A comparative study of dydrogesterone and

Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles Nasrin Saharkhiz, Marzieh Zamaniyan, Saghar Salehpour, Shahrzad Zadehmodarres, Sedighe Hoseini, Leila Cheraghi, Samira Seif & Nafiseh Baheiraei To cite this article: Nasrin Saharkhiz, Marzieh Zamaniyan, Saghar Salehpour, Shahrzad Zadehmodarres, Sedighe Hoseini, Leila Cheraghi, Samira Seif & Nafiseh Baheiraei (2015): A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles, Gynecological Endocrinology, DOI: 10.3109/09513590.2015.1110136 To link to this article: http://dx.doi.org/10.3109/09513590.2015.1110136

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Date: 09 February 2016, At: 02:23

http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, Early Online: 1–5 ! 2015 Taylor & Francis. DOI: 10.3109/09513590.2015.1110136

ORIGINAL ARTICLE

A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles Nasrin Saharkhiz1, Marzieh Zamaniyan1, Saghar Salehpour1, Shahrzad Zadehmodarres1, Sedighe Hoseini1, Leila Cheraghi2, Samira Seif3, and Nafiseh Baheiraei4 Downloaded by [T&F Internal Users], [Alice Shuttleworth] at 02:23 09 February 2016

1

Preventive Gynecology Research Center (PGRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 3Department of Veterinary Theriogenology and Obstetric, Tehran University of Medical Sciences, Tehran, Iran, and 4Department of Anatomy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Abstract

Keywords

The aim of the present study was to compare the efficacy, tolerability and patients’ satisfaction after the use of oral dydrogesterone with vaginal micronized progesterone for luteal-phase support (LPS) among infertile women undergoing in vitro fertilization (IVF). A total of 210 women (aged 20–40 years old) with a history of infertility, who underwent controlled ovarian stimulation for fresh intra-cytoplasmic sperm injection-embryo transfer cycles, were included in the study. Consequently, they were randomized to receive LPS with dydrogesterone 20 mg twice daily (n ¼ 96) or micronized progesterone 400 mg twice daily at the day of oocyte retrieval (n ¼ 114). The clinical success rate (31% versus 33%; p ¼ 0.888), miscarriage rate (5.0% versus 3.0%; p ¼ 0.721), ongoing pregnancy rate (30.0% versus 30.0%; p ¼ 1.000), implantation (22.0% versus 24.0%; p ¼ 0.254) and multiple pregnancy rate (5.30% versus 7.20%; p ¼ 0.394) were comparable among the two groups. Serum progesterone levels were significantly lower among the patients receiving dydrogesterone than the control group (13.62 ± 13.83 ng/ml versus 20.66 ± 18.09 ng/ml; p ¼ 0.001). However, there was no statistically significant difference regarding the patients’ satisfaction (p ¼ 0.825) and tolerability (0.790) between the two groups. Our results showed that oral dydrogesterone (40 mg/day) is as effective as vaginal micronized progesterone considering its clinical outcomes and patients’ satisfaction and tolerability, for LPS among women undergoing IVF.

Dydrogesterone, in vitro fertilization, luteal-phase support, micronized progesterone, progesterone

Introduction Luteal phase defect (LPD) is defined as a disorder in which endogenous progesterone is not enough to preserve a functional endometrium and subsequently the embryo implantation [1]. Luteal phase support (LPS) is recommended in most in vitro fertilization (IVF) cycles based on several reasons: firstly, shortened luteal phase may happen owing to multi follicular growth, which has been induced by controlled ovarian stimulation (COS) [2]. Dydrogesterone is synthetic progesterone available as a retroprogesterone. Several studies have demonstrated that this preparation is safe and does not have androgenic effects compared with previous preparations because of its different structure [3]. One study has reported that the dydrogesterone does not virilize even when used in a high dose [4]. Some studies have compared oral dydrogesterone with other types of progesterone and have found that all kinds of progesterone have the same effectiveness [5,6]. Besides, some authors have compared dydrogesterone with vaginal micronized progesterone and concluded that dydrogesterone has better compliance and tolerability with fewer side effects compared with micronized

Address for correspondence: Marzieh Zamaniyan, Preventive Gynecology Research Center (PGRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran. Tel: +98 21 22432558. Fax: +98 21 22432600. E-mail: [email protected]

History Received 23 June 2015 Revised 30 September 2015 Accepted 15 October 2015 Published online 19 November 2015

progesterone [5,7]. A few studies have reported significantly better clinical outcomes with dydrogesterone compared with micronized progesterone [8,9]. Other studies have reported the benefit of dydrogesterone in prevention of recurrent pregnancy loss (RPL) and preterm delivery and threatened abortion [10–18]. In contrast, some authors have reported that the use of dydrogesterone as luteal support fails to demonstrate secretory transformation of the endometrium and induces higher progesterone and lower LH and FSH concentrations on day 21 of the cycle among donor oocyte recipients [19]. Therefore, the use of dydrogesterone in LPS is still doubtful. Hence, due to the ease of use, better patient compliance and satisfaction [5,7], and negligible use of dydrogesterone in assisted reproductive technology (ART), we decided upon further examine this drug in the infertility field. In a study reported previously, our group compared the effectiveness of oral dydrogesterone 20 mg twice a day for LPS in 80 patients undergoing IVF cycles with vaginal micronized progesterone 400 mg twice daily [20], and found the outcomes to be promising with oral dydrogesterone. This study was initiated using dydrogesterone 20 mg once a day like previous published studies [5,9]; however, due to more vaginal bleeding in dydrogesterone group and no evidence regarding androgenic side effects of this drug during pregnancy [21]; the dosage was increased to 20 mg twice daily. In most previous studies, dydrogesterone 20 mg daily has been used, and only two studies have examined 30 and 40 mg daily doses of dydrogesterone [9,22].

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We thought it possible that prior comparable or undesirable results by dydrogesterone might be related to lower dosage and may be improved by increasing the dosage. This further encouraged us to increase the sample size to verify our former results. The main objective of the present study was to compare the efficacy, tolerability and patients’ satisfaction of oral dydrogesterone (40 mg daily) with vaginal micronized progesterone in LPS among infertile women undergoing IVF.

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Methods We conducted an open-label, prospective randomized clinical trial between April 2014 and January 2015 in two tertiary infertility care units (Taleghani and Mahdieh hospitals, Tehran, Iran). This study was approved by ethics committee and the institutional review board of Shahid Beheshti University of Medical Science. Treatment options were discussed with all patients who enrolled in the study and written informed consent was obtained from all participants. A total of 210 patients met our criteria and were recruited for the study. Women (aged 20–40 years) with body mass index (BMI) 30 kg/m2 or 18 kg/m2, undergoing fresh intra-cytoplasmic sperm injection-embryo transfer (ICSI-ET) cycles, and had normal endometrial thickening (7–12 mm) on the day of oocyte retrieval and no visible endometrial pathology were included in the study. Treatment All women received mid follicular long-protocol GnRH-agonist down-regulation or GnRH-antagonist protocol based on patients’ characteristics (age, AMH, prior failed attempts) [23,24]. In both protocols, 10 000 IU human chorionic gonadotropin (hCG) (5000 IU, Choriomon; IBSA; Lugano) was administered IM when at least two or more follicles reached 17 mm in diameter. Oocytes were recovered under trans-vaginal ultrasound guidance 34–36 h after hCG injection. After egg collection, conventional ICSI was performed. An average of two or three good-quality embryo in cleavage stage (at the 4–8 cell stage) was transferred 72 h after insemination. Luteal-phase support began from the day of oocyte retrieval. Randomization on the day of oocyte retrieval was based on sealed envelopes according to a random-number table. Patients were randomly selected to receive either intra-vaginal micronized progesterone (Cyclogest; Actavis; Barnstaple, UK) 400 mg bid (control group) (n ¼ 114) or oral dydrogesterone (Duphaston, Abbot Biological B.V., Olst, the Netherlands) 20 mg twice a day (intervention group) (n ¼ 96). Pregnancy was determined using blood b-hCG testing 14 days after the embryo transfer (ET). Progesterone concentrations were measured at the same time using radioimmunoassay. If the b-hCG test was positive, then LPS was continued up to 12 weeks of gestation. We did not measure the liver function tests (LFT) in our patients because of no previous reported side effects for these drugs [5]. Possible complications associated with both drugs were documented. Patients’ satisfaction was also evaluated using a questionnaire. Satisfaction was objectively evaluated among the patients. Clinical pregnancy was defined as confirmation of a gestational sac by ultrasonography at 4–5 weeks after embryo transfer (ET). Chemical pregnancy was defined as a pregnancy confirmed by a pregnancy test but not by ultrasonography 4–5 weeks later. Miscarriage was defined as the spontaneous loss of a fetus before the 20th week of pregnancy. Ongoing pregnancy was defined as the presence of at least one viable fetus at 12th weeks of pregnancy.

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Statistical analysis To detect 30% difference in clinical pregnancy rate that is considered significant (9) with a power of 80% and an a ¼ 0.05, the sample size of 80 patients in each group was needed. The data analysis was performed using SPSS for windows, version 21.0 (IBM Corp., Armonk, NY). t-test was used to compare the clinical outcomes between the two groups. The proportions were compared using chi-squared test. The data were reported as mean ± SD and p 0.05 were considered statistically significant.

Results A total of 240 women were recruited into the study; 30 women were excluded from the study due to various causes, including withdrawal of consent, ovarian hyper stimulation syndrome (OHSS), no fertilization, discontinued treatment or loss to follow up, which is summarized in Figure 1. The mean age (± standard deviation (SD)) of the women within the dydrogesterone group and the control group was (30.58 ± 5.35) years and (30.95 ± 5.19) years, respectively (p ¼ 0.6). There were no significant differences between two groups with respect to patients’ baseline characteristics (Table 1) and ICSI cycle characteristics (Table 2). Whereas, Serum progesterone levels were significantly lower among the dydrogesterone group than the control group (13.62 ± 13.83 ng/ml versus 20.66 ± 18.09 ng/ml; p ¼ 0.001). Oral dydrogesterone was associated with similar chemical pregnancy rate (4.0% versus 1.0%; p ¼ 0.369), clinical pregnancy rate (31% versus 33%; p ¼ 0.888) and miscarriage rate (5.0% versus 3.0%; p ¼ 0.721) compared with control group (micronized vaginal progesterone) (Table 3). There was not a significant difference regarding to satisfaction rate between the two groups and similar absolute satisfaction rates was observed between the two groups (92.0% versus 93%; p ¼ 0.825). Results showed no statistically significant differences considering the drugs side effects between two groups (p ¼ 0.790) (Table 3).

Discussion It is well known that in all of ART cycles, the progesterone levels are low and luteal function is insufficient. Therefore, the luteal phase is supported by different supplements such as progesterone, hCG or GnRH agonists. Some evidence has indicated that there is a statistically significant decrease in pregnancy rates in the absence of LPS in women undergoing IVF cycles [24–26]. Linden et al. conducted a Cochrane review and investigated the different kinds and routes of supplementation. They showed a significant effect in favor of progesterone for LPS, especially synthetic progesterone over micronized progesterone [8]. A recent review of birth defects has investigated the use of dydrogesterone during pregnancy and found no evidence of a relationship between maternal usage during pregnancy and birth defects [20]. However, there are only few studies, regarding the use of dydrogesterone in IVF cycles for LPS [5,7,9,14,19,21]. Our previous study about LPS in women undergoing IVF cycles showed no significant differences in pregnancy and miscarriage rates among women receiving oral dydrogesterone and vaginal micronized progesterone [19]. Drug side effects such as vaginal bleeding, nausea and epigastric pain were significantly higher in dydrogesterone group compared with vaginal micronized progesterone group, which may be due to early pregnancy symptoms; therefore, we could not attribute it to the dydrogesterone alone. The present results on a slightly larger population validated our prior results. Baseline and clinical characteristics were similar,

Effect of progesterone on IVF

DOI: 10.3109/09513590.2015.1110136

Figure 1. Flow chart of the eligible patients.

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Evaluaon of eligibility (n=240)

Enrollment

Not included: Did not consent (n=4) Declined to parcipate (n=2)

Randomly allocated (n=234)


Allocaon Allocated to dydrogesterone group (n=117)

Allocated to control group (n=117)

Follow up Lost to follow-up (n= 6) Disconnued (n=5) Withdraw the consent (n=6) OHSS (n=2) No ferlizaon (n=2)

Lost to follow-up (n=1) Disconnued (n=1) OHSS (n=0) No ferlizaon (n=1)

Analysis Analyzed (n= 96)

Table 1. Demographic characteristic of patients in two groups.

Variables Mean age (years) BMI (kg/m2) AFC AMH (ng/ml) Day 3 FSH (mIU/ml) Day 3 LH (mIU/ml) Infertility duration (years) Infertility kind Primary Secondary Infertility etiology Male factor Tubal factor DOR Unexplained infertility PCOS Multiple factors

Oral dydrogesterone group (N ¼ 96)

Micronized progesterone group (N ¼ 114)

30.58 ± 5.35 25.99 ± 3.49 11.87 ± 5.97 4.15 ± 3.32 6.07 ± 2.52 5.53 ± 3.38 4.96 ± 3.93

30.95 ± 5.19 26.19 ± 3.84 11.77 ± 6.82 3.78 ± 26 6.19 ± 3.86 5.70 ± 3.73 6.06 ± 4.21

76% 24%

78% 22%

51% 6% 5% 1% 2% 35%

44% 7% 4% 2% 4% 39%

p Value 0.621 0.709 0.912 0.494 0.843 0.740 0.060 0.867

0.867

Values are given as percentage or mean ± SD unless otherwise indicated. AFC, antral follicle count; DOR, diminished ovarian reserve.

and the difference between two groups was not significant (p40.05). Pregnancy and miscarriage rates were also found to be comparable between the two groups. Our findings are supported by other authors who observed comparable effectiveness by dydrogesterone and natural micronized progesterone in patients undergoing IVF cycles [5,7,8,21,27]. Moreover, serum progesterone concentrations were significantly lower in the dydrogesterone

Analyzed (n=114)

group compared with control group (13.62 ± 13.83 ng/ml versus 20.66 ± 18.09 ng/ml; p ¼ 0.001). In line with our findings, a study on LPS in women undergoing IVF by Ganesh et al., which compared the efficacy of oral dydrogesterone with vaginal progesterone gel and micronized progesterone capsules for LPS among women undergoing IVF cycles, demonstrated that pregnancy and miscarriage rates were similar between the groups [6]. Another randomized clinical trial by Chakravarty et al. supports our results. They compared oral dydrogesterone with vaginal micronized progesterone as LPS in ART cycles, and found that both drugs were associated with similar pregnancy and miscarriage rate [5]. These authors found no effect of dydrogesterone on the liver function tests (LFT). Nerveless, they used lower doses of dydrogesterone compared with our dosage and did not measure the progesterone concentrations in that dose. Patki et al. compared the dydrogesterone with vaginal micronized progesterone and placebo for LPS in ART and reported significant higher pregnancy rates (PR) with dydrogesterone compared with micronized progesterone and placebo in fresh IVF and donor oocyte cycles. They used 20 mg and subsequently 30 mg dydrogesterone once daily in two study periods and found significant higher PR when using 30 mg [9]. Tomic et al. compared oral dydrogesterone with vaginal progesterone gel for LPS and showed that ongoing pregnancy rate was similar between two groups. These authors suggested that earlier prescription of progesterone within 24 h of oocyte pick-up may result in lower pregnancy rates of vaginal progesterone gel because of premature endometrial advancement [7]. We did not find a significant difference considering the satisfaction rate within the dydrogesterone group compared with vaginal micronized progesterone. Other researchers have found more tolerability of dydrogesterone when they compared both drug’s side effects [5,7]. In the present

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Table 2. ICSI cycle characteristics in two groups.

Variables


Endometrial thickness on HCG day No of follicles 14 on HCG day Day number of stimulation Mean no of oocyte retrieval No of fertilized eggs No of embryo transferred No of mature oocytes (metaphase II) Mean embryo quality score Mean embryo cleavage score The mean dose of gonadotropins used Types of IVF protocols Agonist Antagonist Mean serum progesterone levels

Oral dydrogesterone group (N ¼ 96)

Micronized progesterone group (N ¼ 114)

p Value

7.69 ± 1.46 8.29 ± 1.60 9.51 ± 2.06 11.05 ± 5.66 6.45 ± 4.17 2.30 ± 0.74 8.55 ± 5.20 2.42 ± 0.54 2.18 ± 0.56 28.09 ± 11.93

8.25 ± 4.52 8.06 ± 1.6 9.67 ± 1.83 9.68 ± 6.45 5.19 ± 3.97 2.33 ± 0.86 7.43 ± 5.52 2.47 ± 0.53 2.75 ± 0.60 29.25 ± 11.62

0.304 0.604 0.564 0.540 0.390 0.793 0.142 0.460 0.424 0.487

38% 62% 13.62 ± 13.83

62% 38% 20.66 ± 18.09

0.252 0.002

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

Table 3. Clinical outcomes, satisfaction and tolerability of patients in two groups.

Variables Chemical pregnancy rate (%) Clinical pregnancy rate (%) Ongoing pregnancy rate (%) Implantation rate (%) Multiple pregnancy rate (%) Miscarriage rate (%) Patient satisfaction Absolute satisfaction (%) Partial satisfy (%) Absolutely dissatisfaction (%) Side effects Vaginal discharge and irritability (%) Breast fullness (%) Abdominal pain (%) Vaginal bleeding (%) Constipation (%)

Micronized Oral dydrogesterone progesterone (N ¼ 114) p Value (N ¼ 96) 4.0% 31.0% 30.0% 22.0% 5.30% 5.0%

1.0% 33.0% 30.0% 24.0% 7.20% 3.0%

92.0% 1.0% 7.0%

93.0% 2.0% 5.0%

0.0%

2.0%

5.0% 8.0% 14.0% 3.0%

4.0% 6.0% 13.0% 2.0%

0.369 0.888 1.000 0.254 0.394 0.721 0.825

0.790

Values are given as percentage.

study, the tolerability of two different types of progesterone was examined by a questionnaire, including various side effects related to these supplements such as breast fullness, vaginal irritability, abdominal pain, vaginal bleeding and constipation, however; there were no significant differences between two groups regarding these side effects. A limitation of the present study was its relatively small sample size. In addition, this study was not blind for the physicians and patients that could affect the study results. Another concern is about the safety of dydrogesterone during pregnancy; since, only vaginal routes of progesterone such as cream and vaginal insert have been approved by the Food and Drug Administration (FDA), for LPS [26]. In conclusion, oral dydrogesterone even at a dose of 40 mg/day was verified to be similarly effective as the vaginal micronized progesterone in LPS of ART cycles with similar satisfaction and side effects, which should be further examined by the clinical trials with larger patient populations.

Acknowledgements We would like to thank Miss Masoumeh Yazdan Ashouri and Farzaneh Hoseini for their assistance.

Declaration of interest The authors report no conflicts of interest.

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