Committed to the Prevention of Genetic Disease

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Buster J

Managing female sexual dysfunction.
Fertil Steril. 2013;100(4):905-915.
Female sexual dysfunctions (FSDs) range from short-term aggravations to major emotional disturbances adversely affecting family and workplace.

This review highlights diagnosis and management of the four most widely diagnosed FSDs. It initially focuses on hypoactive sexual desire disorder (HSDD) as a driving force at the heart of all other FSDs; nothing happens without sexual desire. Successful resolution of HSDD frequently facilitates resolution of other disorders. Central to understanding HSDD is the impact of aging female sexual endocrinology and its effect on both prevalence and expression patterns of FSD. Advances in this field have enabled introduction of some the most effective treatments yet described for HSDD. Sexual arousal disorder, though commonly affected by the same factors as HSDD, is heavily associated with psychotropic drugs and mood elevators. Orgasmic disorder is frequently the downstream result of other sexual dysfunctions, particularly HSDD, or the result of a major psychosexual trauma. Successful management of the underlying disorder often resolves orgasmic disorder. Sexual pain disorder is frequently the result of a gynecologic disorder, such as endometriosis, that can be substantially managed through successful treatment of that disorder. This article ends with the article’s most important note: how to initiate the conversation.

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Handyside AH.

24-chromosome copy number analysis: a comparison of available technologies
Fertil Steril. 2013;100(3):595-602.
Chromosome aneuploidy, an abnormal number of chromosomes, in human gametes and embryos is a major cause of IVF failure and miscarriage and can result in affected live births.

To avoid these outcomes and improve implantation and live birth rates, preimplantation genetic screening aims to identify euploid embryos before transfer but has been restricted to analysis of a limited number of chromosomes. Over the past 15 years, various technologies have been developed that allow copy number analysis of all 23 pairs of chromosomes, 22 autosomes, and the sex chromosomes, or “24-chromosome” copy number analysis in single or small numbers of cells. Herein the pros and cons of these technologies are reviewed and evaluated for their potential as screening or diagnostic tests when used in combination with oocyte or embryo biopsy at different stages.

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Montag M, Köster M, Strowitzki T, Toth B

Polar body biopsy
Fertil Steril. 2013;100(3):603-607.
Polar body biopsy combined with array comparative genomic hybridization allows detection of maternal chromosomal aberrations.

Although it has limitations, it can be seen as an alternative to blastomere and trophectoderm biopsy.

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Scott KL, Hong KH, Scott RT.

Selecting the optimal time to perform biopsy for preimplantation genetic testing.
Fertil Steril. 2013;100(3):608-14.
A consistent requirement for all preimplantation genetic testing is the need to obtain DNA from the oocyte or embryo. Currently this sample is attained through biopsy of one or both polar bodies, blastomere biopsy at the cleavage stage, or trophectoderm biopsy after blastulation.

Selecting the optimal time for biopsy requires careful consideration. Polar body biopsy is less invasive and provides more time for analysis but fails to capture as many as one in three embryonic aneuploidies. Additionally, the inability to readily distinguish nondysjunction from premature separation of sister chromatids greatly limits the predictive value of the technique and may lead to an overdiagnosis of aneuploidy in as many as 45% of cases with first polar-body errors. Cleavage-stage biopsy provides adequate samples but is detrimental to the embryo. The adverse effect of blastomere biopsy may result in approximately two of every five reproductively competent embryos losing their ability to implant and sustain development. Trophectoderm biopsy does not adversely impact the embryos. However, for the majority of clinical programs without a genetics laboratory, vitrification would be necessary to allow time for the genetic analysis. Although this extends the time required for treatment, clinical outcomes are equivalent after transfer of euploid blasts during fresh IVF and cryopreserved embryo transfer cycles, so that excellent outcomes are maintained. At present the blastocyst stage is the optimal time to perform biopsies for preimplantation genetic testing.

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Scott RT, Upham KM, Forman EJ, Zhao T, Treff NR.

Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial.
Fertil Steril. 2013;100(3):624-30.
Objective: To determine if cleavage- or blastocyst-stage embryo biopsy affects reproductive competence.

Design: Paired randomized clinical trial.

Setting: Academic-assisted reproduction program.

Patient(s): Attempting conception through IVF.

Intervention(s): After selecting two embryos for transfer, one was randomized to biopsy and the other to control. Both were transferred within shortly thereafter. The biopsy was submitted for microarray analysis and single-nucleotide polymorphism (SNP) profiling. Buccal DNA obtained from the neonate after delivery had microarray analysis and SNP profile compared with that of the embryonic DNA. A match confirmed that the biopsied embryo implanted and developed to term, whereas a nonmatch indicated that the control embryo had led to the delivery.

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Brady PD, Devriendt K, Deprest J, Vermeesch JR.

Array-based approaches in prenatal diagnosis.
Methods Mol Biol. 2012;838:151-71.
The diagnostic benefits of array comparative genomic hybridisation (CGH) have been demonstrated, with this technique now being applied as the first-line test for patients with intellectual disabilities and/or multiple congenital anomalies in numerous laboratories.

There are no technical barriers preventing the introduction of array CGH to prenatal diagnosis. The question is rather how this is best implemented, and for whom. The challenges lie in the interpretation of copy number variations, particularly those which exhibit reduced penetrance or variable expression, and how to deal with incidental findings, which are not related to the observed foetal anomalies, or unclassified variants which are currently of uncertain clinical significance. Recently, applications of array technologies to the field of pre-implantation genetic diagnosis have also been demonstrated. It is important to address the ethical questions raised concerning the genome-wide analysis of prenatal samples to ensure the maximum benefit for patients. We provide an overview of the recent developments on the use of array CGH in the prenatal setting, and address the challenges posed.

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Alfarawati S, Fragouli E, Colls P, Wells D.

First births after preimplantation genetic diagnosis of structural chromosome abnormalities using comparative genomic hybridization and microarray analysis.
Hum Reprod. 2011;26(6):1560-74.
Balanced chromosomal rearrangements represent one of the most frequent indications for preimplantation genetic diagnosis (PGD). Although fluorescence in situ hybridization (FISH) has been successfully employed for diagnosis in such cases, this approach usually restricts assessment of the chromosomes involved in the rearrangement.

Furthermore, with FISH-based strategies, it is sometimes necessary to create patient-specific protocols, increasing the waiting time and costs. In the current study, we explored the use of two comprehensive chromosome screening methods, conventional metaphase comparative genomic hybridization (CGH) and microarray-CGH (aCGH), as alternatives for PGD of chromosome rearrangements.

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Schoolcraft WB, Treff NR, Stevens JM, Ferry K, Katz-jaffe M, Scott RT.

Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients.
Fertil Steril. 2011;96(3):638-40.
The combination of trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based technology for comprehensive chromosome screening results in high implantation and live birth rates that could contribute to the practical application of single embryo transfer for infertility patients.

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Garimberti E, Tosi S.

Fluorescence in situ hybridization (FISH), basic principles and methodology.
Methods Mol Biol. 2010;659:3-20.
Fluorescence in situ hybridization (FISH) is widely used for the localization of genes and specific genomic regions on target chromosomes, both in metaphase and interphase cells.

The applications of FISH are not limited to gene mapping or the study of genetic rearrangements in human diseases. Indeed, FISH is increasingly used to explore the genome organization in various organisms and extends to the study of animal and plant biology. We have described the principles and basic methodology of FISH to be applied to the study of metaphase and interphase chromosomes.

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The Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Reproductive Endocrinology and Infertility

Optimizing natural fertility.
Fertil Steril. 2008;90(5 Suppl):S1-6.
This Committee Opinion provides practitioners with suggestions for optimizing the likelihood of achieving pregnancy in couples attempting conception who have no evidence of infertility.

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The Practice Committee of the Society for Assisted Reproductive Technology, Practice Committee of the American Society for Reproductive Medicine.

Preimplantation genetic testing: a Practice Committee opinion.
Fertil Steril. 2008;90:S136-43.
The opportunity to exclude in vitro derived embryos with documented genetic abnormalities before the initiation of pregnancy is an attractive means of preventing heritable genetic disease.

Currently couples who are carriers of genetic disease have the option of undergoing chorionic villus sampling in the first trimester or amniocentesis in the second trimester to determine whether or not their fetus is affected. The advantage of accurately diagnosing these genetic abnormalities in the embryo obviates the 25% to 50% risk of transferring an affected embryo with the specific genetic abnormality in question. It has been more than a decade since the first reported pregnancies using preimplantation genetic diagnosis (PGD) were achieved (1, 2), and as of April 2001, at least 500 babies have been born worldwide using these techniques (3). This document reviews the applications and techniques of PGD and the concerns about the safety and the accuracy of the technique.

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Sher G, Keskintepe L, Mukaida T, et al.

Selective vitrification of euploid oocytes markedly improves survival, fertilization and pregnancy-generating potential.
Reprod Biomed Online. 2008;17(4):524-9.
Enthusiasm for oocyte cryopreservation has been limited by poor pregnancy rates per thawed metaphase II (MII) oocytes (<4%) and low implantation rates per embryos.

The reasons relate to technical limitations in the freezing process, and the fact that <40% of oocytes are euploid and unable to produce 'competent' embryos. Comparative genomic hybridization was performed on the first polar body (PB-1) of 323 MII oocytes retrieved from 16 donors. Of these, 111 were euploid, and were vitrified. Seventy-five of 78 vitrified oocytes (96%) survived warming and were fertilized using intracytoplasmic sperm injection. Thirty-one (41%) subsequently developed into expanded blastocysts, of which no more than two were subsequently transferred per uterus to 16 out of 19 prospective embryo recipients. Twelve of 19 (63%) recipients produced 17 healthy babies (eight singletons, three twins, and one set of triplets) One twin pregnancy miscarried in the late first trimester The birth rate per transfer of a maximum of two blastocysts to 16 recipients was 75%. The implantation rate per vitrified euploid oocyte was 27%. This study showed a six-fold improvement in pregnancy rate per cryopreserved oocyte over previous reports and a marked improvement in implantation rate. If independently validated, this approach could open the door to commercial egg cryobanking, significantly expanding women's reproductive choices.

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Wells D, Alfarawati S, Fragouli E.

Use of comprehensive chromosomal screening for embryo assessment: microarrays and CGH.
Mol Hum Reprod. 2008;14(12):703-10.
One of the most important factors influencing embryo viability is chromosome imbalance (aneuploidy). Embryos derived from aneuploid gametes have little potential for forming a viable pregnancy, but cannot be distinguished from normal embryos using standard morphological evaluation.

For more than a decade, preimplantation genetic screening (PGS) has been used to assist in the identification of aneuploid embryos. However, current strategies, based upon cell biopsy followed by fluorescent in situhybridization, allow less than half of the chromosomes to be screened. In this review, we discuss methods that overcome the limitations of earlier PGS strategies and provide screening of the entire chromosome complement in oocytes and embryos. In recent months, there has been a rapid growth in the number of PGS cycles utilizing one such method, comparative genomic hybridization (CGH). Data from IVF cycles utilizing CGH must be considered preliminary, but appear to indicate a dramatic increase in embryo implantation following comprehensive chromosomal screening. It is expected that methods based upon microarrays will yield similar clinical results and may be sufficiently rapid to permit comprehensive screening without the need for embryo cryopreservation. Some microarray platforms also offer the advantage of embryo fingerprinting and the potential for combined aneuploidy and single gene disorder diagnosis. However, more data concerning accuracy and further reductions in the price of tests will be necessary before microarrays can be widely applied.

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Buster J, Amato P

Low libido after menopause: Considerations and therapy
SRM 2007;Vol.5,No.3:17-21.
If the treatment of low sexual desire in postmenopausal women confounds clinicians, it is no surprise. Criteria and diagnostic tools to define androgen deficiency remain elusive; extant therapeutic agents are not approved by the US Food and Drug Administration (FDA).

Statements from medical associations provide conflicting guidance: the Endocrine Society recommends against the diagnosis of androgen deficiency, citing the absence of a well-defined clinical syndrome and lack of data on normal total or free testosterone levels, and also discourages the generalized use of testosterone until more data are available.1 Conversely, the North American Menopause Society stands by its 2005 position that it is appropriate to treat sexual dysfunction that causes distress with exogenous testosterone after other conditions have been ruled out.2

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Thornhill AR, Dedie-smulders CE, Geraedts JP, et al.

ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'.
Hum Reprod. 2005;20(1):35-48.
Among the many educational materials produced by the European Society of Human Reproduction and Embryology (ESHRE) are guidelines.

ESHRE guidelines may be developed for many reasons but their intent is always to promote best quality practices in reproductive medicine. In an era in which preimplantation genetic diagnosis (PGD) has become a reality, we must strive to maintain its efficacy and credibility by offering the safest and most effective treatment available. The dominant motivators for the development of current comprehensive guidelines for best PGD practice were (i) the absence of guidelines and/or regulation for PGD in many countries and (ii) the observation that no consensus exists on many of the clinical and technical aspects of PGD. As a consequence, the ESHRE PGD Consortium undertook to draw up guidelines aimed at giving information, support and guidance to potential, fledgling and established PGD centres. The success of a PGD treatment cycle is the result of great attention to detail. We have strived to provide a similar level of detail in this document and hope that it will assist staff in achieving the best clinical outcome for their patients.

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Sauer M, Paulson R.

Oocyte and embryo donation
Obstetrics and Gynecology. 1995;7:193-198.
Oocyte and embryo donation has become increasingly common over the past 10 years.

Today, is successfully used to treat women with a variety of disorders, including ovarian failure, avoidance of genetic disease transmission, declining ovarian function, poor oocyte quality following conventional assisted reproduction, and age-related infertility. Success rates do not appear to vary with the recipient’s age or diagnosis, with live birth rates in the 25–35% range. Oocyte and embryo donation represent the most efficacious method of assisted reproduction.

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