Menopause-Associated Depression: Impact of Oxidative Stress and Neuroinflammation on the Central Nervous System-A Review

Abstract

Perimenopausal depression, occurring shortly before or after menopause, is characterized by symptoms such as emotional depression, anxiety, and stress, often accompanied by endocrine dysfunction, particularly hypogonadism and senescence. Current treatments for perimenopausal depression primarily provide symptomatic relief but often come with undesirable side effects. The development of agents targeting the specific pathologies of perimenopausal depression has been relatively slow. The erratic fluctuations in estrogen and progesterone levels during the perimenopausal stage expose women to the risk of developing perimenopausal-associated depression. These hormonal changes trigger the production of proinflammatory mediators and induce oxidative stress, leading to progressive neuronal damage. This review serves as a comprehensive overview of the underlying mechanisms contributing to perimenopausal depression. It aims to shed light on the complex relationship between perimenopausal hormones, neurotransmitters, brain-derived neurotrophic factors, chronic inflammation, oxidative stress, and perimenopausal depression. By summarizing the intricate interplay between hormonal fluctuations, neurotransmitter activity, brain-derived neurotrophic factors, chronic inflammation, oxidative stress, and perimenopausal depression, this review aims to stimulate further research in this field. The hope is that an increased understanding of these mechanisms will pave the way for the development of more effective therapeutic targets, ultimately reducing the risk of depression during the menopausal stage for the betterment of psychological wellbeing.

Keywords: estrogen deprivation; pro-inflammatory cytokines; psychological wellbeing.

Figure 1

Estrogen deficiency and HPA axis dysregulation. (1) Neurons in the hypothalamus release the hypothalamic neuropeptides corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP). (2) CRH and AVP promote a posttranslational cleavage of anterior pituitary pro-opiomelanocortin mRNA (POMC), resulting in the synthesis and secretion of adrenocorticotrophin (ACTH). (3) ACTH stimulates the release of glucocorticoids and mineralocorticoids derived from the adrenal glands. (4) The hippocampus, as an important site of glucocorticoid receptor (GR) and mineralocorticoid (MR) receptors mediated negative feedback regulation, plays a vital role in the end stage of this stress feedback process. (5) TNF-α and IL-1β trigger the imbalance of the HPA axis by inhibiting the transcriptions of c-fos and AVP. (6) Estrogen is able to regulate the hypothalamic response to stress by regulating CRH, oxytocin, and AVP gene expression in hypothalamic neurons and the excitatory inputs to the PVN. Perimenopausal estrogen deficiency leads to weakened regulation of the HPA axis response to external stress. (7) Estrogen can block the actions of CRH on anterior pituitary corticotrophs by increasing the expression of CRH-BP and restricting the amounts of bioactive CRH. Perimenopausal estrogen deficiency increases the sensitivity of the pituitary gland to CRH, thereby resulting in the overactivation of the HPA axis.

Figure 2

Neuroinflammatory pathway following estrogen deficiency. (1) Estrogen can inhibit the secretion of inflammatory factors by T cells and macrophages, and the decrease in estrogen levels leads to chronic inflammation during perimenopause, resulting in an increase in inflammatory mediators in peripheral blood. (2) These peripheral cytokines will directly or indirectly reach the brain via different specific or non-specific pathways. (3) In premenopause, β-estradiol inhibits microglia-mediated astrocytic activation to alleviate neuroinflammation and the secretion of inflammatory mediators by microglia. On the other hand, in perimenopause, estrogen deficiency allows inflammatory cytokines to activate microglia in the brain, which then produce other inflammatory mediators. (4) IL-β, IL-6, and TNF-α reduce the synthesis of 5-HT by stimulating indoleamine 2,3-dioxygenase (IDO). (5) IDO can convert tryptophan into kynurenine, and the activation of the kynurenine pathway results in the production of ROS and RNS. On the other hand, superoxide anion radicals can cause superinduction of the kynurenine pathway. (6) ROS and RNS reduce the synthesis of 5-HT by stimulating IDO and the kynurenine pathway. (7) Neuroglia secrete serotonin, which then promotes BDNF secretion. (8) Similarly, estrogen can promote the synthesis and secretion of BDNF; therefore, after menopause, insufficient estrogen can lead to a decrease in BDNF synthesis. (9) IL-β, IL-6, and TNF-α can inhibit the neuroprotective effect of BDNF. (10) IL-β, IL-6, TNF-α can promote the production of ROS in mitochondria. Furthermore, the ROS can also promote the synthesis and release of inflammatory factors. (11) Estrogen can reduce ROS production by promoting the synthesis of antioxidant enzymes, and insufficient estrogen during perimenopause leads to an increase in ROS. (12) ROS can lead to lipid, DNA, and protein oxidation and damage in the brain. (13) ROS reduces the production of monoaminergic neurotransmitters and other aminergic compounds. (14) IL-β decreases the rate-limiting enzyme in noradrenaline. (15) IL-β, IL-6, and TNF-α can suppress GABAergic inhibitory transmission.

Figure 3

The antioxidant mechanism of estrodiol. (1) Estradiol binds to G-protein-coupled receptor 30 on the cell membrane. (2) GPR30 activation by estradiol elicited the SRC/EGFR/PI3K/Akt signaling pathway. (3) The activation of the GPR30/SRC/EGFR/PI3K/Akt signaling pathway leads to Nrf2 dissociation from Keap1. (4) Nrf2 translocates into the nucleus. Then the heterodimerization of NRF2 with small Maf proteins in AREs occurs and activates transcription of SOD, CAT, HO-1, GPxs, and so on. (5) Insufficient estrogen during perimenopause results in KEAP1-recruited CUL3, RBX, and NRF2 to degrade NRF2 through ubiquitination and ultimately leads to the decrease in antioxidant substances, while the increase in ROS leads to increased levels of oxidative stress and nerve damage in perimenopausal women.