A role for steroid 5 alpha-reductase 1 in vascular remodeling during endometrial decidualization

Decidualization is the hormone-dependent process of endometrial remodeling that is essential for fertility and reproductive health. It is characterized by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodeling. Deficits in decidualization are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and preeclampsia. Androgens are key regulators of decidualization that promote optimal differentiation of stromal fibroblasts and activation of downstream signaling pathways required for endometrial remodeling. We have shown that androgen biosynthesis, via 5a-reductase-dependent production of dihydrotestosterone, is required for optimal decidualization of human stromal fibroblasts in vitro, but whether this is required for decidualization in vivo has not been tested. In the current study we used steroid 5a-reductase type 1 (SRD5A1) deficient mice (Srd5a1-/- mice) and a validated model of induced decidualization to investigate the role of SRD5A1 and intracrine androgen signaling in endometrial decidualization. We measured
decidualization response (weight/proportion), transcriptomic changes, and
morphological and functional parameters of vascular development. These
investigations revealed a striking effect of 5a-reductase deficiency on the
decidualization response. Furthermore, vessel permeability and
transcriptional regulation of angiogenesis signaling pathways, particularly
those that involved vascular endothelial growth factor (VEGF), were disrupted
in the absence of 5a-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualization restored
decidualization responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signaling is required for optimal decidualization in vivo and confirm a major role for androgens in the development of the vasculature during decidualization through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgendependent signaling in the endometrium.