Long Qiqi, Liu Xishi, Guo Sun-Wei
Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China.
Am J Obstet Gynecol. 2016 Sep;215(3):320.e1-320.e15. doi: 10.1016/j.ajog.2016.02.055. Epub 2016 Mar 3.
Surgery is currently the mainstay treatment for solid tumors and many benign diseases, including endometriosis, and women tend to receive substantially more surgeries than men mainly because of gynecological and cosmetic surgeries. Despite its cosmetic, therapeutic, or even life-saving benefits, surgery is reported to increase the cancer risk and promotes cancer metastasis. Surgery activates adrenergic signaling, which in turn suppresses cell-mediated immunity and promotes angiogenesis and metastasis. Because immunity, angiogenesis, and invasiveness are all involved in the pathophysiology of endometriosis, it is unclear whether surgery may accelerate the development of endometriosis.
The objective of the study was to test the hypothesis that surgery activates adrenergic signaling, increases angiogenesis, and accelerates the growth of endometriotic lesions.
This was a prospective, randomized experimentation. The first experiment used 42 female adult Balb/C mice, and the second used 90 female adult Balb/C mice. In experiment 1, 3 days after the induction of endometriosis, mice were randomly divided into 3 groups of approximately equal sizes, control, laparotomy, and mastectomy. In experiment 2, propranolol infusion via Alzet pumps was used to forestall the effect of sympathetic nervous system activation by surgery. In both experiments, mice were evaluated 2 weeks after surgery. Lesion size, hotplate latency, and immunohistochemistry analysis of vascular endothelial growth factor, CD31-positive microvessels, proliferating cell nuclear antigen, phosphorylated cyclic adenosine monophosphate-responsive element-binding protein, β2-adrenergic receptor (ADRB)-2, ADRB1, ADRB3, ADRA1, and ADRA2 in ectopic implants.
Both mastectomy and laparotomy increased lesion weight and exacerbated hyperalgesia, increased microvessel density and elevated the immunoreactivity against ADRB2, phosphorylated cyclic adenosine monophosphate-responsive element-binding protein, vascular endothelial growth factor, and proliferating cell nuclear antigen but not ADRB1, ADRB3, ADRA1, and ADRA2, suggesting activated adrenergic signaling, increased angiogenesis, and accelerated growth of endometriotic lesions. β-Blockade completely abrogated the facilitory effect of surgery, further underscoring the critical role of β-adrenergic signaling in mediating the effect of surgery.
Surgery activates adrenergic signaling, increases angiogenesis, and accelerates the growth of endometriotic lesions in the mouse, but such a facilitory effect of surgery can be completely abrogated by β-blockade. Whether surgery can promote the development of endometriosis in humans warrants further investigation.
手术目前是实体瘤以及包括子宫内膜异位症在内的许多良性疾病的主要治疗方法，而且女性接受的手术往往比男性多得多，主要是因为妇科手术和美容手术。尽管手术具有美容、治疗甚至挽救生命的益处，但据报道手术会增加癌症风险并促进癌症转移。手术激活肾上腺素能信号传导，进而抑制细胞介导的免疫并促进血管生成和转移。由于免疫、血管生成和侵袭性均参与子宫内膜异位症的病理生理学，因此尚不清楚手术是否会加速子宫内膜异位症的发展。
本研究的目的是验证手术激活肾上腺素能信号传导、增加血管生成并加速子宫内膜异位病灶生长这一假说。
这是一项前瞻性随机实验。第一个实验使用了42只成年雌性Balb/C小鼠，第二个实验使用了90只成年雌性Balb/C小鼠。在实验1中，诱导子宫内膜异位症3天后，将小鼠随机分为大小大致相等的3组：对照组、剖腹手术组和乳房切除术组。在实验2中，通过Alzet泵输注普萘洛尔以预先阻止手术激活交感神经系统的作用。在两个实验中，均在手术后2周对小鼠进行评估。评估异位植入物的病灶大小、热板潜伏期，以及对血管内皮生长因子、CD31阳性微血管、增殖细胞核抗原、磷酸化环磷酸腺苷反应元件结合蛋白、β2-肾上腺素能受体（ADRB）-2、ADRB1、ADRB3、ADRA1和ADRA2进行免疫组织化学分析。
乳房切除术和剖腹手术均增加了病灶重量并加剧了痛觉过敏，增加了微血管密度，并提高了对ADRB2、磷酸化环磷酸腺苷反应元件结合蛋白、血管内皮生长因子和增殖细胞核抗原的免疫反应性，但对ADRB1、ADRB3、ADRA1和ADRA2没有影响，这表明肾上腺素能信号传导被激活、血管生成增加以及子宫内膜异位病灶生长加速。β受体阻滞剂完全消除了手术的促进作用，进一步强调了β肾上腺素能信号传导在介导手术效果中的关键作用。
手术激活肾上腺素能信号传导，增加血管生成，并加速小鼠子宫内膜异位病灶的生长，但手术的这种促进作用可被β受体阻滞剂完全消除。手术是否会促进人类子宫内膜异位症的发展值得进一步研究。
