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. 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.
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA ywu@thechr.com.
Yan-Guang
YG
Wu
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA.
David H
DH
Barad
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA.
Vitaly A
VA
Kushnir
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA.
Emanuela
E
Lazzaroni
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA.
Qi
Q
Wang
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA.
David F
DF
Albertini
The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA The Center for Human Reproduction (CHR)21 East 69th Street, New York, New York 10021, USAFoundation for Reproductive MedicineNew York, New York 10021, USADepartment of Obstetrics and GynecologyAlbert Einstein College of Medicine, Bronx, New York 10461, USADepartment of Obstetrics and GynecologyWake Forest University, Winston Salem, North Carolina 27106, USADepartment of Molecular and Integrative PhysiologyUniversity of Kansas Medical Center, Kansas City, Kansas 66160, USAStem Cell Biology and Molecular Embryology LaboratoryThe Rockefeller University, New York, New York 10065, USA.
Norbert
N
Gleicher
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000502:physiology*; D006801:Humans; D034461:Luteinization / Q000502:physiology*; D008875:Middle Aged; D054315:Oocyte Retrieval / Q000379:methods*; D011247:Pregnancy; D011962:Receptors, FSH / Q000235:genetics / Q000378:metabolism; D011974:Receptors, LH / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
D011962:Receptors, FSH; D011974:Receptors, LH; D011980:Receptors, Progesterone; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase
early retrieval; granulosa cell; in vitro fertilization; oocyte; premature luteinization