Effects of Steroid Hormones on Brain☆

Anne-Sophie CAM Koning, Leiden University Medical Center, Leiden, The Netherlands
Russell D Romeo and Bruce S McEwen, Rockefeller University, New York, NY, United States
Onno C Meijer, Leiden University Medical Center, Leiden, The Netherlands
r 2018 Elsevier Inc. All rights reserved.

Glossary Neurogenesis The production of new neurons.

Dendrite Branching neurites that emanate from the neu-
ronal cell body.
Dendritic spine A small protrusion of the cell membrane
of the dendrite that receives excitatory input.
Glucocorticoids Steroid hormones released from the cor-
tex of the adrenal gland such as cortisol and corticosterone.
Sex steroids Steroid hormones released from the gonads
such as androgens, estrogens, and progestins.
Steroid hormones A family of hormones derived from
cholesterol and characterized by their three six'carbon rings
and one five'carbon ring.

Introduction

The brain receives a rich supply of blood and is constantly in contact with circulating hormones in the bloodstream. Thus, it is not
surprising that the brain is influenced and modulated by hormones. One major class of hormones is the steroid hormones, which gain
access to the brain because of their hydrophobic chemical structure that allows them to pass across the blood–brain barrier. Steroid
hormones have a wide range of effects on the brain. For instance, steroids help to shape the brain during perinatal development and
continue to modulate the structure and function of the central nervous system (CNS) into adulthood and throughout the life span.
Specifically, steroids can influence factors such as neuronal survival, neurogenesis, neurite outgrowth, synaptogenesis, receptor expression,
RNA synthesis, and neuronal excitability. These effects at the cellular level affect many aspects of mood, cognition and behavior. The effects
of the steroid hormones on the development, structure, and function of the brain are the focus of this article.

The Mechanisms of Steroid Hormone Action in the Brain

Steroid hormones can be classified into the gonadal sex steroids (androgens, estrogens, progestins) and the adrenal corticosteroids.
Corticosteroids in turn are either mineralocorticoids involved in salt homeostasis (e.g., aldosterone), or the glucocorticoid stress
hormones (e.g., cortisol). During pregnancy, the placenta also produces steroid hormones. The biosynthesis of all steroid hor-
mones starts with enzymatic cleavage of cholesterol. All endocrine organs can convert cholesterol to pregnenolone inside mito-
chondria and further convert pregnenolone to progesterone in the endoplasmic reticulum. Further enzymatic reactions are
performed by tissue specific enzymes that are expressed only in some of the endocrine organs (Hanukoglu, 1992). For example,
testosterone is produced in the gonads by a series of enzymatic reactions that convert cholesterol to progesterone, and then via
other intermediates to testosterone (Payne and Hales, 2004). Testosterone can be converted to estrogen by the aromatase enzyme
in a reaction called aromatization. Although testosterone is considered the “male sex steroid” and estrogen is considered the
“female sex steroid,” it is important to note that testosterone and estrogen are found in both males and females. In fact, estrogen
formed locally in the brain of males by the aromatization of testosterone is responsible for masculinization of the male brain and
plays a major role in activating male sexual behavior during adulthood. Such pre-receptor metabolism also occurs for gluco-
corticoids, that may be inactivated or regenerated by the 11b-hydroxysteroid dehydrogenase 1 or type 2 (11b-HSD1/2). 11b-HSD1
is highly expressed in the hippocampus converting inactive cortisone into active cortisol. Conversely, 11b-HSD2 converts active
cortisol into inactive cortisone to exclude cortisol from binding the mineralocorticoid receptors in, for example the kidney and a
limited number of brain areas to enable aldosterone rather than cortisol to bind the mineralocorticoid receptor (Seckl and Walker,
2001).

Localisation
The steroid hormones bind to specific receptors located throughout the brain. All steroid hormones can bind to cognate nuclear
receptors; intracellular receptor that can bind to DNA to regulate gene expression. This allows for both the “activational” effects

☆
Change History: December, 2017. Anne-Sophie CAM Koning, Russell D Romeo, Bruce S McEwen and Onno C Meijer updated the text and added new
references.
This chapter is an update of Russell D. Romeo, Bruce S. McEwen, Brain, Effects of Steroid Hormones, In Encyclopedia of Endocrine Diseases, edited by Luciano
Martini, Elsevier, New York, 2004, Pages 414–418.

36 Encyclopedia of Endocrine Diseases, Second Edition, Volume 2 doi:10.1016/B978-0-12-801238-3.95781-7

 Effects of Steroid Hormones on Brain 37

within hours of activation and “organizational” effects during development that are very long lasting. The structure of the different
steroid receptors is very similar, with the two estrogen receptors (ER) ERa and ERb being a bit more distant from the androgen,
progesterone, glucocorticoid, and mineralocorticoid receptors. Each of the six classical steroid receptors has a unique expression
pattern in the brain, and this allows for a large number of steroid effects, that may show considerable region specificity even for a
particular steroid (Mahfouz et al., 2016).
The gonadal steroid progesterone binds to the progesterone receptor (PR), which has two isoforms that are derived from the
same gene: PRA and PRB. Both PRA and PRB are expressed in the hypothalamus, hippocampus, and cortex. In addition, pro-
gesterone binds to a G-protein coupled seven transmembrane receptor (GPCR) known as 7TMPR or mPR. mPR has three isoforms
a, b and g, of which the g isoform is specifically expressed in neural tissues (Brinton et al., 2008). Also estrogen can activate a
classical GPCR, GPR30, adding to the signaling repertoire of the steroids (Prossnitz et al., 2008). High expression of the classical
ERa and ERb is found in amygdala, hypothalamus, prefrontal cortex, hippocampus, thalamus, and cerebral cortex (Hara et al.,
2015). The other gonadal steroid testosterone binds to the androgen receptor (AR), which is expressed in the brain both in
hypothalamus and in higher brain regions, such as the hippocampus (Beyenburg et al., 2000).
Cortisol can, in the brain, bind two types of receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor
(MR) (Reul and de Kloet, 1985). Aldosterone also binds to the MR, but is outcompeted by corticosterone (in rats and mice) and
cortisol unless these are enzymatically degraded (Wyrwoll et al., 2011; Funder, 2005). In the brain most MRs are cortisol preferring.
Cortisol has a higher binding affinity for MR than GR. As a consequence, at low cortisol levels MRs are activated and with high
cortisol levels, for example after stress, GRs get activated. MR is abundantly expressed in limbic neurons, most notably the
principal neurons of the hippocampus, while GR is expressed in neurons and glial cells throughout the brain. In the hippocampus,
MR and GR are co-localized and can mediate opposite effects of cortisol. Given its high affinity and pre-stress occupancy, MR is
important in the onset of the stress response and in appraisal of stimuli, while GR is involved in memory storage (de Kloet et al.,
2005). More effects of the individual steroids hormones will be discussed later in this article.

Signaling Mechanisms
There are three mechanisms through which steroid hormones exert their actions on neurons: genomic, indirect genomic, and
nongenomic. The various mechanisms of steroid hormone action are presented in Fig. 1. The fastest, but least understood mode of
action is non-genomic. They may be mediated by dedicated membrane type receptors in case of the sex steroids, but also by
membrane associated variants of the classical nuclear receptors. For instance, steroids have been shown to bind to receptors
located in the plasma membrane of neurons, and rapidly affect synaptic (re-)activity, for example, spontaneous glutamate release
in the hippocampus (Karst et al., 2010). Extranuclear estrogen receptors were found in axon terminals and spines of hippocampal
CA1 pyramidal cells of the female rat. Various mRNAs for synaptic proteins and translation machinery have been localized in
spines, suggesting that translation of such proteins can occur locally in the dendrite. Thus, estrogens may act directly on the
synaptic apparatus and mRNAs to affect synaptic function and synaptogenesis. These non-genomic effects of steroids become
manifest within minutes after receptor activation.
Eventually, events at the cell membrane may also via activation of second messenger pathways lead to the activation of
transcription factors in the cell nucleus. The “classical” and slower genomic mechanism of steroid hormone action begins by the
hormone diffusing through the plasma membrane of the neuron and binding to its intracellular receptor located in either the
cytoplasm or the nucleus. This hormone–receptor complex then undergoes a conformational change allowing the
hormone–receptor complex to migrate, dimerize, and bind to particular hormone response elements (HREs) on the DNA. Once
the hormone–receptor complex binds to its HRE, it subsequently binds co-activators or co-repressors to activate or repress gene
transcription, ultimately affecting the production of proteins that may alter the functioning of the neuron, or glia cell. This mode
of signaling allows cross talk between different steroid receptors, as MR, GR, AR, and PR recognize (in part) the same HRE elements
(Falkenstein et al., 2000).
Steroids receptors may also interact with other, non-receptor, transcription factors. For example, GR may interact with other,
non-receptor, transcription factors. For example, GR may interact with AP-1, where only the latter factor is bound to the DNA.
Genome wide analysis of GR and MR binding at the chromatin for now indicates that direct HRE binding of the receptors is the
dominant mode of action in the rodent hippocampus (van Weert et al., 2017).

Organization Versus Activation

Steroid hormones not only allow for the activation of certain behavioral and physiological events during adulthood but also shape
the nervous system during development. During perinatal development, the brains of males and females are exposed to different
hormonal milieus that ultimately lead to many of the sex differences observed in the brain and behavior of males and females
during adulthood. For instance, males experience increases in testosterone production and secretion during both prenatal and
early neonatal development. This, on conversion in the brain to estradiol via the aromatase enzyme, organizes the brain in a
masculine fashion. This early masculinization of the brain then allows the hormonal stimulation received during adulthood to act
on these organized neural pathways to activate the appropriate male behaviors. In the perinatal female, the estrogen produced by
the mother and the prenatal ovary does not masculinize her brain because this estrogen is bound by alpha fetoprotein and is
38 Effects of Steroid Hormones on Brain

Fig. 1 The genomic, indirect genomic, and nongenomic mechanisms of steroid hormone action on neurons. Indirect genomic mechanisms
include the activation of steroid receptors linked to second messenger cascades that activate gene transcription through DNA-binding domains
such as cAMP response element (CRE) and activator protein-1 (AP-1), ultimately altering neuronal function. In the genomic mechanism, the steroid
binds to the intracellular form of the receptor, permitting the steroid–receptor complex to translocate to the nucleus. This steroid–receptor complex
then binds to the hormone response element (HRE), activating transcription of the genome and altering neuronal function. Nongenomic
mechanisms of steroid action include the ability of steroids to influence ion permeability and possibly to affect local protein synthesis in the spine
head. This later mechanism presumably would allow for the rapid regulation of spine-specific mRNAs and proteins. Akt, protein kinase B; CaMK,
Ca2 þ /calmodulin-dependent protein kinase; CREB, cAMP response element-binding protein; Gas and Gaq, guanosine triphosphate (GTP)-binding
proteins; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; PKC, protein kinase C.

unable to cross the blood–brain barrier. Indeed, the feminized brain appears to be the default pattern of development in that a
brain that does not receive androgenic and estrogenic stimulation during development results in a feminized brain.
The organizing influences of steroid hormones on the perinatal brain and the resulting morphological and functional dif-
ferences between the sexes can be profound. Indeed, the organizing effects of steroids result in certain sexually dimorphic nuclei in
the nervous system that may be as much as five times larger in one sex than in the other. Likewise, early life stress (during the first
weeks of life in the rodent) can have long lasting consequences for the organization of brain circuits. However, in these cases the
role of the actual steroid exposure is less well understood, as there are many other mediators activated upon stress. The effects of
steroids on the adult brain are much more subtle than these organizing effects during perinatal development. However, steroids
are still capable of shaping the adult brain in important ways (Becker et al., 2002).

Effects of Steroids Hormones During Adulthood

Steroid hormones allow for the activation of certain behavior and psychological events during adulthood. For example in rats,
female sexual lordosis behavior does not occur in absence of estrogens, but can be primed by a single estrogen treatment 2 h
before the encounter with a male rat (Becker et al., 2002). Sex steroids do not only affect reproduction but also other mental
domains, such as testosterone effects on aggression. In male mice, aggression is positively correlated with increased circulating
testosterone levels and castration of male mice show decreased aggressive behavior (Book et al., 2001).
 Effects of Steroid Hormones on Brain 39

The stress hormone cortisol has substantial effects on behavior. Cortisol binding to the MR influences emotional and cognitive
processes, such as memory retrieval, appraisal of potentially stressful situations and the response to stress. Binding to GR will lead
to behavioral adaptation and memory storage, and can effect domains as different as reward, eating behavior, anxiety and mood,
decision making and sleep (Meijer and de Kloet, 2017). These immediate effects of cortisol are beneficial, but chronic stress with
long-term exposure to high cortisol levels has negative effects, such as impaired learning, disturbed anxiety and aggression
regulation, increased risk for depression, cardiovascular problems, osteoporosis and obesity (de Kloet et al., 2005). The negative
effects of chronic exposure to high levels of cortisol are underscored by the many psychiatric and cognitive complaints in Cushing's
disease patients, some of which can persist for many years (Andela et al., 2013).

Steroid-Induced Neuronal Plasticity During Adulthood

Sex steroids have been shown to affect the density and morphology of dendritic spines. Spines are membranous protrusions
emanating from dendrites and are sites of synaptic contact between neurons. Neurons receive excitatory input via these dendritic
spines, which contain various types of glutamate receptors, scaffolding proteins, and signaling molecules. Spines come in various
sizes and shapes that may be indicative of their maturity. Different steroids can affect the growth and development of spines,
thereby modulating excitatory neuronal signaling.
The hypothalamus was the first brain area in which sex steroids were shown to influence synapse formation and spine
maturation. Ovariectomized females have significantly fewer synaptic contacts in their ventromedial nucleus (VMN) than do
ovariectomized females treated with estrogen. Furthermore, females in the proestrous stage of their estrous cycle (i.e., when
estrogen levels are high) have a greater spine density than do females in diestrus (i.e., when estrogen levels are relatively low). The
VMN is a fundamental component of the neural circuit that mediates the expression of female reproductive behavior. Thus, it is
not surprising that estrogenic stimulation that activates female mating behavior would also promote spine density and, hence,
increase excitatory input to the VMN. In males, VMN spine density increases after castration, whereas estrogen-treated males
exhibit a relatively low number of spines, similar to the density observed in intact males. Thus, the effect of estrogen on VMN spine
density in males is opposite that in females.
Similar effects have been observed in the arcuate nucleus (ARC) of the hypothalamus, which plays an important role in
mediating the release of the gonadotropins from the anterior pituitary. The dendrites of these neurons in hormone-dependently
females have twice as many spines than males, and presumably the greater excitatory input to the female ARC, may help to
modulate the luteinizing hormone surge that causes ovulation in females.
Interestingly, such estrogen effects also occur in the hippocampus, and may in this way affect the organism's ability to
remember. In females with higher estrogen levels significantly greater numbers of these dendritic spines were found compared
with low estrogen levels. Additional studies have shown that this increased spine density is accompanied by an increased synaptic
input to the apical dendrites of the hippocampal CA1 pyramidal cells. These structural alterations are paralleled by physiological
and behavioral changes as well. Specifically, adult female rats experiencing high levels of estrogen show enhanced hippocampal
long-term potentiation (LTP), a putative electrophysiological correlate of learning and memory, and improved memory retention
on a hippocampal-dependent spatial memory task.
Whether estrogen increases hippocampal spine formation in humans is unknown, but estrogen replacement therapy has been
shown to promote cognition in postmenopausal women (Bean et al., 2014; Hara et al., 2015). It also has been suggested that
estrogen may aid in the prevention or amelioration of neurodegenerative diseases such as Alzheimer's disease. Another study has
shown that estrogen can induce greater spine density in the prefrontal cortex of nonhuman primates. Given that the prefrontal
cortex of primates is involved in many aspects of cognitive function, it is possible that the memory-enhancing effects of estrogen
are mediated, at least in part, by its actions on both the hippocampus and the cortex.
Males do not show the same increase in spine density in response to estrogen. However, testosterone has been shown to
increase the number of spines on the CA1 pyramidal cells of males. In addition, it was shown that neural AR deletion selectively
impairs hippocampal LTP (Picot et al., 2016).
Cortisol daily rhythmicity helps to sustain a normal rate of spine turnover. However, in contrast to the spine-promoting effects
of estrogen and testosterone, high levels of corticosterone induced by repeated stressors, have been shown to decrease the
branching of hippocampal CA3 pyramidal cells and to cause dendritic atrophy. Animals experiencing chronic stress also tend to
perform more poorly on learning and memory tasks than do non-stressed animals. It is important to note that low to intermediate
levels of “stress hormones” enhance performance on learning and memory tasks. Studies have found that high levels of corti-
costerone suppress LTP, whereas intermediate levels enhance plasticity. In general, MRs and GRs activation lead to behavioral
adaptation, but with chronic stress MR and GR gene expression seem to adapt (de Kloet et al., 2005). Both animal studies, and
genetic variants in humans point to GR overactivation as a risk factor for mood disorders. Interesting, the MR gain of function
genetic variant consistently protects against depression in several studies (Meijer and de Kloet, 2017). However, more research is
needed to establish and explain the causal link.
Another mechanism that can alter MR and GR response is glucocorticoid medication. Use of synthetic glucocorticoids, like
dexamethasone, can cause severe adverse effects, especially when high dosage is used. Severe neuropsychiatric consequences like
psychosis, mania, depression, suicide (attempt), delirium, panic disorder and confusion or disorientation are reported (Judd et al.,
2014). In addition, cognitive and memory impairments, changes in mood and sleep disturbances (Meijer and de Kloet, 2017; Judd
40 Effects of Steroid Hormones on Brain

et al., 2014). Normally, MR and GR activation is balanced, but glucocorticoid medication can disturb this balance. For example,
dexamethasone is highly selective for GR and high dosage will lead to a suppressed cortisol production, depleting the MR of its
ligand and resulting in a GR MR imbalance. It is thought that co-administration of cortisol with dexamethasone might prevent
these adverse effects, since MR is re-activated and this way restoring the GR MR balance (Meijer and de Kloet, 2017).

Neuronal Protection and Neurogenesis

As discussed above, steroids can have profound influences on the structure and function of neurons early in development and into
adulthood. In addition to these influences, steroids can alter the survival and production of new neurons, even in the adult brain.
For instance, at high concentrations, estrogen can protect neurons by working as an antioxidant. Estrogen has also been shown to
diminish the neural damage induced by stroke and reduced blood flow to the cortex. These neurotropic effects after stroke may be
through the antioxidant properties and/or through the influence of estrogen on growth factor synthesis and receptor expression.
Steroid hormones have also been shown to affect neurogenesis. Estrogen has been demonstrated to increase the production of
new neurons in the dentate gyrus of the female hippocampus. Conversely, animals experiencing high levels of corticosterone show
less cellular proliferation in the dentate gyrus than do animals experiencing low levels of corticosterone. This corticosterone-
induced decrease in neurogenesis suggests that high levels of corticosterone not only promote atrophy (and even loss) of neurons
in the hippocampus but also slow the production of new neurons that may be needed to replace the lost cells.

Conclusion

Steroid hormones secreted from the gonads and adrenals act on the brain and are known to influence diverse functions such as
reproduction and learning and memory. These hormones can act on neurons through a genomic, an indirect genomic, or a
nongenomic mechanism of action. The sex steroids have been shown to organize the male and female perinatal brain so that the
proper physiology and behavior can be activated by these hormones during adulthood. Furthermore, steroids continue to shape
the adult brain by affecting factors such as synaptogenesis, spine maturation and growth, neuronal branching, neuroprotection,
and neurogenesis. Therefore, steroids not only contribute to the development of the nervous system but also continue to influence
neuronal structure and function throughout the life span.

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Further Reading
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de Kloet, E.R., Joels, M., Holsboer, F., 2005. Stress and the brain: From adaptation to disease. Nature Reviews. Neuroscience 6, 463–575.