Presentation on DSD( Disorders of Sex Development in Human) .

1. DISORDERS OF SEX
DEVELOPMENT (DSD)
Moderator:- Dr. Kankan Talukdar , Asst
Professor,Dept. of Obstetrics and
Gynecology, FAAMCH.
Presenter:- Dr. Bhimi daimari PGT

2. DEFINITION
Disorders of sex development (DSD) are congenital
conditions in which chromosomal, gonadal, or anatomic
sexual development is atypical.
Previously also termed as Intersex ( stigmatising and
controversial).
Atypical /ambiguous genitalia- any case in which the
external genitalia do not appear to be completely male
or female.

3. NORMAL SEXUAL DIFFERENTIATION
It consist of 3 sequential processes—
1. Chromosomal sex- at time of fertilization (XX OR
XY)
2. Gonadal sex- testis or Ovary.
3. Phenotypic sex- internal and external genitalia( male
or female).

4. Normal sex development
Every human foetus is destined to be a female
foetus .
Early embryo is potentially bisexual upto 6th
week of intrauterine life.

5. Flow chart 1: sex determination of embryo ( REF:
Jeffcoate’s principles of Gynaecology 8th ed.

6. Ref:- williams Gynecology 2nd ed.

7. Classification
DSD is broadly classified into 3 categories
according to gonadal histology:-
CAT 1- 46, XX DSD (female
pseudohermaphroditism / Overvirilized XX
female / Masculinized XX female).
CAT 2 – 46,XY DSD (male
pseudohermaphroditism / undermasculinized
XY male / undervirilized XY male).

8. CAT3 – disorders of genetic or gonadal
development .
 Sex chromosome DSD ( Turner syndrome
,Klinefelter syndrome ,mixed gonadal
dysgenesis).
 Ovotesticular DSD (True hermaphroditism).
 Embryonic testicular regression.

9. 46,XX DISORDERS OF SEX DEVELOPMENT
It includes the following conditions:
1. Ovarian development disorders
a) Gonadal dysgenesis
b) Ovotesticular DSD
c) Testicular DSD
2. Excess of androgens
a) Fetal congenital adrenal hyperplasia.
b) Fetoplacental enzymes deficiency ( aromatase
oxidoreductase)
c) Maternal ingestion of androgenic drugs ( e.g danazol,
progestogens , testosterone) or maternal androgen
secreting tumor( e.g luteoma).
3. Misc: vaginal agenesis, cloacal exstrophy.

10. 46, XX DSD
• It occurs due to excessive fetal androgen
exposure in a fetus with karyotype 46 XX at
the time when genitals are forming .
• The ovaries, uterus , cervix and upper vagina
are present.
• Affected Individuals are potentially fertile.
• External genitalia is virilized to varying
degree(clitoromegalyposterior labial
fusionphallus with penile urethra).

11. Normal relations between the hypothalamic pituitary system and adrenal cortex.
(ref: Jeffcoate’s principles of Gynaecology 8th ed.)

12. • Fetal congenital adrenal hyperplasia (CAH)
due to deficiency of 21- hydroxylase enzyme
is most common cause of 46 XX DSD
(incidence=1 in 14000 LB).
• CAH -It is an autosomal reccessive disorder
resulting from an enzymatic defect in the
cortisol synthesis pathway in the adrenal
cortex.

13. Relations between the hypothalamic pituitary system and adrenal cortex in
congenital adrenal hyperplasia. (ref: Jeffcoate’s principles of Gynaecology 8th
ed.)

14. In Classical form of CAH ( 21- hydroxylase
enzyme deficiency) –
 Ambiguous genitalia, non palpable gonads
 In 1st week of life – vomiting, dehydration.
 In milder forms- obesity, hersutism ,amenorrhea
may manifest at puberty.

15. Pic showing baby (case of congenital adrenal hyperplasia) with
ambiguous genitalia.

16. • Diagnosis of CAH –
 Prenatal period- positive family history of CAH –
chorionic villus sampling shows increased levels
of 17-hydroxyprogesterone, androestenedione, 11
deoxycorticosterone.
In Neonatal period-
• Hyponatremia, hypoglycemia, hyperkalemia.
• Raised serum 17 hydroxyprogesterone .

17. • Increased urinary excretion of pregnanetriol and
17- ketosteroids
• USG OR MRI abdomen and pelvis- shows
presence of ovaries, uterus ,fallopian tubes,
vagina.
Late onset of CAH- presents at puberty with
obesity, hirsutism , signs of virilization.
• > 800ng/dl of 17 hydroxyprogesterone in serum
are diagnostic.

18. • The 3 embroyonic structures that are commonly
affected by elevated androgen levels are the
clitoris, labioscrotal folds, and urogenital sinus.
• Objectives of reconstructive surgery (
feminizing genitoplasty)-
To decrease enlarged clitoral size while maintaining
vascularity and sensory innervations( clitoroplasty)-
5-10 years of age.
To reduce and feminize the labioscrotal folds. (
labial separation procedure is done at puberty)
To create a separate vaginal introitus in perineum.

19. 46,XY DISORDERS OF SEX DEVELOPMENT
It includes the following conditions:
1. Testicular development disorders
a) Swyer’s syndrome( complete gonadal dysgenesis)
b) Partial or incomplete gonadal dysgenesis.
c) Gonadal regression.
d) Ovotesticular DSD.
2. Defective androgen synthesis or action
a) Defective biosynthesis of androgen
b) Defective androgen action( complete or partial
androgen insensitivity)
c) LH receptor defects.
3. Misc:cloacal exstrophy , severe hypospadius.

20. 46,XY DSD
• Insufficient androgen exposure of a fetus
destined to be a male ( karyotype 46,XY) leads
to this condition of DSD.
• Etiology-
 Enzyme defect in biosynthesis of testosterone.
 Peripheral enzyme defect (5alpha reductase )-
impaired conversion of testosterone to DHT.
 Abnormalities in the androgen receptors.

21. STEROIDOGENESIS PATHWAY ( ref: williams gynecology 2nd ed.)

22. ANDROGEN INSENSITIVITY SYNDROME(AIS)
• Previously termed as male
pseudohermaphroditism or testicular feminizing
syndrome.
• It is usually X linked recessive disorder.
• Incidence – 1 in 13000 to 1 in 41000 LB.
• 2 TYPES- complete and partial AIS.

23. Partial AIS ( Reifenstein’s sydrome)-
Ambiguous genitalia, poor virilization, severe
male factor infertility are present.
Complete AIS-
• Appears phenotypically as female at birth.
• Presents at puberty with primary amenorrhea,
scanty/absent pubic and axillary hair, short/blind
vagina, absent uterus , ovaries and fallopian
tubes.

24. • May have breasts development during
puberty due to abundant peripheral
androgen to estrogen conversion .
• Testes may be palpable in the labia /
inguinal canal/ intra abdominally.
• S.testosterone level are normal or slightly
raised, LH is elevated.

25. Treatment of CAIS-
• Surgical excision of gonad/testes after puberty- to
reduce risk of germ cell tumors( 20-30% high
risk).
• Individuals are given female gender identity.
• Estrogen replacement therapy is given for
maintaining breast development and bone mass
and to provide relief from vasomotor symptoms.
• Vaginoplasty may be done before marriage after
proper counselling in affected individuals.

26. SWYER’S SYNDROME
• It is also previously known as acquired male
pseudohermaphroditism with pure XY gonadal
dysgenesis.
• Mutation in SRY gene  testes not formed
No testosteronemale internal and external
genitalia fails to develop.
• Absent MIF and AMH female phenotype
with absent secondary sex characters and
primary amenorrhea .
• Individuals are reared as females.

27. • Treatment-
–Gonadectomy done due to 30% malignancy
risk.
–Cyclical estrogen and progesterone therapy
for inducing menses .
–In vitro fertilization with donor egg for
conception.

28. SEX CHROMOSOME DISORDERS OF SEX
DEVELOPMENT
It includes the following conditions:
1. Turner syndrome ( 45,XO)
2. Klinefelter syndrome (47,XXY)
3. Mixed gonadal dysgenesis(45,XO/ 46,XY)

29. TURNER’S SYNDROME
• Karyotype 45XO (50-60% cases).
• Results from nondisjunction of parental
chromosomes.
• Patients are diagnosed at adolescence,
presenting with short stature, prepubertal
female genitalia, primary amenorrhea.
• It is characterized by presence of streak
gonads/ovaries , normal uterus ,fallopian tubes
and vagina.

30. Pic ref: william’s Gynecology 2nd ed.

31. • S. FSH and S. LH are elevated.
• S. Estradiol is low(<25pg/ml).
• Sex chromatin study is negative in absence of
Barr body( Barr body 1st appears in trophoblast
cells at about the 12th day and in the tissue of
foetus itself by the 18th day).

32. TREATMENT-
• Hormone replacement therapy- it is started
near age of 12 years or at time of diagnosis.
• Started with low dose oral estradiol 0.25 mg
daily for 6 months. It is then sequentially
increased every 6 months through daily doses
of .5mg , .75mg . 1mg, and then 2mg.
• Progesterone is begun after approximately 1
year of unopposed estrogen treatment. Each
month , micronized progesterone 200mg orally
at bedtime is given for 12 nights and then
stopped to permit withdrawal bleeding.

33. • This method mimics the normal pubertal
hormonal stimulation of breast tissue .
• The patient is then maintained on 2mg of oral
estradiol and monthly withdrawal to
progesterone. Alternatively a low dose OCPs
can also be used instead as maintainance drug.

34. KLINEFELTER’S SYNDROME
• Karyotype is 47XXY.
• Incidence is 1:500 in males.
• Phenotype is male but individuals affected have tall
stature, eunuchoid appearance, high pitched voice,
gynaecomastia, small or normal penis , small normally
place testes, sterile/infertile , mental retardation.
• Testicular biopsy shows- hyaline degeneration of
seminiferous tubules.
• Treatment include testosterone replacement therapy,
breast surgery for gynecomastia.

35. PIC Ref: Jeffcoate’s principles of Gynecology 8th ed

36. OVOTESTICULAR DSD
• Earlier termed as true hermaphrodite.
• Karyotype is 46XX (most common) followed
by 46XX /46XY.
• Affected individuals have both ovarian and
testicular gonadal tissue.( includes unilateral
ovovtestis with contralateral ovary or testis ,or
bilateral ovatestes). Their fertility remains
poor.

37. • Location of gonads-abdominal/
inguinal/scrotal.
• External genitalia-usually ambiguous but
individuals may have female or male
phenotype.
• Internal ductal system- depends on ipsilateral
gonad and its degree of differentiation.

38. • The amount of AMH and testosterone present
determines the degree to which the internal
ductal system is masculinized or feminized.
• Diagnosis- laparoscopic examination and
gonadal biopsy .
• Dysgenetic or streak gonads are removed due
to risk of malignancy.

39. CLINICAL EVALUATION OF DSD CASE (
NEWBORN WITH AMBIGUOUS GENITALIA)
1. History – family history of dsd,consanguity, antenatal
history of intake of androgenic drugs or hormones ,
hormone secreting tumor.
2. Clinical examination –
 Dysmorphic features- webbing of neck,
hyperpigmentation,edema.
 Overt amiguous genitalia.
 Female genitalia with clitoromegaly, labial fusion
with or without inguinal or labial mass.
 Male genitalia with bilateral undescended testes,
small penis and hypospadias.

40. Flow chart showing Evaluation of a neonate with ambiguous
genitalia.

41. GENDER ASSIGNMENT IN NEONATE:
• At birth , gender assignment to the normal newborn
usually involves a simple assessment of the external
genitalia .
• In cases of baby with ambiguous genitalia , proper
counselling and reassurance to parents is done and
family should be involved in decision making.
• Counselling should include need for hormonal
stimulation at puberty and potential later surgical
reconstruction.

42. • Appropriate assesment must be performed by a
multidisciplinary team .
• Most Patients with 46 XX CAH and all
patients with 46XY complete androgen
insensitivity syndrome should be assigned
female gender.

43. • Patients with 5alpha reductase deficiency and partial
androgen insensitivity syndrome are usually assigned
female gender in infancy but may like to live as males
if virilization is severe at puberty.
• In ovotesticular DSD , gender assignment depends
upon potential for fertility as per gonadal
differentiation, genital development and surgical
procedure performed.

44. SURGICAL TREATMENT
• More emphasis is given to functional outcome
instead of cosmetic outcome.
• Gonadectomy is performed in AIS and gonadal
dysgenesis due to risk of gonadoblastoma.