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Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: randomized controlled trial

European Journal of Obstetrics & Gynecology and Reproductive Biology, March 2015, Pages 49 - 53

Abstract

Objectives

To compare efficacy, satisfaction and tolerability of oral dydrogesterone and micronized vaginal progesterone gel used for luteal supplementation.

Study design

Randomized controlled trial. A total of 853 infertile women undergoing IVF/ICSI treatment in University Hospital Center “Sisters of Mercy”, Zagreb, Croatia.

Luteal support was provided as Crinone 8%® vaginal progesterone gel (90 mg) administered daily, or oral dydrogesterone Duphaston® (2× 10 mg) administered two times daily. Progesterone was administered from the day of oocyte retrieval (day 0) till pregnancy test or in a case of pregnancy, until week 10.

Results

The on-going pregnancy rates were comparable between Crinone 8%® vaginal progesterone gel and oral dydrogesterone – Duphaston® (28.1% versus 30.3%; OR 1.11 (0.82–1.49 with 95% CI)). Overall satisfaction and tolerability were significantly higher in the dydrogesterone group than in the Crinone group. Vaginal bleeding, interference with coitus and local adverse side effects such as vaginal irritation and discharge occurred significantly more in Crinone group than in dydrogesterone group.

Conclusions

Oral dydrogesterone is effective drug, well tolerated and accepted among patients and can be considered for routine luteal support.

Clinical trial registration number: NCT01178931; www.clinicaltrials.gov.

Keywords: Dydrogesterone, Vaginal progesterone, Luteal phase support, IVF/ET, Pregnancy rate.

Introduction

The use of gonadotropin-releasing hormone (GnRH) agonists in the ovarian stimulation, which prevents a premature surge of luteal hormone (LH), ultimately leads to suppression of the pituitary gland [1]. Higher levels of estrogen observed during induced cycles result in inhibiting effect on the implantation of human embryos and though to underlie the corpus luteum dysfunction associated with IVF cycles [2]. The luteal support in in vitro-fertilization (IVF) cycles can be prolonged using human chorionic gonadotropin (hCG) and/or progesterone.

Since it has been noted that the use of hCG was related with higher risks of the onset of ovarian hyperstimulation syndrome (OHSS), progesterone is nowadays a product of choice in luteal support [3] and [4].

Currently vaginal progesterone is widely used, since the classic oral progesterone results in low bioavailability and lower pregnancy rate [5] and the intramuscular progesterone (IM-P) daily injections are painful and may cause abscesses, inflammatory reactions and local soreness [6] and [7]. Polyzos et al. [8] found that no significant difference exists between vaginal gel and all other vaginal progesterone forms in terms of clinical pregnancy rates, but Crinone 8% gel seems to be better accepted and preferred by patients [9] and [10].

However, standard protocol for luteal phase support has not been established (i.e. optimal dosage, route or duration).

Dydrogesterone is a synthetic retroprogesterone with good oral bioavailability [11]. Oral administration is very convenient for the patients and may be even better tolerated than commonly used vaginal or IM-P. There are limited reports on the use of dydrogesterone in IVF cycles as luteal support [12], [13], [14], [15], and [16]. The aim of this randomized controlled trial was to compare efficacy, tolerability and satisfaction rate of oral dydrogesterone and vaginal progesterone gel in the luteal phase support.

Materials and methods

The prospective, randomized, double-blinded clinical trial was conducted from October 2010 to October 2013 in a tertiary infertility unit at University Hospital Center “Sisters of Mercy”, Zagreb, Croatia.

Patients were randomly assigned at the day of oocyte retrieval following computerized random number generator in procedure, to study or control group. Random allocation concealment with intervention drug was ensured by sequentially numbered, sealed, opaque envelopes. Patients were aware of the allocated arm since the treatment drugs have different route of administration, but investigators and outcome assessor were kept blinded to the allocation.

Eligible participants were all women undergoing controlled ovarian stimulation for IVF/ICSI treatment who met the following inclusion criteria: aged 18–45 years, a body mass index (BMI) < 35 kg/m2, applied routine short ovulation induction protocol with GnRH agonist, with less than three prior IVF cycles and at least one aspirated oocyte.

Exclusion criteria included: a history of dysfunctional uterine bleeding, recurrent miscarriage (defined as three or more spontaneous miscarriage), acute urogenital disease, transfer of frozen embryos and previous allergic reactions to progesterone products.

After screening and successful enrollment in the study, the participants underwent standard short ovarian hyperstimulation protocol with GnRH agonists. Gonadotropin releasing hormone (GnRH) analog was introduced with Triptorelin (Decapeptyl®, Ferring, Kiel, Germany) in form of subcutaneous injections, 2× 0.1 mg per day. From the 2nd day of ongoing cycle the recombinant FSH (rFSH, Gonal-F®, Serono, Bari, Italy or Puregon®, Organon Ltd., Dublin, Ireland) was subjoined according to individually adopted dosage, usually 225 IU and reduced to 150 IU in step-down regiment until a day of hCG application. The ovarian response was measured by serum level of estradiol (E2) and ultrasound monitoring. Gonadotropin stimulation was stopped when at least two follicles reached 17 mm in diameter. To trigger the final follicular maturation hCG (Brevactid®, Ferring, Kiel, Germany) 10000 IU was administered. Approximately 36–38 h later the aspiration of oocytes was performed under supervision of transvaginal ultrasound. Oocytes were afterwards cultivated in medium and 3–4 h later associated with sperm. Upon successful fertilization, the two best available embryos were selected and on the 2–5 day transferred into uterine cavity.

Patients were randomly assigned into one of the two groups – study group and the control group. Study group was receiving 2× 10 mg of oral dydrogesterone (Duphaston®, Abbot Biologicals B.V., Olst, Netherlands) from the day of oocyte retrieval until a pregnancy test or in the case of pregnancy until week 10. Control group was receiving 1× 90 mg of vaginal progesterone gel (Crinone 8%, Fleet Laboratories Ltd., Watford, UK) in the same fashion i.e. from the day of oocyte retrieval until pregnancy test or in the case of pregnancy until week 10.

Pregnancy was detected by 10 mIU/L serum level of β-hCG, approximately 2 weeks after ET and confirmed by the presence of gestational sac(s) at 6 weeks’ gestation by transvaginal ultrasound. Spontaneous abortion is defined as the loss of clinical pregnancy before completed 22 weeks’ gestation. An ongoing pregnancy is defined by the identification of fetal heartbeats at 12 weeks’ gestation.

The primary outcome was ongoing pregnancy rate, defined by the presence of gestational sac(s) with viable fetal heart beats at 12 weeks’ gestation by transvaginal ultrasound.

Secondary outcome measures were satisfaction score, determinate on the 5-point level scale (with 1 being “absolutely unsatisfied” and 5 being “absolutely dissatisfied”) and tolerability accessed by questionnaire with different side effects that the supplements could cause.

The side effects included the occurrence of: headache, dizziness, somnolence, breast fullness, nausea/vomiting, bloating, abdominal pain, perineal irritation, vaginal discharge, vaginal bleeding and interference with coitus.

To detect 10% difference in pregnancy rate, which is considered clinically significant with a power of 80% and α 0.05, a sample size of 383 patients was necessary. Given a dropout rate of 10% in total the study should include 421 patients.

SPSS® version 22 statistical package for Windows was used for data analysis. Statistical analysis was made by Chi-square test, Fisher's exact test and t-test for independent samples. Value of p < 0.05 was considered statistically significant.

Results

A total of 853 patients were recruited and 831 completed the study. Drop-out rate was 2.6%, reasons were withdrawal of consent, OHSS, preference for other progesterone drug, discontinued treatment or lost to follow-up which is presented in more details in Fig. 1. Participants were randomized to receive oral dydrogesterone (Duphaston) – study group (n = 415) or vaginal progesterone gel (Crinone 8%) – control group (n = 416). Patients’ demographic data and infertility characteristics (Table 1) did not differ statistically significant regarding patients age (in all three age-subgroups: <35 years, 35–40 and >40 years), BMI, prior IVF attempts, primary or secondary infertility, infertility cause and duration.

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Fig. 1 Participant CONSORT flow diagram.

Table 1 Patients demographic data and treatment characteristics.

Parameters Dydrogesterone group Crinone group p value
(n = 415) (n = 416)
Age 34.1 ± 8.2 32.6 ± 8.8 0.99
<35 years 50.4% 55.8% 0.07
35–40 years 34.7% 30.1% 0.09
>40 years 14.9% 14.2% 0.41
Body mass index (kg/m2) 26.8 ± 4.9 27.1 ± 5.8 0.21
Primary infertility 89.6% 91.2% 0.27
Duration of infertility (year) 4.3 ± 2.8 4.0 ± 3.1 0.93
Prior IVF cycles 1.7 ± 0.4 1.6 ± 0.5 0.99
Tubal factor 20.7% 21.9% 0.37
Endometriosis 8.2% 8.7% 0.45
Ovulatory factor 18.8% 19.3% 0.47
Male factor 40.5% 39.2% 0.37
Mixed factor – female and male 5.1% 2.4% 0.06
Unexplained infertility 6.5% 8.5% 0.18
Aspirated oocytes 5.7 ± 3.2 5.4 ± 2.8 0.92
Fertilized oocytes 4.9 ± 2.5 4.7 ± 2.3 0.89
Embryos transferred 1.3 ± 0.5 1.4 ± 0.5 0.07
Top quality embryos transferred 1.1 ± 0.2 0.9 ± 0.3 1
Implantation rate 22.5% 24.1% 0.27
Ongoing pregnancy rate (per randomized patient) 28.1% 30.3% (OR 1.11*) 0.50
Multiple gestations rate 2.1% 3.2% 0.37
Abortion rate 6.8% 10.1% 0.24
Gonadotropin ampules of 75 IU FSH 20.2 ± 5.9 19.6 ± 7.1 0.91
Endometrial thickness on hCG day (mm) 10.1 ± 2.4 9.8 ± 2.7 0.95
Serum level of E2 on hCG day (pg/mL) 1630.5 ± 564.2 1580.2 ± 490.1 0.91

* Odds ratio 1.11 (0.82–1.49) with 95% confidence interval (CI); by Chi-square test or t-test for independent samples.

Values are given as percentage or mean ± SD unless otherwise indicated.

Primary aim of the study, on-going pregnancy rate showed similar result in dydrogesterone group and Crinone group (OR 1.11 (0.82–1.49) with 95% CI).

Treatment characteristics outcome

There were no statistically significant differences between two groups with the respect of treatment characteristics (Table 1) such as: number of aspirated and fertilized oocytes, total and top quality embryos transferred, implantation rate, multiple gestations rate, abortion rate, number of used gonadotropin ampules, endometrial thickness and serum level of E2.

Treatment satisfaction score and tolerability

The secondary aims of the study were satisfaction score and tolerability, both assessed by the questionnaires. The overall response of the satisfaction questionnaire was 98.9% and for tolerability questionnaire 98.7% respectively. Satisfaction score was established by the 5-point level scale with 1 being the absolutely satisfied and 5 being the absolutely dissatisfied. Patients scored dydrogesterone as absolutely satisfied (p = 0.01) and satisfied (p = 0.01) significantly more than Crinone 8% gel. On the other hand Crinone 8% gel was scored statistically significant with the neither satisfied nor dissatisfied (p < 0.05) and dissatisfied (p = 0.01) in comparison with dydrogesterone. Data are presented in Fig. 2. Tolerability was investigated by the side-effects (headache, dizziness, somnolence, nausea/vomiting, breast fullness, bloating, abdominal pain, perineal irritation, vaginal discharge, vaginal bleeding, interference with coitus and total number of presented side-effects) that both drugs could cause. Results showed statistically significant occurrence of perineal irritation (p = 0.001), vaginal discharge (p = 0.001), vaginal bleeding (p = 0.04) and interference with coitus (p = 0.001) along with the total number of assessed side-effect (p = 0.001) with the use of Crinone 8% gel when compared with the dydrogesterone oral tablets (Fig. 3).

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Fig. 2 Satisfaction score of oral dydrogesterone (n = 411) and vaginal Crinone 8% gel (n = 411) by Chi-square test and Fisher's exact test

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Fig. 3 Tolerability of oral dydrogesterone (n = 412) and vaginal Crinone 8% gel (n = 409) by Chi-square test and Fisher's exact test.

Comment

In IVF/ICSI cycles the progesterone levels are low and the natural process is insufficient, therefore the luteal phase is supported by progesterone, hCG or GnRH agonists. Currently it is thought that LH levels are lowered by high steroid levels [17]. The progesterone is nowadays a product of choice because the hCG could increase the risk of OHSS by twofold [4]. The routes of progesterone supplements could be oral, vaginal, rectal or intramuscular. IM progesterone showed similar effect on the clinical pregnancy as the oral and vaginal/rectal progesterone [7], [18], [19], and [20], but IM progesterone causes more multiple pregnancies than oral progesterone [4].

Few studies compared clinical pregnancy rate between oral dydrogesterone and IM/vaginal progesterone [12], [13], [14], [15], [16], [21], and [22], but whit only one of them with a direct comparison of oral dydrogesterone and vaginal progesterone gel [15].

Van Linden et al. [4] in latest Cochrane review concluded that IM, vaginal or rectal progesterone have similar pregnancy rate as the oral progesterone, although synthetic progesterone seems to give better results, which in most cases was oral dydrogesterone, but the evidence is of low strength because of insufficient randomized controlled trials (RCT), especially in oral progesterone group.

This study is the first RCT that compares the efficacy of oral dydrogesterone and vaginal gel – Crinone 8% in 831 stimulated IVF/ICSI cycles. The result showed similar rates of clinical pregnancy of dydrogesterone (OR 1.11; 0.82–1.49 95% CI) and Crinone 8% gel in luteal support of IVF/ICSI stimulated cycles. Our results are supported with other researchers who observed the similar pregnancy rates results with dydrogesterone and vaginal progesterone gel [15] or micronized vaginal progesterone [12], [13], [14], and [16]. Two studies even compared combination of vaginal plus oral progesterone versus vaginal progesterone support and concluded that combined treatment is superior due to higher pregnancy rate [12] and lower abortion rate [23]. However, early administration of progesterone (within 24 h upon oocyte(s) retrieval) in our study could to some extent lower the pregnancy rate of vaginal gel due to premature advancement of the endometrium in our study.

The dydrogesterone is a stereoisomer of progesterone and its configuration makes it metabolically stable and orally effective. Schindler [24] found that dydrogesterone has a similar profile to progesterone but with better oral availability, and dydrogesterone has been used successfully to treat disorders related to absolute or relative progesterone deficiency.

Secondary outcome measures were satisfaction and tolerability of oral and vaginal P. Satisfaction score was assessed by 5-point scale (with 1 being “absolutely dissatisfied” and 5 being “absolutely satisfied”). Oral dydrogesterone presented statistically higher satisfaction score than vaginal Crinone 8% gel. Patients equally scored high positive and low negative satisfaction score for dydrogesterone when compared with Crinone vaginal gel. Another group of researcher found superior result of dydrogesterone when they compared side-effect and/or convenient of use with a micronized progesterone [14].

Advantage of dydrogesterone is oral administration, easy to use and better patient compliance which results in high satisfaction score of oral dydrogesterone in luteal support of IVF/ICSI cycles.

Tolerability of oral and vaginal P was investigated by questionnaire with different side effects that the supplements could cause. Headache, dizziness, somnolence, breast fullness, nausea/vomiting, bloating and abdominal pain showed similar rates between two progesterone supplements, but vaginal bleeding, perineal irritation, vaginal discharge and interference with coitus were significantly higher among Crinone 8% gel users.

None of the previous studies compared tolerability of oral dydrogesterone and Crinone 8% vaginal gel, but few authors found that vaginal route of progesterone applications is not well accepted by all patients due local adverse side effects such as vaginal irritation and discharge [25]. Oral administration of dydrogesterone clearly avoids local adverse vaginal effect and interference with coitus, and overall tolerability of drug is higher than Crinone 8% vaginal gel.

In conclusion, oral dydrogesterone proved to be equally efficient as the vaginal progesterone gel in luteal support of IVF/ICSI cycles but with higher satisfaction and tolerability rate. Interference with coitus and local adverse side effects such as vaginal irritation and discharge with vaginal progesterone gel could be avoided with the use of oral progesterone-dydrogesterone. Oral dydrogesterone is effective drug, well tolerated and accepted among patients and can be considered for routine luteal support.

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Footnotes

a Department of Gynecology and Obstetrics, University Clinical Centre “Sisters of Mercy”, Zagreb, Croatia

b Department of Gynecology and Obstetrics, DZ Zagreb Centar, Zagreb, Croatia

C Department of Gynecology and Obstetrics, University Clinical Centre “Zagreb”, Zagreb, Croatia

Corresponding author at: DZ Zagreb Centar, Department of Gynecology and Obstetrics, Runjaninova 4, 10 000 Zagreb, Croatia. Fax: +385 1 37 68 272.