STUDY QUESTION

Can time-lapse analysis of cell division timings [morphokinetics (MK)] in mouse embryos detect toxins at concentrations that do not affect blastocyst formation?

SUMMARY ANSWER

An MK algorithm enhances assay sensitivity while providing results 24–48 h sooner than the traditional mouse embryo assay (MEA).

WHAT IS KNOWN ALREADY

Current quality control testing methodology is sensitive but further improvements are needed to assure optimal culture conditions. MKs of embryo development may detect small variations in culture conditions.

STUDY DESIGN

Cross sectional—control versus treatment. Mouse embryo development kinetics of 466 embryos were analyzed according to exposure to various concentrations of toxins and toxic mineral oil.

MATERIALS, SETTING, METHODS

Cryopreserved 1-cell embryos from F1 hybrid mice were cultured with cumene hydroperoxide (CH) (0, 2, 4, 6 and 8 µM) and Triton X-100 (TX-100; 0, 0.0008, 0.0012, 0.0016 and 0.002%). Using the Embryoscope, time-lapse images were obtained every 20 min for 120 h in seven focal planes. End-points were timing and pattern of cell division and embryo development. The blastocyst rate (BR) was defined as the percentage of embryos that developed to the expanded blastocyst stage within 96 h.

MAIN RESULTS AND THE ROLE OF CHANCE

BR was not affected for embryos cultured in the three lowest concentrations of CH and the four lowest concentrations of TX-100. In contrast, a unique MK model detected all concentrations tested (P < 0.05). The MK model identified toxicity in two lots of toxic mineral oil that did not affect BR (P < 0.05).

LIMITATIONS, REASONS FOR CAUTION

A limited number of toxins were used so that the results may not apply to all potential embryo toxins. A larger sample size may also demonstrate other statistically significant developmental kinetic parameters.

WIDER IMPLICATIONS OF THE FINDINGS

MKs in mouse embryos are a sensitive and efficient method for quality control testing of in vitro culture conditions. BR, the end-point of traditional quality control assays, did not detect sublethal concentrations of toxins in the culture milieu in our study. This study demonstrates that temporal variation at key developmental stages reflects the quality of the culture environment. An MEA that incorporates MK will provide enhanced sensitivity and faster turn-around times.

STUDY FUNDING/COMPETING INTEREST(S)

The study was supported by Mayo Clinic Department of Obstetrics and Gynecology Small Grant Program. The authors have no competing interests to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1776?rss=1

STUDY QUESTION

Is there a relationship between body mass index (BMI), body shape and endometriosis?

SUMMARY ANSWER

Endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution.

WHAT IS KNOWN ALREADY

The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth.

STUDY DESIGN, SIZE, DURATION

Prospective cohort study using data collected from 116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study II cohort.

PARTICIPANTS/MATERIALS, METHODS AND SETTING

Cases were restricted to laparoscopically confirmed endometriosis. Weight at age 18 and height were reported at baseline, and current weight was updated every 2 years. Waist and hip measurements were first taken in 1993 and updated in 2005. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models with time-varying covariates.

MAIN RESULTS AND THE ROLE OF CHANCE

A total of 5504 incident cases of endometriosis were reported during 1 299 349 woman-years (incidence rate = 385 per 100 000 woman-years). BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P-value, test for linear trend <0.0001). Both associations were stronger among infertile women. Obese infertile women with current BMIs of 35–39.9 kg/m² and ≥40 kg/m² had a 55% (95% CI 0.30–0.67) and a 62% (95% CI 0.23–0.62) lower risk of endometriosis, respectively, compared with the low-normal BMI referent (18.5–22.4 kg/m²). Rates of endometriosis were nearly 3-fold higher in women with waist-to-hip ratios <0.60 (RR = 2.78, 95% CI 1.38–5.60) compared with those with waist-to-hip ratios between 0.70 and 0.79, although the sample size for this category was very small.

LIMITATIONS AND REASONS FOR CAUTION

Although women with undiagnosed endometriosis certainly remain in the comparison population even in this prospective cohort study, the community prevalence of endometriosis in an asymptomatic population is very low. Moreover, the characteristics of this small proportion of undiagnosed cases are diluted among the >90 000 women accurately defined as being endometriosis-free and are, therefore, unlikely to impact on effect estimation. Although geographically diverse, the NHS II cohort is overwhelmingly Caucasian, which may limit generalizability to more ethnically diverse populations.

WIDER IMPLICATIONS OF THE STUDY

The results of this study suggest that endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution.

STUDY FUNDING/COMPETING INTEREST

This study was supported by research grants HD48544 and HD52473 and HD57210 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Nurses' Health Study II is supported by the Public Health Service grant CA50385 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. None of the authors has a conflict of interest to disclose.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1783?rss=1

STUDY QUESTION

What are the reproductive and obstetric outcomes in patients undergoing radical abdominal trachelectomy (RAT) for early-stage cervical cancer?

SUMMARY ANSWER

When RAT was performed before a pregnancy achieved with fertility treatments, pregnancy rate of 36.2% was obtained and 71.4% of these women gave birth at ≥32 weeks of gestation.

WHAT IS KNOWN ALREADY

Reproductive and obstetric outcomes after radical vaginal trachelectomy (RVT) are well documented; however, these outcomes after RAT have not been well studied.

STUDY DESIGN, SIZE, DURATION

This is a retrospective cohort study of patients at a single institution who underwent RAT and became pregnant. Reproductive and obstetric outcomes of 114 patients who had undergone RAT from September 2002 to December 2010 were investigated.

PARTICIPANTS/MATERIAL, SETTING, METHODS

Women of reproductive age with early-stage cervical cancer who wished to preserve their fertility were documented.

MAIN RESULTS AND THE ROLE OF CHANCE

Patients' median age was 33 years (25–40 years). A total of 31 pregnancies were achieved in 25 patients and 6 patients had 2 pregnancies. Eighteen of 25 patients (72.0%) had infertility problems; 17 patients conceived with IVF-embryo transfer and 1 patient with intrauterine insemination. The pregnancy rate among patients who wished to conceive was 36.2% (25/69). Among 31 pregnancies in 25 patients, 4 patients had first trimester miscarriage and 1 patient had second trimester miscarriage. Excluding the five patients who miscarried and the five ongoing pregnancies, all the 21 patients had deliveries by Cesarean section. Four patients had a preterm birth in the second trimester and 17 patients delivered in the third trimester. Of the 17 pregnancies that reached the third trimester, 2 (11.8%) were preterm births between 29 and 32 weeks, 11 (64.7%) were delivered between 32 and 37 weeks and 4 (23.5%) at ≥37 weeks of gestation.

LIMITATIONS, REASONS FOR CAUTION

Because of the retrospective data collection, not all pregnancies may have been recorded.

WIDER IMPLICATIONS OF THE FINDINGS

Prospective multicenter studies are needed to determine if the results shown in this retrospective cohort can be generalized to all patients with early-stage cervical cancer who wish to undergo the fertility-sparing RAT procedure.

STUDY FUNDING/COMPETING INTEREST(S)

There was no funding for this study. No conflicts of interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1793?rss=1

STUDY QUESTION

Are the vasoactive peptide neurokinin B (NKB) and its preferred NK₃ receptor (NK₃R) differentially expressed in leiomyomas compared with normal myometrium?

SUMMARY ANSWER

In leiomyomas, NKB is up-regulated and delocalized, while its preferred NK₃R is also differentially regulated.

WHAT IS KNOWN ALREADY

The expression of NKB/NK₃R in the central nervous system is essential for proper function of the human reproductive axis. Additionally, this system is also widely expressed throughout the female genital tract. Leiomyomas impair fertility and are a major source of abnormal uterine bleeding. The aberrant synthesis of local factors can contribute to the pathological symptoms observed in women with leiomyomata. NKB could be one of these factors, since a vasoactive role of this peptide at a peripheral level has been observed in different systems and species, including humans. NK₃R is strongly regulated by estrogens and its activation leads to nuclear translocation affecting chromatin structure and gene expression.

STUDY DESIGN, SIZE, DURATION

Samples were obtained between 2006 and 2012 from 28 women of reproductive age at different stages of the menstrual cycle by hysterectomy. Leiomyomas and matched macroscopically normal myometrium from each woman were analysed in vitro.

PARTICIPANTS/MATERIALS, SETTING, METHODS

RT–PCR, quantitative real time, immunohistochemistry and in situ hybridization were used to investigate the pattern of expression of NKB/NK₃R in tissue samples.

MAIN RESULTS AND THE ROLE OF CHANCE

Expression of the gene encoding NKB (TAC3) was up-regulated 20-fold in leiomyomas, compared with matched myometrium (P = 0.0008). In tumour tissue, not only connective cells, but also myometrial, endothelial and vascular smooth muscle cells express TAC3 mRNA. Immunoreactivity to NKB was preferentially located in the smooth muscle cell nuclei from normal myometrium in the secretory phase, unlike matched leiomyoma, which showed a predominant cytoplasmic expression pattern. In the normal myometrium, TACR3 mRNA showed variable expression throughout the menstrual phases, with samples showing strong, reduced or no amplification. In leiomyoma, TACR3 was significantly up-regulated compared with matched myometrium (P = 0.0349).

LIMITATIONS, REASONS FOR CAUTION

This study is descriptive and although we observed clear differential regulation of the NKB/NK₃R system at mRNA and immunohistochemical staining levels in leiomyoma, future functional studies are needed to determine the precise role of NKB in the myometrium in normal and pathological conditions. In addition, further analysis (e.g. in cell culture models) will be required to determine the role of NKB in the nucleus of normal smooth muscle cells, whether nuclear translocation is mediated by NK₃R and the consequences of the cytoplasmic expression of NKB in tumour cells.

WIDER IMPLICATIONS OF THE FINDINGS

The NKB/NK₃R system dysregulation observed in leiomyoma may contribute to the pathological symptoms observed in women with leiomyomata.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported in part by research grants from the Fundación Canaria del Instituto Canario de Investigación del Cáncer (ICIC), Gobierno de Canarias (PI 2007/001), Junta de Andalucía (P08-CVI-04185) and the Spanish Ministerio de Ciencia e Innovación (CTQ2011-25564), with joint financing by FEDER and FSE funds from the European Union. H.C. is supported by a research grant from Gobierno de Canarias. The authors have no conflicts of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1799?rss=1

STUDY QUESTION

Is there a better alternative to the conventional cryopreservation protocols for human testicular tissue banking?

SUMMARY ANSWER

Uncontrolled slow freezing (USF) using 1.5 M dimethylsulphoxide (DMSO) and 0.15 M sucrose as cryoprotectants appears to be a user-friendly and efficient method for the cryopreservation of human testicular tissue.

WHAT IS KNOWN ALREADY

Currently, time-consuming controlled slow freezing (CSF) protocols that need expensive equipment are commonly used for human testicular tissue banking. USF and vitrification are cryopreservation techniques that were successfully applied in several animal models but need further exploration with human tissue.

STUDY DESIGN, SIZE, DURATION

Fragments (n = 160) of testicular tissue from 14 patients undergoing vasectomy reversal were assigned to a fresh control group or one of the following cryopreservation procedures: CSF using DMSO at a concentration of 0.7 or 1.5 M in the presence (+S) or absence of sucrose (–S), USF using either 0.7 or 1.5 M DMSO combined with sucrose, solid-surface vitrification (SSV) or direct cover vitrification (DCV).

MATERIALS, SETTING, METHODS

Light microscopic evaluations were performed to study apoptosis, germ cell proliferation ability, spermatogonial survival, coherence of the seminiferous epithelium and integrity of the interstitial compartment after cryopreservation. Ultrastructural alterations were studied by scoring cryodamage to four relevant testicular cell types.

MAIN RESULTS AND THE ROLE OF CHANCE

The USF 1.5 M DMSO + S protocol proved not solely to prevent cell death and to preserve seminiferous epithelial coherence, interstitial compartment integrity, SG and their potential to divide but also protected the testicular cell ultrastructure. A significant reduction in the number of SG per tubule from 21.4 ± 5.6 in control tissue to 4.9 ± 2.1, 8.2 ± 5.4, 11.6 ± 5.1, 8.8 ± 3.9, 12.6 ± 4.4 and 11.7 ± 5.7 was observed after cryopreservation combined with at least one other form of cryoinjury when using CSF 0.7 M DMSO –S, CSF 0.7 M DMSO + S, CSF 1.5 M DMSO + S, USF 0.7 M DMSO + S, SSV and direct cover vitrification (DCV), respectively (P < 0.001).

LIMITATIONS, REASONS FOR CAUTION

Supplementary research is required to investigate the effect on tissue functionality and to confirm this study's findings using prepubertal tissue.

WIDER IMPLICATIONS OF THE FINDINGS

An optimal cryopreservation protocol enhances the chances for successful fertility restoration. USF, being an easy and cost-effective alternative to CSF, would be preferable for laboratories in developing countries or whenever tissue is to be procured from a diseased child at a site distant from the banking facility.

STUDY FUNDING/COMPETING INTEREST(S)

This study is supported by a PhD grant from the Agency for Innovation by Science and Technology and research grants from the Flemish League against Cancer-Public Utility Foundation, the Scientific Research Foundation Flanders, Methusalem grant and the Vrije Universiteit Brussel. E.G. is a postdoctoral fellow of the Scientific Research Foundation Flanders. The authors declare that no competing interests exist.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1816?rss=1

STUDY QUESTION

Is bacterial vaginosis (BV) associated with the cause of infertility and does BV impinge on conception rates and early pregnancy loss following IVF?

SUMMARY ANSWER

The incidence of BV is significantly higher among patients with tubal infertility when compared with patients with non-tubal infertility. BV does not impinge on conception rates but is significantly associated with preclinical pregnancy loss, though not with first trimester abortion.

WHAT IS KNOWN ALREADY

BV is prevalent in patients with infertility, as evident from studies across the world.

STUDY DESIGN, SIZE, DURATION

This study is a meta-analysis of data on the prevalence of BV in women with infertility, the association between BV and the cause of infertility, and the associations between BV and conception rates and early pregnancy loss following IVF. The meta-analyses of the various topics involved different numbers of studies: prevalence of BV with infertility—12 studies, association with tubal infertility—3 studies and associations with conception rates—6 studies, with early preclinical pregnancy loss—2 studies and with clinical pregnancy loss—4 studies.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Systematic literature searches of the electronic databases, PubMed, EMBASE, CINAHL, the Cochrane Library and ISI Web of Knowledge were performed up to September 2012. Studies were included if they reported on, at least, one of the following: prevalence of BV in infertility patients, association between BV and the cause of infertility, association between BV and conception rates with IVF or association between BV and early pregnancy loss. Studies were considered eligible if BV was diagnosed through standardized criteria like Nugent's criteria or Hay-Ison's criteria. In none of the studies, infertility as such was defined, but patients were described as unselected patients undergoing IVF.

MAIN RESULTS AND THE ROLE OF CHANCE

The estimated prevalence of BV (Nugent score >6) in infertile women is 19% [95% confidence interval (CI): 14–25%]. Abnormal microflora including BV and intermediate microflora (Nugent scores 4–10) occurs in 39% of the infertile patients (95% CI: 26–52%). BV is significantly more prevalent in women with infertility compared with antenatal women in the same population [OR (odds ratio) 3.32, 95% CI 1.53–7.20].

BV is significantly more prevalent in women with tubal infertility compared with women with other causes of infertility (OR 2.77, 95% CI 1.62–4.75). BV is not associated with decreased conception rates (OR 1.03, 95% CI 0.79–1.33). Similarly, none of the studies found an association between abnormal vaginal flora and conception rates following IVF treatment.

BV is associated with a significantly elevated risk of preclinical pregnancy loss (OR 2.36, 95% CI: 1.24–4.51). BV is not associated with an increased risk of first trimester miscarriage (OR 1.20, 95%CI: 0.53–2.75).

LIMITATIONS, REASONS FOR CAUTION

All included studies were centre based. In addition, publication bias cannot be ruled out. Furthermore, all estimates are obtained using an absolute minimum of studies. The standard error on the estimates is so large that it does not allow for any formal statistical conclusions regarding heterogeneity between the effects reported in different studies.

WIDER IMPLICATIONS OF THE FINDINGS

It needs to be recognized that most inferences drawn in our study rely on a limited number of studies, potentially, endangering the generalizability of our findings. Moreover, all studies on cause of infertility in relation to BV included had a cross-sectional design and, therefore, do not allow for causal inferences. Still, there is strong circumstantial evidence that supports a causal link between BV and tubal infertility. Studies with a longitudinal design, on the other hand, strongly support a relation between BV and early pregnancy loss. Unfortunately, no study looked beyond first trimester fetal loss, although it is plausible that the high preterm birth rates with IVF are, at least, in part attributable to BV.

STUDY FUNDING/COMPETING INTEREST

None.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1809?rss=1

STUDY QUESTION

What is the profile of miRNAs in seminal plasma of patients with non-obstructive azoospermia (NOA)?

SUMMARY ANSWER

miR-141, miR-429 and miR-7-1-3p are significantly increased in seminal plasma of patients with NOA compared with fertile controls.

WHAT IS KNOWN ALREADY

There is currently an urgent need to develop a noninvasive diagnostic test for NOA. Altered microRNA (miRNA) profiles have been proposed as potential biomarkers for the diagnosis of disease states.

STUDY DESIGN, SIZE, DURATION

A total of 200 subjects (n = 100 for NOA, n = 100 for fertile control) were recruited to participate in this study. Recruitment took place from May 2008 to June 2010.

PARTICIPANTS/MATERIALS, SETTING, METHODS

We employed a strategy consisting of initial screening by TaqMan Low Density Array then further validation with a TaqMan quantitative RT–PCR assay. Validation of the profiling results was conducted in two independent phases. In addition, the expression of the three validated seminal plasma miRNAs (sp-miRNAs) was examined in testicular tissues of patients with NOA and of fertile controls. Methylation status and functional analyses were also performed for the identified sp-miRNAs.

MAIN RESULTS AND THE ROLE OF CHANCE

miR-141, miR-429 and miR-7-1-3p were significantly increased in seminal plasma of patients with NOA compared with fertile controls. As sensitive and specific biomarkers, the profiling of these three identified sp-miRNAs provides a novel noninvasive, semen-based test for NOA diagnosis. The methylation status of these sp-miRNAs was inversely associated with their expression patterns. Additionally, we found that Cbl and Tgfβ2 were down-regulated by miR-141, while Rb1 and Pik3r3 were down-regulated by miR-7-1-3p.

LIMITATIONS, REASONS FOR CAUTION

miRNA expression profile was investigated in seminal plasma samples from only a small number of NOA patients. In future investigations, a larger sample size should be adopted and the functional role of the three sp-miRNAs should be further characterized in animal models.

WIDER IMPLICATIONS OF THE FINDINGS

Given that sp-miRNAs show reproducible and stable expression levels, they are potentially novel noninvasive biomarkers for the diagnosis of NOA. We propose that the three sp-miRNAs described above may participate in a methylation-miRNA-gene network related to NOA development. This work provides a foundation for interpretation of miRNA changes associated with pathogenesis of NOA and extends the current understanding of human NOA pathogenesis.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the following grants: Key Project of National Natural Science Foundation of China (No. 30930079), National Basic Research Program of China (973 Program) (No. 2009CB941703, 2011CB944304), National Natural Science Foundation of China (No. 81072328 and 30901232); Science and Technology Development Fund Key Project of Nanjing Medical University (No. 2012NJMU002) and Priority Academic Program Development of Jiangsu Higher Education Institutions. The funding organizations played no role in the design and conduct of the study, in collection, management, analysis and interpretation of the data, or in the presentation, review or approval of the manuscript. There are no conflicts of interest to be declared.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1827?rss=1

STUDY QUESTION

Do endometriomas induce an inflammatory reaction with increased cytokine concentrations in nearby follicles and thereby affect follicular development during controlled ovarian stimulation for in vitro fertilization (IVF)?

SUMMARY ANSWER

With most endometriomas, there is no evidence of increased cytokine concentrations in the ipsilateral leading follicle. Infrequently, the concentration of inflammatory cytokines is increased in the follicular fluid (FF) and associated with diminished ovarian response.

WHAT IS KNOWN ALREADY

The link between peritoneal endometriosis, inflammation and infertility is well established; however, the association between intraovarian inflammation and endometrioma is unknown.

STUDY DESIGN, SIZE, DURATION

This prospective cohort study included 117 infertile women undergoing IVF in a tertiary infertility clinic at Oslo University Hospital Rikshospitalet, Norway, during the period May 2009 to September 2011.

PARTICIPANTS, SETTING, METHODS

There were 47 patients with unilateral endometrioma and 17 patients with bilateral endometrioma, while the 53 control patients had unexplained or male factor infertility. Concentrations of IL-1β, IL-6, IL-8, IL-10, IL-12 and TNF-α were measured in serum and in the fluid of the largest pre-ovulatory follicles from each ovary of each participant.

MAIN RESULTS AND THE ROLE OF CHANCE

Cytokine levels in the follicular fluid from the two ovaries in women with unilateral endometriomas were comparable, and were not significantly altered compared with that of control groups with male factor infertility, unexplained infertility or bilateral endometriomas. Compared with serum levels, the follicular fluid levels of IL-8 and IL-6 were higher, suggesting a local production or recruitment. The follicular fluid IL-8 level varied considerably and showed an inverse relationship with IL-12, IL-10 and TNF-, suggesting a complex interaction between various immune cells. A small group of patients (n = 3) had increased levels of all follicular fluid cytokines combined with moderately to slightly elevated serum levels and these patients had a significantly lower ovarian response.

LIMITATIONS, REASONS FOR CAUTION

For ethical reasons, the endometriomas were diagnosed indirectly by ultrasound rather than by histology.

WIDER IMPLICATIONS OF THE FINDINGS

This paper reveals that endometriomas seldom induce inflammation in nearby follicles during IVF; therefore, routine cystectomy prior to IVF may not be necessary. Cytokine levels in the follicular fluid, nonetheless, show distinctive patterns and increased levels may be linked to reduced ovarian response independent of the cause of infertility.

STUDY FUNDING/COMPETING INTERESTS

The project was funded by the Norwegian Resource Centre for Women's Health, Oslo University Hospital. The authors have no conflicts of interests.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1837?rss=1

STUDY QUESTION

Do thrombin generation and haemostatic parameters differ during the two phases of the menstrual cycle?

SUMMARY ANSWER

Total thrombin concentration is higher during the luteal phase compared with the follicular phase of the menstrual cycle.

WHAT IS KNOWN ALREADY

The coagulation cascade is affected by many variables, such as fluctuations in the levels of sex hormones. The studies on the variations in haemostatic parameters during the menstrual cycle have produced diverse results.

STUDY DESIGN, SIZE, DURATION

Thrombin generation and selected haemostatic parameters (fibrinogen, factor II, factor VII, factor VIII, factor X, von Willebrand factor, antithrombin and D-dimer) were measured during the two phases of a normal menstrual cycle in 102 healthy women not taking any form of hormone medication.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The study cohort consisted of 102 healthy women with regular menstrual cycles. Thrombin generation was measured by the calibrated automated thrombogram method. Progesterone and sex hormone-binding globulin were measured by chemiluminescence enzyme immunoassays. Estradiol was measured by a sensitive radioimmunoassay. Fibrinogen was measured by a clotting method, antithrombin was measured by a chromogenic method and factor II, factor VII, factor VIII, factor X, von Willebrand factor and D-dimer were measured by photometric methods.

MAIN RESULTS AND THE ROLE OF CHANCE

It was shown that the total amount of generated thrombin (Endogenous Thrombin Potential) was significantly higher during the luteal compared with the follicular phase (P = 0.027). Factor X was significantly higher during the follicular phase (P = 0.028). Progesterone exhibited significant associations (measured by the least squares regression analysis) with fibrinogen and factor X during the follicular phase (P = 0.043 and P = 0.033, respectively) and with factors II and VII during the luteal phase (P = 0.034 and P = 0.024, respectively). The validity of the results from the regression analysis was further confirmed by performing correlation analyses (Pearson correlation matrix) for haemostatic markers for the luteal and follicular phases (accepted correlation level >0.8).

LIMITATIONS, REASONS FOR CAUTION

The wide confidence interval for the differences in endogenous thrombin potential during the two phases could imply that the size of the cohort may not be sufficient to fully evaluate the biological variations. Additionally, the haemostatic markers were not shown to have significant associations with thrombin generation, suggesting that the increased thrombin concentration during the luteal phase would be mediated by another mechanism, as yet unidentified.

WIDER IMPLICATIONS OF THE FINDINGS

The associations between progesterone and the haemostatic markers, as shown for both phases of the menstrual cycle, suggest a previously unknown or undefined yet potentially significant role for progesterone in the coagulation system. However, it has been shown that the use of progestogen-only preparations does not affect the coagulation system, which is partly the reason why they are considered safe for women with thrombophilia or previous thrombotic event. Further studies are required in order to demonstrate whether our results can be extrapolated for synthetic progestins, which might have significant implication on the indications for their use.

STUDY FUNDING/COMPETING INTEREST(S)

This study was supported by the Karolinska Institutet, Linköping University and the County Council of Östergötland. The authors report no conflicts of interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1846?rss=1

STUDY QUESTION

Do uric acid levels across the menstrual cycle show associations with endogenous estradiol (E₂) and reproductive hormone concentrations in regularly menstruating women?

SUMMARY ANSWER

Mean uric acid concentrations were highest during the follicular phase, and were inversely associated with E₂ and progesterone, and positively associated with FSH.

WHAT IS KNOWN ALREADY

E₂ may decrease serum levels of uric acid in post-menopausal women; however, the interplay between endogenous reproductive hormones and uric acid levels among regularly menstruating women has not been elucidated.

STUDY DESIGN, SIZE, DURATION

The BioCycle study was a prospective cohort study conducted at the University at Buffalo research centre from 2005 to 2007, which followed healthy women for one (n = 9) or 2 (n = 250) menstrual cycle(s).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Participants were healthy women aged 18–44 years. Hormones and uric acid were measured in serum eight times each cycle for up to two cycles. Marginal structural models with inverse probability of exposure weights were used to evaluate the associations between endogenous hormones and uric acid concentrations.

MAIN RESULTS AND THE ROLE OF CHANCE

Uric acid levels were observed to vary across the menstrual cycle, with the lowest levels observed during the luteal phase. Every log-unit increase in E₂ was associated with a decrease in uric acid of 1.1% (β = –0.011; 95% confidence interval (CI): –0.019, –0.004; persistent-effects model), and for every log-unit increase in progesterone, uric acid decreased by ~0.8% (β = –0.008; 95% CI: –0.012, –0.004; persistent-effects model). FSH was positively associated with uric acid concentrations, such that each log-unit increase was associated with a 1.6% increase in uric acid (β = 0.016; 95% CI: 0.005, 0.026; persistent-effects model). Progesterone and FSH were also associated with uric acid levels in acute-effects models. Of 509 cycles, 42 were anovulatory (8.3%). Higher uric acid levels were associated with increased odds of anovulation (odds ratio 2.39, 95% CI: 1.25, 4.56).

LIMITATIONS, REASONS FOR CAUTION

The change in uric acid levels among this cohort of healthy women was modest, and analysis was limited to two menstrual cycles. The women in this study were healthy and regularly menstruating, and as such there were few women with high uric acid levels and anovulatory cycles.

WIDER IMPLICATIONS OF THE FINDINGS

These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E₂ on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). No competing interests declared.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1853?rss=1

STUDY QUESTION

Do cell penetrating peptides (CPPs) translocate into spermatozoa and, if so, could they be utilized to deliver a much larger protein cargo?

SUMMARY ANSWER

Chemically diverse polycationic CPPs rapidly and efficiently translocate into spermatozoa. They exhibit differential accumulation within intracellular compartments without detrimental influences upon cellular viability or motility but they are relatively ineffective in transporting larger proteins.

WHAT IS ALREADY KNOWN

Endocytosis, the prevalent route of protein internalization into eukaryotic cells, is severely compromised in mature spermatozoa. Thus, the translocation of many bioactive agents into sperm is relatively inefficient. However, the delivery of bioactive moieties into mature spermatozoa could be significantly improved by the identification and utility of an efficient and inert vectorial delivery technology.

STUDY DESIGN

CPP translocation efficacies, their subsequent differential intracellular distribution and the influence of peptides upon viability were determined in bovine spermatozoa. Temporal analyses of sperm motility in the presence of exogenously CPPs utilized normozoospermic human donor samples.

MATERIALS AND METHODS

CPPs were prepared by manual, automated and microwave-enhanced solid phase synthesis. Confocal fluorescence microscopy determined the intracellular distribution of rhodamine-conjugated CPPs in spermatozoa. Quantitative uptake and kinetic analyses compared the translocation efficacies of chemically diverse CPPs and conjugates of biotinylated CPPs and avidin. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) conversion assays were employed to analyse the influence of CPPs upon sperm cell viability and sperm class assays determined the impact of CPPs on motility in capacitated and non-capacitated human samples.

MAIN RESULTS

Chemically heterogeneous CPPs readily translocated into sperm to accumulate within discrete intracellular compartments. Mitoparan (INLKKLAKL(Aib)KKIL), for example, specifically accumulated within the mitochondria located in the sperm midpiece. The unique plasma membrane composition of sperm is a critical factor that directly influences the uptake efficacy of structurally diverse CPPs. No correlations in efficacies were observed when comparing CPP uptake into sperm with either uptake into fibroblasts or direct translocation across a phosphatidylcholine membrane. These comparative investigations identified C105Y (CSIPPEVKFNKPFVYLI) as a most efficient pharmacokinetic modifier for general applications in sperm biology. Significantly, CPP uptake induced no detrimental influence upon either bovine sperm viability or the motility of human sperm. As a consequence of the lack of endocytotic machinery, the CPP-mediated delivery of much larger protein complexes into sperm is relatively inefficient when compared with the similar process in fibroblasts.

LIMITATIONS, REASONS FOR CAUTION

It is possible that some CPPs could directly influence aspects of sperm biology and physiology that were not analysed in this study.

WIDER IMPLICATIONS OF THE FINDINGS

CPP technologies have significant potential to deliver selected bioactive moieties and so could modulate the biology and physiology of human sperm biology both prior- and post-fertilization.

STUDY FUNDING/COMPETING INTERSTS

We are pleased to acknowledge financial support from the following sources: the Wellcome Trust, TENOVUS (Scotland), University of Dundee, Medical Research Council, NHS Tayside and Scottish Enterprise and the Research Institute in Healthcare Science, University of Wolverhampton. No conflicts of interest are reported by the authors.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1874?rss=1

STUDY QUESTION

Do mild analgesics affect the endocrine system of the human adult testis?

SUMMARY ANSWER

Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro.

WHAT IS KNOWN ALREADY

Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line.

STUDY DESIGN, SIZE, DURATION

Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10^–4 or 10^–5 M paracetamol, aspirin or indomethacin for 24–48 h. The effect of 10^–5 M ketoconazole, used as an anti-androgenic reference molecule, was also assessed.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods.

MAIN RESULTS AND THE ROLE OF CHANCE

The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play.

LIMITATIONS, REASONS FOR CAUTION

Our studies were performed in vitro.

WIDER IMPLICATIONS OF THE FINDINGS

We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.

STUDY FUNDING/COMPETING INTEREST(S)

This work was funded by Inserm (Institut national de la santé et de la recherche médicale), EHESP (Ecole des Hautes Etudes en Santé Publique), Ministère de l'Enseignement Supérieur et de la Recherche, Région Bretagne and Agence Nationale de sécurité du médicament et des produits de santé (IMPACTESTIS, Project no. AAP-2012-037). The authors declare they have no competing interests, be it financial, personal or professional.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1890?rss=1

STUDY QUESTION

Are there differences in the morphology, spectrum and biochemical phenotype between Sertoli cells from non-obstructive azoospermia (NOA) patients and those from obstructive azoospermia (OA) patients with normal spermatogenesis?

SUMMARY ANSWER

Sertoli cells from NOA patients are distinct from those from OA patients in terms of morphological features, Raman spectrum and phenotype including the expression of genes and proteins (e.g. SCF, BMP4 and GDNF).

WHAT IS KNOWN ALREADY

NOA affects 10% of infertile men and has been diagnosed in 60% of azoospermic men. In contrast with OA patients who have normal spermatogenesis, NOA patients have an impaired spermatogenesis.

STUDY DESIGN, SIZE AND DURATION

This case–control study included 100 NOA patients (as cases) and 100 OA patients with normal spermatogenesis (as controls). The study was performed between January 2012 and January 2013.

PARTICIPANTS/MATERIALS, SETTING AND METHODS

Karyotype analysis was performed to check the chromosome content and multiplex PCR was carried out to determine the expression of numerous Y chromosome genes in NOA patients. Human Sertoli cells were then isolated from the testes of NOA and OA patients by two-step enzymatic digestion and differential plating. Transmission electron microscopy was used to determine the ultrastructure of the Sertoli cells and real-time Raman microspectroscopy was used to assess their spectrum. We further compared the two groups of patients for expression of SCF, GDNF and BMP4 in Sertoli cells, using RT–PCR, microarray analysis, immunofluorescence, immunohistochemistry and Western blots.

MAIN RESULTS AND THE ROLE OF CHANCE

NOA patients had normal chromosome karyotypes and Y chromosome microdeletions were excluded. In morphology, Sertoli cells isolated from NOA patients had a series of abnormal ultrastructural features compared with the control Sertoli cells: (i) existence of small and spindle-shaped nuclei, (ii) smaller diameter, (iii) deficient nucleolus or endoplasmic reticulum and (iv) more vacuoles. Spectral intensities in Sertoli cells of NOA patients were distinct at four typical Raman peaks compared with the control Sertoli cells. In phenotype, SCF, BMP4 and GDNF transcripts and proteins were significantly lower in Sertoli cells of NOA patients than in the control Sertoli cells.

LIMITATIONS AND REASONS FOR CAUTION

The Sertoli cells of NOA patients were not compared with Sertoli cells of normal fertile men due to the fact that it is hard to obtain adult testes from normal donors.

WIDER IMPLICATIONS OF THE FINDINGS

This study provides novel insights into understanding the underlying causes for NOA and might offer a basis for developing new therapeutic strategies for patients with NOA.

STUDY FUNDING/COMPETING INTEREST(S)

This study was supported by China National Key Project (2010CB945200), a key grant from National Nature Science Foundation of China (31230048), grants from National Science Foundation of China (31171422 and 31201109), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Pujiang Program (11PJ1406400) and a key grant from the Science and Technology Commission of Shanghai Municipality (12JC1405900). None of the authors has competing interests with the study.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1863?rss=1

STUDY QUESTION

In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy?

SUMMARY ANSWER

Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy.

WHAT IS KNOWN ALREADY

Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood.

STUDY DESIGN, SIZE, DURATION

Cross-sectional study investigating 270 karyotype proven TS patients aged 0–20 years between 2009 and 2010.

PARTICIPANTS/MATERIALS, SETTINGS, METHODS

Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF.

RESULTS AND THE ROLE OF CHANCE

Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with ‘other’ karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1–175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8–472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9–8.8; P < 0.001).

LIMITATIONS, REASONS FOR CAUTION

The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis.

WIDER IMPLICATIONS OF THE FINDINGS

Serum AMH levels are a useful marker of the follicle pool and thus ovarian function in pediatric patients with TS. These findings are in line with the published literature. The finding that GH therapy may affect AMH levels is novel, but must be confirmed by future longitudinal studies.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1899?rss=1

STUDY QUESTION

Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load?

SUMMARY ANSWER

Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function.

WHAT IS KNOWN ALREADY

Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved.

STUDY DESIGN, SIZE, DURATION

Cross-sectional case–control study including 32 subjects.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC).

MAIN RESULTS AND THE ROLE OF CHANCE

Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex.

LIMITATIONS, REASONS FOR CAUTION

We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here.

WIDER IMPLICATIONS OF THE FINDINGS

Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.

STUDY FUNDING/COMPETING INTEREST(S)

Supported by grants FIS PI080944 and PI1100357 from Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness and grant EC10-096 from Dirección General de Farmacia, Spanish Ministry of Health, Social Services and Equality. The authors have no competing interests to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/7/1908?rss=1

BACKGROUND

Research on noninvasive prenatal testing (NIPT) of fetal trisomy 21 is developing fast. Commercial tests have become available. To provide an up-to-date overview of NIPT of trisomy 21, an evaluation of the methodological quality and outcomes of diagnostic accuracy studies was made.

METHODS

We undertook a systematic review of the literature published between 1997 and 2012 after searching PubMed, using MeSH terms ‘RNA’, ‘DNA’ and ‘Down Syndrome’ in combination with ‘cell-free fetal (cff) RNA’, ‘cffDNA’, ‘trisomy 21’ and ‘noninvasive prenatal diagnosis’ and searching reference lists of reported literature. From 79 abstracts, 16 studies were included as they evaluated the diagnostic accuracy of a molecular technique for NIPT of trisomy 21, and the test sensitivity and specificity were reported. Meta-analysis could not be performed due to the use of six different molecular techniques and different cutoff points. Diagnostic parameters were derived or calculated, and possible bias and applicability were evaluated utilizing the revised tool for Quality Assessment of Diagnostic Accuracy (QUADAS-2).

RESULTS

Seven of the included studies were recently published in large cohort studies that examined massively parallel sequencing (MPS), with or without pre-selection of chromosomes, and reported sensitivities between 98.58% [95% confidence interval (CI) 95.9–99.5%] and 100% (95% CI 96–100%) and specificities between 97.95% (95% CI 94.1–99.3%) and 100% (95% CI 99.1–100%). None of these seven large studies had an overall low risk of bias and low concerns regarding applicability. MPS with or without pre-selection of chromosomes exhibits an excellent negative predictive value (100%) in conditions with disease odds from 1:1500 to 1:200. However, positive predictive values were lower, even in high-risk pregnancies (19.7–100%). The other nine cohort studies were too small to give precise estimates (number of trisomy 21 cases: ≤25) and were not included in the discussion.

CONCLUSIONS

NIPT of trisomy 21 by MPS with or without pre-selection of chromosomes is promising and likely to replace the prenatal serum screening test that is currently combined with nuchal translucency measurement in the first trimester of pregnancy. Before NIPT can be introduced as a screening test in a social insurance health-care system, more evidence is needed from large prospective diagnostic accuracy studies in first trimester pregnancies. Moreover, we believe further assessment, of whether NIPT can be provided in a cost-effective, timely and equitable manner for every pregnant woman, is required.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/318?rss=1

Ectopic Pregnancy

The most reassuring sign that an ectopic pregnancy is not present is the sonographic demonstration of a normal intrauterine pregnancy. The presence of an intrauterine pregnancy decreases the risk of a concurrent ectopic pregnancy to 1 in 30,000 for a low risk patient and 1 in 5,000 for a high risk patient (history of pelvic inflammatory disease (PID), previous ectopic, infertility, tubal surgery). Transvaginal ultrasound, with a reported accuracy of greater than 90%, should routinely be used in the evaluation for ectopic pregnancy.

A variety of uterine findings can be seen with ectopic pregnancies. The uterus may be empty or contain endometrial fluid collection (called pseudo-gestational sac seen in 10-20% of cases). This should not be confused with an intrauterine gestational sac.

The most common adnexal (tubal) finding in the presence of an ectopic pregnancy is a complex adnexal mass which represents hemorrhage. Other adnexal findings include a normal adnexa or a well formed adnexal "ring" with or without a yolk sac or embryo. Hemorrhage, either within a fallopian tube or peritoneal space, may be the only sonographic finding at the lowest HCG levels. The posterior uterine cul-de-sac (Pouch of Douglas) should be carefully investigated since complex peritoneal fluid may be the only finding in 15% of ectopic pregnancies.

An exophytic ovarian corpus luteum can mimic an ectopic pregnancy. However, the corpus luteum usually contains more echoes than an adnexal ring and is demonstrated as intra-ovarian by transvaginal imaging. The majority of ectopic pregnancies. are on the same side as the corpus luteum and we routinely try to identify the corpus luteum in our ectopic searches. Doppler ultrasound may help differentiate luteal flow from trophoblastic flow.

More:
Human Reproduction, Lectures: Clinical Radiology

BACKGROUND

It has been 10 years since we carried out a systematic search of the literature on birth defect risk in infants born following assisted reproductive technology (ART) compared with non-ART infants. Because of changes to ART practice since that review and the publication of more studies the objective of this review was to include these more recent studies to estimate birth defect risk after ART and to examine birth defect risk separately in ART singletons and multiples.

METHODS

We searched Medline, Embase and Current Contents databases (1978–2012). We used the same data extraction sheet and questionnaire we had used previously with the addition of a quality score to the questionnaire. Pooled relative risk (RR) estimates were calculated using a random effects model. All data were analysed using Comprehensive Meta-Analysis V2.

RESULTS

There were 45 cohort studies included in this review. ART infants (n = 92 671) had a higher risk of birth defects [RR 1.32, 95% confidence interval (CI) 1.24–1.42] compared with naturally conceived infants (n = 3 870 760). The risk further increased when data were restricted to major birth defects (RR 1.42, 95% CI 1.29–1.56) or singletons only (RR 1.36, 95% CI 1.30–1.43). The results for ART multiples were less clear. When all data for multiples were pooled the RR estimate was 1.11 (95% CI 0.98–1.26) but this increased to 1.26 (0.99–1.60) when the analysis was restricted to studies of ART twins where some adjustment was made for differences in zygosity distribution between ART and non-ART multiples.

CONCLUSIONS

Birth defects remain more common in ART infants. Further research is required to examine risks for important subgroups of ART exposure.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/330?rss=1

BACKGROUND

Genetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and whole genome sequencing of blastomeres is also expeted to become possible soon. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, will also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues.

METHODS

The paper is a joint endeavour by the presenters at an explorative ‘campus meeting’ organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands).

RESULTS

The increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. Combinations of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others.

CONCLUSIONS

As comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/366?rss=1

BACKGROUND

Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies.

METHODS

Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNP–GDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity.

RESULTS

Overall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (–30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95% CIs) of 1.44 (1.29–1.60, P < 0.001) per T allele of rs7903146 and 1.46 (1.15–1.84, P = 0.002) per T allele of rs12255372.

CONCLUSIONS

In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/376?rss=1