HORMONES‛hormae), an impetus or

stimulus

OUTLINE

• OVERVIEW (NOT QUITE THE BIG PICTURE)• CLASSIFICATIONS & CHEMICAL TYPES• CHARACTERISTICS• SYNTHESIS/ DESTRUCTION (RATES)• ASSAYS• GENERAL MECHANISMS• THE ENDOCRINE SYSTEM• MISCELLANEOUS DETAILS (JUST WHAT YOU WERE WAITING FOR)• SUMMARY (THE END AT LAST)

HORMONES ARE ESSENTIALLY MESSENGERMOLECULES THAT ARE MEANT TO COORDINATETHE OPERATIONS OF BIOLOGICAL ORGANISMS. THIS IS DONE BY INCREASING AND DECREASINGTHE FUNCTIONS OF CELLS. AN EXAMPLE OF TWO RELATED HORMONES ARE:

THESE HORMONESARE SECRETED BYTHE THYROID GLAND.THEY AFFECT GENERALMETABOLIC RATES

THE FIRST HORMONE TO BE DISCOVERED “WAS ANTI-DIABETIC FACTOR” IN 1921 BY BANTING, BEST ANDTHEN COLLIP (in MacLeod’s lab in Toronto, Canada).

TO SHOW YOU HOW DISCOVERIES ARE GENERATED,THE DIABETIC FACTOR IDEA CAME FROM OSKAR MINKOWSKI AND JOSEF von MERING IN 1889 WHEN THEY PRODUCED A DIABETIC DOG BY REMOVING ITS PANCREASBUT ACTUALLY THEY WERE STUDYING FAT DIGESTION!

TYPES (CLASSIFICATIONS) OF HORMONES

EXTERNAL CELL HORMONES: ENDOCRINE, PARACRINE, AND AUTOCRINE

ENDOCRINE HORMONES ARE MADE AND SECRETED BYENDOCRINE GLANDS (HYPOTHALMIC/PITUITARY SYSTEMAND SEMI-INDEPENDENT SYSTEMS). THEY TRAVEL THROUGH THE BLOOD STREAM TO TARGET TISSUES (CELLS).THESE WERE THE ORIGINAL HORMONES TO BE STUDIED.PARACRINE HORMONES ARE MADE BY A LOCAL GROUP OFCELLS IN A SPECIFIED TISSUE. THE HORMONES ARE SECRETED INTO THE INTERSTITIAL FLUID SURROUNDINGTHE CELLS. CHOLECYSTOKININ-8 (GI TRACT HORMONE)

NH3-Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-CONH2

AUTOCRINE HORMONES ARE HORMONES MADE BY THE CELLS THAT USE THEM; SELF-MODULATING HORMONES. ESTRADIOL (SUPPORTS WOMB CELLS)

INTERNAL CELL HORMONES THESE ARE HORMONESTHAT ARE MADE AND FUNCTION ENTIRELY WITHIN THECONFINES OF A CELL. THEY ARE ALSO CALLED 2ND MESSENGERS. THEY ARE TO BE DISTINGUISHEDFROM SOME EXTERNAL HORMONES (SUCH AS STEROIDS)THAT ENTER A CELL FROM THE OUTSIDE.

cAMP TRANSFERS THE SIGNAL FROM ACELL SURFACE RECEPTOR TO A SERIES OFMOLECULES (OFTEN ENZYMES) THAT WILLAMPLIFY THE ORIGINAL SIGNAL MANY FOLDOVER. THIS IS CALLED A CASCADE MECHANISM.cGMP PRODUCES OPPOSING EFFECTS. CALCIUM AND CALMODULIN WORK AS A PAIR IN ANOTHER INTERNAL SYSTEM. NITRIC OXIDE (THE GAS) IS STILL ANOTHERINTERNAL CELL HORMONE.

HORMONE CHARACTERISTICS● SIZE (MOLECULAR WEIGHT) TYPICALLY SMALL MOLECULES (EXCEPTIONS INCLUDE POLYPEPTIDE HORMONES SUCH AS GROWTH HORMONE).

OXYTOCIN IS A CYCLIC PEPTIDE WITH A MOLECULAR WEIGHTOF 1007. IT IS MADE IN THE POSTERIOR PITUITARY GLANDAND STIMULATES UTERINE CONTRACTION AT BIRTH.

DURATION OF EXISTENCE HORMONES GENERALLYHAVE SHORT ½ LIVES* THAT CAN BE MEASURED BY THEAMOUNT OF ACTIVE HORMONE THAT SURVIVES AFTER A GIVEN TIME OR NUMBER OF PASSAGES THROUGH THE CIRCULATION. THIS CONCEPT IS SOME-WHAT DECEIVING SINCE THERE ARE OTHER FACTORS THAT CONTRIBUTE TO HORMONE AVAILABILITYTO CAUSE A CELLULAR RESPONSE:1.BIOAVAILABILITY – IS THE HORMONE FREE OR BOUND?2.RATE OF SYNTHESIS – IS IT MAXIMAL, MINIMAL?3.RATE OF DEGRADATION – TISSUE CONTRIBUTION?

* ½ LIFE = THE AMOUNT OF TIME THAT A SUBSTANCE EXISTS UNTIL IT IS REDUCED BY 1/2. THE REDUCTION OF HORMONE (ACTIVITY) OFTEN FOLLOWS EXPONENTIAL DECAY N(t) = No x 2-t/t1/2

AFTER 3 HALF-LIVES ONLY 1/8 OF AN ACTIVE HORMONE SURVIVES.

MORE INFORMATION ABOUT ½ LIVES:

CONSIDER THE HORMONE T4 (THYROXINE) AS AN EXAMPLE – IT HAS A ½ LIFE OF 7 DAYS WITH A NORMAL BLOOD LEVEL OF 7.5 g PER 100 mL OF BLOOD.

AFTER 21 DAYS (THREE - ½ LIVES), THE AMOUNT WOULD BE REDUCED TO ~0.94 g PER 100 Ml OF BLOOD EXCEPT THAT THE SUPPLY IS CONSTANTLY BEING RENEWED BY THE THYROID GLAND.

SOME TYPICAL ½ LIVES OF HORMONES:

THYROID RELEASING HORMONE……………..2 MININSULIN……………………………………………..6 MINGLUCAGON………………………………………. 7 MINGROWTH HORMONE……………………………25 MINCORTISOL…………………………………………90 MIN

THE VALUE OF KNOWING ½ LIVES – EVEN THOUGH CELLULAR METABOLISM RENEWS MANY HORMONES QUICKLY - IS AS AN INDICATOR OF HOW TIGHTLY THEIR LEVELS AND EFFECTS ARE CONTROLLED. THE SHORTER THE ½ LIFE, THE TIGHTER THE CONTROL.

OVERALL IT CAN BE REASONABLY STATED THATMOST HORMONES, ONCE SYNTHESIZED, ONLY REMAIN FOR MINUTES BEFORE INACTIVATION AND/OR REMOVAL BY TISSUES SUCH AS LIVER,KIDNEYS & LUNGS. THE REASON -- IS TO RETAINTIGHT CONTROL OVER BODILY/ CELLULAR FUNCTIONS IS ONE OF NECESSITY ESPECIALLY WITH FUNCTIONS SUCH AS BLOOD SUGAR LEVELS AND UPTAKE. THEREFORE, BOTH SYNTHESIS AND RELEASE OF HORMONES ARE EQUALLY IMPORTANT. ENDOCRINE HORMONES ARE RELEASED IN THE BLOOD RAPIDLY ONCE SIGNALLED.

AS PART OF THE SYSTEM OF CHECKS & BALANCES -SOME HORMONES HAVE COUNTERPARTS THAT PRODUCE OPPOSING EFFECTS: INSULIN PROMOTES GLUCOSE UPTAKE INTO CELLS WHILE GLUCAGON PROMOTES GLUCOSE RELEASE FROM LIVER.

EXAMPLE OF VARYING LEVELS OF HORMONES DURING THE MENSTRUAL CYCLE

HOW FAST CAN HORMONES CAUSE EFFECTS?

THIS TEST DESIGNED TO TEST INSULIN LEVELS & FUNCTION. NOTE THE NORMAL (GOLD) CURVE. GLUCOSE LEVEL RETURNS TO NORMAL VALUE IN 3 HRS. THEN NOTE THE DIABETICCURVE (RED). AFTER 5 HRS GLUCOSE REMAINS WELL ABOVE NORMAL -- INSUFFICIENTINSULIN TO CAUSE CELL UPTAKE OF GLUCOSE. HYPOGLYCEMIA (PURPLE) HAS MANYCAUSES, ONE BEING A TUMOR CAUSING EXCESSIVE INSULIN OUTPUT. FASTING IS ANOTHER.

THE PRINCIPLE OF RADIOIMMUNOASSAYS

THESE ASSAYS WORK SO WELL SINCE THEY COMBINERADIOACTIVE LABELLING WITH ANTIGEN-ANTIBODYREACTIONS:1)RADIOACTIVE AND NON-RADIOACTIVE COMPOUNDS OF THE SAME CHEMICAL COMPETE FOR REACTION WITH AN ANTIBODY (COMPLEX). 2)THE COMPLEX IS ISOLATED & MEASURED FOR RADIOACTIVTY.3)THE SAMPLE IS NON-RADIOACTIVE WHILE A REFERENCE CHEMICAL IS RADIOACTIVE.

VERY LOW LOW INTERMEDIATE HIGH VERY HIGH SAMPLE SAMPLE SAMPLE SAMPLE SAMPLE

VERY HIGH HIGH INTERMEDIATE LOW VERY LOWRADIOACTIVITY RADIOACTIVITY RADIOACTIVITY RADIOACTIVTY RADIOACTIVTY

HOW ARE HORMONES ASSAYED?HORMONE BLOOD LEVELS ARE QUITE SMALL:1x10-6 to 1x10-15 M

IN THE ASSAY, NON RADIOACTIVEHORMONE (FROM THE PATIENT)COMPETES WITH A STANDARD AMOUNT OF RADIOACTIVEHORMONE FOR BINDING TO AN ANTIBODY. THE AMOUNT OFNON-RADIOACTIVE HORMONE(BOUND TO THE ANTIBODY) ISREAD FROM A STANDARD CURVETHAT IS SHOWN TO THE RIGHT(SEE ARROW).

CHEMICAL CLASSES OF HORMONES(EXAMPLES)

AMINO ACID DERIVED: THYROXINE

PEPTIDE HORMONES: GROWTH HORMONE & OXYTOCIN

Growth hormone:22, 124 daltons

LIPID DERIVED: 1)CHOLESTEROL 2) FATTY ACID DERIVED – DERIVED -- PROSTAGLANDIN F2

THE STEROIDS ARE DERIVEDFROM CHOLESTEROL WHERECORTISOL IS ANTI-INFLAMMATORYAND ESTRADIOL SUPPORTSUTERINE FUNCTIONS. PGF2CAUSESTHE CONTRACTION OF SMOOTHMUSCLES.

GENERAL HORMONE MECHANISMS:(ENDOCRINE TYPES)

1. AT THE CELL SURFACE 2. AT THE CELL NUCLEUS (to a receptor protein) (through a receptor protein)

1

2

THE ENDOCRINE HORMONE SYSTEM

HORMONES OF THE ENDOCRINE (toseparate inside) SYSTEM ARE SECRETED (RELEASED)DIRECTLY INTO THE BLOOD STREAM. THAT IS TO BE DISTINGUISHED FROM EXOCRINE GLANDS THAT SECRETE MOLECULAR PRODUCTS INTO A DUCT. e. g. A SWEAT GLAND.THESE HORMONES ARE MADE IN A PECKING ORDER –STARTING FROM THE BRAIN’S HYPOTHALAMUS. BUT,YOU MAY HAVE GUESSED, THERE ARE INDEPENDENT OPERATORS SUCH AS THE PANCREAS. GENERAL OBJECTIVE:TO COORDINATE BODILY FUNCTIONS.

MAJOR ENDOCRINEORGANS/ GLANDS

THE PANCREAS ISAUTONOMOUS FROMTHE BRAIN AS WELLAS ADIPOSE TISSUE(THAT MAY BE A SUR-PRISE).

NEURAL

THE ENDOCRINE “PECKING ORDER”

PAIN, FEAR,INFECTION,HEMORRHAGE,HUNGER

THE INITIATION OF HORMONALACTION MAY BEGIN WITHAFFERENT NERVE SIGNALS TO THE HYPOTHALAMUS.THIS CAUSES THE DUMPING OF RELEASING FACTORSINTO THE PORTAL ARTERIAL SYSTEM THAT, IN TURN,GO TO THE ANTERIOR PITUITARY. IN SOME CASESNERVE SIGNALS GO TO THE POSTERIOR PITUITARY.BOTH PITUITARY SECTIONS RELEASE THEIROWN HORMONES.

RELEASING FACTORS (WHICH ARE HORMONES)MIGRATE TO A PRIMARY TARGET (THE ANTERIORPITUITARY) WHICH RELEASES ITS OWN HORMONE (HORMONE B). B TRAVELS IN THE CIRCULATORY SYSTEM TO A SECONDARY TARGET TISSUE. THIS CAUSES THE RELEASEOF HORMONE C. HORMONE C, IN TURN, TRAVELSTO ITS ULTIMATE TARGET TISSUE, BINDS TO IT,AND BRINGS ABOUT A PHYSIOLOGICAL EFFECT(S).

REMEMBER THAT EACH STAGE OF BINDING ANDRELEASE AMPLIFIES THE ORIGINAL SIGNALMANY FOLD.

NEURAL

THE ENDOCRINE “PECKING ORDER”

WE CAN FOLLOW A TYPICAL SEQUENCE OFEVENTS TO SIGNAL AN INCREASE IN METABOLICRATE:1)A CONFLICT PRESENTS ITSELF TO THE CNS – e. g. A TASK MUST BE COMPLETED IN A WEEK.2)THE CNS SIGNALS THIS TO THE HYPOTHALAMUS CAUSING THE RELEASE OF THYROTROPIN- RELEASING HORMONE (TRH).3)THIS HORMONE TRAVELS TO THE ANTERIOR PITUI- TARY GLAND (via portal vein) CAUSING THE RELEASE OF THYROID STIMULATING HORMONE (TSH).4)TSH, IN TURN, IS CARRIED TO THE THYROID GLAND (via the blood) WHERE IT CAUSES THE RELEASE OF THYROXINE AND TRIIODOTHYRINE (T4 AND T3).5)T4 AND T3 BIND TO MOST CELLS IN THE NUCLEUS AND STIMULATE AN INCREASE IN METABOLIC RATE.

ALTHOUGH THIS MAY BE AN OVERSIMPLIFICATION – SINCE HORMONES AND THEIR OPERATION ARES COMPLICATED –STILL WE CAN CONSIDER SOME PRACTICAL EXAMPLES.

THESE ARE EASILY SEEN IN COUPLES OR EVEN SMALL GROUPS –

1)ONE LIKES TO HAVE THE THERMOSTAT SET AT 72 deg WHILE THE OTHER WANTS IT AT 66 deg.

2)ONE LIKES TO HAVE HIS/HER WORK DONE IMMEDIATELY WHILE THE OTHER PREFERS A LITTLE MORE TIME.

3)ONE CAN WALK THROUGH THE WOODS AND LEAVE THE OTHER BEHIND IN A FEW MINUTES.

THESE ARE EXAMPLES OF SMALL DIFFERENCES IN METABOLICSET POINTS OF THE THYROID GLAND AND ITS HORMONE OUTPUTS – SOME PEOPLE WOULD DEFINE THEM AS TYPE A AND TYPE B PERSONALITIES.

SOME THINGS NOT PREVIOUSLY EXPLAINED:

1. MANY HORMONES HAVE FEEDBACK AND SHUTDOWN MECHANISMS (e. g., thyroid hormones affect TSH release by TRH)

2. THERE MAY BE A LAG BEFORE AN EFFECT CAN OCCUR (AND THE REVERSE). (e. g., growth hormone’s effects are especially slow)

3. HORMONE EXCESSES AND DIMINUTIONS MAY BE PATHOLOGICAL. (e. g., excess cortisol levels may cause kidney stones)

4. SPECIFIC HORMONE ACTIONS ARE DETERMINED BY THE KIND OF RECEPTORS THAT THEY BIND TO.

5. SOME HORMONES MAY FUNCTION AS EITHER HORMONES OR NEURO- TRANSMITTERS (LOCATION, LOCATION, LOCATION), e. g., epinephrine and nor- epinephrine.

SUMMARY1. HORMONES ARE CHEMICAL MESSENGERS MEANT TO COORDINATE THE PHYSIOLOGICAL SURVIVAL & FUNCTIONS OF AN ORGANISM.

2. TO SAY THAT HORMONES BELONG TO A CHEMICAL CLASS WOULD BE ERRONEOUS – THEY INCLUDE: PEPTIDES, POLYPEPTIDES, AMINO ACID DERIVITIVES, STEROIDS, FATTY ACID DERIVITIVES, CNUCLEOTIDES AND OTHER TYPES.

3. THE CONCENTRATIONS OF HORMONES ARE VERY SMALL, BUT THEIR SIGNALS ARE AMPLIFIED GREATLY. THEY CAN BE ASSAYED BY RIA.

4. THE ENDOCRINE SYSTEM WAS THE 1ST TO BE STUDIED. IT ORIGINATES (FOR THE MOST PART) IN THE HYPOTHALAMIC AND PITUITARY TISSUES FROM CNS SIGNALS.

5. IN THE ENDOCRINE SYSTEM, HORMONES BIND AT EITHER A CELL MEMBRANE RECEPTOR OR AT THE NUCLEUS (via an intracellular cell protein receptor)