199. Sexual Differentiation

Question 1

When does sex differentiation occur?
When do male and female gonads develop?
What genes are necessary for sex development?

Answer 1

W8
Male: W8, Female: W10
genes: SF1 (gonad/adrenal development), SRY/SOX9 (testis), SOX9/WNT4 (ovary)

Question 2

Between males and females, how do gonads influence rest of genitalia development?

Answer 2

Females:
Ovary = Granulosa cell = E = follicle development (Mullerian structures grow, wolffian ducts regress)

Males:
Testis = Sertoli cells = AMH = Mullerian regression (SF1/SOX9 regulated, paracrine effects)
Testis = Leydig Cells = T, DHT = Male Sex differentiation (needs 5a-reductase 2 to convert T to DHT; wolffian grows, mullerian regresses)

Question 3

What are the 4 types of sex chromosome DSD?

• karyotype
• internal gonad
• internal mullerian
• ext anatomy
• cancer risk
• gender
• presentation age
• puberty?

Answer 3

1. Turner Syndrome: 45X
2. Klinefelter Syndrome: 47XXY
3. Mixed Gonadal Dysgenesis: 45X/46XY mosaicism
   - int gonad: streak gonad, dysgenetic testicle (No AMH/T, some AMH/T)
   - int mullerian: usually on one side
   - ext anatomy: variable/asymmetric
   - high cancer risk GCT
   - variable gender (more male)
   - CP: birth
   - some puberty (testicle may have T/sperm)
4. Ovotesticular DSD: Any karyotype
   - int gonad: ovary, testis, ovotestis combo (may be dysgenetic)
   - int mullerian: maybe
   - ext anatomy: variable
   - high cancer risk GCT
   - gender: variable
   - cause: SOX9 duplication, others
   - CP: birth
   - puberty: sometimes

Question 4

What are the two broad categories of 46XY DSD and list the types of each

Answer 4

1. Disorders of Gonadal Development
   - Complete Gonadal Dysgenesis
   - Partial Gonadal Dysgenesis
   - Ovotesticular DSD
2. Disorders of Androgen Synthesis/Action
   - Complete Androgen Insensitivity
   - Partial Androgen Insensitivity
   - 5a-Reductase Deficiency

Question 5

Compare and contrast
Complete gonadal dysgenesis, partial gonadal dysgenesis
- karyotype
- int anatomy
- mullerian
- ext anatomy
- cancer risk
- cause
- cp
- gender
- puberty

Answer 5

both 46XY
Complete GD
- int anatomy: streak gonads (no T, no AMH)
- mullerian: both present
- ext anatomy: female
- high cancer risk
- cause: Sox9 +/- SF1 Mutations
- cp: prenatal or pubertal
- Female gender
- puberty: none, but can carry pregnancy

Partial GD

• int anatomy: dysgenic testicles
• mullerian: maybe
• high cancer risk
• variable gender
• cause: idiopathic
• cp: birth
• puberty: sometimes (virilization)

Question 6

Compare/Contrast these diseases: Complete Androgen Insensitivity, Partial Androgen Insensitivity, 5aReductase Deficiency

• karyotype
• int anatomy
• mullerian
• ext anatomy
• cancer risk
• cause
• cp
• puberty

Answer 6

all 46XY
Complete Androgen insensitivity (high AMH/T but no TR)
- Int Anatomy: Testicles
- Mullerian: No
- Ext Anatomy: female, sparse sexual hair
- LOW cancer risk
- gender: Female
- Cause: AR mutation
- CP: variable
- puberty: breast development (T converted to E)

Partial Androgen Insensitivity (some T)

• Int Anatomy: Testicles
• Mullerian: No
• Ext: Variable
• High cancer risk
• gender: variable
• cause: AR mutation
• CP: birth
• puberty: some virilization

5a-Reductase Deficiency

• Int: Testicles
• Mullerian: No
• Ext: Variable
• No cancer risk
• Variable gender (more male)
• Cause: 5ARD2 mutation
• CP: birth or puberty (where T needed more potently)

Question 7

What are the categories of 46XX DSD and explain the following for each

• int anatomy
• mullerian
• ext anatomy
• cancer risk
• gender
• cause
• cp
• puberty?

Answer 7

1. Disorder of Gonadal Development: Ovotesticular DSD and TESTICULAR DSD
   - int: testicles
   - mullerian: no
   - ext: male
   - NO cancer risk
   - gender: male
   - cause: 46XX + SRY gene (no sperm production but stimulates testicle formation)
   - cp: prenatal/seeking fertility aid
   - normal male puberty

2. Androgen Excess
CAH-21 HYDROXYLASE DEFICIENCY
- int: ovaries
- mullerian: yes
- ext: variable 
- NO cancer risk
- most female
- cause: 21 hydroxylase mutation = high T production
- CP: birth
- normal female puberty

Question 8

Management for DSD Pt

Answer 8

Medical: HRT, assess for other syndromes, fertility tx

Surgical: consider timing, reversibility, decision making
Prophylactic gonadectomy for cancer risk, diagnostic laparascopy, hypospadias repair, caution with genitoplasty (make genitals look normal)

Psychosocial: adapt, understand, discuss