1 How do we (and other animals) become male or female?

1

How do we How do we (and other animals) (and other animals)

become male or become male or female?female?

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Sex DeterminationSex Determination

The event that determines whether The event that determines whether an individual will become male or an individual will become male or femalefemale

Sexual DifferentiationSexual Differentiation

The developmental process of The developmental process of becoming male or femalebecoming male or female

Sexual Differentiation: OverviewSexual Differentiation: Overview

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• • Chromosomal sexChromosomal sex • • Gonadal sexGonadal sex

• • Gametic sexGametic sex • • Hormonal sexHormonal sex • • Morphological sexMorphological sex

• • Behavioral sexBehavioral sex • • Gender identityGender identity • • Gender roleGender role

• • Legal sexLegal sex

What is Sex?What is Sex?


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Jost’s Model of Sexual Differentiation:Jost’s Model of Sexual Differentiation:


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What determines What determines gonadal sex gonadal sex

(development of (development of testes vs. ovaries)?testes vs. ovaries)?

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Germinal ridge:Germinal ridge:

• Thickened ridge of tissue on surface of each mesonephros (protokidney)

• Can develop into a testis or an ovary

Nelson 2005 Fig. 3.4

Gonadal Differentiation Gonadal Differentiation

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Gonadal Differentiation: SRY GeneGonadal Differentiation: SRY Gene (Sex-Determining Region of Y Chromosome)(Sex-Determining Region of Y Chromosome)

TDF binds to DNA and regulates genescontrolling development of testes

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Evidence for role of SRY gene:

• SRY is activated shortly before gonads differentiate.

• XY phenotypic females often have mutations in SRY (humans, mice).

• XX phenotypic males often have SRY-containing translocation to X chromosome.

Gonadal Differentiation: SRY GeneGonadal Differentiation: SRY Gene

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Evidence for role of SRY gene:

• SRY is activated shortly before gonads differentiate.

• XY phenotypic females often have mutations in SRY (humans, mice).

• XX phenotypic males often have SRY-containing translocation to X chromosome.

BUT: Autosomal genes also contribute to testis development.

• XX transgenic mice: introduction of SRY causes testicular development.

Gonadal Differentiation: SRY GeneGonadal Differentiation: SRY Gene

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Gonadal Differentiation: Gonadal Differentiation: Ovary-Determining GenesOvary-Determining Genes

• Unclear if any exist.

• Have been hypothesized to exist and to be switched off in males by activation of SRY gene.

• Two X chromosomes necessary for normal ovarian development.

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Gonadal Differentiation Gonadal Differentiation

• TDF acts locally – not blood-borne.

• In mammals, sex steroids have limited effects.

• Germinal ridge is initially indifferent/bipotential.

• TDF expression

Human fetal Human fetal ovariesovaries

Human fetal Human fetal testestestes

no TDF expression

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What determines What determines differentiation differentiation of the internal of the internal

reproductive tracts?reproductive tracts?

13Nelson 2005 Fig. 3.5

2 duct systems2 duct systemsinitially present initially present in each embryo:in each embryo:Wolffian ductsWolffian ductsMüllerian ductsMüllerian ducts

Reproductive Tract DifferentiationReproductive Tract Differentiation

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Reproductive Tract DifferentiationReproductive Tract Differentiation1.1. Wolffian ductsWolffian ducts

2.2. Müllerian ductsMüllerian ducts

• T

• No T

• Müllerian inhibitory hormone (MIH) from testes

• No MIH

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Silverthorn 2009 Fig. 26-3

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Wolffian ducts

Müllerianducts

Testes No Testes

T

MIH

vas deferensepididymisseminal vesicles

regression

No T

No MIH

fallopian tubesuteruscervix

regression


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What determines What determines differentiation differentiation of the external of the external

genitalia?genitalia?

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Differentiation of External GenitaliaDifferentiation of External Genitalia

Nelson 2005 Fig. 3.7

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Differentiation of External GenitaliaDifferentiation of External Genitalia

•• Bipotential anlagenBipotential anlagenGenital folds, genital tubercleIdentical in males and females until week 6-8

•• Effects of androgens (males)Effects of androgens (males)Genital tubercle penisGenital folds scrotum (testes descend later)

•• Absence of androgens (females)Absence of androgens (females)Genital tubercle clitorisGenital folds labia

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Summary of Sexual DifferentiationSummary of Sexual Differentiation

Silverthorn 2009 Table 26-1

ANOMALIES OF ANOMALIES OF SEXUAL SEXUAL

DIFFERENTIATIONDIFFERENTIATION

What can go wrong, and What can go wrong, and what do the exceptions what do the exceptions tell us about the rules?tell us about the rules?

True HermaphroditismTrue Hermaphroditism• Both ovarian and testicular tissue are

present in the same individual– ovary on one side, testis on the

other – “ovotestes”

• Uncommon• Usually 46,XX; sometimes 46,XX/46,XY

chimerism or mosaicism

• Phenotypically variable

• Some are fertile as females

• Gonadotropin levels: high in infancy and post-pubertally; normal prepubertal hiatus

• Immature genital tract & external genitals; short stature

• Often lethal prenatally

Anomalies in Chromosomal Females: Anomalies in Chromosomal Females: Turner Syndrome (XO)Turner Syndrome (XO)

Wilson & Foster 1987 Fig. 11-28

Anomalies in Chromosomal Females: Anomalies in Chromosomal Females: Turner Syndrome (XO)Turner Syndrome (XO)

• Causes masculinization of the external genitalia in females.

• Can be mild to severe.

• Can be treated with surgery and exogenous steroids.

Anomalies in Chromosomal Females: Anomalies in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH)Congenital Adrenal Hyperplasia (CAH)

X X

Low aldosterone

Low cortisol

High androgens

Adrenal Cortex

Zona reticularisZona fasciculataZona glomerulosa

X


Money 1987


Wilson & Foster 1987 Fig. 11-53


• Testes develop; Wolffian and Müllerian ducts regress; external genitalia appear female.

• Female body type and gender identity, but sterile.

Anomalies in Chromosomal Males: Anomalies in Chromosomal Males: Androgen Insensitivity Syndrome (AIS)Androgen Insensitivity Syndrome (AIS)

(Testicular Feminization (TFM))(Testicular Feminization (TFM))

• No 5-reductase – can’t convert T to DHT.

Anomalies in Chromosomal Males: Anomalies in Chromosomal Males: 55-Reductase Deficiency-Reductase Deficiency

(Guevodoces, Penis at Twelve)(Guevodoces, Penis at Twelve)

55ReductaseReductase

55Dihydro-Dihydro-testosterone testosterone (DHT)(DHT)

H

5

17-beta 17-beta Estradiol Estradiol (E2)(E2)

AromataseAromatase

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A

Testosterone Testosterone (T)(T)

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• XY infants have ambiguous genitalia and small, undescended testes.





1.1. XXY (Klinefelter Syndrome)XXY (Klinefelter Syndrome) Phenotypically maleSmall testes, androgen deficiency, low sperm production (sterile)GynecomastiaLow intelligence

Nelson 2005 Fig 3.14

XXY XYY

2.2. XYYXYYPhenotypically maleNormal sexual

developmentExtremely tallLow intelligence,HyperactiveAntisocial

Anomalies in Chromosomal Males: Anomalies in Chromosomal Males: TrisomiesTrisomies

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1 How do we (and other animals) become male or female?