,
and diminished muscle mass and strength.

137. growth hormone therapy in older people have demonstrated
three important beneficial effects:
(1) increased protein deposition in the body, especially in the
muscles;
(2) decreased fat deposits; and
(3) a feeling of increased energy.
Undesirable side effects
including insulin resistance and
diabetes, edema, carpal tunnel
syndrome, and arthralgias (joint
pain) may be produced.

138. THYROID HORMONE

139. LOCATION
The thyroid gland, located immediately below
the larynx on each side of and anterior to the
trachea,
Is one of the largest of the endocrine glands,
normally weighing 15 to 20 grams in adults.
Thyroid secretion controlled by thyroid-
stimulating hormone (TSH).

140. The thyroid secretes two major hormones, thyroxine and
triiodothyronine, commonly called T4 and T3,
respectively.
Both of these hormones profoundly increase the
metabolic rate of the body.
The thyroid gland also secretes calcitonin.

144. large numbers of closed follicles
(100 to 300 micrometers in
diameter)
filled with a secretory substance
called colloid and lined with
cuboidal epithelial cells that
secrete into the interior of the
follicles.
The major constituent of colloid is
the large glycoprotein
thyroglobulin, which contains the
thyroid hormones.

145. Once the secretion has entered the follicles, it must be absorbed
back through the follicular epithelium into the blood before it
can function in the body.
The thyroid gland has a blood flow about five times the weight
of the gland each minute

146. Iodine Is Required for Formation of Thyroxine
To form normal quantities of thyroxine, about 50 milligrams of
ingested iodine in the form of iodides are required each year, or
about 1 mg/week.
To prevent iodine deficiency, common table salt is iodized with
about 1 part sodium iodide to every 100,000 parts sodium
chloride.

147. Fate of Ingested Iodides
Iodides ingested orally are absorbed from the gastrointestinal
tract into the blood in about the same manner as chlorides.
One fifth are selectively removed from the circulating blood by
the cells of the thyroid gland and used for synthesis of the
thyroid hormones,
rest of the iodides are rapidly excreted by the kidneys.

149. SYNTHESIS OF THYROID
HORMONE
Absorption of ingested iodide
Iodide Pump-the Sodium-Iodide Symporter (Iodide
Trapping)
transported into the follicle by a chloride-iodide ion
counter-transporter molecule called pendrin.
Oxidation of the Iodide Ion(peroxidase)
Iodination of Tyrosine and Formation of T3, T4
(Organification of Thyroglobulin)

150. The major hormonal product of the coupling reaction is the
molecule thyroxine (T4),
Triiodothyronine (T3), which represents about one fifteenth of
the final hormones.

151. Reverse T3 (rT3)
Thyroid hormones are essential in maintaining and
regulating the body’s metabolism.
Triiodthyronine (T3) is the most active of the thyroid
hormones.
Approximately 85% of circulating T3 is produced by
monodeiodination of thyroxine (T4) in tissues such as
liver, muscle and kidney. Selenium and zinc are required
for this process.

152. Reverse T3 (rT3) is an inactive form of T3 that is
produced in the body particularly during periods of
stress.
rT3 differs from T3 in that the missing deiodinated
iodine is from the inner ring of the thyroxine molecule
compared with outer ring on T3. rT3 is measured by a
blood test.

153. Under normal conditions T4 will convert to both T3 and rT3
continually and the body eliminates rT3 quickly.
Under certain conditions, more rT3 is produced and the
desirable conversion of T4 to T3 decreases. This occurs
during fasting, starvation, illness such as liver disease and
during times of increased stress

154. This becomes a vicious cycle as rT3 competes with T3 as
a substrate for the 5-deiodinase enzyme. This inhibits
the conversion of T4 to T3, with more T4 being
converted to more rT3.
An increased production of rT3 is often seen in patients
with disorders such as fibromyalgia, chronic fatigue
sydrome (CFS), Wilson's Thyroid Syndrome and stress.
Measurement of rT3 is also valuable in identifying sick
euthyroid syndrome where active T3 is within normal
range and rT3 is elevated.

155. STORAGE OF THYROGLOBULIN
Store large amounts of hormone.
Each thyroglobulin molecule contains up to 30 thyroxine
molecules and a few triiodothyronine molecules.
Sufficient to supply the body with its normal requirements of
thyroid hormones for 2 to 3 months.
So the physiologic effects of deficiency are not observed for
several months.

156. RELEASE OF THYROXINE AND
TRIIODOTHYRONINE FROM THE THYROID
GLAND
The apical surface of the thyroid cells sends out pseudopod
extensions to form pinocytic vesicles that enter the apex of the
thyroid cell.
Then lysosomes in the cell cytoplasm immediately fuse with
these vesicles to form digestive vesicles.
Multiple proteases digest the thyroglobulin molecules and
release thyroxine and triiodothyronine in free form.
These then diffuse through the base of the thyroid cell into the
surrounding capillaries.

157. About three quarters of the iodinated tyrosine in the
thyroglobulin never become thyroid hormones but remain MIT
and DIT.
Recycling within the gland for forming additional thyroid
hormones*.
In the congenital absence of deiodinase enzyme, many persons
become iodine deficient because of failure of this recycling
process.

158. DAILY RATE OF SECRETION OF
THYROXINE AND
TRIIODOTHYRONINEAbout 93 percent is thyroxine and only 7 percent is
triiodothyronine.
However, during the ensuing few days, about one half of the
thyroxine is slowly deiodinated to form additional
triiodothyronine.
The hormone finally delivered to and used by the tissues is
mainly triiodothyronine, a total of about 35 micrograms of
triiodothyronine per day.

159. Transport of Thyroxine and
Triiodothyronine to Tissues
Thyroxine and Triiodothyronine Are Bound to Plasma Proteins
More than 99 percent of the thyroxine and triiodothyronine
combines with plasma proteins.
Mainly with thyroxine-binding globulin and much less so with
thyroxine-binding prealbumin and albumin.

160. Thyroxine and Triiodothyronine Are Released Slowly to Tissue
Cells
Half the thyroxine is released to the tissue cells about every 6
days, whereas half the TIT-because of its lower affinity-is
released to the cells in about 1 day.
They again bind to proteins with in cells, stored in the target
cells themselves, and they are used slowly over a period of days
or weeks.

161. Thyroid Hormones Have Slow Onset and Long Duration of Action
long latent period of 2-3 days than reaches a maximum in 10 to
12 days, then decreases with a half-life of about 15 days. Some
of the activity persists for as long as 6 weeks to 2 months.
Triiodothyronine acts four times as rapidly as thyroxine, with a
latent period as short as 6 to 12 hours and maximal cellular
activity occurring within 2 to 3 days.

163. FUNCTIONS
The general effect of thyroid hormone is to activate nuclear
transcription of large numbers of genes.
Therefore great numbers of protein enzymes, structural
proteins, transport proteins, and other substances are
synthesized.
Nongenomic functions include regulation of ion channels and
oxidative phosphorylation and appear to involve the activation of
intracellular secondary messengers such as cyclic AMP or protein
kinase signaling cascades.

165. CELLULAR FUNCTIONS
Thyroid Hormones Increase Cellular Metabolic Activity
Increase oxygen consumption
Increase no. of mitochondria
Increase Na/K ATPase

166. EFFECT OF THYROID
HORMONE ON GROWTHGeneral and specific effects on growth
In hypothyroid, the rate of growth is greatly retarded. In
hyperthyroid, excessive skeletal growth often occurs, causing
the child to become considerably taller at an earlier age(early
union of epiphysis).
Promote growth and development of the brain during fetal life
and for the first few years of postnatal life.

167. Stimulation of Carbohydrate Metabolism
rapid uptake of glucose by the cells,
enhanced glycolysis,
enhanced gluconeogenesis,
increased rate of absorption from the gastrointestinal tract,
and even increased insulin secretion with its resultant secondary
effects on carbohydrate metabolism.
All these effects probably result from the overall increase in
cellular metabolic enzymes caused by thyroid hormone.

168. PROTEIN METABOLISM
Both anabolic and catabolic effects
In excess causes catabolism

169. Stimulation of Fat Metabolism
lipids are mobilized rapidly from the fat tissue, which decreases
the fat stores of the body
Increases free fatty acid concentration in the plasma and
increase oxidation of free fatty acids by the cells.

170. Increased thyroid hormone decreases the concentrations of
cholesterol, phospholipids, and triglycerides in the plasma, even
though it increases the free fatty acids.
Decreased thyroid secretion greatly increases the plasma
cholesterol, phospholipids, and triglycerides and almost always
causes excessive deposition of fat in the liver as well.
The large increase in circulating cholesterol can lead to severe
atherosclerosis.

171. Mechanisms:
significantly increase the rate of cholesterol secretion in the bile
and consequent loss in the feces.
increases numbers of low-density lipoprotein receptors on the
liver cells, leading to rapid removal of low-density lipoproteins
from the plasma by the liver and subsequent secretion of
cholesterol in these lipoproteins by the liver cells.

172. Increased Requirement for Vitamins
Because thyroid hormone increases the quantities of many
bodily enzymes and because vitamins are essential parts of
some of the enzymes or coenzymes, thyroid hormone increases
the need for vitamins.

173. Increased Basal Metabolic Rate
Increases metabolism in almost all cells of the body,
excessive quantities of the hormone can occasionally increase
the basal metabolic rate 60 to 100 percent above normal.
Conversely, when no thyroid hormone is produced, the basal
metabolic rate falls to almost one-half normal.

174. Decreased Body Weight
Greatly increased thyroid hormone almost always decreases the
body weight, and greatly decreased thyroid hormone almost
always increases the body weight.

175. EFFECT ON CARDIOVASCULAR
SYSTEM

176. INCREASED BLOOD FLOW
AND CARDIAC OUTPUT
• Increased metabolism in the tissues
• rapid utilization of oxygen
• release of greater metabolic end products
• vasodilation in most body tissues
• increased blood flow
• increased cardiac output

177. Increased Heart Rate
The heart rate increases considerably more under the influence
of thyroid hormone than would be expected from the increase in
cardiac output.
Has a direct effect on the excitability of the heart, which in turn
increases the heart rate.
Important for clinical diagnosis of hyperthyroidism

178. Increased Heart Strength
The increased enzymatic activity increases the strength of the
heart.
Similar increase in heart strength occurs in mild fevers and
during exercise.
Excess of thyroid hormone depresses the heart muscle strength
because of long-term excessive protein catabolism.
Indeed, some severely thyrotoxic patients die of cardiac
decompensation secondary to myocardial failure and to
increased cardiac load imposed by the increase in cardiac
output.

179. Normal Arterial Pressure
The mean arterial pressure usually remains about normal after
administration of thyroid hormone. Because of increased blood
flow through the tissues between heartbeats, the pulse pressure
is often increased, with the systolic pressure elevated in
hyperthyroidism 10 to 15 mm Hg and the diastolic pressure
reduced a corresponding amount.
Increased Respiration
The increased rate of metabolism increases the utilization of
oxygen and formation of carbon dioxide which leads to
increased rate and depth of respiration.

180. Increased Gastrointestinal
Motility
increases appetite
increases food intake,
increases both the rates of
secretion of the digestive juices
Increases the motility of the
gastrointestinal tract.
Hyperthyroidism therefore often
results in diarrhea, whereas lack of
thyroid hormone can cause

181. Effects on the Central Nervous
System
Thyroid hormone increases the
excitability of CNS.
Increased reactivity of the neuronal
synapses
The hyperthyroid individual is likely
to have extreme nervousness and
many psychoneurotic tendencies,
such as anxiety complexes and
extreme worry.

182. Effect on the Function of the Muscles
Slight increase in thyroid hormone usually makes the muscles
react with vigor, but when the quantity of hormone becomes
excessive, the muscles become weakened because of excess
protein catabolism.
lack of thyroid hormone causes the muscles to become sluggish
and they relax slowly after a contraction.

183. Muscle Tremor
Characteristic signs of hyperthyroidism is a fine muscle tremor.
The tremor can be observed easily by placing a sheet of paper
on the extended fingers and noting the degree of vibration of
the paper.
This tremor is believed to be caused by increased reactivity of
the neuronal synapses in the areas of the spinal cord that
control muscle tone.
The tremor is an important means for assessing the degree of
thyroid hormone effect on the central nervous system.

184. Effect on Sleep
Because of the exhausting effect of thyroid hormone on the
musculature and on the central nervous system,
the hyperthyroid subject often has a feeling of constant
tiredness, but because of the excitable effects of thyroid
hormone on the synapses, it is difficult to sleep.
Extreme somnolence is characteristic of hypothyroidism, with
sleep sometimes lasting 12 to 14 hours a day.

185. EFFECT ON OTHER ENDOCRINE
GLANDS
Increased thyroid hormone increases the rates of secretion of
several other endocrine glands, but it also increases the need of
the tissues for the hormones e.g. glucose metabolism and
insulin, bone formation and parathyroid hormone.
Thyroid hormone also increases the rate at which adrenal
glucocorticoids are inactivated by the liver. This leads to
feedback increase in adrenocorticotropic hormone (ACTH)
production.

186. Effect of Thyroid Hormone
on Sexual Function
For normal sexual function, thyroid secretion needs to be
approximately normal.
In men, lack of thyroid hormone is likely to cause loss of libido;
great excesses of the hormone can cause impotence.
In women, lack of thyroid hormone often causes menorrhagia
and polymenorrhea
But may cause irregular periods and occasionally even
amenorrhea.

188. REGULATION OF THYROID
HORMONE SECRETION
ROLE OF TSH (cAMP)
Increased proteolysis of the thyroglobulin
Increased activity of the iodide pump
Increased iodination of tyrosine to form the thyroid hormones
Increased size and increased secretory activity of the thyroid
cells
Increased number of thyroid cells plus a change from cuboidal
to columnar cells and much infolding of the thyroid epithelium
into the follicles

193. Effects of Cold and Other Neurogenic Stimuli on TRH and TSH
Secretion
Cold stimulates the release of TRH and TSH.
Excitement and anxiety-conditions decrease secretion of
TSH(increase BMR and heat, feedback).
Neither these emotional effects nor the effect of cold is observed
after the hypophysial stalk has been cut.

194. Antithyroid Substances Suppress Thyroid Secretion
The best known antithyroid drugs are
thiocyanate,
propylthiouracil,
and high concentrations of inorganic iodides.

195. THIOCYANATE IONS DECREASE
IODIDE TRAPPING
The administration of thiocyanate (or one of the other ions as
well) in high enough concentration can cause competitive
inhibition of iodide transport into the cell-that is, inhibition of
the iodide-trapping mechanism.*

196. The use of thiocyanates and some other ions can lead to
development of goiter.
The decreased availability of iodide in the glandular cells does
not stop the formation of thyroglobulin;
it merely prevents the thyroglobulin that is formed from
becoming iodinated.
This deficiency of the thyroid hormones in turn leads to
increased secretion of TSH which causes overgrowth of the
thyroid gland.

197. PROPYLTHIOURACIL DECREASES
THYROID HORMONE FORMATION
Propylthiouracil (and other, similar compounds, such as
methimazole and carbimazole) prevents formation of thyroid
hormone from iodides and tyrosine.
The mechanism of this is partly to block the peroxidase enzyme.
Propylthiouracil, like thiocyanate, does not prevent formation of
thyroglobulin.
The absence of thyroxine and triiodothyronine in the
thyroglobulin can lead to tremendous feedback enhancement of
TSH secretion by the anterior pituitary gland, thus promoting
growth of the glandular tissue and forming a goiter.

198. IODIDES IN HIGH CONCENTRATIONS
DECREASE THYROID ACTIVITY AND
THYROID GLAND SIZE
Iodides in high concentration (100 times the normal plasma
level), stop most activities of the thyroid gland (for only a few
weeks). This inhibition is known as the Wolff–Chaikoff effect.
The normal endocytosis of colloid from the follicles by the
thyroid glandular cells is paralyzed by the high iodide
concentrations.
there is almost immediate shutdown of thyroid hormone
secretion into the blood.

199. HYPERTHYROIDISM
The thyroid gland is increased to two to three times' normal
size, with tremendous hyperplasia and infolding of the follicular
cell lining into the follicles, so the number of cells is increased
greatly.
Also, each cell increases its rate of secretion severalfold;
radioactive iodine uptake studies indicate that some of these
hyperplastic glands secrete thyroid hormone at rates 5 to 15
times normal.

201. GRAVES DISEASE
the most common form of hyperthyroidism,
is an autoimmune disease
antibodies called thyroid-stimulating immunoglobulins
(TSIs) form against the TSH receptor in the thyroid gland.
These antibodies bind with the same membrane
receptors that bind TSH.
The TSI antibodies have a prolonged stimulating effect
on the thyroid gland, lasting for as long as 12 hours, in
contrast to a little over 1 hour for TSH.

202. EXOPTHALMOS
Is hallmark of Graves disease charecterized by swelling of
tissues in the orbits, producing protrusion of the eyeballs
(exophthalmos).
This occurs in 50% of patients and often precedes the
development of obvious hyperthyroidism.
The eyeball protrusion stretches the optic nerve enough to
damage vision.
The eyelids do not close completely when the person blinks or is
asleep, the epithelial surfaces of the eyes become dry and
irritated and often infected, resulting in ulceration of the cornea.

203. EXOPTHALMOS
The cause of the protruding eyes is edematous swelling of the
retro-orbital tissues and degenerative changes in the extraocular
muscles.
In most patients, immunoglobulins that react with the eye
muscles can be found in the blood.
The exophthalmos is usually greatly ameliorated with treatment
of the hyperthyroidism.

205. GRAVES DISEASE
The high level of thyroid hormone secretion caused by TSI in
turn suppresses anterior pituitary formation of TSH.
TSH concentrations are less than normal (often essentially zero)
in Graves' disease.
The antibodies that cause hyperthyroidism almost certainly
occur as the result of autoimmunity that has developed against
thyroid tissue.*

206. THYROID ADENOMA
Hyperthyroidism occasionally results from a localized adenoma
(a tumor) that develops in the thyroid tissue and secretes large
quantities of thyroid hormone.
The thyroid hormone from the adenoma depresses the
production of TSH by the pituitary gland and inturn hormones
from normal gland.

207. SYMPTOMS OF
HYPERTHYROIDISM(1) a high state of excitability,
(2) intolerance to heat,
(3) increased sweating,
(4) mild to extreme weight loss (sometimes as much as 100
pounds),
(5) varying degrees of diarrhea,
(6) muscle weakness,
(7) nervousness or other psychic disorders,
(8) extreme fatigue but inability to sleep, and
(9) tremor of the hands.
(10)Increased pulse pressure
(11)+10 to +100 increase in BMR

208. DIAGNOSTIC TESTS FOR
HYPERTHYROIDISM
Routine Tests
For the usual case of hyperthyroidism, the most accurate
diagnostic test is direct measurement of the concentration of
"free" thyroxine :
The basal metabolic rate is usually increased to +30 to +60 in
severe hyperthyroidism.
The concentration of TSH in the plasma is measured by
radioimmunoassay.
The concentration of TSI is measured by radioimmunoassay. This
is usually high in thyrotoxicosis but low in thyroid adenoma.

209. TREATMENT OF THE
HYPERPLASTIC THYROID
GLAND WITH RADIOACTIVE
IODINE
Eighty to 90 percent of an injected dose of iodide is absorbed by
the hyperplastic, toxic thyroid gland within 1 day after injection.
If this injected iodine is radioactive, it can destroy most of the
secretory cells of the thyroid gland.
Usually 5 millicuries of radioactive iodine is given to the patient,
whose condition is reassessed several weeks later. If the patient
is still hyperthyroid, additional doses are administered until
normal thyroid status is reached.

210. PHYSIOLOGY OF TREATMENT
IN HYPERTHYROIDISMThe most direct treatment for hyperthyroidism is surgical
removal of most of the thyroid gland. Patient is prepared for
surgical removal by administering:
Propylthiouracil, usually for several weeks, until the basal
metabolic rate of the patient has returned to normal.
Then, high concentrations of iodides for 1 to 2 weeks
immediately before operation causes the gland itself to recede in
size and its blood supply to diminish.

211. Because iodides in high concentrations decrease all phases of
thyroid activity, they slightly decrease the size of the thyroid
gland and especially decrease its blood supply, in
contradistinction to the opposite effects caused by most of the
other antithyroid agents.
IMPORTANCE: iodides are frequently administered to patients for
2 to 3 weeks before surgical removal of the thyroid gland to
decrease the necessary amount of surgery, especially to
decrease the amount of bleeding.

212. HYPOTHYROIDISM
autoimmunity against the thyroid gland (Hashimoto
disease),
Endemic Colloid Goiter Caused by Dietary Iodide
Deficiency
Idiopathic Nontoxic Colloid Goiter
Abnormality of the enzyme system
goitrogenic substances (turnips and cabbages)
Surgical removal of gland
Destruction due to radiation or drugs

213. PHYSIOLOGICAL CHARACTERISTICS
OF HYPOTHYROIDISM
Fatigue and extreme somnolence with sleeping up to 12 to 14
hours a day,
Extreme muscular sluggishness,
Slowed heart rate, decreased cardiac output, decreased blood
volume,
Increased body weight,
Constipation,
Mental sluggishness,
Depressed growth of hair and scaliness of the skin,
Development of a froglike husky voice, and,
In severe cases, development of an edematous appearance
throughout the body called myxedema.

214. ABNORMALITY OF THE ENZYME
SYSTEM
Deficient iodide-trapping mechanism, in which iodine is not
pumped adequately into the thyroid cells
Deficient peroxidase system, in which the iodides are not
oxidized to the iodine state
Deficient coupling of iodinated tyrosines in the thyroglobulin
molecule so that the final thyroid hormones cannot be formed
Deficiency of the deiodinase enzyme, which prevents recovery of
iodine from the iodinated tyrosines that are not coupled to form
the thyroid hormones (this is about two thirds of the iodine),
thus leading to iodine deficiency

215. MYXEDEMA
develops in the patient with almost total lack of thyroid hormone
function.
bagginess under the eyes and swelling of the face.
In this condition, greatly increased quantities of hyaluronic acid
and chondroitin sulfate bound with protein form excessive tissue
gel in the interstitial spaces, and this causes the total quantity of
interstitial fluid to increase.
Because of the gel nature of the excess fluid, it is mainly
immobile and the edema is the nonpitting type.

216. ATHEROSCLEROSIS IN
HYPOTHYROIDISMLack of thyroid hormone increases the quantity of blood
cholesterol because of altered fat and cholesterol metabolism
and diminished liver excretion of cholesterol in the bile.
The increase in blood cholesterol is usually associated with
increased atherosclerosis.
in turn can result in peripheral vascular disease, deafness, and
coronary artery disease with consequent early death.

217. TREATMENT OF
HYPOTHYROIDISM
Daily oral ingestion of a tablet or more containing
thyroxine is given.
Furthermore, proper treatment of the hypothyroid
patient results in such complete normality that formerly
myxedematous patients have lived into their 90s after
treatment for more than 50 years.

218. CRETINISM
Cretinism is caused by extreme hypothyroidism during fetal life,
infancy, or childhood.
The severity of endemic cretinism varies greatly, depending on
the amount of iodine in the diet, and whole populaces of an
endemic geographic iodine-deficient soil area have been known
to have cretinoid tendencies.

220. failure of body growth
mental retardation.
Idiotic look
Dribbling of saliva
Skeletal growth in the child with cretinism is characteristically
more inhibited than is soft tissue growth.
the soft tissues are likely to enlarge excessively, giving the child
with cretinism an obese, stocky, and short appearance.
tongue becomes so large in relation to the skeletal growth that it
obstructs swallowing and breathing, inducing a characteristic
guttural breathing that sometimes chokes the child.

221. TREATMENT
A neonate without a thyroid gland may have normal appearance
and function because it was supplied with some (but usually not
enough) thyroid hormone by the mother while in utero.
Treatment of the neonate with cretinism at any time with
adequate iodine or thyroxine usually causes normal return of
physical growth,
but unless the cretinism is treated within a few weeks after
birth, mental growth remains permanently retarded.
This results from retardation of the growth, branching, and
myelination of the neuronal cells of the central nervous system
at this critical time in the normal development of the mental
powers.