During the establishment of pregnancy, the endometrium undergoes dynamic remodelling in order to establish a receptive microenvironment. Decidualisation, a key part of this process, is characterised by differentiation of endometrial stromal fibroblasts which secrete factors that regulate implantation and placental development. Recent studies in our laboratory have revealed that decidualisation results in altered expression of enzymes that regulate biosynthesis and metabolism of estrogens. These results have prompted us to propose a role for local endometrial steroid biosynthesis in the establishment of a receptive endometrium. In the current study we have investigated whether tissue specific synthesis of androgens might also play a regulatory role in the endometrium during decidualisation.
Primary human endometrial stromal cells were isolated from endometrial biopsies collected from women during the proliferative phase of the cycle (n=20). In vitro decidualisation was induced by treatment with progesterone and cAMP. The expression of androgen biosynthetic enzymes and putative androgen-regulated receptivity markers was assessed by qPCR and western blot. Concentrations of IGFBP1, SPP1, testosterone and dihydrotestosterone (DHT) were determined by ELISA.
We found that decidualisation was associated with biosynthesis of androgens. Time-dependent changes in the expression of androgen biosynthetic enzymes AKR1C3 and SRD5A1 were detected by qPCR and Western blot. Decidualisation was associated with secretion of testosterone and DHT (n=8, P<0.001). When AR was inhibited by co-treatment with the antiandrogen flutamide a significant reduction in secretion of the decidualisation marker IGFBP1 (n=8, P<0.01) was detected. Flutamide also altered expression of putative androgen-regulated receptivity markers; osteopontin (SPP1; n=8, P<0.01), monoamine oxidase (MAOA; n=8, P<0.01), and endothelin receptor type B (EDNRB; n=8, P<0.001).
These data suggest intracrine biosynthesis of androgens plays a key role in decidualisation and endometrial receptivity. We speculate that efficient decidualisation is dependent upon formation of a unique steroid microenvironment that fine tunes the endometrium in preparation for pregnancy.