Reproduction is required for the survival of all mammalian species, and thousands of essential 'sex' genes are conserved through evolution. Basic research helps to define these genes and the mechanisms responsible for the development, function and regulation of the male and female reproductive systems. However, many infertile couples continue to be labeled with the diagnosis of idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For other individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Certainly, progress in the field of reproduction has been realized in the twenty-first century with advances in the understanding of the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and with the promise of regenerative gonadal stem cells. Indeed, the past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples. Additionally, new approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care.

/pdf/the-biology-of-infertility-research-advances-and-clinical-36ufrj51t1.pdf

The biology of infertility: research advances and clinical challenges

We have used multicolour fluorescent in situ hybridisation (FISH) with DNA probes for chromosomes X, Y and l to analyse spare untransferred cleavage-stage embryos after preimplantation diagnosis to avoid X-linked disease. In total, 93 morphologically normal embryos were available from seven patients (six of proven fertility) who had undergone fourteen in vitro fertilisation (IVF) cycles. The chromosome patterns observed were classified into four groups; normal, abnormal (non-mosaic), mosaic and chaotic (uncontrolled division). Approximately half of the embryos were normal for the chromosomes tested. Two embryos only were aneuploid (non-mosaic) throughout but, after excluding those showing chaotic division, 30% were considered to be chromosomal mosaics. Of these, a minority had arisen because of mitotic non-disjunction or chromosome loss or gain, whereas the majority were ploidy mosaics, with haploidy being the most common. The occurrence of chaotically dividing embryos was strongly patient-related, i.e. some patients had 'chaotic' embryos in repeated cycles, whereas other patients were completely free of this type of anomaly. 'Chaotic' embryos are unlikely to progress beyond implantation. These findings have important implications both for routine IVF and preimplantation genetic diagnosis.

Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients

We have previously detected chromosome abnormalities in human embryos whilst identifying the sex for preimplantation diagnosis of X-linked disease. In this study we assess the incidence of these abnormalities, both for sex chromosomes and autosomes 1 and 17, using dual fluorescent in situ hybridization (FISH). Sixty-nine normally fertilized embryos of good morphology at the 6-10 cell stage (day 3 post-insemination) were examined. The embryos were spread whole using HCl and Tween 20 to dissolve the cytoplasm. Thirty-four embryos were analyzed for the sex chromosomes and 35 for autosomes 1 and 17. All probes were directly labelled with fluorochromes allowing analysis in 2 h. Control lymphocytes demonstrated that the probes were of high specificity. For the sex chromosomes, five embryos were mosaic (15 per cent) with the remaining 29 being uniformly XX or XY. In no case was an XX nucleus found in an otherwise XY embryo, indicating that even though mosaicism for the sex chromosomes is present, such abnormalities would not lead to a misdiagnosis of sex. For the autosomes, 16 embryos were abnormal (46 per cent); one embryo was triploid, one was monosomic for chromosome 1, and ten others were diploid mosaics (three diploid/aneuploid, three diploid/polyploid, and four diploid/haploid). A further four embryos had variable chromosome numbers in the majority of nuclei which appeared to be the result of uncontrolled mitotic division. The presence of haploidy or double monosomy, which occurred in 15 per cent of nuclei, has important implications for the diagnosis of trisomies and dominant disorders.

Mosaicism of autosomes and sex chromosomes in morphologically normal, monospermic preimplantation human embryos.

This study examines the relationship between common morphological anomalies of cleaving embryos and their ability to form apparently normal blastocysts in vitro. The impact of cleavage rate, fragmentation, and multinucleation on compaction, cavitation, along with inner cell mass and trophectoderm formation has been assessed. The study population consisted of 102 patients who elected or were selected to have a day 5 embryo transfer. Clinical pregnancy and implantation rates were 66.7 and 49% respectively. Slow and fast cleavage had a significant negative association with normal blastocyst formation. Only 13.8% (67/484) of embryos with 9 cells on day 3 formed blastocysts with apparently normal morphology, compared to 41.9% (252/602) with 7-9 cells on day 3 (P 15% fragmentation formed normal blastocysts at a significantly lower rate (46/279; 16.5%) than embryos with 0-15% fragmentation (311/935; 33.3%) (P < 0. 001). Furthermore, the pattern of fragmentation was associated with blastocyst formation. Type IV fragmentation led to a significant reduction in blastocyst formation (25/170 or 14.7%), compared to types I, II and III which performed much better (38.6, 32.9 and 32.4% respectively). Only 15.9% (22/138) of embryos with one or more multinucleate cells on day 2 and/or 3 formed normal blastocysts compared with 31.9% (335/1051) (P < 0.001) of those without multinucleation. Collectively, the data suggest that cleavage anomalies, some of which do not preclude development after short-term culture, may reduce the developmental competence of embryos after prolonged culture.

/pdf/cleavage-anomalies-in-early-human-embryos-and-survival-after-385amsxnui.pdf

Cleavage anomalies in early human embryos and survival after prolonged culture in-vitro

The presence of numerical chromosome abnormalities in human embryos was studied using fluorescence in-situ hybridization with four or more chromosome-specific probes. When most cells of an embryo are analysed, this technique allows differentiation to be made between aneuploidy, mosaicism, haploidy and polyploidy. Abnormal types of fertilization, such as unipronucleated, tripronucleated zygotes and zygotes with uneven pronuclei, were studied using this technique. We have found a strong correlation between some types of dysmorphism with chromosomal abnormalities. In addition, the more impaired the development of an embryo, the more chromosomal abnormalities were detected in those embryos. Maternal age and other factors were linked to an increase in chromosome abnormalities (hormonal regimes, temperature changes), but not to intracytoplasmic sperm injection.

/pdf/chromosome-abnormalities-in-human-embryos-4mbz0w1qoi.pdf

Chromosome abnormalities in human embryos

Embryos from a couple undergoing routine in-vitro fertilization for unexplained infertility had shown cleavage by day 1 in two consecutive cycles. The response of the woman to fertility drugs had been normal, and there were no known sperm abnormalities. In a subsequent cycle, accelerated cleavage occurred again and we used a modified method of spreading whole embryos and dual fluorescent in-situ hybridization (FISH) with directly labelled probes for chromosomes X and Y to determine if fertilization had occurred in these embryos. Nine oocytes were collected, five of which had cleaved when examined for pronuclei early on day 1 following late insemination. Pronuclei were observed in one of the remaining oocytes, but in this case, three were present. On day 2, all of the oocytes/embryos had cleaved and two were transferred to the patient. The remaining seven were spread for FISH analysis but nuclei were only obtained from five. In three, a Y signal was detected, indicating that fertilization had occurred. In all five embryos, a wide range of X chromosome signals were observed. These data suggest that the embryos had undergone abnormal fertilization and accelerated cleavage.

Detection of fertilization in embryos with accelerated cleavage by fluorescent in-situ hybridization (FISH).

Sex determination of preimplantation embryos

/pdf/selected-oral-communication-session-session-17-embryology-58oqqcnihk.pdf

SELECTED ORAL COMMUNICATION SESSION, SESSION 17: EMBRYOLOGY AND GENETICS, Monday 4 July 2011 15:15 - 16:30

Session 59: embryology – development and quality

The use of FISH for genetic diagnosis and analysis of human preimplantation embryos.

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