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