ABSTRACT
PURPOSE: 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.
Subject(s)
Biomarkers, Tumor/genetics , Mammary Glands, Animal/metabolism , Ovulation Induction/adverse effects , Superovulation , Uterus/metabolism , Animals , Breast Neoplasms/chemically induced , Breast Neoplasms/genetics , Caspase 3/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Macaca mulatta , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/pathology , Ovarian Neoplasms/chemically induced , Ovarian Neoplasms/genetics , Proliferating Cell Nuclear Antigen/genetics , Risk Factors , Uterus/drug effects , Uterus/pathology , Wnt Proteins/geneticsABSTRACT
OBJECTIVE: To assess the long-term effects of repeated controlled ovarian hyperstimulation (COH) on ovarian structure and function. DESIGN: Experimental study. SETTING: Laboratory. ANIMAL(S): Adult female rhesus macaques. INTERVENTION(S): A repeated COH rhesus macaque model (superovulation group) with spontaneously ovulating macaques used as controls (normal group) and samples of serum and ovarian tissue collected over a 5-year period. MAIN OUTCOME MEASURE(S): Steroid hormone levels, and structural, functional, and protein changes in ovaries. RESULT(S): The follicular histology, proportion of follicles at each developmental stage, and expression levels of oocyte-specific genes showed no statistically significant differences between the two groups. However, the superovulation group exhibited mitochondrial abnormalities in the granulosa cells and a low expression of genes involved in steroid hormone synthesis compared with the normal group. A comparison of protein expression in the ovaries of both groups using tandem mass tag labeling with mass spectrometry revealed that most of the differentially-expressed proteins were down-regulated in the superovulation group. These proteins were mainly localized in the mitochondria and cytosol, and changes in protein levels in the superovulation group mainly inhibited cell proliferation and differentiation but promoted apoptosis. CONCLUSION(S): Our study indicates that repeated COH could change the expression of many proteins in the ovaries even after several years, potentially affecting the development and function of ovarian cells.
