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Testosterone is a steroid sex hormone with an important role in the physiology in both sexes. It is involved in the development of morphological and functional parameters of the body via multiple molecular mechanisms. Intensive research focused on testosterone reveals associations with cognitive abilities and behavior and its causative role in sex differences in cognition. Testosterone modulates brain structure and the differentiation of neurons during intrauterine development with profound effects on brain functions during postnatal life. In this review we summarize the effects of testosterone on brain physiology and cognition with respect to the underlying molecular mechanisms.
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Review Acta Neurobiol Exp 2011, 71: 434–454
© 2011 by Polish Neuroscience Society - PTBUN, Nencki Institute of Experimental Biology
Sex steroid hormones are mostly known for their
role in the development of sex organs and physical
maturation during puberty (Powers and Florini 1975,
Kasperk et al. 1989, Toppari and Skakkebaek 1998,
Bhasin 2000). Research on the effects of testosterone
has brought many interesting findings that have radi-
cally changed and broaden the view of testosterone as
a hormonal regulator of development. Animal experi-
ments and human studies illustrate how testosterone
influences putative unrelated features like morpho-
logical characteristics and cognitive abilities or intel-
ligence (Martin et al. 2009, Hodosy et al. 2010). Our
review summarizes the basic physiology of testoster-
one influencing not only morphological features but
also cognition, emotions and behavior with respect to
the underlying molecular mechanisms. The contribu-
tion of sex steroids to organizing structural and func-
tional connections in the human brain is discussed,
both during the prenatal period as well as during other
period characterized by massive sex steroid changes
such as puberty. The prenatal period is a critical time
for sex steroids to shape the brain (Roy and Chatterjee
1995, Cohen-Bendahan et al. 2005, Manson 2008, Bull
et al. 2010) but also for the development of the phalan-
ges (Kempel et al. 2005, Malas et al. 2006). This is the
reason why the length of the fourth digit (ring finger)
is thought to be an index of prenatal testosterone expo-
sure relative to the length of the second digit (index
finger) the marker of prenatal estrogen level. According
to several studies, 2D/4D ratio reflects hormonal back-
ground in uterus and is useful as a parameter to esti-
mate early testosterone exposure (Manning et al. 1998,
Manning and Taylor 2001, Rahman and Wilson 2003,
Lippa 2006, Manning and Fink 2008). In this paper, a
brief overview of studies investigating controversial
relations between 2D/4D, prenatal testosterone expo-
sure and various aspects of behavior and cognition is
All behavioral traits, specific cognitive abilities of an
individual are the result of a cooperation of hormonal,
genetic and environmental factors. There are several
known genetic variants modulating testosterone action
and its final effect on target tissue (Greenland et al. 2004,
Forstmeier et al. 2010, Haggarty et al. 2010). Several stud-
ies concerning genetic regulation of androgen activity are
discussed in term of modulating final androgen activity.
Testosterone and its metabolites
– modulators of brain functions
Jaroslava Durdiakova1, 2, Daniela Ostatnikova2, and Peter Celec1, 3, 4*
1Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia, *Email:; 2Institute
of Physiology, Comenius University, Bratislava, Slovakia; 3Institute of Pathophysiology, Comenius University, Bratislava,
Slovakia; 4 Department of Molecular Biology, Comenius University, Bratislava, Slovakia
Testosterone is a steroid sex hormone with an important role in the physiology in both sexes. It is involved in the development
of morphological and functional parameters of the body via multiple molecular mechanisms. Intensive research focused on
testosterone reveals associations with cognitive abilities and behavior and its causative role in sex differences in cognition.
Testosterone modulates brain structure and the differentiation of neurons during intrauterine development with profound
effects on brain functions during postnatal life. In this review we summarize the effects of testosterone on brain physiology
and cognition with respect to the underlying molecular mechanisms.
Key words: testosterone, cognition, endocrine regulations, 2D/4D, sex differences
Correspondence should be addressed to P. Celec,
Received 06 April 2011, accepted 21 November 2011
Testosterone metabolism and the brain 435
Taken together, the goal of this review is to provide
the comprehensive overview of testosterone physiolo-
gy, cognition, social behavior and brain organization
providing some issues for future research.
Testosterone is conserved through most vertebrates
indicating its importance in evolution and develop-
ment (Hau et al. 2000, Cornil et al. 2011, Sharma and
Chaturvedi 2011). Testosterone is often considered
and called male sex hormone, but in fact, it regulates
sex drive and many other processes in both sexes. In
men, the main production of testosterone is localized
to the smooth endoplasmatic reticulum of Leydig
cells in the testicles (Brown-Séquard 1889). Plasma of
normal healthy women also contains about ten times
lower testosterone concentration than an adult human
male body, but females are more sensitive to the hor-
mone. Half of testosterone amount in females is gen-
erated by the ovaries, the rest by the cortex of supra-
renal glands (Lobotsky et al. 1964, Wu et al. 2010).
Biosynthesis of testosterone occurs also in other tis-
sues, even in some regions of the brain (Mensah-
Nyagan et al. 1996, Matsunaga et al. 2002). A simpli-
fied scheme of testosterone metabolism is illustrated
on Figure 1. This trajectory is essential to be men-
tioned, because all these metabolic steps can influ-
ence final concentration of testosterone and its effect
on target tissues.
Molecular mechanism of testosterone action can
vary (Fig. 2). Testosterone as well as dihydrotestoster-
one are ligands of the nuclear androgen receptor
(Askew et al. 2007). In the classical genomic pathway,
the ligand activated receptor is an important transcrip-
tion factor that regulates expression of genes involved
in cell proliferation, differentiation, metabolism and
apoptosis (Nelson et al. 2002). For the regulation of
expression protein coactivators are recruited
(Estebanez-Perpina et al. 2005). Beyond the genomic
Fig. 1. Testosterone metabolism. Testosterone is a steroid hormone metabolized from cholesterol by desmolase activity.
Pregnenolone is a product of this reaction and is converted to testosterone via intermediates 17-alpha-hydroxypregnelonone,
dehydroepiandrosterone and 4-androstene-3, 17-dione (Yamazaki and Shimada 1997). In the alternative pathway, testoster-
one is produced with intermediates including pregnenolone, progesterone and 17-alpha-hydroxyprogesterone (Rose et al.
1997). In blood circulation, testosterone binds to sex hormone binding globulin (SHBG) and is, thus, protected from meta-
bolic degradation but also biologically inactive. Only a small fraction of the hormone is free and active (able to bind to its
receptor or to be further metabolized) (Maruyama et al. 1987). In some target tissues (adipose tissue, brain) aromatase cata-
lyzes the conversion of testosterone to the female sex steroid hormone estradiol. The effect is then mediated via estrogen
receptors (Carreau et al. 2003). Alternatively, 5α-reductase reduces testosterone to more a potent androgen dihydrotestoster-
one (DHT) which also binds androgen receptor (Askew et al. 2007, Roy and Chatterjee 1995, Shidaifat 2009).
436 J. Durdiakova et al.
response androgen receptor mediates also non-genom-
ic effects (Fig. 2). This response does not involve tran-
scription or translation, and is very rapid in compari-
son to so-called genomic effects. An activated andro-
gen receptor stimulates an increase of intracellular
Ca2+ level, activates multiple protein kinases, thereby
enabling protein interactions and triggering important
signaling cascades (Baron et al. 2004, Foradori et al.
2008, Li and Al-Azzawi 2009). More information
about the androgen receptor, its genomic and non-ge-
nomic effects is available in a recently published
review (Bennet et al. 2010).
Some cells including macrophages lack a typical
androgen receptor but contain testosterone-binding
sites on the surface of the plasma membrane. These
receptors are functionally coupled with intracellular
Ca2+ homeostasis. Testosterone binding stimulates Ca2+
mobilization that results in an increase of its intracel-
lular levels. Membrane-associated testosterone recep-
tors are linked with G-proteins associated with phos-
pholipase C. Interestingly, these receptors are internal-
ized independently on clathrin-coated vesicles and
initiate transcription-independent signaling pathways
(Benten et al. 1999). In neuronal membranes testoster-
one can also bind to a subunit of the ATPase complex
and alters the functional status of ion channels (Ramirez
and Zheng 1996).
Androgenic and anabolic effects of testosterone
responsible for variety of morphological characteris-
tics are well described and widely known. Some
effects require conversion of testosterone to more
potent androgen named dihydrotestosterone playing a
pivotal role in maturation of the sex organs, particu-
larly the penis and the scrotum during the fetal devel-
opment (Toppari and Skakkebaek 1998). In puberty
testosterone stimulates the growth of the genitals,
development of other male secondary sex characteris-
tics (Hiort 2002), induces growth of the prostate, hair
and causes male balding (Shidaifat 2009, Trueb 2002).
A number of studies were published focusing on the
issue how testosterone concentrations influence target
tissue and modulate the final phenotype (Hausmann et
Fig. 2. Genomic and non-genomic effects of testosterone. Unbound bioactive testosterone interacts with the cytoplasmatic
androgen receptor (AR). AR is also activated by dihydrotestosterone in a similar way. Ligand binding induces conforma-
tional changes of the receptor. T-AR complex forms dimers and acts as a functional transcription factor. Activated AR rec-
ognizes the androgen response element in the nucleus due its specific structure. Coactivators (CA) and RNA polymerase II
are recruited for transcription initiation. Gene expression produces a pool of specific proteins that can affect cell character-
istics, metabolism and activity. The non-genomic response is mediated via receptor-tyrosine-kinases (RTK) or G-protein
coupled receptors. Subsequently, downstream signaling cascades are activated, that can result in genomic effect (activation
of various transcription factors, protein activation or new protein synthesis). G-protein coupled receptors can activate phos-
pholipase C and cause an increase of intracellular Ca2+. All these processes are linked with changes in cell activity.
Testosterone metabolism and the brain 437
al. 2000, Janowsky et al. 1994, McEwen et al. 1997).
On the other hand, variety of factors, emotions and
brain activities influence testosterone response itself
(Fig. 3), because testosterone activity is finely regu-
lated and sensitive to endogenous and exogenous
stimuli. For example, sexy thoughts increase testoster-
one levels in women (Goldey and van Anders 2010).
Watching and participating in sexual activity induces
an elevation of testosterone level in men (Escasa et al.
2010). Hormonal changes occur when falling in love.
Testosterone levels are lower in men in love, while
women in love have higher testosterone levels. All
hormonal differences are eliminated during a long-
term stable relationship (Marazziti and Canale 2004).
Human competitive interactions highly influence hor-
monal fluctuation. The victory provokes strong emo-
tions associated with testosterone increased (Carre and
Putnam 2010). Interestingly, home victory of amateurs
hockey players is associated with larger testosterone
rise relative to the away victory (Carre 2009).
In men, high levels of endogenous testosterone seem
to encourage dominant behavior. In some cases, domi-
nant behavior is aggressive, but often dominance is
presented nonaggressively. In other cases, dominant
behavior takes the form of antisocial acting, including
rebellion against authority and law breaking. It is gener-
ally believed that high levels of endogenous testosterone
are associated with higher facing of the challenge and
greater risk taking (Eisenegger et al. 2010, Stanton et al.
2011). Androgens can also modulate almost every
aspect of sexual behavior i.e., not only autonomic
functions, but also emotional, motivational, and cogni-
tive ones. Changes in testosterone levels influence
men’s judgments of womens attractiveness and comple-
ment previous findings showing that testosterone mod-
ulates men’s interest in sexual stimuli. Men report
stronger physical attraction (in term of mate preference)
to feminity in women’s faces when their testosterone
levels are high (Welling et al. 2008). Ovulation in
women that is linked with the peak of testosterone lev-
els might differentially affect attention and memory
processes. Women near ovulation increase their visual
attention to attractive men. However, this increased
visual attention is not translated into better memory
(Anderson et al. 2010). Luteinizing hormone-releasing
hormone (LHRH) neuronal cells possess several ele-
ments of the machinery through which sex steroids may
influence LHRH dynamics and thereby, orchestrate
functions in vivo as diverse as the onset of puberty, the
timing of ovulation, and the duration of lactational
infertility critical for reproduction (Poletti et al. 1994).
Sex steroids achieve this indirectly, however, since
LHRH neurons do not express androgen or estrogen
receptors (Huang and Harlan 1993). It is now thought
that kisspeptin neurons mediate the actions of sex ste-
roids on LHRH neurons (d’Anglemont de Tassigny and
Colledge 2010). The majority of kisspeptin neurons
express estrogen receptor alpha and androgen receptors
(Smith et al. 2005b). In females, high levels of estrogens
and progesterone stimulate kisspeptin neurons of the
anteroventral periventricular nucleus (AVPV) to induce
the preovulatory surge of LHRH and luteinizing hor-
mone, whereas they inhibit KISS1 expression in the
arcuate nucleus (ARC). In males, LHRH release is
negatively regulated by circulating testosterone, partly
through the activity of kisspeptin neurons of the ARC
(Smith et al. 2005a). Although immunocytochemical
and autoradiographic studies failed to detect appreciable
amounts of estrogen or androgen receptor in LHRH-
producing neurons, the recent finding revealed that the
promoter region of the LHRH gene contains several
steroid hormone-responsive elements indicates a possi-
ble direct effect of sex steroids on these specialized neu-
rons (Shakil et al. 2002). Mating behavior is dependent
upon both chemosensory and hormonal cues. Anatomical
data suggest that these signals are transmitted through
parallel pathways in separate subdivisions within brain
regions (Gomez and Newman 1992). Wood and
Newmann (1995) demonstrated communication between
neurons receiving hormonal signals and chemosensory
cues. Chemosensory cues from the vomeronasal organ
and olfactory mucosa are transmitted through limbic
nuclei that contain receptors for gonadal steroid hor-
mones, including the medial amygdaloid nucleus and
medial preoptic area (Wood and Newman 1995). Odor
and hormonal signals must be integrated in the brain for
copulation to occur. Impaired transduction of chemosen-
sory cues in absence of gonadal steroids prevents acti-
vation of neurons in certain brain area of castrate male
resulting in abolish of mating behavior (Wood and
Coolen 1997). Animal experiments in mice pointed out
that gonadal hormones may affect the response of
vomeronasal organ neurons to chemosignals by altering
438 J. Durdiakova et al.
levels of the receptors to which they bind and therefore
are also implicated in the regulation of sexually dimor-
phic behavioral and neuroendocrine functions
(Alekseyenko et al. 2006).
Although intelligence in general is similar in men
and women, cognitive skills in both sexes differ in
detail. During mental rotation tasks men preferentially
use the right hemisphere and are more lateralized,
while women use both hemispheres and present lower
lateralization. In general, men are better in logical rea-
soning and abstract mathematics. Females on average
outperform males in cognitive empathy, verbal com-
munication and emotional intelligence. The male sex
hormone testosterone involved in brain organization is
believed to be involved in these differences (McKeever
1995, Hines 2010).
Behavioral differences can be detected even in
childhood during playing. Boys prefer different toys,
activities and games in comparison to girls of the same
age. Cognitive skills and behavior are the result of con-
temporary action of genetic, environmental factors and
their interaction influencing endogenous factors, such
as testosterone levels. Girls that are affected by higher
fetal testosterone levels display a typical male pattern
of play (Auyeung et al. 2009, Hines et al. 2002). Recent
study of children in the age of 18–24 months revealed
a positive association between high levels of fetal tes-
tosterone and autistic traits (Auyeung et al. 2010).
Mental rotation is one of the cognitive domains often
studied in the context of gender specific testosterone
effect. It is associated with spatial processing. Shepard
and Metzler (1971) introduced the concept of mental
rotation into cognitive science. It has become one of the
best-known experiments in the field. In a mental rota-
tion test, the subject is asked to compare two 3D objects
and state if they are the same image or if they are mirror
images. The subjects will be judged on how accurately
and rapidly they can distinguish between the mirrored
and non-mirrored pairs (Shepard and Metzler 1971).
Men generally outperform women in mental rotation
related to different neurobiological processes, task-
solving strategies or different brain architecture
(Hugdahl et al. 2006). Steroid hormone exposure in
males during early development and during puberty
plays a prominent role in sexually dimorphic brain for-
mation, possibly contributing to sex differences in some
cognitive parameters and behavioral features (Williams
and Meck 1991, Fitch and Denenberg 1998, Goel and
Fig. 3. Schematic illustration of testosterone activity with factors modulating its levels and effects. (↑) stimulation; (↓)
attenuation. Androgen activity is dependent upon testosterone level influenced by various factors. Testosterone influences
body morphology and various functions.
Testosterone metabolism and the brain 439
Bale 2008). It has been shown that women with higher
testosterone levels outperform women with low testos-
terone levels in mental rotation and spatial visualiza-
tion. On contrary, in men a negative correlation between
spatial abilities and testosterone level was found
(Ostatnikova et al. 2002). Abnormally high testosterone
levels are linked with poor spatial ability but better ver-
bal fluency. This paradoxical result indicates that
increasing testosterone levels do not necessarily lead to
an amplification of male characteristics. It seems that
there is something like an optimal level of testosterone
for certain cognitive abilities (O’Connor et al. 2001).
Testosterone, at least in pre-pubertal children, seems to
be related also to general intelligence quotient (IQ).
Boys with an average IQ values have significantly
higher salivary testosterone levels when compared to
intellectually gifted or mentally challenged boys. It is
currently unclear whether genetic and/or metabolic fac-
tors are responsible for the observed differences
(Ostatnikova et al. 2007).
Cognitive abilities seem to be sensitive to sex hor-
mone fluctuations (Gouchie and Kimura 1991, Heil et
al. 2011). Individuals with congenital adrenal hyper-
plasia exposed to higher androgen levels in utero may
manifest long-term changed more masculine pattern in
cognitive function when compared to healthy popula-
tion under the influence of increased prenatal andro-
gen exposure (Maheu et al. 2008, Mueller et al. 2008).
Studies in 5α-reductase deficient subjects, a unique
model to study the effect of a selective inherited defi-
ciency of dihydrotestosterone on cognitive patterns,
indicate that the 5α-reductase deficient subjects have a
higher performance IQ than would be expected in
males from this kindred and show relatively better
right hemisphere function (Lawson and Inglis 1983).
Some cognitive functions are responsive also to cur-
rent testosterone level changes. It is well documented
that spatial ability varies in women during the men-
strual cycle with its maximum in the periovulatory
phase (Ostatnikova et al. 2010) related to maximum
peak of salivary testosterone (Celec et al. 2002).
Plasma testosterone fluctuations during the menstrual
cycle cause a significant difference in spatial ability
with high scores during the menstrual phase and low
scores during the midluteal phase. Testosterone in con-
trast to estradiol has a strong positive influence on
mental rotation performance (Hausmann et al. 2000).
Hormonal contraception with androgenic properties
improves visuo-spatial abilities (Griksiene and
Ruksenas 2011). But contrastingly, administration of
testosterone in young women leads to a significant
impairment in their cognitive empathy (van Honk et al.
2011). Study of human female-to-male transsexuals
brings the evidence that testosterone administration
for at least 6 months improved significantly their per-
formance on a visual memory task that supports the
evidence of activating effect of testosterone (Gomez-
Gil et al. 2009). Aging in men and women is associated
with a decline of bioavailable testosterone levels.
However, unlike menopause when estradiol falls rap-
idly to very low levels, testosterone production declines
slowly in healthy men. Men in their seventies have
approximately 40% lower testosterone than men in
their twenties (Davidson et al. 1983). At the same time,
more sex hormone binding globulin is produced and,
therefore, the bioavailable fraction of testosterone is
reduced even further. Age related loss of testosterone
is tightly linked with cognitive decline and possibly
dementia (Driscoll and Resnick 2007). Men with
Alzheimer disease have lower testosterone levels prior
to their diagnosis in comparison to controls (Hogervorst
et al. 2003). Studies in aging men show that bioavail-
able testosterone levels might influence cognitive per-
formance by modulating attention control (Martin et
al. 2009). Low estradiol concentration and high testos-
terone levels despite older age predict a better cogni-
tive performance in men. Whether age-related decline
in cognition might be reversed by hormonal replace-
ment therapy is not clear despite a number of published
studies (Wolf and Kirschbaum 2002).
Such findings suggest a pivotal role of hormonal
influence on certain cognitive domains in humans,
mirroring results from research on animals (Konkle
and McCarthy 2011, Korenbrot et al. 1975). Hodosy
and coauthors (2010) analyzed the correlation between
testosterone levels and spatial memory in male and
female rats. Intramuscular administration of testoster-
one improves spatial memory in female rats tested in
the Morris water maze. Surprisingly, high doses of
testosterone in male rats cause decrease in reference
memory. These findings suggest that testosterone
affects spatial memory in a dose and gender dependent
manner (Hodosy et al. 2010). There are also several
studies confirming that castration and subsequent tes-
tosterone deprivation impair spatial working memory
retention (Daniel et al. 2003, Daniel and Lee 2004,
Sandstrom et al. 2006). Testosterone injections reduce
the number of working memory errors of castrated
440 J. Durdiakova et al.
male rats. Certain doses of testosterone increase pre-
servative behavior in a reversal-learning task indicat-
ing positive activational effects on spatial learning and
memory, but the duration of testosterone replacement
and the nature of the spatial task modify these effects
(Spritzer et al. 2011). Testosterone, but not dihydrotes-
tosterone, improves working memory and decreases
hippocampal NGF (neural growth factor) protein in
aged male rats. Androgen treatment lowers circulating
estradiol levels in aged male rats, suggesting a feed-
back to the hypothalamic pituitary. Conversion to
estrogen may, thus, not be the underlying biological
mechanism of effects of testosterone on memory. The
ratio of estradiol to testosterone, or the actions of the
aromatase enzyme itself, may be responsible for the
observed effects. These data support the hypothesis
that testosterone therapy in aging individuals may pro-
vide positive effects on cognition and that neural
regions that are linked to cognition, such as the hip-
pocampus and/or entorhinal cortex, may be involved
in such effects (Bimonte-Nelson et al. 2003, Bimonte
et al. 2003).
Testosterone is widely discussed as a cognitive
enhancer. Its effects are not completely understood and
have received attention because of potential therapeutic
applications. Parallel studies in humans and animal
models are not simple. Animal studies enable to induce
androgen deprivation or competitive blockage of testos-
terone function. These circumstances cannot be easily
translated into human analyses, therefore evaluating of
the exact molecular actions how testosterone adminis-
t ra ti on in f lu en ce s c og ni ti ve fu nctio ns in h um ans r em ains
the challenge. Particularly, it is problematic to distin-
guish whether improvement in cognitive skills after
testosterone replacement therapy can be explained with
classical genomic effect or rapid non-genomic pathway.
We are far from a complete understanding of the
detail molecular mechanism behind the
effects of testosterone and other steroids on brain struc-
ture and function. Sex steroids influence myelination
Fig. 4. Schematic link between genetic factors, testosterone and cognitive skills. Cognitive performance is influenced by
genetic factors. Polymorphisms in candidate genes can modulate the activity of the final protein product. Polymorphisms of
the androgen receptor change its activity as a transcription factor. Mutations in the androgen receptor gene cause androgen
insensitivity syndrome. Somatic mutations in genes involved in testosterone metabolism can influence biosynthesis of tes-
tosterone and the concentration of its bioavailable fraction.
Testosterone metabolism and the brain 441
through their direct impact on glial cells, increase syn-
apse number and dendritic branching (Cook et al. 2002,
Romeo et al. 2004). Testosterone was found to change
gene expression in neurons modulating their possible
responses to incoming signals (Fink et al. 1988). Several
studies confirmed the effects of testosterone on forma-
tion and loss of synaptic connections, cells growth,
migration, apoptosis or neurotransmitter metabolism
modulating neuronal activity (Matsumoto 2001, 2005,
MacLusky et al. 2006, Zehr et al. 2006). All these pro-
cesses are crucial for remodeling of brain structures
(Lustig 1996). Traditionally, two types of hormonal
action on the brain have been distinguished.
Organizational effects are irreversible and act on the
CNS to predetermine neural pathways. They can make
neurons more sensitive to the later activational effects
of testosterone that occur at any time of the life.
Activational effect means modulation of neural pathway
affecting certain behavior (Cohen-Bendahan et al. 2005,
Hines 2010, Ngun et al. 2010, Von Horn et al. 2010).
In humans, a critical period for organization of the
brain is thought to be between weak 8 and 24 of gesta-
tion (Collaer and Hines 1995). During this period tes-
tosterone levels are high. Testosterone levels peak in
the fetal serum between weeks 12 and 18 of pregnancy
(Finegan et al. 1989). This developmental period is
essential for normal CNS function, brain masculiniza-
tion in male fetuses and neurological health. The first
trimester is as important as the foundation and frame
of the house. If it is disrupted, the integrity of the
whole house will be compromised (Mrazik and
Dombrowski 2010). This metaphor illustrates the real
situation in human body and brain development
(Mrazik and Dombrowski 2010). The theory of
Geschwind and Galaburda (1985) claims that intellec-
tually gifted children are influenced by higher andro-
gen levels during intrauterine development. High tes-
tosterone concentrations during prenatal life have
effects on the differentiation of the central nervous
system, as they attenuate the growth of the left hemi-
sphere. The resulting right hemisphere dominance is
associated with enhanced lateralization, left handed-
ness, spatial orientation and logical reasoning
(Geschwind and Galaburda 1985). All these features
are supposed to be more common or better developed
in intellectually gifted children (Geschwind and
Galaburda 1985). The redirection of neuronal migra-
tion away from areas responsible for language in favor
of the inferior parietal region of the cortex might lead
to apparent language based disability such as dyslexia.
Albert Einstein was an example of an individual who
experienced an overdeveloped inferior-parietal region
contributing to his extraordinary mathematical capa-
bilities. On the other hand, Einstein did not speak until
age 3 and suffered from language deficits (Anderson
and Harvey 1996). This phenomenon of genius and
disability at the same time can be explained by prena-
tal exposure to higher testosterone levels in uterus
bringing the evidence that testosterone can be consid-
ered very important etiologic factor in brain develop-
ment and modulation of certain cognitive domains.
The second peak of testosterone takes place in the
first 3 months after birth. At the end of the pregnancy,
when a-fetoprotein declines, the fetus is more exposed
to estrogens from the placenta, which inhibits the
hypothalamus–hypophysial–gonadal axis of the child.
This inhibition is lost when the child is born, which
causes a peak in testosterone in boys and a peak in
estrogens in girls (Quigley 2002). The testosterone
level in boys at this time is as high as it will be in adult-
hood. Also at this time the testosterone level is a factor
higher in boys than in girls. The role of this testoster-
one evaluation is not completely clear but it is supposed
to fix the development of structures and circuits in the
brain for the rest of a person’s life (Swaab 2007).
The brain during puberty is sensitive to the organi-
zational effect of gonadal hormones (Ahmed et al.
2008). Animal studies showed that pruning of den-
drites in combination with axonal changes are very
frequent during puberty (Cooke et al. 2007). Prepubertal
gonadectomy in rats results in reduction of cells within
sexually dimorphic area of hypothalamus and amygda-
la and increases the number of androgen receptors in
amygdala (Romeo et al. 2000, Ahmed et al. 2008).
Neuroimaging studies in humans have shown dynamic
changes in brain during puberty. Subcortical gray mat-
ter areas included hypothalamus, thalamus, amygdala,
hippocampus, known for their high density of sex ste-
roid receptors, show a significant susceptibility to
reorganization induced by sex steroid hormones activ-
ity during pubertal development (Gogtay and Thompson
2010, Bramen et al. 2011). Testosterone predicts white
matter increases in whole brain and in areas connect-
ing the frontal and temporal cortices. Maturation of
these regions is implicated in typical adolescent behav-
iors including social development, enhanced reward
sensitivity and reduced cognitive control (Blakemore
2008, Olson et al. 2009).
442 J. Durdiakova et al.
Literature provides evidence for permanent sex hor-
mones effect on brain and behavior during early devel-
opment. Brain remains sensitive to the effects of sex
hormones into adolescence, undergoing structural
changes as a result of hormone exposure. But there are
still many remaining questions including the exact
mechanism of testosterone action and its regulation,
neural substrates for hormone effects or relationship
between prenatal and pubertal period. Another chal-
lenging issue remains to reveal biological determinant
of the intellectually gifted brain. What is the differ-
ence between precocious and average brain? What
biological force is responsible for the exceptional abili-
ties? There are several hypotheses supposing testoster-
one to be important in the development of cognitive
giftedness. Convincing evidence and the exact mecha-
nism of action are still missing.
Understanding of mechanisms that give rise to differ-
ences in the behavior of nonhuman animals may con-
tribute to the understanding of sex differences in
humans. In vertebrate model systems, testosterone
accounts for most known sex differences in neural struc-
ture and behavior. The sex-related morphological differ-
ences of many brain nuclei are mainly determined by the
hormonal environment present during embryonic devel-
opment. It is believed that during the intrauterine period
the fetal brain develops in the male direction through a
direct action of testosterone on the developing nerve
cells, or in the female direction through the absence of
this hormone surge (Morris et al. 2004, Hines 2010).
Animal studies with rats pointed out that nucleus of
preoptic area implicated in male copulatory behavior
present sexual dimorphism. Perinatal aromatized
androgen decreases neural apoptic rate in males, there-
fore it is 2.6 times larger when compare to females.
Treating newborns females with testosterone reduces
the number of dying cells resulting in larger sexual
dimorphic preoptic area (SD-POA) (Davis et al. 1996).
In contrast, hormone manipulations in adulthood have
no impact on the volume of this nucleus (Gorski et al.
1978). Sexually dimorphic region are not always larger
in males. Anteroventral periventricular nucleus
(AVPV), part of hypothalamus associated with regula-
tion of ovulatory cycles, is larger in females with a
higher cell density in both mice and rats. In this case
apoptosis in males is contrastingly enhanced due to
prenatal action of metabolized testosterone resulting in
increased degeneration of cells in this region (Simerly
2002). The opposing responses of SD-POA and AVPV
to testosterone indicate that molecular background in
these different target cells is different. The spinal
nucleus of the bulbocavernosus (SNB) important for
male sexual behavior control also displays sexual
dimorphism relied on apoptosis. Male rats have larger
and more motor neurons than females. Neural cells die
in females around the time of birth unless they are
exposed to testosterone. Although SNB motor neurons
posses androgen receptor, effect of testosterone is pri-
marily to prevent death of the target muscle cells,
which then secondarily protect neurons from apoptosis
and keep them alive (Nordeen et al. 1985).
Taking together testosterone or its metabolites can
affect the rate of apoptosis acting via the specific
receptor. In one type of cells apoptosis can be stimu-
lated, in another target system it can be suppressed as
a consequence of modulation of anti-apoptic gene Bcl2
expression (Morris et al. 2004). Testosterone also acts
on neurons to cause them to release chemo-attractants
promoting sexually dimorphic innervations pattern.
Steroid can induce one population to masculine the
other via the synapse communication (Ibanez et al.
2001). According to the callosal theory, prenatal tes-
tosterone mediates early axon pruning in callosal tis-
sue, and thus the more testosterone a brain is exposed
to in uterus, the more lateralization there is, evidence
of less lateralization in females supports this hypoth-
esis (Witelson and Nowakowski 1991). Increased
androgen sensitivity of preprogrammed brain struc-
tures is believed to result not only in better ability to
undertake 3-dimensional spatial rotation, but also in a
host of behavioral changes such as higher risk taking,
search persistence, heightened vigilance, and faster
reaction times (Chura et al. 2010).
Some of brain structures can be sexually differenti-
ated in adulthood (Cooke et al. 1999). Posterodorsal
medial amygdala (MePD) strongly associated with
emotions, decision making, male sexual arousal, is
strongly dependent on adult testosterone. MePD vol-
ume is 1.5 times larger in males in rats and mice due to
activational effect of circulating androgens. Testosterone
in adulthood manipulations can completely reverse sex
differences (Cooke et al. 2003). Neuroimaging studies
highlight the activational effects of gonadal hormones
on the amygdala and prefrontal cortex also in humans.
Testosterone metabolism and the brain 443
Activational effects strongly contribute to the sex dif-
ferences in the neurocircuitry underlying the regulation
of emotion and affect (Goldstein et al. 2010). Recent
studies indicate that progesterone and testosterone have
diverging effects on the communication between the
amygdala and prefrontal cortex (van Wingen et al.
2010), which may contribute to sex differences in the
vulnerability to various psychiatric disorders. Women
suffer more from mood and anxiety disorders, whereas
men suffer more from impulse-control and substance
use disorders (Kessler et al. 2005). Swaab and his col-
leagues published several remarkable papers about
dimorphism of brain structures in relationship to gen-
der identity (Swaab and Hofman 1990, Garcia-Falgueras
and Swaab 2008). They were the first who showed a
female brain structure in genetically male transsexuals
and supported the hypothesis that gender identity
develops as a result of an interaction between the devel-
oping brain and sex hormones (Zhou et al. 1995).
Future may bring answer to the question about what
genes are directly regulated by androgen action to
induce sexual dimorphic morphology of the brain,
unique gender identity, sexual orientation and behav-
ior. Which of them directly modulated by testosterone
or its metabolites are crucial for initiation of brain dif-
ferentiation and masculinization?
Individual behavioral traits or specific cognitive abili-
ties are the result of a cooperation of genetic, hormonal
Table I
Genetic polymorphisms associated with testosterone metabolism
Gene Protein Polymorphism Consequence Reference
NR3C4 androgen receptor (CAG)n
in exon 1
Number of repeats influences the
function of the androgen receptor
as a transcription factor. Long
CAG repeats are associated with
a decreased transactivation
(Irvine et al. 2000)
(Chamberlain et al. 1994)
CYP19 aromatase C to T substitution in
exon 10
Substitution is characterized by
higher aromatase expression from
an alternative promoter.
(Kristensen et al. 2000)
SRD5A2 5α-reductase Substitution A49T
Alanine in codon 49
is substituted with
Treonine allele in SRD5A gene
leads to fivefold increase of
reductase activity.
(Makridakis et al. 1999)
SHBG sex hormone
binding globulin
Aspartic acid in
codon 327 is replaced
by asparagine
Asn allele in the SHBG gene may
be related to increasing blood
SHBG levels.
(Cui et al. 2005)
ESR1 estrogen receptor
PvuII polymorphism
Transition T to C in
exon 1
Polymorphism enhances estrogen
receptor activity.
(Khosla et al. 2004)
444 J. Durdiakova et al.
and environmental factors (Fig. 4). Testosterone activity
is influenced by variants in genes involved in its meta-
bolic processing. Main candidates possibly considered
modulators of testosterone effect in relation to cognitive
function are summarized in Table I. Gene for aromatase
of testosterone (CY P19 ) is located on chromosome 15. A
genetic variant with C substituted by T in exon 10 in 3´-
UTR region is associated with higher aromatase produc-
tion and increased risk of breast cancer (Kristensen et al.
2000). SRD5A2 gene encoding 5α-reductase is localized
on the chromosome 2. Substitution of alanine with threo-
nine in codon 49 is linked with increased activity of
reductase (Makridakis et al. 1999). Substitution A49T in
enzymatic product of SR D5A2 gene occurs in intellectu-
ally gifted children (boys and girls) more frequently in
comparison with control population. Similarly, C-T sub-
stitution in exon 10 in the aromatase gene was detected
more frequently in intellectually gifted children (boys
and girls) when compared to control group. This genetic
background influences aromatase and reductase activity,
testosterone level and might enhance its androgenic
effects on cognition (Holešová et al. 2006).
Androgen receptor (AR) can be considered a major
modifier of speed of neural transmission (Manning
2007). Gene for AR is located on the X chromosome
and consists of eight exons. AR protein can be divided
into several domains with specific function (Fig. 5).
For detailed information, excellent review about AR is
available (Bennet 2010). A polymorphic three-nucle-
otide (CAG)n repeat in exon 1 encodes a polyglutamic
tract (Choong and Wilson 1998). Normal variation is in
range of 11 to 35 repeats (Greenland and Zajac 2004).
Interestingly, a loss-of-function mutation of AR is not
linked with intelligence impairment, but a short repeat
in the AR is linked with mental disability and retarda-
tion (Kooy et al. 1999). Massive expansion of (CAG)n,
on the other hand, is also associated with severe
pathology in the form of the Kennedy disease
(Greenland et al. 2004). Higher but still normal num-
ber of repeats in exon 1 of the AR gene has been
shown to affect some personality traits (Westberg et al.
2009). In the range of normal variation low number of
repeats causes higher transactivational activity of AR
and, thus, higher sensitivity to androgens (Tut et al.
1997). Comparison of sequences of the AR gene from
five different primate species reveals that there is an
evident increase in number of repeats in the primate
evolution to humans. This expansion has a direct effect
on AR structure, activity and can be also an important
phenomenon in the evolution of intelligence and cogni-
tion (Choong et al. 1998). Remarkable population dif-
ferences in repeats were detected using X-chromosome
analyses. Men of African descent have a mean number
of (CAG)n repeats between 16.7–17.8. Men of European
origin have a mean of 19.7 and men of Asian descent
20.1 repeats. These findings positively correlate with
IQ value measured in meta-analyses (Kittles et al.
2001). On the other hand, evaluation of intellectually
Fig. 5. Scheme of human androgen receptor (AR) gene and AR protein. The gene encoding AR has eight exons and pro-
duces a cDNA approximately 2760 nucleotides in length and a protein of approximately 920 amino acids. The AR protein
consists of four structurally and functionally distinct domains, N-terminal transactivation domain (NTD), DNA binding
domain (DBD), a small hinge region and a C-terminal ligand-binding domain (LBD). Locations of transcriptional activation
units (TAU-1, TAU-5) and some of important coactivators are also illustrated.
Testosterone metabolism and the brain 445
gifted pre-pubertal children shows that there are no
significant differences in the number of repeats
between intellectually gifted boys and controls
(Holešová et al. 2006).
Many coregulators are recruited to AR (Fig. 5) with
and without bound ligand influencing DNA binding,
nuclear translocation, chromatin remodeling, binding
interruption of other co-regulators, AR stability, and
bridging AR with the basal transcriptional machinery
(Shen et al. 2005, Chmelar et al. 2007).
Although knowledge of AR structure, functional
mechanisms within cell, and its molecular biology is
extensive, for complete understanding of AR function
certain issues need to be clarified. Studies on the
androgenic effects on target tissues are difficult to
interpret due to complex molecular background, plenty
of coregulators and corepressors affecting AR activity.
Several animal studies use androgen receptor inactiva-
tion using competitive inhibitors to prove the role of
AR in physiology and pathology. However, it is
unknown what the exact cellular response is after
androgen receptor blockage or how interacting part-
ners exactly behave. Another complicating fact is the
possible switch into the non-genomic pathway that is
not fully characterized and understood.
For comprehensive analysis of testosterone effect,
prenatal influence is needed to be considered. Although
it is not easy to measure hormones during prenatal
development, several researchers have successfully
examined hormones in amniotic fluid and then related
these hormones to behavior, this method was first pro-
posed and used by Finegan and colleagues (1989).
Because such studies are difficult to conduct, there has
been considerable interest in studying indirect indica-
tors of prenatal testosterone exposure in relation to
contemporary behavior in children and adults. These
indicators include sharing the uterine environment
with markers such as fingerprint patterns and length
ratio of the second to fourth finger (2D/4D ratio)
(Manning et al. 1998, Lippa 2006, Malas et al. 2006,).
Male fetuses undergo intensive testosterone pro-
duction during the prenatal period. The peak in
human male testosterone production occurs between
10th and 18th week of gestation (Maccoby et al. 1979).
In this time of early testosterone exposure, sex ste-
roids directly affect not only the brain but also the
bone length by influencing the development of the
phalanges and the metaphyseal growth. In the meta-
physeal tissues, steroids act via estrogen receptor
alpha and beta, as testosterone is locally aromatized
(Ben-Hur et al. 1997, Weise et al. 2001). Genetic
analyses of the androgen receptor short tandem repeat
polymorphism revealed that lower but still normal
number of CAG repeats enhancing androgen effect is
associated with lower 2D/4D ratio (Ding et al. 2004).
Other studies did not find any relationship between
polymorphism in AR and the digit ratio (Hurd et al.
2010). In addition to hormonal regulation, there is a
genetic basis contributing to the differentiation of the
digit ratio pattern. Particularly HOXa and HOX b
genes strongly expressed in gonads are essential for
differentiation of the genital bud and digit growth.
Sharing of causal factors in digit and gonad differen-
tiation supports the hypothesis that patterns of digit
formation can be used as a marker for prenatal sex
hormone concentration.
The length of the fourth digit (ring finger) is thought
to be an index of prenatal testosterone exposure rela-
tive to the length of the second digit (index finger),
which is thought to represent an index of prenatal
estrogen exposure (Manning et al. 1998, Manning and
Taylor 2001, Manning and Fink 2008). According to
several studies, 2D/4D ratio can be considered a rele-
vant indicator of prenatal hormonal environment
(Finegan et al. 1989, Manning et al. 1998, 2000,
Manning and Taylor 2001, Kempel et al. 2005, Manning
and Fink 2008, Manson 2008, Hurd et al. 2010). This
parameter is believed to be fixed in utero. It can be
reliably measured as early as in 2 years of age and is
stable during the entire life, not affected by pubertal
growth (Manning et al. 2000). The relative length of
the second and the fourth finger is sexually dimorphic.
In males the 2D/4D ratio is lower having the mean of
0.98 caused by longer 4D. Females have a higher
2D/4D value with mean of 1.00 explained by equal
lengths of second and fourth finger. Except sexual
dimorphism, remarkable variability was reported in
large-scale population studies. In mixed race samples,
people of African origin had lower 2D/4D at all ages,
but significant differences were detected between
nationalities and ethnic groups (Manning et al. 2000).
Possible explanation is the different androgen expo-
sure in utero (Manning et al. 1998). Supporting data
come from studies on congenital adrenal hyperplasia.
446 J. Durdiakova et al.
Higher androgen exposure caused significantly lower
2D/4D when compared to healthy controls (Brown et
al. 2002). Animal studies on bird eggs confirmed the
prenatal androgen effect on 2D/4D (Romano et al.
The 2D/4D digit ratio was found to be associated
with many physiological, behavioral and cognitive
parameters that are sexually dimorphic and influenced
by hormonal activity, even the sexual orientation (Fig.
6). Homosexuals of both sexes have a lower 2D/4D ratio
when compared to heterosexuals suggesting higher
androgen levels prenatally (van Goozen et al. 2002,
Rahman and Wilson 2003). Finger ratio was measured
in association with reproductive success in healthy men
and women. For men, there is a negative association
between low 2D/4D and higher number of children or
sperm counts. Women display positive relationship
between higher 2D/4D and fertility (Manning and Fink
2008). Very high feminine 2D/4D can be a risk factor
for breast cancer (Belcher et al. 2009, Devine et al.
2010). On the other hand, atypically low digit ratio is
believed to be associated with autism spectrum disor-
ders (Bloom et al. 2010, Krajmer et al. 2011). It is sug-
gested that prenatal testosterone levels promote devel-
opment and maintenance of traits useful in male fight-
ing sports related to aggressiveness. Digit ratio 2D/4D
is negatively associated with sport success in men
(Manning and Taylor 2001). Low 2D/4D is also related
to higher sport abilities in females (Paul et al. 2006).
In studies focused on digit ratio in relation to spatial
orientation, many contradictions were found. Women
exposed to higher prenatal androgen levels have lower
2D/4D (man-like) and perform better in spatial test and
numerical tasks than women with a higher digit ratio
(woman-like) (Kempel et al. 2005). In contrast, in
males improvement in spatial ability occurred after a
decrease in circulating testosterone levels. In the nor-
mal range of testosterone levels, feminine 2D/4D in
males is linked with best results in visual spatial tasks
(Sanders et al. 2002). A recent study investigating
implications for the relationship between prenatal tes-
tosterone and academia shows social scientists of both
sexes have a ratio consistent with the male norm (0.98)
whilst scientists have a digit ratio consistent with the
female norm (1.00). Both of these findings propose that
the relationship between the 2D:4D ratio and visuo-
spatial ability may reveal a U-shaped curve or other
non-linear relationship (Brosnan 2006). They provoke
also some speculations that 2D/4D can be related to
spatial preferences rather than ability per se (Valla and
Ceci 2011). Despite the 2D/4D is consider to be a rele-
vant indicator of prenatal hormonal profile, recent
studies brought inconsistent or controversial results
that are difficult to interpret (Forstmeier et al. 2010,
Medland et al. 2010, Valla and Ceci 2011). In some
studies low 2D/4D on the right hand and high 2D/4D
on the left hand are used as predictors of higher prena-
tal androgen levels. Data from the right hand are
Fig. 6. Schematic illustration of relative finger lengths and possible association with typical physical features. Physical char-
acteristics that develop in distinctly masculine and feminine ways are mostly caused by sex hormones. High prenatal testos-
terone exposure leads to masculine 2D/4D digit ratio (lower than 1). Female undergo less androgenisation that results in
2D/4D digit ratio higher than 1. Finger lengths are associated with some cognitive abilities and also with risk for disease
Testosterone metabolism and the brain 447
argued to be more sensitive to the effects of prenatal
testosterone exposure (Manning et al. 2000). Another
study claims that 2D/4D analyses are more consistent
on the left hand (Von Horn et al. 2010). Due to these
discrepancies in many analyses an average 2D/4D ratio
of both hands was used (Brosnan 2008). Differences in
digit ratios could arise if bones from different fingers
are differentially receptive to sex steroids due to differ-
ences in receptor activity, aromatase activity, or differ-
ent conditions for interaction between steroid receptors
and growth factors. 2D/4D negatively correlated with
math-intensiveness of college major in females, but not
males. According to these results, there is a possibility
of alternative sexually differentiated pathway includ-
ing different trajectory and timescale of development,
so bones differ in their temporal patterns of growth
(Valla et al. 2010, Valla and Ceci 2011).
Regarding the organizational theory of brain, it is
strongly believed that testosterone during prenatal
development is essential biological force influenc-
ing cognitive abilities and intelligence. It could be
interesting to investigate 2D/4D in intellectually
gifted individuals and possibly find correlations
between prenatal hormonal profile, actual testoster-
one levels and cognitive and behavioral characteris-
tics to support the hypothesis about testosterone
involvement in giftedness development. Animal
studies which enable prenatal hormonal manipula-
tions can potentially help to clarify what is the pre-
natal testosterone exposure mechanism. How exact-
ly can prenatal hormonal environment be reflected
into finger ratios or exceptional individual abilities?
Why are there some inconsistencies in left and right
hand or gender differences shown is some studies?
Testosterone is a hormone with many essential roles
in the development of morphological, physiological
and cognitive traits. Hormonal effects and their regula-
tion very likely influenced evolution of humans in a
substantial way. Research on testosterone metabolism
and androgen signaling in relation to cognition is
indeed interdisciplinary linking evolution, psychology,
neuroscience with molecular genetics, biochemistry
and endocrinology. The high number of scientific
teams worldwide focusing on this area indicates that
there are still a lot of aspects that remain unclear and
wait to be discovered.
The authors are supported by grant VEGA-
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... Androgens are key regulators of male sexual differentiation and development of a normal male phenotype. The main human androgen testosterone plays a dominant role in sexual dimorphism (Durdiakova et al. 2011). Genetic and environmental effects modulating gene expression of enzymes for steroid metabolism in the steroidogenic cascade in concordance with the modulation of expression of respective receptors imply complex and sophisticated mechanisms of androgen effects. ...
... Our research group confirmed higher testosterone concentrations in prepubertal boys with ASD in comparison to their peers from general healthy population (Ostatnikova et al. 2016). As aggression is generally more prevalent in males, testosterone was studied in relation to aggressive behavior (Constantino et al. 1993, Durdiakova et al. 2011. In ASD boys a positive correlation was described between explosive aggression and androgenic activity (Tordjman et al. 1997, Pivovarciova et al. 2014, Pivovarciova et al. 2015. ...
... From the evolutionary perspective testosterone is a precursor of estradiol, dihydrotestoterone and other metabolites rather than a hormone per se (Callard et al. 2011, Durdiakova et al. 2011. Studying its effects is, thus, complicated, biased and potentially misleading, since the activation of androgen and estrogen receptors in the particular tissues should be the true modulation factors, not the testosterone concentration in blood plasma (Hodosy et al. 2012b, Hodosy et al. 2012c. ...
Sex and gender matter in all aspects of life. Humans exhibit sexual dimorphism in anatomy, physiology, but also pathology. Many of the differences are due to sex chromosomes and, thus, genetics, other due to endocrine factors such as sex hormones, some are of social origin. Over the past decades, huge number of scientific studies have revealed striking sex differences of the human brain with remarkable behavioral and cognitive consequences. Prenatal and postnatal testosterone influence brain structures and functions, respectively. Cognitive sex differences include especially certain spatial and language tasks, but they also affect many other aspects of the neurotypical brain. Sex differences of the brain are also relevant for the pathogenesis of neuropsychiatric disorders such as autism spectrum disorders, which are much more prevalent in the male population. Structural dimorphism in the human brain was well-described, but recent controversies now question its importance. On the other hand, solid evidence exists regarding gender differences in several brain functions. This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences in healthy individuals and people in the autism spectrum.
... It is expected that the hormones, progesterone and testosterone might interact with nCoV. [12][13][14][15] Progesterone causes the endometrium transition from prolifera-tive phase to the secretory phase for maintain the blastocyst and maintain the pregnancy. It also plays an important role for maintaining the several types of tissues that are not belonged to the reproductive systems like mammary glands for breastfeeding, cardiovascular system bones. ...
SARS-CoV-2 is drastically spread across the globe in a short period of time and affects the lives of billions. There is a need to find the promising drugs like candidates against the inhibition of novel corona virus or SARS-CoV-2. Herein, the interaction on sex hormones (testosterone and progesterone) with Mpro of SARS-CoV-2 was investigated with the help of molecular docking. The binding energy for the formation complex between the progesterone and testosterone with main protease of SARS-CoV-2 are -86.05 and -91.84 kcal/mol, respectively. From this, it can be understood that testosterone showed better binding affinity with Mpro of nCoV and thus, more inhibition of the main protease. Then, the binding was further studied using molecular dynamics simulations at different temperatures (300, 310 and 325) K. It has been observed that the formations of complex between the Mpro of nCoV with testosterone/ progesterone is better at 300 K than 310 and 325 K. Further, it is found that the more effective binding of testosterone with Mpro of nCoV is observed than the progesterone based on the RMSD, RMSF and H-bond trajectories. Results indicate the promising nature of testosterone towards the inhibition of Mpro of nCoV.
... Testosterone regulates genomic expression through its metabolites, dihydrotestosterone (DHT), which binds to the androgen receptor, and estradiol, which binds to the estrogen receptor (Durdiakova et al., 2011). Little is known about the role of the androgen receptor in the mediation of PTSD symptomatology. ...
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Post-traumatic stress disorder (PTSD) is a devastating illness with treatment that is effective in only approximately half of the population. This limited rate of response highlights the necessity for research into underlying individual biological mechanisms that mediate development and progression of this disease, allowing for identification of patient-specific treatments. PTSD has clear sex differences in both risk and symptom patterns. Thus, one approach is to characterize trauma-related changes between men and women who exhibit differences in treatment efficacy and response to trauma. Recent technological advances in sequencing have identified several genomic loci and transcriptional changes that are associated with post-trauma symptomatology. However, although the diagnosis of PTSD is more prevalent in women, the genetic factors underlying sex differences remain poorly understood. Here, we review recent work that highlights current understanding and limitations in the field of sex differences in PTSD and related symptomatology.
... Cholesterol via desmolase activity will produce pregnenolone, converted to 17-alpha-hydroxyprognelonone, to dehydroepiandrosterone, to 4-androstene-3,17-dione, and finally to testosterone. Alternative pathway to produce testosterone is via conversion of cholesterol to progesterone, to 17-alpha-hydroxyprogesterone, to 10 4-androstene-3,17-dione, to testosterone ( Figure 2). This hormone generally plays a role in the formation of masculine characteristics of the body. ...
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Obesity can be defined as the excess of body fat. The prevalence of obesity worldwide increases in the last decades andcauses a higher risk of cardiovascular diseases. Male subjects tend to develop visceral (abdominal) obesity, which producespro-inflammatory adipokines. Obesity in males is associated with low testosterone levels. Several mechanisms have beenproposed to explain the link between male obesity and hypotestosterone, including increased aromatization oftestosterone to form estradiol, suppressing the Hypothalamus-Pituitary (HPT) axis due to pro-inflammatory adipokines, anddecrease of Sex Hormone Binding Globulin (SHBG) production. Because hypotestosterone in males with obesity is afunctional but reversible condition, it is essential to screen testosterone levels in obese males for early intervention andtreatment.
... However, the average serum testosterone levels are between 10-and 20-fold lower in females overall. Due to this difference in concentration between the genders, testosterone is usually recognized as a male sex hormone, but a commonly overlooked fact is that women are more sensitive to fluctuations in testosterone levels [8]. ...
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Testosterone’s role in female depression is not well understood, with studies reporting conflicting results. Here, we use meta-analytical and Mendelian randomization techniques to determine whether serum testosterone levels differ between depressed and healthy women and whether such a relationship is casual. Our meta-analysis shows a significant association between absolute serum testosterone levels and female depression, which remains true for the premenopausal group while achieving borderline significance in the postmenopausal group. The results from our Mendelian randomization analysis failed to show any causal relationship between testosterone and depression. Our results show that women with depression do indeed display significantly different serum levels of testosterone. However, the directions of the effect of this relationship are conflicting and may be due to menopausal status. Since our Mendelian randomization analysis was insignificant, the difference in testosterone levels between healthy and depressed women is most likely a manifestation of the disease itself. Further studies could be carried out to leverage this newfound insight into better diagnostic capabilities culminating in early intervention in female depression.
... Organizational effects during puberty play the important role in brain maturation and connections between brain areas. Progesterone and testosterone have diverging effects on the communication between amygdala and prefrontal cortex (van Wingen et al, 2010) [12]. Prefrontal cortex plays a crucial role in neuroendocrine stress responses and emotion regulation and it is characterized by high expression of genes associated with gonadal and HPA axes [7]. ...
The excessive aggression is an actual problem of modern society but the mechanisms of aggressiveness development have not been sufficiently investigated. Women aggression is considered to differ from men one and results obtained on males cannot be extrapolated on females. Sex hormones have a crucial role in the generation of sexually dimorphic aggression circuits during development and their maintenance during adulthood. Hypothalamic pituitary adrenal axis and sympathoadrenal system are major neuroendocrine systems that respond to stress. Stress hormones are involved into behavioral reactions of organism. Gonadal, hypothalamic pituitary adrenal axes, and sympathoadrenal system are tightly interrelated and every of them can influence another one. The purpose of the study was to estimate correlation differences between sex and stress hormones in men and women. Material and methods. Forty healthy young people aged 18 to 22 years with a body mass index of 19-24 (21 women and 19 men) were enrolled in the study. Hormone levels in blood serum were determined by Testosterone, Estradiol, Cortisol ELISA kits (Italy), Epinephrine/Norepinephrine (EPI) ELISA kit (China). Results and discussion. In all phases of the menstrual cycle, the level of cortisol in women was lower than in men, but in the luteal phase these differences were not statistically significant. In all phases of the menstrual cycle, the blood serum norepinephrine content in women was lower than in men, but in the follicular phase these differences were not statistically significant. The level of epinephrine in women during ovulation and luteal phase did not differ from the level of epinephrine in men, but in follicular phase it was significantly lower. Calculations of correlations between individual hormones revealed a significant difference between them in men and women. Positive correlations between testosterone and estradiol and between cortisol and epinephrine; a strong negative correlation between epinephrine and testosterone/norepinephrine ratio were found in men. Positive correlation between testosterone and cortisol and negative correlation between estradiol and cortisol/testosterone ratio were revealed in women. Conclusion. In women, strong correlations were found between cortisol and sex hormones; in men, strong interrelationship was revealed between cortisol and epinephrine. Both in men and in women (in all phases of the menstrual cycle), high positive correlations between testosterone/norepinephrine and cortisol/norepinephrine ratios were observed
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Para evaluar el costo de alimentación sobre ingresos en la engorda de conejos en dos sistemas de alojamiento (Convencional Vs Piso), tanto en hembras como machos los que se alimentaron con mezcla comercial, donde se utilizaron 80 conejos, 40 hembras y 40 machos de cruza Nueva Zelanda de 35±7 días de edad con peso promedio de 1.324 kg, 75 días de edad al sacrificio. Se midió consumo de alimento, ganancia diaria de peso, conversión alimenticia, rendimiento en canal y costo de alimentación sobre ingresos (CASI). El análisis estadístico se realizó mediante un modelo completamente al azar con arreglo factorial 2x2 (Tipo de jaula*sexo) resultando que no hubo diferencias (P<0.005) en la interacción planteada, así como tampoco en los efectos principales, excepto para la variable consumo de alimento, que fue mayor (P<0.05) en machos tanto en jaula convencional y en piso. No se obtuvieron diferencias entre tratamientos para la variable CASI. Se concluye que la engorda de conejos con alimento comercial, alojados en jaulas convencionales y en piso, es una opción viable para su implementación desde el punto de vista productivo y económico.
The objective of this study was to develop a testosterone sustained release formulation for the treatment of fecal incontinence. To suppress the initial burst release of testosterone, which can lead to systemic toxicity, we incorporated a washing step using an aminoalkyl methacrylate copolymer E solution or propylene glycol solution into a typical o/w emulsion method to prepare polylactic-co-glycolic acid microspheres. We used this method to develop a polylactic-co-glycolic acid microsphere formulation that shows sustained release of testosterone for up to one month. Not only did this formulation show a sustained release profile after administration into the intersphincteric groove in minipigs, it also increased both the anal pressure and mass of the external anal sphincter, while keeping systemic testosterone exposure low. Thus, this formulation successfully affected both the internal and external anal sphincters with a sufficient safety profile, deeming it a promising candidate treatment strategy for fecal incontinence.
Moringa oleifera, Viscum album and Phyllanthus amarus supplements in rabbit diet stimulate better spermatozoa kinetics. Moringa oleifera supplements in bucks’ diets enhanced serum LH and reproductive organ weights. Viscum album supplements in bucks’ diets encouraged daily sperm production, testicular sperm reserves, testosterone, and spermatozoa kinetics over other herbs supplements. Phyllanthus amarus supplementation in bucks’ diet enhanced weight gain, serum FSH, extra-gonadal sperm reserves, over bucks on other herbal supplements. Strategic herbal supplementation would be required to meet different reproductive desires in rabbit bucks.
Background: 47,XYY syndrome (XYY) is a male sex chromosome disorder where subjects have one X chromosome and two copies of the Y chromosome. XYY is associated with a physical phenotype and carries increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Imbalance of excitation and inhibition has been proposed as a putative biological basis of disorders such as ASD [1-3] and several studies have reported atypical brain γ-aminobutyric acid (GABA) levels in this population. Given the male preponderance in the prevalence of ASD, the unique presence of the Y chromosome in males leads to the intriguing possibility of investigating boys with XYY syndrome as a model of excess Y-chromosome genes. Method: In this study, we investigated the associations of genotype and clinical phenotype with levels of GABA, estimated by regionally localized edited magnetic resonance spectroscopy in boys with 47, XYY syndrome compared to age-matched typically developing (XY) peers. Results: Overall, we observed a decrease in GABA levels in XYY vs. XY, which appeared more significant in the left compared to the right hemisphere. There was no additional significant modulation of GABA levels in XYY according to presence/absence of ASD diagnosis. Interestingly, a positive correlation between bilateral GABA levels and testosterone levels was observed in pubescent XY boys that was not observed in XYY. Conclusion: The inhibitory neurotransmitter GABA appears to be reduced in boys with 47,XYY, especially in the left hemisphere. Further, the typical association between GABA and testosterone levels, observed in older typically developing control boys was not evident in boys with 47,XYY.
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Morphometric analysis of the human hypothalamus revealed that the volume of the suprachiasmatic nucleus (SCN) in homosexual men is 1.7 times as large as that of a reference group of male subjects and contains 2.1 times as many cells. In another hypothalamic nucleus which is located in the immediate vicinity of the SCN, the sexually dimorphic nucleus (SDN), no such differences in either volume or cell number were found. The SDN data indicate the selectivity of the enlarged SCN in homosexual men, but do not support the hypothesis that homosexual men have a 'female hypothalamus'.
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Abstract There are no sex differences in general intelligence but, in specific cognitive abilities, men and women,differ. This study was,designed to describe infradian variations in testosterone levels in saliva collected during one month,and to identify relationships between,salivary testosterone and spatial abilities in 53 young,healthy volunteers of both sexes. Our results showed,the effect of testosterone on spatial performance. In accordance with general knowledge, men with higher average testosterone levels scored better than women. A circalunar rhythm of testosterone related to the menstrual,cycle with the highest testosterone concentration in the periovulatory period was confirmed,in women,and,an analogical circalunar cycle was,described,in men. Negative relationships between,testosterone levels and spatial abilities were found in men,whereas,positive relationships between these parameters were found in women. When spatial perfomance,was related to monthly testosterone variations in both sexes, it was found that, in women, the periovulatory testosterone peak was associated with the best spatial performance while, in men, the high testosterone phase was,associated with the worst spatial performance. The understanding,of infradian variations in testosterone levels and their effects on cognitive abilities in humans may,be important in terms of clinical implications. Key,words Salivary testosterone, Spatial ability, Infradian testosterone fluctuations, Sexual dimorphism
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Testosterone (T) is known to affect spatial abilities in men and women. Studies focusing on this relationship showed that both endogenous variability of T and administration of exogenous T, altered mental rotation and spatial visualization. Organizational and activational effects of T can be separately identified. The aim of our study was to evaluate the activational effects of exogenous T on spatial memory in male and female rats. T was administered 3 times a week over a two week period in either 1 mg/kg for low testosterone group or 10 mg/kg for high testosterone group. The Morris water maze was performed to assess the rat’s working and reference spatial memory. T and estradiol levels were measured in plasma. Increase in plasma T levels was confirmed in the experimental groups in comparison to the control groups (receiving sterile oil, 3 times a week over a two week period). Low dose T impaired working, but improved reference memory in female rats. In male rats the negative effects of T (both doses) on reference memory were shown. This experiment showed that the activational effects of exogenous testosterone on spatial memory of rats were gender and dose-dependent.
Brain organization theory posits a cascade of physiological and behavioral changes initiated and shaped by prenatal hormones. Recently, this theory has been associated with outcomes including gendered toy preference, 2D/4D digit ratio, personality characteristics, sexual orientation, and cognitive profile (spatial, verbal, and mathematical abilities). We examine the evidence for this claim, focusing on 2D/4D and its putative role as a biomarker for organizational features that influence cognitive abilities/interests predisposing males toward mathematically and spatially intensive careers. Although massive support exists for early brain organization theory overall, there are myriad inconsistencies, alternative explanations, and outright contradictions that must be addressed while still taking the entire theory into account. Like a fractal within the larger theory, the 2D/4D hypothesis mirrors this overall support on a smaller scale while likewise suffering from inconsistencies (positive, negative, and sex-dependent correlations), alternative explanations (2D/4D related to spatial preferences rather than abilities per se), and contradictions (feminine 2D/4D in men associated with higher spatial ability). Using the debate over brain organization theory as the theoretical stage, we focus on 2D/4D evidence as an increasingly important player on this stage, a demonstrative case in point of the evidential complexities of the broader debate, and an increasingly important topic in its own right.