P-422 Endometrial 17β-estradiol production by local steroid-metabolizing enzymes in IVF patients with recurrent implantation failure (RIF) versus control subjects

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Abstract Study question Is the endometrial synthesis and inactivation of 17β-estradiol by steroid-metabolizing enzymes altered between IVF patients with recurrent implantation failure (RIF) and control subjects? Summary answer Synthesis and inactivation of 17β-estradiol were similar in the endometrium of RIF patients and control subjects, however, distinct steroid-metabolizing enzymes contributed to the 17β-estradiol synthesis. What is known already Implantation failure of high-quality embryos is a major concern in IVF/ICSI treatment. Blood sex-steroid concentrations do not correspond to their concentrations in endometrial tissue. This aligns with the concept that blood steroids (and their precursors) are converted to bioactive metabolites by steroid-metabolising enzymes expressed locally in the endometrium (also referred to as intracrinology). A class of these enzymes is represented by 17β-hydroxy-steroid-dehydrogenases (17β-HSDs), regulating the final step in 17β-estradiol production. Alterations in intracrinology and final 17β-estradiol production might modulate endometrial receptivity. The contribution of different types of endometrial 17β-HSD enzymes in 17β-estradiol production during the window of implantation is unknown. Study design, size, duration Observational cohort study (the MURIM study, NL7571), aimed at exploring differences in endometrial receptivity parameters among IVF patients with RIF versus control subjects, recruited between 2019 and 2024. For the present investigation, mid-luteal phase endometrial biopsies of RIF patients (n = 52) were compared with women that were presumed to be fertile (controls, n = 25). Additionally, RIF patients and control subjects were followed-up to determine their reproductive prognosis in the year after study participation. Participants/materials, setting, methods The study was conducted in our university-hospital. Endometrial biopsies were obtained at LH + 5-8 days (natural cycle). RIF was defined as failed implantation of≥three high-quality embryos or > 10 failed transfers. Exclusion criteria were BMI>35kg/m2, intrauterine pathology, or endocrine abnormalities. Patients with severe male factor/azoospermia, bilateral tubal pathology or pre-implantation genetic testing for hereditary disorders were recruited as control subjects. Synthesizing and inactivating 17β-HSDs and enzyme-inhibition was determined by high-performance liquid-chromatography and analysed with Student’s t-test and Mann-Whitney-U-test. Main results and the role of chance Activity of 17β-HSDs responsible for reduction of estrone to 17β-estradiol (mainly 17β-HSD1, to a lesser extent 17β-HSD5, 17β-HSD7 and 17β-HSD12) did not differ between RIF patients and controls (1074.5 [IQR = 789.8–1519.8] vs. 1259 [749.5–1854.5] pmol 17β-estradiol/mg protein/hour, p = 0.31). The activity of the enzymes responsible for oxidizing 17β-estradiol (mainly 17β-HSD2) into the less active estrone were non-significantly different between RIF patients and controls (786.5 [509 – 1193.5] vs. 1012 [647 - 1532] pmol estrone/mg protein/hour, p = 0.21). An inhibition analysis was performed to determine the contribution of the different 17β-HSD types. Combined inhibition of the reductive 17β-HSD5, 17β-HSD7 and 17β-HSD12 resulted in a higher synthesis of 17β-estradiol in the presence of these inhibitors in RIF patients compared to controls (p = 0.04). Combined inhibition of 17β-HSDs1 and 17β-HSD7 also led to significantly higher synthesis of 17β-estradiol in the presence of these inhibitors in RIF patients (p < 0.01). Immunostaining detected 17β-HSD7 expression in all endometrial samples. A subgroup analysis was performed to compare RIF patients with a poor prognosis (no pregnancy during one-year follow-up, n = 18) with control subjects with ongoing pregnancy during one-year follow-up (n = 13). No statistically significant differences in oxidative and reductive activity were found between these groups (p = 0.75 and p = 0.71, respectively). Limitations, reasons for caution Careful interpretation is necessary due to possible cycle-to-cycle variation, challenges in extrapolating in vitro outcomes to biological conditions, the heterogeneous aetiology of RIF patients with unknown embryo-ploidy status, and the assumption that the endometrium of control patients reflected a receptive state of the endometrium in the cycle of the biopsy. Wider implications of the findings In the presence of 17β-HSD1 and 17β-HSD7 inhibitors, final 17β-estradiol levels differed significantly between groups. Although 17β-HSD1, expressed at the fetal-maternal interface, is associated with fertility, the role for 17β-HSD7 in embryo implantation remains unexplored. This warrants future research on how these specific hydroxysteroid-enzymes influence endometrial receptivity. Trial registration number Yes

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