A novel functional role for apolipoprotein B in male infertility in heterozygous apolipoprotein B knockout mice.

Male infertility, affecting as many as 10% of the adult population, is an extremely prevalent disorder. In most cases, the cause of the condition is unknown, and genetic factors that might affect male fertility, other than some sequences on the Y chromosome, have not been identified. We report here that male mice heterozygous for a targeted mutation of the apolipoprotein B (apo B) gene exhibit severely compromised fertility. Sperm from these mice failed to fertilize eggs both in vivo and in vitro. However, these sperm were able to fertilize eggs once the zona pellucida was removed but displayed persistent abnormal binding to the egg after fertilization. In vitro fertilization-related and other experiments revealed reduced sperm motility, survival time, and sperm count also contributed to the infertility phenotype. Recognition of the infertility phenotype led to the identification of apo B mRNA in the testes and epididymides of normal mice, and these transcripts were substantially reduced in the affected animals. Moreover, when the genomic sequence encoding human apo B was introduced into these animals, normal fertility was restored. These findings suggest that this genetic locus may have an important impact on male fertility and identify a previously unrecognized function for apo B.

Targeted disruption of the mZP3 gene results in production of eggs lacking a zona pellucida and infertility in female mice.

Mammalian eggs are surrounded by a thick extracellular coat, the zona pellucida, that plays important roles during early development. The mouse egg zona pellucida is constructed of three glycoproteins, called mZP1, mZP2, and mZP3. The gene encoding mZP3 is expressed only by growing oocytes during a 2- to 3-week period of oogenesis. Here, the mZP3 gene was disrupted by targeted mutagenesis using homologous recombination in mouse embryonic stem cells. Viable female mice homozygous for the mutated mZP3 allele (mZP3-/-) were obtained. These mice are indistinguishable in appearance from wild-type (mZP3+/+) and heterozygous (mZP3+/-) littermates. However, although ovaries of juvenile and adult mZP3-/- females possess growing and fully grown oocytes, the oocytes completely lack a zona pellucida. Consistent with this observation, eggs recovered from oviducts of superovulated, adult mZP3-/- females also lack a zona pellucida. Thus far, mZP3-/- females mated with wild-type males have failed to become pregnant.

Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility.

In addition to the five 70-kDa heat shock proteins (HSP70) common to germ cells and somatic tissues of mammals, spermatogenic cells synthesize HSP70-2 during meiosis. To determine if this unique stress protein has a critical role in meiosis, we used gene-targeting techniques to disrupt Hsp70-2 in mice. Male mice homozygous for the mutant allele (Hsp70-2 -/-) did not synthesize HSP70-2, lacked postmeiotic spermatids and mature sperm, and were infertile. However, neither meiosis nor fertility was affected in female Hsp70-2 -/- mice. We previously found that HSP70-2 is associated with synaptonemal complexes in the nucleus of meiotic spermatocytes from mice and hamsters. While synaptonemal complexes assembled in Hsp70-2 -/- spermatocytes, structural abnormalities became apparent in these cells by late prophase, and development rarely progressed to the meiotic divisions. Furthermore, analysis of nuclei and genomic DNA indicated that the failure of meiosis in Hsp70-2 -/- mice was coincident with a dramatic increase in spermatocyte apoptosis. These results suggest that HSP70-2 participates in synaptonemal complex function during meiosis in male germ cells and is linked to mechanisms that inhibit apoptosis.

Self-reported difficulty in conceiving as a measure of infertility

BACKGROUND: This study aimed to explore the meaning and potential use of women's self-reported difficulties in conceiving as a measure of infertility in epidemiological studies, and to compare women's stated reasons for infertility with information in their medical records. METHODS: Data were available from a population-based case-control study of ovarian cancer involving 1638 women. The sensitivity and specificity of women's self-reported infertility were calculated against their estimated fertility status based on detailed reproductive histories. Self-reported reasons for infertility were compared with diagnoses documented in women's medical records. RESULTS: The sensitivity of women's self-reported difficulty in conceiving was 66 and 69% respectively when compared with calendar-derived and self-reported times taken trying to conceive; its specificity was 95%. Forty-one (23%) of the 179 women for whom medical records were available had their self-reported fertility problem confirmed. Self-reported infertility causes could be compared with diagnoses in medical records for only 22 of these women. CONCLUSIONS: Self-reported difficulty conceiving is a useful measure of infertility for quantifying the burden of fertility problems experienced in the community. Validation of reasons for infertility is unlikely to be feasible through examination of medical records. Improved education of the public regarding the availability and success rates of infertility treatments is proposed.

Potential causes of ethnic group disparities in infertility:a hospital database study

Introduction - Lower success rates of in vitro fertilisation (IVF) in South East Asian countries compared to Western countries in informal studies and surveys was considered a reflection of variations in methodology and expertise. However, recent studies on the effects of ethnicity on success rates of infertility procedures in western countries have suggested other inherent contributing factors to the ethnic disparity but the evidence evaluating these is lacking. In our study we aim to investigate some of the comorbidities that might cause ethnic disparity to infertility and related procedures from hospital admissions data. Methods - Anonymous hospital admissions data on patients of various ethnic groups with infertility, comorbidities and infertility procedures from multiple hospitals in Birmingham andManchester, UK between 2000 and 2013 were obtained from the local health authority computerised hospital activity analysis register using ICD-10 and OPCS coding systems. Statistical analysis was performed using SPSS version 20.Results Of 522 223 female patients aged 18 and over, there were44 758 (8.4%) patients from South Asian (SA) community. 1156(13.4%) of the 8653 patients coded for infertility were SA, whichis a considerably higher proportion of the background SA population. For IVF procedures, the percentage of SA increased to15.4% (233 of the total 1479 patients). The mean age of SA codedfor infertility (30.6 ± 4.7 SD years versus 32.8 ± 4.9 SD years)and IVF (30.4 ± 4.3 SD years versus 32.7 ± 4.4 SD years) was significantly lower than caucasian patien ts (P < 0.001). A multivariate logistic regression model looking at patients with infertility, accounting for variations in age, showed that SA have significantly higher prevalence of hypothyroidism, obesity andiron-deficiency anaemia compared to caucasians but lower prevalence of endometriosis. Interestingly, psychiatric and psychological conditions diagnoses were seldom registered in infertility patients. Conclusion - Other studies suggest that various cultural, lifestyles, psychosocial and socio-economic factors may explain the disparities in IVF success rates between South Asians and caucasians. The fact that SA infertility and IVF patients, in ou rstudy, were significantly younger than caucasians and that their proportion is considerably higher than the background South Asian population suggests the influence of these factors. A significant psychiatric disease burden in other conditions and low numbers in our data suggest under diagnosis in this group.Despite the limitations of the coding data, from our study, we propose that hypothyroidism, obesity and/or iron-deficiency anaemia should be considered for the ethnic disparity. Further research in this topic is essential to fully investigate the reasons for such ethnic disparities.

Reframing the Debate Around State Responses to Infertility : Considering the Harms of Subfertility and Involuntary Childlessness

Peer reviewed

Mycobacterium tuberculosis infection in women with unexplained infertility

Background: Genital tuberculosis (GTB) is an important cause of female infertility, especially in developing countries. The positive results of polymerase chain reaction (PCR) in endometrial GTB in the absence of tubal damage raise the possibility of the detection of sub-clinical or latent disease, with doubtful benefits of treatment. Objective: To evaluate the mycobacterium tuberculosis infection in endometrial biopsy samples collected from unexplained infertile women attending Yazd Research and Clinical Center for Infertility by using PCR techniques. Materials and Methods: In this cross sectional study, 144 infertile women with unexplained infertility aged 20-35 years old and normal Histro-saplango graphy findings were enrolled. Endometrial biopsy samples from each participant were tested for mycobacterium tuberculosis detecting by PCR. In 93 patients, peritoneal fluid was also taken for culture and PCR. Results: The PCR results of endometrial specimens were negative in all cases, demonstrating that there was no GTB infection among our patients. Conclusion: Our results showed that GTB could not be considered as a major problem in women with unexplained infertility. Although, studies have indicated that PCR is a useful method in diagnosing early GTB disease in infertile women with no demonstrable evidence of tubal or endometrial involvement.

Factor structure of the General Health Questionnaire-28 (GHQ-28) from infertile women attending the Yazd Research and Clinical Center for Infertility

Background: Nowadays, infertility problems have become a social concern, and are associated with multiple psychological and social problems. Also, it affects the interpersonal communication between the individual, familial, and social characteristics. Since women are exposed to stressors of physical, mental, social factors, and treatment of infertility, providing a psychometric screening tool is necessary for disorders of this group. Objective: The aim of this study was to determine the factor structure of the general health questionnaire-28 to discover mental disorders in infertile women. Materials and Methods: In this study, 220 infertile women undergoing treatment of infertility were selected from the Yazd Research and Clinical Center for Infertility with convenience sampling in 2011. After completing the general health questionnaire by the project manager, validity and, reliability of the questionnaire were calculated by confirmatory factor structure and Cronbach's alpha, respectively. Results: Four factors, including anxiety and insomnia, social dysfunction, depression, and physical symptoms were extracted from the factor structure. 50.12% of the total variance was explained by four factors. The reliability coefficient of the questionnaire was obtained 0.90. Conclusion: Analysis of the factor structure and reliability of General Health Questionnaire-28 showed that it is suitable as a screening instrument for assessing general health of infertile women.

Chlamydial infection and spatial ascension of the female genital tract : a novel hybrid cellular automata and continuum mathematical model

Sexually transmitted chlamydial infection initially establishes in the endocervix in females, but if the infection ascends the genital tract, significant disease, including infertility, can result. Many of the mechanisms associated with chlamydial infection kinetics and disease ascension are unknown. We attempt to elucidate some of these processes by developing a novel mathematical model, using a cellular automata–partial differential equation model. We matched our model outputs to experimental data of chlamydial infection of the guinea-pig cervix and carried out sensitivity analyses to determine the relative influence of model parameters. We found that the rate of recruitment and action of innate immune cells to clear extracellular chlamydial particles and the rate of passive movement of chlamydial particles are the dominant factors in determining the early course of infection, magnitude of the peak chlamydial time course and the time of the peak. The rate of passive movement was found to be the most important factor in determining whether infection would ascend to the upper genital tract. This study highlights the importance of early innate immunity in the control of chlamydial infection and the significance of motility-diffusive properties and the adaptive immune response in the magnitude of infection and in its ascension.