Plasma cytokines during pregnancy provide insight into the risk of diabetes in the gestational diabetes risk group.

AIMS/INTRODUCTION: Gestational diabetes (GDM) is characterized by low-grade systemic inflammation, which manifests as changes in the levels of cytokines in the blood. We aimed to investigate plasma immune mediators during gestational weeks 23-28 in 213 women at risk for GDM, and to find associations between GDM and its complications. MATERIALS AND METHODS: We quantified the levels of adipokines: adiponectin, leptin, plasminogen activator inhibitor-1 and resistin; chemokines: C-C motif chemokine ligand 2 (CCL2), CCL4, C-X-C motif chemokine ligand 8 (CXCL8) and CXCL10; and cytokines: granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin (IL)-1ß, soluble (s)IL-1RI, IL-2, sIL-2Ra, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12(p70), IL-13, IL-15, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-27, transforming growth factor (TGF)-ß1, TGF-ß2, TGF-ß3, tumor necrosis factor-α and soluble tumor necrosis factor receptor 2 using the Milliplex®MAP Magnetic Bead assay on Luminex®200™, and compared the results with clinical data from pregnancy and post-partum follow up. RESULTS: Lower levels of adiponectin and higher levels of CCL2 (Wilcoxon test, P = 3.4E-03 and P = 0.03, respectively) were found in women with GDM. IL-27 levels were associated with lower odds of GDM (adjusted logistic regression 0.90, P = 2.4E-03), and showed a risk association with glutamic acid decarboxylase autoantibody positivity (adjusted odds ratio 1.13, P = 2.8E-03). Similarly, higher IL-22 levels increased the odds of glutamic acid decarboxylase autoantibody positivity (adjusted odds ratio 4.23, P = 0.04). TGF-ß1 was associated with post-partum fasting glucose levels, and CCL4 with post-partum C-peptide levels (linear regression, P = 0.04 and P = 0.01, respectively). Women who developed pregnancy complications had higher levels of CXCL10 and CCL4 (linear regression, P = 7.0E-04 and P = 0.01, respectively). CONCLUSIONS: Plasma adiponectin and CCL2 concentrations distinguish women with GDM. IL-27 and IL-22 levels might select women with an autoimmune reaction, whereas increased TGF-ß1 and CCL4 are associated with post-partum glucose and insulin metabolism.

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

Interleukin-7, T helper 1, and regulatory T-cell activity-related cytokines are increased during the second trimester of healthy pregnancy compared to non-pregnant women.

PROBLEM: Healthy pregnancy is associated with a physiologic increase in inflammatory responses. The objective of this study was to assess changes in plasma cytokines associated with uncomplicated pregnancy. METHOD OF STUDY: To examine these changes, plasma levels of immune response mediators from healthy gravidas (N = 115, gestation weeks 23-30) were compared with those from healthy non-pregnant women (N = 42). Comparisons were performed using multiplex analysis for Th1 activity-related cytokines (IFN-γ, IL-2, sIL-2Rα, IL-12[P70], and IL-27), Th2 activity-related cytokines (IL-4, IL-5, and IL-13), other immune response mediators (GM-CSF, IL-1ß, sIL-1RI, IL-6, IL-8, IL-15, IL-17A, IL-17F, IL-21, IL-22, IL-23, TGFß1, TGFß2, TGFß3, and TNFα), regulatory T cell-related cytokines (IL-10 and sTNFRII), adipokines (adiponectin, leptin, PAI-1, and resistin), chemokines (IP-10, MCP-1, and MIP-1ß), and hematopoietic growth factor IL-7. RESULTS: Multivariate linear regression models showed increased levels of IL-7, Th1-, and Treg activity-related cytokines and decreased levels of adipokines and chemokines in healthy gravidas compared with healthy non-pregnant women. Additionally, season of the year, age, pre-pregnancy body mass index, and HLA-DR/DQ genotypes for type 1 diabetes risk showed different and sometimes reciprocal influence on cytokine levels. CONCLUSION: Our study stresses the importance of profiling immune response mediators during pregnancy to better understand the effect of healthy pregnancy on cytokine levels.

Patients with down syndrome have increased prevalence of rheumatoid factor but not autoantibodies to anti-cyclic citrullinated peptide.

The association between Down syndrome (DS), a genetic disorder resulting from trisomy of the 21st chromosome, and the autoantibodies of rheumatoid arthritis (RA) has been proposed but not unequivocally proven. The aim of this study was to determine whether adult patients with DS present higher levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and/or rheumatoid factor (RF) than the general population. Our results showed that none of the 68 patients with DS had anti-CCP antibodies, whereas among 204 age- and sex-matched controls these autoantibodies were present in one person. However, DS patients presented a higher number of RF positive cases than controls (11.7% to 3.2% respectively; Fisher's exact test, p = .027). The higher number of RF positive cases in the DS group without increase of anti-CCP antibodies may be indicative of immune disturbances in general rather than RA in these patients. Our study supports the view that RA does not occur with higher frequency in patients with DS than in the general population.

MicroRNA profiling of second trimester maternal plasma shows upregulation of miR-195-5p in patients with gestational diabetes.

Gestational diabetes (GDM) is defined as glucose intolerance that presents during pregnancy. It increases the risk of developing diabetes later in life. Recent studies indicate the important role of microRNAs (miRNAs) in the pathogenesis of diabetes, including GDM. However, information on the plasma miRNA profile in GDM patients at the late second trimester, at which time the glucose metabolism disorder manifests, is scarce. This study aimed to determine the plasma miRNA expression profiles of the pregnant women with GDM and compare them to those of pregnant controls using the real-time PCR array method. The study involved 22 single-pregnancy women (mean age ±â€¯standard deviation of 29.9 ±â€¯4.5 years old) who underwent a glucose tolerance test between 23 and 31 weeks of gestation. Of them, 13 were diagnosed with GDM. We identified 15 upregulated miRNAs in the GDM patients that were involved in 41 pathways. Among the top 10 associated pathways, fatty acid biosynthesis and fatty acid metabolism were targeted by the most, of the miRNAs investigated, with very low p values (p < 1e-325, false discovery rate corrected). MiR-195-5p, which targeted the highest number of genes important in metabolism, showed the highest fold upregulation. We conclude that increased miRNA expression, especially miR-195-5p, in plasma is characteristic of and causally related to the development of GDM.

Demographic associations for autoantibodies in disease-free individuals of a European population.

The presence of autoantibodies usually precedes autoimmune disease, but is sometimes considered an incidental finding with no clinical relevance. The prevalence of immune-mediated diseases was studied in a group of individuals from the Estonian Genome Project (n = 51,862), and 6 clinically significant autoantibodies were detected in a subgroup of 994 (auto)immune-mediated disease-free individuals. The overall prevalence of individuals with immune-mediated diseases in the primary cohort was 30.1%. Similarly, 23.6% of the participants in the disease-free subgroup were seropositive for at least one autoantibody. Several phenotypic parameters were associated with autoantibodies. The results suggest that (i) immune-mediated diseases are diagnosed in nearly one-third of a random European population, (ii) 6 common autoantibodies are detectable in almost one-third of individuals without diagnosed autoimmune diseases, (iii) tissue non-specific autoantibodies, especially at high levels, may reflect preclinical disease in symptom-free individuals, and (iv) the incidental positivity of anti-TPO in men with positive familial anamnesis of maternal autoimmune disease deserves further medical attention. These results encourage physicians to evaluate autoantibodies in addition to treating a variety of patient health complaints to detect autoimmune-mediated disease early.

Clinical Recommendations for the Use of Islet Cell Autoantibodies to Distinguish Autoimmune and Non-Autoimmune Gestational Diabetes.

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. The prevalence of GDM is highly variable, depending on the population studied, and reflects the underlying pattern of diabetes in the population. GDM manifests by the second half of pregnancy and disappears following delivery in most cases, but is associated with the risk of subsequent diabetes development. Normal pregnancy induces carbohydrate intolerance to favor the availability of nutrients for the fetus, which is compensated by increased insulin secretion from the maternal pancreas. Pregnancy shares similarities with adiposity in metabolism to save energy, and both conditions favor the development of insulin resistance (IR) and low-grade inflammation. A highly complicated network of modified regulatory mechanisms may primarily affect carbohydrate metabolism by promoting autoimmune reactions to pancreatic ß cells and affecting insulin function. As a result, diabetes development during pregnancy is facilitated. Depending on a pregnant woman's genetic susceptibility to diabetes, autoimmune mechanisms or IR are fundamental to the development autoimmune or non-autoimmune GDM, respectively. Pregnancy may facilitate the identification of women at risk of developing diabetes later in life; autoimmune and non-autoimmune GDM may be early markers of the risk of future type 1 and type 2 diabetes, respectively. The most convenient and efficient way to discriminate GDM types is to assess pancreatic ß-cell autoantibodies along with diagnosing diabetes in pregnancy.

GADA and anti-ZnT8 complicate the outcome of phenotypic type 2 diabetes of adults.

BACKGROUND: A proportion of phenotypic type 2 diabetes (T2D) patients produce pancreatic autoantibodies and a majority of T2D patients develop serious life-disabling complications over time despite the implementation of adequate clinical interventions. This study determined whether the presence of pancreatic autoantibodies (GADA, IA-2A, anti-ZnT8, or ICA) was associated with serious complications or concomitant diseases of adult patients diagnosed with T2D (N = 305). MAIN RESULTS: In the study population, 22.3% (N = 68) of subjects were positive for at least 1 of the 4 of the markers associated with autoimmune diabetes (presence of pancreatic autoantibody - pAb), followed by GADA (14.1%, N = 43), ICA (8.9%, N = 27), anti-ZnT8 (5.6%, N = 17) and IA-2A (2.0%, N = 6). Logistic regression analysis adjusted for patient's age, gender and duration of T2D revealed that (i) pAb was associated with higher prevalence of adiposity (odds ratio of adjusted regression model (adOR) 2.51, P = 0.032); (ii) pAb, GADA and anti-ZnT8 were associated with autoimmune thyroid disease (adORs 3.07, P = 0.012; 6.29, P < 0.001 and 3.52, P = 0.052, respectively); (iii) pAb and GADA, in particular, were risk factors for neurological complications (adORs 2.10, P = 0.036; 2.76, P = 0.009, respectively) and polyneuropathy in particular (adORs 2.60, P = 0.012; 3.10, P = 0.007, respectively); and (iv) anti-ZnT8 was a risk factor for developing nephropathy (adOR 4.61, P = 0.022). In addition, adiposity was associated with 5.3-year earlier onset of disease (adjusted linear regression model, P = 0.006). CONCLUSIONS: These results suggest that GADA and anti-ZnT8 are associated with progression of serious T2D complications, including polyneuropathy and nephropathy. In addition, adiposity represents a significant risk for autoimmunity development in T2D patients.

Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta.

Given the possible critical importance of placental gene imprinting and random monoallelic expression on fetal and infant health, most of those genes must be identified, in order to understand the risks that the baby might meet during pregnancy and after birth. Therefore, the aim of the current study was to introduce a workflow and tools for analyzing imprinted and random monoallelic gene expression in human placenta, by applying whole-transcriptome (WT) RNA sequencing of placental tissue and genotyping of coding DNA variants in family trios. Ten family trios, each with a healthy spontaneous single-term pregnancy, were recruited. Total RNA was extracted for WT analysis, providing the full sequence information for the placental transcriptome. Parental and child blood DNA genotypes were analyzed by exome SNP genotyping microarrays, mapping the inheritance and estimating the abundance of parental expressed alleles. Imprinted genes showed consistent expression from either parental allele, as demonstrated by the SNP content of sequenced transcripts, while monoallelically expressed genes had random activity of parental alleles. We revealed 4 novel possible imprinted genes (LGALS8, LGALS14, PAPPA2 and SPTLC3) and confirmed the imprinting of 4 genes (AIM1, PEG10, RHOBTB3 and ZFAT-AS1) in human placenta. The major finding was the identification of 4 genes (ABP1, BCLAF1, IFI30 and ZFAT) with random allelic bias, expressing one of the parental alleles preferentially. The main functions of the imprinted and monoallelically expressed genes included: i) mediating cellular apoptosis and tissue development; ii) regulating inflammation and immune system; iii) facilitating metabolic processes; and iv) regulating cell cycle.

Autoimmune activation toward embryo implantation is rare in immune-privileged human endometrium.

Human embryo implantation represents embryo apposition, adhesion to the endometrial epithelium, and invasion into the stromal extracellular matrix within 1 to 2 days during days 6 to 9 after ovulation. The major molecular mechanisms mediating implantation include adhesion molecules, including mucins, selectins, integrins, and cadherins; extracellular matrix components, such as laminins and collagens and their degrading enzymes; phospholipids and immune regulatory molecules, including prostaglandins, cytokines; and immunosuppressive molecules expressed by invasive trophoblasts and endometrial cells. Many of these molecules are the targets for autoimmune reactions in autoimmune diseases and cancer; however, the relevance of those in immune-mediated implantation failure has not been defined. In this review, we will describe the molecules involved in 2-day event of human embryo implantation, which may also be involved in immune system activation and subsequently cause immune-mediated implantation failure. We speculate that the data in the literature are limited concerning antiendometrial antibodies because the endometrium might be taken as an immune-privileged site that avoids autoimmune activation that might harm the implantation process. Antibodies affecting human fertility in ways other than impairing implantation are outside the scope of the current article and will not be discussed.

Serum sTREM-1 (soluble triggering receptor expressed on myeloid cells-1) associates negatively with embryo quality in infertility patients.

PROBLEM: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker of infection and inflammation. METHOD OF STUDY: We studied serum and follicular fluid sTREM-1 in infertile patients (N = 110) utilizing enzyme-linked immunosorbent assay. RESULTS: Serum and follicular sTREM-1 were in good correlation (Pearson's correlation 0.56, P < 0.0001) with higher values in follicular fluid (140.4 ± 34.4 and 115.6 ± 35.1 pg/mL, t-test, P < 0.0001). Endometriosis associated with lower follicular and serum sTREM-1 compared with male factor infertility patients (age-adjusted r = -25.7 pg/mL, P = 0.018; r = -22.1 pg/mL, P = 0.030). No associations between follicular or serum sTREM-1 and clinical parameters were found, except higher serum sTREM-1 associated with lower embryo quality in all patients (adjusted r = -0.3%, P = 0.033), with a cutoff value between 111.5 and 113.3 pg/mL (OR = 0.38, P = 0.048; OR = 0.34, P = 0.028) predicting that more than 39% of embryos would be with good quality. CONCLUSION: Serum sTREM-1 could represent a prognostic marker for female fecundity, probably indicating impaired inflammatory reaction of immune system.

Follicular proinflammatory cytokines and chemokines as markers of IVF success.

Cytokines are key modulators of the immune system and also contribute to regulation of the ovarian cycle. In this study, Bender MedSystems FlowCytomix technology was used to analyze follicular cytokines (proinflammatory: IL-1ß, IL-6, IL-18, IFN-γ, IFN-α, TNF-α, IL-12, and IL-23;, and anti-inflammatory: G-CSF), chemokines (MIP-1α, MIP-1ß, MCP-1, RANTES, and IL-8), and other biomarkers (sAPO-1/Fas, CD44(v6)) in 153 women undergoing in vitro fertilization (IVF). Cytokine origin was studied by mRNA analysis of granulosa cells. Higher follicular MIP-1α and CD44(v6) were found to correlate with polycystic ovary syndrome, IL-23, INF-γ, and TNF-α with endometriosis, higher CD44(v6) but lower IL-ß and INF-α correlated with tubal factor infertility, and lower levels of IL-18 and CD44(v6) characterized unexplained infertility. IL-12 positively correlated with oocyte fertilization and embryo development, while increased IL-18, IL-8, and MIP-1ß were associated with successful IVF-induced pregnancy.

Review on autoimmune reactions in female infertility: antibodies to follicle stimulating hormone.

Female fertility can be affected by diseases or dysfunctions of reproductive tract, neuroendocrine system, and immune system. Reproductive autoimmune failure can be associated with overall activation of immune system or with immune system reactions specifically directed against ovarian antigens. Majority of the antiovarian autoantibodies are directed against ß-subunit of follicle stimulating hormone (anti-FSH). This paper summarizes a current clinical classification of female infertility in the context of general activation of autoimmunity and antiovarian autoimmunity by describing serum anti-FSH. The presence of naturally occurring anti-FSH in healthy women will be discussed. In addition, the putative impairment of ovarian folliculogenesis in case of increased production of those antibodies in infertile women will be characterized.

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.

Association of CCR5, TLR2, TLR4 and MBL genetic variations with genital tract infections and tubal factor infertility.

Upper genital tract infections can inflict inadequate immune response and cause Fallopian tube damage and concomitant female infertility. However, the exact role of host genetic variation in the development of tubal factor infertility remains unclear. We selected nine genetic variations in four genes involved in immune response modulation (CCR5, TLR2, TLR4 and MBL2) and assessed their association with tubal factor infertility by comparing genotype frequencies among 163 women with tubal factor infertility and 400 control individuals. The CCR5, TLR2 and TLR4 genotypes were not associated with tubal factor infertility, although the TLR4 Asp299Gly and Thr399Ile heterozygosity was associated with a decreased incidence of pathogens associated with genital tract infections in tubal factor infertility patients. In contrast, MBL2 low-producing genotypes were associated with an increased incidence of such pathogens. In addition, hyper-producing MBL2 genotype HYA/HYA and low-producing MBL2 genotypes were associated with susceptibility to tubal factor infertility, while a protective effect was associated with the high-producing MBL2 genotype HYA/LYA. Overall, these data suggest that polymorphisms in TLR4 and MBL2 play a role in receptiveness to pathogens causing genital tract infections, while MBL2 genotypes contribute to susceptibility to tubal factor infertility.

Serum anti-endometrial antibodies in infertile women - potential risk factor for implantation failure.

PROBLEM: Female infertility patients with diverse etiologies show increased production of autoantibodies. METHOD OF STUDY: Immunoblot analysis of sera from patients with endometriosis and tubal factor infertility (TFI) and mass spectrometry identification of candidate antigens. RESULTS: The immunoblot results demonstrated the presence of IgA and IgG anti-endometrial antibodies (AEA) to various antigens at molecular weights ranging from 10 to 200 kDa. Differences were detected in certain AEA reactions between the patients' groups and particular AEA were associated with in vitro fertilization (IVF) implantation failure. IgA AEA to a 47-kDa protein were more prevalent in TFI patients and were associated with unsuccessful IVF treatment. This antigen was subsequently identified as alpha-enolase. CONCLUSION: Determination of the presence and spectra of AEA in patients with endometriosis and TFI undergoing IVF may be a useful marker to predict their pregnancy outcome.

Follicle-stimulating hormone receptor gene haplotypes and male infertility in estonian population and meta-analysis.

Follicle-stimulating hormone (FSH) is crucial for male fertility and it exerts its effects via a gonad-specific receptor (FSHR). In the present study, the common G-29A, A919G, and A2039G polymorphisms in the FSHR gene were analysed in 150 (36 non-obstructive azoospermia and 114 individuals with oligozoospermia) patients and 208 normozoospermic men. The results showed that the FSHR polymorphisms were not associated with either azoo- or oligozoospermia as the distributions of alleles, genotypes, and haplotypes among patients and controls were similar. Amongst normozoospermic men, those carrying at least one minor A allele (GA and AA genotypes) of the G-29A polymorphism had a smaller mean testicular volume compared to men with GG homozygosity (25.8 ml vs. 27.4 ml, respectively; P=0.013). In a subsequent meta-analysis combining our data with previous studies, the G-29-A919-A2039 haplotype was shown to be more prevalent in normozoospermic men than in azoospermic patients (38.4% vs. 33.9%, respectively; chi(2)test, P=0.045), indicating that this haplotype may be a protective factor against male sterility. In conclusion, we suggest that FSHR haplotypes are not considerable risk factors for spermatogenic failure. The protective nature of G-29-A919-A2039 haplotype cannot be concluded without additional studies.

Analysis of polymorphisms in the SRD5A2 gene and semen parameters in Estonian men.

Spermatogenesis is an androgen-dependent process and polymorphisms in genes encoding androgen-metabolizing enzymes may be associated with impaired male fertility. The enzyme steroid 5α-reductase converts testosterone into dihydrotestosterone. We analyzed genotype frequencies of 5 single-nucleotide polymorphisms (SNPs 1-5) (rs632148, rs523349, rs2300701, rs2268797, and rs12470143) in the steroid 5α-reductase type 2 gene (SRD5A2) in 132 azoospermic or oligozoospermic and 211 normozoospermic men. We found no association between investigated genotypes and the occurrence of male infertility. Linear regression analysis revealed a significant correlation between certain alleles of SNP1 and SNP5 and testicular volume among control men. Normozoospermic men carrying the minor allele of all but SNP5 polymorphism exhibited a significantly higher proportion of progressively motile spermatozoa, compared with major homozygotes. However, SRD5A2 genotypes did not influence sperm concentration, serum testosterone, or follicle-stimulating hormone levels in controls. Our results suggest that polymorphisms examined in SRD5A2 exhibit no adverse effect on semen parameters in Estonian men.