Cabergoline Stimulates Human Endometrial Stromal Cell Decidualization and Reverses Effects of Interleukin-1[beta] In Vitro

Context: Human embryonic implantation is regulated by neuroendocrine hormones, ovarian steroids, growth factors, and cytokines. Sympathetic innervation of the uterus also may play a role. Objective: We tested the hypothesis that cabergoline (Cb), an agonist of type 2 dopamine receptors (DRD2), could influence endometrial decidualization in vitro. Methods: Immunohistochemistry confirmed the presence of catecholaminergic neurons in human uterine tissue. DRD2 mRNA and protein expression in endometrial tissue and cells were validated by quantitative RT-PCR, cDNA microarrays, RNA sequencing, and Western blotting. Isolated human endometrial stromal cells (ESC) were subjected to dose-response and time-course experiments in the absence or presence of decidualizing hormones (10 nM estradiol, 100 nM progesterone, and 0.5 mM dibutyryl cAMP). In some cases, interleukin (IL)-1[beta] (0.1 nM) was used as an inflammatory stimulus. Well-characterized in vitro biomarkers were quantified. Results: DRD2 were maximally expressed in vivo in the mid-secretory phase of the cycle and upregulated in ESC in response to decidualizing hormones, as were classical (eg, prolactin) and emerging (eg, VEGF and connexin 43) differentiation biomarkers. Cabergoline treatment more than doubled decidual biomarker expression, whereas risperidone, a dopamine receptor antagonist, inhibited ESC differentiation by >50%. Cabergoline induced characteristic decidual morphology changes and blocked detrimental effects of IL-1[beta] on decidual cytology. Conclusion: Our results support the hypothesis that dopaminergic neurons modulate decidualization in situ. We postulate that dopamine agonists, like Cb, could be developed as therapeutic agents to enhance implantation in couples with inflammation-associated infertility. Key Words: uterus, dopamine receptors, differentiation, steroids, cytokines