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OVULATION INDUCTION OVULATION INDUCTION
IN PERSPECTIVE IN PERSPECTIVE
M h dA M h dA Mochamad Anwar Mochamad Anwar
Division of Reproductive Endocrinology Division of Reproductive Endocrinology
Department of Obstetrics and Department of Obstetrics and
Gynecology Gadjah Mada University Gynecology Gadjah Mada University
The overview of ovulation induction The overview of ovulation induction
The goal of any regimen of ovulation induction is The goal of any regimen of ovulation induction is
to achieve the growth of numerous follicles that to achieve the growth of numerous follicles that to achieve the growth of numerous follicles that to achieve the growth of numerous follicles that
yield numerous preovulatory oocyte suitable for yield numerous preovulatory oocyte suitable for
transfer into the fallopian tube. transfer into the fallopian tube.
Ovulation induction has been one of the most Ovulation induction has been one of the most
significant advances in the treatment of infertility significant advances in the treatment of infertility
Many protocols have been described Many protocols have been described however however Many protocols have been described, Many protocols have been described, however, however,
no one protocol has proved to be more no one protocol has proved to be more
beneficial than another. beneficial than another.
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Maturation
FOLLICULOGENESIS
Recruitment
I n the normal cycle I n the normal cycle one one
follicle follicle is is u usually sually
selected to undergo selected to undergo
maturation during the maturation during the
follicular phase. follicular phase.
(Dominant follicle) (Dominant follicle)
At this stage,
antral follicles
become acutely
.
In response to
unknown
signals, a
hundreds of
primordial
follicles is
recruited to
grow
The selected or dominant follicle was recruited together with other The selected or dominant follicle was recruited together with other
follicle follicless about 10 weeks prior to the onset of menstruation. about 10 weeks prior to the onset of menstruation.
dependent on FSH
for further
development
The physiology of The physiology of
folliculogenesis folliculogenesis
Although FSH is the primary regulator of Although FSH is the primary regulator of
DDominant ominant FFolicle olicle development, it is now development, it is now
clear that growth factors (GFs) produced clear that growth factors (GFs) produced
by the follicle itself can act by autocrine by the follicle itself can act by autocrine
and paracrine mechanisms to modulate, and paracrine mechanisms to modulate, and paracrine mechanisms to modulate, and paracrine mechanisms to modulate,
either amplify or attenuate, FSH action. either amplify or attenuate, FSH action.
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DEVELOPMENT OF A HUMAN OOCYTE AND OVARIAN FOLLICLE
anovulation anovulation
The etiopathogenesis of anovulation is complex The etiopathogenesis of anovulation is complex
and multifactorial. and multifactorial.
WHO
Hypothalamic-pituitary
failure
Hypothalamic-pituitary
dysfunction
WHO
Group-1 Group-2
1. Amenorrhea and do not
bleed in response to
progestin challenge.
1. Variety of cycle disorders (amenorrhae,
oligomenorrhae, anovulatory cycles and
luteal phase difficiency) Bleeding in
2. Endogenous estrogen
deficient.
3. With normal or low FSH or
prolactin levels.
response to progestin challenge.
2. They are not endogenous estrogen
deficient
3. Normal FSH and prolactin levels.
4. The most common cause is PCOS.
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WHO group WHO group--3 3
Women in WHO group Women in WHO group- -3 includes those 3 includes those
with elevated gonadotropins secondary to with elevated gonadotropins secondary to with elevated gonadotropins secondary to with elevated gonadotropins secondary to
primary ovarian failure mainly due to primary ovarian failure mainly due to
diminished ovarian reserve and loss of diminished ovarian reserve and loss of
ovarian follicles. ovarian follicles.
They are resistence to various methods of They are resistence to various methods of
ovarian stimulation ovarian stimulation ovarian stimulation ovarian stimulation..
And the best approach for their infertility is And the best approach for their infertility is
oocyte donation. oocyte donation.
Control Ovarian Hyperstimulation Control Ovarian Hyperstimulation
(COH) (COH)
Initially, drugs such as Clomiphene citrate (CC) Initially, drugs such as Clomiphene citrate (CC)
and Human menopausal gonadotropin (hMG) and Human menopausal gonadotropin (hMG) p g p ( ) p g p ( )
were used for COH were used for COH..
A premature endogenous LH surge was A premature endogenous LH surge was
observed in 40% of cycles, and was reported to observed in 40% of cycles, and was reported to
have a negative effect on the IVF outcome in have a negative effect on the IVF outcome in
terms of oocyte quality and pregnancy rate. terms of oocyte quality and pregnancy rate.
With he introduction of GnRH agonists for COH, With he introduction of GnRH agonists for COH,
th i id f t d LH th i id f t d LH the incidence of premature endogenous LH the incidence of premature endogenous LH
surge was reduced to less than 2%. surge was reduced to less than 2%.
With the advent of GnRH antagonists, new With the advent of GnRH antagonists, new
perspectives for COH have been opened. perspectives for COH have been opened.
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Urinary Gonadotropin Preparation Urinary Gonadotropin Preparation
The first successsful induction of ovulation and The first successsful induction of ovulation and
pregnancy in patients with pituitary gonadotropic pregnancy in patients with pituitary gonadotropic
d fi i i d t i bt i d f d fi i i d t i bt i d f deficiency, using gonadotropins obtained from deficiency, using gonadotropins obtained from
post post- -menopausal urine. menopausal urine.
Human Menopausal Gonadotropin hMG
(1960s)
Pergonal LH : FSH ratio equal to 1
The ratio of The ratio of FS FSH : H : L LHH
It was realized that the response to the therapy was not It was realized that the response to the therapy was not
necessarily dependent upon the total amount of necessarily dependent upon the total amount of necessarily dependent upon the total amount of necessarily dependent upon the total amount of
gonadotropin gonadotropin (hMG) (hMG) administered administered but rather to the but rather to the
ratio of FSH to LH in the preparation used. ratio of FSH to LH in the preparation used.
The pregnancy rate per ovulatory cycle was found to The pregnancy rate per ovulatory cycle was found to
increase with the increase in the FSH : LH ratio increase with the increase in the FSH : LH ratio
(Tillinger, 1966). (Tillinger, 1966).
A urinary gonadotropin preparation with very little LH A urinary gonadotropin preparation with very little LH
contamination was developed : contamination was developed : Metrodine Metrodine
( LH : FSH ( LH : FSH 0,7 0,7 : : 75 75 ) IU/amp. ) IU/amp.
(polyclonal antibody) (polyclonal antibody)
A highly purified urinary FSH gonadotropin : A highly purified urinary FSH gonadotropin :
Metrodin HP. Metrodin HP. (Serono). (Serono). LH = LH = 0,0006 0,0006 IU/amp. IU/amp.
(Monoclonal antibody) (Monoclonal antibody)
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Follicle Stimulating Hormone (FSH)
Hystorically Gonadotropins were extracted from the urine
of post menopausal womenhMG
Pergonal
Polyclonal antibody technology (Metrodin)
Monoclonal Antibody technology
Highly Purified urinary FSH (Metrodin HP)
Genetic EngineeringTechniques Genetic Engineering Techniques
Recombinant FSH (rFSH)
1. Less inter-batch variability
2. Less immunogenic influence
3. Less likely to be contaminated
Follicle Stimulating Hormone Follicle Stimulating Hormone
Complete or partial deficiency of FSH are
common causes of human infertility
I n women, it is
characterized by absence
of or abnormal ovulation
I n men, it leads to the
absence of or abnormally low
spermatozoa production.
The role of FSH in folliculogenesis is:
To stimulate the formationof a large pre-ovulatory follicle To stimulate the formation of a large pre ovulatory follicle
that is capable of ovulation and forming a corpus luteum in
response to the mid-cycle surge of LH.
FSH is widely used in ovarian stimulation for the
assisted reproduction techniques
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THE ROLE OF GONADOTROPINS
RELEASING HORMONE (GnRH) IN
OVULATION INDUCTION
Gonadotropins releasing hormone (GnRH)
GnRH, or luteinizing hormone GnRH, or luteinizing hormone- -releasing hormone releasing hormone
(LHRH), is the hypothalamic hormone releasing (LHRH), is the hypothalamic hormone releasing (LHRH), is the hypothalamic hormone releasing (LHRH), is the hypothalamic hormone releasing
both gonadotropins LH and FSH from the both gonadotropins LH and FSH from the
gonadotroph cell of the anterior pituitary gland. gonadotroph cell of the anterior pituitary gland.
The GnRH receptor is expressed exclusively on The GnRH receptor is expressed exclusively on
pituitary gonadotrophs, which consist of : pituitary gonadotrophs, which consist of :
60 % multihormonal cells (FSH and LH) 60 % multihormonal cells (FSH and LH)
18 % LH cells and 22%FSH 18 % LH cells and 22%FSH--containing cells containing cells 18 % LH cells and 22% FSH 18 % LH cells and 22% FSH--containing cells. containing cells.
Occupancy of only 20% of GnRH binding sites is Occupancy of only 20% of GnRH binding sites is
sufficient to evoke 80% of the biological sufficient to evoke 80% of the biological
response. response.
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Nat Natural ural GnRH GnRH
Plasma half Plasma half--life of circulating Nat life of circulating Natural ural
G RH i t l h t 2 G RH i t l h t 2 5 i t 5 i t GnRH is extremely short : 2 GnRH is extremely short : 2--5 minutes 5 minutes
after release. after release.
GnRH becomes rapidly degraded by GnRH becomes rapidly degraded by
endopeptidases of the pituitary gland, endopeptidases of the pituitary gland,
which preferentlially interact with the which preferentlially interact with the which preferentlially interact with the which preferentlially interact with the
peptide bonds in position 6 of the peptide bonds in position 6 of the
decapeptyde molecule. molecule.
Ami no ac i d sequenc e of
Nat ur al GnRH vs Agoni st der i vat i ves
The decapeptide GnRH
1 2 3 4 5 6 7 8 9 10
By modifying the amino acids
in the position 6 and 10
When the amino acids in position
1, 2, 3 and 8 were also modified
GnRH - Agonist GnRH - Antagonist
GnRH Analog
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RESULTS OF MODIFICATION OF THE AMINO ACIDS IN THE RESULTS OF MODIFICATION OF THE AMINO ACIDS IN THE
DECAPEPTYDE GnRH DECAPEPTYDE GnRH
The difference in the number of amino acids substituted,
leads to a different mechanism of action, mainly caused by
post hormone receptor binding events
Increase in binding affinity to Increase in binding affinity to
Pituitary GnRH receptors Pituitary GnRH receptors
It has an increased resistance It has an increased resistance
post hormone-receptor binding events
GnRH agonist
GnRH antagonist
They have no intracellular activity, They have no intracellular activity,
which avoid a flare which avoid a flare--up effect. up effect.
AAct by the mechanism of ct by the mechanism of
It has an increased resistance It has an increased resistance
to the proteolytic degradation. to the proteolytic degradation.
Increase the half Increase the half--life of GnRH life of GnRH--a a
1.5 to 5 hours, while natural 1.5 to 5 hours, while natural
GnRH has a half GnRH has a half- -life of a few life of a few
minutes minutes
((Albino et.al, 2001) Albino et.al, 2001)
AAct by the mechanism of ct by the mechanism of
competitive receptor binding, which competitive receptor binding, which
leads to an immidiate arrest of leads to an immidiate arrest of
gonadotropin secretion. gonadotropin secretion.
TThe gonadal function will resume he gonadal function will resume
almost immediately after the almost immediately after the
cessation of treatment with the cessation of treatment with the
antagonist. antagonist.
Gly-NH2 Gly-NH2
Natural GnRH
Pyr His Trp Ser Tyr Gly Leu Arg Pro
1 2 3 4 5
6 7 8 9 10
Natural GnRH and their most important synthetic agonist
Gly NH2 Gly NH2
10
Ethylamid
D-Trp6-GnRH
Leuprorelin
acetate
B li
Pyr His Trp Ser Tyr Gly Leu Arg Pro
1
1
2
2
3
3
4
4
5
5
9
9
8
8
7
7
D-Trp
D-Leu
AzGly-NH2
Buserelin
Goserelin
Ethylamid 1
1
2
2
3
3
4
4
5
5
9
9
8
8
7
7
D-Ser
D-Ser
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SUPEROVULASI
(COH)
SUPEROVULASI
(COH)
<30 years 75 150 IU
30-35 years 225 - 300 IU
> 35 years 375 - 450 IU
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GnRH-a Up-Regulation Increase in GnRH
receptors
Fl Hi h l l f d t i
LONG PROTOCOL
Flare up High levels of gonadotropin
Few days (10 -14 days)
Down Regulation Decrease in GnRH
receptors
GnRH-a
Desinsitazion
(Hypogodanotropic and hypoestrogenic state) (Hypogodanotropic and hypoestrogenic state)
Reduce in gonadotropin secretion
Selective medical hypophysectomy
Follicle stimulating hormone (FSH) : Follicle stimulating hormone (FSH) :
FSH has a larger part to play than LH FSH has a larger part to play than LH
in follicular development. in follicular development.
Follicle stimulating hormone (FSH) : Follicle stimulating hormone (FSH) :
1. 1. Affects granulosa cell proliferation Affects granulosa cell proliferation
2. 2. Expression of LH receptors on granulosa cells Expression of LH receptors on granulosa cells
3. 3. Aromatase activation Aromatase activation
4. 4. Increases inhibin production by granulosa cells Increases inhibin production by granulosa cells
Thus during follicular development it is Thus, during follicular development it is
very advantageous to use a very pure FSH
(rFSH) preparation that is devoid of LH
(Bongso,1999)
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High level of LH will lead to hyperandrogenism and will
adversely effect the maturation and fertilisation of oocyte and
embryonic development
Hypothalamus
secrete GnRH
GnRH
(in hypothalamo-pituitary portal vessels) Only LH Only FSH
- -
-
Anterior pituitary
FSH LH
Granulosa cells Theca cells
Ovaries
Two cells
Androgen
Influence
oocyte
Inhibin Estrogen
Reproductive tract and other organs
Respond to estrogen
Estrogen
Two cells
two gonadotropins
theory
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The two The two- -cell, two gonadotropin theory postulated cell, two gonadotropin theory postulated
that FSH concentrations must exceed a certain level that FSH concentrations must exceed a certain level
(FSH threshold) before follicular development will (FSH threshold) before follicular development will
proceed proceed
FSH threshold FSH threshold
proceed. proceed.
The duration of this period in which the threshold is exceeded The duration of this period in which the threshold is exceeded
(the FSH window) is limited in the normal cycle by gradual (the FSH window) is limited in the normal cycle by gradual
decrease in FSH (occuring in the early mid decrease in FSH (occuring in the early mid- -follicular phase), as a follicular phase), as a
response to negative feedback from rising estrogen levels response to negative feedback from rising estrogen levels
produced by the larger follicles. produced by the larger follicles.
Administering Administering exogenous FSH prolongs exogenous FSH prolongs Administering Administering exogenous FSH prolongs exogenous FSH prolongs
the time FSH levels are above the FSH the time FSH levels are above the FSH
threshold and extend the FSH window threshold and extend the FSH window
multiple ovulation by rescuing smaller multiple ovulation by rescuing smaller
follicles that would otherwise have follicles that would otherwise have
undergone atresia. undergone atresia.
Multifollicular development
Smaller follicles, with fewer FSH receptors, are no longer Smaller follicles, with fewer FSH receptors, are no longer
stimulated to grow by FSH levels below FSH threshold and stimulated to grow by FSH levels below FSH threshold and
undergo atresia. undergo atresia.
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Problems of the luteal phase
after ovarian stimulation
Produces multiple
The duration of ovarian
Produces multiple
corpora lutea
The level of E and
P in the early part
of luteal phase are
h i l i l
The duration of ovarian
steroid production is
truncated
Shortening the lutel phase
I nterfering with
implantation
This early and rapid fall of gonadal steroid was
the reason luteal phase support was adopted
in IVF
supraphysiological
implantation
Unlike the conventional protocol, the low-dose protocol employs a
dose of gonadodotropin that is not supra-physiological but reaches
the threshold for a follicular response producing monofolllicular
rather than multifollicular OHSS and multiple pregnancy reduced.
75 IU
112,5 -150 IU
187,5 IU
7-14 days
14 -21 days
21-28 days
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150 IU
37.5 IU every 3 days
a follicle of 10 mm
Reduced
37.5 IU
every 3 days
5 days
every 3 days
Among the protocol described, the long protocol is
probably the most popular and effective and it has
also been proven to be highly efficient in ART
program.
Drawbacks with the use of GnRH agonist
The long protocol requires a relatively long treatment period.
The incidence of OHSS in GnRH agonist cycles may be
increased.
Higher multiple pregnancy rates in patients treated with
GnRH agonist
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Simple method of ovulation Simple method of ovulation
induction induction
Klinik Permatahati RS.Dr.Sarjito Klinik Permatahati RS.Dr.Sarjito
100 200 IU 10 000 IU
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
rFSH
100-200 IU
CC 100 mg USG TV
hCG
10.000 IU
IUI/IVF/ICSI
36 hrs
CC 100 mg USG-TV
Estrogen
progestogen
IUI/IVF/ICSI
Non-endometriosis
Ovarian stimulation for IVF in patients Ovarian stimulation for IVF in patients
with endometriosis with endometriosis
The use of GnRH agonist in a long The use of GnRH agonist in a long
protocol appears to enhance the protocol appears to enhance the protocol appears to enhance the protocol appears to enhance the
probability of conception in the presence probability of conception in the presence
of endometriosis. of endometriosis.
There is evidence to suggest that the use There is evidence to suggest that the use
of prolonged down regulation with GnRH of prolonged down regulation with GnRH
agonists prior to ovarian stimulation for agonists prior to ovarian stimulation for agonists prior to ovarian stimulation for agonists prior to ovarian stimulation for
IVF is beneficial for achieving pregnancy. IVF is beneficial for achieving pregnancy.
(Zikopuolos et al, 2004) (Zikopuolos et al, 2004)
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Two ovulation induction methods for IUI Two ovulation induction methods for IUI
in patients with endometriosis in patients with endometriosis
Two ovulation induction methods for IUI Two ovulation induction methods for IUI
in patients with endometriosis in patients with endometriosis
Monofollicular protocol of Monofollicular protocol of ovulation induction for ovulation induction for
IUI in patients with endometriosis IUI in patients with endometriosis
Monofollicular protocol of Monofollicular protocol of ovulation induction for ovulation induction for
IUI in patients with endometriosis IUI in patients with endometriosis
Endometriosis
Humegone ( 75 IU FSH +75 IU LH )
50 IU
10 000
21, 22, 23, 24, 25, 26, 27, 28, 29, 30.
Days after the last GnRH-a administration
Leuprolein 3.75
mg / months
intramuscularly
for 6 months
Humegone ( 75 IU FSH +75 IU LH )
50 IU
rFSH
Dominant follicle reach
10,000
hCG
36 h
later
Ttrasvaginal
Ultrasound
20mm and endometrial line
was ticker than 9 mm
Estradiol measurement
IUI
(Kereszturi et al, 2002 : Results of AIH following GnRH treatment of
endometriosis- Archieves of Andrology)
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GnRH antagonist GnRH antagonist
The srtuctural variations with modifications in the The srtuctural variations with modifications in the
molecular structure not only at position 6 and 10, but molecular structure not only at position 6 and 10, but y p y p
also, at positions 1,2,3 and 8 result : also, at positions 1,2,3 and 8 result :
In potent antagonistic GnRH receptor ligands with In potent antagonistic GnRH receptor ligands with
approximately 10 approximately 10--20 times higher binding affinity to the 20 times higher binding affinity to the
GnRH receptor than native GnRH. GnRH receptor than native GnRH.
No histamine No histamine--releasing properties releasing properties
There are two GnRH antagonist available : Cetrorelix There are two GnRH antagonist available : Cetrorelix
(Cetrotide) and Ganirelix (Orgalutran, Antagon). (Cetrotide) and Ganirelix (Orgalutran, Antagon).
Ganerilex (GnRH antagonist) study group
The administration of
Granerilex 1 or 2 mg
Serum LH were found
to be <1 iu/L
The adminstration of
Granilex 0,25 mg/day
Implantation rates
were highest
Poor follicular
development
Pregnancy rates
increased (33,8%)
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The advantages of GnRH antagonists The advantages of GnRH antagonists
over agonist treatment are : over agonist treatment are :
Immidiate suppression of gonadotropin Immidiate suppression of gonadotropin
secretion secretion
GnRH antagonist can reduce the
treatment period from several weeks to
several days several days.
Reduction of side Reduction of side--effects effects
Preotocols for GnRH antagonists for Preotocols for GnRH antagonists for
COH COH
Multiple Multiple--dose protocol dose protocol
GnRH antagonist
0.25 mg hCG
1 2 3 4 5 6 7 8 9 10 11 12
Stimulation (rFSH or HMG)
g
GnRHantagonist
Single Single- -dose protocol dose protocol
Stimulation (rFSH or HMG)
hCG
1 2 3 4 5 6 7 8 9 10 11 12
GnRH antagonist
3 mg
GnRH antagonist
0.25 mg
If the criteria for hCG administration
have not been fulfilled
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For over four decades the first line of treatment
CLOMIPHEN CITRATE (CC) CLOMIPHEN CITRATE (CC)
For over four decades, the first line of treatment
for ovulatory disorders has been clomiphene
citrate.
Given in a dose of 50 Given in a dose of 50--150 mg/day from day 4 to 150 mg/day from day 4 to
8 of a spontaneous or progestine 8 of a spontaneous or progestine--induced induced
menstruation menstruation
It is easy to use and results in ovulation in most
patients (6090%), however, the pregnancy
rates are disappointing (1040%)
Clomiphen citrate (CC) Clomiphen citrate (CC)
The reasons for the difference in ovulation and pregnancy The reasons for the difference in ovulation and pregnancy
rates are thought to be due : rates are thought to be due :
11 Mainly to anti Mainly to anti--estrogen effects of CC on endometrial estrogen effects of CC on endometrial 1. 1. Mainly to anti Mainly to anti estrogen effects of CC on endometrial estrogen effects of CC on endometrial
development and cervical mucus development and cervical mucusIn 15% to 50% of In 15% to 50% of
women, women,
2. 2. CC blocks the endometrial estrogen receptors and CC blocks the endometrial estrogen receptors and
suppresses pinopode formation, both essential for suppresses pinopode formation, both essential for
implantation. implantation.
This adverse response to CC canot be overcome by This adverse response to CC canot be overcome by
adding estrogen preparations. adding estrogen preparations. g g p p g g p p
Substitution of CC with aromatase inhibitor or, possibly, Substitution of CC with aromatase inhibitor or, possibly,
tamoxifen (20 mg for every 50 mg of CC) can avoid the tamoxifen (20 mg for every 50 mg of CC) can avoid the
problem. problem.
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In general population there are about 20-30%
of women considered as CC-resistant PCOS
Clomiphen citrate - PCOS
of women considered as CC resistant PCOS
High BMI, larger ovarian volume, higher level of LH,
testosterone and insulin concentration and low SHBG level.
Gonadotropins gave the most consistent high
ovulation rate, and became the first line treatment
of CC-resistant PCOS
1. Diet and exercise followed by CC should be
used for non-surgical ovulation induction.
METFORMIN - PCOS
2. For CC-resistant PCOS women, metformin
may be included in a stepwise approach
before a surgical approach.
(Saleh and Khalil, 2004)
CC-resistant patients with PCOS can be treated
effectively either by metformin or by LOD.
( Malkawi et al., 2003)
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SUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY SUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY
ASSOCIATED WITH PCOS ASSOCIATED WITH PCOS
Oligo/anovulasi with PCOS
Weight loss Pregnancy
Roy Homburg, Best Practice & Research Clin Obstet Gynecol. 18(5):773-88,2004)
Clomiphene citrate
Pregnancy
Add metformin
No response
Ovulatory cycles x 6
Pregnancy
Low dose FSH Pregnancy
Ovulatory cycles x 6
IVF/ET LOD Pregnancy
Pregnancy
Aromatase inhibitors (AIs) Aromatase inhibitors (AIs)
The efficient oestrogen The efficient oestrogen--lowering properties lowering properties
f AI f AI ti f db k ff t f ti f db k ff t f of AIs of AIs negative feedback effect of negative feedback effect of
estrogen estrogen increase discharge of FSH. increase discharge of FSH.
Although the end result of an increased Although the end result of an increased
discharge of FSH is common to both AIs discharge of FSH is common to both AIs
and CC, the differences in their mode of and CC, the differences in their mode of and CC, the differences in their mode of and CC, the differences in their mode of
action confer several advantages on action confer several advantages on
aromatase inhibitor. aromatase inhibitor.
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The advantages of AIs The advantages of AIs
Aromatase inhibitors (AIs) have no effect on Aromatase inhibitors (AIs) have no effect on
estrogen receptors and therefore no deleterious estrogen receptors and therefore no deleterious g p g p
effect on cervical mucus or endometrium. effect on cervical mucus or endometrium.
AIs do not block hypothalamic estrogen AIs do not block hypothalamic estrogen
receptors and, therefore, the negative feedback receptors and, therefore, the negative feedback
mechanism remain intact mechanism remain intact this enables this enables
regulation of FSH discharge when estrogen is regulation of FSH discharge when estrogen is
produced and should reduce the prevalence of produced and should reduce the prevalence of
multiple follicle development consequently multiple follicle development consequently multiple follicle development, consequently, multiple follicle development, consequently,
multiple pregnancies compared with CC. multiple pregnancies compared with CC.
The half The half- -life of the AIs is about 2 days, much life of the AIs is about 2 days, much
shorter than that of CC. shorter than that of CC.
Summaries Summaries
GnRH agonists have been widely used to prevent GnRH agonists have been widely used to prevent
premature LH surge during COH in Assisted premature LH surge during COH in Assisted
Reproductive Technology. Reproductive Technology. p gy p gy
CC will restore ovulation in about 75% , however it will CC will restore ovulation in about 75% , however it will
induce pregnancy in only about 10% to 40% of patients. induce pregnancy in only about 10% to 40% of patients.
Substitution of CC with aromatase inhibitor or, possibly, Substitution of CC with aromatase inhibitor or, possibly,
tamoxifen (20 mg for every 50 mg of CC) can avoid the tamoxifen (20 mg for every 50 mg of CC) can avoid the
problem. problem.
CC-resistant patients with PCOS can be treated
effectively either by metformin or by LOD.
I li i l it ti i hi h i idi t i f I li i l it ti i hi h i idi t i f In clinical situation in which an immidiate suppresion of In clinical situation in which an immidiate suppresion of
gonadotropins is desired, GnRH antagonists have the gonadotropins is desired, GnRH antagonists have the
advantage of producing an instant and dose advantage of producing an instant and dose- -related related
inhibition of LH and FSH by competitive blockage of the inhibition of LH and FSH by competitive blockage of the
receptors. receptors.
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F o r k in d a tte n tio n