BACKGROUND

Since it was established in 1997, the ESHRE PGD Consortium has been collecting data from international preimplantation genetic diagnosis (PGD) centres. Ten papers have been published, including data from January 1997 to December 2007.

METHODS

The data collection originally used a hard-copy format, then an excel database and finally a FileMaker Pro database. The indications are divided into five categories: PGD for chromosome abnormalities, sexing for X-linked disease, PGD for single gene defects, preimplantation genetic screening (PGS) and PGD for social sexing. The main end-points are pregnancy outcome and follow-up of deliveries.

RESULTS

In data collection I, 16 centres contributed data, which increased to 57 centres by data X (average of 39 centres per data collection). These centres contributed data on over 27 000 cycles that reached oocyte retrieval. Of these cycles, 61% were for aneuploidy screening, 17% for single gene disorders, 16% for chromosomal abnormalities, 4% for sexing of X-linked disease and 2% for social sexing. Cumulatively, 5187 clinical pregnancies gave rise to 4140 deliveries and 5135 newborns (singletons: 3182, twins: 921, triplets: 37).

CONCLUSIONS

In this paper, we present an overview of the first 10 years of PGD data, highlighting trends. These include the introduction of laser-assisted biopsy, an increase in polar body and trophectoderm biopsy, new strategies, methodologies and technologies for diagnosis, including recently arrays, and the more frequent use of freezing biopsied embryos. The Consortium data reports represent a valuable resource for information about the practice of PGD.

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BACKGROUND

Endometriosis has been associated with specific morphometric characteristics and pigmentary traits. The purpose of this study was to systematically review prior publications dealing with this aspect in order to revisit phenotypic information in the context of phenomics principles.

METHODS

Comprehensive searches of Pubmed, Medline and Embase were conducted to identify studies, published from 1990 to 2011 in the English language literature, on the relationship between endometriosis and morphometric characteristics/pigmentary traits.

RESULTS

We identified 11 studies on the association between endometriosis and body mass index (BMI) in the adult population and 5 studies on the same association during early life. While a modest inverse correlation was found between endometriosis and adult BMI, a stronger association was consistently demonstrated between endometriosis and early life body size, even after adjusting for confounding factors such as age, birthweight, age at menarche, parity and oral contraceptive use. Four papers have been published on the association between endometriosis and cutaneous naevi and five on the association between the disease and specific pigmentary traits. A skin phenotype characterized by the presence of naevi and freckles and by a high sensitivity to sun exposure is represented more frequently in women with endometriosis.

CONCLUSIONS

Endometriosis appears to be associated with some phenotypic variations likely attributable to the strong effect of the environment on the expression and function of genes influencing the traits. Novel clues on endometriosis pathogenesis may derive from the analysis of the phenotypic traits associated with the disease.

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http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Fertility problems are an important health issue, as 10–15% of couples have difficulties conceiving. Reproductive function is thought to be compromised by lifestyle behaviours, but environmental contaminants and work-related factors are also thought to play a role. The objective of this review was to systematically summarize the available evidence concerning the influence of occupational exposure to chemicals on time to pregnancy (TTP).

METHODS

A structured search on occupational exposure to chemicals and TTP was carried out in PubMed and Embase. Studies were included if TTP was used as outcome measure and exposure to chemicals at the job level was described. In total, 49 studies were included in this review.

RESULTS

Studies varied widely in characterization of exposure, hampering a meta-analytic approach across all studies. For lead, strong indications for adverse effects on TTP were present, supporting the mandatory provisions for pregnant women being exposed to lead in many countries. These indications were also found for pesticide exposure, and one could argue that couples working in agriculture or horticultural trades must be informed about the risks of pesticide exposure. Epidemiologic evidence on other chemicals, such as organic solvents, and other metals remains equivocal, hampering clear counselling of couples who are trying to become pregnant.

CONCLUSIONS

Despite some uncertainties in the evidence base, it may still be prudent to advise against lead and pesticide exposure at the workplace for couples trying to conceive. This review also identifies several priorities for future studies in the field of occupational epidemiology.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Because of the substantial energy demands of reproduction, the brain must temper the fertility of individuals to match nutritional availability. Under-nutrition is associated with infertility in humans and animals. The brain uses adipose- and gut-derived hormones, such as leptin, insulin and ghrelin, to modulate the activity of the GnRH neuronal network that drives reproduction. It is becoming clear that there are both direct and indirect pathways acting on GnRH neurones.

METHODS

A PubMed search was performed using keywords associated with neuropeptides and metabolic hormones that are associated with reproductive and energy balance axes.

RESULTS

Evidence that neurones which produce galanin, galanin-like peptide, kisspeptin, alpha-melanocyte-stimulating hormone, neuropeptide Y and oxytocin convey metabolic information to the reproductive axis is presented. The extent to which these neurones express receptors for metabolic hormones is variable but interactions between them allows for complex intermingling of information. Available metabolic fuels modulate hormone input to these neurones, leading in turn to altered GnRH release and appropriate drive to the gonads. The consequent change in sex steroid production is likely to contribute to co-ordination of the network.

CONCLUSIONS

We hypothesize that the absence of an estrogenic milieu during anovulation compared with presence of estradiol during follicular maturation is important for the regulation of most of the neuropeptides. An improved understanding of the normal responses to energy deprivation may also help to identify novel therapeutic targets for infertility that often accompanies metabolic disorders, such as diabetes, obesity and polycystic ovary syndrome.

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http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Reducing environmental stress imposed upon gametes and embryos in the IVF laboratory is crucial in optimizing culture conditions and development. One environmental parameter of particular importance is external pH (pHe) of culture media. An optimal pHe has not been identified.

METHODS

Electronic searches were performed using keywords focused on pH and the embryo using PUBMED through August 2011, with no limits placed on a beginning time. Examples of keywords include CO₂, bicarbonate and hydrogen ion. Relevant papers were then examined to obtain additional publications.

RESULTS

Determining optimal pHe is problematic due to difficulty in isolating pHe from other variables, such as CO₂ and bicarbonate. Various commercial media companies recommend differing pHe ranges, most within the range of 7.2–7.4, with some companies recommending altering pHe based on the gamete or stage of the embryo. However, changing pHe during culture has not been experimentally shown to improve outcomes. Further complicating attempts to define an optimal pHe is that media components can impact intracellular pH (pHi). As a result, media with different concentrations of substances, such as lactate or amino acids, may have different pHi, despite being in the same pHe.

CONCLUSIONS

Due to the plasticity of embryos, a range of pHe's can support development, and defining an optimal pHe is difficult. It is unclear whether there is any benefit in changing pHe at various steps during IVF. The ideal pHe will likely vary from media to media and, until comparative studies have been performed isolating pHe, adherence to manufacturer recommendations and maintenance of a small acceptable pHe range are advisable.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias.

METHODS

Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995.

RESULTS

The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent.

CONCLUSIONS

Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown.

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BACKGROUND

The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS.

METHODS

Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random-effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs).

RESULTS

The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naïve women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I² = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates.

CONCLUSIONS

In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed.

Source:
http://humupd.oxfordjournals.org/rss/current.xml

BACKGROUND

The prostate and testis expression (PATE)-like family of proteins are expressed mainly in the male genital tract. They are localized in the sperm head and are homologous to SP-10, the acrosomal vesicle protein also named ACRV1. Our aim was to characterize the expression and functional role of three PATE-like proteins in the testis and ejaculated sperm.

METHODS

The expression and localization of PATE-like proteins in human testis biopsies (n= 95) and sperm cells were assessed by RT–PCR, immunohistochemistry and immunofluorescence staining (at least 600 sperm cells per specimen). The function of the PATE protein was tested by the hemizona assay and hamster egg penetration test (HEPT).

RESULTS

PATE and PATE-M genes and proteins were present almost exclusively in germ cells in the testis: immunoflourescence showed that the percentage of germ cells positive for PATE, PATE-M and PATE-B was 85, 50 and 2%, respectively. PATE and PATE-M proteins were localized in the equatorial segment of the sperm head, while PATE-B protein was localized in the post-acrosomal region. A polyclonal antibody (Ab, at 1:50 and 1:200 dilutions) against the PATE protein did not inhibit sperm–zona binding in the hemizona assay (hemizona index of 89.6 ± 10 and 87 ± 36%, respectively). However, there was inhibition of sperm–oolemma fusion and penetration in the HEPT (penetration index: without Ab 7 ± 3.9; Ab dilution of 1:100, 4 ± 3.5; Ab dilution of 1:20, 0.6 ± 1.2, P < 0.001).

CONCLUSIONS

Our data suggest that PATE protein is involved in sperm–oolemma fusion and penetration but not sperm–zona binding.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

Approximately 80% of childhood cancers can now be cured but a side effect of treatment results in about one-third of the surviving boys being infertile or severely subfertile when they reach reproductive age. Currently, more than 1 in 5000 men of reproductive age who are childhood cancer survivors suffer from this serious quality of life problem. It is possible to obtain a testicular biopsy before treatment to preserve the spermatogonial stem cells (SSCs) of the male by cryopreservation, but the results of long-term storage of SSCs on their subsequent functional ability to generate normal offspring has not been examined in any mammalian species. Moreover, it will be necessary to increase the number of these cryopreserved SSCs to remove any contaminating malignant cells and assure regeneration of spermatogenesis.

METHODS AND RESULTS

In this report, we demonstrate that long-term cryopreservation (>14 years) of testis cells from mouse, rat, rabbit and baboon safeguards SSC viability, and that these cells can colonize the seminiferous tubules of recipient testes. Moreover, mouse and rat SSCs can be cultured and re-establish complete spermatogenesis, and fertile mouse progeny without apparent genetic or epigenetic errors were generated by the sperm produced.

CONCLUSIONS

These findings provide a platform for fertility preservation in prepubertal boys undergoing gonadotoxic treatments.

Source:
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BACKGROUND

Gestational iron-deficiency anaemia has adverse pregnancy outcomes. Antenatal iron supplementation can be beneficial in anaemic women, but the effects in non-anaemic women are controversial. This observational study assessed the relationship of maternal iron stores (depleted or non-depleted) at gestational Weeks 8–12 with birthweight, in non-anaemic pregnant women following the guidelines of the Ministry of Health of Spain.

METHODS

Healthy, non-anaemic pregnant women (n = 205) were studied. At the first antenatal visit, a general clinical assessment was conducted, and basal blood taken. Women were classified as having non-depleted or depleted iron stores [serum ferritin (SF) < 12 µg/l)]. Daily antenatal iron supplements (48 mg on average) were started at 17 (range: 16–18) weeks. Blood haemoglobin, SF and transferrin saturation (TS) were measured in each trimester.

RESULTS

Of the study sample, 20, 54 and 66% had SF < 12 µg/l in the first, second and third trimesters, respectively. The prevalence of iron-depletion (SF < 12 µg/l) and iron-deficiency (SF < 12 µg/l and TS < 16%) was greater during the entire pregnancy in women with initial iron depletion versus no depletion (81.6 and 73.7% versus 61.7 and 55.4%, respectively, in the third trimester, P < 0.05). Women with initial iron-depletion delivered babies weighing on average 192 g less than that with initial iron stores, after adjusting for confounding variables (P = 0.028).

CONCLUSIONS

Beginning pregnancy with non-depleted iron stores is beneficial for the maternal iron status during pregnancy and infant birthweight. These findings reaffirm the importance of health promotion to ensure that women have adequate iron stores prior to, or early in, pregnancy when supplemented with moderate daily iron doses.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

BACKGROUND

In primate placenta, extravillous trophoblast (EVT) invades maternal tissue in temporally- and spatially-regulated fashions. We previously identified a novel placenta-specific cell-surface aminopeptidase, laeverin/aminopeptidase Q, which is expressed on EVT-lineage cells in the fetal membrane. Laeverin possesses a peptide-binding site that is evolutionally unique to primates, suggesting possible involvement of laeverin in a primate-specific phenomenon during placentation. Thus, this study was designed to elucidate the molecular characteristics and physiological roles of laeverin in human EVT.

METHODS

Placental tissues of various developmental stages were subjected to immunostaining and western blotting. Effects of siRNA and a soluble form of recombinant laeverin on EVT cells isolated from primary villous explant cultures were examined using Matrigel invasion assays and cell proliferation assays.

RESULTS

Laeverin was specifically immunolocalized to HLA-G-positive EVT in placentas from early and term pregnancy. In primary villous explant cultures, laeverin expression was induced on the cell surface of the outgrowing EVT. In western blotting, laeverin protein was detected as two distinct bands at 130 and 160 kDa along with a broad band ranging from 200 to 270 kDa. De-glycosylation treatment showed that these native laeverin isotypes are N-linked glycoproteins sharing a common 115-kDa core protein. In invasion assays, the reduction of laeverin expression by siRNA suppressed migration of the isolated EVT, while the soluble form of recombinant laeverin enhanced its migration.

CONCLUSIONS

Laeverin is a specific cell-surface marker for human EVT and plays a regulatory role in EVT migration.

Source:
http://humrep.oxfordjournals.org/rss/current.xml