Are ovarian reserve tests reliable in predicting ovarian response? Results from a prospective, cross-sectional, single-center analysis.

OBJETIVE: Several biomarkers of ovarian reserve have been proposed as possible predictors of the response to controlled ovarian stimulation (COS). We aimed to evaluate age, FSH, AMH, antral follicle count (AFC), and ovarian response prediction index (ORPI), as potential predictors of response to COS. METHODS: Cross-sectional study enrolling of 188 infertile women who underwent the first cycle of IVF/ICSI. AFC was evaluated; serum FSH and AMH levels were measured by ELISA. ORPI was calculated as AMH x AFC/patient´s age. RESULTS: As expected, hypo-responder group had less retrieved oocytes, MII, and embryos compared to the good responders. The hyper-response patients were younger, with lower FSH, increased AMH, AFC, and ORPI values. Regarding the assessment of the predictive capacity of ovarian reserve tests, none of them individually or combined showed a good predictive capacity for hypo-response. With respect to the hyper-responder group, individually AMH was the best predictor, while in the multivariable model, ORPI demonstrated the best predictive capacity. Furthermore, patients with serum AMH < 2.09 ng/mL (p25) had fewer AFC than patients with higher AMH values. CONCLUSIONS: Our findings suggest that none of the ovarian reserve tests showed a good predictive capacity for hypo-response, while the ORPI was the strongest predictor of hyper-response in normovulatory infertile women.

Paraoxonase single nucleotide variants show associations with polycystic ovary syndrome: a meta-analysis.

BACKGROUND: Etiology of polycystic ovary syndrome (PCOS) is attributed to genetic and environmental factors. One environmental factor is oxidative stress. Paraoxonase 1 (PON1) is an antioxidant high-density lipoprotein-associated enzyme encoded by the PON1 gene. The PON1 gene has been implicated in the risk for PCOS, the influence of which appears to come from single nucleotide variants (SNVs) at multiple genetic loci. However, association study reports have been inconsistent which compels a meta-analysis to obtain more precise estimates. METHODS: From 12 publications, extracted genotype data were used in two genetic procedures. First, linkage disequilibrium (LD) was used to group eight PON SNVs into three: LD1, LD2 and LD3. Second, frequencies of the variant (var), wild-type (wt) and heterozygous (het) genotypes were used for genetic modeling (allele-genotype for LD1 and standard for LD2 and LD3). Risk associations were expressed in terms of pooled odds ratios (ORs), 95% confidence intervals (CIs) and Pa-values. Evidence was considered strong when significance was high (Pa < 0.0001) and heterogeneity absent (I2 = 0%). Pooled effects were subjected to modifier (power), subgroup (Asian/Caucasian), outlier, sensitivity and publication bias treatments. Multiple comparisons were Bonferroni-corrected. RESULTS: This meta-analysis generated 11 significant outcomes, five in LD1, six in LD2 and none in LD3. All six LD2 outcomes did not survive the Bonferroni-correction but two of the five in LD1 did. These two core LD1 findings conferred greater odds of PCOS to the var allele in the highly significant (Pa < 0.0001) overall (OR 1.44, 95% CI 1.24-1.67) and Asian (OR 1.41, 95% CI 1.20-1.65) outcomes. Of these two core outcomes, the Asian effect was homogeneous (I2 = 0%) but not the overall (I2 = 29%). CONCLUSIONS: Of the eight PON SNVs examined, two (rs854560 and rs662) were associated with PCOS risk. These 1.4-fold increased risk effects rendered Asians susceptible to PCOS. High statistical power, high significance, zero to low-level heterogeneity, robustness and lack of bias in the core outcomes underpinned the strong evidence for association.

Body fat distribution influences ART outcomes.

Body mass index (BMI) is the widely used method to evaluate obesity, but it cannot differentiate lean from fat mass neither mass distribution. Other methods have been proposed for this evaluation, as waist and hip circumferences (WC, HC) and ratio (WHR) and body fat analysis by bioimpedance (BF%), but they have not been applied to evaluate assisted reproduction (ART) outcomes. The present study aims at determining whether body composition and adipose tissue distribution are better than BMI on ART outcomes. Analysis was performed through five anthropometric measurements of 788 women submitted to controlled ovarian hyperstimulation and in vitro fertilization techniques. The increase of body fat, independently of the measurement method, was associated to worse reproductive results. However, a surprising finding was that eutrophic women with WC lower than 80 cm showed gestation rates two times superior (38.9% versus 14.3%) when compared to eutrophic women with WC larger than 80 cm (p = .002). Furthermore, obese women with WHR higher than 0.85 showed worse ART results, considering oocytes retrieved, mature oocytes and fertilization when compared to those with WHR lower than 0.85. As a conclusion, it was observed that the body fat distribution, especially WC, was more relevant than BMI to predict ART outcomes.

Influence of STAT4 gene polymorphisms in the pathogenesis of endometriosis.

The STAT4 gene is vital to signaling pathways in the immune response. Immunological alterations are involved in the pathogenesis of endometriosis, and STAT4 polymorphisms may be linked to disease development. This study's aim is to evaluate the possible association between four STAT4 polymorphisms (rs7601754/G > A, rs11889341/C > T, rs7574865/T > G, and rs7582694/C > G) and the pathogenesis of endometriosis in Brazilian women. This case-control study's sample comprised 238 women with endometriosis and 201 healthy, fertile women without endometriosis (which was surgically confirmed). Genotyping was performed using the TaqMan system with a real-time polymerase chain reaction; the genotype, allele, and haplotype frequencies were then compared between groups. A single-polymorphism analysis revealed that the TT genotype of the rs7574865/T > G polymorphism was significantly more frequent in women with minimal or mild endometriosis than in the controls (10% vs. 5%, p = 0.047). The CGAC, GTAT, and GTAC haplotypes were significantly more frequent in the women with endometriosis-related infertility (5.8%, 4.1%, and 2.9%, respectively) than in the controls (2.4%, 1.1%, and 0.8%, respectively; p = 0.020, p = 0.011, and p = 0.032, respectively), but the GGGC and CTAT haplotypes were significantly more prevalent in the control group (34.7% and 13.9%, respectively) than among the infertile group (26.2% and 9.1%, respectively). In addition, the CGAC haplotype was more frequently found in those with minimal or mild endometriosis (6.8%) than in the controls (2.4%, p = 0.009), and the GTAT haplotype was more commonly found in those with moderate or severe disease (3.6%) than in the controls (1.1%, p = 0.028). These findings suggest that STAT4 polymorphisms can influence the pathogenesis of endometriosis.

New candidate genes associated to endometriosis.

A previous GWAS study performed on Brazilian pooled samples indicated some SNPs (single nucleotide polymorphisms) differentially frequent in infertile patients with endometriosis and controls. Some of them were located in the genes whose biological function suggests that they could be associated with endometriosis pathogenesis; thus, the purpose here was to confirm GWAS findings in a larger group of cases and controls in order to associate the results with the pathogenesis of endometriosis. Then, a genetic association study comprising 394 infertile women with endometriosis and 650 fertile control women was conducted. TaqMan allelic discrimination assays were used to investigate the frequency of three SNPs in the genes KAZN (rs10928050), LAMA5 (rs2427284), and TAC3 (rs733629). The analysis revealed a significant association of KAZN rs10928050 (p = .015) and LAMA5 rs2427284 (p = .0059) SNPs with endometriosis-related infertility, while TAC3 rs733629 showed no difference between cases and controls. As a conclusion, it was possible to observe that individual genotyping of a larger sample of patients and controls confirmed the association among KAZN and LAMA5 with endometriosis-related infertility and revealed new candidate genes contributing to the condition.

Association of BMP15 and GDF9 variants to premature ovarian insufficiency.

PURPOSE: To identify genetic variation associated to premature ovarian insufficiency (POI). METHODS: A total of 74 women with POI (group POI), 45 women with increased FSH levels (group high FSH), and 88 controls (non-POI) were studied. Genotyping of BMP15:c.-9C>G (rs3810682), BMP15:c.328+905A>G (rs3897937), and BMP15:c.852C>T (rs17003221); and GDF9:c.134-694G>A (rs4705974), GDF9:c.-31-951G>A (rs11748063), GDF9:c.-152G>C (rs30177), and GDF9:g.1073C>T (rs803224) was performed by the TaqMan methodology. Chi-square and Fisher's exact tests were performed to evaluate the distribution of genotypes, alleles, odds ratio, and the Hardy-Weinberg equilibrium of each variation. Haplotype analysis was performed for each gene considering the case and control groups. Bonferroni's correction was applied to chi-square and Fisher's exact test data, and p values < 0.007 for genotypes and alleles and < 0.006 for haplotypes were considered significant. RESULTS: It was observed a statistically significant difference in genotype distribution of BMP15:c.852C>T between group POI and controls (p < 0.001). TT and TC genotypes were more frequently observed in group POI. Genotype distribution in case group POI, however, was not in the Hardy-Weinberg equilibrium, due to the increased number of heterozygotes in the sample. Concerning GDF9, no association was found among the studied genetic variants and POI or high FSH groups. CONCLUSION: It is concluded from the present study that the genotypes CT and TT from BMP15:c.852C>T variation may be risk factors for the development of POI.

Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?

Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin releasing hormone (GnRH) secretion; however, studies considering this peptide and infertility are limited. We conducted a review and critical assessment of available evidence considering kisspeptin structure, physiology, function in puberty and reproduction, its role in assisted reproduction treatments, kisspeptin dosage and the impact on KISS1 and GPR54 genes. Literature searches were conducted in PubMed using keywords related to: (i) kisspeptin or receptors, kisspeptin-1 (ii) reproduction or infertility or fertility (iii) gene and (iv) dosage or measurement or quantification or serum level, in human. Kisspeptin is a product of KISS1 gene that binds to a G-protein-coupled receptor (GPR54/KISS1R) stimulating the release of GnRH by hypothalamic neurons, leading to secretion of pituitary gonadotropins (LH and FSH) and sexual steroids, which in turn will act in the gonads to produce the gametes. Kisspeptin is being recognized as a crucial regulator of the onset of puberty, the regulation of sex hormone mediated secretion of gonadotropins, and the control of fertility. Inactivating and activating mutations in both KISS1 or GPR54 genes were associated with hypogonadotropic hypogonadism and precocious puberty. Despite this, studies considering kisspeptin and infertility are scarce. The understanding of the role of kisspeptin may lead to its use as a biomarker in infertility treatments and use in controlled ovarian hyperstimulation.

A new Chlorin formulation promotes efficient photodynamic action in choriocapillaris of rabbit's eyes.

Age-related macular degeneration (AMD) as well as other choroidal diseases, demand novel therapeutic methods. Photodynamic therapy (PDT), which uses light and photosensitizer (PS) to cause specific vascular occlusion in the macula, is an interesting alternative. The only drug approved for the PDT treatment of AMD (Verteporfin) has a natural tendency to aggregate, demanding an expensive separation procedure during purification. We report a novel and affordable PS that is intrinsically protected against aggregation, the Monomeric Chlorin at High Concentration (MCHC-Chlorin), whose liposomal formulation was developed to provoke effective photodynamic action on the choroidal vasculature. Our report starts by stablishing the conditions to allow the efficient synthesis of MCHC-Chlorin in high yields (92%). We then tested the light stimulated occlusion of choriocapillary vessels in rabbit's eyes induced by the two MCHC-Chlorin isomers, which are directly obtained from the synthetic route. The PS formulation was infused in the rabbit's ear vein and eyes were immediately irradiated at 650 nm. Indirect ophthalmoscopy, fundus photography, fluorescein angiography and histopathological evaluations were used to evaluate levels of photo-thrombosis and collateral damage. Choriocapillary occlusion was achieved in all treated rabbits' eyes, while retina and sclera were completely preserved. There was no photochemical reaction in none of the eyes that received LASER without PS. Both MCHC-Chlorin isomers were separately tested and exhibited similar positive results with no systemic toxicity. Therefore, PDT occurred equally well in all treated eyes and none of the controls showed any effect in the ophthalmological exams. MCHC-Chlorin offers great potential and should be further studied as an alternative drug for choroidal diseases.

Potential of RASSF1A promoter methylation as biomarker for endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: An epigenetic approach to explaining endometrial carcinogenesis necessitates good understanding of Ras association domain family 1 isoform A (RASSF1A) promoter methylation data from primary studies. AIMS: Differential magnitude of reported associations between RASSF1A promoter methylation and endometrial cancer (EC) prompted a meta-analysis to obtain more precise estimates. METHODS: Literature search yielded eight included articles. We calculated pooled odds ratios (OR) and 95% confidence intervals and subgrouped the data by race. Sources of heterogeneity were investigated with outlier analysis. RESULTS: The pooled ORs indicated increased risk, mostly significant. The overall effect (OR 11.46) was reflected in the European outcome (OR 15.07). However, both findings were heterogeneous (I2=57-70%) which when subjected to outlier treatment, erased heterogeneity (I2=0%) and retained significance (OR 9.85-12.66). Significance of these pre- and post-outlier outcomes were pegged at P≤0.0001. Only the Asian pre-outlier (OR 6.85) and heterogeneous (I2=82%) outcome was not significant (P=0.12) but when subjected to outlier treatment, erased heterogeneity (I2=0%) and generated significance (OR 23.74, P≤0.0001). CONCLUSIONS: Consistent increased risk associations underpinned by significance and robustness render RASSF1A with good biomarker potential for EC.

Copy number variation analysis reveals additional variants contributing to endometriosis development.

PURPOSE: Endometriosis is a gynecological disease influenced by multiple genetic and environmental factors. The aim of the current study was to use SNP-array technology to identify genomic aberrations that may possibly contribute to the development of endometriosis. METHODS: We performed an SNP-array genotyping of pooled DNA samples from both patients (n = 100) and controls (n = 50). Copy number variation (CNV) calling and association analyses were performed using PennCNV software. MLPA and TaqMan Copy-Number assays were used for validation of CNVs discovered. RESULTS: We detected 49 CNV loci that were present in patients with endometriosis and absent in the control group. After validation procedures, we confirmed six CNV loci in the subtelomeric regions, including 1p36.33, 16p13.3, 19p13.3, and 20p13, representing gains, while 17q25.3 and 20q13.33 showed losses. Among the intrachromosomal regions, our results revealed duplication at 19q13.1 within the FCGBP gene (p = 0.007). CONCLUSIONS: We identified CNVs previously associated with endometriosis, together with six suggestive novel loci possibly involved in this disease. The intergenic locus on chromosome 19q13.1 shows strong association with endometriosis and is under further functional investigation.

Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women with endometriosis.

OBJECTIVE: To evaluate the frequency of polymorphism G-765C (rs20417) of the COX-2 gene and the expression of this gene in the endometrium of women with endometriosis. STUDY DESIGN: This is a case-control study of 365 women with endometriosis (251 infertile and 114 fertile) submitted to laparoscopy/laparotomy with histological confirmation of endometriosis. The control group was composed of 522 fertile women without endometriosis. Of these, 37 patients from the endometriosis group and 47 from the control group were submitted to biopsy of the endometrium for analysis of the expression of the COX-2 gene. The genotypes were determined using analysis by High-Resolution Melt. Gene expression was measured by qRT-PCR with TaqMan methodology using the GAPDH gene as normalizer of the reactions. RESULTS: The distribution of the genotypes and alleles in the group of fertile women with moderate/severe endometriosis showed a statistically significant difference, demonstrating association of the ancestral allele, -765G, with increased risk of endometriosis (p = 0.028; OR 0.53; CI 0.32-0.90). The mean expression of the COX-2 gene (mRNA PTGS2) in the group of women with endometriosis was statistically higher compared to the control group (3.85 versus 2.84, p = 0.028). CONCLUSION: The present study identified that in Brazilian women the presence of the ancestral allele, -765G, of the COX-2 gene is associated with an increased risk for development of moderate/severe endometriosis associated with fertility, and that the eutopic endometrium of women with endometriosis showed increased expression of COX-2 when compared to the control group.

AMH and AMHR2 polymorphisms and AMH serum level can predict assisted reproduction outcomes: a cross-sectional study.

BACKGROUND: In human assisted reproduction, the ovarian response to exogenous recombinant Follicle-stimulating Hormone (FSH) therapy is variable and difficult to predict. The standard protocol of ovarian hyperstimulation can result in satisfactory response; however, an unsatisfactory response necessitates FSH dose adjustment or results in ovarian hyperstimulation syndrome (OHSS). Polymorphisms in AMH and AMHR2 genes appear to affect hormone biological activities, thus affecting follicle recruitment and development, leading to infertility. We aimed to evaluate AMH and AMHR2 polymorphisms in infertile women, and correlate those findings with AMH, FSH and estradiol serum level response to controlled ovarian hyperstimulation (COH), as well as assisted reproduction outcomes. METHODS: A cross-sectional study comprising 186 infertile women that underwent one cycle of high complexity assisted reproductive treatment. Blood samples were collected and a TaqMan assay was used for AMH G146T/rs10407022 and AMHR2 A-482G/rs2002555, A10G/rs11170555, C1749G/rs2071558 and G4952A/rs3741664 genotyping, and FSH, estradiol and AMH levels were measured. The findings were correlated to human reproduction outcomes. RESULTS: AMH rs10407022 and AMHR2 rs2002555 polymorphisms were not associated with hormonal measurements, whereas AMHR2 rs11170555 and rs3741664 were positively associated with AMH, estradiol and FSH levels. The genotype distribution of AMH and AMHR2 genes according to Controlled Ovarian Hyperstimulation did not show a positive association. However, an association with AFC, degree of oocyte maturation (allele G of AMHR2 rs2071558) the number of embryos produced (alleles T and G of AMH rs10407022 and AMHR2 rs2002555, respectively) and frozen embryo (allele G of AMHR2 rs11170555) were found to be statistically associated. Considering COH, serum AMH and AFC were a positive predictor to OHSS. Regarding serum AMH and assisted reproduction outcomes, a positive correlation with all variables studied was found. Comparing AFC and AMH as predictors of human reproduction outcomes, the AFC was less effective than serum AMH. Considering pregnancy rates, no marker was positively associated. CONCLUSION: AMHR2 polymorphisms were associated with estradiol, AMH and FSH measurements, as well as number and quality of embryos, while AMH polymorphisms was associated with number of embryos produced. Serum AMH was correlated with nearly all variables analyzed in assisted reproductive treatment, demonstrating that it represents a better biomarker of OHSS and human reproduction outcomes compared to AMH and AMHR2 polymorphisms.

Chlorophyllin-M: A new substance for photodynamic therapy in the retina and choroid.

BACKGROUND AND OBJECTIVE: Chlorophyllin-M is a new chlorophyll-based derivative photosensitive compound developed by our research group with easy laboratorial synthesis and ideal properties for photodynamic therapy (PDT). It is intended for clinical treatments with simple and low cost techniques and reagents. The objective of this study is to evaluate if intravenous chlorophyllin-M is able to deliver a photosensitizer to rabbit retina and rabbit choroid and promote PDT after ocular irradiation with a 660 nm LASER. METHODS: This is a pre-clinical study. Ten eyes of five pigmented Californian rabbits were included in the study. The right eyes served as the treatment group, and the left eyes served as the control group. All eyes had been ophthalmologically evaluated and were considered normal. RESULTS: Ophthalmic exam with anterior biomicroscopy, dilated fundus examination, and fluorescein angiography after the LASER procedure revealed normal anterior segment, retinal and choroid vessels occlusion, lumen narrowing, and capillary non-perfusion in the treated areas, indicating that PDT was successful in the treatment eyes group. CONCLUSION: The results of this pre-clinical study encourage future studies with this new compound. Chlorophyllin-M may become a new cost-effective agent in the retinal therapeutic arsenal.

Are FSHR polymorphisms risk factors to premature ovarian insufficiency?

Premature ovarian insufficiency (POI) is an ovarian dysfunction characterized by increased FSH levels and amenorrhea before 40 years old. In recent years, the search for genetic causes of POI intensified and studies have been published relating the presence of mutations and polymorphisms in genes associated with development, recruitment and oocyte atresia. The aim of this study was to evaluate the presence of FSHR polymorphisms in our population and contribute with the elucidation of POI etiology. To achieve it, we have studied 100 patients with POI (G1), 60 patients with border line levels of FSH (G2) and 123 controls with regular menopause onset. Cytogenetic analysis of patients' samples and genotyping of Asn680Ser and Ala307Thr polymorphisms were performed in cases and controls. Cytogenetic analysis showed that 92% of G1 patients had normal karyotype, 4% presented polymorphic variants, 3% presented mosaic karyotype involving X chromosome. In G2, 91.6% had normal karyotype results, 3.2% displayed polymorphic variants, and 3.3% presented a mosaic karyotype involving X chromosome. Statistical comparison showed that the polymorphic allele of Ala307Thr polymorphism is more frequent in patients than in controls (G1: p < 0.001 and G2: p = 0.0259). This association has not been previously reported. We concluded that Ala307Thr polymorphism in FSHR can be potentially associated to POI development and can be considered as a screening marker in patients with ovarian failure signals.

45,X karyotype in an infertile man: how is this possible?

The case was male, 32 years old, with a nonobstructive azoospermia diagnosis and an initial 45,X karyotype. We evaluated by classical cytogenetic methods, C and NOR banding, fluorescent in situ hybridization, and polymerase chain reaction investigations. After investigation, we found the following karyotype: 45,X,dic(Y;22)(q11.223;p11.2). This investigation contributes to our understanding of how chromosome rearrangements can influence fertility processes and how important it is to perform a cytogenetic analysis in infertility cases.

Association of WNT4 polymorphisms with endometriosis in infertile patients.

PURPOSE: Recently, several genome-wide association studies have demonstrated an association between endometriosis and markers located in or near to WNT4 gene. In order to assess the validity of the findings, we conducted a replication case-control study in a Brazilian population. METHODS: Genetic association study comprising 400 infertile women with endometriosis and 400 fertile women as controls. TaqMan allelic discrimination technique was used to investigate the relationship between endometriosis and four single-nucleotide polymorphisms (rs16826658, rs3820282, rs2235529, and rs7521902) in WNT4 gene. Genotype distribution, allele frequency, and haplotype analysis of the WNT4 polymorphisms were performed. A p value <0.05 was considered significant. RESULTS: The results revealed a significant association of rs16826658 (p = 7e-04) and rs3820282 (p = 0.048) single-nucleotide polymorphisms (SNPs) on WNT4 gene with endometriosis-related infertility, while rs2235529 and rs7521902 SNPs showed no difference between cases and controls. CONCLUSIONS: Our results suggested that rs16826658 and rs3820282 polymorphisms on WNT4 gene might be involved in the pathogenesis of endometriosis in the infertile women studied. Analysis of WNT4 genetic variants might help to identify patients at high risk for disease development.

CYP2C19 polymorphism increases the risk of endometriosis.

PURPOSE: Estrogen metabolizing gene mutations can be associated with defective hormonal signaling leading to disease processes. Endometriosis is an estrogen dependent that can be influenced by defective signaling in the estrogen pathway. OBJECTIVES: To evaluate the association of A/G 85952 CYP2C19 and A/G 937 HSD17B1 gene polymorphisms with endometriosis through the investigation of a large Brazilian sample of women with endometriosis and a fertile control group. METHODS: Five hundred women with endometriosis and 500 women without endometriosis were tested for CYP2C19 and HSD17B1 polymorphisms, by TaqMan Real Time PCR. The results were statistically analyzed by chi-square, logistic regression and tested for Hardy-Weinberg equilibrium. RESULTS: The comparison of genotype and allelic frequency of CYP2C19 polymorphism (rs11592737) in patients with endometriosis and control group showed a statistically significant difference (p = 0.0203) and for the HSD17B1 polymorphism (rs605059) differences were not significant (p = 0.0687). Comparing the stages I/II and III/IV endometriosis with the control group for the CYP2C19 we observed p = 0.0133 and p = 0.0564, respectively, and for HSD17B1 the values for p = 0.4319 and p = 0.0667. CONCLUSION: We observed that CYP2C19 polymorphism is associated with endometrisis in Brazilian women and can be considered a potential biomarker of the disease.

Association of the intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms with endometriosis: a systematic review and meta-analysis.

BACKGROUND: Reported associations of the G241R and K469E polymorphisms of the intercellular adhesion molecule-1 gene (ICAM-1) gene with endometriosis have differed in magnitude. MATERIALS AND METHODS: In a meta-analysis of six published case-control studies (from five articles), we estimated risk [odds ratio (OR) 95 % confidence intervals (CI)] of associations with these polymorphisms using the Review Manager 5.3 software. RESULTS: Based on 1213 cases and 1103 controls, overall analysis showed significant increased risk in the homozygous (OR 2.83, 95 % CI 0.99-8.10, p = 0.05), dominant (OR 1.86, 95 % CI 1.00-3.46, p = 0.05) and codominant (OR 2.15, 95 % CI 1.06-4.35, p = 0.03) models. Confined to the studies in Hardy-Weinberg Equilibrium erased the significance (OR 1.59-2.59, 95 % CI 0.81-8.22, p = 0.10-0.15). Asian effects were variable (OR 0.93-1.09, p = 0.50-0.57), but Caucasian effects were not (OR 4.09-13.60, p < 0.0001). Independent data for the late stages of endometriosis suggest protection of the ICAM-1 K469E polymorphism among the Asians (OR 0.91-0.95, p = 0.35-0.71). These effects were weak but non-heterogeneous (P heterogeneity = 0.17-0.57, I (2) = 0-40 %). CONCLUSION: In summary, strengths of the overall effects were consistency, significance and robustness but limited by their high heterogeneity. These strengths and limitations were also observed in the Caucasian subgroup which when tested for interaction against the contrasting Asian effects, highlighted Caucasian susceptibility (p = 0.004-0.01). The findings are an interplay of strengths and limitations, which warrant awareness of their interpretation as susceptibility markers for this disorder.

Association of the +331G/A progesterone receptor gene (PgR) polymorphism with risk of endometrial cancer in Caucasian women: a meta-analysis.

PURPOSE: The +331G/A progesterone receptor (PgR) gene polymorphism may influence risk of endometrial cancer. However, data from published studies have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and endometrial cancer, we considered all available studies in a meta-analysis. METHODS: We searched PubMed and EMBASE and identified eight studies representing data for 3,790 cases and 6,458 controls. We estimated risk [odds ratio (OR) and 95 % confidence interval] of these associations, which were non-significant in the entire body of results. RESULTS: Overall effects indicated increased risks, slightly pronounced in the homozygous and recessive models (OR 1.16-1.17, p = 0.57-0.60). These effects were exacerbated when confined to studies in Hardy-Weinberg Equilibrium (OR 1.33-1.36, p = 0.33-0.35) and in the underpowered subgroup (OR 1.62-1.68, p = 0.27-0.30). The exception is the powered subgroup which showed reduced risk (OR 0.96-0.97, p = 0.92-0.93). None of the comparisons were heterogeneous, in fact, 10 of the 16 comparisons had zero heterogeneity (I (2) = 0 %). CONCLUSION: In summary, the non-significant results suggest that the PgR +331G/A polymorphism might not be a conspicuous low-penetrant risk factor for developing endometrial cancer.

Ala307Thr and Asn680Ser polymorphisms of FSHR gene in human reproduction outcomes.

BACKGROUND/AIMS: It is known that some markers of ovarian stimulation can help to personalize the treatment, adjusting the dose of exogenous rFSH, thus preventing excessive wear of the patient. We aimed to evaluate Ala307Thr and Asn680Ser genotypes of the FSHR gene in infertile women and correlate the findings with the results of ovarian response and assisted reproduction outcomes. METHODS: Cross-sectional study covering 149 infertile women submitted to assisted reproduction treatment. Genotyping of FSHR variants were performed using TaqMan methodology by real time PCR. FSH and estradiol were measured by ELFA. The data was analyzed statistically. RESULTS: The frequencies of the FSHR Ala307Thr and Asn680Ser genotypes considering the ovarian hyper stimulation response also did not differ statistically. Considering assisted reproduction outcomes, we observed that the polymorphism Ala307Thr have a statistical difference for the number of MII oocytes and embryos (p=0,051 and p=0.037, respectively), which the genotype Ala/Ala showed more embryos. The polymorphisms did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. CONCLUSIONS: The polymorphisms Ala307Thr and Asn680Ser did not determine the FSH and estradiol serum levels and the ovarian response in the assisted reproduction treatment. However, we observed that the Ala307Thr may influence the number of embryos produced.