Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods

Abstract

Sex hormones have been implicated in neurite outgrowth, synaptogenesis, dendritic branching, myelination and other important mechanisms of neural plasticity. Here we review the evidence from animal experiments and human studies reporting interactions between sex hormones and the dominant neurotransmitters, such as serotonin, dopamine, GABA and glutamate. We provide an overview of accumulating data during physiological and pathological conditions and discuss currently conceptualized theories on how sex hormones potentially trigger neuroplasticity changes through these four neurochemical systems. Many brain regions have been demonstrated to express high densities for estrogen- and progesterone receptors, such as the amygdala, the hypothalamus, and the hippocampus. As the hippocampus is of particular relevance in the context of mediating structural plasticity in the adult brain, we put particular emphasis on what evidence could be gathered thus far that links differences in behavior, neurochemical patterns and hippocampal structure to a changing hormonal environment. Finally, we discuss how physiologically occurring hormonal transition periods in humans can be used to model how changes in sex hormones influence functional connectivity, neurotransmission and brain structure in vivo.

Keywords: estrogens; hormonal transition periods; neurotransmitters; plasticity; progesterone.

Figures

Figure 1

Schematic representation of the main human central glutamatergic system (A, purple), GABAergic system (B, green), dopaminergic system (C, blue) and serotonergic system (D, orange) including a schematic display of estrogen (ERα and ERβ combined) and progesterone receptor distribution in the human brain. No distinction is made between ERα and ERβ sub-specification for this schematic display, however the localization for those subtypes can differ [e.g., so far no evidence could be gathered supporting ERα expression in the dorsal raphe nucleus (DRN) (Sugiyama et al., 2010)], however there have been reports on ERβ expression in primate DRN in the midbrain (Gundlah et al., ; Sugiyama et al., 2010). Estrogen (red triangles) receptors are predominantly present in cerebellum, VTA, hippocampus, amygdala, and frontal cortex; as well as in the raphe nuclei of the midbrain (Gundlah et al., ; Osterlund and Hurd, ; Mitra et al., ; Perlman et al., ; Sugiyama et al., 2010). Progesterone (filled circles) receptor expression could be shown in the amygdala, midbrain, brain stem, hippocampus, cerebellum and frontal cortex with no apparent restrictions to specific cell types (Bethea, ; Gundlah et al., 2001). (A) The cortical glutamatergic projections can be separated in five main pathways (Schwartz et al., 2012): (1) from prefrontal to brainstem areas (dorsal/medial raphe, VTA, substantia nigra); (2) from prefrontal cortex to striatum and nucleus accumbens; (3) the thalamocortical pathway, from thalamus to cortical pyramidal neurons; (4) inverse projections from cortex to thalamus; and (5) intra-cortical glutamate projections. (B) GABAergic projections are widely distributed throughout the brain. Main projections can be found originating in the striatum to the substantia nigra and the brain stem. Further projections innervate the thalamus from the substantia nigra (Fino and Venance, 2010). Moreover, GABAergic projections originate from (1) hypothalamus to occipital cortex and parietal cortex; (2) from hippocampus to thalamus and striatum, and (3) from nucleus accumbens to thalamus. The cerebellum is also highly innervated by GABAergic projections. (C) The cortical dopaminergic pathways build four distinct pathways (Felten and Shetty, 2010): (1) the mesolimbic pathway; with projections from VTA to limbic structures, such as the nucleus accumbens, hippocampus, amygdala and prefrontal cortex, (2) the mesocortical pathway; with projections from the VTA to cerebral cortex, (3) the nigrostriatal pathway; with connections between substantia nigra and striatum, (4) the tuberoinfundibular pathway; with projections starting from the hypothalamus to the pituitary gland. (D) The majority of serotonergic projections originates from the dorsal and median raphe nuclei, innervating the amygdala, hypothalamus, thalamus, striatum, cerebral cortex and hippocampus (Felten and Shetty, 2010): (1) The medial raphe predominantly projects to the frontal cortex and the hippocampus (Hornung, 2003) and (2) the areas of the dorsal raphe mainly innervate the thalamus, striatum and cerebral cortex (Geyer et al., 1976).

Figure 2

Vulnerability for development of a depressive illness corresponds to main hormonal transitions across the female lifespan. During childhood (0–9 years), a phase associated with low estrogen plasma levels, the prevalence rate for depression ranges between 2 and 3% (Kashani et al., ; Lewinsohn et al., 1994). When estrogen levels start rising in puberty (10–15 years), so does the prevalence rate for depression, up to 8% (Angold et al., 1998). During reproductive years, a phase when estrogen and progesterone levels peak, prevalence rates vary between 21 and 38% (Kessler et al., ; Angold et al., 1998). Estrogen and progesterone levels start declining during perimenopause (41–51 years), drop considerably postmenopausally (45–65 years) and remain fairly stable during old age (above 65 years). This drop in sex steroid levels is paralleled by a decrease in prevalence rates for depression from 23 to 26% (Cohen et al., ; Freeman et al., ; Unsal et al., ; Tamaria et al., 2013) during the hormonal transition phases to rates of 1–5% during old age (Tamaria et al., 2013).