O-208 The Programmed Ovulatory Frozen-Thawed Embryo Transfer Cycle (PO-FET): a suggested FET protocol integrating aspects of embryo transfer scheduling, efficacy optimization and maternal/fetal safety
Authors: Eggersmann T  K , Hamala N , Hiller R  A F , Depenbusch M , Schultze-Mosgau A , Edimiris P , Baston-Buest D , Bielfeld A , Krüssel J  S , Von Otte S , Junkers W , Tauchert S , Vonthein R , Griesinger G 
Published: July 2024

Abstract

Study question
What is the effect of 30mg oral dydrogesterone (DYD), given to induce endometrial receptivity in natural-proliferative-phase-FET-cycles (NPP-FET), on ovulation, progesterone and DYD/DHD-levels, respectively, and outcomes?

Summary answer
Oral DYD 30mg allows scheduling endometrial receptivity in natural cycles while not interfering with ovulation in the vast majority of patients.

What is known already
Globally, approximately 60% of all ETs are performed after cryopreservation. Hormone Replacement Treatment (HRT)-FET cycle-regimens have come under scrutiny, because of i) risk of insufficient progesterone exposure with conventional dosing-schemes and ii) maternal/fetal risks stemming from the iatrogenic lack of a corpus luteum. Oral DYD 10mg (tid) supposedly does not interfere with ovulation/corpus luteum formation, and does not cross-react with progesterone in ELISA. It could thus be used for inducing endometrial receptivity (scheduling, in a natural cycle, the time point of ET) and luteal phase support, while allowing ovulation dissociated from the window-of-implantation and monitoring of endogenous progesterone serum levels.

Study design, size, duration
Within a multi-centric, prospective, clinical cohort study (NCT03507673), 559 normally cycling women from the routine care population who underwent FET after IVF/ICSI in a natural cycle (2/2021 – 8/2023) had serum/plasma samples prospectively collected/stored on day of FET for measurement of E2, progesterone and DYD/DHD in Roche Elecsys®-Immunoassay and liquid chromatography/tandem mass spectroscopy (LC-MS/MS), respectively. FET was performed on day 2/3 (cleavage-stage) or day 4/5 (morula/blastocyst) in 17.4% and 82.6% of FETs, respectively.

Participants/materials, setting, methods
From cycle day 10, women underwent endocrine (E2, LH and P) and sonographic monitoring until E2 &gt;180pg/ml, leading follicle &gt;16mm and endometrial thickness was &gt;6mm. Physicians could then initiate oral DYD10mg (tid) or–in absence of LH rise–postpone initiation, under 2-daily monitoring, to meet the organizational preferences of the patient and/or center (for example, avoiding weekends). FET was performed for day 2 (cleavage), 3, 4 or 5 (blastocyst) on day 3-6 of DYD-intake, respectively.

Main results and the role of chance
Previously reported PK of 10mg DYD (tid) are confirmed/extended. While log-levels of DYD and DHD were highly correlated (0.95), P-levels were not (0.02, 0.02). In 94.4% of patients, ovulation could be confirmed by serum-P levels on the day of FET or in late luteal phase. Medians (IQR) of DYD and P on day 3 and days 5, respectively, were 0.93ng/ml (0.93ng/ml) and 2.96ng/ml (3.19ng/ml), and 1.13ng/ml (1.09ng/ml) and 8.50ng/ml (4.40ng/ml). Serum-P levels increased with the FET day (medians 2.0, 3.0, 6.6, and 8.5 ng/ml on days 2, 3, 4, and 5) and only very weakly correlated with LH, E2 levels, and follicular diameter at last monitoring. 42.5% and 34.8% of patients had positive hCG and ongoing clinical pregnancy, respectively. Ongoing pregnancy was independent from plasma-DYD levels (&lt; 25th percentile [&lt;0.66 ng/ml] 37.9% vs. ≥25thperc. [≥0.66 ng/ml] 34.3%, RD 1.5%, 95%CI: -16.5% to 17.4%, p =  0.334), yet dependent from serum-P levels (&lt; 25thperc [&lt;4.85 ng/ml] 25.9% vs. ≥25thperc [≥4.85 ng/ml] 35.3%, RD 9.4%, 95% CI 0.4% to 17.6%, p = 0.0161).However, neither of the two serum hormone values is predictive of a dichotomous outcome in isolation, nor do they demonstrate predictive interaction when considered together in logistic regression modelling.

Limitations, reasons for caution
DYD, like hCG or any other progestin given for LPS, may negatively interfere with LH surge, ovulation and luteal phase characteristics. Controlled studies on different progestin types and doses are necessary to better understand how to optimize luteal phase and thereby optimally support embryo nidation, pregnancy maintenance and maternal/fetal health.

Wider implications of the findings
The PO-FET protocol induces the implantation window, thus offers (some) flexibility in FET timing, shows little interference with ovulation/corpus luteum formation, provides double gestagenic support with no need for monitoring P or DYD levels, however allows corpus luteum activity monitoring in luteal phase and early pregnancy, is injection-free, and low-cost.

Trial registration number
NCT03507673