Oral Dydrogesterone versus Vaginal Micronized Progesterone in Luteal Phase Support after Controlled Ovarian Stimulation Using Long Gonadotropin-Releasing Hormone Agonist in Women Undergoing in Vitro Fertilization/Intracytoplasmic Sperm Injection

Background: Luteal phase support is indicated after Controlled Ovarian Stimulation (COS) using Long Gonadotropin-Releasing Hormone Agonist (GnRHa) protocol in Women undergoing in Vitro Fertilization (IVF)/Intracytoplasmic Sperm Injection (ICSI). Progesterone is widely used for this indication. Objective: The objective of the current trial is to compare both efficacy and safety of oral dydrogesterone and vaginal micronized progesterone in luteal phase support in women undergoing IVF/ICSI using the long GnRHa protocol. Methods: This open-label randomized controlled study conducted at a private fertility and IVF center in Zagazig, Egypt, during the interval between April 2016 and August 2019. The study included women planned to undergo IVF/ICSI for either male factor infertility, tubal factor infertility, or unexplained infertility. Women with pelvic endometriosis, known reduced ovarian reserve, and women who were known to have poor or high response to ovarian stimulation, as well as women who were stimulated using non-long GnRHa protocol were not included. After embryo transfer, eligible women were randomly allocated into one of the two groups: group I, included women who received oral dydrogesterone 10 mg three times


Introduction
Progesterone is a key hormone in the implantation and maintenance of pregnancy [1]. The source of progesterone in women having spontaneous pregnancy or in women undergoing simple ovarian stimulation is from luteinized granulosa and theca cells of the corpus luteum(ei) resulting from ovulation [2]. In women undergoing controlled ovarian stimulation (COS) using the long gonadotropin releasing hormone agonist (GnRHa), however, luteal phase deficiency is evident [3]. The underlying etiology of such luteal phase deficiency includes anterior pituitary gland suppression, supraphysiological levels of estradiol, and aspiration/trauma of granulosa cells during oocyte retrieval [4] [5] [6]. Luteal phase support is, therefore, indicated in women receiving the long GnRHa protocol. Human chorionic gonadotropin (hCG) injection has been shown to be an effective tool for luteal phase support [7] [8] [9]. Nevertheless, the innate risk of ovarian hyperstimulation (OHSS) with hCG limits its use for such an indication.
Progesterone supplementation is a more appropriate option, since it does not add to the risk of OHSS [8]. Natural micronized progesterone has been tried using different routes, including intramuscular, vaginal, rectal, oral and, lately, subcutaneous [9] [10]. Oral administration of natural progesterone is associated with a quite low bioavailability (down to 10%) [5]. Meanwhile, parenteral routes Open Journal of Obstetrics and Gynecology seem to be inconvenient to many women. Injections are not uncommonly associated with pain and local hematomas or abscesses [11]. Vaginal and rectal routes are associated with local burning and irritation [12]. A well-known, long-used oral semisynthetic progestin (dydrogesterone) has been administered orally in women requiring progesterone supplementation for many indications, since it is not degraded by gastric acidity and skips the first pass metabolism, and, therefore, has a quite high bioavailability [13] [14]. Recently numerous clinical trials have investigated the efficacy of oral dydrogesterone as luteal phase support, in women undergoing in Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) and found comparable efficacy to micronized progesterone [15]- [20]. In addition, a recent systematic review and meta-analysis found similar conclusion [21]. The same systematic review, however, found only two clinical trials which investigated the two medications (dydrogesterone and micronized progesterone) from the side of adverse effects, namely women's dissatisfaction [21]. The difference between the two medications in these two clinical trials, as regard dissatisfaction rates, was conflicting [3% vs 26%, respectively, p < 0.0001 in one trial] [17], in contrast to 8% vs 9%, respectively, p > 0.05 in the second trial [18].
Therefore, a need for further randomized clinical trials comparing the adverse effects of both medications remains. The objective of the current trial is to compare both efficacy and safety of oral dydrogesterone and vaginal micronized progesterone in luteal phase support in women undergoing IVF/ICSI using the long GnRHa protocol.

Methods
The current open-label randomized controlled trial was conducted at a private fertility and IVF center in Zagazig, Egypt, during the interval between April 2016 and August 2019. The study protocol was in agreement to the Helsinki declaration of Ethical Medical Research (last updated in Brazil 2013) and had been approved by the Institutional Review Board of Faculty of Medicine, Zagazig University, Egypt. The study included women planned to undergo IVF/ICSI for either male factor infertility, tubal factor infertility, or unexplained infertility.
Women with pelvic endometriosis, known reduced ovarian reserve, and women who were known to have poor or high response to ovarian stimulation, as well as women who were stimulated using non-long GnRHa protocol were not in-

Sample Size Justification
Sample size was calculated using the Online Power and Sample Size Calculator, setting the power (1-β) at 0.8 and the type-1 error (α) at 0.05. Data from a recent meta-analysis [21] showed that the pooled live birth rates were 24% and 25%, respectively. Calculation according to these values, setting the non-inferiority margin at 0.08, produces a minimal sample size of 282 women in each group.

Statistical Methods
Statistical analysis was performed using MedCalc® version 7.0. Difference between two independent metric variables was analyzed using independent student's t-test as well as mean difference and its 95% confidence interval. Difference between two categorical variables was analyzed using chi-squared test as well as risk ratio and its 95% confidence interval. Significance level was set at 0.05. (n = 280). There were no significant differences between women of both groups regarding the age, body mass index (BMI) or duration of infertility (Table 1).

Results
There were no significant differences between women of both groups regarding duration of ovarian stimulation, total dose of gonadotropin given, number of retrieved oocytes, fertilization rate, or number of transferred embryos (  Figure 2).    Data presented as mean ± standard deviation; or frequency (percentage); MD/RR (95% CI) mean difference/risk ratio and their 95% confidence interval; 1 Analysis using independent student's t-test; 2 Analysis using chi-squared test.  Figure 3).

Discussion
The current trial showed similar efficacy of both oral dydrogesterone and vaginal micronized progesterone in terms of comparable rates of live birth, ongoing pregnancy, clinical pregnancy and miscarriage pregnancy in normal-responding women undergoing IVF/ICSI using long GnRHa protocol. Meanwhile, oral dydrogesterone was associated with slightly higher rates of nausea; yet significantly lower rates of vaginal burning, vaginal bleeding and overall women's The current trial results also come in agreement to two systematic reviews.
The first a Cochrane systematic review published in 2015, on 94 randomized trials comparing different luteal phase support regiments. The meta-analysis of this review found a significantly higher clinical pregnancy rate with oral dydrogesterone when compared to both oral and vaginal micronized progesterone [22]. In a more recent systematic review published in 2018 on 8 trials, the rates of live birth, ongoing pregnancy and clinical pregnancy were comparable with either oral dydrogesteroneor vaginal progesterone [21].
One of the apparent limitations in the current trial is absence of blinding of both interventions to the patient and the investigator. In the LOTUS I trial [19] oral placebo was added to the vaginal group and a vaginal placebo was added to the oral group. Such blinding was not adopted in the current trial, as the principal secondary outcome was women's satisfaction. We already know that vaginal route of the medication in the second route per se and its possible consequences of bleeding or irritation contributes in a substantial way to this principal secondary outcome. Therefore, we intentionally restricted the routes of admin- Another limitation of the current trial was lack of data regarding the potential risk of congenital malformations. Results from the LOTUS I study found comparable rates of congenital malformations in both interventions [19]. In addition, both dydrogesterone and micronized progesterone are long-studied and well-known medications with a high safety profile [15] [16] [17] [23].
A third limitation of the current trial is restricting the assessment of efficacy of oral dydrogesterone in women undergoing ovarian stimulation using the long GnRHa protocol and in normal-responding women. Further clinical trials are needed to assess the efficacy of dydrogesterone in poor-and high-responders, and in women undergoing ovarian stimulation using other protocols.

Conclusion
In conclusion, when compared to vaginal micronized progesterone, oral dydrogesterone seems to be associated with comparable live birth, ongoing pregnancy and clinical pregnancy rates, and significantly lower dissatisfaction and Open Journal of Obstetrics and Gynecology side effects rates, when given as luteal phase support in normal responding women undergoing IVF/ICSI using the long GnRHa protocol.