AMBIGUOUS GENITALIA.pdf - Dr. Erfan & Bagedo General Hospital

AMBIGUOUS GENITALIA 

Copyright © 1982 - 2009 Dr. Erfan & Bagedo Hospital 

THANAA A. AMER M.D,FAAP. 

Consultant Pediatric Endocrinologist 

American Board 

DR. ERFAN & BAGEDO GENERAL HOSPITAL.

“‘ Baby born with ambiguous genitalia 

is one of the few pediatric endocrine 

emergencies .” 

Copyright © 1982 - 2009 Dr. Erfan & Bagedo Hospital


Ambiguous Genitalia 

“ An Endocrine Emergency” 

• Having a baby without knowing the sex is very devastating news to 

the family. 

• Ambiguous girl already given a boy’s name but….?! 

• Going through the process of informing the family about the clinical 

findings in a simple way. 

• The possibility of adrenal or salt wasting crises

Ontogeny Of Sex Differentiation 

• Male sex differentiation 

• Ontogeny of the internal genital system 

• Ontogeny of the External genital system 



Male Sex Differentiation

Ontogeny Of The Internal Genitalia 


Ontogeny Of The External Genitalia 


Definition of Ambiguous Genitalia 

• Undervirulized male or Viriulized female 

• A genitalia that has 

– A phallic like structure, which is larger than a Clitoris 

but smaller than a phallus 

– Aberrantly located urethral opening 

– Absent gonads or at least one 

– Phallic like structure ,with no palpable gonads 

– Single urogenital orifice 


Classification of Ambiguous Genitalia 

• Female Pseudohermaphrodite 

• Male pseudohermaphrodite 

• True hermaphrodite 

• Gonadal dysgenesis; 46XY or 45X/46XY 



Female Pseudohermaphrodite 

46XX baby can have variable degree of virilization due to exposure 

to excess androgens in utero 

– The ambiguity ranges from 

• Simple cliteromegally 

• Posterior fusion of the labia 

• Complete labial fusion with the formation of a phallic like 

structure 

• Single perineal opening of the urogenital sinus. 

The phenotypic variability depends on the time of exposure to 

the excess androgens.


Androgens Origin 

• Androgen of maternal origin 

• Androgens origin of fetal origin

Androgen Maternal Origin 

• Exogenous androgens such as androgenic progesterone 

• Virilizing adrenal tumour 

• Mother with uncontrolled congenital adrenal hyperplasia 

• Placental aromatase deficiency 


Androgens Origin Of Fetal Origin 

• Congenital Adrenal hyperplasia 

– 21-hydroxylase Deficiency 

– 3β-hydroxysteroid Dehydrogenase 

– 11β-hydroxylase deficiency 

• Androgen Producing tumors 


Adrenal Steroidogenesis 



21-hydroxylase deficiency 

CTH Cholesterol (outer mitochondrial membrane) 

StAR 

Cholesterol (inner mitochondrial membrane) 

P450scc 

P450c11β 

P450c18 P450c18 

3βHSD Isom P450c21 P450c18 

Pregnenolone Progesterone DOC Corticosterone 180H Aldosterone 

Corticosterone 

P450c17 P450c17 

170H 3βHSD Isom 170H P450c21 P450c11β 

Pregnenolone 

Pregnenolone 11 Deoxycortisol Cortisol 

P450c17 

P450c17 

DHEA 3βHSD Isom Androstenedioe 

17 βHSD 

Tesosterone 

P450 Arom 

P450 Arom 

Estrone 

Estradiol 

17 βHSD


21-hydroxylase Deficiency 

• The most common cause (>90%) of CAH. 

• An autosomal recessive disorder 

• Incidence of 1: 12000 to 1: 15000 livebirth 

• Two types are known, 

– Classic type (severe) : 

• Simple virilizing( cortisol defficiency only) 

• Salt waster type ( +Mineralocorticoid deficiency) 

– Non- classic type


21-hydroxylase Deficiency 

• Biochemical Markers 

– ↑ Testosterone 

– ↑ 17-OH Progesterone 

Salt wasting type 

– ↑ Plasma Renin Activity(PRA) 

– ↓ Aldosterone 

– ↓ Na 

– ↑ K

ACTH 

3β-hydroxysteroid Dehydrogenase 

Cholesterol (outer mitochondrial membrane) 

StAR 


P450scc 

P450c11β 

P450c18 P450c18 

3βHSD Isom P450c21 P450c18 

Pregnenolone Progesterone DOC Corticosterone 180H Aldosterone 

P450c17 P450c17 



Pregnenolone 


P450c17 


P450c17 


17 βHSD 

Tesosterone 

P450 Arom 

P450 Arom 

Estrone 

Estradiol 

17 βHSD



(3-HSD) Deficiency 

• Autosomal recessive disorder 

• Only 5% of the CAH cases 

• Variable degree of virilization 

• Salt wasting.



– ↑ Prognenolone ∕ Progesterone 

– ↑ 17-OH Prognenolone ∕ 17-OH Progesterone 

– DHEA or DHEAS 

Salt wasting type 

– ↑ Plasma Renin Activity(PRA) 


– ↓ Na 

– ↑ K 


11β-hydroxylase Deficiency 

ACTH Cholesterol (outer mitochondrial membrane) 

StAR 


P450scc 

P450c18 P450c18 

3βHSD Isom P450c21 P450c11β 

Pregnenolone Progesterone DOC Corticosterone 180H 


Aldosterone 

P450c17 P450c17 


Pregnenolone 


P450c17 


P450c17 


17 βHSD 

Tesosterone 

P450 Arom 

P450 Arom 

Estrone 

Estradiol 

17 βHSD


• Virilization and hypertension 


Virilization And Hypertension 

• Autosomal recessive inheritance 

• 5-8% of CAH cases 

• Frequency of 1/100,000 live birth in the general Caucasian 

population 

• More common in Jews of North African origin (1/5000-7000)



– ↑ Testosterone 

– ↑ DOC 

– ↑ 11-deoxycorticosterone 

– ↓ Plasma Renin Activity (PRA) 


– ↔ Na 

– ↔↓ K 


Male Pseudo-hermaphrodite 

• Complete newborn male differentiation requires: 

– SRY and downstream genes 

– Antimullerian hormone (AMH) &testosterone 

– Gonadotropin production (during the second and third trimester), 

– Conversion of testosterone to dihydrotestosterone (DHT) by 5 alphareductase 

– End organ response to androgens 


Male Pseudo-hermaphrodite 

• Disorder in androgen biosynthesis 

• Defect in androgen target tissue 

• Persistent mullerian duct syndrome 

• Gonadal dysgenesis 

• Vanishing testes 


Disorder In Androgen Biosynthesis 

• Leydig cell hypoplasia 

• HCG resistance 

• Cholesterol (20,22-desmolase) deficiency 

• 3-HSD deficiency 

• 17-20 lyase (dismulase) deficiency 

• 17-hydroxysteroid dehydrogenase deficiency 


Adrenal Steroidogenesis 


Defect In Androgen Target Tissue 

• 5-alpha-reductase deficiency. 

– Testosterone……→ X→……Didhydrotestosterone (DHT) 

– ↑T / DHT ratio 

• Partial Androgen insensitivity. 



Management 

Of 

A Newborn With Ambiguous Genitalia


Management 

• Carefully Consider the following; 

– Facing the parents is the first challenge to the medical team. 

– Great care is to be taken with words selection. 

– It is advisable to assign one physician to talk to the parents 

– Preferably a pediatric endocrinologist, if not available, the 

pediatrician


Diagnosis 

• Start by taking detailed information: 

– Pregnancy history 

– Previous pregnancies 

– Abortions 

– Maternal drug ingestion. 

– History of consanguinity 

– Infertility and sterility


Physical Examination 

• Vital signs and hydration status. 

• The abdomen and the inguinal canal should be examined for 

possible undescended gonads. 

• The phallic like structure should be assessed for length, curvature, 

and locating the opening of the urethral meatus.


Physical Examination 

• The labioscrotal folds should be examined looking for: 

– Hyperpigmentaion 

– Rogation 

– the extent of fusion or separation 

– Absence or the presence of gonads. 

– Looking for a possible vaginal introitus 

• Gentile rectal examination may demonstrate the presence or absence 

of a uterus.

Radiographic Evaluation 

• Ultrasound is the most common tool used 

for uterine identification 

• MRI gives more accurate identification of 

the internal genital organs 

• The slightly invasive vaginogram 



Treatment 

• Aim of treatment is the prevention of: 

– Salt wasting 

– Progressive virilization 

– Early appearance of pubic hair 

– Bone age advancement and ultimate short stature 

– Precocious puberty


Treatment 

• Hydrocortisone: 

10-20 mg/m2 /day in 3 divided doses 

• Fludrocortisone acetate (Florinef) 

0.05-0.3 mg daily 

• NaCl 

– 1-3 gm per day 

• New treatment modalities under trial 

– Adrenalectomy 

– Using combination of antiandrogen, aromatase inhibitor and a 

reduced dose of hydrocortisone.


• 

•

AMBIGUOUS GENITALIA.pdf - Dr. Erfan & Bagedo General Hospital

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