Objectives: Alterations in 17β-estradiol metabolism are known to potentially impair endometrial receptivity. Previous pioneering studies have investigated the role of endometrial steroid metabolism by determining steroid hormone levels and steroid-metabolizing enzyme activity in endometrial biopsies of patients undergoing IVF. The activity of oxidative and reductive 17β-hydroxysteroid dehydrogenases (17β-HSDs), which catalyze the interconversion between estrone and 17β-estradiol, was found to be similar between IVF patients who - after fresh embryo transfer in the cycle following endometrial biopsy - did and did not become pregnant. However, inhibition of the reductive enzyme 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the most prominent 17β-HSD type in 17β-estradiol formation, was found to differ between groups. The primary objective of this study was to determine oxidative and reductive 17β-HSD enzyme activity in the endometrium of two well-defined groups: IVF patients with recurrent implantation failure (RIF) and control patients.
Design: This is a prospective observational study of IVF patients with RIF (n = 52) and controls (n = 25). Patients undergoing treatment because of pre-implantation genetic testing, a severe male factor, or bilateral tubal pathology were recruited as controls since these conditions did not suggest an endometrial contribution to infertility.
Participants/materials, setting, methods: Endometrial biopsies were obtained 5-8 days after a positive urine ovulation test in a natural cycle using a Pipelle catheter. Activity of oxidative and reductive enzymes, inhibition of 17β-HSD1, 5, 7, and 12, and immunostaining of 17β-HSD7 were performed. The formation of 17β-estradiol by reduction of estrone (reductive enzymes), formation of estrone by oxidation of 17β-estradiol (oxidative enzymes), and inhibition of specific 17β-HSD enzymes were determined using high-performance liquid chromatography. Formalin-fixed paraffin-embedded tissue was used for immunostaining. The Student's t test and Mann-Whitney U test were used for statistical analysis. Multivariate analysis was used to determine the influence of confounders.
Results: No differences were found in activity of oxidative and reductive 17β-HSD enzymes in RIF patients and controls. Combined inhibition of 17β-HSD5, 7, and 12 was significantly lower in the RIF group compared to controls (p = 0.04). Inhibition of 17β-HSD1 and 17β-HSD7 combined was also significantly lower (more production of 17β-estradiol remained) in the RIF group compared to controls (p < 0.01). However, solely inhibiting 17β-HSD1 or 17β-HSD7 showed no significant difference between groups. Immunostaining revealed the expression of 17β-HSD7 in all endometrial samples.
Limitations: Results should be interpreted carefully due to possible cycle-to-cycle variation, challenges to translate in vitro fi
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