Table 4.

Neurological risk factors for disease development arising from ovarian conditions, with evidence from literature

Ovarian condition	Risk factor for brain pathology	Studies
Menopause/POI	Lower endogenous estradiol	A study on women with Down syndrome found a correlation between lower endogenous levels of estradiol post-menopause and higher risk of developing AD (144). Estradiol modulates serotonin signaling (145), and low levels of estradiol-target BDNF are correlated with depression onset (146).
Menopause/POI	High LH and FSH blood concentrations	One study in men found that circulating LH concentration directly correlated with circulating levels of Aβ(1-42) (147). A study in women ages 40 to 65 years found blood FSH and LH levels to be positively correlated to Aβ load and negatively correlated with gray matter volume in the frontal cortex (148). In multiple studies, FSH level positively correlated with onset of depression. It is possible that FSH receptors on monocytes signal to produce proinflammatory cytokines, affecting mood (149). Although less is known about LH in the context of mood modulation, one study on rats found that a gonadotropin inhibitor reduced anxious behaviors following ovariectomy (150).
Menopause/POI/PCOS	Insulin resistance.	Evidence of insulin dysregulation was found in hippocampal and cortical sections of patients with AD (151). IGF-1 can promote vasodilation to protect against stroke, promote integrity of the BBB, promote anti-inflammatory glial states, and enhance insulin signaling and glucose uptake by cells (152). Loss of estradiol and IGF-1 and increases in cortisol and insulin resistance predisposing women to stroke onset (55). Insulin resistance also promotes storage of fat in nonadipose tissues and increases appetite, predisposing patients to obesity (153, 154). Insulin resistance promotes vasoconstriction and stroke onset. Insulin itself promotes clearance of amyloid plaques and tau tangles (153, 154). Hyperinsulinemia can cause adipose tissues to become inflamed and release inflammatory cytokines, with this effect amplified in individuals with obesity (155).
Menopause/POI	High cortisol.	Cortisol binds glucocorticoid receptors in the hippocampus and other areas. Chronic activation of the glucocorticoid receptors was found to damage hippocampal neurons by activation of NLRP1 (156). Levels of cortisol in patients with AD correlated with disease severity and progression (157). Cortisol administration to AD mice increased BACE1, Aβ deposition, and tau hyperphosphorylation (158).
Menopause/POI	Chronic inflammation	In patients with POI, serum concentrations of IL-6, IL-8, IL-17, and TNF-α increase with age in patients (159). Similarly, women undergoing menopause had significantly higher serum levels of IL-1β, IL-8, and TNF-α than in fertile women (160).
Menopause	Structural changes.	During the menopause transition, women were found to experience cerebral decreases in white matter, glucose metabolism, and increases in cerebral blood flow and Aβ load. Metabolism shifted to fatty acid utilization, possibly exacerbated by growing insulin resistance. Cognition was not affected during this transition, suggesting compensatory mechanisms occurring as a response to HPO axis dysregulation (44). Mouse models of menopause using OVX mice found a decrease in acetylcholine neuron density, an increase in anxiety, Aβ load, and decrease in locomotion (161).
PCOS	Hyperandrogenism	Androgen treatment to young biological females was found to increase spatial cognition, but worsen verbal fluency (162). Another study correlated high levels of free testosterone in patients with PCOS to worse verbal fluency, verbal memory, and visuospatial memory than controls (92). Several other studies report mixed results, with one finding testosterone correlated with better performance on visuospatial tasks and frontal gyrus connectivity networks, while others report worse performance on spatial visualization, and no effect on cognition. Overall, women with PCOS were found to perform worse on tasks of verbal fluency, verbal learning, verbal memory, visuospatial and executive functions, spatial reasoning, auditory processing, and finger dexterity than controls (163). Treating rats with a nonaromatizable androgen elevated serum levels of TNF-α and IL-1β compared to controls (164). In adipocytes, androgens affect phosphorylation of PKC, downregulating glucose transport and conferring an effect of insulin resistance on metabolism. In turn, hyperinsulinemia stimulates the ovaries to produce more androgens, propagating the cycle (165).

Abbreviations: Aβ, amyloid β; AD, Alzheimer disease; APP, amyloid precursor protein; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; FSH, follicle-stimulating hormone; FSHR, follicle-stimulating hormone receptor; HPO, hypothalamic-pituitary-ovarian; IGF-1, insulin-like growth factor 1; IL, interleukin; LH, luteinizing hormone; NLRP1, NLR family pyrin domain containing 1; OVX, ovariectomized; PCOS, polycystic ovary syndrome; PKC, protein kinase C; POI, primary ovarian insufficiency; TNF-α, tumor necrosis factor-α.