How to define Disorders

of Sexual Development
Nusratuddin Abdullah
Department of Obs & Gyn
Hasanuddin University Makassar
Normal Sexual Differentiation

The gender identity of a person (whether an

individual identifies as a male or a female) is
determined by their genetic, gonadal, and
phenotypic sex and also is influenced by their
environment.
 Normal Sexual Differentiation
Genetic or
Chromosomal Phenotypic
Gonadal Sex
Sex Sex
• Sex • Gonadal • Appearance of
chromosomes, differentiation, the external
typically XX or into ovaries or genitalia and
XY testes. the secondary
sexual
characteristics
that develop at
puberty.
 Normal Sexual Differentiation
• The biological and physiological characteristic
SEX
that defines men and women

• The socially constructed roles,

GENDER
behaviors, activities and attributes
that a given society considers
appropriate for men and women

GENDER
IDENTITY • Body gestures and mannerisms, habits of speech,
recreational preferences, and content of dreams
 What Determines Gender
 Chromosomes /Karyotype ? XY Females and XX Males
 Its Sex Determines Gender ?

Females with male bodies ( CAH ) and males with females bodies ( AIS )
 Its Genitalia?

People who dont feel that they are their apparent sex ( Transgender / Transexual )
 It Is The Brain?

People who considered themselves male or female still have a range of behaviour (
Straight or Gay )
Formation of Organs Common to Both Sexes
Both 46,XX and 46,XY fetuses have similar sex organs, specifically
• Recognized by 4-5 weeks of gestation and
The gonadal they include the undifferentiated germ cells
ridges which will later develop into either eggs or
sperm

• by 6-7 weeks of fetal life, fetuses of both

The internal sexes have two sets of internal ducts, the
ducts Mullerian (female) ducts and the Wolffian
(male) ducts

• at 6-7 weeks gestation appear female and

The external
genitalia include a genital tubercle, the genital folds,
urethral folds and a urogenital opening
 Gonadal Differentiation
• The gonadal ridge develops into
testes as a result of a product from a
gene located on the Y chromosome.
In males This product has been termed the
"testis determining factor" or "sex
determining region of the Y
chromosome" (SRY)

• The absence of SRY, due to the

absence of a Y chromosome, permits
In females the expression of other genes which
will trigger the gonadal ridge to
develop into ovaries
Differentiation of the Internal Ducts and External
Genitalia
If Testes are developed
normally

Sertoli cells of the The Leydig cells of the

developing testes produce
MIS which inhibits the
growth of the female
Mullerian ducts (the uterus
and fallopian tubes)
testes start secreting
androgens (produce growth
effects on the male Wolffian
ducts (the epididymis, vas
deferens, seminal vesicles
Differentiation of the Internal Ducts and External
Genitalia
If ovaries are
developing normally

Ovaries do not produce Ovaries do not produce

androgens as a result,
the Wolffian ducts fail to
grow and consequently
disappear in fetuses with
ovarian development
MIS at the appropriate
time, and as a
consequence, the
Mullerian (female) ducts
can develop
Normal Sexual Differentiation
SIMPLIFIED MODE FFOR SEXUAL DIFFERENTIATION AND THE DEVELOPMENT OF
INTERNAL AND EXTERNAL GENITALIA
Primodia
l gonads
Y Chromosome
Testis Leydig Cells
(testis determining
factor)
Ovary Sertoli Dihydrotes
cells Testosterone tosterone
5α-
No testosterone reductase (DHT)
No AMH Anti mullerian Wolffian ducts
hormone development

Mullerian ducts  Penis

Mullerian ducts Epididymis  Scrotum
development
regression Vas deferens  Prostate
 Fallopian tube
 Uterus Seminal vesicle
 Upper vagina
 Normal exernal
female
genitalia
 Normal Prenatal Development:
Genetics
 Germ cells:
 male: sperm - contains “X” or “Y”
 female: ovum - contains an “X”
 “Y” chromosome contains less genetic material than
“X” chromosome

It does not require ovaries to have external female

phenotype
Female is the “default pathway”
Indifferent stage
How DSD happen
• Primarily Determined at Time of Conception
• Gain or Loses of Chromosomes may occur during development
Chromosomal
Sex
• Differentiation Occurs 6 weeks post conception
Gonadal sex • Largely determined by Chromosomal Sex
• Influenced by Transcription Factors

• Differentiation varies between boys and girls

• Largely determined by gonadal sex
Phenotip Sex • Determined by dominant hormone actions in
the body
 Genetic Sex
 Problems can arise at fertilization:
 Girls with Turner Syndrome have a 45,XO karyotype
 Boys with Klinefelter Syndrome have a 47,XXY
karyotype
 Some women have a 46,XY or 47,XXY karyotype
 Some men a 46,XX or 47,XYY karyotype
 Usual Sex Differentiation in
Humans: Y Induces Testis
 Presence of a Y Chromosomes Confers
Maleness:
 XY Males
 XXY Kleinfelter Male

 XX Female

 XO
LED TO Turner femaleOF “TDF”- TESTIS DETERMINING
A CONCEPT
FACTOR ON Y CHROMOSOMES
 THE FATE OF BIPOTENTIAL GONAD
Undifferentiated
gonadal ridge

Gata4 Emx2 Lhx9 WT-1 SF-1 Lim1

Bipotential gonad
SRY

Ovary DAX-1 Testis

“Streak
ovary” Ovotestis
Estrogen AMH Testosterone
Oviduct
Uterus Mullerian duct DHT
Upper vagina Epididymis
Wolffian duct Vas Deferens
Genital tubercle Seminal vesicle
Clitoris Penis
Labioscrotal folds
Vulva Scrotum
Urogenital sinus
Lower vagina Prostate
 Mullerian and Wolffian Duct Development
MIS secretion accompanied + the absence of
androgens or the inability to respond to androgens

a fetus lacking both male and female internal duct structures

The absence of MIS + androgen secretion

a fetus possessing both male and female internal duct structures to

varying degrees
 External Genitalia
in female patients when the external genital
structures are exposed to greater-than-
normal amounts of male hormones
(masculinized females)
Ambiguous
external
genitalia
develop
in male patients when less-than-normal
amounts of male hormones (under-
masculinized males) occurs

Thus, in these patients, external genitalia develop in a manner that is neither

female nor male, but rather is somewhere in between the two.
HORMONAL REGULATION OF SEXUAL
DIFFERNTIATION
Leydig Cell Sertoli Cell

AMH
Testosterone
Epididymis
Vas deferens AMH
SeminalVesicle Receptor
Uterus
DHT

Androgen Urogenital sinus

receptor & External
genitalia
 Functions of Testosterone and
Dihydrotestosteronein Males
Normal Androgen Physiology

TARGET CELL Wolffian

T T development
Spermatogenesis
T Gonadotropin
regulation
Testis 5α- External
reductase virilization
Prostate
DHT DHT development
Pubertal
maturatuon
 Sexual Differentiation Problems
Too much Androgen Effect in a Females

• 45 XX DSD
• Congenital Adrenal Hyperplasia
• Maternal Hyperandrogen
Too Little Androgen Effect in a Males

• 46, XY DSD
• Congenital Adrenal Hyperplasia
• 5 alfa Reductase Deficiency
• AIS
• LH Deficiency
• Testoterone Biosynthetic defect
Abnormality of AMH
•Persistence of Mullerian structures in a Male
 DEFINITION
 Disorders of sex development (DSD) are
defined as congenital conditions in which
development of chromosomal, gonadal or
anatomical sex is atypical, and where previously
referred to as intersex conditions
 INCIDENCE
 46,XY to have a DSD : 1 in 20,000 births
 Ovotesticular DSDs : 1 in 100,000 births
 Testicular or mixed gonadal dysgenesis 1:10,000
 46,XX, to have DSD, 1 in 14,000–15,000 births
 All congenital genital anomalies, including cryptorchidism and
hypospadias 1:200 to 1:300
 Incidence those with Klinefelter syndrome 1:500 to 1:1000
births and Turner syndrome 1:2,500 live births
Lee A P et al, Global Disorders of Sex Development Update since 2006: Perceptions,
Approach and Care, Horm Res Paediatr DOI: 10.1159/000442975 ,2016
 OLD TERMS

Male Female
Pseudohermaprodite Pseudohermaprodite

Hermaprodite Sex Reversal

Texticular Intersex
Feminizations
 Nomenclature DSD
AVOID:

• INTERSEX
• SEX REVERSAL
• PSEUDOHERMAPHRODITISM
• UNDERVIRILIZED MALES

TRUE HERMAPHRODITISM OVOTESTICULAR DSD

MALE PSEUDOHERMAPHRODITISM 46, XY DSD

FEMALE PSEUDOHERMAPHRODITISM 46, XX DSD

LWPES/ESPE CONSENSUS SONFERENCE, ARCH DIS CHILD 2006

 SEX REVERSAL
46 XY Complete
46XX Testicular DSD
Gonadal Dysgenesis
Chromosomal Females Chromosomal Males

Gonadal Males Gonadal females

Phenotyphic Females But Delayed

Phenotypic Males But Infertile
Puberty
Revised Terminology for DSD
Old Terminology
Intersex
True Hermaphroditism
New Terminology Description
DSD Development of genitalia is abnormal
Overtesticular DSD Both ovarian and testicular tissue are present; internal
and axternal genitalia are ambiguous

XY sex reversal (XY female sex) Complete Gonadal dysgenesis Streak (nonfunctional) gonads as well as mῠllerian
structures are present; external genitalia are female

XX sex reversal (XX male sex),
female pseudohermaphoditism
Male pseudohermaphroditism,
XV male undermasculinization
46, XX testicular DSD Testes are present; internal and external genitalia are
male
46, XY DSD Male gonadal development is abnormal; androgen
synthesis or action is deficiet; external genitalia are
undermasculinized to a variable degree

Female pseudohermaphoditism, 46, XX DSD Female gonadal development is abnormal; androgen

XX female overvirilization, synthesis or action is excessive; external genitalia are
XX female masculinixation masculinized to a variable degree

Hughes IA, Houk C, Ahmed SF, Lee PA; LWPES Consensus Group; ESPE Consensus Group. Consensus statement
on management of intersex disorders. Arch Dis Child 2006;91(7):554–563
Disorders of sexual development (New DSD nomencalture)
Sex Chromosome 46, XY DSD 46, XX DSD
DSD

• 45, X Turner and Disorders of Disorders of Androgen Disorders of Fetal Androgen Excess
Testicular syntesis/ Action Ovarian
Variants CAH Non CAH
Development • Androgens synthesis Development
• 47, XXY Klinefelter • Complete Gonadal Defect • Ovotesticlar DSD • 21-OH • Aromatase
and Variants Dysgenesis • LH-Receptor Defect • Testicular DSD Deficiency Deficiency
• 45,X/46XY MGD • Partial Gonadal • Androgen Insentivity (eg. SRY+, dup • 11-OH • POR Gene
Dysgenesis • 5α-Reductase SOX9)
• Chromosomal Deficiency Defect
• Gonadal Deficiency • Gonadal
Ovotesticular DSD • Maternal
Regression • Disorders AMH Dysgenesis
• Ovotesticular DSD • Timing Defect • Luteoma
• Endocrine Disruptures • Iatrogenic
• Cloacal Extrophy

MGD : mixed gonadal dysgenesis, DSD : Disorders of sexual development, AMH : Anti Mῠllerian hormone, CAH :
congenital adrenal hyperplasia
Current diagnosis-based recommendations for sex of rearing in some DSD and
consequent gonadal status

Berthelloni S dkk, Disorders of sex development: Hormonal management in adolescence ,

Gynecological Endocrinology, June 2008; 24(6): 339–346
SCHEMATIC DESCRIBING SEX CHROMOSOME INVOLVEMENT
OF DISORDERS OF SEXUAL DEVELOPMENT
46, XY DSD 46, XX DSD
Androgen Synthesis/Action Defects Sex
Fetal Androgen Excess
Chromosome
Malformation Syndromes (Cloacal DSD Malformation Syndromes (Cloacal
Exstrophy, hypospadias, Exstrophy, MURCS,
cryptochidism) Vaginal atresia)
Ovotesticular DSD
Testicular Regression Testicular DSD (SRY +)
46,XY Ovotesticular DSD 45,X/46,XY MGD
46,XX Ovotesticular DSD
47,XXY and 45,XO and
46,XY Complete Gonadal Klinefelter Variants Turner Variants 46,XX Complete Gonadal
Dysgenesis (Swyer Syndrome) (considered male) (considered female) Dysgenesis

46,XY Partial Gonadal Dysgenesis 46,XX Partial Gonadal Dysgenesis

Rothkopf, AC. Journal of Pediatric Nursing , 2014

CLINICAL PRESENTATION OF DISORDERS OF SEXUAL
DEVELOPMENT

 Infants who have the following clinical features

should be evaluated for a DSD
 Micropenis with bilateral nonpalpable testes.
 Clitoromegaly
 Apparent female genitalia with an inguinal or labial mass
 Hypospadias with unilateral nonpalpable testes
 Posterior labial fusion
 Discordant genitalia and prenatal chromosome complemen
 Penoscrotal or perineoscrotal hypospadias with undescended testes
 HOW TO DIAGNOSE
46, XY
genotype

Absent Gonads Present

gonads

Ovotestis Disgenesis 2 Streak 2 Testes

Testis gonads

Uterine + or - Uterine + or - Uterine + Uterine + Uterine -

Testicular Ovotesticular Partial Gonadal Complete Androgen

regression Disorder of Sexual Dysgenesis Gonadal Action or
Development Dysgenesis Syntesis disorer

Adapted from “Current Concepts in Disorders of Sexual Development” by G. Öçal, 2011. Journal of Clinical
Research in Pediatric Endocrinology, 3, p.111.
 46, XX genotype

Ovotestis 2 Streak
2 tetes 2 Ovaries
gonads

Uterine + Uterine - Uterine + Uterine +

Ovotesticular Gonadal Virilized

XX Testicular
Disorder of Dysgenesis female
Disorder of
Sexual 17 – OH
Sexual
Development progesterone
Development Low High
Non – Congenital
Adrenal Congenital Adrenal
Hyperplasia Hyperplasia
Figure 5. Example algorithm for diagnosis of 46, XX DSD. Note. Adapted from “Current concepts in disorders of sexual development,” by
G Ṍḉal, 2011, Journal of Clinical Research in Pediatric Endocrinology, 3, p.111.
 Holistic View on DSD
 Phenotypes Depend on endocrine Action
 Prenatal Development is Driven by Androgens
 Lack of Androgenisation = Female Phenotypes
 Androgenisation = Male Phenotypes
 Postnatal Development is Driven by Androgen and Estrogen
 Androgenisation Will Make Up Phenotype Regardless of
Karyotypes
 Prader staging for scoring the degree of androgenization of
the external genitalia in a female infant with congenital adrenal
hyperplasia
(CAH)
 EMS

External masculinization score (EMS) to assess degree of

underandrogenization in an individual with 46XY disorders of sex
development
(DSD)
 • Term Birth 6 Lb 15 Oz
• Well Formed Phallus With Perineal
Hypospadias
• Well-Formed Scrotum
• No Testes
• U/S Show Uterus and Tubes
• 17-OH Progesterone 10.500 ng/dl
46 XY, NORMAL TESTES, NORMAL SERUM TESTOTERONE
 Boys with a small Phallus
Bifid scrotum
Urogenital sinus with
perineal hypospadias and a
blind vaginal pouch
 Take Home Messages
 DSD due to chromosomal disorders occur at
fertilisation
 DSD occur when a bipotential gonad is incapable
of developing into a testis or an ovary
 The inability to develop testes may occur if a gene
such as SRY is absent or deficient
 Developing testis can be thwarted, and
subsequently MIS and androgen production may
be absent or diminished