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OCR for page 79
4
Sex Affects Behavior
and Perception
ABSTRACT
Basic genetic and physiological differences, in combination with environ-
mentaZ factors, result in behavioral and cognitive differences between males
and females. Sex differences in the brain, sex-typed behavior and gender
identity, and sex differences in cognitive ability should be studied at aZZ
points in the life span. Hormones play a role in behavioral and cognitive sex
differences but are not solely responsible for those differences. In addition,
sex differences in perception of pain have important clinical implications.
Research is needed on the natural variations between and within the sexes
in behavior, cognition, and perception, with expanded investigation of sex
differences in brain structure and function.
The purpose of this chapter is not to review all the evidence about the
nature and determinants of sex differences in behavior or any other char-
acteristic but to describe how basic genetic and physiological differences
between males and females might produce phenotypic differences
throughout the life span.
SEX DIFFERENCES IN BEHAVIOR AND COGNITIVE ABILITIES
Behavioral sex differences may originate in events that begin in the
womb. The fetal environment, particularly hormones present during de-
velopment, affects aspects of later behavioral and cognitive sex differ-
ences. Sex differences in behavior are important in their own right, but
79
OCR for page 80
80
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
also suggest ways in which prenatal influences can contribute to sex dif-
ferences in nonbehavioral traits, including those associated with health
and illness. The information presented in this section should not be inter-
preted to mean that all behavioral sex differences are caused by hormones
during prenatal development but, rather, should serve as an illustration
of the potential role of prenatal hormones in producing phenotypic sex
differences.
No single factor produces sex differences in any one behavioral or
cognitive trait, let alone in all of them. Until recently, it has been popular
to focus on cultural or experiential causes of these differences. Thus, for
example, sex differences in the occurrence of depression have been con-
sidered to reflect women's greater social orientation (which is itself as-
sumed to be cultural) or stresses associated with women's multiple social
roles (as also mentioned in Chapter 3~. In the past 10 years, however,
there has been increasing appreciation of the fact that genetic and physi-
ological differences between males and females might also influence be-
havioral sex differences. Although some might argue that the pendulum
has swung too much in favor of genes and physiology (Fausto-Sterling,
2000), there is considerable interest in examining the joint effects of genes,
physiology, and experiences. In particular, there is recognition that the
environment is not independent of the individual (Scarr and McCartney,
1983~. Individuals actively construct their environments and are re-
sponded to by others in their environments. The effects of imposed envi-
ronments are not the same for everyone. When one considers sex differ-
ences, one must also remember that females and males "inhabit" different
cultures and that some behavioral sex differences are more marked when
people are in social groups than when they are alone. Thus, questions
about sex differences concern not just differences between individual
males and females but also differences between male and female cultures
(Maccoby, 1998~.
Psychosexual Differentiation
Studies with nonhuman vertebrate species suggest that the sexual
role adopted at maturity is determined by the hormonal environment in
early life. As for other aspects of sex differentiation, there appears to be a
predisposition for individuals to develop female sexual postures. The de-
velopment of male patterns of sexual behavior in nonhuman species is
influenced to a large extent by exposure to androgens in particular, tes-
tosterone during the prenatal and perinatal periods. This organizing ca-
pacity of testosterone administered at a critical stage of development has
been localized to specific areas of the brain. Sexually dimorphic organiza-
tions of target cell nuclei detected during behavior-related events in other
species are the result of local aromatization (conversion) of testosterone to
OCR for page 81
SEX AFFECTS BEHAVIOR AND PERCEPTION
81
estradiol in the central nervous systems of these species. In humans, mas-
culinization of the central nervous system does not appear to result from
aromatized estradiol but appears to result from forms of testosterone
(Grumbach and Auchus, 1999~.
Sex Differences in the Central Nervous System and Brain
Sex differences in the central nervous system extend beyond func-
tions and structures traditionally associated with reproduction. These dif-
ferences might be better understood if they were studied in the context of
new and exciting conceptualizations of how the brain works, which en-
compass notions of lifelong plasticity, ensemble processing and distrib-
uted networks, and the brain's role as an endocrine organ.
The classic examples of sex differences in the brain involve neuroana-
tomical differences that are developmentally programmed. In several spe-
cies, sex differences in the patterns of synaptic innervation are observed
in the preoptic area and are influenced by the perinatal hormone environ-
ment but not by hormonal conditions in the adult animal (Gorski et al.,
1978; Nottebohm and Arnold, 1976; Raisman and Field, 1971~. These early
studies reveal the effects of castration of males and the administration of
testosterone to females early in development and established the idea that
differences in the wiring of the brain are programmed at birth. There are
now many documented sex differences in a wide range of species, includ-
ing primates (Forger, 1998~. In canaries and zebra finches, for example,
differences in singing behavior between males and females have been
correlated with differences in the sizes of three vocal control areas in the
brain (Nottebohm and Arnold, 1976), but, importantly, the young male
bird must hear the adult male song to initiate its own repertoire.
There are also sex differences in the human brain, including the higher
cognitive centers. These differences have been observed in adults, and the
nature and origins of these differences are subjects of active investigation.
Recent studies suggest sex differences in brain structure size as the brain
develops in children (Giedd et al., 1987; Lange et al., 1997~. It is important
to remember that these differences are not absolute and that it is currently
not possible, nor may it ever be, to look at a brain or a brain image and
know the sex of its owner.
The principles that have emerged from studies with nonhuman spe-
cies have generally been confirmed in humans, although differences in
details exist. For example, androgens act as masculinizing agents in all
species, but they appear to do so through different metabolites. Another
important principle that has emerged from studies with animals and that
has been confirmed in humans is that the central nervous system remains
plastic throughout the life span. Finally, former notions that discrete brain
regions have specific and static functions have been modified by work on
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EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
ensemble neuronal activity (Laubach et al., 2000) and distributed net-
works (Sanes and Donoghue, 2000~.
Areas that have not been traditionally thought to be sexually dimor-
phic may be involved in sexually dimorphic behavior. Some examples are
(1) dopamine functions within the striatum and nucleus accumbens
(Becker, 1999~; (2) the responsiveness of neurons in the gracile nucleus to
stimulation of skin and pelvic organs (Bradshaw and Berkley, 2000) (neu-
ronal responsiveness and activity in the two regions vary with the estrous
cycle and hormonal manipulation in a manner that correlates with lordo-
sis and other reproductive behaviors; and (3) modulation of functions in
the hippocampus, inferior olive, and cerebellum (Smith et al., 2000~.
The Brain as an Endocrine Organ
A great deal of evidence indicates that the brain functions as an endo-
crine (hormone-secreting) organ. Throughout life, there are profound sex
differences in the brain's responsiveness to sex hormones, some of which
are established early in development and which have implications for
later behavior, including cognitive function.
The brain is also involved in the regulation of other hormones that
show sex differences and that are involved in both reproductive and non-
reproductive behaviors. For example, aggression in male mice is consid-
erably more intense than that in female mice, and this difference is known
to be influenced by testosterone. Recent studies suggest that the story
may be more complex. Nitric oxide, a compound that participates in cell-
to-cell signaling, may be involved. The neural form of nitric oxide is mea-
sured by changes in nitric oxide synthase (nNOS) and plays an important
role in the expression of aggressive behavior in males (Nelson, 1997~. This
was discovered when nNOS knockout mice were created, and informal
observations indicated that nNOS -/- male mice (where -/- indicates the
absence of the gene on both chromosomes) were hyperaggressive but that
female nNOS knockout mice were not (Nelson et al., 1995~. Inappropriate
aggressiveness was never observed among the nNOS -/- female mice.
When given an opportunity to defend their pups, nNOS -/- mice were
very docile, unlike their wild-type sisters. These studies suggest that ni-
tric oxide from neurons has important but opposite effects in the media-
tion of aggression in male and female mice (Nelson and Chiavegatto,
2000~.
In the rat brain, the ventromedial hypothalamus is important in the
regulation of reproductive behavior such as lordosis. The estrogen-induc-
ible progesterone receptors in the ventromedial nucleus appear to play a
role (Parsons et al., 1984; Schumacher et al., 1992~. Estrogens have also
been shown to induce receptors for oxytocin in the hypothalamus, and
blockage of oxytocin receptors interferes with the expression of lordosis
OCR for page 83
SEX AFFECTS BEHAVIOR AND PERCEPTION
83
behavior. Estrogens also cause the formation of new synaptic connections
between ventromedial hypothalamic neurons in the hypothalamus.
Rats display a characteristic set of motor behaviors following activa-
tion of serotonin receptors or elevation of synaptic serotonin levels after
treatment with L-tryptophan. Both males and females exhibit this "sero-
tonin behavioral syndrome," but females display signs of the syndrome
at much lower doses than males. Fischette and colleagues (1984) have
shown that androgens, via androgen receptors, modulate the reduced
sensitivity of male rats to the tryptophan drug challenge.
Sex-Typed Behavior and Gender Identity
Discussions about the determinants of human sex-typed behavior,
especially gender identity, have recently become highly visible because of
scientific and popular accounts of a prominent case (Colapinto, 2000; Dia-
mond and Sigmundson, 1997~. The case challenged the established belief
that individuals are born with the potential to develop male or female
gender identity and that the specific gender identity can be determined
exclusively by sex of rearing (Hampson and Hampson 1961; Money and
Ehrhardt, 1996; Money et al., 1955; reviewed in Grumbach and Conte,
1998~. For detailed reviews and discussions, see Bradley et al. (1998),
Colapinto (2000), Diamond and Sigmundson (1997), Fausto-Sterling
(2000), Kessler (1998), Wilson (1999), and Zucker (1999~.
The case involved a boy (46,XY karyotype) with male-typical devel-
opment whose penis was ablated after a mishandled circumcision and
whose gender was subsequently reassigned and reared as a female. Con-
trary to early reports, the child never adjusted to the female assignment,
despite having no knowledge of his early history. Sex reassignment was
~ 1 1 e1 · 1 · · 1 1 · ~ 1 ~ 1 · ~ 11 1
requested, and the Individual Is now reported to live successfully and
happily as a man. Because this individual is a normal genetic male who
was exposed to male-typical hormones in prenatal and early neonatal life,
this case lends credence to the view that gender identity is determined by
early hormones that act on the developing brain and argues against the
view that rearing sex is the main determinant of gender identity (Dia-
mond and Sigmundson, 1997; Grumbach and Conte, 1998~.
The conclusion, however, must be considered in light of other details
of this case and other cases. The individual described above (Diamond
and Sigmundson, 1997) was reared unequivocally as a boy at least until
age 7 months, when the accident occurred, and perhaps longer, because
the final decision about female reassignment was not made until his sec-
ond year and surgery was not completed until age 21 months. Further-
more, the outcome for another individual with an ablated penis was very
different: after an accident at age 2 months, another child was reassigned
as a female at age 7 months and has reportedly adapted well to this
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84
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
identity. As an adult, she shows no evidence of gender dysphoria,
although she has a male-typical occupation and a bisexual orientation
(Bradley et al., 1998~.
Ongoing studies with boys with cloacal exstrophy (malformed or ab-
sent penis with normal testes) who are reared as girls should help to
provide systematic evidence about the determinants and malleability of
gender identity. These boys are usually reassigned as girls because of
concerns about adjustment problems associated with inadequate male
genitalia. Preliminary reports from an ongoing systematic study (Reiner,
2000) indicate that more than half of these female sex-assigned XY chil-
dren identify as boys, consistent with their male-typical prenatal andro-
gen exposure, and not with their female-typical rearing. Interestingly,
however, some of these children continued to accept their female assigned
sex, so it will be important to determine what differentiates children with
male identity from those with female identity, despite their common 46,XY
chromosome constitutions. This is clearly an area deserving of further
investigation.
Other Sex Differences in Human Behavior
Although identification as male or female is the most obvious psycho-
logical sex difference, it is far from the only one. A variety of important
human behaviors covering a range of domains are more common or occur
at higher levels in one sex than in the other. The behaviors that have
received the most attention include aspects of normal social behavior and
cognition, such as childhood play behavior and related activities and in-
terests, personality (such as aggression and interest in babies), nonverbal
communication, sexuality, and cognitive abilities (Hall and Carter, 1999;
Halpern, 2000; Maccoby, 1998; Ruble and Martin, 1998~. Activities related
to these behaviors are performed at different frequencies by males and
females in most cultures studied (Daly and Wilson, 1990~. Again, the goal
of this chapter is not to provide an exhaustive review of behavioral sex
differences but to illustrate some of the differences and to indicate how
they might be influenced in part by sex hormones.
There are also sex differences in health-related behaviors, such as
frequency of visits to health professionals and use of complementary
medicine, but these have not been well studied. There are also sex differ-
ences in the incidence and course of some mental disorders and substance
abuse (National Institutes of Health, Office of Research on Women's
Health, l999b). These differences in mental health may also produce dif-
ferences in physical health.
OCR for page 85
SEX AFFECTS BEHAVIOR AND PERCEPTION
Cognitive Function
85
A large body of research has now converged to indicate that there are
sex differences in specific areas of cognitive function. Although there has
been some controversy over the proverbial question of which sex is the
smarter one, a reasonable conclusion reached by many scientists is that
there are no meaningful differences in intelligence between males and
females (Halpern, 2000~. A more probing question asks if there are par-
ticular areas of thinking or problem solving in which males and females
differ; such cognitive abilities are referred to as "sexually dimorphic be-
haviors."
Before reviewing the research findings, it is important to bear in mind
several factors. (l) In general, there is a marked overlap in the abilities of
males and females. In some cases, the sex differences are most marked at
the extreme ends of a particular ability, for example, among those who
are the most skilled (Figure 4-l) (Hampson, in press; Hampson and
0.4~
0.3 -
~ 0.2-
IL
0.1 -
o.o
o
m-\
\
\
/ / \ \
, \ \
/ / \ \
/ / \ \
/ / \ \
/ /
/ / \ \
/
-
/ /
///
/
\
\
\
\
\
\
\ \\
\ ·\
\
it"" 1 1 — 1
\
20 40 60 80 100
Test Score
Women
Men
FIGURE 4-1 Frequency distribution of scores on a hypothetical cognitive test
plotted separately by sex. As a consequence of the differences in the means, the
number of individuals scoring above a given point will differ for the two sexes;
for example, the mean for women is higher than the mean for men such that only
25 to 30 percent of males score above the mean score for females. Source: Hamp-
son and Kimura (1992, Figure 12-1) Reprinted, with permission, from l. B. Becker,
S. M. Breedlove, and D. Crews, Behavioral Endocrinology, Cambridge, MA: The
MIT Press, 1992, p. 359.
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86
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
Kimura, 1992~. Although there may be slight but significant differences
between the mean scores for males and females on some tests, they are
invariably smaller than the differences between the highest- and lowest-
scoring males (or females) on the same tests. (2) When differences are
noted, they may apply only to individuals at a specific age or stage of life.
(3) Finally, how an ability is measured may affect the results, for example,
whether the response is multiple choice, fill in the blank, short essay, or
oral.
Cognitive abilities can be subdivided and considered in any number
of ways. Maccoby and lacklin (1974) prepared a useful classification in
which they delineated three general cognitive domains demonstrating
sex differences: verbal, quantitative, and visuospatial abilities. Although
for ease of presentation the report refers to these three main groups of
cognitive abilities, these encompass heterogeneous areas of function, with
each one representing several different functions. Furthermore, the spe-
cific cognitive processes of interest may be assessed quite differently,
often leading to conflicting results.
Despite these caveats, it should be noted that a reasonable consensus
has emerged relating sex differences to specific patterns of cognitive func-
tion: in general, women most often demonstrate an advantage in verbal
abilities particularly verbal fluency, speech production, the ability to
decode a language, and spelling; perceptual speed and accuracy; and fine
motor skills whereas men frequently show an advantage on tests of
spatial abilities, quantitative abilities, and gross motor strength
(Hampson, in press; Hampson and Kimura, 1992~. The following sections
summarize data that support this general statement.
Verbal Abilities
Although it is often stated that females demonstrate better verbal
abilities than males, it is important to note, as Halpern (2000) has, that
"the term verbal abilities is not a unitary concept. The term applies to all
components of language usage: word fluency, which is the ability to gen-
erate words (both in isolation and in a meaningful context), grammar,
spelling, reading, writing, verbal analogies, vocabulary, and oral compre-
hension. The size and reliability of the sex differences depends on which
of these aspects of language is being assessed" (pp.93-94~. Sex differences
have been demonstrated for some but not all of these verbal abilities;
however, when there is a difference, it invariably favors females.
Two aspects of language showing perhaps the most consistent sex
differences are verbal fluency and speech production, both of which share
the need to have the ability to quickly access and to produce speech
sounds and words. Verbal fluency (Hampson and Kimura, 1992; Hines,
1990; Hyde and Linn, 1988) is tested by having a subject name as many
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SEX AFFECTS BEHAVIOR AND PERCEPTION
87
words as rapidly as possible according to either a phonological or sound-
based cue (words that begin with a particular letter) or rhyming with a
specific sound or by having the subject name words that belong to a
certain category such as food or plants. In studies investigating sex differ-
ences in verbal abilities, the largest difference (effect size [D] = 0.33) is
typically found for speech production (Hyde and Linn, 1988), a measure,
as discussed later, that is closely related to both reading and reading
disability. Reliable sex differences have also been reported for spelling,
another verbal ability closely related to reading; however, reports of sex
differences in other areas of verbal ability such as vocabulary or reading
comprehension have been inconsistent and are not considered reliable
(Hampson and Kimura, 1992~.
Sex differences have also been noted in tests of memory, particularly
in tests of working memory (the ability to hold in memory information
intended for temporary use). This is a particularly important ability be-
cause it affects many aspects of a person's everyday life, for example,
remembering a phone number given by the information operator, where
the keys were just put down, or a message on the answering machine.
Females have an advantage over males in remembering both verbal and
nonverbal information. Females' superiority in verbal memory has re-
ceived much attention, although their skill in remembering visual details,
for example, spatial locations, has often been overlooked. As summarized
below, males outperform females in visuospatial abilities when the task
requires the manipulation of the spatial information; females, however,
remember visual information better (Halpern, 2000; Hampson and
Kimura, 1992~.
Articulatory Skills, Manual Fine Motor Skills, and
Perceptual Speed and Accuracy
Females generally perform articulatory tasks or fine motor tasks more
quickly and more adroitly than males. These skills all depend on the
coordination of a sequence of movements. Articulatory skills are assessed
by having the subject quickly repeat several syllables, for example, "pub
tab huh, pub tab huh, pub tab huh," for 1 minute or try to say a tongue
twister such as "sweet Susie swept sea shells" as rapidly as possible.
Females also outperform males in carrying out fine hand movements
such as rapidly placing pegs in small holes or in carrying out a simple
sequence of hand movements (Hampson and Kimura, 1992~. In addition,
females tend to perform better than males on tasks requiring perceptual
speed and accuracy. This ability is assessed by asking subjects to quickly
scan an array of symbols or figures and to indicate which one matches a
previously indicated stimulus; for example, in the "random A's test," the
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88
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
subject rapidly scans letters scattered over a page and is asked to cross out
only the letter "A."
Spatial and Quantitative Abilities
Males demonstrate an advantage on tests of visuospatial ability (as
reviewed by Maccoby and lacklin [1974] and more recently by Halpern
[2000~. According to Halpern (2000), this refers to the ability "to imagine
what an irregular figure would look like if it were rotated in space or the
ability to discern the relationship between shapes and objects" (p. 98~.
Kerns and Berenbaum (1991) noted that a major issue is how to define and
measure spatial ability. In a comprehensive meta-analysis, Linn and
Petersen (1985) focused on three categories of spatial ability: spatial per-
ception, mental rotation, and spatial visualization. The most consistent
sex differences occur with measures of skills referred to as "spatial per-
ception" and "mental rotation" (Linn and Petersen, 1985~. In particular,
the mental rotation task has demonstrated the most sensitivity at detect-
ing sex differences in spatial ability (Sanders et al., 1982~; here, a subject is
asked to imagine how a figure would appear if it were rotated in a two- or
three-dimensional space.
Sex differences in quantitative abilities have also been reported. Here,
it is important to ask "what" particular abilities and in "which people."
Quantitative abilities refer to a heterogeneous group of abilities; depend-
ing on the specific ability tested, males or females will have an advantage.
For example, males seem to outperform females on tests of geometry,
measurement, probability, and statistics as well as on tests of spatial and
mechanical reasoning (Stones et al., 1982; Stumpf and Stanley, 1998~. Some
have suggested that the male advantage in quantitative abilities reflects
the male's use of visuospatial approaches for problem solving. In con-
trast, females perform better on measures of calculation and also on tests
in which the problem requires much reading.
Perhaps the most important finding from the various research studies
is that differences in math ability are much smaller toward the middle of
the distribution, where most males and females are represented, and are
most pronounced at the upper end of the distribution. Males consistently
outperform females on tests of quantitative ability, for example, the math-
ematics portion of the Scholastic Aptitude Test (SAT). Competitions
among seventh and eighth grade boys and girls held to identify math-
ematically precocious youth on the basis of scores on the mathematics
portion of the SAT greatly favor boys. A consistent finding on these tests
is that differences between boys and girls tend to increase at the higher
levels of performance. Thus, boys outscore girls 2:1 at scores of 500 and
above, 5:1 at scores of 600 and above, and 17:1 at the highest scores, 700
and above (Benbow, 1988, Stanley and Benbow, 1982~. One problem in
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SEX AFFECTS BEHAVIOR AND PERCEPTION
89
interpreting such results is that the best predictor of performance on such
standardized mathematics tests is experience. That is, most of the stu-
dents who score the highest are enrolled in high-level mathematics
courses. The data also indicate that many more males than females are
enrolled in these high-level mathematics courses (Iones, 1984~. However,
even when one controls for the number of advanced mathematics courses,
males continue to have an advantage, albeit a much smaller one (Meece et
al., 1982~.
Newer studies are shedding light on the nature of sex differences in
quantitative abilities. A recent analysis (Gallagher et al., 2000) indicated
that males performed better on various types of mathematics questions
that had in common a dependence on a strategy to "construct and men-
tally transform a mental representation" (Halpern, 2000, p.117~. This sug-
gests that it is not the type of mathematics problem that is important in
evaluating sex differences but the kind of strategy required to solve it that
is critical in determining whether males or females have ability. Reviews
of the relationship between quantitative skills and spatial ability find that
spatial ability is an important factor in predicting performance on ad-
vanced mathematics tests and that this relationship is especially strong at
the highest levels of mathematics performance (Halpern, 2000~.
EFFECTS OF HORMONES ON BEHAVIOR AND COGNITION
Prenatal Androgens and Sex Differentiation of Human Behavior
There is now good evidence that human behavioral sex differences
are influenced by sex hormones present during prenatal development,
confirming findings from studies with other mammalian species (de-
scribed in Chapter 3~. These hormones act by "organizing" neural sys-
tems that mediate behavior later in life. Much of the evidence about the
behavioral effects of prenatal sex hormones comes from individuals with
clinical conditions that alter these hormones (so-called experiments of
nature), although in recent years there has been confirming evidence from
studies with individuals with circulating concentrations of hormones in
the normal range. The following section provides an illustration of work
done in this area; for detailed reviews of hormonal influences on human
behavior, see Berenbaum (1998), Collaer and Hines (1995), Hampson and
Kimura (1992), and Wilson (1999~.
Prenatal androgens alone do not determine behavioral sex differences.
Social and environmental factors undoubtedly contribute to differences
between males and females, but the focus of this section is on genetic and
physiological factors. Rather than considering physiological-hormonal
and social explanations as being mutually exclusive, however, it is impor-
tant to think about how they might operate in concert to produce behav-
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106
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
TABLE 4-1 Sex Prevalences of Some Common Painful Syndromes and
Potential Contributing Causes
Female Prevalence
Male Prevalence
Head and Neck
Migraine headache with aura
Chronic tension headache
Postdural puncture headache
Cervicogenic headache
Tic douloureux
Temporomandibular disorder
Occipital neuralgia
Atypical odontalgia
Burning tongue
Carotodynia
Temporal arteritis
Chronic paroxysmal hemicrania
Carpal tunnel syndrome
Raynaud's disease
Chilblains
Reflex sympathetic dystrophy
Chronic venous insufficiency
Piriformis syndrome
Peroneal muscular atrophyC, d
Esophagitis
Gallbladder diseased
Irritable bowel syndrome
Interstitial cystitis
Proctalgia fugax
Chronic constipation
Fibromyalgia syndrome
Multiple sclerosis,Tg
Rheumatoid arthritis, T
Acute intermittent porphyriaC
Lupus erythematosus, T
Migraine without aura
Cluster headache
Posttraumatic headache
Paratrigeminal syndromes
Limbs
Internal Organs
General
Thromboangiitis obliteransb
Hemophilic arthropathyC
Brachial plexus neuropathy
Pancoast tumbrel
Pancreatic disease
Duodenal ulcer
Postherpetic neuralgia
a Raeder's syndrome.
b Buerger's disease.
c Sex-linked inheritance is a potential contributory cause.
d Charcot-Marie-Tooth disease.
e Bronchogenic carcinoma.
f Lifestyle is a potential contributory cause.
g T. autoimmune.
SOURCE: Berkley and Holdcroft (1999~. Sex prevalence information is mainly from Merskey
and Bogduk (1994) and was cross-checked by using MedLine and other search sources.
OCR for page 107
SEX AFFECTS BEHAVIOR AND PERCEPTION
107
fated traits can only be understood in the context of the other. That is, sex
differences vary with, and are specific to, the particular genetic back-
ground in question, and genetic differences (between strains) can some-
times only be observed in one sex but not the other" (Mogil, 2000, p. 26~.
It is important to understand that in these studies the effects were re-
vealed by using a specific set of experimental tests of nociception (tail
withdrawal from a 49°C hot plate) and antinociception (reduction in
nociception with systemic morphine or a K-opioid or cannabinoid recep-
tor agonist). As Mogil readily admits, the results of such tests can be
influenced by many factors, such as time of day, the type of stimulus
(mechanical versus thermal), diet, pre- and postnatal stress, housing (in a
group versus in isolation), current or prior injury, reproductive status of
the comparison females, and more (Berkley,2000~. Thus, Mogil's observa-
tions herald a huge potential for the emergence of individual differences
in phenotype as genotypic influences are further affected by life's accu-
mulating circumstances.
Mechanisms of Analgesia, Sex Steroid Hormones,
and Central Sensitization
An exciting series of findings from research with rodents is that sex
differences emerge from complex interactions between stress and endog-
enous analgesia. In other words, it may be that there are more potent sex
differences in mechanisms of pain and analgesia than in measured pain
behaviors. The differences seem to lie in how sex steroid hormones exert
their effects (Aloisi, 2000; Gintzler and Liu, 2000; Sternberg and
Wachterman, 2000~. Thus, stress gives rise to an analgesia mediated by a
nonopioid, N-methyl D-aspartate (NMDA), that is present primarily in
males but that is also present in some females: those who have been
ovariectomized or who were neonatally exposed to testosterone. Stress
also gives rise to an estrogen-dependent, nonopioid, non-NMDA-medi-
ated analgesia present only in intact females, the mechanisms of which
are unknown. Furthermore, the hormonal milieu of pregnancy creates an
antinociception involving 6- and K-opioid systems but not ,u-opioid sys-
tems.
When such an analgesia is created artificially by hormone treatments
in gonadectomized rats, in females the analgesia results from a synergis-
tic combination of spinal K-opioid, 6-opioid, and oc2-noradrenergic path-
ways but not ,u-opioid pathways, whereas in males the analgesia results
from independent additive contributions of spinal K- and ,u-opioid path-
ways but neither the 6-opioid nor the oc2-noradrenergic pathway.
Finally, estrogen can influence cardiovascular responses (e.g., promo-
tion of vasodilatory or spasmodic effects) and neuronal responses (e.g.,
expression of the trkA gene) to injury, thereby influencing nociception
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EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
differently in females and males. Some of these findings may relate to
recent studies with humans showing that K-opioids are more effective
analgesics in young adult women than in young adult men who have
undergone molar tooth extraction (Gear et al., 1996, 1999~.
Significance for Human Health
Assuming that the two sets of observations just described are appli-
cable to humans, what might their significance be for health? One obvious
area is in the development of analgesic medications. Is it possible that at
some time in the foreseeable future analgesics will be prescribed on the
basis of an individual's genotype, sex, and reproductive status? Given the
first discussion on genotype, such a strategy would likely be pursued
only with great care and only in special circumstances (Mogil et al., 2000~.
For example, individuals with mutations that lead to altered functioning
of the cytochrome P450 2D6 enzyme are likely to be prescribed some
analgesic other than codeine because they are unable to transform co-
deine into morphine (Sindrup and Brosen,1995~. Drug development must
take into consideration both the sex and the reproductive status of the
research subjects not only during all phases of clinical trials but also dur-
ing the drug development stages of basic research with animals.
On the other hand, before concluding that a specific drug may even-
tually be prescribed on the basis of the sex of the individual or the repro-
ductive or hormonal status of the patient, it also seems important to con-
sider how stress exerts its cumulative effects over the life span of an
individual. Of relevance here is the plasticity of neural function: the abil-
ity of neural elements to change their phenotype, to "learn." Considerable
research on these changes in the context of pain has led to the discovery of
what is called "central sensitization," which is an enhanced responsive-
ness of central nervous system neurons induced by intense stimulation or
injury or by a stressor that, importantly, continues long after the initial
noxious event has resolved (Dubner and Ruda, 1992; McMahon et al.,
1993~. Thus, if the different complex modulatory mechanisms of endog-
enous sex steroids discovered in female and male rats also exist in human
females and males, it is likely that how they influence pain behaviors and
the effects of analgesics will change in an ever more complicated manner
as the different sociocultural stressors in human females and males exert
themselves across their life spans. It may therefore be that one of the most
important clinical insights from these two disparate areas of research
(mechanisms of endogenous analgesia and central sensitization) is real-
ization of the importance of understanding the chronology and sociocul-
tural context of stressor events for each individual, with that individual's
being female or male forming only one of many components considered
for drug prescription and therapeutic strategies. Two examples follow.
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SEX AFFECTS BEHAVIOR AND PERCEPTION
Sex Differences in Efficacy of ,u-Opioids in Clinical Setting
109
Miaskowski and colleagues (2000) have carried out an extensive re-
view of the clinical literature and have concluded that ,u-opioid analgesics
are more effective in human females than in human males. Verification of
such a conclusion might lead toward research on the development of
different analgesics or combinations of analgesics for use as treatments
for males. However, it is important to consider the basis for this conclu-
sion. As pointed out by those investigators, the effects have been mea-
sured mainly by determination of the amount of ,u-opioid medication that
females and males consume postsurgically. In most studies males con-
sume more medication than females (when the levels are measured) to
achieve comparable levels of pain reduction. The question of whether the
consumption of larger amounts of ,u-opioids postsurgically by males indi-
cates that they have lower levels of efficacy in males then arises.
One possible way to interpret the finding of greater ,u-opioid usage by
males is to consider the results of other studies demonstrating that fe-
males and males make use of different strategies to reduce pain. As re-
cently reviewed by Robinson and colleagues (2000), females bring a
greater variety of coping strategies to bear on their pains than males; that
is, females make greater use of what might be called self-polytherapy
than males (Berkley and Holdcroft, 1999) (Table 4-2~. It is therefore pos-
sible that females use smaller amounts of ,u-opioids because they are able
to engage other forms of positive coping strategies, thereby reducing their
need for opioids, and that males use more ,u-opioids because that is the
only relief they can find. Thus, efficacy depends not simply on whether
the drug user is female or male but, rather, depends on sociocultural
factors. Such an hypothesis can be tested. Is it in fact the case that in the
postoperative setting females engage more coping mechanisms than
males? On the other hand, do individuals who have learned to engage
multiple coping measures, regardless of their sex, use smaller amounts of
opioid medication than others? If so, could opioid usage be reduced over-
all if individuals were encouraged and educated on how to engage addi-
tional constructive coping mechanisms?
Impact of Menstrual Cycle on Pain
Along with genetic and developmentally programmed sex differences
in neural organization and physiology, the entire nervous system is po-
tently influenced by the hormonal milieu of the individual (McEwen,
1999; McEwen and Alves, 1999~. One arena in which this influence be-
comes evident is the ovarian cycle (one should keep in mind, however,
that the basis for ovarian cyclicity in any realm of physiology or behavior
may not necessarily be entirely due to the hormonal milieu). Several stud-
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EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
TABLE 4-2 Growing List of Therapies for Pain
Somatic Interventions
Drugs
Situational Approaches
Primary analgesics
Nonsteroidal anti-
inflammatory agents
A cet amin op hen
Opioids
Other analgesics
a2 Agonists
p-Adrenergic antagonists
Antidepressants
Antic onvuls ants
Antiarrhythmics
Calcium channel blockers
Cannabinoids
Corticosteroids
Cox-2 inhibitors
y-Aminobutyric acid
type B agonists
Serotonin agonists
Adjuvants
Antihistamines
Laxatives
Neuroleptics
Routes
Topical, transdermal, oral
Buccal, sublingual,
intranasal
Vaginal, rectal
Inhalation
Intramuscular,
intraperitoneal
Intravenous
Epidural, intrathecal
In tr av e nt ri cu. l a r
Simple
Heat or cold
Exercise
Massage
Vibration
Relaxation
Minimally invasive
Physical therapy
Traction
Manipulation
Ultrasound
Transcutaneous electrical
nerve stimulation
Acupuncture
Local anesthetics
Invasive
Radiation therapy
Dorsal column stimulation
Nerve blocks
Neurectomy
Local ganglion blocks
Sympathectomy
Rhizotomy
Dorsal root entry
zone lesions
Punctate midline
myelotomy
Limited myelotomy
Commissural myelotomy
Cordotomy
Brain stimulation
Brain lesions
Clinician
Education
Attitude
Clinical setting and
arrangement
Self
Education
Meditation
Diet
Art, music, poetry,
performing arts
Sports, gardening,
hobbies
Humor
Aroma therapy
Religion
Pets
Interactive
Hypnosis
Biofeedback
Support groups
Advocacy groups
Networking
Self-help groups
Structured settings
Group therapy
Family counseling
Job counseling
Cognitive therapy
Behavioral therapy
Psychotherapy
Multidisciplinary clinic
Hospice
SOURCE: Berkley (2000~.
NOTE: Women are more likely than men to take advantage of most of the therapies listed
in the "simple" and "minimally invasive" sections of the middle column and nearly all of
the therapies listed in the "situational approaches" column (Berkley and Holdcroft, 1999~.
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SEX AFFECTS BEHAVIOR AND PERCEPTION
111
ies with rodents have shown the powerful impact of the ovarian (estrous)
cycle on the functioning not only of the parts of the brain associated with
reproductive functions but on other regions of the brain as well, such as
(so far) the hippocampus, striatum, inferior olive, cerebellum, and dorsal
column nucleus (Becker, 1999; Bradshaw and Berkley, 2000; Smith and
Chapin, 1996a,b; 1998; Woolley and McEwen, 1993; Xiao and Becker,
1994~. Importantly, these changes are not always predictable according to
the hormonal milieu (Bradshaw and Berkley, 2000~.
Given that brain imaging studies show that many parts of the brain
are engaged when the subject is in pain (Ingvar and Hsieh, 1999), it is not
surprising that numerous studies have found that pain can vary with the
menstrual cycle, especially pain that occurs when noxious stimuli are
delivered to healthy individuals under certain tightly controlled experi-
mental conditions (Riley et al., 1999~. One consequence of this situation is
that results of studies comparing pain in young adult females and young
adult males may depend on the time of the menstrual cycle in which the
women's pain was assessed.
The clinical significance of these findings, however, is unclear be-
cause the existence and pattern of the menstrual effects that have been
reported are not consistent, especially for painful clinical conditions
(Berkley, 1997a,b; Fillingim and Ness, 2000~. Part of the inconsistency
across studies may be due to technical factors, such as how different parts
of the menstrual cycle are classified and the manner in which the analysis
has been made. Given that brain imaging studies, however, are beginning
to show that the brain regions engaged while an individual is under
painful conditions vary with the individual (Davis et al., 1998; Gelnar et
al., 1999), it is relevant to consider other factors. For example, a recent
study compared skin and muscle pain thresholds in the lower abdomen
and limbs across the menstrual cycle in women with severe menstrual
pain (dysmenorrhea) and women without dysmenorrhea and across the
month in similarly aged young men (Giamberardino et al., 1997~. For the
men, limb pain threshold did not vary across the month, but abdominal
thresholds could not be measured because of the men's extremely high
sensitivity (all refused further testing of this region after the first set of
trials). For women, the presence of dysmenorrhea gave rise to a general-
ized muscle (but not skin) hyperalgesia and a significant enhancement of
the different patterns for skin and muscle across the menstrual cycle.
Comparison of the limb pain thresholds in men and women showed no
differences between the men and nondysmenorrheic women, regardless
of the time of the month, but did show a higher threshold for both groups
compared with that for the dysmenorrheic women.
Although these results highlight the complexity of the issue of differ-
ences in pain by sex and time of the menstrual cycle, they point to several
potentially important clinical issues. First, the results suggest that dys-
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EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
menorrhea might enhance the severity and cyclicity of other visceral con-
ditions ("viscero-visceral interactions". This hypothesis is being tested in
parallel studies with animals with endometriosis and ureteral stones and
with humans with dysmenorrhea and ureteral stones. So far the results
show significant interactions between the two conditions that have impli-
cations for diagnosis and treatment in both females and males
(Giamberardino, 2000; Giamberardino et al., 1999~.
Second, a number of painful clinical disorders vary significantly with
the menstrual cycle in some women but not others, such as certain types
of headache, irritable bowel syndrome, interstitial cystitis, temporoman-
dibular disorder, and fibromyalgia (Bradley and Alarcon, 2000; Fillingim
and Maixner, 2000; Holroyd and Lipchik, 2000; Mayer et al., 1999; Naliboff
et al., 2000~. It is possible that the women with cyclical pains also suffer
from dysmenorrhea, a possibility that can be tested experimentally. If so,
it is also possible that treatment directed at the dysmenorrhea might alle-
viate those women's other pains, and this is also testable. Furthermore, an
analysis of what factors reduce the pains during certain phases of the
menstrual cycle might yield clues about the mechanism of the pain and
treatments that could be applied to men with similar conditions.
Third, what might be the basis for the surprising extreme abdominal
sensitivity exhibited by the men, and what implications does this sensitiv-
ity have for symptom reporting and clinical testing?
Summary
Overall, the results from research on sex differences in pain mecha-
nisms and responses to treatment provide good examples of a construc-
tive approach toward understanding the mechanisms of other sex differ-
ences. This approach highlights the importance of considering how sex
differences in genetic, hormonal, psychosocial, and stressful environmen-
tal circumstances interact and evolve across the life span to give rise to an
individual's ever-changeable "pain phenotype" at any particular time of
her or his life (Berkley and Holdcroft, 1999; LeResche, 1999~.
ANIMAL MODELS OF CEREBROVASCULAR AND
CARDIOVASCULAR DISEASES
Sex-specific responses to experimental traumatic or ischemic brain
injury have been reported and are summarized in Table 4-3.
The role of sex in behavioral outcomes after traumatic brain injury
has also been studied. Clinical studies report improved outcomes for fe-
male patients with head injuries compared with those for male patients
with head injuries, as determined by the ability of patients with head
injuries to return to their preinjury work levels (Groswasser et al., 1998~.
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SEX AFFECTS BEHAVIOR AND PERCEPTION
TABLE 4-3 Sex-Specific Responses to an Experimental Traumatic or
Ischemic Cerebral Insult
113
Animal Model
Results
Gerbil 3-h carotid occlusion
Permanent carotid occlusion
Rat
Permanent bilateral carotid
occlusion
2-h MCAO
Impact / acceleration
closed-head injury
Traumatic brain injury
Progesterone after traumatic
injury
Entorhinal cortex injury
Ovariectomy, global
ischemic insult
Post menopausal, MCAO
M have more CAT hippocampal and
cortical neuronal loss (Hall et al., 1991)
M have more strokes (Berry et al., 1975)
M have higher rates of mortality and
larger numbers of brain lesions
(Sadoshima et al., 1988)
M have larger infarcts (Alkayed et al.,
1998; Belayev et al., 1996; Zea-Longa
et al., 1989)
M have worse rates of survival (Roof
and Hall, 2000a)
M have more cerebral edema (Roof et
al., 1993a)
Equally beneficial effect on edema in
both M and F (Roof et al., 1993a)
M perform worse in maze test (Roof et
al., 1993b)
Ovariectomized F have greater
neurological dysfunction than intact F
(Wang et al., 1999)
M and F similar in infarct size (Alkayed
et al., 2000)
Estradiol pretreatment of Increased survival and decreased
ovariectomized F. temporary ischemic area in treated versus
MCAO nontreated F (Simpkins et al., 1997)
MCAO, estrogen treatment of M Prognosis improves in estrogen-treated
MCAO, estrogen receptor
antagonist
Mice Unilateral carotid occlusion
Unilateral carotid occlusion in
SOD overexpressers
M (Toting et al., 1998)
Ischemia increases in F but not in M
(Sawada et al., 2000)
Larger lesion in M (Roof and Hall,
2000b)
M protected by overexpression of SOD
(Roof and Hall, 2000b)
NOTE: MCAO, middle cerebral artery occlusion; M, male; F. female; SOD, superoxide
dismutase.
In studies with rats, sex-specific neuroprotection was lost when fe-
male rats were ovariectomized, suggesting that circulating gonadal hor-
mones are responsible for the sex differences (Simpkins et al., 1997~. Sev-
eral reports demonstrate that estrogen and progesterone treatment has a
neuroprotective effect. This area of research has recently been reviewed
(Roof and Hall, 2000b). Results of experiments with rats suggest that
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EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
osteogenic neuroprotection is not sex specific and is not affected by tes-
tosterone.
The mechanisms by which female sex or by which estrogen or proges-
terone attenuates brain damage are complex. Estrogen could preserve
autoregulation or antioxidant activity, affect leukocyte adhesion, or up-
regulate nitric oxide synthase. Estrogen modulates leukocyte adhesion in
the cerebral circulation during resting conditions as well as after transient
forebrain ischemia. Leukocyte adhesion and infiltration have been linked
to the neuropathology in the brain; estrogen's neuroprotective effects may
be due to modulation of this inflammatory pathway (Santizo et al., 2000~.
In a model of the rate of progression of atherosclerosis in rabbits fed a
high-cholesterol diet, the concentrations of lipids (total cholesterol, high-
density lipoprotein cholesterol, and triglycerides) in serum were the same
in males and females; however, the rate of progression of disease as deter-
mined by histological examination of the thoracic aorta differed (greater
in males than in females). Estrogen administration to oophorectomized
rabbits fed high levels of cholesterol resulted in a reduced degree of ath-
erosclerosis (Haarbo et al., 1991~. The inflammatory response that occurs
during atherogenesis involves adhesion of monocytes to endothelial cells
and migration across endothelial cells (Nathan et al., 1999~. Adhesion of
monocytes to endothelial cells is slower in females. In addition, the level
of VCAM-1 protein expression in aortas from oophorectomized rabbits
fed an diet enriched in cholesterol was increased and was attenuated by
the ischemia. These sex differences in VCAM-1 expression in this model
suggest an estrogen-mediated anti-inflammatory mechanism.
Transgenic (TNF1.6) mice with cardiac-specific overexpression of tu-
mor necrosis factor alpha (TNF-oc) develop ventricular hypertrophy, car-
diac dilatation, interstitial infiltrates, massive pleural effusion, and fibro-
sis and die from congestive heart failure (Kubota et al., 1997~. The 6-month
survival rate was significantly better in females. The marked sex differ-
ences in survival cannot be the result of differences in the levels of expres-
sion of TNF-oc since at both the transcript and the protein levels the levels
of expression of TNF-oc was the same in males and females. Rather, male
TNF1.6 mice had higher steady-state levels of messenger RNAs encoding
both TNF-oc and -p receptors. The investigators (Kubota et al., 1997) dem-
onstrated the physiological relevance of this increased level of expression
of TNF receptors in male mice by looking at ceramide production, a TNF-
dependent process, from myocardial tissue (male transgenic mice pro-
duced more ceramide than females). These results suggest that enhanced
survival in female mice in the presence of TNF overexpression may be
attributable to sex-related differences in TNF receptor levels. The etiology
of this differential regulation of TNF receptors remains unknown. In hu-
man patients with heart failure, women live significantly longer than men
(Becker et al., 1994; Greenland et al., 1991; Steingart et al., 1991~.
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SEX AFFECTS BEHAVIOR AND PERCEPTION
115
Animal models provide an important research tool for the study of
pathophysiological mechanisms of disease and therapeutic approaches.
Male animals have predominantly been used in such animal models, how-
ever, on the basis of the assumption that the results obtained from studies
conducted with male animals could be extrapolated to female animals.
Furthermore, the inclusion of female animals in preclinical studies in-
creases the complexity of a study because of the female estrous cycle and
the need to control for the associated hormonal fluctuations (Panetta and
Srinivasan, 1998~. Thus, the roles of sex and sex hormones in mechanisms
of disease outcome have not been routinely studied in animal models. It is
not clear whether estrogen's effects are mediated via receptor-based or
nongenomic mechanisms. However, continuing efforts to tease apart the
mechanisms of sex-based differential vulnerability to traumatic and is-
chemic brain injuries and cardiovascular diseases could lead to improved
understanding of the pathophysiologies of these injuries and diseases
and may suggest new mechanistic approaches to their treatment.
FINDINGS AND RECOMMENDATIONS
Findings
Sex hormones do not act alone. No one factor is responsible for sex
differences; rather, a number of genetic, hormonal, physiological, and
experiential factors operating at different times during development re-
sult in the phenotype called an individual. To better understand the influ-
ences and roles of factors that may lead to sex differences, the committee
makes the following recommendations.
Recommendations
RECOMMENDATION 4: Investigate natural variations.
· Examine genetic variability, disorders of sex differentiation, re-
productive status, and environmental influences to better understand
human health.
· Naturally occurring variations provide useful models that can be
used to study the influences and origins of a range of factors that influ-
ence sex differences.
RECOMMENDATION 5: Expand research on sex differences in brain
organization and function.
New technologies make it possible to study sex-differential environ-
mental and behavioral influences on brain organization and function and
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EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
to recognize modulators of brain organization and function. Explore in-
novative ways to expand the availability of and reduce the cost of new
technologies.
Also see Recommendation 3 (Chapter 3) for a discussion of the need
to mine cross-species information.
Representative terms from entire chapter:
phonological processing
