5.

02 Hormones & Metabolism Regulation I

Floro B. Madarcos, MD | March 4, 2019 
 

OUTLINE
I. Somatostatin
A. Synthesis
B. Mechanism of Action
C. Clinical Correlation
II. Growth Hormone
A. Synthesis
B. Mechanism of Action
C. Metabolic Effects
D. Clinical Correlation
III. Catecholamines
A. Synthesis
B. Mechanism of Action
C. Effects
D. Degradation
E. Clinical Correlation
 
IV.
Cortisol
A. Synthesis
B. Regulation
C. Mechanism of Action
D. Metabolic Effects
E. Clinical Correlation
Figure 2​. Relative lengths ofSomatostatin and its precursors.
V. Thyroid Hormone
A. Synthesis
● Main precursor: ​Preprosomatostatin ​(116 amino acids)
B. Metabolic Effects
→ undergoes proteolytic cleavage to form ​prosomatostatin
C. Disorders of Thyroid
→ proteolytic cleavage results in the formation of​ two isoforms
Function
of the bioactive peptide:
VI. Adipose tissue as an
endocrine organ
VII. Hormones that control
appetite

OBJECTIVES
At the end of the lecture, the student should be able to: Figure 3.​ Structure of SST14
1. Discuss the hormones involved in fuel metabolism in terms of:
→ Chemical structure ▪ SST-14 ​(14 a.a.) - secreted by h
​ ypothalamus​ & ​exocrine
→ Biosynthesis, release/secretion, and degradation pancreas
→ Metabolic/physiologic effects on the major nutrients in central − From alanine to cysteine
organs involved in energy/fuel homeostasis − Internal disulfide bond between ​Cys 3 and Cys 14
→ Diseases arising from hypo- & hypersecretion of the
hormones
→ Biochemical basis of treatment strategies
2. Discuss the role of hormones involved in the maintenance of
body weight & appetite
→ Leptin, Insulin, Ghrelin, PYY & Adiponectin

I. SOMATOSTATIN Figure 4. ​Structure of SST28

● Abbreviation: SST
● Alternate names include: ▪ SST-28​ (28 a.a.) - secreted by the ​GIT
→ Growth Hormone Inhibiting Hormone (GHIH) − C-terminally extended form
→ Somatotropin Release-Inhibiting Factor (SRIF) − 7-10x more ​potent​ in inhibiting ​growth hormone​,
● Characteristics: insulin​ & ​thyroid-stimulating hormone​ (TSH)
→ Lipophobic (cannot penetrate cell membrane)
▪ uses GPCR; cAMP as ​2° messenger B. MECHANISM OF ACTION 
→ Catabolic (counter-regulatory/contrainsulin) ● Action of somatostatin inhibits the secretion of many hormones
● 5 somatostatin receptors have been identified, all from the
A. SYNTHESIS  GPCR superfamily:
→ SSTR1​ to ​SSTR5
● RECALL
SIGNALING PATHWAY FOR LIPOPHOBIC
HORMONES
SST binds ​SSTR (​ receptor) on ​cell membrane

HRC (Hormone-Receptor Complex​)

HRC activates trimeric ​G protein

Activation of ​adenylate cyclase ​(​ATP to cAMP​)

4 molecules of cAMP activate ​PKA

PKA: has 2 regulatory subunits (RR) & 2 catalytic subunits (CC)
Figure 1​. Pathway for Somatostatin Synthesis

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 RR binds to cAMP; CC is released & catalyzes phosphorylation INTRACELLULAR SIGNALING PATHWAY #3:
of Ser, Thr, or Tyr residues of inactive enzyme by ATP REGULATION OF PTPase & MAPK
Somatostatin binds to receptor
Target enzyme (active, phosphorylated) elicits cell response to
hormone signal Activation of several ​protein phosphatases:
● Phosphotyrosine Phosphatase ​(PTPase): SHP1, SHP2
● Activated receptors also interact with multiple intracellular ● Serine/Threonine/Tyrosine ​Phosphatase
signaling pathways ● Ca​2+​-dependent ​Phosphatase
→ in the case of somatostatin, there are ​three signaling ● Mitogen Activated Protein ​Kinase (MAPK)
pathways​ to produce inhibitory effect on most hormones ● Phosphoinositide-Dependent Protein ​Kinase 1 (PDPK1)

INTRACELLULAR SIGNALING PATHWAY #1: Apoptosis & Cytostatic​ action

INACTIVATION OF ADENYLATE CYCLASE (Decreased cell growth & proliferation)
Inhibition of all G-protein coupled receptors
● Signaling pathways #1 & #2 inhibit secretion of
Inactivation​ of adenylate cyclase neurotransmitters & hormones
● Signaling pathway #3 produces an anti-proliferative effect
Decreased​ cAMP synthesis (from ATP) ● Somatostatin acts by both endocrine and paracrine pathways
(Madarcos’ notes)
Inactivation of PKA
Other Physiologic Effects 
Decreased hormone secretion from ​anterior pituitary​ (GH & Decreases rate of nutrient absorption via:
TSH), ​pancrea​s (insulin & glucagon), and ​GIT 1. ↓ ​gastric acid​ & ​pepsin​ secretion via suppression o​f parietal
cells
2. ↓ ​smooth muscle​ ​contraction​ & ​blood flow​ in the intestines
3. ↓ ​pancreatic exocrine secretions​ (i.e., digestive enzymes,
HCO​3​, and H​2​O)
4. prolonging gastric emptying tim​e (by ↓ secretion of gastrin)

Table 1.​ Hormones Inhibited by Somatostatin & their Sources

Source Hormone inhibited
Anterior pituitary GHRH, TSH
GIT Gastrin, secretin, CCK, VIP,
GIP
Pancreas Insulin, glucagon

Regulators of Somatostatin Release 

Table 2.​ Regulators of Somatostatin Release
Stimulators Inhibitors
Neurotransmitters Neurotransmitters
Figure 5.​ Intracellular Signaling Pathways via Adenylate Cyclase ● Ach ● GABA
Inflammatory Cytokines Cytokines
INTRACELLULAR SIGNALING PATHWAY #2:
● IL-1, IL-6, TNF-​α ● TNF-​β​, Leptin
ALTERATION OF INTRACELLULAR ION CONC.
Metabolites
Activation of inward K+ channel (regulated by G-protein)
● Glucose, Fatty acids
● Arg, Leu
Depolarization​ of cell membrane
Hormones
Decreased​ Ca​2+​ influx (voltage-dependent channel) ● Glucagon, GHRH, CRH,
Neurotensin
Decreased ​intracellular [Ca​2+​] ● CCK, Gastric Inhibitory
Peptide (GIP),
Decreased hormone secretion from ​anterior pituitary​ (GH & Glucagon-like Peptide-1
TSH), ​pancrea​s (insulin & glucagon), and ​GIT (GlP-1), VIP

 
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 ● Synthesized, stored & secreted by somatotropic cells in the
C. CLINICAL CORRELATIONS  anterior pituitary gland
A. SYNTHESIS 
● Initially produced as a large precursor protein (217 a.a.
prohormone)
→ cleavage of 26 a.a. near the N-terminal produces the active,
mature hormone (191 a.a.)
▪ most abundant trophic hormone in anterior pituitary gland
● has ​2 strong intramolecular disulfide bonds ​that maintain its
helical structure:
→ Cys 53 - Cys 165
→ Cys 182 - Cys 189
● Actions of GH can be classified as direct or indirect
→ Direct effect​ - occurs as a consequence of the hormone
→ Indirect effect -​ through the ability of GH to generate other
factors, particularly ​IGF-1
● Control of the secretion of GH is through:
→ Stimulatory ​& ​inhibitory m ​ echanisms

Figure 6. ​Acromegaly
Pharmacologic Uses 
● Somatostatin and its synthetic long-acting analogs (Octreotide &
Lanreotide [Somatulin]) are used clinically to treat various
secretory neoplasms:
→ Gigantism ​and ​acromegaly (GH-secreting tumor of the
anterior pituitary gland)​ - due to its ​absence on inhibition
of growth hormone
→ Carcinoid syndrome​ - due to ​serotonin-secreting
carcinoid tumors​ anywhere along the ​GIT ​and the ​lungs

Figure 8. ​Control of GH Secretion

Stimulatory Mechanism 
Figure 7. Carcinoid Tumors ● Hypothalamus​ releases Growth Hormone Releasing Hormone
Carcinoid Tumor  (GHRH)
● A well-differentiated,​ malignant neuroendocrine tumor ​of the → GHRH ​stimulates ​anterior pituitary gland​ to produce ​GH
small intestine, ​often producing hormones such as ​serotonin, ▪ GH ​stimulates ​liver ​to synthesize ​IGF-1​ (high levels
substance P and gastrin produce negative feedback on hypothalamus and anterior
● Octreotide ​(​Sandostatin​®​, a somatostatin analogue​ that pituitary gland to limit GH secretion)
neutralizes serotonin & dec. urinary 5-HIAA, a degradation ▪ Multiple signaling mechanisms:
product of serotonin), is an adjunct in the treatment plan − cAMP
− Ca-Calmodulin
● Other factors stimulate hypothalamus to secrete GHRH
II. GROWTH HORMONE
● Abbreviation: GH or HGH (human growth hormone) → Decreased blood glucose
● Alternate names include Somatotropin, Somatropin ▪ In a way, it’s good to be hypoglycemic once in a while to
● Characteristics: stimulate the release of growth hormone; fasting per se
→ Lipophobic (cannot penetrate cell membrane) can increase GH release
→ Catabolic (counter-regulatory/contrainsulin) → Increased blood amino acids
→ Increased fatty acids
→ Exercise
 
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 → Sleep
→ Stress Activation of several intracellular proteins
→ Ghrelin (hormonal factor)
▪ “the hunger hormone” coming from the stomach (release ● Each of the intracellular proteins have different mechanisms of
occurs in times of fasting or empty stomach) action:
1. STAT​ (Signal Transducer and Activator of Transcription)
Inhibitory Mechanism  ▪ transcription of target genes → ​metabolic & growth
● Hypothalamus​ releases ​Somatostatin promoting effects
→ Somatostatin ​inhibits release of ​GH ​from ​anterior pituitary 2. SHC ​(Src Homology 2 alpha Collagen related)
gland​ → ↓ growth hormone levels ▪ activation of ​MAPK​ (Mitogen-Activated Protein Kinase) →
▪ primary regulator​ of GH secretion and release metabolic & growth promoting effects
▪ Somatostatin level is high when HGH is high, − MAPK​ can also promote​ transcription of target
somatostatin is low when HGH is low genes ​(similar to STATs)
● Obesity​ suppresses growth hormone secretion 3. IRS ​(Insulin Receptor Substrate)
▪ activates ​PI3K ​(Phosphoinositol 3’ Kinase) → central role
in ​glucose transport

Figure 8. ​Other factors that stimulate & suppress release of somatostatin

B. MECHANISM OF ACTION  Figure 10. ​Additional Intracellular Proteins

● Other intracellular signal molecules activated by GHR (and are

involved in transcription of target cells) [​not really discussed in
this lecture; more important to understand in Hormones &
Metab Regulation II]​
→ SOS (sons of sevenless)
→ GRB2 (growth factor receptor bound 2)
→ RAS (proto-oncogene protein P21)
→ SHP-2 (protein tyrosine phosphatase)
→ RAF (protooncogene protein raf)
→ MAPKK (MAPK-Kinase)

C. METABOLIC EFFECTS 

Table 3.​ Effects of FAs, Glucose & AAs on Somatostatin Activity..

Nutrient Effects
Fatty acids ↑ ​availability for energy
synthesis
Figure 9. ​Mechanism of Action of Major Intracellular Proteins Glucose & amino acids ↓ oxidation due to sparing effect
GROWTH HORMONE ACTION of fatty acids
GH binds to GH Receptor (GHR)

Dimerized GHR​ recruits cytoplasmic ​tyrosine kinase

Tyrosine kinase​ phosphorylates tyrosine residues in the

cytoplasmic (intracellular) domain of ​GHR

GH-bound receptor induces ​JAK2 ​(Janus Kinase 2)

phosphorylation
 
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 Anabolic Effects on Muscle 
● Increased protein synthesis
→ GH increased AA transport to muscles (substrate for protein
synthesis)
● Increased DNA and RNA synthesis
● Decreased glucose uptake
→ Increased lipolysis due to GH → increase fatty acid (used as
fuel) → indirectly suppresses glucose uptake
● Decreased glycolysis
→ Decreased glucose uptake → decreased glycolysis
● Positive nitrogen balance
→ Due to protein-sparing effect of GH-induced lipolysis that
makes fatty acids available to muscle as an alternative fuel
source

D. CLINICAL CORRELATION 
Figure 11. ​Anabolic Effects on Different Organs
Disorders of GH Deficiency 
Table 4.​ Causes of Various Congenital & Acquired Disorders of GH
Anabolic Effects on Liver  Deficiency
● Increase ketogenesis CONGENITAL ACQUIRED
→ In fasting state: Anterior pituitary gland Infection (ex. meningitis)
→ GH enhances fatty acid oxidation to acetyl coenzyme A disease
(acetyl-CoA) → increased substrate for hepatic ketogenesis
Part of a syndrome Brain tumors/surgical
● Increase gluconeogenesis**
manipulation/radiation therapy
→ Increased amount of glycerol reaching the liver due to
Congenital deficiency Injury - at birth (ex. difficult
enhanced lipolysis acts as a substrate for gluconeogenesis
delivery) or at later stage
(↑glycerol → ↑ gluconeogenesis)
● Increase glycogenesis
→ Due to increased gluconeogenesis in the liver Manifestations of GH Deficiency 
● Increase IGF-1 (somatomedins) Table 5. ​Manifestations of GH Deficiency in Children & Adults
→ IGF-1, IGF-2​ share structural homologies​ with proinsulin, CHILDREN ADULT
and have ​substantial insulin-like growth activity Short and proportionate No increase in height
→ IGF-1 (somatomedin - C) stature Weight gain (esp. around the
▪ Single peptide chain, 70 AA ↑ fat around the waist waist)
→ IGF-2 (somatomedin-A) Slow growth ↓ energy, strength, and muscle
▪ 67 AA, slightly acidic Delayed onset of puberty mass
→ Both contain structural domain that is homologous to and tooth development ↓ bone density
C-peptide of proinsulin ↑ total cholesterol, LDL,
● Decrease glycolysis apoprotein B and TAG
**Gluconeogenesis counted as a catabolic reaction because Thin and dry skin
substrates come from catabolic reactions Anxiety and depression

Anabolic Effect on Growth Plate  Dwarfism 

● Stimulation of chondrocytes of cartilage
→ promotes growth of long bones (increased linear growth as
long as epiphyseal plate of long bone has not closed)

Anabolic Effects on Adipose Tissue 

● Increase lipolysis
→ GH increases sensitivity of adipocyte to lipolytic action of
catecholamines and lead to release of free FA and glycerol
to be metabolized by liver
● Increased B-oxidation of fatty acids
● Decreased lipogenesis
→ due to decreases sensitivity to lipogenic action of insulin
● Decreased TAG synthesis
→ due to decreased esterification of fatty acids

Figure 12. ​Dwarfism

 
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There are different types of dwarfism: Growth Hormone as Performance-Enhancer 
1. GH-deficient dwarfs ​– lack the ability to synthesize or secrete ● many use as an illicit drug in sports to make one stronger
GH (​pituitary​ ​dwarfism​) ● however, it is illegal and dangerous as it can result in
● Treatment: ​by GH administration​ before fusion of growth acromegaly
plates ● others resort to taking creatine to increase muscle mass
2. Pygmies ​– lack the IGF-1 response to GH but not its metabolic  
effect → deficiency is ​post-receptor in nature III. CATECHOLAMINES
3. Laron dwarfs ​– N or ↑ plasma GH, but lack liver GH receptors ● Secretory products of the sympathoadrenal system
→ ↓ levels of circulating IGF-1 ● Required for body to adapt to a great variety of acute and
● Treatment: ​treated by biosynthetic IGF-1 (Mecasermin chronic stresses
rinfabate) before puberty to be effective ​
  ● Dopamine: acts primarily as a neurotransmitter; little effect on
fuel metabolism
Additional Treatments for Dwarfism 
Table 6. ​Characteristics of Treatments for Dwarfism. A. SYNTHESIS 
Growth Hormone Injection Psychotherapy ● The catecholamines (dopamine, epinephrine, and
1. must be given at the​ soonest Psychotherapy helps to norepinephrine) are synthesized in the chromaffin cells of the
possible time deal with the social adrenal medulla from ​tyrosine​, one of the non-essential amino
2. Given once/day to several/week ramifications of having acids
3. can only be given until age 25 a short stature → Epinephrine: ​80% of stored catecholamines (major product)
(when end plate has already → Norepinephrine: ​15% to 20%; also synthesized in situ
closed) (adrenal medulla, CNS, adrenergic nerve endings)
4. No increase in height during adult ● Cannot cross the blood brain barrier, thus must be synthesized
intake in the brain locally
● if given after 25, acromegalic
features will manifest
(widening of bones)

Disorders of GH Hypersecretion 
Table 7. ​Characteristics of Gigantism & Acromegaly
Gigantism Acromegaly
Occurs in​ children Occurs in ​adults
delayed puberty, double body odor, carpal tunnel syndrome,
visions, headaches, fatigue, weakness,​ increased
increased sweating​, sweating​, joint pains, organ
large hands & feet, enlargement, widely spaced teeth,
weakness, abnormal unintentional weight loss, diabetes
height but proportional mellitus, heart disease
Excessive amounts of Excessive amounts of GH ​AFTER
GH ​BEFORE​ epiphyseal epiphyseal closure; sacral bone
closure of long bones growth leads to characteristic
features
Figure 13. ​Synthesis of Catecholamines
Mechanism 
1. Tyrosine is first hydroxylated to form
Treatments for Disorders of GH Hypersecretion  3,4-dihydroxyphenylalanine (L-DOPA) via ​tyrosine
Table 8. ​Characteristics of GH Hypersecretion Treatments hydroxylase ​in the presence of NADPH as a reductant and
Type of Treatment Rationale/Effect tetrahydrobiopterin as a cofactor
Stereotactic surgery Removal of tumor (60% ● The enzyme requires tetrahydrobiopterin which is abundant
success chance) in the central nervous system, sympathetic ganglia, and the
Radiation therapy adrenal medulla
Slow process of reducing GH
secretion → not as successful ● This is the ​rate-limiting step
as surgery, hence used in 2. DOPA is then decarboxylated to ​dopamine ​via
tandem with surgery copper-containing ​DOPA-decarboxylase ​with PLP as a
Somatostatin agonists​ (ex. Inhibits GH secretion (e.g. cofactor
tuberculin) octreotide, lantreotide) ● In the​ substantia nigra​ and other parts of the brain,
Growth Hormone competitively binds to GH dopamine is the end of this pathway, hence dopamine is the
analogues receptors active neurotransmitter in this part of the brain
Growth Hormone receptor prevent GH from binding with ● Failure of the substantia nigra to synthesize dopamine
antagonists receptor (e.g. Pegvisomant) results to ​Parkinson’s Disease​, a degenerative condition
causing “shaking palsy”
 
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 ● Treatment is via administration of L-DOPA, the immediate
precursor of dopamine
3. In the adrenal medulla, dopamine is hydroxylated to
norepinephrine ​(noradrenaline) via a copper-containing
monooxygenase ​dopamine β-hydroxylase ​in the presence of
ascorbic acid and O​2
4. Norepinephrine is then converted to ​epinephrine ​(adrenaline)
via ​phenylethanolamine N-methyltransferase ​with SAM
(AdoMet) as the methyl group donor; SAM is converted to SAH
● Recall the carbon donors - SAM, Biotin and THF
5. Dopamine, epinephrine, and norepinephrine are termed
catecholamines because they are amine derivatives of catechol
B.MECHANISM OF ACTION OF EPINEPHRINE
● Epinephrine is a lipophobic hormone → impermeable to the
basically phospholipid bilayered cell membrane → hence it
produces its effect via synthesis of a ​second messenger
upon binding to its membrane receptor
● There are 4 general types of adrenergic receptors for
epinephrine: ​⍺​1,​ ⍺​2,​ β​1,​ and β​2
● β-adrenergic receptors​ are found in the liver, muscle, and
adipose tissue
● ɑ-adrenergic receptors​ are a second broad class of
G-protein coupled receptors (GPCRs) different from the
stimulatory G​s​ proteins used by β-receptors
● The ɑ-adrenergic pathway for epinephrine produces 3
second messengers:​ IP​3​, DAG, and Ca​2+
The ​β-adrenergic Pathway  associated protein G​q​ with GTP; in the process G​q​ ​is activated
Figure 14. ​Signal Transduction of Epinephrine via β-receptors
1. Epinephrine binds to its specific membrane-bound receptor,
forming a hormone-receptor complex (HRC).
2. HRC activates the trimeric ​stimulatory G-protein (G​s​) ​present
in the cytoplasmic side of the membrane causing replacement
of the ​GDP ​bound to G​s​ by ​GTP
● Gs protein is a trimeric protein made of ɑ, β, and 𝛄 subunits
● GDP is attached to the ɑ- subunit when inactive; GTP when
active
3. ɑ-subunit ​with bound GTP moves or associates with the
membrane-bound enzyme ​adenylate cyclase, ​causing its
activation
4. Adenylate cyclase catalyzes the synthesis of ​cAMP ​from ATP
5. cAMP in turn allosterically activates ​cAMP-dependent protein
kinase ​(also called ​protein kinase A or PKA)
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6. PKA then catalyzes the phosphorylation of target cellular
proteins → hence the cellular response to epinephrine
7. Finally, the β-adrenergic response is terminated by degrading
cAMP into inactive 5’-AMP via ​cyclic nucleotide
phosphodiesterase
The ɑ-adrenergic Pathway 
Figure 15. ​Signal Transduction of Epinephrine via ɑ-receptors
1. Epinephrine binds to its cell membrane receptor, forming an
epinephrine-receptor complex
2. This complex catalyzes the replacement of GDP bound to the
just like the​ ​β-adrenergic receptor activates G​s
3. Gs with bound GTP activates a membrane-bound enzyme
Phospholipase C (PLC)
4. Active PLC cleaves the minor phospholipid species
phosphatidylinositol 4,5-bisphosphate (PIP​2​) into two potential
second messengers: ​inositol 1,4,5 triphosphate (​ IP​3​; different
from the membrane phospholipid phosphatidylinositol
3,4,5-triphosphate or PIP​3​) and ​diacylglycerol ​(DAG)
5. IP​3​, an H​2​O-soluble compound, diffuses from the plasma
membrane into the cytoplasm and endoplasmic reticulum (ER)
where it binds to a specific receptor, releasing sequestered
intracellular Ca​2+
6. DAG​, a lipid-soluble compound, fulfills its second messenger
role by moving along the plasma membrane (by virtue of its
hydrophobic fatty acid side chains) and together with the
ER-released Ca​2+​ activates protein kinase c (PKC) at the
cytoplasmic surface of the plasma membrane
● DAG cooperates with Ca​2+​ in activating PKC, thus acting as
a second messenger
● Ca​2+​ also activates PKC, thus also acting as a second
messenger
7. PKC then phosphorylates a wide range of target signal
transduction proteins on serine or threonine residues, producing
some of the cellular responses to epinephrine
C. EFFECTS ON FUEL METABOLISM 
● The secretion of catecholamines from storage vesicles in the
adrenal medulla is stimulated by a variety of stresses, including
the following:
→ fright
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 → hemorrhage
→ pain
→ cold
→ exercise
→ hypoglycemia
→ hypoxia
● Catecholamines are ​contrainsulin ​and ​catabolic​ hormones,
hence their metabolic effects are directed towards mobilization
of fuel from their storage sites for oxidation by cells to meet the
increased requirement for energy in the presence of acute and
chronic stresses
● Energy use rather than storage
Effects on Various Metabolic Organs
Figure 16. ​Physiological effects of catecholamines on different organs.
1. Pancreas
● ↓ Insulin secretion​ - to prevent release of fuel storage which
is not needed in times of stress
● ↑ Glucagon secretion​ - to ensure fuel flux towards the
direction of fuel utilization needed in times of stress → further
reinforcement of the similar catabolic effects of epinephrine
on fuel metabolism
2. Liver
● ↑ Glycogenolysis​ - via stimulation of glycogen
phosphorylase → ↑ blood glucose for fuel
● ↑ Gluconeogenesis​ - utilizing such substrates as lactate
and pyruvate from muscle oxidation and glycerol from TAG
degradation in the adipose tissues → ↑ blood glucose for
fuel
● Hence blood glucose may rise in patients with
pheochromocytoma
3. Adipose tissues
● ↑ TAG degradation ​- into glycerol and fatty acids via
activation of hormone-sensitive TAG lipase
● Glycerol moiety is used as substrate for hepatic
gluconeogenesis
● Fatty acids undergo β-oxidation → ​↑ ​ATP synthesis
4. Muscles
● ↑ Glycogenolysis ​via activation of adenylate cyclase → ↑
glucose for fuel (concomitant ​↓ ​glycogenesis)
● ↑ Proteolysis - ​breakdown of proteins into component amino
acids → glucogenic amino acids are used as substrates for
hepatic gluconeogenesis → ​↑ ​glucose for fuel
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● ↑ Anaerobic glycolysis ​- via increasing concentration of
fructose 2,6-bisphosphate (the most potent allosteric
activator of PFK-1) → ATP production in muscle
5. Other organs
● Norepinephrine as a neurotransmitter affects the sympathetic
nervous system in the heart, lungs, blood vessels, bladder,
gut, and other organs, hence the following physiologic effects
aimed at increasing delivery of blood-borne fuels to
metabolically active tissues:
→ ↑HR
→ ↑CO
→ ↑BP
→ ↑ dilation of respiratory passages
● Above effects are part of a coordinated response to prepare
an individual for emergencies, hence “fight-or-flight”reactions
→ hence catecholamines are also called “fight-or-flight”
hormones
D. DEGRADATION OF CATECHOLAMINES
Degradation of Norepinephrine 
Figure 17. ​Degradation pathway of norepinephrine
● Monoamine oxidase (MAO), ​present in the outer mitochondrial
membrane of neural and other tissues (such as GIT and liver),
catalyzes the oxidative deamination of the carbon containing the
amino group of ​Norepinephrine ​to form and aldehyde product;
(NH​4​+​) is released
● This aldehyde product is further oxidized into dihydromandelic
acid, which is then acted upon by
catechol-O-methyltransferase ​(COMT; also present in many
cells, including the RBCs):
→ COMT catalyzes the transfer of the methyl group of SAM to a
hydroxyl group of the intermediate product (O-methylation
reaction).
→ S-adenosyl methionine (SAM) is converted to s-adenosyl
homocysteine (SAH)
● The final product of degradation is
3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid;
VMA)
● Norepinephrine, ​however, can also be acted upon initially by
COMT, again with SAM as the methyl group donor to form a
methylated product normetanephrine
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● Followed by oxidative deamination of normetanephrine by MAO
to form again the final product ​VMA
(​Note: ​Actions of MAO and COMT can occur in almost any
order)
Degradation of Epinephrine  serotonin) that may leak out of synaptic vesicles when the
MAO inhibitors 
● MAO ​is found in neural and other tissues, such as the intestine
and liver (Lippincott, 2011)
→ oxidatively deaminates and inactivates any excess
neurotransmitter molecules (norepinephrine, dopamine, or
neuron is at rest
● MAO inhibitors ​may irreversibly or reversibly inactivate the
enzyme, permitting neurotransmitter molecules to escape
degradation and accumulate within the presynaptic neuron and
leak into the synaptic space (Lippincott, 2011)
→ causes activation of norepinephrine and serotonin receptors
→ may be responsible for antidepressant action in drugs

E. CLINICAL CORRELATION 

Pheochromocytoma  
● Excess catecholamine secretion caused by a tumor of adrenal
medulla
● Signs and symptoms (Sympathetic):
→ hypertension
→ headache
Figure 18. ​Degradation pathway of epinephrine → diaphoresis
● Epinephrine is oxidatively deaminated to an aldehyde product
→ palpitations
via ​MAO​ → O-methylated to vanillylmandelic acid (VMA) via
→ anxiety
COMT
→ tremors
● Epinephrine may also be O-methylated to metanephrine via
→ weight loss
COMT ​→ oxidatively deaminated into vanillylmandelic acid via
● Diagnosis
MAO
→ Measurement of plasma ​metanephrine​ (more ​sensitive​)
→ urine VMA or homovanillic acid
In both Epinephrine and Norepineprine degradation:
● Treatment
● Deamination via ​MAO ​or O-methylation via ​COMT ​can occur in
→ Adrenalectomy
almost any order (Also applies to Dopamine)
→ Preoperative α and β-catecholamine antagonists
● VMA ​is therefore the product of degradation of ​epinephrine
(phenoxybenzamine, propranolol)
and ​norepinephrine
▪ prevent hypertensive crisis (BP elevation during intubation
● Measurement of ​VMA ​in the urine is one way of assessing
or tumor manipulation/malignant hypertension)
adrenal medullary function; however plasma ​metanephrine
▪ patient is already hypertensive due to high
measurement is the most sensitive and less susceptible to
catecholamines + stress because of knowledge of surgery
false-positive test resulting from stress, such as venipuncture
IV. CORTISOL 
Degradation of Dopamine  ● Main glucocorticoid hormone synthesized in the ​Zona
Fasciculata​ of the adrenal cortex.
● Cholesterol (27 C)​ - Parent compound of Cortisol
→ Produced from acetyl CoA or from lysosomal digestion of
lipoproteins
→ stored as cholesterol esters in the adrenal cortex before
being acted upon by lipases to form FA and free cholesterol
● 21-carbon long lipophilic hormone

Figure 19. ​Degradation pathway of dopamine

● Oxidatively deaminated to dihydromandelic acid via ​MAO​ →
O-methylated to homovanillic acid via ​COMT
● May also be O-methylated to 3-methoxytyramine via ​COMT ​→
oxidatively deaminated to homovanillic acid via ​MAP
● Homovanillic acid ​is therefore the product of degradation of
dopamine

 
BCH9 / 24 
  
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CORE ​Marasigan, Mateo, Ng, Ocenar, Ordoñez  Musni 

​ ​ Figure 20. ​Synthesis of Cortical Hormones
A. SYNTHESIS
Synthesis of Cortisol
​Figure 21. ​Steps in Cortisol Synthesis​.
Steps in the Synthesis of Cortisol
1. Transport of Free Cholesterol
● Free Cholesterol (C27)​ is transported into the inner
mitochondrial membrane of the Zona Fasciculata by
steroidogenic acute regulatory protein (StAR)
→ Cholesterol
● RATE LIMITING STEP
2. Cleavage of Cholesterol
● Cleavage of Cholesterol’s side chain to yield
Pregnenolone (C21) ​and​ Isocaproaldehyde (C6)
● Pregnenolone: parent compound for all steroid hormones
→ ​Enzyme: P450 side chain cleavage (or desmolase,
CYP 11A)
→ NADPH, , O​2​, and ACTH as co-factors/co-enzymes
3. Oxidation and Isomerization of Pregnenolone
● Pregnenolone returns to cytosol to be oxidized and
isomerized by ​3-𝛃-hydroxysteroid dehydrogenase
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(3𝛃HSD)​ and ​Δ5,4​
​ isomerase​, respectively, forming
progesterone (C21)​ in the ER
● 3𝛃HSD converts 3-OH group of pregnenolone to
3-keto group
● Δ​5,4​ isomerase moves double bond from B to A ring
4. Hydroxylation of Progesterone
● Via ​17-⍺-Hydroxylase (CYP17)​, progesterone becomes
17-⍺-hydroxyprogesterone (C21)​.
→ addition of -OH group at C17
5. Hydroxylation of 17-⍺-hydroxyprogesterone
● ​11-Deoxycortisol (C21)​ is produced via hydroxylation
by ​21-⍺-Hydroxylase (CYP21)​.
→ addition of -OH group at CH​2​ of C21
6. Transport and hydroxylation of 11-deoxycortisol
● 11- Deoxycortisol is transported back into inner
mitochondrial membrane; ​11- -hydroxylase (CYP11 1)
catalyzes ​-​hydroxylation at carbon 11, forming ​Cortisol
(C21)
→ NADPH and O2 must be present
Cellular Route for Cortisol Synthesis 
​ Figure 22. ​Cellular Route for Cortisol Synthesis
Steps​:
1. Cholesterol Esters stored in the adrenal cortex are acted upon
by lipases to form ​free cholesterol and FA​.
2. Adrenocorticotropic hormones (ACTH)​ activate adenylyl
cyclase via G-coupled cell membrane proteins, forming cAMP
from ATP
→​ cAMP is a secondary messenger of ACTH
3. Increase in cAMP activates ​Protein Kinase A (PKA)
4. StAR transports free cholesterol into the inner mitochondrial
membrane for conversion into pregnenolone via ​p450​SCC
5. Pregnenolone travels to the cytosol and is oxidized and
isomerized into progesterone (C21) via ​3𝛃HSD and Δ5,4”
6. Hydroxylation of Progesterone forms
17-⍺-hydroxyprogesterone, which is further hydroxylated to
form 11-Deoxycortisol
7. 11-Deoxycortisol goes back into the inner mitochondrial
membrane and is converted into cortisol via 11​𝛃-​ hydroxylase
before being sent to the cytoplasm
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 B. REGULATION ● Binds to its receptor protein (​Rec​) in the nucleus to form
a cortisol-receptor complex (​CRC​)
● CRC changes the conformation of the receptor to make
homodimers or heterodimers with other CRCs
→ binds to specific regulatory regions aka
Hormone-response Elements (HREs) in DNA adjacent to
specific genes
● Receptor attracts ​co-activator or co-repressor
proteins
→ Regulates transcription of adjacent genes, and
increasing rate of mRNA synthesis to synthesize new
proteins (translation)
● The synthesized proteins cause the cellular effects of
cortisol.

D. METABOLIC EFFECTS

​ Figure 23.​ Regulation of Cortisol Synthesis and Secretion

● Cortisol release induced in response to non-specific
stresses like:
→ Sleep
→ Hemorrhage
→ Emotions and Trauma
→ Cold pressure
→ Pain
→ Toxins
→ Hypoglycemia
→ Stress
→ Infections
→ diurnal variation: high in early morning, lowest at night
● These factors send signals to the hypothalamus for
secretion of neurotransmitters Acetylcholine and ​ Figure 24.​ Effects of Glucocorticoids on Fuel Metabolism
Serotonin, leading to formation of Corticotropin Releasing
Hormone (​CRH​) ● In general, affects glucose metabolism (glucocorticoid)
→ CRH acts on the anterior pituitary gland, causing the towards promotion of survival in times of stress
release of adrenocorticotropic hormone (​ACTH​) Liver
→ ACTH induces synthesis and secretion of cortisol via ● ↑ Gluconeogenesis from glycogen and glucogenic AA’s
stimulation of the zona fasciculata of the adrenal cortex ● ↑ Glycogenesis but Epi ↑glycogenolysis= net ↑ of glucose
● Feedback Inhibition: high blood cortisol levels inhibits the for survival
release of CRH by the hypothalamus and/or ACTH from Adipose
the anterior pituitary ● ↑ TAG degradation to form FA and glycerol
→ Due to the decrease in CRH and ACTH, cortisol ● ↓ Glucose utilization
synthesis also decreases ● ↑ FA released to circulation, undergoing -oxidation in
the liver to synthesize energy
C. MECHANISM OF ACTION  Muscle
● Cortisol induces synthesis of proteins which will alter cell ● ↑ Proteolysis to release AA’s in the blood
function by entering the nucleus and binding to segments ● ↓ Protein Synthesis
of chromosomes ● ↓ Glucose Utilization
● Cortisol is a Type 1 Hormone = can penetrate cell
membrane and move into the nucleus to bind its receptor
→ lipophilic (hydrophobic) in nature
→ no need for secondary messengers
→ utilizes simple diffusion to pass through the cell
membrane
→ must be bound to ​transcortin​ (carrier protein) for
transport in the blood from the adrenal cortex to target
tissues

 
BCH11 / 24 
  
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CORE ​Marasigan, Mateo, Ng, Ocenar, Ordoñez  Musni 
 E. CLINICAL CORRELATION Cushing’s Syndrome 

Figure 25.​ Blocked steps in cortisol synthesis in Congenital Adrenal

Hyperplasia
Congenital Adrenal Hyperplasia  ​ igure 26. ​Clinical Manifestations of Cushing’s Syndrome
F
Type: Adrenogenital Syndrome, ​Primary Disorder​, hyperfunction ● Type: Hypercortisolism, ​primary disorder​, hyperfunction,
● condition caused by a ​hyperactive adrenal cortex ACTH-independent
● diseases caused by deficiency of enzymes involved in the ● Common Causes:
synthesis of sex hormones and mineralocorticoids (e.g. → prolonged intake of glucocorticoids
aldosterone and cortisol → anterior pituitary adenoma
→ hormone synthesis deficiency ​beyond the affected step → adrenal adenoma
→ hormone excess or metabolites ​before that step ● Signs and symptoms are due to prolonged exposure to high
● Congenital deficiency of steroid hydroxylases​ leads to: levels of cortisol (hypercortisolism)
→ low cortisol = no feedback inhibition on ACTH = adrenal ● Clinical Manifestations
hyperplasia → Body fat​: weight gain, central obesity, “Moon Facies”
● 3-𝛃HSD Deficiency (accumulation of fat in the cheeks, jaw, and neck), “Buffalo
→ no glucocorticoids, mineralocorticoids, and sex hormones Hump” (deposition of fat in the center of the upper back)
→ salt-retention in urine (excessive excretion of salt in → Skin​: facial plethora (due to thinning of skin), thin and brittle
urine or “salt wasting”) skin, easily bruised (due to fragility of capillary walls), broad
→ female-like genitalia and purple stretch marks (due to secondary weakening of
● 17-𝛼-Hydroxylase Deficiency dermal connective tissue), acne, hirsutism (excessive
→ decreased sex hormone and cortisol production hairiness)
→ ↑ mineralocorticoids, leading to ↑ water retention and Na​+ → Bone​: osteopenia, osteoporosis (vertebral fractures),
retention decreased linear growth in children
→ female-ike genitalia → Muscle:​ weakness, myopathy (prominent atrophy of gluteal
● 21-𝛼-Hydroxylase Deficiency & upper leg muscles w/ difficulty climbing stairs or getting up
→ most common Congenital Adrenal Hyperplasia from a chair)
→ decreased production of glucocorticoids and → CVS:​ hypertension, decreased K​+​, edema, atherosclerosis
→ mineralocorticoids → Metabolism​: glucose intolerance, diabetes, dyslipidemia
→ 17-𝛼-hydroxyprogesterone is converted to androgens → Reproductive System​: decreased libido, amenorrhea (due
→ ↑ androgens = masculinization in females to cortisol-mediated inhibition of gonadotropin release)
→ Early virilization in males → CNS:​ irritability, emotional lability, depression, cognitive
● 11-𝛃-Hydroxylase Deficiency defects, paranoid psychosis
→ Most serious → Blood and Immune System​: increased susceptibility to
→ low cortisol, aldosterone, and corticosterone infections, increased WBC, eosinopenia, hypercoagulation
→ ↑ Deoxycorticosterone with increased risk for DVT (deep vein thrombosis) and
→ Masculinization in females pulmonary embolism
→ Early virilization in males
Cushing’s DIsease 
● secondary disorder​ that is ​ACTH-dependent
● caused by an adenoma situated in the anterior pituitary gland,
releasing more ACTH = increased cortisol levels
● Same clinical manifestations as Cushing’s Syndrome

 
BCH12 / 24 
  
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CORE ​Marasigan, Mateo, Ng, Ocenar, Ordoñez  Musni 
Addison’s Disease  → Thyroid gland traps I​-​ coming from capillary blood, increasing
● Type: Hypocortisolism, secondary disorder, hypofunction of
adrenal cortex
● Caused by:
→ Primary ​adrenal insufficiency: adrenal cortex diseases (TB,
autoimmune disease, hemorrhage, etc.)
→ Secondary ​adrenal insufficiency: pituitary adenoma,
irradiation, autoimmune disease, hemorrhage, TB,
actinomycosis
→ Leading to ​decreased ACTH​ and ​cortisol
● Clinical Manifestations:
→ Tiredness, muscle weakness, diarrhea, dehydration, postural
hypotension, hyponatremia, loss of appetite, nausea,
vomiting, depression, salty-food cravings
● Treatment​: Administration of glucocorticoids (plus
mineralocorticoids)
V. THYROID HORMONES
● The thyroid gland synthesizes and releases two thyroid
hormones: ​thyroxine (T4)​ and​ triiodothyronine (T3).
→ 80% of T4 is converted to the more active T3 in the liver and
kidneys, remaining 20% to inactive T3
● Thyroid hormones affect every cell and all the organs of the
body
​Figure 27​. Synthesis of Thyroid Hormones; Top = Follicular Lumen ;
Bottom of diagram = Extracellular space in contact with blood capillaries
A. SYNTHESIS
● Thyroid follicular cells synthesize ​thyroglobulin ​(​Tgb​) and
secrete them into the colloid
● Iodination and coupling of tyrosine residues in Tgb produces T3
and T4 residues, which are released from Tgb via pinocytosis
and lysosomal action
● ALL of the steps in the synthesis of thyroid hormones are
stimulated by TSH.
Steps in Thyroid Hormone Synthesis  → Colloid droplets (T3 and T4 within the thyroglobulin
● Concentration or Iodine Trapping
→ In the presence of anterior pituitary thyroid hormone (TSH),
Iodide (I​-​) enters the follicular cell via a transporter protein
against a strong concentration gradient, using the Na​+​-K
ATPase pump system (​ hence an active process)
▪ Na​+​ goes outside in exchange for I​-
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the concentration of I​-​ in the follicular cell to about 20-30x
that is present in the blood
→ About 80% of total iodide is stored in the thyroid gland
→ Soil in upper regions (mountains) contains less iodine and far
from seafood source, hence higher incidence in mountainous
areas (Baguio, Benguet, Cordillera Region > goitrous belts)
→ Active I​-​ trapping (not stimulated by TSH) also takes place in
the salivary gland, gastric mucosa, placenta and mammary
glands. However, there is no thyroid hormone formations
since they cannot oxidize I​-​ to I​2
● Oxidation
→ passive transport and oxidation of I​-​ to I​2​ across the luminal
surface of the cell via a heme-containing luminal
Thyroperoxidase (TPO)​ in the presence of H​2​O​2 (oxidizing
​
agent) produced by an NADPH-dependent enzyme
resembling cytochrome c reductase.
→ NADPH mainly comes from HMP
→ Thyroid gland is the only organ that can perform the
oxidation step
→ Congenital defect in oxidation is treated by T4 administration
● Iodination or Organification of Thyroglobulin
→ Immediate incorporation of Iodine into the tyrosine ring of
Thyroglobulin (Tgb) to form ​monoiodotyrosine (MIT) and
diiodotyrosine (DIT)
→ Tgb is a large glycoprotein precursor molecule that provides
the polypeptide backbone for thyroid hormone synthesis and
release.
→ Catalyzed by TPO
→ 115 tyrosine residues in the Tgb, only 35 can be iodinated
● Coupling
→ Happens within the thyroglobulin molecule, catalyzed by
TPO and requires the H​2​O​2
→ 1 DIT + 1 MIT = Triiodothyronine (T3)
→ 1 DIT + 1 DIT = Thyroxine (T4)
​ ​Figure 28​. Thyroid Hormone Coupling
→ Thyroid hormones are stored in this state and are only
released when the Tgb molecule is taken back up into the
follicular cell
→ Congenital defect in coupling is treated by T4
● Uptake
molecule) are internalized into the follicle cell via
phagocytosis and pinocytosis (under the influence of TSH
and cAMP) when there is a demand for thyroid hormones
→ Fusion of the colloid droplets with lysosomes will lead to the
formation of phagolysosomes
→ Hydrolysis of Tgb’s peptide bonds by lysosomal activity
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 → Release/secretion of MIT, DIT, T3, and T4 (T3 and T4 are → the pituitary gland is more sensitive to feedback inhibition by
secreted into the blood). the thyroid hormones compared to the hypothalamus
→ 90% of released Thyroid hormone is T4, while T3 is
about 10%.​ Small amounts of Tgb is present in the plasma. Table 9. ​Antithyroid drugs/Goitrogens (Inhibitors of TH Synthesis)
● Deiodination
→ MIT and DIT are deiodinated via NADPH-dependent thyroid
deiodinase into tyrosine + I​-
→ Reutilization of I​-​ and tyrosine: I​-​ is reused and tyrosine
residues are available for incorporation into Tgb molecules
→ Deionization is depressed by I​-​, hence KI is used as an
adjuvant in treatment of hyperthyroidism
→ Congenital deficiency of deiodinase to presence of MIT and
DIT in the urine

Metabolism of Thyroid Hormones 

Mechanism of Action 
● Thyroid hormones belong to the category of ​Group I
(lipophilic) hormones​, hence, can penetrate the cell
→ T​3​ enters the ​cell membrane​ via a specific transport
mechanism and binds to​ nuclear triiodotyronine receptor
in thyroid-sensitive tissues, forming ​T​3​-receptor complex
→ This hormone complex then stimulates specific regions of the
DNA called ​Thyroid Hormone Response Element (THRE​)
and regulate gene transcription, stimulating synthesis of
mRNA which results to protein synthesis via translation
→ Synthesis of new proteins account for various effects of
thyroid hormones, specifically on growth and development
​ igure 29​. Thyroid Hormone Metabolism
F
● T​4​ is considered a prohormone; Around 80% of T​4​ circulating in
the blood is converted into active T​3​ (3,5,3’-Triiodothyronine) in
the presence of Type 1 and 2 deiodinases
→ Types 1 and 2 deiodinases ​catalyze the removal of iodine
of the outer (5’) tyrosine ring of T​4​ to make T​3
→ T​3​ is 10x more potent than T​4
● 20% of the T​4​ is converted into the inactive form, ​reverse T​3
(rT3) ​aka 3,3’,5’-Triiodotyronine via Type 1 and 3 deiodinases
→ no biological activity in rT3
● Propylthiouracil (PTU) ​inhibits peripheral deiodinases
● Peripheral conversion of T​4​ to T​3​ and rT3 is the major pathway
for thyroid hormone deiodination

Feedback Regulation of Thyroid Hormone Secretion 

● The paraventricular nucleus of the hypothalamus secretes TRH ​Figure 30. ​Mechanism of Action of Thyroid Hormones
to stimulate thryrotropes of the anterior pituitary gland for
release of TSH B. METABOLIC EFFECTS 
● TSH stimulates the thyroid gland to capture iodine from the ● Growth and Development
blood for synthesis, release, and storage of T​4 → Prenatally
● T​4​ is deiodinated and converted to the active T​3​ once it reaches ▪ Not required for growth
its target cells (e.g. liver) ▪ Required for normal skeletal and CNS development
● Upon reaching an adequate circulating level, T​3​ and T​4​ cause → Postnatally
negative feedback on the hypothalamus and anterior pituitary ▪ Required for normal growth, maturation and development
gland to reduce output of TRH and TSH ▪ Acts synergistically with GH on growth of long bones
→ output of TRH and TSH resumes once there is a drop in the ▪ Hypothyroidism can cause irreversible damage if
levels of the respective thyroid hormones replacement is delayed
→ this mechanism provides an uninterrupted supply of ● Calorigenesis
biologically active free T​3​ in the blood

 
BCH14 / 24 
  
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 → Increased rate of heat production = increase O​2 ​consumption
and utilization
▪ Measured as increased BMR, CO, HR and RR
→ Causes: Increase Na-K-dependent ATPase and avoidance
of futile metabolic cycles
● Proteins
→ Hypothyroid to euthyroid → Increased protein synthesis
→ Euthyroid to hyperthyroid → increased proteolysis →
negative N​2​ balance
→ Specific proteins may show induction and curve all the way
from the hypothyroid to the hyperthyroid range
● Carbohydrates
→ Glycogen
▪ Hypothyroid to euthyroid → increased glycogenesis
▪ Euthyroid to hyperthyroid → increased
▪ glycogenolysis
● Lipids
→ Cholesterol
▪ Hypothyroid to euthyroid → increased
▪ Euthyroid to hyperthyroid → decreased
→ Fatty Acids
▪ Hypothyroid to euthyroid → increased
▪ Euthyroid to hyperthyroid → decreased
● Other metabolic effects
→ Increased milk production during lactation → Increased Ca2+
mobilization from bones
→ Increased Heart Rate (HR) and muscle contractility
▪ Partly due to increased sensitivity to catecholamines
→ Necessary for normal menstrual cycle and fertility
C. DISORDERS OF THYROID FUNCTION  → Hypermetabolic states
Hypothyroidism  agitation
● Condition in which the body ​lacks sufficient Thyroid hormone
● Clinical manifestations:
→ Mild / Moderate
▪ Lethargy, fatigue, hoarseness, hearing loss, thick/dry/flaky
skin, constipation, cold intolerance, stiff gait, weight gain
→ Severe (Myxedema Coma
▪ Coma, refractory hypothermia, decreased HR, increased
RR, pleural effusion, electrolyte imbalance, seizures
● Hashimoto’s Thyroiditis
→ Presence of autoimmune antibodies​ directed against Tgb
and TPO or both
→ Destruction of thyroid gland
→ Goiter formation in an attempt to compensate
→ Decreased T3 and T4, Increased TSH
● Cretinism
→ ​Congenital hypothyroidism
→ Congenital ​absence of thyroid hormone in infants
→ Causes: The absence of thyroid gland and presence of only
a rudimentary gland or inability of the thyroid to produce
thyroxine
→ Physical Exam: Flat nose and face, macroglossia,
yellow/dry/coarse skin, feeding difficulties, constipation,
stunted growth, umbilical hernia secondary to weakness
→ If untreated in children it can cause: Severe physical and
mental retardation, stunting of growth or severe dwarfism or
(cretinism - physical stature of a child when he/she is older
● Endemic Goiter
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→ Thyroid hypertrophy secondary to​ insufficient dietary
iodine
→ Lab results are: low T​3​ and T​4​ and High TSH
● Myxedema
→ Due to ​prolonged hypothyroidism​ in adults
→ Most frequent causes: atrophy of the gland, surgical removal
or irradiation
→ Manifestations
▪ Hypometabolic state – fatigue, muscle weakness,
decreased BMR, cardiac degeneration
▪ Mental retardation
▪ Low pitch, hoarse voice
▪ Skin manifestations
▪ some women with myxedema cannot bear children due to
the caused reproductive hormone imbalance
● Hypometabolic state ​is due to accumulation of increased
amounts of hyaluronic acid and chondroitin in the dermis of the
skin secondary to TH stimulation of dermal fibroblasts
● Other Diseases
→ surgical removal of thyroid gland
→ Viral infection of thyroid gland (viral thyroiditis)
→ radioactive ablation
→ inadequate replacement
Hyperthyroidism 
● Primary
→ Abnormalities of the thyroid gland
● Secondary
→ Abnormalities of the pituitary & hypothalamus
● Clinical Manifestations
▪ Tremors, excessive sweating, fast reflexes, nervousness,
▪ Increased HR, RR, appetite, bowel movement
→ Smooth, velvety skin, fine hairs
→ Mood swing – depression, panic attacks, insomnia
→ Muscle & joint pains
→ Enlarged thyroid gland w/ characteristic stare
→ Weight loss, fatigue, dec. concentration
● Grave’s Disease
→ Most common cause of hyperthyroidism, between ages
25-50 years; ​female ​preponderance
→ An autoimmune antibody called ​Long ActingThyroid
Stimulator (LATS and IgG)​ is misdirected on TSH receptor
or thyroglobulin or both → increased synthesis of thyroid
hormones
→ Manifestations: goiter, hyperthyroidism, exophthalmopathy
→ Lab results: increased T​3​, T​4​, and TSH; TSH receptor
antibodies
→ Associated eye findings
▪ Periorbital edema​ – secondary to accumulation of
mucopolysaccharides and associated water
▪ Chemosis ​– swelling and redness of conjunctiva
▪ Lid retraction and lid lag
▪ Proptosis or exophthalmos​ – secondary to infiltration of
neorbital tissues by lymphocytes, macrophages, and
plasma cells together with H​2​O accumulation → staring or
frightened look
▪ Diplopia, blurring vision, extraocular muscle involvement
▪ Dryness of the cornea and loss of vision
● Toxic Multinodular Hyperthyroidism
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 → Enlarged thyroid gland containing small rounded masses
called nodules → become “​autonomous ​→ do not respond
to pituitary regulation via TSH → increased independent
synthesis of thyroid hormones →h​yperthyroidism
→ Arise from long standing simple goiter, most often in the
elderly
→ Manifestation: hyperthyroid state, less exophthalmos seen in
Grave’s disease
● Excessive Iodide Intake
→ Excessive intake of iodized salt may cause thyroid gland to
use iodine to produce thyroid hormones.
→ Certain medications, such as ​amiodarone (Cordarone)
▪ used in treatment of heart problems, contain a large
amount if iodine and may be associated with thyroid
function abnormalities
● Excessive Intake of Thyroid Hormones
→ Frequently go undetected due to lack of follow up of patients
taking thyroid medicine
→ Other persons may be abusing the drug in attempt to
achieve other goals such as weight loss
→ These patients can be identified by having a low uptake of
radioactively-labelled iodine (radioiodine) on a thyroid scan
● Abnormal secretion of TSH
→ Tumor in the pituitary gland may produce an abnormally high
secretion of TSH → excessive signaling to thyroid hormone
synthesis
→ Condition is very rare; can be associated with other
abnormalities of the pituitary gland.
→ To identify this disorder, an endocrinologist performs
elaborate tests to assess the release of TSH
Goitrogenic Food  ● Decrease in adipose tissue mass = lowered leptin production
● Prevents utilization of iodine
→ Contains ​goitrin​ that prevents the synthesis of thyroid
hormones via inhibition of iodination or organification
▪ Examples: ​Lithium ​(inhibits thyroid hormone synthesis),
Strawberry, Peas, Spinach, Cabbage, Cauliflower, Turnip,
Rutabaga, Peaches, Peanut, Lettuce, Broccoli, Radish
● Cassava
→ Also a goitrogenic food that contains ​Thiocyanate ​→
competes for transport of I​-​ across the basolateral membrane
of the thyroid follicle cell.
● Avocado & Coconut
→ stimulate synthesis of thyroid hormones
VI. ADIPOSE TISSUE AS AN ENDOCRINE ORGAN
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Figure 31. ​Adipose tissue as an endocrine organ
● The adipose tissue is one of the organs involved in the
maintenance of fuel or energy homeostasis
● Adipose tissue stores TAG when glucose is excessive
with intermediate insulin
● When blood glucose levels are low, glucagon degrades
TAG into glycerol and fatty acids in order to restore blood
glucose
● Plays a critical role in body-mass homeostasis
→ Releases regulatory peptide molecules called
adipose tissue-derived hormones such as:
▪​ ​Leptin, adiponectin,
​▪​ Resistin, TNF-α, IL6 = ↓ insulin action on muscle and
liver
A. SET POINT MODEL FOR MAINTAINING CONSTANT 
MASS
● Our body employs 3 mechanisms to prevent storage of excess
dietary calories:
→ Conversion of excess fat​; stored as TAG in the adipocytes
→ Oxidation of excess fuel​ by exercise
→ Diversion or wasting of fuel to heat production​ by
uncoupled mitochondria
● In mammals, hormonal and neuronal signals keep fuel intake
and energy expenditure balanced in order to hold the amount of
adipose tissue at a suitable level
→ ​Excess fuel intake, more adipose tissues obesity.
→ Excess energy expenditure malnutrition
● In the presence of excess adipose tissue, leptin is released to
inhibit food intake and fat synthesis; FA oxidation is stimulated
favors food intake and less FA oxidation
● ↑ adipose tissue mass, ↑ amount of leptin released & v.v.
● Other tissues that produce lesser amounts of leptin: placenta,
ovaries, skeletal muscles, mammary glands, bone marrow and
gastric chief cells
Figure 32. ​Set-point model for maintaining constant mass
ADIPOSITY NEGATIVE FEEDBACK
● ​Eating behavior is inhibited and energy expenditure is increased
whenever the body weight exceeds a certain value (set point)
●​ ​Inhibition is relieved when body weight drops below the set point
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 B. LEPTIN AND THE HYPOTHALAMUS
Figure 33.​ Leptin regulation
● Leptin​ is a peptide hormone of 167 amino acids, belong to the
family of adipokines
● Leptin sends signals to the brain
→ With ​enough energy reserves and increase in body weight =
decreased​ appetite
→ With ​low energy reserves and decrease in body weight =
increased​ appetite
C. HYPOTHALAMIC REGULATION OF FOOD INTAKE 
AND ENERGY EXPENDITURE
● When there are enough fat reserves in the adipocytes, leptin
binds to its receptor in the neurons of the arcuate nucleus of the
hypothalamus,leading to a reduction of fuel intake and
increased energy expenditure
● Leptin stimulates the sympathetic nervous system — increased
NE release
● Norepinephrine binds to its beta-adrenergic receptor in the
adipose tissue membrane -> stimulation of Gs protein ->
activation of adenylate cyclase -> cAMP synthesis -> stimulation
of PKA, which results to:
Increased expression of uncoupling protein I or thermogenin
in the nucleus
Uncouples oxidative phosphorylation WITH ATP
SYNTHESIS in the mitochondria
Continuous oxidation of fuel WITHOUT ATP SYNTHESIS
dissipating energy as heat and consuming dietary calories
or stored fats in potentially very large amounts
→ Activation of HSL -> degradation of TAGs in the lipid
droplets into FAs and glycerol -> B-oxidation of FAs to
produce energy -> thermogenesis
VII. HORMONES THAT CONTROL APPETITE
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Figure 34. ​Hormones that Control Appetite ​[Lecture PPT]
● Interlocking system of neuroendocrine controls of food intake
and metabolism
→ protect us from starvation
→ eliminate counterproductive accumulation of fat or obesity
● There are two types of neurosecretory cells in the arcuate
nucleus of the hypothalamus
→ Receive hormonal inputs and relay neuronal signals of the
cells of muscles, adipose tissues, and pancreas, respectively
● ↑ body fat mass → release of ​leptin from adipose and ​insulin
from pancreas
● Leptin and insulin act on:
→ Anorexigenic​ (appetite-suppressing) neurons
▪ Medial hypothalamus
▪ Trigger the release of alpha-melanocyte stimulating
hormone aka ​melanocortin​ (hunger-suppressant
hormone) → neuron sends signal to eat less and
metabolize more fuel →​ inhibits hunger
▪ Leptin
− satiety hormone
− enhances insulin sensitivity
− plays a permissive role in the resurgence of
gonadotropin releasing hormone secretion at onset of
puberty
o Leptin-deficient people fail to enter puberty
− During severe nutritional deprivation:
o Inhibit thyroid hormone synthesis
o Decrease sex hormone production
o Increase glucocorticoid synthesis
− Makes cells of liver & muscle more sensitive to insulin
− Leptin resistance – may develop in people whose
leptin receptors become overstimulated, making them
inactivated → obesity ​[Dr. Madarcos]
→ Orexigenic​ (appetite-stimulating) neurons
▪ When leptin and insulin is bound to orexigenic neuron →
inhibits the release of ​Neuropeptide Y
− Neurotransmitter in the hypothalamus and sympathetic
nervous system
− Hunger promoter
▪ Sends signal to the brain to eat more and metabolize less
fuel → ​increase appetite
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● Any stimulus that activates orexigenic cells inactivate 4. P-Tyr residues of leptin receptor bind to the ​SH (Src
anorexigenic cells → strengthening the input of stimulatory homology) 2 domain of STAT → phosphorylation of their Tyr
signals residues catalyzed by a separate activity of JAK
● Ghrelin 5. Phosphorylated STAT dimerize and moves to the nucleus →
→ Hormone from the stomach, hypothalamus bind specific DNA sequences → stimulate expression of
→ Stimulates orexigenic neurons → increase release of NPY → target genes, including gene for ​POMC
↑ appetite (proopiomelanocortin), the precursor of alpha-MSH
→ Hunger hormone 6. Leptin stimulates the release of norepinephrine in the adipose
→ Originally recognized as stimulus for growth hormone tissues
→ Major stimulus for release: ​hunger / fasting/ hypoglycemia → Norepinephrine​, through ​Beta2-adrenergic receptor
▪ Concentration peaks before eating and decreases sharply (adipose tissue), stimulates the transcription of
after a meal → shorter scale mitochondrial ​UCP (uncoupling protein I or thermogenin)
→ Inhibited by food intake, hyperglycemia, obesity gene via cAMP and PKA
→ Injection in humans → immediate sensation of hunger → Thermogenin uncouples oxidative phosphorylation with
▪ Might lead to extreme obesity, especially to those with ATP synthesis → continuous oxidation of fuels, release
Prader-Willi Syndrome whose ghrelin levels are of heat
exceptionally high → uncontrollable appetite → early → Leptin promotes consumption and catabolism of fats via
death AMP-activated protein kinase (AMPK) and
→ Inhibits insulin release and expression of proinflammatory thermogenesis
cytokines
→ Controls gastric motility Other functions / properties of Leptin
→ Influences sleep patterns ● During periods of severe nutritional deprivation, leptin:
→ Memory, anxiety-like behavioral responses → Inhibits TH synthesis → slowing basal metabolism
● PYY​3-36​ / Peptide tyrosine tyrosine → Decrease sex hormone production → preventing
→ Pancreatic peptide reproduction
→ From colon → Increases glucocorticoid synthesis → mobilize body’s
→ Response to food coming from the stomach fuel-generating sources → minimizing energy
→ Inhibit orexigenic neurons → inhibit NPY release → slower expenditure and maximizing use of endogenous reserves
suppression of hunger between meals → ↓ appetite of energy → greater survival
● Leptin makes cells of liver and muscle more sensitive to insulin
A. JAK-STAT MECHANISM OF LEPTIN SIGNAL  ● Giving leptin to leptin-deficient patient will result to weight loss
TRANSDUCTION IN THE HYPOTHALAMUS → However, obese patients have opposite effects due to
development of leptin resistance

Causes of Leptin Resistance

● Constant stimulation of leptin receptors in obese individuals →
receptor desensitization
● Leptin induces the synthesis factors that block leptin-induced
signal transduction
→ Suppressor of cytokine signaling-3 (SOCS3)
synthesized by leptin antagonizes STAT activation
→ Long term leptin stimulation lead to constant expression
of SOCS3 → diminished cellular response to leptin
● In the presence of leptin resistance, obesity develops since
anorexigenic signal is lost
→ Hyperleptinemia ensues → obesity develops along with
insulin resistance, hyperlipidemia, and a plethora of
cardiovascular disorder → development of metabolic
syndrome

Figure 35. ​JAK-STAT mechanism of Leptin action.

1. Leptin receptor dimerizes when leptin binds to the

extracellular domains of the two monomers
2. Phosphorylation of specific Tyr residues of their intracellular
domains by a soluble Janus Kinase (JAK), a tyrosine kinase
3. Phosphorylated Tyr (P-Tyr) residues become docking sites for
three proteins that are ​Signal Transducers and Activators
of Transcription (​STATs 3, 5, 6; aka fat-STATs​)

 
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 B. POSSIBLE MECHANISM FOR CROSS-TALK BETWEEN  → Exclusively synthesized and the most abundant hormone
RECEPTORS FOR INSULIN AND LEPTIN from the adipocyte
→ Adipokine that sensitizes other organs (i.e. muscle, liver) to
the effect of insulin
● Extended fasting / ​prolong starvation​ → ↓ TAG reserves in
adipose → triggers adiponectin production and release
→ Adiponectin secretion is increased as the ​adipocyte gets
smaller

RELATIONSHIPS
Inverse = adipose tissue mass : ​adiponectin
Direct = adipose tissue mass : ​leptin
● Acts through plasma membrane receptors ​(AdipoR1, AdipoR2)
→ Phosphorylates and activates ​AMPK
▪ AMPK can also be activated by exercise and low [AMP]
→ Activation of nuclear transcription factor ​Peroxisome
Proliferator Activated Receptor-α (PPAR-α) ​→ increasing
insulin sensitivity
→ Effect​:
▪ increased insulin sensitivity
▪ stimulates FA uptake and oxidation
▪ inhibits FA synthesis

Table 10. Facilitatory actions of Adiponectin

Figure 36. ​Possible mechanism for cross-talk
Activation (+)
● Leptin receptor bound to leptin → phosphorylation of several PFK2 ↑ cardiac glycolysis
Tyr residues in their intracellular domains, catalyzed by ​JAK GLUT 1, 4 ↑ glucose transport
● Phosphorylated intracellular domains of insulin and leptin Brain ↑ food intake but ↓ energy expenditure
receptors phosphorylate and activate ​insulin receptor ↑ beta-oxidation of FA
substrate-2 (IRS-2) Skeletal ↑ glucose uptake
→ Acts as integrator of the input from two receptors muscles ↑ glycolysis
● Phosphorylated IRS-2 activates PI-3K ↓ FFA and blood glucose
(phosphoinositide-3-kinase) → inhibit food intake ↑ beta-oxidation of FAs
→ Adiponectin is another adipose tissue hormone that Cardiac ↑ glucose uptake
sensitizes other organs to the effects of insulin muscles ↑ glycolysis
↓ FFA, blood glucose
C. FORMATION OF ADIPONECTIN AND ITS ACTIONS  Liver ↑ beta oxidation of FAs
THROUGH AMPK
Table 11. Inhibitory actions of Adiponectin
Inhibition ( - )
FAS 1 and
↓ FA synthesis but ↑ FA oxidation
ACC
HSL ↓ lipolysis
HMGR ↓ cholesterol synthesis
GPAT ↓ TAG synthesis
Glycogen
↓ glycogenesis
synthase
regulates protein synthesis based on nutrient
eF2
availability
mTOR
↓ protein synthesis
Pancreatic
↓ insulin secretion → inhibit gluconeogenesis
beta cell
↓ FA and cholesterol synthesis
Liver
Anti-atherogenesis effect of adiponectin
Adipose
↓ FA synthesis and lipolysis
Figure 37. ​Formation of adiponectin and its actions tissue
● Adiponectin
FAS 1 - Fatty acid synthase I
→ Peptide hormone (224 AA)
ACC - Acetyl-CoA carboxylase

 
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HSL - Hormone-sensitive lipase 5. Which of the following regulators is an inhibitor of
HMGR - HMG-CoA reductase somatostatin release?
GPAT - Acyl transferase a. TNF-β
eF2 - Eukaryotic elongation factor 2 b. Glucagon
mTOR -Mammalian target of rapamycin c. GHRH
● Adiponectin, acting via AMPK which in turn activates PPARα → d. Glucose
stimulates FA uptake and oxidation e. Gastric Inhibitory Peptide
→ Inhibits FA synthesis 6. Which of the following is NOT a characteristic of Growth
→ Sensitizing muscle and liver to insulin Hormone’s mechanism of action?
● Plasma level of adiponectin parallels with HDL level a. JAK2 phosphorylates IRS and leads to the promotion of
→ Low in people with metabolic syndrome and diabetes glucose transport
mellitus b. Activation of MAPK leads to the same effects as activation of
STAT
REVIEW QUESTIONS c. Transcription of target genes is a result of phosphorylation of
1. What is the end product of degradation of epinephrine and SHC
norepinephrine? d. Dimerized GHR recruits nuclear tyrosine kinase
a. SAM 7. Which is NOT a proper type of treatment for those
b. MOA diagnosed with gigantism?
c. VMA a. Somatostatin antagonist
d. COMT b. GH analogue
2. What is the end product of degradation of epinephrine and c. Stereotactic surgery
norepinephrine? d. Radiation therapy
a. SAM 8. True or False: as adipose tissue mass increases, leptin
b. MOA decreases
c. VMA 9. Which of the following hormone stimulates hunger as soon
d. COMT as it is administered?
3. What causes Parkinson’s disease? a. HDH (hatdog stimulating hormone)
a. low dopamine b. Adiponectin
b. high dopamine c. Gherlin
c. low epinephrine d. Leptin
d. high epinephrine
4. Which is NOT a second messenger of the ɑ-adrenergic
pathway? Answers: c, a, b, a, d, a, false, c
a. lP​3
b. PKC REFERENCES 
c. DAG [BCH]2019/03/04. ​Hormones that Regulate Fuel Metabolism.
d. Ca​2+ ​ ​ edition)
Lippincott’s Illustrated Reviews: Biochemistry (5th
Madarcos Lecture.
Madarcos’ notes
2021A 2.03 Hormonal Regulation of Metabolism Trans

 
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 APPENDIX - CLINICAL CORRELATIONS 
Appendix Table 1. Clinical Correlations

HORMONE  DISORDER  DEFICIENCY  CHARACTERISTICS  TREATMENT 

INVOLVED  / ​EXCESS 

Somatostatin Carcinoid n/a occurs secondary to carcinoid tumor (malignant Octreotide, a

Syndrome neuroendocrine tumor of the small intestine or lungs) somatostatin
analog is given

Growth Dwarfism: lack the ability to synthesize or secrete GH (pituitary GH administration

Hormone GH-deficient dwarfism) before fusion of
dwarfs growth plates

Dwarfism: lack the IGF-1 response to GH but not its metabolic

pygmies DEFICIENCY effect (deficiency is post-receptor in nature) -

Dwarfism: Increased plasma GH, but lack liver GH receptors → Biosynthetic IGF-1
Laron dwarfs levels of circulating IGF-1 (mecasermin
rinfabate) is given
before puberty to
be effective

Gigantism abnormal in height but proportionate; excess of GH Stereotactic

BEFORE epiphyseal closure surgery
EXCESS
Acromegaly Excessive GH AFTER epiphsyeal closure, sacral bone Radiation therapy
growth
Somatostatin
agonists

GH analogues

GH receptor
antagonists

Catecholamines Pheochromo Tumor of adrenal medulla Adrenaloctamy

-cytoma EXCESS
Excess catecholamine secretion Preoperative ɑ and
β-catecholamine
antagonists
Dopamine Parkinson’s Neurodegenerative disorder that affects predominantly administration of
Disease dopaminergic neurons of the substantia nigra L-DOPA

DEFICIENCY Dopamine deficiency

Shaking palsy

Cortisol Congenital Low levels of cortisol - No feedback inhibition on ACTH, administration of

Adrenal leading to adrenal hyperplasia corticosteroids;
Hyperplasia: treatment may vary
Congenital depending on the
deficiency of disorder
steroid
hydroxylases
Congenital
Adrenal No glucocorticoids,mineralocorticoids, and sex
Hyperplasia: hormones
3-𝛽HSD Deficiency

 
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 salt retention in urine; “salt wasting” (excessive
excretion of salt in urine)

female-like genitalia
Congenital decreased sex hormone and cortisol production
Adrenal
Hyperplasia: increased levels of mineralocorticoids, leading to
17-𝛼-Hydroxylase increased water and salt retention
Deficiency
female-like genitalia
Congenital DEFICIENCY most common Congenital Adrenal Hyperplasia
Adrenal
Hyperplasia: decreased production of glucocorticoids and
21-𝛼-Hydroxylase
mineralocorticoids
Deficiency

17-𝛼-hydroxyprogesterone is converted to androgens

↑ androgens = masculinization in females → Early

virilization in male

Congenital Most serious Congenital Adrenal Hyperplasia

Adrenal
Hyperplasia: Low cortisol, aldosterone, and corticosterone
11- -Hydroxylase
Deficiency Increased Deoxycorticosterone

Masculinization in females

Early virilization in males

Cushing’s EXCESS primary disorder; ACTH-independent Cortisol synthesis

Syndrome inhibitors:
Body fat​: weight gain, central obesity, “Moon Facies” medications which
help control
(accumulation of fat in the cheeks, jaw, and neck),
production of
“Buffalo Hump” (deposition of fat in the center of the
cortisol
upper back)

Skin​: facial plethora (due to thinning of skin), thin and

brittle skin, easily bruised (due to fragility of capillary
walls), broad and purple stretch marks (due to
secondary weakening of dermal connective tissue),
acne, hirsutism (excessive hairiness)

Bone​: osteopenia, osteoporosis (vertebral fractures),

decreased linear growth in children

Muscle:​ weakness, myopathy (prominent atrophy of

gluteal & upper leg muscles w/ difficulty climbing stairs
or getting up from a chair)

CVS:​ hypertension, decreased K​+​, edema,

atherosclerosis

Metabolism​: glucose intolerance, diabetes,

dyslipidemia

 
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 Reproductive System​: decreased libido, amenorrhea
(due to cortisol-mediated inhibition of gonadotropin
release)

CNS:​ irritability, emotional lability, depression, cognitive

defects, paranoid psychosis

Blood and Immune System​: increased susceptibility

to infections, increased WBC, eosinopenia,
hypercoagulation with increased risk for DVT (deep
vein thrombosis) and pulmonary embolism

Cushing’s Disease EXCESS ACTH-dependent ; secondary disorder

caused by an adenoma situated in the anterior pituitary

gland, releasing more ACTH -- leading to increased
cortisol levels

same manifestations as Cushing’s Syndrome

Addison’s Disease DEFICIENCY secondary disorder, hypofunction of adrenal cortex Administration of
glucocorticoids
decreased ACTH and cortisol levels (plus
mineralocorticoids
Tiredness, muscle weakness, diarrhea, dehydration,
postural hypotension, hyponatremia, loss of appetite,
nausea, vomiting, depression, salty-food cravings
Thyroid Hashimoto’s DEFICIENCY presence of autoimmune antibodies directed against
Hormones Thyroiditis Tgb or TPO (or both) proper iodine
supplementation
destruction of thyroid gland
hormone
goiter formation in an attempt to compensate replacement
therapy
Decreased T3 and T4, increased TSH
Cretinism congenital absence of thyroid hormone in infants

absence of thyroid gland and presence of only a

rudimentary gland or inability of the thyroid to produce
thyroxine

flat nose and face, macroglossia, yellow/dry/coarse

skin, feeding difficulties, constipation, stunted growth,
umbilical hernia secondary to weakness

if untreated, can lead to severe physical and mental

retardation, stunting of growth or severe dwarfism
Endemic Goiter Thyroid hypertrophy secondary to insufficient dietary
iodine

low T3 and T4, high TSH

 
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 Myxedema Atrophy of gland, surgical removal or irradiation

Hypometabolic state - fatigue, muscle weakness,

decreased BMR, cardiac degeneration

mental retardation

low pitch, hoarse voice

skin manifestations

inability to bear children (for some women with

myxedema)
Grave’s Disease EXCESS goiter, hyperthyroidism, exophthalmopathy, periorbital Administration of
edema, chemosis, proptosis Anti-thyroid drugs
increased T3, T4, and TSH; presence of TSH receptor or Radioactive
Iodide
antibodies

Toxic Multinodular EXCESS enlarged thyroid gland containing small rounded Administration of
Hyperthyroidism masses called nodules, does not respond to pituitary Anti-thyroid drugs
regulation via TSH or Radioactive
Iodide
increased independent synthesis of TH

Hyperthyroid state, less exopthalmos, and Goiters;

often seen in elderly

 
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