br Conflict of interest statement
Conflict of interest statement
Acknowledgements We acknowledge the support of Zoetis Animal Health, Estrotect, Select Sires and Texas A&M AgriLife Research. The assistance of Randle Franke and Ernest Soto is also gratefully acknowledged.
Background Luteal phase deficiency (LPD) is caused by impaired Cefotaxime sodium salt (CL) function resulting in abnormal estradiol and progesterone production and shortening of the luteal phase, which can be at the origin 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 CL, echoing the pulsatile release of LH from the pituitary (Filicori et al., 1984). However, a single serum progesterone level below 10 ng/ml (31.8 nmol/ml), measured in the midluteal phase, is considered as a relatively reliable indicator of LPD (Jordan et al., 1994), and a recent study suggests the optimal cut-off of serum progesterone concentration for ongoing pregnancy, measured on pregnancy test day in cryopreserved embryo transfer cycles, to be 35 nmol/l (11 ng/ml) (Alsbjerg et al., 2018). However, in our experience with fresh IVF treatment cycles (unpublished), serum progesterone levels <15 ng/ml (47.7 nmol/l), measured on the day of pregnancy test, are associated with reduced pregnancy rates. Thus 15 ng/ml was chosen as cut-off for the definition of LPD in this study. Infertility treatments using in vitro fertilization (IVF) increase the risk of LPD, in spite of the development of multiple preovulatory follicles (Garcia et al., 1981). Therefore, various regimens of luteal phase support have been widely employed in IVF, using human chorionic gonadotropin (hCG), estradiol or progesterone administration during some time after embryo transfer (Fatemi et al., 2007, Van der Linden et al., 2011). The beneficial effect of GnRH agonist on human embryo implantation was first demonstrated in 2004 (Tesarik et al., 2004). Since 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). However, further studies showed a similar beneficial effect of luteal GnRH agonist in ovulating women, in both GnRH agonist- and antagonist-controlled ovarian stimulation cycles (Pirard et al., 2015, Tesarik et al., 2006), suggesting that GnRH agonist may also affect the CL function. This assumption was further corroborated by the observation that GnRH agonist can rescue the CL 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). Based on 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 the CL deficiency in natural conception cycles (Tesarik et al., 2016). In our IVF program, 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 β-HCG test. Some patients who fail to achieve an ongoing pregnancy show abnormally low progesterone levels at this time. This 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 I, after the first attempt with standard luteal phase support with vaginally administered progesterone, a second attempt was performed with a combination of vaginal progesterone and daily subcutaneous GnRH agonist injections during 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. The two sequential attempts were compared as to the pregnancy outcome, and serum progesterone concentration on the 14th day after oocyte recovery.