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

1. Optimization of ovarian stim‘ m
ulation
‘ART’
to improve success rate in

2. Apollo Medicine 2012 September
Volume 9, Number 3; pp. 228e238 Review Article
Optimization of ovarian stimulation to improve success rate in ‘ART’
Sushma P. Sinha
ABSTRACT
ART is defined as the technique used where there is a need for in-vitro preparation or manipulation of gametes. The
commonest ARTs are intrauterine insemination (IUI) and in-vitro fertilization (IVF). Ovarian stimulation is required with
these procedures to increase the pregnancy rate as ART with natural cycle has a very low pregnancy rate. Optimizing
pregnancy 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 hyperstimulation
syndrome (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 assisted
reproductive techniques (ART).1
Ovarian stimulation is an integral part of assisted repro-ductive
technology (ART) today. Data shows that natural
ovarian cycle leads to a significantly lower pregnancy rate
and the number of oocytes obtained following stimulation
correlates positively with the ongoing pregnancy rate.
Association between the numbers of eggs and live birth
rate in IVF treatment (Fig. 1).
Although the first IVF baby Louise Brown in July 1978
was a result of natural cycle,3 the past 3 decades have intro-duced
revolution in reproductive medicine and ovarian
stimulation happens to be a part of it. Successful outcomes
following assisted reproductive technology are largely
dependent on the patient’s response to controlled ovarian
stimulation i.e. number & quality of oocytes and numbers
of embryo available for transfer in case of IVF. Studies
have found an increase in pregnancy rate with the
increasing number of oocytes upto 14e15, after that there
is a plateau.
There is a marked variability in ovarian response among
assisted reproductive technology (ART) patients. At one
end of the spectrum is poor or no response and at the other
end is the ovarian hyperstimulation syndrome and the
outcome may be no pregnancy to multiple pregnancies.
In the last 3 decades, significant increase in the incidence
of multiple births is almost entirely the result of the use of
ovulation inducing agents in ART.
Spontaneous multiple pregnancies occur in about 1e2%
of women which is increased to 7e10% of women taking
clomiphene citrate (CC) & further to 25% treated with
gonadotrophin, approximately 5e10% are higher order
pregnancies.4 It has been studied that even twins face
greater risks of disability & death than do singletons.5,6.
Multiple pregnancies carry extra risks for both the mother
and fetuses. Obstetric complications include increased inci-dence
of pre-eclampsia, antepartum hemorrhage, preterm
labor and surgical or assisted delivery. The high incidence
of prematurity and low birth weight fetuses among high
order multiple pregnancies result in a four fold rise of peri-natal
mortality for twins & six fold rise in triplets compared
with singleton pregnancy. Multiple gestation children may
suffer long-term consequences of perinatal complications
including cerebral palsy and learning disabilities such as
slow language development & behavioral problems.
Another associated problems of ovarian stimulation is
ovarian hyperstimulation syndrome (OHSS), which is
Senior Consultant Obstetrician & Gynaecologist, Infertility and IVF Expert, Academic Co-ordinator, Department of Obstetrics and Gynaecology,
Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110076, India.
email: sinha_sushma@hotmail.com
Received: 19.6.2012; Accepted: 3.7.2012; Available online: 17.7.2012
Copyright 2012, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2012.07.008

3. Optimization of ovarian stimulation Review Article 229
a potentially fatal iatrogenic condition resulting from exces-sive
stimulation of ovaries. The vast majority of OHSS
occurs in setting of injectables like gonadotrophins in
IVF. Severe form of OHSS occurs in 0.5e5% of IVF
cycles.7 It is more common in young, lean/low BMI/
patients, PCOS, hCG triggering being an initiator, so is
pregnancy. It has been proven time again that polycystic
ovarian syndrome has higher risk of OHSS. It can be life
threatening in up to 1% of cases.
As the ovarian response is not same to all it depends
upon the factors like age, basal metabolic rate (BMI),
ovarian reserve, polycystic ovarian disease, presence of
endometriosis and demographic characteristics of patient
hence, ‘one size fits all’ policy cannot be adopted. Given
the marked variability in ovarian responses among ART
patients the choice of stimulation protocol must be individ-ualized.
Our endeavor should be to use the most suitable
protocol which brings out the best result, avoiding the
complications mentioned above and at reduced cost
(Fig. 2).
CAN WE PREDICT THE OVARIAN RESPONSE?
There are several factors that can predict ovarian response
to ovarian stimulation therefore, the likelihood of success
following ART (Table 1).
Although there is no absolute predicting factor present
but they are used to optimize individual stimulation
protocol while minimizing potential complications.
Age is the most important factor in determining success
rates of ART. The loss of fecundity with age appears to be
a consequence of both oocyte depletion reduced oocyte
quality. It has been demonstrated that maternal age can
predict over 80% of IVF success.9 The 2004 centers for
disease control database indicates that per cycle live birth
rates vary significantly between age groups (from 43%
for women aged 35 to 6%, in women 42 years of age
Fig. 1 Correlation between egg number and live birth rate.
Source: (Ref. 2). By courtesy e Sunkara SK, et al. Hum Reprod.
May 2011.
OVARIAN STIMULATION SHOULD HAVE
Most suitable
RESULT
PROTOCOL
COMPLICATIONS
OHSS, Multiple Pregnancies
COST
Best
Avoid
Reduced
Fig. 2 Optimization of ovarian stimulation.

4. 230 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha
4). There is increased incidence of miscarriage rate
approaching 45% by 43 years of age,10 82% of these
have trisomies (Fig. 3).11
The reduced fertility associated with aging is primarily
associated with aging of ovarian oocytes rather than the
uterus endometrium (donor oocyte cycle result in higher
pregnancy rates among recipient women, irrespective of
their age) (Fig. 4).
A woman has approx. 7 million oogonia by 5th month of
intrauterine life. A constant attrition in germ cell number
leads to only 1e2 millions resting follicles at birth. At
menarche only 300,000 (3 Lacs) primordial follicles
remain. During reproductive life, follicle depletion occurs
at a rate of approximately 1000 per month until the meno-pause
when the stock of resting follicles falls to less than
1000 per ovary.
Depletion of the ovarian follicular pool12 leads to
a diminished production of estradiol (E2) and inhibin-B13
a gradual rise in FSH concentration.14 The study of basal
E2 inhibin-B levels in a systemic review concluded that
they are of limited value for both poor response non-pregnancy.
FSH is most commonly used marker of ovarian reserve
all over the world. Although its assessment is cycle depen-dant
and intercycle variation is common. Recently antimul-lerian
hormone (AMH) is increasingly being used to
predict ovarian reserve. It is highly correlated with the
number of antral follicles the number of oocytes
retrieved.15 It is not cycle dependent and too much extent
predicts OHSS as well. Antral follicle count is another
good predictor of ovarian reserve. Transvaginal ultrasound
on day 2e4 of the period is used to count the number of
antral follicles.
Obesity as measured using BMI and its secondary effects
on insulin resistance and hyperandrogenism may also affect
fertility. Cigarette smoking, alcohol and caffeine are other
lifestyle factors that have a negative impact on fertility.
Genetic traits and abnormalities like abnormal variants
of 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 protocol
becomes important in determining how to adjust subse-quent
treatment regimens. In case of previous history of
OHSS high response, one can reduce the dose of gonad-otrophin,
similarly in case of no or low response dose can
be increased.
Table 1 Factors predicting ovarian response.
1. Age
2. 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. 3 Risk of spontaneous miscarriage with increasing age.
Source: (Ref. 8). By courtesy e Nikolaou D. Curr Opin Obstet
Gynaecol. 2008;20:1e5.
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.

5. 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 protocol
such as the type of ART whether resorting for IUI or IVF,
age of the patient, baseline FSH, BMI, AMH etc and also
the previous history of ovarian stimulation if any, as well
as, the practicing guidelines of individual fertility clinics
(Table 2).
According to the type of ART ovarian stimulation can be
d Controlled ovarian stimulation (COS), in case of intra-uterine
insemination (IUI) where the aim is to get 1e3
follicles.
d Controlled ovarian hyperstimulation (COHS) in IVF
cycles 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 ovarian
stimulation has been demonstrated as effective form of
treatment for subfertile couples. An independent effect of
IUI alone i.e. pregnancy rate per cycle of IUI is 5% which
is no better than the spontaneous chance of conceiving.16,17
Using clomiphene citrate or other ovulation inducing agents
such as letrozole or tamoxifen increases the chance of
conception to double while gonadotrophin stimulation
might result in a 4e5 fold increase of fecundity.
The aim here is controlled ovarian stimulation leading to
the 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 using
gonadotrophin with IUI compared to CC (OR 2.0 95% CI
1.29e3.10), approx. 20% per cycle. Clomiphene
gonadotrophin have not been compared with gonadotrophin
alone by randomized trials however, gives better results
than 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 have
significantly different pregnancy rate than high dose
regimen but OHSS multiple pregnancy rates are signifi-cantly
lower. The metaanalysis concluded that a daily
dosage of ovarian stimulation with gonadotrophin gives
better pregnancy rate than alternate day e Cochrane data-base
systemic review 2011. Hence, a daily low dose of
gonadotrophin 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. A
non-significant trend in favor of rFSH in comparison to
u-FSH was found (OR 1.4 95% CI 0.83e2.5). Adding
GnRH agonists for down regulation to gonadotrophins
does not improve treatment outcome in IUI. Many studies
recently have shown that adding GnRH antagonists to
gonadotrophin compared to gonadotrophin alone shows
promising results. Clinical choice of gonadotrophins should
depend on availability, convenience and costs.
As IUI compared with IVF is less invasive and cost
effective hence, should be used as first-line treatment in
selected group of patients.
Clomiphene is the most widely used drugs since 1962,
with ease of administration, low cost and minimal side
effects. It is available in citrate salt, contains two stereoiso-mers
Zu-clomiphene 38% en-clomiphene (62%). It has
both estrogenic antiestrogenic properties, competes
with estrogen for estrogen receptor binding site at the level
of hypothalamus. Its dose varies from 50 mg to 200 mg, can
be started between 2nd to 5th day in FSH window period
for 5 days. Thinning of endometrium due to its
Table 2 Drugs used for ovarian stimulation.
d Anti estrogens: clomiphene citrate, tamoxifen
d Aromatase inhibitors (letrozole etc)
d Insulin sensitizers (metformin etc)
d Gonadotrophins:
d HMG (both FSH and LH)
d Highly purified urinary FSH
d Recombinant FSH
d Recombinant LH
d GnRH agonist (intranasal/SC/IM)
d GnRH antagonist (involved in final steps of oocyte maturation)
d HCG, urinary/recombinant
d Bromocriptin
Fig. 5 Pregnancy rate in different ovarian stimulation proto-cols
in IUI.

6. 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, has
similar mode of action effectiveness as clomiphene. Aro-matase
inhibitors like letrozole have been recently banned
by FDA of India. The ovulation and pregnancy rate with
letrozole group of drugs is similar to CC, without having
any adverse effect on endometrium.19
Control ovarian hyperstimulation (COH) in IVF
In practice COH is not always ‘controlled’ a range of
inappropriate ovarian response is often present. At one
and of the spectrum, we have inadequate response with
retrieval of few oocytes and increased treatment cancella-tions
and on the other hand, a proportion of exaggerated
response 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 recruitable
follicles, 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 being
used, studies of predictive factors are not always compa-rable
owing to differences in subject characteristics. Hence
no normogram has been devised for ART patients.
There is only one prospective randomized trial that
tested the use of a dosage normogram in standard patients
comparing the individual dose from 100e250 IU per day,
based on the predictive factors, to a standard dose of
150 IU per day20 the parameter taken into consideration
were age, AFC, ovarian volume, power doppler score,
smoking status etc. The results showed that individual
dosage regimen increases the proportion of appropriate
ovarian response and decreases the incidence of dose alter-ation
during the course of COH, ongoing pregnancy rate
was 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 responders
d High responders
d Low responders.
IVF IN NORMAL RESPONDERS
Optimization of starting dose of gonadotrophin FSH is key
component for success. A starting dose of 150e300 IU
gives a low concellation and OHSS rate and adequate live
birth rate. Recent evidence also points to a central role
for LH. Although granulosa cells from early antral follicles
respond only to FSH, those from mature follicles (exhibit-ing
receptors to both gonadotrophin) are responsive to
both FSH and LH based on two cells two gonadotrophin
theory. Although a small amount of LH is required for
optimal ovarian stimulation, high level of LH concentration
in late follicular phase may be detrimental for optimal IVF
outcome. The debate as to the optimal LH exposure for
successful IVF outcome continues.
GnRh agonists have changed the course of ovarian stim-ulation
for in-vitro fertilization. Since 1984, they have been
used to prevent premature surge of LH during controlled
ovarian hyperstimulation.21 This has stopped approx.
20e25% of cycle cancellation due to premature luteiniza-tion.
GnRHa can be used starting from the first day of
menstruation, 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 IVF
cycles worldwide are still being done with long protocol.
The result of the metaanalysis of these two protocols has
shown the GnRh long protocol to give the higher pregnancy
rate in comparison to short protocol e Cochrane database
systemic review 2011.
What is the optimal number of oocytes
retrieved?
Increasing the number of oocytes gives a rise in pregnancy
rates, but eventually levels off while side effects risks
continue to increase22,23 (Fig. 6). Apart from the short-term
risk of OHSS, evidence also is there of potential
detrimental effect on endometrial receptivity embryo
implantation.24,25 Currently, it is clinically accepted that
appropriate ovarian response is achieved with retrieval of
five to fourteen oocytes26.
Fig. 6 Source: (Ref. 27). Popovic-Todorovic, et al. Distribution
of oocytes benefits and risks e the present and the ideal
situation.

7. Optimization of ovarian stimulation Review Article 233
The graph illustrates the concept that patients should be
in the high benefit low risk window.
GnRh antagonist protocols
GnRh antagonist has been introduced recently in ovarian stim-ulation
for pituitary suppression. It causes rapid and reversible
blockade of pituitary GnRH receptors by competitive binding
resulting in immediate suppression within 4 h of injection and
a relative half-life of 13 h and as such are used to prevent
premature LH surges. Antagonist can be started on a fixed
day (day 6) of ovarian stimulation (fixed protocol) or on the
day when leading follicle size is 14 mm (flexible protocol).
Metaanalysis of four randomized controlled trials of
fixed versus flexible protocol shows a trend for increased
pregnancy rate in fixed protocol.28
The advantages of antagonist protocol are ease to start,
low total gonadotrophin dose hence lower cost and reduction
in the incidence of OHSS. The advantage of using GnRh
agonist to trigger the final oocyte maturation has a potential
benefit in patients at risk of OHSS, but the current evidence
suggests that it leads to lower pregnancy rate.
Clinical acceptances of GnRh antagonists have been slow
mostly due to the initial metaanalysis, which has observed
5% difference in clinical pregnancy rate.29 Recent reviews of
randomized controlled trials have no evidence of difference
in live birth rate with the use of GnRh antagonists compared
with agonist (Cochrane database systemic review, 2011).
Antagonist protocols are novel compared to more than
25 years of agonist protocols and optimization progresses
with knowledge accumulation (Fig. 7).
Luteal phase support
The window of implantation is defined as the period when the
uterus is receptive, and it occurs 8e10 days after ovulation.
COH induces supraphysiological levels of steroids during
follicular phase resulting in advanced endometrial develop-ment
regardless of the type of GnRH analogue used.30 In
GnRH agonist cycles, endometrial biopsies taken in the
preovulatory phase prior to hCG injection show accentuated
proliferative aspects and early secretory changes even before
rise in progesterone occurs.31 It has been established that
corpus luteum support is required following ovarian stimula-tion
and GnRH agonist cotreatment32,33 due to the prolonged
pituitary recovery from down regulation and the lack of
support of corpus luteum (Fig. 8).
Due to the fact that after discontinuation of GnRH antag-onists,
pituitary recovery occurs within hours34 it has been
speculated that luteal phase support is not needed in GnRH
antagonist cotreated cycles but that is not true. Luteal
AGONIST VS ANTAGONIST
GnRH antagonist 0.25 mg
hCG
STIMULATION (rFSHor HMG)
HCG
GnRH antagonist 3 mg
Longer
Treatment
Agonist
hCG
Gonadotrophins
administration
Fig. 7 Antagonist and agonist protocols.
support is necessary for a regular endometrial development
as is shown by normal in-phase endometrial histology, irre-spective
of the luteal support used.35 The deleterious effect
of ovarian stimulation lies in the elevated steroid levels of
the follicular phase, which subsequently cause a chain reac-tion,
leading to a defective endometrium receptivity and an
insufficient luteal phase to support embryonic development.
HCG and progesterone have been used for luteal phase
support and have not been found to have significant differ-ence
in pregnancy rate.
OVARIAN STIMULATION IN HYPER
RESPONDERS (PCO GROUP)
Women with PCOS are prone to WHO group II anovula-tory
infertility which may be as high as 65e80% (Fig. 9).
Fig. 8 Source: (Ref. 36). Courtesy e Jones HW. Schematic
representation of changes in luteal phase length and endo-crine
profile induced by ovarian hyperstimulation for IVF.
Hum Reprod. 1996;11(suppl 1):7e24 (381).

8. 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% of
women 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 PCOS
undergoing intrauterine insemination is with clomiphene
citrate. Women with PCOS in a structured weight loss pro-gramme
by diet exercise can improve their pregnancy
rate reduce the miscarriage rate.38
CC is effective in 50e70% cases inducing ovulation
resulting in pregnancy in half of these cases. Women who
are overweight and require ovulation induction need greater
doses of clomiphene citrate and gonadotrophin to induce
follicular developments.
Cumulative pregnancy rate in properly selected patients
is equivalent to normal responders. Gonadotrophin therapy
is often used as a second-line therapy in anovulatory
women with PCOS who either are resistant to ovulation
induction or ovulate but do not conceive. Women with
PCOS are particularly sensitive to gonadotrophin therapy
and 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 to
overcome this risk. Low dose step up protocol where the
treatment is started with the dose mentioned for 7e10
days increased by 37.5 IU every week is well established.
There have been conflicting reports regarding the use
of insulin sensitizers for insulin-resistant patients of
PCO leading to better ovulation pregnancy rates.
A multicenter RCT in 2006 which had studied the effect
of the addition of placebo or metformin to clomiphene
citrate showed no additional benefit derived from the addi-tion
of metformin to CC.39 The European society for human
reproduction and embryology and American society for
reproductive medicine consensus on infertility treatment
for PCOS concluded that there is no role for insulin sensi-tizing
and lowering drugs in the management of PCOS and
should be restricted to those with glucose intolerance or
type 2 diabetes.40 Its power to reduce the first trimester
miscarriage rate is not clear.
If the number of follicles is 4 or more or estradiol level
more than 1000 pg, cycle should be abandoned in view of
the risk of multiple pregnancy/OHSS.
Ovarian hyperstimulation for IVF in PCOS
Women with polycystic ovaries undergoing IVF are at
a seven fold increased risk of developing OHSS.41
A metaanalysis demonstrated that women with PCOS
undergoing IVF have half the chance of reaching the oocyte
retrieval than women without PCOS. They have three times
as many oocytes collected, with a reduced fertilization rate,
and, overall they have similar live birth rates to women
without PCOS.42
The starting dose of gonadotrophins should be based on
age, BMI, previous history of OHSS high response. Low
dose approach reduces the complications of OHSS and
multiple pregnancies. Low dose step up protocol or step
down protocol can be used although there is no difference
in pregnancy rate. A dose of 75e150 IU is sufficient in
most of the cases (Fig. 10).
PCOS will require a longer period of desensitization e
sometimes upon 30 days to bring down the level of LH
below 2.
Monitoring has to be more stringent by using a combina-tion
of transvaginal ultrasound serum estradiol in cases
of 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 rates
whether agonist or antagonist protocol is used for IVF in
PCOS group of patients. Early reports suggested a relation-ship
between OHSS hMG, more recent comparison did
not show a significant difference. There is a statistically
significant reduction in OHSS with antagonist protocol
(OR 061, 95% CI 0.42e0.89%) in comparison to agonist
protocol. In addition, intervention to prevent OHSS (eg.
Coasting, cycle cancellation etc) were administered more
frequently when agonist was used e Cochrane database
Fig. 9 A picture of hyperstimulated ovary. systemic review, 2011.

9. Optimization of ovarian stimulation Review Article 235
Low dose HCG protocol was suggested by Filicori et al
where low dose hCG was used alone in the second day of
the follicular phase after initial induction by FSH. Precise
role is still controversial.
Soft protocol of ovarian stimulation e soft protocol for
ovarian stimulation has been suggested recently where
clomiphene citrate is used alone or in combination with
HMG and GnRH antagonist is used to avoid premature
LH surges. Clomiphene citrate (100 mg) is administered
orally from cycle days 2 to 6 and gonadotrophin is admin-istered
overlapping with CC for 3 days. From cycle day six
onwards cetrorelix is used followed by ovulation induction
with 10,000 IU of hCG. The results of this soft protocol are
still awaited.
Metformin therapy in IVF e the rational for the use of
metformin at the time of an IVF cycle is the expectations
that it may improve IVF outcome by an increase in preg-nancy
rate, due to a reduction in intraovarian androgens
and lead to an improvement in oocyte quality and hence
fertilization rate. It may also be expected to have the addi-tional
benefit of a reduced rate of OHSS; however, the data
do not confirm these assumptions with respect to the dura-tion
of treatment, oocytes retrieved and pregnancy rate
although the review does not exclude a small improvement
benefit of the metformin. Whether PCOS is associated with
an increased rate of miscarriage has been debated, similarly
its in role in IVF patients to reduce the miscarriage rate has
been debated as well.
How to trigger the ovulation?
Human chorionic gonadotrophin is responsible for OHSS
but it is an essential part of ovulation induction in IVF
for final maturation of the follicles. It cannot be substituted
with any other hormone in long protocol. The doses used
have been between 10,000 IU and 25,000 IU in literature.
However, studies have shown that hCG in the dose of
5000 IU is equally effective hence, in PCO lowest possible
dose should be used. Recombinant hCG has not been found
to be superior to urinary hCG. It is used in the dose of
250 mcge500 mcg. In antagonist protocol, hCG can be
replaced by a GnRH agonist to trigger ovulation, but lower
birth rate, reduced ongoing pregnancy rate higher miscar-riage
rate was obtained in women who received GnRH
agonist for final oocyte maturation although OHSS rate
was significantly lower.43 No statistically significant differ-ence
between recombinant hCG verses urinary hCG was
found regarding the incidence of OHSS. New recombinant
LH can be helpful in reducing the incidence of OHSS but it
is required in a very high dose hence the cost is exorbitant.
Luteal phase support in PCOS
Metaanalysis comparing hCG with progesterone for luteal
phase support in PCOS found that the odds of OHSS
were more than three fold higher with treatments involving
hCG than with progesterone alone (OR 3.06 95% C1
1.95e5.86), hence, hCG support is strictly not advised
and progesterone should be used instead. The intramuscular
administration has been found to be superior to vaginal
route of administration of progesterone e Cochrane
database.
OVARIAN STIMULATION IN POOR
RESPONDERS
Poor response to ovarian stimulation is not a rare occur-rence
and is often encountered by US clinicians due to
diminished ovarian reserve. It is a complication in
5e24% of all in-vitro fertilization (IVF) cycles. There is
no universal definition for the poor responder but the
criteria suggested have been three or fewer follicles
recruited and serum estradiol concentration of lower than
500 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 age
but occasionally also encountered in young women
(Fig. 11).
Clearly, the ideal test is the response of the ovaries to
ovarian stimulation but can be predicted to much extent if
there is high level of serum FSH (15 IU/l.) on cycle
day two or three or elevated levels of serum E2 (75 pg/
ml) on cycle day two or three decreased level of serum
inhibin-B (45 pg/ml) on cycle day two or three or
AMH of 1 ng/ml on any day. Other methods of predicting
it are antral follicle count, ovarian volume, ovarian vascular
flow ovarian biopsy. The clomiphene challenge test, the
exogenous FSH ovarian reserve test, the gonadotrophin
Fig. 10 Step up, step down protocol.

10. 236 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha
releasing hormone (GnRh) agonist stimulation test can also
be used. However, the response of some patient will be
poor despite their predictive tests not being suggestive of
low ovarian reserve. It can be confirmed only after having
had a failed standard ovarian stimulation and at least one
canceled IVF cycle.
Various strategies have been tried suggested to
improve the response to stimulation They are e increasing
the dose of gonadotrophins, short protocol, long GnRh
agonist stop protocol, microdose flare up protocol, luteal
start 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 database
systemic review. In IUI, gonadotrophin is found to give
better success rate in poor responders. For IVF, optimistic
data 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 be
considered.
Women who received the long agonist protocol required
higher amount of FSH in IU and had less number of
oocytes retrieved compared to women who received the
multiple dose GnRh antagonist regimen or GnRHa flare
up protocol.45e47 Routine use of ICSI is advised to inform
the pregnancy rate in poor responders. There is no strict
evidence that rFSH has better results in poor responders.
Luteal phase initiation of FSH suggested earlier has not
shown encouraging results. In a small series of cases of
poor responders DHEA supplementation improved the
response to ovarian stimulation even after controlling the
gonadotrophin, but further studies did not substantiate it.
The use of growth hormones adjoint therapy results in no
improvement.
There is insufficient evidence to support the routine use of
any 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 still
remains a challenge. However, one cannot withhold treat-ment
for poor responders. Couples should be counseled about
it at every step of ovarian stimulation and also discussed the
other options such as a donor egg cycle or adoption.
CONCLUSIONS
Successful outcome following assisted reproduction is
largely dependent on the patient’s response to ovarian stim-ulation.
As different group of patients respond differently to
the same type of ovarian stimulation, an individualized
approach to OS is crucial for optimal result. OHSS
multiple pregnancies are unwanted cost has to be taken
in consideration, especially in our scenario. Predictive
factors for optimizing ovarian stimulation treatment are of
value but not absolute in this regard. Gonadotrophins’ use
although requires a strict monitoring, gives a better result
in ovarian stimulation with IUI. To reduce the cost, CC
can be combined with gonadotrophins for OS in PCO
patients. Lower dose of gonadotrophins strict monitoring
should be used. Dose of gonadotrophin needs to be tailored
according to the type of the patient in IVF. Predicting
factors can be helpful in choosing the stimulation protocol
for IVF. Antagonist protocol can reduce the risk of OHSS
in IVF especially in PCOS group of patients. In this group
for induction of ovulation lower HCG dose should be used
progesterone for luteal support instead of HCG. The aim
is to get a single healthy baby at the minimal cost no
health risks to the mother.
The highest success rate with IVF or ovulation induction
is observed in first one to three cycles. For poor responders,
diminished oocytes cohort poor oocytes quality cannot
be reversed, whatever is used.
CONFLICTS OF INTEREST
The author has none to declare.
REFERENCES
1. Sharma S, Mittal S, Aggarwal P. Management of infertility in
low resource countries. Br J Obstet Gynaecol. 2009;116:
77e83.
Fig. 11 Source: (Ref. 8). Nikolaou D. Age related fertility:
from, How old are your eggs? Curr Opin Obstet Gynaecol.
2008;20:1e5.

11. Optimization of ovarian stimulation Review Article 237
2. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S,
Zamora J, Coomarasamy A. Association between the number
of eggs and live birth in IVF treatment. Hum Reprod. 2011;26:
1768e1774.
3. Steptoe PC, Edwards RG. Birth after the reimplantation of
a human embryo. Lancet. 1978;2(8085):366.
4. Fauser BC, Devroey P, Macklon NS. Multiple birth resulting
from ovarian stimulation for subfertility treatment. Lancet.
2005;365:1807e1816.
5. Bergh T, et al. Deliveries and children born after IVF in Swe-den
1982e95: a retrospective Cohort study. Lancet. 1999;354:
1579e1585.
6. Cain JM. Ethical guidelines in the prevention of iatrogenic
multiple pregnancy. Int J Gynaecol Obstet. 2000;71:293e294.
7. Alvarez C, Martí-Bonmatí L, Novella-Maestre E, et al. Dopa-mine
agonist cabergolin reduces haemoconcentration
ascites in hyperstimulated women undergoing assisted repro-duction.
J Clin Endocrinol Metab. 2007;92:2931e2937.
8. Nikolaou D. Age related fertility: from How old are your
eggs? Curr Opin Obstet Gynecol. 2008;20:1e5.
9. Spandorfer SD, Chung PH, Kligman I, et al. An analysis of the
effect of age on implantation rates. J Assist Reprod Genet.
2000;17(6):303e306.
10. Wright VC, Chang J, Jeng G, et al. Assisted reproductive
technology surveillance e United States, 2004. MMWR Sur-veill
Summ. 2007;56(SS06):1e22.
11. Wright VC, Chang J, Jeng G, et al. MMWR surveill summary
2004, Spandrorfer SD et al. Fertil Steril. 2004;81(5):
1265e1269.
12. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ,
Nelson JF. Accelerated disappearance of ovarian follicles in
mid-life: implications for forecasting menopause. Hum
Reprod. 1992;7:1342e1346.
13. Klein NA, Illingworth PJ, Groome NP, McNeilly AS,
Battaglia DE, Soules MR. Decreased inhibin B secretion is
associated with the monotropic FSH rise in older, ovulatory
women: a study of serum and follicular fluid levels of dimeric
inhibin A and B in spontaneous menstrual cycles. J Clin
Endocrinol Metab. 1996;81:2742e2745.
14. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S,
Rosenwaks Z. Follicle-stimulating hormone levels on cycle
day 3 are predictive of in vitro fertilization outcome. Fertil
Steril. 1989;51:651e654.
15. van Rooij IA, Broekmans FJ, te Velde ER, et al. Serum anti-mullerian
hormone levels: a novel measure of ovarian reserve.
Hum Reprod. 2002;17(12):3065e3071.
16. Guzick DS, Carson SA, Coutifaris C, et al. Efficacy of super-ovulation
and intrauterine insemination in the treatment of
infertility. National Cooperative Reproductive Medicine
Network. N Engl J Med. 1999;340:177e183.
17. te Velde ER, Cohlen BJ. The management of infertility.
N Engl J Med. 1999;340:224e226.
18. Coch Datab Syst Rev. 2011.
19. Mitwally MF, Casper RF. Use of an aromatase inhibition for
induction of patients with ovulation in an inadequate response
to clomiphene citrate. Fertil Steril. 2001;75(2):305e309.
20. Popovic-Todorovic B, Loft A, Lindhard A, Bangsboll S,
Andersson AM, Andersen AN. A prospective study of predic-tive
factors of ovarian response in ‘standard’ IVF/ICSI
patients treated with recombinant FSH. A suggestion for
a recombinant FSH dosage normogram. Hum Reprod.
2003;18(4):781e787.
21. Porter RN, Smith W, Craft IL, Abdulwahid NA, Jacobs HS.
Induction of ovulation for in-vitro fertilisation using buserelin
and gonadotropins. Lancet. 1984;2(8414):1284e1285.
22. de Vries MJ, De Sutter P, Dhont M. Prognostic factors in
patients continuing in vitro fertilization or intracytoplasmic
sperm injection treatment and dropouts. Fertil Steril.
1999;72(4):674e678.
23. Sharma V, Allgar V, Rajkhowa M. Factors influencing the
cumulative conception rate and discontinuation of in vitro
fertilization treatment for infertility. Fertil Steril. 2002;78(1):
40e46.
24. Macklon NS, Fauser BC. Impact of ovarian hyperstimulation
on the luteal phase. J Reprod Fertil Suppl. 2000;55:101e108.
25. Van Der Gaast MH, Beckers NG, Beier-Hellwig K,
Beier HM, Macklon NS, Fauser BC. Ovarian stimulation for
IVF and endometrial receptivity e the missing link. Reprod
Biomed Online. 2002;5(3 suppl 1):36e43.
26. Popovic-Todorovic B, Loft A, Lindhard A, Bangsboll S,
Andersson AM, Andersen AN. A prospective study of predic-tive
factors of ovarian response in ‘standard’ IVF/ICSI
patients treated with recombinant FSH. A suggestion for
a recombinant FSH dosagenormogram. Hum Reprod.
2003;18(4):781e787.
27. Popovic-Todorovic B, Loft A, Bredkjaeer HE, Bangsboll S,
Nielsen IK, Andersen AN. A prospective randomized clinical
trial comparing an individual dose of recombinant FSH based
on predictive factors versus a ‘standard’ dose of 150 IU/day in
’standard’ patients undergoing IVF/ICSI treatment. Hum
Reprod. 2003;18(11):2275e2282.
28. Al Inany H, Aboulghar MA, Mansour RT, Serour GI. Opti-mizing
GnRH antagonist administration: meta-analysis of
fixed versus flexible protocol. Reprod Biomed Online.
2005;10(5):567e570.
29. Al Inany H, Aboulghar M. GnRH antagonist in assisted repro-duction:
a Cochrane review. Hum Reprod. 2002;17(4):
874e885.
30. Raga F, Casan EM, Kruessel JS, et al. Quantitative gonado-tropin-
releasing hormone gene expression and immunohisto-chemical
localization in human endometrium throughout the
menstrual cycle. Biol Reprod. 1998;59(3):661e669.
31. Marchini M, Fedele L, Bianchi S, Losa GA, Ghisletta M,
Candiani GB. Secretory changes in preovulatory endometrium

12. 238 Apollo Medicine 2012 September; Vol. 9, No. 3 Sinha
during controlled ovarian hyperstimulation with buserelin
acetate and human gonadotropins. Fertil Steril. 1991;55(4):
717e721.
32. Smitz J, Devroey P, Braeckmans P, et al. Management of failed
cycles in an IVF/GIFT programme with the combination of
aGnRHanalogue andHMG.HumReprod. 1987;2(4):309e314.
33. Akande AV, Mathur RS, Keay SD, Jenkins JM. The choice of
luteal support following pituitary down regulation, controlled
ovarian hyperstimulation and in vitro fertilisation. Br J Obstet
Gynaecol. 1996;103(10):963e966.
34. Frydman R, Cornel C, de Ziegler D, Taieb J, Spitz IM,
Bouchard P. Prevention of premature luteinizing hormone
and progesterone rise with a gonadotropin-releasing hormone
antagonist, Nal-Glu, in controlled ovarian hyperstimulation.
Fertil Steril. 1991;56(5):923e927.
35. Bourgain C, Smitz J, Camus M, et al. Human endometrial
maturation is markedly improved after luteal supplementation
of gonadotrophin-releasing hormone analogue/human meno-pausal
gonadotrophin stimulated cycles. Hum Reprod.
1994;9(1):32e40.
36. Jones HW. The endometrial factor in human embryo implan-tation.
Hum Reprod. 1996;11(suppl 1):7e24 (381).
37. Gambineri A, Pelusi C, Vicennati V, et al. Obesity and the
polycystic ovary syndrome. Int J Obes Relat Metab Disord.
2002;26:883e896.
38. Tang T, Glanville J, Hayden CJ, et al. Combined lifestyle
modification and metformin in obese patients with polycystic
ovary syndrome. A randomized, placebo-controlled, double-blind
multicentre study. Hum Reprod. 2006;21:80e89.
39. Moll E, Bossuyt PM, Korevaar JC, et al. Effect of clomifene
citrate plus metformin and clomifene citrate plus placebo on
induction of ovulation in women with newly diagnosed poly-cystic
ovary syndrome: randomised double blind clinical trial.
BMJ. 2006;332:1485. A multicentre, RCT of the effect of the
addition of placebo or metformin to clomiphene citrate
demonstrated that there is no additional benefit derived from
the addition of metformin to clomiphene citrate.
40. Thessaloniki ESHRE/ASRM Sponsored PCOS Concensus
Workshop Group. Consensus on infertility treatment related
to polycystic ovary syndrome. Hum Reprod. 2008;23:
462e477.
41. Tummon I, Gavrilova-Jordan L, Allemand MC, Session D.
Polycystic ovaries and ovarian hyperstimulation syndrome:
a systematic review. Acta Obstet Gynaecol Scand. 2005;84:
611e616.
42. Heijnen EM, Eijkemans MJ, Hughes EG, et al. A meta-anal-ysis
of outcomes of conventional IVF in women with poly-cystic
ovary syndrome. Hum Reprod Update. 2006;12:13e21.
43. Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P,
Diedrich K, Griesinger G. Among patients treated for IVF
with gonadotrophin and GnRH analogues, is the probability
of live birth dependent on the type of analogue used? A
systematic review and meta-analysis. Hum Reprod Update.
2006;12(6):651e671.
44. Curr Opin Obstet Gynaecol. 2008;20(4):3748.
45. Garcia-Velasco JA, Isaza V, Requena A, et al. High doses of
gonadotrophins combined with stop versus non-stop protocol
of GnRH analogue administration in low responder IVF
patients: a prospective, randomized, controlled trial. Hum
Reprod. 2000;15(11):2292e2296.
46. Malmusi S, La Marca A, Giulini S, et al. Comparison of
a gonadotropin-releasing hormone (GnRH) antagonist and
GnRH agonist flare-up regimen in poor responders under-going
ovarian stimulation. Fertil Steril. 2005;84(2):
402e406.
47. Marci R, Caserta D, Dolo V, et al. GnRH antagonist in IVF
poor-responder patients: results of a randomized trial. Reprod
Biomed Online. 2005;11(2):189e193.

13. Apollo hospitals: http://www.apollohospitals.com/
Twitter: https://twitter.com/HospitalsApollo
Youtube: http://www.youtube.com/apollohospitalsindia
Facebook: http://www.facebook.com/TheApolloHospitals
Slideshare: http://www.slideshare.net/Apollo_Hospitals
Linkedin: http://www.linkedin.com/company/apollo-hospitals
BBlloogg:: http://www.letstalkhealth.in/