The Effect of Luteal Blood Progesterone Levels on Ongoing Pregnancy Rates

Progesterone (P4) is essential for the secretory development of endometrium and the maintenance of early pregnancy. In the luteal phase following controlled ovarian stimulation in in vitro fertilization (IVF) treatment, P4 profile is completely different from natural cycles (Fauser, 2002).

Since the optimal luteal P4 levels are not well known, in normal IVF treatment a standard regime of exogenous P4 is given without considering the ovarian response for stimulation and the steroid levels in luteal phase. In 2005 Humaidan et al, showed that following the fresh embryo transfer, low luteal P4 levels (39 nmol/l) has a negative impact on ongoing pregnancy rates (Humaidan, 2005). In the following randomized controlled trials (RCTs), the use of exogenous human chorionic gonadotropin (hCG) after gonadotropin releasing hormone (GnRH) agonist trigger as a luteal phase support (Humaidan, 2010, 2013), the mid luteal P4 levels increased to 77-409 nmol/l and birth rates per transfer raised to %24.

In the light of these, it is essential that the progesterone levels in luteal phase is above the certain threshold for induction of the normal secretory development of endometrium following the IVF treatment and for the maintenance of pregnancy.

The implantation window is defined as that period when the uterus is receptive for implantation of the free-lying blastocyst. For maximal effectiveness of assisted reproductive technologies in women, it is important to know the optimal time for embryo transfer which implies a need to predict the period of uterine receptivity. Blood progesterone levels can be an indirect indication for implantation window and the embryo transfer timing.

In a recent study by Vuong et al., marked inter-personal variation in early luteal circulating P4 levels have been reported following the same hCG trigger dose; since a freeze-all policy was adopted in that study, the inter-personal variation during the early luteal phase was entirely caused by differences in endogenous P4 production from the CL (Vuong, et al., 2020). In this study, almost one in five patients had already experienced a peak P4 concentration on OPU+2 day to OPU+3 day, and only one in seven had maximal concentrations on OPU+6 day, showing that a total of 85% of women experienced their highest P4 concentration before the period in which the peak was expected to be reached during a natural menstrual cycle (Andersen, et al., 2020). It is noteworthy that more than 40% of patients had a \>50% decrease in P4 concentration between OPU+4 day and OPU+6 day; although exogenous P4 supplementation in women undergoing IVF will ameliorate this drop-in serum P4 to some extent, these findings clearly highlight the requirement for studies examining how the probability of achieving pregnancy in fresh cycles is affected by the timing and magnitude of the reduction in P4 concentrations (Vuong, et al., 2020). Variations in endogenous production might, in theory, originate from differences in "quality" of the CL as seen during the natural cycle (Hull, et al., 1982) and/or differences in serum concentrations of hCG during the early luteal phase used for triggering (Vuong, et al., 2020b).

The aim of this study is two fold; i) to investigate the effect of early and mid luteal P4 levels on ongoing pregnancy rates and to determine the optimal luteal P4 levels in IVF cycles following the fresh blastocyst transfer in order to improve the reproductive outcomes, ii) to investigate the impact of serial P4 levels on OPU+3 and OPU+5 and delta P4 (ΔP4; as calculated by subtracting the P4 level on OPU+3 from the P4 level on OPU+5) on ongoing pregnancy rates.

During Covid-19 pandemic we decided to make an interim analysis in March 2020.

Since the shut down of the IVF clinics due to Covid-19 pandemic was over, we restarted our routine IVF practice and hence restarted recruitment of patients for this study.

Eligibility Criteria:
Inclusion Criteria:

* Cycles induced with GnRH agonist or GnRH antagonist protocol
* BMI\<35 kg/m
* Retrieval of 3 or more metaphase II oocytes, irrespective of ovarian reserve testing

Exclusion Criteria:

* Cycles triggered with GnRH agonist or dual trigger
* Circulating progesterone \> 1.5ng/mL on the day of trigger
* Cleavage stage embryo transfer