A systematic review of randomized trials

for the treatment of poor ovarian responders:

is there any light at the end of the tunnel?
Nikolaos P. Polyzos, M.D., Ph.D., and Paul Devroey, M.D., Ph.D.
Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium

Objective: To assess the definitions for poor ovarian responders used among randomized trials for the treatment
of women with impaired response to stimulation.
Design: Systematic review.
Setting: None.
Patient(s): Poor ovarian responders.
Intervention(s): Treatment modalities for the management of poor ovarian responders.
Main Outcome Measure(s): Number and nature of the criteria used to define poor ovarian response to stimulation
and threshold values used.
Result(s): Among 47 randomized trials, 41 different definitions for the patients with poor ovarian response have
been used. No more than 3 trials used the same definition, whereas even trials from the same research groups used
different definitions across different trials. None of the criteria used was adopted in more than 50% of the trials. Age
and antral follicle count were adopted only in 9% of the definitions, whereas the criteria of number of follicles on the
final stimulation day and number of oocytes retrieved were used in more than 40% of the trials; nonetheless, even
for these criteria, the threshold values were consistently different.
Conclusion(s): The variability regarding the definition of poor ovarian responders appears to be striking. Although
the Bologna criteria developed by European Society for Human Reproduction and Embryology consensus in 2011
aim to define a consistent group of patients, their applicability needs to be tested through clinical trials. Meanwhile,
meta-analyses of the currently available trials should be strongly discouraged because they may lead to the adoption
of interventions of ambiguous value. (Fertil Steril
2011;96:105861. 2011 by American Society for
Reproductive Medicine.)
Key Words: Poor responders, low responders, poor ovarian response, IVF, randomized controlled trials, definition
of poor ovarian response, Bologna criteria

Ovarian stimulation represents the cornerstone of infertility treatment
because it induces the development of several follicles and maturation
of many oocytes to increase the likelihood of conception (1). Despite
the remarkable progress made, and the numerous therapeutic agents
developed for ovarian stimulation during the past decades (2), some
patients do not gain the benefits related to assisted reproductive tech-
nology, simply because they to do not respond to treatment. Early re-
ports suggest that the incidence of poor ovarian responders ranges
from 9% to 24% of women undergoing ovarian stimulation (3). Al-
though various treatment modalities have been adopted to increase
ovarian response to fertility treatment in these patients (4), at the mo-
ment, no single effective agent has been established. One could spec-
ulate that simply the effect of medication in poor ovarian responders is
negligible. However, the crucial question before treating these pa-
tients is: do we actually know who the poor responder patients are?
THE PARADOX: RANDOMIZED TRIALS USING RANDOM
DEFINITIONS?
The great paradox is that although we keep performing randomized
trials and testing drugs in these patients, we have not yet clarified
Received May 3, 2011; revised and accepted September 29, 2011.
N.P.P. has nothing to disclose. P.D. has nothing to disclose.
Reprint requests: Nikolaos P. Polyzos, M.D., Ph.D., Centre for Repro-
ductive Medicine, Laarbeeklaan 101, Brussels 1090, Belgium
(E-mail: n.polyzos@gmail.com).
who these patients are. Surrey and Schoolcraft attempted to cata-
logue the number of available trials published regarding poor re-
sponders in 2000 (5) and highlighted the discrepancies in the
definitions used. Furthermore, recently a consensus paper for poor
ovarian response (6) assessed the definitions of poor ovarian re-
sponse between 2000 and 2009 and reached similar conclusions.
Nonetheless, both articles failed to include all available randomized
trials, also included observational studies, and finally did not per-
form a systematic effort to evaluate what is the diversity of the def-
initions of poor ovarian responders among randomized controlled
trials (which actually represent the highest level of evidence) for
the treatment of these patients. The crucial question therefore re-
mains: do we actually know how many randomized trials for the
management of poor ovarian responders have been published and
how many definitions have been used to define patients with poor
ovarian response?
We aimed to evaluate whether current available evidence from
randomized trials apply to a clearly defined group of patients who
are considered poor responders and in what degree these results
are applicable for these patients. For this reason we searched Med-
line, the Cochrane Library, and the ISI Web of Science through
March 2011 (search details are available from authors) for ran-
domized trials evaluating the effect of different treatment modali-
ties in patients with poor ovarian response undergoing in vitro
fertilization. Our aim was to systematically assess the available
evidence, not to evaluate the efficacy of the different therapeutic

1058 Fertility and Sterility Vol. 96, No. 5, November 2011 0015-0282/$36.00
Copyright 2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.09.048
methods used for patients with poor ovarian response but to exam-
ine whether all this body of evidence applies to a uniform group of
TABLE 1
patients. Criteria used to define patients that poorly respond to
The available evidence from this review appears to be robust. ovarian stimulation among randomized controlled trials
Among 47 randomized trials, 41 different definitions for the patients assessing different treatment modalities.
with poor ovarian response have been used (Supplemental Table 1).
Only one definition, including the need of high daily dose of FSH, Median (IQR)
was used in 3 early trials (Supplemental Table 1). Two more Criteria or n (%)
definitions were used in more than one trial (2 trials) and each of No. of criteria in the definition
them was used by the same group of investigators each time Maximum no. 2 (13)
(Supplemental Table 1). Surprisingly, even trials that were per- Minimum no. 1 (12)
formed by the same groups of investigators used different defini- Criteria related to patients demographics
tions for these patients (Supplemental Table 1). The number of Patients age, 4 (9%)
criteria endorsed in the definition of poor ovarian response consid- >35 y 1
erably differed among the eligible trials and included parameters re- >38 y 1
lated to patients demographic characteristics, ovarian reserve tests >40 y 2
Previous cycle cancellation 14 (30%)
and previous cycles characteristics related to ovarian stimulation
Ovarian reserve markers
(Table 1). The variability regarding the definition of infertile women Antral follicle count 4 (9%)
who poorly respond to ovarian stimulation treatment appears to be <5 1
striking, with the lack of a uniform definition being present not only <7 1
in the number and the nature of the criteria used but also in the <12 2
threshold values used for each criterion among the available ran- High basal FSH (cycle D3) value 10 (21%)
domized trials. Although the vast majority (85%) of the trials >8.5 1
used criteria referring to previous cycles characteristics, none of >10 4
the criteria was used in more than half of the trials (Table 1). Fur- >12 1
thermore, criteria of significant importance were rarely used among >15 2
Not stated 2
the definitions proposed. For example, although a recent trial in-
Previous cycle(s) characteristics
volving more than 400,000 cycles supports that a normogram incor- No. of follicles on the 21 (45%)
porating age and number of oocytes may be potentially valuable for final day of stimulation
planning IVF treatments and counseling women with poor ovarian %2 4
response (7), age was used in only 9% of the definitions analyzed. %3 11
Finally, even for criteria that were used in more than 40% of the tri- %4 4
als (e.g. the number of follicles on the final day of stimulation or the %5 2
number of oocytes retrieved), the threshold values were consistently No. of oocytes retrieved 19 (40%)
different. %2 2
The diversity of the definitions used among available randomized %3 8
%4 7
trials is further reflected by the fact that different nomenclatures
%5 2
were adopted to describe women with impaired ovarian response; No. of mature oocytes retrieved 5 (11%)
hence it is interesting that although 80% of the definitions used %3 4
the term poor responders, 20% of the definitions used other terms %4 1
such as low responders. Levels of E2 on the final 16 (34%)
day of stimulation
450 1
LACK OF DEFINITION OR DEFINITION BY LUCK? 500 9
One could undeniably claim that this extreme diversity simply Other higher threshold 6
Good quality embryos 2 (4%)
shows the arbitrary criteria used by investigators. However, a thor-
Gonadotropin doses per day 14 (30%)
ough look shows that this diversity is not due to the use of arbitrary
225 IU 2
criteria by the primary investigators but probably due to the wide 300 IU 7
number of parameters that can successfully describe the patient Other/not stated 5
with impaired ovarian response and the lack of a consensus on which
Note: Values are median (IQR) or n (%). IQR interquartile range;
of these parameters are clinically significant.
IU international units.
It is a fact that among the criteria used in the randomized trials up
to date, all of them can be characteristics of the poor responders. Pa- Polyzos. Definitions for the poor ovarian responders. Fertil Steril 2011.
tients demographic characteristics, ovarian reserve tests, and previ-
ous cycles characteristics, as shown in Table 1, can define women
that are unlikely to respond to fertility treatment. However, the key
point is to delineate in what degree all these parameters are eventually response and investigators may have presented them in a different
applicable, in order to accurately define a uniform group of patients. way within their manuscript. However this was even more difficult
Furthermore, we have to consider that reporting of the definition for us to define, given that very few of the trials provided a reference
does not always reflect the actual criteria taken into consideration to for the definition adopted. Furthermore, even if this is the case for
recruit patients in randomized trials. It may therefore be likely that several of the trials, it simply shows that reporting of the definition
several of the trials used the same criteria for defining poor ovarian of the poor responder patients should also be more uniform.

Fertility and Sterility 1059

BUT DOES IT REALLY MATTER IF THE DEFINITION OF
POOR OVARIAN RESPONSE IS VAGUE?
The impact of this lack of definition for these patients eventually
may be far greater than we believe. Of course, someone could advo-
cate that even small differences in the definition poor ovarian re-
sponse to ovarian stimulation are not enough to prevent the
applicability of the results derived from randomized trials. However,
can such a generalization of the results be applied? The most prom-
inent consequence of the lack of a uniform definition for the poor re-
sponders is that it prevents us from adopting a uniform management
strategy for these patients. Despite the flourishing of randomized tri-
als and the adoption of new treatment modalities, the dearth of a uni-
form definition makes the applicability of the results in all these
patients almost impossible. Considering that the various approaches
studied may apply to heterogeneous groups of patients, results from
different trials may not even be comparable. Consequently, it seems
like the whole literature regarding poor ovarian response to ovarian
stimulation is dominated by trials that include patients who objec-
tively may have lower ovarian response compared with the general
population but on the other hand by no means can be grouped under
the term poor ovarian responder. Such an approach hints at the
danger of applying treatment strategies in groups of patients who ac-
tually may not experience any substantial benefit from those
strategies.
Furthermore, a logical question would be if we should keep
performing meta-analyses regarding the treatment of poor ovarian
responders. Current available evidence clearly demonstrates the
extreme variability that exists in the available randomized trials
regarding the poor responders, and the huge discrepancies that re-
fer both to the number of the criteria used and the values used
among each criterion. Hence, even the most enthusiastic investiga-
tor would undeniably be hesitant in the conduction or even the
adoption of results derived from meta-analyses regarding the
poor responders, and therefore such an effort should be strongly
discouraged.
THE BOLOGNA CRITERIA
The first attempt to accurately define women with poor ovarian re-
sponse has been performed in 2011 involving all the European So-
ciety for Human Reproduction and Embryology Special Interest
Groups with the collaboration of the Task Force on Mild Stimu-
lation (6). The proposed definition incorporates age, ovarian re-
sponse (number of oocytes retrieved), risk factors for poor
ovarian response, and ovarian reserve tests (AMH and AFC)
and provides operational criteria for the definition of a uniform
group of patients.
CAN THE BOLOGNA CRITERIA IMPROVE THE OUTCOME IN
THESE PATIENTS?
Even this consistent definition among women with poor ovarian
response may not be sufficient to improve the outcome in these
women given that we cannot predict their fertility potential. First
of all, although previous studies report a stable increase in preg-
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dict the fertility potential of these patients, this consistent definition
may be the first step toward the development of a homogenous group
of patients among whom prospective randomized trials would test
different treatment modalities to identify the optimal management
for this difficult group of patients.
CONCLUSION
In conclusion, the huge diversity in the definition of poor ovarian re-
sponders to fertility treatment described here may be acceptable if
we consider that all the definitions describe women with impaired
ovarian response. However, it is worrisome if we take into account
that we cannot identify a suitable management for this group of pa-
tients. The Bologna criteria may be the key step toward the adoption
of a uniform definition, if we would like to conduct methodologi-
cally consistent randomized trials and to make progress in the proper
management of these patients. Nonetheless, even if their widespread
adoption may help us define this difficult group of patients, it is
rather unclear whether it will eventually substantially contribute to
the successful management of the patients who exhibit an impaired
ovarian response to ovarian stimulation.
Proposing other definitions is premature at the moment and hints
a serious danger to continue conducting randomized trials using
random definitions. Thus, future randomized trials should be con-
ducted using the definition for poor ovarian responders as described
by the Bologna criteria; nonetheless, the applicability of these crite-
ria must be reevaluated in the future. In the meanwhile, and until
solid, well-designed, randomized controlled trials using the Euro-
pean Society for Human Reproduction and Embryology definition
of poor response are published, we call for attention to postopone
further meta-analysis using the diverse definitions to be published.
Otherwise, the cumulative analysis of poorly conducted trials in
published meta-analyses may induce clinicians to adopt the results
of such studies as the best evidence available, a practice that
should not be encouraged.
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1061
 SUPPLEMENTAL TABLE 1
Definition of poor ovarian response and treatment modalities compared among eligible trials.

Author, journal name, Treatment modalities Definition of poor ovarian response

year (reference) in brief to ovarian stimulation in IVF/ICSI cycles

Di Luigi et al. GnRH agonists Eligible patients had a poor response in prior IVF cycle
Fertil Steril 2011 (1) vs. (at least one of the following: four or fewer mature
GnRH antagonists follicles, four or fewer oocytes retrieved, peak
E2 %1,000 pg/mL, prior IVF cycle canceled for poor
response) or predicted poor response (at least one
of following: age >40 years, FSH R10 mIU/mL, poor
response in prior gonadotropin stimulation cycle
[E2 <500 pg/mL]).
Karimzadeh et al. GnRH agonists Eligible were women >38 years old who had one or more
Arch Gynecol vs. previous failed IVF cycles in which three or fewer
Obstet. 2011 (2) GnRH antagonists oocytes were been retrieved and/or serum E2 level
<500 pg/mL on the day of hCG administration.
Davar GnRH agonists Poor responders had at least one previous failed IVF
Taiwan J Obstet vs. cycle in which three or fewer follicles with a mean
Gynecol. 2011 (3) GnRH antagonists diameter of 16 mm were achieved and/or serum
E2 levels measured on the day of hCG administration
was 500 pg/mL or less.
Shahine et al. ET We defined poor responders as patients with a limited
Fertil Steril. 2011 (4) Day 2 number of embryos to transfer instead of a limited
vs. number of mature follicles before retrieval.
Day 3
Kim et al. Androgen pretreatment Low responder was defined as patients who failed to
Fertil Steril. 2011 (5) (a) vs. produce three or fewer follicles with a mean diameter
Control group of >16 mm with the result that three or fewer oocytes
were retrieved despite the use of a high gonadotropin
dose (>2,500 IU) in a previous failed IVF/ICSI cycle.
Wiser et al. Androgen pretreatment A poor response in a previous IVF cycle was defined
Hum Reprod. 2010 (6) vs. as retrieval of fewer than five oocytes, poor-quality
No pretreament embryos, or cycle cancellation due to poor response
to ovarian stimulation (Frattarelli et al., 2008), whenever
the gonadotropin starting dose for induction of ovulation
was at least 300 IU/day.
Devesa et al. GnRH agonists Poor responders had at least one of the following: prior
Gynecol Endocrinol. vs. cycle cancellation (follicular development of fewer than
2010 (7) GnRH antagonists four follicles after 810 days of intensive gonadotropin
stimulation), prior poor response to controlled ovarian
hyperstimulation (fewer than five follicles larger than
12 mm in diameter on the day of hCG administration
after intensive stimulation), a pathologic clomiphene
citrate challenge test (FSH day 3 FSH day 10 R25)
and/or antral follicle count %7 follicles.
Ozmen et al. Letrozole FSH Poor response was determined as having at least one
Reprod Biomed vs. of the following criteria regarding the outcomes
Online 2009 (8) FSH of previous ICSIET and ovarian stimulation cycles:
[1] cycle cancellation due to low E2 concentrations
on day 6 of the cycle (<130 pg/mL) or on the day
of hCG-b administration (<450 pg/mL); or [2] less
than four retrieved oocytes.
Kim et al. Different GnRH A low responder was defined as a patient who failed
Fertil Steril. 2009 (9) (a) antagonist protocols to produce three or fewer follicles with a mean
diameter of at least 16 mm with the result that
three or fewer oocytes were retrieved despite
the use of a high gonadotropin dose (>2,500 IU)
in previous failed IVF/ICSI cycles.
Kim et al. GnRH agonists Poor responders were defined as patients with
Fertil Steril. 2009 (10) vs. repeated day 3 levels of FSH >8.5 mIU/mL,
GnRH antagonists and/or antral follicle count of five or fewer and were
eligible to undergo IVF/ICSI.

Polyzos. Definitions for the poor ovarian responders. Fertil Steril 2011.

1061.e1 Polyzos and Devroey Definitions for the poor ovarian responders Vol. 96, No. 5, November 2011
 SUPPLEMENTAL TABLE 1
Continued.

Author, journal name, Treatment modalities Definition of poor ovarian response

year (reference) in brief to ovarian stimulation in IVF/ICSI cycles

Bekkanoglu et al. (b) Low Eligible were patients having fewer than 12 antral follicles
Fertil Steril. 2009 (11) vs. on baseline ultrasound examination.
high dose
FSH
Kansal Kalra et al. Luteal-phase FSH Criteria for poor response were one of the following: history
Reprod Biomed vs. of poor ovarian response (POR) in a previous cycle
Online. 2008 (12) follicular-phase (fewer than five follicles on day of hCG administration;
FSH administration fewer than five oocytes retrieved; or previous IVF cycle
cancellation because of POR).

bregues et al.
Fa Androgen pretreatment Infertile women who had a background of the first IVF
Hum Reprod. 2009 (13) vs. treatment cycle cancelled at our fertility unit because
No pretreament of poor follicular response and fulfilling the inclusion
criteria reported below were included in this study.
Demirol et al. GnRH agonists All patients had three criteria for poor response;
Fertil Steril. 2009 (14) vs. baseline (day 3) FSH >15 mIU/mL, fewer than four
GnRH antagonists oocytes in all previous IVF attempts, and a minimum
two (range, 24) previous IVF cycles with poor
ovarian response (E2 concentration on the day
of hCG injection <500 pg/mL or less than four
mature oocytes retrieved).
Kucuk et al. Luteal-phase FSH Eligible patients had fewer than four oocytes
J Obstet Gynaecol vs. in the previous ICSI cycle.
Res. 2008 (15) (c) follicular-phase
FSH administration
Kahraman et al. GnRH agonists Poor responders were defined when one or more
Fertil Steril. 2009 (16) vs. of the following criteria was present in at least
GnRH antagonists one previous failed assisted reproductive technology
cycle (using a standard GnRH-a long protocol):
[1] no. of mature oocytes retrieved fewer than
four; [2] level of E2 <500 pg/mL on the day of hCG
administration; or [3] a prior cancelled stimulation
cycle due to poor ovarian response.
Lainas et al. GnRH agonists Eligible patients had one or more failed IVF cycles,
Hum Reprod. 2008 (17) vs. in which five or fewer oocytes were retrieved using
GnRH antagonists a high gonadotropin dose (300 IU/day).
Kucuk et al. Growth hormone Eligible were patients who responded poorly
Assist Reprod vs. to high-dose gonadotropin treatment in their
Genet. 2008 (18) (c) No growth hormone first cycles in the same center.
Tazegul et al. GnRH agonists A poor response was defined as failure in obtaining
Arch Gynecol vs. at least three follicles >16 mm in diameter
Obstet. 2008 (19) GnRH antagonists and the number of mature oocytes retrieved fewer
than four after a previous ovarian stimulation cycle.
Kucuk et al. Luteal-phase FSH Eligible were women with fewer than four oocytes
Assist Reprod vs. in previous ICSI cycle.
Genet. 2007 (20) follicular-phase
FSH administration
Barrenetxea et al. Recombinant LH Poor responders were defined when both factors,
Fertil Steril. 2007 (21) vs. age R40 years and elevated 3-day FSH level
Control (R10 mIU/mL), were present.
Berkkanoglu et al. Recombinant LH Poor responders were considered those having
Fertil Steril. 2007 (22) (b) vs. fewer than 12 antral follicles on baseline
Control ultrasound examination.
Bahceci et al. ET Eligible were women with five or fewer follicles
Fertil Steril. 2006 (23) Day 2 (>13 mm diameter) at the end of ovarian
vs. stimulation.
Day 3

Polyzos. Definitions for the poor ovarian responders. Fertil Steril 2011.

Fertility and Sterility 1061.e2

 SUPPLEMENTAL TABLE 1
Continued.

Author, journal name, Treatment modalities Definition of poor ovarian response

year (reference) in brief to ovarian stimulation in IVF/ICSI cycles

Mohamed et al. GnRH agonists Eligible were known low responders (developed
Gynecol Endocrinol. vs. fewer than six follicles <12 mm diameter
2006 (24) GnRH antagonists in a previous IVF cycle under the standard
midluteal phase long down-regulation protocol).
Massin et al. Androgen pretreatment Eligible women had [1] a poor ovarian response to
Hum Reprod. 2006 (25) vs. ovarian stimulation in a previous IVF or ICSI attempt,
placebo defined as plasma E2 value <1,200 pg/mL at HCG
day and number of total retrieved oocytes five or fewer
and [2] evidence of a decreased ovarian reserve,
determined at day 3 of a spontaneous cycle and
defined as plasma hormonal values (FSH, E2, or
inhibin B) outside the normal range of the local
standard (FSH > 12 IU/L, E2 > 70 pg/mL
and inhibin B < 45 pg/mL).
Marci et al. GnRH agonists Poor responders were defined as patients with E2
Reprod Biomed vs. concentrations <600 pg/mL concentration on the
Online. 2005 (26) GnRH antagonists day of HCG administration and a poor response
(number of oocytes retrieved fewer than three)
(Germond et al., 1990) after a previous standard
long protocol using analogues for down-regulation
and recombinant gonadotropin at a dose
of 225 IU for stimulation.
Malmusi et al. GnRH agonists The definition of poor response was an unsuccessful
Fertil Steril. 2005 (27) vs. stimulation (no ovarian response when 300 IU
GnRH antagonists of FSH are administered for 15 days) or low number
of oocytes retrieved (fewer than five).
Schmidt et al. GnRH agonists Poor ovarian response was defined as a serum peak
Fertil Steril. 2005 (28) vs. E2 level 850 pg/mL (conversion factor to international
GnRH antagonists System of Units [SI] unit, 3.67) and/or four preovulatory
follicles 15 mm in average diameter present on the day
of hCG administration during a previous cycle of COH.
Prior stimulation regimens consisted of 300 IU
of gonadotropins with or without leuprolide acetate
pituitary down-regulation.
Cheung et al. GnRH agonists Poor responders were classified as patients who had
Hum Reprod. 2005 (29) vs. exhibited a poor ovarian response with fewer than
GnRH antagonists three mature follicles on a long GnRH agonist protocol
in their previous IVF cycles, or those with repeated
high basal levels of FSH (>10 IU/L).
Goswami et al. Letrozole FSH In the present investigation, women older than age
Hum Reprod. 2004 (30) vs. 35 years exhibiting emergence of fewer than two
GnRHagonist FSH dominant follicles in response to conventional
stimulation protocol were defined as elderly
and poor responders.
Morgia et al. Natural cycle IVF Women had undergone a previous IVF cycle at
Fertil Steril. 2004 (31) vs. our IVF clinic that resulted in a poor response,
GnRH agonist protocol that is, three or fewer follicles recruited or cycle
cancelled because of no follicle activation.
Lok et al. Adjuvant aspirin Poor responders were classified as patients who
Fertil Steril. 2004 (32) vs. had previous IVF cycles cancelled because
placebo of the recruitment of fewer than three mature
follicles (R17 mm) or as patients with repeated
high basal levels of FSH (>10 IU/L).
Weissman GnRH agonists A poor response was defined by the presence of at least
Fertil Steril. 2003 (33) vs. one of the following characteristics in a previous cycle:
GnRH antagonists fewer than five oocytes retrieved, three or fewer
follicles R16 mm on the day of cycle cancellation,
or serum E2 level less than 500 pg/mL on the day
of hCG administration.

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1061.e3 Polyzos and Devroey Definitions for the poor ovarian responders Vol. 96, No. 5, November 2011
 SUPPLEMENTAL TABLE 1
Continued.

Author, journal name, Treatment modalities Definition of poor ovarian response

year (reference) in brief to ovarian stimulation in IVF/ICSI cycles

Akman et al. GnRH agonists Determination of poor response was a clinical

Hum Reprod. 2001 (34) vs. judgement, including at least two failed IVF
GnRH antagonists attempts because of one of the following reasons:
baseline FSH concentrations >15 mIU/mL
(conversion factor to SI unit 1.00) or E2 concentration
on the day of hCG injection <500 pg/mL or the
number of mature oocytes retrieved fewer than
four. FSH was measured by a standard commercial
kit produced by Abbott Laboratories.
Garcia-Velasco et al. Different GnRH Patients had at least one previous cancelled IVF
Hum Reprod. 2000 (35) agonist protocols attempt in which fewer than three follicles
of 18 mm were obtained.
Cedrin-Durnerin et al. Different gonadotropin Patients were enrolled on the basis of a poor ovarian
Fertil Steril. 2000 (36) doses response in a previous IVF cycle (fewer than five
retrieved oocytes) or elevated baseline FSH
or E2 levels on cycle day 3.
Dirnfeld et al. Different GnRH All patients had a previous low response to COH
Fertil Steril. 1999 (37) agonist protocols as evidenced by a peak E2 level of <2,000 pmol/L
and/or retrieval of four or fewer mature oocytes
in at least one previous IVF cycle.
Howles et al. Growth hormone Based on the previous experience obtained in a large
Hum Reprod. 1999 (38) vs. population of patients (>500) treated at
placebo Bourn Hall Clinic, Cambridge, United Kingdom,
a poor-response cycle was defined as one
in which no more than three follicles had a
diameter R16 mm on the day of hCG administration
or cancellation, or in which more than 41 ampoules
of gonadotropin were needed to achieve complete
follicular maturation in a short GnRH-a protocol
(or 47 ampoules in a long GnRHa protocol).
Battaglia et al. L-arginine The women had previously undergone a failed
Hum Reprod. 1999 (39) vs. IVF attempt. The IVF cycles were cancelled
Control when E2 plasma concentrations were
<1.100 pmol/L and/or fewer than three follicles
were recruited by cycle day 8.
Raga et al. Different gonadotropin Women who exhibited a poor response to uFSH
Hum Reprod. 1999 (40) preparations (i.e., fewer than four follicles with a diameter
of R16 mm after 12 days of standard ovarian
stimulation) (Hanoch et al., 1998) in two previous
consecutive cycles (which were therefore
cancelled), despite having normal basal E2
and FSH, were invited to participate in the
present prospective study.
Suikkari et al. Growth hormone Poor IVF responsiveness was defined as having
Fertil Steril. 1996 (41) vs. two or fewer oocytes retrieved or R48 ampoules
placebo of hMG consumed in a stimulation cycle.
Dor et al. Growth hormone The diagnosis of poor response was based on the
Hum Reprod 1995 (42) vs. following criteria observed in previous IVF
placebo treatments: [1] 17-b E2 concentrations on the
day of hCG administration were <501 pg/mL;
[2] number of follicles (>14 mm) observed in
ultrasonography was fewer than four; and
[3] number of retrieved oocytes following
ovum retrieval was three or fewer.

Polyzos. Definitions for the poor ovarian responders. Fertil Steril 2011.

Fertility and Sterility 1061.e4

 SUPPLEMENTAL TABLE 1
Continued.

Author, journal name, Treatment modalities Definition of poor ovarian response

year (reference) in brief to ovarian stimulation in IVF/ICSI cycles

Bergh et al. Growth hormone Women had undergone at least two failed
Fertil Steril. 1994 (43) vs. IVF attempts, defined as no pregnancy
placebo and fewer than five oocytes retrieved after
stimulation with either clomiphene citrate
(CC) and hMG, hMG alone, or hMG stimulation
preceded by GnRH downregulation at doses
normally giving an adequate response.
Hughes et al. Growth hormone A poor response was defined as requiring
Hum Reprod. 1994 (44) (d) vs. >300 IU hMG/day in a previous attempt
placebo to achieve hCG criteria.
Huang Growth hormone Poor responders were considered patients
Hum Reprod. 1993 (45) (d) vs. if the previous treatment cycle required
placebo more than four ampoules (>300 IU FSH)
hMG/day to induce ovulation.
van Hooff et al. Different gonadotropin Criteria for poor ovarian response were
Hum Reprod. 1993 (46) doses as follows: after 5 days of ovarian stimulation
with 225 IU hMG/day there should be
three or fewer follicles <11 mm in diameter
on ultrasonographic examination or one
follicle >11 mm and two or fewer follicles
<11 mm; in both instances E2 levels
should be <500 pmol/L.
Ibrahim et al. Growth hormone Poor responders were defined if the previous
Fertil Steril. 1991 (47) (d) vs. treatment cycle required more than four
placebo ampoules (>300 IU FSH) hMG/day
to induce ovulation.
Note: (a), (b), (c), and (d) are randomized trials that used the same definition. ICSI intracytoplasmic sperm injection.

Polyzos. Definitions for the poor ovarian responders. Fertil Steril 2011.

1061.e5 Polyzos and Devroey Definitions for the poor ovarian responders Vol. 96, No. 5, November 2011
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