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

2. Sexual Differentiation: Overview
Sex Determination
The event that determines whether an individual will become male or female
Sexual Differentiation
The developmental process of becoming male or female

3. Sexual Differentiation: Overview
What is Sex?
• Chromosomal sex
• Gonadal sex
• Gametic sex
• Hormonal sex
• Morphological sex
• Behavioral sex
• Gender identity
• Gender role
• Legal sex

4. Sexual Differentiation: Overview
Jost’s Model of Sexual Differentiation:

5. What determines
gonadal sex
(development of
testes vs. ovaries)?

6. Gonadal Differentiation
Nelson 2005 Fig. 3.4
Germinal ridge:
• Thickened ridge of tissue on surface of each mesonephros (protokidney)
• Can develop into a testis or an ovary

7. Gonadal Differentiation: SRY Gene
(Sex-Determining Region of Y Chromosome)
TDF binds to DNA and regulates genes
controlling development of testes

8. Gonadal Differentiation: SRY Gene
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.

9. Gonadal Differentiation: SRY Gene
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.
• XX transgenic mice: introduction of SRY causes testicular development.
BUT: Autosomal genes also contribute to
testis development.

10. Gonadal Differentiation: Ovary-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.

11. Gonadal Differentiation
• Germinal ridge is initially indifferent/bipotential.
• TDF expression 
no TDF expression 
• TDF acts locally – not blood-borne.
• In mammals, sex steroids have limited effects.
Human fetal
ovaries
Human fetal
testes

12. of the internal reproductive tracts?
What determines
differentiation
of the internal reproductive tracts?

13. Reproductive Tract Differentiation
2 duct systems
initially present
in each embryo:
Wolffian ducts
Müllerian ducts
Nelson 2005 Fig. 3.5

14. Reproductive Tract Differentiation
1. Wolffian ducts
• T 
• No T 
2. Müllerian ducts
• Müllerian inhibitory hormone (MIH) from testes 
• No MIH 

15. Reproductive Tract Differentiation
Silverthorn Fig. 26-3

16. Reproductive Tract Differentiation
Testes
No Testes T
MIH
No T
No MIH
Wolffian
ducts
Müllerian
ducts
vas deferens
epididymis
seminal vesicles
regression
regression
fallopian tubes
uterus
cervix

17. of the external genitalia?
What determines
differentiation
of the external genitalia?

18. Differentiation of External Genitalia
Nelson Fig. 3.7

19. Differentiation of External Genitalia
• Bipotential anlagen
Genital folds, genital tubercle
Identical in males and females until week 6-8
• Effects of androgens (males)
Genital tubercle  penis
Genital folds  scrotum (testes descend later)
• Absence of androgens (females)
Genital tubercle  clitoris
Genital folds  labia

20. Summary of Sexual Differentiation
Silverthorn Table 26-1

21. ANOMALIES OF SEXUAL DIFFERENTIATION
What can go wrong, and
what do the exceptions
tell us about the rules?

22. True 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

23. Anomalies in Chromosomal Females: Turner Syndrome (XO)
• Gonadotropin levels: high in infancy and post-pubertally; normal prepubertal hiatus
Immature genital tract & external genitals; short stature
• Often lethal prenatally

24. Anomalies in Chromosomal Females: Turner Syndrome (XO)
Wilson & Foster 1987 Fig

25. Anomalies in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH)
• Causes masculinization of the external genitalia in females.
• Can be mild to severe.
• Can be treated with surgery and exogenous steroids.

26. Anomalies in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH)
Adrenal Cortex
Zona glomerulosa
Zona fasciculata
Zona reticularis X X
High androgens
Low aldosterone
Low cortisol

27. Anomalies in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH)
Money 1987

28. Anomalies in Chromosomal Females: Congenital Adrenal Hyperplasia (CAH)
Wilson & Foster 1987 Fig

29. Anomalies in Chromosomal Males: Androgen Insensitivity Syndrome (AIS)
(Testicular Feminization (TFM))
• Testes develop; Wolffian and Müllerian ducts regress; external genitalia appear female.
• Female body type and gender identity, but sterile.

30. Anomalies in Chromosomal Males: 5a-Reductase Deficiency
(Guevodoces, Penis at Twelve)
• No 5a-reductase – can’t convert T to DHT.
• XY infants have ambiguous genitalia and small, undescended testes.
5a-Reductase
5a-Dihydro-testosterone (DHT) H 5
17-beta Estradiol
(E2)
Aromatase 17 A
Testosterone (T) 19

31. Anomalies in Chromosomal Males: 5a-Reductase Deficiency
(Guevodoces, Penis at Twelve)

32. Anomalies in Chromosomal Males: 5a-Reductase Deficiency
(Guevodoces, Penis at Twelve)

33. Anomalies in Chromosomal Males:
Trisomies
1. XXY (Klinefelter Syndrome)
Phenotypically male
Small testes, androgen deficiency, low sperm production (sterile)
Gynecomastia
Low intelligence
Nelson 2005 Fig 3.14
XXY
XYY
2. XYY
Phenotypically male
Normal sexual development
Extremely tall
Low intelligence, Hyperactive
Antisocial