Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence

Abstract

Senescence is characterized neurologically by a decline in cognitive function, which we propose is the result of degenerative processes initiated by the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis with menopause and andropause. Compelling epidemiologic evidence to support this assertion includes the increased prevalence of Alzheimer disease (AD) in women, the correlation of serum HPG hormones with disease and the decreased incidence, and delay in the onset of AD following hormone replacement therapy. Dysregulation of the axis at this time leads to alterations in the concentrations of all serum HPG hormones (decreased neuronal sex steroid signaling, but increased neuronal gonadotropin releasing hormone, luteinizing hormone, and activin signaling). Hormones of the HPG axis, receptors for which are present in the adult brain, are important regulators of cell proliferation and differentiation during growth and development. Based on this, we propose that dysregulated HPG hormone signaling with menopause/andropause leads to the abortive reentry of differentiated neurons into the cell cycle via a process we term "dyosis." Interestingly, the major biochemical and neuropathologic changes reported for the AD brain also are intimately associated with neuron division: altered AbetaPP metabolism, Abeta deposition, tau phosphorylation, mitochondrial alterations, chromosomal replication, synapse loss, and death of differentiated neurons. Recent evidence supports the premise that AD-related biochemical changes are likely the combined result of increased mitotic signaling by gonadotropins and GnRH, decreased differentiative and neuroprotective signaling via sex steroids, and increased differentiative signaling via activins. This results in a hormonal milieu that is permissive of cell cycle reentry but does not allow completion of metaphase. Partial resetting of the axis following administration of normal endogenous sex steroids delays the onset and decreases the incidence of AD. Ideally, supplementation with HPG hormones should mimic closely the serum concentrations of all HPG hormones in reproductive men and cycling women to prevent dyotic signaling and attempted neuron division.