This article is part of a Special Issue "SBN 2014". Sex hormones are physiological
factors that promote neurogenesis during embryonic and fetal development. During childhood
and adulthood these hormones support the maintenance of brain structure and function
via neurogenesis and the formation of dendritic spines, axons and synapses required
for the capture, processing and retrieval of information (memories). Not surprisingly,
changes in these reproductive hormones that occur with menopause and during andropause
are strongly correlated with neurodegeneration and cognitive decline. In this connection,
much evidence now indicates that Alzheimer's disease (AD) involves aberrant re-entry
of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very
early in the disease, prior to the appearance of plaques and tangles, and explain
the biochemical, neuropathological and cognitive changes observed with disease progression.
Intriguingly, a recent animal study has demonstrated that induction of adult neurogenesis
results in the loss of previously encoded memories while decreasing neurogenesis after
memory formation during infancy mitigated forgetting. Here we review the biochemical,
epidemiological and clinical evidence that alterations in sex hormone signaling associated
with menopause and andropause drive the aberrant re-entry of post-mitotic neurons
into an abortive cell cycle that leads to neurite retraction, neuron dysfunction and
neuron death. When the reproductive axis is in balance, gonadotropins such as luteinizing
hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent
human and totipotent murine embryonic stem cell and neuron proliferation. However,
strong evidence supports menopausal/andropausal elevations in the LH:sex steroid ratio
as driving aberrant mitotic events. These include the upregulation of tumor necrosis
factor; amyloid-β precursor protein processing towards the production of mitogenic
Aβ; and the activation of Cdk5, a key regulator of cell cycle progression and tau
phosphorylation (a cardinal feature of both neurogenesis and neurodegeneration). Cognitive
and biochemical studies confirm the negative consequences of a high LH:sex steroid
ratio on dendritic spine density and human cognitive performance. Prospective epidemiological
and clinical evidence in humans supports the premise that rebalancing the ratio of
circulating gonadotropins:sex steroids reduces the incidence of AD. Together, these
data support endocrine dyscrasia and the subsequent loss of cell cycle control as
an important etiological event in the development of neurodegenerative diseases including
AD, stroke and Parkinson's disease.