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A. Female Pseudohermaphroditismnavigator

  1. 46 XY female with virilized external genitalia and ovaries
  2. Congenital Adrenal Hyperplasia (CAH)
    1. Enzymatic defect in intermediate hormonal synthesis
    2. Results in decreased cortisol production
    3. Elevated adrenocorticotropic hormone (ACTH) secretion
    4. Increased ACTH secretion leads to overstimulation of the adrenals
    5. Overproduction of testosterone results
    6. Causes male precocious masculinization and female pseudohermaphroditism
    7. Hyperpigmentation of areola and labioscrotal folds occurs
  3. CAH and 21-hydroxylase deficiency
    1. Associated with hyponatremic hyperkalemia
    2. Elevated plasma 17a-hydroxyprogesterone and androstendione levels)
  4. CAH and 11-ß-hydroxylase deficiency
    1. Elevated plasma 11-deoxycortisol and 11-deoxycorticosterone levels
    2. Associated with hypernatremia and hypertension
  5. Maternal Progesterone Ingestion
  6. Maternal Virilizing Tumors
    1. Arrhenoblastoma
    2. Corpus luteoma
    3. Adrenal neoplasms
  7. Idiopathic

B. Male Pseudohermaphroditismnavigator

  1. 46 XY male with testes
  2. Inadequate virilization and persistent Mullerian structures
  3. Causes
    1. Abnormal cellular testosterone sensitivity (80% of cases)
    2. Complete Testicular Feminization: Androgen Insensitivity
    3. Incomplete Testicular Feminization: Incomplete androgen receptor defect
    4. Deficient testosterone production (variety of causes)
  4. Complete Testicular Feminization
    1. Androgen Insensitivity: dysfunction of or reduction in androgen receptors
    2. External genitalia are normal female with a short blind-ending vagina
    3. Large amounts of gonadotropins secreted due to central insensitivity to gonadotropins
    4. Testosterone and estrogen are subsequently over secreted
    5. Ectopic testes have 2-5% chance of developing into a seminoma
    6. Gonadectomy should be done post-pubertally
  5. Incomplete Testicular Feminization
    1. Incomplete androgen receptor defect
    2. X-linked recessive inheritance
    3. Results in ambiguous genitalia with partial Wolffian duct structures
    4. Also with infertility and breast development
    5. Gonadectomy to be done pre-pubertally
  6. Deficient testosterone production
    1. Dysgenic Testes
    2. Bilateral Vanishing Testes Syndrome
    3. Mullerian Duct Syndrome
    4. 17ß-Hydroxysteroid Dehydrogenase Deficiency
    5. 5-alpha-Reductase Deficiency
  7. Dysgenic Testes (Testicular Dysgenesis)
    1. Dysgenic Testes Testes insensitive to gonadotropins
    2. Resulting testosterone production inadequate for virilization
    3. Typically raised as girls after a reduction genitoplasty
    4. Testes abnormal endocrinologically and have increased risk of malignant transformation
  8. Bilateral Vanishing Testes Syndrome
    1. Testes lost during intrauterine development
    2. Results from programmed cell death, teratogenic effect, or bilateral intrauterine loss
    3. No gonadal remnants found on surgical exploration
  9. Mullerian Duct Syndrome
    1. Autosomal or X-linked recessive deficiency of Mullerian inhibiting substance
    2. Both Mullerian and Wolffian duct derivatives are present
    3. Dysgenic Testes Testes undescended with no increased risk of malignancy
  10. 17ß-Hydroxysteroid Dehydrogenase Deficiency
    1. Autosomal or X-linked autosomal recessive trait
    2. Defective testerone synthesis in testes
    3. At birth external genitalia female
    4. With puberty, genitalia undergo virilization
  11. 5-alpha-Reductase Deficiency
    1. Autosomal recessive disorder
    2. External genitalia fail to virilize in utero
    3. Internal male anatomy normal with testes in labioscrotal pouch and ejaculatory ducts terminating in vagina
    4. At puberty normal testosterone and LH levels result in masculinization of the external genitalia without breast budding
    5. Typically undergo prepubertal gonadectomy and female gender assignment

C. True Hermaphroditism navigator

  1. Ovarian and testicular tissue exist in same individual
  2. Rare disorder
  3. Genetics
    1. 70% 46 XX females with SRY genes
    2. 10% 46 XY males
    3. Remainder genetic mosaics or chimeric
  4. Anatomic Types
    1. Lateral - one testes and one ovary
    2. Unilateral - one ovotestis and on normal gonad
    3. Two ovotestes

D. Mixed Gonadal Dysgenesisnavigator

  1. Chromosomal mosaics of 45 X and 45XY with testes and streak ovaries
  2. One third have features of Turner's Syndrome
  3. Testes are dysgenic without germinal elements
  4. Gonads removed for 30% rate of malignant transformation
  5. Increased risk for Wilm's tumor

E. Pure Gonadal Dysgenesisnavigator

  1. 46 XX female with streak gonads
  2. Autosomal recessive disorder
  3. Immature female external genitalia with bilateral streak gonads
  4. Primordial germ cells fail to form or to migrate to the gonadal ridges
  5. Present in adolescence as prepubertal and premenarchial females
  6. Streak gonads have increased risk of dysgenesis
  7. Estrogen supplementation required at the age of puberty

F. Systematic Approach to Evaluation of a Newbornnavigator

  1. Family History
    1. Abnormal development
    2. Amenorrhea
    3. Hirsuitism
    4. Consanguity
  2. Maternal hormone ingestion during pregnancy
  3. Physical Exam
    1. Presence of gonad in scrotum or labioscotal fold
    2. Hyperpigmentation of areola or labioscrotal folds
    3. Assessment for micorphallus, hypospadius, cryptorchidism, and hernias
    4. Rectal examination for uterus or prostate
    5. Genital dimensions in females
  4. Anogenital ratio: distance from anus to vagina over anus to urethra should be less than 0.5
  5. Clitoral width should be less than 0.3 cm

G. Laboratory Evaluation navigator

  1. Androgenic Steroids
    1. Dihydrotestosterone
    2. Testosterone
    3. Androstenedione
    4. 17-Hydroxyprogesterone
    5. 17-Hydroxypregnenolone
  2. Adrenal Steroids
    [Figure] "Steroid Biosynthesis"
    1. Cortisol
    2. 11-Deoxycortisol
    3. Aldosterone
    4. 11-Deoxycorticosterone
  3. Serum Electrolytes
  4. hCG stimulation test
  5. Androgen Resistance: testosterone < 2 ng/mL
  6. 12ß-hydroxysteroid Deficiency: elevation in adrestenedione
  7. 5a-Reductase Deficiency: testosterone to dihydrotestosterone ratio > 30
  8. Karyotype from peripheral leukocytes
  9. Visualization of internal anatomy by genitogram or US
  10. Laparoscopy rarely needed to help determine gender assignment

H. Gender Assignmentnavigator

  1. Choice should be made as soon as possible after birth
  2. Males sex only if
    1. Phallus can function as a penis with:
    2. Adequate corporal tissue and response to androgen stimulation
  3. Majority of ambiguous cases lead to female sex assignment made

I. Treatmentnavigator

  1. Hormonal Replacement
    1. Cortisol replacement for congenital adrenal hyperplasia
    2. Mineralocorticoid replacement for complete 21-hydroxylase defect
    3. Testosterone for estrogen replacement at puberty for many intersex disorders
    4. Recombinant growth hormone for short statures seen with mixed gonadal dysgenesis
  2. Surgery
    1. Gonadectomy for phenotypic males with partial or complete Y chromosome to prevent malignant transformation
    2. Female genitoplasty with clitoroplasty for enlarged phallus with female sex assignment
    3. Vaginal reconstruction with surgery or mechanical dilators

References navigator

  1. Rubenstein SC and Mandell J. 1993. Contemp Pediat. pp. 83
  2. Zaontz MR and Packer MG. 1997. Pediat Clin North Amer. 44(5):1267 abstract
  3. Lee MM and Donahoe PK. 1997. Curr Ther Endocrinol Metab. 6:216 abstract