Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Departments of Obstetrics and Gynecology, Buffalo, NY, USA.
J Clin Endocrinol Metab. 2021 Nov 19;106(12):3591-3604. doi: 10.1210/clinem/dgab511.
Human embryonic implantation is regulated by neuroendocrine hormones, ovarian steroids, growth factors, and cytokines. Sympathetic innervation of the uterus also may play a role.
We tested the hypothesis that cabergoline (Cb), an agonist of type 2 dopamine receptors (DRD2), could influence endometrial decidualization in vitro.
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)-1β (0.1 nM) was used as an inflammatory stimulus. Well-characterized in vitro biomarkers were quantified.
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-1β on decidual cytology.
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.
人类胚胎着床受神经内分泌激素、卵巢甾体、生长因子和细胞因子的调节。子宫的交感神经支配也可能起作用。
我们检验了卡麦角林（Cb），一种 2 型多巴胺受体（DRD2）激动剂，可能影响体外子宫内膜蜕膜化的假说。
免疫组织化学证实人类子宫组织中存在儿茶酚胺能神经元。通过定量 RT-PCR、cDNA 微阵列、RNA 测序和 Western 印迹验证了子宫内膜组织和细胞中 DRD2 mRNA 和蛋白的表达。分离的人子宫内膜基质细胞（ESC）在不存在或存在蜕膜化激素（10 nM 雌二醇、100 nM 孕酮和 0.5 mM 二丁酰环腺苷酸）的情况下进行剂量反应和时间过程实验。在某些情况下，使用白细胞介素（IL）-1β（0.1 nM）作为炎症刺激物。对特征明确的体外生物标志物进行了定量分析。
DRD2 在体内循环的中分泌期表达最高，在 ESC 中对蜕膜化激素的反应上调，同时上调的还有经典（如催乳素）和新兴（如 VEGF 和连接蛋白 43）分化生物标志物。卡麦角林治疗使蜕膜生物标志物的表达增加了一倍以上，而多巴胺受体拮抗剂利培酮则使 ESC 分化抑制超过 50%。卡麦角林诱导特征性蜕膜形态变化，并阻止了 IL-1β对蜕膜细胞学的有害影响。
我们的结果支持多巴胺能神经元调节原位蜕膜化的假说。我们推测，多巴胺激动剂，如 Cb，可被开发为治疗药物，以增强与炎症相关的不孕夫妇的着床。
