Ovulation Bandung-Prof Anwar

8/10/2019 Ovulation Bandung-Prof Anwar

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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%

-

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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