Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits
Version of Record online: 24 NOV 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 112, Issue 4, pages 870–881, February 2010
How to Cite
Bryan, K. J., Mudd, J. C., Richardson, S. L., Chang, J., Lee, H.-g., Zhu, X., Smith, M. A. and Casadesus, G. (2010), Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits. Journal of Neurochemistry, 112: 870–881. doi: 10.1111/j.1471-4159.2009.06502.x
- Issue online: 20 JAN 2010
- Version of Record online: 24 NOV 2009
- Received June 10, 2009; revised manuscript received October 13, 2009; accepted November 13, 2009.
- Alzheimer’s disease;
- cognitive function;
- estrogen replacement;
- leuprolide acetate;
J. Neurochem. (2010) 112, 870–881.
Declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy. However, the role of post-menopausal gonadotropin increases on cognition has not been evaluated. Here, we demonstrate that the down-regulation of ovariectomy-driven LH elevations using the gonadotropin releasing hormone super-analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y-maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors α and β, or activation of CYP19 and StAR, associated with the production of endogenous E2. Importantly, pathways associated with improved cognition such as CaMKII and GluR1-Ser831 are up-regulated by leuprolide treatment but not by chronic long-term E2 replacement suggesting independent cognition-modulating properties. Our findings suggest that down-regulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age-related cognitive decline and/or prevent the development of AD.