title: Surgery accelerates the development of endometriosis in mice.
abstract: 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.
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
authors.forename: Qiqi
authors.initials: Q
authors.lastname: Long
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China.
authors.forename: Xishi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China. Electronic address: hoxa10@outlook.com.
authors.forename: Sun-Wei
authors.initials: SW
authors.lastname: Guo
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D004715:Endometriosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007813:Laparotomy; D051379:Mice; D008807:Mice, Inbred BALB C; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D011943:Receptors, Adrenergic, beta; D042461:Vascular Endothelial Growth Factor A; D050882:CREB-Binding Protein
keywords: adrenergic receptor; angiogenesis; endometriosis; mouse; surgery; β-blocker