Article
GnRH agonist treatment of luteal phase deficiency in HCG-triggered IVF cycles: a matched case-control study

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Abstract

Research question

This study aimed to identify women with IVF failure associated with low serum progesterone levels after embryo transfer in HCG-triggered cycles and to evaluate the effects of gonadotrophin-releasing hormone (GnRH) agonist, administered after embryo transfer, on serum progesterone and pregnancy outcomes in these cases.

Design

Fifty women who failed to achieve an ongoing clinical pregnancy and had abnormally low luteal-phase serum progesterone concentrations in their first IVF attempt were assigned to two matched groups in their subsequent attempt. Twenty-five women were treated with the original protocol plus14 daily injections of GnRH agonist, beginning on the day of oocyte recovery, in their second IVF attempt (group 1). These women were matched to 25 women with the same characteristics and outcomes in their first IVF attempt who underwent the second IVF attempt without the use of GnRH agonist after embryo transfer (group 2). In both groups, the two sequential attempts were compared for serum progesterone concentration 14 days after oocyte recovery and pregnancy outcome.

Results

The patients in group 1 had significantly higher progesterone levels 14 days after oocyte recovery in the second attempt compared with the first attempt (P < 0.001), and 12 (48%) of them achieved clinical pregnancy and birth. No significant differences in pregnancy outcome or in the serum progesterone concentration were observed between the first and the second attempt in group 2.

Conclusions

In patients with luteal phase deficiency, the administration of GnRH agonist after embryo transfer increases serum progesterone concentration and improves the chance of pregnancy and birth.

Introduction

Luteal phase deficiency (LPD) is caused by impaired corpus luteum function resulting in abnormal oestradiol and progesterone production and shortening of the luteal phase, which has been implicated in the cause of irregular menstrual bleeding (Fritz, 2012, Pfeifer et al., 2012), infertility and early pregnancy loss (Ginsburg, 1992). The criteria to be used for the diagnosis of LPD is still a matter of debate. Use of low luteal phase serum progesterone as a diagnostic tool for LPD is plagued by the pulsatile release of progesterone from the corpus luteum, echoing the pulsatile release of LH from the pituitary (Filicori et al., 1984). A single serum progesterone level below 10 ng/ml (31.8 nmol/ml), however, measured in the mid-luteal phase, is considered as a relatively reliable indicator of LPD (Jordan et al., 1994); it has been suggested in a recent study (Alsbjerg et al., 2018) that the optimal cut-off of serum progesterone concentration for ongoing pregnancy, measured on pregnancy test day in cryopreserved embryo transfer cycles, should be 35 nmol/l (11 ng/ml). In our experience with fresh IVF treatment cycles (unpublished), however, serum progesterone levels less than 15 ng/ml (47.7 nmol/l), measured on the day of pregnancy test, are associated with reduced pregnancy rates. Therefore, 15 ng/ml was chosen as cut-off for the definition of LPD in this study.

Infertility treatments using IVF increase the risk of LPD, despite the development of multiple preovulatory follicles (Garcia et al., 1981). Therefore, various regimens of luteal phase support have been widely used in IVF, using HCG, oestradiol or progesterone administration during some time after embryo transfer (Fatemi et al., 2007, Van der Linden et al., 2011).

The beneficial effect of gonadotrophin releasing hormone (GnRH) agonist on human embryo implantation was first demonstrated by Tesarik et al. (2004). As the luteal phase GnRH agonist administration was carried out in women receiving embryos from donated oocytes, in whom ovulation had been previously blocked, it was concluded that GnRH agonist exerted a direct effect on the implanting embryos (Tesarik et al., 2004). Further studies, however, showed a similar beneficial effect of luteal GnRH agonist in ovulating women, in both GnRH agonist- and antagonist-controlled ovarian stimulation cycles (Tesarik et al., 2006, Pirard et al., 2015), suggesting that GnRH agonist may also affect the corpus luteum function. This assumption was further corroborated by the observation that GnRH agonist can rescue the corpus luteum function in GnRH antagonist-controlled and GnRH-agonist triggered ovarian stimulation cycles (Bar-Hava et al., 2016). These protocols of ovarian stimulation, mostly used in women at a high risk of ovarian hyperstimulation syndrome, are known to result in a luteolytic effect that significantly lowers pregnancy rates (Leth-Moller et al., 2014).

On the basis of the above observations, it has been hypothesized that luteal phase support with GnRH agonist may be of help to all women, treated by assisted reproduction, who show low serum progesterone levels in the luteal phase, and even in those with corpus luteum deficiency in natural conception cycles (Tesarik et al., 2016). In our IVF programme, determination of serum progesterone concentration is made in all women on the day of embryo transfer and 14 days after oocyte recovery, together with the first beta-HCG test. Some patients who fail to achieve an ongoing pregnancy show abnormally low progesterone levels at this time.

The present study reports on 50 women falling into this category. Individual women were prospectively assigned to two matched groups, according to their age, body mass index and ovarian reserve. They were informed about the treatment received and signed a corresponding consent form. In group 1, after the first attempt with standard luteal phase support with vaginally administered progesterone, a second attempt was carried out with a combination of vaginal progesterone and daily subcutaneous GnRH agonist injections during the 2 weeks after oocyte recovery. In group II, the second attempt was carried out exactly as the first one, without the use of GnRH agonist after embryo transfer. Pregnancy outcome and serum progesterone concentration in the two sequential attempts were compared on day 14 after oocyte recovery.

Section snippets

Study design and participants

This prospective matched case-control study included data from the medical records of 50 women aged between 25 and 40 years, entering the IVF programme of MARGen Clinic, Granada Spain, between January 2015 and April 2018. All of them failed to achieve an ongoing clinical pregnancy in their first IVF attempt and showed low serum progesterone concentrations (<15 ng/ml) on day 14 after oocyte recovery despite luteal phase support with vaginally administered micronized progesterone (600 mg daily),

Basic characteristics of the two successive IVF attempts

The two successive IVF attempts did not differ in either total number of oocytes recovered or the number of metaphase II oocytes that were treated by ICSI (Table 1). The biological outcomes of both the first and the second IVF attempt, in terms of the number of normal two-pronucleated zygotes, total cleaving embryos and those considered of top quality, were also the same in both attempts (Table 1).

Effect of luteal phase GnRH agonist administration on serum progesterone concentration

As shown in Table 2, serum progesterone concentration, measured on the day of embryo transfer, was

Discussion

Luteal phase deficiency, in terms of insufficient secretion of progesterone by the corpus luteum, reflected by low serum progesterone levels, can occur in IVF attempts using any kind of ovarian stimulation protocol (Garcia et al., 1981, Fatemi et al., 2007, Van der Linden et al., 2011). It is particularly frequent, however, in ovarian stimulation cycles controlled by GnRH antagonist in which GnRH agonist is used as ovulation trigger (Leth-Moller et al., 2014, Bar-Hava et al., 2016). Bar-Hava et

Raquel Mendoza-Tesarik graduated in Biological Science from Granada University in 2002. She has co-authored important research articles in the field of assisted reproduction. She is responsible for the Assisted Reproduction Laboratory at MAR&Gen Clinic in Granada.

Key message

This matched case-controlled study shows that IVF failure associated with low serum progesterone levels after embryo transfer can be successfully treated by supporting the luteal phase with gonadotrophin

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  • Cited by (0)

    Raquel Mendoza-Tesarik graduated in Biological Science from Granada University in 2002. She has co-authored important research articles in the field of assisted reproduction. She is responsible for the Assisted Reproduction Laboratory at MAR&Gen Clinic in Granada.

    Key message

    This matched case-controlled study shows that IVF failure associated with low serum progesterone levels after embryo transfer can be successfully treated by supporting the luteal phase with gonadotrophin releasing hormone agonist.

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