Mechanisms of endocrine disease

• Endocrine disorders result from hormone

deficiency, hormone excess or hormone
resistance
• Almost without exception, hormone
deficiency causes disease
– One notable exception is calcitonin

deficiency

1
Cellular Mechanisms of Hormone Action
• Target cell – recognize, bind and

initiate
• Up – regulation

• Down – regulation

• Hormone effects
– Direct – stimulation

– Permissive – facilitates maximum

response/function
2
3
 Mechanisms of endocrine disease

• Deficiency usually is due to destructive

process occurring at gland in which hormone
is produced—infection, infarction, physical
compression by tumor growth, autoimmune
attack

Type I Diabetes

4
 Mechanisms of endocrine disease

• Deficiency can also arise from genetic

defects in hormone production—gene
deletion or mutation, failure to cleave
precursor, specific enzymatic defect (steroid
or thyroid hormones)

Congenital Adrenal Hyperplasia

5
 Mechanisms of endocrine disease

• Inactivating mutations of receptors can

cause hormone deficiency

Testicular Feminization Syndrome

6
 Mechanisms of endocrine disease

• Hormone excess usually results in disease

• Hormone may be overproduced by gland
that normally secretes it, or by a tissue that
is not an endocrine organ.
• Endocrine gland tumors produce hormone in
an unregulated manner.

Cushing’s Syndrome
7
 Mechanisms of endocrine disease
• Exogenous ingestion
of hormone is the
cause of hormone
excess—for example,
glucocorticoid excess
or anabolic steroid
abuse

8
 Mechanisms of endocrine disease
• Activating mutations of cell surface receptors
cause aberrant stimulation of hormone
production by endocrine gland.
– McCune-Albright syndrome usually
caused by a mutation in a gene called
GNAS1 (Guanine Nucleotide binding
protein, Alpha Stimulating activity
polypeptide 1).

9
 Mechanisms of endocrine disease

• Malignant transformation of non-

endocrine tissue causes
dedifferentiation and ectopic production
of hormones
• Anti-receptor antibodies stimulate
receptor instead of block it, as in the
case of the common form of
hyperthyrodism.

Grave’s Disease

10
 Mechanisms of endocrine disease

• Alterations in receptor number and function

result in endocrine disorders
• Most commonly, an aberrant increase in the
level of a specific hormone will cause a
decrease in available receptors

Type II diabetes

11
 Adrenal Gland

Adrenal glands are located on the top of both kidneys.

Each gland consists of a medulla, the center of the
gland, encased by a cortex.

12
Adrenal Glands
• Adrenal cortex
– 80% of an adrenal gland’s total weight

– Zona glomerulosa – aldosterone 15%

– Zona fasciculata – glucocorticoids 78%

– Zona reticularis – androgens and estrogens

(others)
– 7%

• Adrenal medulla
– Innervation by SNS

13
Adrenal Glands

14
 Anatomy/Physiology of Adrenal Gland
-Inner part “medulla”:
-Chromaffin cells
-Source of catecholamines (Epi/NEpi),
-Innervated by pre-ganglionic sympathetic fibers; forms an
extension of the sympathetic nervous system (fight/flight).

-Outer part “cortex”:

-Source of steroid hormones
-Glucocorticoids, mineralocorticoids and sex steroids

15
 NADP+
NADPH
from phe, diet, or protein
breakdown DHBR

BH4 BH2
1
Tyrosine L-Dopa
Tyrosine hydroxylase 2 Dopa
(rate-determining step) H O decarboxylase
O2 2
pyridoxal
H2O 3 O2 CO2
DPN OHase in neuro- phosphate
scretory granules ascorbate
Norepinephrine Dopamine
Dopamine hydroxylase
Parkinson’s disease: local
NMT
Epinephrine deficiency of dopamine
SAM from
synthesis; L-dopa boosts
metabolism of 4 NMT specific to production
Met adrenal medulla
SAM SAH

Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin;

DHBR, dihydrobiopterin reductase; NMT, N-CH3 transferase; SAH, S-
adenosyl-homocysteine; SAM, S-adenosylmethionine
16
Regulation of the release of Stress
catecholamines and synthesis of Chronic
Hypothalamus
epinephrine in the adrenal medulla regulation
chromaffin cell. ACTH
from adrenal
Cortisol cortex via intra-
Tyrosine adrenal portal
system
Acute L-Dopa DPN
regulation
induction
granule DPN

Neuron
.. .....
.......
. Ca2+ NE

... NE
PNMT
Epinephrine

 E E E
neuro-
acetylcholine promotes NE E
exocytosis secretory
Adrenal Medulla granules
Chromaffin Cell E E
EEE E NE
EE 17
NE
 Epinephrine COMT + MAO
Vanillylmandelic acid
Norepinephrine

COMT + MAO
Dopamine Homovanillic acid

Neuronal re-uptake and degradation of catecholamines quickly

terminates hormonal or neurotransmitter activity.
Cocaine binds to dopamine receptor to block re-uptake of dopamine
Dopamine continues to stimulate receptors of the postsynaptic nerve.

Figure 3. Degradation of epinephrine, norepinephrine and dopamine via monoamine

oxidase (MAO) and catechol-O-methyl-transferase (COMT)

18
Classification of Adrenergic Hormone Receptors

Second
Receptor Agonists G protein
Messenger
alpha1 (1) E>NE IP3/Ca2+; DAG Gq
alpha2 (2) NE>E  cyclic AMP Gi
beta1 (1) E=NE  cyclic AMP Gs
beta2 (2) E>>NE  cyclic AMP Gs

E = epinephrine; NE = norepinephrine
Synthetic agonists:
isoproterenol binds to beta receptors
phenylephrine binds to alpha receptors (nose spray action)

Synthetic antagonists:
propranolol binds to beta receptors
phentolamine binds to alpha receptors
19
 Metabolic and muscle contraction responses to catecholamine binding to
various adrenergic receptors.

2- 1-
1-receptor 2-receptor
receptor receptor
Process
(IP3, DAG) ( cAMP)
( cAMP) ( cAMP)
liver/muscle

Carbohydrat
 liver glycogenolysis;
e No effect No effect
glycogenolysis  liver gluconeogenesis;
metabolism
 glycogenesis
Fat
No effect  lipolysis  lipolysis No effect
metabolism
 insulin,
Hormone  insulin, glucagon and
No effect renine No effect
secretion renin secretion
secretion
Smooth Smooth
Smooth muscle
muscle - blood muscle -
Myocardial relaxation - bronchi,
Muscle vessels, some
- rate, blood vessels,
contraction genitourinary vascular;
force GI tract, genitourinary
tract GI tract
tract 20
contraction relaxation
 1 or 2 2 receptor
receptor

Gs Gi
s  i 
  
  
GTP GTP
i
s
GTP GTP
 
inactive
ACTIVE
X inactive
adenylyl adenylyl
cyclase adenylyl
cyclase
cyclase
ATP cyclic AMP
Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity
21
 "FIGHT OR FLIGHT" RESPONSE

epinephrine/ norepinephrine major elements in the "fight or flight" response

acute, integrated adjustment of many complex processes in organs vital to the
response (e.g., brain, muscles, cardiopulmonary system, liver)
occurs at the expense of other organs less immediately involved (e.g., skin, GI).
epinephrine:
rapidly mobilizes fatty acids as the primary fuel for muscle action
increases muscle glycogenolysis
mobilizes glucose for the brain by  hepatic glycogenolysis/
gluconeogenesis
preserves glucose for CNS by  insulin release leading to reduced glucose
uptake by muscle/ adipose
increases cardiac output
norepinephrine elicits responses of the CV system -  blood flow and  insulin
secretion.

22
ADRENAL “CORTEX”-DERIVED STEROIDS

23
24
Adrenal Cortex
“all hormones derived from cholesterol”
• Stimulated by adrenocorticotropic hormone (ACTH)
• Glucocorticoid hormones
– Direct effect on carbohydrate metabolism

– Anti-inflammatory and growth suppression effects

– Influences awareness and sleep habits

– Inhibits bone matrix-protein matrix

– Cortisol – most potent naturally occurring

25
Adrenal Cortex
• Mineralocorticoid hormones –

Aldosterone
– ↑ Na+ uptake in epithelial cells –

distal nephrons
– ↑ Na retention with loss of K and H
+ +

– Regulation by the renin-angiotensin

system
 Na+ and H2O depletion
 ↑ K+ excreteion
 ↓ blood volume
26
 Adrenal “Cortex”-derived Steroids

Class Major Effects

Glucocorticoids Cortisol Glucose metabolism

control

Mineralocorticoids Aldosterone Na/K/H20 control

Sex steroids DHEA Androgen precursors

Androstendione

27
 CAPSULE

MEDULLA
RETICULARIS

MEDULLA

SECRETION OF INDIVIDUAL
STEROID HORMONES IS
RESTRICTED TO SPECIFIC
REGIONS OF THE ADRENAL
CORTEX 28
SYNTHESIS OF ADRENAL CORTEX HORMONES

29
 (+) Diurnal
Hypothalamus rhythms
(-)

Stre Corticotropin-releasing
ss factor (CRF)
(+) (-) Somatostatin
(+)
Hypoxia Anterior pituitary Hypothalamic
lesions
Hypoglycemia
Hyperthermia
Exercise
Cortisol Adrenocorticotropic hormone
insufficiency (ACTH)

Adrenal cortex

Glucocorticoids
(especially cortisol)
30
 ALL STEROIDOGENIC TISSUES STEROID SYNTHESIS
CHOLESTEROL (C27)
minus side
+ 20-keto chain GONADS
PREGNENOLONE (C21)
DEHYDROEPIANDROSTERONE
SULFATE (C19 :“DHEA-S”)
+ 3-keto + 17-OH
desmolase sulfotransferase

PROGESTERONE 17-OH PREGNENOLONE DEHYDROEPIANDROSTERONE”

’’DHEA”
+ 21-OH + 17-OH + 3-keto + 3-keto Adrenals
desmolase
+ 11-OH 17-OH PROGESTERONE ANDROSTENEDIONE (C19)

CORTICOSTERONE + 21-OH
TESTOSTERONE
aromatase
+ 18-ALDEHYDE + 11-OH
+3-keto ESTRONE
ALDOSTERONE (C21) aromatase
CORTISOL (C21)

ADRENAL CORTEX
DIHYDROTESTOSTERONE (C19) ESTRADIOL (C19) 31
 SYNTHESIS AND “SECRETION” OF STEROID HORMONES BY ADRENAL CORTEX
1 CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA
UPTAKE OF CHOLESTEROL EITHER DIRECTLY FROM PLASMA LDL/HDL OR FROM
ESTER FROM LDL AND HDL INTRACELLULAR CHOLESTEROL ESTERS “STORED”
IN LIPID DROPLETS
KIDNEY
IN PLASMA

StAR facilitates transfer of

cholesterol molecules between
ALDOSTERONE
2 inner and outer membranes

Cholesterol in
Intracellular
Lipid droplets
DIFFUSION OF STEROIDS
CORTISOL
OUT OF CELL
4
P450c11
11-HYDROXYLASE

REMOVAL OF ANDROGEN
SIDE CHAIN PRECURSORS
17-OH PROGESTERONE

ENDOPLASMIC RETICULUM
GONADS
OXIDATION OF STEROID NUCLEUS
3 BY SPECIFIC P-450 HYDROXYLASES
32
 The metabolic effects of glucocorticoids

 They increase glucose production by:

1. Increasing the supply of amino acids to the liver
2. Activating the expression of genes of gluconeogenic enzyme

 Promote lipolysis in peripheral tissues by inducing enzyme synthesis

(Increase mobilization of peripheral fat)

 When at very high levels can cause lipogenesis in face and trunk

 When at a very high levels has catabolic effect on proteins in peripheral

tissues and anabolic effect in the liver

33
The metabolic effects of glucocorticoids

 When at very high levels can cause lipogenesis in face and trunk

34
 Therapeutic Effects of Glucocorticoids
Cortisol (hydrocortisone) and synthetic glucocorticoids
(prednisone): Potent anti-inflammatory and
immunosuppressive agent [topical, oral, aerosolized, injection]
-used to relieve symptoms of inflammation [swelling, heat,
redness, and pain];

-used in cases of insufficient synthesis (hormone replacement);

-used to treat certain forms of arthritis; skin, blood, kidney, eye,

thyroid, and intestinal disorders (e.g., colitis); severe allergies; and
respiratory conditions such as asthma.

-used in the treatment of certain types of cancer.

35
 How glucocorticoids suppress immune and inflammatory reactions
mediated by cytokines
NF-B stimulates the
ultimate production of
inflammatory cytokines
Tumor necrosis factor (TNF)
binding to its receptor leads to
the ultimate degradation of IB

IB binds to
and inhibits the
nuclear translo- Glucocorticoid induction of
cation of NF-B. IB synthesis through GC
binding to its intracellular
receptor and stimulating trans-
cription of the gene.

A glucocorticoid interaction with its receptor results in increasing the transcription

of the protein IB, which binds and inhibits the activity of NF-B, a a transcriptional
activator that stimulates transcription of genes for inflammatory cytokines. NF-B
is normally sequestered in an inactive state through association with IB proteins.
36
(TNF is a proinflammatory cytokine.)
Adrenal Gland Steroids

Cortisol (the naturally-occurring glucocorticoid)

levels are regulated by a hypothalamus-
pituitary-adrenal hormone axis.
Corticotropin releasing hormone
(CRH) controls adrenocortioctropic hormone
(ACTH) release from the pituitary.
ACTH is a trophic hormone that
stimulates:
-synthesis and secretion of cortisol and
-growth of the adrenal gland.

When cortisol levels increase, CRH and ACTH

secretion/release are reduced.

37
 Mineralocorticoids

Mineralocorticoids (e.g. aldosterone)

-enhance renal tubular retention of Na+, HCO3- and water
and increase excretion of K+: this increases serum Na and
decreases serum K
-increased blood volume and pressure

Removal of the adrenal glands leads to death within just a few days due to:

-the concentration of potassium in extracelluar fluid becomes dramatically

elevated;
-urinary excretion of sodium is high and concentrations of sodium in
extracellular fluid decreases significantly;
-volume of extracellular fluid and blood plummet;
-the heart begins to function poorly, cardiac output declines and shock ensues

38
 Control of Aldosterone Secretion

Control over aldosterone secretion is multifactorial:

-The two most significant regulators of aldosterone secretion are:

•Concentrations of K+ in extracellular fluid: Small increases in blood

levels of potassium strongly stimulate aldosterone secretion.

•Angiotensin II: Activation of the renin-angiotensin system as a result of

decreased renal blood flow (usually due to decreased vascular volume)
results in release of angiotensin II, which stimulates aldosterone secretion

39
Disorders of the Adrenal Gland
Adrenal Insufficiency (Addison’s disease, 1:100,000)
Primary Adrenal Insufficiency:
-most common cause is autoimmune-mediated destruction of the adrenal
glands (>80%)
-secondary to tuberculosis, chronic fungal infections, infection by
cytomegalovirus (CMV), metastasis to the glands by cancer cells (~20%)

Secondary Adrenal Insufficiency:

-Addison’s Disease caused by inadequate secretion of ACTH by the
pituitary gland;
-may arise due to the prolonged or improper use of glucocorticoid
hormones( temporary);

40
 Disorders of the Adrenal Gland
Cushing’s Syndrome

-Cushing's Syndrome is EITHER a disease caused by an

excess of cortisol production, or a disorder resulting from
excessive use of glucocorticoids

Disease-related excess production of cortisol (2 types):

1) Excess ACTH Production:
Ex. A pituitary tumor producing too much ACTH
stimulates adrenal growth and increases cortisol
(>70%); Also "ectopic" ACTH production (30%)
2) Adrenal cortex tumours: Tumours can be benign
(an adenoma), or malignant (a carcinoma). Usually
found on only one side.
41
 Hormones and stress
• Stress = any condition that threatens homeostasis
• GAS (General Adaptation Syndrome) is our bodies
response to stress-causing factors
• Three phases to GAS
– Alarm phase (immediate, fight or flight, directed

by the sympathetic nervous system and

dominated by the catecholamines)
– Resistance phase (dominated by

glucocorticoids)
– Exhaustion phase (breakdown of homeostatic

regulation and failure of one or more organ

systems)
42
The General Adaptation Syndrome

43
The General Adaptation Syndrome

Figure 18.21 44
The General Adaptation Syndrome

45
Retinoid Hormones

• Isoprenoid hydrophobic
hormones.
• The pro-hormone, retinol, is
made in the liver.
• Retinol is converted to the
hormone, retinoic acid, by
many tissues.
• Retinoic acid regulates cell
growth and development in
most cells, but the principal
targets are the cornea, skin
and epithelia.
• Excess Vitamin A can cause
birth defects and liver
damage.
• Severe acne is treated with
retinoid creams. 46
THYROID HORMONES

47
 The Thyroid Gland

Thyroglobulin is a protein rich in Tyr (100Tyr/1molecule)

Figure 18.11b, c 48
 Synthesis of T3 and T4

The thyroid gland: Synthesizes and secretes triiodothyronine-T3 and

thyroxine-T4
-the only body tissue that can accumulate iodide

Steps of thyroid hormone synthesis

-accumulation of iodide via a specific iodide pump.
-iodinatition of tyrosine produces monoiodotyrosine (MIT) and
diiodotyrosine (DIT)
- coupling reaction: Synthesis of MIT/DIT:
-MIT +DIT produces T3 (3 iodine)
-DIT+DIT, T4 (4 iodine).
-MIT/DIT are complexed with thyroglobulin.
-Thyroglobin proteolysis liberates T3 and T4
- Released hormones are secreted: 5(T4) to
49
1(T3).
 SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION

TYROSINE THYROGLOBULIN

TYROSINE
IODINATION I

MONOIODOTYROSINE (MIT) Tyr THYROGLOBULIN

Approximately 10% of the tyrosine residues on the

550 amino acid residue Thyroglobulin molecule may
TYROSINE become iodinated by the enzyme - thyroid
IODINATION peroxidase acting on the colloid at the luminal
I surface of the thyroid follicle. These reactions only
occur in the thyroid at specific residues in
“Hormonogenic” sites located at the extreme ends of
the Thyroglobulin molecule.
DIIODOTYROSINE (DIT) Tyr - THYROGLOBULIN

NH2
I
50
 SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES
I I HO I II

5’ 5
HO Tyr CH2CHCOOH + HO Tyr CH2CHCOOH HO Tyr O Tyr
NH2 NH2 3’ 3

I I
Thyroglobulin
I T4 I
Thyroglobulin

3,5,3’5’-tetraiodothyronine
Coupling of iodotyrosine moities results in the loss
of the peptide linkage to thyroglobulin allowing thyroid
hormones to diffuse across the cell membrane
I 3,5,3’-Triiodothyronine
I

HO Tyr CH2CHCOOH + Tyr CH2CHCOOH

NH2 HO Tyr O Tyr

NH2

I I

Thyroglobulin I T3 I
Thyroglobulin
51
 3,5,3’5’-tetraiodothyronine
STEP 3 I I
DEIODINATION

Tyr O Tyr CH2CHCOOH

NH2

I I “ACTIVATION” PATHWAY
“DEACTIVATION” PATHWAY T4 In peripheral tissues

5-deiodination 5’- deiodination

SELENODEIODINASES
rT3
I I I T3 I

Tyr O Tyr CH2CHCOOH Tyr O Tyr CH2CHCOOH

NH2 NH2
I
I

3,3’,5’-Triiodothyronine (reverse T3) 3,5,3’-Triiodothyronine (T3)

53
 SECRETION OF THYROID HORMONE
ENDOCYTOSIS OF
IODINATION OF THYROGLOBULIN
4 ‘COLLOID’ IN FOLLICLE BY
BY THYROID PEROXIDASE PSEUDOPOD

TG
3 TG
TG
I

5
FUSION OF PHAGOSOME
TG WITH LYSOSOMES

TG 6
DEGRADATION DEGRADATION OF
AND THYROGLOBULIN
RECYCLING
OF MIT/DIT 7
BY DEIODINASES FREE THYROXINE RELEASED FROM
T4
PROTEIN INTO CYTOPLASM

2 8
IODIDE UPTAKE “DIFFUSION” OF THYROXINE
BY Na/I THROUGH CELL MEMBRANE
SYMPORTER
T4> > > T3

IODIDE IN Additional metabolism??

1 ECF~20nM 54
 THYROID HORMONES

RELATIVE PLASMA BOUND TO

HORMONE PRODUCTION CONCENTRATION t½
POTENCY PLASMA
PROTEINS
(µg/day) (µg/dL) (days)
(%)

T4 + 80- 90 8 6-7
99.95

T3 ++++ 4-8 (24)* 0.3 99.7 1-3

rT3 - 2-3 (27) * 0.04 99.8 0.1

55
* VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION
Regulated T3/T4 Release

T3/T4 synthesis/release is tightly regulated:

-reduced T3/T4 stimulates TRH release from the
hypothalamus (HPT) which then causes TSH
release from the pituitary (PIT).

TSH stimulates:
1) T3/T4 synthesis and secretion
2) thyroid gland growth.
When T3/T4 levels increase, negative feedback
shuts off TRH and TSH secretion.

56
 Physiological Actions of T3/T4

Play a Central Role in Regulating:

-growth/development of most cells,

-basal metabolic rate and temperature (stimulate cellular
respiration)
-cardiac output by increasing rate/force of contraction,
-metabolism of cholesterol to bile acids,
-LDL receptor expression in hepatocytes,
-TSH secretion

THYROID HORMONES ARE ESSENTIAL TO LIFE!

57
 Hypothyroidism (Myxedema)
Reduced circulating T3/T4 levels

Symptoms include: fatigue/weakness, weight gain/difficulty

losing weight, coarse/dry hair, dry/rough pale skin, cold intolerance,
muscle cramps/muscle aches, constipation, depression, irritability,
memory loss, abnormal menstrual cycles, decreased libido

-Myxedema coma: A medical emergency characterized by

hypothermia, hypotension, hypoventilation and bradycardia
represents the extreme expression of severe hypothyroidism

58
 Problems with the Thyroid Gland
Hyperthyroidism:
• high metabolic rate, hyperactivity, sensitivity to heat, protruding eyes
• Grave’s disease: when hyperthyroidism is due to an autoimmune problem
(TSH is mimicked by autoantibodies)

Hypothyroidism:
• in the adult: myxedema- low metabolic rate, sensitivity to cold,
sluggishness, weight gain/difficulty losing weight, coarse/dry hair, dry/rough
pale skin, constipation, depression, irritability, memory loss, abnormal
menstrual cycles, decreased libido
• in an infant: cretinism-- stunted growth, mental retardation, abnormal bone
formation
• Hashimoto’s disease: when hypothyroidism is due to an autoimmune
problem (autoantibodies attack and destroy follicular cells)
• goiter no T3 and T4 can be made because not enough iodides were
ingested.

59
Primary Hypothyroidism (Myxedema)

-When synthesis of T3/T4 is low, no feedback

inhibition of TSH occurs and TSH levels rise.
-TSH stimulation of the thyroid gland is
increased and lead to:
-the lack of T3/T4 synthesis
in primary hypothyroidism leads to
TSH-mediated increases in size (goiter).

60
Secondary Hypothyroidism

When the pituitary can't make TSH

there is no signal to the thyroid gland
to make T3/T4. Thus secondary
hypothyroidism is (i.e. pituitary-
mediated) associated with decreased
T3/T4 AND TSH and thyroid atrophy.

61
Primary Hyperthyroidism

Primary hyperthyroidism: Thyroid

secretes T3/T4 in a TSH unregulated
fashion

Symptoms:

-heart palpitations, heat intolerance,

nervousness, insomnia, breathlessness,
increased bowel movements, light/absent
menstrual periods and fatigue

62
Secondary Hyperthyroidism

Loss of T3/T4-mediated negative

effects on TSH release by pituitary

-the thyroid is chronically stimulated

to synthesize and secrete T3/T4
and to grow. Thus ,goiter is also a
symptom of secondary
hyperthyroidism

63
 Hyperthyroidism-Treatments
Relief of direct symptoms: Drugs that inhibit thyroid hormone
production/release (methimazole, propylthiouracil (PTU):
-Inhibit hrmone synthesis (iodine organification)
-Inhibit MIT coupling

Limitations: The symptoms associated with hyperthyroidism return

when the drugs are discontinued.

64
 Hyperthyroidism-Treatments
Radioactive Iodine:[135I]
-most widely recommended permanent treatment of
hyperthyroidism

-treatment takes advantage of the fact that only thyroid cells

can incorporate iodine

-[135I] emits gamma (γ) radiation: Directly kills thyroid cells

-There is no evidence that [135I] treatment for hyperthyroidism

causes cancer of the thyroid gland or of any other tissue

65
 CALCITONIN IS SECRETED FROM THE THYROID PARAFOLLICULAR CELLS

BUT IS CALCITONIN AN IMPORTANT PHYSIOLOGICAL SUBSTANCE?

The observation that calcitonin (CT) at supraphysiological doses is hypocalcemic, led to the mistaken
conclusion that it was important for calcium homeostasis and this idea has persisted to this day.
Despite these findings there is no apparent pathology due to CT excess or deficiency and there is no
evidence that circulating CT is of substantial benefit to any mammal.

Mammalian CT at physiological doses is not essential and very likely the CT gene has survived
because of the gene’s alternate mRNA pathway to produce calcitonin-gene-related peptide CGRP
found in neural tissues.

HIRSCH,PF and BARUCH H, ENDOCRINE 2003, 201-208

66
THE PARATHYROID HORMONE

67
 Parathyroid Gland
• This gland only secretes
one hormone:
Parathyroid Hormone
(or PTH)
• PTH function (we began
learning this when we
studied bone):
– increases blood
calcium (Ca2+) levels
and decreases
blood phosphate
(PO42-) levels

68
 PTH function (continued)

• How does PTH work?

– PTH causes Ca2+ & PO42- to be released from

bone into blood (by increasing osteoclast

activity)
– PTH decreases the excretion of PO42- ions

through urine
– PTH increases calcitriol production, so that more

Ca2+ is absorbed during digestion

• PTH is regulated by blood calcium levels-- not by
other glands!

69
The Regulation of Calcium Ion Concentrations

Figure 18.15 70
THE PANCREATIC HORMONES

71
 The pancreatic islets

• Clusters of endocrine cells within the

pancreas called Islets of Langerhans or
pancreatic islets
– Alpha cells secrete glucagons

– Beta cells secrete insulin

– Delta cells secrete GH-IH

– F cells secrete pancreatic polypeptide

72
The Endocrine Pancreas

Figure 18.18a, b 73
ISLETS OF LANGERHANS
BLOOD FLOWS RADIALLY FROM CENTER OF ISLET
TO THE PERIPHERY FACILITATING PARACRINE
1 MILLION ISLETS EACH INHIBITION OF GLUCAGON SECRETION BY INSULIN
CONTAINING 2500 CELLS

CORE FORMED BY BETA CELLS

SECRETING INSULIN
(60-70 % OF TOTAL)

MANTLE FORMED BY  CELLS

SECRETING GLUCAGON (20-25%)

ARTERIAL BLOOD

Canaliculus
 CELL  CELL

SECRETORY
GRANULES

74
VENOUS BLOOD
VENOUS BLOOD
75
Endocrine Pancreas
• Insulin
– Synthesized from proinsulin
– Secretion is promoted by ↑ blood
glucose
– Facilitates the rate of glucose uptake
into the cells
– Anabolic hormone
 Synthesis of proteins, lipids
and nucleic acids
76
Endocrine Pancreas
• Glucagon

– Secretion is promoted by decreased

blood glucose levels
– Stimulates glycogenolysis,

gluconeogenesis and lipolysis

• Somatostatin (delta cells)
– Regulation alpha and beta cell

secretions

77
 PHYSIOLOGICAL ROLE OF INSULIN
MAINTENANCE OF NORMAL PLASMA GLUCOSE LEVELS IN
SPITE OF LARGE CHANGES DUE TO FOOD INTAKE

RAPID UPTAKE OF DIETARY GLUCOSE

STIMULATION OF GLUCOSE TRANSPORT

STIMULATION OF GLUCOSE UTILIZATION

UTILIZATION OF DIETARY GLUCOSE

STIMULATION OF GLYCOGEN SYNTHESIS

STIMULATION OF GLUCOSE OXIDATION

STIMULATION OF LIPID SYNTHESIS

PRESERVATION OF ENERGY STORES

INHIBITION OF GLYCOGEN DEGRADATION

INHIBITION OF GLUCONEOGENESIS
INHIBITION OF LIPOLYSIS
INHIBITION OF PROTEOLYSIS 78
Endocrine Pancreas

79
Figure 18.19 The Regulation of Blood Glucose
Concentrations

Figure 18.19 80
THE PINEAL GLAND

81
 Pineal Gland

Secretes only one hormone: melatonin

- involved in your circadian rhythm (your recognition of day and
night times):
– melatonin secretion decreases in the day

– melatonin secretion increases at night

Melatonin is also involved in longer rhythms, like monthly and

seasonal
- inhibits reproductive function
- protects against damage by free radicals
- has anti-ageing, anti-cancer effects

82
The Endocrine Functions of Other
Organs

83
 The intestines

• Produce hormones important to the

coordination of digestive activities

84
 The kidneys

• Produce calcitriol and erythropoietin (EPO) and the

enzyme rennin
– Calcitriol = stimulates calcium and phosphate ion

absorption along the digestive tract

– EPO stimulates red blood cell production by bone

marrow
– Renin converts angiotensinogen to angiotensin I

85
Angiotensin I converted to angiotensin II in
the lungs

• Stimulates adrenal production of aldosterone

• Stimulates pituitary gland release of ADH
• Promotes thirst
• Elevates blood pressure

86
Endocrine Functions of the Kidneys

87
Endocrine Functions of the Kidneys

LUNGS

88
 The heart

• Specialized muscle cells produce natriuretic

peptides when blood pressure becomes excessive
– Generally oppose actions of angiotensin II

89
 The thymus

• Produces thymosins
– help develop and maintain normal

immune defenses
– are involved in white blood cell production

90
 Adipose tissues secrete

• Leptin, a feedback control for appetite

• Resistin, which reduces insulin sensitivity

91
 The gonads
• Interstitial cells of the testes
produce testosterone
– Most important sex hormone

in males
• In females, oocytes develop in
follicles
– Follicle cells produce

estrogens
• After ovulation, the follicle cells
form a corpus luteum that
releases a mixture of estrogens
and progesterone

92
I fought the law, but the law won…..

93