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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 DMN [283]; white matter [83,84,85] Weakening of the iFC of the DMN in female adolescents, predicting greater internalizing symptoms [127] Reward [96] Network response to hormonal manipulation [131, 138]
Signal transduction Animal Neurotransmission, many isolated differences [16] PFC GABA function/reward [187]; higher HPA activity following stress in females [16, 284] Neurotransmission [285]; reward processing [169, 170] E2 effects on neurotransmission/cell signaling/feedback [142, 286,287,288]; Testosterone effects on HPA response to stress [22]
Human GABA [289] 5HT [199, 200], GABA [207, 208], glutamate [209] 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] DNA methyltransferase [254], miRNA differences [222] 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] E2 effect on epigenesis of puberty [240, 241, 297] Differential expression of ESC/E(Z) complex (a gene silencing complex that functions via methylation) by E2 and P4 in PMDD vs. controls [293]
  1. Examples of sex differences and sex hormone effects at each organizational level. This table serves as a scaled-down version of our framework presented above. As in the body text, the content presented in each box is meant to provide illustrative examples within each category rather than a comprehensive list of findings. Examples for both basal/non-stressed conditions and stressed/affective disorder conditions are shown, and are separated according to human and animal research. mePOA medial preoptic area, E2 estradiol, P4 progesterone, OCP oral contraceptive, PPD peripartum depression, PMDD premenstrual dysphoric disorder, MDD major depressive disorder, PFC prefrontal cortex, iFC intrinsic functional connectivity, DMN default mode network, HPA hypothalamic pituitary axis, 5HT serotonin, OVX ovariectomy