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Gynecol Endocrinol, 2016; 32(2): 97–106

! 2016 [Abbott GmbH & Co. KG]. Published by Taylor & Francis. DOI: 10.3109/09513590.2015.1121982

DYDROGESTERONE AND EARLY PREGNANCY

Dydrogesterone use in early pregnancy

Fadi Ghazi Mirza1, Ameet Patki2, and Claire Pexman-Fieth3
1
American University of Beirut Medical Center, Department of Obstetrics and Gynecology, Beirut, Lebanon, 2Fertility Associates, Mumbai, India, and
3
Abbott GmbH & Co. KG, Ludwigshafen, Germany

Abstract Keywords
Successful oocyte implantation and a favorable pregnancy outcome rely on optimal Assisted reproductive technology,
progesterone levels. Therefore, progesterone deficiencies associated with infertility and dydrogesterone, luteal phase support,
miscarriage have commonly been treated with progestogens that mimic the activity of pregnancy, progestogen, threatened or
progesterone. Among those is dydrogesterone, an oral retrosteroid with a structure closely recurrent miscarriage
related to that of progesterone yet with a greater bioavailability and higher selectivity for the
progesterone receptor. This review describes the efficacy of dydrogesterone for the treatment History
of threatened and recurrent miscarriage, and infertility due to luteal phase insufficiency. Data
from clinical trials evaluating dydrogesterone in assisted reproductive technology are also Received 5 November 2015
discussed. Prospective clinical trials, systematic reviews and meta-analyses have demonstrated Accepted 15 November 2015
that dydrogesterone significantly improves pregnancy outcomes in women with threatened Published online 12 January 2016
miscarriage or with a history of miscarriage. Although this is not yet a registered indication,
dydrogesterone was as effective as vaginal micronized progesterone for luteal phase support in
the setting of assisted reproductive technology. The safety and tolerability of dydrogesterone
treatment in pregnant women are also briefly addressed and the data support a well-
established and favorable benefit–risk profile.

Introduction Therefore, progestogens that mimic the activity of progester-

one have been used extensively in an attempt to overcome
Progesterone is essential for creating a suitable endometrial
progesterone deficiency associated with infertility and miscar-
environment for embryo implantation, as well as for the
riage [3]. However, it is imperative to keep in mind that not all
maintenance of pregnancy. For that purpose, progesterone is
progestogens are the same and differences in their progestogenic
believed to help in mediating an anti-inflammatory immune
potency, receptor-binding selectivity, bioavailability, and route of
response to the allogenic fetus and in inducing uterine smooth-
administration should guide the choice of the most appropriate
muscle relaxation [1–3]. Progesterone is produced by the corpus
agent for each condition [3]. Although micronized progesterone
luteum after ovulation and during the early first trimester, until
has been used since the 1980s [9], high doses are required when it
the placental function is established between 7 and 11 weeks of
is orally administered due to its low and variable bioavailability,
gestation, and thereafter becomes the main source of progesterone
resulting in side effects such as drowsiness, nausea, and headaches
production [1].
[10]. For these reasons, micronized progesterone is now typically
The lack of adequate progesterone production by the corpus
administered vaginally. This approach, in turn, carries its own
luteum after ovulation has been associated with infertility [4]. In
disadvantages. Intravaginal micronized progesterone may not be
successful conception, progesterone levels rise more rapidly
fully absorbed, may be washed out with vaginal bleeding, and
during the early luteal phase and reach higher mid-luteal levels
may cause local irritation [11].
compared with cycles where conception does not occur [5].
Consequently, alternative progestogens have become widely
Likewise after implantation, it has been noted that deficiencies in
used for obstetric indications. One of those is dydrogesterone or
progesterone production or function can lead to pregnancy loss.
6-dehydro-retroprogesterone, a retrosteroid closely related to
This has been supported by studies demonstrating that either a
progesterone [3]. Its bent shape and retro-structure results in
lack of progesterone production due to a lutectomy prior to 7
approximately 5.6 times higher bioavailability than that of
weeks of gestation [6], or disrupted binding to progesterone
progesterone, meaning that it can be administered orally [12].
receptors caused by progesterone agonists, such as mifepristone
Unlike progesterone and other progestogens, dydrogesterone is
[7,8] both result in pregnancy loss.
highly selective for the progesterone receptor, a characteristic also
shared by its main active metabolites [3]. In particular,
dydrogesterone does not bind to androgenic receptors, reducing
Address for correspondence: Dr Claire Pexman-Fieth, Abbott GmbH &
the risk of masculinization of female fetuses [13]. In addition, the
Co. KG, Knollstrasse 50, Building 72, 67061 Ludwigshafen, Germany. anti-androgenic potential of dydrogesterone and its active metab-
Tel: +49 621 6814 4217; Fax: +49 621 594 1874; Mobile +49 160 749 olite dihydrodydrogesterone is less pronounced than that of
0615. E-mail: Claire.Pexman-Fieth@abbott.com progesterone [14], reducing the potential inadequate
98 F. G. Mirza et al.
masculinization of a male fetus (e.g. hypospadias) [15]. The high
bioavailability and receptor selectivity of dydrogesterone translate
into a significantly lower therapeutic dose; it is estimated that
dydrogesterone requires a 10–20 times lower oral dose compared
with micronized progesterone [3].
Dydrogesterone has been marketed since the 1960s and has
been extensively used worldwide for the treatment of threatened
miscarriage (TM) and recurrent miscarriage (RM), as well as for
luteal phase support (LPS) in the setting of infertility. Currently,
dydrogesterone is being investigated for luteal support in the
setting of assisted reproductive technology (ART). Additionally,
dydrogesterone is approved for hormone replacement therapy
(HRT), as well as pregnancy and non-pregnancy-related condi-
tions where there is a progesterone deficiency.
The primary aim of this review is to examine the efficacy of
dydrogesterone use in early pregnancy in its approved pregnancy
indications: TM, RM, and infertility due to luteal phase insuffi-
ciency, and the efficacy data that paved the way to the ongoing,
multicenter Phase III program for LPS after in vitro fertilization
(IVF)/ART. The safety and tolerability of dydrogesterone treat-
ment in pregnant women are also briefly addressed.
Methodology
PubMed literature searches were performed (cut-off date 1 August
2015) using combinations of ‘Duphaston OR dydrogesterone’
with the following key words: ‘pregnancy’ (for general consid-
eration on the role of dydrogesterone during pregnancy);
‘threatened miscarriage OR threatened abortion’ (for the evalu-
ation of dydrogesterone in TM); ‘recurrent miscarriage OR
recurrent abortion OR habitual abortion’ (for the evaluation of
dydrogesterone in RM); ‘luteal’ (for the evaluation of dydroges-
terone in LPS). Prospective controlled clinical trials, as well as
other relevant publications, were identified from these searches
and are included in this review. Relevant studies not indexed on
PubMed but discussed in published meta-analyses are also
described.
Dydrogesterone for the treatment of miscarriage
Threatened miscarriage
Definition and treatment options
Threatened miscarriage is characterized by vaginal bleeding with
or without abdominal pain yet with no cervical dilatation, in the
first 20 weeks of a pregnancy [16]. A prospective study analyzing
a cohort of pregnant women reported that bleeding occurs in
around 20% of recognized pregnancies before week 20, and about
half of these proceed to miscarriage [17]. First trimester bleeding
may also be linked to placental dysfunction, with TM having
been associated with abruptio placentae, premature birth, pre-
eclampsia, gestational hypertension, and fetal growth restriction
[16,18–20]. While fetal chromosomal abnormalities are respon-
sible for approximately half of all miscarriages, other risk factors
have been implicated, including advanced maternal age, smoking,
maternal co-morbidities, infections, abnormal body mass index,
and low serum progesterone and human chorionic gonadotrophin
(hCG) levels [16,18,21].
Once the pregnancy has been confirmed to be viable and
intrauterine (by serum hCG levels and ultrasound), widely used
treatment options include bed rest and luteal support with hCG or
progestogens [18]. However, two Cochrane Reviews evaluating
bed rest [22] and hCG supplementation [23] concluded that the
current evidence available does not support either intervention for
the prevention of miscarriage. In turn, the most recent Cochrane
Review evaluating progestogens for the treatment of TM
suggested that their use was effective, though evidence was
Gynecol Endocrinol, 2016; 32(2): 97–106
limited [24]. The remainder of this section will focus on the use of
dydrogesterone for the treatment of TM.
Six relevant prospective clinical trials [25–30] and a meta-
analysis [31] were identified from the PubMed literature search.
An additional randomized clinical study, which is discussed in the
meta-analysis but was not indexed on PubMed, is also included
[32]. Further details on study design, treatment arms, and
pregnancy outcomes for these clinical trials can be found
in Table 1.
Dydrogesterone versus standard supportive care or placebo
Dydrogesterone, alone or in combination with standard supportive
care (e.g. bed rest, folic acid, and/or multivitamins) was compared
to supportive care alone in three controlled studies [25–27]. Omar
and colleagues [26] found that significantly more women
receiving dydrogesterone together with standard of care (bed
rest and folic acid) continued their pregnancy beyond 20 weeks of
gestation, compared with women allocated to bed rest and folic
acid alone. The miscarriage rate in this study was 4.1% and 13.8%
in the dydrogesterone and control group, respectively (p ¼ 0.037)
[26]. Similar results were observed by El-Zibdeh and Yousef [27],
in whose study women received standard of care consisting of bed
rest and iron, folic acid, and multivitamins with or without
dydrogesterone. In this study, dydrogesterone treatment was
associated with a statistically significant reduction in the rate of
miscarriage compared to the control group (17.5% versus 25.0%,
respectively [p  0.05]) [27]. The incidence of preterm labor, pre-
eclampsia, intrauterine growth restriction (IUGR), antepartum
hemorrhage, and congenital abnormalities was not significantly
different between the two groups. Pandian [25] conducted the
largest study reviewed and compared dydrogesterone treatment
with bed rest alone. It was found that significantly more women
receiving dydrogesterone continued their pregnancy beyond 20
weeks of gestation compared with women prescribed bed rest
alone; the miscarriage rate in this study was 12.5% and 28.4%,
respectively (p50.05) [25]. There were no differences between
the groups in terms of preterm labor, pregnancy-induced hyper-
tension, or incidence of cesarean section; no intrauterine or
congenital abnormalities were reported.
Dydrogesterone was compared to placebo in two historic
studies that recruited a limited number of patients; both reported
fewer miscarriages in women receiving dydrogesterone than in
those receiving placebo [28,29]. In the study by Ehrenskjöld and
colleagues [28], 19.4% and 28.4% of women in the dydrogester-
one and placebo groups, respectively, miscarried or had stillborn
babies. Both treatment groups were combined with strict bed rest.
In the study by Mistò [29], no miscarriages were reported in the
dydrogesterone group, while 22.2% of women receiving placebo
miscarried.
A meta-analysis was published of these five randomized
studies, which showed that dydrogesterone was associated with a
statistically significant reduction of 53% in the odds of miscar-
riage (odds ratio [OR]: 0.47; 95% confidence interval [CI] 0.31,
0.70) [31]. A subgroup analysis of the three most recent open-
label randomized studies showed a statistically significant
decrease of 58% in the odds of miscarriage (OR: 0.42; 95% CI
0.25, 0.69).
Dydrogesterone versus vaginal micronized progesterone
Dydrogesterone was compared with vaginal micronized proges-
terone for the treatment of TM in two studies [30,32]. Czajkowski
and colleagues [30] examined the effects of both drugs on
uteroplacental blood flow, as vascular changes occurring in
the first trimester may predispose the mothers to adverse
third trimester pregnancy outcomes, including IUGR and
Table 1. Dydrogesterone in the treatment of threatened miscarriage.
Study
Dydrogesterone versus standard of care
Omar et al. 2005 [26]
El-Zibdeh and Yousef 2009 [27]
Pandian 2009 [25]
Dydrogesterone versus placebo
Ehrenskjöld et al. 1967 [28]
Mistò 1967 [29]
Dydrogesterone versus vaginal micronized progesterone
Czajkowski et al. 2007 [30]
Vincze et al. 2006 [32]
AE, adverse event; BID, twice daily; N, number of patients included in the efficacy analysis; TID, three-times daily.
Design
Open-label, randomized
Open-label, randomized
Open-label, randomized
Double-blind, placebo-
controlled
Double-blind, placebo-
controlled
Double-blind, double-
dummy, parallel,
randomized
Randomized
Treatment arms
N ¼ 74 Dydrogesterone (40 mg initial dose
then 10 mg BID) until bleeding
stopped, plus bed rest and folic
acid
N ¼ 80 Bed rest and folic acid
N ¼ 86 Dydrogesterone (10 mg BID) until
1 week after bleeding stopped,
plus bed rest, folic acid, iron,
multivitamins
N ¼ 60 Bed rest, folic acid, iron,
multivitamins
N ¼ 96 Dydrogesterone (40 mg initial
dose, then 10 mg BID) until 16
weeks of gestation
N ¼ 95 Bed rest
N ¼ 72 Dydrogesterone (20 mg initial
dose, 20 mg 12 hours later, then
20 mg TID until symptoms
remit then 10 mg BID for 5 days
and 5 mg BID for  7 days),
plus strict bed rest
N ¼ 81 Placebo plus strict bed rest
N¼7 Dydrogesterone (20–40 mg daily for
6–15 days depending on clinical
conditions and laboratory data)
N¼9 Placebo
N ¼ 24 Dydrogesterone (30 mg daily) and
vaginal placebo for 6 weeks
N ¼ 29 Vaginal micronized progesterone
(300 mg daily) and oral placebo
for 6 weeks
N ¼ 86 Dydrogesterone (40 mg initial
dose, then 10 mg TID) until 13
weeks of gestation
N ¼ 63 Vaginal micro-crystallized proges-
terone (300 mg TID) until
13 weeks of gestation
Miscarriage rate Safety data
3/74 (4.1%) (p ¼ 0.037 vs Not reported in the study
control group)
DOI: 10.3109/09513590.2015.1121982
11/80 (13.8%)
15/86 (17.5%) (p  0.05 vs No AEs reported in the dydrogesterone group
control group) No statistically significant differences in preg-
nancy complications or congenital abnormal-
ities between groups
15/60 (25.0%)
12/96 (12.5%) (p50.05 vs No statistical differences in pregnancy compli-
control group) cations between groups
No report of intrauterine death or congenital
abnormalities in either group
27/95 (28.4%)
14/72 (19.4%) (miscarriage No unpleasant side effects were reported
or stillborn) No malformations or virilization reported in the
dydrogesterone group; two babies born with
malformation in the placebo group
23/81 (28.4%) (miscarriage
or stillborn)
0/7 (0%) No masculinization of female babies in the
dydrogesterone group
2/9 (22.2%)
2/24 (8.3%) Not reported in the study
4/29 (13.8%)
7/86 (8.1%) No abnormal fetal development reported
5/63 (7.9%)
Dydrogesterone & pregnancy
99
100 F. G. Mirza et al.
pregnancy-induced hypertension. Of note, in this study, 8.3% and
13.8% of women receiving oral dydrogesterone and vaginal
progesterone, respectively, miscarried [30]; however, these dif-
ferences were not statistically significant.
In the second study, conducted by Vincze and colleagues [32],
8.1% and 7.9% of women in the dydrogesterone and vaginal
micronized progesterone groups, respectively, miscarried;
however, these differences were not statistically significant.
The prospective studies reviewed here show that dydrogester-
one was consistently more effective than standard supportive care
or placebo, and demonstrated a positive trend towards being more
effective than vaginal micronized progesterone in the manage-
ment of TM. Based on evidence from clinical trials, dydrogester-
one, and in some cases progestogens in general, are currently
recommended by various societies worldwide for the management
of TM [33–36].
Recurrent miscarriage
Definition and treatment options
Recurrent miscarriage is defined as the loss of two [37], three
[38], or more consecutive pregnancies before 24 weeks of
gestation. It is estimated that approximately 5% and 2–3% of
couples trying to conceive have two or three consecutive
miscarriages, respectively [39]. The diagnostic approach in
cases of RM remains extremely challenging, particularly as no
clear cause can be identified in half of the cases. In the remaining
cases, etiologic factors include chromosomal abnormalities,
maternal immune dysfunction and endocrine abnormalities,
maternal thrombophilic disorders, or structural uterine
anomalies [39].
Apart from supportive measures, or the so-called ‘tender
loving care’, pharmacological options include administration of
anticoagulants (e.g. aspirin and/or heparins for women with
antiphospholipid syndrome or inherited thrombophilias) or pro-
gestogens [38,40]. The rest of this section will focus on the
assessment of dydrogesterone for the treatment of RM.
Four relevant prospective, controlled studies were identified
from the PubMed literature search [41–44], as well as a meta-
analysis [45]. A non-randomized clinical study, which is
discussed in the meta-analysis but was not indexed on PubMed,
is also described [46]. Full details on study design, treatment
arms, and pregnancy outcomes for these clinical trials can be
found in Table 2.
Dydrogesterone versus standard supportive care or placebo
Controlled studies showed that dydrogesterone was associated
with lower rates of miscarriage than standard of care treatment
alone [41,46] or placebo [42,43]. In a study by Freedman and
Berry [46], pregnant women with proven progesterone deficiency
were allocated to dydrogesterone and supportive care or support-
ive care alone; 33.3% and 92.3% of women miscarried in each
group, respectively (p ¼ 0.001). El-Zibdeh [41] conducted a three-
arm study that compared dydrogesterone treatment with hCG,
both in combination with standard supportive care, and with
standard supportive care alone. Significantly fewer women
miscarried in the dydrogesterone group than in the control
group (13.4% versus 29.2%, respectively [p ¼ 0.028]) [41]. No
significant differences were observed between groups in the
incidence of antepartum hemorrhage, preterm labor, IUGR, pre-
eclampsia, and congenital malformation.
Dydrogesterone was compared with placebo in a study by
MacDonald and colleagues [42], where no differences were seen
between the groups. Kumar and colleagues [43] conducted the
most recent and largest study included here, with women
Gynecol Endocrinol, 2016; 32(2): 97–106
receiving either dydrogesterone (10 mg twice daily; N ¼ 175) or
placebo (N ¼ 173) for 20 weeks. Significantly fewer women in the
dydrogesterone group miscarried compared with placebo (6.9%
versus 16.8%, respectively [p ¼ 0.004]). There was a significant
increase in the mean gestational age at delivery in the
dydrogesterone group compared with placebo (38.0 ± 2.0 versus
37.2 ± 2.4, respectively [p ¼ 0.002]). There was a trend towards
the reduction of preterm birth, cesarean delivery, and low
birth weight.
A 2013 Cochrane Systematic Review analyzed the use of
progestogens for the prevention of miscarriage (up to 20 weeks of
gestation) compared with placebo or no treatment in randomized
or quasi-randomized trials [47]. Overall, no significant differences
in the rates of preterm birth, neonatal death, or fetal genital
anomalies or virilization were found between progestogens and
placebo/no treatment interventions. No adverse maternal effects
were noted. Of interest to the current review, a subgroup analysis
was performed on four trials involving 225 women with RM
(defined as 3 consecutive miscarriages). Progestogen treatment
showed a statistically significant decrease in miscarriage rate
compared to placebo or no treatment (Peto OR: 0.39; 95% CI:
0.21, 0.72), although it was noted that these four trials were of
poor methodological quality and the results should be interpreted
with caution [47].
A meta-analysis of dydrogesterone studies was subsequently
published in 2015, and included two randomized or quasi-
randomized trials [41,43] and one non-randomized trial [46]. It
showed that there was a 10.5% miscarriage rate after dydroges-
terone administration, compared with 23.5% in controls, resulting
in a statistically significant reduction of 71% in the odds for
miscarriage when dydrogesterone is compared to standard care
(OR: 0.29; 95% CI: 0.13, 0.65) [45].
Dydrogesterone versus vaginal micronized progesterone
When dydrogesterone treatment was compared with vaginal
progesterone for the treatment of patients with a history of RM, it
was shown that dydrogesterone may be more effective than
vaginal micronized progesterone in preventing miscarriage (8.0%
and 15.7% of women miscarried, respectively) [44], although
these differences were not quoted as being statistically significant.
Increased vascular resistance in the uterine artery and reduced
uterine blood flow have been associated with miscarriage [48].
That observation is further validated by this study, where
resistance and pulsatility indices were significantly higher in
women with RM than in healthy controls [44]. Following
micronized progesterone or dydrogesterone treatment, endomet-
rial blood-flow parameters were improved in both groups, with
dydrogesterone being significantly more effective than progester-
one at improving peak systolic velocity [44].
Of note, vaginal micronized progesterone administered for the
treatment of RM was compared with placebo in a recent
multicenter, double-blind, randomized trial in women with a
history of three or more miscarriages, conducted by
Coomarasamy and colleagues [49]. Women with a positive
urinary pregnancy test and within 6 weeks of gestation received
either vaginal micronized progesterone (400 mg twice daily;
N ¼ 404) or placebo (N ¼ 432) until 12 weeks of gestation. In the
intention-to-treat population, the live birth rate after 24 weeks of
gestation was not statistically significant between groups (65.8%
and 63.3% in the progesterone and placebo groups, respectively;
relative rate: 1.04; 95% CI: 0.94, 1.15; absolute rate difference:
2.5 percentage point; 95% CI: 4.0, 9.0). An analysis of
secondary outcomes found no significant differences between
groups in clinical pregnancy rates (6–8 weeks), ongoing preg-
nancy (12 weeks), miscarriage, still birth and neonatal outcomes,
Table 2. Dydrogesterone in the treatment of recurrent miscarriage.
DOI: 10.3109/09513590.2015.1121982

Study Design Treatment arms Miscarriage rate Safety data

Dydrogesterone versus standard of care or hCG
Freedman and Berry 1970 [46]
El-Zibdeh 2005 [41]
Open-label, non-randomized N ¼ 18 Dydrogesteronea plus sedation and 6/18 (33.3%) (p ¼ 0.001 vs Not reported in the study
vitamins control group)
N ¼ 13 Sedation and vitamins 12/13 (92.3%)
Open-label, randomized N ¼ 82 Dydrogesterone (10 mg BID until 11/82 (13.4%) (p ¼ 0.028 vs No statistically significant differ-
12 weeks of gestation) plus bed no treatment) ences in pregnancy complica-
rest, vitamins tions, delivery or congenital
N ¼ 50 hCG (5000 IU every 4 days) plus 9/50 (18.0%) abnormalities
bed rest, vitamins No AEs were reported
N ¼ 48 Bed rest, vitamins 14/48 (29.2%)

Dydrogesterone versus placebo

MacDonald et al. 1972 [42]b Double-blind, randomized, N ¼ 20 Dydrogesterone (10 mg BID 3/20 (15.0%) Not reported in the study
placebo-controlled [or 20 mg BID if symptoms
persisted])
N ¼ 20 Placebo 3/20 (15.0%)
Kumar et al. 2014 [43] Double-blind, randomized, N ¼ 175 Dydrogesterone (20 mg daily until 12/175 (6.9%) (p ¼ 0.004 vs Trend in the reduction of preg-
parallel, placebo-controlled 20 weeks of gestation) placebo) nancy or delivery complications
with dydrogesterone
N ¼ 173 Placebo 29/173 (16.8%)
N ¼ 174 Healthy pregnant women with no 6/174 (3.5%)
history of miscarriage

Dydrogesterone versus vaginal micronized progesterone

Ghosh et al. 2014 [44] Single-blind, randomized, N ¼ 50 Dydrogesterone (10 mg BID for up 4/50 (8.0%) Not reported in the study
controlled to 12 weeks)
N ¼ 51 Micronized vaginal progesterone 8/51 (15.7%)
(100 mg TID for 12 weeks)
N ¼ 32 Healthy pregnant women with no No women miscarried
history of miscarriage
a
Administered orally and parenterally; bTreatment duration and patient number in each treatment group were not reported in this study
AE, adverse event; BID, twice daily; hCG, human chorionic gonadotrophin; IU, international unit; N, number of patients included in the efficacy analysis; TID, three-times daily.
Dydrogesterone & pregnancy
101
102 F. G. Mirza et al.
or in the median gestational age at miscarriage. The rate of
adverse events was not significantly different between groups.
A number of important factors may explain the differences
observed between the findings of Coomarasamy and colleagues
[49] (vaginal micronized progesterone versus placebo), and the
positive results seen by Kumar and colleagues [43] (dydrogester-
one versus placebo).
Firstly, the two agents evaluated are different in their structure,
pharmacokinetic properties and binding characteristics. In par-
ticular, the bent structure of dydrogesterone improves its
bioavailability, specificity and affinity for the progesterone
receptor, enhancing its progestogenic effects compared with
progesterone [3,12]. Dydrogesterone benefits from a prolonged
effect with a mean terminal half-life of 5–7 hours [50]; vaginal
micronized progesterone diffuses through the entire uterus within
4–5 hours [51]. Moreover, dydrogesterone has been shown to have
an increased effect on some aspects of uteroplacental blood flow
in RM compared to micronized progesterone [44].
Secondly, the studies used different inclusion criteria, particu-
larly for age and stage of pregnancy. Kumar and colleagues [43]
included women below 35 years of age and at 4–8 weeks of
gestation, once the fetal heart was detected. In the study by
Coomarasamy and colleagues [49], women up to 39 years of age
were enrolled after a positive urinary pregnancy test and before
6 weeks of gestation. Maternal age can impact on the rate of
chromosomal abnormalities in women experiencing 3 miscar-
riages (60.0% for women 535 years of age; 78.3% for women
35 years of age) [52]. The differing inclusion criteria means
pregnancy was likely further advanced in the study conducted by
Kumar and colleagues [43], thus miscarriages happening very
early in pregnancy would have already occurred.
Finally, the studies also differed in terms of treatment duration,
with women treated for up to 12 and 20 weeks in the studies by
Coomarasamy and colleagues [49] and Kumar and colleagues
[43], respectively.
Overall, dydrogesterone use in pregnant women with a history
of RM improved several pregnancy outcomes (e.g. reduction in
miscarriages and improved gestational age and baby weight at
delivery) compared use of placebo, an active comparator (with
or without standard of care), or standard of care alone.
Dydrogesterone is recommended by the guidelines for the
prevention of RM [35,36].
Dydrogesterone for the treatment of luteal phase
insufficiency in infertile women
Luteal phase insufficiency is a condition in which endogenous
progesterone is not sufficient to maintain a functional secretory
endometrium and allow normal embryo implantation and growth
[53]. A number of factors are involved in the regulation of
progesterone formation, such as adrenergic signals, follicle-
stimulating hormone, luteinizing hormone, gonadotropin-releas-
ing hormone (GnRH), and estrogens [3]. Therefore, any
abnormalities in these factors, as well as conditions such as
thyroid and prolactin disorders, renal transplantation, increased
b-endorphin levels, lactation, obesity, and ovarian aging may
result in luteal-phase defects (LPD) and infertility [53].
Dydrogesterone is indicated for the treatment of infertility due
to LPS. One study evaluating dydrogesterone in the treatment of
LPD was identified from the PubMed literature search (Table 3)
[54]. This three-arm study compared dydrogesterone with
progesterone vaginal suppositories and no treatment, and
showed that both dydrogesterone and vaginal progesterone
treatment led to a higher rate of response (defined as correction
of endometrial defect or successful pregnancy) than no treatment
Gynecol Endocrinol, 2016; 32(2): 97–106
(68.7%, 62.5%, and 16.6%, respectively [p50.001 versus no
treatment]).
Dydrogesterone in assisted reproductive technology
Luteal-phase defects may be observed in cycles in which IVF is
performed, due to the use of fertility treatments such as aspiration
of granulosa cells during oocyte retrieval or use of GnRH analogs,
which may impair the estrogen–progesterone ratio [55]. A recent
Cochrane Review examined current LPS options (e.g. progester-
one, hCG, GnRH agonists) in ART [56]. It concluded that
progestogen supplementation was the most appropriate LPS
method and that treatment with hCG was associated with a
higher rate of ovarian hyperstimulation syndrome.
Dydrogesterone has also been assessed for LPS in ART/IVF,
and six relevant prospective clinical trials were identified from the
PubMed literature search [11,57–61]. Full details on study design,
treatment arms, and pregnancy success rates for these clinical
trials can be found in Table 3.
Dydrogesterone was first compared with hCG and with
placebo by Kupferminc and colleagues [57]. No significant
differences were reported between the groups in terms of
pregnancy rates (29.6%, 23.5%, and 27.4%, respectively) [57].
Dydrogesterone was then compared with vaginal micronized
progesterone, which is routinely used in ART centers, in a number
of studies. Overall, similar rates of successful pregnancies were
observed between women receiving dydrogesterone or micronized
progesterone in these studies [11,58–61]. Of note, Patki and
Pawar [58] reported that the pregnancy rate was significantly
higher with dydrogesterone 30 mg daily than vaginal micronized
progesterone 600 mg daily (41.0% versus 29.4%, respectively
[p50.01]).
Two of the studies identified also evaluated patients’ satisfac-
tion with their treatment. The two drugs were administered via
different routes due to their differing bioavailability, with
dydrogesterone being administered orally and micronized pro-
gesterone vaginally. Chakravarty and colleagues [11] reported that
significantly (p50.05) more of those patients given dydrogester-
one were satisfied with the tolerability of their treatment
compared to those receiving vaginal progesterone, 10.5% of
whom reported vaginal discharge or irritation. In a study by
Tomic and colleagues [61], patients receiving oral dydrogesterone
were significantly more satisfied with their treatment than
patients receiving a vaginal progesterone gel (p ¼ 0.01). In
particular, treatment with the progesterone gel was significantly
associated with vaginal discharge (p ¼ 0.001) and vaginal
bleeding (p ¼ 0.04).
Overall, the studies reviewed here show that oral dydrogester-
one is as effective as vaginal progesterone for LPS in women
undergoing ART/IVF. These results reinforce the conclusions of a
2011 Cochrane Review, which showed that a significantly better
outcome of clinical pregnancy was seen with dydrogesterone
versus micronized progesterone (Peto OR: 0.79; 95% CI: 0.65,
0.96) [62]. In terms of live birth rate, miscarriage rate, and
incidence of ovarian hyperstimulation syndrome, dydrogesterone
was comparable to micronized progesterone.
Based on these results, dydrogesterone is currently being
evaluated in two randomized Phase III registration trials for LPS
in ART (Lotus I [Dydrogesterone versus intravaginal micronized
progesterone; double-blind, double-dummy study NCT01850030]
and Lotus II [Dydrogesterone versus 8% intravaginal progesterone
gel; open-label study NCT02491437]). The efficacy and safety of
dydrogesterone treatment (30 mg daily) for LPS support in women
undergoing IVF will be compared to those of micronized
progesterone capsules (600 mg daily, administered vaginally) in
Table 3. Dydrogesterone for the treatment of luteal phase insufficiency.

Study Design Treatment arms Outcomes measures (study endpoint) Safety data
Infertile women with inadequate luteal phase
Balasch et al. 1982 [54] Randomized N ¼ 16 Dydrogesteronea (10 mg BID for 11/16 (68.7%) women responded to therapy The four infants born from women
10 days) (i.e. correction of endometrial defect or receiving dydrogesterone did not
successful pregnancy) (p50.001 vs no have evidence of congenital
DOI: 10.3109/09513590.2015.1121982

Women undergoing in vitro fertilization
Kupferminc et al. 1990 [57]
Chakravarty et al. 2005 [11]
Patki and Pawar 2007 [58]
treatment) malformation
N ¼ 16 Progesterone vaginal suppositoriesa 10/16 (62.5%) women responded to therapy
(25 mg BID for 10 days) (p50.001 vs no treatment)
N ¼ 12 No treatment 2/12 (16.6%) women responded to therapy
Randomized, blind, placebo- N ¼ 54 Dydrogesteroneb (10 mg TID) 16/54 (29.6%) women became pregnant Not reported in this study
controlled
b
N ¼ 51 hCG (2500 IU IM on days 3, 6, and 12/51 (23.5%) women became pregnant
10)
N ¼ 51 Placebob 14/51 (27.4%) women became pregnant
Randomized, comparative N ¼ 79 Dydrogesteroneb (10 mg BID) 19/79 (24.1%) women had a viable delivery No report of vaginal discharge or
N ¼ 351 Intravaginal micronized progester- and 6/79 (7.6%) miscarried irritation in the dydrogesterone
oneb (200 mg TID) 80/351 (22.8%) women had a viable delivery group; this was experienced by
and 29/351 (8.3%) miscarried 10.5% of patients in the vaginal
micronized progesterone group.
Significantly (p50.05) more patients
in the dydrogesterone group than
in the micronized progesterone
group were satisfied with the
tolerability of their treatment.
No statistically significant difference
between group in abnormal liver
function.
Randomized Phase I Micronized progesterone (600 mg) following oocyte retrieval plus Not reported in this study
N ¼ 218 Dydrogesterone (20 mg daily) fol- 79/218 (36.2%) women became pregnant
lowing embryo transfer
N ¼ 280 Placebo following embryo transfer 64/280 (22.9%) women became pregnant

Ganesh et al. 2011 [59]
Salehpour et al. 2013 [60]
Randomized, single-blind
Randomized, single-blind
Phase II
N ¼ 366 Dydrogesterone (30 mg daily) from
the day of oocyte retrieval
N ¼ 309 Micronized progesterone (600 mg
daily) following oocyte retrieval
N ¼ 422 Dydrogesteroneb (10 mg BID)
N ¼ 482 Micronized vaginal progesterone
gelb (90 mg daily)
N ¼ 459 Micronized progesterone capsule
vaginallyb (200 mg TID)
N ¼ 40 Dydrogesteronec (10 mg QID)
150/366 (41.0%) women became pregnant
91/309 (29.4%) women became pregnant
121/422 (28.7%) women became pregnant Not reported in this study
and 14/121 (11.6%) miscarried
138/482 (28.6%) women became pregnant
and 18/138 (13.0%) miscarried
104/459 (22.7%) women became pregnant
and 19/104 (18.3%) miscarried
10/40 (25.0%) women became pregnant

(continued )
Dydrogesterone & pregnancy
103
104 F. G. Mirza et al. Gynecol Endocrinol, 2016; 32(2): 97–106

irritation (p ¼ 0.001), vaginal dis-

Significantly more women receiving

Significantly more women receiving

dydrogesterone reported perineal

(p ¼ 0.008) compared with vagi-

bleeding (p ¼ 0.04) and interfer-

LOTUS I, and to those of 8% intravaginal progesterone gel (90 mg

assessed side-effect (p ¼ 0.001)

(p ¼ 0.009) and epigastric pain

as well as the total number of

vaginal progesterone gel than

ence with coitus (p ¼ 0.001),

daily) in LOTUS II.

dydrogesterone experienced
bleeding (p ¼ 0.03), nausea

BID, twice daily; hCG, human chorionic gonadotrophin; IM, intramuscular; IU, international units; N, number of patients included in the efficacy analysis; QID, four-times daily; TID, three-times daily.
charge (p ¼ 0.001), vaginal
Safety

nal progesterone
Dydrogesterone has been marketed and used worldwide since
the 1960s for a number of conditions related to progesterone
insufficiency. Based on dydrogesterone sales figures, it is
Safety data

estimated that the cumulative exposure for all indications (HRT,

non-pregnancy and pregnancy-related) from April 1960 to April
2014 is494 million patients, of which it is estimated that 420
million pregnancies were exposed to dydrogesterone in utero [63].
Data on birth defects following maternal use of dydrogesterone
28.1% of women had an ongoing pregnancy
30.3% of women had an ongoing pregnancy

during pregnancy, spontaneously reported between 1977 and

Treatment started 3 days after the basal body temperature rise; bTreatment started on the day of embryo transfer; cTreatment started on the day of oocyte retrieval.
2005, were analyzed [64]. During this period, it is estimated that
13/40 (32.5%) women became pregnant
Outcomes measures (study endpoint)

10 million pregnancies were exposed to dydrogesterone. It was

concluded that there was no evidence for an increased risk of birth
defects following maternal use of dydrogesterone [64]. A low
number of cases (28 cases) of potential links between dydroges-
terone exposure during pregnancy and congenital birth defects
were reported; however, no pattern of abnormalities was
identified [64].
In 2008, the British Medicines Healthcare products Regulatory
Agency (MHRA) declared that no significant safety concerns
associated with dydrogesterone have been identified for either the
mother or the fetus [65].
Dydrogesterone safety in pregnancy, in terms of pregnancy
complications or birth defects, as well as tolerability during
treatment, has been briefly addressed, with data from previously
Vaginal progesteronec (400 mg BID)

Vaginal progesterone gelc (90 mg)

referenced clinical trials shown in Tables 1–3.

Table 3. Continued

Overall, clinical and post-marketing experience supports the

Dydrogesteronec (10 mg BID)

well-established and favorable benefit–risk profile of dydroges-

terone in the approved indications.
Treatment arms

Conclusion
Dydrogesterone appears to be an effective treatment for the
management of TM and RM, where it has been shown to
significantly improve pregnancy outcomes compared with pla-
cebo or no treatment. Dydrogesterone was also shown to be as
effective as vaginal micronized progesterone for LPS in the
setting of ART. Yet, according to recent systematic reviews and
N ¼ 415
N ¼ 416
N ¼ 40

meta-analyses, dydrogesterone appears to be superior to vaginal

micronized progesterone for the treatment of TM and RM.
Dydrogesterone has been marketed since the 1960s and, given its
effectiveness as well as its well-established and favorable risk–
benefit profile, wider potential benefits of dydrogesterone therapy
(currently being investigated in Phase III studies for LPS in ART)
Randomized, double-blind

are highly anticipated.

Declaration of interest
The authors would like to thank Dr Camille Bonomelli of Alpharmaxim
Healthcare Communications for medical writing support, which was
funded by Abbott Healthcare Products.
Design

Fadi Mirza has fulfilled speaker engagements with Abbott. He has not
received any form of compensation in return for his efforts in the writing
of the manuscript.
Ameet Patki has been part of the Global Advisory Board for
DuphastonÕ (dydrogesterone) since 2010. He has not received any form
of compensation in return for his efforts in the writing of the manuscript.
Tomic et al. 2015 [61]

Claire Pexman-Fieth is an employee of Abbott and owns shares of

Abbott.

References
1. Schindler AE. First trimester endocrinology: consequences for
Study

diagnosis and treatment of pregnancy failure. Gynecol Endocrinol

2004;18:51–7.
a
DOI: 10.3109/09513590.2015.1121982
2. Szekeres-Bartho J, Barakonyi A, Par G, et al. Progesterone as an
immunomodulatory molecule. Int Immunopharmacol 2001;1:
1037–48.
3. Schindler AE. Progestational effects of dydrogesterone in vitro,
in vivo and on the human endometrium. Maturitas 2009;65:
S3–S11.
4. Blacker CM, Ginsburg KA, Leach RE, et al. Unexplained infertility:
evaluation of the luteal phase; results of the National Center for
Infertility Research at Michigan. Fertil Steril 1997;67:437–42.
5. Baird DD, Wilcox AJ, Weinberg CR, et al. Preimplantation
hormonal differences between the conception and non-conception
menstrual cycles of 32 normal women. Hum Reprod 1997;12:
2607–13.
6. Csapo AI, Pulkkinen MO, Ruttner B, et al. The significance of the
human corpus luteum in pregnancy maintenance. I. Preliminary
studies. Am J Obstet Gynecol 1972;112:1061–7.
7. Couzinet B, Le Strat N, Ulmann A, et al. Termination of early
pregnancy by the progesterone antagonist RU 486 (Mifepristone).
N Engl J Med 1986;315:1565–70.
8. Spitz IM, Bardin CW. Clinical pharmacology of RU 486 – an
antiprogestin and antiglucocorticoid. Contraception 1993;48:
403–44.
9. de Lignières B. Oral micronized progesterone. Clin Ther 1999;21:
41–60.
10. Di Renzo GC, Mattei A, Gojnic M, Gerli S. Progesterone and
pregnancy. Curr Opin Obstet Gynecol 2005;17:598–600.
11. Chakravarty BN, Shirazee HH, Dam P, et al. Oral dydrogesterone
versus intravaginal micronised progesterone as luteal phase
support in assisted reproductive technology (ART) cycles:
results of a randomised study. J Steroid Biochem Mol Biol 2005;
97:416–20.
12. Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens
used in postmenopausal hormone therapy: differences in their
pharmacological properties, intracellular actions, and clinical
effects. Endocr Rev 2013;34:171–208.
13. Kanová N, Biciková M. Hyperandrogenic states in pregnancy.
Physiol Res 2011;60:243–52.
14. Rižner TL, Brožic P, Doucette C, et al. Selectivity and potency of
the retroprogesterone dydrogesterone in vitro. Steroids 2011;76:
607–15.
15. Wang MH, Baskin LS. Endocrine disruptors, genital development,
and hypospadias. J Androl 2008;29:499–505.
16. Coppola PT, Coppola M. Vaginal bleeding in the first 20 weeks of
pregnancy. Emerg Med Clin North Am 2003;21:667–77.
17. Everett C. Incidence and outcome of bleeding before the 20th week
of pregnancy: prospective study from general practice. BMJ 1997;
315:32–4.
18. Qureshi NS. Treatment options for threatened miscarriage. Maturitas
2009;65:S35–S41.
19. Weiss JL, Malone FD, Vidaver J, et al. Threatened abortion: a risk
factor for poor pregnancy outcome, a population-based screening
study. Am J Obstet Gynecol 2004;190:745–50.
20. Verma SK, Premi HK, Gupta TV, et al. Perinatal outcome of
pregnancies complicated by threatened abortion. J Indian Med
Assoc 1994;92:364–5.
21. Arck PC, Rücke M, Rose M, et al. Early risk factors for miscarriage:
a prospective cohort study in pregnant women. Reprod Biomed
Online 2008;17:101–13.
22. Aleman A, Althabe F, Belizán J, Bergel E. Bed rest during
pregnancy for preventing miscarriage. Cochrane Database Syst Rev
2005;2:CD003576.
23. Devaseelan P, Fogarty PP, Regan L. Human chorionic gonado-
trophin for threatened miscarriage. Cochrane Database Syst Rev
2010;5:CD007422.
24. Wahabi HA, Fayed AA, Esmaeil SA, Al Zeidan RA. Progestogen for
treating threatened miscarriage. Cochrane Database Syst Rev 2011;
12:CD005943.
25. Pandian RU. Dydrogesterone in threatened miscarriage: a Malaysian
experience. Maturitas 2009;65:S47–S50.
26. Omar MH, Mashita MK, Lim PS, Jamil MA. Dydrogesterone in
threatened abortion: pregnancy outcome. J Steroid Biochem Mol
Biol 2005;97:421–5.
27. El-Zibdeh MY, Yousef LT. Dydrogesterone support in threatened
miscarriage. Maturitas 2009;65:S43–S46.
28. Ehrenskjöld ML, Bondo B, Weile F. [Treatment of threatened
abortion with dydrogesterone]. Ugeskr Laeger 1967;129:1678–9.
Dydrogesterone & pregnancy 105
29. Mistò A. [Experiences with 6-dehydro-retroprogesterone in the
treatment of placental insufficiency]. Ann Ostet Ginecol Med
Perinat 1967;89:102–12.
30. Czajkowski K, Sienko J, Mogilinski M, et al. Uteroplacental
circulation in early pregnancy complicated by threatened abortion
supplemented with vaginal micronized progesterone or oral
dydrogesterone. Fertil Steril 2007;87:613–8.
31. Carp H. A systematic review of dydrogesterone for the treatment of
threatened miscarriage. Gynecol Endocrinol 2012;28:983–90.
32. Vincze E, Molnár-G B, Földesi I, Pál A. Treatment possibilities for
threatened abortion using progesterone and progesterone-type drugs.
Magyar Noorvosok Lapja 2006;69:281–4.
33. National Institute for Health and Care Excellence (NICE). Ectopic
pregnancy and miscarriage. Diagnosis and initial management in
early pregnancy of ectopic pregnancy and miscarriage. 2012 Dec.
Available from: https://www.nice.org.uk/guidance/cg154/resources/
guidance-ectopic-pregnancy-and-miscarriage-pdf [last accessed 24
Aug 2015].
34. The Royal Australian and New Zealand College of Obstetricians
and Gynaecologists. Progesterone support of the luteal phase and
in the first trimester. 13 A.D. Jul. Available from: http://www.
ranzcog.edu.au/doc/progesterone-support-of-the-luteal-phase-and-early-
pregnancy.html [last accessed 24 Aug 2015].
35. Schindler AE, Carp H, Druckmann R, et al. European Progestin
Club Guidelines for prevention and treatment of threatened or
recurrent (habitual) miscarriage with progestogens. Gynecol
Endocrinol 2015;31:447–9.
36. Arab H, Alsofayan H, Alharbi A, et al. The Saudi Obstetrics and
Gynecological Society (SOGS) National Guidelines for the
Prevention and Treatment of Miscarriage. Saudi J Obstet Gynecol
2014;15:40–64.
37. Practice Committee of American Society for Reproductive
Medicine. Definitions of infertility and recurrent pregnancy loss: a
committee opinion. Fertil Steril 2013;99:63.
38. Royal College of Obstetricians and Gynaecologists. The
Investigation and Treatment of Couples with Recurrent First-
trimester and Second-trimester Miscarriage. Green-top Guideline
No. 17. 2011 Apr. Available from: https://www.rcog.org.uk/
globalassets/documents/guidelines/gtg_17.pdf [last accessed 24
Aug 2015].
39. Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes,
evaluation and management. Postgrad Med J 2015;91:151–62.
40. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-
based guidelines for the investigation and medical treatment of
recurrent miscarriage. Hum Reprod 2006;21:2216–22.
41. El-Zibdeh MY. Dydrogesterone in the reduction of recurrent
spontaneous abortion. J Steroid Biochem Mol Biol 2005;97:431–4.
42. MacDonald RR, Goulden R, Oakey RE. Cervical mucus, vaginal
cytology and steroid excretion in recurrent abortion. Obstet Gynecol
1972;40:394–402.
43. Kumar A, Begum N, Prasad S, et al. Oral dydrogesterone treatment
during early pregnancy to prevent recurrent pregnancy loss and its
role in modulation of cytokine production: a double-blind,
randomized, parallel, placebo-controlled trial. Fertil Steril 2014;
102:1357–63.
44. Ghosh S, Chattopadhyay R, Goswami S, et al. Assessment of sub-
endometrial blood flow parameters following dydrogesterone and
micronized vaginal progesterone administration in women with
idiopathic recurrent miscarriage: a pilot study. J Obstet Gynaecol
Res 2014;40:1871–6.
45. Carp H. A systematic review of dydrogesterone for the treatment of
recurrent miscarriage. Gynecol Endocrinol 2015;31:422–30.
46. Freedman RS, Berry A. Progesterone deficiency in preganancy.
S Afr J Obstet Gynaecol 1970;46:72–6.
47. Haas DM, Ramsey PS. Progestogen for preventing miscarriage.
Cochrane Database Syst Rev 2013;10:CD003511.
48. El-mashad AI, Mohamed MA, Farag MA, et al. Role of uterine
artery Doppler velocimetry indices and plasma adrenomedullin level
in women with unexplained recurrent pregnancy loss. J Obstet
Gynaecol Res 2011;37:51–7.
49. Coomarasamy A, Williams H, Truchanowicz E, et al.
A Randomized Trial of Progesterone in Women with Recurrent
Miscarriages. N Engl J Med 2015;373:2141–8.
50. Abbott B.V. Duphaston 10mg Film-Coated Tablets Summary of
Product Characteristics; 2012.
106 F. G. Mirza et al.
51. Bulletti C, de Ziegler D, Flamigni C, et al. Targeted drug delivery in
gynaecology: the first uterine pass effect. Hum Reprod 1997;12:
1073–9.
52. Choi TY, Lee HM, Park WK, et al. Spontaneous abortion and
recurrent miscarriage: a comparison of cytogenetic diagnosis in 250
cases. Obstet Gynecol Sci 2014;57:518–25.
53. Practice Committee of the American Society for Reproductive
Medicine. Current clinical irrelevance of luteal phase deficiency:
a committee opinion. Fertil Steril 2015;103:e27–e32.
54. Balasch J, Vanrell JA, Márquez M, et al. Dehydrogesterone versus
vaginal progesterone in the treatment of the endometrial luteal phase
deficiency. Fertil Steril 1982;37:751–4.
55. Gidley-Baird AA, O’Neill C, Sinosich MJ, et al. Failure of
implantation in human in vitro fertilization and embryo transfer
patients: the effects of altered progesterone/estrogen ratios in
humans and mice. Fertil Steril 1986;45:69–74.
56. van der Linden M, Buckingham K, Farquhar C, et al. Luteal phase
support for assisted reproduction cycles. Cochrane Database Syst
Rev 2015;7:CD009154.
57. Kupferminc MJ, Lessing JB, Amit A, et al. A prospective
randomized trial of human chorionic gonadotrophin or dydrogester-
one support following in-vitro fertilization and embryo transfer.
Hum Reprod 1990;5:271–3.
58. Patki A, Pawar VC. Modulating fertility outcome in assisted
reproductive technologies by the use of dydrogesterone. Gynecol
Endocrinol 2007;23:68–72.
Gynecol Endocrinol, 2016; 32(2): 97–106
59. Ganesh A, Chakravorty N, Mukherjee R, et al. Comparison of oral
dydrogestrone with progesterone gel and micronized progesterone
for luteal support in 1,373 women undergoing in vitro fertilization:
a randomized clinical study. Fertil Steril 2011;95:1961–5.
60. Salehpour S, Tamimi M, Saharkhiz N. Comparison of oral
dydrogesterone with suppository vaginal progesterone for luteal-
phase support in in vitro fertilization (IVF): a randomized clinical
trial. Iran J Reprod Med 2013;11:913–8.
61. Tomic V, Tomic J, Klaic DZ, et al. Oral dydrogesterone versus
vaginal progesterone gel in the luteal phase support: randomized
controlled trial. Eur J Obstet Gynecol Reprod Biol 2015;186:49–53.
62. van der Linden M, Buckingham K, Farquhar C, et al. Luteal phase
support for assisted reproduction cycles. Cochrane Database Syst
Rev 2011;10:CD009154.
63. Podzolkova N, Tatarchuk T, Doshchanova A, et al. Dydrogesterone
treatment for menstrual-cycle regularization in routine clinical
practice: a multicenter observational study. Gynecol Endocrinol
2015. [Epub ahead of print]. doi: 10.3109/09513590.2015.1115832.
64. Queisser-Luft A. Dydrogesterone use during pregnancy: overview of
birth defects reported since 1977. Early Hum Dev 2009;85:375–7.
65. Medicines and Healthcare products Regulatory Agency (MHRA).
MHRA UK Public Assessment Report. Efficacy of progestogens
in the maintenance of early pregnancy in women with threatened
miscarriage or recurrent miscarriage. 2008 Feb. Available
from: http://www.mhra.gov.uk/home/groups/s-par/documents/
websiteresources/con079333.pdf [last accessed 24 Aug 2015].
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