Disorders of Sex Development

(DSD)
Development of Reproductive System
SEX CHROMOSOMES

• Male  XY chromosome • Female  XX chromosome

determined during fertilization

• SRY (sex-determining region on Y) is responsible for testis formation and

called TDF (testis-determining factor)

• Disorder: monosomy (Turner syndrome, 45XO); trisomy (Klinefelter

syndrome, 47 XXY); mosaic (45 XO/46 XY); and chimera (46 XX/ 46XY)
 Development of Reproductive System
GONAD FORMATION
• Initially, gonad is a pair of • Primordial germ cell: 3rd week (wall of yolk
longitudinal ridges  genital or sac)  4th week (migrate along dorsal
gonadal ridges (10 days gestation) mesentery)  6th week (invade genital ridge)
Development of Reproductive System
GONAD FORMATION MALE

• Genital ridge epithelium proliferates  irregularly

shaped cords (primitive sex cords)
• Indifferent gonad/bipotential gonad

• SRY  testis or medullary cord

• Cords break up into tiny cell strands (rete testis)
• Tunica albuginea separates testis cords from
surface epithelium
• 4th month  horseshoe-shaped, testicular cords
contain primitive germ cell + Sertoli cells
• Interstitial cells of Leydig  testosterone (8th
week)  sex differentiation
 Development of Reproductive System
GONAD FORMATION FEMALE

• No Y chromosome  medullary cord

regress, cortical cord develops
• Primitive sex cords  irregular cell
clusters in medullary part

• 7th week: cortical cords penetrate

underlying mesenchyme
• 3rd month: cortical cords proliferate and
surround each oogonium with a layer
• Oogonia + follicular cells  primordial of epithelial cells  follicular cells
follicle
Development of Reproductive System
GENITAL DUCTS

• Initially, male and female have 2 pairs of

genital ducts:
− Mesonephric ducts (Wolffian)
− Paramesonephric ducts (Müllerian)

• Caudal tip of combined ducts projects

into posterior wall of urogenital sinus 
small swelling (sinus tubercle)

MALE FEMALE
Development of Reproductive System
GENITAL DUCTS MALE

• anti-Müllerian hormone (AMH) by

Sertoli cells  paramesonephric duct
degenerate, except small portion at
cranial ends (appendix testis)

• Testosterone stimulate mesonephric

duct into: efferent ductules,
epididymis, vas deferens, and
seminal vesicles
After descent
4th month of the testis
 Development of Reproductive System
GENITAL DUCTS FEMALE
• Presence of estrogen + absence of
testosterone and AMH  paramesonephric
1
duct develop and mesonephric duct
degenerate
• 3 parts:
1. Cranial vertical part opens into abdominal
cavity
2. Horizontal part crosses mesonephric duct
2 3. Caudal vertical part fuses with opposite
side

3 Part 1+2  Uterine tube (fallopian tube)

After descent
of the ovary Part 3  Uterine canal (uterus, upper
2nd month portion of vagina)
 Development of Reproductive System
EXTERNAL GENITALIA
• 4th – 6th weeks: cloaca divided into
anterior urogenital sinus and posterior
anorectal canal
• Urogenital sinus  prostate (male) and
lower portion of vagina (female)
4th weeks 6th weeks
INDIFFERENT STAGE
• 3rd week of development: cloacal folds
are formed around cloacal membrane
• Cranial to cloacal membrane: genital
tubercle; caudally, subdivided into urethral
folds (anterior) and anal folds (posterior)
• Genital swellings  scrotal swellings
(male) and labia majora (female)
Development of Reproductive System
EXTERNAL GENITALIA MALE
• Scrotal swellings in inguinal region  move
caudally, each swelling makes up half of the
scrotum.
• Disorder: micropenis, hypospadias, epispadias
DHT
• Elongation of genital tubercle 
phallus
• Phallus pulls urethra fold forward 
form lateral walls of urethral groove
• Epithelial lining of the groove 
urethral plate
• 3rd month, urethral fold close over
urethral plate  penile urethra
• 4th month, ectodermal cells from tip of
the glans penetrate inward, form
short epithelial cord (external
urethral meatus)
Development of Reproductive System
EXTERNAL GENITALIA FEMALE
ESTROGEN

• Genital tubercle elongates slightly

clitoris
• Urethral folds do not fuse  labia
minora
• Genital swellings enlarge  labia
majora
• Urogenital groove is open 
vestibule
Development of Reproductive System
MOLECULAR ASPECT

• SRY + SOX9 induce testis to secrete

FGF9  tubules from mesonephric
-
duct penetrate gonadal ridge
• Steroidogenesis factor 1 (SF1) 
differentiation of Sertoli and Leydig
cells -
• SF1 + SOX9  AMH concentration

• WNT4  ovary-determining gene

 Müllerian ducts regression
• Vas deferens
AMH Wolffian ducts • Seminal Vesicles
• Epididymis
SRY (+)
Testis
• Penis
XY 5α-reductase External • Scrotum
Testosterone DHT
genitalia • Urethra
Bipotential Gonad • Prostate

• Fallopian tube
XX Müllerian ducts • Uterus
• Upper portion of vagina
Wolffian ducts regression
Ovum
SRY (-)
• Labia
External • Clitoris
genitalia • Lower portion of vagina
• Urethra
6-9 weeks gestation 9-12 weeks gestation
Determination phase Differentiation phase
 Normal Development of Reproductive System

Determination Differentiation
phase phase
- Development of internal and
- Determine type of gonad
external genitalia
- Affected by chromosomal sex
- Affected by hormonal factor

Disruption in these phases  DSD

DSD are heterogeneous group of congenital conditions that result in

discordance between an individual’s sex chromosomes, gonads, and/or
anatomic sex

46 XX DSD
• DSD ovotesticular
• DSD testicular
• Excess of androgen
• Congenital adrenal
hyperplasia (CAH)
• CYP19 placenta aromatase
enzyme deficiency
• Exogenous androgen
(progestogen)
• Developmental disorders of
Müllerian duct
• Fryns syndrome  uterus
bicornis
• Mayer-Rokitansky-Kruster-
hauser (MRKH) syndrome 
Mülleri agenesis/hypoplasia • Other: isolated hypospadias,
CLASSIFICATION OF DSD Sex chromosome
46 XY DSD DSD
• Complete gonadal dysgenesis
(Swyer syndrome) • 45 XO (Turner syndrome)
• Partial gonadal dysgenesis • 47 XXY (Klinefelter
syndrome)
• Androgen synthesis or action
• Congenital adrenal • 45 X0/46 XXY (Mixed
hyperplasia (CAH) Gonadal Dysgenesis,
• Leydig cells hypoplasia/aplasia Ovotesticular DSD)
• Smith-Lemi-Opitz (DHCR7)
syndrome • 46 XX/46 XY (Chimeric,
• 5α-reductase type 2 deficiency ovotesticular DSD)
• 17βHSD enzyme deficiency
• P450 oxidoreductase (POR)
deficiency
• Androgen Insensitivity
Syndrome (AIS)
micropenis, undescended testis
 Diagnosis of DSD
ANAMNESIS

• History of pregnancy
• tablets/hormones (estrogen,progestin,androgen) taken in the first 2 months
of pregnancy
• Maternal virilization  androgen-producing maternal tumor
(arrhenoblastoma)

• Family history
• neonatal death or genital organ abnormalities in previous siblings
• abnormal puberty development and infertility in close relatives.
 Diagnosis of DSD
PHYSICAL EXAM

• Vital sign : blood pressure  hypertension (DSD - 11β hydroxylase

deficiency)
• Puberty development
• Associated syndrome
• External genitalia
• Palpable and/or symmetrical gonad
• Size of phallus
 Diagnosis of DSD
PHYSICAL EXAM Associated syndrome

Klinefelter syndrome Swyer syndrome Fryns syndrome

Persistent Mullerian Antley-Bixler syndrome Turner syndrome

duct syndrome
Mayer-Rokitansky-
Smith-Lemli-Opitz Meckel-Gruber syndrome
Kruster-hauser
syndrome
syndrome
 Diagnosis of DSD
PHYSICAL EXAM External Genitalia

Gonad

1) Palpable 2) Unilateral/Asymmetries
• Inadequate testosterone • DSD ovotesticular
production • Mixed gonadal dysgenesis
• Androgen receptor
deficiency/defect
3) Unpalpable
• 5 α-reductase enzyme
deficiency • Need additional examination
• Testicular dysplasia
 Diagnosis of DSD
PHYSICAL EXAM External Genitalia

Prader scale Degree of virilization of the external genitalia

 Diagnosis of DSD
External Length of penis based on Schonfeld
PHYSICAL EXAM Genitalia and Bebe
Age Mean + SD (cm)
< 30 weeks + 0,5
Phallus
< 34 weeks + 0,4
• Normal-term male penis: 3,5 + 0,7 cm Aterm + 0,4
0-5 months 3,8 + 0,8
• Normal-term female clitoris: < 1 cm 6-12 months 4,1 + 0,8
1-2 years 4,6 + 0,8
• Micropenis: a stretch penile length of
2-3 years 5,0 + 0,8
less than -2,5 SD according to his age,
3-4 years 5,4 + 1,0
without other structural abnormalities of
4-5 years 5,6 + 0,7
the penis (hypospadias)
5-7 years 6,0 + 0,9
7-9 years 6,3 + 1,0
9-11 years 6,3 + 1,0
 Diagnosis of DSD
PHYSICAL EXAM External Genitalia

Anogenital ratio
• the distance between anus and
posterior fourchette divided by the
distance between anus and base of
phallus/clitoris
• Ratio >0,5  virilization

A = anus
C = phallus/clitoris
F = fourchette posterior
 Diagnosis of DSD
LABORATORY STUDIES IMAGING STUDIES
Chromosomal analysis USG MRI
Hormonal analysis Genitography
• LH/FSH
• 17-OH Progesterone OTHERS
• Testosterone serum & DHT
• Androstenedione
Cystoscopy/Laparoscopy
• Antimüllerian hormone (AMH)/müllerian-
inhibiting substance (MIS) level
Molecular diagnostic
AR, SRY, SF1, WT1, CYP21, DAX-1,
17βHSD, 5α-reductase-2
 Algorithm for
diagnosing DSD

CGD = complete gonadal dysgenesis

PGD = partial gonadal dysgenesis
FSH = follicle-stimulating hormone
LH = luteinizing hormone
DHT = dihydrotestosterone
hCG = human chorionic gonadotropin
 Diagnostic
approach for 46
XY DSD
Approach to investigating
adolescent girls with
primary amenorrhoea
 Management of DSD
Experienced multidisciplinary team
Endocrinology, surgery and/or urology, clinical psychology/psychiatry, radiology, nursing
and neonatology

Ethical principle
• Minimize physical risk
• Minimize psychological risk
• Preserve potential fertility
• Preserve ability to have satisfactory sexual relationships
• Respect parental desires and beliefs

Infertility
• Information about risk of infertile  need oocyte donation, oligo/azoospermia
 Management of DSD
Gender Assignment

Diagnosis Typical gender assignment

46XX CAH Female (advanced Prader stages,
late diagnosis consideration
to male gender assignment)
Complete AIS Female
Partial AIS Male or female
Mixed gonadal dysgenesis (MGD) Male or female
Ovotesticular DSD Male or female
17βHSD/5α-reductase-2 Male
deficiency
 Management of DSD
Hormone Therapy hypogonad

• Initiate & maintain secondary sexual characteristic development and

psychosexual development.
• Initiation and prevention of osteopenia/osteoporosis

• Male : short-acting T esters is 25 to 50 mg/month IM.

T undecanoate & transdermal patch (not available in Indonesia)

• Female : estrogen, 17β-estradiol (oral or transdermal).

Oral: 5 mcg/kg daily. Transdermal: 3,1-6,2 mg/24 h overnight
Progesterone: induce endometrial cycling and menses in patients with a uterus
Medroxyprogesterone acetate 5-10 mg/day, micronized progesterone (200
mg/day)
 Management of DSD
Surgery Case-by-case basis

• Feminizing DSD Timing of Gonadectomy

• Clitoroplasty Partial AIS (with female gender At diagnosis, often in first 6 months of life
• Vaginoplasty assignment) (concern of virilization/malignancy)
• Labioplasty Gonadal dysgenesis with Y chromosome, Childhood (concern of risk of malignancy)
includes MGD with streak gonad
• Masculinizing Androgen biosynthetic defects, ie, 5α Prepuberty (concern of virilization at
• Hypospadias surgery reductase deficiency (female gender puberty)
• Excision of Mullerian assignment)
structure Complete AIS At diagnosis, at time of hernia repair or
• Orchiopexy defer to post puberty (low risk of
• Phalloplasty malignancy)
• Scrotoplasty
Gonadal dysgenesis (scrotal testis) Consider biopsy at puberty, may consider
(male gender assignment) sperm banking if feasible
 Congenital Adrenal Hyperplasia (CAH)

• DEFINITION: family of autosomal recessive disorders that disrupt

adrenal steroidogenesis
• TYPE:
• 21-hydroxylase deficiency (21-OHD)  most common
• 3β-hydroxysteroid dehydrogenase deficiency
• 11β-hydroxylase deficiency
• 17α-hydroxylase deficiency Rare
• Lipoid/StAR CAH
• Oxidoreductase deficiency (PORD)
Hypothalamic–Pituitary-Adrenal (HPA) Axis

Normal HPA Feedback Abnormal HPA Feedback (CAH)

Hypothalamus Hypothalamus

CRH CRH

Anterior Pituitary Anterior Pituitary

ACTH ACTH

Adrenal Cortex Adrenal Cortex

Cortisol Cortisol
 Adrenal steroidogenesis pathway

zona glomerulosa zona fasciculata zona reticularis

21-hydroxylase deficiency

• 95% of CAH case • Mutation in CYP21A2

• Clinical form: Classic CAH and non-classic CAH (NCAH)

• Classic CAH: salt wasting form (75%) and simple virilizing

form (25%)
• Classic CAH 1/15.000 births; NCAH 1:500 to 1:1000 in
various Caucasian population
21-hydroxylase deficiency Classic CAH

• Infant females: • Infant males:

• Ambiguous genitalia
• Clitoromegaly
• Fused rugated labia majora
• Single perineal orifice
• Hyperpigmentation
• Salt-wasting CAH : vomiting, hypotension,
hyponatremia, hyperkalemia  feed poorly,
fail regain birthweight, shock (first 10-14
days)
EMERGENCY

NCAH
• Hyperandrogenic symptoms:
• Premature pubarche, early epiphyseal fusion  tall children,
short adult (childhood)
• Hirsutism, acne, irregular menses, infertility (adulthood)
 Others type

3β-hydroxysteroid dehydrogenase deficiency

• Ambiguous genitalia in males and females. Both gender can lead to salt-wasting

11β-hydroxylase deficiency
• Ambiguous genitalia in females. Salt retention  hypertension

17α-hydroxylase deficiency
• Ambiguous genitalia in males. Lack of pubertal development or menstrual cycles
(amenorrhea) in females
Lipoid/StAR CAH
• Early death due to adrenal crisis. Ambiguous genitalia in males. Both males and
females, if survive, would likely be infertile

Oxidoreductase deficiency (PORD)

• Associated with skeletal disorder known as Antley-Bixler syndrome
 Diagnosis of CAH
Anamnesis : age of pubarche, infertility,
acne, androgenic medications
Clinical feature + Genitalia externa exam.

• Sign of salt-wasting: electrolyte, plasma renin, androstenedione, 17-OHP 

random 17-OHP values > 5000 ng/dL
• Suggestive NCAH: early morning basal 17-OHP >200 ng/dl (6 nmol/L) in early
follicular phase (day 3-7 of menstrual cycle)
• ACTH-stimulation test: 25 IU synthetic ACTH (Cortrosyn) IV/IM  ACTH-
stimulated17-OHP value >1500 ng/dl (45 nmol/L) or between 1000-1500 ng/dl (30-
45 nmol/L)
 Diagnosis of CAH
Newborn screening
• 17-OHP level >242 nmol/L on 3rd day of life
• False positive 0.4-9.3%; false negative 22.4%
• Increased false-positive risk with prematurity, low birthweight, neonatal stress

Imaging studies
• USG
• X-Ray (bone age)
• CT-Scan
 Management of CAH
Acute management Adrenal crisis

• Hydrocortisone bolus 50-100 mg IV or IM continue 100 mg/m2/day as

continues infusion or divided every 6 hours
• Fluid therapy: 20 ml/kg isotonic saline with D5 rapid bolus followed by repeat
boluses or continuous infusion
• Hypoglycemic: 0.5-1 gram/kg of dextrose bolus followed by 2-3 ml/minute
IV
• Hyperkalemia: monitor with ECG  insulin + glucose infusion
• Stress dose: triple the usual oral dose or 45 mg/m2/day
(<12 months: 25 mg, 1-4 years: 50 mg, >4 years: 100mg)
 Management of CAH
• Glucocorticoid replacement for infants, children, adolescent: Hydrocortisone
6-15 mg/m2/day – three times a day (highest dose at night)

• Salt supplementation : 1-2 g daily divided into several feedings

• Transition from pediatric to adult: switch hydrocortisone into dexamethasone,
prednisone, or prednisolone.
• Mineralocorticoid replacement: 9α-fludrocortisone acetate 0.05-0.2 mg/day

• Regular labs: 17-OHP & androstenedione  titration of dose maintaining 17-

OHP < 1000 ng/dL & androstenedione < 200 ng/dL (beware of Cushing
syndrome)
• Annual bone age (x-ray). Measurements of plasma renin & aldosterone.