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fully demonstrated by removing the gonads before
primary determination occurs (Jost, 1953). Without
exception, animals develop as females (e.g., they have
a vagina, a uterus, and oviducts). Furthermore, their
sexual behavior is female-like, presumably because
certain areas of the nervous system have developed
female characteristics (Phoenix et al., 1959). When
genetically female (XX) rats are treated with testos-
terone within a few days of birth, they will not display
female sexual behaviors as adults. That is, they will not
arch their back (lordosis) when approached by a male,
and they will mount a female rat if given another shot
of testosterone. When genetic males (XY) are castrated
soon after birth, they will not mount a female as an
adult, even if given a shot of testosterone.
The testes masculinize the body by releasing the
steroid hormone, testosterone. The level first rises
during the perinatal period, goes down after birth, and
rises again at puberty. The testosterone must be con-
verted to another compound in order to carry out some
of its actions. For example, some members of a small
community in the Dominican Republic carry a dis-
rupted form of the 5a-reductase gene and cannot
convert testosterone to 5a-dihydrotestosterone (DHT).
Although affected genetic males (XY) have functional
testes and plenty of circulating testosterone, their
external genitals are female (Imperato-McGinley et al.,
1979; Thigpen et al., 1992). Interestingly, most of the
individuals who were unambiguously raised as girls
nonetheless chose to adopt a male identity during or
after puberty. The results suggest that testosterone has
a potent influence in determining gender identity, even
overcoming the prolonged “environmental” influence
of being raised as a female. Since DHT is probably not
involved in gender identity (although it is involved in
differentiation of external genitalia), how does testos-
terone masculinize the brain?
In the brains of mammals, testosterone is also con-
verted to the estrogen hormone, estradiol-17b, by an
enzyme called aromatase. At first, this might seem
puzzling because estradiol is secreted by the ovaries
and promotes differentiation of the female reproduc-
tive organs. However, testosterone is also an interme-
diate metabolite of estradiol in the ovaries. Thus, we
should probably not think of hormones as being
“male” or “female.” There are probably two factors
that allow estradiol to act selectively on the brains of
genetic males. First, aromatase activity is higher in the
brains of male mice, particularly during the prenatal
and neonatal periods (Hutchison, 1997). Second, the
blood of young animals contains an estradiol-binding
protein, called a-fetoprotein, that may prevent estro-
gen secreted by the ovaries from reaching the brain
(Uriel et al., 1976). A direct masculinizing role for
testosterone is revealed by examining androgen recep-
tor (AR) null mice (Sato et al., 2004). Genetic males
with the AR mutation do not display male-typical
sexual and aggressive behaviors. Treatment with DHT
does not restore normal sexual behavior but does par-
tially rescue male aggressive behavior.
Since there are many different steroid hormones,
and their actions are quite diverse, there must be spe-
cific transduction pathways. How do sex hormones
influence neuron differentiation and function? Steroid
receptors are cytoplasmic proteins with a steroid-
binding domain and a DNA binding domain. That is,
they provide a very direct pathway to the genome
(Beato et al., 1995). When estradiol binds to its multi-
subunit receptor, it dissociates, and the active
DNA-binding complex enters the nucleus. Estradiol
receptors are found in neurons of the hypothalamus
and amygdala, and they are expressed transiently in
the cortex and hypothalamus. Androgen receptors are
also expressed at highest concentration in the hypo-
thalamus and limbic structures.
HORMONAL CONTROL
OF BRAIN GENDER
One might expect the hypothalamus to be a target of
gonadal hormones during development. Lesion and
stimulation studies show that some hypothalamic
regions are involved directly in the production of
sex-specific behaviors. For example, medial preoptic
neurons fire rapidly just prior to male copulation, and
copulatory behavior is disrupted when this area is
lesioned. Medial preoptic neurons are also known to
take up more testosterone than any other brain region
in adult animals. One of the first studies to show that
male and female brains actually differ in a measurable
way was an ultrastructural study in the preoptic area
(Raisman and Field, 1973). A few years later, it was
found that one part of the preoptic area, aptly named
the sexual dimorphic nucleus of the preoptic area
(SDN-POA), is so much larger in male rats than females
that one can actually see the difference in tissue sec-
tions without using a microscope (Figure 10.18A). A
similar difference is found in the primate hypothala-
mus, including that of humans. Selective cell death
may account for the sexual dimorphism in a human
hypothalamic nucleus, called INAH 1. Until age 5, the
number of INAH 1 neurons is about the same in males
and females, but the number of neurons then declines
more rapidly in females (Swaab and Hofman, 1988).
The sexual dimorphism of SDN-POA is an example
of secondary sex determination in the nervous system.
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