Endocrinology

Magutah (PhD)
9/29/2023 1
 General Introduction
• 2 parallel systems ‘act together’ controlling all physiologic
processes.
• Both generally coordinated from hypothalamus.
– The nervous system
• Fast point-to-point control in an electrical nature.
• Neuronal endocrine function.
– The endocrine system
• Involves hormones, their receptors and the intracellular
signaling pathways they invoke.
• ‘Broadcast’ of hormonal messages - ‘Receptor’ concept –
cell response.
• Hormone: Chemical sub. released into blood from ductless
gland (as opposed to enzymes) & having effects outside the
2
tissue that made it.
 General Introduction
— Neural vs endocrine systems:
§ Each can receive its systemic input and give out the other
systems’ effects:
o Adrenal medulla’s neural stimulation and endocrine output.
- Epinephrine in sympathetic stimulation.
o Endocrine (feedback) stimulation of posterior pituitary and
neurohormone release.
- Osmoreceptors stimulation following in ECF osmolarity
- Vasopressin from supraoptic neuronal tracts.
— Most neurotransmitters (catecholamines, vasopressin…)
are basically hormones released thro’ synaptic jxns or
directly by cells. 3
 General Introduction- principles
• All physiologic and pathophysiologic events influenced by
the endocrine milieu.
– No cell types, organs or processes that are not influenced by
hormone signaling.
• All "large" physiologic effects mediated by multiple
hormones acting in concert.
– Normal growth dependent on GHs, but thyroid hormones,
ILGF-1 & glucocorticoids also critically involved.
• Hormones vs Factors.
– Those identified and whose formulas are known are
hormones ; those not yet are factors .
• ILGF now somatomedin
4
1. Classical endocrine glands 2. ‘Diffuse Endocrine System’
• Other body cells secreting hormones.
– Atrial & ventricular myocytes - ANP &
BNP
– Parathyroid, enteric brain, renal, and
placenta produce significant
hormones
– If ‘hormone’ defined broadly to
include all secreted chemical
messengers, then virtually all cells
part of endocrine system;
• Malignant cells also.

– Bronchocarcinoma cells produce

long acting TSH.
5
 Hierarchy of the Endocrine System
**Hypothalamus PINEAL BODY

*Pituitary
Thyroid

Pancreas

Adrenal
/Renal

Gastro-Intestinal
(Enteric)

Gonads

Local Hormones / Others

 Chemical composition of hormones
• Amine hormones.
– Tyrosine derivatives
– Thyroid, adrenal medullary.
• Protein/polypeptides
– Stored in vesicles until
needed.
– All pituitary, pancreas &
parathyroid
• Steroids
– Not stored
– Derived from cholesterol
– Adrenal cortical & sex
hormones).
• Local hormones
– Amine based histamine,
serotonin
– lipid hormones 7
Sources of hormones prostaglandins
8
 Transport of hormones
• Protective mechanisms necessary – in blood/ECF
– To prolong hormone ‘life’.
– To ensure no action until ‘target’ site reached (covered hormone active
sites)
– To ensure steroid hormones become soluble in plasma (H₂O) medium
– To prevent excess uptake by first cells encountered (uniformity in
distribution) - crucial in T3 binding
• For these reasons;
– Hormones bound to proteins
– Hormones (insulin, PTH…) synthesized as pre/prohormones.
• Large polypeptides initially cover active sites until packaged/ reach
target sites
– Some hormones initially packaged in vesicles
– There are specific enzymes in target cells that ensure hormonal
metabolism only where needed.- leptin receptor:- JAK2-STAT pathway. 9
 Autocrine, Paracrine & Endocrine hormonal fxn
• Autocrine hormonal
functioning
– Act on/in same cell
produced.

• Paracrine
functioning
– Act on other target
cells in vicinity
without entering
circulation

• Endocrine hormonal
functioning
– Target cells thro’
circulation
Hormonal and neurotransmitter actions, and their interrelationships 10
 Hormone Actions: Control of cell function
1. Agonists
Have similar effects . e.g. (PTH vs 1,25-(OH)2D3 - in GIT Ca2+ absorption;
Thyroid hormones vs GH)
2. Antagonists
Have opposing effects. e.g.(glucagon vs insulin; PTH vs calcitonin)
3. Permissive role
One hormone allows another to have its full effects. e.g. (thyroid
hormones vs glucocorticoids; insulin vs prolactin, ovarian vs cortisol on
mammary glands, Calcitriol vs GH, etc, devt.)
• Synergistic effects: Combined effects > than sum of individual effects e.g.
(thyroid & glucocorticoid hormones on growth, insulin & FSH in granulosa
cell differentiation, epinephrine & glucagon on raising plasma glucose)
• Trop(h)ic effects: Hormone stimulate dev’t of other gland / its secretions.
• Hypothalamic & anterior pituitary hormones 11
 Hormone Actions: Physiologic examples
Action Examples of hormones involved

Developmental effects Prolactin

Immunologic function Cortisol (anti-inflammatory effects)
CNS Effects Adrenal medulla hormones (e.g. Epineph)

Metabolism Cortisol, insulin/glucagon, thyroxine, T3.

CVS and Renal fxn Vasopressin, ANP, Renin, BNP

Stimulation (for synthesis) All anterior pituitary hormones,
Ionic &osmotic regulation 1,25-Dihydroxycholecalciferol

Cell growth & Cancer Growth hormones, FSH

Skeletal Function Calcitonin, PTH
GIT functions Gastrin, Secretin
Reproductive Function Testosterone, estrogen, progesterone12
Hormone actions: intracellular receptors & mechanisms

For Steroid & Thyroid (Amine) hormones

1. Cytoplasmic & nuclear hormone-
receptor complex triggers activation
of particular gene (on nuclear DNA)
2. mRNA transcribed
3. Translation and protein formation
13
4. Protein causes the hormonal effect.
 Hormone actions: cell-surface receptors – cAMP 2nd messenger systems

For peptide/protein (mostly pituitary) hormones

Adenyl cyclase - cAMP system
1. cAMP production stimulated or inhibited by G
prot. when bound.
2. Hormone-receptor binding activates G prot.
3. Activated G prot. in turn activates enzyme
adenyl cyclase
4. Adenyl cyclase causes ATP to lose two P,
becoming cAMP
5. cAMP activates protein kinase enzymes that
activate other proteins/enzymes, producing the
hormonal effect

14
Hormone actions: cell-surface receptors – Ca2+-calmodulin 2nd messenger systems

• Hormone binds its specific receptor in plasma memb’,

opening Ca2+ channels
• Intracellular Ca2+ bind with the protein calmodulin.
• Calmodulin changes its shape activating protein kinases.
• Activation of calmodulin-dependent protein kinases causes,
via phosphorylation, activation/inhibition of proteins
involved in the cell’s response to the hormone. e.g.
• Calmodulin’s activation of myosin kinase, which acts directly on
the myosin of smooth mm to cause contraction.

• Ca2+-calmodulin complex activates/inactivates an enzyme,

producing the hormonal effects. 15
Hormone actions: cell-surface receptors - phospholipids 2nd messenger system.
• Utilized by most hypothalamic
‘release’ hormones (except CRH).
• Hormones activate transmembrane
receptors activating phospholipase C.
• Enzyme catalyzes breakdown of
membrane phospholipids
(phosphatidylinositol biphosphate
(PIP2)), into IP3 & DAG.
• IP3 mobilizes Ca2+ from mitochondria
and ER. (Ca2+ 2nd messenger fxns of
mm contraction & cell secretion ∆s).
• DAG activates enzyme protein kinase
C (PKC), which phosphorylates some
proteins, leading to the cell’s
response.
16
Regulation of endocrine function: 2 major types of control
• Feedback control by plasma
hormone levels from
peripheral glands
– -ve feedback (most)

– +ve feedback (prolactin)

• Free standing glands:

regulation through effect
– Parathyroid’s PTH stimulate
target tissue to produce
effect - rise in plasma ca++ -
modifies fxn of gland
17
Feedback loops
18
Feedback loops. A, Endocrine feedback loops involving the hypothalamus–pituitary gland and end organs, in this example, the
thyroid gland (endocrine regulation). B, General model for control and negative feedback to hypothalamic–pituitary target organ
systems. Negative-feedback regulation is possible at 3 levels: target organ (ultrashort), anterior pituitary (short), and hypothalamus
(long). (From McCance KL, Huether SE: Pathophysiology: The biological basis for disease in adults and children, ed 5, St Louis, 2006, Mosby)
 Role of Hypothalamus

‘Conductor of the orchestra of Neuro-endocrine band.’

20
 The Hypothalamohypophysial Axis/tract

(Mamillary body)

(Optic Chiasm)
Neurons
Hypothalamohypophysial
portal vessels

(Anterior lobe) Neurohypophysis

Adenohypophysis

Hormones
21
22
Hypothalamic Hormones Controlling Anterior Pituitary Secretions
Hormone Structure Target Primary Action on
(Hypophysiotropic) Anterior Pituitary

TRH Peptide of 3 AA Thyrotropes Stimulates

secretion of TSH

GnRH Single chain of Gonadotropes Stimulates FSH &

(previously LHRH) 10 AA LH secretion

CRH Single chain of Corticotropes Stimulates

41 AA secretion of ACTH

GHRH Single chain of Somatotropes Stimulates

44 AA secretion of GH
GHIH/Somatostatin Single chain of Somatotropes Inhibits secretion
14 AA of GH
Prolactin-inhibiting Dopamine (a Lactotropes Inhibits secretion
hormone (PIH) catecholamine) of prolactin
23
**Hypothalamic TRH and VIP known to stimulate Prolactin secretion
Pituitary Hormones

Essential to life

24
 Pituitary Hormones
Anterior Pituitary hormones • Intermediate Lobe Hormones
– POMC hydrolyzed to:
1. CLIP (Corticotropin-like
intermediate-lobe peptide)

2. γ-LPH,

3. β-endorphin
ACTH, β-LPH, β-endorphin

• Posterior Pituitary Hormones

– Strictly speaking ‘hypothalamic’

– ADH (5/6th Supraoptic nuclei)

– Oxytocin (5/6th Paraventricular)

25
 Characteristics of Anterior Pituitary hormones
Hormones Secreting Cell % of Total Stain Molecular t1/2 Amino
Type Secretory Affinity weight min Acids in
Cells hormone

GH: it doesn't, Somatotrope 50 Acidophilic 22000 20-50 (6- 50% 191

unlike the other 20 in bound
5, exert its effects circulation)
by stimulating
target glands.
Prolactin Lactotrope 10-30 Acidophilic 22000 20-50 198
ACTh, Corticotrope 10 Basophilic 4500, 30-50 39,91,31
β-LPH, (hydrolyze 11200,
β-Endorphin POMC to yield 4000
the 3)

All have 2
TSH Thyrotrope 5 Basophilic 28000 50-60 subunits: α89, β112
Glycoproteins

Identical α &
FSH, LH Gonadotrope 20 Basophilic Both 50-60 differing β Both
29000 which confer α89, β115
biological
Carbohydrates increase potency by slowing their metabolism specificity.
26
 Growth hormone
Mainly by 2 genes: - hGH-N (for normal) – 75% of circulating hGH (22k hGH); and
hGH-V (for variant), codes for the variant (20 k hGH)

• Utilizes a 620-AA receptor, a member of cytokine receptor superfamily.

• Has two receptor-binding sites: when it binds to one of the receptor subunits,
the other binding site attracts another subunit, producing a homodimer

• Activates JAK2-STAT pathway.

– JAK2 a member of the Janus family of cytoplasmic tyrosine kinases.

– STATs (signal transducers and activators of transcription) a family of inactive

cytoplasmic transcription factors that upon phosphorylation by JAK kinases migrate
to nucleus and activate various genes.

• Effects on growth (mainly) depend on interaction/subsequent release of ILGF I

(somatomedin c), which has much longer half-time (20hrs)

27
 GH effects
• Linear growth in young bones’ epiphyses (also promote cartilage growth).
• protein deposition by chondrocytic and osteogenic cells hence growth
• rate of reproduction of these cells, especially osteoblasts.
• Enhances conversion of chondrocytes into osteogenic cells - causing
deposition of new bone.
• size of most viscera
• protein synthesis ( transcription rate), +ve nitrogen & phosphorus
balance. (Anabolic action)
• catabolism of proteins and AA.
• plasma AA levels (enhanced transport through cell memb).
• hepatic glucose output and circulating FFA (insulin resistance) levels

Diabetogenic
• Has anti-insulin effects (tho’ dependent on insulin); use of
carbohydrates
• Is Ketogenic, facilitating acetoacetic acid accumulation 28
 GH effects
• body fat content & cholesterol (lipolysis) – enhances use of fats for
energy

• Na+ and K+ excretion.

• pancreatic β-cells response to insulinogenic stimuli.

• Interaction with ILGF (Somatomedins)

• It increases GIT absorption of Ca++

• Increases metabolic rate.

• Has intrinsic lactogenic effect.

• Stimulates synthesis of soluble collagen.

29
 Secretion of GH
• Decreases
Stimulate secretionslowly
Inhibit
withsecretion
ageblood
Decreased Increased blood
glucose glucose
• Secreted in a pulsatile
Ghrelin ILGF1
manner, affected by:
Exercise Obesity
GHRH GHIH (somatostatin)
Trauma/stress/excitemen ILGFs
t (Somatomedins)

Decreased blood FFA Increased FFA

ACTH, ADH, Estrogen, Exogenous GH
Testosterone.
Starvation/fasting, Aging
Rythmicity in GH secretion Protein deficiency
Deep sleep (stages II&IV) Glucocorticoids
i.e in deprived REM 30
 Vasopressin regulation
Increase ADH Decrease ADH
Plasma osmolality Plasma osmolality

Blood volume Blood volume

Blood pressure Blood pressure

Drugs: Morphine, Nicotine Drugs: Alcohol, Haloperidol (dopamine

blocker), Clonidine (antihypertensive)

Hypoxia
Nausea
31
 Posterior pituitary (‘neural’)hormones
• Vasopressin
– From supraoptic terminal nn endings
a) Increase thirstfulness
b) Increased renal - water reabsorption
c) Vasoconstriction Antidiuretic effects

d) Causes glycogenolysis in the Liver

e) A neurotransmitter
Secretion osmotically (concentration) regulated.
• Oxytocin
– From Paraventricular nuclei tracts
a) Smooth mm contraction in:
i. Breasts (myoepithelial cells) hence milk ejection
ii. Uterus during labour
iii. Non-pregnant uterus facilitating sperm ‘swim’
iv. Vas deferens at ejaculation
32
Positive feedback control.
Thyroid Hormones

33
 Thyroid Hormones: Formation
Na+/I-
Iodide oxidized back
symporter to iodine

(Glycoprotein)

**Iodotyrosine deiodinases
inhibition produce a rise in
plasma RT3 and a fall in T3 Iodine bound to tyrosine AA at apical
membrane, couples TG and “stored”
23% 33%

7%

35%
In Lysosomes:
<2% RT3 Break peptide
bonds Lumen of follicle - contains colloid
34
 Thyroid Hormones: Secretion

µg (<7% of µg (93% µg
total thyroid of release)
release)

33% 45%
(87%) µg µg
22%

Most T3 & RT3 formed fro’ Much more produced from T4 (at
T4 de-iodination in tissues T3 expense)-
i. in fetal life (adult ratio
attained wk 6 after birth)
ii. During fasting (conserve
calories & proteins)
*overfeeding reverses this,
increasing T3 & reducing 35 RT .
3
 Thyroid hormones: Protein binding in normal adults
Protein involved Plasma T4 (99.98%) T3 (99.8%)
Conc. bound (in lesser binding
(mg/dL) circulation) correlates to
shorter t 1/2

Thyroxine-binding globulin 2 67 46 TBG Elevated by:

Estrogen RX, Pregnancy
(TBG) TBG Lowered by:
Androgens, Anticancer
drugs, Glucocoticoids.

Transthyretin (thyroxine - 15 20 1

binding prealbumin, TBPA)

Albumin 3500 13 53

Attributes
Half life 6-7days 1 day

Action on tissues slow Rapid:

[T3 is less tightly bound to plasma prots
36
but binds more avidly to RXR receptors]
 Thyroid hormones: Effects of various conditions
Binding Total Free Plasma Clinical
Condition Proteins Plasma Plasma TSH State
conc. T4, T3, RT3 T4, T3, RT3
Hyperthyroidism Normal High High Low Hyperthyroid

Hypothyroidism Normal Low Low High Hypothyroid

Estrogen Rx, heroin, High High Normal Normal Euthyroid

major tranquilizers.
(antipsychotics) e.g.
Phenothiazines

Pregnancy High High Normal Normal Euthyroid

Glucocorticoids, Low Low Normal Normal Euthyroid

androgens,
Danazol (Rx endometriosis)
araginase.
37
Thyroid hormones: activation of target cells

T4 & T3 diffuse thro’ cell &

nuclear membs.
Action/effects Interaction thro’ RXR either
or transcription &
translation, thus action.
38
Thyroid Hormones: Slow onset but Long Duration of Action

Latency due to:

1. High percentage bound
2. Manner of performance (process
of proteins formation)

• Following high T4 dose, there is essentially no effect on BMR up to 3 days

• Once activity begins, it increases progressively peaking in 10-12 days
• Activity may persist up to 8 wks (slow metabolism/breakdown: T4 t1/2 = 6-7 days)
39
 Thyroid Hormones: Effects
Target Tissue Effect Mechanism

Heart Chronotropic number and affinity of β-adrenergic receptors.

Inotropic Enhance responses to circulating catecholamines.
α myosin heavy chain (with higher ATPase activity)
Adipose tissue Catabolic Stimulate lipolysis.
Muscle Catabolic protein breakdown (& consequent weight loss).
Bone Dev’tl Promote normal growth and skeletal dev’t (protein synthesis).
Nervous system Dev’tl Promote normal brain dev’t (protein synthesis).
catecholamines responsiveness ( activation of RAS – difficult sleeping)
Gut Metabolic rate of monosaccharides absorption & metabolism.
Renal GFR
Resp. 2,3DPG (hence increasing O2 dissociation from Hgb)
Lipoprotein Metabolic Stimulate LDL receptors formation (liver), lowering plasma cholesterol levels.
All other tissues Calorigenic o2 consumption by metabolically active tissues ( activity/secretions)
(& glands) (exceptions: testes, uterus, lymph nodes, spleen, anterior pituitary).
Mitochondria, BMR, Gluconeogenesis, glycogenolysis, lipolysis
Na+-K+ ATPase (in virtually all tissues)
40
 Thyroid hormones: Regulation of secretion
Feedback control
Other control ‘mechanisms’

• Thro’ glandular tissue growth effect of TSH-

mediated cAMP, ( T3&T4 secretion)

• Hypothalamus’ exposure to cold TRH

/ Thyrotropin secretion
(t1/2= 60 min)
• Stress TRH secretion

• Dopamine, Somatostatin & Glucocorticoids

TSH secretion at pituitary level

• Antithyroid subs (e.g. Thiocynates - inhibit

TSH effects on thyroid-
• proteolysis of the thyroglobulin. iodine trapping) suppress thyroid secretion
• iodide pump activity.
• iodination of tyrosine. • High iodide conc.s thyroid activity & size (1.
• size & secretions of thyrocytes. colloid depletion due to ‘oversecretion’, or 2. reduced
• number of thyroid cells. TSH trophic effects on thyroid following feedback loop)
41
42
Hormones Involved in Calcium & Phosphate
Metabolism

1,25 Dihydroxycholecalciferol, Parathyroid &

Calcitonin hormones
43
Calcium

• Total body calcium in young adult male: - 1100 g (27.5 mol)

• ECF calcium regulated very precisely at ≈ 9.4 mg/dl (2.4 mmol/L), . The ionic
(diffusible) form (important for body ca++ fxns) is 1.2mmol/L in ECF
– Roles in contraction of mm; blood clotting; nn transmission,…

• Excitable cells very sensitive to ∆s in ca++ concs, (e.g hypercalcemia causes

nervous system depression, hypocalcemia making it more excited)

Phosphorus

• Total body phosphorus 500-800 g (16.1-25.8 mol), also closely regulated.

• Absorption linearly proportionate to dietary intake (Calcium’s adaptational)

• 1/3 (4mg/dl) of the total in plasma is inorganic pi, the impt. form.

• Found in bones; ATP; proteins; 2,3,DPG; cAMP, etc

• Amount entering bones ≈ 3 mg (97 µmol)/kg/d. (An equal amount reabsorbed)

44
Calcium exchange between different compartments

1% of total body Ca2+

1000

Promoted by Vit D
98.9%

0.1%

45
 1,25(OH)2D3: formation & role in calcium regulation
[or ingested]
- From 7-dehydrocholesterol by sunlight action

(25-OHD3)

requires PTH
calcidiol

Conversion
Produced in the
body, transported in
blood and has
actions in target cells (1,25-(OH)2D3
hence a ‘hormone’
or calcitriol)

46
 1,25(OH)2D3: Actions
• Increase calcium absorption in GIT.

• Increase Pi absorption in GIT.

• Increase calcium reabsorption in the kidneys.

• Increase osteoblastic activity.

• Stimulated osteoblasts secondarily increase osteoclastic activity (express

RANK ligand, and bind to monocyte receptors hence conversion to osteocytes)
– Extreme calcitriol quantities causes bone absorption

• Facilitate normal calcification of matrix (small quantities).

• Stimulate differentiation of immune cells and keratinocytes in skin.

• Regulates growth and production of growth factors (Permissive role to GH)

• Facilitates formation of the less active 24,25-Dihydroxycholecalciferol.47

 1,25(OH)2D3: feedback control of its formation
High Ca++ (circulation) inhibits PTH,
thereby inhibiting 1,25(OH)2D3

High PTH levels facilitate

1,25(OH)2D3 formation High levels
inhibit PTH

High phosphate levels

inhibit 1,25(OH)2D3

Note: Enhanced prod’n when PTH , when Ca++ & PO43- , and also when prolactin
48
 PTH
• Essential for life

• An 84 AA hormone secreted by chief cells and with a t1/2 ≈ 10 min.

• Regulation of secretion:-
– Direct -ve feedback loop from circulating

Ca2+ effect on parathyroid gland (reduced

by increasing Ca2+ levels) – see fig.

– Increased by increasing phosphate levels

(high phosphate lowers plasma Ca2+ and

inhibits 1,25(OH)2D3 formation)

– Decreased by high levels of 1,25(OH)2D3. Relation between plasma Ca2+ conc. and PTH
response in humans.
– Magnesium a requirement for secretion.
49
 PTH: effects
Effects of PTH infusion
• Increases 1,25(OH)2D3

• Increases ca2+ & phosphate absorption

from GIT mainly by 1,25-(OH)2D3

• Increases ca2+ & phosphate absorption

from bones (mobilizes and activates
osteoclasts)

• Increases ca2+ reabsorption (DT).

• Inhibits Pi reabsorption (PT) - (overrides

absorption from bones & GIT)

• **Anabolic when mildly elevated for a long

time-scale (stimulates more osteoblastic
than osteoclastic activity, and also
increases calcitriol (permissive role to GH))
 Calcitonin
• A 32 AA hormone produced by • Secretion stimulators:
– Increased plasma Ca++ conc.
parafollicular/ ‘c’ cells of thyroid – Gastrin
gland. – Estrogens
– CCK
• t1/2 <10 min
– Dopamine
• A ca++ lowering hormone (effect – β adrenergic agonists
– Secretin
greater in children than adults; -
– Pernicious anaemia
bone remodeling is greater, and the – Zollinger-Ellison disease
counter effect by PTH is reduced) • Actions
– Lowering plasma Ca++ by:-
• Secretion only after calcium
• Directly inhibits bone resorption by
levels rise >9.5mg/dl, (and rises
inhibiting osteoclasts
proportionately). • Ca++ (& phosphate) excretion in urine
51
• Inhibits Ca++ absorption from the GIT
Adrenal cortex (essential hormones) &
medulla (catecholamines) hormones

52
 Adrenal glands’ secretions

[10.8-15% of total adrenal mass]

(Mineralocorticoid) – Controlled by circulating Angiotensin II & K+

[50-54%] Glucocorticoid Largely controlled by

hypothalamic-pituitary
Sex steroid axis via ACTH.
[7-7.2%]
[10-28% of total adrenal mass]

90% of the cells secrete epinephrine, 10% norepinephrine.

53
 Adrenal medulla ‘hormones’
• Epinephrine, norepinephrine and dopamine, all with t1/2 2 mins
• Nor & epinephrine stored in granules with ATP in medulla.
• In plasma, 95% of dopamine and 70% of nor. & epineph. are conjugated to
sulfates.
• Excreted in urine mainly in conjugated forms or after methoxylation and
oxidation to Vanillylmandelic acid (VMA)
• Nor & epinephrine effects:
– Both alertness (epinephrine also evokes anxiety & fear) [secretion
reduced in sleep]
– Both BMR
– Both cause glycogenolysis
– Both Insulin & glucagon secretion via β-adrenergic mxms; inhibiting
the same via α.
– Both force and rate of heart contraction
– Norepinephrine produces vasoconstriction via α1 receptors
– Epinephrine vasodilates (skeletal mm) via β2 receptors; vasoconstricts
elsewhere. 54
 Adrenal cortex hormones (Mineralocorticoids)
• All derivatives of cholesterol

• Aldosterone (t 1/2 20 mins)

– By Zona glomerulosa’s aldosterone synthase activity

– absorption of Na+ and simultaneously secretion of K+ (CT

principle cells)

– Deficiency causes death in as few as 3 days, (K+ accumulation and

Na+ (& Chloride) depletion)

– Accounts 90% of all mineralocorticoid activity (rest by

corticosterone, cortisol, …)
55
Adrenal cortex hormones: Aldosterone effects
Effects of its infusion on arterial pressure
Other effects
1. In excess causes hypokalemia
and mm weakness; deficiency-
hyperkalemia and cardiac
toxicity
2. In excess causes collecting
tubules (intercalated cells) H+
loss (alkalosis)
3. reabsorption of NACL and
secretion of K+ by sweat gland
ducts.

56
Aldosterone: feedback control of secretion
Renin-angiotensin system (& feedback)
Others.
– Rising K+ in ECF
increase secretion
– Secretion increased
(to a lesser degree
tho’) by:
• Administration of
enormous ACTH
amounts,
• hemorrhage,
• surgery,
• Trauma,
• standing
57
 Adrenal cortex hormones (glucocorticoids)
• Cortisol responsible for 95% of glucocorticoid activity
• Levels enhanced in sleep deprivation
• t1/2 60-90 mins [bound to transcortin (corticosteroid-binding globulin -
CBG)]
– Estrogen increases liver’s CBG synthesis, hence cortisol binding
• Cortisol effects:
– Increased gluconeogenesis (protein catabolism) and glycogenesis
Diabetogenic [”adrenal diabetes”]
– Decreases glucose utilization by cells
– Increases liver and plasma prots. (quest to enhance ‘replacement’ of
catabolised proteins elsewhere)
– Mobilization of fatty acids from adipose tissue
– Necessary (permissive) for glucagon & catecholamines to exert
calorigenic effects.
– Necessary for catecholamines’ lipolytic, pressor, bronchodilation &
vascular effects.
– Raise GFR (to excrete osmotically active products of catabolism) 58
 Adrenal cortex hormones (glucocorticoids)
• Cortisol effects: (ctd)
– Impt. in maturation of lung surfactant near term.
– total WBC count, RBC and platelets
– eosinophils, Basophils and lymphocytes (suppress immune system) in
blood
– Levels in stress: necessary for FFA mobilization (emergency energy
supply)
– Stabilizes lysosomes thereby preventing development of inflammation
– Causes resolution of established inflammation
– capillary permeability
– both migration of WBC into inflamed area and phagocytosis of
damaged cells.
– Attenuates fever by reducing release of IL-1 from WBCs
– Bone demineralization when in excess
– Accelerates basic EEG rhythms when in excess hence mental aberrations
(insomnia, euphoria, increased appetite, …) 59
Glucocorticoids: feedback control of secretion
Sum of converging
neural stimuli increase
ACTH secetion

Stimulation causes
Excites
sleep; ?reason ACTH Stress
secretory rhythm in
favor of day-time

Relieves

Free
[0.5 µg/dL (3.7%)]. Gluconeogenesis
The rest IS bound Protein & fat mobilization
(13 µg/dl) to CBG Lysosomes stabilization

60
 Adrenal cortex hormones: (Sex steroid)
• Adrenal androgens (mainly dehydroepiandrosterone which has <20%
of testes’ testosterone activity) continually secreted especially during
fetal life
– Exert masculinizing effects (adolescent)
• After conversion to testosterone in extra-adrenal (mainly in fatty)
tissue.
– Promote protein anabolism
– Promote growth
– growth of pubic and axillary hair in the female.
– In prepubertal boys, excess levels cause precocious pseudopuberty; in
females, female pseudohermaphroditism and androgenital syndrome
• Secretion controlled acutely by ACTH (gonadotropins have no role here)
• Progesterone and estrogens (mainly from androgens, forming a
source of estrogens in men and postmenopausal women) secreted in
61
minute quantities.
Pancreatic ‘hormones’

62
 Pancreatic ‘hormones’

• Insulin function as feedback control systems for maintaining a

normal blood glucose conc.
• Glucagon

• Somatostatin- by δ cells. - Hormonal inhibitions; check

cancer growth; slows GIT functions

• Amylin- by β cells. - Satiety agent; inhibition of glucagon;

delay of gastric emptying

• Pancreatic polypeptide – by F (also γ) cells – regulates

(slows) pancreatic secretions – enzymes and fluids
63
 Insulin
• By β cells (Centrally located in islet & make ????60-75% of its cells)
• A 51 AA polypeptide of 2 chains linked by disulfide bridges; MW 5808
• Synthesized as part of a larger preprohormone; - preproinsulin
• t1/2 5mins.
• Glucose transported in to and out of cells (basolateral memb) via:
– Secondary active transport (Na+-glucose co-transport) – SGLT
– Facilitated transport (GLUT)
• Only GLUT 4 stimulated by insulin. Expressed in skeletal & cardiac
mm, & adipose tissue (FAs synthesis from glucose, and storage)
• When insulin receptors activated, cytoplasmic vesicles (GLUT 4
pools) move to and fuse cell memb., inserting transporters.
– All other GLUTs ‘stay’ in the cell memb. 64
 Insulin: activation of target cells & resultant effects
to AA, K+, Po43- also (now)
Memb. more permeable

A tetramer of
glycoprotein
Binding triggers autophosphorylation subunits
of β subunits on tyrosine residues

65
 Insulin: actions
• Rapid (seconds):
– Increased transport of glucose, amino acids, and K+ into insulin-
sensitive cells
• Intermediate (minutes):
– Stimulation of protein synthesis
– Inhibition of protein catabolism (inhibits gluconeogenesis)
– Activation of glycolytic enzymes and glycogen synthase
– Inhibition of phosphorylase and gluconeogenic enzymes
– Promotion of lipogenesis (glycolytic enzymes enhances entry into TCA
cycle) hence glucose conversion into FAs.
• Decreased utilization of fats
• Delayed (hours)
– Increase in mRNAs in cells and enzymes, and therefore increased cell
growth
Net effect is storage of carbohydrates, proteins and fats, hence anabolic.
Insulin: dramatic growth caused by synergistic
effects of GH and Insulin

67
 Insulin: factors regulating secretion
Stimulators Inhibitors
• Glucose (Fasting blood levels >90- • Somatostatin
100mg/100ml). • 2-Deoxyglucose,
• Mannose, AA, FFA, Ach, β-Keto acids. • Mannoheptulose
• α-Adrenergic stimulators
• Intestinal hormones (GIP, Gastrin, (norepinephrine, epinephrine)
Secretin, CCK) • β-Adrenergic blockers
• Glucagon, GH, Cortisol, Epinephrine (β- (propranolol)
Adrenergic stimulation) • Thiazide diuretics
• K+ depletion
• Insulin resistance; obesity.
• Phenytoin (anticonvulsant),
• cAMP • Alloxan
• β-Adrenergic stimulators, Theophylline, • Microtubule inhibitors
Sulfonylureas (sulfonylureas bind ATP- • Insulin
sensitive K+ channels blocking their activity. • Leptin
Depolarized effect triggers insulin secretion) • Fasting 68

• Decreased blood glucose

 Glucagon (‘hyperglycemic hormone’)
• By α cells (surround β cells and make 20% of islet cells).
• A catabolic hormone, mobilizing glucose, FAs and AA from stores.
• A 29 AA linear polypeptide, MW 3485
• Also produced in the brain and GIT
• Functions:
– Glycogenolysis
In the liver, enhancing glucose availability elsewhere
– Gluconeogenesis
– Activates adipose cell lipase, making increased quantities of FAs
available to the energy systems of the body.
– Inhibits storage of triglycerides (prevents the liver from removing
FAs from blood)
– In high concs, enhances cardiac strength, increases blood flow in
kidneys, enhances bile secretion, and inhibits HCL secretion. 69
 Glucagon: regulation of secretion
Stimulators Inhibitors
• AA (e.g after a protein meal) • Glucose
• CCK, Gastrin (increased after a • Somatostatin
protein meal) • Secretin
• Cortisol • FFA
• Exercise (increases circulating AA) • Ketones
• Infections and other stresses • Insulin
• β-Adrenergic stimulators • Phenytoin
• Theophylline • α-Adrenergic stimulators
• Acetylcholine • GABA
70
Kidney’s endocrine functions:-

Three hormones
71
 1. 1,25-dihydroxycholecalciferol √
2. Renin (juxtaglomerular cells)
– A glycoprotein synthesized as preprohormone but most converted
to renin in kidneys, rest secreted as prohormone prorenin
– t1/2 ≤ 80 min
Secretion increased by Secretion Inhibited by
Prostaglandins Angiotensin II
Catecholamines Vasopressin,
sympathetic discharge of renal nn. afferent arteriolar
pressure

CVP (Na+ depletion, diuretics, hypotension, Na+ & Cl- reabsorption

upright posture, hemorrhage, dehydration,
renal aa constriction). 72
– Renin splits angiotensin I (inactive) from
angiotensinogen (synthesised in liver)
• Angiotensinogen synthesis enhanced by Glucocorticoids,
Estrogens, T3 & T4, Angiotensin II
– Angiotensin I split by ACE to form Angiotensin II mainly
in endothelial cells in lungs.
• Produces arteriolar constriction
• Increases secretion of Aldosterone (but mainly a reserve of
Angio III)
• Facilitates Nor-epinephrine release
• Directly increases renal Na+ reabsorption
• Decreases (brain) Baroreflex, potentiating its own pressor
effect
• Increase thirstfulness
• Increases Vasopressin and ACTH secretion 73
Renin-angiotensin-aldosterone system components

74
3. Erythropoietin.
– A 165 AA glycoprotein, 85% produced in kidneys, 15% in
liver (adults); [in neonates and fetuses, major site is liver].
– Increases number of erythropoietin sensitive committed
stem cells that are converted to RBC precursors
– Inactivated in the liver
– t1/2 5hrs
– Secretion stimulated by Hypoxia (usually), cobalt salts and
androgens
– Secretion facilitated by high altitude alkalosis and
catecholamines.

75