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Detrimental Effects of High-Dose Gonadotropin on Outcome of IVF: Making a

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Detrimental Effects of High-Dose Gonadotropin on Outcome of IVF: Making a Case for Gentle Ovarian
Stimulation Strategies
Peter Kovacs, Attila Sajgo, Steven G. Kaali and Lubna Pal
Reproductive Sciences 2012 19: 718 originally published online 28 February 2012
DOI: 10.1177/1933719111432859

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 Reproductive Sciences
19(7) 718-724
Detrimental Effects of High-Dose ª The Author(s) 2012
Reprints and permission:
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Gonadotropin on Outcome of IVF: DOI: 10.1177/1933719111432859
http://rs.sagepub.com
Making a Case for Gentle Ovarian
Stimulation Strategies

Peter Kovacs, MD1, Attila Sajgo, MD1,

Steven G. Kaali, MD1, and Lubna Pal, MBBS2

Abstract
Objective: Limited data identify detrimental influences of aggressive use of gonadotropins (G) for controlled ovarian hyperstimulation
(COH); the underlying mechanisms however remain unclear. We report on the relationship between G dose and in vitro fertili-
zation (IVF) cycle parameters (ovarian response, endometrial thickness [EMT]) and cycle outcome (implantation rate [IR] and clinical
pregnancy [CP] rate) in a cohort of women undergoing IVF. Methods: Retrospective analysis of fresh embryo transfer (ET) cycles.
Univariate and multivariable regression analyses assessed relationship between G dose and outcomes of interest. Results: Higher G
dose related positively with advancing age (P < .001) and inversely with EMT (P < .001). The overall CP rate was 30%. Significantly
lower IR (.003) and CP rate (.002) were observed across increasing tertiles of G dose. Increasing G dose was identified as an
independent negative predictor of EMT after adjusting for age, COH protocol and duration, infertility diagnosis, and ovarian
response (P ¼ .016). Adjusting for age, suppression protocol (gonadotropin-releasing hormone agonist vs antagonist), infertility diag-
noses, EMT, quality, and cleavage of ET, lower G dose was an independent positive predictor of CP rate (odds ratio for CP rate was
1.57 for G dose in middle compared to the highest G dose quartile (95% confidence interval 1.09-2.24). Stratified analyses identified
detrimental associations of higher G dose with CP rate to be relevant in women aged 35 years and younger. Conclusions: Our analyses
suggest detrimental influences of higher G dose on the endometrium and confirm the previously reported adverse association
between higher G dose and IVF outcome. Gentler COH regimens may be of particular benefit in women aged 35 years.

Keywords
gonadotropin dose, endometrium, endometrial thickness, clinical pregnancy, implantation, IVF.

Introduction
Quantitative ovarian response to ovarian stimulation strategies
is a recognized contributor to the success of assisted reproduc-
tive technologies (ARTs). Conversely, the art of assisted ART
lies in an individualized approach that allows optimization of
oocytes yield, while avoiding the risk of ovarian hyperstimula-
tion syndrome. Patient’s age, body mass, the dose of gonadotro-
pins (G), and ovarian suppression protocols are all recognized as
determinants of oocyte yield following controlled ovarian hyper-
stimulation (COH).1 The initial decades following introduction
of ART witnessed efforts at maximizing oocytes yield; soon
followed the realization that ‘‘more may not be better.’’2 This
latter appreciation has led to widening acceptance of ‘‘minimal
stimulation’’ and ‘‘patient friendly’’ protocols despite a dearth
of prospective data supporting this concept.3
The dynamics of reproductive physiology are well described
and the initial stages of folliculogenesis are well characterized,
although the exact mechanisms remain far from understood.4
Age, the size of the residual follicular cohort, and local growth
factors all influence the processes of follicular recruitment and
commitment to growth; pituitary G, follicle-stimulating hor-
mone (FSH), and luteinizing hormone become increasingly
important relatively late in this process.4 This latter apprecia-
tion is particularly relevant to ART as the currently available
strategies do little for increasing the pool of ‘‘recruitable’’
follicles. A finite spectrum of ‘‘poor responder’’ protocols has
surfaced in attempts to maximize quantitative ovarian response
1
Kaali Institute IVF Center, Budapest, Hungary
2
Department of Obstetrics Gynecology & Reproductive Sciences, Yale Uni-
versity School of Medicine, Yale Reproductive Endocrinology, New Haven,
USA
Corresponding Author:
Peter Kovacs, Kaali Institute IVF Center, Istenhegyi út 54a, 1125 Budapest,
Hungary
Email: peterkovacs1970@hotmail.com

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Kovacs et al
with COH strategies; the commonest of these themes involves
use of increasing doses of exogenous G.5–9 While reduction in
cycle cancellations is recognized with the implementation of
the various ‘‘poor responder protocols,’’ these successes have
not translated into improved treatment-related pregnancy
rates.5–12 More recently, higher G dose regimens have come
under scrutiny not just for a lack of benefit but even more
importantly for a potential for detriment.12–14 Indeed, a small
yet accruing body of literature is suggestive of an inverse
relationship between G dose and pregnancy rates following
IVF.11–14 While the mechanisms remain far from clear, adverse
influences of high G doses on the developing oocyte as well as
the endometrium are suggested.15–19
We herein present retrospective analyses of data on IVF
cycles undertaken in an otherwise healthy population of
European women attending a single infertility center, exploring
the relevance of G dose on IVF cycle parameters and on the
outcome of ART. Beyond demonstrating that higher G doses
may indeed adversely influence cycle success in women under-
going IVF, our analyses identify that endometrial thickness
(EMT) may be negatively influenced by higher G dose.
Furthermore, our data suggest that negative influences on cycle
outcome are particularly evident in women under age 35 and
highlight that gentler COH regimens offer not just the benefit
in minimizing risk of ovarian hyperstimulation syndrome but
may additionally maximize pregnancy success following IVF
in the younger population of infertile women undergoing ART.
Methods
All fresh embryo transfer (ET) nondonor egg IVF cycles under-
taken at Kaali Institute IVF Center in Budapest, Hungary
between January 2008 and December 2008 were assessed. The
IVF cycles utilizing preimplantation genetic diagnosis however
were excluded as were natural cycle IVF and ART cycles in
which clomiphene citrate was used alone or in combination
with G. Due to the retrospective nature of the study, institu-
tional review board approval was not required according to the
institutional protocol. The IVF cycles that did not progress to
ET were further excluded since the aim of the study was to
evaluate the association between COH parameters and cycle
outcome.
The COH protocols were employed per clinical care
standards. Ovarian suppression strategies either utilized
gonadotropin-releasing hormone agonist ([GnRHa]; Buserelin,
Suprefact; Aventis, Germany) or flexible GnRH antagonist
(cetrorelix 0.25 mg; Cetrotide, Merck Serono, Switzerland);
GnRHa was initiated either in the late luteal phase of the pre-
ceding cycle (long protocol) or in the early follicular phase
(short protocol) of the treatment cycle. The GnRH antagonist
protocol was initiated once the largest follicle reached a size
of 13 to 14 mm.20 Recombinant FSH (Gonal F, Merck Serono),
human menopausal G (Merional, IBSA, Switzerland), highly
purified human menopausal G (Menopur, Ferring, Switzerland)
or the combination of these G was used for COH. When at least 2
follicles reached 17 mm in diameter, human chorionic G (hCG)
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719
was used to trigger ovulation (250 mg rHCG, Ovitrelle, Merck
Serono); EMT measurement (mm) observed on transvaginal
ultrasound (TVS) performed on the day of hCG trigger was
recorded. The EMT was measured in the mid-saggital plane
by setting the calipers to the outside edges of the triple line
endometrium. Transvaginal oocyte retrieval was performed
35 to 36 hours later. Fertilization was achieved using standard
IVF or intracytoplasmic sperm injection (ICSI).21 Embryos
were graded for quality on day 3; embryo scoring was based
on the blastomere number and fragmentation.22 Embryos that
reached at least the 6-cell stage and contained less than 20%
fragmentation were considered good quality embryos.22
Embryo transfer was performed on either day 3 or day 5 after
fertilization using Wallace catheters. The luteal phase was sup-
ported with vaginal micronized progesterone (3  200 mg Utroge-
stan, Lab Besius Int, France). Two weeks after ET, cycle outcome
was determined by assessing serum bHCG; level > 10 IU/L was
considered as consistent with a biochemical pregnancy. Two
weeks after the pregnancy test, a TVS was performed to assess for
the number and location of the gestational sac(s). Clinical preg-
nancy (CP) was defined as evidence of an intrauterine gestation
sac on TVS. Implantation rate (IR) was calculated (# gestational
sacs/#ET  100).
Patient characteristics (age, ovarian reserve as reflected by
baseline FSH, first vs repeat ART cycle, and etiology for infer-
tility), COH parameters (ovarian suppression protocol, G dose,
response to COH [ie, # follicles over 14 mm in size, duration of
COH (days), # of eggs retrieved, EMT on day of hCG admin-
istration], fertilization rate, #ET, day of ET [D3 vs D5], cryo-
preservation of surplus embryos), and outcome of IVF cycles
(CP rate, IR) were assessed in the context of G dose (indepen-
dent variable of interest). Mean daily G dose was calculated
(total G dose IU/#days of COH).
Data distribution was assessed using Shapiro-Wilk test.
Data on G dose were observed to be non-Gaussian and was
categorized into quartiles. Univariate analyses (Student t test
or Mann-Whitney U test as appropriate) compared patient and
cycle characteristics according to cycle outcome. Age was used
as a continuous variable as well as was dichotomized at thresh-
olds of 35 (35 vs <35) and 38 (38 vs <38). Clinical preg-
nancy rate and IR across quartiles of G dose were assessed
using Kruskal-Wallis rank test. Multivariable logistic regres-
sion analyses assessed the relationship between G dose
(in quartiles) and CP outcome after adjusting for potential con-
founders (age, COH stimulation protocol, infertility diagnosis
[tubal infertility vs other etiologies], quality and developmental
stage [blastocyst vs day 3] of ET, EMT, and cryopreservation
of surplus embryos). Multivariable linear regression analyses
assessed the relationship between G dose and EMT after adjust-
ing for age, duration of COH and COH protocol, infertility
diagnosis (male factor vs other causes), and ovarian response
as reflected by the total number of follicles measuring
>14 mm on the day of hCG. Model fit for logistic regression
analyses was assessed using Hosmer-Lemeshow test.23
The magnitude of associations for logistic and linear regres-
sion analyses is presented as odds ratio (OR) + 95%
720
Figure 1. Flow diagram reflecting enrollment scheme.
confidence interval (95% CI) and regression coefficient,
respectively. STATA 10.0 (Intercool, Collage Station, Texas)
was used for analyses and a 2-way P < .05 was considered as
being statistically significant.
Results
The relevance of G dose for IVF cycle outcome was assessed in
1385 cycles. Enrollment details are outlined in Figure 1.
Continuous data are presented as mean + standard deviation
(SD) and categorical data are presented as percentage (%).
Table 1 presents participant and IVF cycle characteristics
according to CP outcome; as is evident, younger age, better
ovarian reserve as reflected by lower serum FSH levels, use
of luteal GnRHa protocol, utilization of lower G dose, inferti-
lity etiology other than tubal factor, attainment of EMT
>10 mm on the day of hCG administration, better ovarian
response (as reflected by higher number of eggs retrieved and
availability of surplus embryos to freeze), better quality
embryos, and blastocyst ET were predictive of IVF success.
Significant reduction in CP rate (P < .001) and IR (P < .001)
was observed with the use of higher G dose, as reflected by
declining CP rate and IR across second to fourth dose quartile
(Figure 2).
An inverse association was observed between EMT on the
day of hCG administration and G dose (Figure 3). Multivari-
able linear regression analyses identified higher G dose as
detrimental to EMT after adjusting for age, duration of COH, and
ovarian response (as reflected by number of follicles over 14 mm
on the day of hCG, b 0.002, standard error 0.001, P ¼ .007).
Multivariable logistic regression analyses identified G dose
as an independent and negative predictor of CP (Table 2).
Other than the G dose, patient’s age, infertility diagnosis (tubal
factor vs other causes), luteal GnRHa protocol, quality and
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Reproductive Sciences 19(7)
developmental stage of transferred embryos, and attainment
of cryopreservation of surplus embryos were identified as pre-
dictors of cycle outcome (Table 2). Model diagnostics identi-
fied the full statistical model to exhibit 67% sensitivity in
predicting likelihood of CP following fresh ET. Sensitivity
analyses further examined the observed relationship between
G dose and CP in the context of age; analyses were stratified
by age categories as previously specified. Significant detriment
of increasing G dose was apparent in women 35 compared to
those older than 35, in whom the association failed to reach sta-
tistical significance (Table 2); model diagnostics identified
comparable predictive ability of the stratified models for cycle
outcome (67% vs 65% sensitivity; P ¼ .360).
Discussion
In a homogeneous population of healthy albeit infertile women,
our analyses demonstrate adverse implications of increasing
G dose used during IVF for cycle outcome. This difference was
independent of patient’s age and was particularly prominent in
women 35. Our findings are consistent with published litera-
ture. Martin et al, found an inverse relationship between G dose
and pregnancy rate in their retrospective analysis.11 Lekamge
et al, reported similar egg/embryo yield and pregnancy rates
among women with low ovarian reserve when 150 IU versus
200 to 300 IU G was administered daily.12 Pal et al, in their ret-
rospective analysis, described lower pregnancy and live birth
rates with higher G dose.13 Berkkanoglu et al, in a prospective
randomized study, found similar pregnancy rates with G doses
of 300, 450, and 600 IU in low responders.14 Hoffmann et al, on
the other hand, reported higher pregnancy rates among poor
responders when 450 IU G was used daily versus 300 IU during
their previous attempt.5 Blankstein et al also reported improved
Kovacs et al 721

Table 1. Patient and IVF Cycle Parameters According to Cycle Outcomea

Parameter Clinical Pregnancy, N ¼ 414 (30%) Not Pregnant, N ¼ 971 (70%) P Value

Age, years 33.50 + 3.64 34.97 + 4.34 <.001

Day 3 FSH, mIU/mL 7.26 + 2.3 7.73 + 3.0 .005
Tubal infertility, % 92 (22.20%) 278 (28.63%) .014
First ART cycle 191 (46.14%) 441 (45.42%) .806
GnRH antagonist, % 89 (21.50%) 214 (22.04%) .823
GnRH agonist, % 141 (34.06%) 239 (24.61%) <.001
Gonadodropin dose, IU 175.6 + 59 195 + 73 <.001
Duration of COH, days 9.83 + 1.9 9.82 + 2.6 .299
Endometrial thickness, mm on day of ET 11.26 + 1.66 11.11 + 1.62 .083
EMT > 10 mm 276 (67%) 585 (60%) .024
Number of eggs retrieved 9.78 + 4.83 8.46 + 4.56 <.001
Good quality embryos, % 55.05 + 29.08 47.09 + 30.94 <.001
Number embryos transferred 2.21 + 0.70 2.21 + 0.65 .653
Day of embryo transfer (ET) 3.87 + 0.99 3.66 + 0.95 <.001
Blastocyst ET 181 (44%) 320 (33%) <.001
Cryopreservation of surplus embryos, % 152 (36.71%) 213 (21.94%) <.001
Abbreviations: IVF, in vitro fertilization; FSH, follicle-stimulating hormone; ART, antiretroviral therapy; COH, controlled ovarian hyperstimulation.
a
Continuous data are presented as mean (+standard deviation) and categorical as number (%).

Figure 2. Declining clinical pregnancy and implantation rates with increased gonadotropin dose from the second through the fourth quartile of
gonadotropin dose.

follicle development with higher G dose among patients who
did not respond to lower dose in a previous attempt.6
Exogenous G are suggested to have an impact on both
embryo quality and endometrial receptivity. Several groups
reported lower aneuploidy rates with gentler COH strategies
using lesser doses of G.15,16 Baart et al, randomly assigned
women to mild stimulation versus standard ‘‘high-dose’’ regi-
mens and identified a significant reduction in the aneuploidy
rate with the mild COH approach.16 Rubio et al, demonstrated
lower aneuploidy rates in donor egg embryos resulting from
milder COH strategy (with use of 150 IU vs 225 IU G).15 Oth-
ers make a case that milder ovarian stimulation strategies may
translate into better embryo quality.24
Another mechanism by which high G dose may have a neg-
ative impact on cycle outcome is by altering the endometrial
environment. During the luteal phase of the cycle, there is sig-
nificant modulation of genes that participate in processes of
implantation.25 Several groups reported altered gene expres-
sion profiles in the luteal phase endometrium when natural and
stimulated cycles were compared.17,18 In addition, differences

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722 Reproductive Sciences 19(7)

In the current study, the use of GnRHa was associated with

500

higher CP rates when compared to other protocols, and this

observation is consistent with existing literature. Superior preg-
Daily Dose of Gonadotropins (U)
400

nancy rates with GnRHa use were reported in a meta-analysis

comparing the agonist and antagonist protocols.28 Blastocyst
ET cycles are recognized to yield higher IR and CP rates, and
300

out data are in keeping with this observation.29,30 Blastocyst ET

was associated with a 45% increase in CP rate in women under
200

35, and to a more than 2-fold increase in cycle success in

patients over 35 years of age. Our finding that tubal infertility
100

related to a lower chance for CP following fresh ET contrasts

with existing data that suggests similar IVF outcome with mild
0

5 10 15 20 tubal disease when compared to other indications.31 While

Endometrial Thickness (mm)
coexisting hydrosalpinges can be theorized to explain the
r: -0.12, p<0.001 adverse association between tubal infertility and cycle out-
come, we are unable to expand on this possibility given lacking
Figure 3. Endometrial thickness on the day of hCG administration pertinent details in our sample.32
correlates inversely with gonadotropin dose. hCG indicates human Despite the large sample size and the stringency of our
chorionic gonadotropin. analyses, our study is limited by the retrospective study design
that does not allow insight regarding causality to the observed
were noted in the endometrial gene expression with various associations. In a busy multiphysician practice, the observed
stimulation protocols. When compared with the GnRHa short heterogeneity in treatment protocols primarily relates to physi-
protocol, the use of the GnRH antagonist regimen resulted in cian preference, although on occasion, financial considerations
an endometrial profile the resembled the natural cycle.19 Exist- and time constraints may influence this decision. A lack of
ing literature however is equivocal, as van der Gaast and col- standardization of ART treatment is a shortcoming of this ret-
leagues failed to observe a difference in the expression of rospective analysis, although we have attempted to address any
various markers of endometrial receptivity when natural and potential for confounding by incorporating ovarian suppressive
stimulated cycles were compared.26 In addition to these find- regimen (GnRHa vs antagonist) as covariates in multivariable
ings, our analyses reveal an inverse relationship between analyses. Information on potential confounders including body
G dose and EMT, an observation not previously reported. Rele- mass index (BMI), serum estradiol levels, and existence of
vance of endometrial thickness for cycle success is well hydrosalpinx for women with tubal disease is lacking. The
described; several studies have shown that pregnancy rates strengths of the study come from the fairly homogenous patient
improve with increasing endometrial thickness.27 Given that population and large number of subjects included. The applica-
endometrial proliferation is directly influenced by circulating tion of complex statistical methods allows objective analysis of
estradiol, achievement of adequate endometrial thickness can the data. Furthermore, there are known biological mechanisms
be considered a biomarker of ovarian function. Our analyses (discussed above) that support our findings.
suggest that higher G dose may be detrimental to endometrial The treatment of the poor responder patients remains clini-
physiology, as reflected by the thickness of the endometrium. cally challenging. Attempts at maximizing oocyte yield, by
Given that higher G dose correlated with advancing age and increasing G dose allow the potential for selecting the ‘‘best’’
with reduced ovarian response (reflected by the number of among the available embryos, as well as offering the possibility
growing follicles), it is possible that the observed relationship of achieving blastocyst transfer. This quantitative gain however
between G dose and EMT may just be a reflection of lower does not necessarily translate to qualitative benefit as seen in
estradiol levels. While this latter impression may not be the presented data. Our findings clearly demonstrate that esca-
substantiated given that serum estradiol measurements for day lating G dose not only does not translate into improved preg-
of hCG administration are lacking in our population (not routi- nancy rates following fresh ET, but on the contrary, is
nely undertaken at our center), our analyses adjusted for the detrimental to cycle success. We further identify that this detri-
number of follicles >14 mm, a parameter that may be construed mental association between G dose and cycle outcome may be
as a surrogate for serum estradiol; the relationship between G particularly meaningful in younger women in whom gentler
dose and EMT was independent of age, ovarian response, and COH regimens are likely not just to minimize risk of ovarian
duration of COH. While our study design does not allow us to hyperstimulation syndrome but may additionally enhance cycle
comment on the processes that may underlie the observed success; this latter assumption however merits being tested in
adverse implications of increasing G dose on IVF outcome, prospective randomized studies. While it can be theorized that
direct endometrial detriment relating to higher G dose can also higher G doses may ‘‘salvage’’ a qualitatively suboptimal pool
be postulated; indeed, this latter conjecture is supported by of follicles, yielding a higher proportion of relatively poor
previous reports identifying adverse impact of high-dose quality oocytes and thence embryos, our data suggest that the
G on endometrial gene expression.17–19 detriment may lie at the endometrial level.

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Kovacs et al 723

Table 2. Multivariable Logistic Regression Analyses Identifying Predictors of Clinical Pregnancy Following Fresh Embryo Transfera

Likelihood for Clinical Pregnancy Age Stratified Adjustedb Likelihood

Odds Ratio (95% CI) Odds Ratio (95% CI)

Variables Unadjusted Adjustedb Age  35 (n ¼ 863) Age > 35 (n ¼ 509)

c
Quartiles of G dose
First (lowest) 1.55 (1.09-2.19)d 0.98 (067-1.44) 1.11 (0.69-1.80) 0.25 (0.05-1.14)
Second 2.14 (1.53-2.98)d 1.57 (1.09-2.24)d 1.61 (1.01-2.57)d 1.19 (0.64-2.22)
Third 1.43 (1.00-2.04) 1.18 (0.81-1.71) 1.09 (0.66-1.81) 1.20 (0.68-2.11)
GnRH agonist 1.58 (1.22-2.04)d 1.35 (1.04-1.76)d 1.51 (1.12-2.04)d 0.95 (0.54-1.68)
Age, years 0.92 (0.89-0.94)d 0.94 (0.91-0.97)d 0.98 (0.92-1.03) 0.81 (0.73-0.91)d
Tubal disease 0.71 (0.54-0.94)d 0.69 (0.52-0.92)d 0.67 (0.48-0.94)d 0.69 (0.41-1.16)
Percentage of good quality ET 1.01 (1.00-1.01)d 1.01 (1.00-1.01)d 1.01 (1.00-1.01)d 1.01 (1.01-1.02)d
Blastocyst ET 1.58 (1.24-2.01)c 1.75 (1.34-2.28)c 1.45 (1.06-1.98)d 2.78 (1.66-4.63)d
EMT >10 mm 1.32 (1.04-1.68)c 1.16 (0.90-1.49) 1.10 (0.81-1.50) 1.19 (0.75-1.89)
Cryopreservation 2.06 (1.61-2.65)d 1.42 (1.07-1.88)d 1.37 (0.99-1.90) 1.44 (0.83-2.50)

Abbreviations: G, gonadotropin dose (IU); ET, embryos transferred; GnRH, gonadotropin-releasing hormone agonist; EMT, endometrial thickness; CI, confidence
interval.
a
Data are presented as odds ratio (95% CI).
b
Analyses adjusted for gonadotropin dose, suppression protocol, patient’s age, infertility diagnoses (tubal disease versus other etiologies), quality, number and
developmental stage (blastocyst versus cleaving status) of transferred embryos and cryopreservation of surplus embryos.
c
Highest G dose quartile is used as reference; mean (standard deviation) daily G dose (in units) across the quartiles is as under:
First 130.67 (26.05) IU
Second 156.00 (27.46) IU
Third 200 (39.62) IU
Fourth 281.46 (62.24) IU
d
P < .05.

Conclusion low-responder patients for in vitro fertilization. J In Vitro Fert

Our findings add to the existing literature that is supportive of
gentler COH regimens for patients undergoing IVF and suggest
that this concept may be particularly meaningful in the young
(35) population of infertile women. An inverse relationship
between G dose and EMT suggests that higher G doses may
be detrimental to the endometrial physiology, although the
mechanisms therein remain unclear; future effort should target
study of endometrial molecular markers in an attempt to under-
stand the processes underlying these observed associations.
Author’s Note
The work was done at Kaali Institute IVF Center.
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