ENDOCRINOLOGY Notes 2 PDF

ENDOCRINOLOGY
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OUTLINE
• Chemical messenger systems • Hypothalamic-Hypophysial
• Classification of hormones system
• Synthesis • Anterior pituitary hormones
• Storage • ACTH
• Secretion • TSH
• Regulation • LH and FSH
• Transport • GH
• Plasma levels and plasma • Proalctin
activity
• Clearance • Clinical correlation
• Properties of receptors • Posterior pituitary hormones
• ADH
• Mechanism of action of • Oxytocin
hormones
Introduction to Endocrinology
The body’s many functions are
regulated by:
1.Nervous system
2.Endocrine / Hormonal system
CHEMICAL MESSENGER (SIGNAL) SYSTEMS
o The body’s multiple activities are coordinated

by the chemical messengers (signals) oTypes (1/more):
o Autocrines
o A chemical messenger is a molecule produced
at one location, then transported to another o Paracrines
location to produce a response o Telecrine hormones
o Neurotransmitters
o Cytokines
Telecrines
ENDOCRINE SYSTEM
oHormone
 Any compound produced by a cell, which by

binding to its specific receptor alters the
metabolism of the cell
 May be autocrine, paracrine, or telecrine in

function
o Endocrine Hormones
 Secreted by the endocrine glands and tissues
 Distributed by the circulation throughout the body
 Target may be different types of cells or a specific

type of cell
 Produces global effects in the control of almost all

body functions
Classification of Hormones
2 Major Classes of Hormones Classification according to chemical

structure
 Water-soluble hormones
o Peptides and proteins
 Lipid-soluble hormones o Amines – derivatives of tyrosine
 Catecholamines
 Thyroid hormones
o Steroids
Water-soluble Hormones Lipid-soluble Hormones
Chemical Structure Peptides & proteins Steroids
Catecholamines Thyroid hormones (T3 & T4)
Synthesis Peptides & proteins – in ribosomes Steroids – from cholesterol
Catecholamines – from tyrosine T3 & T4 – from tyrosine
Storage Stored in vesicles Synthesized as needed (except thyroid

hormones)
Plasma Transport Dissolved in plasma (free, unbound) Attached to protein carriers
(except adrenal androgens)
Half-life Short (minutes) Long (hours, days)
Proportional to molecular weight Proportional to affinity for carrier
Receptor Membrane Cytoplasm or nucleus
Intracellular actions Second messengers Synthesis of specific new proteins
Protein phosphorylation
Onset of Action Fast-acting Slow-acting
Intake Injection, mucosal Oral

SYNTHESIS of PEPTIDES & PROTEINS
o Synthesized in the rough

endoplasmic reticulum initially
as large PREPROHORMONE
(biologically inactive)
o Cleaved to smaller
PROHORMONE that contains
the active hormone + inactive
peptide
o Packaged into storage vesicles

SYNTHESIS of STEROIDS
 Similar structure as cholesterol
 Synthesized from cholesterol by a

series of enzymatic modifications
that confer specificity
SYNTHESIS of AMINE DERIVATIVES
 CATECHOLAMINES
o Dopamine, epinephrine, norepinephrine
 Synthesized from tyrosine by a series of

enzymatic modifications that confer
specificity
o Produced in the adrenal medulla and

neurons
SYNTHESIS of AMINE DERIVATIVES
 THYROID HORMONES
 Synthesis of thyroglobulin from tyrosine
 Iodide uptake
 Oxidation of iodide to iodine
 Organification
 Iodination of thyroglobulin
 Formation of MIT & DIT
 Coupling to form T3 & T4


hormones)

o Storage of Water-soluble Hormones
 SECRETORY VESICLES
o Store the prohormone (active hormone + inactive peptide)
o Also contain endopeptidase that will release active
hormone
o Hormones are released by regulated exocytosis
o Secretion occurs in response to a stimulus
o Increased cytosolic Ca+ - main stimulus
o Vesicle fuses with the membrane, granular contents are

extruded into interstitial fluid or directly into the blood
stream
STORAGE & SECRETION of LSH
o Storage of Lipid-soluble Hormones o Secretion of Lipid-soluble Hormones
 Hormones are synthesized as needed  Hormones diffuse across the cell
membrane to enter interstitial fluid
 Usually very little hormone storage in endocrine then the blood
cells
 Large stores of cholesterol esters in cytoplasmic

vacuoles can be rapidly mobilized for steroid
synthesis
 Exception: Thyroid hormones

 Have a large reservoir in thyroid gland follicles by
incorporation into thyroglobulin
REGULATION of SECRETION
o Plasma concentrations of hormones are o FEEDBACK CONTROL
closely controlled within a narrow range  POSITIVE FEEDBACK
of values o Less commonly, the biological action of a
hormone results in additional secretion
o 3 Mechanisms of Regulation o “Gives” at a critical point
 Plasma level of a chemical
(hormone or its product)  NEGATIVE FEEDBACK
o Main mechanism of control for most hormones
 Another hormone
o After a stimulus causes hormone release, the
 Nervous system conditions or products resulting from hormone
action will suppress further release
o To ensure the proper level of hormone activity at
the target tissue
Physiologic-response driven feedback
loop
o Regulation by the hormone product or an

extracellular parameter that represents the
conditions resulting from the physiologic
actions
o A change in the levels of the hormone

product or the extracellular parameter will
increase or decrease hormone secretion
o The controlled variable is the activity of the

target tissue
Endocrine-axis driven feedback loop
o Regulation by a hormone itself

o Hormone in the axis will suppress
further secretion of other hormones in
the axis
o e.g. HPO axis
 CYCLIC VARIATION
o Periodic variations in hormone release
o Influenced by:
o Seasonal changes
o Stages of development and aging
o Circadian (diurnal) rhythm
o Sleep
o Usually due to changes in activity of

neural pathways that control hormone
secretion

hormones)

PLASMA TRANSPORT
o Water-soluble Hormones o Lipid-soluble Hormones
 Dissolves in plasma
 Covalently bound to protein carriers
 Proteins and peptides are in the plasma
transported free or unbound  Usually albumin, globulin
 Exception: IGF and GH – may be  Protein carriers are produced by the
protein-bound liver
 Catecholamines are transported in  Exception: ADRENAL ANDROGENS

the plasma free, conjugated with  Rendered water-soluble by
other substances, or may be loosely- conjugation to sulfate
bound to albumin
PLASMA TRANSPORT
 Free / unbound hormones  Protein-bound hormones

 Biologically active  Bound hormones cannot easily
diffuse across capillaries and gain
 Act on the target tissues and exert the access to target tissues
peripheral physiologic effects of the
hormone  Biologically inactive (until they
dissociate)
 Exert negative feedback  Protein-binding will slow

clearance and prolong the half-
life
 Cleared by cellular uptake and
metabolism
PLASMA LEVELS & PLASMA ACTIVITY
 Bound fraction is in equilibrium with
the free fraction
 Bound fraction is used to replenish the
free fraction
 Bound fraction provides a reservoir to

buffer acute changes in hormone
secretion
 Free fraction levels are precisely regulated
 Any changes in the bound fraction will cause a transient and opposite change
in the free fraction
 Precise negative feedback mechanisms will be activated to modify the rate of

hormone secretion and return the free fraction to its normal level
 Total hormone level will change in the same direction as the bound fraction
PLASMA LEVELS
o Water-soluble Hormones
o Total hormone level = total circulating hormones
o Lipid-soluble Hormones
o Most of the circulating hormones are bound to plasma
proteins
o Total hormone level = bound + free hormones

 < 1% free, unbound
 > 99% bound
o Index of plasma hormone activity
 Normally, determined by the free unbound

from only
 Water-soluble Hormones
 Total circulating hormone level indicates
plasma activity
 Lipid-soluble hormones
 Free fraction level – better index of plasma
activity

hormones)

PROPERTIES of RECEPTORS
Specificity of receptors
o Hormones are distributed by the blood
throughout the body but will bind only to target
cells with the specific, cognate receptors
o Only the target cells for the hormone can respond
Hormone activity
o Under normal conditions, receptors are not
saturated
o The number of receptors is not the rate limiting
factor for hormone action
o Plasma activity is usually indicated by the plasma
concentration of the free hormone
MECHANISM of ACTION
 When a hormone binds to its specific receptor, a cascade of

reactions in the cell is initiated, resulting in the physiologic actions of
the hormone
Receptor Membrane Steroids - cytoplasm
Thyroid hormones - nucleus
Intracellular signalling Formation of second Hormone-receptor complex binds
after receptor activation messengers to a HRE in the enhancer or
silencer region of certain genes
Activation of protein kinases
Cascade of reactions Protein phosphorylation to Activation of enhancer or silencer
modify the activity of enzymes, region controls gene expression
ion channels, and other proteins (requires hours)
(requires minutes)
No kinase activity
Phosphorylation of gene
regulatory proteins such as
CREB to control gene expression
(requires hours)
Actions that mediate Modified activity of proteins, Synthesis of new proteins (hours)
physiologic effects of e.g. activation/inactivation of
hormone enzymes, open/close ion
channels (minutes)
Mechanism of Action for Water-soluble Hormones
o Hormones bind to cognate membrane

receptors
 Ion channel-linked receptors (inotropic)
 G protein-linked receptors (metabotropic)
 Enzyme-linked receptors (catalytic)

Mechanism of Action of Water-soluble
Hormones
 Ion channel-linked Receptors  G protein-linked Receptors
 Enzyme-linked Receptors
 Utilized by almost all neurotransmitters and
some hormones o Hormones indirectly exert their effects via
intracellular cell signaling mechanisms (signal
 Binding to an ion channel-linked receptor will transduction)
directly open or close an ion channel
o Initiates a cascade of reactions leading to the
 The resulting alteration of ion flux across the modification of the cell’s metabolism and gene
membrane will exert the physiologic effects of expression
the chemical messenger
oG protein
 GTP-binding protein
 Trimeric – α, ß, ϒ subunits
 Coupled to cytosolic domain of the

membrane receptor of a water-soluble
hormone
 Subtypes:
 Gs – stimulatory
 Gi – inhibitory
• G protein-linked Receptors and
Second Messengers
 Events that occur upon binding of a

water-soluble hormone to its cognate G
protein-linked receptor:
 The hormone binding to receptor acts as

the “first messenger”
 The receptor undergoes a conformational
change that activates the G protein
 G protein becomes activated by binding to
GTP
 The activated α subunit dissociates from
complex
 Events that follow activation of the G
protein α subunit:
o Opening/closing of an ion channel
o Modification of the activity of an enzyme
 The activated enzyme acts as an effector

molecule
 The effector molecule forms second
messengers
 The second messenger activates a protein
kinase
 An enzyme cascade is initiated leading to the
phosphorylation of proteins in the cell
o Results of protein phosphorylation:

 Modification of enzyme activity
 Modification of gene expression to promote
protein synthesis
SECOND MESSENGER SYSTEMS
o cAMP system
o PIP2 system
o Calcium-Calmodulin system
ocGMP system
Summary of Signal Transduction by Water-
Soluble Hormones
Pathway G-protein Enzyme (effector Second Protein kinase Examples
molecule) Messenger
cAMP system Gs Adenyl cyclase cAMP Protein kinase A Glucagon

ADH (V2)
G-protein-linked Epinephrine (ß)
Gi Epinephrine (α2)
PIP2 system Gq Phospholipase C IP3 Protein kinase C ADH (V1)
DAG Epinephrine (α1)
G-protein-linked Calcium
cGMP system No G-protein Guanyl cyclase cGMP Protein kinase G ANP

Nitric oxide
Enzyme-linked
Enzyme-linked Monomeric No effector No second Tyrosine kinase Insulin

p21ras molecule messenger IGF
PDGF
No trimeric EGF
G-protein
cAMP
Hormones that use the cAMP messenger
system
• CRH
• GHRH (Levy) • PTH
• GHIH • Calcitonin
• TSH • Glucagon
• ACTH • HCG
• LH • Catecholamines (ß1, β 2, α2)
• FSH • Secretin
• ADH (V2) • Somatostatin
Phosphatidylinostol Bisphosphate (PIP2)
Hormones that use the Phospholipase C Messenger
System
• Angiotensin II
• Catecholamines (α1)
• Vasopressin (V 1)
• Oxytocin
• GnRH
• GHRH
• TRH
oCalcium-Calmodulin Messenger
System
 Calcium enters when calcium channels open due
to:
 Changes in membrane potential
 Interaction between hormone and ion-linked
receptor
 Results of activation:
 Activation/inhibition of protein kinases
 Phosphorylation and activation of proteins
ENZYME-LINKED RECEPTORS
 Receptor with intrinsic enzyme activity
 Insulin – tyrosine kinase
 ANP – guanylate cyclase
 Receptor closely associated with an intracellular

enzyme
 Leptin – tyrosine kinase
cGMP
• ANP
• Nitric oxide
Insulin
o Leptin (adipokine, adipocytokine)
 Secreted by adipocytes
 JAK2 – tyrosine kinase of the janus kinase family
 Activation:
 Hormone binds to receptor
 Phosphorylation and activation of JAK2
 JAK2 phosphorylates other tyrosine residues within the

receptor-JAK2 complex and initiates intracellular
signaling
 Phosphorylation of proteins
o STAT
o MAPK
o PI3K
Lipid-soluble Hormones (GENE ACTIVATION)
o Lipophilic hormones will diffuse

across the target cell membrane
o Cytosolic or nuclear receptors

have DNA-binding domains
o Steroids – cytosolic receptors

o Thyroid hormones – nuclear
receptors
Lipid-soluble Hormones (GENE ACTIVATION)
o Hormone-receptor complex interacts with

specific hormone response element (HRE) in
enhancer (or possibly silencer) regions
associated with certain genes
o Promotion or inhibition of gene expression
o Leads to synthesis of new proteins that will

control new or altered cellular function and carry
out hormone’s physiologic actions
o Takes min, hours, even days

Hypothalamic-Hypophysial System
HYPOTHALAMUS Hypothalamic Nuclei
o Site of synthesis of releasing and inhibitory
hormones that regulate anterior pituitary
secretion
o Site of synthesis of hormones that are
transported to the posterior pituitary
HYPOTHALAMIC NUCLEI RELEASING/INHIBITING
HORMONES
Preoptic GnRH
Supraoptic ADH
Oxytocin
Paraventricular CRH
TRH
ADH
Oxytocin
Arcuate PIF (DA)
GHIH (SST)
GHRH
Ventromedial GHRH
PITUITARY GLAND (HYPOPHYSIS)
Lies in the sella turcica, below the
hypothalamus
Connected to the hypothalamus by the

PITUITARY (HYPOPHYSIAL) STALK
Physiologically divided into 2 lobes:

o Anterior pituitary (adenohypophysis)
o Posterior pituitary (neurohypophysis)
o Intermediate lobe (pars intermedia)

 Rudimentary in humans
 Site of synthesis of MSH
 Hypothalamic Control of Pituitary Secretion
o The hypothalamus receives signals from

various sources in the nervous system
o Collects information concerning the internal

well-being of the body
o Information is used to control secretions of

many globally important pituitary hormones
ANTERIOR PITUITARY
o Regulated by hypothalamic
releasing and inhibitory hormones
o The hypothalamic hormones are

transported to the anterior pituitary
via the HYPOTHALAMIC-
HYPOPHYSIAL PORTAL SYSTEM
o Hypothalamic hormones are released from the nerve
terminals into the tissue fluids
o The hypothalamic hormones are absorbed into the

PRIMARY CAPILLARY PLEXUS in the lower
hypothalamus
o Then the hypothalamic hormones continue down the

HYPOTHALAMIC HYPOPHYSIAL PORTAL VESSELS
along the pituitary stalk
o Then they are carried directly into the SECONDARY

CAPILLARY PLEXUS in the anterior pituitary
o Hypothalamic hormones diffuse out of

capillaries into secretory cells in anterior
pituitary to promote/inhibit secretion of
pituitary hormones
o Anterior pituitary hormones are secreted and

absorbed by the anterior pituitary capillaries,
then carried out by the venous outflow into
general circulation
POSTERIOR PITUITARY
o Regulated by neural signals that

originate in the hypothalamus
o Hormones are transported down

HYPOTHALAMIC-HYPOPHYSIAL
TRACT
o ADH and oxytocin are synthesized in the cell bodies

of MAGNOCELLULAR NEURONS in the
hypothalamus
o The hormones are packaged into granules then

transported by carrier proteins called
NEUROPHYSINS
o The hormones are carried down axons forming the

HYPOTHALAMIC-HYPOPHYSIAL TRACT
o The hormones are delivered to the nerve terminals

located in the posterior pituitary
o When nerve signals are transmitted

downward along the nerve fibers, the
hormones are released from the secretory
granules in the nerve terminals
o Hormones are absorbed into the posterior

pituitary capillaries located adjacent to the
nerve terminals
o Hormones are carried out of the posterior

pituitary by venous outflow into the general
circulation
ANTERIOR PITUITARY (ADENOHYPOPHYSIS)
Secretory cell Tropic % of cell Histological
hormone population staining
o Arises embryologically from the Rathke’s produced
pouch Corticotrophs ACTH 20% Basophilic
Thyrotrophs TSH 3-5% Basophilic
o Histology Gonadotrophs LH 3-5% Basophilic
 Secretory cells FSH
 Sinusoidal capillaries Somatotrophs Growth 30-40% Acidophilic

hormone (GH)
Lactotrophs Prolactin (PRL) 3-5% Acidophilic
(mammotrophs)
ANTERIOR PITUITARY
• Regulation: Endocrine Axis (HPO Axis)
• Hypothalamus
• Anterior pituitary
• Target organ (peripheral endocrine gland)
• The axis functions semi-autonomously relative to the physiologic changes

that it produces
• The axis activity has a set-point generated by the integration of

hypothalamic stimulation and peripheral hormone negative feedback
• The hormones in the axis are secreted in a pulsatile manner

• Except: thyroid system
• The pulsatile secretion of an axis is entrained to the daily and seasonal

rhythms through CNS input
o Anterior Pituitary secretion is
controlled by HYPOTHALAMIC
RELEASING & INHIBITORY HORMONES
(FACTORS)
 TRH
 CRH
 GnRH
 GHRH
 GHIH (Somatostatin)
 PIF (Dopamine)
DAMAGE TO PITUITARY STALK
o Connection between the
hypothalamus and anterior pituitary
is severed
o Secretion of all anterior pituitary

hormones decreases
o Exception: Prolactin increases due to

removal of chronic inhibition by PIF
POSTERIOR PITUITARY
o Histology
 Arises embryologically from a neural tissue
outgrowth of the hypothalamus
 Composed mainly of PITUICYTES
 Contains the terminal nerve fibers and

terminal nerve endings of the supraoptic and
paraventricular axons
 Nerve endings lie on the surfaces of

fenestrated capillaries
POSTERIOR PITUITARY
o Secretions Synthesized in the Hypothalamus
 ADH
 Oxytocin
o If pituitary stalk is severed or if posterior

pituitary loses function (with intact
hypothalamus)
 Hormones have a transient decrease for a

few days
 Then continue to be secreted normally
 Released out of the cut ends of the nerve
fibers within the hypothalamus
ANTERIOR
PITUTIARY
HORMONES
ACTH & β-LPH
Growth Hormone
TSH
LH & FSH
Prolactin
ACTH
 ACTH is packaged as the POMC
prohormone in vesicles in the
corticotrophs of the anterior pituitary
 PRO-OPIOMELANOCORTIN (POMC)
 ACTH
o ACTH is the only active
o Contains sequence for α-MSH
 N-terminal peptide
 ß-Lipotropin
o ß-MSH
o Endorphins
 Modulate pain perception
 Useful feature in response to
stress
ACTH
ACTH acts on the adrenal gland
o ACTH acts on the zona fasciculata-

reticularis of the adrenal cortex
o ACTH stimulates and controls the

release of both cortisol and adrenal
androgens
o Aldosterone produced in the zona

glomerulosa is mainly regulated by
angiotensin II
Region Hormone produced Regulation
Zona glomerulosa Aldosterone Angiotensin II

ECF potassium
Zona fasciculata Cortisol ACTH
Zona reticularis Androgens ACTH

ACTH
Normal hormonal output of zona fasciculata-reticularis
 11-Deoxycorticosterone
 Weak mineralocorticoid
 Corticosterone
 Weak glucocorticoid
 Adrenal Androgens (DHEA and A)
 Weak androgens
 Cortisol
 Main glucocorticoid
 Responsible for most of the hypothalamic and anterior pituitary negative feedback
control
ACTH
 Acute Actions
 Increases steroid synthesis in
the adrenal cortex
 Increased pregnenolone
 Seen within minutes
 Chronic Actions
 Increases gene expression of
steroidogenesis enzymes and
cholesterol receptors
 Seen within hours
 Trophic actions on zona

fasciculata/reticularis
ACTH
HPA axis
o CRH
 Synthesized in the paraventricular nuclei
 Co-expressed with ADH - will potentiate CRH action
 Actions:
 Acutely, it increases ACTH secretion
 Less acutely, it increases POMC gene transcription
 Chronically, it promotes corticotroph hypertrophy and proliferation
ACTH HPA axis
o CRH, ACTH, and cortisol secretion are pulsatile
and diurnal
o Factors that stimulate the axis:

 Early morning
 Peak cortisol secretion occurs early in the
morning (between 6-8th hours of sleep)
 Cortisol secretion declines during the day
and reaches a low point in the late evening
 Stress
 Cortisol is a key stress/catabolic hormone
 Overrides circadian rhythm and negative
feedback
 Persistent and exaggerated secretion
 Cytokines (IL-1, IL-2, IL-6)

ACTH
HPA axis
 CRH & ACTH release are
suppressed by cortisol
(negative feedback)
 Hypothalamus
 Decreased CRH secretion
 Decreased pro-CRH gene expression
 Anterior pituitary
 Decreased ACTH secretion
 Decreased POMC gene expression
ACTH
 MSH
 Supraphysiologic ACTH
 ACTH binds to low-affinity
receptors in melanocytes
 Stimulation of melanin synthesis
causes skin darkening
 Uncertain whether d/t α or ß-MSH
 e.g. Addison disease (primary

hypocortisolism)
ACTH
Enzyme Deficiencies
 Congenital “inborn errors of metabolism”
 21 β-Hydroxylase
 11 β-Hydroxylase
 17 α-Hydroxylase
 Always cause cortisol deficiency

 Loss of negative feedback on ACTH
 High ACTH secretion
 Complete adrenal hyperplasia
 Due to high ACTH levels that overstimulate the adrenals
• Disorders of Cortisol Secretion
Plasma Cortisol Plasma ACTH
Primary Hypercortisolism ↑ ↓
Secondary (Pituitary) ↑ ↑
Hypercortisolism
Primary Hypocortisolism ↓ ↑
(Addison’s Disease)
Secondary Hypocortisolism ↓ ↓
TSH
Promotes the secretion of the thyroid hormones
o T4 (Thyroxine)
 Main circulating form
 Exerts most of the negative feedback on TSH & TRH secretion
o T3 (Triidothyronine)
 More active form
 In peripheral tissues, T4 is converted to T3
 T3 will mediate the peripheral effects, including the effects on the anterior pituitary and
hypothalamus
TSH
Promotes the secretion of the thyroid
hormones
Negative Feedback
o Negative feedback is mainly exerted at the anterior
pituitary level, but also occurs at the hypothalamic level
o T4 exerts principal negative feedback
o Within the thyrotrophs, T4 is converted to T3

 T3 will decrease TSH secretion
 Decrease in the sensitivity of thyrotrophs to
TRH
 Decrease in expression of TSH-β and prepro-
TRH genes
 Other factors for TRH & TSH
secretion
o TRH
 Diurnal – peak during overnight hours,
lowest around dinnertime
 Numerous CNS-mediated stimuli
 Inhibited by stress
o TSH
 Inhibited by somatostatin
TSH
Overall Effects of TSH on the Thyroid
o Rapidly induced TSH effects (minutes or 1 hr)
 Increase all steps in synthesis and degradation of thyroid
hormones
o Slowly induced TSH effects (hours or days)

 Increased blood flow to the thyroid gland
 Increased hypertrophy of the thyroid cells, initially leading to
goiter
o Goiter
 Eventually formed due to excessive amounts of TSH
 Simply an enlarged thyroid gland
 Does not reflect functional status
 May exist in hypo-, hyper-, euthyroid
TSH
• Disorders of Thyroid Hormone Secretion
T4 TSH TRH
Primary hypothyroidism ↓ ↑ ↑
* goiter
Secondary (Pituitary) Hypothyroidism ↓ ↓ ↑
Tertiary (Hypothalamic) Hypothyroidism ↓ ↓ ↓
Secondary (Pituitary) Hyperthyroism ↑ ↑ ↓

*goiter
Graves’ disease (autoimmune) ↑ ↓ ↓

*goiter
FSH & LH
GnRH
o Released from the pre-optic nucleus of the
hypothalamus
o Promotes the release of LH & FSH from
gonadotrophs
o Regulation of LH & FSH secretion are both

under GnRH control but are independent
of each other
 Not co-secreted in equimolar quantities
 Pulse frequency
 1/hr – preferential secretion of LH
 1/3 hrs – preferential secretion of FSH
 Androgen secretion
o LH has no role in the regulation of adrenal androgens
o Gonadal and adrenal androgen secretion are independently regulated
FSH & LH
• MALE REPRODUCTIVE SYSTEM
Target Cells of LH & FSH in the Testis

o LH acts on Leydig cells that secrete testoserone
o FSH acts on Sertoli cells that support
spermatogenesis
Negative Feedback
o Testosterone from Leydig cells suppresses LH &
GnRH secretion
o Inhibin from Sertoli cells suppresses FSH secretion
FSH & LH
MALE REPRODUCTIVE SYSTEM
 LH Actions on the Leydig cell:
 Acutely, it activates desmolase to

promote synthesis of testosterone
 Less acutely, it increases gene expression

of steroidogenic enzymes and of LDL &
SR-BI receptors
 Chronically, it promotes Leydig cell

growth & proliferation
FSH & LH
• MALE REPRODUCTIVE SYSTEM
o Sertoli cell
o Target cell of FSH

o Nurse cell for sperm
o Normal spermatogenesis requires both
FSH & testosterone
 FSH is essential for the initiation of
spermatogenesis
 Testosterone acts locally to facilitate
spermatogenesis
o Secretes inhibin
 Exerts negative feedback on FSH
FSH & LH MALE REPRODUCTIVE SYSTEM
o NEGATIVE FEEDBACK
 Testosterone and its metabolites will exert
negative feedback on LH and GnRH
secretion
 Anterior pituitary
 Decreases LH-ß gene expression
 Decreases GnRH receptor gene
expression
 Hypothalamus
 Decreases GnRH secretion
 Inhibin from Sertoli cell will

suppress FSH secretion
Sex steroids LH FSH
Primary ↓ ↑ ↑
hypogonadism
Pituitary ↓ ↓ ↓
hypogonadism
Anabolic steroid ↑ ↓ ↓
therapy
GnRH infusion ↓ ↓ ↓
(constant)
GnRH infusion ↑ ↑ ↑
(pulsatile)
FSH & LH
• FEMALE REPRODUCTIVE SYSTEM
Target cells in the ovary (follicular  Negative feedback
phase)  Estrogen from granulosa cell (follicular phase)
 Initially exerts negative feedback on LH & FSH from the
o LH – theca cells anterior pituitary, and GnRH from the hypothalamus
o FSH – granulosa cells  Later in the phase, there is a switch to positive
feedback on LSH & FSH from the anterior pituitary
Target cells in the ovary (luteal

 Progesterone from luteal cells (luteal phase)
phase)  Negative feedback on LH from the anterior pituitary,
and GnRH from the hypothalamus
o LH – theca lutein cells and granulosa
lutein cells
 FOLLICULAR PHASE
o LH acts on theca cells
 LH promotes the synthesis of androgens
 Androgens diffuse to adjacent granulosa cells
o FSH acts on granulosa cells

 FSH promotes the conversion of androgens to
estrogen
 ESTROGEN
 Exerts negative feedback on:
 LH & FSH secretion by the anterior
pituitary
 GnRH secretion by the hypothalamus
 Granulosa cell secretes inhibin
o High circulating estrogen causes LH & FSH surge
 The estrogen-induced negative feedback on LH &
FSH is converted to a positive feedback
 Increased GnRH pulse amplitude and frequency
 Increased sensitivity of gonatotrophs to GnRH
o Increased GnRH receptors
o Increased post-receptor cell signaling
components
oLH surge is essential to ovulation

LUTEAL PHASE
o LH stimulates lutein theca and
granulosa cells
o Secretes mostly progesterone, some

estrogen
o Progesterone exerts negative

feedback on LH
o As LH decreases, progesterone and

estrogen decrease
 Effect of Suckling on FSH & LH
Secretion
 Inhibits GnRH and decreases FSH
& LH secretion
 Inhibits PIF and increases PRL

secretion
 Further inhibits GnRH and
decreases FSH & LH secretion
 Result in suppression of follicular

growth, ovulation, and menses
PROLACTIN
Other factors affecting secretion:
Secreted by lactotrophs  Decrease
 PRL negative feedback – release of PIF
 Dopamine agonists (Bromocriptine)
Secretion is controlled almost entirely  Somatostatin (GHIH), GH, TSH
by PIF (dopamine)
 From the hypothalamus  Increase
 Prolactin releasing factor
 Provides tonic inhibition
 TRH, glucagon family
 High plasma estrogen in pregnancy
 Breastfeeding
 Dopamine antagonists
 Sleep
 Stress
PROLACTIN
Actions:
o Contributes to estrogen and progesterone for growth of mammary tissue
o Milk Synthesis (Lactation)
o Inhibits ovulation in women and spermatogenesis in men
 PRL decreases the release and synthesis of GnRH
 Thus, FSH & LH secretion are likewise decreased
PROLACTIN
oMilk Synthesis (Lactation)
 Suckling reflex
 Inhibits PIF release from the
hypothalamus, thus increasing PRL
secretion
 Sustains lactation
 Plasma PRL surges

 Intermittent PRL secretion during
breastfeeding
 Lasts approximately 1 hr
 Directly proportional to duration and
frequency of breastfeeding
PROLACTIN
o Milk Synthesis / Lactation
 Pregnancy
 PRL is secreted in response to high plasma
estrogen in late pregnancy
 PRL peripheral effects are blocked by high plasma
estrogen & progesterone
 Parturition
 Sudden drop in plasma estrogen removes the block
 High PRL levels combined with increased PRL
receptors in mammary tissue leads to milk
synthesis
 Breastfeeding
 Plasma PRL returns to non-pregnant levels a few
weeks after birth
 Suckling will generate surges in prolactin secretion
GROWTH HORMONE (SOMATOTROPIN or
SOMATOTROPIC HORMONE)
 Half-life is < 20 min  Normal GH plasma

o Only weakly bound to protein concentration
o Wide variation – 0-30 ng/ml
 Secretion o Usually 0-3 ng/ml
o Pulsatile
o Diurnal
 Entrained to sleep/wake cycle  Actions
 Increase in pulses in evening, o General growth-promoting effect
during deep sleep o Specific metabolic effects – both
catabolic/stress and anabolic
effects
 CATABOLIC/STRESS
EFFECTS
o All are direct actions
o Consistent with
acute actions
 ANABOLIC EFFECTS
o Most are indirect,
except for direct
protein effects
o Most are consistent
with chronic/long-
term actions
 DIRECT CATABOLIC EFFECTS
o Mobilizes fat from adipose tissues and raises

free fatty acids in the plasma
 Fats are preferentially metabolized over

carbohydrates and proteins
 Increases the activity of hormone-sensitive

lipase in adipocytes (lipolysis)
 Increased fatty acid uptake in muscle and

liver
 Free fatty acids undergo β-oxidation to

produce energy
 If GH is excessive, it may become ketogenic
 Increases lean body mass and decreases

body fat
DIRECT CATABOLIC EFFECTS
o Decreases glucose utilization throughout
the body and raises plasma glucose
 Decreases glucose uptake in tissues

(muscle and fat)
 Increases liver gluconeogenesis
 Increases insulin secretion due to high

plasma glucose
o Decreases glucose utilization throughout the body and raises plasma
glucose
 GH is hyperglycemic and diabetogenic
 GH attenuates the action of insulin and causes insulin resistance
 Normal levels of GH are needed for normal pancreatic islet cell function and
insulin secretion
 Adequate insulin activity and carbohydrate availability is necessary for GH to

be effective
DIRECT ANABOLIC EFFECTS
o Increased uptake of amino acids into

cells for protein synthesis
 Enhancement of amino acid transport
through cell membranes
 Enhancement of RNA translation
 Enhancement of DNA transcription
 Decreased catabolism of protein and

amino acids
INDIRECT ANABOLIC EFFECTS
o Major growth-promoting hormone

 Causes growth of almost all tissues
capable of growing
 Promotes bone growth
• GH possibly acts directly to promote growth
• It is believed that most, if not all, of its actions
on bone and other peripheral tissues are
mediated by IGFs
GROWTH HORMONE
• Actions of GH on Bone
 Bone length
 Promotes chrondrogenesis in the epiphyseal plates
 Converts cartilage into new bone, thus increasing the
length of long bones
 Once epiphyseal cartilage is consumed and epiphyses fuse
with the shaft, no further lengthening can occur
 Bone thickness
 GH strongly stimulates osteoblasts to form new bone
 Thickness increases when the rate of bone deposition
exceeds the rate of resorption
 Can occur throughout life
 Especially in membranous bones (jaw, skull)
GROWTH HORMONE
o GH promotes growth via growth factors
o INSULIN-LIKE GROWTH FACTORS (SOMATOMEDINS)

 Synthesized by liver and other tissue due to GH
 Mediate most, if not all, of the GH actions on bone and other

peripheral tissues
 Have a potent effect on increasing all aspects of bone growth
 Increases protein synthesis in most cells and increases organ size
 Increase in lean body mass
 Serum IGF correlates well with growth in children and accounts

for the pubertal growth spurt
 Most important is IGF-I (Somatomedin C)

 IGF-I
 Structure similar to proinsulin
 Have insulin-like activity
 Circulates tightly-bound to a large protein
IGFBP-3 o Plasma concentration closely follows rate of
 Half-life: 20 hrs. GH secretion
 Protein-binding prolongs IGF-I half-life
 IGF-I prolongs the growth-promoting effects of the o Plasma IGF-I is a good index of 24-hr GH
bursts of GH secretion secretion
 Release of IGF-I into plasma depends on GH
secretion
 IGF-II  Long half-life allows for fairly similar results
 Not well understood when tested at any time of the day
 Major fetal IGF  Protein-binding minimizes the diurnal and
pulsatile changes
 Fetal growth regulator
GROWTH HORMONE
REGULATION OF GROWTH HORMONE
SECRETION
o HYPOTHALAMIC REGULATION
 GHRH
 Released from ventromedial nucleus of
the hypothalamus
 Mediates most of the control of GH
secretion
 Acutely, promotes GH secretion by
increase in Ca influx
 Chronically, stimulates synthesis of new
GH by increased gene expression
 GHIH (Somatostatin)
 Inhibits GH secretion
REGULATION OF GROWTH HORMONE SECRETION
 Regulation of long-term anabolic effects

 Pulses are more frequent in pubertal
 Diurnal rhythm
 Peak in early AM (just before awakening) adolescents than in younger children or
 Entrained to the sleep-wake pattern adults
o Accounts for pubertal “growth spurt”

 Pulsatile secretion
o Major drive: pubertal increase in
 Pulses are more likely to occur during the
androgens secretion
night
o In males – testicular
o Pulses increase in first 2 hours of deep
testosterone
sleep (stage 3 & 4 NREM)
o In females – adrenal androgens
 Plasma level is very low in the daytime
REGULATION OF GROWTH HORMONE
SECRETION
 T3 & T4  After adolescence, GH slowly decreases with
 Normal plasma levels of T3 & T4 are age
required for GH secretion
 Decreases significantly during 6th decade
of life and later
 Hypothyroidism is characterized by
reduced GH secretion  In very old age, GH is only 25% of
adolescent level
 May account for muscle wasting in

elderly
REGULATION OF GROWTH HORMONE
SECRETION
o ACUTE CONTROL
 Regulates acute/stress effects
 Related to person’s state of nutrition or stress
 Plasma glucose, free fatty acids, and amino
acids
 All stresses (e.g. starvation/fasting, trauma,
illness, surgery, exposure to cold, and exercise)
 Negative feedback
 GH itself
 IGF-I (HPO axis)
• Factors that promote GH release
• Deep sleep
• All stress situations
• Nutrient factors
• Low plasma glucose or free fatty acids – major regulator in acute
conditions
• Protein deficiency – major regulator in chronic conditions
• Protein meal and increased plasma levels of certain amino acids
• Hormonal factors
• Testosterone and estrogen
• Thyroid hormones
• Catecholamines, dopamine, serotonin
• Glucagon
• Ghrelin
• Stresses
GROWTH HORMONE
• Factors that inhibit GH release

• Negative feedback from GH (endogenous and exogenous) and from
IGF-I
• High plasma glucose or free fatty acids
• Cortisol
• Medroxyprogesterone
• Aging
• Obesity
• Pregnancy
• REM sleep
GROWTH HORMONE
Disorders of GH Secretion
oGH or IGF-1 Deficiency

 Prepuberty – Dwarfism
 Postpubety
oHypersecretion of GH
 Prepuberty – Gigantism
 Postpubety – Acromegaly
GROWTH HORMONE
GH or IGF-1 Deficiency
 Dwarfism
 All body parts develop in appropriate proportion to one another, but
at a greatly decreased rate
 Most cases are due to panhypopituitarism
 Laron Dwarfism
o GH insensitivity due to loss of function mutation of GH receptors
o Normal GH secretion
 African Pygmy and Levi-Lorain dwarf

o Hereditary inability to form IGF-1
o Normal or elevated GH secretion
 Pure GH deficiency
 Can be completely cured if treated with recombinant GH early in life
GROWTH HORMONE
o Hypersecretion of GH
 Gigantism
 Possible causes:
 Overactive somatotrophs
 Acidophilic tumors in anterior pituitary
 Eventual destruction of the pituitary gland by the

tumor causes panhypopituitarism
 Death in early adulthood usually due to

consequences of panhypopituitarism
GROWTH HORMONE
o Hypersecretion of GH
 Acromegaly
 Insidious, chronic, debilitating disease
 Usually due to acidophilc tumors in anterior pituitary
 Characterized by bony and tissue overgrowth

o Enlargement of hands & feet (acral parts)
o Acromegalic facies
 Protrusion of lower jaw (prognathism)
 Overgrowth of facial bones
 Forehead slants forward
 Larger nose
o Kyphosis
o Increase in size of visceral organs
o Impaired cardiac function
o Impaired glucose tolerance
• Panhypopituitarism Sheehan Syndrome
 Decrease in all anterior pituitary
hormones Infarction of the pituitary gland
 Dwarfism Pathophysiology
 In adults  Severe blood loss during delivery
 General effects:  Hypovolemic (hemorrhagic) shock
o Secondary hypothyoroidism  Arteriolar spasm in the pituitary
o Secondary hypocortisolism  Subsequent ischemic necrosis of the
o Secondary hypogonadism pituitary gland
o Lethargy, weight gain, loss of
sexual functions 32% of women with severe post-
 Treated with hormone replacements
partum hemorrhage have some
degree of panhypopituitarism
POSTERIOR PITUITARY
HORMONES
ADH (Vasopressin)
OxYtocin
ADH (Anti-Diuretic Hormone, Vasopressin)
Primarily synthesized in the

supraoptic nucleus, also in
paraventricular nucleus
Released from the posterior pituitary

• ADH (Anti-Diuretic Hormone,
Vasopressin)
Actions
o Increases water permeability of the renal
collecting ducts
 V2 receptors acting via cAMP
 Inserts AQASPORINS into the apical
membranes to form water channels
 Water is passively absorbed
 Urea is also absorbed
 No effect on electrolyte reabsorption
o Vasoconstriction
o At higher concentrations
o V1 receptors acting via PIP2
ADH
• Regulates ECF Volume
 ADH is the major controller of ECF volume
and water excretion
 Stretch receptors
 Chronically inhibit ADH secretion
 Monitor ECF volume using the stretch on
vessel walls
 Atrial and large veins receptors

o Main source of stimulation
o Monitor low pressure side of the
systemic circuit
 Carotid sinus receptors
o Monitor high pressure side of the
systemic circuit
ADH
Regulates ECF Osmolarity
 Osmoreceptors
 Located in or near the hypothalamus
 Very sensitive to changes in osmolarity of

ECF bathing hypothalamus
 As little as 1% change will activate receptors
• Weightlessness suppresses ADH secretion

OXYTOCIN
Primarily synthesized in the
paraventricular nucleus, also in
supraoptic nucleus
Released from the posterior

pituitary
Actions
o Myometrial contraction
o Milk let down / ejection
Oxytocin
o Myometrial contraction
 Plays a role in parturition but is not the initiating  Clinical uses
factor  Administration can be used
to induce labor
 Facilitates delivery
 More important role in
 In latter months of pregnancy, high estrogen levels will causing the uterus to
up-regulate the oxytocin receptors in the myometrium contract immediately after
expulsion of fetus to limit
 Increase in oxytocin secretion rate during labor blood flow and blood loss
 Stimulated by cervical dilation
 Increases prostaglandin synthesis in the uterus

 Prostaglandins increase myometrial contractions
Oxytocin oMilk Let Down
 Milk is secreted continuously into the
alveoli, but does not flow easily from alveoli
into the ducts
 For milk to be expressed, it must be ejected
from the alveoli and into the ducts
 Occurs via the suckling reflex
oSuckling Reflex
 Oxytocin will stimulate the contraction of
myoepthelial basket cells surrounding
alveoli to eject preformed milk from the
alveoli into the ducts
 Will also allow expression in other breast
 Usually within 30 sec – 1 min of suckling
• References:
• Guyton and Hall: Textbook of Medical Physiology
• Bruce M. Koepen, Bruce A. Stanton: Berne and Levy Physiology
• Kim E. Barrett, et. al: Ganong’s Review of Medical Physiology
• Tortora, et. al: Principles of Anatomy and Physiology
• Dunn, et.al: Kaplan Medical - Physiology

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ENDOCRINOLOGY

o The body’s multiple activities are coordinated

 Any compound produced by a cell, which by

 May be autocrine, paracrine, or telecrine in

 Secreted by the endocrine glands and tissues

 Distributed by the circulation throughout the body

 Target may be different types of cells or a specific

 Produces global effects in the control of almost all

2 Major Classes of Hormones Classification according to chemical

Storage Stored in vesicles Synthesized as needed (except thyroid

Intracellular actions Second messengers Synthesis of specific new proteins

Intake Injection, mucosal Oral

o Synthesized in the rough

o Packaged into storage vesicles

 Similar structure as cholesterol

 Synthesized from cholesterol by a

o Dopamine, epinephrine, norepinephrine

 Synthesized from tyrosine by a series of

o Produced in the adrenal medulla and

 Synthesis of thyroglobulin from tyrosine

 Oxidation of iodide to iodine

 Coupling to form T3 & T4

Storage Stored in vesicles Synthesized as needed (except thyroid

Intracellular actions Second messengers Synthesis of specific new proteins

Intake Injection, mucosal Oral

o Hormones are released by regulated exocytosis

o Secretion occurs in response to a stimulus

o Increased cytosolic Ca+ - main stimulus

o Vesicle fuses with the membrane, granular contents are

 Large stores of cholesterol esters in cytoplasmic

 Exception: Thyroid hormones

o Regulation by the hormone product or an

o A change in the levels of the hormone

o The controlled variable is the activity of the

o Regulation by a hormone itself

o Usually due to changes in activity of

Storage Stored in vesicles Synthesized as needed (except thyroid

Intracellular actions Second messengers Synthesis of specific new proteins

Intake Injection, mucosal Oral

 Catecholamines are transported in  Exception: ADRENAL ANDROGENS

 Free / unbound hormones  Protein-bound hormones

 Exert negative feedback  Protein-binding will slow

 Bound fraction provides a reservoir to

 Precise negative feedback mechanisms will be activated to modify the rate of

o Total hormone level = bound + free hormones

 Normally, determined by the free unbound

Storage Stored in vesicles Synthesized as needed (except thyroid

Intracellular actions Second messengers Synthesis of specific new proteins

Intake Injection, mucosal Oral

 When a hormone binds to its specific receptor, a cascade of

o Hormones bind to cognate membrane

 Ion channel-linked receptors (inotropic)

 G protein-linked receptors (metabotropic)

 Enzyme-linked receptors (catalytic)

 Coupled to cytosolic domain of the

 Events that occur upon binding of a

 The hormone binding to receptor acts as

o Modification of the activity of an enzyme

 The activated enzyme acts as an effector

o Results of protein phosphorylation:

cAMP system Gs Adenyl cyclase cAMP Protein kinase A Glucagon

cGMP system No G-protein Guanyl cyclase cGMP Protein kinase G ANP