Reduced Foxo3a, FoxL2, and p27 mRNA expression in human ovarian tissue in premature ovarian insufficiency.

PURPOSE: Previous studies have suggested that deletion of Foxo3a, FoxL2, PTEN, p27, and AMH leads to early exhaustion of the primordial follicle pool and premature ovarian insufficiency (POI) in transgenic mice. Our aim was to assess for the first time, to our knowledge, messenger RNA (mRNA) expression of these genes and AMHR2 in human ovarian tissue from women with POI. We hypothesized that these genes would be underexpressed in POI women compared with healthy controls. METHODS: mRNA levels were evaluated by quantitative reverse transcription-polymerase chain reaction and real-time polymerase chain reaction in cortical ovarian tissue obtained by laparoscopy from Caucasian Greek women with POI (n = 5) and healthy women with normal menstruation (n = 6). Morphological analysis of the ovarian biopsies was also performed to assess the presence of primordial or other types of growing follicles. RESULTS: Ovarian tissue from POI patients showed lower Foxo3a, FoxL2, and p27 mRNA expression compared with controls (p = 0.017, p = 0.017, and p = 0.030, respectively). mRNA expression of AMH, PTEN, and AMHR2 was reduced in ovarian biopsies from POI patients as well. However, these differences were not statistically significant (p = 0.143, p = 0.247, and p = 0.662, respectively). Morphological analysis showed complete lack of follicular structures in all POI biopsies. CONCLUSIONS: Our findings suggest a possible role of Foxo3a, FoxL2, and p27 in the pathogenesis of human POI, which may prove to be of great diagnostic-therapeutic value. Further larger studies are needed to identify a similar pattern for AMH, PTEN, and AMHR2 and to investigate gene expression at a protein level.

Implementation of HPV-based Cervical Cancer Screening Combined with Self-sampling Using a Midwifery Network Across Rural Greece: The GRECOSELF Study.

Self-sampling for human papillomavirus (HPV) testing is an alternative to physician sampling particularly for cervical cancer screening nonattenders. The GRECOSELF study is a nationwide observational cross-sectional study aiming to suggest a way to implement HPV-DNA testing in conjunction with self-sampling for cervical cancer screening in Greece, utilizing a midwifery network. Women residing in remote areas of Greece were approached by midwives, of a nationwide network, and were provided with a self-collection kit (dry swab) for cervicovaginal sampling and asked to answer a questionnaire about their cervical cancer screening history. Each sample was tested for high-risk (hr) HPV with the Cobas HPV test. HrHPV-Positive women were referred to undergo colposcopy and, if needed, treatment according to colposcopy/biopsy results. Between May 2016 and November 2018, 13,111 women were recruited. Of these, 12,787 women gave valid answers in the study questionnaire and had valid HPV-DNA results; hrHPV prevalence was 8.3%; high-grade cervical/vaginal disease or cancer prevalence was 0.6%. HrHPV positivity rate decreased with age from 20.7% for women aged 25-29 years to 5.1% for women aged 50-60 years. Positive predictive value for hrHPV testing and for HPV16/18 genotyping ranged from 5.0% to 11.6% and from 11.8% to 27.0%, respectively, in different age groups. Compliance to colposcopy referral rate ranged from 68.6% (for women 25-29) to 76.3% (for women 40-49). For women residing in remote areas of Greece, the detection of hrHPV DNA with the Cobas HPV test, on self-collected cervicovaginal samples using dry cotton swabs, which are provided by visiting midwives, is a promising method for cervical cancer secondary prevention.

Correction to: Reduced Foxo3a, FoxL2, and p27 mRNA expression in human ovarian tissue in premature ovarian insufficiency.

The original version of this article, published 21 October 2019, unfortunately contained a mistake. The presentation of Fig. 1 was incorrect. The corrected figure is given below.

The curious case of premature luteinization.

PURPOSE: Premature luteinization (PL) affects 12.3-46.7% of fresh in vitro fertilization cycles, and there is accumulating evidence confirming its negative effect on success rates. However, despite its clinical significance, PL is poorly understood and defined. This narrative review aims to provide a fresh look at the phenomenon of PL by summarizing the existing evidence and re-evaluating fundamental issues. METHODS: A thorough electronic search was conducted covering the period from 1978 until January 2018 in PubMed, Embase, and Medline databases, and references of relevant studies were cross-checked. Meeting proceedings of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine were also hand searched. RESULTS: In the curious case of PL, one should go back to the beginning and re-consider every step of the way. The pathogenesis, definition, measurement methods, clinical implications, and management strategies are discussed in detail, highlighting controversies and offering "food for thought" for future directions. CONCLUSIONS: Authors need to speak the same language when studying PL in order to facilitate comparisons. The terminology, progesterone cut-off, measurement methods and days of measurement should be standardized and globally accepted; otherwise, there can be no scientific dialog. Future research should focus on specific patient profiles that may require a tailored approach. Progesterone measurements throughout the follicular phase possibly depict the progesterone exposure better than an isolated measurement on the day of hCG. Adequately powered randomized controlled trials should confirm which the best prevention and management plan of PL is, before introducing any strategy into clinical practice.

The Impact of Adenomyosis on Women's Fertility.

Until recently, adenomyosis has been associated with multiparity, not impaired fertility. Currently, adenomyosis is diagnosed with increasing frequency in infertile patients since women delay their first pregnancy until their late 30s or early 40s. Although an association between adenomyosis and infertility has not been fully established, based on the available information, recent studies suggested that adenomyosis has a negative impact on female fertility. Several uncontrolled studies with limited data also suggested that treatment of adenomyosis may improve fertility. This article discusses (i) the hypothesis and epidemiology of adenomyosis, (ii) diagnostic techniques, (iii) clinical evidence of correlation between adenomyosis and infertility, (iv) proposed mechanism of infertility in women with adenomyosis, (v) different treatment strategies and reproductive outcomes, and (vi) assisted reproductive technology outcome in women with adenomyosis.

Intertwin estimated fetal weight or crown rump length discordance and adverse perinatal outcome.

AIM: In the current review study, we present recent data regarding the importance of intertwin estimated fetal weight (EFW) and crown rump length (CRL) discordance for the prediction of adverse perinatal outcome both in monochorionic and in dichorionic diamniotic gestations. RESULTS: Twins with significant weight disparity are associated with higher rates of perinatal morbidity and mortality, regardless of gestational age at delivery. However, there is no agreement regarding as to the cut off value above which the perinatal outcome is unfavorably affected and the threshold range from 10 to 30%. On the other hand, CRL discrepancy has proved to be a weak predictor of adverse outcomes, such as fetal or neonatal death in fetuses without chromosomal and structural abnormalities. In clinical practice, decisions about obstetric surveillance of discordant twin gestations, frequency of fetal sonographic monitoring and time of delivery are usually based on amniotic fluid volume and Doppler assessments on a weekly basis. CONCLUSION: Significant EFW discordance leads to adverse perinatal outcome, although the cut-off value has not yet been estimated. CRL discrepancy is not correlated well with adverse perinatal outcome. However, increased monitoring of women with EFW and CRL discrepancy is suggested.

Current treatment of endometrioma.

IMPORTANCE: Ovarian endometrioma is the most common form of endometriosis. Laparoscopy is frequently chosen for its treatment because medical treatment alone is inadequate. However, the role of laparoscopic treatment of ovarian endometriomas has been challenged by evidence questioning the benefits of surgery, especially in cases of young or infertile women. Other therapeutic modalities include expectant management, medical therapy, and, in cases of infertility, ovulation induction and assisted reproductive technology. None of these treatments offer cure of endometriosis. OBJECTIVE: The objective of this study was to present data concerning the current management of endometrioma. Benefits and complications after treatment and the impact on in vitro fertilization outcome are also highlighted. EVIDENCE ACQUISITION: An extensive literature search (PubMed) and Cochrane Library review up to December 2013 were performed using the following keywords: "endometrioma," "cystectomy," "infertility," "IVF," "malignant transformation," "management," and "recurrence." RESULTS: There is a lack of data from randomized trials to inform the optimal management of endometriomas with respect to pain relief, recurrence, and fertility. CONCLUSIONS AND RELEVANCE: Further studies are needed to determine the optimal management of endometrioma. Currently, there is no evidence that surgical management improves the fertility of women with endometrioma.

Spontaneous uterine rupture in a primigravid woman in the early third trimester attributed to adenomyosis: a case report and review of the literature.

We report a rare case of spontaneous uterine rupture of an unscarred uterus caused by adenomyosis in the early third trimester. A 33-year-old primigravid woman was referred to our department because of severe acute abdominal pain and signs and symptoms of hemorrhagic shock. Ultrasound exanimation performed at admission revealed a living, intrauterine fetus of 28 weeks gestational age with reduced amniotic fluid and presence of free peritoneal fluid. The fetal heart rate was non-reassuring with variable decelerations and severe fetal bradycardia. Emergency cesarean section revealed massive hemoperitoneum and complete rupture in the uterine fundus. Subtotal peripartum hysterectomy with conservation of adnexae was performed. Histological examination revealed adenomyosis at the site of uterine rupture.

A case of severe ADAMTS13 deficiency presenting as thrombotic thrombocytopenic purpura in pregnancy.

INTRODUCTION: Thrombotic thrombocytopenic purpura is a rare life-threatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by the absent or severe deficiency of the von Willebrand Factor-cleaving protease named ADAMTS13. Pregnancy is a well recognized factor precipitating the appearance of the disease both in women that had reduced levels of ADAMTS13 activity prior to gestation and in those with other inherited or acquired thrombophilic syndromes. CASE REPORT: We report a 25-year old woman with severe ADAMTS13 deficiency presented early in her 1st pregnancy and relapsed in two subsequent gestations. This presentation is uncommon for thrombotic thrombocytopenic purpura is associated with pregnancy (ADAMTS13 deficiency < 5%, without an inhibitor). In the first pregnancy she started with daily plasma exchange 1.5 x volume, corticosteroids and IV immunoglobulin and finally entered remission after 23 sessions and termination of pregnancy. In the second pregnancy she did not receive prophylactic treatment and relapsed in the 3rd trimester. Prophylactic treatment during the third pregnancy with plasma infusions proved also ineffective to prevent relapse. DISCUSSION: Many issues regarding treatment and prevention of thrombotic thrombocytopenic purpura relapses in subsequent pregnancies are unclear. Proposed guidelines recommend that the same treatment should be performed on pregnant and non pregnant patients without modification of plasma replacement dose according to ADAMTS13 levels. In addition, many authors suggest that pregnant patients with history of thrombotic thrombocytopenic purpura and severe deficiency of ADAMTS13 levels should received prophylactic treatment for prevention of relapses in the subsequent pregnancies. CONCLUSION: Severe ADAMTS 13 deficiency may present as thrombotic thrombocytopenic purpura of pregnancy. Pregnant women with thrombotic thrombocytopenic purpura and especially with severe deficiency of ADAMTS13 levels require specific consideration regarding treatment and prophylaxis in subsequent pregnancies.

Association of estrogen receptor alpha (ERα) gene polymorphisms with endometrial thickness and lipid profile in women with breast cancer treated with aromatase inhibitors.

Aromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for post-menopausal, hormone-receptor positive breast cancer patients. The aim of the present study was to evaluate the effect of PvuII and XbaI polymorphisms of the ERα gene at ΑΙs treatment's adverse effects in post-menopausal women with breast cancer. The study included 87 post-menopausal women with ER-positive breast cancer treated with AIs and 80 healthy controls. The overall presence of ERα polymorphisms in all women with breast cancer was not different from the healthy controls. Endometrial thickness under AIs treatment was reduced from (mean value ± SD) 6,404 ± 2,901 mm to 3,666 ± 1,4656 mm. Moreover, the AA XbaI genotype was associated with greater reduction in endometrial thickness during therapy with AIs (p = 0.005). The presence of the CC PvuII and the AA XbaI genotypes were associated with elevated LDL levels and elevated triglycerides. In conclusion, the results of the present study showed that the genotype of women with breast cancer under AIs treatment might influence treatment's adverse effects, as, the presence of the CC PvuII and the AA XbaI genotypes of the ERα were associated with elevated LDL and triglycerides serum levels, while the AA XbaI genotype was associated with a greater reduction in endometrial thickness.

The role of NF-kappaB in endometriosis.

The nuclear factor kappaB (NF-kappaB) is a ubiquitously expressed transcription factor playing vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. This review highlights the importance of NF-kappaB in the pathophysiology of endometriosis. Constitutive activation of NF-kappaB has been shown in endometriotic lesions. Complex interactions of NF-kappaB with steroid receptors and apoptotic molecules in endometriosis resulting in opposing roles of NF-kappaB are discussed. NF-kappaB regulates the expression of cytokines mediating autocrine self-amplifying cycles of cytokine release and NF-kappaB activation, leading to maintenance of inflammatory reactions in endometriosis. NF-kappaB can contribute to the increased ability of endometriotic cells to invade and adhere to the peritoneal surface by regulating the expression of matrix metaloproteinases. We are presenting the role of NF-kappaB to regulate vascularization and oxidative stress in endometriotic cells. Effects of drugs used for the treatment of endometriosis on NF-kappaB pathway are presented and we show how drugs that inhibit the NF-kappaB can mediate the progression of endometriosis. Novel therapeutic strategies involving the NF-kappaB and applied in endometriosis are also discussed.

Increased plasma viscosity in young women with polycystic ovary syndrome using an oral contraceptive containing 35 µg ethinyl estradiol and 2 mg cyproterone acetate.

OBJECTIVES: To investigate the influence of 6 months of treatment with an oral contraceptive (OC) containing 35 µ g ethinyl estradiol and 2 mg cyproterone acetate on plasma viscosity (PV) in young women with polycystic ovary syndrome (PCOS). DESIGN: Patients with PCOS were assessed for PV before and after 6 months of treatment with an OC containing 35 µg ethinyl estradiol and 2 mg cyproterone acetate. PV was determined by a viscometer Type 53610/I SCHOTT-Instruments, Mainz at 37°C. SETTINGS: Subjects were recruited from the Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology at the University Hospital of Patras, Greece. PATIENTS: The study included 66 young women with PCOS. MAIN OUTCOME MEASURES: PV. RESULTS: In PCOS women as a whole, PV at baseline was 1.249 ± 0.049 mm(2)/s (n = 66). After 6 months of treatment with an OC containing 35 µg ethinyl estradiol and 2 mg cyproterone acetate, PV was increased to 1.268 ± 0.065 mm(2)/s (p = 0.038). The difference between PV before and after 6 months of treatment with an OC containing 35 µg ethinyl estradiol and 2 mg cyproterone acetate (Δviscosity) was 0.01864 ± 0.071452 mm(2)/s. ΔViscosity was related to ?fibrinogen (r = 0.270, p = 0.046), to Δhematocrit (r = 0.514, p = 0.09) and to Δtriglycerides (r = 0.292, p = 0.021). CONCLUSION: Young women with PCOS presented an increased PV under OC treatment with 35 µg ethinyl estradiol and 2 mg cyproterone acetate.

The importance of venous Doppler velocimetry for evaluation of intrauterine growth restriction.

The management of growth-restricted fetuses requires accurate diagnosis to optimize the timing of delivery. Doppler velocimetry is the only noninvasive method for assessing the fetoplacental hemodynamic status. This review will give a critical overview of the current knowledge on fetal venous blood flow in pregnancies complicated by in-trauterine growth-restricted fetuses. Adaptation of the circulation in intrauterine growth-restricted fetuses is described. Normal and abnormal venous Doppler waveforms are presented. Correlations of abnormal waveforms with the presence of acidemia and perinatal outcomes are emphasized. Limitations of venous Doppler velocimetry for optimizing the time for delivery and the perinatal outcome are also presented.

The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia.

OBJECTIVE: To assess the impact of metformin and of two different oral contraceptives (OCs) containing cyproterone acetate and drospirenone, on serum anti-Müllerian hormone (AMH) levels, in a cohort of women with polycystic ovary syndrome (PCOS) with hyperandrogenism. DESIGN: Prospective randomised study. SETTING: Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki. PATIENTS: Forty-five (45) women with PCOS diagnosed according to the criteria proposed in 1990 by the NIH. INTERVENTIONS: Women with PCOS were randomised into three groups, all treated for 6 months: Group A received an OC containing 35 µg ethinylestradiol plus 2 mg cyproterone acetate, Group B received an OC containing 30 µg ethinylestradiol plus 3 mg drospirenone and Group C received metformin 850 mg × 2. Main outcome measure(s). Anti-Müllerian hormone levels were measured by a specific ELISA. RESULTS: AMH was significantly decreased under treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate (p = 0.002 at 3 months and p < 0.001 at 6 months). Treatment with 30 µg ethinylestradiol plus 3 mg drospirenone, and treatment with metformin 850 mg × 2 did not significantly affect serum AMH levels. AMH was significantly decreased under OCs treatment compared to metformin 850 mg × 2 (p = 0.005). CONCLUSION(S): AMH serum levels were significantly decreased under treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins.

Prediction of respiratory failure in late-preterm infants with respiratory distress at birth.

The aim of this study was to evaluate indices of respiratory failure in terms of their ability to predict respiratory impairment and need for ventilatory support in late-preterm neonates with respiratory distress. Arterial blood gas data during the first 12 postnatal hours or until intubation were recorded in 155 neonates with gestational age 34(0/7)-36(6/7) weeks admitted in the NICU with respiratory distress between January 2006 and June 2008. Alveolar-arterial oxygen tension difference (A-aDO(2)), arterial to alveolar oxygen tension ratio (a/A ratio), and partial arterial oxygen tension to inspired oxygen fraction ratio (PaO(2)/FiO(2)) were calculated. Considering the worst single value of each parameter, receiver operating characteristic curve analyses and area under the curve (AUC) comparisons were used to evaluate their predictive performance. Fifty-five neonates (35.5%) required mechanical ventilation. The predictive performances of the maximum A-aDO(2) (AUC 0.97), minimum a/A ratio (AUC 0.95), and minimum PaO(2)/FiO(2) (AUC 0.95) were similar. The A-aDO(2) at a threshold of >200 mmHg proved to be more effective than the other parameters, having excellent positive and negative likelihood ratios of 24.5 and 0.02, respectively. This threshold was achieved by 98.25% of the neonates who developed respiratory failure at a median of 3 h before the ventilatory support to be definitely decided. Composite indices, such as A-aDO(2), a/A ratio, and PaO(2)/FiO(2), can reasonably predict respiratory failure in late-preterm neonates with respiratory distress, allowing for closer monitoring, early medical intervention, or transfer to a level III neonatal unit.

Determinants of morbidity in late preterm infants.

OBJECTIVE: To assess the effect of selected maternal medical conditions and complications of pregnancy on the risk for morbidity among late preterm neonates. DESIGN: Prospective cohort study. MATERIAL AND METHODS: A total of 548 late preterm neonates (34(0/7) to 36(6/7)weeks' gestation) delivered from August 2006 to July 2009, were included. Information regarding demographics, gestational age, mode of delivery, maternal age and parity, pre-existing medical conditions and complications of pregnancy were obtained and associated with neonatal morbidity, both independently and as joint exposures. Newborn morbidity was defined by combining specific diagnoses, length of hospital stay, and transfer to the Neonatal Intensive Care Unit. RESULTS: Overall, 165 (30.1%) of the late preterm infants suffered from morbidity. The morbidity rates were 16.8% at 36 weeks' gestation, and then approximately doubled from 38.2% at 35 weeks to 59.7% at 34 weeks. The joint effect of gestational age (OR 8.43 for 34 weeks and 3.60 for 35 weeks' gestation), small for gestational age (SGA) (OR 4.18), multiple gestation (OR 3.68) and lack of antenatal steroid administration (OR 4.03), was greater than the independent effect of each of these factors, and greater than additive. Emergency caesarean section (OR 1.43) and antepartum haemorrhage (OR 3.07) were also associated with a significant impact on neonatal morbidity. CONCLUSIONS: The risk for morbidity among late preterm infants, changes with each passing week of gestation. This risk seems to be intensified, when other exposures such as SGA, multiple gestation, emergency caesarean section, lack of antenatal steroid administration and antepartum haemorrhage, are also present.

Decreased active, total and altered active to total ghrelin ratio in normal weight women with the more severe form of polycystic ovary syndrome.

OBJECTIVE: To assess total, active and active to total serum ghrelin ratio in normal weight women with polycystic ovary syndrome (PCOS) and in healthy ovulatory control women. STUDY DESIGN: The study included 50 normal weight women with PCOS with a mean age of 23.70+/-4.99 years and 10 control women with a mean age of 30+/-5.80 years. The diagnosis of PCOS was based on the presence of biochemical hyperandrogenemia, chronic anovulation and polycystic ovarian morphology according to the Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Serum total and active ghrelin were measured by RIA, using commercially available kits. RESULTS: A significantly lower serum active/total ghrelin ratio was noted in the more severe form of PCOS with hyperandrogenemia, chronic anovulation and polycystic ovarian morphology. Both total and active serum ghrelin levels were negatively correlated to hirsutism score, to plasma glucose levels and to QUICKI and HOMA-IR indices of Insulin Resistance. A statistically significant difference was detected between the more severe and the milder forms of PCOS, concerning serum levels of total ghrelin (p=0.017), active ghrelin (p=0.007) and the active/total ghrelin ratio (p=0.026). CONCLUSIONS: The results of the present study demonstrate an altered active to total ghrelin ratio, as well as a tendency towards lower both total and active fasting serum ghrelin levels in normal weight PCOS, more pronounced in the more severe forms of the syndrome.

No association of the G972S polymorphism of the insulin receptor substrate-1 gene with polycystic ovary syndrome in lean PCOS women with biochemical hyperandrogenemia.

PURPOSE: The aim of the present study was to determine the prevalence and association of the G972S polymorphism of the insulin receptor substrate-1 gene (IRS-1 G972S SNP) with polycystic ovary syndrome (PCOS) and insulin resistance-related traits in a distinct phenotypic group of lean PCOS women with biochemical hyperandrogenemia, excluding obesity, which is considered to be an aggravating parameter of insulin resistance. METHODS: The study included 162 women with PCOS and 122 regularly menstruating, ovulatory women as controls. Physical measurements included weight, height, fat-free mass, fat mass, systolic and diastolic blood pressure and resting heart rate. Biochemical parameters included the serum testosterone, free testosterone, androstenedione, total cholesterol, triglycerides, HDL and LDL cholesterol and glucose levels. Insulin resistance was assessed by determining fasting insulin levels, fasting glucose levels, the fasting glucose/insulin ratio, as well as the HOMA and QUICKI indexes. All DNA samples were genotyped by a PCR-restriction fragment length polymorphism (RLFP) assay. RESULTS: No association of the genotype frequencies of the G972S polymorphism in insulin receptor substrate-1 gene (IRS-1 G972S SNP) with PCOS phenotype and insulin resistance was detected. CONCLUSION: The G972S polymorphism of the IRS-1 gene should not be viewed as major contributor to the development of PCOS or as a causative variant for insulin resistance.