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R E S E A R C H Open Access
Progestin-primed milder stimulation with
clomiphene citrate yields fewer oocytes
and suboptimal pregnancy outcomes
compared with the standard progestin-
primed ovarian stimulation in infertile
women with polycystic ovarian syndrome
Hongjuan Ye
1*
, Hui Tian
1
, Wen He
2
, Qifeng Lyu
2
, Yanping Kuang
2
, Qiuju Chen
2*
and Lihua Sun
1*
Abstract
Background: Oral progestin has recently been used to prevent premature LH surges in ovarian stimulation, and
this progestin-primed ovarian stimulation (PPOS) is effective and safe in patients with different ovarian reserves.
The current data are lacking regarding how to individualize the gonadotropin dose and regimen for women with
polycystic ovarian syndrome (PCOS). A retrospective cohort trial was performed to evaluate the efficacy of progestin-
primed milder stimulation with clomiphene citrate (CC) compared to the standard progestin-primed ovarian stimulation
(PPOS) protocol for infertile women with PCOS.
Methods: A total of 220 PCOS women were collected and classified into the study group (HMG 150 IU/d +
CC 50 mg/d + MPA 10 mg/d) and control group (HMG 225 IU/d + MPA 10 mg/d). Ovulation was triggered
by GnRH agonist 0.1 mg and hCG 1000 IU when dominant follicles matured. Viable embryos were cryopreserved for later
transfer. The primary endpoint was the ongoing pregnancy rate. Secondary outcomes included the cycle characteristics
and the live birth rate.
Result(s): The study group consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± 372.0 IU, P< 0.001) and harvested fewer
oocytes than the control group (12.2 ± 7.4 vs 18.2 ± 9.7, P< 0.001). The study group showed a higher mid-follicular LH
concentration (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 mIU/ml, P< 0.05) but no endogenous LH surge. No between-group
difference was found in the incidence of ovarian hyperstimulation syndrome (OHSS) (0.91% vs 0.91%, P> 0.05).
The cumulative ongoing pregnancy rate and live birth rate per patient were lower but did not reach significance
compared with the control group (71.8% vs 81.8 and 64.5% vs 75.5%, respectively, both P> 0.05).
(Continued on next page)
* Correspondence: yehongjuan7777@163.com;chenqj75@126.com;
lihua-sun@163.com
1
Centre of assisted reproduction, Shanghai East Hospital, Tongji University,
Shanghai, People’s Republic of China
2
Department of Assisted Reproduction, Shanghai Ninth People’s Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai, People’s
Republic of China
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Ye et al. Reproductive Biology and Endocrinology (2018) 16:53
https://doi.org/10.1186/s12958-018-0373-7
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(Continued from previous page)
Conclusion(s): The milder PPOS with CC in PCOS women led to lower oocyte yields and suboptimal pregnancy
outcomes compared to the standard PPOS treatment. The two regimens both achieved a low incidence of OHSS.
The results from the CC combination regimen provide a new insight for developing a more patient-friendly protocol
for PCOS women.
Keywords: Polycystic ovarian syndrome, Progestin-primed ovarian stimulation, Clomiphene citrate, In vitro fertilization,
Freeze-only
Background
Polycystic ovarian syndrome (PCOS) is an endocrine dis-
order affecting 5–10% of reproductive-age women world-
wide [1]. Approximately 74% of women with PCOS seeks
pregnancy assistance, including induced ovulation, in-
semination or in vitro fertilization (IVF) [2]. However,
PCOS women undergoing IVF treatment typically pro-
duce an increased number of oocytes, which are often
of poor quality, leading to a lower fertilization rate and
a higher miscarriage rate [3]. They also face a higher
risk of moderate/severe ovarian hyperstimulation syn-
drome (OHSS) [4,5].
Thanks to the progress of vitrification, oral progestin
has been successfully used to prevent premature LH surges
in women undergoing ovarian stimulation [6–8]. This
progestin-primed ovarian stimulation (PPOS) yields a com-
parable pregnancy outcome, although it consumes a slightly
higher gonadotropin dosage than conventional short proto-
cols [6]. PPOS is approved its efficacy and safety in the
population of low-ovarian-reserve, normal-ovarian-reserve
and PCOS women [8–10], so PPOS in combination with a
freeze-only policy shows good potential to compete with
conventional protocols. The existing data from clinical trials
often use the equal initiating doses of gonadotropin for
women with or without PCOS, but relevant data are lack-
ing about how to individualize the gonadotropin dose and
regimen for PCOS women undergoing ovarian stimulation.
Clomiphene citrate (CC) has been a first-line drug for
ovulation induction for anovulatory infertility. Its advan-
tages include its oral route, low costs and easy access
compared to gonadotropins [11,12]. CC is also used in
GnRH antagonist protocols, and the combination of CC
and GnRH antagonist is likely to reduce the risk of OHSS,
medication costs and gonadotropin duration compared to
those without CC, but it accompanies with an increased
risk of premature LH surges [13–15]. Limited data are
available about the role of CC in PPOS for PCOS women
[16]. In this trial, we attempted to test the hypothesis that
in women with PCOS, the milder stimulation of PPOS in
combination with CC would provide an acceptable clinical
outcome compared with standard PPOS protocol using
conventional initiating dose of gonadotropin. Our ultimate
aim was to optimize the PPOS protocol and make it more
patient-friendly.
Methods
Study setting and subjects
A retrospective cohort trial was conducted at the depart-
ment of assisted reproduction of the Ninth People’sHospital
of Shanghai Jiaotong University School of Medicine. This
study was approval by the Ethics Committee (Institutional
Review Board) of Shanghai Ninth People’sHospital.
The PCOS diagnosis criteria followed the Rotterdam
consensus. PCOS was diagnosed by the presence of
menstrual disturbance combined with either hyperandro-
genism (hirsutism or hyperandrogenaemia) or polycystic
ovary on ultrasonography (defined as an ovary that con-
tained ≥12 antral follicles) and excluded other causes of
hyperandrogenism (congenital adrenal hyperplasia, Cushing’s
syndrome, androgen-producing tumours) and ovulation
dysfunction (hyperprolactinaemia and thyroid dysfunc-
tion). In addition, this study only included women no
more than 40 years of age and with baseline serum FSH
no more than 10 mIU/ml. Women with functional cysts
on the ovaries or medical conditions that contraindicated
assisted reproductive technology and/or pregnancy were
excluded. A total of 220 infertile women with PCOS from
April 2014 to November 2015 were included and classified
into the study group (HMG + MPA + CC) and the control
group (HMG + MPA). A flowchart of the study is shown
in Fig. 1.
Ovarian stimulation protocol
In the study group, a low dose of HMG (150 IU daily),
CC 50 mg and MPA 10 mg daily were started from cycle
day 3 or after an episode of withdrawal bleeding. MPA
was used to prevent premature ovulation during the
ovarian stimulation. Follicle monitoring by transvaginal
ultrasound and serum hormone measurements (FSH,
LH, E
2
and progesterone) were performed 5 days later.
HMG doses were then adjusted according to the ovarian
response (range 150–300 IU daily). Oocyte maturation
was triggered by triptorelin 0.1 mg (Decapeptyl, Ferring
Pharmaceuticals, Germany) and urinary human chori-
onic gonadotropin (hCG 1000 IU, Lizhu Pharmaceutical
Trading Co., China) when at least three follicles reached
diameters of 18 mm or more. Cumulus oocyte com-
plexes were collected 36 h later. All follicles larger than
10 mm in diameter were aspirated.
Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 2 of 8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
In the control group, HMG 225 IU and MPA 10 mg
daily were initiated from cycle day 3 or after an episode
of withdrawal bleeding. Follicle monitor and hormone
assay were performed 5 days later. HMG dose was then
adjusted according to the ovarian response, and MPA
dose was consistent up to the trigger day. The criteria of
mature follicle and the trigger methods were the same as
above.
Fertilization was carried out in vitro after oocyte re-
trieval depending on the semen parameters and previ-
ous fertilization situation. Embryos were examined for
the number or regularity of blastomeres and the degree
of fragmentation. All top-quality cleavage-stage em-
bryos (grade 1 and grade 2, 6-cell embryos and above)
were frozen within three days after oocyte retrieval.
The non-top-quality embryos were placed in further
extended culture, and good-morphology blastocysts
were frozen. Cleavage-stage embryos and blastocysts
were frozen by vitrification as described previously [17].
Endometrium preparation and FET
Endometrium preparation for FET was arranged on the
second cycle after oocyte retrieval. The first choice was
using a letrozole-induced- ovulation cycle. Letrozole
5 mg was administered for 5 days, and then, follicle
growth was monitored beginning on day 10. At times, a
low dose of HMG (75 IU/day) was used to stimulate fol-
licle growth and endometrial lining. The timing of FET
was performed 4 or 5 days later, after a spontaneous or
hCG-induced LH surge. Hormone replacement treat-
ment was recommended for patients with thin endomet-
rium and patients in whom letrozole failed. Oral ethinyl
oestradiol 75 mcg/day was administered from cycle day
3 onwards. Once the endometrial lining was > 8 mm
thick, femoston (Solvay Pharmaceuticals B.V.) 8 mg/day
was started. The time of thawing and transfer was deter-
mined on the third day after femoston administration
[17]. Each patient received no more than two embryos
at one time. Once pregnancy was achieved, the luteal
support was continued until 10 weeks of gestation.
Hormone measurement
Serum FSH, LH, E
2
, and progesterone were measured
on menstrual cycle day 3, day 8–11 (after 5–7 days of
stimulation), the trigger day and the day after trigger.
Hormone levels were determined with chemilumines-
cence (Abbott Biological B.V. Netherlands). The lower
limits of sensitivity were as follow: FSH 0.06 mIU/ml,
LH 0.09 mIU/ml, E
2
10 pg/ml and progesterone 0.1 ng/ml.
The upper limit of E
2
measurement was 5000 pg/ml. If
Fig. 1 Study flowchart
Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 3 of 8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
serum E
2
onthetriggerdayorthedayafterwashigher
than the upper limit, it was recorded as 5000 pg/ml.
Outcome variables
Theprimarymeasureanalysedwasthecumulativeongoing
pregnancy rate, which was defined as the proportion of
patients with ongoing pregnancy after the gestation age of
12 weeks. The secondary measures included the stimula-
tion duration, gonadotropin consumption, incidence of
premature LH surge and OHSS, the number of oocytes re-
trieved, the number of viable embryos, the proportion of
mature oocytes and the live birth rate. The implantation
rate was calculated as the number of gestational sacs visual-
ized on transvaginal ultrasound divided by the number of
transferred embryos. Clinical pregnancy was defined as the
presence of foetal cardiac activity confirmed by transvaginal
ultrasound. The cumulative live birth rate was defined as
the total number of live births divided by all participants.
Statistical analysis
The data were evaluated by Student’st-testforcontinuous
variables of normal distribution, the Mann-Whitney U-test
for continuous variables of non-normal distribution, the
x
2
-test or Fisher’s exact for categorical variables, as appro-
priate. All tests were two-sided, and P<.05wasconsidered
statistically significant. All data were analysed using the
Statistical Package for the Social Sciences for Windows
(SPSS, version 19).
Results
Patient characteristics
The basal demographical and hormonal characteristics
are shown in Table 1. A total of 220 patients completed
this trial. There were no significant between-group dif-
ferences in age, body mass index (BMI), previous IVF
failures, infertility duration, menstrual cycle, indication
for IVF or basal hormonal profile. All women completed
one oocyte retrieval cycle, 208 patients had 1–15 viable
embryos harvested, and 12 cases were cancelled before
transfer due to either non-fertilization or no transferra-
ble embryos. A total of 205 women completed 287 FET
cycles in the following two years.
Ovarian stimulation, follicle development, and oocyte
performance
Clinical and cycle characteristics of ovarian stimulation
in both groups are shown in Table 2. The study group
(HMG + MPA + CC protocol) had a similar stimulation
duration (9.2 ± 1.3 days vs 9.1 ± 1.2 days, P> 0.05) and
consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ±
372.0 IU, P< 0.05). The numbers of oocytes retrieved,
MII oocytes, and fertilized oocytes in the study group
were significantly lower than those in the control group
(P< 0.05). Consequently, the number of viable embryos
in the study group was significantly lower than in the
control group (4.8 ± 3.5 vs. 6.2 ± 3.7, P< 0.05). No
between-group differences were found in the oocyte re-
trieval rate, but the maturation rate and the proportion
of viable embryos per oocyte retrieved were better in the
study group (respectively, 87.4% vs 80.3 and 39.5% vs
34.0%, both P< 0.05). The cycle cancellation due to zero
viable embryos was significantly higher in the study
group (9.1% vs 1.8%, P< 0.05). One patient experienced
moderate or severe OHSS in each group (P> 0.05).
Hormone profile during treatment
The serum concentrations of FSH, LH, E
2
and P in the
two groups are presented in Fig. 2. FSH in the study
group was slightly lower than in the control group dur-
ing the mid-follicular phase (P< 0.05). LH gradually de-
creased during ovarian stimulation in the control group;
in contrast, LH in the study group showed a slight rise
initially, followed by a downward trend, and the mean
Table 1 The basic characteristics of PCOS women in this trial
Study group
(HMG + MPA + CC;
n= 110)
Control group
(HMG + MPA;
n= 110)
Age (y) 30.5 ± 3.7 30.6 ± 3.4
Duration of infertility (y), 3.5 ± 2.6 3.9 ± 2.3
BMI (kg/m
2
) n (%)
19~ 24.9 80(72.7%) 81(73.6%)
25~ 29.9 25(22.7%) 24(21.8%)
> =30 5(4.5%) 5(4.5%)
Previous IVF failures, n(%)
0 89(80.9%) 88(80.8%)
1–3 21(19.1%) 22(19.2%)
Indication for IVF n (%)
PCOS only 27(24.5%) 30(27.3%)
PCOS+ male factor 21(19.1%) 25(22.7%)
PCOS+ tubal factor 52(52.7%) 49(44.5%)
PCOS+ other 4(3.6%) 6(5.5%)
Menstrual cycle n (%)
Regular 3(2.1%) 3(2.7%)
Oligomenorrhea 82(74.5%) 91(82.7%)
Amenorrhea 25(22.7%) 16(14.5%)
Antral follicle counts 17.9 ± 6.3 18.8 ± 7.1
Baseline hormones
FSH (mIU/ml) 4.94 ± 1.10 5.0 ± 1.17
LH (mIU/ml) 5.03 ± 3.18 5.61 ± 3.36
E
2
(pg/ml) 32.54 ± 10.34 30.32 ± 12.52
P(ng/ml) 0.26 ± 0.19 0.27 ± 0.19
T (ng/ml) 0.35 ± 0.13 0.40 ± 0.19
No significant difference was found between the two groups (P> 0.05)
Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 4 of 8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
LH value on the trigger day was significantly higher than
in the control group (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09
mIU/ml, P< 0.05). No endogenous LH surge occurred in
either group (P> 0.05). The LH value on the post-trigger
day showed a dramatic increase in the two groups, with
no between-group difference (P> 0.05).
E
2
increased gradually, accompanied by with multiple
growing follicles during the ovarian stimulation, and no
difference was found between the two groups (P> 0.05).
The measured E
2
values were underestimated in 114
cases due to the upper limit of 5000 pg/ml, so the compari-
son of E
2
between the two groups was compromised.
Serum P showed a gradual increase during ovarian stimula-
tion and increased significantly after trigger in both groups.
Pregnancy outcomes in FET cycles
The pregnancy outcomes from FET are shown in Table 3.
A total of 287 FET cycles were completed in the two
groups, including 66 women who finished at least two
transfers. The control group yielded more embryos,
which were able to finish more FET cycles in the follow-
ing two years. The mean transfer cycles per patient were
1.5 in the control group and 1.1 in the study group in
the following two years. A total of 560 embryos were
thawed and the survival rate was 99.3% (556/560). The
remnant embryos were, respectively, 350 and 303 in the
control and study group, which were the suplus embryos
in pregnant cases except for three cases in study group
without their transfer.
Table 2 The cycle characteristics of controlled ovarian stimulation in the two groups
Study group
(HMG + MPA + CC; n= 110)
Control group
(HMG + MPA; n= 110)
Pvalue
hMG doses (IU) 1470.0 ± 360.1 1943.8 ± 372.0 < 0.001
hMG duration (days) 9.2 ± 1.3 9.1 ± 1.2 0.594
No. of > 10 mm follicles on trigger day 17.6 ± 8.4 21.2 ± 8.3 0.001
No. of > 14 mm follicles on trigger day 13.8 ± 8.4 17.2 ± 9.3 0.004
No. of oocytes retrieved(n) 12.2 ± 7.4 18.2 ± 9.7 < 0.001
No. of maturation oocytes (n) 10.7 ± 6.3 14.6 ± 8.2 < 0.001
No. of fertilization (n) 8.6 ± 5.6 12.6 ± 7.7 < 0.001
No. of viable embryos(n) 4.8 ± 3.5 6.2 ± 3.7 0.007
Oocyte retrieval rate (%) 58.8% (1343/2285) 60.1% (2006/3335) 0.302
Oocyte maturation rate (%) 87.4% (1174/1343) 80.3% (1610/2006) < 0.001
The proportion of viable embryo per oocyte retrieved (%) 39.5% (531/1343) 33.8% (678/2006) 0.001
Cancellation for no viable embryos (%) 9.1% (10/110) 1.8% (2/110) 0.018
Incidence of moderate/severe OHSS (%) 0.91% (1/110) 0.91% (1/110) 1.00
Fig. 2 The dynamic changes in hormones during ovarian stimulation in the two groups
Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 5 of 8
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The synchronization methods of endometrium and
embryo were similar between the two groups. The on-
going pregnancy rate per transfer and the implantation
rate were significantly higher in the study group (re-
spectively, 66.4% vs 53.6%; 52.2% vs 42.7%, P< 0.05) but
the live birth rate per transfer was comparable between
two groups (59.7% vs 49.4%, P> 0.05). Sixty-four women
experienced twin pregnancies, including 6 women with
vanishing syndrome. One triplet pregnancy occurred in
each group, and both resulted in live births after oper-
ation of multifetal reduction. The proportions of mul-
tiple pregnancies, miscarriage and ectopic pregnancy
were similar between groups (P> 0.05). The cumulative
ongoing pregnancy and live birth rate per patient were
lower in the study group but did not reach the signifi-
cant difference (respectively 71.8% vs 81.8%; 64.5% vs.
75.5%; P> 0.05).
All newborns were examined with no congenital mal-
formation except that oesophageal atresia was found in
one baby of the control group and ventricular septal de-
fect in one of the twin babies of the study group.
Discussion
Milder stimulation, with its advantages of patient-friendliness,
is a good solution for producing an acceptable preg-
nancy outcome and eliminating OHSS for high re-
sponders. This retrospective cohort trial demonstrated
that the milder PPOS with CC led to lower oocyte yields
and suboptimal pregnancy outcomes compared to the
standard PPOS protocol in PCOS women, and the inci-
dence of OHSS was low in both groups (0.91%).
In contrast to the standard protocol of HMG/MPA,
the combination protocol of HMG/CC/MPA showed the
characteristics of milder stimulation, such as fewer oo-
cytes, fewer embryos, and a higher cancellation rate for
non-transferrable embryos, but the harvested embryos
showed good developmental potential in terms of im-
plantation rate. This protocol led to fewer oocytes at
the cost of low gonadotropin consumption. Serum FSH
in mid-follicular phase was slightly lower in the CC com-
bination protocol. The extent of ovarian stimulation may
be regulated by using low dose of gonadotropin and CC,
which leaves much flexibility for controlled ovarian stimula-
tion. Although the proportion of viable embryos per re-
trieved oocyte was better in the CC combination protocol
(39.5% vs 33.8%), the number of viable embryos was less
than the 1.5 embryos from the standard protocol. The total
number of transferrable embryos originating from the CC
group was significantly lower, meaning the milder CC
combination stimulation yielded suboptimal pregnancy
outcomes compared with the standard protocol. But
these results from a CC combination regimen may pro-
vide a new insight for develop a more patient-friendly
protocol for PCOS women.
One of the strengths of this trial is that it verified the
feasibility of CC co-administration in the PPOS protocol
in PCOS women. Our results showed that the endogenous
LH was well-suppressed during ovarian stimulation, and
Table 3 Pregnancy and live birth outcomes after FET
Study group
(HMG/MPA/CC)
Control group
(HMG/MPA)
Risk Ratio (95% CI) Pvalue
Rates per embryo transfer
Clinical pregnancy rate 73.9%(88/119) 62.5%(105/168) 1.70 (1.02, 2.85) 0.042
Implantation rate 52.2%(119/228) 42.7%(140/328) 1.47(1.04, 2.06) 0.027
Ectopic pregnancy rate 1.1%(1/88) 1.9%(2/105) 0.59(0.05, 6.64) 0.667
Miscarriage rate
Early miscarriage 9.1%(8/88) 12.4%(13/105) 0.71(0.28,1.79) 0.465
Later miscarriage 6.8%(6/88) 5.7%(6/105) 1.21(0.38,3.89) 0.752
Ongoing pregnancy rate 66.4%(79/119) 53.6%(90/168) 1.71(1.05,2.78) 0.030
Live-birth rate 59.7%(71/119)
a
49.4%(83/168)
a
1.52(0.94,2.44) 0.086
Rates per participant
Ongoing pregnancy rate 71.8%(79/110) 81.8%(90/110) 0.57(0.30,1.07) 0.079
Live birth rate 64.5%(71/110)
a
75.5%(83/110)
a
0.59(0.33,1.06) 0.077
Newborns
Single birth (n) 50 60
Single birthweight (g) 3270.4 ± 644.9 3357.0 ± 437.1 0.422
Twin birth (n) 21 23
Twin birthweight (g) 2371.7 ± 460.7 2460.0 ± 423.5 0.497
a
3 pregnant women lost to follow up to live birth (2 in study group and 1 in control group)
Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 6 of 8
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no spontaneous LH surge occurred in either group. CC
increased endogenous gonadotropin secretion by blocking
oestrogen’s negative feedback mechanism [11], as evi-
dencedbyarelativelyhigherLHlevelduringthestimula-
tion with CC in this trial. More important, no spontaneous
LH surge occurred even with the relatively higher LH,
which indicated that P’s suppression of pituitary function
was still dominant. This phenomenon has also occurred in
normo-ovulatory women using a CC combination protocol
of PPOS [18]. These data indicate that, although CC and
progesterone have separate action sites and pathways, the
changed LH trend was the result of their collaborative
action, so the two drugs may act independently and have
the possibility to act collaboratively.
In PCOS women, multiple follicle growth in controlled
ovarian stimulation leads to a higher risk of OHSS due
to the higher sensibility and exaggerated response to
gonadotropins. The incidence of moderate or severe OHSS
in PCOS women is approximately 3.0 to 8.0% [5,19].
Therefore, it is important to decide the initiating gonado-
tropin dosage to avoid OHSS. The goal of the CC combin-
ation protocol using a low dose of initiating gonadotropin
is to maximize the advantages of CC administration.
Although CC milder stimulation has the theoretical
advantages of a low risk of OHSS, less gonadotropin
consumption, and avoiding the resource wastage of
cryopreserving more embryos, but in this trial, only 0.91%
of patients had OHSS, with no difference between the two
groups. This is due to multiple preventive treatments used
in this trial: 150–225 IU HMG initiation, a co-trigger
using GnRHa and low-dose hCG and a freeze-only strat-
egy. The current data indicate that CC made it possible to
reduce the gonadotropin initiating dose in the PPOS
protocol in PCOS women, which is helpful to establish a
new, milder stimulation regimen with CC and yields an
acceptable pregnancy outcome with the benefit of lower
gonadotropin dosage.
It is worth noting that most PCOS women in China
have a relatively low BMI. The proportion of higher-BMI
(> 25 kg/m
2
) women among PCOS patients is approxi-
mately one third. Previous studies reported an association
between obesity and an increased gonadotropin require-
ment [20,21], so we must be cautious about generalizing
our conclusions, especially on the choice of the HMG
initiating dose for obese PCOS women. This trial had a
relative small sample size, with insufficient power to com-
pare the live birth rate and incidence of OHSS, so a
large-sample, prospective randomized controlled trial
using milder PPOS with CC is needed to further confirm
our conclusions.
Conclusions
This retrospective cohort trial showed that the milder
PPOS protocol with CC in PCOS women led to lower
oocyte yields and suboptimal pregnancy outcomes com-
pared to the standard PPOS protocol. The two regimens
both achieved a low incidence of OHSS. Milder PPOS
with the CC combination regimen showed a higher
cancellation rate in exchange for low gonadotropin
consumption, but the proportion of viable embryos per
oocyte and the implantation rate were higher. Our find-
ings from this CC combination regimen provide a new
insight for developing a more patient-friendly protocol
for PCOS women.
Abbreviations
AFC: Antral follicle count; CC: Clomiphene citrate; FET: Frozen embryo transfer;
FSH: Follicle-stimulating hormone; ICSI: Intracytoplasmic sperm injection; IVF: In
vitro fertilization; LH: Luteinizing hormone; MPA: Medroxyprogesterone acetate;
OHSS: Ovarian hyperstimulation; P: Progestin; PCOS: Polycystic ovarian
syndrome; PPOS: Progestin-primed ovarian stimulation
Acknowledgements
We thank the entire staff of the Department of Assisted Reproduction,
Shanghai Ninth People’s Hospital, for their support in this trial.
Funding
This study was funded by the National Natural Science Foundation of China
(grant numbers: 81671520 and 81571397) and the Natural Science Foundation
of Shanghai (grant numbers: 16411963800).
Availability of data and materials
Data are not publicly shared; please contact the authors for data requests.
Authors’contributions
Dr. Sun, Dr. Ye and Dr. Chen were the chief investigators who completed the
entire study, including procedures, conception, design and completion. Dr.
Tian, Dr. Lyu and Dr. He were responsible for the collection of data. Dr. Ye
and Dr. Chen analysed the data and drafted the manuscript together.
Professor Kuang supervised the study. All authors participated in the ultimate
interpretation of the study data and manuscript revisions. All authors read
and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Shanghai Ninth
People’s Hospital (Institutional Review Board) (No: 2014–94).
Consent for publication
All patients have provided their consent for the data to be used for research
and publications.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 23 March 2018 Accepted: 23 May 2018
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