 The Endocrine System

 Mechanism of Hormone Action

 Control or regulation of Hormone action
 Endocrine System: Overview
• Endocrinology is the study of the endocrine glands
and their secretions.
• The science of endocrinology also includes the study of paracrines.
Paracrines are chemical messengers that are produced by endocrine cells
and diffuse to act locally on adjacent target cells with the appropriate
receptors.
• Reproductive endocrinologists therefore study both longrange and short-
range chemical signaling among the cells and tissues involved in
reproduction.

• Endocrine system – the body’s second great controlling system which

influences metabolic activities of cells by means of hormones
• Endocrine glands – pituitary, thyroid, parathyroid, adrenal, pineal, and
thymus
• The pancreas and gonads produce both hormones and exocrine products
 Endocrine System: Overview
• The hypothalamus has both neural functions and releases hormones
• Other tissues and organs that produce hormones – adipose cells, pockets
of cells in the walls of the small intestine, stomach, kidneys, and heart
• examples:
Atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type
natriuretic peptide (CNP)). Among these, ANP and BNP are secreted by the heart and act
as cardiac hormones.
Cholecystokinin: A small intestinal hormone that stimulates secretion of pancreatic
enzymes and bile. Secretin: Another hormone secreted from small intestinal epithelial
cells; stimulates secretion of a bicarbonate-rich fluids from the pancreas and liver.
 Study of Endocrine System
• A “classical” approach used by early endocrinologists is as follows:
(1) Remove the gland,
(2) Observe the effects of gland removal on the body,
(3) Replacement therapy, which involves administration of a preparation of the
removed gland, and
(4) Observe to see if the replacement therapy reverses the effects of gland removal.
Bioassay was commonly used to indirectly measure the amount of a given hormone in
glandular tissue or blood.
Direct and accurate way to measure the amount of a hormone in tissues or in blood is
radioimmunoassay. Radioimmunoassay is used to measure blood levels of
hormones in humans and other animals, and it has been a valuable tool in
reproductive biology and in tests for disorders of the endocrine system. In 1977,
Rosalyn S. Yalow received theNobel Prize in Physiology or Medicine for her
development of this technique.
• ELISA assays are used for measuring a wide variety of hormones and hormone
products. High performance liquid chromatography (HPLC)
techniques coupled with spectrophotometric analyses are used to identify
hormones and other regulators in biological fluids.
• To measure mixed steroids in plasma or urine samples is gas chromatography
with mass spectrometry.
• Endocrinologists studying the structure and function of endocrine cells use
techniques such as immunocytochemistry and immunofluorescent staining of
cells, imaged with the confocal microscope.
• Advancement: The development of probes to measure mRNA
production to determine when a gene is activated or shut down by a
hormone. Genetically engineered knockout and knock-in mice and rats
are widely used to investigate problems of sexual differentiation and in
behavioral studies. Yeast cells genetically engineered to contain genes
for human estrogen receptors, with the help of reporter genes, can be
used in assays for measuring estrogen activity.
Major Endocrine Organs

Figure 16.1
 Autocrines and Paracrines
• Autocrines – chemicals that exert effects on the
same cells that secrete them
• Paracrines – locally acting chemicals that affect
cells other than those that secrete them
• These are not considered hormones since
hormones are long-distance chemical signals
The hypothalamus, pituitary gland (or hypophysis), pineal gland, gonads (testes and
ovaries), and placenta—all organs of primary importance in human reproduction.
 Hormones
• Hormones – chemical substances secreted by
cells into the extracellular fluids
– Regulate the metabolic function of other cells
– Have lag times ranging from seconds to hours
– Tend to have prolonged effects
– Are classified as amino acid-based hormones, or
steroids
• Eicosanoids – biologically active lipids with
local hormone–like activity
 Types of Hormones
• Amino acid based
– Amines, thyroxine, peptide, and protein hormones
• Steroids – gonadal and adrenocortical hormones
• Eicosanoids – leukotrienes and prostaglandins
• Male sex hormones (androgens) and female sex hormones
(estrogens and progestins) are examples of steroid hormones.
• Androgens are substances that promotethe development and
function of the male reproductive structures.
• Estrogens stimulate the maturation and function of the female
reproductive structures.
• Progestins (or progestogens) are substances that cause the uterus to
be secretory.
 Hormone Action
• Hormones alter target cell activity by one of
two mechanisms
– Second messengers:
• Regulatory G proteins
• Amino acid–based hormones
– Direct gene activation
• Steroid hormones
• The precise response depends on the type of
the target cell
 Mechanism of Hormone Action
• Hormones produce one or more of the
following cellular changes in target cells
– Alter plasma membrane permeability
– Stimulate protein synthesis
– Activate or deactivate enzyme systems
– Induce secretory activity
– Stimulate mitosis
 Amino Acid-Based Hormone Action:
cAMP Second Messenger
• Hormone (first messenger) binds to its
receptor, which then binds to a G protein
• The G protein is then activated as it binds GTP,
displacing GDP
• Activated G protein activates the effector
enzyme adenylate cyclase
• Adenylate cyclase generates cAMP (second
messenger) from ATP
• cAMP activates protein kinases, which then
cause cellular effects
 Amino Acid-Based Hormone Action: cAMP Second
Messenger
Extracellular fluid

Hormone A Adenylate cyclase Hormone B

1 1

2 GTP 3 GTP GTP 3 GTP 2

4
Receptor Gs Gi Receptor
GTP GDP GDP GTP
ATP
cAMP
Catecholamines
ACTH 5
FSH Triggers responses of target
LH cell (activates enzymes,
Glucagon stimulates cellular
PTH secretion, opens ion
TSH Inactive Active channels, etc.)
Calcitonin protein protein
kinase A kinase A
Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second
Messenger
Extracellular fluid

Hormone A Adenylate cyclase

Receptor Gs

Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Hormone A Adenylate cyclase

1

Receptor Gs

Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Hormone A Adenylate cyclase

1

2 GTP
Receptor Gs
GTP GDP
Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Hormone A Adenylate cyclase

1

2 GTP 3 GTP
Receptor Gs
GTP GDP
Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Hormone A Adenylate cyclase

1

2 GTP 3 GTP
4
Receptor Gs
GTP GDP
ATP
cAMP
Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Hormone A Adenylate cyclase

1

2 GTP 3 GTP
4
Receptor Gs
GTP GDP
ATP
cAMP
Catecholamines
ACTH 5
FSH Triggers responses of target
LH cell (activates enzymes,
Glucagon stimulates cellular
PTH secretion, opens ion
TSH Inactive Active channels, etc.)
Calcitonin protein protein
kinase A kinase A
Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Adenylate cyclase Hormone B

Gi Receptor

Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Adenylate cyclase Hormone B

1

Gi Receptor

Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Adenylate cyclase Hormone B

1

GTP 2
Gi Receptor
GDP GTP

Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Adenylate cyclase Hormone B

1

GTP 3 GTP 2
Gi Receptor
GDP GTP

Catecholamines
ACTH
FSH
LH
Glucagon
PTH
TSH
Calcitonin

Cytoplasm
 Amino Acid-Based Hormone Action: cAMP Second Messenger
Extracellular fluid

Hormone A Adenylate cyclase Hormone B

1 1

2 GTP 3 GTP GTP 3 GTP 2

4
Receptor Gs Gi Receptor
GTP GDP GDP GTP
ATP
cAMP
Catecholamines
ACTH 5
FSH Triggers responses of target
LH cell (activates enzymes,
Glucagon stimulates cellular
PTH secretion, opens ion
TSH Inactive Active channels, etc.)
Calcitonin protein protein
kinase A kinase A
Cytoplasm
 Amino Acid-Based Hormone Action:
PIP-Calcium
• Hormone binds to the receptor and activates
G protein
• G protein binds and activates phospholipase
• Phospholipase splits the phospholipid PIP2 into
diacylglycerol (DAG) and IP3 (both act as second
messengers)
• DAG activates protein kinases; IP3 triggers
release of Ca2+ stores
• Ca2+ (third messenger) alters cellular responses
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

DAG
1

4 5 Active
2 GTP 3 GTP PIP2 protein
Receptor Gq kinase C
Inactive
GTP GDP protein
IP3
Catecholamines Phospholipase C kinase C
TRH Triggers responses
ADH 5 of target cell
GnRH
Oxytocin
Endoplasmic 6
reticulum

Cytoplasm Ca2+ Ca2+- calmodulin

 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

Receptor Gq

Catecholamines
TRH
ADH
GnRH
Oxytocin

Cytoplasm
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

Receptor Gq

Catecholamines
TRH
ADH
GnRH
Oxytocin

Cytoplasm
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

2 GTP

Receptor Gq
GTP GDP
Catecholamines
TRH
ADH
GnRH
Oxytocin

Cytoplasm
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

2 GTP 3 GTP PIP2

Receptor Gq
GTP GDP
Catecholamines Phospholipase C
TRH
ADH
GnRH
Oxytocin

Cytoplasm
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

DAG
1

4
2 GTP 3 GTP PIP2
Receptor Gq
GTP GDP
IP3
Catecholamines Phospholipase C
TRH
ADH
GnRH
Oxytocin

Cytoplasm
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

DAG
1

4 5 Active
2 GTP 3 GTP PIP2 protein
Receptor Gq kinase C
Inactive
GTP GDP protein
IP3
Catecholamines Phospholipase C kinase C
TRH
ADH 5
GnRH
Oxytocin
Endoplasmic
reticulum

Cytoplasm Ca2+
 Amino Acid-Based Hormone Action:
PIP Mechanism
Extracellular fluid

Hormone

DAG
1

4 5 Active
2 GTP 3 GTP PIP2 protein
Receptor Gq kinase C
Inactive
GTP GDP protein
IP3
Catecholamines Phospholipase C kinase C
TRH Triggers responses
ADH 5 of target cell
GnRH
Oxytocin
Endoplasmic 6
reticulum

Cytoplasm Ca2+ Ca2+- calmodulin

 Steroid Hormones
• This interaction prompts DNA transcription to
produce mRNA
• The mRNA is translated into proteins, which
bring about a cellular effect
 Steroid Hormones
• This interaction prompts DNA transcription to
produce mRNA
• The mRNA is translated into proteins, which
bring about a cellular effect
 Steroid
hormone
Cytoplasm

Steroid
hormone
Receptor-
chaperonin
complex

Receptor-hormone
complex
Molecular
chaperones

Binding Hormone
response
elements

Chromatin
Transcription

mRNA
mRNA

Nucleus

Ribosome
New protein
Translation

Figure 16.4
Steroid
hormone
Cytoplasm

Figure 16.4
Steroid
hormone
Cytoplasm

Steroid
hormone

Figure 16.4
Steroid
hormone
Cytoplasm

Steroid
hormone
Receptor-
chaperonin
complex

Figure 16.4
Steroid
hormone
Cytoplasm

Steroid
hormone
Receptor-
chaperonin
complex

Receptor-hormone
complex
Molecular
chaperones

Figure 16.4
Steroid
hormone
Cytoplasm

Steroid
hormone
Receptor-
chaperonin
complex

Receptor-hormone
complex
Molecular
chaperones

Binding Hormone
response
elements

Chromatin

Figure 16.4
Binding Hormone
response
elements

Chromatin
Transcription

mRNA

Nucleus

Figure 16.4
 Binding Hormone
response
elements

Chromatin
Transcription

mRNA
mRNA

Nucleus

Ribosome

Figure 16.4
 Binding Hormone
response
elements

Chromatin
Transcription

mRNA
mRNA

Nucleus

Ribosome
New protein
Translation

Figure 16.4
 Steroid
hormone
Cytoplasm

Steroid
hormone
Receptor-
chaperonin
complex

Receptor-hormone
complex
Molecular
chaperones

Binding Hormone
response
elements

Chromatin
Transcription

mRNA
mRNA

Nucleus

Ribosome
New protein
Translation

Figure 16.4
 Target Cell Specificity
• Hormones circulate to all tissues but only
activate cells referred to as target cells
• Target cells must have specific receptors to
which the hormone binds
• These receptors may be intracellular or
located on the plasma membrane
 Target Cell Specificity
• Examples of hormone activity
– ACTH receptors are only found on certain cells of
the adrenal cortex
– Thyroxin receptors are found on nearly all cells of
the body
 Target Cell Activation
• Target cell activation depends on three factors
– Blood levels of the hormone
– Relative number of receptors on the target cell
– The affinity of those receptors for the hormone
• Up-regulation – target cells form more
receptors in response to the hormone
• Down-regulation – target cells lose receptors
in response to the hormone
Hormone Concentrations in the Blood
• Hormones circulate in the blood in two forms
–
free or bound
– Steroids and thyroid hormone are attached to
plasma proteins
– All others are unencumbered
Hormone Concentrations in the Blood
• Concentrations of circulating hormone reflect:
– Rate of release
– Speed of inactivation and removal from the body
• Hormones are removed from the blood by:
– Degrading enzymes
– The kidneys
– Liver enzyme systems
Interaction of Hormones at Target Cells

• Three types of hormone interaction

– Permissiveness – one hormone cannot exert its
effects without another hormone being present
– Synergism – more than one hormone produces
the same effects on a target cell
– Antagonism – one or more hormones opposes the
action of another hormone
 Control of Hormone Release
• Blood levels of hormones:
– Are controlled by negative feedback systems
– Vary only within a narrow desirable range
• Hormones are synthesized and released in
response to:
– Humoral stimuli
– Neural stimuli
– Hormonal stimuli
 Humoral Stimuli
• Humoral stimuli – secretion of hormones in
direct response to changing blood levels of
ions and nutrients
• Example: concentration of calcium ions in the
blood
– Declining blood Ca2+ concentration stimulates the
parathyroid glands to secrete PTH (parathyroid
hormone)
– PTH causes Ca2+ concentrations to rise and the
stimulus is removed
Humoral Stimuli

Figure 16.5a
 Neural Stimuli
• Neural stimuli – nerve
fibers stimulate
hormone release
– Preganglionic
sympathetic nervous
system (SNS) fibers
stimulate the adrenal
medulla to secrete
catecholamines

Figure 16.5b
 Hormonal Stimuli
• Hormonal stimuli – release of hormones in
response to hormones produced by other
endocrine organs
– The hypothalamic hormones stimulate the
anterior pituitary
– In turn, pituitary hormones stimulate targets to
secrete still more hormones
Hormonal Stimuli

Figure 16.5c
 Nervous System Modulation
• The nervous system modifies the stimulation
of endocrine glands and their negative
feedback mechanisms
 Nervous System Modulation
• The nervous system can override normal
endocrine controls
– For example, control of blood glucose levels
• Normally the endocrine system maintains blood
glucose
• Under stress, the body needs more glucose
• The hypothalamus and the sympathetic nervous system
are activated to supply ample glucose
 Major Endocrine Organs: Pituitary
(Hypophysis)
• Pituitary gland – two-lobed organ that
secretes nine major hormones
• Neurohypophysis – posterior lobe (neural
tissue) and the infundibulum
– Receives, stores, and releases hormones from the
hypothalamus
• Adenohypophysis – anterior lobe, made up of
glandular tissue
– Synthesizes and secretes a number of hormones
Major Endocrine Organs: Pituitary
(Hypophysis)

Figure 16.6
Pituitary-Hypothalamic Relationships:
Posterior Lobe
• The posterior lobe is a downgrowth of
hypothalamic neural tissue
• Has a neural connection with the
hypothalamus (hypothalamic-hypophyseal
tract)
• Nuclei of the hypothalamus synthesize
oxytocin and antidiuretic hormone (ADH)
• These hormones are transported to the
posterior pituitary
Pituitary-Hypothalamic Relationships:
Anterior Lobe
• The anterior lobe of the pituitary is an
outpocketing of the oral mucosa
• There is no direct neural contact with the
hypothalamus
Pituitary-Hypothalamic Relationships:
Anterior Lobe
• There is a vascular connection, the
hypophyseal portal system, consisting of:
– The primary capillary plexus
– The hypophyseal portal veins
– The secondary capillary plexus
Pituitary-Hypothalamic Relationships:
Anterior Lobe

Figure 16.6
 Adenophypophyseal Hormones
• The six hormones of the adenohypophysis:
– Abbreviated as GH, TSH, ACTH, FSH, LH, and PRL
– Regulate the activity of other endocrine glands
• In addition, pro-opiomelanocortin (POMC):
– Has been isolated from the pituitary
– Is split into ACTH, opiates, and MSH
 Activity of the Adenophypophysis
• The hypothalamus sends a chemical stimulus
to the anterior pituitary
– Releasing hormones stimulate the synthesis and
release of hormones
– Inhibiting hormones shut off the synthesis and
release of hormones
 Activity of the Adenophypophysis
• The tropic hormones that are released are:
– Thyroid-stimulating hormone (TSH)
– Adrenocorticotropic hormone (ACTH)
– Follicle-stimulating hormone (FSH)
– Luteinizing hormone (LH)
 Growth Hormone (GH)
• Produced by somatotropic cells of the anterior
lobe that:
– Stimulate most cells, but target bone and skeletal
muscle
– Promote protein synthesis and encourage the use
of fats for fuel
• Most effects are mediated indirectly by
somatomedins
 Growth Hormone (GH)
• Antagonistic hypothalamic hormones regulate
GH
– Growth hormone–releasing hormone (GHRH)
stimulates GH release
– Growth hormone–inhibiting hormone (GHIH)
inhibits GH release
Metabolic Action of Growth Hormone
• GH stimulates liver, skeletal muscle, bone, and
cartilage to produce insulin-like growth factors
• Direct action promotes lipolysis and inhibits
glucose uptake
Metabolic Action of Growth Hormone
(GH)

Figure 16.7
 Thyroid Stimulating Hormone
(Thyrotropin)
• Stimulates the normal development and
secretory activity of the thyroid
• Triggered by hypothalamic peptide
thyrotropin-releasing hormone (TRH)
• Rising blood levels of thyroid hormones act on
the pituitary and hypothalamus to block the
release of TSH
 Adrenocorticotropic Hormone
(Corticotropin)
• Stimulates the adrenal cortex to release
corticosteroids
• Triggered by hypothalamic corticotropin-
releasing hormone (CRH) in a daily rhythm
• Internal and external factors such as fever,
hypoglycemia, and stressors can trigger the
release of CRH
 Gonadotropins
• Gonadotropins – follicle-stimulating hormone
(FSH) and luteinizing hormone (LH)
– Regulate the function of the ovaries and testes
– FSH stimulates gamete (egg or sperm) production
– Absent from the blood in prepubertal boys and
girls
– Triggered by the hypothalamic gonadotropin-
releasing hormone (GnRH) during and after
puberty
 Functions of Gonadotropins
• In females
– LH works with FSH to cause maturation of the
ovarian follicle
– LH works alone to trigger ovulation (expulsion of
the egg from the follicle)
– LH promotes synthesis and release of estrogens
and progesterone
 Functions of Gonadotropins
• In males
– LH stimulates interstitial cells of the testes to
produce testosterone
– LH is also referred to as interstitial cell-stimulating
hormone (ICSH)
 Prolactin (PRL)
• In females, stimulates milk production by the
breasts
• Triggered by the hypothalamic prolactin-
releasing hormone (PRH)
• Inhibited by prolactin-inhibiting hormone
(PIH)
• Blood levels rise toward the end of pregnancy
• Suckling stimulates PRH release and
encourages continued milk production
 The Posterior Pituitary and
Hypothalamic Hormones
• Posterior pituitary – made of axons of
hypothalamic neurons, stores antidiuretic
hormone (ADH) and oxytocin
• ADH and oxytocin are synthesized in the
hypothalamus
• ADH influences water balance
• Oxytocin stimulates smooth muscle
contraction in breasts and uterus
• Both use PIP-calcium second-messenger
mechanism