GnRH ANALOGUES

IN REPRODUCTIVE
MEDICINE

Tono Djuwantono
Bagian Obstetri dan
Ginekologi FKUP / RSHS
Bandung
 GnRH

NATURAL ANALOGUES

AGONISTS ANTAGONISTS

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 Gonadotropin releasing hormone

Pyro CONH2
Glu His Trp Ser Tyr Gly Leu Arg Pro Gly

Endopeptidase Carboxyamide
peptidase

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 GnRH agonists

Tapros®

D- D-
Leu Trp

Pyro NH-
Glu His Trp Ser Tyr Leu Arg Pro Ethylamide

D- D-
His Ser

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 GnRH antagonists (Cetrotide®)

Acetyl-D-2- D-3-
naphthylalanyl pyridylalanyl D-alaninamide

Ser Tyr Leu Arg Pro

D-4- D-citrullyl
chlorophenylalanyl

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 Down and • Down-regulation
– Number of
Up-Regulation receptors
decreases within
target cells (after
exposure to
certain ligands)
• Up-regulation
– Some stimulus
causes number of
receptors for a
hormone to
increase within
target cell
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 Pituitary Gland and
Hypothalamus • Pituitary
gland/hypophysis
Where nervous and – Secretes 9 major
endocrine systems hormones
interact • Hypothalamus
– Regulates
secretory activity
of pituitary gland
through
neurohormones
and action
potentials
– Posterior pituitary
is an extension of
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Pituitary Gland • Posterior or
neurohypophysis
Structure – Continuous with the
brain
– Secretes
neurohormones
• Anterior or
adenohypophysis
– Consists of three
areas with indistinct
boundaries: pars
distalis, pars
intermedia, pars
tuberalis

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Relationship of Pituitary to Brain

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 Hypothalamus, Anterior
Pituitary and Target Tissues

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Pituitary Gland • Anterior
Hormones – Growth hormone (GH)
or somatotropin
• Posterior – Thyroid-stimulating
hormone (TSH)
– Antidiuretic
– Adrenocorticotropic
hormone (ADH)
hormone (ACTH)
– Oxytocin
– Melanocyte-
stimulating hormone
(MSH)
– Luteinizing hormone
(LH)
– Follicle-stimulating
hormone (FSH)
– Prolactin
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Positive and Negative
Feedback

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 Control of Secretion Rate
• Negative-feedback
– Mechanisms that function to maintain
homeostasis control most of hormone
secretion
• Mechanisms of hormone secretion
from endocrine tissue
– Nonhormone substance
– Stimulation by nervous system
– Hormone from another endocrine tissue

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 Transport and • Hormones dissolve
Distribution in blood plasma and
are transported in
free form or bound
to plasma proteins
• As concentration of
free hormone
molecules increase,
more hormones
molecules diffuse
from capillaries into
interstitial spaces to
bind to target cells
Hormone concentration at the
target cell
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 Transport and • A large decrease in
plasma protein
Distribution concentration can
result in loss of a
hormone from the
blood because free
hormones are rapidly
eliminated from
circulation through
kidney or liver
• Hormones are
distributed quickly
because they
Effect of plasma protein circulate in the blood
concentration on the
concentration of free hormone
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 Metabolism and Excretion
• Half-life: The length of time it takes for half a dose
of substance to be eliminated from circulatory
system
– Long half-life
• Regulate activities that remain at a constant rate
through time
– Short half-life
• Water-soluble hormones as proteins, epinephrine,
norepinephrine
• These hormones have a rapid onset and short duration
• Hormones also eliminated by blood by excretion
– Kidneys and liver
– Enzymatic degradation
– Conjugation
– Active transport
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Hormone Interaction with Target Tissues
• Hormones
– Ligands or
chemical signals
• Binding site
• Receptor site
• Specificity

The shape and chemical characteristics of receptor sites

on receptor molecules make them very specific so that
certain ligands can bind to a receptor site, but others
cannot Tono, 6/4/2003 17-17
Target Cell Response
Target tissues have
to Hormones receptor molecules
specific for
particular hormone
TSH is secreted into
the blood and
distributed
throughout the body,
where TSH diffuses
from the blood into
the interstitial fluid.
Only target cells, however, have receptors for TSH;
therefore, although TSH is distributed throughout the
body, only target cells forTono,
that hormone can respond to it17-18
6/4/2003
 Classes of Hormone Receptors

• Membrane-bound receptors bind to water-

soluble or large-molecular-weight hormones
• Intracellular receptors bind to lipid-soluble
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hormones
Membrane-Bound • Proteins or
glycoproteins that
Hormone Receptors have polypeptide
chains folded to
cross cell several
times
• Results of ligand
binding
– Changes
permeability of
plasma membrane
– Alters activity of G
proteins
– Alters activity of
intracellular
enzymes
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Membrane-Bound Receptors and
Activation of G Proteins

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Membrane-Bound receptors, G
Proteins and Ca2+ Channels

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Membrane-Bound receptors, G Proteins
and Synthesis of cAMP

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Membrane-Bound Receptors

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Cascade Effect

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 Intracellular Hormone Receptors
• Are proteins in cytoplasm or nucleus
• Hormones bind with intracellular receptor
and receptor-hormone complex activates
genes, DNA activated to produce mRNA,
mRNA initiates production of certain
proteins (enzymes) that produce response
of target cell to hormone
• Slow-acting because time is required to
produce mRNA and protein
• Processes limited by breakdown of
receptor-hormone complex

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Intracellular Receptor Model

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 First established pregnancy using rec-hFSH and
GnRH-a for IVF-ET treatment

hCG 10,000
amps. OC
4 ET - 4
rec-hFSH
1
18
Mid-luteal E2
phase
14

Buserelin 0.2 mg
8

Menses
21 2 7 14
Germond et al. Lancet 1992
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Evidence based about GnRH
analogues in the management of
endometriosis

Cochrane Review 2001

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Kadar serum FSH dan E2 setelah pemberian
GnRH-Analog

Minggu

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 Catecholestrogen

Norepinephrine Dopamine Endorphin

+ -
Tyrosine
+ Arcuate - hydroxylase
nucleus

2-Methoxy-estradiol
Tyrosine 2-OH-estradiol
GnRH pulses
-
Anterior
pituitary
Estrogen
Progesterone Prolactin
FSH & LH
Ovary

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Control of GnRH 17-34
Pulses
 Cholesterol
Sex Steroid Synthesis
HO

StAR
P450scc CH3 17 hydroxy CH3  Pathway
DMTH C=O Pregnenolone C = O O
OH
Pregnenolone
AMG 17-hydroxylase/ 17-hydroxylase/
17,20 lyase 17,20 lyase
Dihydroepiandrosterone
HO HO HO

3-HSD 3-HSD
3-HSD
CH3 CH3
CKT CKT CKT
TLS
C=O
17-hydroxylase/ TLS
C=O
OH
17-hydroxylaseTLS
/ O

17,20 lyase 17,20 lyase

Androstenedione
O O O

Progesterone 17 hydroxy
P450arom -HSD
4 Pathway Progesterone AMG
PRO O OH

5-reductase
Ketoconazole (various P450 sites)
5-DHT
Testosterone
Cyanoketone [CKT] HO O

Estrone
Trilostane [TLS] -HSD P450arom

Dimethoate [DMTH] AMG

OH
PRO
Aminoglutethimide [AMG]
Prochloraz [PRO] Estradiol
23 HO

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 Cholesterol
Sex Steroid Synthesis
HO

StAR
P450scc CH3 17 hydroxy CH3  Pathway
C=O Pregnenolone C = O O
OH
Pregnenolone 17-hydroxylase/ 17-hydroxylase/
17,20 lyase 17,20 lyase
Dihydroepiandrosterone
HO HO HO

3-HSD 3-HSD
3-HSD
CH3 CH3

C=O
17-hydroxylase/ C=O
OH
17-hydroxylase/ O

17,20 lyase 17,20 lyase

Androstenedione
O O O

Progesterone 17 hydroxy
P450arom -HSD
4 Pathway Progesterone
O OH

5-reductase
5-DHT
Testosterone
HO O
P450scc - CYP11A1
Estrone
-HSD P450arom
3-HSD - 3-hydroxysteroid dehydrogenase/ 5-4-isomerase

17-hydroxylase/ 17,20 lyase - CYP17 OH

P450arom - CYP19
Estradiol
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HO

17-36
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