Introduction to Endocrinology

Coordination of Body Functions by Chemical Messengers

• Neurotransmitters –released by axon terminals into
synaptic junctions and act locally to control
nerve cell functions
• Endocrine Hormones –released into the blood and
affect target cells at another location in the body
• Neuroendocrine Hormones –secreted by neurons into
the blood and affect target cells at another location
• Paracrines –secreted by cells into the ECF and affect
neighboring target cells
• Autocrines –secreted by cells into the ECF and affect
the function of the same cells that produced them
• Cytokines –peptides secreted into the ECF and can
function as paracrines, autocrines, or endocrine
hormones
❑ some endocrine hormones
affect many different types
of cells of the body
(growth hormone,
thyroxine)
❑ other hormones affect
mainly specific target
tissues (ACTH – adrenal
cortex)
❑ regulation: metabolism,
growth and development,
water and electrolyte
balance, reproduction, and
behavior

Anatomical location of the principal endocrine glands and tissues

 Chemical Structure and Synthesis
Three General Classes of Hormones

1) proteins and polypeptides

2) steroids
3) derivatives of the amino acid tyrosine (thyroid
and the adrenal medullae)
❑ there are no known polysaccharides or nucleic
acid hormones
 1) Protein Hormones
❑ widespread, water soluble
❑ from 3 to 200 amino acids (growth hormone and prolactin)
❑ more than100 amino acids – proteins
❑ synthesized on the rough end of the ER
❑ preprohormones – prohormones (ER) – hormones (Golgi
apparatus & secretory vesicles) – exocytosis (Ca, cAMP)
a. First made as a preprohormone which is cleaved into a prohormone

b. Stored in vesicles as an active hormone and are released by exocytosis

c. Trigger for release can be cAMP, calcium, or some other chemical

2) Steroid Hormones
❑ usually synthesized from
cholesterol
❑ are not stored
❑ lipid soluble
❑ most of cholesterol comes
from plasma, but there is
also de novo synthesis
❑ consist of three cyclohexyl
rings and one cyclopentyl
ring combined into a single
structure
 3) Amine Hormones
❑ derived from tyrosine
❑ most of the thyroid hormones combine with
plasma proteins
❑ Adrenal medulla secretes 4x more epinephrine
than norepinephrine
❑ taken up into preformed vesicles and stored until
secreted (exocytosis)
❑ in the plasma in free form or in conjugation with
other substances
Hormone Secretion
Each hormone has its own characteristic onset and duration of action
❑ some hormones (epinephrine) are secreted within seconds after
stimulation, and develop action within seconds to minutes
❑ thyroxine or growth hormone may require months for full effect
❑ concentrations of hormones are incredibly small (from 10-12 to 10-
6g/ml) – rates of secretion are extremely small (μg-mg/day)
 Hormone Secretion, Transport, and Clearance

• Feedback Control

a. Negative feedback prevents overactivity of hormone

systems

b. Surges of hormones can occur with positive feedback

(i.e. LH)

c. Cyclical variations occur in hormone release

(seasonal changes, aging, diurnal cycles, and sleep)
 Hormone Secretion, Transport, and Clearance

• Transport of Hormones in the Blood

a. Water soluble hormones are dissolved in plasma

and diffuse into the interstitial spaces to the target
cell

b. Steroid and thyroid hormones-circulate in the

blood bound to plasma proteins; must dissociate
from the carrier to be active (can act as hormone
reservoirs (greatly slows their clearance from the plasma)
 Hormone Secretion, Transport, and Clearance

• Clearance of Hormones from the Blood- two factors

affect the increase or decrease of hormone
concentration in the blood

a. Rate of hormone secretion into the blood

b. Rate of removal of the hormone from the blood

(metabolic clearance rate)
 Hormone Secretion, Transport, and Clearance

• Clearance of Hormones from the Blood

c. Hormones are cleared from the plasma in several ways:

1. Metabolic destruction by the tissues

2. Binding with the tissues
3. Excretion by the liver into the bile
4. Excretion by the kidneys into the urine
 Mechanisms of Action

• Hormone Receptors and Their Activation

a. First step is to bind at a specific receptor at the target cell

b. Cells without receptors do not respond to a given hormone

c. Receptors may be
1. In or on the surface of the cell membrane- mostly
for the protein, peptide, and catecholamine
hormones
2. In the cell cytoplasm- primary receptors for steroid
hormones
3. In the cell nucleus- receptors for thyroid hormone
 Mechanisms of Action
• Number and Sensitivity of Hormone Receptors
Are Regulated

a. Down Regulation- increased hormone concentration

and increased binding with its receptors causes the
number of active receptors to decrease; occurs as a
result of:
1. Inactivation of some of the receptor molecules
2. Inactivation of some of the intracellular signals
3. Temporary sequestration of the receptor to
the inside of the cell
4. Destruction of the receptors by lysosomes
5. Decreased production of the receptor
 Mechanisms of Action

• Number and Sensitivity of Hormone Receptors

Are Regulated

b. Up Regulation- the stimulating hormone induces

greater than normal formation of receptor or
signaling molecules; the target tissue becomes
progressively more sensitive to the hormone
Intracellular Signaling
❑ formation a hormone-receptor
complex – alteration of function of
receptor :
1) ion channel-linked receptors
2) G protein-linked hormone receptors
3) enzyme-linked hormone receptors
4) intracellular hormone receptors and activation of
genes
 Mechanisms of Action

• Intracellular Signaling After Hormone Receptor

Activation

a. Ion channel linked receptors-most neurotransmitters

combine with receptors at the surface of the post-
synaptic membrane Ex. Ach, Norepinephrine

b. Binding usually opens or closes channels (i.e. Na, K,

or Ca ions)

c. Altered movements of ions may cause the effects or

more commonly attach to G-proteins or enzyme-linked
receptors
❑ 2) G Protein-Linked Hormone Receptors
❑ heterotrimeric GTP-binding proteins
❑ > 1000 known G protein-coupled receptors
❑ all have 7 transmembrane segments that loop in and out of the cell membrane
❑ cytoplasmic tail is coupled to G protein (include three parts – α, β, and γ subunits)
❑ binding of hormone – conformational change in receptor – activation of G protein
❑ activated G proteins
- open or close cell membrane ion channels
- change the activity of an enzyme in the cytoplasm
❑ G proteins binds GDP (α subunit)
❑ displacement of GDP by GTP causes the α subunit to dissociate from the trimeric
complex and to associate with other intracellular signaling proteins
❑ inhibitory (Gi) & stimulatory (Gs) proteins
3) Enzyme-Linked Hormone Receptors
❑ some receptors, when activated,
function directly as enzymes or are
closely associated with enzymes that
they activate
❑ pass through the membrane only
once
❑ hormone-binding site on the outside
of the cell membrane
❑ catalytic or enzyme-binding site on
the inside
❑ leptin receptor
❑ member of a large family of cytokine
receptors that do not themselves
contain enzymatic activity but signal
through associated enzymes
❑ one of the signaling pathways occurs
through a tyrosine kinase of the
janus kinase (JAK) family, JAK2
4) Intracellular Hormone Receptors and
Activation of Genes
❑ steroid hormones, thyroid hormones, retinoid hormones, and vitamin D
❑ receptors in the cytoplasm or nucleus
❑ binding with a specific regulatory (promoter) sequence of the DNA – hormone
response element
❑ transcription of specific genes and formation of mRNA
Second Messenger Mechanisms
1. cAMP, cGMP
2. calcium ions and associated calmodulin

a. Calcium entry is initiated by (1) changes in the membrane potential that opens calcium
channels, or (2) hormones that interact with membrane receptors and open the calcium
channels

b. Calcium binds with calmodulin(has 4 binding sites)

c. When 3 binding sites are filled, the calmodulin initiates multiple effects inside the cell
Such as:
-activation/inactivation of protein kinases
-phosphorylation of proteins (myosin light chain kinase – smooth muscle
contraction)
3. products of membrane phospholipid breakdown
 Mechanisms of Action

• Hormones That Act Mainly on the Genetic

Machinery of the Cell

a. Steroid hormones increase protein synthesis

b. Thyroid hormones increase gene transcription in

the nucleus
Steroid Hormones Increase Protein
Synthesis
❑ these proteins then function as enzymes,
transport proteins, or structural proteins
❑ aldosterone – for 45 minutes, protein which
promote sodium reabsorption and potassium
secretion
❑ full action is delayed for at least 45 minutes-up to
several hours or even day
Thyroid Hormones Increase Gene
Transcription in the Cell Nucleus
❑ thyroxine and triiodothyronine
❑ bind directly with receptor proteins in the
nucleus (activated transcription factors located
within the chromosomal complex)
❑ they control the function of the gene promoters
❑ formation of many types of intracellular proteins
❑ thyroid hormones can continue to express their
control functions for days or even weeks
Measurement of Hormone Concentrations in the Blood

❑ extremely minute quantities

(pg/mL)
❑ radioimmunoassay
❑ production of antibody that is
highly specific for the hormone
to be measured is produced
❑ small quantity of this antibody
(smaller than total possible) is
mixed with:
1) sample containing the hormone to be
measured
2) appropriate amount of purified
standard hormone that has been
tagged with a radioactive isotope
❑ error of 10 to 15 percent
Measurement of Hormone
Concentrations in the Blood
❑ ELISA (enzyme-linked immunosorbent assay)
1) it does not employ radioactive
isotopes
2) much of the assay can be
automated using 96-well plates
3) cost-effective and accurate
method for assessing hormone
levels
Basic principles of the enzyme-linked
Immunosorbent assay for measuring the concentration of a hormone
(H). AB1 and AB2 are antibodies that recognize the hormone at
different binding sites, and AB3 is an antibody that recognizes AB2. E is
an enzyme linked to AB3 that catalyzes the formation of a colored
fluorescent product (P) from a substrate (S). The amount of the product
is measured using optical methods and is proportional to the amount of
hormone in the well if there are excess antibodies in the well