Down‐regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause‐associated cognitive deficits

Abstract

J. Neurochem. (2010) 112, 870–881. Abstract 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.

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

“…Consistent with this, preliminary data on infusion of deglycosylated hCG (dg-hCG), an LH receptor antagonist, into the dorsal hippocampus indicates that it also rescues memory deficits induced by ovariectomy (Burnham et al, 2014). Similar effects were observed when leuprolide acetate was given to ovx female mice (Bryan et al, 2010). In an aged transgenic mouse model of Alzheimer's disease, which features an isoform of human AβPP heavily associated with early onset AD (Tg2576), cognitive Y-maze performance is impaired.…”

“…In a number of experiments, Antide or leuprolide was administered to block pituitary LH, and it was assumed that the resulting behavioral and histopathological results were due to the downregulation of LH rather than GnRH or FSH (Bowen et al, 2004;Bryan et al, 2010;Palm et al, 2014;Ziegler and Thornton, 2010). However, GnRH and FSH receptors have been found in the hippocampus (Jennes and Conn, 1994;Chu et al, 2008;Schang et al, 2011;Wilson et al, 2007).…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…tive function follows the same pattern, with low LH levels improving memory and cognition and high levels making them worse, provided LH receptors are present (Casadesus et al, 2006(Casadesus et al, , 2007Bryan et al, 2010;Ziegler and Thornton, 2010;McConnell et al, 2012). We have discussed previously the developing field of physiological sex hormone replacement therapy for AD treatment (Clark and Atwood, 2011).…”

Doping for Chess Performance

“…Bryan [110] could indeed show, that restoration of cognitive impairments is possible in laboratory animals (mice) by downregulation of gonadotropins without use of estrogens. Similar results were published by Casadesus [114], which showed that transgenic mice with overexpressed LH showed decreased mental performance.…”

“…These processes are considered to be crucial for the development of agerelated cognitive impairments and even the progression of AD [110]. The question arises, whether the loss of estrogens or the high levels of gondadotropins are the cause for the cognition decline.…”