Lean Women Research Articles

Clinical-exome sequencing unveils the genetic landscape of polycystic ovarian syndrome (PCOS) focusing on lean and obese phenotypes: implications for cost-effective diagnosis and personalized treatment.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies among reproductive women worldwide, contributing greatly on the incidence of female infertility and gynecological cancers. It is a complex health condition combining of multiple symptoms like androgen excess, uncontrolled weight gain, alopecia, hirsutism, etc. Conventionally PCOS was associated with obesity while it is often found among lean women nowadays, making the disease more critical to diagnose as well treatment. The disorder has an impact on several signal transduction pathways, including steroidogenesis, steroid hormone activity, gonadotrophin regulation, insulin secretion, energy balance, and chronic inflammation. Understanding the aetiology and pathophysiology of PCOS is difficult due to its multiple causes, which include environmental factors, intricate genetic predisposition, and epigenetic modifications. Despite research supporting the role of familial aggregations in PCOS outcomes, the inheritance pattern remains unknown. Henceforth, to reduce the burden of PCOS, it is inevitably important to diagnose at early ages as well as intervene through personalized medicine. With this brief background, it was imperative to elucidate the genetic architecture of PCOS considering BMI as an controlling factor. This study aims to investigate the genetic basis behind obesity-mediated PCOS, focusing on both obese and lean individuals. It uses a comprehensive bioinformatics methodology to depict pathways and functionality enrichment, allowing for cost-effective risk prediction and management. In the present research, the representative study participants (N = 2) were chosen from a cross-sectional epidemiological survey, based on their anthropometric parameters and confirmation of PCOS. Upon voluntary participation and written consent, biological fluids (whole blood and buccal swab) were taken from where DNA was extracted. The clinical-exome sequencing was performed by the Next-generation Illumina platform using the Twist Human Comprehensive Exome Kit. A comprehensive bioinformatics methodology was employed to identify the most important, unique, and common genes. A total of 26,550 variants were identified in clinically important exomes from two samples, with 5170 common and 2232 and 2322 unique among PCOS lean and obese phenotypes, respectively. Only 262 and 94 variants were PCOS-specific in lean and obese PCOS. Three filters were applied to shortlist the most potent variants, with 4 unique variants in lean PCOS, 2 unique variants in obese PCOS, and 5 common variants in both. The study found that leptin signalling impairment and insulin resistance, as well as mutations in CYP1A1, CYP19A1, ESR1, AR, AMH, AdipoR1, NAMPT, NPY, PTEN, EGFR, and Akt, all play significant roles in PCOS in the studied group. Young women in West Bengal, India, are more likely to have co-occurring PCOS, which includes estrogen resistance, leptin receptor insufficiency, folate deficiency, T2DM, and acanthosis nigricans, with obesity being a common phenotypic expression.

High BMI Is Associated with Changes in Peritumor Breast Adipose Tissue That Increase the Invasive Activity of Triple-Negative Breast Cancer Cells

Breast cancer is the most common cancer in women with multiple risk factors including smoking, genetics, environmental factors, and obesity. Smoking and obesity are the top two risk factors for the development of breast cancer. The effect of obesity on adipose tissue mediates the pathogenesis of breast cancer in the context of obesity. Triple-negative breast cancer (TNBC) is a breast cancer subtype within which the cells lack estrogen, progesterone, and HER2 receptors. TNBC is the deadliest breast cancer subtype. The 5-year survival rates for patients with TNBC are 8–16% lower than the 5-year survival rates for patients with estrogen-receptor-positive breast tumors. In addition, TNBC patients have early relapse rates (3–5 years after diagnosis). Obesity is associated with an increased risk for TNBC, larger TNBC tumors, and increased breast cancer metastasis compared with lean women. Thus, novel therapeutic approaches are warranted to treat TNBC in the context of obesity. In this paper, we show that peritumor breast adipose-derived secretome (ADS) from patients with a high (>30) BMI is a stronger inducer of TNBC cell invasiveness and JAG1 expression than peritumor breast ADS from patients with low (<30) BMI. These findings indicate that patient BMI-associated changes in peritumor AT induce changes in peritumor ADS, which in turn acts on TNBC cells to stimulate JAG1 expression and cancer cell invasiveness.

Expression levels of ACE and ACE2 in the placenta and white adipose tissue of lean and obese pregnant women

Background This study evaluated the expression of ACE and ACE2 in the placenta and white adipose tissue in lean and obese women, and correlated their levels with anthropometric, clinical, and laboratory parameters, and tissue count of inflammatory cells. Methods A cross-sectional analytical study was performed with 49 pregnant women and their respective newborns. Samples of placenta and adipose tissue were used for measuring mRNA expression for ACE and ACE2 through qRT-PCR. Inflammatory cell counting was performed through conventional microscopy. Results An increase in ACE expression and a decrease in ACE2 were observed in the placenta and adipose tissue of women with obesity. ACE2 levels showed a negative correlation with pre-pregnancy BMI and total cholesterol. Conclusion Maternal obesity can modulate the expression of RAS components in the placenta and white adipose tissue, with ACE2 correlated with pre-pregnancy BMI and total cholesterol.

Obesity alters adipose tissue response to fasting and refeeding in women: A study on lipolytic and endocrine dynamics and acute insulin resistance

Fasting induces significant shifts in substrate utilization with signs of acute insulin resistance (IR), while obesity is associated with chronic IR. Nonetheless, both states substantially influence adipose tissue (AT) function. Therefore, in this interventional study (NCT04260542), we investigated if excessive adiposity in premenopausal women alters insulin sensitivity and AT metabolic and endocrine activity in response to a 60-h fast and a subsequent 48-h refeeding period. Using physiological methods, lipidomics, and AT explants, we showed that obesity partially modified AT endocrine activity and blunted the dynamics of AT insulin resistance in response to the fasting/refeeding challenge compared to that observed in lean women. AT adapted to its own excess by reducing lipolytic activity/free fatty acids (FFA) flux per mass. This adaptation persisted even after a 60-h fast, resulting in lower ketosis in women with obesity. This could be a protective mechanism that limits the lipotoxic effects of FFA; however, it may ultimately impede desirable weight loss induced by caloric restriction in women with obesity.

Anatomical Analysis of the Superior Gluteal Artery in 100 Women for Superior Gluteal Artery Perforator Flap Breast Reconstruction.

The superior gluteal artery (SGA) perforator (SGAP) flap is used more rarely for breast reconstruction with autologous tissue than other flaps because the SGA is often narrow, and the SGAP can be short. However, it provides ample fat, including in lean women. To improve its safety and utility, the preoperative SGA course in women who underwent autologous breast reconstruction was determined with three-dimensional computed tomography angiography. Consecutive deep inferior epigastric perforator, profunda artery perforator, and SGAP flap cases in 2019-2023 were identified. Frequencies of the following favorable preoperative SGA-anatomy variables were determined: branching of the main-SGA trunk on top/posterior of the greater sciatic foramen (designated M1/2), which allows access to a sufficiently wide SGA artery; superolateral perforating location of the superficial-SGA branch (SP3), which means the perforator is sufficiently long for uncomplicated flap placement; and nonbranching of the deep-SGA branch (D1/D2), which means this branch can used a venous and an arterial graft to extend an insufficiently long perforator. A total of 100 cases of deep inferior epigastric perforator (n = 80), profunda artery perforator (n = 13), and SGAP flap-based breast reconstructions (n = 7) were identified. Out of 200 buttocks, 89%, 91.5%, and 62% had the favorable M1/2, SP3, and D1/D2 variables, respectively. An atypical descending branch feeding the lower buttocks (DES1/2) was observed in 34%. The branching position of the main-SGA trunk, perforating location of the SGAP, and the shape of the deep branch were classified in detail in 100 patients. By creating a surgical plan that understands the anatomy taking preoperative three-dimensional computed tomography angiography, the SGAP flap can accommodate many patterns, increasing the possibility of safe execution.

Impaired left ventricular function in lean women with PCOS: Insights from speckle tracking echocardiography

Aims: We aimed to conduct a study examining left ventricular function (LVEF) in lean women PCOS patients with speckle tracking echocardiography. Methods: The study included 60 patients diagnosed with PCOS and 30 healthy controls matched for age and body mass index. Morning fasting blood samples were collected to measure levels of glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), and lipids. Left ventricular function (LVF) was evaluated using two-dimensional speckle tracking echocardiography (2D-STE) and real-time three-dimensional echocardiography (3D-Echo). Global strain was assessed from three standard apical views using 2D-STE. Results: The hs-CRP levels in lean women with PCOS were significantly higher compared to the control group (2.34±1.07 vs. 1.13±0.54; p=0.01). The peak longitudinal strain values in the 2-chamber, 4-chamber, and long-axis views were lower in lean women with PCOS compared to the control group (15.9±1.2 vs. 19.4±1.2; p=0.01, 17.0±1.1 vs. 19.2±1.4; p=0.01, 16.3±1.3 vs. 19.2±1.5; respectively, p=0.01). According to the multiple regression model, global strain was independently associated with hs-CRP (β=0.31, p=0.04), the ratio of early diastolic mitral inflow velocity (E) to early diastolic annular velocity (E/E’ ratio) (β=0.33, p=0.01), and ejection fraction (EF) (β=0.35, p=0.01). Conclusion: Our findings reveal that lean women with PCOS exhibit significantly higher levels of high-sensitivity C-reactive protein (hs-CRP) compared to healthy controls. Furthermore, the peak longitudinal strain values across multiple cardiac views were notably lower in the PCOS group, suggesting impaired left ventricular function. These results highlight the importance of monitoring cardiovascular health in lean women with PCOS, as they are at an increased risk of developing left ventricular dysfunction despite their lean body mass index.

Obesity-associated non-oxidative genotoxic stress alters trophoblast turnover in human first-trimester placentas.

Placental growth is most rapid during the first trimester (FT) of pregnancy, making it vulnerable to metabolic and endocrine influences. Obesity, with its inflammatory and oxidative stress, can cause cellular damage. We hypothesized that maternal obesity increases DNA damage in the FT placenta, affecting DNA damage response and trophoblast turnover. Examining placental tissue from lean and obese non-smoking women (4-12 gestational weeks), we observed higher overall DNA damage in obesity (COMET assay). Specifically, DNA double-strand breaks were found in villous cytotrophoblasts (vCTB; semi-quantitative γH2AX immunostaining), while oxidative DNA modifications (8-hydroxydeoxyguanosine; FPG-COMET assay) were absent. Increased DNA damage in obese FT placentas did not correlate with enhanced DNA damage sensing and repair. Indeed, obesity led to reduced expression of multiple DNA repair genes (mRNA array), which were further shown to be influenced by inflammation through in vitro experiments using tumor necrosis factor-α treatment on FT chorionic villous explants. Tissue changes included elevated vCTB apoptosis (TUNEL assay; caspase-cleaved cytokeratin 18), but unchanged senescence (p16) and reduced proliferation (Ki67) of vCTB, the main driver of FT placental growth. Overall, obesity is linked to heightened non-oxidative DNA damage in FT placentas, negatively affecting trophoblast growth and potentially leading to temporary reduction in early fetal growth.

Analysis of early-pregnancy metabolome in early- and late-onset gestational diabetes reveals distinct associations with maternal overweight.

It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m2) and women with overweight (BMI ≥25 kg/m2) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM). We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method. In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM. GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.

Changes in maternal blood and placental lipidomic profile in obesity and gestational diabetes: Evidence for sexual dimorphism.

Obesity and gestational diabetes (GDM) are associated with adverse pregnancy outcomes and program the offspring for cardiometabolic disease in a sexually dimorphic manner. The placenta transfers lipids to the fetus and uses these substrates to support its own metabolism impacting the amount of substrate available to the growing fetus. We collected maternal plasma and placental villous tissue following elective cesarean section at term from women who were lean (pre-pregnancy BMI 18.5-24.9), obese (BMI>30) and type A2 GDM (matched to obese BMI) with male or female fetus (n=4 each group). Lipids were extracted and fatty acid composition of different lipid classes were analyzed by LC-MS/MS analysis. Significant changes in GDM vs obese, GDM vs lean, and obese vs lean were determined using t-test with a Tukey correction set at p<0.05. In placental samples 436 lipids were identified, among which 85 showed significant changes. Of note only in male placentas significant decreases in C22:6 - docosahexaenoic acid (DHA) in phosphatidylcholine (PC) and triglyceride lipid species were seen when comparing tissue from GDM women to lean. In maternal plasma we observed no effect of obesity. GDM or fetal sex. This is the first study assessing fatty acid composition of lipids in matched maternal plasma and placental tissue from lean, obese, and GDM women stratified by fetal sex. It highlights how GDM affects distribution of fatty acids in lipid classes changes in a sexually dimorphic manner in the placenta.

O-192 Kisspeptin as a test of hypothalamic function in women presenting with oligo-amenorrhea

Abstract Study question Can kisspeptin be used as a novel tool to interrogate hypothalamic function in women presenting with oligo-amenorrhea? Summary answer The hormonal response to kisspeptin offers a novel approach for the assessment of hypothalamic function in patients presenting with oligo-amenorrhea of different aetiologies. What is known already Polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhea (FHA) are the two commonest causes of anovulation causing oligo-amenorrhea in pre-menopausal women. Additionally, congenital (CHH) and functional hypogonadotropic hypogonadism can present with similar endocrine profiles. Importantly, these conditions are caused and characterised by abnormal hypothalamic function. For instance, gonadotropin-releasing hormone (GnRH) pulsatility is increased in PCOS but reduced in FHA. Despite differences in pathophysiology, differentiating these diagnoses can be challenging in clinical practice. Kisspeptin is known to stimulate hypothalamic GnRH neurons. Thus, kisspeptin could represent a novel tool to interrogate hypothalamic function in women presenting with reproductive disorders causing oligo-amenorrhea. Study design, size, duration Single-centre, prospective, experimental study of healthy women (n = 33), women with PCOS (n = 30), FHA (n = 30), or CHH (n = 8), aged 18-35 years and not taking hormonal treatment. Participants were recruited for clinical studies between September 2019 and September 2023 and underwent two separate study visits. The visits assessed the gonadotropin response to hypothalamic stimulation with an intravenous bolus of kisspeptin-54 (9.6nmol/kg) and the pituitary response to an intravenous bolus of GnRH (100 mcg). Participants/materials, setting, methods All participants took part in two study visits. Serum luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels were measured every 15 minutes for 8 hours after administration of kisspeptin-54 and GnRH. The maximal rise in LH and FSH from baseline was compared between groups using an unpaired t-test. Receiver operator characteristic (ROC) analysis was used to assess the discriminatory potential of the hormone response to kisspeptin and GnRH. Main results and the role of chance The gonadotropin response to kisspeptin was increased in women with FHA compared to all other groups. The mean (SD) of the maximal rise in LH (IU/L) after kisspeptin was 9.7 (11.4) in healthy women, 9.7 (8.3) in women with PCOS, 17.6 (10.8) in women with FHA, and 1.0 (1.1) in women with CHH. The mean (SD) of the maximal rise in FSH (IU/L) after kisspeptin was 4.2 (3.4) in healthy women, 2.8 (2.1) in women with PCOS, 9.2 (5.6) in women with FHA, and 0.7 (0.5) in women with CHH. In lean women (BMI &amp;lt;25 kg/m2), the maximal rise in FSH after kisspeptin differentiated women with PCOS from those with FHA (area under ROC curve 0.91, p = 0.0001). Furthermore, the maximal rise in FSH after kisspeptin differentiated women with FHA from women with CHH (auROC 1.00, p &amp;lt; 0.0001), whereas the equivalent auROC for FSH rise after GnRH was 0.7 (p = 0.086). Limitations, reasons for caution Participants included in this study had clearcut diagnoses of PCOS, FHA, or CHH prior to inclusion, however this could increase the risk of spectrum bias. Whilst this study provides mechanistic insight into hypothalamic dysfunction in these conditions, further prospective validation of discriminatory thresholds in different settings is required. Wider implications of the findings The specific action of kisspeptin at hypothalamic GnRH neurons enables its use to assess hypothalamic function in patients with oligo-amenorrhea due to different anovulatory disorders. Our data suggests that the hormonal response to kisspeptin has promising diagnostic potential to aid in the evaluation of women with oligo-amenorrhea. Trial registration number ISRCTN21681316

P-650 Cumulative live birth rate after use of capacitation in vitro maturation in women with predicted excessive response to ovarian stimulation: an analysis of 1,563 cycles

Abstract Study question What is the cumulative live birth rate in biphasic (capacitation) in vitro maturation (CAPA-IVM) cycles in women with predicted excessive response? Summary answer The cumulative live birth rate achieved after CAPA-IVM in women with predicted excessive response was 37.8%. What is known already In vitro maturation (IVM) is an alternative infertility treatment for women at high risk of complications during conventional in vitro fertilisation with ovarian stimulation. There is debate about the merits of a newer biphasic approach (capacitation [CAPA]-IVM) versus standard IVM. At centres where it is used, CAPA-IVM has increased the maturation rate, and therefore the number of embryos available for transfer. However, there is a lack of data from large numbers of CAPA-IVM cycles, especially cumulative outcomes. Study design, size, duration This analysis included data from 1,563 individuals who underwent CAPA-IVM at a tertiary IVF center in Ho Chi Minh City, Vietnam from January 2016 to December 2023. Participants/materials, setting, methods All CAPA-IVM cycles in women with predicted excessive response (polycystic ovary syndrome or high antral follicle count) were included. Mean age was 29.6±3.5 years. Median duration of infertility was 3.3±2.5 years. CAPA-IVM was the first assisted reproductive technology in 90.5% of participants. Cumulative live birth rate was defined as the number of live births after using all embryos generated from a CAPA-IVM cycle. Main results and the role of chance Cumulative rates of clinical pregnancy, ongoing pregnancy and live birth were 54.9%, 44.4% and 37.8%, respectively. The median proportion of mature oocytes per cumulus-oocyte complex was 61.3% (IQR 50.0–73.3) and the median proportion of fertilized oocytes per cumulus-oocyte complex was 72.2% (IQR 55.6-85.7). The median total number of day-3 embryos per patient was 4.0 [IQR 3.0–7.0] and the total number of good day-3 embryos per patient was 3.0 [IQR 2.0–5.0]. The proportion of patients with no embryo was 5.2%. The number of frozen embryo transfer cycles was 1 (53.6% of patients), 2 (24.9%), 3 (7.0%), 4 (0.8%) or 5 (0.3%); 7.9% of patients had not undergone transfer of day-3 embryos at the time of analysis. Median [IQR] number of embryos and good embryos transferred was 2.0 [2.0–4.0] and 2.0 [1.0–2.0], respectively. No case of ovarian hyperstimulation syndrome recorded. Limitations, reasons for caution The characteristics of the study population (relatively young, lean women from Vietnam with predicted excessive response to ovarian stimulation) limit the external generalisability of the findings. Wider implications of the findings The cumulative live birth rate from all CAPA-IVM cycles performed in women with predicted excessive response at our centre was comparable to that of IVF. CAPA-IVM could be an alternative for this selected group of patients to avoid ovarian hyperstimulation. Trial registration number not applicable

O-190 Hormone-free versus FSH-primed infertility treatment of women with polycystic ovary syndrome using biphasic in vitro maturation: a randomised clinical trial

Abstract Study question Is any hormone stimulation needed to treat infertility in women with polycystic ovary syndrome (PCOS) using in vitro maturation (IVM)? Summary answer Number of matured oocytes and pregnancy outcomes were similar without or with FSH-priming in women with PCOS undergoing IVM. What is known already In vitro maturation (IVM) is a low-intervention alternative to in vitro fertilisation (IVF) for infertility treatment. Current standard clinical practice for human IVM is to prime patients for 2–5 days with follicle-stimulating hormone (FSH) and/or human chorionic gonadotropin (hCG) before harvesting immature or mixed maturity oocytes for infertility treatment. This gonadotropin priming is thought necessary to induce sufficient follicle and oocyte development in vivo to support subsequent oocyte maturation and embryo development in vitro when using a single step (monophasic) oocyte maturation culture system. It is not clear whether hormone-free IVM can generate satisfactory pregnancy and live birth rates. Study design, size, duration This randomised, controlled trial was conducted at an tertiary IVF center, Ho Chi Minh City, Viet Nam. Between January 2023 and June 2023, 120 women (60 per group) were randomised. Participants/materials, setting, methods Eligible women were aged 18–37 years and had PCOS with an indication for biphasic capacitation-IVM (CAPA-IVM). After providing written informed consent, participants were randomised (1:1) to undergo CAPA-IVM with or without FSH-priming. Participants in the FSH-priming group received two days of FSH injections before oocyte pick-up; no FSH was given in the non-FSH group. After CAPA-IVM, day-5 embryos were vitrified for transfer in a subsequent cycle. The primary endpoint was number of matured oocytes. Main results and the role of chance The number [interquartile range] of matured oocytes after CAPA-IVM did not differ significantly between the non-FSH and FSH groups (13 [9; 18] vs. 14 [7; 18]; absolute difference –1 [95% confidence interval –5, 4]). There were also no significant between-group differences in other oocyte and embryology outcomes, including the number of cumulus-oocyte complexes, number of fertilized oocytes, total number of blastocysts and good blastocysts, and total number of frozen embryos. No between-group differences were found in the rates of ongoing pregnancy and live birth, which were both 38.3% in the non-FSH group and both 31.7% in the FSH group; the miscarriage rate at &amp;lt; 12 weeks’ gestation was 5.0% in both groups. Maternal complications were infrequent and occurred at a similar rate in the non-FSH and FSH groups; there were no preterm deliveries before 32 weeks’ gestation. Limitations, reasons for caution The characteristics of the study population (relatively young, lean women with PCOS from Viet Nam) limit the external generalisability of the study findings, and the findings need to be replicated in other populations. Wider implications of the findings Hormone-free assisted reproductive technology (ART) for women with PCOS appears to be feasible when using CAPA-IVM, and does not result in any loss of clinical efficacy. Benefits of hormone-free ART would be a reduction in medical risk, lower cost, fewer monitoring requirements, and greater convenience and flexibility. Trial registration number NCT05600972

P-631 Extended letrozole regimen versus routine letrozole regimen in women with polycystic ovary syndrome undergoing their first ovulation induction cycle

Abstract Study question Whether an extended letrozole regimen could result in a higher ovulatory rate than a routine regimen in PCOS women undergoing their first ovulation induction cycle. Summary answer PCOS women using the extended letrozole regimen failed to obtain a statistically higher rate of ovulation in comparison with the routine letrozole regimen. What is known already Letrozole has become the first-line agent for ovulation induction, however, nonresponsive cycles occurred in 10-58.8% of PCOS women during their ovulation induction therapy with letrozole alone. The extended letrozole regimen has been demonstrated to be a feasible method for inducing ovulation in those nonresponders. However, whether it could be applied to all the PCOS women as a first choice in the induction of ovulation remains to be explored. Study design, size, duration This is a prospective randomized controlled trial including 148 women with PCOS undergoing their first ovulation induction cycle with letrozole from January 2021 to October 2022. Participants/materials, setting, methods Participants were randomly assigned to receive an extended letrozole regimen (5 mg letrozole daily for 7 days) or a routine regimen(5 mg letrozole daily for 5 days) for one treatment cycle. Ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, the rate of multiple pregnancies. Main results and the role of chance The ovulation rate among women receiving a 7-day regimen was slightly higher than the rate with a 5-day regimen, but it did not reach a statistical significance in both the intention-to-treat analysis (90.54%[67/74]vs. 82.43%[59/74], P = 0.065) and per-protocol analysis (90.54%[67/74]vs. 84.29%[59/70], P = 0.257). The number of preovulatory follicles was nearly identical in the two groups (1.39±0.62 vs.1.37±0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. In the per-protocol analysis, the rates of clinical pregnancy (20.27%[15/74]vs.16.95%[10/70], P = 0.343) and live birth (13.51%[10/74]vs.11.43%[8/70], P = 0.976) did not differ significantly between treatment groups. Moreover, all the conceptions were singletons without neonatal defects. Limitations, reasons for caution The major concern of the current research is its single-centre and open label nature. Additionally, the limited number of lean PCOS women with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restrict the generalizability of our findings. Wider implications of the findings Letrozole 5-day regimen remains to be the first choice for PCOS women undergoing ovulation induction therapy. Additional prospective trials with a larger sample size and different subgroups of PCOS are needed to assess the ovulatory effects of different letrozole treatment duration. Trial registration number ChiCTR2100042082

P-616 Impact of Dehydroepiandrosterone sulfate and Free Androgen Index on pregnancy and neonatal outcomes in PCOS patients

Abstract Study question What were the effects of free androgen, DHEAS on pregnancy and neonatal outcomes and the cut-off value of East Asian population with PCOS ? Summary answer PCOS patients with biochemical hyperandrogenism show unsatisfactory clinical PR and CLBR when undergoing assisted reproductive technology (ART). What is known already Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with infertility and pregnancy complications. The pathogenesis of PCOS and its impact on reproductive function may be influenced by different source of androgens, including testosterone, free androgen, dehydroepiandrosterone sulfate (DHEAS). However, the differential effects of these androgen on pregnancy and neonatal outcomes and the cut-off value of East Asian population with PCOS remain unclear. Study design, size, duration A retrospective cohort study was conducted at the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University from January 2015 to November 2022, involving 636 cycles of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Subgroup analyses were performed using cut-off values of 6.4 for free androgen index (FAI), 9.5 μmol/L for DHEAS. Pregnancy and neonatal outcomes were compared between groups. Restricted cubic spline (RCS) was used to identify significant cut-off values affecting pregnancy. Participants/materials, setting, methods This retrospective cohort study included 1647 PCOS patients. The diagnosis of PCOS was based on the Rotterdam criteria.Exclusion criteria included patients with congenital adrenal hyperplasia, androgen-secreting masses, oocyte donation cycles, and PGT cycles. Main results and the role of chance Higher FAI levels (&amp;gt;6.4) were associated with decrease in clinical pregnancy rate (PR) (58.91% vs. 51.47%, p = 0.064), live birth rate (LBR) (42.42% vs. 32.35%, p = 0.011), cumulative pregnancy rate (CPR) (p = 0.032), and cumulative live birth rate (p = 0.032). When DHEAS levels exceeded 9.5 μmol/L, there was a significant decrease in clinical PR (60.33% vs. 49.55%, P = 0.008), LBR (42.73% vs. 32.73%, P = 0.012). Negative correlations were also observed between DHEAS levels and cumulative pregnancy rate (p = 0.031) and cumulative live birth rate (CLBR) (p = 0.031). Both FAI and DHEAS elevated is associated with the lowest clinical pregnancy rate (45.95%). Conversely, when solely FAI is elevated, the pregnancy rate increases to 58.10%, while an elevation in DHEAS alone is associated with a pregnancy rate of 61.44%, both of which are lower than when neither FAI nor DHEAS are elevated(62.73%). The live birth rates exhibit a similar trend(30.00%vs40.00%vs41.83%vs44.48%). RCS revealed a significant decrease in CPR and CLBR when DHEA levels exceeded 7.69 umol/L, while the cut-off value of FAI was 6.36 for CPR and CLBR. Limitations, reasons for caution Firstly, the data used to develop the model were obtained from a single center with a relatively small sample size. Secondly, the patients included in this study were predominantly of slim physique with a lower proportion of obesity. Wider implications of the findings Both adrenal-derived DHEAS and ovarian-derived FAI are responsible to the unfavorable pregnancy outcomes in lean PCOS women. Trial registration number 2020B1212060029

Placental structural adaptation to maternal physical activity and sedentary behavior: findings of the DALI lifestyle study.

Are maternal levels of moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) in obese pregnant women associated with placental structural adaptations for facilitating oxygen delivery to the fetus? Higher maternal MVPA and ST are associated with a higher density of villi, a proxy measure of placental surface area for oxygen delivery to the fetus, without further added placental vessels. Physical activity during pregnancy intermittently reduces uterine blood flow, potentially limiting placental and fetal oxygen supply. The placenta can mount several adaptive responses, including enlargement of the surface area of villi and/or feto-placental vessels to accommodate fetal needs. Early research on the morphology and growth of the placenta with exercise interventions has shown inconsistencies and is lacking, particularly in non-lean pregnant women. This study is a secondary longitudinal analysis of the vitamin D and lifestyle intervention for gestational diabetes prevention (DALI) randomized controlled trial. The prospective study was conducted between 2012 and 2015 in nine European countries at 11 different sites. In this analysis, 92 pregnant women with a BMI ≥ 29 kg/m2 were combined into one cohort. MVPA and percentage of time spent sedentary (% ST) were measured with accelerometers during gestation. Placental sections were immunostained for endothelial cell-specific CD34. Artificial intelligence (AI)-based stereology assessed villous density, number, and cross-sectional area of vessels on whole-slide images and in selected regions comprising peripheral villi only, where the majority of vascular adaptations occur. Expression of pro- and anti-angiogenic factors was quantified using molecular counting analysis. In multivariable regression, higher levels of maternal MVPA (min/day) were associated with a higher density of villi in both whole-slide images (beta 0.12; 95% CI 0.05, 0.2) and selected regions (0.17; CI 0.07, 0.26). Unexpectedly, ST was also positively associated with density of villi (0.23; CI 0.04, 0.43). MVPA and ST were not associated with vessel count/mm2 villous area, vessel area, or pro- and anti-angiogenic factor mRNA expression. All estimates and statistical significance of the sensitivity analyses excluding smokers, women who developed gestational diabetes or pre-eclampsia and/or pregnancy-induced hypertension were similar in the main analysis. The placenta is a complex organ undergoing dynamic changes. While various adjustments were made to account for different maternal contributing factors, in addition to the outcome measures, various other factors could impact oxygen delivery to the fetus. For the first time, we evaluated the association between placental structures quantified using an AI-based approach with objectively measured physical activity and ST at multiple time points in pregnant women with obesity. The observed adaptations contribute to the advancement of our understanding of the hemodynamics and adaptations of the placental unit in response to MVPA and ST. However, our results might not be generalizable to lean pregnant women. The DALI project has received funding from the European Community's 7th Framework Program (FP7/2007-2013) under grant agreement no. 242187. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. ISRCTN70595832.

Is gestational diabetes mellitus in lean women a distinct entity warranting a modified management approach?

During pregnancy, insulin resistance and impaired insulin secretion may lead to the development of Gestational Diabetes Mellitus (GDM). Although a higher Body Mass Index (BMI) is often cited as a risk factor for the development of GDM, lean pregnant women are also at risk of developing GDM based on evidence from several studies. It is proposed that insulin deficiency (more than insulin resistance) leads to the development of GDM in women with low BMI (BMI <18.5 kg/m2). Neonates of these women are more at risk of preterm birth and small-for-gestational-age. Given this unique pathophysiology and phenotype, this entity needs a modified management approach. This article aims to raise awareness of GDM in lean women to encourage more research on this topic and create a modified management approach.

Diagnosis experiences in an international sample of lean women with PCOS

Diagnosis experiences in an international sample of lean women with PCOS

Abstract PO3-13-08: D17104: Aryl Hydrocarbon Receptor Signaling and Other Biomarkers of Fat Metabolism in Human Mammary Adipose Tissue from Women with Malignant Breast Disease

Abstract Background: Obesity is a recognized risk factor for the development of metabolic disease and breast cancer possibly due to chronic inflammation mediated by cytokines secreted by adipose tissue. Given this, our group examined differential expression of several markers of chronic inflammation in adipose tissue of both benign and malignant breast tissue from patients. The aryl hydrocarbon receptor (AhR) is an important cytosolic, ligand-dependent transcription factor found within hepatocytes and adipocytes that is upregulated in many types of cancer. AhR promotes the initiation, progression, and metastasis of cancer cells allowing certain cancers to evade immune recognition (Xue et al. Front. Immunology 2018). Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that generates kynurenine (KYN) from tryptophan (TRP), which acts as an AhR agonist. We sought to determine expression of IDO1 via immunohistochemistry (IHC) in mammary adipose tissue associated with benign or malignant breast. We hypothesized that adipose tissue adjacent to malignant breast tissue may have heightened expression of IDO1 in addition to Cyp1b1, and SPP1; both of which are also markers of increased aryl-hydrocarbon transcriptional activity, compared to adipose tissue noncontiguous to malignant lesions. KYN affects gene expression for insulin resistance and levels are elevated in plasma of older obese women compared to lean women; however, the relationship to breast malignancy is not known. Methods: IDO1 (Cell Signaling, 1:200), Cyp1b1 (Thermo Fisher, 1:300), and SPP1 (Thermo Fisher, 1:200) IHC was performed according to the manufacturers' protocols. Adipose tissue immediately adjacent to, and &amp;gt;2 mm away from, tumors (three DCIS, 11 invasive carcinomas) was evaluated in 14 patients. Adipose tissue in separate tissue blocks from benign breast tissue (three ipsilateral, 11 contralateral) in the same patients was also evaluated. Human plasma KYN levels were assayed by HPLC in the Dartmouth Clinical Pharmacology Shared Resource as described previously (Rojas et al. Obesity 2021). Results: In this preliminary pilot study, there was no difference in staining pattern for IDO1 in adipose tissue present in malignant and benign samples. Two patients showed increased Cyp1b1 and SPP1 staining immediately adjacent to the invasive carcinoma (Figure 1). Patients with benign breast disease did not show increased Cyp1b1 or SPP1 staining. Results will be confirmed using qPCR for mRNA. Plasma samples from patients with benign disease showed a lower level of KYN expression on average (0.370 ug/mL, N = 8) compared to plasma from patients with malignant disease (0.424, N = 10). Additionally, the ratio of KYN:TRP was lower in the benign group (0.065) compared to the cohort with malignancy (0.080). Univariate linear regression will be used to further assess relationships between continuous variables in the study population (e.g., patient age, BMI, KYN plasma levels, benign vs malignant breast disease). Regression lines and the associated slope estimates (b-value) and p-values for regression models will be provided on scatter plots. Conclusions: While there was no difference in IDO1 staining patterns in adipose tissue of malignant and benign samples in this group, tissue samples from patients with invasive carcinoma demonstrated increased Cyp1b1 and SPP1 staining adjacent to the malignant tumor; while benign tissue samples did not show a positive stain. This suggests increased aryl-hydrocarbon transcriptional activity in invasive breast carcinoma—further linking AhR signaling with adipose tissue immune dysregulation and invasive malignancy. Additionally, KYN plasma levels were higher in patients with malignant disease indicating a possible relationship between insulin resistance and breast malignancy. Additional research may offer new insights relating to this important pathway and ultimately treatments aimed at blunting its nefarious effects. Citation Format: Adam Ephraim, Jonathan Pirruccello, Scott Palisoul, Jonathan Marotti, Mary Chamberlin. D17104: Aryl Hydrocarbon Receptor Signaling and Other Biomarkers of Fat Metabolism in Human Mammary Adipose Tissue from Women with Malignant Breast Disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-08.

Understanding metabolic patterns in polycystic ovary syndrome: Comparing lean and obese women at a family medicine clinic.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder and various phenotypes have been described. While most women with PCOS are obese, women who are lean also suffer from PCOS. Metabolic derangements often accompany this syndrome. Family physicians, being the first point of contact in the healthcare system, play a vital role in the early diagnosis and management of this condition through diet and lifestyle modifications. The present study was conducted at the Diet and Lifestyle Diseases Management Division of a Family Medicine Clinic. We conducted a retrospective analysis of the correlation between body mass index (BMI) and metabolic parameters in women diagnosed with PCOS. The case records of women with PCOS, diagnosed as per modified Rotterdam criteria and who attended the outpatient clinic from January 2020 to December 2022, were chosen. Data on BMI and metabolic parameters were retrieved and statistically analyzed. Upon analysis of 51 case records, 25.49% of women were in the lean group and 74.51% were overweight or obese. Triglycerides/HDL ratio (1.91 ± 0.47 vs 3.97 ± 5.89) and Vitamin D levels (Median 14.12 vs 16.10 ng/ml) were abnormal in both the obese and the lean women groups. However, there was no significant difference between the groups. Other metabolic parameters were within normal ranges. The present study indicates that metabolic derangements are associated with PCOS, irrespective of BMI. More robust studies in larger population samples are needed to elucidate the role of metabolic derangements and mainly insulin resistance in the pathophysiology of PCOS and its different phenotypes.

Postmenopausal Women with Obesity have Reduced Leg Endothelial Function and Exercise Vasodilatory Capacity

Background: Obesity (OB) is highly prevalent in postmenopausal women; particularly increased abdominal visceral adipose tissue contributes to endothelial dysfunction and cardiovascular risk. The endothelium plays an important role on blood flow (BF) and pressure control at rest and during exercise. However, it is unknown how different body mass index (BMI) categories influence upper and lower limb endothelial function and BF responses to exercise in postmenopausal women. Purpose: The purpose was to examine upper and lower limb endothelial function at rest and BF regulation during low-intensity exercises in OB, overweight (OW), and lean (LN) postmenopausal women. We hypothesized that endothelial function and BF responses to submaximal exercise in both limbs will be attenuated in OB compared to the OW and LN groups. Methods: Women were classified as OB (30.0-39.9 kg/m2; n = 13), OW (25.0-29.9 kg/m2; n = 15), and LN (18.5-24.9 kg/m2; n = 11) by BMI. Flow-mediated dilation (FMD) of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were measured using ultrasound. BF and vascular conductance (VC) in the brachial (BA-BF and BA-VC) and femoral (FA-BF and FA-VC) arteries were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises (PFE) at 5, 15, and 30 % of maximal strength and calculated 1-repetition max (1RM), respectively. Results: No differences in BA-FMD were observed among the groups. FA-FMD was significantly lower in OB (2.6 ± 1.4%) compared to OW (4.3 ± 1.9%) and LN (4.2 ± 0.7%) groups (P &lt; 0.05). Increases in FA-BF (OB: 462 ± 229 vs. OW: 616 ± 173 vs. LN: 640 ± 141 mL/min; P &lt; 0.001) and FA-VC (OB: 410 ± 176 vs. OW: 585 ± 155 vs LN: 623 ± 153 mL/min*100mmHg; P &lt; 0.001) were attenuated during PFE at 30% of 1RM in OB compared to OW and LN. Upper-body exercise vasodilation was not attenuated by OB. FA-BF and FA-VC during PFE at 30% of 1RM were correlated with FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -.386, P = 0.015, FA-VC: r = -.456, P = 0.004). Conclusion: Postmenopausal women with OB have blunted leg endothelial function and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. These findings suggest that OB may contribute to reduce leg endothelial function, and vasodilator function during exercise in postmenopausal women. No support of funding information to disclose. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.