Serum Progesterone Profile Across the Mid and Late Luteal Phase in Artificial Cycles Is Associated With Pregnancy Outcome

Abstract

IntroductionRecent studies have shown that low serum progesterone levels on the day of embryo transfer (ET) are associated with poorer pregnancy outcome in hormonal replacement therapy cycles. It is of interest to know if serum progesterone levels during late luteal phase (following days after ET) are also related with the chances of ongoing pregnancy.ObjectiveTo evaluate the luteal phase endocrine profile through measurements of serum progesterone and estradiol on days ET+4, ET+7 and ET+11, to test their predictive value in relation to pregnancy outcome.SettingPrivate infertility center, Valencia, Spain.Materials and MethodsProspective cohort study performed between June 2017 and August 2018. Eligible patients were aged between 18-42 years, with a normal uterus, and being transferred 1-2 good quality blastocysts in a frozen ET cycle after an artificial endometrial preparation with estradiol valerate and vaginal micronized progesterone (400 mg/12 hours).ResultsA total of 127 patients were included. Mean age = 38.0 ± 3.9 years; BMI = 23.6 ± 3.6 kg/m2; endometrial thickness = 9.1 ± 1.6mm. Overall ongoing pregnancy rate = 47.2% (95%CI:38.3-56.3). Significantly higher levels of serum progesterone were observed on ET+4 (13.6 ± 6.0 vs. 11.1 ± 4.6ng/ml, p = 0.03) and ET+11 (15.7 ± 1.2 vs. 10.3 ± 0.6ng/ml, respectively; p = 0.000) in ongoing pregnancies versus negative β-hCG (β-human chorionic gonadotrophin) cases. On ET+7, ongoing pregnancies also had higher serum progesterone levels (14.2 ± 0.9 vs. 11.7 ± 0.8ng/ml, but did not reach statistical significance (p = 0.07). Serum estradiol levels were not related with pregnancy outcome at any moment of the luteal phase (p > 0.05). On days ET+4, +7 and +11, the ROC analysis showed that serum progesterone levels were predictive of ongoing pregnancy, and Pearson’s coefficient showed a significant association (p<0.05) of serum β-hCG levels with serum progesterone.ConclusionsIn hormonal replacement therapy cycles, serum progesterone levels across luteal phase days are associated with pregnancy outcome. Ongoing pregnancies were associated with a higher exposure to progesterone in comparison with pregnancy losses or negative β-hCG. Therefore, serum progesterone might be playing an important role not only during implantation, but also in pregnancy maintenance. It remains unknown if the variability in serum progesterone levels among patients, after receiving the exact same progesterone dose for luteal phase support, is the cause or just a consequence of pregnancy results.

The addition of dydrogesterone improves the outcomes of pregnant women with low progesterone levels when receiving vaginal progesterone alone as luteal support in HRT‐FET cycles

“…However, if P levels are extremely low during embryo transfer, even implantation cannot occur. 20 The data from the present study imply that luteal support with vaginal P alone seems inadequate in terms of P actions in a considerable proportion of women. As possible explanations for this, first, one may argue that there might be inter-individual variability in the absorption of P through the vaginal wall.…”

“…Although highly speculative, peri‐implantation may be a P‐dependent critical period during which the pregnancy outcome is predetermined. However, if P levels are extremely low during embryo transfer, even implantation cannot occur 20 …”

Assessment of progesterone levels on the day of pregnancy test determination: A novel concept toward individualized luteal phase support

“…Although having different timing in the P4 assessment, quite impressively, all the previous studies nearly showed the same outcome, having higher values of luteal P4 (>9 ng/ml) related to higher outcomes rate. More specifically, the consistency of these results goes beyond the timing in which progesterone was evaluated (day of FET, day before FET, or 11 days after FET, respectively, for 10 , 16 , 18 , 19 , 22 ). In fact, the common feature of all the results was that whenever P4 was in the lower limit, the cycle outcomes were hindered.…”

“…Progesterone has two key features: one is that pharmacokinetics depends on the route of administration and consequently the serum values (13); the other one is the daily variability (14,15). Despite the high variability of P4, all the recent studies published on luteal serum P4 showed that low serum levels of P4 (below 9-10 ng/ml) are associated with worse cycle outcomes (10,(16)(17)(18)(19)(20), independently from the day of the assessment.…”

Preparation of the endometrium for frozen embryo transfer: an update on clinical practices

“…Once pregnancy is established, it appears that the higher the progesterone concentration, the more likely the pregnancy continues. A recent prospective cohort study [ 130 ] sought to evaluate potential differences in serum P levels throughout the late luteal phase (days 4, 7, and 11 after ET) based on pregnancy outcomes and reported that patients with an ongoing pregnancy had higher levels of serum P than the rest, particularly those with a negative result or pregnancy loss. And there was an increasing trend of serum P level throughout the luteal phase days.…”