Download Antagonists

Hormone Action
Brian Feldman, MD, PhD
Department of Pediatrics/
Endocrinology
[email protected]
NRs vs. Membrane Receptors
Hormones that act at the membrane also have the
potential to have nuclear (genomic) actions but
usually not by translocating the receptor to the
nucleus.
Outline
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Major steroid hormones and their source
General properties of NHRs
Specificity of hormone activity
Therapeutic uses of hormones
Diseases caused by hormonal
abnormalities
Major Types of Steroid
Hormones
Class
Mineralocorticoid
Glucocorticoid
Androgen
Estrogen
Progestin
Vitamin D
Major Active Human
Hormone
Aldosterone
Cortisol
Dihydrotestosterone
(Testosterone?)
Estradiol
Progesterone
1,25Dihydroxycholecalciferol
Source
Adrenal
Glomerulosa
Adrenal Fasiculata
Testis
Ovary
Corpus Luteum
Kidney
Molecular Structure of Hormones
General Properties of NRs
This is not your mother’s Endo lecture
• BUT hormones have tissue and context
specific effects
• Some genes are regulated by a hormone
in one cell type but not another
• Other genes are regulated by a hormone
only during specific times (i.e. cell division,
differentiation, etc)
• We need to understand these details to
understand physiology, pathophysiology
and pharmacology
Major Active Hormones and Receptors
Specificity of hormone activity
Hormones have complex systemic
and tissue specific effects
•Cushing’s syndrome:
increased fat (central),
decreased bone and
muscle; metabolic
syndrome
•Metabolic syndrome:
Insulin resistance/
diabetes , HTN,
dyslipidemia
Larsen: Williams Textbook of Endocrinology
How is Diversity and Specificity
Achieved?
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(We don’t really know but part of)
the explanation:
• Intracellular regulation of hormone
• Allosteric effects on receptor caused by
hormone and other factors binding to receptor
• DNA (availability and sequence)
• Co-factor interactions (availability and complex)
• RESULT: receptor/ligand complex form highly
context specific structures
Role of Intracellular Enzymes to
Regulate Ligand Availability
Testosterone
DHT
5alpha reductase
Cortisol
11BHSD
Or
Hormone Activation
Cortisone
3 Ways to Decorate A Nuclear
Receptor at the Response
Element
• Simple: Homodimer
• Complex: Heterodimer
• Tethering: Intermediate Protein
Steroid Hormones Regulate transcription
Via a Variety of Mechanisms
Nuclear envelope
GR
NHR Co-regulator
GR
GR
GR
Response element
Target gene
Simple
Steroid Hormones Regulate transcription
Via a Variety of Mechanisms
Nuclear envelope
GR
GR
GR
Response element
Target gene
Complex
Steroid Hormones Regulate transcription
Via a Variety of Mechanisms
Nuclear envelope
GR
GR
GR
NHR Co-regulator
Response element
Target gene
Tethering
Allostery
Receptor Conformation with Agonist or Antagonist
Agonist Bound
Antagonist Bound
Note different positions of Helix 12 if an agonist or antagonist is bound in the LBD
pocket.
Antagonists alter receptor
structure
Availability of DNA is Regulated
DNA sequence
regulates
Receptor complex
formation
AGGTCAxxxAGGTCA
AGGTCAxxxxAGGTCA
AGGTCAxxxxxAGGTCA
The DNA Sequence Regulates
Receptor Structure
Meijsing et al , Science, 2009
Small Structural Differences Produce
Specificity of Receptor Activity
Meijsing et al , Science, 2009
Therapeutics
With Complexity Comes Opportunity
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Physiologic replacement
Design of potent agonists
Design of potent antagonists
Design of selective hormone
receptor modifiers
Pharmacological Use of Hormones
• Use of hormones at physiological levels for
replacement
– Glucocorticoids, thyroid, estrogens, androgens,
vitamin D
• Use of hormones at pharmacological levels as
drugs
– Glucocorticoids, PPAR ligands, ATRA
• Use of hormone antagonists as drugs
– Spironolactone (anti-MR), anti-androgens
• Use of selective receptor modifiers
– (SERMs) to treat breast cancer
– tamoxifen, raloxifene
Agonist therapy: Differentiation Therapy for Acute
Promyelocytic Leukemia (APL) with Retinoids (ATRA)
APL is caused by a gene rearrangment of RAR
(ch.15)
and PML (ch.17) to give the PML-RAR fusion
gene that acts as an oncoprotein and blocks
normal RAR action. PML gene function is unclear.
RAR action is essential to differentiate PMLs.
Rx with ATRA overcomes the block and
differentiates the malignant clone.
Use of Hormone Receptor
Antagonists as Drugs
• Mineralocorticoid blockerspironolactone
• Androgen blocker - flutamide,
bicalutamide
• Estrogen blocker - fluvestrant
• Glucocorticoid blocker - RU486
• Progesterone blocker - RU486
What is the basis of antagonist
or SERM activity?
• How can a hormone/drug bind to the
receptor but fail to act?
• How can a hormone/drug have
different actions in different organs
although binding to the same
receptor?
Molecular basis for SERMs
SERM Activity in Different Organs
Breast
Tamoxifen
Antagonist
Raloxifene
Antagonist
Uterus
Agonist
Neutral
Bone
Agonist
Agonist
Diseases caused by hormonal
abnormalities
What is your Dx?
Patient also has
decreased bone,
muscle; diabetes
Sperling: Pediatric Endocrinology
5 alpha reductase deficiency
• 2% of live births in isolated village of
Dominican Republic
• Pseudohermaphrodites: first females, then
males
• Deficient in 5a-reductase
• Lack dihydrotestosterone (DHT)
• Adult males: scant beard, no acne, small
prostate, small testes
Hints:
Patient did not shave
Karyotype: 46 XY
Androgen Insensitivity Syndrome
• Absent pubic and axillary hair
• Normal female external anatomy
• Male internal anatomy (undescended
testis)
• Results from mutations in AR
Hereditary 1,25 Dihydroxyvitamin D
Resistant Rickets
• AR disease
• Early onset rickets, hypo Ca, elevated
1,25(OH)2D3, often alopecia
• Results from mutation in VDR
Clinical Importance of Steroid
Receptor Mutations
• Vitamin D receptor
– hereditary vitamin D resistant rickets
• Androgen receptor
– testicular feminization
– androgen independent prostate
cancer
• Estrogen receptor
– ER negative breast cancer
• Thyroid receptor
– Thyroid hormone resistance