Table 1 Examples of sex differences and sex hormone effects, by level of observation
From: In search of sex-related mediators of affective illness
Level of observation | Data source | Basal sex difference | Sex difference in stress and affective disorders | Sex hormone effect (non-stress) | Sex hormone effect (stress and affective disorders) |
|---|---|---|---|---|---|
Brain structure | Animal | Sexually dimorphic brain regions, (e.g., mePOA) [41, 268]; locus coeruleus structural dimorphism [54] | Regional morphology differences following prenatal stress [55,56,57,58,59,60] | E2 impact on physiologic development [269] | E2 neuroprotective in brain injury [270]; neuronal loss in the prefrontal cortex, hippocampus, hypothalamus, and amygdala following OVX [271] |
Human | Women increased gray/white matter ratio [42, 43]; gray matter density differences in several brain regions [45]; different developmental rates[46, 47]; cortical surface area trajectory [272]; volumetric differences at birth [273] | In childhood stress: lower gray matter thickness and caudate volumes in females, decreased thickness of rostral anterior cingulate cortex in males [64]; amygdala differences following prenatal stress [65,66,67,68,69]; differences in cortical gyrification [70] | Volumetric changes during different menstrual phases [274, 275]; regional differences between OCP users and cycling women [275] | Effects of menstrual cycle on hippocampus in PMDD [276] | |
Network connectivity | Animal | Sex differences in circuits implicated in parenting behavior [277] | Differential network activation in response to pain [278,279,280]; differences in network organization following prenatal ethanol exposure [281] | Dendritic spine density fluctuation during estrous cycle [166]; E2-dependent reward circuitry [282] | Hippocampal/PFC remodeling following stress mediated by E2 [122] |
Human | Weakening of the iFC of the DMN in female adolescents, predicting greater internalizing symptoms [127] | Reward [96] | |||
Signal transduction | Animal | Neurotransmission, many isolated differences [16] | PFC GABA function/reward [187]; higher HPA activity following stress in females [16, 284] | E2 effects on neurotransmission/cell signaling/feedback [142, 286,287,288]; Testosterone effects on HPA response to stress [22] | |
Human | GABA [289] | E2 x genetic background influence on dopamine-mediated reward [171] | Hormone withdrawal/allopregnanolone in PPD [174]; Altered estradiol-dependent cellular Ca 2 + homeostasis and endoplasmic reticulum stress response in PMDD [290] | ||
Transcription/Translation | Animal | Basal differences secondary to direct sex hormone effects [291] | Differential transcription—minimal overlap in stress-associated genes [218,219,220] | Direct sex hormone effects (e.g., classical sex hormone effects) [292] | change in protein expression associated with depressive behavior following OVX [271] |
Human | Basal differences secondary to direct sex hormone effects [291] | transcriptional differences by sex in MDD and controls [218, 223] | Direct sex hormone effects [291] | Differential transcriptional effect of E2 and P4 in PMDD vs. controls [293] | |
Epigenesis | Animal | Widespread basal differences, including brain [233, 234, 239] | E2/estrogen receptors regulate DNA methylation, demethylation, histone modification, chromatin remodeling [294] | In-utero stress produces differential epigenetic response in offspring [295, 296] | |
Human | Widespread basal differences, including brain [227,228,229,230,231,232] | Methylation differences following prenatal stress [263] | Differential expression of ESC/E(Z) complex (a gene silencing complex that functions via methylation) by E2 and P4 in PMDD vs. controls [293] |