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.

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The biology of infertility: research advances and clinical challenges

The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common “complex” diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these “heteroplasmic” mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical variability of a range of diseases. Maternal inheritance and heteroplasmy also pose major challengers for the diagnosis and prevention of mtDNA disease.

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Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease

Mitochondrial DNA content varies considerably in oocytes, even when collected from the same patient. In the present study, real-time quantitative polymerase chain reaction analysis of 113 unfertilized oocytes obtained from 43 patients revealed an average of 193 000 (range: 20 000 to 598 000) mitochondrial genomes per cell. We compared several groups of oocytes to investigate the relationship between mitochondrial DNA content and fertilizability. The average mitochondrial DNA copy number was significantly lower in cohorts suffering from fertilization failure compared to cohorts with a normal rate of fertilization. In addition, the mitochondrial copy number of oocytes from patients with fertilization failure due to unknown causes was significantly lower than that of oocytes from patients in which IVF failure was due mainly to a severe sperm defect. The lower mtDNA copy number could be due to defective cytoplasmic maturation of oocytes. We conclude that low mitochondrial DNA content, due to inadequate mitochondrial biogenesis or cytoplasmic maturation, may adversely affect oocyte fertilizability.

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Mitochondrial DNA content affects the fertilizability of human oocytes.

Preimplantation genetic diagnosis

Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial.

The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate

Pregnancies and live births after trophectoderm biopsy and preimplantation genetic testing of human blastocysts

Blastocysts more commonly have a normal karyotype than cleavage-stage embryos do. Moreover, blastocysts have also made a metabolic transition from catabolism and recycling of the oocyte's reserves and resources, processes that fuel the first 3 days of cleavage. Although not all blastocysts are karyotypically equal, it is still to be determined to what extent a mosaic karyotype might be a normal feature among embryos, both at the cleavage stage and the blastocyst stage--and when looking for karyotypic abnormalities by embryo biopsy might help the chance of implantation rather than harm it. It is also still impractical to look at all the chromosomes that can, through their aneuploidy, stand in the way of successful embryonic and fetal development. We report a randomized clinical trial of blastocyst biopsy followed by preimplantation genetic screening (PGS) for aneuploidy using 5-colour FISH. The trial was suspended and then terminated early when we were unable to show an advantage for PGS. If we are correct in assuming that mitotic non-disjunction is common by the stage of the blastocyst (and that it is much less ominous than meiotic non-disjunction), then further studies of effective PGS of blastocysts for aneuploidy require methods of analysis that cover all the chromosomes and can differentiate the triallelic and monoallelic states of meiotically derived aneuploidies from the biallelic state of mitotic aneuploidies.

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What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy

Moving to blastocyst biopsy for preimplantation genetic diagnosis and single embryo transfer at Sydney IVF.

Elective transfer of single fresh blastocysts and later transfer of cryostored blastocysts reduces the twin pregnancy rate and can improve the in vitro fertilization live birth rate in younger women.

Kylie A. de Boer

Papers

The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate

Pregnancies and live births after trophectoderm biopsy and preimplantation genetic testing of human blastocysts

What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy

Moving to blastocyst biopsy for preimplantation genetic diagnosis and single embryo transfer at Sydney IVF.

Elective transfer of single fresh blastocysts and later transfer of cryostored blastocysts reduces the twin pregnancy rate and can improve the in vitro fertilization live birth rate in younger women.