The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease

Abstract

The peri-menopause or menopausal transition-the time period that surrounds the final years of a woman's reproductive life-is associated with profound reproductive and hormonal changes in a woman's body and exponentially increases a woman's risk of cerebral ischemia and Alzheimer's disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

Keywords: Alzheimer’s disease; Cerebral ischemia; Estrogen receptors; Inflammasome; Menopause; Mitochondria; Stroke.

Fig. 1

At the reproductive senescence/menopausal transition the ovarian failure is associated with release of extracellular vesicles containing inflammasomes, which may be responsible for low-grade systemic inflammation. This low-grade inflammation may compromise the blood-brain barrier (BBB), making the brain more susceptible to inflammation and neurodegenerative diseases

Fig. 2

Putative mechanism of inflammasome activation in the neuron during pre- and peri-menopause. During pre-menopause, cyclic estradiol-17β(E2) maintains expression of nuclear, membrane, and mitochondrial estrogen receptor-beta (ER-β) expression, which in turn inhibits inflammasome activation by regulating mitochondrial functions, regulating biogenesis through cyclic AMP response element binding (CREB), and by reducing mitochondrial reactive oxygen species (ROS) formation. ER-β also increases expression of anti-inflammatory protein expression and reduces pro-inflammatory proteins. Decline in circulating estradiol-17β decreases estrogen receptor-beta (ER-β), causing activation of the inflammasome by reactive oxygen species (ROS). The inflammasome activates pro-caspase-1 into caspase-1, resulting in the processing of pro-IL-1β into IL-1β. Once active, IL-1β is secreted, resulting in a spread of the inflammatory response into neighboring cells. Similarly, extracellular vesicles containing inflammasome proteins get secreted, thus also contributing to the spread of the inflammatory response. ASC, Apoptosis-Associated Speck-Like Protein Containing CARD; ER-β, estrogen receptor subtype beta; ILR, interleukin receptors; IL-1β, interleukin 1β; NLR, nod-like receptor; NF-κB, nuclear factor κB; ROS, reactive oxygen species; TLR, toll-like receptors; TNFα, tumor necrosis factor alpha