Molecular and Cell Biology of the Endocrine System

Hormone-Receptor Interactions and
Signal Transduction Mechanisms
Molecular and Cell Biology
of the Endocrine System
Marc Imhotep Cray, M.D.

Marc Imhotep Cray, MD
Learning Objectives
2
1. Describe the four classes of chemical messengers and
how they signal cells.
2. Understand the similarities and differences between
the autonomic nervous system and endocrine system
in maintaining homeostasis and integrated cellular
communication.
3. Describe the common characteristics of all hormones.
4. Describe the four major families of receptors.
5. Describe hormone-receptor interactions and signal
transduction mechanisms.

Learning Objectives cont.
3
6. Describe the organization and functional anatomy of the
endocrine system.
7. Describe the chemical nature and classification of hormones.
8. Explain the molecular-cellular mechanism of action of
peptide hormones and how they exert their effects on target
cells.
9. Explain the molecular-cellular mechanisms of action of
steroid and thyroid hormones and how they exert their
effects on target cells.
10. Define binding protein, bound hormone, and free hormone
and discuss the effect of binding proteins on circulating
hormone levels

Organization of
Endocrine System
4
 Hormones are secreted into
blood by endocrine organs
throughout body, affecting
physiological function at various
target sites
Illustration Ledger:
ACTH, adrenocorticotropic hormone;
ADH, antidiuretic hormone; CCK, cholecystokinin;
CRH, corticotropin-releasing hormone; FSH, follicle-
stimulating hormone; GH, growth hormone;
GHRH, growth hormone–releasing hormone;
GIP, gastric inhibitory peptide; GLP-1, glucagon-like
peptide-1; GnRH, gonadotropin releasing hormone;
LH, luteinizing hormone; MSH, melanocyte stimulating
hormone; PRL, prolactin; TRH, thyrotropin-releasing
hormone; TSH, thyroid-stimulating hormone
Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed.
Philadelphia: Elsevier, 2016.

Overview of Endocrine System
5
 Endocrine system uses hormones to transfer information between different
tissues
 It is a finely regulated machine that uses feedback loops and sensors to
ensure constant homeostasis within body
 It plays some form of regulatory role in almost all physiologic processes
 It has effects on development, growth, metabolism and reproduction
and works with almost every organ system, including the nervous and
immune system
 Control is mediated by a combination of neural and endocrine systems
located in hypothalamus and pituitary gland (“The Master Gland”)
 In contrast to neurotransmitters--which work in synapse between neuron
endplate and receptors they act on-- hormones are secreted into circulation
and can work on tissues far away from source of origin

6
Nervous Endocrine
WirelessWired
Closeness Receptor Specificity
Rapid Onset Delayed Onset
Short Duration Prolonged Duration
Rapid Response Regulation
versus
Neurotransmitters Hormones
Short Distance Long Distance
Nervous system vs Endocrine system in homeostasis
 Two major regulatory systems
make important contributions
to homeostasis:
 the nervous system and
 the endocrine system
 Common properties:
 maintain homeostasis
 extensive use of negative
feedback
 high-level integration in brain
 ability to influence processes in
distant regions of body
 both systems use chemicals for
transmission of information

NS vs ES in homeostasis: Differences
7
Nervous system is hard-wired with signalling molecule delivered precisely to
point where it is needed
 This means that only a few different signalling molecules are required as they do not
affect any cells except at their site of delivery
In nervous system specificity is conferred by hard-wiring: neurotransmitter
is delivered directly and specifically to cell which has receptor and responds
to transmitter
Endocrine system is not hard-wired All cells in body are exposed to
hormones so there is a wide range of signalling molecules needed
In endocrine system, where hormones are delivered to all cells, specificity
comes only from expression of the receptor for hormone.
 Only cells with receptors for a hormone can respond to that particular hormonal signal

Overview of Endocrine System
Classes of Hormones
8
 Hormones can be divided into five major classes:
1. amino acid derivatives such as dopamine, catecholamine, and thyroid hormone
2. small neuropeptides such as gonadotropin-releasing hormone (GnRH), thyrotropin-
releasing hormone (TRH), somatostatin, and vasopressin
3. large proteins such as insulin, luteinizing hormone (LH), and PTH produced by classic
endocrine glands
4. steroid hormones such as cortisol, estrogen, progesterone and testosterone that are
synthesized from cholesterol-based precursors and
5. vitamin derivatives such as retinoids (vitamin A) and vitamin D
As a rule
 amino acid derivatives and peptide hormones are water-soluble and
interact with cell-surface membrane receptors
 Steroids, thyroid hormones, vitamin D, and retinoids are lipid-soluble and
interact with intracellular--cytoplasmic & nuclear--receptors

Peptides
Thyrotropin-releasing hormone (TRH)
Gonadotropin-releasing hormone (GnRH)
Vasopressin
Oxytocin (OT)
Vasoactive intes tinal peptide (VIP)
Glucagon
Adrenocorticotropic hormone (ACTH)
Somatostatin
Steroid
Estrogens (e.g. estradiol)
Androgens (e.g.
testosterone)
Progesterone
Cortisol
Aldosterone
Chemical Classes and Hormones
Amino acid derivative
Epinephrine (adrenaline)
Thyroid hormones (T3, T4)
Proteins
Insulin
Insulin-like growth actors (IGFs )
Growth hormone (GH)
Prolactin (PRL)
Placental lactogen (PL)
Parathyroid hormone (PTH)
Glycoproteins
Thyroid-stimulating hormone (TSH)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Chorionic gonadotropin (CG)
Vitamin derivatives
vitamin A
vitamin D
9

Overview of Endocrine System cont.
Hypothalamus
10
 One of most important function of hypothalamus is to link the
nervous system to the endocrine system via pituitary gland
(hypophysis)
 Hypothalamus is also responsible for certain metabolic processes
and other activities of autonomic nervous system (See Lect. 2)
 Hypothalamus synthesizes and secretes neurohormones, often
called “hypothalamic-releasing hormones” (next slide)which in
turn stimulate or inhibit secretion of pituitary hormones

Chemical nature of hypothalamic factors
11
1. Thyrotropin releasing hormone (TRH)
2. Corticotropin releasing hormone (CRH)
3. Gonadotropin releasing hormone (GnRH),
(LH-RH/FSH-RH)
4. Prolactin release inhibitory hormone (PRIH)
5. Growth hormone releasing hormone (GHRH)
6. Somatostatin (Growth hormone release
inhibitory hormone)
Tripeptide
Peptide (41 AAs)
Decapeptide
Dopamine
Peptide (40, 44 AAs)
Peptide (14 AA)
Chemical natureHypothalamic hormone/factor
Hypothalamus, which is a part of CNS and not a gland, produces many
releasing and inhibitory hormones which control secretion of anterior
pituitary hormones

Functional classification of hormones
12
 Tropic hormones are hormones that have other endocrine glands as their
target (endocrine target tissues)
 Most tropic hormones are produced and secreted by anterior pituitary
 For example: Hypothalamus secretes tropic hormones that target anterior pituitary,
and thyroid gland secretes thyroxine, which targets hypothalamus and therefore can be
considered a tropic hormone (Other examples: TSH, FSH, LH, ACTH)
 Non-tropic hormones are hormones that directly stimulate target cells to
induce effects (nonendocrine target tissues)
 Non-tropic hormones are those that act directly on targeted tissues or cells, and not on
other endocrine gland to stimulate release of other hormones (Ex. GH, PTH, prolactin,
oxytocin, vasopressin, aldosterone and MSH)
 Trophic hormones are hormones that have a growth effect, hyperplasia or
hypertrophy, on tissue they are stimulating. (Ex. TSH, GH, ACTH)
Tropic hormone vs Non-tropic hormone vs Trophic hormone

Schematic Overview of Endocrine System
13
Costanzo LS. BRS Physiology. 5th ed. (Board review series). New York: Elsevier; 2009.

Overall Function
14
 A hormone is a substance secreted into bloodstream by one
tissue but has actions at remote tissues
 Hormones maintain homeostasis by regulating processes such
as growth & development, metabolism, and reproduction
 Hormones: maintain homeostasis through feedback loops
 Hormones: act slowly relative to nervous system
Nervous System chemical mediator (neurotransmitter)
Endocrine system chemical mediator (hormone)
Basic physiologic, biochemical and pharmacologic principles are same.

Routes by which chemical signals are delivered to cells
15
Modified from: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed.
Saunders, 2013
1. Autocrine chemical messengers
stimulates the cell that originally
secreted it (e.g. WBCs)
2. Paracrine chemical messengers act
locally on nearby cells (e.g. cytokines)
3. Neurotransmitters secreted by
neurons that activate an adjacent
cell another neuron, a muscle cell,
or a glandular cell (e.g. acetylcholine)
4. Endocrine chemical messengers are
hormones secreted into bloodstream
by certain glands and cells– and act
at a distant site (e.g. insulin)

16
 Classically, hormones are released into bloodstream and act on
tissues distant from site of hormone production an endocrine
effect
 Some hormones act locally within tissue where they are
produced called “local hormones” or paracrine effects
 Some hormones have both local and systemic effects  act in a
paracrine and endocrine manner
 Example is testosterone, has local actions in testes and hormonal effects
on muscle
 Some hormones, particularly growth factors, exert their actions
on cells which secrete them called autocrine effects
however,

Hormone Action
17
 True hormones (endocrine secretions) are released by “ductless glands” and
are carried by bloodstream to their sites of action
 Hormones are part of a larger group of substances that includes autocrine,
paracrine, and neuroendocrine secretions
Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.

Sites and mechanisms of hormone action
18
 Body releases a wide range of endogenous substances,
including: neurotransmitters from neuronal cells (e.g.
acetylcholine), hormones (e.g. insulin) or cytokines (e.g.
interferon), that alter function of target cells
 Hormones act on their specific receptors located on or within
their target cells
 Receptor activation by hormones is translated into response
in a variety of ways
1. At cell membrane receptors
2. At cytoplasmic receptors
3. At nuclear receptor

Sites and mechanisms of hormone action (2)
19
 Binding of a hormone to its receptor initiates intracellular events
that direct hormone’s action
 Ultimately, all hormones produce their effects by altering
intracellular protein activity
 mechanism by which this occurs depends on location of
hormone receptor
 Receptors are typically located on cell surface or in cell nucleus
 As a result, most hormones carry out their effects by means
of two general mechanisms:
1. Signal transduction and second messenger systems
2. Gene activation

Receptors
20
A receptor is a cell macromolecule either on surface cell or
within cytoplasm or nucleus of a cell that is recognized by
endogenous or exogenous substances (ligands) with specificity
Receptors account for a majority of chemical signalling that
occurs within body and are fundamental to ability of chemical
messengers to alter function of living cells
There are four major families of receptors:
 (LGICs) ligand-gated ion channels (e.g. nicotinic ion channel)
 (GPCRs) G-protein-coupled receptors (e.g. β-adrenoceptor)
 (RTKs) tyrosine kinase receptors (e.g. insulin receptor)
 (NHRs) intracellular receptors (e.g. glucocorticosteroid receptor)

21
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated
Edition. Philadelphia: Sanders, 2014
Receptors

Functional anatomy of endocrine and
metabolic systems
22
 Endocrine and metabolic systems regulate seven major bodily
functions (detail slides follow)
 For each target tissue effect, endocrine glands release
hormones in response to regulating factors, which include
 physiologic (e.g. sleep and stress),
 biochemical (e.g. glucose and Ca2+) and
 hormonal (e.g. hypothalamic and enteric hormones) stimuli

metabolic systems (2)
23
 Endocrine and metabolic system consists of a variety of organs (glands) that
secrete substances (hormones) into blood which affect function of target
tissues elsewhere in body
 Glands include hypothalamus, pituitary, thyroid, adrenals, gonads, pancreatic
islets of Langerhans and parathyroids
 Endocrine system regulates seven major physiologic functions:
1) Availability of metabolic energy (fuel), 2) Metabolic rate, 3) Circulatory volume, 4) Somatic
growth, 5) Calcium homeostasis , 6) Reproductive function 7) Adaptation to stress
 A cardinal feature of drug therapy of endocrine diseases is the interaction
between exogenously administered drugs and “endogenous biochemistry
and physiology” of hormones

24
Endocrine function
1. Availability of metabolic energy (fuel)
Regulatory factors
Serum glucose, amino acids, enteric hormones (somatostatin,
cholecystokinin, gastrin, secretin), vagal reflex, sympathetic
nervous system
Endocrine organ / hormone
Pancreatic islets of Langerhans/insulin, glucagon
Target tissues
All tissues, especially liver, skeletal muscle, adipose tissue,
indirect effects on brain and red blood cells

25
Endocrine function
2. Metabolic rate
Regulatory factors
Hypothalamic thyrotropin-releasing hormone (TRH), pituitary
thyrotropin (TSH)
Thyroid gland/triiodothyronine (T3)
Target tissues
All tissues

26
Endocrine function
3. Circulatory volume
Regulatory factors
Renin, angiotensin II, hypothalamic osmoreceptors
Adrenals /aldosterone, Pituitary/vasopressin
Target tissues
Kidney, blood vessels, CNS

27
Endocrine function
4. Somatic growth
Regulatory factors
Hypothalamic growth hormone-releasing hormone (GHRH),
somatostatin, sleep, exercise, stress,hypoglycemia
Pituitary/growth hormone, Liver/insulin-like growth factors (IGFs)
Target tissues
All tissues

28
Endocrine function
5. Calcium homeostasis
Regulatory factors
Serum Ca+ + and Mg++ concentration
Parathyroid glands/parathyroid hormone, calcitonin,
vitamin D
Target tissues
Kidney, intestines, bone

29
Endocrine function
6. Reproductive function
Regulatory factors
Hypothalamic gonadotropin- releasing hormone (GnRH), pituitary,
follicle stimulating hormone (FSH) and luteinizing hormone (LH),
inhibins
Gonads / sex steroids, Adrenals/ androgens
Target tissues
Reproductive organs, CNS, various tissues

30
Endocrine function
7. Adaptation to stress
Regulatory factors
Hypothalamic corticotropin- releasing hormone (CRH), pituitary
adrenocorticotropic hormone (ACTH), hypoglycemia, stress
Adrenals/glucocorticosteroids, epinephrine
Target tissues
Many tissues:CNS, liver, skeletal muscle, adipose tissue,
lymphocytes, fibroblasts, cardiovascular system

Endocrinology Basic Concepts
31
Endocrine system’s target organ are usually located far from
site of release of chemical mediator (hormone) of the signal
 A hormone is a substance secreted by one tissue or gland
that is transported via circulation to a site where it exerts its
effects on different tissues (target cells)
Signaling mechanisms which use enzymes, neurotransmitters,
hormones, and receptors are similar (aside from distance)
 Hence, basic pharmacologic principles of therapy are same

Endocrinology Basic Concepts (2)
Feed-forward and feed-back mechanisms
32
Key to understanding endocrine pharmacology are feed-forward
and feed-back mechanisms that govern how “releasing” factors
in hypothalamus control release of hormones in pituitary
(regulatory hormones) that in turn cause release of second-tier
hormones that target multiple organs within body
For example,
 Anterior pituitary hormones are transported to their target organs via
systemic circulation In target organs, they stimulate growth,
development, and secretion of other hormones, which both
 activate specific functions in various organs and
 exert negative feedback inhibition of the corresponding hypothalamic
and pituitary hormones

Hormone-Receptor Interactions
33
 There are three major biochemical classes of hormones:
1. proteins, peptides
2. modified amino acids (catecholamines and TH)
3. steroids
 All known hormones, and drugs that mimic hormones, act via
one of two basic receptor systems:
 membrane-associated receptors and
 intracellular receptors
1. Membrane-associated receptors: (peptide & protein hormones)
Membrane-associated receptors bind hydrophilic hormones (which
penetrate plasma membrane poorly), such as
 Insulin
 Adrenocorticotropic hormone (ACTH), and
 Epinephrine, outside the cell

Hormone-Receptor Interactions cont.
34
1. Membrane-associated receptors transmit signals into cell by
a variety of “second messenger” mechanisms, including:
 Changes in cyclic adenosine monophosphate (cAMP) or cyclic
guanosine monophosphate (cGMP) caused by changes in activity of
cyclases
 Increased phosphoinositide turnover via increased phospholipase
activity
 Increased intracellular Ca2+ by action on Ca2+ channels
 Increased tyrosine phosphorylation on specific proteins by action of
tyrosine kinases (TKR)

What are the four primary classes of membrane-
spanning receptors to which peptide hormones bind?
35
 The four primary classes of membrane-spanning receptors to which
peptide hormones bind are (Illust. next slide):
1) tyrosine and serine kinase receptors
2) receptor-linked kinases
3) G protein–coupled receptors, and
4) ligand-gated ion channels
 “Prototypical” agonists (respectively) for the above receptor types:
1) insulin, growth factors (IGF-1, PDGF, EPO etc. )
2) growth hormones (GHs), prolactin, cytokines (activate receptors of
JAK/STAT superfamily)
3) peptide hormones, neurotransmitters and prostaglandins
4) neurotransmitters, amino acids

The four major classes of membrane receptors for
peptide hormones and neurotransmitters
36
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015
Hormone 2nd -messenger systems (signal transduction)
*Mechanism using a G protein, as shown in D (Next slide)37

38
McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition.
Wolters Kluwer, 2015
Hormone 2nd messenger systems, GPCRs
G-protein mechanism
1. Messenger system before
hormone binding
2. After hormone binding, GTP
replaces GDP on G protein
3. GTP, attached to α subunit,
dissociates from β−γ complex and
converts ATP to cAMP
4. Hormone is released from
binding site and complex returns to
inactive state when GTPase cleaves
GTP to GDP

39
Hormone 2nd messenger system: G-Protein Classes
G Protein Class Action Examples
ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol triphosphate; PIP2,
phosphatidylinositol 4,5-bisphosphate.

Basic Concepts (4) Hormone Receptors cont.
40
2. Intracellular receptors: (steroid hormones, TH, retinol & vitamin D)
Intracellular receptors bind hydrophobic (lipophilic) hormones
(which penetrate plasma membrane easily) such as
 Cortisol
 Aldosterone
 Estrogen
 Progesterone
 Testosterone
 T3/T4
 Retinol
 vitamin D
inside cell-either in cytoplasm or nucleus
 Intracellular receptors modulate transcription rate of specific
target genes to change levels of cellular proteins
Note:
Nuclear Receptors T3, T4, Estrogen, Progesterone,
Testosterone
Cytoplasmic Receptors Glucocorticoids &
Mineralocorticoids

Summary: molecular-cellular mechanisms of
hormone action (illustrations next 6 slides)
41
 Hormones act on their specific receptors located on or within
their target cells
 Receptor activation by hormones is translated into response
in a variety of ways
1. At cell membrane receptors (proteins and peptides
hormones)
(steroids, T4/T3, Vit. D, retinol)

Summary:
42
a. Through alteration of intracellular cAMP concentration alteration of
protein kinase A regulation of cell function: Ca2+ acting as third
messenger in some situations
 Epinephrine, Glucagon, TSH, FSH, LH , PTH, Calcitonin, ACTH, some
hypothalamic releasing hormones, Vasopressin (V2)
RaffRB,RawlsSM,BeyzarovEP.Netter'sIllustrated
Pharmacology,UpdatedEdition.Saunders,2014

Summary:
43
b. Through IP3 DAG generation: release of intracellular Ca2+
and protein kinase C activation
 Vasopressin (V1) ,Oxytocin

Summary:
44
c. Direct transmembrane activation of tyrosine protein kinase
phosphorylation cascade regulation of various enzymes
 Insulin, Growth hormone , Prolactin

Summary:
45
Penetrating cell membrane, hormone
combines with a cytoplasmic receptor 
exposes its DNA binding domain migrates to
nucleus and binds to specific genes DNA
mediated mRNA synthesis synthesis of
functional proteins
 Steroidal hormones: Glucocorticoids,
Mineralocorticoid, Androgens,
Estrogens , Progestins
 Calcitriol (also called 1,25-
dihydroxycholecalciferol or 1,25-
dihydroxyvitamin D)
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill, 2011

Summary:
46
Hormone penetrates nucleus, combines with its receptor alters DNA- RNA
mediated protein synthesis
 Thyroid hormones: Triiodothyronine, Thyroxine
 Estrogen, testosterone, glucocorticoids, vitamin D, aldosterone,
progesterone

Receptor Families and Signaling Pathways:
47
Receptor Class Hormones and Related Substances
cAMP LH, FSH, ACTH, TSH, PTH, hCG, CRH, glucagon, ADH (V2)
cGMP NO, ANP
IP3 GnRH, GHRH, oxytocin, TRH, ADH (V1)
Steroid receptor
(intracellular)
Estrogen, testosterone, glucocorticoids, vitamin D,
aldosterone, progesterone, T3/T4
Tyrosine kinase Insulin, growth factors (e.g., IGF, PDGF), GH, prolactin
Ledger:
ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; cAMP, cyclic adenosine
monophosphate; cGMP, cyclic guanosine monophosphate; CRH, corticotropin-releasing hormone; FSH,
follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH,
gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IGF, insulin-like growth factor;
IP3, inositol triphosphate; NO, nitric oxide; PDGF, platelet-derived growth factor; PTH, parathyroid
hormone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone.
Redrawn after: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
Class of Receptors Used by Various Hormones

Hypothalamic-pituitary signaling pathways
48
Response of an anterior pituitary gland cell to a hypothalamic
factor (neurohormone) is initiated when hypothalamic factor
(a peptide) binds to specific G protein-coupled receptors
located on plasma membrane of appropriate anterior pituitary
cell type
 Most of these receptors alter levels of intracellular cAMP
or IP3 and calcium
 Molecular details of receptor signaling provide a
biochemical basis for understanding hypothalamic factor
action (example in next slide)

49
For example:
 Growth Hormone-Releasing Hormone
(GHRH) binding to its receptors on
somatotrophs increases intracellular cAMP
and Ca2+ levels,
whereas
 Somatostatin (Somatotropin Release-
Inhibiting Hormone, SRIH) binding to its
receptors on somatotrophs decreases
intracellular cAMP and Ca+2
 These signaling pathways provide a
biochemical explanation for opposing
activities GHRH and somatostatin on
pituitary somatotroph release of GH
Hypothalamic-pituitary signaling pathways (2)
Costanzo LS. Physiology (Basic Review Series), 5th ed. New York: Elsevier,
2009.

50
Hormone-Receptor Interactions cont.
 We have just completed a discussion of hormone-
receptor interactions from the vantage point of the
receptor
 In the next 5 slides we will view the interaction from
the hormone side

Cellular MOA of steroid & TH hormones
51
 Steroid hormones are lipophilic therefore, they diffuse across plasma
membrane and form complexes with cytosolic or nuclear receptors
bound complexes then activate transcription of various genes
 B/C steroid hormones rely on the intermediary process of
gene expression and protein translation it can take hours to days for their
effects to manifest
 Examples of steroid hormones are testosterone, estrogen, progesterone,
cortisol, and aldosterone
 Cholesterol is precursor to all steroid hormones
 Although thyroid hormone is not a steroid hormone TH uses same
cellular mechanism as steroids

Transport of steroid and thyroid hormones
Why are total serum steroid hormone & TH levels not an accurate reflection of
hormone activity?
52
 Most of steroid hormones & TH in serum are inactive because
they are attached to serum binding proteins
 Only free hormone is biologically active
Free hormone is in equilibrium with bound hormone:
[Free hormone] + [Binding protein] [Hormone-binding protein complex]
For example: In circulation, T3/T4 exist in both active free and inactive protein-bound forms
 T4 is 99.98% bound, with only 0.02% circulating free.
 T3 is slightly less protein bound (99.8%), resulting in a considerably higher circulating free
fraction (0.2%)
 Another important factor that affects hormone activity is
concentration (represented as []) of cellular hormone receptors
available for binding a specific hormone and mediating its action

Transport of steroid & thyroid hormones (2)
53
Binding of steroid and thyroid hormones to plasma proteins has several
beneficial effects, including:
 Facilitation of transport
 Prolonged half-life
 Hormone reservoir
 Steroid and thyroid hormones are minimally soluble in blood binding
to plasma proteins renders them water soluble and facilitates their transport
 Protein binding prolongs circulating half-life of these hormones e.g., not
filtered/excreted by kidney
 Protein-bound form of hormone serves as a “reservoir” of hormone that
minimizes changes in free hormone concentration when hormone secretion
from its endocrine gland changes abruptly

MOA of peptide hormones & catecholamines
54
 Peptide hormones and catecholamines are not highly lipid-diffusible and
thus cannot cross plasma membrane
 They bind to cell surface membrane receptors (next slide), which
initiate a variety of biochemical events, including:
o activation or inhibition of enzymes
o alteration of membrane proteins, and
o mediation of cellular trafficking
 These processes can occur within seconds to minutes
o Nevertheless, peptide hormones can stimulate gene expression as
well, and this effect can be delayed as it is with steroid hormones
 Examples of peptide hormones are insulin, parathyroid hormone (PTH),
vasopressin (antidiuretic hormone), and oxytocin
N.B. intact peptides and proteins are not absorbed across the intestinal
lumen; local proteases digest them into their constituent amino acids.
Thus, therapeutic administration of a peptide hormone or hormone
antagonist must be accomplished by a non-oral routes (IM, SQ, IV ).

To summarize:
Mechanisms by which peptide and steroid hormones signal
55
Remember:
 amino acid derivatives and
peptide/protein hormones are
water-soluble and interact with
cell-surface membrane receptors
 Steroids, thyroid hormones,
vitamin D, and retinoids are lipid-
soluble and interact with
intracellular(cytoplasmic &
nuclear) receptors

56
Kelly LJ. Essentials of Human Physiology for Pharmacy. Boca Raton: CRC Press, 2004.
Summary of distinguishing features of steroid,
protein/peptide, and amine hormones

Pathophysiologic & Pharmacologic Concepts
57
Hypopituitarism may be partial or complete and may result
from hypothalamic disease (leading to deficiency of
hypothalamic-releasing hormones) or intrinsic pituitary
disease(causing pituitary hormone deficiency)
Hypopituitarism may affect any of these pituitary hormones:
 thyrotropin (TSH)
 growth hormone(GH)
 luteinizing hormone (LH)
 follicle stimulating hormone (FSH) and
 corticotropin (ACTH)

Pathophysiologic & Pharmacologic Concepts (2)
58
 In targeting one of these hormones of hypopituitarism  therapy
for GH deficiency aims to restore normal body composition, as
well as, in children, to promote linear growth
 Therapy for acromegaly, caused by excessive GH secretion,
includes
 surgery and (or) radiation, or
 use of a GH inhibitor
o Octreotide
o Lanreotide
o Pegvisomant

59
Hypothyroidism can result from either thyroid (high TSH, low T3
&T4) or hypothalamic (or) pituitary dysfunction (low T3, T4, TSH)
 Treatment of choice is hormone substitution by using a
synthetic hormone
Hyperthyroidism (thyrotoxicosis) is characterized by increased
metabolism, and primary treatment options include
 surgery
 radioactive iodine or
 drugs that inhibit formation of T3 &T4 by blocking
utilization of iodine

60
Principal functions of glucocorticoids involve regulation of
carbohydrate metabolism and a variety of other physiologic
actions
Synthetic corticosteroids (eg, hydrocortisone, prednisone, and
dexamethasone) are widely used as therapeutic agents in Tx of
cancer and autoimmune or inflammatory-type disorders
Pharmacologic treatment is also available for
 insufficient adrenal function manifested as Addison
disease
 excess glucocorticoid exposure Cushing syndrome

61
Diabetes mellitus (DM) is a syndrome caused by a relative or absolute
deficiency of insulin, with hyperglycemia being hallmark medical finding
 DM can occur as either an early onset form (type 1) or a gradual-onset
form (type 2)
 In T1DM, insulin-producing β cells of pancreas are destroyed or
insufficiently active, and patients require lifelong treatment with
exogenous insulin
 In T2DM, adequate control of disease may be achieved by means of diet
and exercise if these methods fail, patients take oral hypoglycemic
agents, which cause
o lower plasma glucose levels
o improve insulin resistance, and
o reduce long-term complications (macrovascular and microvascular
problems such as neuropathy, nephropathy, retinopathy and CVD)

62
 For type 1 DM Insulin is sole treatment and is sometimes also used for type
2 DM
 For type 2 DM, drugs include
 sulfonylureas, which stimulate insulin secretion from pancreatic β cells
 metformin, a biguanide that decreases blood glucose levels by
reducing hepatic glucose production and glycogen metabolism in liver
and improving insulin resistance
 meglitinides, which increase insulin secretion from pancreatic β cells
 α-glucosidase inhibitors, which delay carbohydrate digestion and
glucose absorption and
 thiazolidinedione (TZD) derivatives (eg, rosiglitazone and pioglitazone),
which reduce insulin resistance

Hormones of hypothalamic-pituitary axis
63
McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015.
Individual Axes:
(Hormonal Feedback Regulatory Systems)
Anterior Pituitary Gland
Hypothalamic-Pituitary–Growth Hormone Axis
Hypothalamic-Pituitary–Prolactin Axis
Hypothalamic-Pituitary–Thyroid Axis
Hypothalamic-Pituitary–Adrenal Axis
Hypothalamic-Pituitary–Gonadal Axis
Posterior Pituitary Gland
Antidiuretic Hormone (ADH)
Oxytocin

Hypothalamus
64
1. Thyrotropin releasing hormone (TRH)
2. Corticotropin releasing hormone (CRH)
3. Gonadotropin releasing hormone (GnRH),
(LH-RH/FSH-RH)
4. Prolactin release inhibitory hormone (PRIH)
5. Growth hormone releasing hormone (GHRH)
6. Somatostatin (Growth hormone release
inhibitory hormone)
Tripeptide
Peptide (41 AAs)
Decapeptide
Dopamine
Peptide (40, 44 AAs)
Peptide (14 AA)
Chemical natureHypothalamic hormone/factor
Hypothalamus, which is a part of CNS and not a gland,
produces many releasing and inhibitory hormones which control
secretion of anterior pituitary hormones

Pituitary gland
65
 Pituitary gland is composed of two morphologically and
functionally distinct components:
 Anterior lobe (adenohypophysis) and
 Posterior lobe (neurohypophysis)
 Anterior pituitary constitutes about 80% of gland
 Production of most pituitary hormones is controlled by
positively and negatively acting factors from
hypothalamus carried to anterior pituitary by a portal
vascular system (hypothlamic-hypophesal portal system)

66
Hormones released by anterior pituitary
The adenohypophysis releases five hormones that are in turn under the control of various stimulatory and inhibitory
hypothalamic releasing factors. TSH, Thyroid-stimulating hormone (thyrotropin); PRL, prolactin; ACTH, adrenocorticotropic
hormone (corticotropin); GH, growth hormone (somatotropin); FSH, follicle-stimulating hormone; LH, luteinizing hormone.
The stimulatory releasing factors are TRH (thyrotropin-releasing hormone), CRH (corticotropin-releasing hormone), GHRH
(growth hormone-releasing hormone), GnRH (gonadotropin-releasing hormone). The inhibitory hypothalamic influences
comprise PIF (prolactin inhibitory factor or dopamine) and growth hormone inhibitory factor (GIH or somatostatin).
Kumar V, Abbas AK. Robbins and Cotran Pathologic Basis of Disease 9th Ed. Philadelphia: Saunders, 2015.

Hormonal Feedback Regulatory Systems
67
 Feedback control , both negative and positive, is a fundamental feature of
endocrine systems
 Each of major hypothalamic-pituitary- hormone axes is governed by negative
feedback, a process that maintains hormone levels within a relatively narrow
range
Examples of hypothalamic-pituitary negative feedback include
(1) thyroid hormones on TRH-TSH axis
(2) cortisol on CRH-ACTH axis
(3) gonadal steroids on GnRH-LH/FSH axis, and
(4) IGF-I on growth hormone-releasing hormone (GHRH)-GH axis
 These regulatory loops include both positive (e.g., TRH, TSH) and negative
(e.g., T 4 , T 3 ) components, allowing for precise control of hormone levels

Feed-forward and Feed-back Mechanisms
68
 Key to understanding
endocrinology are feed-forward
and feed-back mechanisms that
govern how “releasing” factors
in hypothalamus control release
of hormones in pituitary
(regulatory/tropic hormones)
that in turn cause release of
second-tier hormones that
target multiple organs within
body
Hypothalamic Releasing Hormone
Pituitary Tropic (Signal) Hormone
Target Glands
Second-tier Hormone
Organ-System Effect
Negative
Feedback

Negative and Positive Feedback Regulation
69
 In most cases, a hypothalamic– pituitary–target gland axis is
regulated by negative feedback, whereby tropic hormone of
anterior pituitary gland has negative feedback effects on
hypothalamus and target gland hormone has negative
feedback effects on both hypothalamus and anterior pituitary
 By way of these mechanisms levels of target gland hormone
are maintained within normal physiological range
N.B. Positive Feedback
Although negative feedback is primary homeostatic mechanism in endocrine system,
rare examples of positive feedback exist (e.g., menstrual cycle ). These positive
feedback mechanisms are, by nature, self-limited, as dictated by need for homeostasis in
physiological systems.

Example of positive feedback
70
 Prime example of positive feedback occurs during menstrual cycle
 In late follicular phase of cycle, estradiol levels rise above a
critical point, above which positive feedback occurs
 High estradiol concentration results in a surge in hypothalamic
secretion of GnRH and pituitary secretion of LH and FSH,
inducing ovulation
 Ovulation and transformation of ovarian follicular cells into
corpus luteum signals end of positive feedback

Concept of Feedback Loop
71
What is a feedback loop?
Hormone synthesis and release are governed at multiple levels
 Hormone synthesis and release (secretion) from an organ of
interest typically involves regulation by a pituitary hormone,
which itself is regulated by a hypothalamic hormone
This general pathway structure is commonly referred to as a
hypothalamic-pituitary-(organ) axis  e.g., HPO axis refers to
ovary, HPA axis refers to adrenal gland
These relationships are often depicted using feedback loops
(next 2 slide)

Regulation of hormone synthesis
and secretion cont.
72
 It is essential to understand “the negative
feedback principle” of hypothalamic
/pituitary/ target organ axis
 A negative feedback mechanism is an
example of a negative effect
 Negative feedback occurs when a product
downstream of an axis inhibits production of
a reactant by which it is regulated
 for example, thyroid hormone inhibition of
thyroid-stimulating hormone (TSH)
Solidlines=positiveeffect
Dashedlines=negativeeffect
Pazdernik TL, Kerecsen L. Rapid Review
Pharmacology, 3rd Ed. Mosby, 2010

Example, thyroid hormone feedback loop
73
A small reduction of thyroid
hormone triggers a rapid
increase of TRH and TSH
secretion, resulting in thyroid
gland stimulation and increased
thyroid hormone production
When thyroid hormone reaches
a normal level, it feeds back to
suppress TRH and TSH, and a
new steady state is attained

Anterior Pituitary Gland Cell Types, Hypothalamic
Control Factors, and Hormonal Targets
74
Golan DE et.al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3rd Ed. Lippincott Williams & Wilkins, 2012

Relationships Among Hypothalamic, Pituitary,
and Target Gland Hormones
75
HYPOTHALAMIC PITUITARY TARGET ORGAN TARGET ORGAN
HORMONES
GHRH (+), SRIH (–) GH (+) Liver Somatomedins
CRH (+) ACTH (+) Adrenal cortex Glucocorticoids
Mineralocorticoids
Androgens
TRH (+) TSH (+) Thyroid T4, T3
GnRH or LHRH (+) FSH (+), LH (+) Gonads Estrogen
Progesterone
Testosterone
Dopamine (–), PRH (+), TRH (+) Prolactin (+) Breast —
+, stimulant; –, inhibitor; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-
stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-
releasing hormone; LHRH, luteinizing hormone-releasing hormone; LH, luteinizing hormone; PRH, prolactin-releasing
hormone; SRIH, somatotropin-releasing inhibiting hormone; TRH, thyrotropin releasing hormone; TSH, thyroid-
stimulating hormone.
Redrawn after: Pazdernik TL, Kerecsen L. Rapid Review Pharmacology, 3rd Ed. Mosby, 2010

76
Some disorders often requiring applications
of endocrine and metabolic medications:
Kibble J , Cannarozzi ML. Pathophysiology Flash Cards. New York: McGraw-Hill, 2013

77
THE END
See next slide for hypermedia to further study tools and resources.

Further study tools and resources:
Also see Medical Pathology Cloud Folder
Inside the Endocrine System BMS Cloud Folder:
 Endocrine System Pathology Outline
 Endocrine System Pathology Ppt.
 Endocrine Pathology Case 1 SDL Tutorial
 Endocrine Pathology Case 2 SDL Tutorial
 Endocrinology Tutorial 1 Postpartum Necrosis
 Endocrinology Tutorial 2 MEN Syndromes
 Endocrinology Tutorial 3 Anterior Pituitary
 Diabetes mellitus Type 1 SDL Tutorial
 Diabetes mellitus Type 2 SDL Tutorial
 Endocrine Pathology Clinical Vignettes
 Endocrine Pathology Rapid Review Notes
78

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