Homeostasis
• Maintenance of internal environment within certain limits.
• Endocrine system is one of two major systems that maintain homeostasis.
• It is a “wireless” communication system that utilizes chemical messages to perform its functions.
Endocrinology
• Study of glands and tissues that secrete chemical messages, called hormones, which travel by way of body
fluids and affect the function of target cells/tissues.
Hormone
Endocrine
Target
Paracrine
Three modes of hormonal communication:
long distances via the bloodstream (the
classical endocrine definition), or through
extracellular fluid to neighboring cell
(paracrine) or on to itself (autocrine).
Target
Autocrine
Hormones communicate by first binding to receptors. Hormones are produced in the hypothalamus,
pituitary glands and in peripheral endocrine glands.
• An endocrine axis involves the secretion of a specific releasing hormone &/or inhibitory hormone from the
hypothalamus, (a) specific trophic hormone(s) from the pituitary and usually a third level of hormone(s)
secreted from a peripheral gland.
Classic Endocrine Organs
Hypothalamus
Releasing Hormones:
GnRH, CRH
TRH, GHRH
Inhibitory Hormones:
Somatostatin
Dopamine
Pituitary Gland
Anterior Pituitary:
ACTH, TSH
FSH, LH
Growth Hormone
Prolactin
Posterior Pituitary:
Vasopressin
Oxytocin
Thyroid Gland
Parathyroid Gland
T3 , T4
Calcitonin
Parathyroid Hormone
Adrenal Gland
Cortisol
Aldosterone
Androgens
Estrogens
Epinephrine
Pancreas
Insulin
Glucagon
Somatostatin
Ovaries
Estradiol
Progesterone
Testes
Testosterone
For each endocrine axis, you will learn:
• Regulation of hormone synthesis
 biochemistry, serum protein carriers,
relative t1/2, metabolism
• Regulation of secretion - feedback loops
• Mechanism of action of hormone
 Receptor/post receptor signaling
• Typical symptoms of hormone excess and
deficiency
• Manipulation of endocrine system to enhance or
suppress hormonal responses
Peripheral endocrine glands include: thyroid,
parathyroid, adrenal cortex, endocrine pancreas and
gonads.
Hormones
1. Secreted by a cell or group of cells some contained within glands.
2. Secreted into blood. Ectohormones, such as pheromones are signal molecules (alarm or attractants) secreted
into the external environment.
3. Transported to a distant target tissue/cells in blood. Paracrine effects of some hormones also is recognized.
4. Exert their effects at very low concentrations; nanomolar 10-9 to picomolar 10-12 levels.
5. Act by binding to receptors. The hormone-receptor complex initiates cellular changes.
6. Action is terminated: Circulatory half-life determined by rate of hormone metabolism in liver and kidney.
Hormone bound to receptors get degraded: hormone:receptor complex is often endocytosed and undergoes
lysosomal degradation.
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Biochemical Nature of Hormones
1) THE Peptides/protein HORMONEs:
 most hypothalamic & pituitary hormones
 coded in genome i.e., are transcribed, translated and packaged in the endocrine cell (in contrast to
endocrine cells which generate steroid hormones, in that case endocrine cells take up cholesterol and
convert it, via converting enzymes, to the appropriate hormone)
 hydrophilic so blood soluble
Post-translational modification, storage,
and routing of proteins assembled in ER.
Protein hormones are made in cells with rough endoplasmic reticulum and are often synthesized as
preprohormones in the ER are enzymatically cleaved to prohormone state and are secreted as mature hormone.
Peptide hormones typically are made as inactive preprohormones
Peptide hormones are made as large, inactive preprohormones that include a signal sequence, one or more copies
of the hormone and additional peptide fragments that often have other biological functions. The signal sequence in
(a) the preproTRH directs movement into the rough endoplasmic reticulum (RER). Preprohormones and
prohormones are inactive. As pre/prohormones move through the Rough Endoplasmic Reticulum and Golgi
complex they are packaged into secretory vesicles with proteolytic enzymes that lyse the protein into the various
biologically active subparts and fragments shown in (a)-(c).The active peptide is secreted systemically, usually in
response to a hormonal signal.
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Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues.
Background: This gene encodes a polypeptide hormone precursor that undergoes extensive, tissue-specific, posttranslational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are
eight potential cleavage sites within the polypeptide precursor and, depending on tissue type and the available
convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions.
The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites
are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal
weight, and lipotropin beta are the major end products. ACTH is made up of 39 aa.
In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to
peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These
include several distinct melanotropins, lipotropins, and endorphins that are contained within the
adrenocorticotrophin and beta-lipotropin peptides.
C-peptide function is
still being studied. It is
often used clinically as a
measure of Insulin
production as 1
molecule of c-peptide =
1 molecule of insulin.
Protein Hormones bind to Membrane Receptors
Protein hormones are hydrophilic so dissolve nicely in water however cannot cross cell membranes. Most protein
hormones bind to cell membrane receptors which traverse the lipid bilayer. Receptors can act as channels, are
kinases so transfer energy via ~P, &/or G protein coupled. Responses can be both rapid (release of secretory
product such as another hormone) and slow (induction of transcription after a cascade of intracytoplasmic events
leading to changes in nucleus).
blood
Plasma membrane
cytoplasm
Biochemical Nature of Hormones
2) Steroid HORMONEs
• Produced in peripheral endocrine organs (not in hypothalamus or pituitary gland).
• Constructed from dietary or liver synthesized cholesterol
• Converted in endocrine gland by enzymes in mitochondrial membrane & smooth ER
• Are hydrophobic- traverse cell membranes but need carrier proteins to circulate
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Steroid hormones readily traverse cell membranes
(when free, i.e.not bound to carrier proteins)
Carrier protein bound-steroid hormone   Free hormone + carrier protein
Steroid hormones are synthesized
from plasma cholesterol. Steroid
hormones are made in the adrenal
cortex, gonads and placenta.
Steroidogenic cells have large
amounts of smooth ER
(endoplasmic reticulum) which is
where steroidogenesis occurs, as
well as enzymes in the
mitochondrial membranes.
Steroids are lipophilic so traverse
lipid membranes easily. This
means they are not stored in
vesicles as peptide hormones are.
They generally are synthesized on
demand and hormone leaves cells
by simple diffusion down a
concentration gradient. Because
they a lipophilic, most is bound
bound to carrier proteins I- this
makes it miscible in the circulation.
There is an equilibrium
between bound and free steroid
hormone in circulation. Some
carrier proteins are specific to
the hormone, binding
hormones at 10-10 to 10-8, ,
however, the concentration of
specific binding protein is
generally low. Other proteins,
such as albumin, also bind
hormones but binding requires
high concentrations of
hormone (at 10-6 to 10-4).
Binding is nonspecific in this
case.. There are several
implications: (1)methods of
measurements of circulating
hormones may measure bound
and/or free hormone, (2)
reductions in specific carrier
protein and albumin levels
(liver disease) alter this
reservoir of bound hormone.
(3) Steroid hormones that are
bound to carrier proteins are
protected from degradation.
Biochemical Nature of Hormones
3) HORMONES constructed from the amino acid, tyrosine
 mostly synthesized in cytoplasm
 Can be either Hydrophilic (e.g., catecholamines) or similar to steroid hormones, hydrophobic (e.g., thyroid
hormones)
Mode of Hormone Transport in the Circulation
• Hydrophilic hormones circulate “free” in the plasma. Can also have specific and nonspecific (albumin) binding proteins.
• Hydrophobic hormones are generally bound to a specific plasma binding/carrier protein. Albumin also can bind these
hormones.
• There is a small amount of “free” unbound hormone and this is the active form of the circulating hormone.
• Carrier/binding proteins protect hormones from degradation by liver and act as a reservoir.
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Nuclear Receptor Signaling Paradigm
E2
SHBG
E2
2. ligand-independent
GF
GF
R
HSP
R HSP
R HSP
R
SHBG
E2
E2
R
E2
HSP
R
R
E2
E2
1. classical
E2
4. nongenomic
SHBG
R
R
E2
E2
R
HSP
E2
E2
R
P P
3. ERE-independent
R
mRNA
E2
E2
Polysomes
E2
Tissue Responses
Protein
E2= estrogen (specifically
estradiol 17beta);
E circulates in the blood bound
to SHBG; Free hormone binds
to receptor in cytoplasm.
Receptors are stabilized in
cytoplasm by binding to heat
shock protein (HSP). Ligand:
receptor moves into the
nucleus, dimerizes and binds to
ERE domain which some Eresponsive genes contain (type
1: classical ERE binding.
E:receptor dimers can also bind
other transcription cofactors
(jun/fos) which bind AP-1 sites
on another type of estrogen
responsive genes (type 3; EREindependent signaling).
SHBG: Steroid hormone binding globulin; GF: Growth Factor
HSP: Heat shock protein; E2=Estrogen; R=receptor;
Under conditions when growth factor stimulation occurs, ligand-independent ER (estrogen receptor) binding to
ERE sites can occur (type 2 signaling). Type 4 signaling is termed nongenomic because the ligand receptor binding
occurs at the cell membrane which initiates signal cascades in the cytoplasm similar to protein hormone: receptor
responses. This paradigm described for estrogen and estrogen receptor is similar for the other steroid hormones.
Short = Minutes
Long = Minutes - Hours
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Mode of Hormone Transport in the Circulation
• Hydrophilic hormones circulate “free” in the plasma. Can also
• ave specific and nonspecific (albumin) binding proteins.
• Hydrophobic hormones are generally bound to a specific plasma binding/carrier protein. Albumin also can
bind these hormones.
• There is a small amount of “free” unbound hormone and this is the active form of the circulating hormone.
• Carrier/binding proteins protect hormones from degradation by liver and act as a reservoir.
What is the clinical relevance of binding proteins?
• bound, free or total hormone values may be presented in assays
• diseases may decrease binding proteins (e.g. liver)
**Peptide hormone concentration is between 10-12 mol/L to 10 -10 mol/L. Steroid and thyroid hormone
concentrations are 10-9 and 10-6 mol/L respectively.
The endocrine system includes the hypothalamus and pituitary glands.
The pituitary gland is made of two embryologically separate structures.
Neurons producing hormones have
cell bodies in the hypothalamus and
project tand secrete their hormones
into either the hypothalamichypophyseal portal system or into the
vessels bathing the posterior pituitary
gland. Capillaries carrying the newly
secreted hypothalamic hormones
from the hypothalamic-hypophyseal
portal system bathe the anterior
pituitary endocrine cells. Hormones
secreted into the blood supply of the
posterior pituitary are immediately
available in the general circulation.
Most of the hormones we will be
considering involve the anterior
pituitary gland.
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Posterior Pituitary
Posterior pituitary hormones are vasopressin and oxytocin.
An endocrine axis involves negative feedback so that when there is an increase of hormone produced in the
peripheral endocrine gland it feeds back negatively to the hypothalamus and pituitary, reducing the release of their
respective hormones (Long loop feedback). In most cases when the pituitary releases its hormone, it feeds back
negatively to the hypothalamus (short loop feedback).
Hormone secretion/circulating levels fluctuate during the day.
Hypothalamic & pituitary hormones are released in pulses…… which is due to fluctuations of peripheral indicators
(e.g. glucose) in the case of insulin or due to a hypothalamic pulse generator in the case of GnRH release. This is
also true for hypothalamic and pituitary hormones.
Circadian secretion of hormones also occurs with light and sleep as major environmental clues.
Permissive Action
So hormone deficiencies or excesses may impact the
function of another hormone.
Some hormones promote the action of other
hormones.
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Endocrine imbalances
Here is an example of endocrine imbalance which
occurs with the administration of exogenous hormone,
in this case cortisol. High levels of circulating cortisol
reduces the levels of hypothalamic releasing hormone
(corticotrophic releasing hormone) and anterior
pituitary hormone (adrenocorticotrophic hormone) due
to long loop negative feedback. Cortisol is typically
produced by the adrenal cortex. Target cells/tissues
respond to cortisol (whether it is endogenous or
exogenously provided). Usually excess cortisol is
provided exogenously due to need to reduce immune
reaction Once the reaction subsides, exogenous cortisol
is withdrawn. Slow withdrawal from exogenous cortisol
is necessary to allow a smooth transition back to
endogenous regulation of cortisol. Too rapid of
exogenous cortisol withdrawal would lead to cortisol
crash because the hypothalamo- pituitary-adrenal axis
is temporarily shut down. The adrenal glands are
incapable of producing cortisol without a transition
period to normal production levels. FYI: Look to specific
lecture on adrenal gland physiology.
If the endocrine imbalance, in this
case hypersecretion, is due to
problems at the level of the
peripheral endocrine gland, then it
is called “primary hypersecretion”
If the problem is at the level of the
hypothalamus it is known as
secondary. Some references
suggest that problems at the level
of the pituitary is referred to as
“tertiary” but others lump this into
“secondary hypersecretion” along
with the hypothalamus. One can
distinguish the problem endocrine
gland by measuring hormone levels
in the peripheral blood.
* Too little glucocorticoid causes symptoms of adrenal
insufficiency, such as anorexia, nausea, vomiting,
abdominal pain, asthenia, poor weight gain, and weight
loss.
* Too much glucocorticoid causes excessive weight
gain, cushingoid features, hypertension, hyperglycemia,
cataracts, and growth failure.
* In children, growth failure is a sensitive indicator of
exposure to excessive glucocorticoids.
Expected circulating levels of hormone:
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