HORMONES

Raymond Oliver A. Cruz, MD

WHAT ARE HORMONES?
n Hormones are chemical substances,
present in very low concentrations in the
blood, that regulate the metabolism of at
least one specific organ or tissue
n The site of secretion is distant from the
target organ
n
WHAT ARE GLANDS?
n A gland is a group of cells specialized to
secrete hormones into the bloodstream
WHAT ARE RECEPTORS?
n Receptors are proteins or glycoproteins
that specifically binds a hormone and
produces a biologic action after such
binding
n Have high specificity
n May be found on the plasma membrane or
inside the nucleus of the cell
 Comparison of Receptors with
Transport Proteins
Feature Receptors Transport Proteins
Concentration Very low (thousands/cell) Very high (billions/
Binding affinity High (pmol/L to nmol/L Low
µ L) (µ mol/L range)
Binding specificity Very high
range) Low
Saturability Yes No
Reversibility Yes Yes
Signal Yes No
transduction
n Feedback mechanisms are usually the
means by which hormones are regulated
n Before we discuss the individual
hormones, we will first look into how
these hormones work
n


n
HORMONES CAN AFFECT ANY
OF THE FOLLOWING STEPS:
n Hormones can be thought of as signals,
and receptors are signal detectors
n Each component serves as a link in the
communication process between
extracellular events and chemical
changes within the cell
 General Features of Hormone
Classes
Group I Group II
Types Steroids, Polypeptides, proteins, glycoproteins,
Solubility Lipophilic
iodothyronines, Hydrophilic
catecholamines
Transport Yes No
Plasma calcitriol, retinoids
proteins half-life Long (hours to days) Short (minutes)
Receptor Intracellular Plasma membrane
Mediator Receptor-hormone cAMP, cGMP, Ca2+ , metabolites of
complex complex phosphoinositols, kinase
cascades
Classification of Hormones by
Mechanism of Action
I. Hormones that bind to intracellular receptors
 Androgens
 Calcitriol (1,25[OH]2-D3)
Estrogens
 Glucocorticoids
 Mineralocorticoids
 Progestins
 Retinoic acid
 Thyroid hormones (T3 and T4)
Classification of Hormones by
Mechanism of Action
II. Hormones that bind to cell surface receptors
A. The second messenger is cAMP

α 2-Adrenergic Corticotropin-releasing hormone

catecholamines (CRH)
β -Adrenergic Follicle-stimulating hormone (FSH)
catecholamines Glucagon
Adrenocorticotropic Lipotropin
hormone (ACTH) Luteinizing hormone (LH)
Antidiuretic Melanocyte-stimulating
hormone (ADH,Vasopressin)
Calcitonin hormone (MSH)
Chorionic gonadotropin, Parathyroid hormone (PTH)
human (hCG) Somatostatin
Thyroid-stimulating hormone (TSH)
Classification of Hormones by
Mechanism of Action
II. Hormones that bind to cell surface receptors
B. The second messenger is cGMP

 Atrial natriuretic factor (ANF)

 Nitric oxide (NO)
Classification of Hormones by
Mechanism of Action
II. Hormones that bind to cell surface receptors
C. The second messenger is calcium or
phosphatidylinositols (or both)
 Acetylcholine (muscarinic)
 1-Adrenergic catecholamines
Angiotensin II
 Antidiuretic hormone(vasopressin)
 Cholecystokinin
 Gastrin
 Gonadotropin-releasing hormone (GnRH)
 Oxytocin
 Platelet-derived growth factor
 Substance P
 Thyrotropin-releasing hormone (TRH)
Classification of Hormones by
Mechanism of Action
II. Hormones that bind to cell surface receptors
D. The second messenger is a kinase or
phosphatase cascade

Adiponectin
 Chorionic somatomammotropin
 Epidermal growth factor
 Erythropoietin
 Fibroblast growth factor
 Growth hormone
 Insulin
 Insulin-like growth factors I and II
 Leptin
 Nerve growth factor
 Platelet-derived growth factor
 Prolactin
 SPECIFICITY AND SELECTIVITY

A cell may have no hormone receptors (1), have one

receptor (2+5+6), have receptors for several hormones
(3), or have a receptor but no hormone in the vicinity (4).
SIGNAL TRANSDUCTION BY
INTRACELLULAR RECEPTORS
n Utilized by molecules such as steroid
hormones, Vitamin D, retinoic acid, and
thyroxine
n Act through intracellular receptors located
in the cytosol or the nucleus
n Why do you think these classes of
hormones can enter the cell?
 Ans: They are all lipid-soluble
 Repressor
removed

TRE- Thyroid response element GRE- glucocorticoid response element

HSP- heat shock protein - transcribed gene
+
SIGNAL TRANSDUCTION BY
INTRACELLULAR RECEPTORS
n The effects of agonists acting through
intracellular receptors are not immediate
n For example, hours to days are required to
achieve the therapeutic effects of
steroids for the treatment of asthma
n How do steroids help in the treatment of
asthma?
 TRANSDUCTION BY CELL-
SURFACE RECEPTORS
n Initiated by ligand binding to receptors
located in the plasma membrane
n In contrast to intracellular receptors, cell
surface receptors do not regulate gene
expression directly
n Do they also need to be lipophilic to be
effective?
 G-PROTEIN COMPLEX

E can be adenylyl cyclase, Ca2+, Na+, or Cl– channels, or it could be a K+ channel,

phospholipase C, or cGMP phosphodiesterase
n There is a large family of G proteins, and
these are part of the superfamily of
GTPases
n The G protein family is classified
according to sequence homology into
four subfamilies (See table 43-3 of
Harpers 26th ed.)
n Some G proteins are also involved in
olfaction and vision
3 GENERAL
CLASSES OF CELL-
SURFACE
RECEPTORS
1. NEUROTRANSMITTER RECEPTORS
LINKED TO ION CHANNELS
n The receptor and ion channel are part of a
single multimolecular complex
n Seen in nerve and muscle (GABA,
acetylcholine)
n The binding of a neurotransmitter causes
a rapid opening of ion channels that are
selectively permeable to certain ions
(remember your action potential in
physiology?)
n
2. CATALYTIC RECEPTORS
n Have an inherent enzymatic activity as
part of their structure
n In most cases the enzyme activity is a
tyrosine-specific protein kinase
n For example, the binding of insulin to its
receptor activates the intrinsic tyrosine
kinase activity to initiate insulin’s effects
3. RECEPTORS INVOLVING
SECOND MESSENGERS
n Many receptors signal their recognition of
a bound hormone neurotransmitter by
initiating a series of reactions that
ultimately result in a specific intracellular
response
n These intracellular messengers serve to
amplify signals to initiate its effects
INTRACELLULAR
MESSENGER SYSTEMS
n “Second messenger” molecules
n Intervene between the original message
(the hormone) and the ultimate effect on
the cell
n Are the hormones that utilize second
messengers usually lipophilic or not?
 Ans: They are usually not lipophilic, so
they use these 2nd messengers to initiate
their effects on cell function
ADENYLATE CYCLASE SYSTEM
n A membrane-bound enzyme that converts
ATP to 3’, 5’-adenosine monophosphate
(also calles cyclic AMP or cAMP)
n
PKA exists in an inactive form as an R2C2
heterotetramer consisting of two regulatory and
two catalytic subunits.
cAMP generated by the action of adenylyl cyclase
binds to the regulatory (R) subunit of PKA. This
results in dissociation of the regulatory and
catalytic subunits and activation of the latter.
The active catalytic subunits phosphorylate a
number of target proteins on serine and threonine
residues.
Phosphatases remove phosphate from these
residues and thus terminate the physiologic
response.
A phosphodiesterase can also terminate the
response by converting cAMP to 5'-AMP.
Subclassification of Group II.A
Hormones.
Hormones That Stimulate Hormones That Inhibit
Adenylyl Cyclase (HS) Adenylyl Cyclase (HI)

ACTH Glucagon Acetylcholine

ADH hCG
β -Adrenergics LH α 2-Adrenergics
Calcitonin LPH Angiotensin II
CRH MSH Somatostatin
FSH PTH
TSH
n In prokaryotic cells, cAMP binds to a
specific protein called catabolite
regulatory protein (CRP) that binds
directly to DNA and influences gene
expression.
n In eukaryotic cells, cAMP binds to a
protein kinase called protein kinase A
(PKA) that is a heterotetrameric
molecule consisting of two regulatory
subunits (R) and two catalytic subunits
(C).
n Inhibitors of phosphodiesterase, most
notably methylated xanthine derivatives
such as caffeine, increase intracellular
cAMP and mimic or prolong the actions
of hormones through this signal
CALCIUM-PHOSPHATIDYLINOSITOL
SYSTEM n Many receptors respond
to hormones by
activating a
membrane-bound
phophodiesterase
called Phospholipase
C
n Activated Phospholipase
C subsequently
cleaves membrane-
bound
phophatidylinositol
1,4,5-trisphosphate,
releasing two
fragments (inositol
n Inositol 1,4,5-
trisphosphat
e (IP3)
binds to
receptors
on the
endoplasmi
c reticulum,
causing a
rapid
release of
calcium
from
intracellular
stores
n
n Released
calcium
ions permits
the
formation of
a calcium-
calmodulin
complex
that
mediates a
wide variety
of effects
n IP3 is a short-
lived signal
and is
inactivated
to inositol
1,4-
bisphosphat
e and
inositol 1-
phosphate
n
 Diacylglycerol
n (DAG) activates
n protein kinase C,
an enzyme that
phosphorylates
proteins

Protein kinase C
requires calcium
for maximum
activity

DAG and IP3 act

synergistically to
cause increased
phosphorylation of
proteins
WHAT IS CALMODULIN?
n Calmodulin is a protein that acts as a
mediator of calcium-linked effects in the
cell
n It is structurally and functionally related to
troponin C, which mediates the role of
calcium in skeletal and cardiac muscle
contraction
CYCLIC GUANOSINE
MONOPHOSPHATE
n Analogous to the cAMP pathway
n Synthesized from GTP by a membrane-
bound form of guanylate cyclase
n Activates cGMP-dependent protein kinase
or protein kinase G
n Action also terminated by
phophodiesterase
CYCLIC GUANOSINE
MONOPHOSPHATE
n Unlike cAMP which affects a wide variety
of processes, cGMP functions as a
specialized messenger, being involved
in smooth muscle relaxation, platelet
aggregation, and the visual system
CYCLIC GUANOSINE
MONOPHOSPHATE
n Nitroprusside, nitroglycerin, nitric oxide, sodium
nitrite, and sodium azide, all cause smooth
muscle relaxation and are potent vasodilators.
n These agents increase cGMP by activating the
soluble form of guanylyl cyclase, and inhibitors
of cGMP phosphodiesterase (the drug
sildenafil [Viagra], for example) enhance and
prolong these responses
Insulin Transmits Signals by
Several Kinase Cascades

Tyrosine (Y)
JAK-STAT signaling pathway
n Takes part in the regulation of cellular
responses to cytokines and growth
factors
n Cytokines are a group of proteinaceous
signalling compounds that, like
hormones and neurotransmitters, are
used extensively for inter-cell
communication.
JAK-STAT signaling pathway
n Employing Janus kinases (JAKs) and
Signal Transducers and Activators of
Transcription (STATs), the pathway
transduces the signal carried by
extracellular polypeptides to the cell
nucleus, where activated STAT proteins
modify gene expression
n JAKs, which have tyrosine kinase activity, bind to some
cell surface cytokine receptors
n The binding of the ligand to the receptor triggers
activation of JAKs. Jak-P, an active kinase,
phosphorylates the receptor on tyrosine residues
n The STAT proteins associate with the phosphorylated
receptor and then are themselves phosphorylated by
Jak-P
n STAT dimerizes, translocates to the nucleus, binds to
specific DNA elements, and regulates transcription
n The transcription factor NF- κ B (Nuclear Factor
kappa B) is a heterodimeric complex typically
composed of two subunits termed p50 and
p65
n Normally, NF- κ B is kept sequestered in the
cytoplasm in a transcriptionally inactive form
by members of the inhibitor of NF- κ B (Iκ B)
family
n Extracellular stimuli such as proinflammatory
cytokines, reactive oxygen species, and
mitogens lead to activation of the Iκ B kinase
complex, IKK, which is a heterohexameric
structure consisting of α , β , and γ
subunits.
n IKK phosphorylates Iκ B on two serine
residues, and this targets Iκ B for
ubiquitination and subsequent
degradation by the proteasome
n Following Iκ B degradation, free NF- κ B can
now translocate to the nucleus, where it binds
to a number of gene promoters and activates
transcription, particularly of genes involved in
the inflammatory response
n Glucocorticoid hormones are
therapeutically useful agents for the
treatment of a variety of inflammatory
and immune diseases
n Their anti-inflammatory and
immunomodulatory actions are
explained in part by the inhibition of NF-
κ B and its subsequent actions.
Evidence for three mechanisms for the inhibition


of NF- κ B by glucocorticoids has been

presented:


(1)Glucocorticoids increase Iκ B mRNA, which

leads to an increase of Iκ B protein and more
efficient sequestration of NF-κ B in the
cytoplasm
(2)The glucocorticoid receptor competes with NF-
κ B for binding to coactivators
(3)The glucocorticoid receptor directly binds to the
p65 subunit of NF- κ B and inhibits its
activation
n
n Incorrect regulation of NF-κ B has been
linked to cancer, inflammatory and
autoimmune diseases, septic shock,
viral infection and improper immune
development
HOW DO HORMONES AFFECT
TRANSCRIPTION?
n
(1)Hormones allow the access of transcription factors to
DNA
(2)Genes have regulatory regions, and transcription factors
bind to these to modulate the frequency of
transcription initiation
(3)Hormone-receptor complexes bind to hormone response
elements (HRE’s) to initiate transcription
(4)Other hormone-generated signals can modify the
location, amount, or activity of transcription factors
and thereby influence binding to the regulatory or
response element
WHAT IS A HORMONE
RESPONSE ELEMENT?
n A hormone response element (HRE) is a short
sequence of DNA within the promoter of a
gene that is able to bind a specific hormone
receptor complex and therefore regulate
transcription
n The sequence is most commonly a pair of
inverteD repeats separated by three
nucleotides, which also indicates that the
receptor binds as a dimer
n A gene may have many different response
elements, allowing complex control to be
exerted over the level and rate of transcription.
n Hormone response elements resemble
enhancer elements in that they are not
strictly dependent on position and
location
n They generally are found within a few
hundred nucleotides upstream (5') of the
transcription initiation site, but they may
be located within the coding region of
the gene
The DNA Sequences of Several Hormone
Response Elements (HREs)
Hormone or Effector HRE DNA Sequence

Glucocorticoids GRE
Progestins PRE
Mineralocorticoids MRE
Androgens ARE
Estrogens ERE

Thyroid hormone TRE

Retinoic acid RARE
Vitamin D VDRE
cAMP CRE
n Members of the
nuclear
receptor family
are divided into
six structural
domains (A–F)
n Domain A/B is also
called AF-1, or
the modulator
region, because
it is involved in
activating
transcription
n The C domain
consists of the
DNA-binding
domain (DBD)
n The D region
contains the
hinge, which
provides
flexibility
between the
DBD and the
ligand-binding
domain (LBD,
n The LBD binds
hormones or
metabolites with
selectivity and
thus specifies a
particular
biologic
response
n The F region is
poorly defined
Functional Anatomy of the
Hypothalamus and Pituitary Gland

n The hypothalamus is a region of the brain

that controls an immense number of
bodily functions
n It is located in the middle of the base of
the brain, and encapsulates the ventral
portion of the third ventricle.
Hypthalamus
Optic chiasm

Pituitary Gland
HYPOTHALAMIC HORMONES
n Controls the release of pituitary
hormones
n Hypothalamic hormones are released
from the hypothalamic nerve fiber
endings around the capillaries of the
hypothalamic-hypophysial system in
the pituitary stalk
n Released in a pulsatile manner
PITUITARY
HORMONES
GROWTH HORMONE (GH)
n Also called somatropin or
somatotropin
n Synthesized in somatotropes, a
subclass of the pituitary acidophilic
cells
n The genes for human growth hormone
are localized in the q22-24 region of
chromosome 17
n
Disulfide bonds
GROWTH HORMONE (GH)
n Peptides released by neurosecretory
nuclei of the hypothalamus into the
portal venous blood surrounding the
pituitary are the major controllers of GH
secretion by the somatotropes.
GROWTH HORMONE (GH)
n Growth hormone releasing hormone
(GHRH) from the arcuate nucleus of the
hypothalamus and ghrelin* promote GH
secretion, and somatostatin from the
periventricular nucleus inhibits it.
Secretes GHRH
n Ghrelin is a hormone produced by P/D1 cells
lining the fundus of the human stomach that
stimulate appetite
n Ghrelin levels increase before meals and
decrease after meals
n It is considered the counterpart of the hormone
leptin, produced by adipose tissue, which
induces satiation when present at higher
levels.
n Much of the growth hormone in the
circulation is bound to a protein (growth
hormone binding protein, GHBP) which
is derived from the growth hormone
receptor
n Growth hormone receptor is a member of
the cytokine receptor superfamily.
n One growth hormone molecule binds to
one receptor and then recruits a second
receptor to form a dimer through which
signalling occurs.
n The effects of growth hormone on the
tissues of the body can generally be
described as anabolic
n
n Height growth in childhood is the best known
effect of GH action, and appears to be
stimulated by at least two mechanisms:


 1. GH directly stimulates division and

multiplication of chondrocytes of cartilage.


 These are the primary cells in the growing

ends (epiphyses) of children's long bones

2. GH also stimulates production of insulin-like
growth factor 1 (IGF1, formerly known as
somatomedin C), a hormone homologous to
proinsulin
 The liver is a major target organ of GH for
this process, and is the principal site of IGF-1
production
 IGF-1 has growth-stimulating effects on a
wide variety of tissues.
 Additional IGF-1 is generated within target
tissues, making it apparently both an endocrine
and an autocrine/paracrine hormone.
 IGF-1 will also have stimulatory effects on
osteoblast and chondrocyte activity to promote
bone growth.
n
GROWTH HORMONE (GH)
n GH secretion is also affected by negative
feedback from circulating concentrations
of GH and IGF-1
n
EFFECTS OF GROWTH
HORMONE
n Stimulators of GH secretion include exercise,
hypoglycemia, dietary protein, and estradiol.
Inhibitors of GH secretion include dietary
carbohydrate and glucocorticoids.
n Increases the transport of amino acids into muscle
cells and also increases protein synthesis
n Antagonizes the effects of insulin
n Decreases the peripheral utilization of glucose
n Increases hepatic glucose glucose production via
gluconeogenesis
n
EFFECTS OF GROWTH
HORMONE
n In liver, GH increases liver glycogen
n Promotes the release of free fatty acids and glycerol
from adipose tissue
n Increases oxidation of free fatty acids in the liver
n Promotes a positive calcium, magnesium, and
phosphate balance
n Causes retention of sodium, potassium and chloride
ions
n Promotes the growth of long bones
n Stimulates lactogenesis
n
Genetic deficiencies associated
with GH
n GH-deficient dwarfs lack the ability to
synthesize or secrete GH, and these short-
statured individuals respond well to GH
therapy
n Pygmies lack the IGF-1 response to GH but
not its metabolic effects; thus in pygmies
the deficiency is post-receptor in nature
n Laron dwarfs have normal or excess plasma
GH, but lack liver GH receptors and have
low levels of circulating IGF-1. The defect
in these individuals is clearly related to an
inability to respond to GH by the
production of IGF-1
n The production of excessive amounts
of GH before epiphyseal closure of
the long bones leads to gigantism
n When GH becomes excessive after
epiphyseal closure, acral bone
growth leads to the characteristic
features of acromegaly
n
 PROLACTIN
n Peptide hormone
synthesized and
secreted by lactotrope
cells in the anterior
pituitary gland
n Prolactin is a single chain
polypeptide of 199 amino
acids with a molecular
weight of about 24,000
daltons
n The molecule is folded due
to the activity of three
disulfide bonds
n The prolactin receptor - encoded by a
gene on Chromosome 5 - interacts with
the prolactin molecule as a
transmembrane receptor
n A specific second messenger has not yet
been identified.
n Pituitary prolactin
secretion is
regulated by
neuroendocrine
neurons in the
hypothalamus,
most importantly by
neurosecretory
dopamine neurons
of the arcuate
nucleus, which
inhibit prolactin
secretion.
n
n Prolactin has many effects, the most important
of which is to stimulate the mammary glands
to produce milk (lactation).
n Increased serum concentrations of prolactin
during pregnancy cause enlargement of the
mammary glands of the breasts and increases
the production of milk.
n However, the high levels of progesterone during
pregnancy act directly on the breasts to stop
ejection of milk. It is only when the levels of
this hormone fall after childbirth that milk
ejection is possible.
n Another effect, recently discovered by the
University of Paisley and the Technische
Hochschule Zürich, is to provide the
body with sexual gratification after
sexual acts
n The hormone represses the effect of
dopamine, which is responsible for
sexual arousal, thus causing the male's
refractory period. The amount of
prolactin can be an indicator for the
amount of sexual satisfaction and
relaxation. Unusual high amounts are
suspected to be responsible for
impotence and loss of libido
n The prolactin receptor, a member of the
hematopoietin/cytokine receptor
superfamily, is ubiquitously expressed
by cells in the immune system
n Certain subpopulations of lymphocytes
synthesize and secrete biologically
active prolactin, which suggests that
prolactin can act as an autocrine and/or
paracrine factor to modulate the
activities of cells of the immune system.
n Tumors of prolactin-secreting cells
cause amenorrhea and galactorrhea
in women
n Excess PRL is associated with
gynecomastia and impotence in men
CHORIONIC
SOMATOMAMMOTROPIN (CS;
PLACENTAL LACTOGEN)
n a polypeptide placental hormone
n structure and function is similar to that of
human growth hormone
n modifies the metabolic state of the mother
during pregnancy to facilitate the energy
supply of the fetus
n HPL is an anti-insulin.