Repeated implantation failure (RIF) is an intriguing, massive failure of reproductive treatment in otherwise healthy women leading to the introduction of empirical adjuvant interventions that are costly, inefficient, and frustrating for our patients. In this article, we will try to convince the readers that RIF is neither a stigma nor a mysterious pathology but rather our failure to diagnose and properly synchronize the euploid blastocyst with the patient's personalized window of implantation.

Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance and electron microscopy. Our results demonstrate that lean PCOS mice have similar weight to that of the controls but exhibit glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS) and increased RNA transcript abundance. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.

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NCT02205866.

Background: Hyperandrogenemia in an obese polycystic ovary syndrome (PCOS) mouse model results in altered glucose/insulin metabolism and mitochondrial structure and function in the oocytes, in part explaining adverse outcomes and inheritance patterns seen in PCOS.Objective: To study the oocyte quality by means of mitochondrial structure and function in a well-established classic PCOS mouse model. Design: Animal study using an obese PCOS mouse model compared with control.Setting: Animal research facility in a tertiary care university hospital setting. Animals: C57/B6J mice. Intervention(s): Three-week-old mice had subdermal implants of dihydrotestosterone controlled release pellet or placebo for 90 days. Main Outcome Measure(s): The mouse model was validated by performing glucose tolerance test and glycated hemoglobin level, body weight, and estrous cycle analyses. Oocytes were subsequently isolated and were used to investigate mitochondrial membrane potential, oxidative stress, lipid peroxidation, adenosine triphosphate production, mitochondrial DNA copy number, transcript abundance, histology, and mitochondrial ultrastructure. Result(s): Results showed glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of the oocytes indicated impaired inner mitochondrial membrane function, increased adenosine triphosphate production and mitochondrial DNA copy number, altered RNA transcript abundance, and aberrant ovarian histology. Electron microscopy of the oocytes revealed severely impaired mitochondrial ultrastructure. Conclusion(s):The obese PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial function. (Fertil Steril Sci Ò 2021;2:101-12. Ó2020 by American Society for Reproductive Medicine.

Background Type 2 diabetes in lean individuals is not well studied and up to 26% of diabetes occurs in these individuals. Although the cause is not well understood, it has been primarily attributed to nutritional issues during early development. Objective Our objective was to develop a lean type 2 diabetes model using gestational low protein programming. Study Design Pregnant rats were fed control (20% protein) or isocaloric low protein (6%) diet from gestational day 4 until delivery. Standard diet was given to dams after delivery and to pups after weaning. Glucose tolerance test was done at 2, 4 and 6 months of age. Magnetic resonance imaging of body fat for the females was done at 4 months. Rats were sacrificed at 4 months and 8 months of age and their peri-gonadal, peri-renal, inguinal and brown fat were weighed and expressed relative to their body weight. Euglycemic-hyperinsulinemic clamp was done around 6 months of age. Results Male and female offspring exposed to a low protein diet during gestation developed glucose intolerance and insulin resistance. Further, glucose intolerance progressed with increasing age and occurred earlier and was more severe in females when compared to males. Euglycemic hyperinsulinemic clamp showed whole body insulin resistance in both sexes, with females demonstrating increased insulin resistance compared to males. Low protein females showed a 4.5-fold increase in insulin resistance while males showed a 2.5-fold increase when compared to their respective controls. Data from magnetic resonance imaging on female offspring showed no difference in the subcutaneous, inguinal and visceral fat content. We were able to validate this observation by sacrificing the rats at 4 and 8 months and measuring total body fat content. This showed no differences in body fat content between control and LP offspring in both males and females. Additionally, diabetic rats had a similar body mass index to that of the controls. Conclusion LP gestational programming produces a progressively worsening type 2 diabetes model in rats with a lean phenotype without obesity.

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