Archives of Gynecology and Obstetrics

https://doi.org/10.1007/s00404-018-4856-8

GYNECOLOGIC ENDOCRINOLOGY AND REPRODUCTIVE MEDICINE

New trial of progestin‑primed ovarian stimulation using

dydrogesterone versus a typical GnRH antagonist regimen in assisted
reproductive technology
Nanako Iwami1 · Miho Kawamata1 · Naoko Ozawa1 · Takahiro Yamamoto1 · Eri Watanabe1 · Osamu Moriwaka1 ·
Hirobumi Kamiya1

Received: 1 March 2018 / Accepted: 28 July 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose To compare the clinical and ongoing pregnancy rates between a protocol using oral dydrogesterone with human
menopausal gonadotropin (HMG) for progestin-primed ovarian stimulation (PPOS) and the typical gonadotropin-releasing
hormone (GnRH) antagonist regimen in women undergoing controlled ovarian hyperstimulation (COH).
Methods This was a prospective, controlled study of 251 women who underwent COH for in vitro fertilization between
October 2016 and July 2017. The patients were allocated alternately into two groups: a dydrogesterone protocol (study group)
and a GnRH antagonist protocol (control group). In study group, dydrogesterone (20 mg/day) plus HMG (150 or 225 IU)
were administered simultaneously beginning on days 2 or 3 of the menstrual cycle. In both groups, all high-quality embryos
were cryopreserved for later transfer. The primary outcome was the ongoing pregnancy rate at 12 weeks per frozen–thawed
embryo transfer (FET) and the secondary outcome was the clinical pregnancy rate.
Results None of the patients experienced a premature luteinizing hormone surge. During the follow-up period, 397 FET
cycles were completed. The ongoing pregnancy rates at 12 weeks were 40.0% in study group versus 38.1% in control group
(absolute difference 1.9%; 95% CI − 6.83 to 17.2%). The clinical pregnancy rate in study group (52.8%) was also not inferior
to that in control group (49.5%; absolute difference 3.3%; 95% CI − 4.02 to 20.2%).
Conclusions The clinical and ongoing pregnancy rates in study group were comparable to those in control group. Therefore,
PPOS with dydrogesterone is a reasonable option to provide COH.

Keywords Dydrogesterone · Progestin-primed ovarian stimulation · Premature LH surge · GnRH antagonist · Controlled
ovarian stimulation

Abbreviations hCG Human chorionic gonadotropin

AMH Anti-Müllerian hormone HMG Human menopausal gonadotropin
ART​ Assisted reproductive technology HRT Hormone replacement therapy
BMI Body mass index IVF In vitro fertilization
CI Confidence interval ICSI Intra-cytoplasmic sperm injection
COCs Cumulus–oocyte complexes LH Luteinizing hormone
COH Controlled ovarian hyperstimulation OHSS Ovarian hyperstimulation syndrome
E2 Estradiol 2 P4 Progesterone
FET Frozen embryo transfer PPOS Progestin-primed ovarian stimulation
GnRH Gonadotropin-releasing hormone SD Standard deviation
USD United States dollar

* Nanako Iwami
[email protected]
1
Department of Reproductive Health, Kamiya Ladies Clinic,
Nittsu Bldg 2nd Floor 2‑1, Nishi 2chome, Kita 3jo, Chuo‑ku,
Sapporo, Hokkaido 060‑0003, Japan

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Introduction [14–16]. The oral route of administration of dydrogester-

one is thought to be a more patient-friendly regimen that
During controlled ovarian hyperstimulation (COH), sup- might improve compliance with treatment. Therefore, here
pressing the premature luteinizing hormone (LH) surge is we compared the clinical and ongoing pregnancy rates for
important for good outcomes in assisted reproductive tech- a COH protocol using oral dydrogesterone plus HMG
nology (ART). The protocols for COH generally use gon- (study group) with a standard GnRH antagonist protocol
adotropin-releasing hormone (GnRH) agonists and antago- (control group).
nists to prevent an endogenous LH surge from occurring
before follicular maturation [1]. The most recommended
protocols for COH are the use of a GnRH antagonist pro- Materials and methods
tocol, a GnRH agonist trigger, and freezing all embryos
with later transfer to prevent ovarian hyperstimulation Study setting and allocation of patients
syndrome (OHSS) [2]. GnRH antagonists are effective
for rapid and reversible suppression of LH release. There- This prospective, controlled study was conducted at a pri-
fore, using a GnRH agonist trigger for the final oocyte vate infertility clinic between October 2016 and July 2017,
maturation can prevent severe OHSS [3]. However, the and was performed in accordance with the Declaration
conventional GnRH antagonist protocol is expensive and of Helsinki for medical research and Good Clinical Prac-
some patients experience a premature LH surge, result- tice guidelines. The study protocol was also approved by
ing in undesired ovulation [4]. If an LH surge occurs and the Ethics Committee of the Institutional Review Board
some follicles ovulate before oocyte retrieval, the cycle of the clinic. Written informed consent was obtained
cancellation rate rises. Therefore, new protocols need to from all of the enrolled patients. This trial has been reg-
be established with improved efficacy and for the patients’ istered with the UMIN Clinical Trial Registry in Japan
convenience to effectively prevent a premature LH surge. (R000033778UMIN000029564).
The previous studies have demonstrated that the admin- Inclusion criteria were as follows: age younger than
istration of several progestins during COH can effectively 41 years, anti-Müllerian hormone (AMH) levels greater
suppress a premature LH surge [5–8]. Progesterone (P4), than 1.00 ng/ml, and first or second cycle of IVF or intra-
which is secreted by the corpus luteum, strongly inhibits cytoplasmic sperm injection (ICSI) at the Kamiya Ladies
pulsatile GnRH and LH secretion, and prevents estradiol Clinic. Patients who had endometriosis grade 3 or higher,
(E2)-induced positive feedback effects during the luteal documented cycles with no oocyte retrieved, and any con-
phase. High baseline P4 levels in COH have no negative traindications for COH were excluded.
effect on oocyte/embryo quality [9, 10]. In the last dec- Patients were allocated consecutively to one of two COH
ades, when IVF relied on fresh embryo transfer, high P4 groups in an alternating fashion. Odd-numbered patients
levels on the day of trigger had a negative effect on endo- were allocated to study group and even-numbered patients
metrial receptivity. Currently, superior quality of cryo- were assigned to control group in a non-blinded fashion. A
preserved embryos and precise thawing are possible by total of 251 women were enrolled in the study, comprising
advanced vitrification techniques, and in vitro fertilization 125 in study group and 126 in control group.
(IVF) no longer requires the transfer of fresh embryos. The
“freeze-all” strategy can increase cumulative pregnancy
rates, and decrease multiple pregnancy rates, ectopic preg-
nancy rates, and the risk of OHSS [11, 12]. Study protocol
Only a few studies have reported the efficacy of a com-
bination of dydrogesterone and human menopausal gon- Controlled ovarian hyperstimulation
adotropin (HMG) for progestin-primed ovarian stimula-
tion (PPOS) in IVF cycles [8, 13]. Dydrogesterone is a In study group, patients were administered HMG ­(Teizo®,
synthetic progestin that is closely related to endogenous 150 or 225 IU; ASKA Pharmaceutical Co., Ltd., Tokyo,
P4 in its molecular structure and its pharmacological Japan) and dydrogesterone ­(Duphaston®, 20 mg; Abbott
effects. Moreover, dydrogesterone does not interfere with Healthcare, Tokyo, Japan) daily from days 2 or 3 of the
the measurement of endogenous P4 production. Dydro- menstrual cycle onward, following ultrasound confirmation
gesterone has less androgenic activity and enhanced oral of the absence of follicles larger than 10 mm. The initiat-
bioavailability (28%) compared with other progestins, with ing dose of 150 IU/day HMG was used for patients with
a half-life of 8 h, and it is highly selective for the P4 recep- an AMH level greater than 3.00 ng/ml or an antral follicle
tor and has fewer adverse effects than other progestins count > 15. A dose of 225 IU/day HMG was used for other
patients.

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Archives of Gynecology and Obstetrics

In control group, patients were administered HMG (150 12–14 in patients undergoing a HRT cycle, and progestin
or 225 IU per day) on days 2 or 3 of the menstrual cycle. capsules (500 mg P4 vaginal suppositories) and oral proges-
The choice of the initial HMG dose was decided in the same tin ­(Duphaston®; 30 mg dydrogesterone) were administered
manner as for study group. When either the leading folli- daily in patients with an endometrial thickness > 7 mm. The
cle reached 14 mm or serum E2 levels exceeded 1000 pg/ transfer of day 3 embryos or blastocyst was scheduled based
ml, a GnRH antagonist ­(Ganirelix® 0.25 mg; MSD, Tokyo, on embryo and endometrium synchronization. Once preg-
Japan or C­ etrotide® 0.25 mg; EMD-Serono, Tokyo, Japan) nancy was achieved (see below), the exogenous estrogen and
was administered by subcutaneous injection every 24 h to progestin supplementation were continued until 10 weeks
suppress premature LH surges following a flexible protocol. of gestation.
In both groups, follicular monitoring using ultrasonogra- The primary outcome was defined as the ongoing preg-
phy started on day 8 of the menstrual cycle. This monitor- nancy rate per FET cycle. The secondary outcomes were the
ing was performed every 2 or 3 days, and a blood sample numbers of cumulus–oocyte complexes (COCs) retrieved
was taken at every visit to check serum follicle-stimulating per COH cycle, the fertilization rate, the numbers of viable
hormone, LH, E2, and P4 concentrations. The HMG dose embryos, the clinical pregnancy rate, and the early miscar-
was increased by 75 IU when the speed of follicle growth riage rate. Clinical pregnancy was defined as the presence
was assessed as slow. When the main dominant follicle size of gestational sacs during an ultrasound examination up
was close to 20 mm in diameter, the final stage of oocyte to 7 weeks of gestation. Ongoing pregnancy was defined
maturation was triggered using a nasal spray of GnRH ago- as continuous fetal heartbeats as assessed by ultrasound at
nist ­(Buserecur®; Fuji Pharma, Tokyo, Japan). Patients were 12 weeks. The early miscarriage rate was defined as the pro-
given a low dose of human chorionic gonadotropin (hCG; portion of pregnancies arresting before 12 weeks of gesta-
­Gonatropin® 1000 IU; ASKA Pharmaceutical Co., Ltd. or tion. Cycle cancellation refers to patients who completed
hCG ­F® 2500 IU; Fuji Pharma) added as a co-trigger for oocyte retrieval without producing viable embryos.
ovulation only for those with hypothalamic–pituitary insuf-
ficiency or those with poor COH responses in the previ-
ous ART cycles. Patients who received the final trigger Statistical analysis
underwent transvaginal ultrasound-guided oocyte retrieval
35–37 h later. All follicles with diameters larger than 10 mm According to the previous reports, the ongoing pregnancy
were aspirated. rate of GnRH antagonist protocol was assumed to be
Insemination of the aspirated oocytes was carried out 27–30% [3]. Therefore, control group was assumed to have
in vitro, by either conventional insemination or ICSI, a pregnancy rate of 30%. Study group was expected to have
depending on the partner’s semen parameters. Embryos were a pregnancy rate of ~ 40%. One hundred two patients per
examined for the number and regularity of blastomeres and group were required to achieve at least 85% probability that
the degree of embryonic fragmentation to assess quality on the lower limit of the Wald 95% confidence interval (CI) for
the 2nd or 3rd day of culture, according to published crite- the difference of pregnancy rates exceeded − 10% (a non-
ria [17]. One or two good quality embryos were frozen by inferiority margin of 10%). Given the possibility of a 10%
vitrification on the 2nd or 3rd day after oocyte retrieval. dropout rate, we designed the study to include a total of 110
The other embryos were placed in extended culture until women in each group.
they reached the blastocyst stage. At this point, only blas- Data are shown as the mean ± standard deviation (SD).
tocysts with good morphology were frozen on days 5–7. Statistical analysis was performed using StatFlex version 6.0
Any instance of OHSS was defined according to a published (Artech Co., Ltd., Osaka, Japan). The results were compared
classification system [18]. between the two groups using the Chi squared test, unpaired
Student’s t test, or the Mann–Whitney nonparametric U test.
Endometrial preparation and frozen–thawed P < 0.05 was considered statistically significant. The primary
embryo transfer (FET) outcome analysis used a one-sided 95% CI with a non-infe-
riority margin of 10% for the difference in pregnancy rates
The method of endometrial preparation was similar in both between the two groups. The dydrogesterone protocol was
groups. A hormone replacement therapy (HRT) cycle was declared non-inferior if the lower boundary of the 95% CI
performed for all of the patients. They received dermal was less than 10% below that of the control. This margin was
patches of 1.44 mg estradiol every other day ­(Estrana®; defined based on historical evidence of the active compara-
Hisamitsu Pharmaceutical Co., Ltd., Tokyo, Japan) and tor (a well-established standard treatment). In clinical trials,
oral estradiol valerate 2.00 mg × 2 ­(Progynova®; Bayer, given patient and treatment variability, a new treatment that
NSW, Australia) from days 2 or 3 of the menstrual cycle. performs within 10–20% of an old treatment is often the
The endometrial thickness was checked on cycle days margin that used to be called non-inferior [19–21].

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Results completed oocyte retrieval and 397 completed FET cycles.

Figure 1 shows an outline of this study.
Patients’ characteristics
Ovarian stimulation, follicular development, oocyte
Table 1 shows the patients’ characteristics, including performance, and hormonal profile
age, body mass index, basal hormone profile, duration of
infertility, and the indications for IVF/ICSI treatment. We The mean numbers of retrieved COCs (10.71 ± 6.56) and
treated couples with tubal infertility, endometrial infer- meiosis stage II (MII) oocytes (8.53 ± 5.39) in study group
tility, male infertility, and idiopathic infertility. There were similar to those of control group (8.71 ± 4.27 and
were no significant differences in the incidences of these 11.10 ± 5.19, respectively). Six patients in study group and
variables between the two groups. A total of 251 women five in control group had either unfertilized oocytes or
poor-quality embryos. Table 2 shows the clinical and cycle
outcomes of COH treatment in both groups. The duration

Table 1  Basic characteristics Characteristic Study group (dydrogester- Control group (GnRH antago- P value
of the patients undergoing IVF/ one protocol n = 125) nist protocol, n = 126)
ICSI treatment
Age (years) 34.81 ± 3.49 34.21 ± 3.73 0.1883
AMH (ng/ml) 4.05 ± 2.12 4.48 ± 2.17 0.1140
BMI (kg/m2) 21.75 ± 2.64 21.60 ± 2.46 0.6445
Duration of infertility (months) 35.32 ± 25.20 38.17 ± 31.05 0.4261
Primary infertility, n (%) 101 (83.4) 103 (85.1) 0.8477
IVF count, n 1.24 ± 0.43 1.21 ± 0.41 0.5239
AFC 9.50 ± 5.24 9.54 ± 5.59 0.9546
Indication of ART, n (%)
Male factor 27 (18.6) 36 (23.4) 0.2028
Tubal factor 13 (9.0) 18 (11.7) 0.3495
Endometriosis 9 (6.2) 16 (10.4) 0.2136

AMH Anti-Mullerian hormone, BMI body mass index, ART​ assisted reproductive technology, IVF in vitro
fertilization, ICSI intra-cytoplasmic sperm injection, AFC antral follicle counts, SD standard deviation,
GnRH gonadotropin-releasing hormone

Fig. 1  Flowchart of patient

selection and treatment

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Table 2  Outcomes of ovarian Characteristics Study group (dydro- Control group (GnRH P value
hyperstimulation and hormonal gesterone protocol) antagonist protocol)
data on the trigger day in two
regimens hMG doze (IU) 1957.30 ± 682.86 1519.84 ± 541.86 > 0.001
hMG duration (day) 14.74 ± 1.99 14.11 ± 1.73 0.0076
No. of > 10 mm follicles on the trigger day 14.01 ± 7.17 13.76 ± 6.40 0.7744
No. of COCs 10.71 ± 6.56 11.10 ± 5.14 0.5993
No. of MIIoocytes 8.53 ± 5.39 8.71 ± 4.27 0.3499
Mature oocyte rate (%) 79.6 (1066/1339) 78.2 (1080/1381) 0.3684
Fertilization rate (IVF) (%) 61.5 (198/322) 64.2 (183/285) 0.4891
Fertilization rate (ICSI) (%) 77.8 (579/744) 81.8 (650/795) 0.0542
Viable embryo rate (%) 65.5 (607/927) 68.1 (680/998) 0.2161
Cancellation rate (%) 2.5 (34/1339) 1.6 (22/1381) 0.1038
LH on the trigger day (mIU/ml, mean ± SD) 1.85 ± 1.37 2.74 ± 2.28 0.0003

Data are mean ± SD unless otherwise specified

SD Standard deviation, GnRH gonadotropin-releasing hormone, hMG human menopausal gonadotropin,
OHSS ovarian hyperstimulation syndrome, IVF in vitro fertilization, ICSI intra-cytoplasmic sperm injec-
tion, LH luteinizing hormone, COCs cumulus–oocyte-complexes, MII meiosis stage II

of HMG administration and HMG doses in study group in each group experienced moderate OHSS during the
were significantly greater than those in control group study period, both of them recovered within 7 days after
(both P < 0.001). No significant difference were found oocyte retrieval without any treatment. The rate of moder-
in the numbers of retrieved COCs, the oocyte maturation ate OHSS was similar between the groups. Thus, we could
rates, the fertilization rates, the cleavage rates, the viable control the incidence of OHSS using these COH protocols.
embryo production rates, or the cycle cancellation rates The mean LH value on the trigger day was significantly
between the two groups. The duration of restarting men- lower in study group than in control group (P < 0.001;
struation after oocyte retrieval was significantly shorter in Table 2). No incidence of an LH surge was found in either
study group than in control group (9.5 ± 2.2 days versus group. Although two patients in each group experienced
12.2 ± 2.7 days, respectively; P < 0.001; Fig. 2). Restarting premature partial ovulation, oocyte retrieval was possible
menstruation after oocyte retrieval early is favorable for for the remaining follicles.
preventing an early onset of OHSS. Although one patient

Fig. 2  Duration of restart-

ing menstruation after oocyte
retrieval

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 Archives of Gynecology and Obstetrics

Pregnancy outcomes in FET cycles group (absolute difference 1.9%; 95% CI − 6.83 to 17.2%).
The clinical pregnancy rate in study group (52.8%) was
During the 10 months of observation, 240 women in also not inferior to that in control group (49.5%; absolute
both groups completed a total of 397 FET cycles and 437 difference 3.3%; 95% CI − 4.02 to 20.2%). Therefore, non-
embryos were thawed. Among these FET cycles, single- inferiority of the dydrogesterone protocol versus the GnRH
embryo transfer was performed in 90.8% patients in both antagonist protocol was demonstrated, because the lower
groups. The mean number of embryos per FET cycle was boundary of the CI was closer to zero than − 10% (Fig. 3).
similar. The clinical pregnancy rate per transfer in study
group was slightly higher than in control group, but this did
not reach significance. These results indicated that embryos Discussion
in study group shared better development potential than did
those in control group (Table 3). This study showed that the PPOS protocol with dydroges-
The primary outcome of this study, the ongoing preg- terone was not inferior to the GnRH antagonist protocol for
nancy rate at 12 weeks of gestation was met, with the dydro- the primary outcome: the ongoing pregnancy rate. Similarly,
gesterone protocol demonstrating non-inferiority to the the results of the PPOS protocol with dydrogesterone for
GnRH antagonist protocol. The ongoing pregnancy rates at one secondary outcome—the clinical pregnancy rate—also
12 weeks were 40.0% in study group versus 38.1% in control showed non-inferiority compared with those of the GnRH

Table 3  Pregnancy outcomes Outcomes The study group (dydroges- Control group (GnRH P value
of frozen–thawed embryos terone protocol) antagonist protocol)
originating from two protocols
FET cycles (n) 195 202
Thawed embryos (n) 217 220
Transferred embryos (n) 1.11 1.08 0.3303
Endometrial thickness (mm) 9.54 ± 1.65 9.38 ± 1.69 0.3404
Pregnancy outcome of FET (%)
Biochemical pregnancy rate 19.0 (37/195) 13.9 (28/202)) 0.1687
Clinical pregnancy rate 52.8 (103/195) 49.5 (100/202) 0.5088
Early miscarriage rate 24.3 (25/103) 23.0 (102/100) 0.8312
Multiple pregnancy rate 2.9 (3/103) 2.0 (2/100) 0.9733
Ectopic pregnancy rate 0 (0/122) 0 (0/140) 1.000
Ongoing pregnancy rate 40.0 (78/195) 38.1 (77/202) 0.7001

Data are mean ± SD unless otherwise specified

SD Standard deviation, GnRH gonadotropin-releasing hormone, FET frozen–thawed embryo transfer

Fig. 3  Pregnancy status in both

groups. A non-inferiority mar-
gin of 10% was used, whereby
the dydrogesterone protocol
(study group) was judged to be
non-inferior if the lower bound-
ary of the 95% CI showed a dif-
ference of < 10% compared with
that for the GnRH antagonist
protocol (control group)

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Archives of Gynecology and Obstetrics

control group protocol. Several studies have already com- have been exposed to it in the uterus [14, 16, 31, 32]. This
pared the PPOS protocol with the typical short GnRH ago- compound is structurally and pharmacologically similar to
nist protocol and demonstrated that they are equivalent in the natural endogenous P4. Moreover, it has greater affinity
efficacy and safety [5–7]. In this study, single-embryo FET for P4 receptors than P4 itself. Therefore, it can be used in
was performed in most (90.8%) patients and the clinical lower doses than P4 to promote endometrial proliferation
and ongoing pregnancy rates were similar to the previous thanks to its better bioavailability and to the P4-like activ-
reports [5–8, 22]. Therefore, this study was considered a ity of its metabolites [14]. Dydrogesterone also appears to
high-quality comparative study. have no affinity for androgen, estrogen, glucocorticoid, or
A premature LH surge can compromise the yield of mineralocorticoid receptors [15]. In Japan, dydrogesterone
oocytes and reduce the pregnancy rate [23]. The previous is popular as an oral medicine for luteal support. However,
studies have shown that P4 when administered during the some reports have shown the efficacy of Utorogestan for
normal follicular phase reduces the LH pulse frequency, preventing a premature LH surge during COH [6, 22, 33].
amplifies LH pulse amplitude, and reduces mean plasma Utorogestan is approved only as a vaginal agent in Japan.
LH levels compared with those in untreated women [24]. This is why we chose oral dydrogesterone, which is a more
The previous studies in animal models have shown that P4 convenient form than vaginal Utorogestan, for this PPOS
can block the E2-induced GnRH/LH surge-generating sig- protocol of COH.
nal soon after the onset of signal transmission (immediately Based on the limited available data, high P4 levels have
after E2 removal), but not during the later stages of signal no negative effect on follicular maturation, fertilization, and
transmission (at the time of onset of the surge) [25–29]. In blastocyst formation [9, 10, 34]. Kuang et al. also reported
addition, exogenous P4 administration timing is critical in that more than 500 children born from luteal-phase ovar-
determining whether it will stimulate or block the LH surge ian stimulation with high P4 levels in COH did not have an
[25, 27, 28]. Zhu et al. reported that LH surge blockade increased risk of congenital malformations compared with
failed if Utrogestan administration was started when the early-phase stimulation [9]. We need to confirm the long-
diameter of multiple follicles was > 10 mm [22]. Kuang term safety of ovarian stimulation using the dydrogesterone
et al. also showed that the medroxyprogesterone acetate and plus HMG protocol for the offspring of these women.
HMG protocol should be used when basal E2 levels are no Using a GnRH agonist trigger for final maturation of
greater than 50–70 pg/ml in cycles for avoiding a premature oocytes is effective for preventing OHSS. In addition, the
LH surge [5]. Therefore, we modified the regimen using incidence of immature oocytes is reduced as a result of a
dydrogesterone from days 2 to 3 of the menstrual cycle. We GnRH agonist trigger [35]. This approach might enhance
decided on a dosage of dydrogesterone at 20 mg per day, as maturity of the oocyte nucleus and eventually increase the
reported by Kuang et al. [5, 30]. number of MII oocytes [36–38]. Therefore, we used a GnRH
In the current study, pituitary LH levels on the trigger agonist trigger as our basic protocol.
day were more strongly suppressed by daily oral dydroges- Cost analysis for the medicines used in this study showed
terone than by injection of a GnRH antagonist. This find- markedly lower costs for suppressing the premature LH
ing suggests that the hypothalamus and pituitary were more surge in study group compared with control group. In study
strongly suppressed in study group than in control group. group, the overall cost of the LH surge suppression was
This suppression might have resulted in a higher total HMG around 13.1 United States Dollars (USD) compared with
dose required, and earlier restarting of menstruation in study 189.6 USD in control group. Thus, study group achieved a
group than in control group. 93.0% cost reduction compared with control group.
No significant difference was found in the incidence of The dydrogesterone plus HMG protocol has the advan-
partial ovulation between study group (2/125) and control tage of oral administration and user convenience; it is less
group (2/126). In all four cases of partial ovulation, the LH painful and cheaper than GnRH antagonist protocols. How-
level on the triggering day did not rise, but leading follicle ever, a major limitation of this study is that the patients were
sizes were actually > 25 mm at retrieval. Partial ovulation not assigned to groups using randomization. We used alter-
can be caused by the sensitivity of ovaries and follicles to nating allocation to the two groups for this study, and this
mechanical stimulation, such as puncturing, suggesting that could not completely control for possible interfering factors.
partial ovulation was not associated with the protocol used. Therefore, fully validating this protocol for COH will need a
Dydrogesterone is an established oral retroprogesterone randomized, controlled trial. In addition, a larger sample is
that is approved for treatment of threatened and recurrent required to confirm the feasibility of this new regimen and
miscarriage, and infertility caused by luteal phase insuffi- to evaluate the outcomes for children arising from it.
ciency. It has been used extensively for a variety of indica- In conclusion, this prospective, controlled study showed
tions worldwide for an estimated 113 million women since that the dydrogesterone plus HMG protocol was not inferior
1960 (based on sales data). Approximately 20 million fetuses to the GnRH antagonist protocol in terms of the ongoing

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 Archives of Gynecology and Obstetrics

pregnancy rate. The PPOS protocol using dydrogesterone in in vitro fertilization cycles. Fertility Steril 102(1):99–102.
may help to avoid a premature LH surge and decrease the https​://doi.org/10.1016/j.fertn​stert​.2014.04.010
5. Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Sho-
incidence of OHSS while maintaining good pregnancy out- ham Z (2015) Medroxyprogesterone acetate is an effective oral
comes. Further research is required to confirm the feasibility alternative for preventing premature luteinizing hormone surges
of this regimen, such as the optimal dose of dydrogesterone, in women undergoing controlled ovarian hyperstimulation for
the method of triggering ovulation, and the long-term safety in vitro fertilization. Fertility Steril 104(1):62–70.e63. https​://
doi.org/10.1016/j.fertn​stert​.2015.03.022
of progestin used for ART. 6. Zhu X, Ye H, Fu Y (2016) The utrogestan and hMG protocol
in patients with polycystic ovarian syndrome undergoing con-
Acknowledgements The authors wish to thank Ms. Mika Matsuoka for trolled ovarian hyperstimulation during IVF/ICSI treatments.
data collection, and Ms. Nami Hirayama and Ms. Yumiko Kobayashi Medicine (Baltimore) 95(28):e4193. https​://doi.org/10.1097/
for statistical analysis (clinical staff in the Kamiya Ladies Clinic). We md.00000​00000​00419​3
also thank Dr. Shigeo Araki (Chief Director of the International Insti- 7. Wang Y, Chen Q, Wang N, Chen H, Lyu Q, Kuang Y (2016)
tute of Medical Technology IMT College) and Dr. Daiki Iwami (staff Controlled ovarian stimulation using medroxyprogester-
member of the Department of Renal and Genitourinary Surgery, Hok- one acetate and hMG in patients with polycystic ovary syn-
kaido University, Graduate School of Medicine) for proofreading the drome treated for IVF: a double-blind randomized crossover
manuscript, and Dr. Kota Ono (staff member of the Department of clinical trial. Medicine (Baltimore) 95(9):e2939. https​://doi.
Biostatistics, Hokkaido University, Graduate School of Medicine) as org/10.1097/MD.00000​00000​00293​9
a statistical adviser. We thank Ellen Knapp, PhD, and James Cummins, 8. Zhu X, Ye H, Fu Y (2017) Duphaston and human menopausal
PhD, from Edanz Group (http://www.edanz​editi​ng.com/ac) for editing gonadotropin protocol in normally ovulatory women undergoing
drafts of this manuscript. controlled ovarian hyperstimulation during in vitro fertiliza-
tion/intracytoplasmic sperm injection treatments in combination
Author contribution NI: Protocol development, data analysis, data col- with embryo cryopreservation. Fertility Steril 108(3):505–512.
lection, manuscript writing. MK: Data collection. NO: Data collection. https​://doi.org/10.1016/j.fertn​stert​.2017.06.017 (e502)
TY: Data collection. EW: Data collection. OM: Data collection. HK: 9. Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z
Data collection, protocol development. (2014) Luteal-phase ovarian stimulation is feasible for produc-
ing competent oocytes in women undergoing in vitro fertiliza-
Funding None. tion/intracytoplasmic sperm injection treatment, with optimal
pregnancy outcomes in frozen–thawed embryo transfer cycles.
Fertility Steril 101(1):105–111. https​://doi.org/10.1016/j.fertn​
Compliance with ethical standards stert​.2013.09.007
10. Wang N, Wang Y, Chen Q, Dong J, Tian H, Fu Y, Ai A, Lyu Q,
Conflict of interest The authors declare that they have no conflict of Kuang Y (2016) Luteal-phase ovarian stimulation vs conventional
interest. ovarian stimulation in patients with normal ovarian reserve treated
for IVF: a large retrospective cohort study. Clin Endocrinol (Oxf)
Ethical approval All procedures performed in this study were in 84(5):720–728. https​://doi.org/10.1111/cen.12983​
accordance with the ethical standards of the Kamiya Ladies Clinic 11. Kwik M, Maxwell E (2016) Pathophysiology, treatment and pre-
and with the 1964 Helsinki declaration and its later amendments or vention of ovarian hyperstimulation syndrome. Curr Opin Obstet
similar ethical standards. Gynecol 28(4):236–241. https:​ //doi.org/10.1097/gco.000000​ 0000​
00028​4
Informed consent Informed consent was obtained from all individual 12. Atkinson P, Koch J, Ledger WL (2014) GnRH agonist trigger
participants included in the study. and a freeze-all strategy to prevent ovarian hyperstimulation
syndrome: a retrospective study of OHSS risk and pregnancy
rates. Aust N Z J Obstet Gynaecol 54(6):581–585. https​://doi.
org/10.1111/ajo.12277​
13. Yu S, Long H, Chang HY, Liu Y, Gao H, Zhu J, Quan X, Lyu Q,
References Kuang Y, Ai A (2018) New application of dydrogesterone as a
part of a progestin-primed ovarian stimulation protocol for IVF:
1. Firouzabadi RD, Ahmadi S, Oskouian H, Davar R (2010) Com- a randomized controlled trial including 516 first IVF/ICSI cycles.
paring GnRH agonist long protocol and GnRH antagonist pro- Hum Reprod 33(2):229–237. https​://doi.org/10.1093/humre​p/
tocol in outcome the first cycle of ART. Arch Gynecol Obstet dex36​7
281(1):81–85. https​://doi.org/10.1007/s0040​4-009-1073-5 14. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini
2. Mourad S, Brown J, Farquhar C (2017) Interventions for the JR, Schweppe KW, Thijssen JH (2008) Classification and phar-
prevention of OHSS in ART cycles: an overview of Cochrane macology of progestins. Maturitas 61(1–2):171–180
reviews. Cochrane Database Syst Rev 1:CD012103. https​://doi. 15. Schindler AE (2009) Progestational effects of dydrogester-
org/10.1002/14651​858.cd012​103.pub2 one in vitro, in vivo and on the human endometrium. Matu-
3. Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, ritas 65(Suppl 1):S3–11. https ​ : //doi.org/10.1016/j.matur​
Broekmans FJ (2016) Gonadotrophin-releasing hormone antago- itas.2009.10.011
nists for assisted reproductive technology. Cochrane Database Syst 16. Nadarajah R, Rajesh H, Wong KY, Faisal F, Yu SL (2016) Live
Rev 4:CD001750. https​://doi.org/10.1002/14651​858.cd001​750. birth rates and safety profile using dydrogesterone for luteal phase
pub4 support in assisted reproductive techniques. Singap Med J. https​
4. Reichman DE, Zakarin L, Chao K, Meyer L, Davis OK, Rosen- ://doi.org/10.11622​/smedj​.20160​80
waks Z (2014) Diminished ovarian reserve is the predominant 17. Cummins JM, Breen TM, Harrison KL, Shaw JM, Wilson LM,
risk factor for gonadotropin-releasing hormone antagonist Hennessey JF (1986) A formula for scoring human embryo growth
failure resulting in breakthrough luteinizing hormone surges rates in in vitro fertilization: its value in predicting pregnancy and

13
Archives of Gynecology and Obstetrics

in comparison with visual estimates of embryo quality. J In Vitro 29. Dierschke DJ, Yamaji T, Karsch FJ, Weick RF, Weiss G, Knobil
Fertilization Embryo Transf 3(5):284–295 E (1973) Blockade by progesterone of estrogen-induced LH and
18. Toftager M, Bogstad J, Bryndorf T, Lossl K, Roskaer J, Holland FSH release in the rhesus monkey. Endocrinology 92(5):1496–
T, Praetorius L, Zedeler A, Nilas L, Pinborg A (2016) Risk of 1501. https​://doi.org/10.1210/endo-92-5-1496
severe ovarian hyperstimulation syndrome in GnRH antagonist 30. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini
versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI JR, Schweppe KW, Thijssen JH (2003) Classification and phar-
cycles. Hum Reprod 31(6):1253–1264. https​://doi.org/10.1093/ macology of progestins. Maturitas 46(Suppl 1):S7–S16
humre​p/dew05​1 31. Schindler AE (2016) Present and future aspects of dydroges-
19. Robert J (2009) Guidance for industry non-inferiority clinical tri- terone in prevention or treatment of pregnancy disorders: an
als. Food and Drug Administration, US Department of Health and outlook. Horm Mol Biol Clin Investig 27(2):49–53. https​://doi.
Human Services Publishing online. https​://www.fda.gov/downl​ org/10.1515/hmbci​-2016-0028
oads/drugs​/drugs​afety​/infor ​matio​nbydr ​ugcla​ss/ucm18​7447.pdf. 32. Tournaye H, Sukhikh GT, Kahler E, Griesinger G (2017) A Phase
Accessed 31 July 2018 III randomized controlled trial comparing the efficacy, safety and
20. Althunian TA, de Boer A, Groenwold RHH, Klungel OH (2017) tolerability of oral dydrogesterone versus micronized vaginal pro-
Defining the noninferiority margin and analysing noninferiority: gesterone for luteal support in in vitro fertilization. Hum Reprod
an overview. Br J Clin Pharmacol 83(8):1636–1642. https​://doi. 32(5):1019–1027. https​://doi.org/10.1093/humre​p/dex02​3
org/10.1111/bcp.13280​ 33. Zhu X, Ye H, Fu Y (2017) Use of utrogestan during controlled
21. Hahn S (2012) Understanding noninferiority trials. Korean. J Pedi- ovarian hyperstimulation in normally ovulating women under-
atr 55(11):403–407. https​://doi.org/10.3345/kjp.2012.55.11.403 going in vitro fertilization or intracytoplasmic sperm injection
22. Zhu X, Zhang X, Fu Y (2015) Utrogestan as an effective oral treatments in combination with a “freeze all” strategy: a rand-
alternative for preventing premature luteinizing hormone surges omized controlled dose-finding study of 100 mg versus 200 mg.
in women undergoing controlled ovarian hyperstimulation for Fertility Steril 107(2):379–386. https:​ //doi.org/10.1016/j.fertns​ tert​
in vitro fertilization. Medicine (Baltimore) 94(21):e909. https​:// .2016.10.030 (e374)
doi.org/10.1097/MD.00000​00000​00090​9 34. Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colama-
23. Messinis IE (2006) Ovarian feedback, mechanism of action and ria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L
possible clinical implications. Hum Reprod Update 12(5):557– (2016) Follicular versus luteal phase ovarian stimulation dur-
571. https​://doi.org/10.1093/humup​d/dml02​0 ing the same menstrual cycle (DuoStim) in a reduced ovarian
24. Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremner reserve population results in a similar euploid blastocyst forma-
WJ (1984) Progesterone modulation of pulsatile luteinizing tion rate: new insight in ovarian reserve exploitation. Fertility
hormone secretion in normal women. J Clin Endocrinol Metab Steril 105(6):1488–1495.e1481. https​://doi.org/10.1016/j.fertn​
58(2):378–383. https​://doi.org/10.1210/jcem-58-2-378 stert​.2016.03.002
25. Harris TG, Dye S, Robinson JE, Skinner DC, Evans NP (1999) 35. Griffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Eng-
Progesterone can block transmission of the estradiol-induced sig- mann L (2012) Dual trigger of oocyte maturation with gonado-
nal for luteinizing hormone surge generation during a specific tropin-releasing hormone agonist and low-dose human chorionic
period of time immediately after activation of the gonadotropin- gonadotropin to optimize live birth rates in high responders. Fer-
releasing hormone surge-generating system. Endocrinology tility Steril 97(6):1316–1320. https​://doi.org/10.1016/j.fertn​stert​
140(2):827–834. https​://doi.org/10.1210/endo.140.2.6490 .2012.03.015
26. Richter TA, Robinson JE, Evans NP (2002) Progesterone blocks 36. Zelinski-Wooten MB, Hutchison JS, Hess DL, Wolf DP, Stouffer
the estradiol-stimulated luteinizing hormone surge by disrupting RL (1995) Follicle stimulating hormone alone supports follicle
activation in response to a stimulatory estradiol signal in the ewe. growth and oocyte development in gonadotrophin-releasing hor-
Biol Reprod 67(1):119–125 mone antagonist-treated monkeys. Hum Reprod 10(7):1658–1666
27. Richter TA, Robinson JE, Lozano JM, Evans NP (2005) Pro- 37. Imoedemhe DA, Sigue AB, Pacpaco EL, Olazo AB (1991) Stimu-
gesterone can block the preovulatory gonadotropin-releasing lation of endogenous surge of luteinizing hormone with gonad-
hormone/luteinising hormone surge in the ewe by a direct inhib- otropin-releasing hormone analog after ovarian stimulation for
itory action on oestradiol-responsive cells within the hypothala- in vitro fertilization. Fertility Steril 55(2):328–332
mus. J Neuroendocrinol 17(3):161–169. https​://doi.org/10.111 38. Humaidan P, Bredkjaer HE, Bungum L, Bungum M, Gron-
1/j.1365-2826.2005.01287​.x dahl ML, Westergaard L, Andersen CY (2005) GnRH agonist
28. Pohl CR, Richardson DW, Marshall G, Knobil E (1982) Mode of (buserelin) or hCG for ovulation induction in GnRH antagonist
action of progesterone in the blockade of gonadotropin surges in IVF/ICSI cycles: a prospective randomized study. Hum Reprod
the rhesus monkey. Endocrinology 110(4):1454–1455. https:​ //doi. 20(5):1213–1220. https​://doi.org/10.1093/humre​p/deh76​5
org/10.1210/endo-110-4-1454

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