Aromatase gene (CYP19A1) variants, female infertility and ovarian stimulation outcome: a preliminary report.

Progress has been made towards ascertaining the genetic predictors of ovarian stimulation in IVF. Aromatase cytochrome P450, encoded by the CYP19A1 gene, catalyses a key step in ovarian oestrogen biosynthesis. Hence, the aromatase gene is an attractive candidate for genetic studies. This study aimed to examine the genetic influences of CYP19A1 TCT trinucleotide insertion/deletion (Ins/Del) and (TTTA)(n) microsatellite intronic polymorphisms on ovarian stimulation outcome and aetiology of female infertility. IVF patients (n = 152) underwent ovarian stimulation according to recombinant FSH and gonadotrophin releasing hormone antagonist protocol. Del/Del homozygous patients with shorter TTTA repeats exhibited decreased ovarian FSH sensitivity in ovarian stimulation, which may reflect variations in aromatase gene expression during early antral follicle development. Accordingly, this study demonstrates correlations between Del allele and shorter (TTTA)(n) repeat sizes with smaller ovaries (r = -0.70, P = 0.047) and fewer antral follicles (r = 0.21, P = 0.018) on days 3-5 of spontaneous menstrual cycle, respectively. Furthermore, Del variation linked with low-repeat-number (TTTA)(n) alleles are involved in enhanced genetic susceptibility to unexplained infertility (adjusted OR = 4.33, P = 0.039) and endometriosis (r = -0.88, P = 0.026), which corroborates evidence on the overlapping patient profiles of ovarian dysfunction in both types of female infertility.

Anti-FSH antibodies associate with poor outcome of ovarian stimulation in IVF.

FSH is required for spontaneous folliculogenesis and is widely used in ovarian stimulation in IVF. Previously, increased concentrations of antibodies against FSH (anti-FSH) have been demonstrated in infertile women. This study aimed to: (i) assess the possible association of anti-FSH with an adverse outcome of IVF with regard to clinical parameters characterizing the ovarian reserve; and (ii) compare serum and follicular fluid (FF) anti-FSH concentrations in relation to follicle size and endocrine markers. IVF patients (n = 182) subjected to gonadotrophin-releasing hormone-antagonist protocol were assessed for anti-FSH using enzyme-linked immunosorbent assay. Increased concentrations of serum anti-FSH immunoglobulin (Ig)G and IgA were associated with impaired ovarian stimulation outcome, with cut-off values <1.0 arbitrary units predicting poor ovarian response (

Circulating anti-follicle-stimulating hormone immunoglobulin A in women: a sperm-prone reaction of mucosal tolerance?

Antibodies against follicle-stimulating hormone (anti-FSH) are present in infertile female sera. Follicle-stimulating hormone as antigen is present in female sera and introduced to the genital tract mucosa as a constituent of semen. The female immune system is activated by semen constituents during insemination to induce mucosal tolerance. We found that circulating anti-FSH IgA correlated with IgA against sperm surface antigens in female patients undergoing IVF. Our results suggest that anti-FSH and anti-sperm IgA could share antigenic origin, being induced possibly by mucosal tolerance to semen.

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.

The contribution of genetic variations of aryl hydrocarbon receptor pathway genes to male factor infertility.

OBJECTIVE: To determine whether the polymorphisms in aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor repressor (AHRR), and aryl hydrocarbon receptor nuclear translocator (ARNT) genes are associated with male factor infertility. DESIGN: An association study. SETTING: University research laboratory and andrology clinic. PATIENT(S): The subjects were infertile Estonian men (n = 112) with azoospermia or oligozoospermia and controls (n = 212) with normal sperm parameters. INTERVENTION(S): Blood samples were obtained for DNA extraction and genotyping. MAIN OUTCOME MEASURE(S): AHR (Arg554Lys), AHRR (Pro185Ala), and ARNT (G/C allele) polymorphisms were genotyped using allele-specific polymerase chain reaction. Allele and genotype frequencies were compared between infertile men and controls and separately in the normozoospermia, oligozoospermia, and azoospermia groups. RESULT(S): The AHRR Ala185Ala genotype was implicated in susceptibility to male factor infertility. Ala/Ala genotype frequency increased in the following order: normozoospermia (18.0%), oligozoospermia (26.0%), azoospermia (42.1%). Allele and genotype frequencies of AHR and ARNT polymorphisms were similar between cases and controls. CONCLUSION(S): We demonstrated that the AHRR Pro185Ala polymorphism contributed to a predisposition to male factor infertility in the Estonian population. A greater prevalence of the Ala/Ala genotype was found among infertile patients.

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.

Putative predictors of antibodies against follicle-stimulating hormone in female infertility: a study based on in vitro fertilization patients.

PROBLEM: We have previously demonstrated the presence of naturally occurring antibodies against follicle-stimulating hormone (FSH) in patients with endometriosis and polycystic ovary syndrome (PCOS). Here, we investigated the parameters associated with anti-FSH antibodies in in vitro fertilization (IVF) patients. METHODS OF STUDY: The following parameters were studied in 135 patients: peripheral FSH levels, FSH beta-subunit gene (FSHB) haplotypes, history of previous IVF, and susceptibility to autoimmune reactions in general [seven common autoantibodies (against nuclear antigens on human and rodent substrates, smooth muscle, gastric parietal cells, beta2-glycoprotein I, cardiolipin, and thyroid peroxidase) and HLA-DQB1 alleles]. RESULTS: Although the anti-FSH levels were higher in patients when compared with controls, those higher levels were not associated with FSHB haplotypes. The anti-FSH IgM associated with (i) the levels of FSH in women with male and tubal factor infertility; (ii) the history of IVF in patients with PCOS, endometriosis, and unexplained infertility; and (iii) the production of common autoantibodies among all IVF patients. The anti-FSH IgA associated with HLA-DQB1*03. The anti-FSH IgG correlated with the values of anti-FSH IgA and IgM. CONCLUSION: Anti-FSH may be naturally occurring antibodies associated with peripheral FSH concentrations, but increased in infertile women with dysregulation of immune reactions and repeatedly performed IVF.

Controlled ovarian hyperstimulation changes the prevalence of serum autoantibodies in in vitro fertilization patients.

PROBLEM: Autoimmune mechanisms are involved in etiology of female infertility, the medical problem frequently treated by in vitro fertilization (IVF). Controlled ovarian hyperstimulation (COH) with supraphysiological levels of sex hormones is achieved by IVF. METHODS OF STUDY: Anti-human-ovary and eight common autoantibodies [nuclear (ANA-H, ANA-R on human HEp-2 cell line and rodent antigen, respectively), smooth muscle (SMA), parietal cell, thyroid microsomal, mitochondrial, beta2-glycoprotein-I, cardiolipin antibodies] found in IVF patients (n = 129) were analyzed with regard to the number of previous IVF procedures and the age of the patient. The changes in autoimmune reactions caused by the COH were determined. RESULTS: Endometriosis and polycystic ovary syndrome were associated with a higher number of common serum autoantibodies compared with the tubal factor infertility (Proportion test, P < 0.05). ANA-R was associated with unexplained infertility [adjusted odds ratio (aOR) 8.79, P = 0.038]. SMA correlated with endometriosis (aOR 37.29, P = 0.008), male factor infertility (aOR 20.45, P = 0.018) and with the previous IVF procedures (aOR 2.87, P = 0.013). There was an overall decrease in the number of detectible autoantibodies after COH (Proportion test, P < 0.05). CONCLUSION: COH may have a suppressive effect on the humoral immunity by the time of embryo transfer but more conclusive studies are needed.

IgG, IgA and IgM antibodies against FSH: serological markers of pathogenic autoimmunity or of normal immunoregulation?

PROBLEM: Autoimmune mechanisms are often involved in causing infertility. Among the possible targets of autoantibodies, the follicle-stimulating hormone (FSH) which regulates the follicular maturation in human ovary is a promising candidate. We aimed to study whether anti-FSH-antibodies might be involved in different clinical types of infertility. METHOD OF STUDY: The study group consisted of 178 patients (75 with polycystic ovary syndrome (PCOS), 103 with endometriosis) and 75 pregnant women. Female blood donors formed the control group (n = 85). Indirect enzyme-linked immunosorbent assay tests were performed using purified FSH as antigens and a synthetic peptide corresponding to the 78-93 region (V14D) of the human FSH beta-chain. CONCLUSION: We showed that anti-FSH-antibodies were present in controls and their production decreased during pregnancy. Endometriosis and PCOS were associated with higher values of anti-FSH-immunoglobulin (Ig)A, anti-V14D-IgA, and endometriosis with anti-V14D-IgG. Our data suggest that anti-FSH-IgA could be a marker of ovarian disorders that cause infertility.