Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. The prevalence of endometriosis is ~5–10% in reproductive-age women, increasing to 20–30% in women with subfertility. The current anti-estrogen therapies can be prescribed only for a short time because of the undesirable side effects on menstruation, pregnancy, bone health, and failure to prevent a recurrence. The causes of endometriosis-associated infertility are multifactorial and poorly understood. The objective of the present study was to determine the inhibitory effects of AKT and/or ERK1/2 pathways on the microenvironment of the endometrium in a xenograft mouse model of endometriosis of human origin. Results indicate that dual inhibition of AKT and ERK1/2 pathways, but not inhibition of either AKT or ERK1/2 pathway, suppresses the growth of the endometriotic lesions in vivo. Dual inhibition of AKT and ERK1/2 pathways suppresses the production of proinflammatory cytokines, decreases E₂ biosynthesis and signaling, and restores progesterone receptor-B signaling components in the epithelial and stromal cells of the endometrium in a cell-specific manner. These results together suggest that dual inhibition of AKT and ERK1/2 pathways suppresses the estrogen-dominant state and concomitantly increases the progesterone-responsive state of the endometrium. Therefore, dual inhibition of AKT and ERK1/2 pathways could emerge as long-term nonsteroidal therapy for endometriosis.

子宫内膜异位症是一种雌激素依赖性和孕激素抵抗的育龄妇女妇科炎症性疾病。育龄妇女子宫内膜异位症的患病率约为 5-10%，而生育力低下的妇女则增加到 20-30%。由于对月经、怀孕、骨骼健康的不良副作用以及无法防止复发，目前的抗雌激素疗法只能在短时间内开出处方。子宫内膜异位症相关不孕症的原因是多因素的，并且知之甚少。本研究的目的是确定 AKT 和/或 ERK1/2 通路对人类子宫内膜异位症异种移植小鼠模型中子宫内膜微环境的抑制作用。结果表明 AKT 和 ERK1/2 通路的双重抑制，但不抑制 AKT 或 ERK1/2 通路，抑制体内子宫内膜异位病变的生长。AKT 和 ERK1/2 通路的双重抑制抑制促炎细胞因子的产生，降低 E₂生物合成和信号传导，并以细胞特异性方式恢复子宫内膜上皮和基质细胞中的孕酮受体-B 信号传导成分。这些结果共同表明 AKT 和 ERK1/2 通路的双重抑制抑制了雌激素主导状态并同时增加了子宫内膜的孕激素反应状态。因此，AKT 和 ERK1/2 通路的双重抑制可能成为子宫内膜异位症的长期非甾体治疗。