LOWPLASMA DYDROGESTERONE (DYD) LEVEL ON DAY OF ET IS ASSOCIATED WITH REDUCED ONGOING PREGNANCY RATE IN HRT PROGRAMMED FET CYCLES: A PROSPECTIVE OBSERVATIONAL STUDY.

In an artificial FET-cycle, a corpus luteum is absent and therefore the exogenous support by progestogens is key to pregnancy establishment. Dydrogesterone (DYD) is an oral, systemic alternative to vaginal progesterone for luteal phase support. Measurement of DYD and and its metabolite, 20α-Dihydrodydrogesterone (DHD), is only feasible by LC/MS. While oral DYD is widely used in fresh IVF cycles, circulating concentrations vs. successful treatment have never been explored. This study determines plasma concentrations of DYD and DHD, measured on day of ET in a programmed anovulatory FET cycle, and describes the association with the outcome. Prospective, clinical cohort study (5/2018-11/2021) (NCT03507673); university IVF-center; women (n=217) undergoing a programmed FET-cycle with 2mg oral estradiol (tid) and, for luteal support, 10mg oral dydrogesterone (tid); main inclusion criterion: absence of follicle and low progesterone (<1.5ng/ml) on day 12-15 of estradiol intake; serum and plasma samples taken on day of ET and stored at -80°C for analysis by LC/MS; each patient could contribute only one cycle to the analyses. Women undergoing FET on embryo development day 2 (D2), 3 (D3) or 5 (D5) had blood sampling on the 3rd, 4th or 6th day of DYD intake, respectively. The patient population was stratified by DYD and DHD plasma levels by percentiles (<25th vs. >25th) separately by day of ET. Ongoing pregnancy rates (a viable pregnancy at >10th GW) were compared between <25th percentile vs. >25th percentile for DYD and DHD levels (adjusted for day of ET). In 14/217 (6.4%), an ‘escape ovulation’ was detected (defined as progesterone-levels >1.5 ng/ml on day of ET) and these patients were excluded from the analysis. In five patients, no LC/MS results were available, leaving for D2/3 FET n=41 and D5 FET n=157 observations. Mean (± SD) plasma levels of DYD and DHD were 1.6 ng/ml (±1.3) and 41.3 ng/ml (±28.4) on D2, 1.6 (±1.1) and 40.4 ng/ml (±24.4) on D3 and 1.3 ng/ml (±0.9) and 35.8 ng/ml (±21.2) on D5, respectively, suggesting that steady-state is reached already after 3 or 4 days of treatment. Body weight (R2=0.02 for DYD), but not BMI was associated with DYD and DHD plasma levels, albeit very weakly. Levels of DYD and DHD were strongly correlated (correlation coefficients 0.924 for D2/3 and 0.932 for D5, respectively). The 25th percentile of DYD and DHD levels were 0.74ng/ml and 19.85ng/ml on D2/3 and 0.71ng/ml and 20.80ng/ml on D5, respectively. The ongoing pregnancy rate was significantly reduced in patients in the lower quarter of DYD or DHD levels: <25th percentile DYD or DHD 3/49 (6%) vs. >25th percentile DYD or DHD 42/149 (28.2%) (adjusted difference -22.1%, 95% CI: -32.3 to -11.8, p<0.0001). Plasma levels after oral daily 30mg DYD reach stady state rapidly and show considerable variation, the latter mostly independent of BMI and body weight; low DYD/DHD plasma levels appear to be associtead with a suboptimal outcome.