sHORMONES AND THE ENDOCRINE SYSTEM
= 2 Physiologic Regulatory System: (both are intricately related
as each system can influence the function
of the other)
1. endocrine system - consists of the ductless glands the
produce highly active chemical regulators
called hormones (these chemical messengers are secreted into the
bloodstream & some
flow in the extracellular fluid, where they have the opportunity
to act upon all organs by
interacting w/ specific receptor on cells)
2. nervous system - acts locally at tissue or cellular sites
FUNCTIONS OF HORMONES:
= hormones regulate metabolism, preserve homeostasis, control
the rates of growth & devt, & influence
behaviour by affecting a wide variety of biologic system
= functions of hormones:
1. to maintain homeostasis (a constant internal environment in
the body fluids)
2. to regulate the growth & devt of the body as a whole
3. to promote sexual maturation, maintain sexual rhythms, &
facilitate the reproductive process
4. to regulate energy production and stabilize the metabolic
rate
5. to help the body to adjust to stressful or emergency
situations
6. to promote or inhibit the production & release of certain
other hormones
= hormones usually do not act alone (any physiologic effect of a
particular hormone is the result of it & any
counter regulatory hormones that may be circulating)
= example of individual hormones:
a. parathyroid hormone (concerns with the maintenance of a
constant plasma concentration of calcium ion)
b. thyroid hormones (regulate the basal metabolic rate of all
cells in the body)
c. growth hormones (essential for proper growth and devt)
FUNCTIONAL TYPES:
= 4 functional types of hormones:
1. releasing hormones from the hypothalamus that promote the
secretion of anterior pituitary hormones
2. inhibitory hormones from the hypothalamus or gastrointestinal
tract that suppress the secretion of particular hormones
3. tropic hormones that stimulate the growth & activity of
other endocrine glands
4. effector hormones secreted by all the endocrine glands other
than the anterior pituitary & hypothalamus
target cells of the effector hormones are the nonendocrine
tissue cells
ex: gonadal hormones
STRUCTURAL CLASSES:
= 5 general classes of hormones are:
1. proteins (MW > 5,000 daltons) or polypeptides (> 20
amino acids)
2. glycoprotein composed of polypeptide chains containing
covalently linked carbohydrate
3. peptides (< 20 amino acids)
4. steroids- acts intracellularly that directly affects genes.5.
amino acid derivatives
HORMONAL SECRETION AND REGULATION:
Secretion
= the production & secretion of hormones by an endocrine
gland may be initiated by one or more of the ff
signals:
1. stimulation of the cerebral cortex or neural centers by
thoughts; emotions; stress; circadian (periodic) rhythms that may
be daily, monthly, or seasonal; & chemical transmitters such as
norepinephrine, dopamine, acetylcholine, & serotonin
2. a change in the plasma conc of particular ions or compounds
(secretion of parathyroid hormone when the plasma conc of CA2+ is
low or of insulin when the plasma level of glucose is hight)
3. secretion of tropic hormones (ex: ACTH & TSH cause the
adrenal & thyroid glands to produce & secrete cortisol
& thyroxine, respectively)
4. variation in blood osmolality (secretion of antidiuretic
hormone, ADH, by the posterior pituitary when the plasma osmolality
increases)
5. release of hormones in the GIT in the presence of various
foods (food in the stomach stimulates gastrin secretion by the
stomach)
Regulation by the Central Nervous System
= the secretion of the endocrine glands are carefully regulated
by the complex interaction between the
nervous & endocrine system (Fig. 13.1)
= neural centers may trigger the release or suppression of
particular hormones by means of an action
potential or neurotransmitter fired or released w/in the gland
(ex. feeling of fear or anxiety transmit a
message from the brain by way of the sympathetic nervous system
to the adrenal medulla that results in
epinephrine secretion; anxiety or stress can disturb the
regularity of the menstrual cycle)
= (Fig. 13.1) the hypothalamus may be stimulated by the CNS or
by stress to secrete releasing factors
(GHRF, TRF, LHRF, or FSHRF - these are the respective releasing
factors for growth hormone), ADH,
or oxytocin
GHRF stimulates the anterior pituitary to secrete growth
hormone, w/c acts directly upon target cells
Other releasing factors evoke secretion of tropic hormones that
stimulate the adrenal cortex, thyroid, or gonads to secrete their
respective hormones, w/c then act upon target cells
Hormones ADH, & oxytocin travel down the pituitary stalk
into the posterior pituitary, where they are secreted
Broken lines represent feedback control of secretion of
hypothalamic or anterior pituitary
GH growth hormone; PRL prolactin; TSH thyroid-stimulating
hormone; ACTH adrenocortocotropin; thyrotropin TSH; LH luteinizing
hormone; FSH follicle-stimulating hormone
Regulation by the Hypothalamus
= hypothalamus is located at the base of the brain &
connected to the pituitary stalk, contains many
neurosecretory cells & neurosecretory nerve fibers; it plays
a major role in endocrine regulation bec of
its ability to release hormones that selectively stimulate or
inhibit the secretion of specific anterior
pituitary hormones (Table 13.1)
= the hypothalamus may be activated by the CNS, emotion, or
stress to secrete one or more of a group of
releasing factors; these releasing factors are peptides or
polypeptides that stimulated the anterior
pituitary to elaborate and secrete the appropriate tropic
hormone
Regulation by the Anterior Pituitary
= 4 of the 6 hormones (Table 13.2) elaborated by the anterior
pituitary are tropic hormones (adrenocorticotropic hormone-ACTH;
thyroid-stimulating hormone-TSH; follicle-stimulating hormone-FSH;
& luteinizing-stimulating hormone-LH), act upon the adrenal
cortex, thyroid , & gonads to stimulate production &
secretion of their particular hormones
Hormonal actions upon Target Cells
= hormones act in different ways on their target cells
= the protein & peptide hormones & the catecholamines
(epinephrine & norepinephrine) become attached
to target cell membranes & activate adenyl cyclase to
produce cyclic adenosine monophosphate (c-AMP)
= c-AMP activates protein kinases, enzymes that activate
phosphorylases; liver phosphorylase for
example converts glycogen to glucose
= hormonal action on the cell membrane is usually short-lived
bec of rapid conversion to inactivate
metabolite by enzymes
= the chemical nature of the steroid & thyroid hormones
enables them to enter their target cells & penetrate
to the cell nuclei
= bec the main function of a hormone is to exert a fine
regulatory control over metabolic processes or
over growth & devt, either overproduction or underproduction
of various hormones leads to
abnormalities
= a problem lies, in ascertaining whether an endocrine
dysfunction is caused by a malfunction of the
endocrine gland in question, a deficiency of a tropic hormone
(pituitary dysfunction), a deficiency of
releasing factors (hypothalamus or feedback control
dysfunction), a defect in the target cell, or other
factors involving transport proteins or autoimmune dses
= entopic hormones are hormones produced elsewhere in the body
than in the customary endocrine gland
ANTERIOR PITUITARY HORMONES
Pituitary gland = composed of 2 distinct parts:
1. anterior lobe / adenohypophysis controls the hormonal outputs
of some endocrine glands by its
secretion of tropic hormones
- also secretes 2 effector hormones:> growth hormone
> prolactin
2. posterior lobe / neurohypo physis
* commercial kits are available for the measurement of all
pituitary hormones of clinical interest
Effector Hormones:
1. GROWTH HORMONE (GH, Somatotropin)
= is the hormone produced in the largest quantity by the
anterior pituitary
= affects many metabolic processes in addition to promoting
skeletal growth & CHON synthesis
esp in young ones
= many of the growth-promoting effects of GH upon cartilage
& the long bones are mediated by
insulin-like growth factors (IGF), previously called
somatomedins (that are secreted by the liver
in response to GH secretion)
= GH has many metabolic effects that are antagonistic to those
of insulin (but 3 IGFs are
structurally related to the glucose-regulating hormone insulin:
IGF-I, IGF-II, IGF-III)
= the plasma conc of GH during the day is low in humans ( 10
ng/ml in normal individuals; values < 5 ng/ml are highly
suggestive of GH insufficiency
= prolonged excess of GH secretion prior to closure of the long
bones at puberty causes excessive
growth or gigantism
= hypersecretion of GH by a pituitary tumor in adulthood (after
closure of the long bones) causes
a condition known as acromegaly ( in w/c the person is large
& has gross features; plasma
levels of GH & IGF-I are frequently elevated in this
condition)
2. PROLACTIN
= a hormone similar in structure to GH
= participates with gonadal steroids in breast growth during
pregnancy
= after parturition, prolactin stimulates milk secretory
activity, although the initiation of milk flow
is induced by one of the posterior pituitary hormones,
oxytocin
= elevated levels of prolactin may result in menstrual
irregularity, infertility, & galactorrhea
(inappropriate production of breast milk)
= prolactinomas, prolactin-secreting tumors, are the most common
type of secretory pituitary
tumor (> 100 ng/ml)
= NV: women = < 30 ng/ml
men = < 20 ng/ml
= factors that may result in elevated levels: exercise, fasting,
stress, or breast examination during
a physical examination
Tropic Hormones:
1. Thyroid-Stimulating Hormone (TSH, Thyrotropin)
= like FSH & LH, is a glycoprotein composed of 2 chains
= is the major regulator of thyroid secretion & function;
its output by the pituitary is under
negative feedback control by the level of circulating thyroid
hormone, T4
= its measurement is of value in the differential dx of thyroid
disease
= Increased:
> primary hypothyroidism bec of the lack of negative feedback
by thyroid hormones
= Decreased:
> primary hyperthyroidism bec of the excessive negative
feedback by elevated levels
of thyroid hormones
2. ADRENOCORTICOTROPIN (ACTH)
= a polypeptide that binds to cells of the adrenal cortex &
influences their activities
= stimulates the formation of adrenal steroids by increasing the
synthesis of pregnenolone from
cholesterol; the net effect is an increase in the secretion of
cortisol & adrenal androgens (Fig.
13.4)
= the conc of ACTH in plasma is highest between 6-8 am &
lowest in the evening between 6-11
pm
= NV: < 50 ng/ml
= Increased in 3 pathologic conditions:
a. primary adrenal cortical deficiency
b. cushings disease (hyperactivity of the adrenal cortex caused
by excessive pituitary ACTH
secretion)
c. ectopic tumors that produce ACTH
3. GONADOTROPINS (FSH, LH)
= are necessary for proper maturation & function of the
gonads in both men & women w/c is
necessary for the reproductive process (devt of mature ova in
females & of spermatozoa in
males)
= RIA methods are sufficiently sensitive methods for
measurement
= both FSH & LH are present in the plasma of both males
& females at all ages; a small rise
occurs at puberty in both sexes; but a great increase in the
conc of plasma LH & FSH takes
place in women after the menopause & remains elevated for
the remainder of their lives
= in ovulating females, the conc of both FSH & LH rise
sharply from the basal level just before
ovulation & then fall
= measurements of both FSH & LH are useful in diagnosing
menstrual & fertility disorders
= ELISA-based LH kits for home use are now available for
ascertaining the day of ovulation
4. OTHER ANTERIOR PITUITARY HORMONES
= peptide hormones produce by anterior pituitary that do not
have much clinical relevance at this
time:
a. melanocyte-stimulating hormone ((-MSH) = a peptide
b. endorphins are polypeptides that raise the pain threshold by
exerting an opiate-like
actions on portions of the brain
POSTERIOR PITUITARY HORMONES
Posterior lobe of the pituitary gland = is connected
anatomically to the hypothalamus by a stalk through
which a nerve tract & blood vessels pass
= stores & secretes 2 closely related peptide hormones:
(Table 13.3)
1. ADH (antidiuretic hormone, vasopressin)
2. oxytocin
= both are synthesized in the hypothalamus & travel through
the nerve tract in the pituitary stalk
to the posterior pituitary lobe, where they are stored until
secreted
1. Antidiuretic Hormone (ADH)
= primary function is to increase the reabsorption of water by
the renal tubules when the plasma
osmolality becomes elevated
= also affects blood pressure
= deficiency of ADH is associated with diabetes insipidus, w/c
is characterized by the passage of
large volumes of dilute urine
2. Oxytocin = is a potent stimulant for the contraction of
smooth muscle
= sometimes used to induce labor by promoting uterine
contractions
= also stimulates the ejection of milk from the mammary
glands
= no particular medical need is served to present by measuring
the conc of circulating oxytocin
Table 13.3
POSTERIOR PITUITARY HORMONES
HORMONE
TYPE
TARGET TISSUE
PRINCIPAL ACTION___
Antidiuretic hormonepeptide
renal tubules, arterioles
( water reabsorption,
(ADH, vasopressin)
( blood pressure
Oxytocin
peptide
uterus, breasts
contracts uterus, ejection
of milk
THYROID HORMONES, T4 AND T3
Thyroid gland = is a small tissue situated in the neck just
below the larynx (voice box)
= its hormones increase the basal metabolic rate & are
necessary for proper growth & devt
= it also secretes calcitonin ( a hormone that participates in
the regulation of plasma Ca2+ conc by
inhibiting bone resorption)
= circulating thyroid hormones:> thyroxine /
tetraiodothyronine (T4)
> triiodothyronine (T3)
THYROID HORMONES
HORMONE
TYPE
TARGET TISSUE PRINCIPAL ACTION
Thyroxine (T4) & iodo-derivatives All tissues
( metabolic rate (O2 Triiodothyronine (T3) of tyrosine
consumption)
Calcitonin (CT)
polypeptide
bone osteoclasts inhibits bone resorption
EVALUATION OF THYROID FUNCTION
= the plasma conc of thyroid hormone is normal individuals is
kept relatively constant by a
sensitive negative feedback control by free T4 on pituitary
release of TSH
= the hypothalamus with its releasing hormone
(thyrotorpin-releasing hormone, TRH); the
anterior pituitary with its tropic hormone (TSH); & the
thyroid gland with its secretion of T4
interact in a dynamic fashion to regulate T4 & T3 levels
= thus the evaluation of thyroid status is not a simple
procedure bec it does not depend solely on
the measurement of circulating thyroid hormones
T4 & T3 BY IMMUNOASSAY
= serum T4 conc is a better indicator of the thyroid secretory
rate than is T3 bec T4 is the
thyroids principal secretory product
= most of the circulating T3 comes from the peripheral
deiodination of T4, a process that is
depressed by severe illness or stress
= in immunoassay, labeled T4 or T3 compete with unlabeled
hormone (either in pxs samples or
in calibrators) for binding sites on Abs specific for either T4
or T3; the amount of labeled
hormone bound to the Ab is inversely proportional to the amount
of unlabeled hormone present;
after separation of the bound from the free fraction of labeled
hormone, the bound fraction is
counted in an appropriate counter & a standard curve is
drawn where the amount of bound
hormone is plotted as a function of the conc of hormone in the
calibrators; the conc of hormone
in the pxs sample is then determined from the standard curve
= increased conc of T3 & T4:hyperthyroidism
pregnancy, taking of birth control pills, or estrogen
= decreased conc of T3 & T4:hypothyroidism
when TBG level has been decreased by disease
by medications that reduce the synthesis of TBG
by medications that compete with T4 & T3 for binding
sites
T3 UPTAKE (T3U) AND FREE THYROXINE INDEX (FTI)
= physiologic variation in conc of TBG & the other
thyroid-binding proteins may occur in a
fashion unrelated to thyroid disease; thus TBG synthesis &
plasma conc are increased by
estrogens & pregnancy; they are decreased by depressed
synthesis or loss through the kidney
in theses instances, the individual is usually euthyroid bec the
thyroid gland adjust its secretory
rate so that the plasma conc of free hormone remains within
normal limits after equilibration
with bound hormone is reached
= T3 uptake (T3U) test provides an indirect estimate of the
binding capacity of the plasma
thyroid-binding proteins
= typical reference range:
%T3U = 25-35%
= increased values of T3U:hyperthyroidism
when theres decrease in TBG conc
drugs that lower the serum T3 & T4 conc by competitive
binding to TBG increase the T3U bec the labeled T3 cannot
displace the drugs from their binding to TBG; more of the labeled
T3 is taken up by the adsorbent
= decreased values of T3U:hypothyroidism
estrogens
= normal FTI:euthyroid subjects, pregnancy, women taking
estrogens, nephrosis or hepatitis,
& drugs that elevate T3U
= increased FTI:hyperthyroidism
= decreased FTI: hypothyroidism
FREE T4 & FREE T3
= the effective thyroid hormones are free T4 & T3, bec these
hormones act upon tissue cells while
T4 & T3 bound to plasma proteins function as a reservoir
& are in equilibrium with the free
forms
= the levels of free T4 & T3 correlate much better with the
thyroid status than does total T4 or T3
& are not affected by an abnormal TBG conc
THYROID-STIMULATING HORMONE (TSH) & THYROID-RELEASING
HORMONE (TRH)
= reference values:euthyroid persons = 0.4-6 uU/mL (adults)
3-15 uU/mL (newborns)
= increased TSH level:hypothyroidism (bec of the absence of the
negative feedback control;
values as high as 500 uU/mL or mostly above 30 uU/mL)
= decreased TSH level:hyperthyroidism
= immunoradiometric assay (IRMA) or sandwich technique have the
ability to differentiate
euthyroid from hyperthyroid pxs; such differentiation was not
possible with the less sensitive
RIA for TSH
= THYROTROPIN-RELEASING HORMONE (TRH) STIMULATION TEST
injection of TRH & measurement of the output of TSH have
some value as a test for indicating combined pituitary &
thyroid function or for separating hypothalamic from pituitary
disease
GUIDELINES FOR USED OF THYROID TESTS
@ When clinical evidence of hyperthyroidism exists, measure
T4:
1. Elevated serum conc of T4 is found in most cases, thus
confirming the dx
2. If T4 is normal, measure serum T3 & free T4 index (FTI).
Increased T3 indicates T3
hyperthyroidism, whereas increased FTI signifies a decreased
plasma conc of TBG. A free T4
assay may be substituted for the FTI. Use of sensitive TSH tests
usually reveals a decreased
TSH in primary hyperthyroidism.
@ When clinical evidence of hypothyroidism exists:
1. Decreased T4 is found in many cases.
2. Increased TSH confirms the diagnosis.
3. If T4 is normal & TSH elevated, an FTI is indicated for
evaluation of the TBG conc
4. In a few cases, measurement of free T4 or T3 may be
necessary; sometimes an rT3 assay may
help to clarify an ambiguous situation
** sick low T4 euthyroid syndrome = a condition where in a low
serum T4 level but no specific
symptoms of hypothyroidism bec thyroid function returns to
normal upon recovery
= measurement of serum TSH differentiates those with primary
hypothyroidism (TSH > 20
uU/mL) from those with sick low T4 euthyroid syndrome (TSH <
10 uU/mL)
** Screening of newborns for hypothyroidism = in most states,
measurement of serum T4 & checking of
all low or questionable values with a TSH test are customary
= an increased TSH confirms a dx of hypothyroidism
= in other states, the TSH assay may be performed first, &
elevated values confirmed by a
decreased T4 conc
= ex: a serum T4 < 6 ug/dL should be confirmed by finding a
serum TSH > 30 uU/mL & vice
versa
= dx must be make early so that treatment with T3 or T4 can be
started before arrested devt
occurs.PARATHYROID HORMONE (PARATHORMONE, PARATHYRIN, PTH)
SYNTHESIS AND SECRETION:
= the parathyroid glands consist of 4 small glands that are
found at the pole of the thyroid / embedded in
the thyroid glands in the neck (2 parathyroid gland in each
thyroid gland)
= is a polypeptide hormone consisting of 84 amino acids
= PTH is a secretory product of the parathyroid glands
= PTH is synthesized as a longer chain precursor called
pre-pro-parathyroid hormone (Fig 19-1)
= none of the PTH precursors enter the circulation
= a decrease in the serum ionized calcium level triggers the
release of PTH (even a drop of only 0.1 mg/dL
below the normal limit of ionized calcium is sufficient to
trigger an increase PTH in the circulation
= magnesium is another essential ingredient for PTH release; if
serum Mg++ levels drop much below the
normal limits, PTH secretion is inhibited
METABOLISM AND EXCRETION: (Fig 19-1)
= once in the circulation, the serum conc of PTH decreases
rapidly
= half life:> intact hormone (w/the N-terminal fragment) = 5
min
> c-terminal segment = roughly 1 hr
> accdg to some books half life of PTH is approximately 12
min
= major sites of PTH breakdown are liver, kidney & bone
= the liver is the primary location for fragmentation of the
intact 84-amino acid PTH chain
= the kidney is important to the metabolism & excretion of
PTH & its fragments
the small MW of the intact molecule (under 10,000) means this
molecule is filtered readily at the glomerulus
the fragments also undergo glomerular filtration since they are
smaller than the intact hormone
the intact hormone & the N-terminal fragment undergo tubular
secretion
a fraction of all 3 forms of the hormone are reabsorbed by the
tubule
= little metabolic uptake of intact hormone by bone occurs (10%
or less of the total utilization by liver &
kidney)
= some inactivation of PTH by bone cells must occur after the
hormone interacts with a receptor to
promote specific receptor to promote calcium resorption back
into the circulation
BIOCHEMICAL EFFECTS: (Table 19-4)
= the direct effect of PTH is on bone
PTH causes calcium (& phosphate) to be released from bone
back into the circulation
= PTH acts on the kidney
inhibiting the tubular reabsorption of phosphate while enhancing
the reabsorpion of Ca++ & Mg++
= PTH stimulate the formation of a Vit D derivative w/c is also
involved in calcium retention by the
kidney & in the enhancement of Ca++ absorption across the
inteatinal tract
= major role is the maintenance of Ca++ homeostasis /
responsible Ca++ utilization & bone metabolism
= parathyroid gland maintains the plasma Ca++ conc w/in narrow
limits by secreting PTH in response to a
small decrease in Ca++ conc
= a negative feedback control inhibits the secretions of PTH
when Ca++ is elevated
ASSAY:
= there are several different methods for measuring PTH, wither
as the intact molecular or as the C-
terminal or N-terminal fragment; with intact molecule, Abs can
be specifically directed to either the N-
or C-terminal portion of the hormone
= the major problems associated with specificity in the assay of
PTH center on the heterogeneity of serum
proteins w/c react with a particular Ab (if an assay is employed
for the C-terminal portion of the
hormone molecule, the Ab detects both the intact PTH molecule
and the C-terminal fragment produced
by proteolysis and similar problems occur with an N-terminal
assay)
= the current approach is to measure intact PTH with IRMA assays
which utilize Abs to both the C- & N-
terminal portions
= PTH raises Ca++ directly by:
1. mobilizing calcium from bone
2. decreasing renal excretion of Ca++ by stimulating tubular
reabsorption
= increases Ca++ indirectly by enhancing the renal formation of
1,25-(OH)2D3; the biologically active
form of Vit D that increases the absorption of calcium
= reduces the phosphate load arising from the bone reabsorption
by promoting its excretion by the kidney
(inhibiting tubular reabsorption)
= PTH assay is used for investigating primary
hyperparathyroidism (for assessing the hypercalcemia of
malignant growths, & for checking for possible
hypoparathyroidism)
= ELEVATED:primary parathyroidism
pregnancy (provide some index of enhanced bone growth during
this period)
= NORMAL/UNDETECTABLE:hypercalcemia
hypoparathyroidism
Parathyroid Hormone
Hormone
Type
Target TissuePrincipal Action
Parathyroid hormonePolypeptideBone, Kidney
( plasma Ca++, ( bone resorption
( Ca++ excretion, ( phosphate
excretion
HYPERCALCEMIA:
= px demonstrate a number neurologic symptoms, including
fatigue, muscle weakness, & disorientation
= in extreme cases, stupor & coma may result
= other symptoms:nausea, vomiting, gastrointestinal distress
psychiatric abnormalities may be seen (depression or psychotic
behaviour)
= increased calcium levels in cancer pxs esp if the tumor has
metastasized to bone (bone destruction by the
cancer is occurring thus producing increased release of bone
mineral of w/c Ca++ is one)
= defective PTH:
> many cancers produce PTH w/in the cancer cell (ectopic
production of PTH)
> this fraction of PTH is not regulated by the normal
feedback mechanism
> if Ca++ levels rise, there is no compensatory shutdown of
ectopic hormone
release; as a result, bone deterioration occurs & calcium
loss is enhanced
= primary hyperparathyroidism is responsible for most cases of
hypercalcemia
in majority, the excess release of PTH is caused by a tumor on
the parathyroid gland, parathyroid hyperplasia (enlargement of the
parathyroid gland); in either situation, there is a higher blood
level of PTH & increased serum Ca++ values
= increased bone resorption & inhibition of Ca++ excretion
by the kidney
= excessive intake of Vit D promotes calcium increases through
enhanced absorption of calcium by way of
the gastrointestinal tract & increased bone resorption
= in pxs with multiple myeloma, elevated calcium levels could be
attributed to 2 factors:
a. first is associated with tumor of the bone so increased
calcium produced
b. pxs with MM exhibit hight conc of immunoglobulin fragments
(Bence Jones proteins) more
calcium is bound by the excess of proteins, consequently
lowering of the ionized calcium fraction; to compensate, the body
releases more calcium from bone, giving rise to an elevated total
calcium level
HYPOCALCEMIA:
= the most striking feature of this problem is TETANY: muscle
spasm, cramps, & irritability produced by
lowered availability of calcim for the contraction / relaxation
processes in muscle tissue
= dementia, mental retardation & other neurologic problems
are often associated w/ lowered serum Ca2+
= decreased in the serum albumin conc
since albumin serves as a major transport protein for calcium ,
any drop in the conc of this protein lowers the amt of bound
calcium & increases the level of ionized calcium
= hypoparathyroidism is a common cause of lowered serum
calcium
hypocalcemia occurs bec of the manufacture of defective PTH
= decreased in Vit D intake & metabolism are linked with
lowered Ca++ levels
in liver disease, impaired conversion of precursor to active
forms of the vitamin may be seen
in renal disease, theres a decrease in the conversion of the
inactive form of the Vit D to active form 1,25-dihydroxy compound,
often produces lowered serum calcium values
CALCITONIN (CT)
SYNTHESIS & METABOLISM:
= a peptide hormone synthesized in the thyroid gland
= before release into the circulation, small peptides from each
end of the precursor are removed by the
enzymes to yield the smaller, active calcitonin
= CTs half life is about 10 min, calcitonin is rapidly cleared
from the bloodstream once it is in the
circulation
= the major means of calcitonin removal is the kidney
= the peptide is filtered at the glomerulus, partially
reabsorbed in the tubules o& metabolized to small
fragments while still in the kidney
biochemical effects:
= major effects of calcitonin on calcium metabolism is to lower
blood levels of this mineral
= participates to a limited extent in Ca++ homeostasis by
responding to a hypercalcemia
= when calcitonin interacts with bone, calcium is absorbed by
bone and bone increases
= under the influence of increased calcitonin, the kidney
decrease the renal tubular absorption of calcium,
phosphate, & magnesium are excreted in the urine
= depresses the release of Ca++ from bone by inhibiting the
bone-dissolving activity of osteoclasts
= individuals without CT do not develop hypercalcemia (for ex,
after complete removal of the thyroid)
= can be used as a marker for medullary thyroid carcinoma
ASSAY:
= the major assay for calcitonin at present is radioimmunoassay
(RIA), but there are still problems with
specificity & sensitivity
= serum samples seem to yield higher calcitonin levels than do
plasma samples
= hemolysis falsely elevates values in some RIA procedures
= since sensitivity is a problem, only elevated calcitonin
values can be assessed with confidence, not
decreased values
HORMONAL REGULATION OF BONE FORMATION & METABOLISM:
= calcium & phosphate are the primary constituents of the
mineralized portion of bone
= bone is formed from either calcium phosphate or the more
complex salt hydoxyapatite
[Ca10(PO4)6(OH)2]
= 3 hormones PTH, calcitonin, & Vit D act in concert to
maintain calcium homeostasis & appropriate bone
development
= this balance is accomplished by effects on the intestinal
absorption of calcium, rate of calcium deposition
into bone or loss from bone, and reabsorption of calcium by the
kidney
= changes in the serum ionized calcium (Ca++) conc trigger the
release of specific hormones to maintain
the proper calcium balance in the system
a decreased in Ca++ (for whatever reason) promotes an increase
in the blood levels of PTH & Vit D
if Ca++ levels rise, calcitonin conc increase to promote calcium
uptake by the bone
= a decrease in Ca++ triggers a complex series of events
PTH output is increased, which stimulates loss of calcium from
bone & increased calcium resorption in the proximal tubule of
the kidney
at the same time, PTH also acts on the kidney to produce larger
amounts of 1,25-dihydroxyvitamin D derivative necessary for
enhanced absorption of calcium from the intestine
= when ionized calcium (Ca++) levels are high, the opposite
processes occur
calcitonin levels rise to promote calcium uptake by the bone
PTH & 1,25-dihydroxyvitamin D conc decrease, allowing less
Ca++ to be absorbed by the intestines & permitting more Ca++
excretion in the urine.
ADRENOCORTICAL HORMONES
= adrenal gland is situated above each kidney
= composed of an outer cortex & an inner core or medulla
= cortex produces many steroid hormones derived from cholesterol
(a waxlike lipid found in all cells)
= adrenal cortex is the only gland containing the enzymes with
the ability to hydroxylate steroid
molecules in the C-21 (21-hydroxylase) and C-11
(11(-hydroxylase) positions (Fig 13.4; rxns A & B)
= different types of steroid hormones synthesized by the adrenal
cortex (Table 13.7 & Fig 13.4) are /
3 categories of steroid hormones according to function:
1. glucocorticoids / cortisol affect protein, carbohydrate &
lipid metabolism
- regulate glucose production and protein metabolism
- is the main hormonal product of the adrenal cortex in both
males & females
2. mineralocorticoids / aldosterone is the most potent & is
responsible for fluid & electrolyte
balance
- affect the conc of plasma Na+ & K+
- present in plasma in 1/1000 the conc of cortisol
3. sex steroids regulate sexual development and control many
aspects of pregnancy
- androgens (masculinizing hormone) & minute amounts of
estrogen (female sex
hormones)
@ in each case, the major effect of the steroid is at the
cellular level, where it interacts with
receptors in the cytoplasm to produce the appropriate
biochemical effect
= a change in the proportions or activities of some of the key
enzymes in the adrenal cortex, can lead to a
serious hormonal imbalance (overproduction or some hormones
& underproduction of others); this
imbalance may be caused by disease processes, radiation damage,
genetic defects, or drugs that inhibit
some of the key enzymes
= the most commonly encountered defect is a congenital
deficiency or absence of the 21-hydroxylase
enzyme
ADRENAL CORTICAL HORMONES
HORMONETYPE
TARGET TISSUE
PRINCIPAL ACTION
Cortisol
C21 steroidall tissues
affects CHO, CHON, & fat
metabolism
AldosteroneC21 steroid kidney
( Na+ excretion, ( K+ excretion
Cortisol
= the principal glucocorticoid
= acts on target cells by penetration & transport to the
cell nucleus, binding to DNA, & altering the
transcription of RNA
= accelerates the enzymatic breakdown of muscle proteins and
conversion of their amino acids into
glucose by the liver / or the enhancement of glucose production
from proteins and amino acids is the
major role for cortisol in metabolic control (in this function,
cortisol works in a way opposite that of
insulin)
= it mobilizes fat in adipose tissue for energy purposes
= it inhibits the uptake of glucose by muscle (thus cortisol
acts as an insulin antagonist)
= it reduces cellular reaction to inflammatory agents & it
lessens the immune response by inhibiting Ab
formation / increased amounts of cortisol diminish the synthesis
of Abs and can produce
immunosuppression; the anti-inflammatory properties of cortisol
may be due to its effect on protein
synthesis
= is the only adrenal hormone to inhibit the anterior pituitary
secretion of ACTH by negative feedback
= the plasma conc of cortisol closely follows the diurnal
variation pattern of ACTH & is highest in the
early morning hours & lowest at night
= together with cortisone (a less clinically important
glucocorticoid) are converted to inactive tetrahydro
derivatives through reduction reactions; conjugation with
glucoronic acid or sulfate yields water-soluble
derivatives which can be excreted in the urine
= is transported n three (3) ways:
a. 75% is transported by corticosteroid-binding globulin (CBG,
transcortin)
b. 15% is bound to albumin
c. 10% is free (not bound to protein) moving through the
circulation
= not more than 1% of the total cortisol synthesized daily is
excreted as such in the urine
= Evaluation of adrenocorticol function:
* blood should be collected at approximately 8 am (near peak
time for cortisol conc) & allowed to
clot (serum is the spn of choice)
* serum cortisol is frequently measured by RIA or fluorescence
polarization immunoassay (FPIA)
after displacing the cortisol from corticosteroid-binding
globulin (CBG) [by lowering the pH,
by heat treament, or by displacing the cortisol by chemical
means]
* NV: morning plasma cortisol con in adults (5-22 ug/dL or
138-607 nmol/L
* cortisol levels in the afternoon & evening are
considerably lower
* urine free cortisol: the small amt of cortisol in urine
reflects the plasma level of free cortisol (not bound to CBG) bec
only the unbound hormone can be excreted; method similar to serum
cortisol determination; ELEVATED URINE FREE CORTISOL IS THE
HALLMARK FOR THE DX OF CUSHINGS SYNDROME
HYPERSECRETION OF CORTISOL
= Cushings syndrome, the cause can be primary to the adrenal
cortex (adrenal hyperplasia or rarely
carcnoma) or 2ndary to overproduction of ACTH (pituitary adenoma
or an ectopic carcinoma elsewhere
that produces ACTH; ex. oat cell carcinoma of the lung)
= dx can be confirmed by:
means of a dexamethasone suppressin test
administration of the drug suppresses normal secretion of ACTH,
as evidenced by a fall in plasma cortisol conc & excretion of
free cortical in the urine, but has no effect on ACTH secretion by
tumors
HYPOSECRETION OF CORTISOL
= adrenocortical deficiency may be primary to the adrenal cortex
bec of destruction of cortical tissue by
autoimmune dse or infection (Addisons dse) or secondary to ACTH
deficiency
= dx is confirmed by:
finding a subnormal cortisol response to the administration of
exogenous ACTH (rapid ACTH stimulation test)
= prolong therapy with anti-inflammatory steroids (ex
prednisone) can suppress ACTH secretion
sufficiently to cause adrenal insufficiency
Aldosterone
= is the most potent mineralocorticoid secreted or synthesized
primarily by the adrenal cortex
= like cortisol, is a C21 compound & has a 11-hydroxy group,
but lacks a hydroxyl at C17
= differs from all the other steroids by the presence of an
aldehyde grouped at C18
= > 30% of the total aldosterone in plasma circulates bound
to cortisol-binding globulin
> 42% are interacting with albumin
> the high fraction of unbound aldosterone permits rapid
metabolism and inactivation, mainly through
the formation of a glucuronide derivative in the liver
= increases the plasma conc of Na+ by increasing Na+
reabsorption in the renal tubules; the plasma K+
conc falls bec of the concomitant exchange of K+ for Na+
= actually the chief effect of aldosterone is the promotion of
Na+ ion reabsorption by the kidney to
maintain an appropriate Na+/K+/H+ balance; this reabsorption
process also affects water retention by
the body
= present in low conc in plasma & is difficult to measure
accurately
= a normal person who has been in the upright position for
several hours has a plasma aldosterone conc of
5-20 ng/dL (0.14-0.55 nmol/L); if the subject is recumbent for
several hours, the plasma aldosterone
level falls to 10-40% of that conc in the upright positon
= hyperaldosteronism found in patients with some adrenal tumors;
have elevated serum Na+ conc,
lowered K+, & hypertension, & an increasd excretion in
the urine
Androgens
= the adrenal androgens: (these androgens are also synthesized
by the testes)
1. dehydroepiandrosterone (DHEA)
2. DHEA sulfate
3. androstenedione
4. testosterone production of testosterone appears to be cyclic,
w/ a peak around 7 am & a
trough at approximately 8 pm
- > 98% of testosterone circulates bound either to serum
albumin or to sex-hormone-
building globulin
- primary function is to facilitate development of 2ndary male
sexual characteristics;
protein synthesis is enhanced leading to growth in both skeletal
muscle & bone; this is
particularly significant during puberty
= all are weak androgens except testosterone
= all are C19 compounds & are 17-ketosteroids (17-KS) except
for testosterone (w/c has a hydroxyl
instead of a ketone group at C17 & is a 17-ketogenic steroid
(17-KGS)
ANDROGEN EXCESS (Hirsutism, Virilism)
= congenital adrenal hyperplasia or adrenal carcinoma (in
children)
= precocious puberty (in boys)
= hirsutism (in women) the growth of body hair- in a male-like
pattern
= virilism (usually a result of a combination of adrenal &
ovarian disorders)
STEROID METABOLITES IN URINE
= the metabolites of all androgens appear in the urine as:
1. 17-KS or were quantitated colorimetrically after rxn w/
m-dinitrobenzene (Zimmerman rxn)
2. as their glucuronide or
3. sulfates conjugates
= method for 17-hydroxycortisteroids (17-ohcs) is more
restrictive & measures fluorometrically only cortisol-like
compounds (Porter-Silber fluorometric method was used for
quantitation of 17-OHCS
FEMALE SEX HORMONES
Ovarian Hormones
= the female gonad, or ovary, has a double function:
1. produces & secretes the female sex hormones
2. site of production & maturation of the ova one mature
ovum is released approximately every
4 weeks by a nonpregnant woman during the years between the
onset of menstruation &
the menopause
= 2 different chemical types of steroid hormones are produced
& secreted by the ovary in nonpregnant
woman; during pregnancy, the same hormones are produced by the
ovary, but in different proportions
= the placent also makes the hormones that are necessary for the
maintenance of pregnancy
1. ESTROGENS
= comprise a number of C18 steroids (structurally different from
androgens in that 1 methyl
group has been lost & ring A of the estrogen steroid is
phenolic [has 3 double bonds])
= originate in the ovarian follicles (& also in the placenta
during pregnancy)
= participates in the menstrual cycle & are essential for
the development & maintenance of the
reproductive organs & secondary sex characteristics
= 3 clinically important estrogens / 3 major estrogens:
a. estradiol (E2) principal & most potent estrogen
- it exist in a reversible state with E1, a hormone with weaker
biologic action,
but must be converted into E1 before it is degraded
- plasma E2 levels are valuable for the investigation of women
with menstrual
difficulties bec it is an indicator of ovarian function (since
it plays an
important role in the regulation of the menstrual cycle)
- the primary source is the ovary (where it is produced in a
cyclic fashion
throughout the 28-day menstrual period)
- 2 peaks in the blood level for estradiol are seen:
> the 1st peak occurs at the same time as the midcycle peak
for luteinizing
hormone (LH) [approximately day 13]; a declince in production
then occurs,
followed by a 2nd peak seen at the same time as the progesterone
peak
[approximately day 21]
- 38% is bound to sex-hormone-binding globulin
60% / majority are circulating attached to serum albumin
2-3% exists as unbound
- conjugation is the major form of inactivation
- as the level of estradiol decreases near the end of the cycle,
the drop in its
concentration triggers the process of menstruation
b. estrone (E1) w/ weaker biologic action
c. estriol (E3) is the final degradation; a steroid w/o
biologic/hormonal action
- is produced in large quantities during the last trimester of
pregnancy by the
placental conversion of fetal adrenal steroids
- its conc in the urine or plasma of pregnant women provides
some indication of
fetal well-being (fetoplacental viability)
- a sudden drop in estriol conc or output during late pregnancy
is a danger
signal of fetoplacental dysfunction; the serum is preferred
(thus is used to
monitor the course of fetal growth and development)
@ estrone & estriol are of clinical significance only during
pregnancy
= RIA kit methods are available for the measurement of serum
estrogens (principles like those of
cortisol & thyroid methods)
= more information can be gained if the pituitary tropic
hormones (FSH & LH) are measured at
the same time to ascertain whether a problem is of pituitary or
ovarian origin
2. PROGESTERONE
= is a C12 compound & chemically more related to the adrenal
steroids (in fact is an intermediate
in the production of adrenal steroids) [Fig 13.4 & 13.7]
= progesterone & its metabolites (progestational hormones)
are formed in the corpus luteum (the
body that develops from the ruptured ovarian follicles) thus the
major tissue responsible for
progesterone synthesis is the ovary; but is also produced by the
adrenal cortex
= its primary role at adrenal cortex is to furnish a precursor
for the formation of other steroids
= stimulates the uterus to undergo changes that prepare it for
implantation of the fertilized ovum
& suppresses ovulation & secretion of pituitary LH
= during pregnancy, it suppresses menstruation for the duration
of the pregnancy
= the entire time of enhanced progesterone synthesis covers
about 12 days, with peak production
occupying only 4-5 days; by the end of the menstrual cycle,
progesterone production has once
again declined to its low baseline level
= most progesterone in the circulation exists unbound (since
cortisol occupies the vast majority
of the binding sites)
= the major route for progesterone inactivation and excretion is
through the formation of
conjugates rendering the molecule more water-soluble
= progesterone serves mainly to promote the growth of the
endometrial cells, which must be
present before the fertilized ovum can be implanted and
pregnancy develop
= the changing level of progesterone also exert negative
feedback control on the synthesis and
release of LH & FSH
@ Fig 13.6 Hormonal changes during normal menstrual cycle
OVARIAN HORMONES
HORMONETYPE
TARGET TISSUE
PRINCIPAL ACTION
Estrogens C18 steroidsfemale accessory sex organspromotes 2ndary
sex characteristics
(E1,E2)
ProgesteroneC21 steroiduterus
prepares form ovum implantation,
maintains pregnancy
Placental Hormones
= the placenta in the pregnant woman serves as an endocrine
organ in addition to its providing nutrients to
the developing embryo & removing its waste products
= in humans, the placental are identical to those produced by
the ovarian follicle & corpus luteum except
for chorionic gonadotropin (hCG) & lactogen (hPL)
= placenta, unlike the gonads & the adrenal cortex, cannot
synthesize steroids from acetyl CoA units, but
requires sterols or steroids as precursors, depending on
specific hormone to be made
1. HUMAN CHORIONIC GONADOTROPIN (hCG)
= is a glycoprotein hormone
= its action is similar to LH bec it also stimulates the corpus
luteum to produce progesterone (w/c
the latter helps to maintain the pregnancy by preventing
menstruation)
= under normal circumstances, hCG is not detected in the urine
& serum of a nonpregnant
woman; when pregnancy occurs, the hCG level begins to be seen as
early as 10 days after the
preovulation LH surge
= the chorion of the developing placenta begins to secrete hCG
shortly after implantation of the
fertilized egg; its conc in plasma & urine rises steadily
from the first few days after conception
until the 10th or 12th week of pregnancy
= the detection of hCG in urine or serum is a biochemical
confirmation of pregnancy
= urine test are less sensitive & do not show a positive
response to the presence of hCG until 30-
35 days after fertilization; the serum levels continue to rise
markedly to a peak sometime
between 60-80 days into the pregnancy, then decline
significantly during the last trimester
= the urine tests are simple to perform & are fairly rapid
(as little as 2 min); but false (+) results
may be seen if there is an increased amount of protein in the
urine; a dilute urine may produce
a false (-) result
= phynothiazines, barbiturates, chlorpromazine, methadone, &
penicillin can produce false (+)
results
= IRMA assays for hCG are the most sensitive tests bec it
confirm pregnancy 7-10 days post
conception (4-7 days before the next expected menstrual period)
& it utilize 2 Abs to recognize
the hormone (1 specific for the alpha subunit & another for
the usually beta subunit, so called
beta hCG, to eliminate cross-reactivity with LH)
= most tests for hCG should be positive in 90% of patients 14-21
days after the next expected
menstrual period
= also used to diagnose a hydatidiform mole (a cyst-like
structure in the uterus that develops from
an aberration in a normal pregnancy; may become locally invasive
or even malignant) in
pregnancy
= women with choriocarcinoma, a malignant condition resulting
from retained products of
conception, have greatly elevated concentrations of hCG (usually
> 150,000 mIU/mL)
= hCG levels are also elevated in approximately 40-60% of men
with testicular carcinoma
= useful for monitoring the course of therapy or the
reoccurrence of tumor
= however, the rate of hCG production in some patients may be
very slow & levels may not reach
the same high concentration seen in a normal pregnancy; these
data suggest the presence of an
ectopic pregnancy (the fertilized ovum does not implant in the
uterus to begin normal devt; this
decline in the rate of hCG synthesis is a warning sign of a
possibly life-threatening situation
= HOME PREGNANCY TESTS
these urine assays for hCG are usually based on some type of
ELISA, w/c is fairly simple, w/ a color change indicating a (+)
rxn
have unacceptable high false (+) & (-) rates due to problems
in technique & failure to use an appropriate sample
Biochemical Changes During Pregnancy:
PARAMETER
OBSERVED CHANGE
REASONS
Albumin
decrease
increased CHON demand by the growing
child
Immunoglobulins
some increase
in response to the need for increased
immunogical protection for both mother
& child
Alkaline phosphatase increased esp during last trimesterdue to
bone devt of fetus & elevations of
placental ALP during the last trimester
Lipids
increase
body mobilizes lipids for nutrition of child
FSG & LH
decrease
since ovulation is no loner occurring
T3 and T4
sl increase
due to increased metabolic demands of the
mother
Parathyroid hormoneincrease
due to enhanced bone growth
Vit D
increase
Estrogens
increase esp during last trimesterduring the last trimester
(reflection of the
enhanced feto/maternal synthesis of these
steroid hormones
2. HUMAN PLACENTA LACTOGEN (hPL)
= a protein hormone that shares some properties with both growth
hormone & prolactin
= acting in concert with prolactin, hPL helps to prepare the
mammary gland for lactation
= has also some metabolic activities similar to those of GH
PLACENTAL HORMONES
HORMONE
TYPE
TARGET TISSUE
PRINCIPAL ACTION
Estrogens &
see ovarysee ovary
see ovary
progesterone
Chorionic gonado-glycoproteinsame as LH
same as LH
tropin (hCG)
Placental lactogen (hPL)protein
same as PRL
same as PRL
MALE SEX HORMONES
= the male gonads are the testes
= testes have a double function like the ovary:
to produce & secrete the male hormone testosterone
to produce the spermatozoa (w/c are essential for fertilization
of the ovum in the reproductive process
1. Testosterone
= primary function is to facilitate development of 2ndary male
sexual characteristics
= 80% of the circulating testosterone is being transported by a
specific plasma globulin known as
sex hormone binding globulin (SHBG)
17-18% bound to albumin
the remainder is the unbound, the active hormone
= all the testosterone is derived from the testis; the
contribution of the adrenal cortex is negligible
= its measurement is useful in the study of hypogonadism &
hypergonadism
= reference range:man = 350-850 ng/dL (12.1-29.5 nmol/L)
woman = 20-80 ng/dL (0.8-2.8 nmol/L) [lower than man &
arises
from the tissue conversion of androgens]
= RIA methods are the sensitive way of measurement; same
principles as those for the T3T4
= formation of testosterone:
once cholesterol is formed, further transformation is possible
to provide specialized molecules
cholesterol is the initial steroid in the complex pathway
leading to the formation of all the steroid hormones:
> cortisol (which controls many metabolic processes)
> testosterone (male sex hormone)
> estrogens (female sex hormone)
> aldosterone (involved in sodium retention and regulation of
blood pressure)
= production of testosterone appears to be cyclic, with the peak
around 7 am & a trough at
approximately 8 pm
= testosterone conc in plasma decrease after ethanol intake,
even in normal individuals (due to
enhanced production of reducing enzymes in the liver responsible
for the degradation of
testoseterone and there is no compensatory increase in the
synthesis of testosterone, so the
overall level declines)
= INCREASED CONC:men:> testicular carcinomas
> abnormalities of pituitary gonadotropin
woman: > virilism or hirsutism (as a result of adrenal /
ovarian tumor)
= DECREASED CONC:men:> any conditions directly affecting the
testes by pituitary
failure, & in certain chromosomal abnormalities
involving
the sex chromosomes
2. Luteinizing hormone (LH)
= a pituitary gonadotropin
= stimulates interstitial cells (Leydigs cells) in the testis to
produce testosterone
3. Follicle-stimulating hormone (FSH)
= also a pituitary gonadotropin, promotes spermatogenesis by the
germinal cells in the
seminiferous tubules
Testicular Hormone
HORMONE
TYPE
TARGET TISSUE
PRINCIPAL ACTION
Testosterone
C19 steroidmale accessory sex organs
promotes 2ndary sex
characteristics
ADRENOMEDULLARY HORMONES
(Hormones from the adrenal medulla)
CATECHOLAMINES
= all catecholamines are formed by conversions of TYROSINE (an
amino acid containing a substituted
benzene ring
= the name catecholamine derives from the common catechol
structure (1,2-dihydroxybenzene) possessed
by all these compounds
= the best known catecholamines are EPINEPHRINE (ADRENALINE) and
NOREPINEPHRINE
(NONADRENALINE), responsible in part for the regulation of blood
pressure
1. Epinephrine / Adrenaline
= is the principal medullary hormone (comprises 80-90% of the
medullary hormones)
= produces effects on tissues & organs similar to those
following stimulation of the sympathetic
nervous system by fear, anger, or aggression (ex. increases in
heart rate & B/P)
2. Norepinephrine / Noradrenaline
= is a neurotransmitter produced in the brain & at the
synapses with peripheral nerves
= end products of catecholamine metabolism are homovanillic acid
and vanillylmandelic acid
= SOURCES:
catecholamines are primarily synthesized & stored in
vesicles of the chromaffin cells in the adrenal medulla until
released into the circulation
the chromaffin cells are located at the top of the kidneys &
are part of the adrenal gland w/c comprises bothe the adrenal
cortex & the adrenal medulla
the other site of catecholamine formation is in the sympathetic
neuron, part of the CNS
= SYNTHESIS & STORAGE IN CHROMAFFIN CELL:
tyrosine resulting from protein metabolism or formed by
conversion of phenylalanine enters the chromaffin cell &
undergoes ring hydroxylation (catalyzed by tyrosine hydroxylase) to
form dopa
removal of the carboxyl groups from dopa by the enzyme dopa
decarboxylase produces dopamine
dopamine enters the chromaffin vesicle inside the cell to
undergo further conversion; rxn with dopamine-beta-hydroxylase adds
an OH to the side chain, producing norepinephrine
norepinephrine then leaks out of the granule & is
N-methylated to yield epinephrine (catalyzed by
phenylethanolamine-N-methyltransferase)
re-uptake of epinephrine in the chromaffin vesicle completes the
synthesis & storage process
= CATECHOLAMINE RELEASE:
a. neuronal control release
> the splanchnic nerves of the CNS are connected to the
adrenal medulla, impulses from which
cause the nerve endings to release acetylcholine
> acetylcholine (a neurotransmitter) binds to receptors sites
on the cells of the adrenal medulla
w/c allow calcium ions to enter the cell
> the influx of Ca++ is a trigger for the release of
catecholamines from the granules into the
bloodstream
> the process by which catecholamines leave the cell is
called exocytosis
> this process is energy-efficient (it requires no metabolism
of ATP & no active transport system
b. effect of adrenal cortex hormones
> conversion of norepinephrine is profoundly affected by
cortisol (an adrenal cortex hormone)
> decrease in the conc of this steroid hormone (cortisol)
enhance breakdown of the enzyme
phenylethanolamine-N-methyltransferase, leading to the decrease
in the amount of epinephrine
synthesized
c. inactivation & excretion of catecholomines
> unlike many other hormones, the catecholamines circulate
free, not bound to any plasma
proteins; as a result uptake by tissues is rapid
> in the circulation, platelets play an important role in the
uptake & removal of catecholamines
> liver & other tissues also contain enzymes involved in
catecholamine inactivation
> conjugation of catecholamines & metabolites is an
important means of inactivating & excreting
these compounds
d. role in transmission of nerve impulses (Fig 16-5)
> catecholamines are also stored in presynaptic membranes of
nerve tissue; when a nerve
impulse is propagated, the particular catecholamine involved in
that system is released; the
compound passes across the synapse to interact with specific
receptors on the postsynaptic
membrane, continuing the process of impulse propagation; release
from the receptor is followed
either by inactivation (catalyzed by
catecho-0-methyltransferase) or re-uptake by the presynaptic
membrane; inactivation at this site is under the control of
monoamine oxidase
e. metabolic & physiological effects of catecholamines
> metabolic effects: (when catecholamine levels increase in
the circulation)
1. increased breakdown of triglycerides (thus increasing the
availability of free fatty acids)
2. enhanced synthesis of glucose from amino acids
3. enhanced breakdown of liver glycogen (with glucose is the end
product)
4. decrease in protein synthesis
5. increase in blood glucose level (since the release of insulin
is inhibited by the elevated amounts of catecholamines)
> physiologic effects
1. stimulate cardiac muscle (the more significant contributor to
increased heart rate & enhanced strength of contraction is
epinephrine)
2. primary role of norepinephrine is to promote vasoconstriction
(regulates blood pressure)
3. controls some aspects of kidney function
= both hormones raise the plasma conc of glucose by inducing
liver glycogenolysis & of free fatty acids
by promoting lipolysis in adipose tissue
= both hormones are derived from tyrosines via dopamine (Fig
13.8)
epinephrine is formed from norepinephrine by methylatioin of the
amino group
dopamine is an intermediary product in the adrenal medulla; but
when synthesized in the brain cells, it serves as a
neurotransmitter
= both hormones are so potent that only small amounts are needed
to obtain their effects; their action is
transitory bec of rapid inactivation
= Principal metabolites: (the metabolites in the urine are a
mixture of the free form & sulfate or
glucuronate conjugates)
b. vanillylmandelic acid (VMA, 3-methoxy-4-hydroxymandelic
acid)
c. metanephrine
d. normetanephrine
e. homovanillic acid
ANALYSIS OF PLASMA & URINE CATECHOLAMINES
Sample collection & stability
= since standing has been shown to increase norepinephrine
levels markedly, the px should be
lying down for approximately 15-30min prior to sample collection
(though sitting also causes
increases but to a lesser extent)
= after collection immediately separate plasma from cells (any
prolonged contact with platelets
& other cellular components decreases the catecholamine
content)
= repeated thawing & refreezing of the sample leads to
significant loss of catecholamines
= 24-hr collection of urine is usually used (during the period
of sample collection, the urine
should be refrigerated to minimize degradation of materials;
after the collection is complete,
the pH should be adjusted to between pH 2 5 with 6M HCl
= antihypertensive medication may give a false high results
Urine catecholamines are excreted both in the free
(unconjugated) & conjugated states
- fluorometeric assay
Urine metanephrines - colorimetric assay
Urine vanillylmandelic acid - colorimetric assay
Plasma catecholamines radiometric analysis
High-performance liquid chromatographic (HPLC) determination
PHYSIOLOGICAL FACTORS AFFECTING CATECHOLAMINE LEVELS:
= release into circulation is greatest during the waking hours
& is 3-5 times higher than the
production during the night
= no definite diurnal cycle like in the case of cortisol,
rather, the increase in output during the day
is more likely a response to the increases in physic activity
(including the simple task of
standing) & the emotional stress w/c accompany our waking
hours
= epinephrine production increases markedly during time of
mental stress, pain, loud noises or
other situations producing stress; norepinephrine also increase
but not much like epinephrine
= increase in physical activity involving heavy muscular work
provoke a marked elevation in
norepinephrine output (maybe due to vasodilation in the muscle
circulatory system)
PATHOLOGICAL FACTORS AFFECTING CATECHOLAMINE LEVELS:
@ Increased catecholamines:
1. Pheochromocytoma
= a tumor of the adrenal gland / neuroectodermal origin
= is responsible for only 0.1-0.7% of those patients with
hypertension; detection is important
since surgical treatment is usually quite successful
= 90% of pheochromocytomas are benign & can be removed
completely by surgery; a missed dx
is a lost opportunity for correction & may lead to an early
death
= the tumor may secrete catecholamines intermittently in spurts,
so the plasma level of these
hormones may be elevated for only a short time; thus a randomly
drawn blood sample may
miss the rise
= measurement of urine metanephrines & VMA usually provides
sufficient diagnostic
information
= but a (+) test should be confirmed by direct measurement of
plasma catecholamines or by
analysis of a different catecholamine or metabolite in urine
2. Neuroblastoma
= due to lack of enzyme responsible for the conversion of
norepinephrine to epinephrine
= analysis of urine free catecholamines appears to be most
reliable biochemical indicator for the
presence of tumor
= a high excretion of HVA or VMA (or both) occurs in most cases
of neuroblastoma
= both VMA & HVA may be measured by use of gas
chromatography or high-performance liquid
chromatography (HPLC)
3. Essential hypertension
= is a poorly understood disorder of high B/P of unknown
cause(s)
= studies show that plasma norepinephrine increases in this
disorder while little or no change in
epinephrine
4. Hypothyroidism
5. Diabetic acidosis
6. Cardiac disease are stressful situations, thus elevate
catecholamines in both plasma
7. Burns and urine
8. Septicemia
9. Depression
@ Decreased Catecholamines:
1. Hyperthyroidism
2. Diabetes: long term
PANCREATIC HORMONESPANCREAS = like some few glands the pancreas
has both an exocrine & an endocrine function
= secretes somatostatin, a hormone that helps to regulate the
secretion of various gastrointestinal
fluids & enzymes
= is the source of insulin & glucagons (2 major hormones for
regulating plasma glucose conc)
1. Insulin
= originally synthesized in the islet beta cells
= a rise in plasma glucose conc induces an enzyme to cleave the
stored protein into the active
hormone, insulin, & an inactive fragment called
C-peptide
= is the only hormone with the ability to lower the plasma
glucose conc by:
a. promoting glucose uptake by muscle & fat cells
b. inducing glycogen storage in the liver
c. inhibiting lipolysis & promoting triglyceride synthesis
in adipose tissue
d. increasing protein synthesis from amino acids
e. enhancing glucose utilization
= INCREASED:
adenoma of the pancreas (insulinoma)
those w/ excessive GH secretion (gigantism in children,
acromegaly in
adults)
= quantitation of plasma protein is of no value in the diagnosis
of diabetes mellitus
2. Glucagon
= a polypeptide made by islet alpha cells
= is the primary counterregulatory hormone to insulin action
= the pancreas secretes glucagons in response to a fall in
plasma glucose level
= it increases the glucose conc by inducing rapid breakdown of
stored liver glycogen & by
promoting the formation of glucose from amino acids
= in pxs with insulinoma, the injection of glucagons produces
hyperglycemia, followed by
hypoglycemia (the hypoglycemia does not occur to a significant
extent in individuals with an
insulinoma)
= if glucagons is injected into pxs with von Gierkes disease
((Type 1 glycogen storage disease)
- the plasma glucose con does not rise bec the hepatic enzyme,
glucose-6-phosphate, is missing;
this outcome helps to confirm the diagnosis
3. Somatostatin
= is a polypeptide hormone made in the delta cells of the
pancreatic islets, in the hypothalamus, &
elsewhere
= in addition to regulating gastrointestinal secretions,
somatostatin inhibits the secretion of insulin
& glucagons by nearby islet cells.HORMONES OF THE
GASTROINTESTINAL TRACT= exert their actions through one or more of
the ff ways:
a. act as true hormones on distant target cells after transport
in plasma (ex secretin)
b. act upon neighboring target cells after secretion into
extracelular fluid or a lumen (ex somatostatin)
c. mediate their effects through stimulation of nearby nerve
cells (ex vasoactive intestinal peptide)
= food in the gut is the usual stimulus for GIT hormonal release
w/ some neural control
1. Gastrin
= secreted primarily by the antrum of the stomach
= are powerful inducers of gastric HCl secretion
= 3 biologically active gastrins (differ only in the chain
length of the N-terminal end):
a. big gastrin composed of 34 amino acids
b. little gastrin 17 amino acids; most potent of the group
c. mini gastrin 14 amino acids; has the least activity
= total gastrins are usually measured by RIA methods
= overproduction of gastrin causes ulcers in the upper GIT
= Zollinger-Ellison syndrome detection is the most impt clinical
use of gastrin test (in this dse, non-beta cell tumors of the
pancrease produce large amounts of gastrin & px suffers
severely from ulcers
2. Vasoactive Intestinal Peptide (VIP)
= is an intestinal hormone that stimulates nerve cells in the
GIT
= its overproduction by tumor cells produces an intractable
diarrhea called pancreatic cholera
= are measurable by RIA methods
= used for screening pxs with severe, persistent diarrhea
3. Secretin both are sometimes injected to study pancreatic
response; but no clinical
4. Cholecystokinin demand exists as yet for measurement of the
plasma conc of these hormones
GIT Hormones
HORMONE
TYPE
TARGET TISSUE
PRINCIPAL ACTION
Gastrin
Peptide
Stomach
( Secretion of gastric HCl
Secretin
PolypeptidePancreas
( Secretion of pancreatic fluid & HCO-3
Cholecystokinin-
PolypeptideGallbladder, pancreasGallbladder contraction, (
pancreatic
pancreosymin
secretion
Somatostatin
Peptide
GIT
( Secretions & motility
(somatostatin is also secreted by the hypothalamus, it is
carried to the anterior pituitary, where it
inhibits the release of growth hormone)
Vasointestinal peptidePolypeptideGIT
( Secretions, relaxes gut muscles
(VIP)
RENAL HORMONES
= kidneys are usually not considered endocrine glands, but they
secrete several hormones that are impt in
regulating Ca++ metabolism, erythropoeisis, & salt
metabolism
1. 1,25-Dihydroxyvitamine D3 / 1,25-dihydroxycholecalciferol
= is the active form of Vit D that has hormonal action in the
homeostasis of Ca++ metabolism
2. Erythropoietin
= a 166 amino acid glycoprotein that is an impt factor in the
regulation of hematopoiesis
= is secreted in response to anoxia resulting from anemia,
exposure to high altitude, or
hypoventilation
= it results in increased rbc production
= pxs with end-stage renal failure are usually anemic bec of the
inability of their kidneys to
secrete erythropoietin
= the availability of recombinant erythropoietin has become an
impt therapeutic aid in the
treatment of anemia in pxs with end-stage renal failure
Renal Hormones
HORMONE
TYPE
TARGET TISSUE
PRINCIPAL ACTION1,25-dihydroxyvitamin D3sterol
Intestine, bone, kidney( Ca++ absorption in gut, synergistic
with PTH
Erythropoietin
GlycoproteinBone marrow
( Erythrocyte formation
ENDOCRINOLOGY