Polycystic Ovary Syndrome Mothers Research Articles

O-191 Delayed fetal growth in pregnant women with polycystic ovary syndrome using serial ultrasonographic biometry

Abstract Study question To investigate the effect of maternal polycystic ovary syndrome (PCOS) on intrauterine growth and perinatal outcome of offspring. Summary answer Maternal PCOS might have an adverse impact on fetal growth, represented by serial biometric measurements, and consequently lower the birth weight. What is known already Women with PCOS often have low fertility and high risk of certain pregnancy complications, including miscarriage, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP) and preterm birth (PTB). In addition, the offspring of PCOS mothers are susceptible to short- and long-term health consequences, such as metabolic diseases and neuropsychiatric disorders. And the suboptimal intrauterine environment caused by maternal PCOS condition might be the origin of impaired long-term health of the offspring. Study design, size, duration A total of 1153 pregnant women with pregestational diagnosis of PCOS and 1383 non-PCOS controls were included in the retrospective case-control study for clinical record and ultrasonographic database at women’s hospital, school of medicine, Zhejiang university over a 6-year period. Participants/materials, setting, methods Maternal demographic data, fetal biometric measurements with ultrasound, obstetrical and neonatal outcomes were analyzed. A meta-analysis of birth weight in PCOS offspring in the literature was performed to assess the relationship between the maternal PCOS and neonatal growth. Main results and the role of chance After adjustment for potential confounding variables, we found that biparietal diameter (BPD) and femur length (FL) were notably smaller in fetuses of women with PCOS than controls across the entire gestation. This effect still existed after excluding three major pregnancy complications of PCOS, including GDM, HDP and PTB. Although other fetal biometry including estimated fetal weight and birth weight in PCOS offspring were comparable with controls in our study, the meta-analysis of 22 studies showed that the birth weight in offspring of women with PCOS was lower than controls (WMD -37.813, 95%CL [-69.713, -5.913]), especially for offspring in South America (WMD -84.69, 95%CL [-166.69, -2.68]). Limitations, reasons for caution First, data of other fetal parameters like abdominal and head circumference was scanty. Second, neonatal anthropometric parameters apart from the birth weight were not included. Lastly, we did not have the long-term follow-up results of the offspring to explore the potential effect of delayed fetal biometry in their later life. Wider implications of the findings More attention needs to be paid to the smaller-than-average fetuses in PCOS mothers, and proper management may be needed during and after pregnancy. Further studies are needed to confirm the intrauterine growth pattern of the PCOS offspring and its clinical significance in the neonatal period and beyond. Trial registration number N/A

Anthropometric Measurements in Newborns: A Comparative Study of Infants Born to Mothers With and Without Polycystic Ovary Syndrome.

Objective Fetal growth can be affected by maternal PCOS and may have an impact on offspring and childhood growth. The current findings across studies are divergent and controversial. This study aims to determine whether maternal PCOS can affect the physical measurements of newborns and to establish the differences in birth weight, length, head, and chest circumference between newborns of mothers with polycystic ovarian syndrome and those of mothers without polycystic ovarian syndrome. Methods In this study, we examined the gestational age, birth weight, length, head circumference, chest circumference, and ponderal index of 75 infants born to mothers with polycystic ovary syndrome (PCOS) and compared them to those of 94 infants born to mothers without PCOS. Result Compared with the other groups, the PCOS group does not show significant differences in anthropometric indices compared to the control group. Infants born to normal and PCOS mothers birth weight were categorized as SGA (small for gestational age) if birth weight was less than the 5thpercentile. LGA is large for gestational age if birth weight is greater than the 90thpercentile. Other appropriate for gestational age if infant birth weight is between> 5thand < 90th percentile. Significant differences in anthropometric indices like birth weight, head circumference, and Ponderal index were observed in SGA and LGA newborns of normal and PCOS mothers. Conclusion The study findings indicate that neonates born to mothers with PCOS have higher rates of SGA and LGA newborns, and differences in anthropometric indices (birth weight, head circumference, and Ponderal index) were observed between SGA and LGA newborns of PCOS mothers.

O-013 Metabolic characteristics of offspring born to women with polycystic ovary syndrome in childhood

Abstract Study question Does polycystic ovary syndrome (PCOS) affect the metabolic characteristics of offspring in childhood? Summary answer Girls born to PCOS mothers had increased cholesterol (CHOL) and low-density lipoprotein cholesterol (LDL) levels, whereas boys had comparable CHOL and LDL levels to controls. What is known already Maternal PCOS status may negatively influence childhood growth, endocrine and metabolic function. The long-term impact of PCOS on children health is poorly understood. Current findings reported by previous studies are divergent. Propensity score matching can reduce bias where strong confounding by indication is expected. Study design, size, duration This was a cohort study including 223 singletons born to women with PCOS and 2326 singletons born to non-PCOS women. All offspring were conceived by in-vitro fertilization (IVF) or Intracytoplasmic sperm injection (ICSI) from January 2001 to January 2018 in reproductive center of Women’s hospital, Zhejiang University, School of medicine. Growth and development parameters and metabolic parameters were collected at age 3-6 years in Follow-up center of Women’s hospital, Zhejiang University, School of medicine. Participants/materials, setting, methods We used the propensity score (PS) to match PCOS women and non-PCOS women in a 1:4 ratio. The variables in the PSM included maternal age at conception, paternal age at conception, maternal height, maternal preconception BMI, IVF or ICSI, fresh-embryo transfer (ET) or frozen-embryo transfer (FET), gender of offspring, age at follow-up, year of follow-up. The PCOS group consisted of 217 patients and the non-PCOS group consisted of 787 patients after PS matching. Main results and the role of chance Maternal preconception weight (58.3±0.6 vs. 56.0±0.2, P&amp;lt;0.001) and body mass index (BMI) (23.0±0.2 vs. 21.9±0.1, P&amp;lt;0.001) were significantly higher in mothers with PCOS before PS matching. After PS matching, parental demographic characteristics were similar between groups including maternal preconception weight and BMI. In PS matching cohort, the height, weight, BMI of children at age 3-6 years were comparable between PCOS group and non-PCOS group. Singletons born to PCOS women had significantly higher CHOL levels (4.43±0.05 vs. 4.29±0.01, P=0.013) and LDL levels (2.45±0.04 vs. 2.37±0.01, P=0.049) compared with non-PCOS group. Even though the girls had similar BMI in childhood between the two groups(15.26±0.15 vs.15.13±0.80, P=0.449), the girls born to PCOS women still exhibited elevated CHOL levels (4.52±0.08 vs. 4.33±0.04, P=0.024) and LDL levels (2.55±0.06 vs. 2.39±0.03, P=0.007). These differences in CHOL (4.34±0.07 vs. 4.26±0.04, P=0.196) and LDL levels (2.36±0.05 vs. 2.36±0.03, P=0.866) were not observed in male offspring between the two groups. Limitations, reasons for caution Mothers’ weight gain during pregnancy, offspring lifestyle were not available for this study. This was a study carried out in a single center and was therefore susceptible to bias. Further studies remain necessary to fully confirm these results. Wider implications of the findings Our results support CHOL and LDL lipid metabolism as two of the earliest metabolic abnormalities features of the female offspring born to PCOS women. These findings suggest that further studies are needed to investigate the potential mechanisms and long-term metabolic changes associated with these differences. Trial registration number not applicable

Cardiometabolic consequences of maternal hyperandrogenemia in male offspring.

Polycystic ovary syndrome (PCOS) in women is characterized by hyperandrogenemia, obesity, and oligo‐ or anovulation. In addition, women with PCOS are often obese, with insulin resistance, hyperlipidemia, and elevated blood pressure. The cardiometabolic consequences for the male offspring of maternal hyperandrogenemia are unclear. The present studies tested the hypothesis that male offspring of a rat model of PCOS would develop cardiometabolic disease as adults. Female Sprague–Dawley rats (hyperandrogenemic females (HAF)) were implanted with dihydrotestosterone or placebo pellets (controls) at 4 weeks of age, and were mated at 10–12 weeks and allowed to lactate their offspring after birth. Body weights in male HAF offspring were lower at birth than in controls until postnatal day 4, but body weights remained similar between male control and HAF offspring from 2 to 8 weeks of age. However, at 16 weeks of age, body weight was lower in HAF male offspring, but there were no differences in fat mass or lean mass factored for body weight in HAF males, compared to controls. Plasma total cholesterol and HDL and proteinuria were higher and nitrate/nitrite excretion was lower in male HAF offspring than in controls. Baseline blood pressure was similar between HAF male offspring and controls, but HAF offspring had an exaggerated pressor response to angiotensin II infusion. These data suggest that adult sons of PCOS mothers may be at increased risk of cardiometabolic disease.

Elevated Anti-M\xfcllerian Hormone Levels in Newborns of Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis Based on Observational Studies

We performed this updated systematic review and meta-analysis to evaluate anti-Müllerian hormone levels (AMH) in newborns of mothers with polycystic ovary syndrome (PCOS) compared with healthy controls. A search of the literature was conducted in the PubMed, MEDLINE, EMBASE, Cochrane Library, CBM, CNKI, WANFANG, and VIP for articles to assess AMH levels in offspring of PCOS and non-PCOS mothers irrespective of language. These databases were searched from their inception to December 7, 2020. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS) scoring system. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were adopted to calculate the overall estimates with random-effects models. A total of 6 studies with 846 participants were included. The pooled analysis found an increased AMH level in the umbilical cord blood in newborns of PCOS mothers (SMD =0.62, 95% CI [0.28, 0.95]). Subgroup analyses revealed an elevation of AMH concentrations in female neonates, neonates born to American and Asian PCOS mothers. In addition, higher AMH levels were also found in studies diagnosed by the National Institute of Health (NIH) criteria, maternal clinical/biochemical hyperandrogenism, or maternal body mass index (BMI) >30 kg/m2. Meta-regression analysis suggested that diagnostic criterion contributed mostly to the high heterogeneity. We demonstrated that AMH levels in neonates born to PCOS mothers were essentially higher, which indicates that AMH may act as an enigmatic role in the pathogenesis of PCOS which inhibits folliculogenesis in the fetal stage.

Mother’s PCOS Diagnosis Is Not Associated With Behavioral Symptoms in Offspring at 4-5 years

Introduction: Variation in prenatal sex steroid concentrations has been linked to child behavioral problems, with higher maternal total and free testosterone associated with child internalizing and externalizing symptoms. Polycystic Ovary Syndrome (PCOS) is a hyperandrogenic disorder that results in elevated testosterone levels during pregnancy among affected women. Population-based analyses suggest a higher risk of depression and anxiety diagnosis in children of women with PCOS. Animal models of prenatal hyperandrogenism further support an association with increased anxiety in offspring. Within the context of a multi-center U.S. pregnancy cohort, we examined early childhood behavioral and social responsiveness in children born to mothers with and without PCOS. Methods: Pregnant women were recruited in their first trimester for The Infant Development and Environment Study (TIDES). PCOS status was determined by maternal reports of PCOS diagnosis or history of hirsutism/oligomenorrhea. Women who reported neither a history of PCOS or symptoms of hirsutism or oligomenorrhea served as a comparison group. When participating children were age 4, mothers completed the Behavioral Assessment System for Children, 2nd Edition (BASC-2), a measure of child behavior problems, and the Social Responsiveness Scale, 2nd Edition (SRS-2), a measure of social impairment consistent with autistic traits. We fit linear regression models considering three outcomes: (1) BASC-2 externalizing composite score (e.g., hyperactivity, aggression); (2) BASC internalizing composite score (e.g., anxiety, depression, somatization); and (3) SRS-2 total score, adjusting for covariates, maternal age, child age, race, study center, income, education, alcohol and tobacco use, child sex, maternal depression. For all outcomes, higher scores indicate more problematic behaviors. Results: A total of 360 mother/child pairs completed the 4-year assessment and were included in this analysis. This included 81 mothers with PCOS (37 male, 44 female) and 279 comparison mothers (132 male, 147 female). Mean maternal age at delivery was 30.7 years (±4.7) for PCOS cases and 31.9 years (±5.4) for comparison mothers. Interaction terms indicated no effect modification by child sex. In analyses combining both sexes, maternal PCOS was not associated with externalizing behaviors (β=1.81; 95% CI: ‐2.37, 6.0; p=0.40), internalizing behaviors (β=2.20; 95% CI: ‐2.14, 6.53; p=0.32), or social impairment (β=-0.34; 95% CI: ‐3.34, 2.65; p=0.82). Conclusions: In this prospective evaluation, we observed no association between maternal PCOS and neurobehavioral symptoms in children at age 4. Given that prior literature using population databases suggested increased behavioral symptoms in school-aged and older children of PCOS mothers, these symptoms may become more apparent with development and continued assessment is warranted.

Foetal Sonographic Anogenital Distance Is Longer in Polycystic Ovary Syndrome Mothers.

Anogenital distance (AGD) is a biomarker for the prenatal hormonal environment. Androgen excess is a key element in polycystic ovary syndrome (PCOS). The aim of this study was to assess the sonographic foetal AGD in a population of PCOS mothers in comparison to the general population. Foetal AGD was measured prospectively by 2D ultrasound in PCOS mothers and compared to prenatal AGD nomograms. The results were interpreted regarding maternal and foetal characteristics. The mean sonographic foetal AGD centile measurement in PCOS mothers was significantly longer in comparison to the general population (86.04% ± 18.22; p < 0.001). Estimated foetal weight and birthweight were appropriate for gestational age and did not correlate with AGD. Sonographic foetal AGD was significantly longer in PCOS diabetic mothers and in those who conceived following assisted reproduction treatments when compared to the general population (p < 0.001). Our results support the role of AGD as a biomarker of the prenatal hormonal environment and provide evidence for the hyperandrogenic effect in PCOS pregnancies on foetal androgenic status and genitalia development.

Transmission of polycystic ovary syndrome susceptibility single-nucleotide polymorphisms and their association with phenotype changes in offspring.

Does the inheritance of polycystic ovary syndrome (PCOS) susceptibility single-nucleotide polymorphism affect the phenotype of offspring? Male offspring who inherit PCOS-related genetic variations from PCOS mothers were more susceptible to developing the metabolic abnormality in their later life. Genetic factors are considered the major etiology of PCOS. Previous studies have highlighted that offspring of women with PCOS had an increased risk of the same disease or PCOS-like symptoms. The study involved 172 children born to women with PCOS and 529 children born to non-PCOS women. All offspring were conceived by assisted reproductive technologies. The offspring ranged from 1 to 8 years old. Metabolic phenotype analyses were performed in offspring aged from 2 to 8 (N = 619). Sanger sequencing, TaqMan and Sequenom MassARRAY were used to sequence the samples. In male offspring, the fasting insulin (FINS) (P = 0.037) homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.038) and the homeostasis model assessment of pancreatic beta-cell function (HOMA-β) (P = 0.038) levels were higher in offspring of PCOS mothers compared to controls. In female offspring, PCOS offspring had a significantly higher anti-Müllerian hormone levels (P = 0.001) compared to those from control mothers. In male offspring of PCOS mothers, subjects with a T allele at rs2349415 in the gene FSHR had higher FINS (P = 0.023), HOMA-IR (P = 0.030) and HOMA-β levels (P = 0.013) than those in the homozygous CC group. The same increased trend in FINS, HOMA-IR and HOMA-β levels could be found in the CC and TC group in rs2268361 located in gene FSHR compared to the TT group (P = 0.029, P = 0.030, P = 0.046, respectively). As for rs10818854 in the DENND1A gene, the AA and AG group had a higher FINS (P = 0.037) and HOMA-β (P = 0.008) levels than the homozygous CC group. Firstly, the offspring may be too young to see any phenotype changes. Secondly, this study only analyzed the differences of genotype frequency using the dominant model instead of all three models due to the limited sample size of the homozygous model. The results, therefore, should be replicated and performed in a larger sample size population. Thirdly, environmental impacts cannot be ruled out. The findings presented in this thesis add to our understanding the changes in offspring born to PCOS women and remind us to consider early intervention to avoid more severe effects. This study was supported by the National Key Research and Development Program of China 2017YFC1001000 (to Z.-J.C.), the National Natural Science Foundation of China 81430029 (to Z.-J.C.), 81622021 and 31571548 (to H.Z.), the National Natural Science Foundation of Shandong Province JQ201816 (to H.Z.) and Shandong Provincial Key Research and Development Program 2017G006036 (to L.-L.C.) and 2018YFJH0504 (to Z.-J.C.). There are no conflicts of interest to declare. N/A.

Comparison of the umbilical cord Blood\u2019s anti-Mullerian hormone level in the newborns of mothers with polycystic ovary syndrome (PCOS) and healthy mothers

BackgroundPolycystic ovary syndrome (PCOS) is one of the most common endocrine diseases. At present, the cause of the disease is not fully understood, but many studies have shown that PCOS is associated with genetic and environmental factors. The present study aimed to assess the umbilical cord blood’s Anti-mullerian hormone (AMH) level in the newborns of mothers suffering from PCOS comparing to healthy mothers.MethodsThis prospective cohort study was conducted on 120 pregnant women with PCOS, who were selected through Rotterdam criteria, and 60 healthy pregnant women as the control group. The subjects in each group were divided into obese and non-obese mothers according to their body mass index (BMI) before pregnancy. The cord blood samples were collected from the offsprings on the time of childbirth. Finally, the circulating concentrations of AMH in both sexes of the newborns were determined by specific assays.ResultsThe research results showed that the blood level of AMH was higher in the neonates of obese mothers with PCOS comparing to the controls (P < 0.001). Mean AMH level was higher in male neonates born from non-obese PCOS mothers than in the controls (P < 0.001); however, there was not a significant difference in the level of AMH in female neonates between these two groups (P = 0.264). Also the level of the above biomarker was higher in both sexes of the neonates belonging to obese PCOS mothers compared with the neonates born from non-obese PCOS mothers (P < 0.001).Conclusion(s)It can be said that the cord blood AMH level of neonates from obese women with PCOS is higher than that in the newborns of non-obese PCOS mothers. Further longitudinal studies are needed to confirm the clinical findings of the present research.

OC23.02: Fetal anogenital distance is longer in polycystic ovary syndrome mothers

OC23.02: Fetal anogenital distance is longer in polycystic ovary syndrome mothers

Abstract 018: Female Offspring of Polycystic Ovary Syndrome Rat Model Exhibit Insulin Resistance and Tendency Toward Increased Blood Pressure With Aging

Background: Polycystic ovary syndrome (PCOS) is associated with metabolic dysfunction and elevated blood pressure (BP). Whether daughters born to PCOS mothers exhibit a PCOS phenotype is controversial. In addition, whether daughters of PCOS women develop metabolic dysfunction and elevated BP with aging has not been reported. Objectives: The present study tested the hypothesis that aging causes an increase in MAP and metabolic dysfunction in female offspring of PCOS rats (F1 DHT ) along with changes in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β (TGF-β). Methods: PCOS was induced in SD females by implantation of 5α-dihydrotestosterone pellets (DHT; 7.5 mg/90 days, sc) starting at 4 wks of age. Rats were mated with SD males, and allowed to deliver and lactate. F1 DHT were left untreated and were studied at 14-16 wks or 16-18 mos of age. Control dams were implanted with placebo pellets sc, allowed to mate, deliver and suckle their offspring (F1 PL ). Results: MAP (radiotelemetry) in 14-16 wk F1 DHT females was not different from F1 PL, nor did they exhibit other PCOS characteristics. With aging, F1 DHT rats showed a strong tendency for increased MAP compared to F1 PL (107 ± 4 versus 93 ± 1 mmHg; p = 0.07 (n=2-4)). Plasma MMP-9 and TGF- β1, 2 and 3 were not different between groups. Fasting blood glucose was not different between groups (91 ± 2.6 vs 90 ± 1.6 mg/dl), but F1 DHT rats showed significant hyperinsulinemia (0.9 ± 0.05 vs 0.78 ± 0.03 ng/ml, p ≤ 0.05) and insulin resistance (increased HOMA-IR index; 3.3 ± 0.2 vs 2.8 ± 0.1, p ≤ 0.05, (n = 5-6)). Lean mass (248.3 ± 5.5 vs 241.2 ± 2.5 g), fat mass (38.7 ± 4.8 vs 39.7 ± 2.2 g) and total water (185.8 ± 4.8 vs 179.9 ± 3 g) by Echo MRI, in addition to body weight (310.7 ± 7.7 vs 298.1 ± 4.6 g ; (n = 6-8)) were also not different between groups. Conclusion: MAP in aging female offspring of PCOS rat model tends to be increased along with hyperinsulinemia and insulin resistance with no changes in fasting glucose, lean/fat mass, body weight, MMP9 or TGF-β. The data suggest that women whose mothers had PCOS may be at increased risk for hypertension and metabolic dysfunction with aging, although the mechanisms for the hypertension are not clear.

Origins and Impact of Psychological Traits in Polycystic Ovary Syndrome.

Women with polycystic ovary syndrome (PCOS) exhibit compromised psychiatric health. Independent of obesity, women with PCOS are more susceptible to have anxiety and depression diagnoses and other neuropsychiatric disorders. During pregnancy women with PCOS display high circulating androgen levels that may cause prenatal androgen exposure affecting the growing fetus and increasing the risk of mood disorders in offspring. Increasing evidence supports a non-genetic, maternal contribution to the development of PCOS and anxiety disorders in the next generation. Prenatal androgenized rodent models reflecting the anxiety-like phenotype of PCOS in the offspring, found evidence for the altered placenta and androgen receptor function in the amygdala, together with changes in the expression of genes associated with emotional regulation and steroid receptors in the amygdala and hippocampus. These findings defined a previously unknown mechanism that may be critical in understanding how maternal androgen excess can increase the risk of developing anxiety disorders in daughters and partly in sons of PCOS mothers. Maternal obesity is another common feature of PCOS causing an unfavorable intrauterine environment which may contribute to psychiatric problems in the offspring. Whether environmental factors such as prenatal androgen exposure and obesity increase the offspring’s susceptibility to develop psychiatric ill-health will be discussed.

Cord Blood Sex Hormones Concentration: Relation to Birth Weight and Pregnancy Complications

Objectives: Umbilical cord blood can be taken at birth and largely gives indication of fetal and maternal conditions. The aim of the study was to investigate the relation between sex hormones in cord blood and birth weight of newborns and pregnancy complications.&#x0D; Materials and methods: Fifty cord blood samples were collected from newborns at labor room of Baghdad Teaching Hospital between May and October 2018. Blood was withdrawn from their mothers for lead analysis. Five milliliters (ml) of cord blood was taken, 3 ml was used for testosterone and estradiol analysis (using enzyme-linked immunosorbent assay) and 2 ml for lead measurement by lead care analyzer. Newborns weight and head circumference were measured. Delivered women were divided into 4 groups: Women with normal pregnancy, women with preeclampsia, diabetic women and polycystic ovary syndrome (PCOS) women.&#x0D; Results: There was no significant difference in age between women in all groups (p˃0.05). Birth weights, estradiol, and testosterone were significantly different between groups. Estradiol was higher in cord blood of newborns of PCOS women (p˂0.05) than others. Testosterone was higher in cord blood of babies of PCOS and preeclampsia women compared to those of diabetes (p˂0.05). There were no significant differences between male and female neonates regarding cord estradiol (3596.27±1934.69, 3714.57±1581.47 pg/ml respectively), and testosterone (393.18±87.14, 361.43±102.14 ng/ml respectively) (p˃0.05). Maternal lead levels correlated positively with cord lead (r=0.905, p˂0.05), which correlated negatively with head circumference (r=-0.766, p˂0.05). Birth weight correlated negatively with estradiol (r=-0.295), but positively with testosterone (r=0.006) (p˃0.05). &#x0D; Conclusion: Cord blood estradiol and testosterone levels do not differ between males and females. Estradiol was high in cord blood of PCOS mothers. Testosterone was high in cord blood of PCOS and preeclampsia mothers. The increase in cord lead causes decrease in babies head circumference.

Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS.

Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Post hoc analysis of a randomized controlled trial. Double-blind, placebo-controlled, multicenter study. 258 offspring born to mothers with PCOS. 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age- and sex-adjusted z-scores. Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = -0.96 versus -0.42, P = 0.04) and weight (z-score = -0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = -0.40; 95% confidence interval, -0.60 to -0.40), but similar birth weight and HC. Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population.

Reproductive and metabolic features during puberty in sons of women with polycystic ovary syndrome.

ContextIntrauterine life may be implicated in the origin of polycystic ovary syndrome (PCOS) modifying the endocrine and metabolic functions of children born to PCOS mothers independently of the genetic inheritance and gender. The aim of the present study was to evaluate the reproductive and metabolic functions in sons of women with PCOS during puberty.MethodsSixty-nine PCOS sons (PCOSs) and 84 control sons of 7–18 years old matched by the Tanner stage score were studied. A complete physical examination was conducted including anthropometric measurements (weight, height, waist, hip and body mass index). An oral glucose tolerance test was performed and circulating concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), sex hormone-binding globulin, testosterone, androstenedione (A4), 17α-hydroxyprogesterone (17-OHP) and AMH were determined in the fasting sample.ResultsWaist-to-hip ratio, FSH and androstenedione levels were significantly higher in the PCOSs group compared to control boys during the Tanner stage II–III. In Tanner stages II–III and IV–V, PCOSs showed significantly higher total cholesterol and LDL levels. Propensity score analysis showed that higher LDL levels were attributable to the PCOSs condition and not to other metabolic factors. AMH levels were comparable during all stages. The rest of the parameters were comparable between both groups.ConclusionsSons of women with PCOS show increased total cholesterol and LDL levels during puberty, which may represent latent insulin resistance. Thus, this is a group that should be followed and studied looking for further features of insulin resistance and cardiovascular risk markers. Reproductive markers, on the other hand, are very similar to controls.

Intrauterine programming of polycystic ovary syndrome: evidence from cord blood global methylation analysis

Polycystic ovary syndrome (PCOS) affects 5-15% of women. PCOS is a heterogeneous disorder displaying endocrine, metabolic, reproductive dysfunction and cardiovascular risk manifestations. Evidence of heritability exists, but only a portion of the genetic transmission is identified by genome-wide association studies and linkage studies, suggesting that epigenetic influences play a role. Evidence implicates intrauterine influences in the genesis of PCOS. The study aims to identify unique epigenetic reprogramming of cord-blood gene networks in progeny of PCOS mothers by comparing global DNA methylation patterns in cord blood of neonates of infertile women with and without PCOS.

Assessment of growth and metabolism characteristics in offspring of dehydroepiandrosterone-induced polycystic ovary syndrome adults.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder that has many characteristic features including hyperandrogenemia, insulin resistance and obesity, which may have significant implications for pregnancy outcomes and long-term health of women. Daughters born to PCOS mothers constitute a high-risk group for metabolic and reproductive derangements, but no report has described potential growth and metabolic risk factors for such female offspring. Hence, we used a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS to study the mechanisms underlying the pathology of PCOS by investigating the growth, developmental characteristics, metabolic indexes and expression profiles of key genes of offspring born to the models. We found that the average litter size was significantly smaller in the DHEA group, and female offspring had sustained higher body weight, increased body fat and triglyceride content in serum and liver; they also exhibited decreased energy expenditure, oxygen consumption and impaired glucose tolerance. Genes related to glucolipid metabolism such as Pparγ, Acot1/2, Fgf21, Pdk4 and Inhbb were upregulated in the liver of the offspring in DHEA group compared with those in controls, whereas Cyp17a1 expression was significantly decreased. However, the expression of these genes was not detected in male offspring. Our results show that female offspring in DHEA group exhibit perturbed growth and glucolipid metabolism that were not observed in male offspring.

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome.

Little is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls. Prospective case-control study. Maternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E1), estradiol (E2), estriol (E3)) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. At 20 weeks of gestation: T (P=0.019) and ADION (P=0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E1, E2, and E3 were not different. Maternal concentration at birth: T (P=0.004) and ADION (P=0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E1, E2 and E3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E2, E3, and AMH between the PCOS mothers and the controls respectively. E1 was lower in girls from PCOS mothers (P=0.007). Despite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods.

Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.

Pregnancy and perinatal outcomes in women with polycystic ovary syndrome and twin births: a population-based cohort study.

To investigate pregnancy and perinatal outcomes in twin births among women with and without polycystic ovary syndrome (PCOS) diagnosis. Population-based cohort study. Sweden. We identified 20,965 women with twin births between 1995 and 2009 of whom 226 had a PCOS diagnosis through linkage between the Swedish Medical Birth Register and the Swedish National Patient Register. Calculating risk ratios (RR) with 95% confidence intervals (CI) using a log-binomial regression model and hazard ratios (HR) with 95% CI for preterm birth. Preterm birth, low birthweight, caesarean section, pre-eclampsia, Apgar score <7 at 5 minutes and perinatal mortality. PCOS diagnosis in twin pregnancy was associated with increased risk of preterm delivery (51% versus 43%, RR 1.18 [95% CI 1.03-1.37]), particularly spontaneous preterm delivery (37% versus 28%; RR 1.30 [95% CI 1.09-1.55]) and very preterm birth (<32 weeks) (14% versus 8%, RR 1.62 [95% CI 1.10-2.37]). Twins of PCOS mothers had more often low birthweight (48% versus 39%, adjusted RR 1.40 [95% CI 1.09-1.80]). This difference disappeared when adjusting for gestational age. No risk difference was found for caesarean section, pre-eclampsia, low 5-minute Apgar score or perinatal mortality. The risk of preterm delivery in twin pregnancies is increased by having a PCOS diagnosis. This should be considered in risk estimation and antenatal follow-up of twin pregnancies.