endocrinology supplement

7/24/2019 Endocrinology Supplement

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THE ENDOCRINE SYSTEM

1

WELCOME TO THE WONDERFUL WORLD OF

as described by

JAMES L. CAFFREY, PH.D.

Professor of Integrative Physiology

Rm. 2-302D Phone 735-2085

Basic Human SciencesENDOCRINE PHYSIOLOGY

A STUDY AID

DEPARTMENT OF INTEGRATIVE PHYSIOLOGY

UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER

Please direct any discrepancies to the author

Rights reserved to the author 1980Most recent revision Fall 2009.


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GENERAL OBJECTIVES: 3Primary Text: Berne and Levy 5

thed

INTRODUCTORY PRINCIPLES: 4Berne & Levy 719-742, (Review cell signaling 61-76)

MECHANISMS OF HORMONE ACTION 8Berne & Levy 719-742, (Review cell signaling 61-76)

PANCREAS AND HUMORAL CONTROL OF ENERGY 16Berne & Levy 5th ed. 766-791.

HYPOTHALAMUS AND POSTERIOR PITUITARY 24Berne & Levy 5th ed. 819-857

HYPOTHALAMUS AND ANTERIOR PITUITARY 30Berne & Levy 5th ed. 819-857

THYROID 35Berne & Levy 5th ed. 861-881

CALCIUM METABOLISM 42Berne & Levy 5

thed 794-817

ADRENAL CORTEX, STEROIDOGENSESIS 48Berne & Levy 5th ed. 883-917

ADRENAL MEDULA AND CATECHOLAMINES 66

Berne & Levy 5th ed. 909-917

REPRODUCTION FEMALE 66Berne & Levy 5

thed 926-932, 947-963

REPRODUCTION MALE 79Berne & Levy 5

thed 926-947

ESSAY QUESTIONS 84

1 Physiology Berne & Levy 5th ed. Endocrine/reproduction section Strong/Comprehensive excellent

text and resource.2 Porterfield; Endocrine Physiology Excellent to the point; with study questions, only negative

endocrine only, 3rded 2007.3 Rhoades and Tanner: Medical Physiology Endocrine/reproduction section Strong/Comprehensive4 Griffin and Ojeda: Textbook of Endocrine Physiology Good Year One Medical School Orientation but

few illustrations5 Ganong: Lange Review of Medical Physiology Endocrine/reproduction: good to the point.6 Larson et al: Williams Textbook of Endocrinology...Encyclopedic Reference Source7 DeGroot and Jameson: Endocrinology 5thed. Mega-Encyclopedic Reference


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I. Objectives for Topics 1 and 2A. To develop a general understanding of:

1) functional, spatial and temporal relationships of hormones within the body;

2) general mechanisms controlling hormonal synthesis, secretion & degradation;

3) the relationships among the types of molecules their mechanism of action and biologicalproperties;

4) factors which modify circulatory hormone concentrations or their effects.

II. Objectives for succeeding topics A. To develop for each hormone an understanding of:

1) how and where it is synthesized, stored, secreted;

2) the principal stimuli for release of hormone;

3) functionally relevant characteristics of the hormone molecule;

4) hormone transport in the circulation;

5) the principal target tissues and type of receptor interaction;

6) the main biological effects and general duration of action (sec., min., hrs., days);

7) how does this hormone differ from other hormones which effect similar or related functions;

8) how the hormone is degraded or excreted;

9) How the System is controlled;

10) what happens when the system is disturbed;

11) which other hormones influence (facilitate or antagonize) the actions of this hormone;

12) what physiological consequences result from too much or too little of this hormone.


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GENERAL PRINCIPLES

Berne & Levy 5th ed. 719-742, (Review cell signaling 61-76 and Fall 2008)

A. Exocr ine Glands like the sweat or salivary glands are equipped with ducts through whichsecretory products are released on to external surfaces.

B. Endocrine Glandssecrete their products (hormones) into the blood stream which carriesthem to specific target tissues. Upon reaching the target a recognition phenomenon occurs(usually with a specific receptor) which stimulates an alteration in target cell function consistentwith the effects of that hormone and the capabilities of that target tissue to respond.

II. Characterist ics of endocrine hormones and their effects.

A. Effects are noton and off but graded up or down.1) Hormone levels are seldom zero.2) Hormones alter the rates of ongoing reactions.

B. Hormones don't act alone.1) Hormones act with or against them (e.g. blood glucose regulation)2) Responses depend on starting hormone concentration and status

(young, old, healthy, sick).

C. Secretion is not constantbut usually occurs in pulses. [What is the value of a singlemeasurement? Why do lab reports have normal ranges?] Episodic release may necessitatecollecting sequential samples to evaluate endocrine status. A provocative test may be needed(e.g. glucose tolerance test, TRH stimulation test) to determine if the system is hyper or hyporesponsive. [Can the rate of pulses be a signal? (Leuprolide).]

D. Effects of the hormones continue after the hormone is gone. (e.g. the increase incalcium transport following the administration of vitamin D may continue for days after thehormone is metabolized and gone). Some hormones exert both acute and chronic effects (e.g.

ACTH stimulates adrenal steroid secretion and adrenal growth). [What is the difference betweentropic and trophic?]

E. Some hormones do similar things at different rates.Glucagon and cortisol raise bloodglucose, however glucagon's effect is rapid and temporary while cortisols effect is slow &sustained. [compare epinephrine, glucagon, growth hormone and cortisol on blood glucose].

F. Some hormones accomplish similar results with different tissue specificities e.g..

glucagon and epinephrine both stimulate glycogenolysis but epinephrine works better on muscleand glucagon works better on liver. [Does muscle secrete glucose?]

G. Sometimes the tissue determines the quality of the response:e.g. epinephrine stimulatesglycogenolysis (phosphorylase) in muscle and lipolysis (hormone sensitive lipase) in adipose.

H. Hormones don't always fit the classical definition:e.g. what is the specific target forthyroid or growth hormone or the discrete source for norepinephrine? Many traditional hormoneshave been identified in non-traditional sites; e.g. ACTH in brain.


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I. HORMONE TYPES

1) Systemic: classical definition: ACTH, TSH.2) Local autocrine (acting on the cell which produced it) and paracrine (acting on neighboring

cells) hormones are sometimes found in the circulation but probably were not intended toescape the tissue of origin: e.g. histamine, prostaglandins, kinins, most circulating

norepinephrine.3) intracellular: cyclic-AMP, cyclic-GMP, phosphatidylinositol (PIP2), diacylglycerol (DAG),inositoltriphosphate (IP3).

J. MOLECULAR TYPES

1) proteins, glycoproteins, peptides: GH, ACTH, LH, oxytocin2) amino acids derivatives: thyroxine, epinephrine, serotonin3) steroids: cortisol, testosterone4) phospholipids and prostaglandins: PGE1, PGF2, PIP2, DAG.

III. INTERPRETATION OF PLASMA HORMONE CONCENTRATIONS.

A. PLASMA CONCENTRATIONS are a balance between input (secretion or administration),output (excretion or degradation) and volume of distribution. [What are the effects of renalfailure, liver disease or dehydration?]

B: HALF-LIFEis the time required for one-half the plasma hormone concentration to disappearfrom the plasma compartment. Half-lives are thought to be constants over the physiologic rangeof hormone concentrations [how is metabolic clearance rate different?].

C. BINDING PROTEINS. Many small easily degraded hormones are transported in blood

bound to specific proteins. The binding proteins protect the hormone from rapid degradation andexcretion. They also provide a ready, circulating storehouse of extra hormone. Since mostendocrine systems monitor and regulate the concentration of freehormone, alterations in theavailability of binding proteins will alter totalhormone concentration & half-life (e.g. T4).

D. PHARMACOLOGIC EFFECTS ON HORMONE CONCENTRATIONS

1) Estrogens (e.g. contraceptives, prostatic cancer therapy, pregnancy) increase hepaticglobulin production which includes several hormone binding proteins. The resulting decrease infree hormone decreases feedback and may produce a compensatory increase total hormoneconcentration. [What would the free be after compensation?]

2) Drugs which compete for binding proteinsmay decrease total circulating hormone sincedisplaced hormone disappears faster than bound hormone. Dilantin and some non-steroidalanti-inflammatory agents compete with thyroxine for binding to thyroxine binding globulin.

3) Drugs which stimulate or inhibit release. Some drugs (tolbutamide) are designed tostimulate hormone release (insulin). Other drugs do so as a side effect. For examplenoxious/stressful/toxic drugs will probably release adrenocortical hormones (e.g. chemotherapy).


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4) Drugs which alter metabolism or excretion.Many drugs alter hepatic microsomal enzymesand therefore modify the metabolism of steroid hormones which are metabolized by the samesystems. Drugs which alter urine flow or urine pH might also influence hormone excretion(NH4Cl, Diamox).

5) Drugs that facilitate hormones by blocking their degradation. GLP-1 potentiates the

effect of glucose on insulin secretion. GLP-1 is rapidly degraded by circulating enzymes. Drugsare now available which enhance the effect of GLP-1 by slowing down its degradation. {DPP4inhibitors)

6) Iatrogenic or fictitious. Hormone concentrations may be deranged from misuse ofprescribed medications due to physician error, incomplete patient education or failure of thepatient to comply properly. Some secretly abuse therapeutic hormones to attract attention.

6) Drugs which interfere with action. This broad category includes receptor and ion channelblockade. The beta blocker propranolol is used to great advantage to reduce sympatheticstimulation of the heart.

7) Drugs which interfere with hormone activation. For most actions thyroxine must beactivated by deiodination to T3. The enzyme responsible is inhibited by drugs likepropylthiouracil and propranolol. ACE inhibitors (captropril) inhibit conversion of angiotensin I toangiotensin II.

8) Drugs which interfere with physiologic regulation. Many hormones have regulatorycomponents involving the nervous system and drugs which stimulate or depress the nervoussystem will alter hormonal regulation.

E. Preprohormones, prohormones, & active forms. Many hormones are synthesized and

then mature or are activated before they are effective. Testosterone, a prohormone in sometissues, is converted to the more active form, dihydrotestosterone. Preprohormones are proteinswhich contain additional amino acid sequences which are necessary for their intracellulartransport and packaging prior to secretion. When this sequence is removed, the remainingpeptide is a prohormone since it usually requires further modification before it is fully active.Most prepro and prohromones have little activity (like proinsulin) but when secreted in grossexcess, effects may be seen. These "Big" or incompletely processed hormones are oftensecreted by cancers. Prohormones are precursor forms which are then converted to activeforms.

F. Hormone concentrations resulting from when, where and how samples were drawn

and handled afterward. Examples: drawing a cortisol from stressed children; trying to measurecortisol on patients taking prednisone; trying to measure prostaglandins in blood left in lab coatfor several hours (platelets make prostaglandins). How does episodic secretion affectmeasurements?

G. Bioactivi ty vs Immunoactivi ty. Many hormone assays do not specifically measurebiologically active hormone. When altered or fragmented hormones circulate, lab values andclinical conditions may not agree (e.g. PTH vs iPTH). Some hormone assays do not distinguishwell between the prohormone and the active form, resulting in falsely high values. Some less


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specific assays measure related hormones. LH, FSH, TSH, and hCG all have similar alphasubunits; thus assays that see the alpha subunit fail to discriminate among them.

H. Lab error. When laboratory values disagree with the physical findings always consider laberror. Know the reliability of criticallab tests and retest when they don't make sense.

I. Resistance to hormones.Resistance may include auto-antibodies which bind the hormoneor its receptor. Resistance may also result from lowered receptor numbers or lowered receptoraffinities. Obese patients and patients with polycystic ovary disease usually show insulinresistance. Some patients with acanthosis nigrans [Whats that?] have antibodies directed at theinsulin receptor. Resistance to hormones is usually characterized by INCREASED OR

NORMAL HORMONE CONCENTRATIONSAND CLINICAL SIGNS AND SYMPTOMS OF AHORMONE DEFICIENCY.

IV. FeedbackFeedback regulation in endocrine systems can be negative or positive.

A. Negative feedbackThe hormone produced feeds back in order to reduce the stimulus for its

release (ACTH stimulates cortisol release and increasing cortisol suppresses further ACTHsecretion). Negative feedback typically regulates functions around a mean or normal value aswith plasma cortisol or thyroid hormone concentrations.

1) Ultrashort-loop feedback, the hormone produced inhibits its own secretion. (norepinephrine

shuts off its own secretion via presynaptic 2-receptors).2) Short-loop feedback, the hormone produced inhibits the stimulus for its own secretion

(testosterone inhibits pituitary LH secretion).3) Long-loop feedback, the hormone reduces the stimulus for the stimulator of its own

secretion (testosterone inhibits the secretion of LH-RH from the hypothalamus).

B. Positive feedback, the hormone released produces an effect resulting in secretion of morehormone. During the period just prior to ovulation, LH stimulates estradiol secretion andestradiol stimulates more LH secretion. This type of feedback tends to terminate as a result ofthe explosive effects of the increasing hormone, like for instance ovulation which results from theLH surge described disrupts the ovarian follicle, the source of the estradiol.


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REVIEW SECTION: FALL CORE CELL SIGNALINGMECHANISMS OF HORMONE ACTION: Examples Specific to Endocrine Cell Signaling ....Berne

and Levy 61- 77, 719-742

There are many mechanisms by which hormones produce their effects. There are two majortypes of mechanism based on the cellular location of the receptor, those which behave likeprotein hormones, having cell membrane receptors and those which behave like steroid

hormones, having intracellular receptors.

A. Protein Hormone Action I. This includes the mechanism for most protein and peptidehormones and includes some epinephrine and norepinephrine effects.

1) The hormone binds to specific receptor located on the cell membrane.

2) Binding results in the activation of a local membrane GDP bound protein called "Gs-alpha"which immediately releases GDP in exchange for GTP. The Gs-alpha-GTP then activates theassociated adenylylcyclase within the cell membrane. Gs-alpha has GTPase which turns theresponse off. [how do cholera, whooping cough influence these responses?]

3) This results in an increased production of intracellular cyclic-AMP. Phosphodiesterasehydrolyzes cyclic-AMP as part of the off mechanism. [How might coffee, tea, hot chocolate,methylxanthenes influence the system?].

4) The cyclic-AMP binds to the intracellular protein kinase A, causing dissociation of regulatoryand catalytic subunits and activation of the catalytic subunits.

5) The active protein kinases increase cellular activities by phosphorylating cellular componentsresulting in the characteristic effect of that hormone. For instance: activation of phosphorylase-b-kinase and inhibition of glycogen synthetase.

Examples might include phosphorylation of:a) ribosomes to increase protein synthesisb) transport proteins conferring binding affinity or initiating transportc) enzymes converting them to active configurations

B.Protein Hormone Action II. Alternative mechanism of protein/peptide hormone action.

1) Hormone binds to specific receptor located on the cell membrane.

2) Binding results in the hydrolysis of phosphatidylinositol (PIP2) to release inositol triphosphate

(IP3) and diacylglycerol (DAG).

3) IP3enters the cytoplasm, binds to an intracellular receptor on the endoplasmic reticulumwhich stimulates the endoplasmic reticulum to release Ca into the cytoplasm.

4) DAG activates membrane bound or membrane associated protein kinase C.

5)DAG, IP3and Ca cooperate to stimulate the entrance of additional extracellularCa


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6.) Increased intracellular Ca binds to calmodulin and calmodulin activates enzymes (e.g.calmodulin activates myosin light chain kinase which phosphorylates myosin to contract smoothmuscle).

Examples might include:

a) norepinephrine action at alpha-1 receptors initiating contraction of vascular smooth muscleby raising intracellular free Ca

b) vasopressin acting at specific V1receptors in vascular smooth muscle to increase intracellularCa leading to contraction.

C. Protein Hormone Action III. Tyrosine Kinases. This is a third mechanism includes insulinand a large number of lesser known growth factors such as somatomedin and platelet derivedgrowth factor. The external cell membrane receptor is part of or is attached to an intracellulartyrosine kinase. Most of these receptors function as dimmers. When the receptor is occupied,

the tyrosine kinase is activated to phosphorylate intracellular proteins that are responsible for thehormonal effect. This usually includes autophosphorylation of the receptor itself. In other casesthe protein is JAK or STAT. [What happens if the extracellular part is absent?]

D. Steroid Hormone Action. This includes the mechanism by which most steroids are believedto act and includes vitamin D and thyroxine.

1) Lipid soluble steroids diffuse thorough the cell membrane and bind to specific intracellularreceptors which may be located in either the cytoplasm or nucleus.

2. The receptor is composed of three domains:

a. Steroid binding siteb. DNA binding site (normally obscured by heat shock proteins)c. Gene transactivating site

4) The steroid/receptor combinations undergo a transformation which alters the sedimentationcoefficient (i.e. its size or shape) of the receptor. This most likely involves the release of the heatshock protein to expose the DNA binding site.

3) The receptor may facilitate the movement of the hydrophobic steroid through the hydrophilicintracellular environment.

4) If not already in the nucleus the steroid/receptor complex enters the nucleus and binds toacceptor or hormone response elements (HREs) on the chromosomes.

5) Nuclear binding alters gene expression increasing RNA synthesis and subsequent proteinsynthesis to produce the characteristic effect of that hormone. Example: Vitamin D increases thesynthesis of calcium transport proteins (calbindin) in the intestinal mucosa which then increasethe absorption of dietary calcium.


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C. Hormone\receptor interactions tend to resul t in an amplification of effect.

D. Protein hormonesgenerally have short half lives, with primary effects having rapid on andoff (minutes) mechanisms. Steroid hormones by comparison have longer half lives and primaryeffects are slow in onset (due to action through nuclear mechanisms) and slow to subside(hours-days).

E. Receptor Characteristics

1. Macromolecules.2. Binding affinity is proportional to the potency of the hormonal ligand.3. Binding is saturable (i.e. there are limited numbers of receptors).4. Binding is high affinity (requires only small quantities of hormone).5. Binding is stereospecific (optical isomers much less effective).6. Binding occurs at physiological hormone concentrations.7. Often only a small fraction of the cells receptors need to be occupied to elicit a maximum

response (there are extra or "spare" receptors)

F. Receptor Movement.Current evidence indicates that most receptors are not stationary andthat they move into and back out of an intracellular environment where they are not available tointeract with new hormone. The proportion or number of surface receptors available at any one

time can vary dramatically. The process is referred to as up (sensitization) or down(desensitization) regulation.

NOTE:Five figures that follow are for convenient review/reference from Cell Signaling in thebiochemistry core. Virtually all of the hormones we will discuss will use one or more of thesemechanisms.


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Insulin Receptor

Substrate ( IRS )

Target Effector

( e.g. enzyme )

SRC Reco nition Site

Intracellular Tyrosine

Kinase

Insulin & Related Growth Factor Receptors

T rosine Kinase Rece tors

SRC Se uence

Hormone Binding Units

SubunitsSubunit


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REGULATION OF BLOOD GLUCOSEBerne & Levy 5th ed. 766-791.

A. The pancreasis both an exocrine (trypsin, chymotrypsin, lipase) and an endocrine gland(insulin and glucagon). The endocrine pancreas is composed of islands of tissue called Islets ofLangerhans dispersed through the pancreas. Three quarters of the islet cells are insulin

secreting beta cells and most of the remainder are glucagon secreting alpha cells. There arealso small numbers of other cell types. Of these the delta cells secrete somatostatin and gastrin.

B. Mature insulinis a polypeptide with two subunits (alpha and beta) linked by two disulfidebridges. Insulin starts as the single chain proinsulin which folds on itself to form the disulfidebridges found in mature. During storage, the connecting peptide (c-peptide) is removed fromproinsulin leaving mature insulin, equal amounts of the c-peptide and variable amounts ofunhydrolyzed proinsulin in beta cell vesicles. The insulin and c-peptide are secreted instochiometric amounts and proinsulin may be 5- 30% of the secreted total. Proinsulin haslittle biological activity and there is no evidence for cleavage to insulin after secretion.

Shaw WN & RR Chance

Diabetes 17: 737, 1968


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C. STIMULI FOR INSULIN RELEASE:

1) Blood glucose - elevated blood glucose is sensed directly by the pancreas. This effectappears to be some combination of:

a) a glucose receptor,

b) glucose metabolism andc) glucose as an energy source.

The insulin secretion is a combination of stored insulin and newly synthesized insulin. Thelonger secretion continues the more dependent the gland becomes on newly synthesized insulin.The higher the blood glucose, the greater the rate of insulin secretion (100 faster

>300 maximum). The loss or blunting of the early phase is characteristic of type II DM.

2) Amino acids: elevated plasma amino acids increase insulin secretion. All amino acids arenot equal, arginine is best.


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3) GI hormones The insulin response to amino acids or glucose is greater if they areadministered orally instead of intravenously even when plasma concentrations of each reachhigher peaks after i.v. administration. This is explained by the release of gastrointestinalhormones after oral but not after i.v. administration. These hormones Glucagon-LikePolypeptide (GLP-1) and (Gastric insulinotropic peptide (GIP formerly gastric inhibitory peptide)are weak stimulators of insulin secretion alone but potentiate the action of the glucose and

amino acids on insulin secretion. This response anticipates the arrival of glucose or amino acidsin the blood and minimizes caloric and nutritional losses in the urine. A new class of drugsfacilitate this mechanism by blocking the hydrolysis of GLP and GIP by the enzyme DPP-IV.Thus, DPP-4 inhibitors increase the pancreatic secretion of insulin but only really work well whenglucose is present.

4) Autonomic influences:Vagal (acetylcholine) stimulation increases insulin secretion. Some insulin is released whileeating and may represent a vagally mediated anticipatory response. Catecholamines usuallyinhibit insulin release due to a predominant alpha receptor effect. If the alpha effect is blockeda beta-mediated stimulation of insulin secretion can be demonstrated. One can easily see how

stress or apprehension can ruin blood glucose evaluations or make diabetic control moredifficult. Direct stimulation of the ventral medial nucleus (satiety center) increases glucagonsecretion and decreases insulin secretion with an increase in blood glucose; while stimulation ofthe lateral hypothalamus increases both insulin and glucagon secretion.

CatecholamineReceptorType

Pancreatic Cell Type

Beta Cell (Insulin) Alpha Cell (Glucagon)

Alpha inhibits secretion inhibits secretion

Beta stimulates secretion stimulates secretion

Which One Wins alpha beta

D. The effects of insul in - THE ANABOLIC HORMONE

1) Insulin stimulates:a) Transport of glucose into cells by facilitated diffusion (primarily muscle and adipose).

Transport of glucose into muscle and adipose tissue is mediated by a carrier, glut-4. Insulin

stimulates the movement of extra glut-4 transporters from intracellular storage sites to thecell membrane in order to increase glucose transport. Insulin stimulates the number ofglucose transporters and their affinity for glucose 2-8 fold.

Tissues NOTaa) nervous system dd) retina

needing insulin for glucose transport are:

bb) RBC ee) germinal epitheliumcc) renal medulla


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Some of these same tissues are particularly susceptible to the late complications ofdiabetes mellitus. (Note: insulin does not influence renal tubular reabsorption orgastrointestinal absorption of glucose).

b) glucose utilizationc) glycogen synthesis

d) amino acid transport by an active transport mechanisme) protein synthesisf) fatty acid transport (?)g) lipogenesish) potassium and magnesium transport

2) The effect of insul in is somewhat tissue specific . As the anabolic hormone, it stimulatesthe type of anabolic activity characteristic of that tissue.a) muscle: insulin stimulates glycogen synthesis and protein synthesis

b) adipose: insulin stimulates lipogenesis and inhibits lipolysis

c) liver: insulin stimulates glycogen synthesis first and then lipogenesis. (Note: liver does notrequire insulin for glucose transport however, insulin stimulates the synthesis of glucokinase,


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an enzyme which allows the liver to phosphorylate and retain incoming glucose.) Theanalogous enzyme hexokinase is saturated at normal glucose concentrations, soglucokinase permits the liver to cope with the increased glucose loads following mealsreducing the loss of glucose in the urine and preventing protracted hyperglycemia. Insulinhas a potent action to inhibit the release of fatty acids and glucose from the liver.

3) In general insul in is anti-catabolic and decreases catabolic processes.

4) Insulin stimulates potassium influx into cells.

E. GLUCAGONa single chain polypeptide secreted by pancreatic alpha cells was discoveredshortly after insulin by Kimball and Marlin. Only recently has it received attention in thepathogenesis of diabetes. Be aware that there are other molecules which behave functionallyand/or immunologically like pancreatic glucagon (including gut glucagon) which sometimes makethe interpretation of glucagon measurements very difficult.

F. Stimuli for the Release of Glucagon

1) Plasma Glucose. When plasma glucose perfusing the pancreas falls, the alpha cellsincrease the secretion of glucagon. There is a question regarding the functional location of thealpha cell glucose sensor. One hypothesis states that the sensor is inside the alpha cell and thatthe alpha cell requires insulin for the glucose to enter the cell and reach the sensor. This line ofthinking would explain the normal or increased level of glucagon in diabetics. In the face ofhyperglycemia, glucagon levels should be low but not if alpha cells are unable to monitor bloodglucose in the absence of adequate insulin levels.

2) Amino Acids. An increase in plasma amino acids stimulates an increase in glucagonrelease. This may be a protective mechanism. Following a high protein meal the flood of amino

acids arriving in the circulation will stimulate insulin release. Insulin moves the AAs into the cellsbut will also move any plasma glucose into cells. The resulting hypoglycemia would bedangerous for the CNS. This does not, however, occur since the AAs simultaneously stimulateglucagon release opposing insulin induced hypoglycemia.

3) Autonomic nervous system. Sympathetic stimulation will increase glucagon secretion.This is a beta receptor effect. Parasympathetic stimulation also increases glucagon release.

4) Circulating Ketoneswill also stimulate glucagon secretion.

G. Effects of glucagon. The principal importance of glucagon is its ability to prevent

hypoglycemia by raising blood glucose which is accomplished by stimulating:1) glycogenolysis (primarily in liver)2) gluconeogenesis3) hormone sensitive lipase: provides fatty acids which spare glucose and supply energy to run

hepatic gluconeogenesis.

In addition to effects on blood glucose, glucagon stimulates insulin release and glucagon alsohas a positive inotropic effect on the heart (pharmacologic doses).


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I. Fine Tuning. The antagonistic actions of the pancreatic hormones on blood glucose plusthe actions of several other hormones (cortisol, growth hormone, catecholamines) constitute anelaborate system to finely and continuously control the concentration of glucose in the blood.Since the CNS is almost completely dependent on blood glucose, the regulation of bloodglucose is extremely important.

J. Diabetes Mellitus. This is a metabolic syndrome which results primarily from the absenceof insulin or the absence of effective insulin. The later situation is thought to result from cellularinsulin receptors which are decreased in number or affinity. It may also result in rare cases fromautoantibodies directed against insulin receptors or against circulating insulin which neutralizes

the hormone. The syndrome, Diabetes Mellitus, is characterized by persistent fastinghyperglycemia which is accompanied by a glucose induced osmotic diuresis. Thesyndrome is divided into major subgroups.

1) Type I or insulin-dependent diabetes (IDDM), formerly called juvenile onset diabetes(JOD). This subgroup produces little or no insulin. Genetic transmission is not obvious buta genetically inherited trait may make individuals more susceptible to toxic, viral or bacterial

attack on the beta cells. Because of insulin deficiency, IDDM is harder to control and ketosismore prevalent.

2) Type II or non-insulin-dependent diabetes (NIDDM), former called maturity onset diabetes(MOD) (85-95%). In this subgroup there are adequate or elevated amounts of insulinproduced but there is resistance to the effect of both endogenous and exogenous insulin.Larger quantities of insulin are required to produce the normal glucose control. Becausepancreatic insulin production is present, they are more ketosis resistant, and can frequentlybe treated satisfactorily with diet and weight reduction (Note: only small amounts of insulinare required to prevent hepatic fatty acid secretion and therefore ketosis). There is a highfamilial correlation in NIDDMs.

Even though Type I and II are distinctly different diseases victims of both suffer thesame secondary complications of diabetes (retinopathies, micro & macro vasculardisease and neuropathies).


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3) Secondary diabetesdue to pancreatic disease, medications, endocrine dysfunction otherthan insulin pituitary diabetes, genetic hyperglycemia

4) Impaired glucose tolerance; patients have normal fasting blood glucose but abnormallyhigh glucose levels following glucose ingestion.

5) Diabetes expressed during pregnancy (gestational diabetes).

6) Metabolic consequences in diabetes:a) reduced insulin, or insulin effectsb) inappropriately high glucagonc) decreased anabolism (reduced insulin)

1) lipogenesis down2) protein synthesis down3) glycogen synthesis down

d) increased catabolism (reduced insulin and increased glucagon)

1) increased glycogenolysis which raises blood glucose2) increased lipolysis - which spares blood glucose and promotes ketosise) increased gluconeogenesis (glucagon and increased availability of amino acids) raises blood

glucosef) blood glucose exceeds the renal threshold and initiates an osmotic diuresisg) excess lipid utilization results in rising blood ketones and falling pH. The excess hydrogen

ions exhaust the plasma buffers and hydrogen ions begin to enter cells to use the cellularproteins as buffers. In order to maintain ion balance intracellular potassium leaks out.

h) in the absence of insulin, large quantities of this intracellular potassium are lost with theurinary diuresis

i) The combination of acidic, ionic and osmotic factors when unchecked may lead to diabetic

coma. When treating diabetic ketoacidosis (DKA) two potentially lethal conditions should bekept in mind.

1) People with DKA often have depleted potassium regardless of what plasma levels say.Rapid insulin replacement will push potassium into cells, deplete extracellular potassium,thus precipitating cardiac arrhythmias.

2) Poorly controlled diabetics may have excessively high (hyperosmolar) glucoseconcentrations which have equilibrated into the CNS. Rapid insulin replacement mayreduce blood glucose faster than it re-equilibrates out of the CNS resulting in cerebraledema.


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POSTERIOR PITUITARYBerne & Levy 5th ed. 819-857.

Neurohypophysis, Pars Nervosa

I. Functional Anatomy


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A. The posterior pituitary (P-Pit) arises from neural origins and has direct neural connectionswith hypothalamus.

B. Axons from cell bodies in the supraoptic (SON) and paraventricular (PVN) nuclei passthrough the medial basal hypothalamus (median eminence) down the pituitary stalk & end in theP-Pit. The axons contain electron dense granules which give them a beaded appearance.

C. The axons end not on dendrites but among capillary networks in the P-Pit.

D. The cells found in the P-Pit are called pituicytes. They are non-endocrine cells thought toperform glial-like functions (maintenance of neural elements).

II. Hormone synthesis, storage and release

A. Oxytocin and vasopressin are synthesized as preprohormones in the cell bodies ofhypothalamic neurons (SON or PVN). Each precursor is distinct and includes another proteincalled neurophysin.

B. After post-translational processing, they are packaged in vesicles with neurophysin.

C. The vesicles are transported down the axons and stored in axon terminals in the P-Pit.

D. Physiological stimuli generate action potentials in the SON or PVN which proceed downaxons to the P-Pit. Depolarization of terminals is followed by calcium influx and release of boththe hormone & neurophysin by exocytosis. Released products diffuse into the blood stream.

III. The Hormones

A. Oxytocin is an nonapeptide which in man originates in the PVN and SON and is stored in theP-Pit. The precursor molecule, preprooxyphysin, also includes its own neurophysin I. Part of thepeptide is arranged in a ring with a disulfide bond. Oxytocin has a short half life, 3-5 minutes.

1. Stimulus for Release of Oxytocina) Suckling. When an infant suckles at the breast, sensory receptors send afferent signals to theCNS generating action potentials in neurons with nerve endings in the P-Pit which releaseoxytocin.

b) Distention of the uterus and cervix during pregnancy and movements of the infant result intransmission of neural signals to the CNS. Subsequent action potentials release oxytocin from

the P-Pit.

c) Stimulation of the cervix during sexual intercourse also sends signals to release oxytocin fromthe P-Pit.


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2. Oxytocin Effects

a) Milk Letdown or Milk Ejectionb) Parturitionc) Sperm Transport

a) Milk letdown: oxytocin stimulates contraction of breast myoepithelial cells. Milk secreted intomammary alveoli is unavailable to the suckling infant. Oxytocin induces contraction of epithelialcells surrounding the alveoli extruding the milk. Extruded milk collects in cisternae or lactiferoussinuses from which the infant can obtain it. This movement of the milk from the alveoli to thecisternae is called "milk letdown" or "milk ejection". This should always be distinguished frommilk synthesis and secretion called lactation or more specifically galactopoiesis.

b) Oxytocin facili tates deliveryof the infant at term in a positive feedback cycle by stimulatingcontraction of the uterus. Frequency and force of oxytocin contractions are enhanced sharply inthe presence of estrogen. The effect of oxytocin increases with the development ofspontaneous activity in the third trimester (There is an eight fold increase in the force, durationand frequency of uterine activity between weeks 20-39 of pregnancy. Much of this is attributedto interactions among oxytocin, estrogen and uterine prostaglandins).


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OXYTOCIN RECEPTORS OXYTOCIN CONCENTRATIONS

Myometrium Decidua Mom Umbilical Artery

Non-pregnant .................................... 28 .......................... 25

13-17 weeks .................................... 172 ........................ 629

Term .............................................. 1391 ...................... 1510 ......................... 276 .......................... 12

Labor ............................................. 3468 ...................... 3177

Early ................................................... .............................. ........................... 23 .......................... 36

Advanced ........................................... .............................. ........................... 45 .......................... 58

Hypothesis re: Initiation of parturition1) as receptors rise, uterine sensitivity to oxytocin rises,2) maternal oxytocin declines (rising maternal oxytocinase) suggesting the initiating signal does

not come from the mom,

3) oxytocin is produced by the kid,4) oxytocin from the kid initiates labor through the stimulation of decidual prostaglandins.

Role of Estrogen:1) Induces oxytocin receptors2) Induces uterine (cyclooxygenase) prostaglandin synthesis. [Why do premenstrual women

feel bad, have cramps, why does Midol help]


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c) Oxytocin facilitates sperm transport into the vicinity of the egg after intercourse viaactions on the female reproductive tract. Oxytocin is also found in the testis suggesting apotential role in testicular sperm transport via an action on the seminiferous tubules.

Note: Oxytocin's weak ADH activity can cause water intoxication during long infusions and canprecipitate hypotension during acute administration.

B. Antidiuretic Hormone (ADH), Vasopressinalso a nonapeptide ring is synthesized in theSON and PVN. The precursor molecule, prepropressophysin, contains a differentneurophysin (II). After synthesis, ADH is transported to the P-Pit and stored in axonterminals. ADH has a circulatory half-life of about 5 minutes.

1. Stimuli for Release of ADH

a) Increased extracellular fluid osmolarity(NaCl is best). This is most likely perceived byosmoreceptors located in the hypothalamus probably in or near the SON and PVN.

b) Declin ing blood pressure or volumeparticularly hemorrhage is sensed by receptors in theleft atrium, aorta, carotids and lungs. This response is the basis for a clinical test forposterior pituitary function in which ADH is measured when a patient is moved from thehorizontal to the vertical position.

c) Some Non-specific stimuli will release ADH including trauma, pain, anxiety, nicotine, andbarbiturate anesthetics.

2. Effects of ADH

a) ADH increases the water permeabili ty of collecting ducts (V2receptor, cyclic-AMP).

ADH induces aquaporin in distal convoluted tubule and collecting duct. Collecting ducts passthrough areas of high osmolarity and increased permeability results in the rapid absorption

of water (more negative free water clearance CH2O). The resulting concentration of the urineincreases its specific gravity (saltier). The physiologic effect is to dilute extra-cellular fluidosmolarity and maintain vascular volume. Another clinical function test involves waterdeprivation which will increase urine concentration if the neurohypophysis is healthy. [Whydo water, beer, coffee and tea make you pee?]

b) Contracts vascular smooth muscle (V1receptor, IP3). Like oxytocin, ADH is a smoothmuscle agonist, and is responsible for about 10% of normal vascular tone. ADH plays animportant role in vascular blood pressure compensations during hemorrhage.

c) Pharmacology. The principle use for ADH is for patients without P-Pit function. ADH as apowder may be insufflated (snorted) for short term control, injected i.m. for longer control(2-8 hours) or injected i.m. as a tannate derivative for longest control (1-3 days).


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d) Clinical Problems

1. Too Little ADH:Diabetes Insipidus; polyuria, polydipsia, dilute urine (low urinary specificgravity,


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THE ANTERIOR PITUITARY (AP)


ADENOHYPOPHYSIS, PARS DISTALIS

PROLACTIN

LH, FSH, TSH

ACTH, GH, MSH

-ENDORPHIN


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A. FUNCTIONAL ANATOMY

1. The AP, derived from the oral ectoderm of Rathke's pouch, has no direct neural connectionswith the hypothalamus.

2. Hypothalamic nuclei control secretion by the AP. These nuclei are analogous to the SON and

PVN since they synthesize hormones in their cell bodies, package and transport them to themedian eminence (medial basal hypothalamus) for storage in axon terminals and subsequentrelease into the blood.

3. The capillary bed in the median eminence into which these "releasing" or "release inhibiting"hormones are secreted is the primary capillary bed of the hypothalamic hypophyseal portalsystem. The capillaries collect into venules, traverse the pituitary stalk and reopen as asecondary capillary bed in the AP.

4. Hypothalamic hormones delivered by this route enter the AP, interact with their target cellsand increase or decrease the release of that particular AP hormone.

5. The hormones released by the AP are synthesized and stored in the different AP cell typesand released by exocytosis.

6. Interference with portal blood flow results in partial or complete loss of the endocrine functionin affected pituitary regions and a loss of hormone secretion. Most AP hormone secretion ispredominantly controlled by a releasing hormone with the exception of prolactin which isprimarily controlled by an inhibitory hormone. When portal blood flow is interrupted, the releaseof surviving lactotrophs from chronic inhibition may increase prolactin secretion while secretion ofother AP hormones falls precipitously.

B. RELEASE AND RELEASE INHIBITING HORMONES

1. There may be separate releasing and release inhibiting hormones for each AP hormone.Those isolated thus far are: thyrotropin releasing hormone (TRH-3AA), somatostatin (growthhormone inhibiting hormone-14AA), and growth hormone releasing hormone (GHRH, 48-AA),luteinizing hormone releasing hormone (LH-RH-10AA, also called gonadotropin releasinghormone GnRH because it also releases FSH), and corticotropin releasing hormone (CRH-41AA). Sometimes old nomenclature persists (e.g.CRH often called CRF, F for factor).

2. Although releasing hormones (RH) were thought to be quite specific this has not proved true.LH-RH also releases FSH hence the name GnRH. TRH also stimulates the secretion of

prolactin [Why might patients with primary hypothyroidism sometimes have high serumprolactin]. Somatostatin has potent extra pituitary actions, notably inhibition of glucagon andinsulin secretion. The pulsatile release of hormones contains information (Continuous exposure(no pulses) to GnRH inhibits LH release).

3. The action of Prolactin Inhibiting Factor (PIF) is related to activation of dopamine receptors.Dopamine inhibits prolactin release, and drugs which stimulate dopamine receptors (ergotalkaloids like bromocryptine & ergonovine) will depress prolactin secretion. Dopamineantagonists may produce hyperprolactinemia and inappropriate lactogenic effects. Multiple


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prolactin releasing factors (PRFs) probably exist. A PIF different from dopamine may also exist.

4. The releasing hormones are thought to be trophic to their pituitary target cells. E.g.:Continued exposure to CRH is necessary to maintain the differentiated ability of thecorticotrophs to synthesize and secrete ACTH in acute response to CRH.

C. GROWTH HORMONE (Somatotropin)a protein hormone secreted by AP somatotrophs(acidophils) is primarily regulated by its releasing hormone GHRH and less so by somatostatin.It is also stimulated by the gastrointestinal hormone ghrelin.

1. Stimuli for GH release

a) amino acids(particularly arginine)b) ingestion of a protein meal (which results in increased serum amino acids)c) starvation, (Ghrelin goes up when you are hungry. Starvation may increase stimulatory aminoacids by catabolism of endogenous protein).

d) hypoglycemia- falling blood sugar results in a prompt GH release

e) exercise, stress, excitement, trauma

f) sleep- GH secretion normally increases during deep sleep (Stage IV).

(Note: arginine infusion, exercise and insulin induced hypoglycemia are the basis forseveral clinical tests of GH secretion.)

2. Effects of GH.a) GH generally stimulates cell growth in size and number. Prior to closure of the epiphyseal

plates it stimulates the growth of long bones. Clinical note: administration of androgens orestrogens to children can precipitate premature closure of the growth plates and subsequentshort stature.

b) GH increases protein synthesis by:1) increasing AA transport into cells2) increasing ribosomal protein synthesis3) increasing RNA synthesis4) reducing the rate of protein catabolism

c) Stimulates lipolysis and lipid utilization "Spares blood glucose"

d) Inhibits carbohydrate (CHO) utilization by:

1) increasing glycogen deposition2) reducing cellular glucose uptake once glycogen stores are saturated

Net result: blood glucose rises (slow compared to glucagon)

e) Stimulates the release of the insulin-like growth factor, IGF-l(somatomedin) from liver andkidney. IGF-l mediates many of growth hormones actions. IGFsare a family of peptide growth


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factors some of which have insulin like effects increasing glucose utilization by connectivetissues. Probably the best studied of these is insulin-like growth factor-I (IGF-I, somatomedin C).Their plasma concentrations do not decline (suppress) like insulin does during hypoglycemia so

they were originally called the non-suppressible insulin like activity NSILA. They were also calledsulfation factor for their ability to stimulate cartilage, in particular the incorporation of sulfur intochondroitin sulfate.

3. Pharmacology of GH

a) Synthetic hGH is used primarily for the treatment of hypopituitary children but it increaseavailability leads to it evaluation for a variety of other problems. [Potential for abuse?]

b) Somatostatin analogues (e.g. octreotide) are useful in treating acromegaly and are beinginvestigated for their ability to retard the development of IGF-1 mediated diabetic retinopathy. Itmay also be valuable in a variety of other medical conditions (e.g. hyper-insulin syndromes).

4. Beta Endorphin (-endo)a) -endo, an opioid peptide hormone (31 AA) found in brain and elsewhere is concentrated inthe AP.

b) -endo is synthesized as part of a 31KD precursor called proopiomelanocortin (POMC). Inthe pituitary POMC is synthesized by the corticotrophs which make and release ACTH. ACTH is

also part of POMC and both ACTH and -endo have some regulatory controls in common (bothcan be released during stress and suppressed by cortisol administration).

Liver

SRIH GHRH

GrowthHormone IGF-I

_

+

+


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c) -endo belongs to a class of hormones and neurotransmitters called endogenous opioids.They interact with one or more of several known opiate receptors (currently termed Mu, Delta,and Kappa receptors, newer terminology MOR, DOR, KOR). The biological opiate activity ofvarious peptides appears to rest in identical N-terminal (4 AA) sequences.

d) Endogenous opioids are most likely involved in a host of physiologic processes but classicallyopiates are characterized by:

1) relief of pain 4) tolerance2) euphoria 5) physical dependence3) increased intestinal tone [enkephalinase inhibitors as an antidiarrhea strategy?].

5. Melanocyte Stimulating hormone - MSH is a peptide hormone contained in POMC. Thefirst 13AA of ACTH are identical to the sequence of alpha MSH and ACTH is also effective atincreasing pigmentation. Although, plasma MSH activity may be comprised of differentmolecules, MSH activity is primarily regulated in tandem with ACTH. The secretion of MSH

activity is inhibited by cortisol. MSH activity darkens the skin by stimulation of pigment cells(melanocytes) in the skin to secrete the dark pigment melanin (stored in vesicles calledmelanosomes) out of the cell to be accumulated by surrounding cells. Because of therelationship between ACTH, cortisol, and MSH activities patients with disorders resulting in high

ACTH secretion develop hyperpigmentation.

6. Disorders of AP Function

a) Hypopituitarism is a disorder which may have many different causes including congenitalproblems, necrosis secondary to vascular failure or hemorrhage (Scheehans Syndrome),space occupying tumors, and head trauma. The deficiencies may be partial or complete.

The target organ failures which result (i.e. adrenal, thyroid etc.) are referred to as secondarydisorders. The lack of GH in children results in dwarfism. All dwarfism is notpituitary inorigin. Larons dwarfism is an example of resistance to hormone in that pituitary GHproduction is ok but receptors for GH or for IGF-I (Somatomedin) or IGF-I production aredefective. Inadequate thyroid production, inadequate insulin production, or too muchchildhood androgen production (or external androgens) can also lead to short stature.

b) Gigantismis the physical enlargement of the body which results from the hypersecretion ofGH during childhood.

c) Acromegaly, the adult equivalent of gigantism, results from the hypersecretion of GH after

closure of the epiphyseal plates. The hypersecretion may result from a pituitary tumor or atumor (hypothalamic or ectopic) secreting GHRH. In cases of pituitary tumors otherhormone deficits may result because the growing tumor crowds and destroys other anterioror posterior pituitary cells. In both gigantism and acromegaly the individuals tend to developother diseases including heart disease and diabetes. Why does too much GH cause othermetabolic diseases?]


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THE THYROID


The thyroid is bilobed butterfly shaped gland with a variably present third or pyramidal lobe. Thefunctional unit or follicle is a small extracellular space surrounded by the glandular or follicularcells. The follicular space is filled with a protein called thyroglobulin and since it is not in

solution, the substance is called colloid. Additional parafollicular cells, located near the follicles,secrete (thyro)calcitonin which is a lesser component of normal Ca

++regulation..

A. Thyroid Hormone Synthesis and Secretion

1. The follicular cells synthesize thyroglobulin by typical protein synthetic mechanisms,assemble the subunits, package it in vesicles and secrete it into the colloid by exocytosiswhere it is stored.

Parafollicular cell(C-Cell)

Calcitonin

Follicular CellT3& T4

Colloid


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2. Follicle cells transfer circulating iodine into the cytoplasm via a gradient limited active

transport. When dietary iodine intake is low the efficiency of the "pump" or "trap" isincreased under the influence of TSH. [Note: this influences an important thyroid test, theradioactive iodine uptake (RAIU). In geographical regions where dietary iodine is low, RAIUvalues are high, likewise persons who have had radiological procedures using iodine-based

dyes (e.g.: mylograms) will have low RAIUs which will not be meaningful for months oryears]. The iodine pump will also transport other similar anions including thiocyanate,perchlorate and pertechnetate. In sufficient quantity, they will competitively inhibit the pumpreducing its ability to concentrate iodine. [Note: pertechnetate TC99M, a short lived (T1/2= 6hr) radioisotope concentrated by the thyroid, can be used to visualize the functional anatomyof the gland (technesium scan). TC is not incorporated into thyroglobulin and therefore israpidly cleared from the gland.]

3. Oxidation. Shortly after trapping, the iodine is oxidized and rapidly transported to thecolloidal side of the cell where it is oxidized by thyroidal peroxidases located on the colloidalside membranes.

4. Organification. At the colloidal interface, oxidized iodine is immediately incorporated intophenyl sidechains of tyrosines which are part of the colloidal thyroglobulin. With one iodine,the modified amino acid is called mono-idotyrosine (MIT) and with two iodines,diiodotyrosine (DIT). This process is subject to interference from excess iodine and fromspecific inhibitors such as propylthiouracil (PTU).

OH

OH

I I

O

I I

O

I I

OH

I I

OH

I

I

DIT

T3 T4

MIT

Thyroglobulin

(Thyroxine)


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5. Coupling. After iodination of thyroglobulin certain favored or adjacent iodinated tyrosinescouple. The phenyl ring from one iodinated tyrosine is separated and covalently bonded to

another creating a new molecular species called thyronine. If MIT and DIT are coupled withMIT on the outside the result is triiodothyronine (T3)and when DITs are coupled the product istetraiodothyronine or thyroxine (T4). Remember the MIT, DIT, T3& T4are still part of thethyroglobulin molecule stored in the colloidal space. If MIT and DIT are coupled in reverse the

product, reverse T3is largely inactive. Normal individuals have 2-3 months of stored thyroidhormone within the colloid.

6. Secretion. When increased demand for thyroid hormone is signaled by secretion of TSH,the gland activates. Microvilli extend from follicular cells into the colloid and endocytose colloidinto the cell as membrane bound vesicles. Vesicles move toward the opposite surface of the celland merge with lysosomes during transit. Lysosmal enzymes reduce the thyroglobulin toindividual amino acids. The amino acids including MIT, DIT, T3 and T4 diffuse out of the vesicle.The AAs are reused for subsequent protein synthesis. The iodine in MIT and DIT is removed

and recovered by the gland through a thyroidal enzyme, iodotyrosine deiodinase. The T3 andT4 diffuse from the cell into the blood stream. TSH appears to stimulate all phases of thyroid

hormone synthesis and secretion.

B. The Thyroid Hormones:1) There is more T4secreted than T3(9:1)2) T4has a longer T1/2than T3(7 days vs. 2 days)3) T3 is more potent than T4(4:1)4) T3 acts faster than T4(3:1)5) T4is more avidly bound to plasma protein than T3(0.1% free vs 1% free). Although there is

much more T4in the circulation, free T3and T4are more closely comparable.6) The free hormone is the functionally effective form.7) All of the circulating T3does not result from thyroid secretion of T3. Peripheral tissues

convert T4to T3with iodothyronine 5'-deiodinase which removes one iodine. As much as50% of the circulating T3 may result from peripheral conversion of T4. If T4to T3conversionis inhibited, many hormonal effects of administered T4are lost, reduced or delayed.

Binding in general:

% of TOTAL CAPACITY AFFINITY

TBG 75 3rd

1st

TBPA 15 2nd

2nd

Albumin 10 1st 3rd

T3 The Big Dog. Most endocrinologists feel T3is the active form of thyroid hormone. The largemass of circulating protein bound T4 functions as a circulating store of readily availableprohormone.


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C. Thyroid stimulating hormone (TSH, Thyrotropin)

1) TSH, a two chain glycoprotein, the alpha chain is nearly identical to alpha chains found inLH, FSH & hCG The beta-chain is responsible for its distinct biological activity.

2) TSH stimulates both the size and number of the follicular cells.

3) TSH is both tropic (stimulates the specific glandular activity, T3& T4synthesis & secretion)and trophic (maintains gland's health, size and differentiated function) to the thyroid.

4) TSH stimulates all steps in hormone synthesis and secretion including the size of thegradient against which the pump will operate. TSH effects are primarily mediated bymembrane receptors, Gs-alpha, and CAMP etc.

D. Function of the hypothalamic-pitui tary-thyroid axis.

1) As stated above the activity of the thyroid is regulated by the pituitary hormone TSH which is

in turn regulated by the hypothalamic hormone TRH. TRH is a tripeptide synthesized as sixrepeat copies in a larger precursor, preproTRH.

2) TRH is stimulated by cold and suppressed by anxiety and excitement.

TRH

AP

Tonic

TSH

T3& T4


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3) The secretion of both TSH and TRH are suppressed by increasing serum T3. (Note: recent

evidence indicates that it's free T3 which exerts the negative feedback at both thehypothalamus and pituitary.) The secretion of TSH is the sum of the positive (TRH) andnegative (T3) effects. TRH secretion is more constant or tonic so that changes in TSHsecretion are largely the result of changes in the feedback by T3.

4) Iodine deficiency. In mild iodine deficiencies more MITs form and fewer DITs leading togreater T3synthesis. An individual can remain euthyroid by secreting more of a more potenthormone (T3). In severe iodine deficiency iodine supplies are insufficient to meet hormonalneeds. Circulating T3 concentrations fall reducing negative feedback and increasingcompensatory TSH secretion. TSH activates the thyroid further but since iodine suppliesare low, no additional hormone results and TSH concentrations remain high. Under thiscontinuous trophic influence the thyroid continues to enlarge into a goiter. [Note: the termgoiter refers to gland size not to its hormonal output.]

5) Iodine excess. Excess dietary iodine pharamcologically blocks thyroid hormone synthesis

and has an anti-TSH-like (antitrophic) effect on the gland, particularly with respect to itsvascularity. This effect is usually transient (2 weeks), and is useful prior to thyroid surgery tofacilitate the operation and minimize post-operative complications (thyroid storm).

6) Estrogen therapy. Estrogens, elevated naturally during pregnancy, are also usedtherapeutically for contraception, for post-menopausal symptoms and for prostatic cancer.Estrogens stimulate a generalized increase in hepatic globulin synthesis which includesTBG. When the TBG is increased, the plasma equilibrium is shifted so more T3and T4arebound and less are free. The pituitary interprets this declining feedback and quicklysecretes enough TSH to return free T3and T4to normal. With each increment in TBG theprocess repeats itself until the estrogen stimulated TBG production reaches a new plateau.

When this occurs the individual has a normal concentration of free T3 and T4 and iseuthyroid. However, the amount of hormone bound to TBG is increased in proportion withthe increased TBG. Some laboratory tests measure total T4and T3and therefore would bereported high or high normal. Newer tests estimate the free hormone and circumvent thisproblem.

An effect opposite to estrogen (lowered TBG) is seen after androgen therapy. TBG may also below in liver disease and in rare cases of congenital TBG deficiencies. In these cases the processreverses resulting in normal free hormone but low totals.

7) Goitrogens: Numerous natural products are capable of inhibiting thyroid hormone synthesis

and producing a goiter. Some block organification as goitren (from cabbage) andpropylthiouracil and others compete for the iodine pump as thiocyanate and perchlorate.Prescribed lithium can fit into this category.

E. Peripheral Effects of Thyroid Hormone.1) T3regulates the rate of most cellular processes. Too little and metabolism is sluggish and

ineffective, too much and it's rapid and wasteful. Degradative as well as syntheticprocesses are stimulated. Fasting or serious illnesses decrease the conversion of T4to T3(5'diodinase) perhaps to conserve calories. [Does this make weight loss easier or harder?]


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E. Peripheral Effects of Thyroid Hormone.

a) Physiological processes are increased i.e. heart rate (practical for adjusting dosage),neural activity.

b) Protein and RNA synthesis and degradation are increased.c) Enzyme activities and reaction rates are increased.

d) Oxygen consumption and heat production are increased.

2) T3 is necessary for the normal development and differentiation of the CNS. Neonatalhypothyroidism if untreated results in permanent mental retardation.

3.) Normal thyroid function is necessary for normal growth hormone secretion so untreatedhypothyroidism results in retarded somatic growth.

F. Mechanism of ActionT3

1) T3behaves like a steroid hormone influencing RNA and protein synthesis through nuclear

receptors without associated heat shock proteins. The thyroid receptor appears to reside inthe nucleus and suppress mRNA synthesis until occupied by thyroid hormone.

2) The best explanation of the calorigenic action of T3results from its ability to stimulate themembrane Na-K ATPases responsible for maintenance of transmembrane potentials. Theresult is an increased membrane potential difference in affected tissues. Membranepotentials utilize 10-30% of the total body energy. Since much energy liberated for work islost as heat, higher membrane potentials and their maintenance result in the production oflarge amounts of extra heat. The higher body temperature heat in turn can explain otherincreased body functions.

G. Thyroid disease

1) Hyperthyroidism results from excess thyroid hormone secretion. The term denotes thephysiologic condition of the individual NOTthe size of the gland.

a) Toxic multinodular goiter is believed to result from the conversion of a long standingnon-toxic goiter to an autonomous hyperactive gland.

b) Single nodular goiters are usually thyroid adenomas secreting excess T3& T4 withoutpituitary control. Continuous suppression of TSH secretion results in regression or atrophyof remaining TSH dependent thyroid tissue.

c) Graves disease is the most common form of hyperthyroidism. Graves is an autoimmuneform of hyperthyroidism. The thyroid is enlarged and secretes excess hormone. The growthand secretion are stimulated by Long Acting Thyroid Stimulator (LATS) also called thyroidstimulating immunoglobulin (TSI). LATS are immunoglobulins that mimic the effects of TSHon the thyroid. LATS are not subject to feedback suppression and constantly stimulate thegland creating hyperthyroidism and goiter. Graves disease has eye and skin symptoms(exophthalmos & pretibial myxedema). The exophthalmos may not be directly related to thehyperthyroidism and can even get worse after successful treatment of the hyperthyroidism.


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d) Hyperthyroidism is characterized by enhanced beta adrenergic activity and many of thesymptoms reflect this change. Beta blockade is sometimes used to control sympatheticallymediated symptoms in severe cases.

e) excess TRH or TSH are extremely rare conditions.

2) Hypothyroidism results from reduced T3& T4secretion.

a) Primary hypothyroidism describes conditions in which defect is in the thyroid.

1) iodine deficiency2) genetic loss of one or more parts of the synthetic apparatus3) bacterial or viral damage to the thyroid4) Surgical or radioactive damage to the thyroid

b) Secondary hypothyroidism develops when the pituitary fails to produce sufficient TSH.

1) Brain or AP tumor which crowds or destroys TSH producing regions.2) Pituitary infarction due to trauma, vascular blockade, or hemorrhage.3) Congenital hypopituitarism

c) Tertiary hypothyroidism results when TRH producing areas of the hypothalamus areimpaired for reasons similar to those in b) above.

H. Signs and symptoms of thyroid dysfunction

Parameter Hyperthyroidism Hypothyroidism

heart rate ................sinus tachycardia .................................... bradycardiarespiratory rate ........increased ................................................ decreasedGI motility ................increased ................................................ decreasedbowel activity ..........frequent .................................................. constipationmental presence .....hyperactive ............................................. slowmuscle activity ........tremors, weakness ................................. sluggishsleep .......................insomnia ................................................. somnolencethermoregulation .....intolerance to heat .................................. cold intoleranceedema .....................pretibial ................................................... generalizedhair ..........................fine, silky ................................................. loss

skin .........................warm, moist & smooth ............................ rough, drylipid ......................................................................................... increasedcholesterol .............................................................................. increasedatherosclerosis ........................................................................ increasedbone ........................demineralization .....................................


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CALCIUM METABOLISM Berne & Levy 5th

ed 794-817

Calcium homeostasis is critical for nerve and neuromuscular transmission, blood clotting, musclecontraction, and a host of enzymatic and secretory (exocytosis) processes. Three hormones areinvolved with parathyroid hormone (PTH), and vitamin D (1, 25 dihydroxycholecalciferol ) mostimportant and calcitonin (CT) least important.

A. Free ionized calc ium is hormonally regulated:Most of the body calcium (99%) is stored inbone. The remaining 1% is found in the blood and soft tissues. About 1% of the skeletalcalcium is easily released and can exchange quickly with soft tissue calcium. The remaining98% exchanges slowly. There is a dynamic equilibrium between the free ionized calcium in theblood and the exchangeable pools in the soft tissues and bone. The hormonal systems thatregulate this equilibrium respond almost entirely to changes in the free ionized calcium thatcirculates in the plasma. When plasma calcium rises or falls, hormonal adjustments are made toreturn the free ionized calcium in plasma back to normal.

PX=parathyroidectomy TX=thyroidectomy

Without hormones, Ca

++

control is poor and severe neural/neuromuscular disturbances anddeath result. With hormonal participation the same systems work better and faster providingcloser control of plasma Ca.

B. Plasma calcium - normal plasma Ca averages 10 mg/100 mls. This total plasmaCaincludes free Ca (45%) protein bound Ca (50%) and chelated Ca (5%). Since the free ionizedCa is hormonally regulated, the total Ca will rise or fall when plasma proteins change. Patientswith elevated serum albumin may have increased total plasma Ca but normal free ionized Ca.

Since the free is normal they would be asymptomatic for hypercalcemia.

Hard

Bone

(98%)

Releasable

Bone(1%)

PlasmaCa++

SoftTissues


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The Metabolism of Calcium.

1) Bone. Ca stored in bone is in equilibrium with the serum Ca. Ca is added to bone(formation) by osteoblasts and removed (resorption) by osteoclasts. Both activities proceedcontinuously but the rate of remodeling varies with age, faster in children.

2) The GI Tract. The digestive tract handles large amounts of Ca each day. This includes bothCa in food and calcium secreted in the digestive juices. Even in the absence of dietary Cathe GI tract must reabsorb large quantities of secreted Ca to prevent net fecal calciumlosses. Intestinal Ca is absorbed by facilitated transporters whose presence in the intestinalepithelium depends on vitamin D.

Formation

Ca

Absorption

Fecal

Excretion

Urinary Excretion

Resorption

Secretion

(PTH)(Vitamin D)

(PTH)

GI + Renal Excretions

equals dietary intake


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3) The Kidneys. Ca is reabsorbed by the renal tubule along most of its length.

E. Vitamin D (see following page for functional pathway) is derived from cholesterol andbehaves like a steroid (cytoplasmic receptor, transport to nucleus, hours/days to peak effectetc). Complete synthesis of Vitamin D requires the liver, skin and kidneys (see diagram).

When provided adequate exposure to the sun, vitamin D is synthesized by the body.7-Dehydrocholesterol is synthesized in the liver and secreted into the blood and istransported to the skin where it is converted to cholecalciferol (CC) in the presence ofsunlight. The CC returns to the liver where it is stored and slowly converted to 25-hydroxyCC. The hepatic 25-hydroxylase is subject to product inhibition from 25OHCC. Thisproduces a feedback loop which helps to regulate the rate of vitamin D synthesis. The250HCC is released and is hydroxylated at the one position in the kidney to form 1,25dihydroxyCC, the active form of vitamin D. In addition the kidney can also 24-hydroxylatethe steroid which prepares it for excretion. The choice of enzymatic route taken depends onrenal phosphate levels. If renal phosphate levels are high, 24- hydroxylase is favored and iflow, 1-hydroxylase is favored. As will be seen later parathyroid hormone stimulates renal

phosphate excretion which would then indirectly favor 1-hydroxylase and vitamin D activation.Vitamin D induces the synthesis of an intestinal Ca

++transport protein called calbindin. This

then facilitates the absorption of dietary Ca++

. Vitamin D also synergizes with parathyroidhormone to stimulate the resorption of bone. This direct action on bone can be seenindependent of parathyroid hormone if pharmacologic concentrations of vitamin D areadministered.

F. Parathyroid Hormone (PTH) This protein hormone is secreted by the chief cells of theparathyroid glands. PTH is secreted when free ionized plasma Ca declines. Plasma Caappears to regulate via a Ca-receptor on the parathyroid cells. PTH raises blood Ca by:

1) PTH stimulates bone resorption; this effect is more pronounced in presence of vit D

2) PTHincreases renal Ca reabsorption

3) PTH increases renal phosphate excretion which (by mass action) favors boneresorption and vitamin D synthesis (which facilitates GI absorption and bone resorption)

G. Calci tonin (CT) is a protein hormone secreted by the parafollicular cells of the thyroid.The parafollicular cells in fish form a separate gland called the ultimobrachial body. FishCT is more potent than human CT. Synthetic salmon CT (Calcimar) is used to treat bone

disease.

1) CTis released from the thyroid when plasma Ca rises.2) CT reduces plasma Ca in two ways. First and more important, CT inhibits bone

resorption while formation continues causing a net increase in bone Ca deposition. Theeffectiveness of this mechanism depends on the rate of remodeling, with CT workingbetter when the remodeling rate is high (e.g. in children). The second action of CT is tolower Ca by increasing its renal clearance (excretion).


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CHOLESTEROL

LIVER

SKINhv light

CHOLECALCIFEROL (D3)

LIVER(25-hydroxylase)

25-hydroxy Vitamin-D325-OH-CHOLECALCIFEROL

(Calcidiol)

Kidney

Active Vitamin D31,25-Dihydroxy-D3

(Calcitriol)

Inactive Vitamin D3

24,25-Dihydroxy-D3

Degradation

7-DEHYDROCHOLESTEROL

LOW Renal PO4

1-hydroxylase

HIGH Renal PO4

24-hydroxylase

Intestine Bone

liver storage +

slow release

reduces waste

and toxicity


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H. Disorders of Ca metabolismFYI:Osteoporosis = loss of mineral and matrix. Osteomalacia= loss of mineral.

1)Hypercalcemiais characterized by increased blood Ca, hypophosphatemia, skeletal wasting,

and personality, neural (may lead to coma) and GI disturbances. Primary hyperparathyroidismusually results from parathyroid adenomas and less often from glandular hyperplasia. (somecancers secrete PTH or "PTH-like" substances which act on bone). The following are importantnon-parathyroid related causes of hypercalcemia; malignancy, hypervitaminosis, sarcoidosis,thyrotoxicosis, thiazide diuretics (temporary), Paget's disease and milk-alkali syndrome.

2)Hypocalcemiais characterized by low blood Ca which leads to hyper-reflexia, paraesthesias,muscle cramps and in severe cases convulsions, laryngeal spasm and death. Indications ofhypocalcemia are Chvostek's (cheek tap) & Trousseau's (carpal spasm) signs.

a. Hypoparathyroidism. The most common cause of this disorder is damage to the parathyroid

during thyroidectomies or subsequent to parathyroid surgery. More rarely it results fromunknown causes.

b. Pseudohypoparathyroidism is really secondary hyperparathyroidism due to PTH resistance.

c. Magnesium deficiencies reduce the ability to secrete PTH which results in low Ca. This iscommonly observed in liver disease in alcoholics.

d. Renal failure may interfere with the activation of vitamin D (and therefore dietary Caabsorption) and the renal responses to PTH. There is a compensatory increase in PTH andprogressive depletion of bone minerals. One approach to this condition is to administer 1-OHCCwhich is picked up by the liver and 25-hydroxylated to active vitamin D. This circumvents theloss of renal 1-hydroxylase.[GI malabsorption of Ca produces similar increases in PTH but urinary phosphates also increasebecause the kidneys function normally.]

SYMPTOMS

CAUSE NEURONAL MUSCULAR CARDIOVAS GI TRACT RENAL

Hyper-calcemia

drowsinessirritabilitydepressionconfusionstupor, coma

weaknessareflexia

contractilityhypertensionabnormal ECG

anorexiaconstipationvomiting

concentrationcalcificationlithiasis failure

Hypo-calcemia

anxietyseizures

twitchinghyperreflexiastridorbronchospasmtetany

cramps PO4excretion


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Menopause has been implicated in asymptomatic pathologies including osteoporosis andcoronary artery disease. The efficacy of estrogen replacement therapy is now being questioned.

Menopause and Mineral Metabolism. Post-menopausal women lose about 1% of their skeletalmass (osteoporosis) each year. Although it remains controversial, estrogen replacement therapyreduces this rate of loss initially after which it gradually loses its effectiveness. Estrogen inhibits

bone resorption but does not stimulate mineralization so its effect is dependent on the initialamount of bone mass and how quickly after menopause the therapy is instituted. Because ofthis progressive osteoporosis in the absence of ovaries, attempts should be made in anyreproductive surgery to spare an ovary in young females. Dietary calcium (400-600 mg) inwomen in the US is generally below the RDA (1000 mg premenopause, 1500 mgpostmenopause) and appears to fall further with increasing age. Dietary calcium and vitamin Dshould be adequate and moderate exercise is encouraged. Newer pharmaceuticals for retardingbone loss are being widely substituted for estrogen replacement [e.g. bisphosphonates].


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ADRENAL GLANDS

Berne & Levy 5th ed. 883-917DIET

TISSUE PLASMA

CHOLESTEROL CHOLESTEROLESTERS ESTERS

GLANDULAR PLASMA

SYNTHESIS CHOLESTEROL CHOLESTEROL

(acetate)

HEPATIC

SYNTHESIS

DHEA 17-OH PREGNENALONE PREGNENALONE

3HSD isomerase

ANDROSTENEDIONE 17-OH PROGESTERONE PROGESTERONE

21-hydroxylase

CORTEXOLONE 11-DEOXYCORTICOSTERONE

(17-OH DOC) (DOC)

11-hydroxylase Aldosterone

Synthetase

CORTISOL CORTICOSTERONE CORTICOSTERONE

TESTOSTERONE

18-OH

CORTICOSTERONE

ESTRADIOL ESTRONE

ESTRIOL ALDOSTERONE


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A.Steroidogenesis is a general process common to several endocrine tissues.

1) Secretory products. The end product each tissue secretes depends on the relativeconcentrations of enzymes from each steroid pathway present in the tissue. The highestconcentrations of 11-Beta-hydroxylase (cortisol pathway) are found in the zona fasiculata ofthe adrenal while the most aromatase (estrogen pathway) is the ovary. The Adrenal has

aromatase but the activity is low and adrenal estrogens are minor secretory products.

2) Cholesterol, a common precursor to all steroids, is both synthesized from acetate bysteroidogenic tissues and extracted from the plasma as cholesterol esters via the LDLreceptor system. Many of the tropic hormones (ACTH, LH, FSH) exert their primary effecton steroidogenesis by stimulating cholesterol's entry into the steroidogenic pathways(cholesterol esterase & cholesterol side chain cleavage).

3) Common enzymes. Some of the synthetic pathways use identical enzymes and if anenzyme is blocked or defective, multiple pathways are affected. The cortisol andaldosterone pathways have several common enzymes. When 21-hydroxylase is reduced

both cortisol and aldosterone secretion are reduced.

4) Missing enzymes. There are rare disorders in which steroidogenic enzymes are absent orreduced in quantity. The best examples involve the adrenal cortex. When an enzyme in thecortisol pathway is missing or reduced in concentration, serum cortisol levels fall and ACTHrises to compensate. This introduces large quantities of cholesterol into the pathway andintermediate products begin to accumulate behind missing enzymes. The accumulatedprecursors spill over into the circulation and the expanded tissue pools of precursors arenow available to proceed down some of the minor pathways. In this case substrate flow canincrease through adrenal androgen and estrogen pathways. As result of a primary enzymedefect we can have:

1) a) fall in the secretion of the major hormoneb) excess secretion of the immediate precursors to the block (which may have

alternative or intermediate hormonal potencies)c) inappropriate secretion of hormones from minor pathways.

A defect in the cortisol pathway can result in the abnormal production of progestins, androgens,estrogens or mineralocorticoids.

Steroid secretory mechanisms are not completely understood. Traditionally steroids arethought to diffuse out due to their lipid solubility.

Metabolism and excretion. Most biologically active steroids (except estrogens) have 4-3ketone configurations (see figure). The liver which is the major site for steroid metabolism canmake many modifications to steroids. The principal route of degradation involves saturation ofthe 4-5 double bond followed by conversion of the 3-ketone to a hydroxyl. This inactivates moststeroids. To facilitate the excretion of these hydrophobic molecules the liver conjugates themthrough the number three hydroxyl to a sulfate or glucuronide molecule rendering them watersoluble for easier fecal or urinary excretion. Estrogens are similarly conjugated prior toexcretion.


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Orally administered steroidstravel first to the liver and as a result much of the administereddose may be metabolized before actually entering the systemic circulation.

O

CHO

OH

CH2OH

O

O

HO

3 4 Ketone

Dihydro

Tetrahydro

5 Reductase

3 -HydroxysteroidDehydrogenase

OR

R = Glucuronide or Sulphate


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B. Adrenalcortical Hormones

1) Glucocorticoidsare a class adrenal hormones with profound effects on carbohydrate(hence the name), lipid and protein metabolism. The principal glucocorticoid in man iscortisol, also called hydrocortisone. This class of hormones arises in the zona fasiculataand is important in the response to stress, injury and immune challenge.

2) Aldosterone is the primary member of the mineralocortocoids, a second class of steroidhormones involved with maintaining electrolyte balance particularly with respect to Na+, K+and H+. Aldosterone originates in the zona glomerulosa.

3) Progestins. Several progestational steroids are synthesized by the adrenal. Some aresecreted in small quantities. Little is known about the role of adrenal progestins.

4) Androgens and Estrogensare secreted by the adrenal in small but biologically significantquantities. Their major significance is in the opposite gender. Adrenal estrogens contributeto female characteristics in men and adrenal androgens are responsible for malecharacteristics in women (axillary & pubic hair, libido, etc.).

O

C

HO OH

CH2OH

O

O

OHO

17 Hydroxy steroid

17-Ketosteroids

17-ketone

17-hydrolyl


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Synthetic steroids.Steroid categories are artificial and there are varying degrees of cross overactivity. Aldosterone has a small amount of glucocorticoid activity while cortisol has somemineralocorticoid activity. This is important because excess secretion of cortisol is often firstdetected because of resulting electrolyte imbalances. Perhaps the greatest advantage of thesynthetic substitutes is that pharmaceutical chemists tailor these molecules to maximize one

activity while minimizing another. Dexamethasone and prednisolone are strong glucocorticoidswith very little mineralocorticoid activity. Fludrocortisone, a selective mineralocorticoid, has littleglucocorticoid activity. Most synthetic steroids are less readily metabolized with longer half livescompared to native steroids.

Gluco-activity*

Mineralo-activty*

PlasmaConcetrations

Glucocorticoids

Cortisol 1 113

Replacement**(20 mg/day)Corticosterone 0.5 1.5 1

Gluco-DrugsCortisone-acetate 0.8 0.8

Prednisone 4


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C. Operation of the Hypothalamic-Pituitary-Adrenal Axis.

CRH

AP

ACTH

Adrenal

Cortex

Hypothalamus

Cortisol


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1) Feedback control: Similar to thyroid hormones, serum cortisol is also closely regulated.The hypothalamus produces corticotropin releasing hormone (CRH) which stimulates thepituitary to release ACTH (corticotropin) which subsequently stimulates the adrenal cortex tosecrete cortisol. When the plasma cortisol rises, it inhibits further secretion of CRF and ACTHvia negative feedback. In addition to its direct stimulatory effect (tropic) on the adrenal, ACTH

also maintains the health and integrity of the adrenal cortex (trophic).

2) Diurnal Rhythm. There is a rhythmic variation in plasma cortisol concentrations. Cortisol ishighest before rising in the morning and declines gradually during the day until it rises again inthe next early a.m. This rhythm is not

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