From physiology to psychology: An integrative review of menopausal syndrome

Table 1 Neuroinflammatory mechanisms linking menopause to mood disorders

Mechanism	Description	Effects	Relevance to mood disorders
Reduction in estrogen’s anti-inflammatory effects[46]	Estrogen normally inhibits pro-inflammatory cytokine production, suppresses microglial activation, and reduces oxidative stress	Decline in estrogen during menopause leads to enhanced pro-inflammatory state	Creates neurobiological environment conducive to mood disturbances
Elevated pro-inflammatory cytokines[47]	Increased levels of IL-6, TNF-α, and CRP in postmenopausal women	Impact neurotransmitter metabolism and neural function	Associated with depression and anxiety, particularly robust during menopausal transition (SWAN study)
Altered tryptophan metabolism[48]	Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase	Metabolizes tryptophan away from serotonin synthesis toward neurotoxic kynurenine metabolites	Reduces serotonin availability, contributing to mood disorders
Serotonin transporter activity	Pro-inflammatory cytokines increase serotonin transporter activity	Reduces serotonin availability at the synapse	Contributes to serotonergic dysfunction in mood regulation
Glutamate dysregulation	Pro-inflammatory cytokines stimulate microglial glutamate release and reduce astrocytic glutamate reuptake	Potential excitotoxicity in mood-regulating brain regions	Disrupts normal brain function in regions critical for emotional processing
Vasomotor symptoms and inflammation	Hot flashes associated with elevated inflammatory markers	Activate similar brain regions involved in interoception and emotional processing (insula, anterior cingulate cortex)	Shared neural circuitry may explain co-occurrence of vasomotor and mood symptoms
Oxidative stress	Reduced antioxidant effects of estrogen during menopause	Increased markers of oxidative damage	Associated with depressive symptoms in menopausal women
HPA axis-inflammation interaction	Bidirectional relationship between HPA axis and inflammatory systems	HPA hyperactivity promotes inflammation; pro-inflammatory cytokines stimulate cortisol release	Creates self-reinforcing cycle maintaining both inflammation and stress dysregulation

IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; CRP: C-reactive protein; HPA: Hypothalamic-pituitary-adrenal.