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Apollo Medicine 2012 SeptemberVolume 9, Number 3; pp. 228e238 Review Article

Optimization of ovarian stimulation to improve success rate in ‘ART’

Sushma P. Sinha

SeniorIndrapemail:ReceivCopyrihttp://d

ABSTRACT

ART is defined as the technique used where there is a need for in-vitro preparation or manipulation of gametes. Thecommonest ARTs are intrauterine insemination (IUI) and in-vitro fertilization (IVF). Ovarian stimulation is required withthese procedures to increase the pregnancy rate as ART with natural cycle has a very low pregnancy rate. Optimizingpregnancy rates per cycle is the real basis for ovarian stimulation protocols in ART.

Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved.

Keywords: Assisted reproductive technology (ART), in-vitro fertilization, Gonadotrophins, Ovarian hyperstimulationsyndrome (OHSS), Polycystic ovarian syndrome (PCOS)

ROLE OF OVARIAN STIMULATION IN ART

It is estimated that of all the couples who embark on infer-tility treatment up to 10% will require some form of assistedreproductive techniques (ART).1

Ovarian stimulation is an integral part of assisted repro-ductive technology (ART) today. Data shows that naturalovarian cycle leads to a significantly lower pregnancy rateand the number of oocytes obtained following stimulationcorrelates positively with the ongoing pregnancy rate.

Association between the numbers of eggs and live birthrate in IVF treatment (Fig. 1).

Although the first IVF baby Louise Brown in July 1978was a result of natural cycle,3 the past 3 decades have intro-duced revolution in reproductive medicine and ovarianstimulation happens to be a part of it. Successful outcomesfollowing assisted reproductive technology are largelydependent on the patient’s response to controlled ovarianstimulation i.e. number & quality of oocytes and numbersof embryo available for transfer in case of IVF. Studieshave found an increase in pregnancy rate with theincreasing number of oocytes upto 14e15, after that thereis a plateau.

There is a marked variability in ovarian response amongassisted reproductive technology (ART) patients. At one

Consultant Obstetrician & Gynaecologist, Infertility and IVF Expert, Arastha Apollo Hospitals, Sarita Vihar, New Delhi 110076, India.sinha_sushma@hotmail.comed: 19.6.2012; Accepted: 3.7.2012; Available online: 17.7.2012ght � 2012, Indraprastha Medical Corporation Ltd. All rights reservedx.doi.org/10.1016/j.apme.2012.07.008

end of the spectrum is poor or no response and at the otherend is the ovarian hyperstimulation syndrome and theoutcome may be no pregnancy to multiple pregnancies.

In the last 3 decades, significant increase in the incidenceof multiple births is almost entirely the result of the use ofovulation inducing agents in ART.

Spontaneous multiple pregnancies occur in about 1e2%of women which is increased to 7e10% of women takingclomiphene citrate (CC) & further to 25% treated withgonadotrophin, approximately 5e10% are higher orderpregnancies.4 It has been studied that even twins facegreater risks of disability & death than do singletons.5,6.Multiple pregnancies carry extra risks for both the motherand fetuses. Obstetric complications include increased inci-dence of pre-eclampsia, antepartum hemorrhage, pretermlabor and surgical or assisted delivery. The high incidenceof prematurity and low birth weight fetuses among highorder multiple pregnancies result in a four fold rise of peri-natal mortality for twins & six fold rise in triplets comparedwith singleton pregnancy. Multiple gestation children maysuffer long-term consequences of perinatal complicationsincluding cerebral palsy and learning disabilities such asslow language development & behavioral problems.

Another associated problems of ovarian stimulation isovarian hyperstimulation syndrome (OHSS), which is

cademic Co-ordinator, Department of Obstetrics and Gynaecology,

.

Fig. 1 Correlation between egg number and live birth rate.Source: (Ref. 2). By courtesy e Sunkara SK, et al. Hum Reprod.May 2011.

Optimization of ovarian stimulation Review Article 229

a potentially fatal iatrogenic condition resulting from exces-sive stimulation of ovaries. The vast majority of OHSSoccurs in setting of injectables like gonadotrophins inIVF. Severe form of OHSS occurs in 0.5e5% of IVFcycles.7 It is more common in young, lean/low BMI/patients, PCOS, hCG triggering being an initiator, so ispregnancy. It has been proven time & again that polycysticovarian syndrome has higher risk of OHSS. It can be lifethreatening in up to 1% of cases.

As the ovarian response is not same to all & it dependsupon the factors like age, basal metabolic rate (BMI),

OVARIAN STIMULATION SHOULD H

RESULT

COST

Most suitable

Avoid

Fig. 2 Optimization of ovarian stimulation.

ovarian reserve, polycystic ovarian disease, presence ofendometriosis and demographic characteristics of patienthence, ‘one size fits all’ policy cannot be adopted. Giventhe marked variability in ovarian responses among ARTpatients the choice of stimulation protocol must be individ-ualized. Our endeavor should be to use the most suitableprotocol which brings out the best result, avoiding thecomplications mentioned above and at reduced cost(Fig. 2).

CAN WE PREDICT THE OVARIAN RESPONSE?

There are several factors that can predict ovarian responseto ovarian stimulation therefore, the likelihood of successfollowing ART (Table 1).

Although there is no absolute predicting factor presentbut they are used to optimize individual stimulationprotocol while minimizing potential complications.

Age is the most important factor in determining successrates of ART. The loss of fecundity with age appears to bea consequence of both oocyte depletion & reduced oocytequality. It has been demonstrated that maternal age canpredict over 80% of IVF success.9 The 2004 centers fordisease control database indicates that per cycle live birthrates vary significantly between age groups (from 43%for women aged <35 to 6%, in women >42 years of age

AVE

COMPLICATIONS OHSS, Multiple Pregnancies

Best

Reduced

PROTOCOL

Table 1 Factors predicting ovarian response.

1. Age2. Ovarian reserve predictors

A. Endocrine markers- Day 3 FSH- AMH- Day 3 inhibin-B- Day 3 estradiol

B. Function biomarkers- Antral follicle count & ovarian volume

C. Genetic traits & abnormalities- Abnormal variants of the FSH receptors- Mutation in the gene coding for LH & LH receptors Fig. 4 Live births per transfer for fresh embryos from own and

donor eggs, by age of recipient. Source: (Ref. 8). By courtesy e

Nikolaou D. Curr Opin Obstet Gynaecol. 2008;20:1e5.

230 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha

4). There is increased incidence of miscarriage rateapproaching 45% by 43 years of age,10 82% of thesehave trisomies (Fig. 3).11

The reduced fertility associated with aging is primarilyassociated with aging of ovarian oocytes rather than theuterus & endometrium (donor oocyte cycle result in higherpregnancy rates among recipient women, irrespective oftheir age) (Fig. 4).

A woman has approx. 7 million oogonia by 5th month ofintrauterine life. A constant attrition in germ cell numberleads to only 1e2 millions resting follicles at birth. Atmenarche only 300,000 (3 Lacs) primordial folliclesremain. During reproductive life, follicle depletion occurs

Fig. 3 Risk of spontaneous miscarriage with increasing age.Source: (Ref. 8). By courtesy e Nikolaou D. Curr Opin Obstet

Gynaecol. 2008;20:1e5.

at a rate of approximately 1000 per month until the meno-pause when the stock of resting follicles falls to less than1000 per ovary.

Depletion of the ovarian follicular pool12 leads toa diminished production of estradiol (E2) and inhibin-B13

& a gradual rise in FSH concentration.14 The study of basalE2 & inhibin-B levels in a systemic review concluded thatthey are of limited value for both poor response & non-pregnancy.

FSH is most commonly used marker of ovarian reserveall over the world. Although its assessment is cycle depen-dant and intercycle variation is common. Recently antimul-lerian hormone (AMH) is increasingly being used topredict ovarian reserve. It is highly correlated with thenumber of antral follicles & the number of oocytesretrieved.15 It is not cycle dependent and too much extentpredicts OHSS as well. Antral follicle count is anothergood predictor of ovarian reserve. Transvaginal ultrasoundon day 2e4 of the period is used to count the number ofantral follicles.

Obesity as measured using BMI and its secondary effectson insulin resistance and hyperandrogenism may also affectfertility. Cigarette smoking, alcohol and caffeine are otherlifestyle factors that have a negative impact on fertility.

Genetic traits and abnormalities like abnormal variantsof the FSH receptors, mutation in the gene coding for LH& LH receptors can reduce ovarian response.

It is not always possible to predict response in the treat-ment naive patient and the outcome of the first protocolbecomes important in determining how to adjust subse-quent treatment regimens. In case of previous history ofOHSS & high response, one can reduce the dose of gonad-otrophin, similarly in case of no or low response dose canbe increased.

Optimization of ovarian stimulation Review Article 231

In other words one has to match the patient and proto-cols. Multiple factors make one select the type of protocolsuch as the type of ART whether resorting for IUI or IVF,age of the patient, baseline FSH, BMI, AMH etc and alsothe previous history of ovarian stimulation if any, as wellas, the practicing guidelines of individual fertility clinics(Table 2).

According to the type of ART ovarian stimulation can bed Controlled ovarian stimulation (COS), in case of intra-

uterine insemination (IUI) where the aim is to get 1e3follicles.

d Controlled ovarian hyperstimulation (COHS) in IVFcycles where the aim is to get 6e12 follicles.We need different ovarian stimulation protocols for

intrauterine insemination (IUI) and for IVF.

COS IN INTRAUTERINE INSEMINATION (IUI)

Intrauterine insemination (IUI) combined with ovarianstimulation has been demonstrated as effective form oftreatment for subfertile couples. An independent effect ofIUI alone i.e. pregnancy rate per cycle of IUI is 5% whichis no better than the spontaneous chance of conceiving.16,17

Using clomiphene citrate or other ovulation inducing agentssuch as letrozole or tamoxifen increases the chance ofconception to double while gonadotrophin stimulationmight result in a 4e5 fold increase of fecundity.

The aim here is controlled ovarian stimulation leading tothe formation of 2e3 follicles. As per the Cochrane data-base systemic review 2011, combined treatment of clomi-phine citrate (CC) gives a pregnancy rate of approx.8e10%. Metaanalysis shows higher pregnancy rate usinggonadotrophin with IUI compared to CC (OR 2.0 95% CI1.29e3.10), approx. 20% per cycle. Clomiphene &

Table 2 Drugs used for ovarian stimulation.

d Anti estrogens: clomiphene citrate, tamoxifend Aromatase inhibitors (letrozole etc)d Insulin sensitizers (metformin etc)d Gonadotrophins:

d HMG (both FSH and LH)d Highly purified urinary FSHd Recombinant FSHd Recombinant LH

d GnRH agonist (intranasal/SC/IM)d GnRH antagonist (involved in final steps of oocyte maturation)d HCG, urinary/recombinantd Bromocriptin

gonadotrophin have not been compared with gonadotrophinalone by randomized trials however, gives better resultsthan clomiphine citrate alone and reduces the cost of stim-ulation.18 The data below is from my own unit (Fig. 5).

A low dose protocol 50e75 IU per day does not havesignificantly different pregnancy rate than high doseregimen but OHSS & multiple pregnancy rates are signifi-cantly lower. The metaanalysis concluded that a dailydosage of ovarian stimulation with gonadotrophin givesbetter pregnancy rate than alternate day e Cochrane data-base systemic review 2011. Hence, a daily low dose ofgonadotrophin should be used instead of high dose or alter-nate day regimen. Comparing rFSH to urinary gonadotro-phins no significant difference in birth rate was found. Anon-significant trend in favor of rFSH in comparison tou-FSH was found (OR 1.4 95% CI 0.83e2.5). AddingGnRH agonists for down regulation to gonadotrophinsdoes not improve treatment outcome in IUI. Many studiesrecently have shown that adding GnRH antagonists togonadotrophin compared to gonadotrophin alone showspromising results. Clinical choice of gonadotrophins shoulddepend on availability, convenience and costs.

As IUI compared with IVF is less invasive and costeffective hence, should be used as first-line treatment inselected group of patients.

Clomiphene is the most widely used drugs since 1962,with ease of administration, low cost and minimal sideeffects. It is available in citrate salt, contains two stereoiso-mers Zu-clomiphene 38% & en-clomiphene (62%). It hasboth estrogenic & antiestrogenic properties, competeswith estrogen for estrogen receptor binding site at the levelof hypothalamus. Its dose varies from 50 mg to 200 mg, canbe started between 2nd to 5th day in FSH window periodfor 5 days. Thinning of endometrium due to its

Fig. 5 Pregnancy rate in different ovarian stimulation proto-cols in IUI.

232 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha

antiestrogenic property may require estrogen supplementa-tion. Tamoxifen is given in the dose of 20e40 mg, hassimilar mode of action & effectiveness as clomiphene. Aro-matase inhibitors like letrozole have been recently bannedby FDA of India. The ovulation and pregnancy rate withletrozole group of drugs is similar to CC, without havingany adverse effect on endometrium.19

Control ovarian hyperstimulation (COH) in IVF

In practice COH is not always ‘controlled’ & a range ofinappropriate ovarian response is often present. At oneand of the spectrum, we have inadequate response withretrieval of few oocytes and increased treatment cancella-tions and on the other hand, a proportion of exaggeratedresponse is observed increasing the risk of OHSS. The vari-ability of response may be due to inherent biological mech-anism in relation to differences in the number of recruitablefollicles, follicles sensitivity to FSH, and pharmacody-namics, but it may also be due to factors that may be pre-dicted and at least partially controlled.

Despite multiple predictors of ovarian response beingused, studies of predictive factors are not always compa-rable owing to differences in subject characteristics. Henceno normogram has been devised for ART patients.

There is only one prospective randomized trial thattested the use of a dosage normogram in standard patientscomparing the individual dose from 100e250 IU per day,based on the predictive factors, to a standard dose of150 IU per day20 the parameter taken into considerationwere age, AFC, ovarian volume, power doppler score,smoking status etc. The results showed that individualdosage regimen increases the proportion of appropriateovarian response and decreases the incidence of dose alter-ation during the course of COH, ongoing pregnancy ratewas higher in individualized dose group.

The highest success rates with IVF or ovulation induc-tion are observed in the first one to three cycles.

Patient of IVF can be divided into three groups:d Normal respondersd High respondersd Low responders.

Fig. 6 Source: (Ref. 27). Popovic-Todorovic, et al. Distributionof oocytes benefits and risks e the present and the idealsituation.

IVF IN NORMAL RESPONDERS

Optimization of starting dose of gonadotrophin FSH is keycomponent for success. A starting dose of 150e300 IUgives a low concellation and OHSS rate and adequate livebirth rate. Recent evidence also points to a central rolefor LH. Although granulosa cells from early antral follicles

respond only to FSH, those from mature follicles (exhibit-ing receptors to both gonadotrophin) are responsive toboth FSH and LH based on two cells two gonadotrophintheory. Although a small amount of LH is required foroptimal ovarian stimulation, high level of LH concentrationin late follicular phase may be detrimental for optimal IVFoutcome. The debate as to the optimal LH exposure forsuccessful IVF outcome continues.

GnRh agonists have changed the course of ovarian stim-ulation for in-vitro fertilization. Since 1984, they have beenused to prevent premature surge of LH during controlledovarian hyperstimulation.21 This has stopped approx.20e25% of cycle cancellation due to premature luteiniza-tion. GnRHa can be used starting from the first day ofmenstruation, taking advantage of its initial flare up effect(short protocol) or starting from 7 days prior to the menstru-ation, in the previous cycle (long protocol). Most of the IVFcycles worldwide are still being done with long protocol.The result of the metaanalysis of these two protocols hasshown the GnRh long protocol to give the higher pregnancyrate in comparison to short protocol e Cochrane databasesystemic review 2011.

What is the optimal number of oocytesretrieved?

Increasing the number of oocytes gives a rise in pregnancyrates, but eventually levels off while side effects & riskscontinue to increase22,23 (Fig. 6). Apart from the short-term risk of OHSS, evidence also is there of potentialdetrimental effect on endometrial receptivity & embryoimplantation.24,25 Currently, it is clinically accepted thatappropriate ovarian response is achieved with retrieval offive to fourteen oocytes26.

AGONIST VS ANTAGONIST

Optimization of ovarian stimulation Review Article 233

The graph illustrates the concept that patients should bein the high benefit low risk window.

GnRH antagonist 0.25 mg

hCG

HCG

GnRH antagonist 3 mg

STIMULATION (rFSHor HMG)

Longer Treatment

Agonist

Gonadotrophins

hCG

administration

Fig. 7 Antagonist and agonist protocols.

GnRh antagonist protocols

GnRh antagonist has been introduced recently in ovarian stim-ulation for pituitary suppression. It causes rapid and reversibleblockade of pituitary GnRH receptors by competitive bindingresulting in immediate suppression within 4 h of injection anda relative half-life of 13 h and as such are used to preventpremature LH surges. Antagonist can be started on a fixedday (day 6) of ovarian stimulation (fixed protocol) or on theday when leading follicle size is 14 mm (flexible protocol).

Metaanalysis of four randomized controlled trials offixed versus flexible protocol shows a trend for increasedpregnancy rate in fixed protocol.28

The advantages of antagonist protocol are ease to start,low total gonadotrophin dose hence lower cost and reductionin the incidence of OHSS. The advantage of using GnRhagonist to trigger the final oocyte maturation has a potentialbenefit in patients at risk of OHSS, but the current evidencesuggests that it leads to lower pregnancy rate.

Clinical acceptances of GnRh antagonists have been slow&mostly due to the initial metaanalysis, which has observed5% difference in clinical pregnancy rate.29 Recent reviews ofrandomized controlled trials have no evidence of differencein live birth rate with the use of GnRh antagonists comparedwith agonist (Cochrane database systemic review, 2011).

Antagonist protocols are novel compared to more than25 years of agonist protocols and optimization progresseswith knowledge accumulation (Fig. 7).

Fig. 8 Source: (Ref. 36). Courtesy e Jones HW. Schematicrepresentation of changes in luteal phase length and endo-crine profile induced by ovarian hyperstimulation for IVF.Hum Reprod. 1996;11(suppl 1):7e24 (381).

Luteal phase support

Thewindow of implantation is defined as the periodwhen theuterus is receptive, and it occurs 8e10 days after ovulation.COH induces supraphysiological levels of steroids duringfollicular phase resulting in advanced endometrial develop-ment regardless of the type of GnRH analogue used.30 InGnRH agonist cycles, endometrial biopsies taken in thepreovulatory phase prior to hCG injection show accentuatedproliferative aspects and early secretory changes even beforerise in progesterone occurs.31 It has been established thatcorpus luteum support is required following ovarian stimula-tion and GnRH agonist cotreatment32,33 due to the prolongedpituitary recovery from down regulation and the lack ofsupport of corpus luteum (Fig. 8).

Due to the fact that after discontinuation of GnRH antag-onists, pituitary recovery occurs within hours34 it has beenspeculated that luteal phase support is not needed in GnRHantagonist cotreated cycles but that is not true. Luteal

support is necessary for a regular endometrial developmentas is shown by normal in-phase endometrial histology, irre-spective of the luteal support used.35 The deleterious effectof ovarian stimulation lies in the elevated steroid levels ofthe follicular phase, which subsequently cause a chain reac-tion, leading to a defective endometrium receptivity and aninsufficient luteal phase to support embryonic development.

HCG and progesterone have been used for luteal phasesupport and have not been found to have significant differ-ence in pregnancy rate.

OVARIAN STIMULATION IN HYPERRESPONDERS (PCO GROUP)

Women with PCOS are prone to WHO group II anovula-tory infertility which may be as high as 65e80% (Fig. 9).

234 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha

The cause of anovulation in PCOS is believed to be hyper-insulinemia accentuated by obesity. Approx. 50% ofwomen in PCOS are overweight37 and in excess of 50%of lean women with PCOS are insulin resistant.

Controlled ovarian stimulation in IUI in PCOS

The first-line method of ovulation induction in PCOSundergoing intrauterine insemination is with clomiphenecitrate. Women with PCOS in a structured weight loss pro-gramme by diet & exercise can improve their pregnancyrate & reduce the miscarriage rate.38

CC is effective in 50e70% cases inducing ovulationresulting in pregnancy in half of these cases. Women whoare overweight and require ovulation induction need greaterdoses of clomiphene citrate and gonadotrophin to inducefollicular developments.

Cumulative pregnancy rate in properly selected patientsis equivalent to normal responders. Gonadotrophin therapyis often used as a second-line therapy in anovulatorywomen with PCOS who either are resistant to ovulationinduction or ovulate but do not conceive. Women withPCOS are particularly sensitive to gonadotrophin therapyand have a significant chance of multiple follicular develop-ment and hence multiple pregnancy or cycle cancellation.Low dose FSH 50e75 IU in general should be used toovercome this risk. Low dose step up protocol where thetreatment is started with the dose mentioned for 7e10days & increased by 37.5 IU every week is well established.

There have been conflicting reports regarding the useof insulin sensitizers for insulin-resistant patients ofPCO leading to better ovulation & pregnancy rates.

Fig. 9 A picture of hyperstimulated ovary.

A multicenter RCT in 2006 which had studied the effectof the addition of placebo or metformin to clomiphenecitrate showed no additional benefit derived from the addi-tion of metformin to CC.39 The European society for humanreproduction and embryology and American society forreproductive medicine consensus on infertility treatmentfor PCOS concluded that there is no role for insulin sensi-tizing and lowering drugs in the management of PCOS andshould be restricted to those with glucose intolerance ortype 2 diabetes.40 Its power to reduce the first trimestermiscarriage rate is not clear.

If the number of follicles is 4 or more or estradiol levelmore than 1000 pg, cycle should be abandoned in view ofthe risk of multiple pregnancy/OHSS.

Ovarian hyperstimulation for IVF in PCOS

Women with polycystic ovaries undergoing IVF are ata seven fold increased risk of developing OHSS.41

A metaanalysis demonstrated that women with PCOSundergoing IVF have half the chance of reaching the oocyteretrieval than women without PCOS. They have three timesas many oocytes collected, with a reduced fertilization rate,and, overall they have similar live birth rates to womenwithout PCOS.42

The starting dose of gonadotrophins should be based onage, BMI, previous history of OHSS & high response. Lowdose approach reduces the complications of OHSS andmultiple pregnancies. Low dose step up protocol or stepdown protocol can be used although there is no differencein pregnancy rate. A dose of 75e150 IU is sufficient inmost of the cases (Fig. 10).

PCOS will require a longer period of desensitization esometimes upon 30 days to bring down the level of LHbelow 2.

Monitoring has to be more stringent by using a combina-tion of transvaginal ultrasound & serum estradiol in casesof PCOS. Cycle cancellation should be considered if folli-cles are more than 20 in number or estradiol level more than>3500 pg/ml.

Recent data suggest no difference in live birth rateswhether agonist or antagonist protocol is used for IVF inPCOS group of patients. Early reports suggested a relation-ship between OHSS & hMG, more recent comparison didnot show a significant difference. There is a statisticallysignificant reduction in OHSS with antagonist protocol(OR 061, 95% CI 0.42e0.89%) in comparison to agonistprotocol. In addition, intervention to prevent OHSS (eg.Coasting, cycle cancellation etc) were administered morefrequently when agonist was used e Cochrane databasesystemic review, 2011.

Fig. 10 Step up, step down protocol.

Optimization of ovarian stimulation Review Article 235

Low dose HCG protocol was suggested by Filicori et alwhere low dose hCG was used alone in the second day ofthe follicular phase after initial induction by FSH. Preciserole is still controversial.

Soft protocol of ovarian stimulation e soft protocol forovarian stimulation has been suggested recently whereclomiphene citrate is used alone or in combination withHMG and GnRH antagonist is used to avoid prematureLH surges. Clomiphene citrate (100 mg) is administeredorally from cycle days 2 to 6 and gonadotrophin is admin-istered overlapping with CC for 3 days. From cycle day sixonwards cetrorelix is used followed by ovulation inductionwith 10,000 IU of hCG. The results of this soft protocol arestill awaited.

Metformin therapy in IVF e the rational for the use ofmetformin at the time of an IVF cycle is the expectationsthat it may improve IVF outcome by an increase in preg-nancy rate, due to a reduction in intraovarian androgensand lead to an improvement in oocyte quality and hencefertilization rate. It may also be expected to have the addi-tional benefit of a reduced rate of OHSS; however, the datado not confirm these assumptions with respect to the dura-tion of treatment, oocytes retrieved and pregnancy ratealthough the review does not exclude a small improvementbenefit of the metformin. Whether PCOS is associated withan increased rate of miscarriage has been debated, similarlyits in role in IVF patients to reduce the miscarriage rate hasbeen debated as well.

How to trigger the ovulation?Human chorionic gonadotrophin is responsible for OHSSbut it is an essential part of ovulation induction in IVFfor final maturation of the follicles. It cannot be substitutedwith any other hormone in long protocol. The doses usedhave been between 10,000 IU and 25,000 IU in literature.However, studies have shown that hCG in the dose of5000 IU is equally effective hence, in PCO lowest possible

dose should be used. Recombinant hCG has not been foundto be superior to urinary hCG. It is used in the dose of250 mcge500 mcg. In antagonist protocol, hCG can bereplaced by a GnRH agonist to trigger ovulation, but lowerbirth rate, reduced ongoing pregnancy rate & higher miscar-riage rate was obtained in women who received GnRHagonist for final oocyte maturation although OHSS ratewas significantly lower.43 No statistically significant differ-ence between recombinant hCG verses urinary hCG wasfound regarding the incidence of OHSS. New recombinantLH can be helpful in reducing the incidence of OHSS but itis required in a very high dose hence the cost is exorbitant.

Luteal phase support in PCOSMetaanalysis comparing hCG with progesterone for lutealphase support in PCOS found that the odds of OHSSwere more than three fold higher with treatments involvinghCG than with progesterone alone (OR 3.06 95% C11.95e5.86), hence, hCG support is strictly not advisedand progesterone should be used instead. The intramuscularadministration has been found to be superior to vaginalroute of administration of progesterone e Cochranedatabase.

OVARIAN STIMULATION IN POORRESPONDERS

Poor response to ovarian stimulation is not a rare occur-rence and is often encountered by US clinicians due todiminished ovarian reserve. It is a complication in5e24% of all in-vitro fertilization (IVF) cycles. There isno universal definition for the poor responder but thecriteria suggested have been three or fewer folliclesrecruited and serum estradiol concentration of lower than500 pg/ml at the time of human chorionic gonadotrophin(hCG) administration during COH for IVF.44

It is not limited to women of advanced reproductive agebut occasionally also encountered in young women(Fig. 11).

Clearly, the ideal test is the response of the ovaries toovarian stimulation but can be predicted to much extent ifthere is high level of serum FSH (>15 IU/l.) on cycleday two or three or elevated levels of serum E2 (>75 pg/ml) on cycle day two or three decreased level of seruminhibin-B (<45 pg/ml) on cycle day two or three orAMH of <1 ng/ml on any day. Other methods of predictingit are antral follicle count, ovarian volume, ovarian vascularflow & ovarian biopsy. The clomiphene challenge test, theexogenous FSH ovarian reserve test, the gonadotrophin

Fig. 11 Source: (Ref. 8). Nikolaou D. Age related fertility:from, How old are your eggs? Curr Opin Obstet Gynaecol.2008;20:1e5.

236 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha

releasing hormone (GnRh) agonist stimulation test can alsobe used. However, the response of some patient will bepoor despite their predictive tests not being suggestive oflow ovarian reserve. It can be confirmed only after havinghad a failed standard ovarian stimulation and at least onecanceled IVF cycle.

Various strategies have been tried & suggested toimprove the response to stimulation They are e increasingthe dose of gonadotrophins, short protocol, long GnRhagonist stop protocol, microdose flare up protocol, lutealstart of rFSH, antagonist protocol, rFSH with HMG addi-tion of growth hormones, testosterone, bromocriptin,estrogen or DHEA, nitric oxide, L-arginine etc.

But only few have been found to be studied by random-ized controlled trials and included in Cochrane databasesystemic review. In IUI, gonadotrophin is found to givebetter success rate in poor responders. For IVF, optimisticdata have been presented by the use of high doses of gonad-otrophins, flare up protocol, stop protocols, soft protocols &natural cycle etc seem to be an appropriate strategy to beconsidered.

Women who received the long agonist protocol requiredhigher amount of FSH in IU and had less number ofoocytes retrieved compared to women who received themultiple dose GnRh antagonist regimen or GnRHa flareup protocol.45e47 Routine use of ICSI is advised to informthe pregnancy rate in poor responders. There is no strictevidence that rFSH has better results in poor responders.Luteal phase initiation of FSH suggested earlier has notshown encouraging results. In a small series of cases ofpoor responders DHEA supplementation improved theresponse to ovarian stimulation even after controlling thegonadotrophin, but further studies did not substantiate it.The use of growth hormones adjoint therapy results in noimprovement.

There is insufficient evidence to support the routine use ofany of particular intervention either for pituitary down regula-tion, ovarian stimulation or adjoined therapy in the manage-ment of the poor responders to controlled ovarian stimulation.

The ideal stimulation protocol for poor responders stillremains a challenge. However, one cannot withhold treat-ment for poor responders. Couples should be counseled aboutit at every step of ovarian stimulation and also discussed theother options such as a donor egg cycle or adoption.

CONCLUSIONS

Successful outcome following assisted reproduction islargely dependent on the patient’s response to ovarian stim-ulation. As different group of patients respond differently tothe same type of ovarian stimulation, an individualizedapproach to OS is crucial for optimal result. OHSS &multiple pregnancies are unwanted & cost has to be takenin consideration, especially in our scenario. Predictivefactors for optimizing ovarian stimulation treatment are ofvalue but not absolute in this regard. Gonadotrophins’ usealthough requires a strict monitoring, gives a better resultin ovarian stimulation with IUI. To reduce the cost, CCcan be combined with gonadotrophins for OS in PCOpatients. Lower dose of gonadotrophins & strict monitoringshould be used. Dose of gonadotrophin needs to be tailoredaccording to the type of the patient in IVF. Predictingfactors can be helpful in choosing the stimulation protocolfor IVF. Antagonist protocol can reduce the risk of OHSSin IVF especially in PCOS group of patients. In this groupfor induction of ovulation lower HCG dose should be used& progesterone for luteal support instead of HCG. The aimis to get a single healthy baby at the minimal cost & nohealth risks to the mother.

The highest success rate with IVF or ovulation inductionis observed in first one to three cycles. For poor responders,diminished oocytes cohort & poor oocytes quality cannotbe reversed, whatever is used.

CONFLICTS OF INTEREST

The author has none to declare.

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Optimization of ovarian stimulation Review Article 237

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