Drugs Used in Disorders of the Endocrine System, Lectures 1 through 6

Photos: The surgeon in this photo is transfusing donor islet cells into a diabetic patient. The islet cells may take residence in the pancreas and secrete insulin for the patient. Note the new islet
cells in the right-hand photo. They are now functioning normally. This patient will never again need to inject insulin. From: Seeley’s Anatomy & Physiology 10th ed. New York, NY: McGraw-Hill 2010.

Marc Imhotep Cray, MD
Overall Goals this of Sequence
2
With exception of endocrine pharmacology of the reproductive
organs, kidneys, GIT and adrenal medulla (covered in other modules),
by the end of this sequence the learner will:
 Understand the functional anatomy, biochemistry and
physiology of the endocrine system, including negative feedback
inhibition and endocrine axes.
 Understand the principles governing disease states that result
from over- or under-production of key hormones.
 Know the biologic and therapeutic effects of the most
commonly used endocrine agonists and antagonists.
 Know the indications, contraindications, drug interactions and
adverse effects of the most commonly used endocrine agents.

Topical Outline:
3
 Lect. 1: Overview of Endocrine Pharmacology:
Some of major applications of endocrine drugs, including:
 Lect. 2: Hypothalamic and Pituitary Disorders
 Lect. 3: Thyroid Disorders
 Lect.4: Parathyroid Disorders & Calcium Homeostasis
 Lect. 5: Corticosteroids & Adrenocortical Dysfunction
 Lect. 6: Diabetes Mellitus

Endocrine Pharmacology Focus of Study
Endocrine and Reproductive System Pharmacology
See companion eNotes:
Focus of study for each drug: (as applicable)
 Classification and class prototype/s
 Mechanisms of action
 Indications [diagnostic and (or) therapeutic use]
 Adverse effects
 Drug-drug interactions, cautions and contraindications
 Pharmacokinetic properties, drug-disease interactions and other
patient-specific considerations
 Toxicities and antidotes (or) treatment
4

5
Some Key Abbreviations
ACTH, Adrenocorticotropic hormone
AVP, Arginine vasopressin, antidiuretic
hormone
cAMP, Cyclic adenosine monophosphate
CRH, Corticotropin-releasing hormone
DHEA, Dehydroepiandrosterone
DHT, Dihydrotestosterone
FSH, Follicle-stimulating hormone
LH, Luteinizing hormone
TSH, Thyroid-stimulating hormone
TRH, Thyrotropin-releasing hormone
GH, Growth hormone
GHRH, Growth hormone-releasing
hormone
GnRH, Hypothalamic gonadotropin-releasing
hormone
GIP, gastric inhibitory peptide
GLP-1, glucagon-like peptide-1
hCG, Human chorionic gonadotropin
hGH, Human growth hormone
hMG, Human menopausal gonadotropin
JAK2 janus kinase 2
IRS-1, insulin receptor substrate-1
PI3K, phosphatidyl inositol- 3 kinase
STAT, signal transducer and activator of
transcription
MAPK, mitogen-activated protein kinase
SHC, Src homology containing

Lect. 1 of 6
Overview of Endocrine Pharmacology:
Functional Anatomy, Hormone-Receptor Interactions
& Basic Pathophysiologic and Pharmacologic Concepts
6
The aim of this lecture is to present a detailed overview of endocrinology—that is, a structural
and functional analysis of general features of hormones. Major emphasis will be placed on how
the endocrine system uses its chemical messengers (hormones) to communication between
cells by way of discussing the principles of hormone-receptor interactions and cell signaling, as
these principles form the basis for the mechanisms by which hormones exert their actions and
thus, serve as the foundation for understanding the pharmacology of important endocrine-
hormonal systems presented in subsequent lectures.

Learning Objectives
7
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.
3. Describe the chemical nature and various classifications of hormones.
4. Describe the four major families of cell receptors.
5. Describe hormone-receptor interactions and signal transduction mechanisms.
6. Explain the molecular & cellular mechanism of action of peptide/protein and
catecholamine hormones and how they exert their effects on target cells.
7. Explain the molecular & cellular mechanisms of action of steroid and thyroid
hormones and how they exert their effects on target cells.
8. Define binding protein, bound hormone, and free hormone and the effects of
binding proteins on circulating hormone levels and activity
9. Describe the organizational and functional anatomy of the endocrine system.
10. Understand basic endocrine pathophysiologic and pharmacologic concepts

8
Organization & Responsibilities
of Endocrine System
 Hormones are secreted into blood by
endocrine organs throughout body, affecting
physiological function at various target sites
 Endocrine, or hormonal, system is responsible
for regulating most of systems of body,
including:
 energy metabolism
 bone metabolism
 cardiovascular system
 bone marrow and hematopoiesis
 renal system
 gastrointestinal system
 regulation of food intake and
 regulating reproductive processes Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed.
Philadelphia: Elsevier, 2016.

Schematic Overview of Endocrine System
9Costanzo LS. Physiology. 5th ed., (Board review series). New York: Elsevier; 2009
Neurohormones, often called
“hypothalamic-releasing hormones”
Pituitary hormones
(regulatory hormones)
(tropic hormones)
Second-tier hormones

Feed-forward and Feed-back mechanisms
Hypothalamic Releasing Hormone
Pituitary Tropic (Signaling) Hormone
Target Glands
Second-tier Hormone
Tissue/Organ-System Effect
Negative Feedback (by second-tier hormone)
NB: 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 /tropic hormones) that in turn
cause release of second-tier hormones that target multiple organs within body
Feed-forward
Feed-backward

Hormones and Their Sites of Production
Hormones Synthesized and Secreted by Dedicated Endocrine Glands
Pituitary Gland
Growth hormone (GH)
Prolactin
Adrenocorticotropic hormone (ACTH)
Thyroid-stimulating hormone (TSH)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Thyroid Gland
Tetraiodothyronine (T4; thyroxine)
Triiodothyronine (T3)
Calcitonin
Parathyroid Glands
Parathyroid hormone (PTH)
Islets of Langerhans
(Endocrine Pancreas)
Insulin
Glucagon
Somatostatin
Adrenal Gland
Epinephrine
Norepinephrine
Cortisol
Aldosterone
Dehydroepiandrosterone
sulfate (DHEAS)
Hormones Synthesized by Gonads
Ovaries
Estradiol-17β
Progesterone
Inhibin
Testes
Testosterone
Antimullerian hormone (AMH)
Inhibin
White BA & Porterfield SP. Endocrine and Reproductive Physiology, 4th ed.
(Mosby physiology monograph series). Mosby, 2013.

Marc Imhotep Cray, MDWhite BA & Porterfield SP. Endocrine and Reproductive Physiology,
4th ed. (Mosby physiology monograph series). Mosby, 2013.
Hormones and Their Sites of Production (2)
Hormones Synthesized in Organs with a Primary Function Other Than
Endocrine
Brain (Hypothalamus)
Antidiuretic hormone (ADH; vasopressin)
Oxytocin
Corticotropin-releasing hormone (CRH)
Thyrotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH)
Growth hormone–releasing hormone (GHRH)
Somatostatin
Dopamine
Brain (Pineal Gland)
Melatonin
Heart
Atrial natriuretic peptide (ANP)
Kidney
Erythropoietin
Adipose Tissue
Leptin
Adiponectin
Stomach
Gastrin
Somatostatin
Ghrelin
Intestines
Secretin
Cholecystokinin
Glucagon-like peptide-1 (GLP-1)
Glucagon-like peptide-2 (GLP-2)
Glucose-dependent insulinotropic peptide
(GIP; gastrin inhibitory peptide)
Motilin
Liver
Insulin-like growth factor-1 (IGF-I)

Hormones and Their Sites of Production (3)
Hormones Produced to a Significant Degree by Peripheral Conversion
Lungs
Angiotensin II
Kidney
1α,25-dihydroxyvitamin D
Adipose, Mammary Glands, Other Organs
Estradiol-17β
Liver, Sebaceous Gland, Other Organs
Testosterone
Genital Skin, Prostate, Other Organs
5-Dihydrotestosterone (DHT)
Many Organs
T3
White BA & Porterfield SP. Endocrine and Reproductive Physiology,

Marc Imhotep Cray, MD 14
Some disorders often requiring applications
of endocrine and metabolic drugs:
Kibble J , Cannarozzi ML. Pathophysiology Flash Cards. New York: McGraw-Hill, 2013

Overview of Endocrine System
 Endocrine system uses hormones to transfer information between different
tissues
 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

16
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
 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
 both systems use receptors

Pathways by which nervous system
influences hormone secretion
Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The Mechanisms of Body Function,
11th ed. New York, NY: McGraw-Hill, 2008.

Nature of Hormones
18
 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
Jameson JL. Principles of Endocrinology (Ch.338). In: Longo DL, Fauci AS, et al. Harrison's Principles
of Internal Medicine,18th Ed. New York: McGraw-Hill, 2012.
NB: As a rule 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 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
Biochemical classification of 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
NB: Chemical nature of a hormone determines:
1. How it is synthesized, stored, and released
2. How it is carried in blood
3. Its biologic half-life (t1/2) and mode of clearance
4. Its cellular mechanism of action
White BA & Porterfield SP. Endocrine and Reproductive Physiology, 4th ed. (Mosby physiology monograph series). Mosby, 2013.

Overview of Endocrine System cont.
Functional classification of hormones
20
 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

Hypothalamus
21
 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” which in turn,
stimulate or inhibit secretion of pituitary hormones (regulatory
hormones) in turn, stimulate or inhibit second-tier hormones

Chemical nature of hypothalamic factors
22
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 (neurohormones)
Hypothalamus, which is a part of CNS and not a gland, produces many
releasing and inhibitory hormones (neuropeptides) which control
secretion of anterior pituitary hormones

Overall Function
23
 A hormone is a substance secreted into bloodstream by one
tissue but has actions at remote tissues
 widespread delivery of hormones in bld makes endocrine
system ideal for functional coordination of multiple organs
and cell types
NB: Signaling mechanisms which use enzymes, neurotransmitters,
hormones, and receptors are similar (aside from distance)
 Nervous System chemical mediator (neurotransmitter)
 Endocrine system chemical mediator (hormone)
 Physiologic, biochemical and pharmacologic principles are same

Routes by which chemical signals are delivered to cells
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) Medical Sciences 2nd Edn. Naish J & Court DS. Eds. Elsevier, 2015.

25
 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
26
 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
27
 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)
28
 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, respectively

Sites and mechanisms of hormone action (3)
 To function, hormones must bind to specific receptors
expressed by specific target cell types within target organs
 Hormones are also referred to as ligands, in context of ligand-
receptor binding, and as agonists, in that their binding to
receptor is transduced into a cellular response
 Constitutive activation of a receptor leads to unregulated, hormone
independent activation of cellular processes
 Receptor antagonists typically bind to a receptor and lock it in
an inactive state unable to induce a cellular response
 Loss or inactivation of a receptor leads to hormonal resistance

Cellular Responses to Hormones
 A single hormone controls a subset of cellular functions in only cell
types that express receptors for that hormone (i.e., target cell)
 Specificity of hormonal responses resides in
 The structure of hormone itself
 The receptor for the hormone, and
 The cell type in which the receptor is expressed
 Serum hormone concentrations are extremely low (10 -11 to 10-9
M) thus, a receptor must have a high affinity, as well as
specificity, for its cognate hormone

Cellular Responses to Hormones (2)
 Hormone receptors fall into two general classes: transmembrane receptors
and intracellular receptors (belong to nuclear hormone receptor family)
Transmembrane Receptors
 Most hormones are proteins, peptides, or catecholamines that cannot pass
through cell membrane must interact with transmembrane protein
receptors
 Transmembrane receptors are proteins that contain three domains:
(1)an extracellular domain that harbors a high-affinity binding site for a
specific hormone
(2) one to seven hydrophobic, transmembrane domains that span cell
membrane, and
(3)a cytosolic domain that is linked to signaling proteins

Hormone binding to a transmembrane receptor induces a
conformational shift in all three domains of receptor protein
 hormone receptor binding–induced conformational change
is referred to as a signal
 The signal is transduced into activation of one or more
intracellular signaling molecules (protein)
Intracellular signaling molecules then act on effector proteins,
which, in turn, modify specific cellular functions

White BA & Porterfield SP. Endocrine and Reproductive Physiology, 4th ed. (Mosby physiology monograph series). Mosby, 2013.
 This often promotes dimerization of receptors as well as conformational
changes in cytosolic domain that unmasks a specific activity
(e.g., tyrosine kinase activity)
Example of hormone induced conformational change in transmembrane receptor.

Transmembrane receptor cont.
The combination of…
 hormone receptor binding (signal)
 activation of signaling molecules (transduction), and
 the regulation of one or more effector proteins
…is referred to as a signal transduction pathway and the
final integrated outcome is referred to as the cellular
response

Covalent phosphorylation of proteins & lipids
Enzymes that phosphorylate proteins or lipids are called kinases,
whereas
Enzymes that catalyze dephosphorylation are called phosphatases
Protein kinases and phosphatases can be classified as either
 tyrosine-specific kinases and phosphatases or
 serine/threonine-specific kinases and phosphatases
Phosphorylated state of a signaling component alters activity
 Phosphorylation can activate or deactivate a substrate
 proteins often have multiple sites of phosphorylation that induce
quantitative and (or) qualitative changes in protein’s activity

Covalent phosphorylation of proteins & lipids (2)
 Protein, peptide, and catecholamine hormones signal through
transmembrane receptors and use several common forms of
informational transfer:
 Conformational change
 Binding by activated G proteins
 Binding by Ca2+ or Ca2+ -calmodulin
 IP3 is a major lipid messenger that increases cytosolic Ca2+
levels through binding to IP3 receptor
 Phosphorylation and dephosphorylation, using kinases and
phosphatases, respectively
 Phosphorylation state of a protein affects
 activity, stability, subcellular localization, and recruitment binding
of other proteins

Phosphorylation/ dephosphorylation in signal
transduction pathways
Phosphotyrosine is shown.
White BA & Porterfield SP. Endocrine and Reproductive Physiology, 4th ed. (Mosby physiology monograph series).
Mosby, 2013.

 Drugs act at four different levels:
1) Molecular: protein molecules are the immediate targets for
most drugs. Action here translates into actions at next level.
2) Cellular: biochemical and other components of cells
participate in the process of transduction.
3) Tissue: the function of heart, skin, lungs, etc., is then altered.
4) System: the function of the cardiovascular, nervous,
gastrointestinal system, etc., is then altered.
“A general principles refresher.”
Re of: Mechanisms of Drug Action (MOA)

“A general principles refresher.”
Mechanisms of Drug Action (2)
39
 To most clearly understand pharmacologic actions of drugs (e.g.,
hormone analogs, agonist and antagonist) it is necessary to know:
 which molecular targets are affected by the drug,
 the nature of this molecular interaction,
 the nature of the transduction system (the cellular response),
 the types of tissue that express the molecular target and
 the mechanisms by which the tissue influences the body system
NB: You are learning pharmacology in a format that integrates the actions of drugs
 from the level of molecular targets (biologic effects)
 to the level of whole-organism/clinical patient (therapeutic and adverse effects),
using kindred sciences (biochem, physio and pathophys. ) as the scaffolding.

Answer: Combination of messenger with receptor causes a change in
conformation (three-dimensional shape) of receptor = receptor activation
always initial step leading to cell’s responses to messenger
 responses (five types of ultimate responses):
1. permeability, transport properties, or electrical state of plasma membrane
2. cell’s metabolism
3. cell’s secretory activity
4. cell’s rate of proliferation and differentiation, or
5. cell’s contractile activity
 Despite five different types of responses, there is a common denominator
They are all directly due to alterations of particular cell proteins
Signal Transduction Pathways Capsule:
Question: What are the sequences of events by which binding of a chemical
messenger (hormone, neurotransmitter, or paracrine/ autocrine agent) to a
receptor causes the cell to respond?

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)
Endocrine Pharmacology Basic Concepts
Receptors

Endocrine Pharmacology Basic Concepts (2)
Hormone-Receptor Interactions
 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 42

Endocrine Pharmacology Basic Concepts (3)
Hormone-Receptor Interactions cont.
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)
43

What are the four primary classes of membrane-spanning
receptors to which peptide hormones & NTs bind?
44
 The four primary classes of membrane-spanning receptors to which
peptide hormones & neurotransmitters 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
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013
45

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)

 G-protein–coupled receptors,
compose largest class of receptors,
mediate effects of NTs, hormones,
and drugs
 All receptors have seven
transmembrane segments, three
intracellular loops, and an
intracellular carboxy-terminal tail
 The biologic activity of receptors is
mediated via interaction with a
number of G (GTP binding) proteins
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014
Transmembrane receptor
families: GPCRs

Transmembrane receptor families: GPCRs (2)
 G-protein-coupled receptors (GPCRs) act as guanine nucleotide
exchange factors (GEFs) to activate Gα subunit of heterotrimeric
α/β/Ƴ G-protein complex
 Depending on type of Gα subunit that is activated, this will
increase cAMP levels, decrease cAMP levels, or increase protein
kinase C activity and Ca2+ levels
 All catecholamine receptors (adrenergic receptors) are GPCRs
 Endocytosis results in lysosomal clearance of hormone
 Receptor digested in lysosome or recycled to cell membrane

Marc Imhotep Cray, MD 49McInnis 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

50
Hormone 2nd messenger system: G-Protein Classes
Modified from: McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015
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.
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 51

Summary: molecular-cellular
mechanisms of hormone action
52
 Hormones act on their specific receptors located on or within
their target cells
 Receptor activation by hormones is translated into responses in
a variety of ways
1. At cell membrane receptors (proteins and peptides hormones)
(steroids, T4/T3, Vit. D, retinol)
(illustrations next 5 slides)

Summary:
53
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:
54
b. Through IP3 DAG generation: release of intracellular Ca2+
and protein kinase C activation
 Vasopressin (V1) ,Oxytocin

Summary:
55
c. Direct transmembrane activation of tyrosine protein kinase
phosphorylation cascade regulation of various enzymes
 Insulin, Growth hormone , Prolactin
NB:
Cytoplasmic (Nonreceptor) tyrosine
kinase: Prolactin, Immunomodulators
(eg, cytokines IL-2, IL-6, IFN), GH, G-
CSF, Erythropoietin, Thrombopoietin
JAK/STAT pathway
Think acidophils and cytokines
Receptor tyrosine kinase
Insulin, IGF-1, FGF, PDGF, EGF
MAP kinase pathway
Think growth factors

Summary:
56
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:
57
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:
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
58
Class of Receptors Used by Various Hormones

Hormone-Receptor Interactions cont.
 We have just completed a discussion of hormone-
receptor interactions from the vantage point of the
receptor.
 In the next 9 slides we will view the interaction from
the hormone (ligand) side of the interaction.

MOA of peptide hormones & catecholamines
 Peptide hormones and catecholamines are not highly lipid-diffusible and
thus cannot cross plasma membrane
 They bind to cell surface membrane receptors 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
 Examples of catecholamines norepinephrine, epinephrine, and dopamine
60

Characteristics of Protein/Peptide Hormones
 Synthesized as prehormones or preprohormones
 Stored in membrane-bound secretory vesicles (sometimes called
secretory granules)
 Regulated at level of secretion (regulated exocytosis) and synthesis
 Often circulate in blood unbound
 Usually administered by injection
 Hydrophilic and signal through transmembrane receptors

Characteristics of Catecholamines
 Derived from enzymatic modification of tyrosine
 Stored in membrane-bound secretory vesicles
 Regulated at level of secretion (regulated exocytosis) and through
regulation of enzymatic pathway required for their synthesis
 Transported in blood free or only loosely associated with proteins
 Often administered as an aerosol, and several specific analogs
(agonists and antagonists) can be taken orally
 Hydrophilic and signal through transmembrane G-protein-coupled
receptors called adrenergic receptors

Cellular MOA of steroid & TH hormones
 Steroid hormones are lipophilic they diffuse across plasma membrane
and form complexes with cytosolic or nuclear receptors bound complexes
then activate transcription of various genes
 Because 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, nonetheless uses
same cellular mechanism as steroids
63

Transport of steroid and thyroid hormones
Why are total serum steroid hormone & TH levels not an accurate
reflection of hormone activity?
64
 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%)

Transport of steroid and thyroid hormones (2)
65
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

Characteristics of Steroid Hormones
 Derived from enzymatic modification of cholesterol
 Cannot be stored in secretory vesicles because of lipophilic nature
 Regulated at level of enzymatic pathway required for their
synthesis
 Transported in blood bound to transport proteins (binding
globulins)
 Signal through intracellular receptors (nuclear hormone receptor
family)
 Can be administered orally

Characteristics of Thyroid Hormones
 Derived from iodination of thyronines
 Lipophilic, but stored in thyroid follicle by covalent
attachment to thyroglobulin
 Regulated at level of synthesis, iodination, and secretion
 Transported in blood tightly bound to proteins
 Signal through intracellular receptors (nuclear hormone
receptor family)
 Can be administered orally

To summarize:
Mechanisms by which peptide/amine and steroid hormones signal
Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013 68
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

69
Kelly LJ. Essentials of Human Physiology for Pharmacy. Boca Raton: CRC Press, 2004.
Summary of distinguishing features of steroid,
protein/peptide, and amine hormones

Functional anatomy of endocrine and
metabolic systems
70
 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)
71
 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 interaction
between exogenously administered drugs and endogenous biochemistry,
physiology and (pathophysiology) of hormones

72
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

73
Endocrine function
2. Metabolic rate
Regulatory factors
Hypothalamic thyrotropin-releasing hormone (TRH), pituitary
thyrotropin (TSH)
Thyroid gland/triiodothyronine (T3)
Target tissues
All tissues

74
Endocrine function
3. Circulatory volume
Regulatory factors
Renin, angiotensin II, hypothalamic osmoreceptors
Adrenals /aldosterone, Pituitary/vasopressin
Target tissues
Kidney, blood vessels, CNS

75
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

76
Endocrine function
5. Calcium homeostasis
Regulatory factors
Serum Ca+ + and Mg++ concentration
Parathyroid glands/parathyroid hormone, calcitonin, vitamin D
Target tissues
Kidney, intestines, bone

77
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

78
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

Hormones of hypothalamic-pituitary axis
79McInnis 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

Hypothalamic-pituitary signaling pathways
80
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)

81
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
somatotroph release of GH
Hypothalamic-pituitary signaling pathways (2)
Costanzo LS. Physiology (Basic Review Series), 5th ed. New York:
Elsevier, 2009.

Hormonal Feedback Regulatory Systems
82
 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 (set-points or set ranges)
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-1 on 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
83
 As discussed previously, key to
understanding endocrine
pharmacology is to be clear on
feed-forward and feed-back
mechanisms
 Feedback regulation is particularly
critical to physiologic control of
thyroid, adrenal cortical, and
gonadal function
 and is also important in
pharmacologic treatments that
affect these systems
Hypothalamic Releasing Hormone
Pituitary Tropic (Signal) Hormone
Target Glands
Second-tier Hormone
Organ-System Effect
Negative
Feedback

Negative and Positive Feedback Regulation
84
 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
NB: Positive Feedback
Although negative feedback is the primary homeostatic mechanism in
endocrine system, rare examples of positive feedback exist (e.g., menstrual
cycle).

Example of positive feedback
85
 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
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 slide) 86

Regulation of hormone synthesis
and secretion cont.
 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, TH inhibition TSH
Solidlines=positiveeffect
Dashedlines=negativeeffect
Pazdernik TL, Kerecsen L. Rapid Review
Pharmacology, 3rd Ed. Mosby, 2010 87

Basic Pathophysiologic and Pharmacologic
Concepts
 Endocrine systems regulating
 metabolic rate (thyroid hormone)
 reproductive function (sex steroids)
 adaptation to physiologic stress (glucocorticosteroids) and
 somatic growth (growth hormone-IGF axis)
share common disease patterns affecting each level of regulation
 While disease at any level in regulatory system may produce a
similar effect (i.e. hypo- or hyperstimulation of end-organ
effects) different approaches to drug therapy are preferred
depending on site of pathology
 Example: hypogonadism due to failure of pituitary gonadotrophs responds
therapy with exogenous gonadotropins, but gonadal failure will not

Concepts (2)
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)
89

Concepts (3)
 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
90

Concepts (4)
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 synthetic
thyroid 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 (Thioamides)=Methimazole, PTU
91

Concepts (5)
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 results in Cushing syndrome
92

Concepts (6)
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 (microvascular and macrovascular
problems such as neuropathy, nephropathy, retinopathy and CVD) 93

Concepts (7)
 For type 1 DM Insulin is sole treatment and is sometimes also used for type
2 DM
 For type 2 DM, drugs (oral hypoglycemic agents) 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
94

Concepts (8)
 Diagnostic strategies in endocrine disease attempt to identify
site of pathology by identifying pattern of hormonal
responses characteristic for different diseases
 Primary alterations and compensatory responses of
regulatory hormones accompanying different patterns of
endocrine disease must be understood to allow both,
accurate diagnosis and treatment

Concepts (9)
Strategies to Manage the Levels and Action of Hormones
Mechanisms to Increase Hormone Levels and Activity
 Increase endogenous hormone synthesis, release, and transport
 Reduce endogenous hormone metabolism and excretion
 Increase peripheral activation of circulating hormone (if required)
 Hormone replacement therapy
Mechanisms to Decrease Hormone Levels and Activity
 Lower endogenous hormone synthesis, release, or both
 Reduce peripheral conversion to activated forms
 Promote hepatic/renal metabolism/excretion
 Decrease receptor activity by reducing receptor number or affinity for
hormone or use competitive receptor antagonists
 Suppress response of target tissue to receptor-hormone interaction by
interfering with generation of second messengers
 Modify tissue metabolism to blunt the effects of hormone excess

97
Effectors of Hormone Release/Reuptake
Bromocriptine—antagonizes release of GH and prolactin
Octreotide—inhibits selective release of GH
Analogs of GnRH—elevated levels desensitize anterior pituitary;
pulsatile exposure to physiological levels simulates GnH release
Sulfonylureas, Meglitinides and Incretins—promote insulin
release from pancreatic beta cells
Pramlintide—inhibits glucagon secretion
Alteration of Peripheral Conversion of Hormones
Finesteride—blocks conversion of testosterone to 5α
dihydrotestosterone
Aromatase inhibitors—antagonize interconversion of estrogen
and androgens
Propylthiouracil—blocks conversion of thyroxine to
triiodothyronine in tissues
Dipeptidyl peptidase-IV inhibitors—block digestion of incretins
Competitive Receptor Antagonists
Spironolactone—aldosterone receptor antagonist
Raloxifene—estrogen receptor tissue-specific agonist/
antagonist
Tamoxifen/Clomiphene—estrogen receptor agonist/
antagonist
Mifprostone—progesterone receptor antagonist
Danazol/ Cyproterone acetate/Flutamide—androgen
receptor antagonists
Alteration of Metabolism
Metformin—decreases hepatic glucose production
Thiazolidinediones—improves insulin-facilitated metabolic
effects in patients with insulin resistance
Bisphosphonates—cytotoxic effects on osteoclasts
Effectors of Hormone Synthesis
Thioamides—inhibit synthesis of thyroid hormones
Metyrapone—inhibits synthesis of cortisol
Thumbnail: Some Drugs Known to Affect Hormonal Balance
Lynn Wecker et.al. Brody’s Human Pharmacology: Molecular to Clinical, 5th Ed. Philadelphia: Mosby, 2010

Lect. 2 of 6
Hypothalamic and
Pituitary Disorders
98
Hormones produced by hypothalamus and pituitary gland are key regulators of
metabolism, growth, and reproduction. Preparations, including products made by
recombinant DNA technology and drugs that mimic or block their effects, are used in
treatment of a variety of endocrine disorders.
Three concepts are of special importance in this presentation:
(1) hypothalamic control of pituitary hormone release
(2) negative feedback inhibition and
(3) endocrine axes

Neuroendocrine Pharmacology: Hypothalamic and Pituitary Hormones
1. The physiology of neuroendocrine hormonal regulation, including
a) Hypothalamus-Pituitary-Growth Hormone Axis,
b) Hypothalamus-Pituitary-Reproductive Axis,
c) Hypothalamus-Pituitary-Prolactin Axis
2. The use of specific neuroendocrine agents in treatment of following
neuroendocrine disorders:
a) growth hormone deficiency
b) growth hormone excess
c) infertility
d) hyperprolactinemia
3. Indications, mechanism of action, adverse effects, contraindications and
therapeutic considerations for major neuroendocrine hormones and
pharmacological agents.
Learning Objectives
99

Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009
100

Some hormones and drugs affecting the
hypothalamus and pituitary glands
HYPOTHALAMIC AND ANTERIOR PITUITARY
HORMONES
HCG
Corticotropin
Cosyntropin
Urofollitropin
Follitropin alfa
Follitropin beta
Goserelin
Histrelin
Leuprolide
Menotropins
Nafarelin
Pegvisomant
Somatropin
HORMONES OF THE POSTERIOR PITUITARY
Desmopressin DDAVP
Oxytocin
Vasopressin (ADH)
NB (note well [Lat. nota bene])
 The ending –relin indicates a hypothalamus-related hormone.
 Drugs that end in –tropin are related to the pituitary hormones.
Corticorelin (CRH)
Gonadorelin (GnRH)
Octreotide
Somatostatin
Triptorelin
GnRH antagonists
Ganirelix
Cetrorelix
101

Case 39
Drugs Active on the Hypothalamus and Pituitary Gland
A 67-year-old man complains of pain in his right hip for the past few weeks.
He has had no injury to the area and describes the pain as a “bone ache” that
does not radiate. Review of systems is positive only for some weakness of
urinary stream and having to get up twice a night to go to the bathroom.
His general physical examination is normal. His hip examination is normal with
a full range of motion and no tenderness. Examination of his prostate reveals it
to be firm, enlarged, and nodular. Blood tests show a markedly elevated
prostate-specific antigen (PSA), and biopsy of the prostate shows carcinoma.
A bone scan confirms the presence of metastatic disease in the right hip.
Along with other adjuvant therapies, a decision is made to start depot
leuprolide acetate.
_ Leuprolide acetate is an analog of which hypothalamic hormone?
_ What is the mechanism of action of leuprolide acetate?
_ Which pituitary hormones are affected by leuprolide acetate, and how are they affected?
102

Relationship between Hypothalamus and
Pituitary Gland
103
 Hypothalamus and pituitary gland function cooperatively as
master regulators of endocrine system
 Together, hormones secreted by hypothalamus & pituitary control
important homeostatic and metabolic functions, including:
 reproduction
 growth
 lactation
 thyroid gland physiology
 adrenal gland physiology and
 water homeostasis

Relationships among hypothalamic and
pituitary hormones, and target organs (2)
104
 Posterior pituitary hormones, formed in supraoptic and
paraventricular nuclei, are transported by nerve axons to
posterior lobe, where they are released by physiologic stimuli
 Oxytocin induces milk ejection by breast and stimulates
uterine contractions during labor
 Vasopressin increases water and sodium reabsorption by
the kidneys

Relationship between Hypothalamus and
Pituitary Gland (3)
105
Although anterior and posterior pituitary glands derive from
different embryologic origins, hypothalamus controls activity of
both lobes
Connection between hypothalamus and pituitary gland is one of
most important points of interaction between nervous and
endocrine systems
 Hypothalamus acts as a neuroendocrine transducer by integrating
neural signals from brain and converting those signals into chemical
messages (largely peptides) that in turn regulate secretion of pituitary
hormones which in turn, alter activities of peripheral endocrine
organs

106
Relationships among hypothalamic hormones,
pituitary hormones, and target organs
 Numerous hormone-releasing and hormone-inhibiting factors
(neurohormones) formed in arcuate and other hypothalamic nuclei are
transported to anterior pituitary by hypophyseal portal system
 In response to hypothalamic hormones, anterior pituitary secretes following:
 Corticotropin (ACTH) evokes corticosteroid secretion by adrenal cortex
 Growth hormone (GH) elicits production of insulin-like growth factors by liver
 Follicle-stimulating hormone (FSH) stimulates spermatogenesis and facilitates ovarian
follicle development
 Luteinizing hormone (LH) elicits testosterone secretion by testes, facilitates ovarian
follicle development, and induces ovulation
 Thyroid-stimulating hormone (TSH) stimulates thyroxin secretion by thyroid gland
 Prolactin (PRL) induces breast tissue growth and lactation

Marc Imhotep Cray, MD 107Brenner GM & CW Stevens. Pharmacology , 4th ed. Philadelphia: Saunders, 2013.
Relationships among
hypothalamic and
pituitary hormones,
and target organs (3)
Remember:
Hypothalamic Releasing
Hormone Pituitary Tropic
(Signal) Hormone Target
Glands Second-tier
Hormone Organ-System
Effect Negative Feedback

108
Anterior Pituitary Gland Cell Types, Hypothalamic
Control Factors, and Hormonal Targets
Golan DE et.al. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3rd Ed. Lippincott Williams & Wilkins, 2012

Pharmacologic applications of hypothalamic
and pituitary hormones
109
Drugs that mimic or block effects of hypothalamic and
pituitary hormones have pharmacologic applications in three
primary areas:
(1) as replacement therapy for hormone deficiency states
(2) as antagonists for diseases caused by excess production of
pituitary hormones
(3) as diagnostic tools for identifying several endocrine
abnormalities

Pharmacologic applications of hypothalamic
and pituitary hormones (2)
110
 Due to greater ease of administration of target endocrine gland
hormones or their synthetic analogs, related hypothalamic and
pituitary hormones (i.e., TRH, TSH, CRH, ACTH, GHRH) are used
infrequently as treatments
 Some, such as CRH and ACTH, are used for specialized
diagnostic testing as tools for stimulation to diagnose
hypofunctioning or hyperfunctioning endocrine states
 In contrast, GH, SST, LH, FSH, GnRH, and dopamine or analogs
of these hormones are commonly used therapeutic agents

Hypothalamus
111
Hypothalamus is a small area, weighing about 4g of the total
1,400g of adult brain weight only 4g of brain without which life
itself is impossible
Hypothalamus is so critical for life because it contains integrative
circuitry that coordinates autonomic, endocrine, and behavioral
responses that are necessary for basic life functions, such as
 thermoregulation
 control of electrolyte and fluid balance
 feeding and metabolism
 responses to stress, and
 reproduction
NB: Hypothalamic regulatory factors are
peptides (neuropeptides) with exception of
dopamine (an amine/tyrosine derivative).

Hypothalamus (2)
Hypothalamus is not an endocrine gland, but a part of the brain
 Nonetheless, the hypothalamus is vital part of endocrine
system
o This is b/c chemical messengers released by certain
neuron terminals in both hypothalamus and its extension,
posterior pituitary, do not function as neurotransmitters
affecting adjacent cells rather enter blood as
neurohormones Bld then carries them to their sites of
action

Hypothalamus (3)
113
Hypothalamus is responsive to:
 Light and day length for regulating circadian and seasonal rhythms
 Olfactory stimuli, including pheromones
 Steroids including gonadal steroids and corticosteroids
 Neurally transmitted information arising in heart, stomach & reproductive
tract
 Autonomic inputs
 Blood-borne stimuli including leptin, ghrelin, angiotensin, insulin,
pituitary hormones, cytokines, plasma [glucose] and osmolarity
 Stress
 Invading microorganisms by increasing body temperature and resetting
body’s thermostat upward

Hypothalamus (4)
114Felten, DL. Netter's Atlas of Neuroscience, 2nd Ed. Philadelphia, PA: Saunders, 2010

Hypothalamus (5)
115
 One of most important functions of hypothalamus is to link 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
 It synthesizes and secretes neurohormones, often called “hypothalamic-
releasing hormones” which in turn stimulate or inhibit secretion of
pituitary hormones
 Hypothalamus also controls body temperature, hunger, thirst, fatigue and
circadian rhythm cycles
 Hypothalamus synthesizes & secretes the posterior pituitary hormones
vasopressin [antidiuretic hormone (ADH)] and oxytocin

1. Thyrotropin releasing hormone (TRH)
2. Corticotropin releasing hormone (CRH)
3. Gonadotropin releasing hormone (GnRH)
4. Prolactin release inhibitory hormone (PRIH=DA)
5. Growth hormone releasing hormone (GHRH)
6. Somatostatin (Growth hormone release
inhibitory hormone/GHRIH)
Tripeptide
Peptide (41 AAs)
Decapeptide
Dopamine
Peptide (40, 44 AAs)
Peptide (14 AA)
Chemical natureHypothalamic hormone/factor
Hypothalamus produces many releasing and inhibitory
hormones which control secretion of anterior pituitary
hormones
Note: Nearly all hypothalamic hormones stimulate release of pituitary hormones;
dopamine and somatostatin are exceptions.
 Dopamine (DA) acts as an inhibitory factor, preventing release of prolactin
 Somatostatin (SST) prevents release of growth hormone
 With exception of dopamine, all hypothalamic releasing factors are peptides

Hypothalamic hormonal control of Growth
Hormone (GH) and Prolactin (PRL)
117
Hypothalamic hormonal control of GH and PRL (structurally
homologous) differs from regulatory systems for TSH, FSH, LH
and ACTH (activate G protein-coupled receptors )
 GH and PRL are single-chain protein hormones both activate
receptors of JAK/STAT superfamily
Growth Hormone (GH)
Hypothalamus secretes two hormones that regulate GH
 growth hormone-releasing hormone (GHRH) stimulates GH
production,
whereas
 peptide somatostatin (SST) inhibits GH production
 GH and its primary peripheral mediator, insulin- like growth factor-I
(IGF-I) , also provide feedback to inhibit GH release

Hypothalamic hormonal control of Growth
Hormone (GH) and Prolactin (PRL) cont.
Prolactin structurally homologous to growth hormone
 Prolactin production is tonically inhibited by catecholamine dopamine acting
through D2 subtype of DA receptors
 Hypothalamus does not produce a hormone that specifically stimulates prolactin
secretion, although TRH can stimulate prolactin release particularly when TRH
concentrations are high in setting of primary hypothyroidism
 PRL decreases GnRH, thus In pts w pituitary prolactinoma amenorrhea,
osteoporosis, hypogonadism, galactorrhea
 DA agonists (eg, bromocriptine) inhibit PRL secretion and can be used in
treatment of prolactinoma
 DA antagonists (eg, most antipsychotics) and estrogens (eg, OCPs,
pregnancy) stimulate prolactin secretion
See: Anterior Pituitary Case-based Tutorial 3

119
Hypothalamic Control of
ANS
 Hypothalamus is highest level of neuraxis
that provides input to ANS
 It regulates virtually all autonomic functions
and coordinates them with each other, and
with ongoing behavioral, metabolic, and
emotional activity
 Hypothalamus contains several sets of
neurons, using different NTs, that provide
innervation to sympathetic and
parasympathetic preganglionic neurons, as
well as brainstem areas that regulate
autonomic nervous system

Pituitary gland (hypophysis)
120
Pituitary weighs about 0.6 g and rests at base of brain in bony sella
turcica near optic chiasm and cavernous sinuses
Pituitary is composed of two lobes:
 Anterior pituitary (adenohypophysis)
 Posterior pituitary (neurohypophysis)
Pituitary is functionally linked to hypothalamus by pituitary stalk
Neuroendocrine neurons in hypothalamus project axons to
median eminence at base of brain
 neurons release substances (releasing hormones) into special capillary
system, called “hypothalamic-hypophyseal portal system”,  travel to
anterior pituitary gland releasing hormones in turn stimulate release
of pituitary hormones from anterior lobe

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated
Pharmacology, Updated Edition. Saunders, 2014 121
From a developmental perspective,
pituitary gland consists of two closely
associated organs
 Anterior pituitary (adenohypophysis) is
derived from ectodermal tissue
 Rathke’s pouch
 Posterior pituitary (neurohypophysis) is
a neural structure derived from ventral
surface of diencephalon
 a ventral outgrowth of the primitive
hypothalamus
 Prefixes adeno- and neuro- denote oral
ectodermal and neural ectodermal origin
of anterior and posterior pituitary gland
components, respectively
Pituitary gland (2)

122
Normal pituitary gland, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

123
Normal pituitary, microscopic

124
Normal pituitary, microscopic (2)

The hypothalamic-pituitary portal system
 As stated, neurons in hypothalamus release
regulatory factors that are carried by hypothalamic-
pituitary portal system to anterior pituitary gland,
where they control release of anterior pituitary
hormones
 Posterior pituitary hormones are synthesized in cell
bodies of supraoptic and paraventricular neurons
in hypothalamus then transported down axonal
pathways to terminals in posterior pituitary gland
 These hormones are stored in posterior
pituitary gland, from which they are released
into systemic circulation
Note the separate vascular supplies to
anterior and posterior lobes of pituitary gland.
Golan DE et.al. Principles of Pharmacology: The Pathophysiologic
Basis of Drug Therapy 3rd Ed. Lippincott Williams & Wilkins, 2012

Regulation of Hypothalamic & Pituitary
Hormones
 Hormones secreted by hypothalamus and pituitary are all
peptides or low molecular weight proteins that act by binding to
specific receptor sites on their target tissues
 Hypothalamic hormones trigger release of anterior pituitary
hormones which are sent to target organs  where they induce
hormone synthesis
 Hormones of anterior pituitary are regulated by neuropeptides
called either “releasing” or “inhibiting” factors or hormones
produced in hypothalamus, reaching pituitary by hypophyseal
portal system 126

Regulation of Hypothalamic & Pituitary
Hormones cont.
127
Interaction of releasing hormones with their receptors results in
activation of genes that promote synthesis of protein
precursors protein precursors then undergo posttranslational
modification to produce hormones which are released into
circulation
Each hypothalamic regulatory hormone controls release of a
specific hormone from anterior pituitary
 Endocrine-organ systems function via negative feedback
o e.g., hypothalamic CRH stimulates  pituitary ACTH secretion
stimulates adrenal cortisol secretion which in turn inhibits CRH
and ACTH secretion

Relationships Among Hypothalamic, Pituitary,
and Target Gland Hormones
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
128

Marc Imhotep Cray, MD Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology 6th Ed. Wolters Kluwer, 2015
Hormones secreted by
anterior pituitary include:
FSH, LH, ACTH, TSH, Prolactin, and GH
FLAT P(i)G is a useful mnemonic to
remember these hormones
129

Anterior Pituitary & Hypothalamic Hormone Receptors
 Anterior pituitary hormones can be classified according to
hormone structure and types of receptors that they activate
 Anterior pituitary gland hormones are proteins and glycoproteins
Anterior pituitary gland hormones fall into three groups:
1. Somatotropic hormones, consisting of growth hormone (GH)
and prolactin activate receptors of JAK/STAT superfamily
2. Glycoprotein hormones, consisting of luteinizing hormone
(LH), follicle-stimulating hormone (FSH), and thyroid-
stimulating hormone (TSH) (also shared by hCG) activate G
protein-coupled receptors
3. Adrenocorticotropin (ACTH) a separate class, as it is processed
by proteolysis from a larger precursor protein (pro-
opiomelanocortin activate G protein-coupled receptors Katzung, etal. Basic and Clinical
Pharmacology, 12th ed. McGraw-Hill, 2012

Anterior pituitary (adenohypophysis)
131
 Secretes FSH, LH, ACTH, TSH, prolactin, GH
 FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH
 Melanotropin (MSH) secreted from intermediate lobe of pituitary
 Adenohypophysis is derived from oral ectoderm (Rathke pouch)
 α subunit—hormone subunit common to TSH, LH, FSH, and hCG
 β subunit—determines hormone specificity
 ACTH and MSH are derivatives of proopiomelanocortin (POMC)
Histology: Each anterior pituitary hormone is produced by a separate group
of cells, which according to their staining characteristic are either
 Basophils: FSH, LH, ACTH, TSH (B-FLAT)
 Acidophils: GH, PRL

Hypopituitarism
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)
 Patients may present with, for example, adrenal insufficiency or
hypothyroidism
Clinical signs depend on degree and rapidity of onset of
deficiency
 For example, basal cortisol secretion is normal in partial ACTH deficiency,
but during an illness, adrenal insufficiency may occur
 In complete ACTH deficiency, cortisol secretion is always subnormal
132

Hypopituitarism (2)
 Diagnosis of complete deficiency is relatively easy:
 most patients have symptoms, and
 serum levels of target-organ hormone (eg, cortisol, thyroxine, and
testosterone in men) and pituitary hormone (eg, ACTH, thyrotropin,
and luteinizing hormone, respectively) are low
 Causes of hypopituitarism include
 pituitary tumor (most common)
 hypothalamic tumor or cyst
 infiltrative and vascular disorders
 pituitary or cranial radiotherapy
 pituitary necrosis caused by ischemia
133
 Treatment: hormone replacement therapy (corticosteroids, thyroxine, sex
steroids, human growth hormone)

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 134
Hypopituitarism (3)

135Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014
Hypopituitarism (4)

 In this condition, ischemic necrosis of
pituitary causes hypopituitarism caused by
severe hypotension from postpartum
hemorrhage
 Pituitary is particularly vulnerable during
pregnancy because of reduced blood flow
associated with its enlargement at this time
 Result of damage to gland is permanent
underproduction of essential pituitary
hormones (hypopituitarism)
 Agalactia, amenorrhea, hypothyroidism and
adrenocortical insufficiency are important
consequences
 Treatment of Sheehan syndrome is
hormone replacement therapy
Sheehan syndrome:
Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Sheehan syndrome (2)
137
 The specific association with
postpartum shock or hemorrhage was
described in 1937 by British pathologist
Harold Leeming Sheehan (1900–1988),
whereas Simmond's disease occurs in
either sex due to causes unrelated to
pregnancy
 Characterized clinically by asthenia, loss
of weight and body hair, arterial
hypotension, and manifestations of
thyroid, adrenal, and gonadal
hypofunction (See Endocrine Tutorial 1)
Young WF. The Netter Collection of Medical Illustrations Vol 2-
The Endocrine System 2nd Edn. Philadelphia: Saunders, 2011.

Question
138
A 53-year-old woman is diagnosed with hypopituitarism. Which of
the following hormones is most likely to be affected first?
A. Follicle stimulating hormone (FSH) and luteinizing hormone (LH)
B. Thyroid stimulating hormone (TSH)
C. Adrenocorticotropic hormone (ACTH)
D. Prolactin
E. Growth hormone

Question
139
A 25-year-old woman is diagnosed with hypopituitarism. Which of
the following hormones is essential to replace first when managing
her condition?
A. Thyroid hormone
B. Estrogen
C. Growth hormone
D. Luteinizing hormone
E. Follicle stimulating hormone

Growth hormone-releasing hormone (GHRH)
140
GHRH is an active peptide of 44 amino acids produced by
hypothalamus within arcuate nucleus
 GHRH binds to specific membrane GHRH receptors on
pituitary somatotrophs
 GHRH rapidly elevates serum growth hormone
(somatotropin) levels with high specificity
GHRH release is also modulated by “GH secretagogues” via a
unique GH secretagogue receptor which is actually ghrelin
receptor
 Ghrelin is a peptide secreted by stomach in response to fasting
 Ghrelin also stimulates appetite

Growth Hormone (somatotropin)
normal physiologic functions and regulation
 GH secretion occurs primarily at night and in response to various stressors
such as starvation and hypoglycemia
 When released during a good night of sleep, its anabolic actions on
muscle and bone are of primary importance
 When released in response to physiologic stressors such as starvation
and hypoglycemia, its metabolic actions to conserve carbohydrate fuels
(for use by central nervous system and other glucose-dependent tissues)
and maintain protein stores (to preserve muscle strength needed for
mobility) take center stage
 GH secretion is inhibited by elevated somatostatin, somatomedins increase
glucose levels, emotional stress, illness, malnutrition, obesity, glucocorticoids,
and TH and pregnancy
141
N.B. Triiodothyronine (T3) is
required for normal function of GH.

Actions of growth hormone (STH)
142
 In liver, growth hormone generates production of somatomedins [insulin-
like growth factors (IGF)] serve as intermediaries of several physiologic
actions
 IGF receptor has tyrosine kinase activity, similar to insulin receptor
(1) Direct actions of growth hormone
(a) ↓ glucose uptake into cells (diabetogenic)
(b) ↑ lipolysis
(c) ↑ protein synthesis in muscle and ↑ lean body mass
(d) ↑ production of IGF
(2) Actions of growth hormone via IGF
(a) ↑ protein synthesis in chondrocytes and ↑ linear growth (pubertal growth spurt)
(b) ↑ protein synthesis in muscle and ↑ lean body mass
(c) ↑ protein synthesis in most organs and ↑ organ size
Note: In both children and adults,
GH has anabolic effects in muscle
and catabolic effects in lipid cells.
Shift balance of body mass to an
increase in muscle mass and a
reduction in adiposity

Physiologic actions
of growth hormone
143Brown TA. Rapid Review Physiology 2nd Ed. Philadelphia: Mosby, 2012

Somatomedins
144
 Somatomedins are produced, predominantly by liver, when
growth hormones act on target tissue
 Somatomedins inhibit release of growth hormones by acting
directly on anterior pituitary and by stimulating secretion of
somatostatin from hypothalamus
 Somatomedins are a group of hormones that promote cell
growth and division in response to stimulation by growth
hormone (GH) also known as somatotropin (STH)
 Somatomedins have similar biological effects to somatotropin

Somatomedins cont.
145
 In addition to actions that stimulate growth somatomedins also stimulate
production of somatostatin which suppresses growth hormone release
 Thus, levels & GH effects of somatomedins are controlled via negative
feedback through intermediates of somatostatin and growth hormone
 Somatomedins are produced in many other tissues (besides liver) and have
autocrine and paracrine actions in addition to their endocrine action
 Three forms of somatomedin include:
 somatomedin A, another name for insulin-like growth factor 2 (IGF-2)
 somatomedin B, derived from vitronectin
 somatomedin C, another name for insulin-like growth factor 1 (IGF-1)

Mecasermin
146
 Mecasermin is a recombinant form of human IGF-1
 Produced by Escherichia coli bacteria that have been stably
transfected with human gene for IGF-1
 Uses mecasermin is indicated for
 treatment of growth failure in children with severe primary IGF-1
deficiency
 those with a growth hormone receptor mutation, and
 those who have developed neutralizing antibodies to growth hormone
 Adverse Effect main adverse effect is hypoglycemia controlled
by eating a meal or snack before or soon after time of injection

147
Somatostatin (SST)
 Somatostatin is a peptide hormone that regulates endocrine system and affects
neurotransmission and cell proliferation via interaction with G protein-coupled
somatostatin receptors and inhibition of release of numerous secondary hormones
 Secreted by hypothalamus, GIT and δ-cells of pancreas
 SST receptors= five subtypes, SR1 through SR5
 Octreotide (SST analog) acts primarily on SR2 and SR5
 Classified as an inhibitory hormone whose actions are spread to different parts of body
In anterior pituitary effects of somatostatin are:
 Inhibit release of GH (thus opposing effects of GHRH)
o decreases sensitivity of anterior pituitary to GHRH
 Inhibit release of TSH
 Inhibit adenylyl cyclase in parietal cells
 Inhibits release of prolactin (PRL)
 Also inhibits secretion of insulin, glucagon, gastrin, and HCl
Synonyms of somatostatin:
• growth hormone–inhibiting hormone (GHIH)
• growth hormone release–inhibiting hormone (GHRIH)
• somatotropin release–inhibiting factor (SRIF)
• somatotropin release–inhibiting hormone (SRIH)

Somatostatin (2)
148
Indicated for management of
 acromegaly
 islet cell tumors
 bleeding due to esophageal varices and
 secretory diarrhea
disadvantages short duration of action and multiple effects in many
secretory systems
 A series of longer-acting SST analogs have been developed
 Octreotide is a somatostatin analog having high potency and
long duration of action
o Preferred over somatostatin for all indications

Somatostatin (3)
149Bardal SK et.al. Applied Pharmacology. St. Louis: Saunders, 2011.

150
 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
somatotroph release of GH
Hypothalamic-pituitary GH signaling pathway
Costanzo LS. Physiology (Basic Review Series), 5th ed. New York:
Elsevier, 2009.

Growth Hormone Deficiency and Treatment
Growth hormone promotes linear growth by regulating endocrine and
paracrine production of IGF-1 (insulin-like growth factor 1)
 Besides disruption in growth, GH deficiency also causes
 increased subcutaneous visceral fat
 reduced muscle mass
 reduced bone density and
 Reduced exercise performance
 Children have short stature and low growth velocity for age and pubertal
stage
 Adults, who usually have had pituitary tumors or head trauma, show
 low energy
 reduced strength
 weight gain
 anxiety
 reduced libido and
 impaired sleep
151

GH Deficiency and Treatment (2)
 A GH deficiency before puberty will result in pituitary dwarfism
 Somatrem (Protropin) and somatropin (Humatrope) are human
growth hormone produced by recombinant DNA technology (rhGH)
 Replacement therapy will increase growth
o However, replacement therapy cannot induce linear growth after
epiphyseal closure has occurred in the long bones
 Androgens and estrogens also increase growth however,
they are less effective than GH and can induce epiphyseal
closure which limits further growth

GH Deficiency and Treatment (3)
 GH therapy goals differ in children and adults
 In adults, they are to improve conditioning and strength, restore normal
body composition, and improve quality of life
 In children, therapy promotes linear growth and restores body
composition
 rhGH (synthetic growth hormone) is effective for children with GH
deficiency as long as epiphyses are not closed
Other Therapeutic Uses
 GH stimulates growth in patients with Turner syndrome
 long-term replacement of GH deficiency in adults
 treatment of cachexia and AIDS wasting
 patients with severe burns
 Prader-Willi syndrome in children
 short bowel syndrome 153

Molecular and Cellular Bases of Somatotropic
Hormone Action
154
 All of effects of GH (and prolactin) result from their interactions
with specific membrane receptors on target tissues
 i.e., receptors associated with cytoplasmic Tyrosine Kinases
 GH (and prolactin) receptors are widely distributed cell surface
receptors that belong to cytokine receptor superfamily
 share structural similarity with receptors for leptin, erythropoietin,
granulocyte-macrophage colony-stimulating factor (GM-CSF), and
several interleukins
 Like other cytokine receptor family, GH receptors contain
 an extracellular hormone-binding domain
 a single membrane-spanning region, and
 an intracellular domain that mediates signal transduction

Molecular and Cellular Bases of Somatotropic
Hormone Action (2)
155
 These receptors (cytokine receptor superfamily) have no intrinsic
enzymatic activity, rather intracellular domain binds a separate,
intracellular tyrosine kinase termed a Janus kinase (JAK)
 Upon dimerization induced by ligand binding JAKs
phosphorylate other proteins termed signal transducers and
activators of transcription (STATs) which translocate to nucleus
and regulate transcription
 Entire pathway is termed the JAK-STAT pathway
 There are four JAKs and six STATs in mammals, depending on cell
type and signal, combine differently to activate gene transcription

Signaling from cytokine receptor family
JAK-STAT Receptor Pathway
White BA & Porterfield SP. Endocrine and Reproductive Physiology,
 Growth Hormone (and prolactin) bind to
transmembrane receptors that belong to cytokine
receptor family
 These are constitutively dimerized receptors
bound by janus kinases (JAKs)
 Hormone binding interacts with both extracellular
domains and induces JAK-JAK cross-
phosphorylation followed by recruitment and
binding of STAT proteins
 Phosphorylation of STATs activates them and
induces their translocation to nucleus, where they
act as transcription factors

157
Growth Hormone -JAK-STAT Receptor Pathway
Brunton L, Chabner B, Knollman B, eds. Goodman & Gilman’s The Pharmacological
Basis of Therapeutics, 12th ed. McGraw-Hill, 1110; Pg. 1242, Figure 38–5.
See: The Growth Hormone Receptor_A Tutorial
 Binding of GH to a homodimer of
growth hormone receptor (GHR)
induces autophosphorylation of JAK2
 JAK2 then phosphorylates
cytoplasmic proteins that activate
downstream signaling pathways,
including
o STAT5 and mediators upstream of
MAPK, which ultimately modulate
gene expression

Growth Hormone (rhGH) Adverse effects
158
Adverse effects
 In about 2% of patients, anti-GH antibodies develop
 edema
 muscle and joint pain
 benign intracranial hypertension
 hair loss
 hypothyroidism
 hypoglycemia or hyperglycemia, and
 risk of cancer
 Administration of GH is contraindicated in
 obese patients
 patients with closed epiphyses who do not have GH deficiency, patients
with neoplastic disease

Question
A 38-year-old man presents complaining of gradually enlarging hands and feet
over the past several years. In comparison with a photo from 15 years ago, his
facial features have become obviously coarsened. Laboratory evaluation shows
mildly elevated plasma glucose, and MRI of the brain reveals an enlarged mass
in the sella turcica. Given the suspected diagnosis, specialized testing is
performed in which GH levels are measured following administration of an
oral glucose load; no measurable decrease is seen.
What is the diagnosis?
Note: One good way to diagnose this disorder is to look at an old picture
of the patient and compare it with the patient’s current appearance.
Because the physical changes take place over decades, family members
and friends often do not recognize them.
159

A. A 26-year-old attractive woman prior to acromegaly changes.
B. Facial changes 20 years later in the same woman.
Note the coarse facial features with large nose, lips, and chin.
Protrusion of lower jaw is visible.
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. McGraw-Hill, 2013 160

Features of acromegaly /gigantism
 A 22-year-old man with
gigantism due to excess
growth hormone is shown to
left of his identical twin
 increased height and
prognathism (A) and
enlarged hand (B) and foot
(C) of affected twin are
apparent
 Their clinical features began
to diverge at age of
approximately 13 years

GH Excess (Acromegaly) and Treatment
Acromegaly is a disfiguring hormonal disorder caused by excessive GH
secretion from a pituitary tumor
 a rare condition, most common cause is a benign GH (hyper)secreting pituitary
adenoma
Signs of acromegaly include
 coarse facial features and
 enlarged hands, feet, tongue, and internal organs (which lead to heart
disease, hypertension, diabetes, arthralgias)
 Treatments includes
 surgical removal of tumor and (or)
 radiation, or
 subcutaneous use of octreotide a GH inhibitor, analogs are available in
a long-acting depot form or
 pegvisomant (prototype growth hormone receptor antagonist) 162

GH Excess (Acromegaly) and Treatment (2)
Octreotide is a synthetic analog of somatostatin having a longer
duration of action (t½ 1.5 h)
MOA
 inhibition of GH and IGF-1 levels
 suppression of response of LH to GnRH
 also inhibits secretion of thyrotropin, serotonin
 By normalizing levels of GH and IGF-1 (both markers for acromegaly)
octreotide controls clinical signs and symptoms
Uses
 Uses include acromegaly, carcinoid (serotonin-secreting) tumors and other
rare tumors of GI tract (VIPomas) and bleeding esophageal varices
 See Vasoactive Intestinal Peptide tumor and Multiple Endocrine Neoplasia (Tutorial 2)
163
Note: Octreotide is 45 times more
potent than SST in inhibiting GH
release, but only twice as potent
in reducing insulin secretion.

Octreotide
164
 Common adverse effects of octreotide are
 gastrointestinal
more serious effects include
 cardiac arrhythmias
 hypoglycemia or hyperglycemia
 suppression of thyrotropin
 pancreatitis and
 biliary tract abnormalities
 It is admin. SQ two or three times daily
 a depot formulation is available for deep intramuscular injection
 Lanreotide is much longer acting than octreotide admin. IM
twice a month

Octreotide cont.
165
 Octreotide also inhibits TSH secretion and is treatment of
choice for TSH-secreting adenoma in patients who are not
candidates of surgery
 Lanreotide is another somatostatin analog that can be given
i.m. in slow release formulation (longer acting)
 Vapreotide and seglitide are other somatostatin analogs
 Pasireotide is new somatostatin analog approved for treatment
of Cushing‘s disease

Pegvisomant (GH receptor antagonist)
166
 GH is a protein substitution of one amino acid converts endogenous GH
into an antagonist
 Commercial GH antagonists have multiple substitutions to enhance binding affinity
MOA
 Pegvisomant block action of GH at GH receptor in liver prevents GH from
activating GH signaling pathways
Pharmacokinetics
 Addition of polyethylene glycol 500 (PEG-500) to GH  GH antagonists,
increases its half-life from 30 minutes to about 2 days
 As a protein, it cannot be taken orally; it is injected subcutaneously
Uses
 Acromegaly
 For patients with persistently elevated IGF-1 despite other therapy
 Possibly as monotherapy (more research required)

Pegvisomant cont.
167
Contraindication
 Severe liver disease (because of risk of liver damage)
Adverse Effects
 Elevated liver enzymes (transaminases) are seen in 25% of patients,
indicating liver damage. Liver enzymes must be routinely monitored
Important Notes
 Surgery, dopamine agonists, and somatostatin are standard first-line
treatments for acromegaly
 DA agonists and somatostatin are inhibitors of GH secretion but are
not direct antagonists of GH therefore their MOA is slightly
different, and they act at a different location in biochemical pathway

Pegvisomant cont.
168Bardal SK et.al. Applied Pharmacology. St. Louis: Saunders, 2011.

Drugs Used in Disorders of the Endocrine System, Lectures 1 through 6

Drugs Used in Disorders of the Endocrine System, Lectures 1 through 6

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