title: Long-term effects of repeated superovulation on the uterus and mammary gland in rhesus monkeys.
abstract: OBJECTIVE
  The aim of this study is to evaluate the effect of repeated controlled ovarian hyperstimulation (COH) on the structure and function of the uterus and mammary gland.
  
  
  METHODS
  Three adult female rhesus monkeys were superovulated up to four times, and three spontaneously ovulating monkeys were used as controls. After a 5-year period, the uterus and mammary gland tissue samples were collected for examination of their structure and function. Further, the expression of certain tumor markers was examined to assess the cancer risk for each organ.
  
  
  RESULTS
  Expression of Wnt7a (associated with the functional/developmental status of the uterus) was significantly decreased in the uterus of superovulated monkeys, and decreased expression of proliferation marker PCNA was found in uterine cells. Meanwhile, abnormal Golgi-derived secretory vesicles with an irregular shape were observed in the mammary glands of the superovulated monkeys, and decreased PCNA expression together with increased expression of caspase-3 (an apoptosis marker) was indicated in the mammary cells. The expression of tumor molecular markers of the uterus and mammary gland was not significantly different between the two groups.
  
  
  CONCLUSIONS
  Repeated COH affects the expression of the uterine development-related gene several years later, and uterine cells exhibited a low proliferation status. The ultrastructure of the mammary gland epithelial cells was abnormal, and the cells exhibited both low proliferation and high apoptosis status. Cancer risk for these organs was not observed. Given that primates are the closest relatives of humans, the results obtained from this study provide more intuitive information for optimization of clinical COH.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Huarong
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
authors.forename: Meimei
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China. njzhuhui@njmu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008253:Macaca mulatta; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000139:chemically induced / Q000235:genetics; D010062:Ovulation Induction / Q000009:adverse effects*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D012307:Risk Factors; D013480:Superovulation; D014599:Uterus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018809:Proliferating Cell Nuclear Antigen; C092778:WNT7A protein, human; D051153:Wnt Proteins; D053148:Caspase 3
keywords: Controlled ovarian hyperstimulation (COH); Mammary gland; Rhesus monkey; Safety assessment of ART; Uterus