An additive opinion to the committee opinion of ASRM and SART on the use of preimplantation genetic testing for aneuploidy (PGT-A).

After over 20 years of progressively increasing clinical utilization of PGT-A (and its precursors), the American Society for Reproductive Medicine (ASRM) and its daughter society, the Society for Assisted Reproduction (SART), for the first time published a committee opinion clearly acknowledging that "the value of PGT-A as a routine screening test for patients undergoing in vitro fertilization (IVF) has not been demonstrated." This statement is timely and welcome but requires some additions and raises some new questions, among those why, if PGT-A in a general population does not improve IVF cycle outcomes, the routine clinical utilization of PGT-A should continue.

We have reached a dead end for preimplantation genetic testing for aneuploidy.

The hypothesis of preimplantation genetic testing for aneuploidy (PGT-A) was first proposed 20 years ago, suggesting that during IVF elimination of aneuploid embryos prior to transfer will improve implantation rates of remaining embryos and, therefore, increase pregnancy and live birth rates, while also reducing miscarriages. Subsequently, unvalidated and increasingly unrestricted clinical utilization of PGT-A called for at least one properly randomized controlled trial (RCT) to assess cumulative live birth rates following a single oocyte retrieval, utilizing all fresh and frozen embryos of an IVF cycle. Only recently two such RCTs were published, however both, when properly analysed, not only failed to demonstrate significant advantages from utilization of PGT-A, but actually demonstrated outcome deficits in comparison to non-use of PGT-A, when patient selection biases in favour of PGT-A were reversed.

Preimplantation Genetic Testing for Aneuploidy - a Castle Built on Sand.

Preimplantation genetic testing for aneuploidy (PGT-A) has become a routine add-on for in vitro fertilization (IVF) to determine whether human embryos are to be clinically utilized or disposed of. Studies claiming IVF outcome improvements following PGT-A, however, used highly selected patient populations or inappropriate statistical methodologies. PGT-A was never clinically validated in its ability to define a human embryo as chromosomal normal, mosaic, or aneuploid, nor certified by a regulatory body, or an authoritative professional organization.

Hormonal Effects in Reproductive Technology with Focus on Diminished Ovarian Reserve.

Modern use of reproductive technologies has revolutionized the treatment of infertile couples. Strategies to improve ovarian function in cases of diminished ovarian reserve are perhaps the least understood area in this field and will be the chief focus of this chapter.

Association of skewed X-chromosome inactivation with FMR1 CGG repeat length and anti-Mullerian hormone levels: a cohort study.

Background: Premutation range CGGn repeats of the FMR1 gene denote risk toward primary ovarian insufficiency (POI), also called premature ovarian failure (POF). This prospective cohort study was undertaken to determine if X-chromosome inactivation skew (sXCI) is associated with variations in FMR1 CGG repeat length and, if so, is also associated with age adjusted antimüllerian hormone (AMH) levels as an indicator of functional ovarian reserve (FOR).

Methods: DNA samples of 58 women were analyzed for methylation status and confirmation of CGG repeat length.

Associations between peripheral androgens and cortisol in infertile women.

Testosterone has in recent years been proven essential for normal growth and maturation of small growing follicles. Concomitantly, low functional ovarian reserve (LFOR), characterized by a small growing follicle pool, has been associated with low testosterone levels, which can be of ovarian and/or adrenal origin. In this study we, therefore, investigated whether peripheral sex steroid precursors and testosterone levels potentially reflect on adrenal function.

Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval.

Why IVF pregnancy rates decline sharply after age 43 is unknown. In this study, we compared granulosa cell (GC) function in young oocyte donors (n=31, ages 21-29), middle-aged (n=64, ages 30-37) and older infertile patients (n=41, ages 43-47). Gene expressions related to gonadotropin activity, steroidogenesis, apoptosis and luteinization were examined by real-time PCR and western blot in GCs collected from follicular fluid.

Establishment of comparative performance criteria for IVF centers: correlation of live birth rates in autologous and donor oocyte IVF cycles.

Background: To assess whether an objective performance criterion for in vitro fertilization (IVF) centers can be established.

Methods: A retrospective analysis of 2011 National ART Surveillance System data for 451 U.S.

Ovarian reserve screening before contraception?

Women are increasingly delaying conception to later years. Hormonal contraception induces artificial cyclicity, which does not, like natural cyclicity, reflect normal, physiological ovarian behaviour. Therefore, long-term users of hormonal contraceptives, in particular, fail to derive potential diagnostic benefits from changes in menstrual cyclicity, which usually alerts patients and physicians to developing ovarian pathology.

Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review.

Only a few years ago the American Society of Assisted Reproductive Medicine (ASRM), the European Society for Human Reproduction and Embryology (ESHRE) and the British Fertility Society declared preimplantation genetic screening (PGS#1) ineffective in improving in vitro fertilization (IVF) pregnancy rates and in reducing miscarriage rates. A presumably upgraded form of the procedure (PGS#2) has recently been reintroduced, and is here assessed in a systematic review. PGS#2 in comparison to PGS#1 is characterized by: (i) trophectoderm biopsy on day 5/6 embryos in place of day-3 embryo biopsy; and (ii) fluorescence in-situ hybridization (FISH) of limited chromosome numbers is replaced by techniques, allowing aneuploidy assessments of all 24 chromosome pairs.

A randomized clinical trial of endometrial perfusion with granulocyte colony-stimulating factor in in vitro fertilization cycles: impact on endometrial thickness and clinical pregnancy rates.

Objective: To investigate whether granulocyte colony-stimulating factor (G-CSG) affects endometrial thickness, implantation rates, and clinical pregnancy rates in routine, unselected IVF cycles.

Design: Registered, individually randomized, two-group, parallel double-blinded placebo-controlled clinical trial.

Setting: Academically affiliated private clinical and research center.

Endocrine autoimmune diseases and female infertility.

An increasing body of evidence suggests that immune-mediated processes affect female reproductive success at multiple levels. Crosstalk between endocrine and immune systems regulates a large number of biological processes that affect target tissues, and this crosstalk involves gene expression, cytokine and/or lymphokine release and hormone action. In addition, endocrine-immune interactions have a major role in the implantation process of the fetal (paternally derived) semi-allograft, which requires a reprogramming process of the maternal immune system from rejection to temporary tolerance for the length of gestation.

Why are reproductive cancers more common in nulliparous women?

It has been known for decades that nulliparity is associated with an increased risk for certain reproductive malignancies, including breast, ovarian and uterine cancers. A recent commentary in The Lancet summarized the available evidence based on data in nulliparous women and concluded that the risk of nulliparity was related to the increased number of ovulatory cycles, and so might be preventable by utilization of oral contraceptives. That communication described significant differences in age-dependent cancer mortality in nulliparous nuns, as well as in parous controls, between breast, ovarian and uterine cancers.

The irrational attraction of elective single-embryo transfer (eSET).

In this issue of the journal, Niinimäki et al., colleagues from a pioneering Finnish center in the development of elective single-embryo transfer (eSET), propose the expansion of eSET to suitable women at ages of 40-44 years. This paper offers not only a critique of their proposal but also of eSET in general.

A review of, and commentary on, the ongoing second clinical introduction of preimplantation genetic screening (PGS) to routine IVF practice.

Purpose: Current re-introduction of "improved" preimplantation genetic screening (PGS#2) raises the question whether PGS#2 is ready for routine clinical application.

Methods: We assessed available evidence via review of published data for years 2005-2012, and review of currently ongoing registered clinical trials, based on searches under appropriate key words in PubMed, MEDLINE, Cochrane Database System Review and Google Scholar and http://www.ClinicalTrials.

Differences in ovarian aging patterns between races are associated with ovarian genotypes and sub-genotypes of the FMR1 gene.

Background: Ovarian aging patterns differ between races, and appear to affect fertility treatment outcomes. What causes these differences is, however, unknown. Variations in ovarian aging patterns have recently been associated with specific ovarian genotypes and sub-genotypes of the FMR1 gene.

Eliminating multiple pregnancies: an appropriate target for government intervention?

The manuscript in this issue of the journal by Bissonette et al. reports on a new government-sponsored intervention into the practice of IVF within the province of Quebec, Canada, which in the authors' opinion highly successfully reduced twinning rates, while maintaining overall acceptable pregnancy rates. Given the opportunity to comment, their manuscript, in my opinion, only reemphasizes why, despite wide professional support, the concept of single embryo transfer (SET) is: (i) damaging to most infertility patients by reducing pregnancy chances; (ii) does so without compensatory benefits; (iii) impinges on patients' rights to self-determination; (iv) has significant negative impact on IVF-generated birth rates; and (v) thus, demonstrating, once more, that governments should not interfere with the patient-physician relationships.

Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR).

Background: With infertility populations in the developed world rapidly aging, treatment of diminished ovarian reserve (DOR) assumes increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances with DOR, and is now utilized by approximately one third of all IVF centers world-wide. Increasing DHEA utilization and publication of a first prospectively randomized trial now warrants a systematic review.

Do chromosomally abnormal pregnancies really preclude autoimmune etiologies of spontaneous miscarriages?

Objective: At least 60% of spontaneous pregnancy loss is considered genetic in nature. Miscarriages can, however, also be autoimmune-induced or have other etiologies. Current clinical dogma in rheumatology as well as obstetrics/gynecology holds that evidence of aneuploidy in products of conception establishes the cause of miscarriage and rules out other potential causes, including autoimmunity.

FMR1 genotype with autoimmunity-associated polycystic ovary-like phenotype and decreased pregnancy chance.

The FMR1 gene partially appears to control ovarian reserve, with a specific ovarian sub-genotype statistically associated with a polycystic ovary (PCO)- like phenotype. Some forms of PCO have been associated with autoimmunity. We, therefore, investigated in multiple regression analyses associations of ovary-specific FMR1 genotypes with autoimmunity and pregnancy chances (with in vitro fertilization, IVF) in 339 consecutive infertile women (455 IVF cycles), 75 with PCO-like phenotype, adjusted for age, race/ethnicity, medication dosage and number of oocytes retrieved.

Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS).

Background: Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR), and to reduce miscarriage rates by 50-80%. Such an effect is mathematically inconceivable without beneficial effects on embryo ploidy. This study, therefore, assesses effects of DHEA on embryo aneuploidy.