Obesity and oocyte quality: significant implications for ART and emerging mechanistic insights

Abstract

The prevalence of obesity in adults worldwide, and specifically in women of reproductive age, is concerning given the risks to fertility posed by the increased risk of type 2 diabetes, metabolic syndrome and other non-communicable diseases. Obesity has a multi-systemic impact in female physiology that is characterized by the presence of oxidative stress, lipotoxicity, and the activation of pro-inflammatory pathways, inducing tissue-specific insulin resistance and ultimately conducive to abnormal ovarian function. A higher body mass is linked to Polycystic Ovary Syndrome, dysregulated menstrual cycles, anovulation, and longer time to pregnancy, even in ovulatory women. In the context of ART, compared to women of normal BMI, obese women have worse outcomes in every step of their journey, resulting in reduced success measured as live birth rate. Even after pregnancy is achieved, obese women have a higher chance of miscarriage, gestational diabetes, pregnancy complications, birth defects, and most worryingly, a higher risk of stillbirth and neonatal death. The potential for compounding effects of ART on pregnancy complications and infant morbidities in obese women has not been studied. There is still much debate in the field on whether these poorer outcomes are mainly driven by defects in oocyte quality, abnormal embryo development or an unaccommodating uterine environment, however the clinical evidence to date suggests a combination of all three are responsible. Animal models of maternal obesity shed light on the mechanisms underlaying the effects of obesity on the peri-conception environment, with recent findings pointing to lipotoxicity in the ovarian environment as a key driver of defects in oocytes that have not only reduced developmental competence but long-lasting effects in offspring health.

Alteration of the embryonic microenvironment and sex-specific responses of the preimplantation embryo related to a maternal high-fat diet in the rabbit model

“…29,31 Environmental conditions during maturation can influence the pattern of transcripts in matured oocytes. 32 In rodents, [33][34][35] non-human primates 36 and women, 37,38 maternal metabolic dysfunctions were shown to impair meiotic resumption and oocyte gene expression. Here, in agreement with these reports, a small number of genes involved in the regulation of meiosis were differentially expressed in HH oocytes.…”

Obesity and reproduction

“…Several studies have shown that obese ovulatory women undergoing IVF also respond poorly with lower peak oestradiol levels, prolonged stimulation, need for higher gonadotropin doses and an increased risk of cycle cancellation [27 ▪ ,28,29]. IUI, oocyte retrieval and embryo transfer procedures may be more technically challenging in obese women leading to a higher incidence of infection, bleeding and injury [28]. Aside from these technical aspects, obese women are also more likely to have complications with anaesthesia during retrievals [27 ▪ ].…”

“…Obesity decreases the success of all fertility treatments, with reduction in the number of mature follicles and probability of ovulation when gonadotropins are utilized for ovulation induction. Excess adiposity ultimately reduces live birth rates following intrauterine insemination (IUI) treatments [28]. Several studies have shown that obese ovulatory women undergoing IVF also respond poorly with lower peak oestradiol levels, prolonged stimulation, need for higher gonadotropin doses and an increased risk of cycle cancellation [27 ▪ ,28,29].…”

“…Excess adiposity ultimately reduces live birth rates following intrauterine insemination (IUI) treatments [28]. Several studies have shown that obese ovulatory women undergoing IVF also respond poorly with lower peak oestradiol levels, prolonged stimulation, need for higher gonadotropin doses and an increased risk of cycle cancellation [27 ▪ ,28,29]. IUI, oocyte retrieval and embryo transfer procedures may be more technically challenging in obese women leading to a higher incidence of infection, bleeding and injury [28].…”

Implications of High-Density Cholesterol Metabolism for Oocyte Biology and Female Fertility

“…In this regard, exposure of preovulatory follicles to high levels of oxLDL in women with obesity and the resulting adverse effects on the oocyte viability and function may be one of the mechanisms contributing to infertility in obesity. Additional studies from different perspectives are required to underscore the complex mechanisms through which an adverse cholesterol metabolism may hinder fertility in women with obesity ( Gonzalez et al, 2022 ).…”