Search

PURPOSE: To evaluate the association of objectively measured physical activity (PA) and sedentary behaviour before and during in vitro fertilization (IVF) with controlled ovarian stimulation (COS) and pregnancy outcomes. METHODS: This longitudinal study involved 107 infertile women undergoing IVF treatment. PA and sedentary behaviour were measured for 14 consecutive days using accelerometry as follows: (1) before IVF treatment, (2) during IVF at the implantation time, immediately after embryo transfer, and (3) after positive pregnancy test. Total screen time was assessed by questionnaires. COS results were measured as the number of oocytes and embryos obtained, and the study outcomes included positive hCG, clinical pregnancy, and live birth. RESULTS: Compared with baseline activity levels, women significantly reduced their PA and increased sedentary behaviour during IVF (p ≤ 0.001). Higher average PA, light PA, and ratio between breaks in every ≥ 30-min blocks of sedentary time showed positive associations, while sedentary time, number, and time accumulated in blocks of ≥ 30 min of sedentary time associated negatively with oocyte and embryo counts (all p

STUDY QUESTION Are the genetic variants FSHB -211 G>T (rs10835638), FSHR c.2039 A>G (Asn680Ser, rs6166) and FSHR -29 G>A (rs1394205) associated with serum FSH, LH and anti-Mullerian hormone (AMH) levels in reproductive age women, their menstrual cycle parameters and risk of infertility? SUMMARY ANSWER Only the FSHB -211 G>T variant was a major genetic determinant of serum gonadotropin levels in both, eumenorrheic healthy women and female infertility patients, and the T-allele carrier status was enriched among idiopathic infertility cases. WHAT IS KNOWN ALREADY There are accumulating data on common genetic variants modulating reproductive parameters and fertility potential. FSHB -211 G>T represents the strongest acknowledged genetic factor contributing to male circulating gonadotropins levels. Respective data in women are limited and the two previously published studies have reached conflicting results. In addition, previous studies have consistently associated FSHR c.2039 A>G (but not FSHR -29 G>A) with female serum FSH level. STUDY DESIGN, SIZE, DURATION The study aimed to test robust and clinically meaningful genetic effects (if present) of the FSHB -211 G>T, FSHR c.2039 A>G and FSHR -29 G>A variants on female basal FSH, LH and AMH levels, and linked reproductive parameters. Genetic association testing was performed in two independent and clinically different study groups (i) eumenorrheic healthy women without known fertility problems (n = 169; 27.6 ± 6.1 years) and (ii) female partners of infertile couples (n = 186; 32.4 ± 4.7 years). The study groups were compared for allelic and genotypic distributions of the analysed variants. PARTICIPANTS/MATERIALS, SETTING, METHODS All participants were recruited during the HAPPY PREGNANCY study (2013-2015) at the Women's Clinic, Tartu University Hospital, Estonia. Serum FSH, LH and AMH were measured in the follicular phase (Days 2-6) of the menstrual cycle. All three single nucleotide polymorphisms (SNPs) were genotyped by PCR and Taqman allelic discrimination assay. The effect of the analysed variants on hormonal measurements and menstrual cycle data was assessed using linear regression under additive and recessive models adjusted by age, BMI and smoking status. Results of the two subgroups were combined in a meta-analysis applying the fixed effects model. Restricted maximum likelihood analysis was applied to estimate the proportion of total phenotypic variance of analysed reproductive parameters, explainable by the tested genetic variants. In case-control analysis, genetic association with infertility status was tested using Fisher's exact test and logistic regression adjusted by age, BMI and smoking status. MAIN RESULTS AND THE ROLE OF CHANCE In both study groups, T-allele of the FSHB -211 G>T was associated with significantly higher serum levels of FSH and LH. Results of the meta-analysis (additive genetic model) remained significant after Bonferroni correction for multiple testing: FSH, T-allele effect 0.80 IU/L, P = 1.2 × 10-3; LH, 1.58 IU/L, P = 1.8×10-8. A more pronounced effect of T-allele of the FSHB -211 G>T on circulating LH was identified as a driving factor to increased LH/FSH ratio (meta-analysis, P = 4.7 × 10-3). In healthy women, the FSHB -211 G>T variant was estimated to explain 3.5 and 7.1% of the total variance of the measured serum FSH and LH levels, respectively. The corresponding numbers for the infertility patients were 1.6 and 10.5%. Women with idiopathic infertility compared to controls exhibited a doubled T-allele frequency (23.6 versus 12.4%; P = 8.9 × 10-3) and a >3-fold excess of TT homozygotes (5.6 versus 1.8%; P = 3.5 × 10-2). The only association of the FSHR c.2039 A>G was detected with serum FSH levels in eumenorrheic healthy women, explaining 3.9% of the total parameter variance (G-allele effect 0.56 IU/L, P = 4.6 × 10-3). In the study group of healthy reproductive age women, the highest serum FSH levels were detected among the FSHB -211 T-allele carriers with the FSHR c.2039 GG-genotype (median 7.7 IU/L). In contrast, the lowest hormone concentrations were measured for the women carrying the combination of the FSHB -211 GG- and the FSHR c.2039 AA-homozygosity (median 5.8 IU/L, P = 9.6 × 10-3). None of the analysed reproductive parameters was associated with the FSHR -29 G>A variant. In our study groups, the tested polymorphisms did not reach significant associations with serum AMH measurements, menstrual cycle length or age at menarche. LIMITATIONS, REASONS FOR CAUTION Small sample size and the design involving two clinical groups with different reproductive histories may have limited the capacity to replicate the associations with the age at menarche and length of menstrual cycle, initially reported in large genome-wide association studies. Small sample size may have also affected the accuracy in estimating the contribution of the tested variants to the total phenotypic variance of measured gonadotropin concentrations. The group of eumenorrheic healthy women had its limitations as a control to estimate the true effect of analysed genetic variants on individual's fertility potential as the recruitment strategy had been targeted mostly towards younger women, who may not yet have planned to conceive a child by this age. WIDER IMPLICATIONS OF THE FINDINGS We propose that like in men, also in women the FSHB -211 G>T represents a key genetic modulator of circulating gonadotropin, leading to various possible downstream effects on reproductive physiology. This claim is strongly supported by the reports of genome-wide association studies on various female reproductive traits and diseases. In perspective, FSHB -211 G>T may have a diagnostic value in fertility clinics to detect female patients with genetically inherited elevated basal FSH and LH levels. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by Estonian Science Foundation Grant (ETF9030 for M.L.); Institutional Research Grant (IUT34-12 for M.L.) and European Union through the European Regional Development Fund (project HAPPY PREGNANCY, 3.2.0701.12-0047; for M.L. and K.R.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article. We have no competing interests to declare. TRAIL REGISTRATION NUMBER Not applicable.

Context Clinically used endometrial (EM) receptivity assays are based on transcriptomic patterning of biopsies at midsecretory endometrium (MSE) to identify the possible displacement or disruption of window of implantation (WOI) in patients with recurrent implantation failure (RIF). However, biopsies are invasive and cannot be performed in the same cycle with in vitro fertilization embryo transfer, while uterine fluid (UF) analysis is considered minimally invasive and can immediately precede embryo transfer. Objective To determine whether UF proteome can be used for WOI monitoring and whether it would highlight the etiology of RIF. Patients Paired early secretory endometrial (ESE) and MSE UF samples from six fertile control women for discovery, and an additional 11 paired ESE/MSE samples from controls and 29 MSE samples from RIF patients for validation. Results Using discovery mass spectrometry (MS) proteomics we detected 3158 proteins from secretory phase UF of which 367 undergo significant (q < 0.05) proteomic changes while transitioning from ESE to MSE. Forty-five proteins were further validated with targeted MS, and 21 were found to display similar levels between control ESE and RIF MSE, indicating displacement of the WOI. A panel of PGR, NNMT, SLC26A2 and LCN2 demonstrated specificity and sensitivity of 91.7% for distinguishing MSE from ESE samples. The same panel distinguished control MSE samples from RIF MSE with a 91.7% specificity and 96.6% sensitivity. Conclusion UF proteins can be used for estimating uterine receptivity with minimal invasiveness. Women with RIF appear to have altered MSE UF profiles that may contribute to their low IVF success rate.

The purpose of this study was to establish the first-trimester screening for Down syndrome (DS) in Estonia and to evaluate the potential of a contingent screening in the population of pregnant women. A prospective cohort study included non-selected pregnancies during the programme of first-trimester screening for DS in a 4-year period at a single centre. The following screening tests were evaluated: measurement of nuchal translucency (NT) and serum screening [pregnancy-associated plasma protein A and free beta subunit of human chorionic gonadotropin (fβ-HCG)]; results were given as combined screening. After first-trimester screening, contingent screening protocol was used, and women were divided into three groups: high risk, low risk and an intermediate risk group. In the last group, a second-trimester triple test (AFP; total HCG and uE3) was also performed. The study group consisted of 3,194 non-selected pregnancies. In 1,387 (43.4%) women, first-trimester serum screening showed low risk (risk ≤ 1:5,000), and no future testing was performed, in 30 (0.9%) women screening test showed high risk (risk ≥ 1:50) and a diagnostic test was offered, and in 1,777 (55.7%) women repeated risk calculation in the second trimester was done. During the study period, there were 17 cases of trisomy 21, of which 15 (88.3%) were detected with the described screening programme. In conclusion, two-step contingent sequential screening is a better choice for Down syndrome screening in Estonia instead of previously used second-trimester screening, and it offers the advantage of earlier diagnosis.

The presence and composition of amniotic fluid (AF) microflora, as well as AF glucose concentration and white blood cell (WBC) count, were investigated in 22 consecutive asymptomatic women with intact membranes at mid-gestation. AF was retrieved by trans-abdominal amniocentesis. Three of the 22 women (13.6%) had microorganisms in their AF: Chlamydia trachomatis in 2 and both Corynebacterium group absolute nonfermenter (ANF) group and Propionibacterium spp. in 1. No differences were found in clinical characteristics, glucose concentration or WBC count in patients with and without microorganisms in their AF.