Sex, sexuality, and the brain

Antonio CANOVA (1757 – 1822)

Psyche Revived by Cupid’s Kiss
Paris, Musée du Louvre
• effect of steroids on phenotypic sex
• sexual dimorphism
• sex-based differences in cognitive functions
 Definitions
• “sex” has a range of meanings defined by biology, individual
preferences, culture, and tradition
• chromosomal sex – defined by individual’s set of chromosomes
• phenotypic sex – determined by physical state of gonads and
external genitalia as well as secondary sex characteristics (not
always matches chromosomal sex)
• gender identity- refers to an individual’s subjective perception of
their sex and their sexual orientation, which is harder to define
than chromosomal or phenotypic sex. It should also be apparent
that some people consider gender to be a political and social
construct.

• To understand the neurobiology of sex, it is helpful to think of

chromosomal sex as largely immutable; phenotypic sex as
modifiable by developmental processes, hormone treatments,
and/or surgery; and gender as a more complex social and cultural
construct that an individual may or may not want to accept.
• primary sex characteristics – gonadal tissues that
support either male or female gametes
• secondary sex characteristics – mammary glands in
females, sex-specific hair patterns, musculoskeletal
and organismal size differences; regulated by
hormonal secretions from the gonads
• female by default (unlike in Bible)
 SRY
• XX –female (ovaries, oviducts, uterus, cervix, clitoris, labia, vagina)
• XY – male (testicle, epididymis, vas deference, seminal vesicles, penis, scrotum)
• defining gene for male genotypic and phenotypic sex is found on the Y
chromosome – gene for transcription factor – testis-determining factor (TDF) or
SRY (sex reversal on the Y chromosome)
• TDF/SRY – sole determinant for establishing male gonadal tissues, and male
phenotypic sex
 SRY translocation to X chromosome

What genotypic sex?

What phenotypic sex?

- SRY alone is sufficient to masculinize the individual, phenotypically male

- similar in Kleinfelter’s syndrome – XXY - phenotypically male
- deletion of SRY with otherwise intact Y chromosome – phenotypically females
 Hormonal influences on sexual dimorphism

• steroid hormones testosterone and estrogen,

secreted by testes and ovaries, respectively,
influence sexual dimorphism
• organizational effect – differing levels influence the
distinct male versus female differentiation in a
variety of tissues, including brain
- surge of testosterone in second trimester in male fetus results in masculinization of genitalia
- testosterone also affect masculinization of nervous system, including brain, later in
development; many effects on brain is via estrogen (testosterone is converted)
 Testosterone
- testosterone is converted to estradiol (form of estrogen) in
neurons
- estradiol affects brain development

- what about mother’s estrogens?

- developing fetus produces alpha-fetoprotein, protein

that binds circulating estrogens (mother’s), and only
fetal estrogen that is produced from testosterone in
neurons acts on brain; alpha-fetoprotein doesn’t bind
testosterone
- KO of α-fetoprotein leads to infertility in female mice
due to failure of hypothalamic control of ovulation,
possibly, the result of masculinizing overexposure to
estrogen during embryonic development
- male KO mice are healthy and fertile
 Congenital adrenal hyperplasia
- 21-hydroxylase deficiency (synthesis of cortisol)
- high levels of androgens (testosterone) produced by adrenal gland
- masculinization of genitals in female (ambiguous genitals)

Sleeping Hermaphrodite - Uffizi Gallery

How would you assign the phenotypic sex to these girls?

What about brain under androgens?
• Gonadal steroids act by binding to specific
receptors for either testosterone or estrogen
• receptors belong to a large family of proteins
called the steroid- thyroid nuclear receptors
• cytoplasmic, ligands diffuse through the
membrane
• after binding to receptor, regulate gene
expression
Steroids have direct and indirect effects on neurons. Dashed line shows direct effects
of hormones on the pre- or postsynaptic membrane, which alters neurotransmitter
release, and affects neurotransmitter receptors. Solid line shows indirect effects of hormones,
which act at the level of the nucleus to alter protein synthesis.
 Steroid receptors distribution
- limited population of cells
- concentrated at sites where
reproductive and parenting functions
are presented and sexual dimorphism
is seen

Distribution of estradiol-sensitive neurons illustrated in a sagittal section of the rat brain.

Animals were given radioactively labeled estradiol; dots represent regions where the label
accumulated. In the rat, most estradiol-sensitive neurons are located in the preoptic area,
hypothalamus, and amygdala
Estrogen causes exuberant outgrowth of neurites in hypothalamic explants from newborn mice.
(A) Control explant showing only a few silver impregnated processes growing from the explant.
(B) An estradiol-treated explant has many more neurites growing from its center. (From Toran-
Allerand, 1978.)
 Effect of testosterone on rat pelvic
ganglion in cell culture

- enlarged cell body

- elaborated dendritic tree
 Cellular and molecular basis of sexual
dimorphism

Changes in the dendrites of rat hippocampal neurons following various hormonal regimes.
Left: Dendritic spine density under each of the indicated conditions
Right: Tracings of representative apical dendrites from hippocampal pyramidal neurons:
(1) After administration of progesterone and estrogen in high dosage.
(2) After administration of progesterone and estrogen at basal levels.
(3) After administration of a progesterone receptor antagonist. (After Woolley and McEwen,
1992.)
 Spinal cord sexual dimorphism

The number of spinal motor neurons related to the perineal muscles is different in female and
male rodents.
(A) Diagram of the perineal region of a male rat.
(B) A histological cross section through the fifth lumbar segment of the male. Arrows indicate
the spinal nucleus of the bulbocavernosus.
(C) Same region of the spinal cord in the female rat. There is no equivalent grouping of densely
stained neurons.
 Onuf’s nucleus

(A) Histograms showing motor neuron counts in the dorsal-medial and ventral-lateral groups of
Onuf’s nucleus in human females and males.
Organization of the components of the hypothalamus involved in regulating sexual functions.
The human hypothalamus, illustrating the location of the anterior hypothalamic area and other
nuclei in which sexual dimorphisms have been observed in either humans or experimental
animals.
 AVPV, rats

- anteroventral paraventricular nucleus (AVPV) – regulates the ovulatory cycle; very distinct
between different sexes: female gametes mature at distinct times, male gametes – constantly
- cells are numerous in females than in males
- modulate the systematic release of gonadotropin-releasing hormone as well as prolactin
secretion
- dimorphism is due to negative influence of high testosterone level in males (induces cell
death)
- what would elevated testosterone cause during female development?
 INAH, human

- Sexual dimorphisms in the interstitial nuclei of the human anterior hypothalamus (INAH).
- The four interstitial nuclei of the anterior hypothalamus (red) are indicated by the numbers
1–4.
- (B–D) Micrographs showing the interstitial
nuclei from a male (left column) and a female (right
column). The male examples were taken from the
left side of the brain, female examples from the
right side at the same level.
(B) INAH- 1.
(C) INAH-1 and 2. Note that INAH-2 is less compact
in the female.
(D) INAH-3 and 4. INAH-4 is well represented in
both the male and female, whereas INAH-3 is
clearly less distinct in the female. (B–D from Allen et
al., 1989.)
 Homo-heterosexual hypothalamus
INAH (interstitial nuclei of the hypothalamus)
- post mortem tissues
- results are modestly significant, not absolutely predictive, not a reliable indicator of sexual
orientation
- INAH – homolog of the SDN-POA in rodents, reduced in homosexual men, similar to
heterosexual women
- HIV-patients were involved, HIV leads to degeneration within brain

Micrographs showing difference in INAH-3 between heterosexual and homosexual

males. Arrowheads outline the nucleus. (from LeVay, 1991)
 Hypothalamic activation by estrogen and androgens in
heterosexual and homosexual women and men

- Inhaling androgens elicits focal activation of hypothalamus in heterosexual women and

homosexual men; no activation in heterosexual men
- estrogen activates cingulate cortex in heterosexual women, hypothalamus in heterosexual
men and homosexual women
- there may be some acquisition of female characteristics in the brains of homosexual men and
male characteristics in the brains of homosexual women
Sex-based differences in cognitive
functions
- corpus callosum
- orbitofrontal cortex
- anterior commissure
- amygdala
- BUT
- studies are complicated by
small samples, not always
replicated
- don’t have predictive value (by
measuring the areas it is
impossible to tell the sex of the
person)
- effect on cognition is not
known
Stressed Hippocampus

"THE OPPOSITE EFFECTS OF STRESS ON

DENDRITIC SPINES IN MALE VS. FEMALE RATS
ARE NMDA RECEPTOR-DEPENDENT," BY T. J.
SHORS, J. FALDUTO AND B. LEUNER,
IN EUROPEAN JOURNAL OF NEUROSCIENCE,
VOL. 19; JANUARY 2004 (top); SOURCE:
Cheryl D. CONRAD Arizona State
University (bottom)

http://palgrave.nature.com/scientificamerica
nmind/journal/v20/n3/box/scientificamerica
nmind0509-40_BX3.html
 Amygdala

• connected to hypothalamus
• hypersexuality in animals with bilateral lesion
• some MRI – male amygdala is bigger, when
corrected for brain size – not significant
difference
• BUT
• robust functional distinction in subjects
performing emotional memory tasks
 Sex-based differences in cognitive functions

"SEX-RELATED HEMISPHERIC LATERALIZATION OF AMYGDALA FUNCTION IN EMOTIONALLY

INFLUENCED MEMORY: AN FMRI INVESTIGATION," BY larry cahill et al., in LEARNING AND
MEMORY, vol. 11, No. 3; 2004
• dimorphisms are statistical rather than absolute
(visuospatial functions, working memory,
language)
• performance on these tasks or observation of the
size or shape of the structures, cannot reliably
predict an individual’s sex
• language dimorphism: controversial, men tend to
process language information in a more
lateralized manner
 Sexual identity science
• “… since sexual differentiation of the genitals takes place in
the first two months of pregnancy and sexual differentiation
of the brain starts in the second half of pregnancy, these
two processes can be influenced independently, which may
result in extreme cases in transsexuality”
• “… in the event of ambiguous sex at birth , the degree of
masculinization of the genitals may not reflect the degree of
masculinization of the brain”
• “There is no indication that social environment after birth has
an effect on gender identity or sexual orientation”

Garcia-Falgueras A., Swaab DF. Sexual hormones and the brain: an essential alliance for sexual
identity and sexual orientation. PEDIATRIC NEUROENDOCRINOLOGY 17: 22-35 (2010)
• 1973, the American Psychiatric Association eliminated
homosexuality from its disorders’ list.
• American Psychiatric Association – Gender dysphoria -
a general descriptive term refers to an individual’s
discontent with the assigned gender (according to DSM
V - Diagnostic and Statistical Manual of Mental
Disorders, released May 22, 2015 ) Formerly known as
Gender Identity Disorder. The shift reflects recognition
that the disagreement between birth gender and
identity may not necessarily be pathological if it does
not cause the individual distress.
• Treatment options for gender dysphoria include
counseling, cross-sex hormones, puberty suppression
and gender reassignment surgery.

https://www.psychiatry.org/patients-families/gender-dysphoria/what-is-gender-dysphoria
 Theory of Gender Neutrality
• John Money
• gender identity developed primarily as a result of
social learning from early childhood and that it could
be changed with the appropriate behavioral
interventions
 David Reimer

- born 1965 – twin to Brian

- Bruce- Brenda-David
- 7 mo – unlucky circumcision
- penis is destroyed
- the decision to convert to a girl (Brenda)
- 14 yo – changes gender to become David
- 35 yo - marriage
- 38 yo -suicide

https://www.youtube.com/watch?v=-i1Oe6zcaw8
 Summary
• masculinizing transcription factor SRY determines
genetic and phenotypic sex
• brain masculinization is influenced by testosterone
• brain gender is shaped during embryonic development
• sexual dimorphism is observed in structures important
for reproduction (hypothalamus)
• sexual dimorphism doesn’t have a predictive value
• effect of sexual dimorphism in brain structures on
cognitive functions is not known