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

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

http://www.rmanj.com/wp-content/uploads/2012/11/BEST-Trial-Forman-et-al-2013-In-Press-Version.pdf

In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial

https://www.fertstert.org/article/S0015-0282(09)03875-8/pdf

Clinical application of comprehensive chromosomal screening at the blastocyst stage

Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization.

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

Objective
Modern in vitro fertilization practices involve transfer of embryos as blastocysts, when anabolic metabolism is well established and pregnancy rates can be maintained while transferring embryos singly to avoid multiple pregnancies. Embryo biopsy for preimplantation genetic diagnosis (PGD), however, is generally performed on day 3, when the embryo comprises just 6 to 8 cells, one or two of which are removed for testing. Implantation rates and clinical pregnancy rates have remained relatively low and a harmful effect from losing one or more cells from such early embryos has not been excluded.

Methods
We performed a sequential study involving 399 egg retrievals and 1879 embryo biopsies for patients undergoing PGD to avoid a serious monogenic disease or an unbalanced chromosomal translocation. We compared implantation and viable pregnancy rates after biopsies taken on day 3 (cleavage-stage biopsy) with biopsies delayed until day 5 or 6, when the embryo is a blastocyst and 5 or more cells can be sampled from the trophectoderm while the inner cell mass, from which the fetus develops, remains intact. All embryos were transferred as blastocysts.

Results
Despite fewer blastocysts than cleavage embryos biopsied and tested (3.6 compared to 6.6), implantation rates per embryo transferred were 43.4% if biopsied at the blastocyst stage and 25.6% if biopsied at the cleavage stage (P < 0.01), with ongoing or live-birth pregnancy rates per egg retrieval of 34.2% (average transfer number 1.1) for blastocyst biopsies and 25.5% (transfer number 1.6) for cleavage stage biopsies (P < 0.05, 1-tailed). The multiple pregnancy rate for monogenic disease exclusion fell from 16.7% to 2% (P = 0.04, 1-tailed).

Conclusions
For exclusion of genetic disease, day 5-6 blastocyst-stage biopsies are more likely to be followed by implantation and singleton births than is the case after PGD performed on day 3. Copyright © 2008 John Wiley & Sons, Ltd.

Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations.

The genetic screening of preimplantation embryos by comparative genomic hybridisation.

To date, it is blastocyst-stage biopsy that has given valuable improvement in implantation rates, and it waits to be seen whether the still prevalent day 3 biopsies and day 0–1 biopsies of polar bodies can achieve the same outcomes. With the use of a DNA amplification-based approach, the interpretation problems associated with low-level somatic mosaicism common in embryos and seen with FISH are partially overcome. The tissue sample, typically consisting of 3–5 cells, is analyzed as a whole (and is taken to represent the embryo as a whole), thus producing an averaging effect for the constitutional chromosomes under investigation.

Embryo Biopsy for PGD: Current Perspective

Background and Methods In Southeast Asia and particularly in Thailand, β0-thalassemia/hemoglobin E (HbE) disease is a common hereditary hematological disease In a retrospective analysis, we investigated the outcomes of blastocyst preimplantation genetic diagnosis (PGD) for α- and β-thalassemia exclusion, with human leukocyte antigen (PGD-HLA) matching, from 2007 to 2016 at Superior ART (Bangkok, Thailand) and subsequent hematopoietic stem cell transplantation (HSCT) treatment of affected siblings The main outcome measures included the proportion of biopsied cycles with at least one screened embryo suitable for transfer, implantation rate, live birth rate, and curative HSCT post-PGD-HLA Results In 221 cycles from 138 patients (104 cycles requiring HLA matching), 905% had embryo(s) biopsied for genetic testing There were 119 embryo transfers for thalassemia (76) and thalassemia-HLA cases (43), respectively, resulting in overall clinical pregnancy rates of 546%, implantation rates of 457%, and live birth rates of 441% Our dataset included fifteen PGD-HLA live births with successful HSCT in twelve affected siblings, 67% using umbilical cord blood stem cells (UCBSC) as the only SC source Conclusions We report favorable thalassemia PGD and PGD-HLA laboratory and clinical outcomes from a single center The ultimate success in PGD-HLA is of course the cure of a thalassemia-affected sibling by HSCT Our PGD-HLA HSCT series is the first and largest performed entirely in Asia with twelve successful and two pending cures and predominant UCBSC use

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The First Asian, Single-Center Experience of Blastocyst Preimplantation Genetic Diagnosis with HLA Matching in Thailand for the Prevention of Thalassemia and Subsequent Curative Hematopoietic Stem Cell Transplantation of Twelve Affected Siblings.

J Marshall

Papers

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

Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations.

The genetic screening of preimplantation embryos by comparative genomic hybridisation.

Embryo Biopsy for PGD: Current Perspective

The First Asian, Single-Center Experience of Blastocyst Preimplantation Genetic Diagnosis with HLA Matching in Thailand for the Prevention of Thalassemia and Subsequent Curative Hematopoietic Stem Cell Transplantation of Twelve Affected Siblings.