PAKISTAN SOCIETY OF CHEMICAL PATHOLOGISTS

DISTANCE LEARNING PROGRAMME IN CHEMICAL PATHOLOGY

LESSON NO 17
INTERSEX
(SHORT NAME: MRDI)
BY
SURG COMMODORE AAMIR IJAZ
MCPS, FCPS, FRCP (EDIN)

PROFESSOR OF PATHOLOGY /
CONSULTANT CHEMICAL PATHOLOGIST
BAHRIA UNIVERSITY MEDICAL &DENTAL COLLEGE /
PNS SHIFA KARACHI
INTERSEX
 Synonyms
• Pseudohermaphroditism
• Intersex
• Disorders of Sexual Development
(DSD) ---since 2006
 Androgen Insensitivity Syndrome

Disorders of Sex Development (DSD)

• Disorder of Sex Development (DSD) defined as a
condition in which chromosomal sex is inconsistent
with phenotypic sex.

• Previously used terms like intersex, sex reversal,

pseudohermaphroditism, hermaphroditism are
replaced by the umbrella term DSD
 Androgen Insensitivity Syndrome

Classification of DSD
Disorders of Sex Development

Mixed Sex
XX DSD XY DSD
Chromosome DSD

Congenital Adrenal Androgen Insensitivity

Syndrome Mixed gonadal
Hyperplasia
5 alpha reductase dysgenesis
Gestational
deficiency, Gonadal Ovotesticular DSD
hyperandrogenism
dysgenesis
INTERNATIONAL CONSENSUS CONFERENCE ON INTERSEX ORGANIZED BY THE
LAWSON WILKINS PEDIATRIC ENDOCRINE SOCIETY AND THE EUROPEAN SOCIETY FOR
PAEDIATRIC ENDOCRINOLOGY CONSENSUS STATEMENT 2006;118:488-500
 Androgen Insensitivity Syndrome

Normal Sexual Development

• Female and male
external genitalia ---
common developmental
origin
• Prenatal sex
development --- weeks
8 through 24
• The testicles descend
during development

.
www.uptodate.com,
 Androgen Insensitivity Syndrome

Normal Sexual Development

Wolffian and Mullerian

ducts develop in both
sexes

www.uptodate.com,2015
 ‫ن‬
‫گڑی ا کی کہا ی‬
 The Story of Guria
 A baby girl was born to an educated middle class family
 The happy parents called her Guria
 Just when Guria completed first month, a ‘lady next door’
cautioned the mother of Guria that her daughter is ‘not a girl’.
 Actually Guria had Ambiguous genitalia
 The Story of Guria (cont)
 The worried parents went to a well-reputed paediatrician who
advised a test named “Karyotyping”
 The karyotyping showed that Guria has XX chromosome
pattern and therefore ‘a girl’
 Karyotyping
The study of chromosomes
 The Story of Guria (cont)
 The Paediatrician then advised
Serum 17 Hydroxprogesteron (17OHP)
 17 OHP was markedly raised
What is 17 Hydroxprogesteron (17OHP)

•
 Summary of Guria`s finding
Age: 31 day
Ambiguous genitalia: Since birth
Karyotype: XX
17-Hydroxyprogesteron: Markedly Increased
What is your diagnosis ??
a. Adrenocortical Carcinoma
b. Androgen Insensitivity Syndrome
c. Congenital Adrenal Hyperplasia
d. Cushing Syndrome

c. Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia
(CAH)
 What is CAH?
 It is a familial disorder of adrenal steroid
biosynthesis
 Autosomal recessive mode of inheritance.
 Enzyme Deficiency
Three major Enzymes deficiency are clinically
important
• 21-Hydroxylase
• 11-b-Hydroxylase
• 17-a-Hydroxylase
• 3 BETA DEHYDROGENASE DEF
• 17,20 desmolase
21-Hydroxylase Deficiency
Most common type, (accounts for >80% of
cases of CAH).
Incidence is 1:5000 to 1:15000 live birth.
 21-Hydroxylase deficiency (Cont)
It is characterized by reduced production of
cortisol and aldosterone and increased
production of 17OHP.
Result of a 21-Hydroxylase Deficiency
 Pathogenesis
 Autosomal recessive disorders of adrenal
steroidogenesis leading to deficiency of
cortisol.
 Low cortisol level leads to increase
secretion of ACTH, leading to
adrenocortical hyperplasia .

21
 Pathogenesis (cont)
Increased production of 17OHP
 17OHP has androgenic activity
 Most clinical features are due to
virilization (maleness!!)

22
 Clinical Types

The clinical types of CAH (21-Hydroxylase

deficiency) are
Non-salt-losing CAH
Salt-losing CAH
 Non-classic 21-hydroxylase Deficiency

23
 Clinical presentations of CAH in
Females (XX) Infants (non-salt losing)
 Ambiguous genitalia i.e. Enlarged Clitoris
 It is also called ‘46 XX intersex’.
 It has many causes but CAH is the most common
 Clinical presentations of CAH in
Females (XX) Infants (salt losing type)
Ambiguous genitalia i.e. Enlarged Clitoris
and Salt wasting
Clinical presentations of CAH in Adult
Females (Non-classical variety)
Growth of male like hair on face (Hirsutism)
This is the most common cause of hirsutism after PCOS
 Clinical presentations of CAH in Male
(XY) (salt losing type)
 Loss of Sodium (in salt losing variety)
 Normal Genitalia
Clinical presentations of CAH in boys
 Precocious Puberty i.e. early puberty
 Salt-losing CAH

 Symptoms appear shortly after birth with

failure to regain birth weight.
 Dehydration, vomiting ,anorexia
 Disturbances in Pulse, cyanosis ,
dyspnea.
 Without treatment collapse & death may
occur with in a few weeks .
29
Nonclassic 21-(OH)lase deficiency
 Affected females have normal genitals at
birth.
 Early development of pubic axillary hair
 Hirsutism, acne ,menses disorders &
infertility later in life

30
What Happened To Our Guria
 Management of CAH
 Minor surgery of genitalia
 Cortisone therapy
 She started normal development

32
 Am
big
ous
Ge
nital
ia in
XX

Salt-losing
in neonates
XX and XY
CAH Precocious
Puberty in
boys and girls

Hirsuiti
sm in
adult
females

33
 ‫ن‬ ‫ن‬
‫ن‬
‫گ ی ہ کی کہا ی‬
 The Story of Nagina
 A baby girl born named Nagina
 She had normal female genitalia.
 She was having bilateral inguinal hernias.
 Ultrasonography showed testes in the inguinal region and
some müllerian duct remnants in the lower abdomen
 Provisional Diagnosis
• Karyotyping showed 46 XY but
Nagina was phenotypically female.
• Provisional Diagnosis:
Complete Androgen Insensitive
Syndrome (CAIS)
 The story of Nagina (Cont)
At 9 years of age Parents of Nagina brought her to a Consultant
Chemical Pathologist who carried out some preliminary tests
including:
• Karyotyping : 46 XY (for confirmation)
• Serum Testosterone and LH : Low but fail to distinguish from
normal pre-pubertal levels.
• Ultrasound examination reveals presence of both testes in the
inguinal regions, rudimentary internal female genitalia i.e. uterus
and tubes etc.
 The story of Nagina (Cont)
HCG stimulation test was carried out which
showed:
• An increase in serum testosterone to 200 ng/dL
after administration of 1000 international units of
hCG per day for three to five days.
• Testosterone / Dihydrotestosterone ratio :
Normal
 Final Diagnosis
Complete Androgen Insensitivity
Syndrome (CIAS)
 Androgen Insensitivity Syndrome

Definition
“It is an X- linked recessive disorder characterized
by end organ resistance to androgens preventing
the normal development of both internal and
external genital structures in 46 XY individuals.”
 Spectrum of AIS
CIAS • Phenotypically Female

Partial AIS • Ambiguous Female Genitalia

(Female)
Partial AIS • Large Hypospadias etc.
• (Rifenstein Syndrome)
(Male)

Partial or Mild AIS Infertile male

(Male) Azospermic
 Androgen Insensitivity Syndrome

Pathophysiology
SRY

Gonads=Testes
Defective
Sertoli Cells Leydig Cells AR, No
effect to
Testo-
Antimullerian Testosterone sterone
Hormone

Wolffian ducts develop into

Mullerian ducts degenerate
male internal genitalia
Figure 1. Human androgen receptor gene is mapped to the long arm of
the X-chromosome (Xq11-12). The human androgen receptor protein is
encoded by 8 exons (1-8). Similarly to other nuclear receptors, the
protein consists of several distinct functional domains: the NH2-terminal
domain (NTD) containing two polymorphic stretches [(Gln)n and
(Gly)n], the DNA-binding domain (DBD), the hinge region and the
ligand binding domain (LBD).
Figure 2. Ligand-dependent activation of the androgen receptor.
Androgens such as DHT diffuse through the plasma membrane and bind
to the AR. Upon ligand binding, the AR undergoes conformational
changes involving an NH2-/carboxyl-terminal interaction and receptor
stabilization. The AR translocates to the nucleus where dimerization and
DNA binding to regulatory androgen response elements occurs. AR
(androgen receptor); DHT (dihydrotestosterone); CBP (CREB-binding
protein); ARE (androgen response element); hsp (heat shock protein);
SRC-1 (steroid receptor coactivator
 Androgen Insensitivity Syndrome
(AIS)
 Previously called Testicular Feminization Syndrome
 Also called 46XY DSD
 Resistant to androgens.
 Some or all of the physical characteristics of a woman.
 Counseling of Nagina`s Parents
• Reassurance that CIAS is not a life
threatening disorder
• Nagina will remian a girl.
• Specific treatment e.g. Oestrogen
therapy and bilateral gonadectomy
at a later age.
 A Bonus Question
 Can an XY baby with ambigous genitalia have CAH ??

Yes with 3 beta dehydrogenase def CAH

17 alpha hydroxylase
Lipoid hyperplasia(17,20 desmolase def,but rare)
 Androgen Insensitivity Syndrome

Differential Diagnosis

 Androgen Insensitivity Syndrome (AIS)

 5 alpha reductase deficiency
 Congenital adrenal hyperplasia (CAH) due to 3 beta
hydroxysteroid dehydrogenase deficiency
 Androgen Insensitivity Syndrome

Laboratory Investigations

• Serum DHEA-S 0.32 ( 0.03-1.1umol/L)

• 17 hydroxy progesterone 2.4 (0.1- 2.7nmol/L)

3 beta hydroxysteroid dehydrogenase deficiency ruled out

 Androgen Insensitivity Syndrome

Laboratory Investigations
hCG Stimulation Test
Basal
• S.Testosterone 1.5 (0.07-0.24nmol/l)
• S.LH 1.2 (0.5-1.9mIU/l)
• S.FSH 1.1 (0.4-2.1mIU/ml)
72 hrs after first injection
• Testosterone 13 (2 to 9 fold increase)
Normal response to hCG stimulation test
5 alpha reductase deficiency ruled out
 Androgen Insensitivity Syndrome

Diagnostic Approach
History

Clinical Findings

Imaging Studies

Cytogenetic Studies

Lab Investigations

Genetic Analysis
 Androgen Insensitivity Syndrome

Diagnosis
Family history of X-linked inheritance

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

 Androgen Insensitivity Syndrome

Diagnosis
Clinical Examination
Quigley clinical classification of AIS phenotype
MAIS------ grade 1
PAIS------- grade 2-6
CAIS------ grade 7

MAIS PAIS CAIS

Quigley et al;Androgen receptor defects: historical,clinical, and molecular perspectives.Endocr Rev
1995; 16: 271–321
 Androgen Insensitivity Syndrome

Diagnosis
Cytogenetic Studies
46 XY-karyotype

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

www.Uptodate.com
 Androgen Insensitivity Syndrome

Diagnosis
Imaging Studies
• USG Abdomen/ Pelvis
• MRI

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

 Androgen Insensitivity Syndrome

Diagnosis
Laboratory Investigations
• Serum LH
• Serum FSH
• Serum Testosterone
• Serum Dihydrotestosrerone
• hCG Stimulation test
• Androgen Insensitivity Index
(LH X Testosterone)
Hughes IA, Deeb A. Androgen resistance. Best Pract Res Clin Endocrinol Metab 2006; 20: 577–98
 Androgen Insensitivity Syndrome

Diagnosis
Age LH Testosterone

First three Normal/ Mildly Normal/

months of life raised Mildly raised

Pre-pubertal Normal Normal

At Puberty Elevated Elevated

HUGHES IA, DEEB A. ANDROGEN RESISTANCE. BEST PRACT RES CLIN ENDOCRINOL
METAB 2006; 20: 577–98
 Androgen Insensitivity Syndrome

Diagnosis
hCG Stimulation Test
Indications
• Infants with ambiguous
genitalia and palpable
gonads
• In males with delayed
puberty and/or undescended
testes
• To confirm the presence of
testes www.Uptodate.com, 2015
 Androgen Insensitivity Syndrome

Diagnosis
hCG Stimulation Test
Test Protocol
Day 1
• Samples for basal
testosterone, FSH and
LH
• Inj. hCG 100 IU/Kg, IM
Day 3
• Sample for testosterone
www.Uptodate.com, 2015
 Androgen Insensitivity Syndrome

Diagnosis
Ambiguous Genitalia

USG+ Karyotyping

Testes present + 46 XY No testes + 46XX

Hormonal profile Hormonal profile

including 17 OH including 17 OH
progesterone + hCG progesterone + ACTH
stimulation test stimulation test
www.Uptodate.com,2015
 Androgen Insensitivity Syndrome

Diagnosis
Ambiguous Genitalia with XY Karyotype

hCG Stimulation Test

Normal Response Abnormal Response

( 2 – 9 times)
Exaggerated Inadequate
AIS (>10 times) (<2 times)
3 beta HSD
5 alpha
deficiency,
reductase
deficiency Gonadal
www.Uptodate.com,2015 dysgenesis
 Androgen Insensitivity Syndrome

Management
• Multidisciplinary team

• Sex assignment
• Surgical correction
• Gonadectomy
• Hormone replacement
• Psychological issues

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

 Androgen Insensitivity Syndrome

Management
• Sex assignment in AIS may be sometimes
difficult and complicated
• Testosterone treatment trial in patients with PAIS
• In some grades of PAIS
sex of rearing should be assigned keeping in mind
psychosocial aspects

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

 Androgen Insensitivity Syndrome

Management
Surgery
• Orchidectomy
• Gonadectomy
• Vaginal lengthening
• Genital plastic or
reconsrtuctive surgery

ANDROGEN INSENSITIVITY SYNDROME,LEVEN A HUGHES ET AL, LANCET, 2012

 Androgen Insensitivity Syndrome

Management
Hormone Replacement Therapy (HRT)

• CAIS: Estrogen,
Progesterone
postorchidectomy
• PAIS: Testosterone
and DHT

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

 Androgen Insensitivity Syndrome

Management
Psychological Issues
• Emotional and psychological support
• When and how to disclose the news to the patient
• Family guidance if they are carriers and decision on further child birth
• AIS Support Groups

Androgen Insensitivity Syndrome,leven A Hughes et al, Lancet, 2012

 Androgen Insensitivity Syndrome

Complications

• Infertility
• Psychological issues
• Testicular carcinoma
• Osteoporosis
• Hernia

Kravarusic D, Seguier-Lipszyc E, Feigin E et al. Androgen insensitivity syndrome: Risk of

malignancy in a paediatric and adolescent population. Afr J Paediatr Surg 2011; 2: 194–198 .
Q:16: Please refer to the infant mentioned in Q. 14 above. As she grew up she was named
Nagina by her parents. After 9 years of her birth Nagina, who is now a normal looking girl,
is referred to you for final diagnosis. As a Consultant Chemical Pathologist you carry out
certain investigations which show following findings:
Karyotyping : 46 XY
Serum Testosterone and LH : Low but fail to distinguish from normal pre-pubertal levels.
Ultrasound examination reveals presence of both testes in the inguinal regions, rudimentary
internal female genitalia i.e. uterus and tubes etc.
Now how will you address following issues in this patient:
a. What is the Pathogenesis of the disease? Please write THREE lines only.
b. What Functional Endocrinal Test you will like to carry out in this patient, which can
be further helpful in elucidation of the disease in this age? How will you interpret
it?
c. A congenital enzyme deficiency can also produce a disease with similar
biochemical features. How will you exclude this enzyme deficiency in this patient?
d. What gender you will like to assign to this patient i.e. would you like her parents to
continue rearing her as a girl or change her gender to a boy?
 Suggested Answer to Q.16a
What is the Pathogenesis of the disease? Please write
THREE lines only.
1. Complete androgen insensitivity syndrome (CAIS) is due to mutations that
cause severe impairment of androgen receptor function in a 46,XY person.
2. Serum testosterone concentrations in the adult male range but all its
actions are impaired leading to a typical phenotypic woman with primary
amenorrhea with little or no axillary and pubic hair, and affected women
have unambiguously female external genitalia.
3. Anti-mullarian Hormone (AMH) activity is normal so there is no uterus or
tubes or only rudimentary. The vagina is either absent or short and blind-
ending.
 Suggested Answer to Q.16b
What Functional Endocrinal Test you will like to carry out
in this patient, which can be further helpful in elucidation
of the disease in this age? How will you interpret it?
1. In prepubertal children, human chorionic gonadotropin (hCG)
is administered to confirm normal testosterone production.
2. In normal prepubertal boys the administration of 1000 to
2000 int. units of hCG per day for three to five days causes an
increase in serum testosterone to above 200 ng/dL.
3. The majority of prepubertal children with AIS have normal
serum testosterone responses after the administration of
hCG
 Suggested Answer to Q.16c
A congenital enzyme deficiency can also produce a
disease with similar biochemical features. How will you
exclude this enzyme deficiency in this patient?

• 5 α reductase deficiency. It can be excluded by

assaying Dihydrotestosterone (DHT) alongwith
Testosterone in an HCG test (or directly in adults).
• A higher T / DHT ratio shows 5 α reductase
deficiency.(>5)
 Suggested Answer to Q.16d
What gender you will like to assign to this patient i.e.
would you like her parents to continue rearing her as a
girl or change her gender to a boy?
a. The patient is to be reared as a girl as there is no
choice of giving external androgen because of
resistance in their action.
b. Gonadactomy has to be done to prevent malignancy
c. Oestrogen supplements can be given
d. In Parial AIS, this question is much more difficult.
Q 8. An infant with ambiguous genitalia (clitoral
enlargement, labial fusion, and formation of a urogenital
sinus)

• Karyotyping: 46 XX
• Serum Sodium: 141 mmol/L (131-147)
• Serum Potassium : 4.7 mmol/L (3.5 -5.5)
• 17-Hydroprogesterone: 3760 ng/dL (ref value < 35)

What is your diagnosis?

e. Non-salt losing CAH

28/04/2024 01:30 PM 73
Q 9. A 23 y male has infertility for the last 2 y of marriage.
All his primary and secondary sexual characters are
normal. He has azoospermia but normal testosterone and
LH levels.

What is your diagnosis?

f.Mild AIS

28/04/2024 01:30 PM 74
Q 10. An infant, with normal genitalia, is failing to thrive has
following lab findings:

Karyotyping: 46 XY
Serum Sodium: 121 mmol/L (131-147)
Serum Potassium : 5.7 mmol/L (3.5 -5.5)
17-Hydroprogesterone: 3412 ng/dL (ref value < 35)

What is your diagnosis?

h. Salt-losing CAH

28/04/2024 01:30 PM 75
Q 11. An infant has clitoromegaly and short vagina which ends
blindly. Ultrasonography shows absent müllerian structures (uterus
and tubes etc), but incompletely developed Wolffian duct derivatives
(epididymides, vasa deferentia, seminal vesicles, and ejaculatory
ducts).

• Karyotyping: 46 XY

What is your diagnosis?

f. Partial AIS
28/04/2024 01:30 PM 76
Q 12. An 18 year old girl has hirsuitism and
menstrual abnormalities.

17-Hydroprogesterone: 123 ng/dL (ref value < 35)

What is your diagnosis?

d. Non-classical CAH
28/04/2024 01:30 PM 77
Q 13. A 4 y boy astonished his parents by developing facial
and pubic hair. His external genitalia also enlarged and
height was at 92nd percentile

• 17-Hydroprogesterone: 2841 ng/dL (ref value < 35)

What is your diagnosis?

e. Non-salt losing CAH

28/04/2024 01:30 PM 78
Q 14. An infant with female genitalia and bilateral inguinal
hernias. Ultrasonography showed testes in the inguinal
region and some müllerian duct remnants in the lower
abdomen.

• Karyotyping: XY

What is your diagnosis?

b. Complete AIS
28/04/2024 01:30 PM 79
 Patient no 2
An 18 years old female presented with the complaints of irregular menstruation
and hirsuitism. This problem is present for four years but becoming worse for
the last one year. Her lab investigations revealed:
FSH: 21.1 mIU/ml (1.4-9.9)
LH: 19.3 mIU/ml (1.7-15)
Prolactin 20 ng/ml (3.8-23.0)
Testosterone 24.8 ng/dl (0.6-5.0)
DHEAS 15.3 umol/L (1.2- 11.0)
17-hydroxyprogesterone (Basal): 13.0 nmol/L
 17-hydroxyprogesterone (30 min after synacthen injection): 272 nmol/L
a. What is the most probable diagnosis?
b. Give TWO other Differential Diagnoses.

a. Late onset congenital adrenal

hyperplasia (CAH)
b. (1) Polycystic Ovary Syndrome
(PCOS)
(2)Androgen secreting adrenal tumour
 Late-onset CAH

Interestingly it is more common than ‘Classical Variety’ (see ref)

In this patient basal level of 17-OH progesterone was quite high
and indication of Synacthen Test was challenged by some
(intelligent!) trainees.
In adults it can be done to confirm diagnosis (see ref).
However, one really wonders why this girl did not present at an
early age but then in medicine and biology such variations do
occur.
 Nonclassic 21-(OH)lase deficiency

• Affected females have normal

genitals at birth.
• Early development of pubic
axillary hair
• Hirsutism, acne ,menses
disorders & infertility later in
life
82
 Patient no 3
A 7 years old male reported in an Endocrine Clinic with
early appearance of secondary sexual characteristics,
facial, axillary and pubic hair, phallic enlargement, voice
change and rapid increase in height. His Hormonal
investigation revealed:
TSH 2.96 mIU/L (0.4- 4.0)
Cortisol (0800 h) 190 nmol/L (138-690)
ACTH (0800 h) 499 pg/ml (10.0-85.0)
LH < 0.07 mIU/ml (1.0-3.5l)
FSH <1 mIU/ml (0.0- 5.0)
17 Hydroxy Progesterone4.95 ng/ml (0.03-0.90)
Testosterone 222 ng/dl (3.0 -30.0

a. Name the most probable cause of precocious puberty

in this patient.
b. Write TWO more causes of similar clinical condition in
boys of this age group (ignoring hormonal results).
a. CAH due to 21 hydroxylase deficiency (Both classical
and non-classical)
b. Central variety and CNS diseases
 Precocious Puberty in Males

In this patient its due to 21 hydroxylase deficiency

In males, difficult to differentiate between
‘Classical’ and ‘Late-onset’.
Other causes include:
 Central due to brain lesions
 Pituitary
 Adrenal
 Patient no 4
A 6 years old patient presented in an Endocrine
Clinic with labial fusion but absent testes.
Patient had dark pigmentation and grown-up
beard on the face. Height of the patient was at
93rd percentile.
Lab investigations revealed:
 Karyotyping: 46 XX
17 Hydroxyprogesterone: 46.2 nmol/L
(0.5-7.2)
 Serum Cortisol (0800 h): 187 nmol/L
(138-634)
a. Heterosexual
 Plasma ACTH:precocious puberty
87 pmol/L
b. CAH
(<26)due to 21-hydroxylase deficiency 85
 Heterosexual Precocious Puberty

•Precocious Puberty is a manifestation of CAH in male.

•In XX persons CAH presents as ambiguous genitalia
•But in some XX the genitalia may appear normal and the
diagnosis is missed at this age.
•In later age these patients may present with signs of
excessive androgens i.e. excessive facial hair and other
male features
•High ACTH keeps cortisol within reference limits by
enlarging the adrenals
•High ACTH may cause pigmentation
 Patient no 5
An XX female neonates has clitoral enlargement with labial
fusion. She has hypertension Her biochemical picture
shows:
pH: 7.46 (7.35-7.45)
PCO2: 40 mmHg (35-45)
HCO3: 30 mmol/L (23-28)
PO2: 103 mmHg (80-110)
Na : 146 mmol/L (135-150)
K : 2.2 mmol/L (3.5-5.0)
Cl 101 mmol/L (98-106)
DHEA-S: Raised
Testosterone: Raised
a.What is the most probable diagnosis?
b.Name TWO steroid metabolites which are raised in this
condition.

a. 11-B dehydroxylase deficiency

11-deoxycortisol and 11-deoxycorticosterone,
 11-B dehydroxylase deficiency
CYP11B1 (or 11-beta-hydroxylase) deficiency
is the second most common cause of congenital
adrenal hyperplasia after 21-Hydroxylase def.
Two Cardinal Presentations:
Virilization of female neonate
Hypertension
Biochemical Findings: High serum concentrations
of 11-deoxycortisol, 11-deoxycorticosterone, and
dehydroepiandrosterone sulfate (DHEA sulfate),
androstenedione, and testosterone.
04/28/2024 89
 Patient no 6
A male (46,XY) neonate presents with feeding difficulties and
vomiting. His electrolyte report shows hyponatremia, and
hyperkalemia. His external genitalia are nearly like a normal
female but with blind vagina. His hormonal profile showed:
Cortisol : Mildly decreased
Serum Progesterone: Low
Serum Pregnenolone: High
Serum 17-hydroxypregnenolone: High
Serum DHEA-S : High
Serum androstenedione : Low
Testosterone and estradiol: Lower than pre-pubertal levels
What is the most probable biochemical defect in this patient?

04/28/2024 90
 Patient no 6
A male (46,XY) neonate presents with feeding difficulties and
vomiting. His electrolyte report shows hyponatremia, and
hyperkalemia. His external genitalia are nearly like a normal
female but with blind vagina. His hormonal profile showed:
Cortisol : Mildly decreased
Serum Progesterone: Low
Serum Pregnenolone: High
Serum 17-hydroxypregnenolone: High
Serum DHEA-S : High
Serum androstenedione : Low
Testosterone and estradiol: Lower than pre-pubertal levels
What is the most probable biochemical defect in this patient?

3 β hydroxysteroid dehydrogenase
deficiency
04/28/2024 91
 3 β hydroxysteroid dehydrogenase deficiency
(3BHSD)

Clinical Findings MALE WITH AMBIGUOIOS GENITALIA

• Early presentation in neonatal or infancy in most cases
• Genotypic male with female like external genitalia (male
pseudohermaphroditism)
• Feeding difficulties and vomiting
Biochemical findings – Substrate for 3 β hydroxysteroid
dehydrogenase enzyme i.e. serum pregnanolone, 17-OH pregnanolone and
DHEA are increased due to enzyme deficiency
o Low levels of serum progesterone, androstenedione and sex steroid
also revealed deficiency of same enzyme as these are formed by action of 3 β
hydroxysteroid dehydrogenase.

04/28/2024 92
 Patient no 7
A 13 year female (46,XX) patient presented with primary
amenorrhea and absent secondary sexual characteristics. She has
hypertension (BP: 170/130 mm Hg). Her routine biochemical profile
carried out at multiple occasions sometimes indicated hypokalaemia.
Her hormonal profile showed:
Cortisol : Mildly decreased
Serum Progesterone: High
11-deoxycorticosterone: High
11-deoxycortisol: Low
DHEA-S and androstenedione : Low
Testosterone and estradiol: Low
Plasma renin: Low
What is the most probable biochemical defect in this patient?

17 α hydroxylase deficiency
04/28/2024 93
17 α hydroxylase deficiency
Clinical findings
Female with typical presentation at puberty with hypogonadism
(absent puberty), hypertension and hypokalemia
Biochemical findings
Decreased cortisol and its precursors (11 deoxycortisol) and
decreased adrenal androgens and sex steroids are typical
biochemical findings of 17 α hydroxylase deficiency.
Decreased serum cortisol results in activation of HPA axis
Substrate for 17 α hydroxylase i.e. serum progesterone is high
with increased formation of 11 deoxycorticosterone
As 11 deoxycorticosterone has mineralocorticoid activity, it
results in suppression of rennin thus low plasma renin and
serum aldosterone levels

04/28/2024 95
 Precocious Puberty
Sexual development < 8 y (in girls) and
<9 y in boys
Types:
Gonadotropic Dependant Precocious
Puberty (CDPP) also called Central PP
Gonadotropic Independent Precocious
Puberty (GIPP) also called Peripheral
PP

97
PRECOCIOUS PUBERTY
•Complete (central and peripherial)
•Isolated(theralache, adrenache, pubarche) may progress to
complete
•Non progressive pp-non persist

1. Among complete central is most common in boys than female

2. FSH>0.1 &LH>0.1 miu/ml and very younger age <3y indicative
of central pp
Benign pubertal variants
These isolated and usually non-
progressive pubertal variants include:
Premature Thelarche: Isolated breast
development
Premature Adrenarche: Early
development of pubic and axillary hair,
acne and odor may be due to adrenal
androgen excess e.g. DHEAS

99
Cont’d

•GnRH stimulation test with 100ug GnRH or its analog(a) given i.v
after base line FSH &LH and meaurement after 30 and 60 MIN
FSH & LH .
•LH rp required priming before pubertal rise ,as it is gradually done
in central but not in peripherial pp so no response of LH obtained in
peripherial pp on this test
•While FSH rp do not req priming before pubertal rise so it is
elvated both in peripheral and central pp.(>5mIU/ml)
•PRIMING IS USUALLY DONE WITH 100ug s/c GnRH injection
daily for 2 weeks to reduced inhibition /suppression
contd
1. A6yrs old boy with pp with FSH and LH in prepubertal range
and TSH >75mIU/L.What is the cause and diagnosis.
Hypothyroidism leading to peripherial pp due to structural
resemblance with LH and stimulating testosterone release.
AND
And if TSH IS NORMAL AND THERE IS TESTICULAR TUMOR
THEN Hcg secreating testicular tumour is the cause with above
same reason
Cont’ d
Can Hcg secreating tumour produced pp in female also due to
structural resemblance. Yes or no
No
Because ovarian rp of LH do not respond to hcg. They req priming
with LH rp first and then priming should be done first with LH.
 Patient nO 6 (cont)
A 7 years old female presented with bleeding PV and and presence of pubic and
axillary hair growth and development of breast for the last one year. USG showed
enlarged uterus and ovaries for this age. Her fertility profile showed:
FSH 1.4 mIU/ml
LH 0.1 mIU/ml
Estradiol 132 pg/ml
a. What is the most probable diagnosis
Precocious puberty
b. Name the test which can be helpful for further elucidation of the disease.

GnRH stimulation Test

 GnRH Stimulation test
FSH (Basal) 1.4
FSH(30 min) 8.2
FSH(60 min) 11.6

LH(Basal) 0.1
LH(30 min) 1.6
LH(60 min) 1.8

What is the FINAL diagnosis

Peripheral Precocious
Puberty
 Patient nO 7
A 3.5 years old female presented with bleeding PV and and presence
of pubic and axillary hair growth and development of breast for the
last one year. USG showed enlarged uterus and ovaries for this age.
Her fertility profile showed:
FSH 3.9 mIU/ml
LH 3.0 mIU/ml(<0.1)
Estradiol 199 pg/ml (prepubertal <20pg/ml)
a. What is the most probable diagnosis
b. Name the test which can be helpful for further elucidation of the
disease.
 Patient nO 7
A 3.5 years old female presented with bleeding PV and and presence of pubic
and axillary hair growth and development of breast for the last one year. USG
showed enlarged uterus and ovaries for this age. Her fertility profile showed:

FSH 3.9 mIU/ml

LH 3.0 mIU/ml(<0.1)
Estradiol 199 pg/ml (prepubertal <20pg/ml)
a. What is the most probable diagnosis
Precocious puberty
b. Name the test which can be helpful for further elucidation of the disease.

GnRH stimulation Test

 GnRH Stimulation test

FSH (Basal) 5.9

FSH(30 min) 16.8
FSH(60 min) 17.5
LH(Basal) 2.8
LH(30 min) 44.1
LH(60 min) 35.4
 GnRH Stimulation test
FSH (Basal) 5.9
FSH(30 min) 16.8
FSH(60 min) 17.5
LH(Basal) 2.8
LH(30 min) 44.1
LH(60 min) 35.4

What is the FINAL diagnosis

Central Precocious
Puberty
 Patient nO 8

A 6 years old male presented with testicular swelling and

lengthening of the phallus as per his age. He also developed
secondary sexual characteristic at this age.
FSH 0.9 mIU/ml
LH 0.4 mIU/ml(<0.1)
TSH: 34 mIU/ml (0.4-4.5)
a. What is the most probable diagnosis
b. Write ONE cause of the clinical features of the boy..
 Patient nO 8

A 6 years old male presented with testicular swelling and

lengthening of the phallus as per his age. He also developed
secondary sexual characteristic at this age.
FSH 0.9 mIU/ml
LH 0.4 mIU/ml(<0.1)
TSH: 34 mIU/ml (0.4-4.5)
a. What is the most probable diagnosis
Hypothyroidism leading to Peripheral PP
b. Write ONE cause of the clinical features of the boy..
Structural resemblance of TSH and LH
 Patient nO 9

A 9 years old male presented with enlargement of right testis and

signs of premature puberty. His hormonal profile showed:
FSH 0.6 mIU/ml
LH < 0.1 mIU/ml(<0.1)
Testosterone: In pubertal range
a. What is the most probable cause of precocious puberty in this
boy?
b. Can this condition cause precocious puberty in a girl?
 Patient nO 9
A 9 years old male presented with enlargement of right testis and signs of premature
puberty. His hormonal profile showed:
FSH 0.6 mIU/ml
LH < 0.1 mIU/ml(<0.1)
Testosterone: In pubertal range
a. What is the most probable cause of precocious puberty in this boy?
High HCG from a germ cell testicular
tumour e.g. embroynal cell carcinoma
b. Can this condition cause precocious puberty in a girl?
No. In girls HCG cannot cause secretion of estrogen from ovaries because LH
and FSH activation is required
Thank You and Best Of Luck