TY - JOUR
T1 - 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
AU - Bernstein, Lori R.
AU - Mackenzie, Amelia C.L.
AU - Lee, Se Jin
AU - Chaffin, Charles L.
AU - Merchenthaler, István
N1 - Funding Information:
We thank Dr John Morley and Dr Susan Farr (St Louis University) for SAMP8 mice and Thaddeus Nnuabue (University of Maryland, Baltimore) and Lisa Hester (University of Maryland, Baltimore Cytokine Core Laboratory) for technical assistance. We also thank expert advice from Dr Tom Thompson of the University of Cincinnati and from statistician Rachel Braun. Address all correspondence and requests for reprints to: Lori R. Bernstein, PhD, Pregmama, LLC, Gaithersburg, MD 20886. E-mail: lbernstein@cvm.tamu.edu. This work was supported by Maryland Industrial Partnerships (I.M. [University of Maryland of School of Medicine] and L.R.B. [Pregmama]), Technology Development Corporation of Maryland (Pregmama), the Max and Victoria Dreyfus Foundation (I.M. and L.R.B.), Grant R01AR060636 from the National Institutes of Health (to S.-J.L.), the Department of Epidemiology and Public Health (University of Maryland, Baltimore), an Indiegogo Crowd funding campaign (Pregmama), and the Bernstein and Pine families (University of Maryland, Baltimore and Pregmama). Present address for A.C.L.M.: Department of Maternal and Child Health, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599. Disclosure Summary: L.R.B. is Founder and Chief Scientific Officer of Pregmama, LLC. All other authors have nothing to disclose.
Publisher Copyright:
© Copyright 2016 by the Endocrine Society.
PY - 2016/3
Y1 - 2016/3
N2 - 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 continueto examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improvestimulation responsiveness in AMA women.
AB - 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 continueto examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improvestimulation responsiveness in AMA women.
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U2 - 10.1210/en.2015-1702
DO - 10.1210/en.2015-1702
M3 - Article
C2 - 26713784
AN - SCOPUS:84960540044
SN - 0013-7227
VL - 157
SP - 1234
EP - 1247
JO - Endocrinology
JF - Endocrinology
IS - 3
ER -