4/12/21

Sex Determination and

Differentiation

http://www.livescience.com/14210-gynandromorphs-dual-sex-disorder-strange-birds-
butterflies-gallery.html

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Sex Differences*
● Common in humans and non-human animals.
◦ How do they come about?
◦ What role do hormones play?

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Evolution of Sex Evolution of Sex

— Parthenogenesis: Some vertebrate species are • Advantage of sex:
asexual – only females, produce eggs, clones of • Genetic diversity as a result of the
themselves (over 70 known species) • Recombination of genetic
◦ Obligate – exclusively through asexual means material during sexual reproduction
between 2 major distinct forms within the
◦ Facultative – in the absence of males/viable males
same species: male and female
◦ Disadvantages
• Sexual Dimorphism – existence of two distinct forms
–Accumulation of mutations
within the same species
–Pathogens may become specialized to exploit a
single genotype – pathogens reproduce faster
than their hosts
–Risk extinction if environmental conditions change
drastically (no natural selection at work)

Komodo Dragon (ZZ = male, WZ = female)

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Sexual Dimorphism*Dimorphism – the existence among animals Polygamous mating systems

of the same species of two distinct forms that differ in one or more characteristics
● Typically males compete, females choose
◦ Example: Largest bucks have best territory, which they get
by fighting for it – so these guys are the biggest, and have
the biggest antlers. Able to mate with the best females
and pass on the most genes.
◦ Females choose these males with the best territories, and
in doing so, choose the males with good genes.

Monogamous and Polygamous mating systems – more sexual dimorphism in

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For animals reproducing sexually

Why the big differences between the sexes?
Sexual Selection can take many
Differences are driven by sexual selection (a subcategory of
natural selection) forms
• Sexual selection is a mode of natural selection in which some
individuals out-reproduce others of a population because they are
better at securing mates
• In other words: natural selection is about living long enough to
reproduce ; sexual selection (a form of natural selection) is about
convincing others to mate with you

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Sexual Selection can take many What are humans?

forms ● Humans – mildly to moderately polygamous –
and have sexual dimorphisms in the way we
look, behave, reproduce, etc.

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Sexual Differentiation
Therefore there are 5 levels of sexual dimorphism* :
Sexual Differentiation 1)Chromosomal (or genetic) sex
2)Gonadal sex
3)Hormonal
- development of sexually reproducing organisms into separate
sexes. 4)Phenotypic sex
Specifically, as it applies to us humans. 5)Behavioral

AND…

Chromosomal sex determines gonadal sex determines

hormonal sex determines phenotypic sex and
behavioral sex
Gender identity
Sexual orientation (preference)
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Legal sex

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In the beginning Every germ cell (gamete) has 23 chromosomes

Every somatic cell has 46 chromosomes – 22 pairs of

autosomes which look the same in both males and
females. The 23rd pair, the sex chromosomes, differ
between males and females

or Ovum (pl. ova) and sperm

Combine their chromosomes

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The Beginning of Life: Conception*

● For conception to occur there must be a released ovum
(14 days into a cycle) and a sperm (can last 2-5 days in
a woman`s body)
● Ovulation releases the ovum, and if sperm available,
fertilization can occur (24 hour fertilization window).
● 23 chromosomes from the ovum pair up with the 23
chromosomes from the sperm

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How do we get from…

Here…
(zygote - essentially a
clump
of undifferentiated
cells)

To
… OR h
re er
he e…
To

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Organizational effects
Genetic sex
?????
Gonadal sex: testes or ovaries

Hormonal sex

Phenotypic sex
External sex Brain sex
Internal sex organs
organs
Activational effects - at puberty:
2nd sex characteristics Sexual behavior
Male/female stereotypic behaviors
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Organizational and Activating Effects

● Organizational effect – long-lasting effect of a hormone that First level: chromosomal sex
occurs mostly at an early sensitive stage of development around
birth. They determine whether the brain and body will develop
female or male characteristics. XY = male (testes)
● Activating effects can occur at any time in life when a hormone XXY, XXYY, XXXY, XXXXY = male (testes: from testify = witness), but
activates a particular response in an organ triggering impaired sperm production, infertility
reproduction-related behavior in mature individuals. XX*
● The distinction between the two kinds of effects are not
absolute: hormones early in life exert temporary effects while
they are organizing body development, and during puberty,
XX or XXX = female (ovaries)
hormones induce long-lasting structural changes as well as XO = female with incomplete ovarian development
activating effects.

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First level: chromosomal sex Embryo immediately before

Each reproductive cell has a single set of 22 chromosomes and a single sex
chromosome, either X or Y
differentiation
●At 6 weeks: males and females are identical
●Initially gonads are identical in both sexes, termed
indifferent gonads
●Bipotential tissues: genes & hormones direct
differentiation

Reproductive cells, or gametes

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“One might expect that reproductive

mechanisms as unlike as those of adult
males and females would be sharply
differentiated from one another from their
earliest appearance. Such is not t he
case…”
Patten, 1946

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Therefore: Gonadal sex: If the SRY gene is expressed,

Y chromosome makes you Male
then
HOW? •The protein encoded by this gene, TDF (testes
●The Y chromosome contains a gene known as the SRY (sex determining factor) is produced
determining region on the Y chromosome) gene.
●This gene is responsible for the development of testes in • And the gonads become testes
mammals – it is both necessary and sufficient for male sex •If TDF is not expressed, then ovaries form
determination
●XX males: SRY gene translocated from the Y to the X
chromosome during the production of father`s sperm
●Individuals with Y chromosome almost always have a male
phenotype…
●why almost ????
●Stay tuned!

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Internal (accessory) reproductive systems immediately

before differentiation – dual anlagen (the rudimentary
basis of a particular organ or other part, especially in an
embryo)
● Also, at 6 weeks postconception, two sets of
ducts run from each gonad to the future site of
This means: a conditional must be met (SRY the external genitalia.
gene) for the male gonadal differentiation ◦ Wolffian ducts
◦ Müllerain ducts
Differentiation of the female gonads requires
no condition, it is default

Or is it not…?

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In other words: in the beginning

Internal sex organs: There is no difference in male and female
●The precursor of the development during the first 6 weeks of
●The precursor of the
internal male sex organs is conception – BIPOTENTIAL STAGE
internal female sex organs
is called the Müllerian called the Wolffian
system. system.

“…the hermaphroditic condition is potentially

Develop into: present in every individual during the earliest
Females Males stages of development; the most remarkable
Fallopian tubes Epididymis fact that it is not more common”
Bailey and Miller
Uterus Vas deferens
Text Book of Embryology, 1929
Inner 2/3ds of Seminal vesicles
vagina
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Individuals with Y chromosome almost always have a male phenotype… If SRY gene is present, and testes form, and
why almost ???? at 3 months they start to release:
● What would happen if we injected SRY
protein, TDF, or knock in SRY gene into a ● Sertoli cells: MIS = Müllerain inhibiting
genetic female? substance, or AMH (anti-mullerian hormone)
which defiminizes internal genitalia
- a genetic female (XX) with testes!
● Leydig cells: Testosterone which masculinizes
● What would happen if we knock-out SRY internal genitalia (accessory)
gene or block the effects of TDF?
- a genetic male (XY) with ovaries!
- Humans: Swyer syndrome: XY female who can carry a
pregnancy to term.
https://www.youtube.com/watch?v=vvg5J2x5IBo 35 36

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● As a result:
● Wolffian system develops and Müllerain
system degenerates - third month of the
fetal development

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Internal genitalia – 3d month of the fetal

development* *
● If the testes are formed, they start secreting
testosterone (masculinization) and Müllerian
inhibitory hormone (MIH) (defeminization) and
the Wolffian duct develops further and the
Müllerian duct system regresses
● If no Y chromosome – no SRY gene is present, or in
Wolffian duct
the complete absence ! of gonads, normal Müllerain duct regression
development of the Müllerian ducts is accompanied regression
by the regression of the Wolffian duct system. Feminization
Masculinization
● If you inject testosterone in female fetus she will &
&
develop male reproductive ducts long with the female Demasculinization
Defeminization
reproductive ducts
Default
Requires
hormones
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External Genitalia
External Genitalia ● 5α reductase converts some testosterone into
dihydrotestosterone – DHT that masculinizes external
● External reproductive structures – genitalia genitalia
◦ (….hypospadias….clitoromegaly….)
– develop from one bipotential precursor
(in contrast to internal genitalia)

● Without testosterone, female structures develop

Copyright © 2009 by Allyn & Bacon 42

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9 week old embryo: which is which?

External genitalia

The development of
male and female
external
reproductive organs
from the same ● 1. Anus
2. Labio scrotal folds
bipotential 3. Legs
4. Genital tuber
precursor 7. Urethral groove
8. Urogenital folds
At the ninth week, there are not yet any notable differences.

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Sex Determination: 5 criteria

Conclusions: ●Chromosomal sex:
● Males need SRY gene to be expressed to develop ● Males usually have one X and one Y chromosome
● Females usually have two X chromosomes
testes
● Testes need to produce Testosterone and anti- ●Gonadal sex:
Müllerian hormone to produce internal sex organs – ●Males usually have testes
Wolffian system ● Females usually have ovaries

● Testosterone is also needed to produce external ●Hormonal sex:

male genitalia ●Androgens
● Wolffian system must have receptor for the ●Estrogens
hormones ● Phenotypic sex (the “look”):
● In the absence of hormones or receptors a genetic ● Males and females have different internal and external genitalia
male (XY) will develop internal and external ● Males and females look different –have different secondary sex
female sex organs characteristics!

●Behavioral Sex
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Alfred Jost’s experiments on rabbits

● What about females?

◦ Without testosterone, female structures
develop
●But is it really all there is to it…?

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Androgen insensitivity syndrome

● XY genotype – genetic male
● Testes are present
●But is it really all there is to it…?
● Testes produce testosterone and anti-Müllerian
◦ The role of Foxl2 hormones
● But: Wolffian system lacks testosterone receptors and
male internal organs do not develop
● Without testosterone receptors external genitalia
develops female by default
● Anti-Müllerian hormones still have defeminizing effect –
female internal organs do not develop
● At puberty the person develops female body
● No ovaries, no uterus, infertile

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Androgen insensitivity syndrome Androgen insensitivity syndrome

● Individuals with complete androgen insensitivity, as well as
individuals with severe deficit in testosterone production are born
with a complete female phenotype, despite having a 46, XY
karyotype. They have no signs of genital masculinization.

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Androgen insensitivity syndrome

genetic males (XY)
Testes produce AMH no
internal female genitalia, unable ● Graphic Image next!
to bear children

Testes produce testosterone but

in the absence of functional
receptors internal and external
male genitalia fail to develop;
external genitalia develops along
the female default line

What about the brain?

Testes
Brain is less affected by
androgens than in a “typical”
female – is it a female or a male?
Role of the Y chromosome in the
brain?
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Androgen insensitivity syndrome

genetic males (XY)
● cryptorchidism
5alpha-reductase deficiency

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Male External Genitalia: 5alpha-reductase deficiency: normal internal

male organs, but external male organs fail to develop, b/c you need DHT 5alpha-reductase deficiency
for their development

Lacking External genitalia develop as In utero, DHT is essential

female. However, internally for the normal male
5-alpha-reductase type 2 deficiency is an autosomal recessive sex-limited condition. dihydrotestosterone (DHT)
the gonadal tissue is that of development of the
Mutations of this enzyme result in the impossibility to convert testosterone into the in utero, at 18 months, the
external genitalia. After
appearance is female normal male and his
more physiologically active dihydrotestosterone essential to provide masculinization of
though undescended karyotype is 46 XY (normal complete maturation, DHT
male external genitalia in uterus. As a result individuals with mutant 5-alpha-reductase male). seems to have no
testes are present.
type 2 are born with ambiguous genitalia. important biological
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5alpha-reductase deficiency 5alpha-reductase deficiency

With the testosterone surge 69

at puberty, the phenotype
Just before puberty, And for the rest of their lives, the
changes to male: the voice
prior to the guevedoces resemble the other
deepens, the testes descend,
testosterone Dominican men in all respects
the phallus grows, erection
outpouring, the except:
and ejaculation begin, and a
phenotype is still * Beard growth is scanty.
male psychosexual
female. * There is no hairline recession.
orientation develops.
* None has acne.
* The prostate remains small.
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Persistent Mullerian Duct Syndrome

Remember:
● SRY: testes
● Testosteron: internal male genitalia
● DHT: external male genitalia
● AMH: destroy Mullerian system
● True hermaphrodite (very rare)?
● AMH is not produced or there are no
receptors for it
● As a result both sets of internal
reproductive organs develop

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Turner Syndrome: ovarian hormones are not required for

the development of the external female genitalia*
Abnormalities in genetic females
● Lack or damage to the second
chromosome that comes from the
father (X or Y): X0
● Ovaries rarely develop completely,
b/c 2 X chromosomes are needed,
but:
● Phenotypic females: female external
and internal genitalia
● Ovaries fail to produce steroid
hormones – need hormonal therapy
at puberty
● Slow growth rates
● Can have hearing loss, mental
retardation, kidney dysfunction and
webbing of the neck

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Congenital adrenal hyperplasia (CAH)

Phenotypic sex: External genitalia is an overdevelopment of the adrenal glands from birth
Females Most common cause of the intersex condition.
Caused by a genetic defect in which not enough cortisol is
● Turner syndrome: produced, which leads to overstimulation of the adrenal gland
and excessive release of adrenal androgens.
◦ Girls without normal ovaries
The female fetus becomes partly masculinized/virilized.
◦ But normal internal and external sex organs
Thus:
A conditional must be met (male hormones) for
the differentiation of the internal male genitalia
Differentiation of internal and external female sex
organs requires no hormones – it has been
considered default

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Congenital adrenal hyperplasia (CAH)

Super Female Syndrome
● Too much testosterone can create female
(XX) Pseudohermaphrodites ● XXX genotype
•Usually normal gonads and ● Female phenotype
internal sex organs b/c androgens
are released later in the ● Diminished fertility
development
● Occasionally mental retardation
•Administration of cortisol is
prescribed to counteract the effect
of androgen release
•more tomboyish than unaffected
sisters
•more aggressive than unaffected
sisters
•increased likelihood of
masculinized gender identity 67 68

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Klinefelter Syndrome
● Extra X chromosome: XXY
● Presence of Y is sufficient
for the SRY gene to be
Abnormalities in genetic males activated, so:
● Phenotypic males
● Testes are developed but
reduced sperm
production
● Learning disabilities

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Super Male Syndrome

● XYY genotype
● Phenotypic male
● Can be sterile
● Increased aggressiveness?
● famous serial murder case: Richard Speck, 1970s, murdered
8 women
● subsequent studies indicate inconsistent findings
● Cognitive skills:
● intelligence within normal range
● some learning and school related difficulties

Intersex Society of North America

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