G2. Development of Female Genitalia

I. Indifferent Stage and Sex Determination

Basic Principle

• Early embryo: internal and external genitalia are initially indifferent.
• Before week 7: male and female external genital regions look similar; female external genitalia become clearer around 12 weeks.
• Female development: occurs in the absence of testicular differentiation, anti-Mullerian hormone and high androgen effect.
• Male pathway: Y chromosome with SRY gene → testis-determining factor → testes.
• Sertoli cells: anti-Mullerian hormone → regression of Mullerian ducts.
• Leydig cells: testosterone → Wolffian ducts; testosterone → DHT → male external genitalia.

Exam Logic

• No SRY/testis → no anti-Mullerian hormone → Mullerian ducts persist.
• No strong androgen/DHT effect → external genitalia differentiate in female direction.
• Disorders of sex development: abnormal chromosome, gonad, hormone production, hormone action, or duct development.

II. Gonadal Development

Primordial Germ Cells and Ovary Formation

• Primordial germ cells: first appear in yolk sac endoderm near the primitive hindgut around week 3.
• Migration: yolk sac → hindgut dorsal mesentery → undifferentiated gonadal ridge.
• By week 6-8: germ cells reach the gonadal ridge and proliferate.
• Indifferent gonad: can become testis or ovary depending on genetic signals.
• Ovary pathway: absence of SRY/testis-determining factor → cortical sex cords predominate → ovarian differentiation.
• Follicles: first recognizable around mid-gestation, classically about 20 weeks.
• Primary follicle: primary oocyte surrounded by granulosa cells and theca cells.
• Oogonia enter meiosis I → primary oocytes; arrest in prophase I until puberty/ovulation.

Clinical Points

• Failure of germ cell survival or ovarian development → streak gonads / gonadal dysgenesis → primary amenorrhea and hypergonadotropic hypogonadism.
• Y-chromosome material in dysgenetic gonad → gonadoblastoma risk → gonadectomy is often indicated.
• Ovarian development is separate from Mullerian duct development → ovaries may be normal even if uterus/upper vagina are absent.

III. Internal Genital Ducts

Mullerian / Paramesonephric Ducts

• Mullerian ducts: main source of female internal genital tract.
• Derivatives: fallopian tubes, uterus, cervix and upper vagina.
• Development: paired ducts form, elongate, cross medially and fuse caudally.
• Cranial unfused parts → fallopian tubes; fused caudal part → uterus, cervix and upper vagina.
• Septum resorption after fusion → single uterine cavity and cervical canal.
• Absence of anti-Mullerian hormone in female fetus → Mullerian ducts persist and develop.

Wolffian / Mesonephric Ducts

• Wolffian ducts: embryonic ducts that form male internal genitalia under testosterone effect.
• Female fetus: absence of strong testosterone effect → Wolffian ducts regress.
• Female remnants: Gartner duct cyst, epoophoron, paroophoron.
• Clinical: Gartner duct cyst may present as a lateral vaginal wall cyst.

IV. External Genitalia and Lower Vagina

External Genital Development

• Indifferent external structures: genital tubercle, urogenital folds, labioscrotal swellings and urogenital sinus.
• Female differentiation occurs without high DHT effect.
• Genital tubercle → clitoris; urogenital folds → labia minora; labioscrotal swellings → labia majora.
• Urogenital sinus → vestibule and lower vagina contribution.
• Clinical point: androgen excess in fetal life → virilized external genitalia / ambiguous genitalia.

Vagina

• Upper vagina: Mullerian origin.
• Lower vagina: urogenital sinus origin.
• Canalization failure → imperforate hymen or transverse vaginal septum → primary amenorrhea with cyclic pain.

V. High-Yield Developmental Anomalies

Mullerian Development Problems

1. Agenesis/hypoplasia: Mullerian agenesis / Mayer-Rokitansky-Kuster-Hauser syndrome → absent uterus/upper vagina, normal ovaries, 46,XX.
2. Fusion defect: uterus didelphys or bicornuate uterus.
3. Septum resorption defect: septate uterus.
4. Obstructive anomaly: transverse vaginal septum, obstructed hemivagina.

Sex Differentiation Disorders

• Complete androgen insensitivity: 46,XY + testes + anti-Mullerian hormone present → no uterus; androgen receptor defect → female phenotype.
• Congenital adrenal hyperplasia: 46,XX + excess androgens → virilized external genitalia, internal female organs present.
• Gonadal dysgenesis: abnormal gonadal development → low sex steroids → delayed puberty / primary amenorrhea.