Impact of body mass index on assisted reproductive technology outcomes in patients with polycystic ovary syndrome: a meta-analysis.

The effect of obesity on pregnancy outcomes of patients with polycystic ovary syndrome (PCOS) undergoing assisted reproductive technology (ART) remains unclear. As such, a meta-analysis of recent studies was conducted to probe the effect of being overweight or obese on ART pregnancy outcomes in patients with PCOS. PubMed, Embase, MEDLINE, Scopus and Web of Science were searched from inception to 22 July 2023 without language restrictions. The main indicators were: live birth rate, clinical pregnancy rate, spontaneous abortion rate and multiple pregnancy rate. Ten studies were analysed, with a combined sample size of 247,845. Among patients with PCOS undergoing ART who were overweight or obese, the live birth rate, clinical pregnancy rate, implantation rate and number of retrieved oocytes were lower than in normal-weight patients with PCOS, and the spontaneous abortion rate was higher than in normal-weight patients with PCOS. Obese patients with PCOS undergoing ART had a lower multiple pregnancy rate and a lower number of mature oocytes compared with normal-weight patients with PCOS. The data showed that, among patients with PCOS, being overweight or obese has a negative effect on ART pregnancy outcomes. This meta-analysis may inform guidelines for pregnancy with ART, and encourage overweight or obese patients with PCOS to lose weight.

Set7 Deletion Prevents Glucose Intolerance and Improves the Recovery of Cardiac Function After Ischemia and Reperfusion in Obese Female Mice.

BACKGROUND/AIMS: An obesogenic diet (high fat and sugar, low fiber) is associated with an increased risk for metabolic and cardiovascular disorders. Previous studies have demonstrated that epigenetic changes can modify gene transcription and protein function, playing a key role in the development of several diseases. The methyltransferase Set7 methylates histone and non-histone proteins, influencing diverse biological and pathological processes. However, the functional role of Set7 in obesity-associated metabolic and cardiovascular complications is unknown. METHODS: Wild type and Set7 knockout female mice were fed a normal diet or an obesogenic diet for 12 weeks. Body weight gain and glucose tolerance were measured. The 3T3-L1 cells were used to determine the role of Set7 in white adipogenic differentiation. Cardiac morphology and function were evaluated by histology and echocardiography. An ex vivo Langendorff perfusion system was used to model cardiac ischemia/reperfusion (I/R). RESULTS: Here, we report that Set7 protein levels were enhanced in the heart and perigonadal adipose tissue (PAT) of female mice fed an obesogenic diet. Significantly, loss of Set7 prevented obesogenic diet-induced glucose intolerance in female mice although it did not affect the obesogenic diet-induced increase in body weight gain and adiposity in these animals, nor did Set7 inhibition change white adipogenic differentiation in vitro. In addition, loss of Set7 prevented the compromised cardiac functional recovery following ischemia and reperfusion (I/R) injury in obesogenic diet-fed female mice; however, deletion of Set7 did not influence obesogenic diet-induced cardiac hypertrophy nor the hemodynamic and echocardiographic parameters. CONCLUSION: These data indicate that Set7 plays a key role in obesogenic diet-induced glucose intolerance and compromised myocardial functional recovery after I/R in obese female mice.

Female obesity does not impact live birth rate after frozen-thawed blastocyst transfer.

STUDY QUESTION: Does female obesity affect live birth rate after frozen-thawed blastocyst transfer? SUMMARY ANSWER: Live birth rate was not statistically different between obese and normal weight patients after frozen-thawed blastocyst transfer (FBT). WHAT IS KNOWN ALREADY: Obesity is a major health problem across the world, especially in women of reproductive age. It impacts both spontaneous fertility and clinical outcomes after assisted reproductive technology. However, the respective impact of female obesity on oocyte quality and endometrial receptivity remains unclear. While several studies showed that live birth rate was decreased in obese women after fresh embryo transfer in IVF cycle, only two studies have evaluated the effects of female body mass index (BMI) on pregnancy outcomes after frozen-thawed blastocyst transfer (FBT), reporting conflicting data. STUDY DESIGN, SIZE, DURATION: This retrospective case control study was conducted in all consecutive frozen-thawed autologous blastocyst transfer (FBT) cycles conducted between 2012 and 2017 in a single university-based centre. A total of 1415 FBT cycles performed in normal weight women (BMI = 18.5-24.9 kg/m2) and 252 FBT cycles performed in obese women (BMI ≥ 30 kg/m2) were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial preparation was standard and based on hormonal replacement therapy. One or two blastocysts were transferred according to couple's history and embryo quality. MAIN RESULTS AND THE ROLE OF CHANCE: Female and male age, smoking status, basal AMH level and type of infertility were comparable in obese and normal weight groups. Concerning FBT cycles, the duration of hormonal treatment, the stage and number of embryos (84% single blastocyst transfer and 16% double blastocysts transfer) used for transfer were comparable between both groups. Mean endometrium thickness was significantly higher in obese than in normal weight group (8.7 ± 1.8 vs 8.1 ± 1.6 mm, P < 0.0001). Concerning FBT cycle outcomes, implantation rate, clinical pregnancy rate and live birth rate were comparable in obese and in normal weight groups. Odds ratio (OR) demonstrated no association between live birth rate after FBT and female BMI (OR = 0.92, CI 0.61-1.38, P = 0.68). LIMITATIONS, REASONS FOR CAUTION: Anthropometric parameters such as hip to waist ratio were not used. Polycystic ovarian syndrome status was not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Our study showed that live birth rate after frozen-thawed blastocyst transfer was not statistically different in obese and in normal-weight women. Although this needs confirmation, this suggests that the impairment of uterine receptivity observed in obese women after fresh embryo transfer might be associated with ovarian stimulation and its hormonal perturbations rather than with oocyte/embryo quality. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

The role of female obesity on in vitro fertilization outcomes.

The aim of this review is to analyze the role of obesity on fertility outcome in women undergoing in vitro fertilization (IVF) with respect to clinical or live birth rates and pregnancy loss rates. Despite findings from several earlier and newer studies that obesity does not adversely affect pregnancy outcome in women attempting conception, numerous reports from mostly recent studies suggest that obesity undoubtedly impairs IVF outcomes. Obesity impairs ovarian responsiveness to gonadotrophin stimulation, requiring higher doses of medication, increased risk of cycle cancelation, pre-term delivery, low birth weight or miscarriage, and decreases implantation, clinical pregnancy or live birth rates compared to women of normal weight. The mechanisms underlying the adverse effects of female obesity on IVF outcome may be primarily explained by functional alterations to the hypothalamic-pituitary-ovarian axis. Additionally, obesity appears to affect deleteriously the number and quality of oocytes or embryos, and impairs endometrial decidualization which is necessary for uterine receptivity. Nevertheless, attaining normal body weight by the use of lifestyle modifications, including a healthy diet and exercise over time of several months before and during an IVF treatment, may be successful in achievement of gradual and sustainable weight loss with improvement of IVF outcome.

AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.

Due to the exclusive maternal transmission, oocyte mitochondrial dysfunction reduces fertility rates, affects embryonic development, and programs offspring to metabolic diseases. However, mitochondrial DNA (mtDNA) are vulnerable to mutations during oocyte maturation, leading to mitochondrial nucleotide variations (mtSNVs) within a single oocyte, referring to mtDNA heteroplasmy. Obesity (OB) accounts for more than 40% of women at the reproductive age in the USA, but little is known about impacts of OB on mtSNVs in mature oocytes. It is found that OB reduces mtDNA content and increases mtSNVs in mature oocytes, which impairs mitochondrial energetic functions and oocyte quality. In mature oocytes, OB suppresses AMPK activity, aligned with an increased binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions. Similarly, AMPK knockout increases the binding affinity of ATF5-POLG proteins to mutated mtDNA, leading to the replication of heteroplasmic mtDNA and impairing oocyte quality. Consistently, AMPK activation blocks the detrimental impacts of OB by preventing ATF5-POLG protein recruitment, improving oocyte maturation and mitochondrial energetics. Overall, the data uncover key features of AMPK activation in suppressing mtSNVs, and improving mitochondrial biogenesis and oocyte maturation in obese females.

Estradiol cycling drives female obesogenic adipocyte hyperplasia.

White adipose tissue (WAT) distribution is sex dependent. Adipocyte hyperplasia contributes to WAT distribution in mice driven by cues in the tissue microenvironment, with females displaying hyperplasia in subcutaneous and visceral WAT, while males and ovariectomized females have visceral WAT (VWAT)-specific hyperplasia. However, the mechanism underlying sex-specific hyperplasia remains elusive. Here, transcriptome analysis in female mice shows that high-fat diet (HFD) induces estrogen signaling in adipocyte precursor cells (APCs). Analysis of APCs throughout the estrous cycle demonstrates increased proliferation only when proestrus (high estrogen) coincides with the onset of HFD feeding. We further show that estrogen receptor α (ERα) is required for this proliferation and that estradiol treatment at the onset of HFD feeding is sufficient to drive it. This estrous influence on APC proliferation leads to increased obesity driven by adipocyte hyperplasia. These data indicate that estrogen drives ERα-dependent obesogenic adipocyte hyperplasia in females, exacerbating obesity and contributing to the differential fat distribution between the sexes.

Increased Oxidative Stress, Altered Trace Elements, and Macro-Minerals Are Associated with Female Obesity.

Generally female individuals are more prone to obesity due to their lifestyle and physiology. However, female individuals have got little attention in this aspect. This pioneering study designed to find the level of serum malondialdehyde (MDA), non-enzymatic antioxidant (vitamin C), other trace elements (zinc and iron), and macro-minerals (sodium, potassium, and calcium) for female obesity determining its role and action in disease diagnosis along with propagation. For this prospective case-control study, 70 female obese and 70 healthy individuals were evaluated. Serum lipid peroxidation product malondialdehyde (MDA) concentration was measured to determine the level of lipid peroxidation. UV spectrophotometric method was implemented for vitamin C concentration to measure serum ascorbic acid. Atomic absorption spectroscopy (AAS) was implemented to determine serum macro-minerals (Na, K, and Ca), and trace elements (Zn and Fe) were estimated. For statistical analysis, student's t-test and Pearson's correlation test were executed. A significantly higher concentration of serum MDA (p < 0.001) and low concentration of antioxidants (vitamin C) (p < 0.001) are observed in patient than control group. We found a lower concentration of trace elements (zinc, iron) and macro-minerals (sodium, potassium, and calcium) in patients compared to control except sodium. The mean concentrations for serum Zn, Fe, Na, K, and Ca were 0.34 ± 0.01, 0.25 ± 0.01, 3828.91 ± 205.09, 90.42 ± 6.45, and 43.04 ± 2.38 mg/L and 0.78 ± 0.08, 0.84 ± 0.08, 2600.97 ± 99.79, 223.79 ± 14.64, and 86.43 ± 2.78 mg/L, respectively, for female obese patients and control subjects (p < 0.001). We can suggest from our study that there is a strong association of female obesity with increased serum concentrations of MDA and reduced non-enzymatic antioxidant vitamin C and different serum trace metals and macro-minerals.

Identification of Genetic Variants for Female Obesity and Evaluation of the Causal Role of Genetically Defined Obesity in Polycystic Ovarian Syndrome.

PURPOSE: Observational studies have demonstrated an increased risk of polycystic ovarian syndrome (PCOS) in obese women. This study aimed to identify genetic variants influencing obesity in females and to evaluate the causal association between genetically defined obesity and PCOS in Korean women. METHODS: Two-stage GWAS was conducted to identify genetic variants influencing obesity traits (such as body mass index [BMI], waist-hip ratio [WHR], and waist circumference [WC]) in Korean women. Two-sample Mendelian randomization (MR) analysis was employed to evaluate the causal effect of variants as genetic instruments for female obesity on PCOS. RESULTS: Meta-analysis of 9953 females combining discovery (N = 4658) and replication (N = 5295) stages detected four (rs11162584, rs6760543, rs828104, rs56137030), six (rs139702234, rs2341967, rs73059848, rs5020945, rs550532151, rs61971548), and two genetic variants (rs7722169, rs7206790) suggesting a highly significant association (P < 1×10-6) with BMI, WHR, and WC, respectively. Of these, an intron variant rs56137030 in FTO achieved genome-wide significant association (P = 3.39×10-8) with BMI in females. Using variants for female obesity, their effect on PCOS in 946 cases and 976 controls was evaluated by MR analysis. MR results indicated no significant association between genetically defined obesity and PCOS in Korean women. CONCLUSION: This study, for the first time, revealed genetic variants for female obesity in the Korean population and reported no causal association between genetically defined obesity and PCOS in Korean women.

The herbal extract ALS-L1023 from Melissa officinalis alleviates visceral obesity and insulin resistance in obese female C57BL/6J mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Melissa officinalis L. (Labiatae; lemon balm) has traditionally been used as a medicinal herb to treat stress, anxiety, and insomnia. Current reports suggest that not only chronic stress stimulates angiogenesis, but angiogenesis also regulates adipogenesis and obesity. Because the herbal extract ALS-L1023 from Melissa officinalis inhibits angiogenesis, we hypothesized that ALS-L1023 could suppress visceral obesity and insulin resistance in obese female C57BL/6J mice, a mouse model of obese premenopausal women. MATERIALS AND METHODS: The mice were grouped and fed for 16 weeks as follows: 1) low-fat diet (LFD), 2) high-fat diet (HFD), or 3) HFD supplemented with 0.4 or 0.8% ALS-L1023. Variables and determinants of visceral obesity, insulin resistance, and pancreatic dysfunction were then assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: ALS-L1023 decreased weight gain, visceral adipocyte size, and serum lipid levels in HFD-fed obese mice. ALS-L1023 also normalized hyperglycemia and hyperinsulinemia and concomitantly reduced blood glucose levels during oral glucose tolerance tests. The pancreatic islet size and insulin-positive ß-cell area were significantly reduced in ALS-L1023-treated mice compared with untreated obese controls, reaching a level similar to that of LFD-fed lean mice. ALS-L1023 suppressed pancreatic lipid accumulation, infiltration of inflammatory cells, and collagen levels. ALS-L1023 treatment altered the pancreatic expression of genes involved in steatosis, inflammation, and fibrosis. CONCLUSIONS: Our findings indicate that the herbal extract ALS-L1023 from Melissa officinalis not only inhibits visceral obesity, but also attenuates the increased fasting blood glucose, impaired glucose tolerance, and pancreatic dysfunction seen in female obese mice. These results suggest that ALS-L1023 may be effective in the prevention of visceral obesity and insulin resistance in obese premenopausal women.

Female obesity is negatively associated with live birth rate following IVF: a systematic review and meta-analysis.

BACKGROUND: A worldwide increase in the prevalence of obesity has been observed in the past three decades, particularly in women of reproductive age. Female obesity has been clearly associated with impaired spontaneous fertility, as well as adverse pregnancy outcomes. Increasing evidence in the literature shows that obesity also contributes to adverse clinical outcomes following in vitro fertilization (IVF) procedures. However, the heterogeneity of the available studies in terms of populations, group definition and outcomes prevents drawing firm conclusions. A previous meta-analysis published in 2011 identified a marginal but significant negative effect of increased female body mass index (BMI) on IVF results, but numerous studies have been published since then, including large cohort studies from national registries, highlighting the need for an updated review and meta-analysis. OBJECTIVE AND RATIONALE: Our systematic review and meta-analysis of the available literature aims to evaluate the association of female obesity with the probability of live birth following IVF. Subgroup analyses according to ovulatory status, oocyte origin, fresh or frozen-embryo transfer and cycle rank were performed. SEARCH METHODS: A systematic review was performed using the following key words: ('obesity', 'body mass index', 'live birth', 'IVF', 'ICSI'). Searches were conducted in MEDLINE, EMBASE, Cochrane Library, Eudract and clinicaltrial.gov from 01 January 2007 to 30 November 2017. Study selection was based on title and abstract. Full texts of potentially relevant articles were retrieved and assessed for inclusion by two reviewers. Subsequently, quality was assessed using the Newcastle-Ottawa Quality Assessment Scales for patient selection, comparability and assessment of outcomes. Two independent reviewers carried out study selection and data extraction according to Cochrane methods. Random-effect meta-analysis was performed using Review Manager software on all data (overall analysis), followed by subgroup analyses. OUTCOMES: A total of 21 studies were included in the meta-analysis. A decreased probability of live birth following IVF was observed in obese (BMI ≥ 30 kg/m2) women when compared with normal weight (BMI 18.5-24.9 kg/m2) women: risk ratio (RR) (95% CI) 0.85 (0.82-0.87). Subgroups analyses demonstrated that prognosis was poorer when obesity was associated with polycystic ovary syndrome, while the oocyte origin (donor or non-donor) did not modify the overall interpretation. WIDER IMPLICATIONS: Our meta-analysis clearly demonstrates that female obesity negatively and significantly impacts live birth rates following IVF. Whether weight loss can reverse this deleterious effect through lifestyle modifications or bariatric surgery should be further evaluated.

Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice.

Inhibition of the aryl hydrocarbon receptor (AHR) prevents Western diet-induced obesity and fatty liver in C57Bl/6J (B6) male mice. The AHR is a ligand-activated nuclear receptor that regulates genes involved in xenobiotic metabolism and T-cell differentiation. Here, we tested the hypothesis that AHR antagonism would also prevent obesity and fatty liver in female mice and that B6 mice (higher-affinity AHR) and congenic B6.D2 mice (lower-affinity AHR) would differentially respond to AHR inhibition. Female and male adult B6 and B6.D2 mice were fed control and Western diets with and without α-naphthoflavone (NF), an AHR inhibitor. A nonlinear mixed-model analysis was developed to project asymptote body mass. We found that obesity, adiposity, and liver steatosis were reduced to near control levels in all female and male B6 and B6.D2 experimental groups fed Western diet with NF. However, differences were noted in that female B6.D2 vs B6 mice on Western diet became more obese; and in general, female mice compared with male mice had a greater fat mass to body mass ratio, were less responsive to NF, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing NF or CH-223191, another AHR inhibitor, caused reduced mRNA levels of several liver genes involved in metabolism, including Cyp1b1 and Scd1, offering evidence for a possible mechanism by which the AHR regulates obesity. In conclusion, although there are some sex- and Ahr allelic-dependent differences, AHR inhibition prevents obesity and liver steatosis in both males and females regardless of the ligand-binding capacity of the AHR. We also present evidence consistent with the notion that an AHR-CYP1B1-SCD1 axis is involved in obesity, providing potentially convenient and effective targets for treatment.

Influence of Donor, Recipient, and Male Partner Body Mass index on Pregnancy Rates in Oocyte Donation Cycles.

OBJECTIVE: A high body mass index (BMI) has been shown to associate with negative reproductive outcomes. Women with high BMI have in general lower chances of getting pregnant as well as higher risk of pregnancy complications. Several studies have described in the past the relationship between high BMI and the pregnancy outcome, however, some of them have a small sample size or fail to control for variables associated with a diminished probability of pregnancy. In the present study, we aim to analyze the role of the BMI of all parties involved in oocyte donation cycles (that is: the oocyte donor, the recipient woman, and the male partner) on pregnancy outcomes. METHODS: This study includes 1092 oocyte donation cycles. Inclusion criteria were: fertilization by ICSI, frozen semen, transfer of 2 embryos at day 3 of in vitro development. For statistical analysis, BMI was divided in: low weight (<20 kg/m2), normal (20-24 kg/m2), overweight (25-29 kg/m2) and obesity (≥30 kg/m2). Quantitative and categorical variables were assessed by squared-Chi test and one-way ANOVA. The association between the BMI (recipient, oocyte donor and partner) and pregnancy rate was assessed by multivariate logistic regression. RESULTS: Laboratory outcomes and pregnancy rates do not differ among the different BMI categories of recipient, oocyte donor or partner. After adjusted analyses (for oocyte donor age, for laboratory outcomes and for age and BMI of all the parties for pregnancy outcomes), no difference was found either. CONCLUSION: In oocyte donation cycles, where donors BMI is by law mandated to be in the 18-30 range, the pregnancy rate of the oocyte recipient does not seem to be affected by the BMI of any of the parties involved.

Day-3 embryo metabolomics in the spent culture media is altered in obese women undergoing in vitro fertilization.

OBJECTIVE: To determine whether the global metabolomic profile of the spent culture media (SCM) of day-3 embryos is different in obese and normoweight women undergoing in vitro fertilization (IVF). DESIGN: Prospective cohort analysis. SETTING: IVF clinic. PATIENT(S): Twenty-eight young, nonsmoking women with normoweight, nonsmoking male partners with mild/normal sperm factors undergoing a first IVF attempt for idiopathic infertility, tubal factor infertility, or failed ovulation induction: obese ovulatory women (n = 12); obese women with polycystic ovary syndrome (PCOS; n = 4); normoweight ovulatory women (n = 12). INTERVENTION(S): Fifty µl of SCM collected from two day-3 embryos of each cohort. MAIN OUTCOME MEASURE(S): Metabolomic profiling via ultrahigh performance liquid chromatography coupled to mass spectrometry of SCM from a total of 56 embryos. RESULT(S): The untargeted metabolomic profile was different in obese and normoweight women. Partial least squares discriminant analysis resulted in a clear separation of samples when a total of 551 differential metabolites were considered. A prediction model was generated using the most consistent metabolites. Most of the metabolites identified were saturated fatty acids, which were detected in lower concentrations in the SCM of embryos from obese women. The metabolomic profile was similar in obese women with or without PCOS. CONCLUSION(S): The metabolomic profile in the SCM of day-3 embryos is different in normoweight and obese women. Saturated fatty acids seem to be reduced when embryos from obese patients are present. CLINICAL TRIAL REGISTRATION NUMBER: NCT01448863.

Weighing the impact of obesity on female reproductive function and fertility.

Obesity in women is associated with serious reproductive sequelae. Given its prevalence among women of reproductive age, much recent attention has focused on the mechanisms by which obesity affects female reproductive function and fertility. This review summarizes the literature investigating the epidemiology and pathophysiology of obesity in women of reproductive age and proposes research strategies that may help inform approaches to improve reproductive function and outcomes among obese women.

Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors.

OBJECTIVE: To analyze the reproductive outcome of recipients of donated ova according to their body mass index (BMI). DESIGN: Twelve-year retrospective cohort analysis. SETTING: Fertility clinics. PATIENT(S): 9,587 first cycles of ovum donation with ova from normoweight donors. INTERVENTION(S): Recipients divided according to their BMI to analyze IVF laboratory and outcome parameters: lean with BMI <20 kg/m(2) (n = 1,458; 15.2%); normoweight with BMI 20-24.9 kg/m(2) (n = 5,706; 59.5%), overweight with BMI 25-29.9 kg/m(2) (n = 1,770; 18.5%), and obese with BMI ≥30 kg/m(2) (n = 653; 6.8%). MAIN OUTCOME MEASURE(S): Implantation, biochemical and clinical pregnancy, miscarriage, and live-birth rates. RESULT(S): In vitro fertilization laboratory parameters did not differ according to BMI. However, implantation, pregnancy, clinical pregnancy, twin pregnancy, and live-birth rates were significantly reduced as BMI increased. In the lean, normoweight, overweight, and obese groups, the implantation rate was 40.4%, 39.9%, 38.5%, and 30.9%, clinical pregnancy rate was 56.9%, 55.9%, 54.3%, and 45.3%, and live-birth rate was 38.6%, 37.9%, 34.9%, and 27.7%, respectively. However, clinical miscarriage rates were similar in all the groups. CONCLUSION(S): Female obesity impairs the reproductive outcome of ovum donation probably as a result of reduced uterine receptivity.