J Gynecol Obstet Hum Reprod 50 (2021) 102030

Contents lists available at ScienceDirect

Journal of Gynecology Obstetrics

and Human Reproduction
journal homepage: www.elsevier.com

Original Article

Oral dydrogesterone vs. micronized vaginal progesterone gel for luteal

phase support in frozen-thawed single blastocyst transfer in good
prognosis patients
Gonul Ozera,* , Beril Yuksela , Ozge Senem Yucel Cicekb , Semra Kahramana
a
Istanbul Memorial Hospital IVF and Reproductive Genetics Centre, 34385, Sisli, Istanbul, Turkey
b _
Kocaeli University Faculty of Medicine, Department of Obstetrics and Gynecology, 41380, Izmit, Kocaeli, Turkey

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To investigate the efficacy of oral dydrogesterone for luteal phase support (LPS) in modified
Received 29 June 2020 natural cycle frozen-thawed embryo transfers (mNC-FET) compared to micronized vaginal progesterone
Received in revised form 2 September 2020 (MVP) gel.
Accepted 25 November 2020
Methods: This was a randomized, single-center, parallel controlled trial conducted at an ART and
Available online 30 November 2020
Reproductive Genetics Centre within a private hospital between January and August 2019. A total of 134
women, aged below 38, were assigned randomly to receive oral dydrogesterone (n = 67) or MVP (n = 67)
Keywords:
for LPS in mNC-FET. The primary outcome was ongoing pregnancy rate (OPR) and secondary outcomes
Frozen-thawed embryo transfer cycle
In vitro fertilization
were clinical pregnancy and miscarriage rates, patients’ satisfaction and tolerability of oral and vaginal
Luteal phase support progesterone. A questionnaire was developed to compare patient satisfaction and side effect profiles.
Oral dydrogesterone Results: There was no significant difference in demographic features such as female age, body mass index,
Randomized controlled trial AMH levels and fresh cycle characteristics between two groups (p > 0.05). When mNC-FET outcomes
were compared, OPR was 68.7 % in MVP gel group and 71.6 % in the dydrogesterone group respectively
percentage difference, -2.99; 95 % CI: -17.96, 13.10) Biochemical and clinical pregnancy rates and
biochemical and clinical miscarriage rates were also similar between two groups. A significantly higher
patient tolerability score was present in the dydrogesterone arm (4.09  0.96 vs 3.36  1.23, p = 0.001).
Conclusion: Our results suggest that oral dydrogesterone provides similar ongoing pregnancy rates
compared to MVP gel as a LPS in mNC FET. Since dydrogesterone is an effective and easy-to-use option
with fewer intolerable side effects including vaginal irritation, vaginal discharge, and preventing sexual
intercourse, it can be used as LPS in mNC FET.
© 2020 Elsevier Masson SAS. All rights reserved.

Introduction endometrium is very important to achieve successful implanta-

tion in FET cycles. There are two basic alternative approaches. One
The frozen-thawed embryo transfers (FET) have been widely of them is an artificial cycle in which estrogen and progesterone
applied all around the world since 1983. Improvements in replacement treatment and the other one is a natural cycle that
cryopreservation techniques caused a noticeable increase in FET needs to have a regular menstrual cycle [6]. Endometrial
cycles [1]. Also, freezing of all embryos to avoid ovarian preparation in a natural cycle includes two protocols: true
hyperstimulation syndrome (OHSS) risk [2,3] increasing live birth natural cycle and modified natural cycle (mNC). While the true
rates of freezing all embryos in patients undergoing preimplanta- natural cycle requires more frequent ultrasonographic exam-
tion genetic diagnosis/screening (PGD) [4], freezing surplus inatıon and hormone tests [7], mNC-FET removes the need for
embryos after elective single embryo transfer policy [5] contrib- frequent monitoring of hormone levels and follicular size in
uted to that increase. ovulatory patients. A few studies comparing different endome-
A successful FET cycle requires a high-quality embryo, trial preparation protocols found that mNC-FET is more successful
receptive endometrium and a successful synchronization be- in regards to clinical and ongoing pregnancy rates [8–10].
tween transferred embryo and endometrium. Preparation of the Additionally, in 2017 review by Mackens et al. on the optimal
endometrial preparation and timing in FET, it has been reported
that the optimal endometrial preparation protocol was not
* Corresponding author. determined yet, but the natural cycle is better than artificial
E-mail address: [email protected] (G. Ozer). cycle [11].

http://dx.doi.org/10.1016/j.jogoh.2020.102030
2468-7847/© 2020 Elsevier Masson SAS. All rights reserved.
G. Ozer, B. Yuksel, O.S. Yucel Cicek et al. J Gynecol Obstet Hum Reprod 50 (2021) 102030

Progesterone recommended for luteal phase support (LPS) can demonstrated that oral MVP should be used 20 times more to
be oral, intramuscular, vaginal, and subcutaneous, each of which show the same effect. The Lotus II study that is a multicenter
has various tolerability and bioavailability profiles. In a review by study involving 11,034 women indicated that oral dydrogester-
Casper et al. on optimal endometrial preparation and progester- one can be replaced by MVP due to its patient-friendly oral
one support, the authors reported that there was no optimal form administration and tolerability profile [16,17].
of progesterone recommended for luteal phase support and that Therefore, this prospective, randomized controlled study
different forms of progesterone could be used depending on the compared the pregnancy results, side effects and satisfaction
side effect, cost, and patient preference [12]. It is known that scores after the use of oral dydrogesterone with micronized
intramuscular progesterone has some adverse effects, such as progesterone vaginal gel (MVP) for LPS in patients undergoing
pain and local abscesses. The use of vaginal progesterone also mNC-FET. Our aim was to determine the type of progesterone,
causes side effects such as vaginal discharge, vaginal irritation which has minimum side effects and high satisfaction scores for
and preventing sexual intercourse [13]. Also, oral micronized LPS without affecting ongoing pregnancy rates and to contribute to
progesterone and synthetic oral progesterone are used in luteal the literature with this.
phase support. Oral micronized progesterone is degraded due to
hepatic first-pass metabolism, therefore its bioavailability is very Materials and methods
low (<10 %) and it is used only in 2 % of IVF centres for LPS [14].
Dydrogesterone is a synthetic oral progesterone which is a Ethical approval
stereoisomer of the natural progesterone. The positions of the
atoms in the two carbons found in natural progesterone were This study was approved by the Institutional Review Board of
reversed in dydrogesterone, therefore, it is called retro proges- Istanbul Memorial Sisli Hospital, Istanbul, Turkey (approval
terone. While this change in the pharmacological structure of number 2019/001) and written informed consents were obtained
dydrogesterone increases its affinity for progesterone receptors, from all patients. The study is also registered at ClinicalTrials.gov
it is not suitable for binding to other steroid receptors. In the (NCT04124913). Since the ethics committee approval of our study
recent review study by Glisenger et al. analyzing all the was obtained in December 2018, we started the study in January
pharmacological properties and mechanisms of Dydrogesterone, 2019. However, the registration of our study at ClinicalTrials was
they indicated that Dydrogesterone has a favourable pharmaco- late due to the lack of awareness of this requirement at the
logical profile due to its properties [15]. It has better bioavail- beginning of our research.
ability and progestogenic activity than oral micronized
progesterone because it is absorbed in intestines faster than Study design and participants
oral micronized progesterone and it reaches a maximum level in
the blood 2 5 hours later. The Lotus I study compared 30 mg This was a randomized, single-center, parallel controlled trial
dydrogesterone with 600 mg MVP for luteal phase support and conducted at Istanbul Memorial Hospital IVF and Reproductive

Fig. 1. CONSORT flow diagram.

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G. Ozer, B. Yuksel, O.S. Yucel Cicek et al. J Gynecol Obstet Hum Reprod 50 (2021) 102030

Genetics Centre, Istanbul, Turkey between January and August were continued until the 12th week of gestation in the control
2019. group.
The following exclusion criteria were used for this study: two or
more previous unsuccessful FET cycles and two or more early Embryo cryopreservation and thawing
pregnancy losses, any uterine abnormality such as adhesions,
fibroids, adenomyosis, congenital malformations. Patients with All embryos were frozen by Vitrification technique. Gardner
severe endometriosis, azoospermia, and women with serious and Schoolcraft blastocyst grading system was used for blastocyst
endocrine or metabolic disorders and patients enrolled for an scoring. Blastocysts with a score of 3–6 AA were TQ blastocysts and
artificial cycle were also excluded. 3–6 AB or 3–6 BA were considered GQ blastocysts. Only GQ and TQ
A total of 147 women aged below 38 years, undergoing mNC- embryos were vitrified on the 5th and 6th days after oocyte pick up
FET were eligible for the study between January and August 2019. by Kitazato vitrification kit (Kitazato, BioPharmaceuticals, Shi-
Four patients declined to participate, 5 patients were excluded as zuoka, Japan) using the cryotop as a carrier according to
there was no follicular development in the natural cycle and 4 manufacturer’s instructions.
patients were excluded due to spontaneous ovulation which is 6 days after the LH surge, thawing and transferring of the
defined as the presence of a corpus luteum and no visible follicle embryo were planned. Kitazato warming media was used for the
during ultrasound evaluation. In conclusion, a total of 134 women thawing of embryos according to the manufacturer’s instructions.
were assigned randomly in a ratio of 1:1 based on a computer- The viability of embryos was controlled 30 min after warming.
generated list to administer oral dydrogesterone (n = 67) or MVP Then, blastocysts were checked for re-expansion, cytoplasmic
(n = 67) for LPS (Fig. 1). granulation, and the presence of necrotic foci, 2 h after vitrification.
This study was an open-label study in which both patients and In the absence of re-expansion or the presence of signs of
investigators were aware of the treatment that the participants degeneration, surplus embryos were thawed. Only blastocyst stage
were receiving. Pregnancy was detected by a positive serum beta- TQ or GQ single embryos were transferred in all cases.
human chorionic gonadotropin (hCG) test (20 IU/L) done 9 days
after a blastocyst transfer. Clinical pregnancy is defined as the Outcome measures
presence of an intrauterine gestational sac with a fetal heartbeat at
the 7th week of gestation. The presence of at least one live fetus at The primary outcome of this study was the ongoing pregnancy
the end of the 12th gestational week is considered as an ongoing rate (OPR). Secondary outcomes were clinical pregnancy rates,
pregnancy. Pregnancy loss before biochemical and clinical miscarriage rates as well as patients’
ultrasonographic detection of an intrauterine gestational sac is satisfaction with oral and vaginal progesterone.
defined as biochemical miscarriage and pregnancy loss after A five-point scale ranging from 1="extremely dissatisfied" to
ultrasonographic detection of an intrauterine gestational sac is 5="extremely satisfied" was used to measure patients’ attitudes
defined as clinical miscarriage. towards drug use (Table 3). In addition, a questionnaire was
developed to compare side effect profiles of oral dydrogesterone
Protocol and MVP gel including mastalgia, somnolence, dizziness, headache,
vaginal discharge, vaginal irritation, flatulence and preventing
All patients undergoing mNC-FET were examined on the second sexual intercourse (Supplementary File 1). Data was collected
day of the menstrual period by transvaginal ultrasonography and through telephone interviews on the 10th day of progesterone usage.
the patients with any uterine or ovarian abnormalities were
excluded. After the first examination, the patients were invited Power analysis and sample size
again 8–9 days later according to the length of their menstrual
cycles. The follicle diameter and endometrial thickness of the A power analysis was conducted using G*Power (v3.1.9)
patients were followed. When follicular diameter exceeded 15 mm, software. A total of 88 subjects would be required to detect a
luteinizing hormone (LH) and estradiol levels were checked for medium effect size (Cohen’s w: 0.3) for goodness of fit tests, with
monitoring. As the endometrial thickness reached above 8 mm and 80 % power at a level of α = 0.05. Considering the dropouts, 67
the LH level raised above a critical threshold level (>15 IU/L), patients were recruited to each group. Eligible subjects were
recombinant hCG (r-hCG) (Ovitrelle, Merck-Serono, Switzerland) randomly assigned to two groups using a computer-generated
was administered. In the randomization process, the participants random number list with a ratio of 1:1.
were randomly assigned in a ratio of 1:1 at the day of trigger
ovulation day by means of computer-generated random numbers Statistical analysis
to duphaston or MVP gel group. Since this study was an open-label
study, both patients and investigators were aware of the treatment Statistical analysis was performed with NCSS (Number Crunch-
that the participants were receiving and randomization was not er Statistical System) 2007 (Kaysville, Utah, USA). Numerical
done in blocks. variables with normal distribution were given as mean  standard
In the study group, oral dydrogesterone (Duphaston 10 mg deviation, the numerical variables without normal distribution
tablet, Abbott Healthcare Products, Netherlands) was started as were given as median (minimum-maximum), and categorical
3  10 mg a day for LPS 36 h after r-hCG. In the control group, MVP variables were given as frequency (percentage). The normal
gel (Crinone 8%, Serono, Switzerland) was started as once a day distribution suitability test was evaluated by the Shapiro-Wilk
administration 36 h after r-hCG for LPS. Six days after ovulation Test. Differences between the groups were determined by
trigger, single blastocyst embryo transfer was performed at the Student’s t-test for numerical variables having normal distribution
stage of top quality (TQ) or good quality (GQ). Serum β-hCG was and by Mann Whitney U test for numerical variables without
tested 9 days after blastocyst transfer. normal distribution. Tukey and Dunn tests were used for multiple
When the pregnancy test was positive, the same daily doses of comparisons. The relationships between categorical variables were
oral dydrogesterone were continued until the 12th week of evaluated by Pearson chi-square, Fisher’s exact test. A p-value
gestation in the study group and the same daily doses of MVP gel <0.05 was considered as statistically significant.

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G. Ozer, B. Yuksel, O.S. Yucel Cicek et al. J Gynecol Obstet Hum Reprod 50 (2021) 102030

Results There are also some reviews that compare oral dydrogesterone and
MVP gel used for luteal supplementation in fresh IVF cycles.
Baseline characteristics Barbosa et al., in their systemic review and meta-analysis, reported
‘’Oral dydrogesterone seems to be as effective as vaginal
The demographic and clinical characteristics of patients are progesterone for LPS in ART cycles, and appears to be better
presented in Table 1. The mean female age was 32.4 years in the tolerated’’ [20], Tomic et al., in their more recent systematic review
MVP gel group and 31.8 in the dydrogesterone group. When all published in 2019 on the importance of luteal support in fresh IVF,
patients were evaluated, there was no statistical difference stated that oral dydrogesterone and subcutaneous dydrogesterone
between the two groups in any of the parameters of the mean are well tolerated by patients than vaginal and intramuscular
body mass index (BMI), the mean AMH level, and the mean progesterone and have similar clinical outcomes [21].
endometrial thickness on the day of rhCG. When the infertility As far as we know, there are only two randomized controlled
reasons of all cases were analyzed, no significant difference was trials (RCT) comparing the efficacy of oral dydrogesterone with
found in terms of the causes of infertility between the study and MVP capsule in artificial FET cycle in the current literature. One of
control groups either (Table 1). All patients in the study consisted the two RCT studies for artificial FET cycles, compared the clinical
of good prognosis patients who have a mean of 14.43 retrieved outcomes of oral dydrogesterone with both MVP capsule and
oocytes, 12.41 metaphase II oocytes, 10.04 fertilized oocytes, and intramuscular progesterone and reported similar pregnancy rates
5.84 vitrified blastocysts. All patients were transferred to a single [22]. Another study compared four protocols including only oral
thawed blastocyst. There was no statistically significant difference dydrogesterone, only MVP capsule, hCG plus oral dydrogesterone
as blastocyst quality in either group (Table 2). (Author’s note: The and gonadotropin-releasing hormone analogue (GnRH-a) plus oral
values that are the same on the table and text were removed from dydrogesterone in artificial FET cycles. In the group that used only
here.) dydrogesterone for LPS, it was found to have a lower clinical
pregnancy rate compared to the other three groups. The authors
Pregnancy outcomes stated that the reason for the lower clinical pregnancy rate in the
oral dydrogesterone group could be the administration of a lower
Table 2 shows the comparison of groups regarding pregnancy dose of dydrogesterone (20 mg/daily) compared to the other
rates. Ongoing pregnancy rate which is the primary outcome was studies that used 30 mg/daily [23].
found 71.6 % (48/67) in the dydrogesterone group, while it was Several studies have demonstrated that luteal phase progester-
found 68.7 % (46/67) in MVP gel group (percentage difference, one supplementation improved live birth rates in mNC-F [24–26].
-2.99; 95 % CI: -17.96, 13.10).However, OPR did not reach statistical One of the hypotheses that this positive outcome has been based
significance (p = 0.706). Biochemical and clinical pregnancy rates on is that endogen production of progesterone from the corpus
were similar between the two groups (p = 0.382, p = 0.547 luteum in fertile women is sufficient for the embryo implantation,
respectively). Also, no significant difference was observed regard- but this production in infertile women may be insufficient and may
ing biochemical and clinical miscarriage rates between groups (5.8 cause luteal phase deficiency (LPD) during their natural cycles. LPD
% vs 7.1 %; 6.1 % vs 7.7 %). may cause implantation failure or spontaneous abortion and most
importantly, there is no diagnostic test for LPD [27]. Moreover,
Patient tolerability some studies have speculated that progesterone supplementation
in the luteal phase reduces abortion rates by regulating the
Overall patient tolerability score was 4.09  0.96 in the oral immune system [28]. Based on these hypotheses, we prefer the
dydrogesterone group and 3.36  1.23 in the MVP gel group administration of LPS in all patients undergoing mNC FET.
(Table 3). A significantly higher patient satisfactıon score was Our study is the first RCT that compares the clinical effective-
present in the dydrogesterone arm (p = 0.001). Table 4 shows the ness, patient satisfaction of oral dydrogesterone vs. MVP gel for LPS
comparison of side effect profiles between two groups. in mNC frozen-thawed single blastocyst transfer in good prognosis
patients. Our sample size was small, because our study was
Discussion restricted to good prognosis patients who were transferred a single
blastocyst-stage embryo. The reason for selecting only good
To the best of our knowledge, no randomized clinical trial that prognosis patients was to prevent poor clinical features of the
compares the clinical results and patient satisfaction of oral cases from affecting the results of the study.
dydrogesterone with micronized progesterone gel in mNC-FET has The primary outcome of our study showed no significant
been reported in the literature. Several RCT studies compared oral difference between MVP gel and oral dydrogesterone group
dydrogesterone and MVP gel used for luteal supplementation in regarding pregnancy rates.
fresh IVF cycles [17–20]. Of these recent studies, Lotus-II reported The satisfaction of oral dydrogesterone and MVP gel, a
similar pregnancy rates and similar safety profiles to oral secondary outcome in our study, was investigated in only a few
dydrogesterone and MVP gel for LPS in fresh IVF cycles [17]. randomized studies conducted in fresh embryo transfer cycles

Table 1
Baseline characteristics of patients.

MVP gel (n=67) Dydrogesterone (n=67)

Female age (years) 32.403.74 31.885.20
BMI (kg/m2) 23.233.88 24.444.85
Endometrial thickness on hCG day (mm) 10.702.20 10.701.80
AMH (ng/ml) 2.4 (0.4-13.1) 3 (0.11-13.6)
Infertility etiology
Female 22 (32.8) 18 (26.9)
Female-Male 14 (20.9) 21 (31.3)
Male 20 (29.9) 18 (26.9)
UEI 11 (16.4) 10 (14.9)

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G. Ozer, B. Yuksel, O.S. Yucel Cicek et al. J Gynecol Obstet Hum Reprod 50 (2021) 102030

Table 2
Comparison of fresh and FET cycle outcomes between two groups.

Outcomes of fresh cycles MVP gel (n=67) Dydrogesterone (n=67) Difference (95%CI) p value
a
Retrieved oocytes 14.258.11 14.618.57 0.36 (-3.21, 2.49) 0.804
a
Metaphase II oocytes 12.036.61 12.817.46 0.78 (-3.18, 1.63) 0.525
a
Fertilized oocytes 9.845.58 10.256.11 0.42 (-2.41, 1.58) 0.680
a
Vitrified blastocysts 5.523.55 6.164.29 0.64 (-1,99, 0.70) 0.347
Blastocyst quality
b
Good quality 22 (32.8) 20 (29.9) 2.99 (-12.98, 18.95) 0.852
Top quality 45 (67.2) 47 (70.1) 2.99 (-18.95, 12.98)
Outcomes of FET cycles
b
Biochemical pregnancy 52 (77.6) 56 (83.6) 5.97 (-18.73, 7.66) 0.382
c
Biochemical pregnancy loss 3 (5.8) 4 (7.1) 1.37 (-10.80, 7.70) 0.999
b
Clinical pregnancy 49 (73.1) 52 (77.6) 4.48 (-18.77, 11.15) 0.547
c
Clinical miscarriage 3 (6.1) 4 (7.7) 1.57 (-12.36, 8.37) 0.999
b
Ongoing pregnancy 46 (68.7) 48 (71.6) 2.99 (-17.96, 13.10) 0.706

FET, frozen embryo transfer.

a
Independent samples t test.
b
Pearson chi-square test.
c
Fisher’s exact test.

Table 3
Comparison of patient satisfaction scores between two groups.

MVP gel (n=67) Dydrogesterone (n=67) Difference (95%CI) p value

a
Overall satisfaction score 3.361.23 4.090.96 0.73 (-1.11, -0.35) 0.001
Score 1 8 (11.9) 1 (1.5) 0.10 (0.02, 0.19)
Score 2 4 (6.0) 4 (6.0) 0 (-0.08, 0.08)
Score 3 25 (37.3) 10 (14.9) 0.22 (0.08, 0.37)
Score 4 16 (23.9) 25 (37.3) 0.13 (-0.29, 0.02)
Score 5 14 (20.9) 27 (40.3) 0.19 (-0.35, -0.04)
a
Independent samples t-test.

Table 4
Comparison of drug side effect profiles between two groups.

MVP gel (n=67) Dydrogesterone (n=67) Difference (95%CI) p value

b
Mastalgia 3 (4.6) 24 (36.9) 32.31 (-45.32, -19.29) 0.001
b
Somnolence 1 (1.5) 25 (38.5) 36.92 (-49.34, -24.51) 0.001
c
Headache 0 (0.0) 9 (13.8) 13.85 (-22.39, -5.3) 0.003
c
Dizziness 0 (0.0) 6 (9.4) 9.38 (-16.59, -2.16) 0.013
b
Flatulance 8 (12.3) 21 (32.8) 20.5 (-34.72, -6.29) 0.005
b
Vaginal irritation 29 (44.6) 1 (1.6) 43.05 (30.29, 55.82) 0.001
b
Vaginal discharge 50 (76.9) 8 (12.3) 64.62 (51.4, 77.83) 0.001
b
Preventing sexual intercourse 32 (50.0) 1 (1.6) 48.44 (35.59, 61.28) 0.001
b
Pearson chi-square test.
c
Fisher’s exact test.

[18,29] In our study, a satisfaction scoring system was used to vascular, gastrointestinal, nervous systems as well as liver function
determine the tolerability of the two routes of progesterone analysis compared to MVP and dydrogesterone [16,17,19].
supplementation. As a result, although some adverse effects such In conclusion, our results suggest that in mNC FET, oral
as mastalgia, dizziness were less tolerable, overall total satisfaction dydrogesterone provides an effective, safe and easy-to-use option
scores were higher in the dydrogesterone group. The side effects compared to MVP gel as a LPS with similar ongoing pregnancy rates
including vaginal discharge, vaginal irritation and preventing and with fewer intolerable side effects including vaginal irritation,
sexual intercourse were observed more often in the MVP gel group vaginal discharge, and preventing sexual intercourse. This study
and the patients were dissatisfied (Table 3). These results were in consisted of only good prognosis patients with top and good
concordance with the results of Tomic et al. and Chakravarty et al. quality blastocysts to avoid any possible selection bias, which can
who reported higher tolerability rates in the dydrogesterone result from compromised clinical feature.
group. Unlike the other types of progesterone, dydrogesterone is
selective progesterone receptor agonist and does not affect Funding
androgen, glucocorticoid, estrogen and mineralocorticoid recep-
tors [30]. This feature of dydrogesterone may cause fewer adverse None.
effects.
One of the most common concerns about dydrogesterone usage Ethics approval
is the safety of the drug for mother and fetus during pregnancy.
Robust clinical studies demonstrated that the use of dydrogester- This study was performed in line with the principles of the
one was safe. These studies reported similar adverse effects in Declaration of Helsinki. Approval was granted by the Ethics

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G. Ozer, B. Yuksel, O.S. Yucel Cicek et al. J Gynecol Obstet Hum Reprod 50 (2021) 102030

Committee of Istanbul Memorial Hospital (Date: 20.12.2018/No. GnRHa suppression, a prospective randomized clinical trial. J Assist Reprod
2019/001). Genet 2019;36(3):453–9.
[7] Irani M, et al. Optimal parameters for determining the LH surge in natural cycle
frozen-thawed embryo transfers. J Ovarian Res 2017;10(1):70.
Consent to participate [8] Morozov V, et al. Natural cycle cryo-thaw transfer may improve pregnancy
outcome. J Assist Reprod Genet 2007;24(4):119–23.
[9] Levron J, et al. Comparison between two protocols for thawed embryo
Informed consent was obtained from all individual participants transfer: natural cycle versus exogenous hormone replacement. Gynecol
included in the study. Endocrinol 2014;30(7):494–7.
[10] Guan Y, et al. A modified natural cycle results in higher live birth rate in
vitrified-thawed embryo transfer for women with regular menstruation. Syst
Consent to publish Biol Reprod Med 2016;62(5):335–42.
[11] Mackens S, et al. Frozen embryo transfer: a review on the optimal endometrial
Not applicable. preparation and timing. Hum Reprod 2017;32(11):2234–42.
[12] Casper RF, Yanushpolsky EH. Optimal endometrial preparation for frozen
embryo transfer cycles: window of implantation and progesterone support.
Availability of data and material (data transparency) Fertil Steril 2016;105(4):867–72.
[13] Ghanem ME, Al-Boghdady LA. Luteal phase support in ART: an update.
The datasets used and/or analyzed during the current study are Enhancing Success Assist Reprod 2012;1:155–72.
[14] Vaisbuch E, Leong M, Shoham Z. Progesterone support in IVF: is evidence-
available from the corresponding author on reasonable request. based medicine translated to clinical practice? A worldwide web-based
survey. Reprod Biomed Online 2012;25(2):139–45.
Code availability [15] Griesinger G, et al. Dydrogesterone: pharmacological profile and mechanism of
action as luteal phase support in assisted reproduction. Reprod Biomed Online
2018.
Not applicable. [16] Tournaye H, et al. A Phase III randomized controlled trial comparing the
efficacy, safety and tolerability of oral dydrogesterone versus micronized
vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod
CRediT authorship contribution statement 2017;32(5):1019–27.
[17] Griesinger G, Blockeel C, Tournaye H. Oral dydrogesterone for luteal phase
Gonul Ozer: Methodology, Formal analysis, Investigation, support in fresh in vitro fertilization cycles: a new standard? Fertil Steril
2018;109(5):756–62.
Writing - original draft, Writing - review & editing. Beril Yuksel:
[18] Tomic V, et al. Oral dydrogesterone versus vaginal progesterone gel in the
Methodology. Ozge Senem Yucel Cicek: Writing - original draft, luteal phase support: randomized controlled trial. Eur J Obstet Gynecol Reprod
Writing - review & editing. Semra Kahraman: Conceptualization, Biol 2015;186:49–53.
[19] Yang D-Z, et al. A Phase III randomized controlled trial of oral dydrogesterone
Writing - review & editing, Supervision.
versus intravaginal progesterone gel for luteal phase support in in vitro
fertilization (Lotus II): results from the Chinese mainland subpopulation.
Declaration of Competing Interest Gynecol Endocrinol 2019;1–9.
[20] Barbosa M, et al. Dydrogesterone vs progesterone for luteal-phase support:
systematic review and meta-analysis of randomized controlled trials.
The authors report no declarations of interest. Ultrasound Obstet Gynecol 2016;48(2):161–70.
[21] Tomic V, Kasum M, Vucic K. The role of luteal support during IVF: a qualitative
systematic review. Gynecol Endocrinol 2019;35(10):829–34.
Appendix A. Supplementary data [22] Rashidi BH, et al. Oral dydrogesterone for luteal support in frozen-thawed
embryo transfer artificial cycles: a pilot randomized controlled trial. Asian
Supplementary data associated with this article can be found, in Pacific J Reprod 2016;5(6):490–4.
[23] Zarei A, et al. Comparison of four protocols for luteal phase support in frozen-
the online version, at https://doi.org/10.1016/j.jogoh.2020.102030. thawed Embryo transfer cycles: a randomized clinical trial. Arch Gynecol
Obstet 2017;295(1):239–46.
[24] Kim C-H, et al. The effect of luteal phase progesterone supplementation on
References natural frozen-thawed embryo transfer cycles. Obstet Gynecol Sci 2014;57
(4):291–6.
[1] AbdelHafez FF, et al. Slow freezing, vitrification and ultra-rapid freezing of [25] Schwartz E, et al. Luteal phase progesterone supplementation following
human embryos: a systematic review and meta-analysis. Reprod Biomed induced natural cycle frozen embryo transfer: a retrospective cohort study. J
Online 2010;20(2):209–22. Gynecol Obstet Hum Reprod 2019;48(2):95–8.
[2] Borges Jr E, et al. Strategies for the management of OHSS: results from [26] Bjuresten K, et al. Luteal phase progesterone increases live birth rate after
freezing- all cycles. JBRA Assist Reprod 2016;20(1):8–12. frozen embryo transfer. Fertil Steril 2011;95(2):534–7.
[3] Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF [27] Jordan J, et al. Luteal phase defect: the sensitivity and specificity of diagnostic
treatment. Hum Reprod 2011;26(10):2593–7. methods in common clinical use. Fertil Steril 1994;62(1):54–62.
[4] Roque M, et al. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: [28] Szekeres-Bartho J, et al. Progesterone as an immunomodulatory molecule. Int
a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Immunopharmacol 2001;1(6):1037–48.
Update 2018;25(1):2–14. [29] Chakravarty BN, et al. Oral dydrogesterone versus intravaginal micronised
[5] Freeman MR, et al. Guidance for elective single-embryo transfer should be progesterone as luteal phase support in assisted reproductive technology
applied to frozen embryo transfer cycles. J Assist Reprod Genet 2019;36 (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol
(5):939–46. 2005;97(5):416–20.
[6] Kahraman S, et al. Transdermal versus oral estrogen: clinical outcomes in [30] Schindler AE, et al. Classification and pharmacology of progestins. Maturitas
patients undergoing frozen-thawed single blastocyst transfer cycles without 2008;61(1-2):171–80.