Although assisted reproductive technologies (ARTs) have allowed millions of otherwise infertile couples to conceive children of their own, concerns remain about the safety of these procedures due to an increased incidence of epigenetic disorders in children born following the use of ART. Specifically, abnormal genomic imprinting and/or diseases caused by abnormal imprinting have been reported. While the frequencies of these defects among all ART offspring remain very low, studies have shown that children born using ARTs can be up to six times more likely to develop certain imprinting disorders than those who are naturally conceived. In addition, studies of animals produced from ART-derived embryos and/or superovulated oocytes have revealed abnormal allele-specific expression and DNA methylation profiles at imprinted genes. Many different aspects of ART procedures have been implicated in the etiology of imprinting disorders. However, it remains difficult to distinguish between abnormalities that develop as a result of inherent consequences of infertility and those induced directly by ART procedures. In support of the latter, there is a growing body of evidence suggesting that the use of exogenous gonadotropins to stimulate folliculogenesis (superovulation) in females undergoing ARTs may contribute to the induction of abnormal genomic imprinting. The association between superovulation and imprinting disorders is difficult to fully assess because of the high variability in ART protocols, especially those applied to human patients, and the small number of animal studies published to date. However, because the use of ARTs is becoming increasingly prevalent in developed countries, and ovarian stimulation is typically an indispensable part of these procedures, further investigation into the potential for these procedures to induce epigenetic defects is highly warranted. Here, we review the existing literature suggesting a potential causal relationship between endocrine stimulation and the induction of imprinting abnormalities. In addition, we suggest directions for future research in this area.
