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Gleicher N.,Center for Human Reproduction New York | Gleicher N.,Foundation Medicine | Gleicher N.,Yale University | Weghofer A.,Center for Human Reproduction New York | And 3 more authors.
Reproductive Biology and Endocrinology | Year: 2011

Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes. © 2011 Gleicher et al; licensee BioMed Central Ltd.


Gleicher N.,Center for Human Reproduction New York | Gleicher N.,Foundation Medicine | Gleicher N.,Yale University | Weghofer A.,Center for Human Reproduction New York | And 4 more authors.
Reproductive Biology and Endocrinology | Year: 2011

Background: Effects of androgens on follicle maturation have been controversial for some time. Here, we review the potential of their applications in improving human ovulation induction, based on human and animal data, reported in the literature.Methods: We reviewed the published literature for the years 2005-2011, using relevant key words, in PubMed, Medline and Cochrane reviews, and then performed secondary reviews of referenced articles, which previously had not been known or preceded the searched time period. A total of 217 publications were reviewed.Results: Contrary to widely held opinion, recent data, mostly developed in the mouse, convincingly demonstrate essential contribution of androgens to normal follicle maturation and, therefore, female fertility. Androgens appear most engaged at preantral and antral stages, primarily affect granulosa cells, and exert effects via androgen receptors (AR) through transcriptional regulation but also in non-genomic ways, with ligand-activated AR modulating follicle stimulating hormone (FSH) activity in granulosa cells. While some androgens, like testosterone (T) and dehydroepiandrosterone (DHEA), appear effective in improving functional ovarian reserve (FOR) in women with diminished ovarian reserve (DOR), others may even exert opposite effects. Such differences in androgens may, at least partially, reflect different levels of agonism to AR.Discussion: Selective androgens appear capable of improving early stages of folliculogenesis. They, therefore, may represent forerunners of a completely new class of ovulation-inducing medications, which, in contrast to gonadotropins, affect follicle maturation at much earlier stages. © 2011 Gleicher et al; licensee BioMed Central Ltd.


Gleicher N.,Center for Human Reproduction New York | Gleicher N.,Foundation Medicine | Barad D.H.,Center for Human Reproduction New York | Barad D.H.,Foundation Medicine
Journal of Assisted Reproduction and Genetics | Year: 2012

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.gov. In absence of prospective clinical trials, and due to limited available data, individual publications/ongoing studies are assessed. Results: PGS#2 offers significant improvements in accuracy of aneuploidy diagnosis over PGS#1. By moving embryo biopsy from day-3 after fertilization (6-8 cell stage) to trophectoderm biopsy at blastocyst stage (day 5-6), PGS#2, however, adds additional co-variables to the analysis of efficacy of the procedure, which have special relevance for women with diminished ovarian reserve (DOR), who usually produce small egg and embryo numbers. Limited published data, claiming efficacy of PGS#2, as well as ongoing clinical trials, do not consider these additional co-variables, do not analyze outcomes by intent to treat and, therefore, have to be considered biased in patient selection. Conclusions: Here reached conclusions are based on absence of adequate data rather than affirmative outcome assessments. They, therefore, are subject to change at any future date with generation of significant new data. Premature introduction of PGS#1 caused significant damage to patients. As currently no reliable PGS#2 data are available to suggest improvements in IVF outcomes, to avoid a repeat of the PGS#1 experience, PGS#2 should be considered experimental until data show otherwise. © 2012 Springer Science+Business Media New York.


PubMed | Center for Human Reproduction New York
Type: | Journal: Reproductive biology and endocrinology : RB&E | Year: 2011

Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes.


PubMed | Center for Human Reproduction New York
Type: | Journal: Reproductive biology and endocrinology : RB&E | Year: 2010

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.In a 1:2, matched case control study 22 consecutive women with DOR, supplemented with DHEA, underwent preimplantation genetic screening (PGS) of embryos during in vitro fertilization (IVF) cycles. Each was matched by patient age and time period of IVF with two control IVF cycles without DHEA supplementation (n = 44). PGS was performed for chromosomes X, Y, 13, 16, 18, 21 and 22, and involved determination of numbers and percentages of aneuploid embryos.DHEA supplementation to a significant degree reduced number (P = 0.029) and percentages (P < 0.001) of aneuploid embryos, adjusted for relevant covariates. Short term supplementation (4-12 weeks) resulted in greatest reduction in aneuploidy (21.6%, 95% CI -2.871-46.031).Beneficial DHEA effects on DOR patients, at least partially, are the likely consequence of lower embryo aneuploidy. DHEA supplementation also deserves investigation in older fertile women, attempting to conceive, where a similar effect, potentially, could positively affect public health.

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