The expression pattern of endometrial receptivity genes is desynchronized between endometrium and matched endometriomas.

RESEARCH QUESTION: Are paired samples of endometrium and ovarian endometriomas synchronous with each other throughout the menstrual cycle? DESIGN: The expression levels of 57 endometrial receptivity-associated genes were determined from matched endometrial and endometrioma samples (n=31) collected from women with endometriosis throughout the menstrual cycle. RESULTS: The expression profile of endometrial receptivity genes divided endometrial samples according to their menstrual cycle phase. Endometrioma samples grouped together irrespective of the menstrual cycle phase and formed a cluster distinct from endometrial samples. Pairwise comparison showed 21, 16, 33 and 23 differentially expressed genes (adjusted P < 0.001-0.05) between the lesions and endometria collected in the proliferative, early-secretory, mid-secretory and late-secretory menstrual cycle phases, respectively, confirming the distinct expression profiles of endometrium and endometrioma. CONCLUSIONS: No menstrual cycle synchronicity was found between matched eutopic and ectopic endometrium, suggesting that the concept of cycling endometrial tissue inside the endometrioma should be revised.

What do we know about the impact of sexual violence on health and health behaviour of women in Estonia?

BACKGROUND: Sexual violence against women is a major public health issue and a breach of human rights. Although various consequences of sexual violence on health have been described in a large number of scientific publications, very little is known about this topic in Estonia. The aim of this study was to examine the prevalence of sexual violence and associations between exposure to sexual violence and risky health and sexual behaviours among women in Estonia. METHODS: A population-based cross-sectional study was carried out in Estonia in 2014. Self-reported data regarding selected indicators of risky health and sexual behaviours were collected from 1670 women, aged 18-44 years, via a self-administered questionnaire. To measure the prevalence of sexual violence, questions from the NorVold Abuse Questionnaire were included. Chi-square and multivariate logistic regression were used to analyse the data. RESULTS: Of the respondents, 22.7% (n = 379) reported being exposed to sexual violence during their lifetime, and over half of these women had had these experiences before the age of 18. Statistically significant associations were found between sexual violence and smoking (adjusted odds ratio (AOR) 1.32, 95% CI 1.03-1.70), alcohol consumption (AOR 1.52, 95% CI 1.18-1.95), illicit drug use (AOR 2.21, 95% CI 1.70-2.89), sexual intercourse for money or other material reward (AOR 3.51, 95% CI 1.62-7.61), concurrent sexual relationships (AOR 2.64; 95% CI 1.80-3.86), and being diagnosed with sexually transmitted infections (AOR 1.48, 95% CI 1.09-2.01). CONCLUSIONS: In Estonia, sexual violence against women is widespread and is associated with several risky health and sexual behaviours. Efforts should be made, both among the general public and professionals, to raise awareness regarding the prevalence and negative impact of sexual violence. Women who have been exposed to sexual violence are in need of professional medical, legal and psychological help free from prejudice to help them recover from such traumatic events.

Awareness of polycystic ovary syndrome among obstetrician-gynecologists and endocrinologists in Northern Europe.

OBJECTIVE: To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia. METHODS: This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015-2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS. RESULTS: Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6-8.1) or metformin (OR = 5.0, CI 2.5-10.2), but less frequently OCP (OR = 0.5, CI 0.2-0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged <35 years were 2.2 times (95% CI 1.1-4.3) more likely than older physicians to recommend lifestyle management for patients with PCOS for fertility concerns. Physicians aged 46-55 years were less likely to recommend oral contraceptive pills (OCP) for patients with PCOS than physicians aged >56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2-0.8). CONCLUSION: Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed.

Differentially-Expressed miRNAs in Ectopic Stromal Cells Contribute to Endometriosis Development: The Plausible Role of miR-139-5p and miR-375.

microRNA (miRNA) expression level alterations between endometrial tissue and endometriotic lesions indicate their involvement in endometriosis pathogenesis. However, as both endometrium and endometriotic lesions consist of different cell types in various proportions, it is not clear which cells contribute to variability in miRNA levels and the overall knowledge about cell-type specific miRNA expression in ectopic cells is scarce. Therefore, we utilized fluorescence-activated cell sorting to isolate endometrial stromal cells from paired endometrial and endometrioma biopsies and combined it with high-throughput sequencing to determine miRNA alterations in endometriotic stroma. The analysis revealed 149 abnormally expressed miRNAs in endometriotic lesions, including extensive upregulation of miR-139-5p and downregulation of miR-375 compared to eutopic cells. miRNA transfection experiments in the endometrial stromal cell line ST-T1b showed that the overexpression of miR-139-5p resulted in the downregulation of homeobox A9 (HOXA9) and HOXA10 expression, whereas the endothelin 1 (EDN1) gene was regulated by miR-375. The results of this study provide further insights into the complex molecular mechanisms involved in endometriosis pathogenesis and demonstrate the necessity for cell-type-specific analysis of ectopic tissues to understand the interactions between different cell populations in disease onset and progression.

Knowledge and Practices Regarding Polycystic Ovary Syndrome among Physicians in Europe, North America, and Internationally: An Online Questionnaire-Based Study.

BACKGROUND: To inform knowledge translation by identifying evidence-practice gaps in polycystic ovary syndrome (PCOS) care and variations between disciplines and across world regions via an online, anonymous, devised questionnaire distributed via professional societies and completed by 1,495 physicians (2015-2016). METHODS: Multivariable logistic regression analyses generated adjusted odds ratios (OR) and 95% confidence intervals (CI) for associations between outcome measures and world region, specialty, annual patients with PCOS, age, and sex. RESULTS: Features corresponding to Rotterdam diagnostic criteria were well recognized (e.g., irregular menstrual cycles by 99% of physicians), but psychological implications were recognized only by 29 to 64%. Reproductive endocrinologists were more likely to use Rotterdam diagnostic criteria (OR: 3.1; 95% CI: 2.3-4.3; p < 0.007) than obstetrician-gynecologists. Reproductive (OR: 2.0; 95% CI: 1.5-2.8; p < 0.007) and medical endocrinologists (OR: 3.1; 95% CI: 1.7-5.7; p < 0.007) were more likely to recommend lifestyle management than obstetrician-gynecologists. Physicians in Europe (OR: 4.7; 95% CI: 3.5-6.1; p < 0.007) and other regions (OR: 4.0; 95% CI: 2.8-5.9; p < 0.007) were more likely to use Rotterdam diagnostic criteria than physicians in North America. CONCLUSION: Knowledge gaps in PCOS care to be addressed internationally include physician awareness of the breadth of PCOS features, application of diagnostic criteria, and recommending lifestyle management effectively.

High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium.

The aetiology of endometriosis is still unclear and to find mechanisms behind the disease development, it is important to study each cell type from endometrium and ectopic lesions independently. The objective of this study was to uncover complete mRNA profiles in uncultured stromal cells from paired samples of endometriomas and eutopic endometrium. High-throughput mRNA sequencing revealed over 1300 dysregulated genes in stromal cells from ectopic lesions, including several novel genes in the context of endometriosis. Functional annotation analysis of differentially expressed genes highlighted pathways related to cell adhesion, extracellular matrix-receptor interaction and complement and coagulation cascade. Most importantly, we found a simultaneous upregulation of complement system components and inhibitors, indicating major imbalances in complement regulation in ectopic stromal cells. We also performed in vitro experiments to evaluate the effect of endometriosis patients' peritoneal fluid (PF) on complement system gene expression levels, but no significant impact of PF on C3, CD55 and CFH levels was observed. In conclusion, the use of isolated stromal cells enables to determine gene expression levels without the background interference of other cell types. In the future, a new standard design studying all cell types from endometriotic lesions separately should be applied to reveal novel mechanisms behind endometriosis pathogenesis.

The influence of menstrual cycle and endometriosis on endometrial methylome.

BACKGROUND: Alterations in endometrial DNA methylation profile have been proposed as one potential mechanism initiating the development of endometriosis. However, the normal endometrial methylome is influenced by the cyclic hormonal changes, and the menstrual cycle phase-dependent epigenetic signature should be considered when studying endometrial disorders. So far, no studies have been performed to evaluate the menstrual cycle influences and endometriosis-specific endometrial methylation pattern at the same time. RESULTS: Infinium HumanMethylation 450K BeadChip arrays were used to explore DNA methylation profiles of endometrial tissues from various menstrual cycle phases from 31 patients with endometriosis and 24 healthy women. The DNA methylation profile of patients and controls was highly similar and only 28 differentially methylated regions (DMRs) between patients and controls were found. However, the overall magnitude of the methylation differences between patients and controls was rather small (Δß ranging from -0.01 to -0.16 and from 0.01 to 0.08, respectively, for hypo- and hypermethylated CpGs). Unsupervised hierarchical clustering of the methylation data divided endometrial samples based on the menstrual cycle phase rather than diseased/non-diseased status. Further analysis revealed a number of menstrual cycle phase-specific epigenetic changes with largest changes occurring during the late-secretory and menstrual phases when substantial rearrangements of endometrial tissue take place. Comparison of cycle phase- and endometriosis-specific methylation profile changes revealed that 13 out of 28 endometriosis-specific DMRs were present in both datasets. CONCLUSIONS: The results of our study accentuate the importance of considering normal cyclic epigenetic changes in studies investigating endometrium-related disease-specific methylation patterns.

Pregnancy rate in endometriosis patients according to the severity of the disease after using a combined approach of laparoscopy, GnRH agonist treatment and in vitro fertilization.

AIM: To evaluate the effects of combined treatment approaches on endometriosis-associated infertility in different stages of endometriosis using laparoscopy, gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and in vitro fertilization (IVF). METHODS: This retrospective study was carried out on 179 women with surgically confirmed endometriosis. Patients were divided into subgroups: group 1 (stage I-II, n = 121) and group 2 (stage III-IV, n = 58). Patients eligible for IVF, who were found to have adenomyosis or moderate to severe endometriosis, were also given postoperative GnRHa. Pregnancy and delivery rates were cumulatively calculated during 5 years according to the severity of the disease. RESULTS: The overall pregnancy, delivery and miscarriage rates were 66.5, 56.4 and 15.1%, respectively, for all patients following spontaneous and assisted conception. There were no significant differences in reproductive outcomes between the study groups. The pregnancy and delivery rates were also comparable within group 1 between the patients with and without GnRHa treatment. CONCLUSION: Pregnancy and delivery rates at different stages of endometriosis were not affected by the different approaches used for infertility treatment, with >60 and >50% of patients having conceived and delivered a baby, respectively, in both groups. The usefulness of GnRHa treatment for endometriosis patients with minimal to mild forms is questionable and deserves further studies.

High-throughput sequencing approach uncovers the miRNome of peritoneal endometriotic lesions and adjacent healthy tissues.

Accumulating data have shown the involvement of microRNAs (miRNAs) in endometriosis pathogenesis. In this study, we used a novel approach to determine the endometriotic lesion-specific miRNAs by high-throughput small RNA sequencing of paired samples of peritoneal endometriotic lesions and matched healthy surrounding tissues together with eutopic endometria of the same patients. We found five miRNAs specific to epithelial cells--miR-34c, miR-449a, miR-200a, miR-200b and miR-141 showing significantly higher expression in peritoneal endometriotic lesions compared to healthy peritoneal tissues. We also determined the expression levels of miR-200 family target genes E-cadherin, ZEB1 and ZEB2 and found that the expression level of E-cadherin was significantly higher in endometriotic lesions compared to healthy tissues. Further evaluation verified that studied miRNAs could be used as diagnostic markers for confirming the presence of endometrial cells in endometriotic lesion biopsy samples. Furthermore, we demonstrated that the miRNA profile of peritoneal endometriotic lesion biopsies is largely masked by the surrounding peritoneal tissue, challenging the discovery of an accurate lesion-specific miRNA profile. Taken together, our findings indicate that only particular miRNAs with a significantly higher expression in endometriotic cells can be detected from lesion biopsies, and can serve as diagnostic markers for endometriosis.

Elevated blood plasma antioxidant status is favourable for achieving IVF/ICSI pregnancy.

The aim of the study was to determine the roles of intrafollicular and systemic oxidative stress and antioxidant response in ovarian stimulation and intracytoplasmic sperm injection (ICSI) outcomes. For this purpose, 102 ICSI patients undergoing controlled ovarian stimulation were enrolled and samples were collected on the day of follicle puncture. Total peroxide (TPX) concentrations and total antioxidant response (TAR) were measured in follicular fluid and blood plasma, and an oxidative stress index (OSI) was calculated based on these two parameters. Urinary concentrations of 8-iso-prostaglandin F2a (F2IsoP) were measured. Elevated intrafollicular oxidative stress was positively correlated with ovarian stimulation outcome: less FSH per retrieved oocyte was used, more oocytes were collected and higher serum oestradiol concentrations were measured in patients with higher follicular OSI. However, high urinary F2IsoP related to lower embryo quality and F2IsoP was also elevated in smoking patients. Patients with endometriosis had lower follicular antioxidant status. Most importantly, higher systemic blood TAR was significantly favourable for achieving clinical pregnancy (P=0.03). In conclusion, the findings suggest clear associations between oxidative stress, antioxidant status and several aspects of ovarian stimulation and IVF/ICSI outcome, including pregnancy rate. Several oxygen-dependent biochemical reactions produce reactive oxygen species as by-products that may eventually lead to oxidative stress, which is detrimental to cells and tissues. Total antioxidant status, on the other hand, comprises several agents that balance the excess of these reactive oxygen species and reduce potential damage to the body. The aim of the current work was to study this balance in 102 patients participating in an ICSI programme and to examine the degree to which total peroxide content and antioxidant status influence infertility and pregnancy outcome. During the study, several tests were performed to characterize oxidative stress levels in ovarian follicular fluid, blood plasma and urine. We found a significantly higher oxidative stress environment in the ovary when compared with blood plasma. This suggests a prominent role of oxidative stress in the ovaries of these patients. The elevated oxidative stress levels were correlated to a higher number of oocytes that could be obtained via the procedure and to a lower amount of FSH needed to mature the oocytes, suggesting that oxidative stress, to some degree, is favourable for hormone stimulation outcome. A high level of lipid peroxidation products in the urine, another marker of oxidative stress, was observed in smokers and this marker was elevated in patients with embryos that had lower developmental potential. A higher overall antioxidant status in blood plasma was advantageous for achieving pregnancy.

Survivin promoter polymorphisms and autoantibodies in endometriosis.

Expression of survivin, an inhibitor of apoptosis, is increased in endometriotic lesions and probably favors the survival of endometrial fragments in the peritoneal cavity. The aim of this study was to evaluate associations between survivin promoter polymorphisms and the risk of endometriosis, as well as to compare the immunoreactivity to survivin in sera of patients with and without endometriosis. We studied 149 women with endometriosis, 196 fertile women from the general population (control group A) and 47 women who had undergone diagnostic laparoscopy and had no evidence of endometriosis (control group B). There were no significant differences in the genotypic distribution of the survivin gene promoter region -241C/T, -235G/A and -31G/C single nucleotide polymorphisms (SNP) between endometriosis patients and the two control groups. In addition, also median anti-survivin autoantibody levels were similar among patients and controls (group B). However, anti-survivin antibody concentrations seemed to be influenced by cigarette smoking, being significantly lower in sera of actively smoking women compared to non-smokers (median OD: 0.019 vs. 0.155, respectively, P<0.001), and by the -235G/A SNP, as A allele carriers were significantly more frequent among women with a high antibody level (OD≥2.0) compared to those with lower concentrations (OD<2.0) (23.1% vs. 4.1%, respectively, P=0.008). Based on these results, we conclude that survivin promoter polymorphisms are not associated with susceptibility to endometriosis in the Estonian population, and though the expression of survivin is increased in endometriotic lesions, autoimmune reactivity against it is similar in women with and without the disease.

Ethnic differences in factors associated with the use of contraception among 20- to 44-year-old women in Estonia and St. Petersburg, Russia.

BACKGROUND: The aim of this study was to explore factors associated with contraception among 20- to 44-year-old women in different ethnic groups in two Eastern European countries. STUDY DESIGN: Data on sexually experienced women in need of contraception taken from population-based cross-sectional surveys, conducted in Estonia (n=1680) and in St. Petersburg (n=798), were analyzed. Factors associated with contraception nonuse or the use of unreliable contraceptive methods were explored using multivariate logistic regression analysis. RESULTS: The age-standardized prevalence rate of contraception nonuse or the use of unreliable contraceptive methods was high (27.3% among Estonian-speaking women in Estonia, 39.9% and 42.5% among Russian-speaking women in Estonia and in St. Petersburg, respectively). Age, economic subsistence, high-risk sexual behavior and smoking did not correlate with contraception nonuse or the use of unreliable contraceptive methods among Russian-speaking women in Estonia and in St. Petersburg; this was in contrast to Estonian-speaking women in Estonia. Previous childbirth and abortion reduced the risk of contraception nonuse or the use of unreliable contraceptive methods among Estonian-speaking women in Estonia (adjusted odds ratio, 0.50; 95% confidence interval [CI], 0.31-0.81) but elevated the risk among Russian-speaking women in St. Petersburg (1.99; 1.17-3.40). Abortion, not previous childbirth, was associated with an increased risk among Russian-speaking women in Estonia (2.94; 1.25-6.95). CONCLUSIONS: The importance of different risk factors associated with contraceptive use varies between different ethnic groups. Cross-national comparisons are essential for the design of public health policies that decrease the burden of sexual ill health.

Gender differences in factors associated with sexual intercourse among Estonian adolescents.

AIMS: To examine factors associated with early sexual intercourse among 15 to 16-year-old adolescents by gender. METHODS: The data were collected from a random sample of Estonian basic schools' ninth grade pupils in 1999 using self-completed questionnaires. A multivariate logistic regression analysis for boys and girls was used to test for associations between sexual intercourse, and personal gender role-related attitudes, attitudes towards sexual intercourse, pubertal timing, smoking status and experience of drunkenness. RESULTS: Of the respondents, 14.6% of boys and 13.1% of girls had experienced sexual intercourse. Traditional gender role-related attitudes were associated with sexual intercourse among girls, but not among boys. Smoking and experience of drunkenness was strongly associated with sexual intercourse for both genders. CONCLUSIONS: Gender differences in the association between gender role-related attitudes and early sexual intercourse were observed among 15 to 16-year-olds in Estonia. Smoking and experience of drunkenness were strongly related to sexual intercourse for both genders.

Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis.

OBJECTIVE: To investigate whether polymorphisms in genes involved in biosynthesis and signalling of sex steroids influence susceptibility to endometriosis and to infertility associated with it. MATERIALS AND METHODS: Patients with endometriosis (n = 150) and fertile controls (n = 199) were genotyped for polymorphisms in oestrogen receptor genes ESR1 (rs2234693 - T/C single nucleotide polymorphism (SNP), dinucleotide (TA)(n) repeat) and ESR2 (dinucleotide (CA)(n) repeat), progesterone receptor gene PGR (rs10895068 - G/A SNP, 306-bp Alu-insertion), 17ß-hydroxysteroid dehydrogenase type 1 gene HSD17B1 (rs605059 - A/G SNP), and aromatase gene CYP19A1 (rs10046 - C/T SNP, (TTTA)(n) tetranucleotide repeat, 3-bp TCT insertion/deletion polymorphism). RESULTS: The HSD17B1 A/G SNP A allele increased overall endometriosis risk and the risk of stage I-II disease, while ESR1 longer (TA)(n) repeats only correlated with susceptibility to stage I-II endometriosis. When considering patients' fertility status, HSD17B1 A/G SNP A allele and ESR1 longer (TA)(n) repeats were associated with endometriosis accompanied by infertility, while ESR2 shorter (CA)(n) repeats were linked with endometriosis without infertility. Other polymorphisms were distributed similarly among patients and controls. CONCLUSIONS: Genetic variants in ESR1, ESR2, and HSD17B1 genes could modify susceptibility to endometriosis and might influence the fertility status in endometriosis patients.

Androgen receptor epigenetic variations influence early follicular phase gonadotropin levels.

OBJECTIVE: we examined the influence of the androgen receptor gene (AR) CAG microsatellite (AR-CAG) repeat polymorphism and X-chromosome inactivation (XCI) pattern on ovarian reserve markers (follicle stimulating hormone (FSH) and antral follicle count on menstrual cycle day 3-5) and disease etiology in patients with polycystic ovarian syndrome (PCOS) or premature ovarian failure (POF). DESIGN: case-control study. Population. In all, 32 women with PCOS, 26 women with POF and 79 controls were investigated. METHODS: AR-CAG and XCI were analyzed using polymerase chain reaction-based assays following DNA digestion with the methylation-sensitive restrictase HpaII. MAIN OUTCOME MEASURES: distribution of AR-CAG alleles and XCI patterns. RESULTS: POF patients had shorter AR-CAG microsatellites than controls. AR-CAG microsatellite length was negatively associated with serum dehydroepiandrosterone sulfate level. The magnitude of XCI skewing was negatively and positively correlated with luteinizing hormone (LH) and FSH serum levels, respectively, during the early follicular phase, but showed no correlation with the number of early antral follicles. CONCLUSIONS: our results suggest that AR-CAG variations and XCI pattern exert an effect on FSH and LH values, and also have the potential to influence the etiopathogenesis of POF.

Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women.

OBJECTIVE: To determine plausible associations between endometriosis and vascular endothelial growth factor gene (VEGF -2578 A/C, -1154 G/A, -634 G/C and 936 C/T), also angiotensin I-converting enzyme gene (ACE -240 A/T and 2350 A/G) single nucleotide polymorphisms (SNPs), as well as their respective haplotypes. STUDY DESIGN: PCR-based restriction fragment length polymorphism analysis was used to detect SNPs in VEGF and ACE genes in 150 Estonian women with endometriosis and 199 control subjects. RESULTS: The CC genotype of the VEGF -2578 A/C SNP was correlated with a decreased risk of endometriosis (OR=0.40, 95% CI 0.20-0.78). Other VEGF and ACE SNPs and haplotypes were not associated with endometriosis. CONCLUSION: This case-control study demonstrated that the VEGF -2578 A/C SNP may influence susceptibility to endometriosis in the Estonian population, while associations between endometriosis and other VEGF and ACE SNPs, as well as the respective haplotypes are unlikely.

Symptom reporting and quality of life in the Estonian Postmenopausal Hormone Therapy Trial.

BACKGROUND: The aim of the study was to determine the effect of postmenopausal hormone therapy on women's symptom reporting and quality of life in a randomized trial. METHODS: 1823 women participated in the Estonian Postmenopausal Hormone Therapy (EPHT) Trial between 1999 and 2004. Women were randomized to open-label continuous combined hormone therapy or no treatment, or to blind hormone therapy or placebo. The average follow-up period was 3.6 years. Prevalence of symptoms and quality of life according to EQ-5D were assessed by annually mailed questionnaires. RESULTS: In the hormone therapy arms, less women reported hot flushes (OR 0.20; 95% CI: 0.14-0.28), sweating (OR 0.56; 95% CI: 0.44-0.72), and sleeping problems (OR 0.66; 95% CI: 0.52-0.84), but more women reported episodes of vaginal bleeding (OR 19.65; 95% CI: 12.15-31.79). There was no difference between the trial arms in the prevalence of other symptoms over time. Quality of life did not depend on hormone therapy use. CONCLUSION: Postmenopausal hormone therapy decreased vasomotor symptoms and sleeping problems, but increased episodes of vaginal bleeding, and had no effect on quality of life. TRIAL REGISTRATION NUMBER: ISRCTN35338757.

Allelic estrogen receptor 1 (ESR1) gene variants predict the outcome of ovarian stimulation in in vitro fertilization.

The outcome of in vitro fertilization (IVF) depends substantially on the effectiveness of controlled ovarian hyperstimulation (COH) induced by administration of follicle-stimulating hormone (FSH). In COH, endogenously produced estrogens extend the action of FSH in stimulating folliculogenesis. We determined the associations between genetic variations in estrogen receptor ESR1 and ESR2 genes and etiology of female infertility, and analysed the influence of these variations on COH outcome-the quantity and quality of oocytes retrieved. ESR1 PvuII T/C (rs2234693) and XbaI A/G (rs9340799) single-nucleotide polymorphisms (SNPs) and (TA)n microsatellite polymorphism, as well as ESR2 RsaI G/A (rs1256049) SNP and (CA)n microsatellite polymorphism were genotyped in 159 IVF patients. The ovarian response to FSH was diminished in patients with endometriosis when compared to tubal factor infertility. ESR1 PvuII and XbaI as well as ESR2 RsaI SNPs were associated with the microsatellite length of the respective genes. Shorter ESR1 (TA)n was linked with a higher risk for unexplained infertility, whereas longer ESR1 (TA)n associated with PvuII*C allele were predictive of a better COH, but not clinical pregnancy outcome in an age-independent manner. These data suggest the variations in ESR1 gene, in addition to the age of a woman, may predict the COH outcome in IVF.

VNTR I/I genotype of insulin gene is associated with the increase of follicle number independent from polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is accompanied by selective insulin resistance and enhanced ovarian steroidogenic effects of insulin. We analysed the minisatellite variations of the insulin gene (INS VNTR) with regard to the clinical features of PCOS. METHODS: Retrospective, adjusted association study. Infertile patients with PCOS (n=30) and tubal factor (n=75) were screened for anthropometrical, clinical and ovarian morphology parameters, as well as hormonal values. INS VNTR was genotyped by its surrogate marker at -23 HphI locus. RESULTS: INS VNTR genotype distribution was similar in PCOS and tubal infertility group. The mean ovarian follicle number was higher in VNTR I/I individuals compared to VNTR I/III and III/III individuals (adjusted OR=1.28, p=0.03), independent from the cause of infertility, the age, the follicle stimulating hormone level on day 3-5 of menstrual cycle, BMI and the previous surgical ovarian tissue removal. In addition, higher level of the luteinising hormone in VNTR I/I individuals was associated with the increase in follicle number. CONCLUSIONS: We suggest that INS VNTR genotypes are not associated with PCOS in general, but could have a certain influence on the phenotypic spectrum of the syndrome.