Obesity and female infertility: potential mediators of obesity's impact

The worldwide upward trend in obesity has been dramatic, now affecting more than 20% of American women of reproductive age. Obesity is associated with many adverse maternal and fetal effects prenatally, but it also exerts a negative influence on female fertility. Obese women are more likely to have ovulatory dysfunction due to dysregulation of the hypothalamic-pituitary-ovarian axis. Women with polycystic ovarian syndrome who are also obese demonstrate a more severe metabolic and reproductive phenotype. Obese women have reduced fecundity even when eumenorrheic and demonstrate poorer outcomes with the use of in vitro fertilization. Obesity appears to affect the oocyte and the preimplantation embryo, with disrupted meiotic spindle formation and mitochondrial dynamics. Excess free fatty acids may have a toxic effect in reproductive tissues, leading to cellular damage and a chronic low-grade inflammatory state. Altered levels of adipokines, such as leptin, in the obese state can affect steroidogenesis and directly affect the developing embryo. The endometrium is also susceptible, with evidence of impaired stromal decidualization in obese women. This may explain subfecundity due to impaired receptivity, and may lead to placental abnormalities as manifested by higher rates of miscarriage, stillbirth, and preeclampsia in the obese population. Many interventions have been explored to mitigate the effect of obesity on infertility, including weight loss, physical activity, dietary factors, and bariatric surgery. These data are largely mixed, with few high quality studies to guide us. As we improve our understanding of the pathophysiology of obesity in human reproduction we hope to identify novel treatment strategies. The worldwide upward trend in obesity has been dramatic, now affecting more than 20% of American women of reproductive age. Obesity is associated with many adverse maternal and fetal effects prenatally, but it also exerts a negative influence on female fertility. Obese women are more likely to have ovulatory dysfunction due to dysregulation of the hypothalamic-pituitary-ovarian axis. Women with polycystic ovarian syndrome who are also obese demonstrate a more severe metabolic and reproductive phenotype. Obese women have reduced fecundity even when eumenorrheic and demonstrate poorer outcomes with the use of in vitro fertilization. Obesity appears to affect the oocyte and the preimplantation embryo, with disrupted meiotic spindle formation and mitochondrial dynamics. Excess free fatty acids may have a toxic effect in reproductive tissues, leading to cellular damage and a chronic low-grade inflammatory state. Altered levels of adipokines, such as leptin, in the obese state can affect steroidogenesis and directly affect the developing embryo. The endometrium is also susceptible, with evidence of impaired stromal decidualization in obese women. This may explain subfecundity due to impaired receptivity, and may lead to placental abnormalities as manifested by higher rates of miscarriage, stillbirth, and preeclampsia in the obese population. Many interventions have been explored to mitigate the effect of obesity on infertility, including weight loss, physical activity, dietary factors, and bariatric surgery. These data are largely mixed, with few high quality studies to guide us. As we improve our understanding of the pathophysiology of obesity in human reproduction we hope to identify novel treatment strategies. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/14712-23481 Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/14712-23481 Obesity has become a global epidemic, affecting more than 600 million adults worldwide (1World Health Organization. Obesity and overweight fact sheet 2016. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/. Last accessed March 6, 2017.Google Scholar). Rates of obesity in the United States are significantly higher than in other developed nations, with more than one-third of adult Americans affected (2National Institute of Diabetes and Digestive and Kidney Diseases. Overweight and obesity statistics 2012. Available at: https://www.niddk.nih.gov/health-information/health-statistics/Pages/overweight-obesity-statistics.aspx. Last accessed March 6, 2017.Google Scholar). The number of obese Americans has doubled since 1960 (2National Institute of Diabetes and Digestive and Kidney Diseases. Overweight and obesity statistics 2012. Available at: https://www.niddk.nih.gov/health-information/health-statistics/Pages/overweight-obesity-statistics.aspx. Last accessed March 6, 2017.Google Scholar). Women of reproductive age have not been spared from this dramatic trend, with 23% of this cohort now obese (3Vahratian A. Prevalence of overweight and obesity among women of childbearing age: results from the 2002 National Survey of Family Growth.Matern Child Health J. 2009; 13: 268-273Crossref PubMed Scopus (156) Google Scholar). Certain risks associated with obesity target this cohort, including menstrual irregularity, endometrial pathology, and infertility. Obese women also have higher rates of many complications in pregnancy, including hypertensive disorders, gestational diabetes, preterm birth, and rates of cesarean delivery (4Knight M. Kurinczuk J.J. Spark P. Brocklehurst P. Extreme obesity in pregnancy in the United Kingdom.Obstet Gynecol. 2010; 115: 989-997Crossref PubMed Scopus (123) Google Scholar). Although the clinical impact of obesity on female infertility has been well characterized, the mechanistic underpinnings that can lead to effective treatment are still being elucidated. Obesity has a negative effect on reproductive potential, primarily thought to be due to functional alteration of the hypothalamic-pituitary-ovarian (HPO) axis. Obese women often have higher circulating levels of insulin, which is a known stimulus for increased ovarian androgen production (5Rachon D. Teede H. Ovarian function and obesity—interrelationship, impact on women’s reproductive lifespan and treatment options.Mol Cell Endocrinol. 2010; 316: 172-179Crossref PubMed Scopus (96) Google Scholar). These androgens are aromatized to estrogen at high rates in the periphery owing to excess adipose tissue, leading to negative feedback on the HPO axis and affecting gonadotropin production (6Jungheim E.S. Moley K.H. Current knowledge of obesity’s effects in the pre- and periconceptional periods and avenues for future research.Am J Obstet Gynecol. 2010; 203: 525-530Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). This manifests as menstrual abnormalities and ovulatory dysfunction. Hyperinsulinemia is highly implicated in the pathogenesis of the polycystic ovarian syndrome (PCOS), characterized by oligomenorrhea and hyperandrogenism. Obesity contributes to insulin resistance and appears to exacerbate the symptoms of PCOS, with obese women often demonstrating a more severe phenotype (7Pasquali R. Obesity and androgens: facts and perspectives.Fertil Steril. 2006; 85: 1319-1340Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 8Moran L.J. Norman R.J. Teede H.J. Metabolic risk in PCOS: phenotype and adiposity impact.Trends Endocrinol Metab. 2015; 26: 136-143Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Elevated androgen levels in PCOS lead to deposition of visceral fat, leading to insulin resistance and hyperinsulinemia, further stimulating ovarian and adrenal androgen production in a perpetual cycle (9Escobar-Morreale H.F. Surgical management of metabolic dysfunction in PCOS.Steroids. 2012; 77: 312-316Crossref PubMed Scopus (17) Google Scholar). 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Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization.Obstet Gynecol. 2011; 118: 63-70Crossref PubMed Scopus (165) Google Scholar). Multiple studies have demonstrated a negative impact on live birth rates (LBRs), and this appears to correlate with increasing BMI (17Shah D.K. Missmer S.A. Berry K.F. Racowsky C. Ginsburg E.S. Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization.Obstet Gynecol. 2011; 118: 63-70Crossref PubMed Scopus (165) Google Scholar, 18Luke B. Brown M.B. Stern J.E. Missmer S.A. Fujimoto V.Y. Leach R. Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates.Hum Reprod. 2011; 26: 245-252Crossref PubMed Scopus (218) Google Scholar, 19Jungheim E.S. Lanzendorf S.E. Odem R.R. Moley K.H. Chang A.S. Ratts V.S. 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Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring.Endocrinology. 2010; 151: 4039-4046Crossref PubMed Scopus (250) Google Scholar). Closer examination of these abnormal oocytes in DIO mice reveals high rates of meiotic aneuploidy with fragmented disorganized meiotic spindles and chromosomes not properly aligned on the metaphase plate (31Luzzo K.M. Wang Q. Purcell S.H. Chi M. Jimenez P.T. Grindler N. et al.High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects.PLoS One. 2012; 7: e49217Crossref PubMed Scopus (227) Google Scholar). Machtinger et al. examined the oocytes that failed to fertilize in IVF cycles of morbidly obese women and similarly described disarrayed meiotic spindles with misaligned metaphase chromosomes (32Machtinger R. Combelles C.M. Missmer S.A. Correia K.F. Fox J.H. Racowsky C. The association between severe obesity and characteristics of failed fertilized oocytes.Hum Reprod. 2012; 27: 3198-3207Crossref PubMed Scopus (83) Google Scholar). Independently from aneuploidy, obesity also appears to alter mitochondrial function in the oocyte. Mitochondria in DIO mice have disrupted architecture with fewer cristae, more vacuoles, and evidence of swelling (31Luzzo K.M. Wang Q. Purcell S.H. Chi M. Jimenez P.T. Grindler N. et al.High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects.PLoS One. 2012; 7: e49217Crossref PubMed Scopus (227) Google Scholar). There is also a change in mitochondrial distribution, with clumping throughout the ooplasm compared with uniform perinuclear localization in control subjects (33Igosheva N. Abramov A.Y. Poston L. Eckert J.J. Fleming T.P. Duchen M.R. et al.Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes.PLoS One. 2010; 5: e10074Crossref PubMed Scopus (337) Google Scholar). These abnormal mitochondria show evidence of metabolic stress, with lower levels of citrate, a tricarboxylic acid cycle end-product. This stress may lead to a compensatory increase in production of mitochondria, supported by elevated mitochondrial DNA copy number in oocytes of obese mice (31Luzzo K.M. Wang Q. Purcell S.H. Chi M. Jimenez P.T. Grindler N. et al.High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects.PLoS One. 2012; 7: e49217Crossref PubMed Scopus (227) Google Scholar, 33Igosheva N. Abramov A.Y. Poston L. Eckert J.J. Fleming T.P. 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Mouse embryos created in dams with DIO have lower expression of insulin-like growth factor 1 receptor (IGF-1R), negatively affecting insulin sensitivity and glucose transport at a critical stage in development (30Jungheim E.S. Schoeller E.L. Marquard K.L. Louden E.D. Schaffer J.E. Moley K.H. Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring.Endocrinology. 2010; 151: 4039-4046Crossref PubMed Scopus (250) Google Scholar). Leary et al. noted that embryos from women with BMI ≥25 kg/m2 were less likely to develop after fertilization, and those that did reached the morula stage more quickly. In addition, those that reached the blastocyst stage had fewer cells in the trophectoderm and demonstrated poor glucose uptake and increased levels of triglycerides (54Leary C. Leese H.J. Sturmey R.G. Human embryos from overweight and obese women display phenotypic and metabolic abnormalities.Hum Reprod. 2015; 30: 122-132Crossref PubMed Scopus (99) Google Scholar). Embryos may also be susceptible to lipotoxicity as previously discussed regarding the oocyte. Murine embryos cultured in excess palmitic acid, which is the most common free fatty acid in human serum, have fewer nuclei and altered IGF-1R expression. Wh