Obesity, which affects over one-third of reproductive-age women, has negative effects on reproduction and results in oocyte defects in both mice and humans. In this study, we used a mouse model to examine whether the adverse effects of an obesogenic diet, specifically abnormal oocyte spindle formation, mitochondrial metabolism, and lipid accumulation, can be reversed by return to normal weight and metabolic profile. Female C57BL6/J mice were placed on either a high-fat diet (HFD; 35.8% fat and 20.2% protein by nutritional content) or an isocaloric control diet (CD; 13% fat and 25% protein) for six weeks. All mice were then maintained on CD for eight weeks. We found that whereas metabolic parameters (weight, glucose tolerance, and cholesterol levels) of the HFD mice returned to normal after this “diet reversal” period, several oocyte defects were not reversible. Oocytes from the diet reversal mice demonstrated a significantly higher percentage of abnormal meiotic spindles than those from control mice. The HFD diet reversal GV oocytes also had lower mitochondrial membrane potential, lower levels of ATP and citrate, and higher percentages of abnormal lipid accumulation and distribution and abnormally distributed mitochondria than oocytes from control mice. Thus, despite normalization of weight, glucose utilization, and cholesterol levels eight weeks after switching from a high fat to a regular chow, oocytes from diet reversal mice exhibited significantly higher rates of meiotic spindle, lipid, and mitochondrial defects than found in mice maintained on regular chow. These results suggest that the negative effects of an obesogenic diet on oocyte quality are not as reversible as the overall metabolic parameters. These data may provide better insight when counseling obese women regarding reproductive options and success.

NIH K12 HD063086 (ESJ, MGT), NIH T32 HD0040135-11 (KAR), F32 HD040135-10 NIH (KRO), 5K12HD000849-25 (PTJ). No competing interests.

Women with polycystic ovary syndrome (PCOS) and hyperandrogenism have altered hormone levels and suffer from ovarian dysfunction leading to subfertility. We have attempted to generate a model of hyperandrogenism by feeding mice chow supplemented with dehydroepiandrosterone (DHEA), an androgen precursor that is often elevated in women with PCOS. Treated mice had polycystic ovaries, low ovulation rates, disrupted estrous cycles, and altered hormone levels. Because DHEA is an inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway, we tested the hypothesis that oocytes from DHEA-exposed mice would have metabolic disruptions. Citrate levels, glucose-6-phosphate dehydrogenase activity, and lipid content in denuded oocytes from these mice were significantly lower than controls, suggesting abnormal tricarboxylic acid and pentose phosphate pathway metabolism. The lipid and citrate effects were reversible by supplementation with nicotinic acid, a precursor for reduced nicotinamide adenine dinucleotide phosphate. These findings suggest that elevations in systemic DHEA can have a negative impact on oocyte metabolism and may contribute to poor pregnancy outcomes in women with hyperandrogenism and PCOS.

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Fertility is important to women and men with cancer. While options for fertility preservation (FP) are available, knowledge regarding the medical application of FP is lacking. Therefore we examined FP practices for cancer patients among reproductive endocrinologists (REs). A 36 item survey was sent to board-certified REs. 98% of respondents reported counseling women with cancer about FP options. Oocyte and embryo cryopreservation were universally offered by these providers, but variability was noted in reported management of these cases—particularly for women with breast cancer. 86% of the respondents reported using letrozole during controlled ovarian stimulation (COS) in patients with estrogen receptor positive (ER+) breast cancer to minimize patient exposure to estrogen. 49% of respondents who reported using letrozole in COS for patients with ER+ breast cancer reported that they would also use letrozole in COS for women with ER negative breast cancer. Variability was also noted in the management of FP for men with cancer. 83% of participants reported counseling men about sperm banking with 22% recommending against banking for men previously exposed to chemotherapy. Overall, 79% of respondents reported knowledge of American Society for Clinical Oncology FP guidelines—knowledge that was associated with providers offering gonadal tissue cryopreservation (RR 1.82, 95% CI 1.14–2.90). These findings demonstrate that RE management of FP in cancer patients varies. Although some variability may be dictated by local resources, standardization of FP practices and communication with treating oncologists may help ensure consistent recommendations and outcomes for patients seeking FP.

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