title: Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice.
abstract: Women of advanced maternal age (AMA) (age ≥ 35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with equine chorionic gonadotropin (eCG) for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that although eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG cotreatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.
authors.affiliation: Pregmama, LLC (L.R.B.), Gaithersburg, Maryland 20886; Departments of Epidemiology and Public Health (L.R.B., A.C.L.M., I.M.), Obstetrics, Gynecology, and Reproductive Sciences (C.L.C.), and Anatomy and Neurobiology (I.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Molecular Biology and Genetics (S.-J.L.) and Gynecology and Obstetrics, Johns Hopkins University School of Medicine (L.R.B.), Baltimore, Maryland 21205; and Department of Veterinary Integrative Biosciences (L.R.B.), Texas A&M College of Veterinary Medicine, College Station, Texas 77843.
authors.forename: Lori R
authors.initials: LR
authors.lastname: Bernstein
authors.affiliation: Pregmama, LLC (L.R.B.), Gaithersburg, Maryland 20886; Departments of Epidemiology and Public Health (L.R.B., A.C.L.M., I.M.), Obstetrics, Gynecology, and Reproductive Sciences (C.L.C.), and Anatomy and Neurobiology (I.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Molecular Biology and Genetics (S.-J.L.) and Gynecology and Obstetrics, Johns Hopkins University School of Medicine (L.R.B.), Baltimore, Maryland 21205; and Department of Veterinary Integrative Biosciences (L.R.B.), Texas A&M College of Veterinary Medicine, College Station, Texas 77843.
authors.forename: Amelia C L
authors.initials: AC
authors.lastname: Mackenzie
authors.affiliation: Pregmama, LLC (L.R.B.), Gaithersburg, Maryland 20886; Departments of Epidemiology and Public Health (L.R.B., A.C.L.M., I.M.), Obstetrics, Gynecology, and Reproductive Sciences (C.L.C.), and Anatomy and Neurobiology (I.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Molecular Biology and Genetics (S.-J.L.) and Gynecology and Obstetrics, Johns Hopkins University School of Medicine (L.R.B.), Baltimore, Maryland 21205; and Department of Veterinary Integrative Biosciences (L.R.B.), Texas A&M College of Veterinary Medicine, College Station, Texas 77843.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Pregmama, LLC (L.R.B.), Gaithersburg, Maryland 20886; Departments of Epidemiology and Public Health (L.R.B., A.C.L.M., I.M.), Obstetrics, Gynecology, and Reproductive Sciences (C.L.C.), and Anatomy and Neurobiology (I.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Molecular Biology and Genetics (S.-J.L.) and Gynecology and Obstetrics, Johns Hopkins University School of Medicine (L.R.B.), Baltimore, Maryland 21205; and Department of Veterinary Integrative Biosciences (L.R.B.), Texas A&M College of Veterinary Medicine, College Station, Texas 77843.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Chaffin
authors.affiliation: Pregmama, LLC (L.R.B.), Gaithersburg, Maryland 20886; Departments of Epidemiology and Public Health (L.R.B., A.C.L.M., I.M.), Obstetrics, Gynecology, and Reproductive Sciences (C.L.C.), and Anatomy and Neurobiology (I.M.), University of Maryland School of Medicine, Baltimore, Maryland 21201; Departments of Molecular Biology and Genetics (S.-J.L.) and Gynecology and Obstetrics, Johns Hopkins University School of Medicine (L.R.B.), Baltimore, Maryland 21205; and Department of Veterinary Integrative Biosciences (L.R.B.), Texas A&M College of Veterinary Medicine, College Station, Texas 77843.
authors.forename: István
authors.initials: I
authors.lastname: Merchenthaler
mesh_terms: D030301:Activin Receptors, Type II / Q000494:pharmacology*; D028341:Activins / Q000187:drug effects* / Q000378:metabolism; D000375:Aging / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D020090:Chromosome Segregation / Q000187:drug effects*; D003412:Cricetulus; D005260:Female; D005298:Fertility / Q000187:drug effects* / Q000235:genetics; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006736:Horses; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D008098:Litter Size; D008423:Maternal Age; D008540:Meiosis / Q000187:drug effects; D051379:Mice; D054315:Oocyte Retrieval; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012102:Reproductive Control Agents / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects*
chemical_list: D006063:Chorionic Gonadotropin; D007141:Immunoglobulin Fc Fragments; D012102:Reproductive Control Agents; D028341:Activins; D005640:Follicle Stimulating Hormone; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B