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AMBIGUOUS GENITALIA

Dr Mohd Maghayreh
PRTH /IRBID
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 ■ Intersex disorders: discordance between gender


genotype and phenotype
 ■ Intersex disorders: medical & psychosocial emergencies
 ■ External genitalia will develop along female lines unless
systemic
 androgens (dihyrotestosterone [DHT]) inducemale
differentiation
 ■ Male differentiation requires:
 ➣ Sex determining region of Y (SRY) gene
 ➣ Bilateral testes producing Mullerian inhibiting substance
(MIS)
 & testosterone
 ➣ 5-alpha reductase enzyme (external genitalia)
 ➣ Functional testosterone & DHT receptor (internal &
external
 genitalia)
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 history & physical


 History
 ■ Family Hx – Many intersex states are genetic, therefore
family history
 is important:
 ➣ Infertility➣ Consanguinity
 ➣ Prior infant demise
 ➣ Hirsutism
 ➣ Acne
 ➣ Oligo- or amenorrhea
 ➣ Hypospadias
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 ■ Maternal conditions
 ➣ Use of birth control pills after conception
 ➣ Maternal virilization (androgen-secreting tumors)
 ➣ Maternal exposure to androgens, progestins or other meds
 (seizure meds)
 ■ Assoc conditions
 ➣ Turner syndrome: female phenotype w/ streak gonads
 ➣ Klinefelter syndrome: micropenis w/ small testes
 ➣ Camptomelic dwarfism (XY gonadal dysgenesis)
 ➣ Denys-Drash syndrome
 Nephropathy, genital abnormalities &Wilms’ tumor
 ➣ Congenital adrenal hyperplasia
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 Signs
 ■ If gonad descended & palpable, most likely testis or, rarely, ovotestis
 ■ If gonads not palpable in scrotum, check inguinal canal
 ■ Rectal exam: uterus palpable in females during 1st 48 h of life due
 to maternal estrogen
 ■ Intersex problem should be suspected in apparent males w/:
 ➣ Micropenis (<2.0 cmin terminfant)
 ➣ Bilateral cryptorchidism, especially impalpable testes
 ➣ Bifid scrotum
 ➣ Severe hypospadias
 ➣ Any hypospadias with undescended testicle
 ■ Intersex problem should be suspected in apparent females w/:
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 ➣ Enlarged, rugated labioscrotal folds


 ➣ Clitoromegaly (>1 cm)
 ➣ Posterior labial fusion (same differential as clitoromegaly)
 ➣ Labial or inguinal mass
 ■ Hyperpigmentation of areola or scrotum w/ CAH
 ■ Dehydration, hypotension w/:
 ➣ 21-hydroxylase deficiency (CAH), virilization of females
 ➣ 3-beta-hydroxysteroid dehydrogenase deficiency (CAH), mild
 virilization in females, severe hypospadias inmales
 ➣ Congenital lipoid hyperplasia, incompletemasculinization
 ■ Hypertension w/:
 ➣ 11-beta-hydroxylase deficiency (CAH), virilization of females
 ➣ 17-alpha-hydroxylase deficiency (CAH), incomplete masculinization
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 tests
 ■ Serumelectrolytes
 ■ Expedited karyotype
 ■ Abd US for presence/absence of uterus
 ➣ Presence of uterus indicates bilateral ovaries or dysgenetic
 gonads that failed to produceMullerian inhibiting substance
 ■ 17-hydroxyprogesterone, androstenedione & serum testosterone
 (T) (obtained between 24–48 h)
 ➣ Decreased levels of testosterone
 Leydig cells deficient
 Luteinizing hormone (LH) activity impaired
 Testosterone biosynthetic defect
 ➣ Markedly elevated 17-hydroxyprogesterone, androstenedione,
 & testosterone w/ 21-hydroxylase deficiency (CAH)
 ■ Genitography
 ➣ To determine anatomy of urethra, vagina
 ➣ To assess presence/absence of urogenital sinus
 ■ HCG stimulation test
 ➣ Useful to assess for presence/absence of testicular tissue or to
 diagnose testosterone biosynthetic defect
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 ■ Additional studies
 ➣ XX infant w/Mullerian ducts
 17-hydroxyprogesterone
 11-deoxycortisol
 Cortisol
 Renin
 17-hydroxypregnenolone
 Testosterone
 ➣ XX infant w/oMullerian ducts
 Testosterone
 Estradiol (E2)
 Luteinizing hormone
 Follicle-stimulating hormone (FSH)
 SRY
 ➣ XY infant w/Mullerian ducts
 Testosterone
 Estradiol
 Luteinizing hormone
 Follicle-stimulating hormone
 ➣ XY infant w/oMullerian ducts
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 Testosterone & dihydrotestosterone (DHT)


 If testosterone/DHT increased, consider HCG stimulation
 test
 If testosterone normal/low, obtain:
 Androstenedione
 Dihydro-epiandrosterone
 17-hydroxy-pregnenolone
 17-hydroxy-progesterone
 Deoxycorticosterone (DOC)
 Cortisol
 Consider ACTH stimulation test
 Luteinizing hormone
 Follicle-stimulating hormone
 differential diagnosis
 ■ Genetic male w/ severe hypospadias or undescended testes
 ■ Female pseudohermaphroditism
 ➣ CAH (most common)
 Karyotype 46 XX
 Androgenized females

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 Autosomal recessive inborn error of steroidogenesis 90%


 due to 21-hydroxylase deficiency, leading to impaired cortisol
 synthesis resulting in elevation of serum 17-hydroxyprogesterone,
 androstenedione & testosterone
 Can have severe, life-threatening salt wasting from reduced
 aldosterone production
 Acute adrenal insufficiency as early as day 5 of life
 Increased melanocyte-stimulating hormone darkens areola,
 scrotum
 Internal organs female
 Phenotype typically incl single urogenital opening along ventral
 shaft of enlarged clitoris, absence of palpable gonads,
 rugated & enlarged labioscrotal folds
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 ➣ Maternal androgens
 Exogenous (i.e., medication)
 Endogenous (i.e., androgen-secreting
tumors)
 ■ Male pseudohermaphroditism
 ➣ Karyotype 46 XY
 ➣ Defective virilization
 ➣ NoMullerian organs (MIS intact)
 ➣ Etiologies
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 Complete androgen insensitivity syndrome


 Androgen receptor abnormal
 Unable to respond to circulating testosterone
 Presentation: bilateral inguinal hernias
 Phenotypically normal female w/ Blind-ending vagina, no
 Mullerian structures secondary to MIS secretion from normal
 Sertoli cells
 Testis in inguinal canal or intra-abdominal
 Partial androgen insensitivity syndrome – phenotype varies
 from apparently normal female w/ clitoral hypertrophy to
 apparently normal male w/ hypospadias
 Decreased testosterone synthesis – severe hypospadias, small
 penis, cryptorchidism

 5-alpha-hydroxylase deficiency
 Inability to convert testosterone to DHT, which promotes
 virilization of external genitalia
 Autosomal recessive
 Severe hypospadias, bifid scrotum, cryptorchidism
 Can be phenotypically female at birth
 Anorchia (testis syndrome) – results in loss of
 testosterone after 14 wk gestation
 PersistentMullerian duct syndrome
 MIS receptor abnormal or no secretion of MIS
 Presents w/ undescended testis, which can be impalpable,
 or hernia
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 Mullerian structures (uterus, fallopian tubes) remain


 ■ Chromosomal anomalies
 ➣ Pure gonadal dysgenesis
 Karyotype usually 46 XY, but may be XO (Turner syndrome) or
 XX
 MIS & testosterone both absent because of failed gonadal differentiation
 Phenotypically normal females
 Increased risk of malignancy
 ➣ Turner’s syndrome
 45 XO or 46 XX/45 XO mosaic
 Female phenotype w/ streak gonads
 Somatic abnormalities: short stature, webbed neck, shield
 chest,
 coarctation of aorta, horseshoe kidney
 Sexual infantilism: amenorrhea, sparse hair, no pubertal
 development
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 ➣ Mixed gonadal dysgenesis


 Karyotype 46 XY or 45 XO/46XYmosaic
 Asymmetric gonads, one streak gonad or one dysgenetic testis
 Streak gonad: 25% risk of malignancy (gonadoblastoma);
 must remove
 Usually incompletely virilized males w/ microphallus,
 hypospadias, partial labioscrotal fusion, only one palpable
 gonad
 ➣ True hermaphroditism
 Karyotype usually 46 XX, but can be 46 XY or 46 XX/46 XY
 mosaic
 Asymmetric gonads: testis on 1 side/ovarian tissue on other
 or combined ovotestis on 1 or both sides
 Varies from female phenotype w/ clitoromegaly to male w/
 hypospadias & asymmetrically descended testes
 management
 ■ What to do first
 ➣ Salt-wasting CAH requires aggressive treatment (see CONGENITAL
 ADRENAL HYPERPLASIA)
 Correction of hypovolemia (normal saline w/ 5% glucose)
 Glucocorticoid replacement w/ hydrocortisone at 3–6×maintenance
 Mineralocorticoid replacement (Florinef)
 ■ General measures
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 ➣ Expeditious & appropriate sex assignment


 ➣ Interdisciplinary team approach: neonatology, endocrine, psychiatry,
 genetics & urology should all be involved early
 ➣ Surgical Rx
 Isolated hypospadias usually repaired at 9mo
 Female pseudohermaphrodite usually assigned female sex,
 treated w/ clitoral reduction, vaginoplasty by age 6 mo
 Male pseudohermaphrodite: sex assignment varies depending
 on external phenotype & Dx
 Gonadal dysgenesis usually assigned female sex; gonadectomy
 for high risk ofmalignancy
 specific therapy
 ■ Depends on underlying etiology
 follow-up
 ■ Depends on underlying etiology