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Norbert Gleicher The Center for Human Reproduction, New York, New York, USA
The Foundation for Reproductive Medicine, New York, New York, USA
The Brivanlou Stem Cell Biology and Molecular Embryology Laboratory, The Rockefeller University, New York, New York, USA

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Vitaly A Kushnir The Center for Human Reproduction, New York, New York, USA
Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem, North Carolina, USA

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David F Albertini The Center for Human Reproduction, New York, New York, USA
Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas, USA

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David H Barad The Center for Human Reproduction, New York, New York, USA
The Foundation for Reproductive Medicine, New York, New York, USA

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Women above age 40 years in the US now represent the most rapidly growing age group having children. Patients undergoing in vitro fertilization (IVF) are rapidly aging in parallel. Especially where egg donations are legal, donation cycles, therefore, multiply more rapidly than autologous IVF cycles. The donor oocytes, however, are hardly ever a preferred patient choice. Since with use of own eggs, live birth rates decline with advancing age but remain stable (and higher) with donor eggs, older patients always face the difficult and very personal choice between poorer chances with own and better chances with donor oocytes. Physician contribution to this decision should in our opinion be restricted to accurate outcome information for both options. Achievable pregnancy and live birth rates in older women are, however, frequently underestimated, thereby mistakenly biasing fertility providers, private insurance companies and even regulatory government agencies. Restriction on access to IVF for older women is then often the consequence. In this review, we summarize the limited published data on best treatments of ‘older’ ovaries, while also addressing treatment approaches that should be avoided in older women. This focused review, therefore, to a degree is subjective. Research addressing aging ovaries in IVF has been disappointingly sparse, and has in our opinion too heavily concentrated on methods of embryo selection (ES), which, especially in older women, not only fail to improve IVF outcomes, but actually, negatively affect live birth chances. We conclude that, aside from breakthroughs in gamete creation, only pharmacological interventions into early (small growing follicle stages) follicle maturation will offer new potential to positively impact oocyte and embryo quality and, therefore, IVF outcomes. Research, therefore, should be accordingly redirected.

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Yan-Guang Wu The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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David H Barad The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA
The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA
The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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Vitaly A Kushnir The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA
The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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Emanuela Lazzaroni The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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Qi Wang The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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David F Albertini The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA
The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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Norbert Gleicher The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA
The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA
The Center for Human Reproduction (CHR), Foundation for Reproductive Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Department of Molecular and Integrative Physiology, Stem Cell Biology and Molecular Embryology Laboratory, 21 East 69th Street, New York, New York 10021, USA

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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. FSH receptor (FSHR), aromatase (CYP19A1) and 17β-hydroxysteroid dehydrogenase (HSD17B) expression were found down regulated with advancing age, while LH receptor (LHCGR), P450scc (CYP11A1) and progesterone receptor (PGR) were up regulated. Upon in vitro culture, GCs were found to exhibit lower proliferation and increased apoptosis with aging. While FSH supplementation stimulated GCs growth and prevented luteinization in vitro. These observations demonstrate age-related functional declines in GCs, consistent with premature luteinization. To avoid premature luteinization in women above age 43, we advanced oocyte retrieval by administering human chorionic gonadotropin at maximal leading follicle size of 16 mm (routine 19–21 mm). Compared to normal cycles in women of similar age, earlier retrieved patients demonstrated only a marginal increase in oocyte prematurity, yet exhibited improved embryo numbers as well as quality and respectable clinical pregnancy rates. Premature follicular luteinization appears to contribute to rapidly declining IVF pregnancy chances after age 43, and can be avoided by earlier oocyte retrieval.

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