Controlled ovulation of the dominant follicle using progestin in minimal stimulation in poor responders
Chen et al. Reproductive Biology and Endocrinology
Controlled ovulation of the dominant follicle using progestin in minimal stimulation in poor responders
Qiuju Chen 0
Yun Wang 0
Lihua Sun 0
Shaozhen Zhang 0
Weiran Chai 0
Qingqing Hong 0
Hui Long 0
Li Wang 0
Qifeng Lyu 0
Yanping Kuang 0
0 Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Zhizaoju road no 639, Shanghai , People's Republic of China
Background: The use of progestin (P) during ovarian stimulation is effective in blocking the luteinizing hormone (LH) surge in women with normal ovarian reserve, however, its effects have not been determined in poor responders. This study aimed to explore the follicular dynamics in P-primed minimal stimulation in poor responders. Methods: A total of 204 infertile women with diminished ovarian reserve were allocated into the medroxyprogesterone acetate (MPA) group or the natural-cycle control group in an alternating order. MPA (10 mg) was administered daily beginning from the early follicular phase and a low dose of hMG was added in the late follicular phase if the serum FSH level was lower than 8.0mIU/ml. When a dominant follicle reached maturity, triptorelin 100 μg and hCG 1000 IU were used for trigger, and oocytes were retrieved 34-36 h later.All viable embryos were cryopreserved for subsequent frozen embryo transfer. Natural cycle IVF was used as controls. Results: Compared with the natural cycle group, the MPA group exhibited a larger pre-ovulatory follicle (18.7 ± 1.8 mm vs 17.2 ± 2.2 mm), a longer follicular phase (13.6 ± 3.6 days vs 12.3 ± 3.2 days), and higher peak oestradiol values (403.88 ± 167.16 vs 265.26 ± 122.16 pg/ml), while maintaining lower LH values (P < 0.05). The incidences of spontaneous LH surge and premature ovulation decreased significantly (1.0% vs 50%; 2% vs. 10.8%, respectively; P < 0.05). A greater number of oocytes and viable embryos were harvested from the MPA group than from the natural cycle group (P < 0.05). Moreover,the clinical pregnancy rate was slightly higher in the MPA group than in the natural cycle controls, but the difference was not significant (11.8% vs 5.9%, P > 0.05). Conclusion: This study supported the hypothesis that P-primed minimal stimulation achieved ovulation control of the dominant follicle and did not adversely affect the quality of oocytes in poor responders. Therefore, P-priming is a promising approach to overcome premature ovulation in minimal stimulation for poor responders. Trial registration: ChiCTR-OCH-14004176. Registered on January 8, 2014.
Poor responder; Natural cycle; Progestin; Premature ovulation
Improvements in cryopreservation techniques for assisted
reproductive technology (ART) have allowed reproductive
physicians to consider a new strategy of using progestin
(P) as an oral alternative to GnRH analogues for
improving in vitro fertilization (IVF) practices [
can be used in two ways: whether it be endogenously
(as in the luteal-phase stimulation) or exogenously (as
in the use of P in the follicular phase) [
ovarian stimulation (PPOS) protocols have been
confirmed to effectively block the rise of luteinizing
hormone (LH) and demonstrate a comparable pregnancy
outcome to that of classical protocols for infertile
women with normal ovarian reserve and polycystic
ovarian syndrome [
1, 2, 4–7
]. However, the potential
usefulness of PPOS protocols in clinical practice needs
to be determined, for example, there is a lack of
relevant data regarding its efficacy in poor responders.
Several reports confirm that poor responders cannot
benefit from increasing gonadotropin doses; thus, natural
cycle IVF or minimal stimulation is a patient-friendly
option, especially for patients with low antral follicle counts
]. Natural cycle IVF faces the problems of untimely
premature ovulation and individualized schedules for
oocyte retrieval [
]. Although a modified natural cycle
with a GnRH antagonist at the mid-late follicular phase
has lowered the occurrenceof premature ovulation, this
problem has still not been completely resolved [
8, 10, 12
Oral P has been demonstrated to effectively block LH
rise and premature ovulation in controlled ovarian
]. Therefore, we explored the role of P in
blocking premature ovulation in minimal stimulation
for poor responders.
The goal of P-primed minimal stimulation is to
develop a single dominant follicle in the P-primed status,
and a low dose of hMG is administered at the late
follicular phase to avoid possible suppression by P. To
explore follicular phase dynamic changes in the P-primed
status, natural cycle IVF was used as a blank control to
compare follicle growth dynamics with or without
Pprimed minimal stimulation.Therefore, a prospective
controlled study was performed to investigate the
follicular and endocrinological characteristics of P-primed
minimal stimulation in poor responders.
A prospective cohort study was conducted at the
Department of Assisted Reproduction of the Ninth
People’s Hospital of Shanghai Jiaotong University School
of Medicine. Women undergoing IVF/intracytoplasmic
sperm injection (ICSI) regimens for the treatment of
infertility were recruited between January 2014 and
December 2014. The study protocol was approved by
the Ethics Committee (Institutional Review Board) of
the Ninth People’s Hospital of Shanghai and registered
with the Chinese Clinical Trial Registry
(ChiCTROCH-14004176). The trial was conducted according to
the Declaration of Helsinki for medical research. All
participants provided informed consent after
undergoing counselling for infertility treatments and routine
Patients planning to undergo IVF/ICSI treatments
were screened for eligibility by transvaginal ultrasound
and serum hormone testing on menstrual cycle day 3.
Participants met the following criteria: 1) aged 25–
45 years; 2) spontaneous menstrual cycle (21–35 days
in duration); and 3) bilateral antral follicle counts
(AFC) <5 on menstrual cycle day 3 and a basal serum
follicle-stimulating hormone (FSH) concentration
between 10 and 30 mIU/ml. We excluded cases with
higher basal oestradiol (E2) levels (E2 > 70 pg/ml) or
ovarian functional cysts on menstrual cycle day 3
because the higher basal E2 values would potentially
interfere with the ability of P to suppress pituitary
Patients were recruited consecutively and assigned to
one of two groups, namely, the medroxyprogesterone
acetate (MPA) group or the natural cycle group, in an
alternating manner. Odd-number-assigned patients were
allocated to the MPA group, and even-number-assigned
patients were allocated to the natural cycle group. Each
woman completed only one cycle in this trial.
Sample size estimate
For the power calculation, previous studies reported that
17% of oocyte retrievals were cancelled due to a
premature LH surge or ovulation in natural cycle IVF patients
]. Because there were no relevant data regarding the
efficacy of MPA in poor responders, we hypothesized
that the administration of MPA would decrease the
incidence of premature LH surges and ovulation to 8%;
therefore,the superiority margin was set at 8%. A
sample size of 97 in each group would yield 90.0%
power to establish superiorityat the 0.01 level of
significance. Assuming a drop-out rate of approximately 5%,
the number of participants needed was 102 subjects in
each group in this trial.
Natural cycle IVF
In the natural cycle group, oocyte pick-up (OPU) was
performed within a pure natural cycle that excluded any
hormonal stimulation except for GnRH agonist (GnRHa)
administration for ovulation induction. Ultrasound
monitoring began on cycle day 7 until the dominant
follicle presented. When the follicle reached a diameter
of 13 mm or greater and the E2 exceeded 150 pg/ml,
patients were monitored every day or every other day.
When the dominant follicle reached 18 mm in diameter,
in the absence of a LH rise, the final stage of oocyte
maturation was induced around midnight with 100
μgof triptorelin (Decapeptyl, Ferring GmbH, Germany).
A nonsteroidal anti-inflammatory drug, ibuprofen
(0.6 g), was used on the trigger day and the following
day.Transvaginal ultrasound-guided oocyte retrieval
was scheduled 32-36 h later. For cases with a mature
follicle and the occurrence of a spontaneous LH surge
(LH >20 mIU/ml), GnRHa was not administered, and
only ibuprofen was used. Oocyte retrieval was arranged
18-30 h later, according to the presumed stage of the
spontaneous LH surge on the scheduled day [
MPA(10 mg) was administered daily from menstrual cycle
day 3 onwards. After 5 days, transvaginal ultrasonography
and serum hormone measurements were performed every
2–4 days.When the follicle began to grow, the E2 level
increased, and FSH significantly decreased to ≤8.0 mIU/ml,
a low dose of hMG(75-150 IU/d) was administered to
promote late follicular development. When the
dominant follicle reached a diameter of 18 mm, the final stage
of oocyte maturation was stimulated with triptorelin
(100 μg) and hCG (1000 IU). Oocyte retrieval was
performed 34-36 h later. The co-trigger method was based
on our previous studies [
In vitro fertilization and embryo culture
Before oocyte retrieval, the presence of a dominant
follicle was confirmed by transvaginal ultrasound. If the
dominant follicle disappeared, it was assumed that
premature ovulation had occurred before the scheduled
time. Oocyte retrieval was performed without sedation
or local anaesthesia with a double-lumen aspiration
needle. The follicle was flushed three times at most if
no cumulus cell oocyte complexes (COC) were present.
All follicles >10 mm in diameter were retrieved. If an
oocyte was obtained, standard insemination or ICSI
was performed within 6 h of retrieval. Embryos were
examined for the number and regularity of the
blastomeres and the degree of embryonic fragmentation. All
top-quality embryos (including grade I and grade II
8cell blastomere embryos) were frozen by vitrification on
the third day following oocyte retrieval. The
non-topquality embryos were placed in extended culture, and
only blastocysts with good morphology were frozen on
day 5 or day 6. The cryopreservation procedure has
been described previously [
]. Hormone replacement
treatment was recommended for endometrial
preparation. Briefly, ethiny estrogen (25 μg tid) was
administered for 14 days, and the treatment was then shifted to
oral progesterone (4 femoston yellow tablets daily,
including 8 mg oestradiol and 40 mg dydrogesterone)
and soft vaginal progesterone capsules (200 mg bid).
Day-3 embryo transfer was arranged three days later.
Blastocyst transfers were performed on the fifth day.
Once pregnancy was achieved, exogenous oestrogen
and progesterone supplements were continued until
10 weeks of gestation.
Serum FSH, LH, E2 and progesterone levels were collected
on cycle day 3, cycle days 8–10, the trigger day and the
following day (approximately 10 h after the trigger). In the
natural cycle group, multiple hormone measurements
were obtained during the late follicular phase. Hormone
levels were measured by chemiluminescence (Abbott
Biologicals B.V., The Netherlands). The lower limits of
sensitivity were as follows: FSH = 0.06 mIU/ml,
LH = 0.09 mIU/ml, E2 = 10 pg/ml and P = 0.1 ng/ml.
The primary measurement in this study was the
incidence of spontaneous LH surge and premature
ovulation.The secondary measurement included the dynamic
characteristics of the steroid hormone profiles, the
number of retrieved oocytes and the number of viable
embryos. Spontaneous LH surge was defined as LH > 20
mIU/ml during minimal stimulation. Premature LH
surge was defined as LH >20 mIU/ml when the
dominant follicle was <15 mm in diameter. Premature
ovulation was defined as a follicle rupture before the
Efficacy analysis was based on the intention-to-treat
(ITT) population. Analyses of the primary and secondary
endpoints were carried out for each initiating cycle.
Student’s t-test and the Man-Whitney U-test were used
for normal and non-normal distributions,
respectively.The Kruskal-Wallis test was used for comparison of
hormone profiles, and the chi-square test was used for
binary variable comparisons. A P-value <0.05 indicated
statistical significance. All data were analysed using the
Statistical Package for the Social Sciences for Windows
(SPSS, Version 16.0, SPSS Inc., Chicago, IL, USA).
Basic patient characteristics
A total of 204 women were enrolled and allocated to
either the natural cycle or MPA group according to the
study protocol. In the MPA group, the average age was
37.3 ± 4.7 years, the basal FSH was 13.3 ± 5.8 mIU/ml,
and the AFC was 2.2 ± 1.4. A total of 77.4% (79/102) of
the women had previously undergone unsuccessful IVF/
ICSI attempts, including 34 women who had failed at
least 3 times.There were no statistically significant
differences in the basic characteristics between the MPA and
control groups (Table 1).
Dynamic characteristics of thehormone concentrations
In the natural cycle control group, the growth of one or
two dominant follicles was accompanied by a gradual
increase of E2 levels in 101 cases, except for one case in
which there was no follicle growth. Serum FSH values
decreased slightly during the follicular phase, and LH
values demonstrated a gradual increasing trend; 50% of
all cases (51/102) presented a spontaneous LH surge
(>20 mIU/ml), with an average LH peak value of
35.1 ± 16.0 mIU/ml, and the patients underwent oocyte
retrieval after 18-30 h based on the presumed stage of
ovulation.The remaining 50 cases in the natural cycle
group did not exhibit spontaneous LH surges, their
mean LH level on the trigger day was 9.27 ± 4.52 mIU/
ml, which was close to the onset of the LH surge. These
patients were triggered and oocyte retrieval was
completed 32-36 h later. Therefore, based on the diagrams
of the hormone profiles, the natural cycle group was
divided into two subgroups: a spontaneous LH surge and
an induced LH surge (Fig. 1). In Fig. 1, the LH surge
day is denoted day 0, and the trigger day is denoted
LH-1. In the subgroup of the natural cycle women with
a spontaneous LH surge, E2 values reached a peak one
day before the LH surge. In the subgroup of the natural
cycle women with an induced LH surge, the E2 values
continued to increase after the trigger.
In the MPA group, the dominant follicle continued to
grow in 101 cases, except for one case with no developing
follicle. Serum FSH levels during the later follicular phases
(LH surge day-3, day −1 and day 0) were higher than those
in the natural cycle group (P < 0.05). The mean LH value
on the trigger day was 4.75 ± 2.36 mIU/ml and the
median value was 4.11mIU/ml. The incidences of
spontaneous LH surges were lower in the MPA group than in the
natural control group (1.0% vs 50.0%, P < 0.05). Serum LH
values in the later follicular phases were significantly lower
in the MPA group than in the natural control group
(P < 0.05). The observed trend in LH level changes during
the follicular phase was either stable or slightly increasing,
and the ratio of the LH value on the trigger day to the
basal LH level was significantly lower in the MPA group
than in the control group (P < 0.01).
E2 levels demonstrated an increasing trend in the
MPA group. Peak E2 values in the MPA group were
significantly higher than the values in the natural cycle
group (403.88 ± 167.16 pg/ml vs 265.26 ± 122.16 pg/ml,
P < 0.05). Progesterone levels were consistently in the
lower range during the follicular phase in both groups;
however, progesterone values in the MPA group were
slightly higher after the trigger (P < 0.05).
Follicular dynamics during P-primed minimal stimulation
Compared with the natural cycle group, the duration of
the follicular phase in the MPA group was one day
longer (13.6 ± 3.6 days vs. 12.3 ± 3.2 days, P < 0.05).The
numbers of pre-ovulatory follicles were comparable
(1.2 ± 0.5 vs. 1.0 ± 0.3, P > 0.05), and the average diameter
of the pre-ovulatory follicle on the trigger day was larger
(18.7 ± 1.8 mm vs. 17.2 ± 2.2 mm, P < 0.05). Additional
evidence of controlled ovulation was the interval between
the trigger and oocyte retrieval in the MPA group, which
remained steady (35.4 ± 0.6 h). In the natural cycle group,
the interval depended on the hormone profile and
expected ovulation time; thus, the oocyte retrieval timing
varied from 18 to 36 h after spontaneous or induced LH
surge. Although multiple treatments were administered
in the natural cycle control group (using nonsteroidal
anti-inflammatory drugs and advanced oocyte retrieval),
the incidences of premature ovulation were significantly
higher in the natural cycle group than in the MPA group
(10.8% vs 2.0%, P < 0.05).
Association between serum LH level and pre-ovulatory follicle diameter
Correlations between the maximum diameter of the
follicle and serum hormones (FSH, LH, E2 and
progesterone values) on the trigger day or
spontaneous-LHsurge day in the two groups are shown in Fig. 2. Briefly,
8.8% (9/102) of the cases in the natural cycle group had
smaller dominant follicles with premature LH surges
(the diameter of the pre-ovulatory follicles < 15 mm),
indicating that poor responders tend to ovulate with
a smaller mean follicle diameter in the natural cycle.
In contrast, no events of small pre-ovulatory follicles
and premature LH surges occurred in the MPA group
(P < 0.05), which is further evidence of well-controlled
ovulation of the dominant follicle using P-primed
Table 2 displays the cycle characteristics of the two
regimens. A total of 77 oocytes were retrieved from 73 women
in the natural cycle group, whereas 103 oocytes were
retrieved from 87 women in the MPA group. The mean
MPA duration was 9.2 ± 2.3 days, and the hMG duration
was 2.9 ± 2.0 days.The mean hMG dose administered to
the MPA group was 357.49 ± 272.4 IU. The numbers of
oocytes retrieved, metaphase II (MII) oocytes, fertilization
and viable embryos were significantly higher in the MPA
group than in the natural cycle group. However, no
between-group differences were observed in the
proportion of mature oocytes (88.9% vs. 84.4%), fertilization rate
(76.2% vs. 69.0%) and cleavage rate (96.1% vs. 98.0%)
(P > 0.05).The number of viable embryos was significantly
higher in the MPA group than in the control group
(P < 0.05).The proportion of cycles with at least one viable
embryo in the MPA group was higher than that in the
natural cycle group, but this difference was not significant
(50.0% vs. 38.3%, P > 0.05).
Forty-two viable embryos in the natural cycle group
and 56 viable embryos in the MPA group were
cryopreserved for frozen embryo transfer (FET). The MPA group
demonstrated a slightly higher clinical pregnancy rate than
the natural cycle group, but this difference was not
significant due to the small sample size (11.8% (12/102) vs. 5.9%
(6/102), P < 0.05). The live birth rate was 8.3% (10/102) in
the MPA group and 3.9% (4/102) in the natural control
group (P > 0.05). The implantation rate was comparable
in the two groups, indicating that the administration of P
did not adversely affect the embryo developmental
potential in the poor responders (21.4% vs. 15.4%, P > 0.05).
In this trial, we prospectively compared the follicular
phase dynamics of P-primed minimal stimulation and
natural cycle IVF in poor responders.The results
indicated that ovulation of the dominant follicle in P-primed
minimal stimulation was well-controlled and facilitated
the IVF programme. IVF results demonstrated that the
MPA group produced more oocytes and embryos than
the control group, and the comparable pregnancy
outcome indicated that P did not adversely affect oocyte
quality. Therefore, P-priming is a promising approach
toward overcoming premature ovulation during minimal
stimulation for poor responders.
In this trial, we included participants with diminished
ovarian reserve (with high FSH values and AFC < 5) who
still had regular menstrual cycles.The criteria for this trial
were under the widely-used Bologna criteria, and a regular
cycle was listed as one of the inclusion criteria for it was
one of the prerequisites for performing natural cycle IVF.
These poor responders had small quantities of primordial
follicle pools and FSH-sensitive follicles, wherein the
follicles biologically “matured” quickly and were prone to
experience premature luteinization [
reproductive hormone profiles demonstrated higher FSH
levels in the early follicular phase, exaggerated
amplitudes, protracted LH durations, declined E2 and
progesterone levels and shared similarities with profiles
described during menopausal transition . These poor
responders provide a good model for investigating single
follicle development and ovulation using P treatment.
Natural cycle IVF is aimed at developing a naturally
mature follicle, and the timing of oocyte retrieval is
dependent on the spontaneous LH surge. A spontaneous
LH surge cannot be clearly predicted; therefore, follicle
monitoring was frequently performed in the late follicular
phase, and 50% of the cases presented with a spontaneous
LH surge. Oocyte retrieval was arranged according to
the presumed stage of spontaneous ovulation [
remaining patients did not present spontaneous LH surges
until the follicle reached a diameter of 18 mm, we then
triggered and arranged oocyte retrieval, as is routinely
performed. Thus, half of the cases demonstrated a
spontaneous LH surge in the natural control group. The process
of waiting for follicles to mature gave us a good
opportunity to distinguish the changes incurred by MPA.
In this trial, ovulation of the dominant follicle in the
MPA group was controlled, as indicated by the following
evidence: a single large follicle developed, spontaneous
LH surge was prevented (1.0%), and ovulation and
luteinization rarely occurred unless a GnRHa/HCG bolus
was administered. Moreover, P-priming prolonged the
follicular phase by one more day, and the diameter of
the pre-ovulatory follicle was larger than that of the
natural cycle patients.These data indicated that MPA
treatment significantly suppressed follicular rupture,
which undoubtedly postponed hCG administration with
less concern for the development of a premature LH
surge. This treatment enabled most of the oocytes to
achieve greater maturity before aspiration. Thus,
Pprimed minimal stimulation provides a wide window
for oocyte retrieval.
The normal mechanism of follicle rupture may be
disturbed by continuous exogenous administration of P
], which may be due to at least two factors. First,
P-priming during the follicular phase prevents the
occurrence of the GnRH surge even when the quantity of
oestradiol administration is well above that needed for
surge induction [
]. P-priming slows the LH pulse
frequency, augments the pulse amplitude and reduces
the mean plasma LH levels compared with those in
untreated women [
]. In this trial, the decreased LH
values and low incidences of spontaneous LH surges in
the MPA group are signs of the hypophyseal suppression
that is induced by exogenous P or the combined action
of oestradiol and P. Second, the continuous
administration of P may directly interfere with a follicle’s
spontaneous rupture by modulating the progesterone receptor
(PR). In PR-null mice, the follicles mature to the
preovulatory stage in response to exogenous gonadotropins;
however, in the absence of PR signalling, they fail to
rupture and release oocytes [
].Ulipristal acetate, which is
a progesterone receptor modulator, blocks ovulation by
inhibiting PR-dependent pathways that are intrinsic to
the ovary when administered within a critical time
window following the LH surge (<6 h) [
Most studies demonstrate that follicular development
continues during treatment with hormonal
contraceptives because the P contained in most combined oral
contraceptives has a low influence on FSH secretion
]. In this trial, the patients had higher basal FSH
levels and follicular-phase FSH values were maintained
near the physiological range (5–10 mIU/ml) [
cases demonstrated that follicular growth continued
after the daily administration of 10 mg MPA. The
possibility of P-mediated inhibition of dominant follicle
development has been reported in animal models [
hMG was administered during the late follicular phase to
avoid regression of the dominant follicle.
In this trial, the oocyte/embryo results reflected the
efficacy of the different treatment strategy.Oocyte retrieval
in natural cycle is individualized based on the
occurrence of a spontaneous LH surge; therefore, frequent
monitoring and a 7-day-per-week working schedule are
unavoidable for natural cycle IVF. A large studyof 1048
patients who underwent modified natural-cycle IVF
demonstrated a 66% oocyte retrieval rate per scheduled
retrieval and confirmed that the use of GnRH
antagonists did not substantially improve the outcome [
trial demonstrated an efficacy of 71.57% for the retrieval
rate and 38.24% for the embryo transfer rate in natural
cycle IVF patients, which is in accordance with previous
]; the MPA group demonstrated superior
oocyte and embryo outcomes. Notably, the higher
number of retrieved oocytes and embryos may be associated
with the administration of hMG during the late follicular
phase of the MPA treatment. However, the rate of
successfully retrieved, mature oocytes and cleaved
embryos was comparable between the two groups, and the
embryonic developmental potential was approved by
the slightly better or similar clinical pregnancy rate and
live birth rate.These data suggest that P-priming does
not adversely affect oocyte quality. Another retrospective
trial of 993 cycles of P-primed mild stimulation in
our clinic demonstrated no adverse effects of P on
the embryo developmental potential in poor responders
One limitation of this trial is its quasi-randomized
nature. Some potential confounding factors could not be
excluded due to the alternating group assignments. The
sample size was designed to have sufficient power to
distinguish the difference in the presence of LH surge;
however, it was underpowered for comparisons of pregnancy
outcomes.Therefore, our trial focused on a detailed
observation of follicular dynamics and endocrinological profiles.
Thus, the results of the embryos and pregnancy outcomes
should be interpreted with caution.
In poor responders undergoing P-priming minimal
stimulation, the follicle continuously grows and appears more
robust, and spontaneous LH surges and premature
ovulation are inhibited. Oocyte quality is not adversely affected
by continuous administration of P. This treatment
provides a novel insight into the prevention of premature
ovulation and improvement in the IVF programme for
poor responders, although questions regarding possible
effects on the embryo developmental potential remain to
be investigated. A well-designed randomized controlled
trial should be performed to compare the efficacy of P
and GnRH antagonists in preventing premature
ovulation in poor responders.
AFC: Antral follicle count; AMH: Anti-Mullerian hormone.; FET: Frozen
embryo transfer; FSH: Follicle-stimulating hormone; ICSI: Intracytoplasmic
sperm injection; IVF: In vitro fertilization; LH: Luteinizing hormone;
MPA: Medroxyprogesterone acetate; P: Progestin
We thank the entire staff of the Department of Assisted Reproduction in
Shanghai Ninth People’s Hospital for their support in this trial.
This study was funded by the National Nature Science Foundation
of China (grant numbers: 81671520, 81571397 and 31101070), the
Natural Science Foundation of Shanghai (grant numbers: 14411964300,
15411953000, 15411964500, 15ZR1424900 and 16411963800) and the
Merckserono China Research Fund for Fertility Experts.
Availability of data and materials
Data are not publicly shared; please contact the authors for data requests.
Professor YK and Dr. QC supervised the entire study, including procedures,
conception, design and completion. Dr. YW, Dr. WC, Dr. QH, Dr. SZ, Dr. QL,
Dr. LW and Dr. HL were responsible for the collection of data. Dr. QC
contributed to the analysis of data and drafted the manuscript. 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: 2013–46).
Consent for publication
All patients have provided their consent for the data to be used for
research and publications.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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