Posted: April 24th, 2025

Discussion

Discuss the following (total of 150-250 words):

1. Discuss one (1) of the following:

a. What factors drive how genes are expressed differently in males and females to create the distinct male and female phenotypes? (MO 10.4)

b. How can hormones account for sexual orientation? (MO 10.5)

c. Name and describe some of the differences in brain structure that were found between persons who are homosexual and persons who are heterosexual. (MO 10.5)

d. How can a disorder like congenital adrenal hyperplasia explain some differences of sexual orientation in women? (MO 10.5)

e. How is fraternal birth order associated with homosexuality in men? (MO 10.5)

f. For a long time, hormones have been viewed as the main cause behind our behavior. Now, we’re starting to rethink that as we learn more about the body’s complexity. Still, these chemicals clearly have some kind of influence over us. What do you think? Are hormones primarily responsible for our behavior? (MO 10.2)

2. After reading the

Stark and Gibbs (201

8) article and visiting the

InterAct websiteLinks to an external site.

, choose one (1) of the following

interviewsLinks to an external site.

: Allie (they/them), Jubi (they/them), Mari (they/them), Bria (they/she), Sophia (she/her). What might be/have been helpful for this person or important others in their lives to have known to improve their experiences living with CAH? (MO 10.6)

CHAPTER 14

Hormones and Development
Rachel Stark and Robbin Gibb
University of Lethbridge, Lethbridge, AB, Canada

14.1 INTRODUCTION

With the advances in science and technology made in the 20th century, it is remark-

able that it was not until 1959 that a group of researchers began the pioneering studies

in the field of sexual development. Phoenix and colleagues injected pregnant guinea

pigs with testosterone and noted that while the male offspring seemed unaffected, the

prenatal exposure of testosterone created females that were phenotypically male in

characteristic but genetically female (Phoenix, Goy, Gerall, & Young, 1959). Thus,

they published what is known today as the organizational/activational hypothesis of

sexual differentiation. Phoenix and colleagues proposed that the androgens act at a

specific time or times (critical period) during development to permanently alter the

tissue. They suggested a dichotomy between organizational and activational effects.

During the prenatal period the androgens acted to organize the tissue, meaning it pre-

pared certain tissues in the body to respond differently to gonadal hormones in adult-

hood. Then, in adulthood, the gonadal hormones worked to activate the tissues, thus

affecting sexual behavior (Arnold, 2009). Their belief that male hormones changed

the brain was a new and very controversial idea that caused an explosion in the

research of sexual differentiation (Wallen, 2009).

Although this hypothesis has been adapted and changed over time, the main ideas

that Phoenix and his colleagues proposed still hold true today. This chapter will focus

on sexual differentiation, and how this differentiation affects both brain development

and the behaviors that emerge. Factors that impact this development are also dis-

cussed. Finally, we delve into our current understanding of sexual differentiation and

how this idea has changed over time.

14.2 GENETIC FACTORS INFLUENCING SEXUAL DIFFERENTIATION

14.2.1 Sex differences in gene expression
Gonadal hormones are the defining factor in sexual differentiation of the body and

brain, but where do these differences in hormones arise? What causes the gonads to

become either testis or ovaries in the first place? This is where genetics plays an

The Neurobiology of Brain and Behavioral Development r 2018 Elsevier Inc.
DOI: http://dx.doi.org/10.1016/B978-0-12-804036-2.00014-5 All rights reserved. 391

http://dx.doi.org/10.1016/B978-0-12-804036-2.00014-5

392 The Neurobiology of Brain and Behavioral Development

important role. Biological sex in humans is determined by the presence or absence of

the Y sex chromosome. During gamete production in males, spermatocytes undergo

division so that the gametes contain half the parents’ genetic material. This results in

sperm that either possesses an X or a Y chromosome. The same process happens dur-

ing female gamete production but since females possess two X chromosomes the

gametes that are formed all contain an X chromosome. This gives rise to the typical

XX female and XY male sex chromosomes once fertilization has occurred (Cheng &

Mruk, 2010).

Gonadal hormones function as secondary factors that act downstream of the pri-

mary factors, the X and Y chromosomes (Arnold, 2009). The expression of genes on

the sex chromosomes influences the sexual differentiation of the brain, and sequen-

tially behavior prior to the onset of gonadal hormone secretion. This suggests that

there is a gene-hormone interaction (Davies & Wilkinson, 2006). The Ar gene
encodes the androgen receptor and is found on the X chromosome. This receptor is

critical for male development. Because it is found on the X chromosome, females

carry and express this gene, but circulating progestins, expressed in high levels in

females, inhibit the activity of the receptor. Acting as antiandrogen agents, progestins

block the male typical mode of development (Raudrant & Rabe, 2003). The Ar gene
provides a useful example for how genes may encode one mode of development but

the interaction with hormones changes it. It is, therefore, important to understand the

role sex-linked genes have on development (Fig. 14.1). The three mechanisms by

which this may occur include X-linked gene dosage effects, X-linked imprinting, and

Y-specific gene expression.

Figure 14.1 The organization/activation affects the sex chromosomes and hormones have on the
brain. Adapted from McCarthy, M.M., & Arnold, A.P. (2011). Reframing sexual differentiation of the
brain. Nature Neuroscience, 14(6), 677�683.

Hormones and Development 393

14.2.1.1 X-linked gene dosage
Genetic females, as we have established, possess two X chromosomes. This puts

females at risk of potentially fatal levels of gene product from the second X chromo-

some. A mechanism, called x-inactivation, has evolved to cope with this issue. In this

process, one of the X chromosomes is condensed into a Barr body but not all of the

genes on the inactivated chromosome are silenced. In fact, approximately 15% escape

inactivation (Nieschlag, Werler, Wistuba, & Zitzamm, 2014). The escaped genes will

be expressed in higher levels in females than in males, who only have one X chromo-

some. In other words, the genes that escape X-inactivation are more likely to be phe-

notypically expressed in females (Davies & Wilkinson, 2006). For example, color

vision deficiencies like color blindness occur in about 8% of men (according to the

National Eye Institute) while only .5% of the female population is affected. If a female

is missing the functional gene on one chromosome, the other is able to compensate

for this loss. Furthermore, women are able to express tetrachromacy (although this is

fairly rare) as opposed to the normal trichromacy vision due to a double dosing effect

(Jornda, Deeb, Bosten, & Mollon, 2010). This suggests that escaped genes may

account for some of the sexually dimorphic differences seen between males and

females.

14.2.1.2 X-linked imprinting
Genomic imprinting involves the preferential expression of a subset of genes that are

marked indicating parental origin. As such, some genes are preferentially expressed

from either the paternal or maternal X chromosome (Reik & Walter, 2001). This

process serves to sexually differentiate males and females as males inherit their X chro-

mosome solely from their mother and females inherit an X chromosome from both

parents. Genetic differences in females arise as the result of expression of the paternal

X chromosome that would not occur in males, while the maternal X chromosome

would be expressed in both sexes (Davis, Isles, Burgoyne, & Wilkinson, 2006). For

example, females with Turner’s Syndrome (possessing only one X chromosome; dis-

cussed in more detail below) show stark differences depending on whether they

received their X chromosome from their mother or father (Iwasa & Pomiankowski,

2001). As such, the parental origin and the preferential expression of genes have been

shown to influence fundamental sex differences in the brain and behavior.

14.2.1.3 Y-specific gene expression
The Y chromosome is functionally different from the X chromosome, mainly because

it possesses a region that cannot recombine with the X chromosome during division.

This nonrecombinant region (NRY) has genes on it that are specific to the Y chro-

mosome and comprises 95% of the chromosome’s length. As a result, genes in this

region are only expressed in males (Skaletsky et al., 2003). For example, the Sry gene

394 The Neurobiology of Brain and Behavioral Development

is found on the mammalian Y chromosome and is known as the testis determining

factor (Prokop et al., 2013). This gene is critical for male typical development of the

testis and is another way in which genes account for sexual differentiation.

Originally, it was thought that the Sry gene promoted the growth of the male

reproductive tracts (Wollfian system) and eliminated the female reproductive tracts

(Müllerian system). This in turn caused the production of testosterone, which acts to

masculinize and defeminize the tissues of the body, including the brain. Further

research into the Sry gene has shown that the presence of a Y chromosome may play

a larger role in brain development (McCarthy & Arnold, 2011). In one study,

researchers created phenotypic female mice. The catch is that they had XY chromo-

somes. They did this by removing the Sry gene from the Y chromosome, and as a

result these animals developed in the default female typical pattern (these animals will

be denoted XY2). They furthered this research by mating these genetic XY2 females

and found them to be fertile (Lovell-Badge & Robertson, 1990). More recent studies

using the XY2 females showed that there may be sex differences in the brain due to

the expression of genes found on either the X or Y chromosome. For example, it was

demonstrated that when the Sry gene was present there were more dopaminergic neu-

rons in the brain and further that the XY2 females had significantly lower numbers of

dopaminergic neurons than the XY males. This is thought to be due to the absence

of the Sry gene in the XY2 females (Carruth, Reisert, & Arnold, 2002). Lastly,

research by Dewing et al. (2006) looked at expression of the Sry gene and its protein
product. They found that there was increased expression of the Sry gene in the sub-
stantia nigra of the midbrain, the thalamus, and, although not to the same extent,

throughout the cortex (Dewing et al., 2006).

14.2.2 Clinical populations
One way in which to understand more about the function of the human body, aside

of manipulations to animals (see Chapter 4: The Role of Animal Models in Studying

Brain Development), is to study clinical populations. There are several different sex-

linked gene abnormalities that have been pivotal in understanding the interactions

between genes and hormones, and their effect on sexual differentiation of both the

body and brain.

14.2.2.1 Triple X syndrome
Triple X syndrome (XXX) is the addition of an X chromosome, with an incidence

rate of 1/1000 females, that is a result of nondisjunction of the sex chromosomes dur-

ing oogenesis. (Essentially, during gamete development the X chromosomes fail to

separate.) As such, the extra chromosome has a maternal origin (May et al., 1990).

The number of individuals affected may actually be significantly higher as majority of

cases go undiagnosed because some individuals may experience only mild symptoms

Hormones and Development 395

(Gustavson, 1999). Phenotypically, individuals with XXX tend to be tall and thin.

Behaviorally, they show motor coordination difficulties, auditory processing disorders,

psychological and personality disturbances, and an IQ 20 points below the control

level. Anatomically, individuals with XXX have lower total brain volumes and larger

ventricles with reported asymmetries. Some studies report reductions in amygdala

volumes as well (Otter, Schrander-Stumpel, & Crufs, 2009). Most XXX females have

normal ovarian and menstrual functions (Stagi et al., 2016) but occasionally cases of

birth defects (such as overlapping digits) and some of ovarian and menstrual problems

are reported in the literature.

14.2.2.2 Turner syndrome
Turner syndrome (TS) is a sex chromosome disorder resulting from complete or par-

tial loss of the X chromosome, affecting 1 in 2000 females. Nondisjunction in gamete

development in either parents results in an individual with only one X chromosome,

XO. This causes a reduction in X-linked gene dosing with the individual only expres-

sing male typical levels of gene expression (Uematsu et al., 2002). Physical characteris-

tics include short stature, infantilism, webbed neck, and cubitus valgus (an abnormal

carrying position for the arm). Along with these physical signs are cognitive deficien-

cies including lowered performance IQ, and impairments in visuospatial skills, short-

term memory, attention, and social interactions (Nijhuis-van der Sanden, Eling, &

Otten, 2003). MRI studies assessing anatomical features of individuals with TS have

found smaller bilateral brain volumes in the hippocampus, caudate, lenticular, thalamic

nuclei (all smaller in the right hemisphere), and the parieto-occipital regions (Murphy

et al., 1993). Moreover, depending on the parental origin of the X chromosome

certain symptoms are exaggerated. For example, individuals that inherited their X

chromosome from their mother lack social awareness, flexibility, and scored lower on

formal tests of social cognitive skills compared to individuals that received their X

chromosome from their father (Skuse et al., 1997).

14.2.2.3 Klinefelters syndrome
The most frequent type of congenital chromosomal disorders in males is Klinefelters

syndrome (KS), with a prevalence rate of 1 in 426 to 1 in 1000 (Ngun et al., 2014).

KS is characterized by an extra X chromosome (XXY) and as in females, the second

X chromosome is silenced via X-inactivation and the escaped genes are the cause of

the dosing affects that are seen in KS (Nieschlag, Werler, Wistuba, & Zitzamm, 2014).

Typical symptoms are due to hypogonadism, mainly infertility and testosterone defi-

ciencies as a result of X-linked dosing. Along with these symptoms are those of a

more feminized phenotype including female typical distribution of adipose tissue, and

absent or decreased facial hair. In addition, learning difficulties and a below normal

verbal IQ have been reported (Bojesen, Juul, & Gravholt, 2003). To further

396 The Neurobiology of Brain and Behavioral Development

understand the behavioral deficits observed, researchers have conducted MRI studies

to evaluate the link between brain and behavior. Studies report enlargement of ven-

tricular volume, and a bilateral reduction of cerebellar hemispheres, as well as a signifi-

cant reduction in temporal lobe volume (Itti et al., 2006).

14.2.2.4 Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) occurs when there is a mismatch between

gonadal hormones and sexual differentiation. CAH is the result of an autosomal-

recessive inherited disorder caused by a mutation in the enzyme, 21-hydroxylase,

which is involved in the pathway that converts precursor products into cortisol and

aldosterone. In the case of CAH, these precursors are unable to form the respective

corticosteroids and are metabolized into androgen. This disorder affects both males

and females and occurs in 1 in 15,000 births (White, 2009). Females born with CAH

tend to have ambiguous genitalia due to the high levels of androgens in utero, males

at birth are harder to diagnose without blood tests and tend to go untreated depend-

ing on the severity (Merke & Bornstein, 2005). In the brain, CAH causes a decrease

in amygdalar volume (Merke et al., 2003) and individuals affected with CAH have

symptoms that range from mild to severe depending on the degree of corticosteroid

deficiencies. Behaviorally, there are mixed reviews with some papers reporting

increased IQ and some reporting decreased IQ (Nass & Baker, 1991; Wenzel et al.,

1978). However, females with CAH are reported to have better spatial abilities,

whereas males with CAH are reported to have poorer spatial abilities. This gives some

insight into how the overabundance of androgens may act to organize the tissue of

the developing fetus. Since the discovery in the 1950s that cortisone was an effective

treatment for CAH, the lives of these patients have improved greatly. Screening is

done at birth to detect CAH and treatment can begin (Hampson, Rovet, & Altmann,

1998).

14.2.2.5 Androgen insensitivity
Androgen insensitivity (AI) is relatively rare, compared to the other disorders men-

tioned, with a population prevalence of 1 to 5 in 100,000. Individuals with AI are

genetic males, XY. The main pathology of this disorder stems from the lack of func-

tioning androgen receptors. The circulating androgens are at normal levels but the tis-

sues lacking the functioning receptors cannot be activated by androgens and

consequentially develop in a more female typical manner (Cohen-Bendahan, van de

Beek, & Berenbaum, 2005). There are three categories of AI and they have a varying

degree of effects on the body. The first is complete AI syndrome (CAIS), wherein the

tissues of the body are insensitive to androgen (i.e., testosterone) and, consequently,

the external genitalia differentiate in a female-typical direction. Therefore, CAIS indi-

viduals are generally raised as female and are not diagnosed until puberty when they

Hormones and Development 397

fail to menstruate (Ehrhardt & Meyer-Bahlburg, 1979). The second type is mild AI

syndrome (MAIS), this results from the mild impairment of the cells ability to respond

to androgens. The male typical genitalia differentiate during fetal development but

there is impaired development of secondary sexual characteristics during puberty and

infertility (Zuccarello et al., 2008). Partial AI syndrome (PAIS) is the third type.

Partial unresponsiveness to androgens results in impairments in the masculinization of

the male genitalia during fetal development and impairments to male secondary sexual

characteristics. Individuals with PAIS have ambiguous genitalia because not enough

testosterone was available during pregnancy to fully complete the development in a

typical manner (Hughes & Deeb, 2006). Since there is a spectrum in terms of the

etiology of the disorder, there is a varying degree of cognitive sequelae. Impairments in

visuospatial tasks and verbal comprehension have been reported (Imperato-McGlnley,

Plchardo, Gautier, Voyer, & Bryden, 1991).

14.3 ENVIRONMENTAL FACTORS

The relationship the environment has on development has been well established.

Gonadal hormones are an important fetal secondary factor that has the potential to

interact with environmental risk factors and experiences that may impact sexual devel-

opment. Sexual differentiation is vulnerable to pre- and perinatal factors that may

have estrogenic-like or antiandrogenic properties. These deviations can interfere with

development and cause a masculinization or feminization of the brain and as a result,

alter behavior. Here we will consider the effects of prenatal exposures, including

maternal exposure to drugs, nutritional status, and environmental contaminants.

14.3.1 Drugs
14.3.1.1 Nicotine
According to the Centers for Disease Control and Prevention (2016), an estimated

15% of US adults report daily smoking. Tobacco use is considered the largest

preventable cause of death and disease. It costs an estimated $96 billion dollars in

direct medical expenses and causes 443,000 smoking related deaths per year (Centers

for Disease Control and Prevention, 2016). Females are particularly susceptible to

developing tobacco-related morbidities and mortalities (Allen, Oncken, & Hatsukami,

2014). Resent research has also suggested that women who smoke have a much lower

success rate of quitting (Piper et al., 2010). Thus, it has been estimated that 10% of

women continue to smoke during pregnancy (Tong et al., 2013).

Alongside a large body of literature indicating the negative impact on overall

health, there is a growing evidence of the consequences of nicotine exposure on the

developing brain. Women who smoke during pregnancy generally have children born

with increased risk for sudden infant death syndrome, low birth weights, attentional

398 The Neurobiology of Brain and Behavioral Development

and cognitive deficits (including learning and memory impairments), and an increased

risk for developing ADHD (Ernst, Moolchan, & Robinson, 2001; Fried, Watkinson,

& Gray, 1998). In rodent studies, prenatal exposure of nicotine reduces birth weight,

increases locomotor activity, and causes poor performance in maze tasks and perma-

nent changes to dendritic morphology (Ernst et al., 2001; Mychasiuk, Muhammad,

Gibb, & Kolb, 2013). These results mimic the deficits observed in the human popula-

tion and provide insight into the etiology of the effects of nicotine.

In the brain, nicotine from tobacco products acts on nicotinic acetylcholine recep-

tors (nAChR), which are ligand-gated channels that mediate the release of the neuro-

transmitter, acetylcholine (Ach). These receptors are expressed in the human brain

during the first trimester. NAChR expression has also been reported to increase dur-

ing critical periods of development, leaving the brain extremely susceptible to envi-

ronmental factors (Dwyer, McQuown, & Leslie, 2009). Sex steroids play a role in the

modulation of the nAChR. Specifically, progesterone and estradiol have been shown

to increase the expression of the genes encoding the nAChR. While progesterone

decreases activity of nAchRs, estradiol increases their activity (Centeno, Henderson,

Pau, Bethea, 2006; Gangitano, Salas, Teng, Perez, & De Biasi, 2009; Jin & Steinbach,

2015; Ke & Lukas, 1996). These findings may shed some light on sex differences

observed with nicotine use in adulthood such as low success for cessation in women,

higher rates of cortisol during withdrawal, and subsequent higher rates of depression

and anxiety during periods of nicotine abstinence (Cross, Linker, & Leslie, 2017).

14.3.1.2 Alcohol
Alcohol can readily cross the placenta and as such, it has the potential for affecting

fetal development. Prenatal alcohol exposure can result in fetal alcohol spectrum dis-

order (FASD), with a prevalence rate of 9/1000 births in North America (Thanh &

Jonsson, 2010). FASD presents itself in clinical populations with growth retardation,

impairments in cognition and self-regulation, and substance-use disorders (O’Connor

& Paley, 2009). Prenatal exposure to alcohol has been shown to decrease testosterone

surges, which can lead to feminization of the brain and other tissues in males.

In females, prenatal alcohol exposure has been shown to cause delays in secondary

sexual characteristics later in life, which has been linked to dysregulation of the

hypothalamic�pituitary�adrenal (HPA) axis (see Chapter 16: Socioeconomic Status

for more information). Furthermore, the symptoms seen with prenatal alcohol

exposure may be exacerbated by the changes to the HPA axis in the mother, which

acts as an additional perturbation to the developing fetus (Weinberg, Silwowska, Lan,

& Hellemans, 2008). Alcohol consumption works to increase the activity of the HPA

axis, thereby inducing a stress response in the body. However, chronic alcohol

consumption causes the HPA axis to build up a tolerance to alcohol thereby reducing

Hormones and Development 399

cortisol levels. This tolerance may negatively affect the ability of the HPA axis to

respond to future stressors (Spencer & Hutchison, 1999).

14.3.1.3 Marijuana
In 2015, the National Survey on Drug Use and Health found that approximately 20.5

million individuals 18 years of age or older were current users of marijuana, with

117.9 million individuals 12 years of age or older reporting marijuana use at least

once in their lifetime (Center for Behavioral Health Statistics and Quality, 2016).

Although controversy remains on the effects of chronic use on the brain, marijuana is

the most commonly used illegal drug, and its use is on the rise among today’s youth

(Leatherdale, Hammond, & Ahmed, 2008; Wilson et al., 2000).

Individuals who begin smoking marijuana before the age of 17 have brain changes

that include decreases in gray matter and increases white matter. Males who start

smoking early have significantly higher global brain volumes. This has been hypothe-

sized to be a result of the rapid growth observed in the brain during this period of

adolescence (Wilson et al., 2000).

Delta-9-tetrahydrocannabinol (THC) has been implicated in reducing circulating

levels of estradiol and progesterone in females, and testosterone in males. In female

rats, administration of THC has been shown to block ovulation. In rhesus monkeys,

three weekly injections of THC are enough to disrupt normal menstrual cycling; an

effect that lasts for several months. Similar clinical reports have been made in women

who chronically use marijuana. In male rats, THC administration drastically lowers

circulating levels of testosterone (Murphy, Muñoz, Adrian, & Villanúa, 1998).

THC freely crosses the blood brain barrier, the placenta, and is secreted in breast

milk (Kumar et al., 1990). Individuals exposed to marijuana prenatally generally suffer

from poor executive function, working memory, poor attention span, and altered

acoustic profiles of their cries (Eyler & Behnke, 1999; Fried et al., 1998). In rodents,

THC administered to pregnant dams increases reabsorption of pups, and perinatal

exposure has been shown to decrease binding capabilities of dopamine receptors.

Most striking in its effect is the demasculinization of male rats pre- or perinatally

exposed to THC. This could be due to the interaction THC has on GnRH and

therefore decreased circulating testosterone during development (Kumar et al., 1990).

Imaging studies show functional abnormalities in individuals with THC dependence

in the orbitofrontal cortex, insula, basal ganglia, anterior cingulate, with men showing

greater activation in left brain regions while women show more activation in right

brain regions (Franklin et al., 2002; Li, Kemp, Milivojevic, & Sinha, 2005).

14.3.1.4 Cocaine
According to the National Institute on Drug Abuse, cocaine use has fallen in 2017

compared to 2007, with 1.5 million individuals 12 years of age or older reporting as

400 The Neurobiology of Brain and Behavioral Development

current users (NIDA, 2015). Cocaine is highly addictive and individuals that have

been abstinent show enhanced sensitivity to stress-induced drug/alcohol cue-related

responses. Fox et al. (2006) showed that cocaine-dependent women have increased

anxiety and negative emotion, along with increases in blood pressure when compared

to men. Cocaine- dependent men have greater variability in psychological and physi-

ological responses (Fox et al., 2006). Researchers have shown that during the first 28

days of cocaine abstinence, women have significantly higher levels of cortisol and pro-

gesterone indicating possible changes to the HPA axis (Sinha et al.,

2007).

Prenatal exposure to cocaine in rodents causes feminization of male genitalia.

Vathy, Katay, and Mini (1993) found a significantly shorter ano-genital distance in

male rat pups, while females remained unaffected. In adulthood, female rats prenatally

exposed to cocaine showed an overall decrease in sexual behavior, while the exposed

males had increased mounting and intromission behaviors. Anatomically, there were

increases in dopamine and norepinephrine in males in the preoptic area, whereas no

differences were found in the females (Vathy et al., 1993).

14.3.2 Diet
Diet is important for overall health and proper development. Maternal and infant

diet play a role in hormone levels in the mother, which in turn has an effect on the

developing fetus, but formula choices may interfere with infant hormone levels. For

example, there has been a major switch in Canada to use soy-based formula, around

20% in 1998. Soy-based formulas contain phytoestrogens; these compounds have

estrogen like activity (although weakly so) and may provide doses of 4�11 mg/kg in

infants consuming soy-based products. This dose range is much higher than that

incurred by traditional Japanese diets (1 mg/kg; “Concerns for the use of soy-based

formulas in infant nutrition.” 2009). These elevated doses may have effects on the

developing male infant. Sharpe et al. (2002) found that when comparing marmoset

monkeys hand fed with either soy-based formula or standard cow-based formula,

males on the soy diet had significantly decreased testosterone levels. This demon-

strates the importance of infant diet on development as it can disturb sex hormone

production and/or function, thus leading to changes in the masculinization or femi-

nization of the brain.

The maternal diet plays an important role in the development of the fetus and in

the newborn infant through nursing. Low-protein diets during pregnancy in rats result

in females that have lower birth weights, and both male and female offspring that

become obese in adulthood. Protein restriction after birth slowed the growth of both

male and female offspring (Zambrano et al., 2006). Maternal obesity has been linked

with lowered sperm counts and decreased sperm quality in male offspring. It has been

hypothesized that maternal obesity results in increased fetal exposure to estrogens and

Hormones and Development 401

this may account for the sperm effects reported in this study (Ramlau-Hansen et al.,

2007).

14.3.3 Environmental contaminants
14.3.3.1 Bisphenol A
Bisphenol A (BPA) is used in the manufacturing of plastics and epoxy resins.

Estimates on the amount of BPA used each year are upwards of 8 billion pounds,

100 tons of which may be released into the atmosphere (Vandenberg et al., 2010).

BPA is a known endocrine disruptor and in the 1930s it was studied for its potential

use as a synthetic estrogen. It binds both nuclear and plasma membrane bound estro-

gen receptors and can be found in detectable levels in urine, blood, amniotic fluid,

placenta, and breast milk. The greater the exposure to BPA, the more severe the

resulting symptoms (Maffini, Rubin, Sonnenschein, & Soto, 2006). In adolescents,

studies have linked exposure of BPA to altered time of puberty, altered estrous cycles,

prostate changes, and altered mammary gland development. BPA exposure in adults is

linked to diabetes and cardiovascular disease. In women, increased exposure is corre-

lated with recurrent miscarriages, and in men exposure is linked to decreased semen

quality and sperm DNA damage (Rubin, 2011). With the substantial perturbations to

the heath and development observed in children and adults, exposure during the pre-

natal period may be more deleterious. BPAs may have permanent organizational

effects on the developing fetus. Mean BPA levels reports indicate that children have

the highest amount of BPA in their urine as compared to adolescents who have higher

levels than adults. This observation is important as it shows that exposure is increasing

and that the younger generation is more at risk (Vandenberg et al., 2010).

14.3.3.2 Polychlorinated biphenyls
Although the use of polychlorinated biphenyls (PCBs) has been banned, this class of

contaminants has a long half-life and is still found in high levels in the environment.

PCBs are fat-soluble and are therefore biomagnified through the food chain, with

humans at the top. PCBs are readily transferred to newborns through lactation. The

structural similarities of PCBs to thyroid hormones cause a decrease in circulating

thyroid hormones in the body through negative feedback loops. This decrease has

implications for brain development including consequences on cognitive function,

behavioral responses, and decreased brain weights in rodents. PBCs have been corre-

lated with early menarche, abnormal menstrual cycles, increased incidence of endo-

metriosis, spontaneous abortion, fetal death, premature delivery, and low birth

weights (Leon-Olea et al., 2014). In men, PCBs have been shown to decrease sperm

motility, and to cause sex reversal (male to female) in some animal species with prena-

tal exposure (Guillette, Crain, Rooney, & Pickford, 1995). More subtly, PCB expo-

sure has been shown to masculinize or defeminize the female hypothalamus whereas

402 The Neurobiology of Brain and Behavioral Development

in males it has been shown to feminize or demasculinize the hypothalamus (Gore,

Martien, Gagnidze, & Pfaff, 2014). Depending on the chemical makeup of the PCB,

either an antagonistic or agonistic effect on androgen, progesterone, and estrogen

receptors can result therefore confirming the mixed effects observed in both males

and females (Hammers et al., 2006).

14.4 SEX DIFFERENCES IN THE BRAIN

As previously discussed, the sex chromosomes have a large impact on sexual dimor-

phism via the expression of more genes in X-linked gene dosing, as well as the inter-

actions between genes and hormone production. Here, we will discuss sex differences

observed in the brain and the mechanisms that may account for these

differences. Finally, we will delve into the implications these differences have on sex

differences observed in individuals with neurological disorders.

14.4.1 Anatomical differences
A meta-analysis performed by Ruigrok et al. (2014) looked at sex differences in brain

structures reported in the literature since 1990. The Ruigrok study found that overall

males are reported to have larger brain volumes by between 8% and 13%. With regard

to specific brain regions, males appear on average, to have more gray matter in the

bilateral amygdalae, hippocampi, putamen, and temporal poles. In addition, the left

posterior and anterior cingulate gyri and multiple areas in the cerebellum were larger

in males than females. Females, on the other hand, were found to have larger volumes

at the right frontal pole, inferior and middle frontal gyri, anterior cingulate gyrus, pla-

num temporale/parietal operculum, insular cortex, and Heschl’s gyrus. In addition,

the bilateral thalami, precuneus, left parahippocampal gyrus, and lateral occipital cor-

tex are reported to be larger in females (Ruigrok et al., 2014).

14.4.1.1 Sex differences in brain maturation
It is well documented that as humans age, their brain develops and matures. Neurons

begin developing in the prenatal period and as a child experiences the world they

begin making synapses. Once puberty begins the number of neurons and synapses

decrease remarkably. A loss of 100,000 synapses per second (synaptic pruning) is esti-

mated to occur in adolescence. The last phase of brain development is the maturation

and myelination of the brain, specifically the cortex. This process continues until at

least 30 years of age (Kolb & Whishaw, 2015). Although this process is standard in all

humans, sex differences are apparent. Females show more rapid brain growth than

their male counterparts and attain their maximum brain volume about 5 years earlier.

Myelination of the brain requires more time to complete in males relative to females

(Lenroot, Gogtay, & Greenstein, 2007). These results suggest that behavioral

Hormones and Development 403

development in males should also show delay in some domains and that brain plastic-

ity associated with development persists over a longer time period in males.

There is evidence of sex-specific changes to brain regions during brain maturation.

A larger increase in hippocampal and striatal volume in females, and a larger increase

in amygdala volume in males, this is thought to result from the activational effects

brought on by the changes in hormones levels during puberty. In parallel, it has been

shown that in primates that there are more androgen receptors in the amygdala and

more estrogen receptors in the hippocampus (Neufang et al., 2009).

Finally, in a diffusion tensor imaging study published in 2013 with more than 400

participants of each sex, it was noted that sex differences arise in brain connectivity

with maturation. Adult females show greater interhemispheric connectivity than males

whereas males show greater intrahemispheric connectivity than females (Fig. 14.2).

These differences were not observed in children, adolescents, or even young adults.

As a consequence, males demonstrate enhanced spatial processing, sensorimotor speed

and a more modular brain, whereas females show enhanced attention, word and face

memory, and a more integrated brain. Overall, these findings suggest that males are

likely to complete a task in progress before moving on to another. In contrast, females

are multitaskers (Ingalhalikar et al., 2013).

14.4.2 Biological differences
Although sex chromosomes play a huge role in sexual differentiation, they are not the

only genetic factor affecting sexual differentiation. In a recent study analyzing over

1100 postmortem brain samples from various brain regions (frontal cortex, occipital

cortex, temporal cortex, intralobular white matter, hypothalamus, medulla, cerebral

Figure 14.2 Sex differences in brain connectivity: (A) male and (B) female brain. From Kolb, B.,
Teskey, G.C., & Whishaw, I.Q. (2016). An introduction to brain and behavior. NY: Worth Publishers.

404 The Neurobiology of Brain and Behavioral Development

cortex, and spinal cord), originating from 137 individuals, it was discovered that 448

genes (2.6%) of the total genes expressed in the human central nervous system are dif-

ferentially expressed based on sex (Trabzuni et al., 2013). Of these differentially

expressed genes, over 85% were detected based on sex-biased splicing. Splicing is a

posttranslational modification process where introns are removed from immature

mRNA and the exons are then spliced back together to create the mature mRNA

(Roy & Gilbert, 2006). This suggests that on top of gene differences, the mechanisms

underlying the production of proteins are also different between the sexes. Most

notable is the finding from Trabzuni et al. (2013) that 95% of genes with sex-biased

splicing and 34% of genes with sex-biased expression were mapped to autosomes.

This demonstrates that not all sex differences observed in the brain are due to differ-

ences in sex chromosomes alone. It appears that the other chromosomes are also

important for observed differences.

14.4.2.1 Sex differences in HPA axis regulation
The HPA axis is an important signaling cascade used to maintain homeostasis in living

organisms. The HPA axis is designed to regulate internal and external stressors

through the use of various hormones. The response starts in the hypothalamus with

the release of corticotropin-releasing hormone (CRH), which acts on the pituitary to

release adrenocorticotropic hormone (ACTH). ACTH then stimulates the release of

adrenal glucocorticoids into the blood stream, which creates the body’s stress response.

Finally, glucocorticoids act as negative feedback messengers in the brain to dissipate

the stress response (Young, Korszun, Figueiredo, Banks-Solomon, & Herman, 2008).

Animal studies of the development of the HPA axis have provided insight into the

importance of the hypothalamic�pituitary�gonadal (HPG) axis and subsequent sex

differences. A persistent observation is that female rats have a significantly higher

response to stress, and therefore increased corticosterone secretion after stress, com-

pared to males (Panagiotakopoulos & Neigh, 2014). It has been shown that male rats

castrated after birth and reared under normal conditions, when supplemented with

testosterone in adulthood show female typical patterns in response to stressors. This

suggests that testosterone may have an organizational effect on the development of the

HPA axis.

In the human literature, sex differences in the HPA axis appear during develop-

ment with the interaction between the HPA axis and the HPG axis. CRH has an

inhibitory impact on the HPG axis directly (acts on specific brain structures) and indi-

rectly (acts on neurotransmission), and has been shown to decrease testosterone levels

in men and inhibit ovulation in females. And in a reciprocal fashion, the HPG axis

can modulate CRH. For example, estrogen has been shown to increase transcription

of the CRH gene whereas androgens have been shown to downregulate CRH gene

transcription (Panagiotakopoulos & Neigh, 2014). Dahl et al. (1992) found that

Hormones and Development 405

prepubescent boys and girls differ in their HPA axis response, with boys reaching

higher peak values of cortisol 30 minutes later after CRH infusion than girls. In a

study done with adults, response to CRH resulted in a greater increase in cortisol

levels in women compared to men, suggestive of “activational” sex differences in the

postpuberty period (Born, Ditschuneit, Schreiber, Dodt, & Fehm, 1995). To further

the evidence of “organizational” effects on the HPA axis, Heim, Newport, Mletzko,

Miller, and Nemeroff (2008) looked at early life stressors (for more information on

early life stressors see Chapter 16: Socioeconomic Status) and found that women with

childhood stress had an increased ACTH response to stress as adults compared to con-

trols. Men with childhood stress, on the other hand, had increased cortisol levels in

response to stress as an adult (Heim et al., 2008).

14.4.3 Differences in immunity
Microglial cells comprise the brain’s immune system and play a critical role in the

brain during injury, degeneration, and chronic stress (Ajami et al., 2007). More

recently, research has uncovered other roles for microglia in the brain including

plasticity, neurogenesis, apoptosis, and most notable for this discussion, sexual differen-

tiation of the brain (Nimmerjahn, Kirchhoff, & Helmchen, 2005; Sierra et al., 2010;

Lenz, Nugent, Hailyur, & McCarthy, 2013). During development, microglia begin

populating the brain and by birth in rodents, there are already significant sex differ-

ences in the number and morphology of microglia in various areas of the brain

(preoptic area, hippocampus, parietal cortex, and amygdala). For example, in the pre-

optic area the microglia in the male brain have larger cell body size and a decrease in

process length and branching when compared to females (Lenz & McCarthy, 2015).

The roles of microglia in the immature brain differ significantly from those attributed

to microglia in the mature brain (injury or inflammation response), and these func-

tional differences are thought to support the developing brain (Lenz et al., 2013).

Research has shown that microglia regulate processes that are critical for development

including synapse elimination, spinogenesis, and spine elimination (Tremblay et al.,

2011). Lenz et al. (2013) found that treating 2-day-old female rats with estradiol (the

precursor to testosterone) led to complete masculinization of microglial expression.

This finding adds to previous findings showing that microglia are critical for sex-

specific development.

14.4.4 Sex differences in behavior
It is not far-fetched to believe that with all the sex differences reported in the brain

and its development, sex differences exist in behavior. There is compelling evidence

for sex differences in at least five cognitive domains; verbal abilities, spatial analysis,

motor skills, mathematical aptitude, and perception. In regards to verbal fluency and

406 The Neurobiology of Brain and Behavioral Development

memory, women are superior. It has long been known that girls begin talking before

boys and this may contribute to the observed sex differences (Wallentin, 2009).

However, when comparing spatial abilities men outperform women on mental rota-

tion, spatial navigation, and geographical knowledge, while women are better at spa-

tial memory (McBurney, Gaulin, Devineni, & Adams, 1997; Voyer & Voyer, 1995).

There seems to be a mix of sex differences when it comes to motor skills; with men

being better at throwing and catching and women being better at fine motor skills

(Hall & Kimura, 1995; Nicholson & Kimura, 1996). The same is seen with mathe-

matical abilities, where females are better at computation and males better at mathe-

matical reasoning (Hyde, Fennema, & Lamon, 1990). Lastly, when it comes to

perception, females seem to have an advantage over males to sensory stimuli (having a

lower threshold), sensory speed (faster detection), noticing subtle body and facial cues,

and better recognition memory (Kolb & Whishaw, 2015).

14.5 CONCLUSION

The developing brain is remarkable and the processes behind its development are

complex. Although the organizational/activational theory originally proposed by

Phoenix and colleagues still holds true today, much has been added to expand and

understand this phenomenon. As shown, the sex differences seen in humans are a

complex interaction between, not only, the sex chromosomes but dimorphic gene

expression, sex hormones, and the prenatal and perinatal environment. Environmental

contaminants, drugs, and diet can interfere with typical development. In addition, sex

differences that arise in response to trauma, addiction, and social influences are well

described (see Chapter 16: Socioeconomic Status for more details).

REFERENCES
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W., & Rossi, F. M. (2007). Local self-renewal can sustain

CNS microglia maintenance and function throughout adult life. Nature Neuroscience, 10, 1538�1543.
Allen, A. M., Oncken, C., & Hatsukami, D. (2014). Women and smoking: The effect of gender on the

epidemiology, health effects, and cessation of smoking. Current Addiction Reports, 1, 53�60.
Arnold, A. P. (2009). The organizational-activational hypothesis as the foundation for a unified theory of

sexual differentiation of all mammalian tissues. Hormones and Behavior, 55, 570�578.
Bojesen, A., Juul, S., & Gravholt, C. H. (2003). Prenatal and postnatal prevalence of Linefelter syndrome:

A national registry study. Journal of Clinical Endocrniology and Metabolism, 88, 622�626. Available from
http://dx.doi.org/10.1210/jc.2002-021491.

Born, J., Ditschuneit, I., Schreiber, M., Dodt, C., & Fehm, H. L. (1995). Effects of age and gender on
pituitary�adrenocortical responsiveness in humans. European Journal of Endocrinology, 132(6),
705�711.

Carruth, L. L., Reisert, I., & Arnold, A. P. (2002). Sex chromosome genes directly affect grain sexual
differentiation. Nature Neuroscience, 5(10), 933�934. Available from http://dx.doi.org/10.1038/
nn922.

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref101

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref1

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref2

http://dx.doi.org/10.1210/jc.2002-021491

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref3

http://dx.doi.org/10.1038/nn922

Hormones and Development 407

Centeno, M. L., Henderson, J. A., Pau, K. Y. F., & Bethea, C. L. (2006). Estradiol increases alpha7
nicotinic receptor in serotonergic dorsal raphe and noradrenergic locus coeruleus neurons of maca-
ques. Journal of Comparative Neurology, 497, 489�501.

Center for Behavioral Health Statistics and Quality. (2016). 2015 National survey on drug use and health:
Detailed tables. Substance Abuse and Mental Health Services Administration, Rockville, MD.

Centers for Disease Control and Prevention. (2016). Current cigarette smoking among adults—United
States, 2005�2015. Morbidity and Mortality Weekly Report.

Cheng, C. Y., & Mruk, D. D. (2010). The biology of spermatogenesis: The past, present and future.
Philosophical Transactions of the Royal Society B—Biological Sciences, 365(1546), 1459�1463.

Cohen-Bendahan, C. C., van de Beek, C., & Berenbaum, S. A. (2005). Prenatal sex hormone effects on
child and adult sex-typed behavior: Methods and findings. Neuroscience and Biobehavioral Reviews, 29,
353�384.

Concerns for the use of soy-based formulas in infant nutrition (2009). Paediatrics & Child Health, 14(2),
109�113.

Cross, S. J., Linker, K. E., & Leslie, F. M. (2017). Sex-dependent effects of nicotine on the developing
brain. Journal of Neuroscience Research, 95(1�2), 422�436. Available from http://dx.doi.org/10.1002/
jnr.23878.

Dahl, R. E., Siegel, S. F., Williamson, D. E., Lee, P. A., Perel, J., Birmaher, B., & Ryan, N. D. (1992).
Corticotropin releasing hormone stimulation test and nocturnal cortisol levels in normal children.
Pediatric Research, 32(1), 64�68.

Davies, W., Isles, A. R., Burgoyne, P. S., & Wilkinson, L. S. (2006). X-linked imprinting: Effects on
brain and behaviour. BioEssays, 28, 35�44.

Davies, W., & Wilkinson, L. S. (2006). It is not all hormones: Alternative explanations for sexual differ-
entiation of the brain. Brain Research, 1126, 36�45.

Dewing, P., Chiang, C. W. K., Sinchak, K., Sim, H., Fernagut, P.-O., Kelly, S., . . . Vilain, E. (2006).
Direct regulation of adult brain function by the male-specific factor SRY. Current Biology, 16(4),
415�420. ,http://dx.doi.org/10.1016/j.cub.2006.01.017..

Dwyer, J. B., McQuown, S. C., & Leslie, F. M. (2009). The dynamic effects of nicotine on the develop-
ing brain. Pharmacology & Therapeutics, 122(2), 125�139. ,http://dx.doi.org/10.1016/j.pharmthera.
2009.02.003..

Ehrhardt, A. A., & Meyer-Bahlburg, H. F. L. (1979). Prenatal sex hormones and the developing brain:
Effects on psychosexual differentiation and cognitive function. Annual Review of Medicine, 30,
417�430.

Ernst, M., Moolchan, E. T., & Robinson, M. L. (2001). Behavioral and neural consequences of prenatal
exposure to nicotine. Journal of the American Academy of Child & Adolescent Psychiatry, 40(6), 630�641.
Available from http://dx.doi.org/10.1097/00004583-200106000-00007.

Eyler, F. D., & Behnke, M. (1999). Early development of infants exposed to drugs prenatally. Clinics in
Perinatology, 26(1), 107�150.

Fox, H. C., Garcia, M., Kemp, K., Milivojevic, V., Kreek, M. J., & Sinha, R. (2006). Gender differences
in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individual.
Psychopharmacology, 185, 348�357.

Franklin, T. R., Acton, P. D., Maldjian, J. A., Gray, J. D., Croft, J. R., Dackis, C. A., & Childress, A. R.
(2002). Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal
cortices of cocaine patients. Biological Psychiatry, 51(2), 134�142. Available from http://dx.doi.org/
10.1016/S0006-3223(01)01269-0.

Fried, P. A., Watkinson, B., & Gray, R. (1998). Differential effects on cognitive functioning in 9- to
12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratology, 20(3),
293�306. ,http://dx.doi.org/10.1016/S0892-0362(97)00091-3..

Gangitano, D., Salas, R., Teng, Y., Perez, E., & De Biasi, M. (2009). Progesterone modulation of alpha5
nAChR subunits influences anxiety-related behavior during estrus cycle. Genes, Brain and Behavior, 8,
398�406.

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref5

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref6

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref7

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref8

http://dx.doi.org/10.1002/jnr.23878

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref10

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref11

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref12

http://dx.doi.org/10.1016/j.cub.2006.01.017

http://dx.doi.org/10.1016/j.pharmthera.2009.02.003

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref15

http://dx.doi.org/10.1097/00004583-200106000-00007

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref17

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref18

http://dx.doi.org/10.1016/S0006-3223(01)01269-0

http://dx.doi.org/10.1016/S0892-0362(97)00091-3

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref21

408 The Neurobiology of Brain and Behavioral Development

Gore, A. C., Martien, K. M., Gagnidze, K., & Pfaff, D. (2014). Implications of prenatal steroid perturba-
tions for neurodevelopment, behavior, and autism. Endocrine Reviews, 35(6), 961�991. Available
from http://dx.doi.org/10.1210/er.2013-1122.

Guillette, L. J., Crain, D. A., Rooney, A. A., & Pickford, D. B. (1995). Organization versus activation:
The role of endocrine-disrupting contaminants (EDCs) during embryonic development in wildlife.
Environmental Health Perspectives, 103(Suppl 7), 157�164.

Gustavson, K. H. (1999). Triple X syndrome deviation with mild symptoms. The majority goes undiag-
nosed. Lakartidningen, 96(50), 5646�5647.

Hall, J. A. Y., & Kimura, D. (1995). Sexual orientation and performance on sexually dimorphic motor
tasks. Archives of Sexual Behavior, 24(4), 395�407. Available from http://dx.doi.org/10.1007/
bf01541855.

Hamers, T., Kamstra, J. H., Sonneveld, E., Murk, A. J., Kester, M. H. A., Andersson, P. L., . . . Brouwer,
A. (2006). In vitro profiling of the endocrine-disrupting potency of brominated flame retardants.
Toxicological Sciences, 92(1), 157�173. Available from http://dx.doi.org/10.1093/toxsci/kfj187.

Hampson, E., Rovet, J. F., & Altmann, D. (1998). Spatial reasoning in children with congenital adrenal
hyperplasia due to 21-hydroxylase deficiency. Developmental Neuropsychology, 14(2�3), 299�320.

Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2008). The link between
childhood trauma and depression: Insights from HPA axis studies in humans. Psychoneuroendocrinology,
33(6), 693�710. ,http://dx.doi.org/10.1016/j.psyneuen.2008.03.008..

Hughes, I. A., & Deeb, A. (2006). Androgen resistance. Best Practice & Research Clinical Endocrinology &
Metabolism, 20(4), 577�598. Available from http://dx.doi.org/10.1016/j.beem.2006.11.003.

Hyde, J. S., Fennema, E., & Lamon, S. J. (1990). Gender differences in mathematics performance: A
meta-analysis. Psychological Bulletin, 107(2), 139�155.

Imperato-McGlnley, J., Plchardo, M., Gautier, T., Voyer, D., & Bryden, M. P. (1991). Cognitive abilities
in androgen-insensitive subjects: Comparison with control males and females from the same kindred.
Clinical Endocrinology, 34(5), 341�347. Available from http://dx.doi.org/10.1111/j.1365-2265.1991.
tb00303.x.

Itti, E., Gonzalo, I. T. G., Pawlikowska-Haddal, A., Boone, K. B., Mlikotic, A., Itti, L., . . . Swerdloff,
R. S. (2006). The structural brain correlates of cognitive deficits in adults with Klinefelter’s syn-
drome. The Journal of Clinical Endocrinology & Metabolism, 91(4), 1423�1427. Available from http://
dx.doi.org/10.1210/jc.2005-1596.

Ingalhalikar, M., Smith, A., Parker, D., Satterthwaite, P. D., Elliot, M. A., Ruparel, K., et al. (2013). Sex
differences in the structural connectome of the human brain. Proceedings of the National Academy of
Sciences of the United States of America, 111, 823�828.

Iwasa, Y., & Pomiankowski, A. (2001). The evolution of X-linked genomic imprinting. Genetics, 158,
1801�1809.

Jin, X., & Steinbach, J. H. (2015). Potentiation of neuronal nicotinic receptors by 17b-estradiol: Roles of
the carboxy-terminal and the amino-terminal extracellular domains. PLoS ONE, 10, e0144631.

Jornda, G., Deeb, S. S., Bosten, J. M., & Mollon, J. D. (2010). The dimensionality of color vision in car-
riers of anomalous trichromacy. Journal of Vision, 10(8), 1�19.

Ke, L., & Lukas, R. (1996). Effects of steroid exposure on ligand binding and functional activities of
diverse nicotinic acetyicholine receptor subtypes. Journal of Neurochemistry, 67, 1100�1112.

Kolb, B., Teskey, G. C., & Whishaw, I. Q. (2016). An introduction to brain and behavior. NY: Worth
Publishers.

Kolb, B., & Whishaw, I. Q. (2015). Fundamentals of Human Neuropsychology, (7th ed.). New York:
Worth Publishers.

Kumar, A. M., Haney, M., Becker, T., Thompson, M. L., Kream, R. M., & Miczek, K. (1990). Effect
of early exposure to δ-9-tetrahydrocannabinol on the levels of opioid peptides, gonadotropin-
releasing hormone and substance P in the adult male rat brain. Brain Research, 525(1), 78�83.
,http://dx.doi.org/10.1016/0006-8993(90)91322-8..

Leatherdale, S. T., Hammond, D., & Ahmed, R. (2008). Alcohol, marijuana, and tobacco use patterns
among youth in Canada. Cancer Causes & Control, 19(4), 361�369. Available from http://dx.doi.
org/10.1007/s10552-007-9095-4.

http://dx.doi.org/10.1210/er.2013-1122

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref23

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref24

http://dx.doi.org/10.1007/bf01541855

http://dx.doi.org/10.1093/toxsci/kfj187

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref27

http://dx.doi.org/10.1016/j.psyneuen.2008.03.008

http://dx.doi.org/10.1016/j.beem.2006.11.003

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref29

http://dx.doi.org/10.1111/j.1365-2265.1991.tb00303.x

http://dx.doi.org/10.1210/jc.2005-1596

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref32

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref33

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref34

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref35

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref36

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref37

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref38

http://dx.doi.org/10.1016/0006-8993(90)91322-8

http://dx.doi.org/10.1007/s10552-007-9095-4

Hormones and Development 409

Leon-Olea, M., Martyniuk, C. J., Orlando, E. F., Ottinger, M. A., Rosenfeld, C. S., Wolstenholme,
J. T., & Trudeau, V. L. (2014). Current concepts in neuroendocrine disruption. General and
Comparative Endocrinology, 203, 158�173. Available from http://dx.doi.org/10.1016/j.ygcen.2014.
02.005.

Lenroot, R. K., Gogtay, N., Greenstein, D. K., et al. (2007). Sexual dimorphism of brain development
trajectories during childhood and adolescence. NeuroImage, 36, 1065�1073.

Lenz, K. M., & McCarthy, M. M. (2015). A starring role for microglia in brain sex differences.
Neuroscientist, 21(3), 306�321. Available from http://dx.doi.org/10.1177/1073858414536468.

Lenz, K. M., Nugent, B. M., Haliyur, R., & McCarthy, M. M. (2013). Microglia are essential to mascu-
linization of brain and behavior. The Journal of Neuroscience, 33(7), 2761�2772. Available from
http://dx.doi.org/10.1523/JNEUROSCI.1268-12.2013.

Li, C. R., Kemp, K., Milivojevic, V., & Sinha, R. (2005). Neuroimaging study of sex differences in the
neuropathology of cocaine abuse. Gender Medicine, 2(3), 174�182. ,http://dx.doi.org/10.1016/
S1550-8579(05)80046-4..

Lovell-Badge, R., & Robertson, E. (1990). XY female mice resulting from a heritable mutation in the
primary testis-determining gene, Tdy. Development, 109, 635�646.

Maffini, M. V., Rubin, B. S., Sonnenschein, C., & Soto, A. M. (2006). Endocrine disruptors and repro-
ductive health: The case of bisphenol-A. Molecular and Cellular Endocrinology, 254�255, 179�186.
http://doi.org/10.1016/j.mce.2006.04.033.

May, K. M., Jacobs, P. A., Lee, M., Ratcliffe, S., Robinson, A., Nielsen, J., & Hassold, T. J. (1990). The
parental origin of the extra X chromosome in 47, XXX females. American Journal of Human Genetics,
46, 754�761.

McBurney, D. H., Gaulin, S. J. C., Devineni, T., & Adams, C. (1997). Superior spatial memory of
women: Stronger evidence for the gathering hypothesis. Evolution and Human Behavior, 18(3),
165�174. http://doi.org/10.1016/S1090-5138(97)00001-9.

McCarthy, M. M., & Arnold, A. P. (2011). Reframing sexual differentiation of the brain. Nature
Neuroscience, 14(6), 677�683. Available from http://dx.doi.org/10.1038/nn.2834.

Merke, D. P., & Bornstein, S. R. (2005). Congenital adrenal hyperplasia. The Lancet, 365(9477),
2125�2136.

Merke, D. P., Fields, J. D., Keil, M. F., Vaituzis, A. K., Chrousos, G. P., & Giedd, J. N. (2003). Children
with classic congenital adrenal hyperplasia have decreased amygdala volume: Potential prenatal and
postnatal hormonal effects. The Journal of Clinical Endocrinology & Metabolism, 88(4), 1760�1765.
Available from http://dx.doi.org/10.1210/jc.2002-021730.

Murphy, D. G. M., DeCarli, C., Daly, E., Haxby, J. V., Allen, G., McIntosh, A. R., . . . Powell, C. M.
(1993). X-chromosome effects on female brain: A magnetic resonance imaging study of Turner’s syn-
drome. The Lancet, 342(8881), 1197�1200. Available from http://dx.doi.org/10.1016/0140-6736
(93)92184-U.

Murphy, L. L., Muñoz, R. M., Adrian, B. A., & Villanúa, M. A. (1998). Function of cannabinoid recep-
tors in the neuroendocrine regulation of hormone secretion. Neurobiology of Disease, 5(6), 432�446.
Available from http://dx.doi.org/10.1006/nbdi.1998.0224.

Mychasiuk, R., Muhammad, A., Gibb, R., & Kolb, B. (2013). Long-term alterations to dendritic mor-
phology and spine density associated with prenatal exposure to nicotine. Brain Research, 1499,
53�60. Available from http://dx.doi.org/10.1016/j.brainres.2012.12.021.

Nass, R., & Baker, S. (1991). Learning disabilities in children with congenital adrenal hyperplasia. Journal
of Child Neurology, 6(4), 306�312. Available from http://dx.doi.org/10.1177/088307389100600404.

Neufang, S., Specht, K., Hausmann, M., Güntürkün, O., Herpertz-Dahlmann, B., Fink, G. R., &
Konrad, K. (2009). Sex differences and the impact of steroid hormones on the developing human
brain. Cerebral Cortex, 19(2), 464�473. Available from http://dx.doi.org/10.1093/cercor/bhn100.

Ngun, T. C., Ghahramani, N. M., Creek, M. M., Williams-Burris, S. M., Barseghyan, H., Itoh, Y., . . .
Vilain, E. (2014). Feminized behavior and brain gene expression in a novel mouse model of
Klinefelter syndrome. Archives of Sexual Behavior, 43(6), 1043�1057.

Nicholson, K. G., & Kimura, D. (1996). Sex differences for speech and manual skill. Perceptual and Motor
Skills, 82(1), 3�13. Available from http://dx.doi.org/10.2466/pms.1996.82.1.3.

http://dx.doi.org/10.1016/j.ygcen.2014.02.005

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref42

http://dx.doi.org/10.1177/1073858414536468

http://dx.doi.org/10.1523/JNEUROSCI.1268-12.2013

http://dx.doi.org/10.1016/S1550-8579(05)80046-4

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref44

http://doi.org/10.1016/j.mce.2006.04.033

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref46

http://doi.org/10.1016/S1090-5138(97)00001-9

http://dx.doi.org/10.1038/nn.2834

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref49

http://dx.doi.org/10.1210/jc.2002-021730

http://dx.doi.org/10.1016/0140-6736(93)92184-U

http://dx.doi.org/10.1006/nbdi.1998.0224

http://dx.doi.org/10.1016/j.brainres.2012.12.021

http://dx.doi.org/10.1177/088307389100600404

http://dx.doi.org/10.1093/cercor/bhn100

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref56

http://dx.doi.org/10.2466/pms.1996.82.1.3

410 The Neurobiology of Brain and Behavioral Development

Nieschlag, E., Werler, S., Wistuba, J., & Zitzmann, M. (2014). New approaches to the Klinefelter syn-
drome. Annales d’Endocrinologie, 75(2), 88�97. Available from http://dx.doi.org/10.1016/j.
ando.2014.03.007.

NIDA (2015). Nationwide trends. Retrieved March 24, 2017, from https://www.drugabuse.gov/publi-
cations/drugfacts/nationwide-trends.

Nijhuis-van der Sanden, M. W. G., Eling, P. A. T. M., & Otten, B. J. (2003). A review of neuropsycho-
logical and motor studies in Turner Syndrome. Neuroscience & Biobehavioral Reviews, 27(4), 329�338.

Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic sur-
veillants of brain parenchyma in vivo. Science, 308(13), 14�18.

O’Connor, M. J., & Paley, B. (2009). Psychiatric conditions associated with prenatal alcohol exposure.
Developmental Disabilities Research Reviews, 15, 225�234.

Otter, M., Schrander-Stumpel, C. T. R. M., & Curfs, L. M. G. (2009). Triple X syndrome: A review of
the literature. European Journal of Human Genetics, 18(3), 265�271.

Panagiotakopoulos, L., & Neigh, G. N. (2014). Development of the HPA axis: Where and when do sex
differences manifest? Frontiers in Neuroendocrinology, 35(3), 285�302. Available from http://dx.doi.
org/10.1016/j.yfrne.2014.03.002.

Phoenix, C. H., Goy, R. W., Gerall, A. A., & Young, W. C. (1959). Organizing action of prenatally
administered testosterone propionate on the tissues mediating mating behavior in the female guinea
pig. Endocrinology, 65, 369�382.

Piper, M. E., Cook, J. W., Schlam, T. R., Jorenby, D. E., Smith, S. S., Bolt, D. M., & Loh, W. Y.
(2010). Gender, race, and education differences in abstinence rates among participants in two ran-
domized smoking cessation trials. Nicotine and Tobacco Research, 6, 647�657.

Prokop, J. W., Underwood, A. C., Turner, M. E., Miller, N., Pietrzak, D., Scott, S., . . . Milsted, A.
(2013). Analysis of Sry duplications on the Rattus norvegicus Y-chromosome. BMC Genomics, 14, 15.
Available from http://dx.doi.org/10.1186/1471-2164-14-792.

Ramlau-Hansen, C. H., Nohr, E. A., Thulstrup, A. M., Bonde, J. P., Storgaard, L., & Olsen, J. (2007).
Is maternal obesity related to semen quality in the male offspring? A pilot study. Human Reproduction,
22(10), 2758�2762. Available from http://dx.doi.org/10.1093/humrep/dem219.

Raudrant, D., & Rabe, T. (2003). Progestogens with anitandrogenic properties. Drugs, 63(5), 463�492.
Reik, W., & Walter, J. (2001). Genomic imprinting: Parental influence on the genome. Nature Reviews

Genetics, 2, 21�32.
Roy, S. W., & Gilbert, W. (2006). The evolution of spliceosomal introns: Patterns, puzzles and progress.

Nature Reviews, 7, 211�221. Available from http://dx.doi.org/10.1038/nrg1807.
Rubin, B. S. (2011). Bisphenol A: An endocrine disruptor with widespread exposure and multiple

effects. The Journal of Steroid Biochemistry and Molecular Biology, 127(1�2), 27�34. http://doi.org/
10.1016/j.jsbmb.2011.05.002.

Ruigrok, A. N. V., Salimi-Khorshidi, G., Lai, M.-C., Baron-Cohen, S., Lombardo, M. V., Tait, R. J., &
Suckling, J. (2014). A meta-analysis of sex differences in human brain structure. Neuroscience &
Biobehavioral Reviews, 39, 34�50. Available from http://dx.doi.org/10.1016/j.neubiorev.2013.12.004.

Sharpe, R. M., Martin, B., Morris, K., Greig, I., McKinnell, C., McNeilly, A. S., & Walker, M. (2002).
Infant feeding with soy formula milk: Effects on the testis and on blood testosterone levels in mar-
moset monkeys during the period of neonatal testicular activity. Human Reproduction, 17(7),
1692�1703. Available from http://dx.doi.org/10.1093/humrep/17.7.1692.

Sierra, A., Encinas, J. M., Deudero, J. J. P., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., &
Maletic-Savatic, M. (2010). Microglia shape adult hippocampal neurogenesis through apoptosis-cou-
pled phagocytosis. Cell Stem Cell, 7(4), 483�495. Available from http://dx.doi.org/10.1016/j.
stem.2010.08.014.

Sinha, R., Fox, H., Hong, K.-I., Sofuoglu, M., Morgan, P. T., & Bergquist, K. T. (2007). Sex steroid
hormones, stress response, and drug craving in cocaine-dependent women: Implications for relapse
susceptibility. Experimental and Clinical Psychopharmacology, 15(5), 445�452. Available from http://dx.
doi.org/10.1037/1064-1297.15.5.445.

http://dx.doi.org/10.1016/j.ando.2014.03.007

https://www.drugabuse.gov/publications/drugfacts/nationwide-trends

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref58

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref107

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref59

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref60

http://dx.doi.org/10.1016/j.yfrne.2014.03.002

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref62

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref63

http://dx.doi.org/10.1186/1471-2164-14-792

http://dx.doi.org/10.1093/humrep/dem219

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref66

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref67

http://dx.doi.org/10.1038/nrg1807

http://doi.org/10.1016/j.jsbmb.2011.05.002

http://dx.doi.org/10.1016/j.neubiorev.2013.12.004

http://dx.doi.org/10.1093/humrep/17.7.1692

http://dx.doi.org/10.1016/j.stem.2010.08.014

http://dx.doi.org/10.1037/1064-1297.15.5.445

Hormones and Development 411

Skaletsky, H., Kuroda-Kawaguchi, T., Minx, P. J., Cordum, H. S., Hillier, L., Brown, L. G., . . . Page,
D. C. (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence
classes. Nature, 423, 825.

Skuse, D. H., James, R. S., Bishop, D. V. M., Coppin, B., Dalton, P., Aamodt-Leeper, G., . . . Jacobs,
P. A. (1997). Evidence form Turner’s syndrome of an imprinted X-linked locus affecting cognitive
functions. Nature, 387, 705�708.

Spencer, R. L., & Hutchison, K. E. (1999). Alcohol, aging, and the stress response. Alcohol Research &
Health, 23(4), 272�283.

Thanh, N. X., & Jonsson, E. (2010). Drinking alcohol during pregnancy: Evidence from Canadian
Community Health Survey 2007/2008. Journal of Population Therapeutics and Clinical Pharmacology, 17,
302�307.

Tong, V. T., Dietz, P. M., Morrow, B., D’Angelo, D. V., Farr, S. L., Rockhill, K. M., . . . Centers for
Disease Control and Prevention (2013). Trends in smoking before, during, and after pregnancy—
Pregnancy risk assessment monitoring system, United States, 40 sites, 2000�2010. MMWR
Surveillance Summaries, 62, 1�19.

Trabzuni, D., Ramasamy, A., Imran, S., Walker, R., Smith, C., Weale, M. E., & Ryten, M. (2013).
Widespread sex differences in gene expression and splicing in the adult human brain. Nature
Communications, 4, 1�7. Available from http://dx.doi.org/10.1038/ncomms3771.

Tremblay, M.-E., Stevens, B., Sierra, A., Wake, H., Bessis, A., & Nimmerjahn, A. (2011). The role of `

microglia in the healthy brain. The Journal of Neuroscience, 31(45), 16064�16069. Available from
http://dx.doi.org/10.1523/jneurosci.4158-, 11.2011

Uematsu, A., Yorifuji, T., Muroi, J., Kawai, M., Mamada, M., Kaji, M., & Nakahata, T. (2002). Parental
origin of normal X chromosomes in Turner syndrome patients with various karyotypes: Implications
for the mechanism leading to generation of a 45,X karyotype. American Journal of Medical Genetics,
111, 134�139.

Vandenberg, L. N., Chahoud, I., Heindel, J. J., Padmanabhan, V., Paumgartten, F. J. R., & Schoenfelder,
G. (2010). Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to
bisphenol A. Environmental Health Perspectives, 118(8), 1055�1070.

Vathy, I., Katay, L., & Mini, K. N. (1993). Sexually dimorphic effects of prenatal cocaine on adult
sexual-behavior and brain catecholamines in rats. Developmental Brain Research, 73(1), 115�122.
http://dx.doi.org/10.1016/0165-3806(93)90053-d.

Voyer, D., & Voyer, S. (1995). Magnitude of sex differences in spatial abilities: A meta-analysis and con-
sideration of critical variables. Psychological Bulletin, 117(2), 250�270.

Wallen, K. (2009). The organizational hypothesis: Reflections on the 50th anniversary of the publication
of Phoenix, Goy, Gerall, and Young (1959). Hormones and Behavior, 55(5), 561�565. Available from
http://dx.doi.org/10.1016/j.yhbeh.2009.03.009.

Wallentin, M. (2009). Putative sex differences in verbal abilities and language cortex: A critical review.
Brain and Language, 108(3), 175�183. http://doi.org/10.1016/j.bandl.2008.07.001.

Weinberg, J., Sliwowska, J. H., Lan, N., & Hellemans, K. G. C. (2008). Prenatal alcohol exposure:
Foetal programming, the hypothalamic�pituitary�adrenal axis and sex differences in outcome.
Journal of Neuroendocrinology, 20(4), 470�488. Available from http://dx.doi.org/10.1111/j.1365-
2826.2008.01669.x.

Wenzel, U., Schneider, M., Zachmann, M., Knorr-Murset, G., Weber, A., & Prader, A. (1978).
Intelligence of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, their
parents and unaffected siblings. Helvetica Paediatrica Acta, 33(1), 11.

White, P. C. (2009). Neonatal screening for congenital adrenal hyperplasia. Nature Reviews Endocrinology,
5, 490�499.

Wilson, W., Mathew, R., Turkington, T., Hawk, T., Coleman, R. E., & Provenzale, J. (2000). Brain
morphological changes and early marijuana use. Journal of Addictive Diseases, 19(1), 1�22. Available
from http://dx.doi.org/10.1300/J069v19n01_01.

Young, E. A., Korszun, A., Figueiredo, H. F., Banks-Solomon, M., & Herman, J. P. (2008). Sex differences
in HPA axis regulation. In J. B. Becker, K. J. Berkley, N. Geary, E. Hampson, J. P. Herman, & E. A.
Young (Eds.), Sex differences in the brain (pp. 95�105). New York, NY: Oxford University Press.

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref71

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref72

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref73

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref74

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref75

http://dx.doi.org/10.1038/ncomms3771

http://dx.doi.org/10.1523/jneurosci.4158-

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref76

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref77

http://dx.doi.org/10.1016/0165-3806(93)90053-d

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref79

http://dx.doi.org/10.1016/j.yhbeh.2009.03.009

http://doi.org/10.1016/j.bandl.2008.07.001

http://dx.doi.org/10.1111/j.1365-2826.2008.01669.x

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref83

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref84

http://dx.doi.org/10.1300/J069v19n01_01

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref86

412 The Neurobiology of Brain and Behavioral Development

Zambrano, E., Bautista, C. J., Deás, M., Martı́nez-Samayoa, P. M., González-Zamorano, M., Lesesma,
H., . . . Nathanielsz, P. W. (2006). A low maternal protein diet during pregnancy and lactation has
sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabo-
lism and serum leptin in the rat. The Journal of Physiology, 571(1), 221�230. Available from http://
dx.doi.org/10.1113/jphysiol.2005.100313.

Zuccarello, D., Ferlin, A., Vinanzi, C., Prana, E., Garolla, A., Callewaert, L., & Foresta, C. (2008).
Detailed functional studies on androgen receptor mild mutations demonstrate their association with
male infertility. Clinical Endocrinology, 68, 580�588. Available from http://dx.doi.org/10.1111/
j.1365-2265.2007.03069.x.

FURTHER READING
Cota, D. (2008). The role of the endocannabiniod system in the regulation of hypothala-

mic�pituitary�adrenal axis activity. Journal of Neuroendocrinology, 20, 35�38. Available from http://
dx.doi.org/10.1111/j.1365-2826.2008.01673.x.

Kirschbaum, C., Schommer, N., Federenko, I., Gaab, J., Neumann, O., Oellers, M., . . . Hellhammer,
D. H. (1996). Short-term estradiol treatment enhances pituitary�adrenal axis and sympathetic
responses to psychosocial stress in healthy young men. The Journal of Clinical Endocrinology &
Metabolism, 81, 3639�3643.

Reynolds, R. M., Hii, H. L., Pennell, C. E., McKeague, I. W., Kloet, E. R., Lye, S., . . . Foster, J. K.
(2013). Analysis of baseline hypothalamic�pituitary� adrenal activity in late adolescence reveals gen-
der specific sensitivity of the stress axis. Psychoneuroendocrinology, 38, 1271�1280.

Uban, K. A., Comeau, W. L., Ellis, L. A., Galea, L. A. M., & Weinberg, J. (2013). Basal regulation of
HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure
and chronic variable stress. Psychoneuroendocrinology, 38(10), 1953�1966. Available from http://dx.
doi.org/10.1016/j.psyneuen.2013.02.017.

http://dx.doi.org/10.1113/jphysiol.2005.100313

http://dx.doi.org/10.1111/j.1365-2265.2007.03069.x

http://dx.doi.org/10.1111/j.1365-2826.2008.01673.x

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref89

http://refhub.elsevier.com/B978-0-12-804036-2.00014-5/sbref90

http://dx.doi.org/10.1016/j.psyneuen.2013.02.017

14 Hormones and Development

14.1 Introduction

14.2 Genetic Factors Influencing Sexual Differentiation

14.2.1 Sex differences in gene expression

14.2.1.1 X-linked gene dosage

14.2.1.2 X-linked imprinting

14.2.1.3 Y-specific gene expression

14.2.2 Clinical populations

14.2.2.1 Triple X syndrome

14.2.2.2 Turner syndrome

14.2.2.3 Klinefelters syndrome

14.2.2.4 Congenital adrenal hyperplasia

14.2.2.5 Androgen insensitivity

14.3 Environmental Factors

14.3.1 Drugs

14.3.1.1 Nicotine

14.3.1.2 Alcohol

14.3.1.3 Marijuana

14.3.1.4 Cocaine

14.3.2 Diet

14.3.3 Environmental contaminants

14.3.3.1 Bisphenol A

14.3.3.2 Polychlorinated biphenyls

14.4 Sex Differences in the Brain

14.4.1 Anatomical differences

14.4.1.1 Sex differences in brain maturation

14.4.2 Biological differences

14.4.2.1 Sex differences in HPA axis regulation

14.4.3 Differences in immunity

14.4.4 Sex differences in behavior

14.5 Conclusion

References

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