SULFATION PATHWAYS: A role for steroid sulphatase in intracrine regulation of endometrial decidualisation.

Douglas A Gibson,Frances Collins,Olympia Kelepouri,Philippa T K Saunders,Hilary O D Critchley,Ioannis Simitsidellis,Paul A Foster

doi:10.1530/jme-18-0037

Abstract

In women, establishment of pregnancy is dependent upon ‘fine-tuning’ of the endometrial microenvironment, which is mediated by terminal differentiation (decidualisation) of endometrial stromal fibroblasts (ESFs). We have demonstrated that intracrine steroid metabolism plays a key role in regulating decidualisation and is essential for time-dependent expression of key factors required for endometrial receptivity. The primary aim of the current study was to determine whether sulphated steroids can act as precursors to bioactive sex steroids during decidualisation. We used primary human ESF and a robust in vitro model of decidualisation to assess the expression of genes associated with sulphation, desulphation and transport of sulphated steroids in human ESF as well as the impact of the steroid sulphatase (STS) inhibitor STX64 (Irosustat). We found evidence for an increase in both expression and activity of STS in response to a decidualisation stimulus with abrogation of oestrone biosynthesis and decreased secretion of the decidualisation marker IGFBP1 in the presence of STX64. These results provide novel insight into the contribution of STS to the intracrine regulation of decidualisation.

Highlights

Decidualisation is a fundamental process of endometrial remodelling that is required for the establishment of pregnancy
Whilst the post-ovulatory rise in progesterone acts as an endocrine signal to stimulate decidualisation of oestrogen-primed human endometrial stromal fibroblast, we have demonstrated an important role for local steroid metabolism in fine-tuning the cellular differentiation of hESFs (Gibson et al 2016b)
Expression of STS was increased at all time points in hESF stimulated with DEC; results reached statistical significance in samples recovered on Day 1 (Fig. 1A; n = 6; P < 0.0001), 2 (Fig. 1B; n = 6; P < 0.0001) and 4 (Fig. 1C; n = 6; P < 0.01)

Summary

Introduction

Decidualisation is a fundamental process of endometrial remodelling that is required for the establishment of pregnancy It is associated with unique time-dependent transcriptomic and proteomic changes (reviewed in Gellersen & Brosens 2014), which are reported to be disordered in women with recurrent implantation failure (Ruiz-Alonso et al 2013, Koot et al 2016). We have established that expression of CYP19A1 (aromatase, the key enzyme required for conversion of androgens to estrogens) as well as AKR1C3 and SRD5A1 (enzymes that convert precursor androgens into testosterone and dihydrotestosterone (DHT), respectively) are altered in a time-dependent manner (Gibson et al 2013, 2016a).

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