NORMAL SEXUAL DIFFERENTIATION

• Genetic or chromosomal sex is defined by the sex chromosomes,

Normal and Abnormal Sexual
Development
Maryam Asyah R. Macapasir
1st year Resident
typically XX or XY.
• Gonadal sex is defined by the direction of gonadal differentiation, into
ovaries or testes.
• Phenotypic sex is defined primarily by the appearance of the external
genitalia and the secondary sexual characteristics that develop at puberty.

• Gender identity includes all behavior having any sexual connotation, such as
body gestures and mannerisms, habits of speech, recreational preferences,
and content of dreams.

• Sexual expression reflects the sum of all sexual influences on the individual,
both prenatal and postnatal.



 Genetics of Sex Determination
Genetics of Sex Determination

• SRY (Sex-determining Region on Y) • Both testis and ovary differentiation require dominantly acting genes, with SRY inducing testis
development via up-regulation of SOX9.
– “testis-determining factor”
– located on the distal short arm of the Y (Yp11.3)
• Genes WNT4 and RSPO1, teaming to promote ovary development via repression of SOX9.
– Generally established as the primary genetic signal determining the
direction of gonadal differentiation in mammals.
• In XY gonads, SRY induces SOX9 and tips differentiation toward testis development.

• In XX gonads lacking SRY, other genes combine to repress SOX9 and promote ovary
development.

Germ Cell Sex Differentiation Genital Duct Differentiation and Development

• Wolffian duct
– develops first
– differentiates into the epididymis, vas deferens, and seminal vesicles in
males and regresses in females

• Mullerian duct
– develops later
– differentiates into the fallopian tubes, uterus, and upper portion of the
vagina in females and regresses in males








 Mesonephric (Wolffian) Duct Development

Genital Duct Differentiation and Development

• Hormones produced by the testis direct the sexual differentiation of both the • Testosterone is secreted by the fetal testes soon after Leydig cell formation (at 8
internal and external genitalia in the male. weeks of gestation) and rises rapidly to peak concentrations at 15–18 weeks.

• Testosterone stabilizes and promotes development of the wolffian ducts, • High local concentrations of testosterone stimulate the ipsilateral wolffian
AMH directs the regression of the mullerian system. duct to differentiate into the epididymis, vas deferens, and seminal vesicle.

• In females, the wolffian ducts regress, in the absence of testosterone, and

the mullerian ducts develop fully, in the absence of AMH.

Paramesonephric (Mullerian) Duct Development and Regression Paramesonephric (Mullerian) Duct Development and Regression

• The mullerian ducts begin by invagination of the coelomic epithelium, which

progresses until reaching the wolffian ducts, then elongate, by cellular
proliferation, along the length of the wolffian ducts until reaching and fusing
with the urogenital sinus.

• If the wolffian ducts do not form, mullerian duct development also fails.



 Development of the External Genitalia

Paramesonephric (Mullerian) Duct Development and Regression

• AMH gene expression is induced by SOX9 in Sertoli cells soon after testicular • In the bipotential state, which persists until 9 weeks of gestation, the external
differentiation and results in the ipsilateral regression of the mullerian ducts by genitalia consist of a genital tubercle, a urogenital sinus, and lateral
8 weeks of gestation, before the emergence of testosterone and stimulation of labioscrotal folds or swellings.
the wolffian ducts.

Development of the External Genitalia Development of the External Genitalia

• In the male, the Leydig cells of the fetal testis begin to secrete testosterone at 8–9 • In the female, and in males with defects in androgen synthesis or action, the
weeks of gestation, and masculinization of the external genitalia begins 1 week later, external genital primordia do not masculinize.
at approximately 10 weeks.
– Genital tubercle remains small and becomes the clitoris.
• The genital tubercle grows, forming the penis, the edges of the urogenital
sinus fuse to form the penile urethra, and the labioscrotal folds fuse to form a
– Margins of the urogenital sinus remain separate and form the labia minora.
scrotum.

– Labioscrotal folds form the labia majora, and the urogenital sinus develops into
• Process typically is completed by 12–14 weeks of gestation. the lower vagina and urethra.










 Development of the External Genitalia
Sexual Differentiation of the Central Nervous
System
• In female fetuses, testosterone is markedly elevated and causes
masculinization of the external genitalia (clitoral enlargement and labial
fusion).
• Studies in girls with classical CAH indicate that increased prenatal androgen
exposure also affects their brains and behavior.
Development of the External Genitalia
• Abnormal androgen exposure between 9 and 14 weeks of gestation
• FEMALE: clitoral hypertrophy and labial fusion
• MALE: small phallus, hypospadias, or scrotal defects
DISORDERS OF SEXUAL DEVELOPMENT
• Disorders of sexual development (DSD) are congenital conditions
characterized by atypical development of chromosomal, gonadal, or
phenotypic sex. Traditionally, they have been classified according to gonadal
sex.

 DISORDERS OF SEXUAL DEVELOPMENT

DISORDERS OF SEXUAL DEVELOPMENT

• True hermaphrodite- both ovarian and testicular tissue

• Male pseudohermaphrodite-testes, but a female genital phenotype

• Female pseudohermaphrodite-ovaries, but masculine genital characteristics

Disorders of Gonadal (Ovarian) Development

• Ovotesticular DSD (true hermaphroditism)

• Testicular DSD (46,XX sexreversal)
• Gonadal dysgenesis
46,XX Disorders of Sexual Development





 Ovotesticular Disorder of Sexual Development Testicular Disorder of Sexual Development

(True Hermaphroditism) (46,XX Sex Reversal)

• Rare condition characterized by mixed ovarian and testicular tissue, which may • Rare “sex reversal” syndrome in which the chromosomal sex (46,XX) is not
include bilateral ovotestes or an ovotestis and a contralateral ovary or testis. consistent with the gonadal sex (testes).

• Mullerian and wolffian internal genital structures are present.

• Have a vagina, uterus can be normal and functional, hypoplastic, vestigial, or

altogether absent.

Testicular Disorder of Sexual Development Testicular Disorder of Sexual Development

(46,XX Sex Reversal) (46,XX Sex Reversal)

• SRY-positive testicular DSD • SRY-negative XX males

- Ambiguous genitalia
-Sterile males with normal genital development, a
normal male hair pattern, and short stature
-Not recognized until after puberty (hypogonadism,
gynecomastia, and/or infertility)
-Ambiguous genitalia and often develop gynecomastia
or fail to masculinize fully after puberty
-May exhibit occult gonadal mosaicism for SRY

Gonadal Dysgenesis Androgen Excess—Fetal Origin
(Congenital Adrenal Hyperplasia)

• Individuals with primary amenorrhea, hypergonadotropic

hypogonadism, and gonadal dysgenesis (streak gonads)
have a normal 46,XX karyotype.

• Normal in stature and, in most cases, have no apparent

somatic anomalies.

Congenital Adrenal Hyperplasia:

Androgen Excess—Fetal Origin 21-Hydroxylase (P450c21) Deficiency
(Congenital Adrenal Hyperplasia)

• Most frequent cause of sexual

• Clitoral enlargement and ambiguity and the most common
labial fusion and endocrine cause of neonatal
abnormalities of the urethra death.
and vagina.

• Urethra and vagina share a

urogenital sinus that opens
at the base of the clitoris.












 Congenital Adrenal Hyperplasia: CAH: 11β-Hydroxylase (P450c11) Deficiency

21-Hydroxylase (P450c21) Deficiency

• TYPES: • Excess production of adrenal androgens

and the mineralocorticoid action of 11-
>“Salt-Wasting” variety deoxycorticosterone
(Virilization, Salt wasting and Dehydration) • Second most common cause of CAH
• Accounts for only about 5–8%
>“Simple Virilizing” form
(Masculinization of the external genitalia)

>“Nonclassical” form
(Hirsutism and menstrual irregularities)

CAH: 11β-Hydroxylase (P450c11) Deficiency CAH: 3β-Hydroxysteroid Dehydrogenase Deficiency

• The external genitalia of females with
3β-HSD deficiency can be mildly
• Severe salt-wasting and simple virilizing forms and a milder late-onset form. virilized.

• Virilization of the external genitalia.

• The most reliable diagnostic criterion
is the serum 17α
• Approximately two-thirds of patients with 11β-hydroxylase deficiency exhibit hydroxypregnenolone concentration
hypertension due to an increased production of mineralocorticoids. after ACTH stimulation.






 Treatment of Congenital Adrenal Hyperplasia Androgen Excess—Fetoplacental Origin

→Aimed at providing sufficient amounts of
the deficient hormone, cortisol, to reduce
excessive ACTH secretion and to prevent the
consequences of excessive androgen
production.
→Preimplantation Genetic Diagnosis -
Polymerase chain reaction (PCR)-based
genotyping
→Prenatal diagnosis or Neonatal screening.
Aromatase (P450arom) Deficiency
→Administration of fluids, correction of any significant
– Rare autosomal recessive disorder caused by mutations in the
hypoglycemia, hyperkalemia should be corrected by
administering glucose and insulin. CYP19A1gene.
→Treatment of Mothers - Dexamethasone, decrease
or prevent fetal female genital virilization. – Affected females classically present with ambiguous genitalia at birth
→Children-hydrocortisone (cortisol). and, at puberty, exhibit signs of hyperandrogenism, absent breast
development, primary amenorrhea associated with hypergonadotropic
→Adults-long-acting glucocorticoids hypogonadism, and multicystic ovaries.
(e.g.,dexamethasone, prednisone)

Androgen Excess—Fetoplacental Origin Androgen Excess—Maternal Origin

(Gestational Hyperandrogenism)

I. Drug Ingestion
P450 Oxidoreductase Deficiency – Most cases of female fetal virilization resulting from maternal drug ingestion have involved
treatment with danazol for endometriosis or with progestins for threatened or recurrent
-An autosomal recessive disorder, identified abortion.
missense mutations in the central electron transfer
domain of the protein.
– Virilization of female infants has not been observed in women exposed to oral
-Phenotype of POR deficiency varies widely. contraceptives after conception.

Antley-Bixler syndrome
-craniosynostosis
-midface hypoplasia
-choanal atresia or stenosis
-radiohumeral and/or radioulnar synostosis
-femoral bowing and fractures
-joint contractures

 Androgen Excess—Maternal Origin

(Gestational Hyperandrogenism)
Other Disorders of Genital Development
II.Excess Androgen Production Cloacal Exstrophy
– Pregnancy Luteoma – Rare and complex anorectal and genitourinary malformation in which the rectum, vagina,
• Hyperplastic masses of luteinized cells and not true tumors. and urinary tract share a common everted orifice, accompanied by an omphalocele, and
• Solid masses ranging between 6 and 10 cm in size, they are bilateral. an imperforate anus.
• There is essentially no risk that the female fetus of a woman with a luteoma will
become virilized if the mother herself does not.

– Theca-Lutein Cysts
• Also known as hyperreactio luteinalis
• Develop most frequently in women with multiple pregnancies, isoimmunized mothers,
those with molar pregnancies or gestational trophoblastic disease, and women with
diabetes mellitus.
• Approximately 30% of pregnant women with clinically apparent theca-lutein cysts
become hirsute or virilize.

Other Disorders of Genital Development

Other Disorders of Genital Development

Mullerian Agenesis Mullerian Agenesis (Mayer-Rokitansky-Kuster-Hauser Syndrome)

(Mayer-Rokitansky-Kuster-Hauser Syndrome)
– Urologic anomalies (unilateral renal agenesis, ectopic or horseshoe kidney, and
duplication of the collecting systems).
Failure of mullerian duct development.
– Skeletal malformations.
Characterized by absence of the vagina, an absent or
hypoplastic uterus, and normal or hypoplastic fallopian tubes. – The cause is unknown, although some cases are associated with chromosomal
translocations or occur in familial aggregates.

7% to 10% of women with vaginal agenesis have rudimentary

uterine tissue present

Normal pubertal development, normal ovarian function, and a

46,XX karyotype.





Other Disorders of Genital Development Other Disorders of Genital Development

Mullerian Agenesis (Mayer-Rokitansky-Kuster-Hauser Syndrome) Mullerian Renal Cervicothoracic Somite Dysplasia

(The MURCS Association)

-Typically present in late adolescence or as
young adults with primary amenorrhea,
exhibiting normal breast and pubic hair
development and no visible vagina.
-Primary amenorrhea at 15 to 16 years of age
Physical examination:
-Absence of a vaginal opening
-Presence of a short vaginal pouch
-An inability to palpate a uterus on
rectal examination
– A syndrome characterized by mulerian (MU) aplasia or hypoplasia, unilateral renal (R)
agenesis or ectopy and cervicothoracic somite (CS) dysplasia, which results in vertebral
defects (e.g., Klippel-Feil anomaly, scoliosis), and abnormalities of the ribs, upper limbs,
and scapula.
– May involve an event occurring very early in development when the blastemas of the
pronephric buds and cervicothoracic buds are closely located.

Disorders of Gonadal (Testicular) Development

• Complete Gonadal Dysgenesis (Swyer Syndrome)

• Partial Gonadal Dysgenesis
• Testicular Regression Syndrome
46,XY Disorders of Sexual Development






 Disorders of Gonadal (Testicular) Development Disorders of Gonadal (Testicular) Development

Complete Gonadal Dysgenesis (Swyer Syndrome) Partial Gonadal Dysgenesis

Characterized by a 46,XY karyotype. Mullerian structures may be present or absent, the external genitalia may be female,
ambiguous, or male, and the phenotype can include developmental abnormalities outside
Despite the presence of a Y chromosome, the phenotype is female because the of the reproductive tract.
dysgenetic (streak) gonads produce neither AMH nor androgens.

Present after the expected time of puberty with delayed sexual maturation, primary
amenorrhea, normal pubic hair, and normal female internal and external genital anatomy.

Gonadectomy is indicated soon after diagnosis due the significant risk for development
of germ cell tumors in occult testicular elements (20–30%).

Disorders of Gonadal (Testicular) Development

Testicular Regression Syndrome

Condition in which a developmentally normal testis existed during fetal life but
subsequently regressed or was lost.

The disorder can be unilateral or bilateral and is characterized by partial or Disorders of Androgen Synthesis
complete absence of testicular tissue in the presence of normal male external
genitalia.










 Disorders of Androgen Synthesis Disorders of Androgen Synthesis
Steroid 5α-Reductase Deficiency
Steroid 5α-Reductase Deficiency

– An autosomal recessive disorder characterized by a

46,XY karyotype. • Classical Presentation:
– External genitalia are predominantly female at birth,exhibiting failed fusion of the labioscrotal folds and a
urogenital sinus or separate urethral and vaginal openings, with or without clitoromegaly.
– Severe perineal hypospadias
– The internal genitalia are male; the epididymides, vasa deferentia, seminal vesicles, and
• Describing a genital configuration consisting of a phallus
midway in size between penis and clitoris ejaculatory ducts form, but empty into a shortened, blind vagina.
• A chordee tethering the phallus to the perineum
• Urethral opening usually on the perineum
• The distinguishing feature of the disorder is that affected individuals virilize, to varying
• Incompletely closed urogenital opening resembling a small and
shallow vagina degrees, at the time of puberty.

– Results from impaired virilization during embryogenesis

due to defective conversion of testosterone to
dihydrotestosterone (DHT).

Disorders of Androgen Synthesis Disorders of Androgen Synthesis

17α-Hydroxylase Deficiency 3β-Hydroxysteroid Dehydrogenase Deficiency

– Present with delayed puberty, primary amenorrhea, – Causes of female virilization (46,XX DSD).
and hypergonadotropic hypogonadism.
– Enzyme defect can cause incomplete
– Most are hypertensive (due to hypernatremia and masculinization of males as well as virilization in
hypervolemia) and some also have hypokalemia. females.

– Affected males usually have female external genitalia

(male pseudohermaphroditism), a blind vagina, and
intra-abdominal testes.

– Most have been raised as girls, with the underlying

disorder recognized only later during evaluation for
delayed puberty.








 Disorders of Androgen Synthesis
17β-Hydroxysteroid Dehydrogenase Deficiency
Most common hereditary defect in
testosterone synthesis.
Males with homozygous or compound
heterozygous mutations have testes and n o r m a l l y
developed internal genitalia but h a v e s e v e r e l y
undervirilized external genitalia, which typically
appear female and include a short, blind vagina,
much like patients with incomplete androgen
insensitivity.
Most are assigned a female gender at birth
and are raised as females.
Disorders of Androgen Action
Steroid Acute Regulatory (StAR) Protein Deficiency
Alternatively, they can exhibit
genital ambiguity, with varying
degrees of clitoromegaly and
labial fusion, or have male
genitalia with micropenis or
hypospadias.
Disorders of Androgen Synthesis
– Congenital lipoid adrenal hyperplasia is an
autosomal recessive disorder that results from
mutations in the gene encoding the steroidogenic
acute regulatory (StAR) protein.
– Typically present very soon after birth or in early infancy
with symptoms of severe adrenal insufficiency (vomiting,
diarrhea, volume depletion, hyponatremia,
hyperkalemia).
Disorders of Androgen Action
Complete Androgen Insensitivity Syndrome
– Coined the name “testicular feminization”
– In women with complete AIS, serum testosterone concentrations are normal or moderately
increased, LH levels are increased, and the serum FSH usually is in the normal range.
– Present with primary amenorrhea, normal breast development, absent or scant
pubic and axillary hair, a short vagina, and an absent cervix and uterus.
– A serum testosterone in the normal male range and a 46,XY karyotype establish the
diagnosis.

Disorders of Androgen Action Disorders of Androgen Action

Incomplete Androgen Insensitivity Syndromes

– The spectrum of clinical presentations can vary from phenotypic females

with mild virilization to undervirilized males who may be fertile or infertile,
even within one affected family.

– Reifenstein syndrome describes individuals having a predominantly male

phenotype who are undervirilized. TABLE 8.4 Androgen Insensitivity Syndromes

– The most common clinical presentation is an infertile man with a bifid

scrotum and perineoscrotal hypospadias.

Disorders of Androgen Action

LH Receptor Defects

– Leydig cell hypoplasia

• absence of mature Leydig cells in the testes
Disorders of Antimullerian Hormone and Its Receptor
• a rare autosomal recessive 46,XY disorder of sexual development caused by
inactivating mutations in the LH/hCG receptor

• phenotype of patients with Leydig cell hypoplasia otherwise generally correlates with
the level of residual LH/hCG receptor activity, ranging from completely female external
genital development to nearly normal male genitalia

Disorders of Antimullerian Hormone and Its Receptor

Hernia uterine inguinale syndrome

• rare autosomal recessive disorder that results from a failure of mullerian duct
regression

• mutations in the genes encoding AMH or its receptor

Sex Chromosome Disorders of Sexual Development

• affected patients appear as normal males having an inguinal hernia containing

relatively well-differentiated mullerian duct structures, usually including a uterus and
fallopian tubes

• normal male internal and external genitalia and, usually, cryptorchid testes

Sex Chromosome Disorders of Sexual Development 45,X (Turner Syndrome and Variants)

• 45,X (Turner Syndrome and Variants) • Results from loss of all or part of an X chromosome.

• 47,XXY (Klinefelter Syndrome and Variants)

• Sine qua non of Turner syndrome is short stature.
• 45,X/46,XY (Mixed Gonadal Dysgenesis)
• 45,XX/46,XY (Chimerism) • Approximately 30–50% have renal anomalies

• Cardiac malformations also are common.

• Typically have normal intelligence.

45,X (Turner Syndrome and Variants)

45,X (Turner Syndrome and Variants)Treatment
• The classical phenotype of Turner syndrome • Estrogen treatment should begin at a low dose (0.25–0.5 mg micronized estradiol or
– absence of sexual development its equivalent) and increase gradually at 3–6- month intervals until reaching the final
– a webbed neck dose (2.0 mg micronized estradiol or its equivalent).
– low set ears and posterior hairline
– widely spaced nipples (“shield chest”) • The goal is to complete sexual maturation over a period of 2–3 years.
– short fourth metacarpals
– increased carrying angle at the elbow
(“cubitus valgus”)

Karyotyping is recommended for all girls with unexplained

short stature, delayed puberty, a webbed neck,
lymphedema, or aortic coarctation .

47,XXY (Klinefelter Syndrome and Variants) 45,X/46,XY (Mixed Gonadal Dysgenesis)

• Most common congenital cause of hypogonadism in • A term used to describe asymmetrical gonadal dysgenesis, where one gonad can be
males, affecting approximately 1 in 1,000 male births. identified as a testis and the other is a streak or absent altogether.

• Body habitus exhibits long arms and legs, due both to a • Typically, the genitalia are ambiguous, but also can be female or male.
long bone abnormality and the influence of testosterone
deficiency, and a short trunk.

• Affected individuals may have IQ scores that are lower

than those of their siblings.

• Diagnosis of Klinefelter syndrome is made by

karyotype.

• Hypogonadism can be treated effectively with

testosterone.

 45,XX/46,XY (Chimerism)
• Term used to describe one body derived from the fusion of cells from both twins of a dizygotic
pair.

• All chimeras are, by definition, mosaics but are derived from two distinct zygotes
rather than from a single zygote.

END

• REFERENCES: