Luteinizing hormone: Evidence for direct action in the CNS

Abstract

This article is part of a Special Issue "SBN 2014". Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic-pituitary-gonadal (HPG) axis has long been implicated in changes in behavior and neuronal morphology. Most notably, estrogens have proven beneficial in the healthy brain through a host of different mechanisms. Recently, luteinizing hormone (LH) has emerged as a candidate for further investigation for its role in the CNS. The basis of this is that both LH and the LH receptor are expressed in the brain, and serum levels of LH correlate with cognitive deficits and Alzheimer's disease (AD) incidence. The study of LH in cognition and AD primarily focuses on evaluating the effects of downregulation of this peptide. This literature has shown that decreasing peripheral LH, through a variety of pharmacological interventions, reduces cognitive deficits in ovariectomy and AD models. However, few studies have researched the direct actions of LH on neurons and glial cells. Here we summarize the role of luteinizing hormone in modulating cognition, and we propose a mechanism that underlies a role for brain LH in this process.

Keywords: Estrogen; HPG axis; Leuprolide acetate; Luteinizing hormone; Memory; Ovariectomy.

Figure 1. LH Expression and Localization

LHβ expression (NHP Program Harbor-UCLA Medical Center, Torrance, CA) in a coronal mouse brain slice (A). LHβ immunoreactivity co-localizes with the neuronal marker NeuN. LHβ (green), NeuN (red), Nuclei are stained with DAPI (blue) (B). Electron microscopy demonstrates that LHβ is contained in vesicles of sizes corresponding to secretory vesicles (C).

Figure 2. Mechanism of action for luteinizing hormone modulating learning and memory

In the aged female brain estrogen replacement after ovariectomy does not improve cognitive function or associated underlying mechanisms such as dendritic spine density changes. Drugs that reduce peripheral levels of LH, which surge after ovariectomy or during menopause, rescue ovariectomy-dependent cognitive dysfunction and increase signaling events associated with synaptic plasticity. The LH receptor is localized to cognition-associated areas and it is described both at a level of function and plasticity. Brain-derived LH protein levels are present in cognition associated areas and are reduced by ovariectomy. The drugs that reduce peripheral LH levels also normalize brain-LH levels and these positively correlate with markers of neuroplasticity and cognitive improvement.