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Review
. 2010 Jun;62(2):155-98.
doi: 10.1124/pr.109.002071. Epub 2010 Apr 14.

Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines

Glenda E Gillies  1 , Simon McArthur
Affiliations
Review

Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines

Glenda E Gillies et al. Pharmacol Rev. 2010 Jun.

Abstract

The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mammalian species studied, including humans. Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry. There are notable sex differences in the incidence and manifestations of virtually all central nervous system disorders, including neurodegenerative disease (Parkinson's and Alzheimer's), drug abuse, anxiety, and depression. Understanding the cellular and molecular basis of sex differences in brain physiology and responses to estrogen and estrogen mimics is, therefore, vitally important for understanding the nature and origins of sex-specific pathological conditions and for designing novel hormone-based therapeutic agents that will have optimal effectiveness in men or women.

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Figures

Fig. 1.
Fig. 1.
Patterns of hormone exposure throughout life: a biological basis for sex differences in the brain. In male rats (A) and humans (C), a transitory activation of the testes during a critical developmental window means that the brain develops in a different hormonal environment in males and females, which establishes irreversible sex dimorphisms in specific neural circuits. After puberty, the rise in gonadal steroids in males and females activates the sexually dimorphic circuitry; the rodent (A) and human (C) male brain is exposed to a relatively steady level of the main gonadal steroid, testosterone, for most of adult life. In contrast, the rodent (B) and human (D) female brain is exposed to a cyclical pattern of the main gonadal steroid, estradiol, for a certain period of adult life, until levels fall precipitously at reproductive senescence or menopause.
Fig. 2.
Fig. 2.
Adult sexually dimorphic circuitry is imprinted by neonatal hormone action. In the adult male HPG axis (A), GnRH is released from hypothalamic neurons in a pulsatile manner to stimulate the release of LH and follicle-stimulating hormone (FSH), which in turn stimulate testosterone (T) production and spermatogenesis. T exerts a negative feedback (-ve) at hypothalamic and pituitary levels to maintain a steady state in the hypothalamo-pituitary-gonadal axis. In females (B), estradiol (E2) and progesterone (P) produced by the ovaries also exert a negative feedback in the early follicular phase and luteal phase, respectively, of the menstrual cycle, but in the late follicular phase, as E2 levels peak, this converts to a positive feedback (+ve), which augments GnRH release and triggers an LH surge and ovulation at mid-cycle. In gonadectomized female rats (C), activation of the LH surge can be induced experimentally by the injection of E2 followed 48 h later by P. In male rats gonadectomized as adults (D), the hypothalamic circuitry, and hence the LH surge, fails to respond to hormonal priming, whereas the LH surge can be induced in adult male rats if they were gonadectomized as newborns (E). These and related studies demonstrate that early exposure to T, after its aromatization to E2, suppresses the circuitry responsible for the positive feedback of E2 on GnRH release.
Fig. 3.
Fig. 3.
Simplified schema describing the main components of midbrain dopaminergic systems (circuitry), the behavioral domains they influence, and association of their malfunction with some CNS disorders. The NSDA (or mesostriatal) system has its origins in the perikarya of the SNc and projects to the dorsal striatum. This regulates locomotor activity and is involved in stereotypical behaviors (e.g., grooming and gnawing in rats). The NSDA pathway degenerates in Parkinson's disease. The mesolimbic dopaminergic system (MLDA) originates in the perikarya of the ventral tegmental area (VTA) and projects to the ventral striatum, especially the N.Acc. This pathway also has some influence on locomotor behavior and is involved primarily in regulating motivation, reward, and reinforcement. Altered activity in the MLDA is associated with addictive behaviors and drug abuse. Perikarya in the VTA also project to the PFC, forming the mesocortical dopaminergic system (MCDA) involved in higher cognitive functions, which may deteriorate in AD. Release of DA from the VTA projections to the PFC trans-synaptically attenuates subcortical/mesoaccumbens DA activity and N.Acc DA release; hypofunction in the mesocortical dopaminergic system and hyperfunction in the MLDA activity to the N.Acc is characteristic of schizophrenia.
Fig. 4.
Fig. 4.
Sex differences in the topographical organization of the midbrain dopaminergic neurons (mid-DAs) of the SNc and VTA. Adult male and female rat brain slices (30 μm) were processed immunocytochemically for identification of tyrosine hydroxylase immunoreactive (TH-IR) cells as a marker of dopaminergic cell bodies in the SNc (A and B) and VTA (C and D). Cavalieri's principle was used to calculate the volume delineated by TH-IR, and the total number of TH-IR cells was counted. For data analysis, the midbrain region was divided through its rostrocaudal extent into anatomically defined regions (I –IV), each separated by 300 μm, beginning at bregma −4.8; the SNc traversed all four levels, and the VTA was clearly distinguished at 3 levels (II–IV). For SNc, the total volume (I + II + III + IV) was greater in female than in male brains (A, Total) but total cell numbers were significantly greater in males (B, Total); because there were no sex differences in cell size, this suggests a greater packing density in the male brain. Analysis at each level (I–IV) showed significant differences in volume between males and females, indicating sex differences in the overall shape (A). The percentage of TH-IR cells located at each level was also calculated, and revealed a significant sex difference in the distribution of the dopaminergic cells throughout the nucleus (B). For VTA, like the SNc, the total volume (II + III + IV) was greater in the female compared with the male brain (C), but, unlike the SNc, the total cell counts were also greater in females (D). Analysis at each level (II–IV) showed a significant sex difference in volume, indicating differences in the overall shape (C), as well as a significant sex difference in the percentage of TH-IR cells located at each level, indicating male/female differences in the distribution of the dopaminergic cells throughout the nucleus (D). These results identify structural sex dimorphisms in the mid-DAs that are likely to underpin sex differences in physiology and behaviors governed by these pathways. + indicates a significant difference for male versus female, P < 0.05. Further details in McArthur et al. (2007a).
Fig. 5.
Fig. 5.
Systemic and central sex hormones: schematic representation of potential modes of action and interaction on the intact and damaged NSDA system in male and female brains. Circulating estradiol (E2) up-regulates activity in the NSDA system in females but not males (evidence discussed in section V.B.2) This could be due to sex differences in the response of the NSDA neurons to the direct effects of circulating E2 or to indirect effects on networks interacting with and regulating the system, which are differentially sensitive to E2 in males and females. The schema shows one such indirect pathway, the nor-adrenergic (norepinephrine, NE) neurons of the locus ceruleus (LC). These positively influence neurotransmission in the NSDA system and play an important role in adaptive responses within the injured NSDA system in Parkinson's disease. This influence is up-regulated by circulating E2 in females (arrows), but down-regulated in males (blocked line). This systemic E2 may promote adaptive responses to neurodegeneration in the female NSDA system, whereas in males circulating E2 or testosterone (after conversion to E2) would not have this effect and might even exacerbate lesions. However, local up-regulation of aromatase activity to promote E2 production at the site of NSDA injury has the potential to protect in brains of both sexes. See the section V.B.2 for further discussion.
Fig. 6.
Fig. 6.
Sex-specific effects of antenatal glucocorticoid treatment on dopaminergic neurons in the adult rat VTA. Fetal rats were exposed to antenatal glucocorticoid treatment (AGT) by including dexamethasone (0.5 μg/ml) in the mother's drinking water between gestational days 16 and 19. The dams of control animals received normal drinking water. Offspring were allowed to grow to adulthood, when brains were processed immunocytochemically for identification of TH-IR cells as a marker of dopaminergic cell bodies in the VTA, as described in the legend to Fig. 4. Top, sex differences in the overall total number of TH-IR cells were preserved after AGT, but the total cell counts increased dramatically. Bottom, the distribution of TH-IR cells through the VTA (percentage at each level II–IV) was sexually dimorphic and AGT altered the topographical distribution in male and female brains such that more cells were located in the caudal regions. Further details in McArthur et al. (2007a). *, p < 0.05 versus male. ▴/▾ significant increase/decrease versus respective controls; p < 0.05.
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