hormone metabolism
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BELLA MARILOU BAXA-DAGUPLO, MDBELLA MARILOU BAXA-DAGUPLO, MD
Department of Biochemistry & NutritionDepartment of Biochemistry & NutritionFatima College of MedicineFatima College of Medicine
Our Lady of Fatima UniversityOur Lady of Fatima University
(Review ’09)
HormonesHormones from the Greek termfrom the Greek term ((ὁρμήὁρμή ) "impetus“ ) "impetus“
- “to arouse to activity”- “to arouse to activity”
substance synthesized in one tissue & transported substance synthesized in one tissue & transported by circulatory system to act on another organby circulatory system to act on another organ
“ON”
“OFF”
Targetcell
Cellorigin
(Effects)
Hormone Metabolism
Hormone Metabolism
EndocrineEndocrine ParacrineParacrine AutocrineAutocrine
Functions of HormonesFunctions of Hormones
Hormone and Neurotransmitters… Hormone and Neurotransmitters…
Hormone Metabolism
Norepinephrine/Serotonin → depression
oversensitivity to serotonin → OCD behaviors
Dopamine → Parkinson’s disease
Too much dopamine in the limbic system and not enough in the cortex → personality given to bouts of paranoia or (-) social interaction
norepinephrine (NE)→ aggression
Hormone and Neurotransmitters… Hormone and Neurotransmitters…
Hormone Metabolism
Phenylethylamine + dopamine → mild anti-depressant effect
Phenylethylamine in the limbic system → “feelings of bliss”
oxytoxin → impulse to “cuddle”; multiple orgasm
norepinephrine w/ dopamine & phenylethylamine → give us the feeling of infatuation
too much stress in children can create permanently levels of serotonin and levels of NE → creating a potential of violent behavior
Hormone Metabolism
General General Characteristics Characteristics
of Hormonesof Hormones Not secreted at a uniform rateNot secreted at a uniform rate Exert their effects in biocatalytic amountsExert their effects in biocatalytic amounts Turnover is varied and usually rapidTurnover is varied and usually rapid Exert multiple actionsExert multiple actions Exhibit high degree of specificityExhibit high degree of specificity Different tissues may respondDifferent tissues may respond
differently to a given hormonedifferently to a given hormone
Regulation of Hormone SecretionRegulation of Hormone Secretion
A. Feedback ControlA. Feedback Control1) Negative Feedback2) Positive Feedback
Hormone Metabolism
B. Neural ControlB. Neural Control- visual/ olfactory/ gustatory
C. Chronotropic ControlC. Chronotropic Control- sleep-wake cycle/ physiologic cycle
Regulation of Hormone SecretionRegulation of Hormone Secretion……
Hormone Metabolism
Feedback ControlFeedback Control
Negative Feedback
T3 and T4 inhibits secretion of TRH and TSH
HPT AxisHPT Axis
Hypothalamus
TRH
TSH
T3 , T4
+-
+
+
-
AnteriorPituitary
Thyroid
Increasedmetabolism
Regulation of Hormone SecretionRegulation of Hormone Secretion……
Hormone Metabolism
Feedback ControlFeedback Control
Positive Feedback
Female HPG AxisFemale HPG Axis
+
+
Hypothalamus+
AnteriorPituitary
Ovaries
Estrogen Progesterone
+
+
+
-
- FSHLH
GnRH
estrogen level results to LH surge during ovulation
Forms of Hormone in theForms of Hormone in theCirculationCirculation
Hormone Metabolism
A. Free Molecules (unbound)A. Free Molecules (unbound)- water-soluble hormones
B. Bound MoleculesB. Bound Molecules- water insoluble hormones- bound with specific globulins or transport proteins such as albumin, “cortisol-binding globulin”, and “thyroid-binding globulin”
Fates of HormoneFates of Hormone
Hormone Metabolism
A. Target cell uptakeA. Target cell uptake
B. Metabolic degradationB. Metabolic degradation
C.C. Urinary or biliary excretionUrinary or biliary excretion
kidney and liver are the major sites of hormone metabolism and degradation
Classification of HormonesClassification of Hormones
I. According to StructureI. According to StructureA. Protein hormones
1) Simple or polypeptide [insulin, glucagon, somatostatin, growth h., ACTH, MSH, PRL, CS …]
2) Complex or glycoprotein [TSH, FSH, LH, hCG…]
B. Steroid hormones [glucocorticoids, mineralocorticoids, sex androgens, retinoic a., calcitriol…]
C. Biogenic amine hormones [thyroxine,catecholamines]
II. According to Mechanism of ActionII. According to Mechanism of ActionA. Group 1B. Group 2
Hormone Metabolism
Hormone Metabolism
Classification of HormonesClassification of Hormones…… [Protein]
Insulin and C-peptide Formation
Ribosome ER Golgi A. Vesicles
A-Chain
B-Chain
Hormone Metabolism
Pro-opiomelanocortin Peptide Family
Classification of HormonesClassification of Hormones…… [Protein]
Hormone Metabolism
Classification of HormonesClassification of Hormones…… [Steroids]
Classification of HormonesClassification of Hormones…… [Amines]
Hormone Metabolism
Some Biogenic Amines
Dopamine
CH2 - CH2 – NH2 HO
HO
CH - CH2 – NHCH3
OH
HO
HO
Epinephrine Tetraiodothyronine
Norepinephrine
CH - CH2 – NH2
OH
HO
HO
Classification of HormonesClassification of Hormones
Hormone Metabolism
Group 1 Group 2
Type Steroids, thyroid h., Polypeptides and retinoic acid …. catecholamines…
Solubility Lipophilic Hydrophilic
Transport Protein Yes No
Plasma T1/2 Longer Shorter
Receptor Intracellular Plasma membrane
Mediator HRC/HRE 2nd messengers
According to Mechanism of ActionAccording to Mechanism of Action
Hormone Metabolism
Steps Involved in ElicitingSteps Involved in ElicitingResponse of Target CellResponse of Target Cell
1)1) Recognition and binding of the hormoneRecognition and binding of the hormoneto specific receptorto specific receptor
2) Coupling to generate signal2) Coupling to generate signal
3)3) Changes in intracellular processesChanges in intracellular processesbrought about by the generated signalbrought about by the generated signal
Hormone Metabolism
ReceptorsReceptors
specific proteins that must first bind aspecific proteins that must first bind a hormone before cellular response canhormone before cellular response can be elicitedbe elicited
have at least 2 Functional domains:have at least 2 Functional domains:
1) Recognition domain - binding domain 2) Coupling domain - generates signal that
couples hormone recognition to someintracellular function
Hormone Metabolism
Classes:Classes:
A. Cell surface receptors
B. Intracellular receptors
1) Nuclear receptors2) Cytoplasmic receptors
ReceptorsReceptors
Cell Membrane ReceptorsCell Membrane Receptors
Functional Domains:Functional Domains:
1) Ligand-binding domain 2) Transmembrane domain 3) Cytoplasmic domain
Hormone Metabolism
ReceptorsReceptors
N
C
Typical cell membrane receptor(seven membrane-spanning domain)
Extracellular
Intracellular
Intracellular ReceptorsIntracellular Receptors
Functional Domains:Functional Domains:
1) A hormone bindinghormone binding region in the C-terminal 2) An adjacent DNA bindingDNA binding region 3) A specifier regionspecifier region (N-terminal) necessary for
high-affinity binding to the proper region ofDNA
4) One or more regions that activate or repressactivate or repressgene transcriptiongene transcription
Hormone Metabolism
ReceptorsReceptors
(1)(2)(3)
N C
Hormone Metabolism
Signal TransductionSignal Transduction
process which occurs after a hormoneprocess which occurs after a hormone binds to a receptorbinds to a receptor
an intracellular signal is generatedan intracellular signal is generated [second messenger][second messenger] which delivers which delivers the hormonal messagethe hormonal message
amplifies the original signal convertingamplifies the original signal converting substrate molecules to productssubstrate molecules to products
Hormone Metabolism
Signal TransductionSignal Transduction
PeptidesCatecholamines
Neurotransmitters…Steroids
Thyroid hormonesEstrogen, RA…
Insulin, EGF, IGF-1
Growth hormoneProlactin…
Signal Transduction PathwaysSignal Transduction Pathways
Enzyme Activation Nucleus
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 1][Group 1]
CytoplasmNucleus
Hormone Action with intracellular receptorsHormone Action with intracellular receptors
+
“Activation”
+
Specific Protein
TranscriptionmRNA
TranslationmRNA
Metabolic response
Hormone response element (HRE)
Hormone receptor complex (HRC)
ReceptorSteroid/Thyroid h.
Thyroid h.
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 1][Group 1]
Structural requirements for hormonal regulation of gene transcription
5’ 3’
Hormone responseelements (HRE)
Promoterelement (PE) Gene
TranscriptionInitiation site
TerminationSite
1+
Regulatory DNA region Structural DNA region
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 1][Group 1]
Hormones that bind to Intracellular receptorsHormones that bind to Intracellular receptors(Group 1)(Group 1)
Mineralocorticoids Glucocorticoids Androgens Progestins Estrogens Calcitriol (1,25[OH]2-D3) Retinoic acid Thyroid hormones (T3 and T4)
Hormone Metabolism
Mechanism of Action of Group 2 HormonesMechanism of Action of Group 2 Hormones
Effector SystemsEffector Systems
I. Effector systems that produce cytosolicsecond messengerssecond messengers (couple w/ G-protein) for signal transduction
Adenylyl cyclase - cAMP Guanylyl cyclase - cGMP Phospholipase C - phosphoinositides
(DAG & IP3) Calcium - calmodulin (Ca++)
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Effector SystemsEffector Systems
II. Effector system as an intrinsic part of thereceptor
- does not require G-protein to transduce the physiologic action of the ligand
- contains an enzymatic activity within the intracellular domain that phosphorylates tyrosine kinase residues
Mechanism of Action…Mechanism of Action… [Group 2][Group 2]
Mechanism of Action…Mechanism of Action… [Coupling w/ G-protein][Coupling w/ G-protein]
Mechanism of Action…Mechanism of Action… [Coupling w/ G-protein][Coupling w/ G-protein]
Mechanism of Action…Mechanism of Action… [Coupling w/ G-protein][Coupling w/ G-protein]
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Adenylate cyclase – cAMP ESAdenylate cyclase – cAMP ES
Regulation through cAMP-dependent protein kinases
Adenylate
cyclase
ATP Mg2+ cAMP (•)
5’-AMPPhosphodiesterase
4 cAMP
C
RR
C
Inactiveprotein kinase
RR•
•
•
• C
Activeproteinkinase
2+Protein
Phosphoproteins
Phosphatase
Physiologic effects
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Adenylate cyclase – cAMP ESAdenylate cyclase – cAMP ES
1. Activators of adenylyl cyclase1. Activators of adenylyl cyclase Cholera toxin – inactivates GTPase;
s is frozen in active form
Pertussis toxin – prevents activation ofi subunit
2. Inhibitor of adenylyl cyclase2. Inhibitor of adenylyl cyclase Phosphodiesterase – hydrolyzes cAMP
to 5’-AMP
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Hormone Action using cAMP Second MessengerHormone Action using cAMP Second Messenger
Glycogen synthase a
Glycogen synthase b
Protein kinase(Inactive)
Protein kinase(Active)
Phosphoproteinphosphatase
Insulin
(+)
(+)(+)
(+)Glycogen
Phosphorylase bGlycogen
Phosphorylase a
Glycogen
Glucose-1-PO4
(+)
GLYCOGENOLYSIS
Phosphorylasekinase (inactive)
Phosphorylasekinase (active)
Phospho-protein
phosphatase
Adenylatecyclase
ATP
cAMP
(+)(-)
(+)
Muscles Liver
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Hormone Action using cAMP Second MessengerHormone Action using cAMP Second Messenger
Specific Protein
or TranscriptionmRNA
TranslationmRNA
Metabolic response cAMP response element (CRE)
Adenylatecyclase
ATP
cAMP
Protein kinase(Inactive)
Protein kinase(Active)
CREB
CREB-P
(+)(-)
(+)
Muscles Liver
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Receptor
DAG
IP3
Ca++
Protein kinase C
Phosphoproteins
Proteins
Physiologic responses
Ca++-Calmodulin
Calmodulin kinases
(+)
(+)GDP GTP
Phospholipase C
GTP GDP
(+)
PIP2
Hormone Action using DAG, IPHormone Action using DAG, IP33 and Ca and Ca++++
as Second Messengersas Second Messengers
Phosphatidylinositol Cycle and CalciumPhosphatidylinositol Cycle and Calcium
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Kinase Cascade System 1 Kinase Cascade System 1 [Autophoshorylation][Autophoshorylation]
(Autophosphorylation)Phosphorylation ofprotein substrates
(Tyrosine)
Cell growthDNA synthesis
Early response genes
Enzyme Activity
Protein Translocation
Gene Expression
P P
ES utilized by Insulin, EGF PDGF and IGF-1ES utilized by Insulin, EGF PDGF and IGF-1
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Kinase Cascade System 2Kinase Cascade System 2
ES utilized by Growth hormone, Prolactin, EPO, cytokines…ES utilized by Growth hormone, Prolactin, EPO, cytokines…
Regulates transcription
Nucleus
Dimerization
X = SHC GRB2 PLC PI-3K GAP
JAK PJAKP
P PP P
STATs
XSH2P
P)(
JAK PJAKP
P PP P
JAK JAK
Hormone Metabolism
Mechanism of Action… Mechanism of Action… [Group 2][Group 2]
Hormones that bind to CM receptorsHormones that bind to CM receptors
2a2a – second messenger is cAMP
2b2b – second messenger is cGMP
2c2c – second messenger is Ca++orphosphoinositols or both
2d2d – second messenger is kinase/phosphatase cascade
Hormone MetabolismHormone Metabolism
Factors Affecting Response ofFactors Affecting Response ofTarget Cells to HormonesTarget Cells to Hormones
concentration of the hormoneconcentration of the hormone number of receptorsnumber of receptors duration of exposureduration of exposure intracellular conditions such as intracellular conditions such as
conc. of rate-limiting enzymes, conc. of rate-limiting enzymes, substrates or cofactorssubstrates or cofactors
antagonistic or synergistic hormonesantagonistic or synergistic hormones
Hormones That AffectHormones That AffectFuel metabolismFuel metabolism
Hormone Metabolism
InsulinInsulin GlucagonGlucagon SomatostatinSomatostatin CatecholaminesCatecholamines Steroid HormonesSteroid Hormones Thyroid HormonesThyroid Hormones Growth HormonesGrowth Hormones
Metabolic Effects of HormonesMetabolic Effects of Hormones
Pathways Insulin Glucagon Epi T3, T4 Cortisol GH
Glycolysis
Glycogenesis
Glycogenolysis
Gluconeogenesis
Lipogenesis
Lipolysis
Protein Synthesis
Pathology
(+) Stimulated; (-) Inhibited(+) Stimulated; (-) Inhibited
(+)(+)
(+)(+)
(+)(+)
(+)(+)
(-)(-)
(-)(-)
(-)(-)
(-)(-)
(-)(-)
(-)(-)
(-)(-)
(+)(+)
(+)(+)
(+)(+)
(+)(+)
(-)(-)
(-)(-)
(-)(-)
(+)(+)
(+)(+)
(+)(+)
(+)(+)
(-)(-)
(-)(-)
(+)(+)
(+)(+)
(+)(+)
(+)(+)
(-)(-)
(+)(+)
(+)(+)
(+)(+)
(-)(-)
(+)(+)
(+)(+)
(-)(-)
(+)(+)
(-)(-)
(++)(++)
(+)(+)
(+)(+)
(+)(+)
““central”central”
““peripheral”peripheral”
““Liver”Liver” ““L & M”L & M”
DM,DM,Lepre-Lepre-chaunismchaunism
GlucagonomaGlucagonomaParkinson’sParkinson’sPheochromo-Pheochromo-cytomacytoma
Grave’s D.Grave’s D.MyxedemaMyxedemaCretinismCretinismGoiterGoiter
Cushing’sCushing’sConn’sConn’sAddison’sAddison’s
DwarfismDwarfismGigantismGigantism
Hormone Metabolism
Insulin …Insulin …
Mechanism of ActionMechanism of Action
Transduction thru tyrosine kinaseTransduction thru tyrosine kinase
Autophosphorylation [-subunit]
(+)/(-) of cytoplasmic proteins
Phosphorylation of proteins
(+) of tyrosine kinase activity
Biologic effects [long term effects]
Hormone Metabolism
Insulin …Insulin …
Mechanism of ActionMechanism of Action
Second MessengersSecond Messengers
Release of glycoinositol derivative
(+)/(-) of cytoplasmic proteins
Dephosphorylation of proteins
(+) Phosphoprotein phosphatase
Biologic effects [short term effects]
Hormone Metabolism
Insulin …Insulin …
Mechanism of ActionMechanism of Action
Hormone Metabolism
Insulin …Insulin …
Effects on MetabolismEffects on Metabolism
Enzyme Change in Activity Possible Mechanism
cAMP metabolism Phosphodiesterase (low Km) Increase Phosphorylation Protein kinase (cAMP-dependent) Decrease Association of R
and C subunitsGlycogen metabolism Glycogen synthase Increase Dephosphorylation Phosphorylase kinase Decrease Dephosphorylation Phosphorylase Decrease Dephosphorylation
Glycolysis & Gluconeogenesis Pyruvate dehydrogenase Increase Dephosphorylation Pyruvate kinase Increase Dephosphorylation Phosphofructokinase Increase Dephosphorylation Fructose-2,6-bisphosphatase Decrease Dephosphorylation
Hormone Metabolism
Insulin …Insulin …
Effects on MetabolismEffects on Metabolism
Enzyme Change in Activity Possible Mechanism
Lipid metabolism Acetyl-CoA carboxylase Increase Dephosphorylation HMG-CoA reductase Increase Dephosphorylation Triacylglycerol lipase Decrease Dephosphorylation
Signaling molecules p42/44MAP kinase Increase Dephosphorylation p90RSK Increase Dephosphorylation GSK3 Decrease Dephosphorylation p70 S6 kinase Increase Dephosphorylation Phosphoprotein phosphatase Increase Dephosphorylation 1G
Hormone Metabolism
Insulin …Insulin …
PathophysiologyPathophysiology
Diabetes MellitusDiabetes Mellitus
Type 1 – Insulin dependent DM (IDDM)
Type 2 – Non-insulin dependent DM (NIDDM)
Insulin …Insulin …
Leprechaunism Leprechaunism
[“Donohue’s Syndrome”][“Donohue’s Syndrome”]
Metabolic Syndrome / Insulin Resistance SyndromeMetabolic Syndrome / Insulin Resistance Syndrome
Hormone Metabolism
Insulin …Insulin …
Syndrome X, Syndrome X, Reaven Syndrome Reaven Syndrome Dysmetabolic S. Dysmetabolic S. The “H” phenomenonThe “H” phenomenon
The “Deadly Quartet”The “Deadly Quartet”
Hormone Metabolism
Insulin …Insulin …
PathophysiologyPathophysiology
Somogyi Effect Somogyi Effect [rebound hyperglycemia]
- rapid in blood glucose that generates the release of counterregulatory hormones (Epi, glucagon, cortisol) rapid of glucose
- hypoglycemia results from:1) autonomic neuropathy2) inappropriate timing of insulin3) exercise w/o adequate caloric intake4) excessive insulin treatment
Hormone Metabolism
Insulin …Insulin …
PathophysiologyPathophysiology
Dawn Phenomenon Dawn Phenomenon
- early morning (5:00 to 6:00AM) increase in blood glucose associated with the release of nocturnal growth hormone
- 3:00 AM glucose is normal, while 8:00 AM glucose is
Hormone Metabolism
Insulin …Insulin …
PathophysiologyPathophysiology
Maillard reaction Maillard reaction
- non-enzymatic glycosylation of proteins due to high blood glucose levels
- sugar aldehyde or ketone group condenses with a free amino group Schiff base Amadori productsAmadori products (stable ketoamines) degrade into reactive carbonyl-containing products react w/ amino groups cross-linkages and adducts DAMAGEDAMAGE
Hormone Metabolism
Catecholamines …Catecholamines …
Synthesis & StructuresSynthesis & Structures
CH2 - C – NH2
HO H
COOH
Tyrosine Dopa
HO
HO
CH2 - C – NH2
H
COOH
Dopamine
HO
HO
CH2 - CH2 – NH2
Norepinephrine
HO
HO
CH - CH2 – NH2
OH
Epinephrine
HO
HO
CH - CH2 – NHCH3
OH
Tyrosine hydroxylaseDopa
decarboxylase
Dopamine-hydroxylase
PNMT
Catecholamines …Catecholamines …
Chromaffin CellChromaffin Cell
TyrosineTyrosine
(+) - adrtenergic & cholinergic agents(-) -adrenergic agents
E
ENE
NE
Tyrosine
Dopa
Dopamine
Granule
E
NE
NE
DBH
TH
DD PNMT
BiosynthesisBiosynthesis
Hormone Metabolism
Hormone Metabolism
Catecholamines …Catecholamines …
Secretion of Stress HormonesSecretion of Stress Hormones
Stress
Hypothalamus
ACTH
Cortisol EP
Blood glucose
Blood
Tyr, PheChromaffin CellChromaffin Cell
EP
EP
Tyrosine
NEPPNMT
Catecholamines …Catecholamines …
MetabolismMetabolism
rapidly metabolized in the liver andskeletal muscles
metabolized by: catechol-O-methyl transferase (COMT)monoamine oxidase (MAO)
free catecholamines may also be inactivated by conjugated with sulfate orglucoronide in the liver
Hormone Metabolism
Hormone Metabolism
Catecholamines …Catecholamines …
Mechanism of ActionMechanism of Action
act through 2 major classes of receptors:-Adrenergic (1, 2)-Adrenergic (1, 2)
Epinephrine binds and (+) both and R:- much greater affinity with R
Norepinephrine primarily binds with R
Hormone Metabolism
Catecholamines …Catecholamines … Mechanism of ActionMechanism of Action
1, 2 (+) adenylyl cyclase
2 (-) adenylyl cyclase
1 couples to processes that alter Ca++ concentration or modify phosphatidylinositol metabolism or both
Binding of catecholamines to:
PathophysiologyPathophysiology
Hormone Metabolism
Catecholamines …Catecholamines …
Parkinson’s disease
Pheochromocytoma
Thyroid Hormones …Thyroid Hormones …
Hormone Metabolism
PathophysiologyPathophysiology
Hypothyroidism/MyxedemaHypothyroidism/Myxedema- T3 and T4; BMR
Hyperthyroidism/ThyrotoxicosisHyperthyroidism/Thyrotoxicosis- T3 and T4; BMR- Grave’s disease
GoiterGoiter- enlarged thyroid gland ; elevated TSH- due to iodine deficiency or excess - defect in any steps in the synthesis
Steroids …Steroids …
Hormone Metabolism
SynthesisSynthesis
Pregnenolone
ProgesteroneCortisol,
Aldosterone ,etc.
Cholesterol
(1) SCC
(2) Oxidation & isomerization
(3) Hydroxylation
Steroids …Steroids …
Hormone Metabolism
Subcellular comparmentalization of Glucocorticoid biosynthesis
R
ACTH
G AC
Cortisol
CholesterolEster
Cholesterol
Lipase
Pregnenolone
ATP
cAMPProtein kinase A
Cholesterol
Cortisol
Progesterone
11-Deoxycortisol
ER
LDL
Steroids …Steroids … Mechanism of ActionMechanism of Action
Steroids …Steroids …
Hormone Metabolism
PathophysiologyPathophysiology
Cushing’s syndromeCushing’s syndrome - glucocorticoid excess- due to pharmacologic use of steroids- ACTH-secreting pituitary adenoma or ca.- hyperglycemia or glucose intolerance; truncal obesity; severe CHON metabolism
Conn’s syndromeConn’s syndrome- primary aldosteronism- hypertension, hypokalemia, hypernatremia and alkalosis
Steroids …Steroids …
Hormone Metabolism
PathophysiologyPathophysiology
Addison’s diseaseAddison’s disease - primary adrenal insufficiency- severe hypoglycemia - decrease BP, decrease GFR, decrease ability to excrete a water load- skin pigmentation
22° Adrenal Insufficiency° Adrenal Insufficiency- deficiency of ACTH from tumors, infarct, or infection- metabolic syndrome w/o hyperpigmentation
Steroids …Steroids …
Hormone Metabolism
““High level of serum cortisol may High level of serum cortisol may be responsible for stress-induced be responsible for stress-induced memory loss.”memory loss.”
““Physiologic response to stress Physiologic response to stress does not impair the learning aspect does not impair the learning aspect of memory but only the free recall of memory but only the free recall of information.”of information.”
““Elevated glucocorticoid level may Elevated glucocorticoid level may induce impairment in such induce impairment in such stressful conditions as job stressful conditions as job interviews, combat, courtroom interviews, combat, courtroom testimony and examinations.”testimony and examinations.”
[Nature Neuro-science 2000; 3:313-4 (April)][Nature Neuro-science 2000; 3:313-4 (April)]
Growth H. …Growth H. … SecretionSecretion
Growth H. …Growth H. …Mechanism of ActionMechanism of Action
Growth H. …Growth H. …
Hormone Metabolism
Pathophysiology Pathophysiology
GH deficiency dwarfismGH deficiency dwarfism
Laron type dwarfismLaron type dwarfism
PygmiesPygmies
Growth H. …Growth H. … Pathophysiology Pathophysiology
PygmiesPygmies
PygmiesPygmies
Growth H. …Growth H. … Pathophysiology Pathophysiology
GigantismGigantism
Growth H. …Growth H. … Pathophysiology Pathophysiology
AcromegalyAcromegaly
Hormone Metabolism
neuromuscular excitabilityneuromuscular excitability blood coagulationblood coagulation secretory processessecretory processes membrane integrity/plasmamembrane integrity/plasma
membrane transportmembrane transport enzyme regulationenzyme regulation release of hormones and release of hormones and
neurotransmittersneurotransmitters
CalciumCalcium
CalciumCalcium
Ca and phosphate are necessary Ca and phosphate are necessary for bone mineralizationfor bone mineralization 1 kg Ca [human body]1 kg Ca [human body] 99% 99% bone bone (hydroxyapatite)(hydroxyapatite) miscible pool miscible pool (1% of the skeletal (1% of the skeletal muscle Ca and 1% periosteal space)muscle Ca and 1% periosteal space) 7.5-10.5 mg/dl or 1.1-1.3 mmol/L7.5-10.5 mg/dl or 1.1-1.3 mmol/L
Hormone Metabolism
Hormones That AffectHormones That AffectCalcium metabolismCalcium metabolism
Hormone Metabolism
PTHPTH
CalcitriolCalcitriol
CalcitoninCalcitonin
Hormone Metabolism
Parathyroid Hormone [PTH]Parathyroid Hormone [PTH]
84 amino acid peptide84 amino acid peptide regulates plasma Ca++ levelregulates plasma Ca++ level synthesized in the parathyroid glandsynthesized in the parathyroid gland t½t½ = 20 min after proPTH is synthesized = 20 min after proPTH is synthesized metabolized in the parathyroid tissue metabolized in the parathyroid tissue
and liverand liver
Hormone Metabolism
PTH …PTH …
preproPTH preproPTH proPTH proPTH PTH PTH (115 a.a) (115 a.a) (84 a. a.) (84 a. a.)
ERERRibosomeRibosome GAGA
PTH 1-34 (full biologic activity)PTH 1-34 (full biologic activity)
PTH 25-34 (receptor binding)PTH 25-34 (receptor binding)
Hormone Metabolism
Fates of PTHFates of PTH
Transport to a storage poolTransport to a storage pool
DegradationDegradation
Immediate secretionImmediate secretion
Hormone Metabolism
PTH Secretion PTH Secretion
Regulated by plasma Ca++:Regulated by plasma Ca++:
acute acute Ca++ Ca++ PTH mRNA PTH mRNA PTH synthesisPTH synthesis
1,25(OH)2-D3 1,25(OH)2-D3 VDRC/VDHRE VDRC/VDHRE PTH mRNA transcriptionPTH mRNA transcription
(+) G-protein (+) G-protein (+) phospholipase C (+) phospholipase C IP3 IP3 Ca++Ca++ secretion secretion
Hormone Metabolism
PTH MetabolismPTH Metabolism
metabolized in the parathyroid tissuemetabolized in the parathyroid tissue
Cathepsins B and DCathepsins B and D Cathepsins B cleaves:Cathepsins B cleaves:
PTH PTH [1-36 and 37-84] [1-36 and 37-84]
principal site of peripheral proteolysisprincipal site of peripheral proteolysisoccurs in the liver occurs in the liver (Kuppfer cells)(Kuppfer cells)
excretion of metabolites excretion of metabolites (kidneys)(kidneys)
Hormone Metabolism
PTH ActionsPTH Actions
PTHPTH
(+) G-protein(+) G-protein
cAMPcAMP
BONESBONES KIDNEYSKIDNEYS INTESTINESINTESTINES
Hormone Metabolism
PTH ActionsPTH Actions
BONESBONES KIDNEYSKIDNEYS INTESTINESINTESTINES
Direct EffectsDirect Effects Indirect EffectIndirect Effect
Increase bone Increase bone resorptionresorption
Decrease renal Decrease renal Ca++ Ca++ excretionexcretion
Increase Ca++Increase Ca++absorptionabsorption
(CALCITRIOL)(CALCITRIOL)
CALCITRIOLCALCITRIOL
derivative of vitamin Dderivative of vitamin D
regulates plasma Ca++ levelregulates plasma Ca++ level
synthesized in the kidneysynthesized in the kidney
ensures Ca and phosphate for ensures Ca and phosphate for bone mineralizationbone mineralization
Hormone Metabolism
Synthesis of CalcitriolSynthesis of Calcitriol
Hormone Metabolism
7-dehydrocholesterol 7-dehydrocholesterol
25-OH-D325-OH-D3
SKINSKIN
Vit D3 Vit D3
1, 25-(OH)1, 25-(OH)22-D3-D3
LIVERLIVER
KIDNEYKIDNEY [placenta][placenta]
(Photolysis)(Photolysis)
(25-hydroxylase)(25-hydroxylase)
(1-hydroxylase)(1-hydroxylase)
Mechanism of ActionMechanism of Action
Hormone Metabolism
Nuclear actionNuclear action (+) VDRE(+) VDRE
Induces Ca binding protein (CBP)Induces Ca binding protein (CBP)
Increases transfer of Ca & PO4 acrossIncreases transfer of Ca & PO4 acrossthe intestinal mucosathe intestinal mucosa
When you do not succeed in taking giant steps on the road to your goal,
be satisfied with little steps, and wait patiently till the time that
you are able to run, or better still, to fly.
Be satisfied to be a little bee in the hive who will soon become a big bee
capable of making honey…
Thank you …Thank you …
(Padre Pio)
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