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OVULATION INDUCTIONOVULATION INDUCTIONIN PERSPECTIVEIN PERSPECTIVE
oc ama nwaroc ama nwarDivision of Reproductive EndocrinologyDivision of Reproductive Endocrinology
Department of Obstetrics andDepartment of Obstetrics andGynecology Gadjah Mada UniversityGynecology Gadjah Mada University
The overview of ovulation inductionThe overview of ovulation induction
The goal of any regimen of ovulation induction isThe goal of any regimen of ovulation induction is
yield numerous preovulatory oocyte suitable foryield numerous preovulatory oocyte suitable for
transfer into the fallopian tube.transfer into the fallopian tube.
Ovulation induction has been one of the mostOvulation induction has been one of the most
significant advances in the treatment of infertilitysignificant advances in the treatment of infertility
,, ,,
no one protocol has proved to be moreno one protocol has proved to be more
beneficial than another.beneficial than another.
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Maturation
FOLLICULOGENESIS
Recruitment In the normal cycleIn the normal cycle oneonefolliclefollicleisis uusuallysually
selected to undergoselected to undergomaturation during thematuration during the
follicular phase.follicular phase.(Dominant follicle)(Dominant follicle)
At this stage,antral follicles
become acutely
.
In response tounknownsignals, a
hundreds ofprimordialfollicles is
recruited togrow
The selected or dominant follicle was recruited together with otherThe selected or dominant follicle was recruited together with otherfolliclefollicless about 10 weeks prior to the onset of menstruation.about 10 weeks prior to the onset of menstruation.
dependent on FSHfor further
development
The physiology ofThe physiology of
folliculogenesisfolliculogenesis
Although FSH is the primary regulator ofAlthough FSH is the primary regulator of
DDominantominant FFolicleolicle development, it is nowdevelopment, it is now
clear that growth factors (GFs) producedclear that growth factors (GFs) producedby the follicle itself can act by autocrineby the follicle itself can act by autocrine
and aracrine mechanisms to modulateand aracrine 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
anovulationanovulationThe etiopathogenesis of anovulation is complexThe etiopathogenesis of anovulation is complex
and multifactorial.and multifactorial.
WHO
Hypothalamic-pituitaryfailure
Hypothalamic-pituitarydysfunction
Group-1 Group-2
1. Amenorrhea and do notbleed in response toprogestin challenge.
1. Variety of cycle disorders (amenorrhae,oligomenorrhae, anovulatory cycles andluteal phase difficiency) Bleeding in
2. Endogenous estrogendeficient.
3. With normal or low FSH orprolactin levels.
response to progestin challenge.
2. They are not endogenous estrogendeficient
3. Normal FSH and prolactin levels.
4. The most common cause is PCOS.
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WHO groupWHO group--33 Women in WHO groupWomen in WHO group--3 includes those3 includes those
primary ovarian failure mainly due toprimary ovarian failure mainly due todiminished ovarian reserve and loss ofdiminished ovarian reserve and loss of
ovarian follicles.ovarian follicles.
They are resistence to various methods ofThey are resistence to various methods of
..And the best approach for their infertility isAnd the best approach for their infertility is
oocyte donation.oocyte donation.
Control Ovarian HyperstimulationControl Ovarian Hyperstimulation
(COH)(COH) Initially, drugs such as Clomiphene citrate (CC)Initially, drugs such as Clomiphene citrate (CC)
and Human meno ausal onadotro in hMGand Human meno ausal onadotro in hMGwere used for COHwere used for COH..
A premature endogenous LH surge wasA premature endogenous LH surge was
observed in 40% of cycles, and was reported toobserved in 40% of cycles, and was reported tohave a negative effect on the IVF outcome inhave a negative effect on the IVF outcome interms 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,e nc ence o prema ure en ogenouse nc ence o prema ure en ogenous
surge was reduced to less than 2%.surge was reduced to less than 2%.
With the advent of GnRH antagonists, newWith the advent of GnRH antagonists, newperspectives for COH have been opened.perspectives for COH have been opened.
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Urinary Gonadotropin PreparationUrinary Gonadotropin PreparationThe first successsful induction of ovulation andThe first successsful induction of ovulation and
pregnancy in patients with pituitary gonadotropicpregnancy in patients with pituitary gonadotropic
e c ency, us ng gona o rop ns o a ne rome c ency, us ng gona o rop ns o a ne rom
postpost--menopausal urine.menopausal urine.
Human Menopausal Gonadotropin hMG(1960s)
Pergonal LH : FSH ratio equal to 1
The ratio ofThe ratio of FSFSH :H : LLHH
It was realized that the response to the therapy was notIt was realized that the response to the therapy was notnecessaril de endent u on the total amount ofnecessaril de endent u on the total amount of
gonadotropingonadotropin (hMG)(hMG) administeredadministered but rather to thebut rather to theratio 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 toThe pregnancy rate per ovulatory cycle was found toincrease with the increase in the FSH : LH ratioincrease with the increase in the FSH : LH ratio
(Tillinger, 1966).(Tillinger, 1966).
A urinary gonadotropin preparation with very little LHA urinary gonadotropin preparation with very little LHcontamination was developed :contamination was developed : MetrodineMetrodine
( LH : FSH( LH : FSH 0,70,7 :: 7575 ) 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 = 0,00060,0006 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 women hMG
Pergonal
Polyclonal antibody technology (Metrodin)
Monoclonal Antibody technologyHighly Purified urinary FSH (Metrodin HP)
Recombinant FSH (rFSH)
1. Less inter-batch variability
2. Less immunogenic influence
3. Less likely to be contaminated
Foll icle Stimulating HormoneFoll icle Stimulating HormoneComplete or partial deficiency of FSH are
common causes of human infertility
In women, it ischaracterized by absenceof or abnormal ovulation
In men, it leads to theabsence of or abnormally low
spermatozoa production.
The role of FSH in folliculogenesis is:
-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 theassisted reproduction techniques
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THE ROLE OF GONADOTROPINS
RELEASING HORMONE (GnRH) IN
OVULATION INDUCTION
Gonadotropins releasing hormone (GnRH)
GnRH, or luteinizing hormoneGnRH, or luteinizing hormone--releasing hormonereleasing hormone
LHRH is the h othalamic hormone releas inLHRH is the h othalamic hormone releas in,,
both gonadotropins LH and FSH from theboth 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 onThe 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)
-- ..
Occupancy of only 20% of GnRH binding si tes isOccupancy of only 20% of GnRH binding si tes is
suffic ient to evoke 80% of the biologicalsuffic ient to evoke 80% of the biological
response.response.
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RESULTS OF MODIFICATION OF THE AMINO ACIDS IN THERESULTS OF MODIFICATION OF THE AMINO ACIDS IN THE
DECAPEPTYDE GnRHDECAPEPTYDE GnRH
The difference in the number of amino acids substituted,
leads to a different mechanism of action, mainly caused by
Increase in binding affinity toIncrease in binding affinity toPituitary GnRH receptorsPituitary GnRH receptors
-
GnRH agonist GnRH antagonist
They have no intracellular activity,They have no intracellular activity,
which avoid a flarewhich avoid a flare--up effect.up effect.
to the proteolytic degradation.to the proteolytic degradation. Increase the halfIncrease the half--life of GnRHlife of GnRH--aa
1.5 to 5 hours, while natural1.5 to 5 hours, while naturalGnRH has a halfGnRH has a half--life of a fewlife of a fewminutesminutes((Albino et.al, 2001)Albino et.al, 2001)
competitive receptor binding, whichcompetitive receptor binding, which
leads to an immidiate arrest ofleads to an immidiate arrest of
gonadotropin secretion.gonadotropin secretion.
TThe gonadal function will resumehe gonadal function will resume
almost immediately after thealmost immediately after the
cessation of treatment with thecessation of treatment with the
antagonist.antagonist.
Gl -NH2Gl -NH2Natural GnRH P r Tr Ser T r Gl Leu Ar Pro
1 2 3 4 5 6 7 8 9 10
Natural GnRH and their most important synthetic agonist
10
Ethylamid
D-Trp6-GnRH
Leuprorelin
acetate
1
1
2
2
3
3
4
4
5
5
9
9
8
8
7
7
D-Trp
D-Leu
AzGly-NH2
us ere n
Goserelin
Ethylamid1
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)
35 years 375 - 450 IU
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GnRH-a Up-Regulation Increase in GnRH
receptors
LONG PROTOCOL
are up g eve s o gona o rop n
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
FSH has a larger part to play than LHFSH has a larger part to play than LH
in follicular development.in follicular development.
1.1. Af fects granulosa cell prol iferationAffects granulosa cell prol iferation2.2. Expression of LH receptors on granulosa cellsExpression of LH receptors on granulosa cells
3.3. Aromatase activationAromatase activation
4.4. Increases inhibin production by granulosa cellsIncreases inhibin production by granulosa cells
,
ver y advant ageous t o use a ver y p ure FSH
(rFSH) pr epara t ion t hat is devoi d of LH
(Bongso,1999)
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High level of LH will lead to hyperandrogenism and wi ll
adversely effect the maturation and fertilisation of oocyte and
embryonic development
Hypothalamus
secrete GnRH
GnRH
(in hypothalamo-pituitary portal vessels) Only LHOnly FSH
- -
-
An ter io r p itui tary
FSH LH
Gran ulos a c el ls Th ec a c el ls
Ovaries
AndrogenInfluenceoocyte
Inhibin Estrogen
Reproductive tract and other organs
Respond to estrogen
Estrogen
two gonadotropins
theory
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The twoThe two--cell, two gonadotropin theory postulatedcell, two gonadotropin theory postulatedthat FSH concentrations must exceed a certain levelthat FSH concentrations must exceed a certain level
(FSH threshold) before follicular development will(FSH threshold) before follicular development will
FSH thresholdFSH threshold
..
The duration of this period in which the threshold is exceededThe duration of this period in which the threshold is exceeded
(the FSH window) is lim ited in the normal cycle by gradual(the FSH window) is lim ited in the normal cycle by gradual
decrease in FSH (occuring in the early middecrease in FSH (occuring in the early mid --folli cular phase), as afollicular phase), as a
response to negative feedback from rising estrogen levelsresponse to negative feedback from rising estrogen levels
produced by the larger follicles.produced by the larger follicles.
the time FSH levels are above the FSHthe time FSH levels are above the FSH
threshold and extend the FSH windowthreshold and extend the FSH window multiple ovulation by rescuing smallermultiple ovulation by rescuing smaller
follicles that would otherwise havefollicles that would otherwise have
undergone atresia.undergone atresia.
Multifollicular development
Smaller follicles, with fewer FSH receptors, are no longerSmaller follicles, with fewer FSH receptors, are no longer
stimulated to grow by FSH levels below FSH threshold andstimulated 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 multi lecorpora lutea
The level of E andP in the early partof luteal phase are
steroid production istruncated
Shortening the lutel phase
Interfering with
This early and rapid fall of gonadal steroid wasthe reason luteal phase supportwas adopted
in IVF
suprap ys o og ca
Unlike the conventional protocol, the low-dose protocol employs adose of gonadodotropin that is not supra-physiologicalbut reachesthe threshold for a follicular response producing monofolllicularrather than multifollicular OHSS and multiple pregnancy reduced.
75 IU112,5 -150 IU
187,5 IU
7-14 days 14 -21 days21-28 days
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150 IU37.5 IU every 3 days
a follicle of 10 mmReduced37.5 IU
5 days
Among the protocol descr ibed, 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 beincreased.
Higher multiple pregnancy rates in patients treated withGnRH agonist
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GnRH antagonistGnRH antagonistThe srtuctural variations with modifications in theThe srtuctural variations with modifications in the
molecular structure not only at position 6 and 10, butmolecular structure not only at position 6 and 10, butalso, at positions 1,2,3 and 8 result :also, at positions 1,2,3 and 8 result :
In potent antagonistic GnRH receptor ligands withIn potent antagonistic GnRH receptor ligands withapproximately 10approximately 10--20 times higher binding affinity to the20 times higher binding affinity to the
GnRH receptor than native GnRH.GnRH receptor than native GnRH.
No histamineNo histamine--releasing propertiesreleasing properties
There are two GnRH antagonist available : CetrorelixThere are two GnRH antagonist available : Cetrorelix(Cetrotide) and Ganirelix (Orgalutran, Antagon).(Cetrotide) and Ganirelix (Orgalutran, Antagon).
Ganerilex (GnRH antagonist) study group
The administration ofGranerilex 1 or 2 mg
Serum LH were foundto be
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The advantages of GnRH antagonistsThe advantages of GnRH antagonists
over agonist treatment are :over agonist treatment are :
Immidiate suppression of gonadotropinImmidiate suppression of gonadotropin
secretionsecretion
GnRH antagonist can reduce the
treatment period from several weeks to
. Reduction of sideReduction of side--effectseffects
Preotocols for GnRH antagonists forPreotocols for GnRH antagonists for
COHCOH MultipleMultiple--dose protocoldose protocol
GnRH antagonist0.25 mg hCG
1 2 3 4 5 6 7 8 9 10 11 12
Stimulation (rFSH or HMG)
SingleSingle--dose protocoldose protocol
Stimulation (rFSH or HMG)
hCG
1 2 3 4 5 6 7 8 9 10 11 12
3 mg
GnRH antagonist0.25 mg
If the criteria for hCG administrationhave not been fulfilled
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CLOMIPHEN CITRATE (CC)CLOMIPHEN CITRATE (CC)
,for ovulatory disorders has been clomiphene
citrate.
Given in a dose of 50Given in a dose of 50--150 mg/day from day 4 to150 mg/day from day 4 to8 of a spontaneous or progestine8 of a spontaneous or progestine--inducedinduced
menstruationmenstruation
It is easy to use and results in ovulation in mostpatients (6090%), however, the pregnancy
rates are disappointing (1040%)
Clomiphen citrate (CC)Clomiphen citrate (CC)The reasons for the difference in ovulation and pregnancyThe reasons for the difference in ovulation and pregnancy
rates are thought to be due :rates are thought to be due :
--.. development and cervical mucusdevelopment and cervical mucus In 15% to 50% ofIn 15% to 50% of
women,women,
2.2. CC blocks the endometrial estrogen receptors andCC blocks the endometrial estrogen receptors andsuppresses pinopode formation, both essential forsuppresses pinopode formation, both essential for
implantation.implantation.
This adverse response to CC canot be overcome byThis adverse response to CC canot be overcome byaddin estro en re arations.addin estro en re arations.
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 thetamoxifen (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%
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Clomiphen citrate - PCOS
High BMI, larger ovarian volume, higher level of LH,
testosterone and insulin concentration and low SHBG level.
Gonadotropins gave the most consistent highovulation 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 t reated
effectively either by metformin or by LOD.
( Malkawi et al., 2003)
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SUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITYSUGGESTED STEPWISE TREATMENT SCHEME FOR INFERTILITY
ASSOCIATED WITH PCOSASSOCIATED 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 PregnancyPregnancy
Aromatase inhibitors (AIs)Aromatase inhibitors (AIs)
The efficient oestrogenThe efficient oestrogen--lowering propertieslowering properties
o so s nega ve ee ac e ec onega ve ee ac e ec o
estrogenestrogen increase discharge of FSH.increase discharge of FSH.
Although the end result of an increasedAlthough the end result of an increaseddischarge of FSH is common to both AIsdischarge of FSH is common to both AIs
and CC the differences in their mode ofand CC the differences in their mode of
action confer several advantages onaction confer several advantages on
aromatase inhibitor.aromatase inhibitor.
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The advantages of AIsThe advantages of AIs Aromatase inhibitors (AIs) have no effect onAromatase inhibitors (AIs) have no effect onestrogen receptors and therefore no deleteriousestrogen receptors and therefore no deleterious
effect on cervical mucus or endometrium.effect on cervical mucus or endometrium.
AIs do not block hypothalamic estrogenAIs do not block hypothalamic estrogenreceptors and, therefore, the negative feedbackreceptors and, therefore, the negative feedback
mechanism remain intactmechanism remain intact this enablesthis enablesregulation of FSH discharge when estrogen isregulation of FSH discharge when estrogen isproduced and should reduce the prevalence ofproduced and should reduce the prevalence of
, ,, ,multiple pregnancies compared with CC.multiple pregnancies compared with CC.
The halfThe half--life of the AIs is about 2 days, muchlife of the AIs is about 2 days, muchshorter than that of CC.shorter than that of CC.
SummariesSummaries GnRH agonists have been widely used to preventGnRH agonists have been widely used to prevent
premature LH surge during COH in Assistedpremature LH surge during COH in AssistedReproductive Technology.Reproductive Technology.
CC will restore ovulation in about 75% , however it willCC will restore ovulation in about 75% , however it willinduce 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 thetamoxifen (20 mg for every 50 mg of CC) can avoid theproblem.problem.
CC-resistant patients with PCOS can be treatedeffectively either by metformin or by LOD.
In clinical situation in which an immidiate suppresion ofIn clinical situation in which an immidiate suppresion ofgonadotropins is desired, GnRH antagonists have thegonadotropins is desired, GnRH antagonists have theadvantage of producing an instant and doseadvantage of producing an instant and dose--relatedrelatedinhibition of LH and FSH by competitive blockage of theinhibition of LH and FSH by competitive blockage of thereceptors.receptors.
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