Sexual Ambiguity

Sexual Ambiguity: Excerpt from The 5-Minute Pediatric Consult

J. Nina Ham, MDLorraine E. Levitt Katz, MD

Sexual Ambiguity - BASICS

Sexual Ambiguity - description

Genitalia can be defined as ambiguous when it is not possible to categorize the gender of the child based on outward appearances.

• Pitfalls: Girls with congenital adrenal hyperplasia (CAH) may appear quite virilized at birth and be mistaken for boys. Nevertheless, they have good female reproductive potential with adequate control of their disease and should be assigned a female sex.

Sexual Ambiguity - general prevention

• Avoid the use of androgenic steroids during pregnancy.
• Prenatal diagnosis of CAH and maternal steroid treatment to prevent virilization of female fetuses is available.

Sexual Ambiguity - epidemiology

Disorders causing sexual ambiguity occur congenitally, and the time of presentation is the newborn period. Children with 5α-reductase deficiency demonstrate virilization with puberty.

Sexual Ambiguity - risk factors

Sexual Ambiguity - genetics

• Inherited adrenal enzymatic defects of adrenal biosynthesis are the most common cause of virilization of the newborn female. 90% of these females have 21-hydroxylase deficiency.
• Gonadal dysgenesis is associated with chromosomal aberrations.
• Syndromes of gonadal dysgenesis can also arise from mutations in the Wilms tumor-suppressor gene (WT-1), steroidogenic factor 1 (SF-1), sex-determining region Y (SRY), and the SRY homeobox gene SOX9.
• CAH is caused by defects in the genes encoding adrenal steroidogenic enzymes. It follows an autosomal recessive inheritance pattern.
  • The most common form is 21-hydroxylase deficiency (encoded by the gene CYP21), but sexual ambiguity can also be seen in defects in 17-hydroxylase (CYP17), 3β-hydroxysteroid dehydrogenase (HSD3B2), 17-ketosteroid reductase (HSD17B3), and 11β-hydroxylase (CYP11B1).
  • Congenital lipoid adrenal hyperplasia has been associated with defects in steroidogenic acute regulatory protein (StAR) and, less commonly, cholesterol desmolase.
• 5α-Reductase deficiency is an autosomal recessive disorder that manifests only in genetic males.
• Androgen resistance syndromes are due to defects in the androgen receptor, the gene of which is located on the X chromosome. Thus, they follow an X-linked recessive pattern.

Sexual Ambiguity - pathophysiology

• Gonadal dysgenesis:
  • Partial dysgenesis of the gonads following differentiation into testes will result in a spectrum of abnormalities ranging from phenotypically female external genitalia with the absence of Müllerian structures to micropenis or cryptorchidism.
  • Mixed gonadal dysgenesis: Individuals with the mosaic genotypes XO/XY and XX/XY have gonads containing both ovarian and testicular elements and external genitalia ranging from normal female, intersex, to normal male.
  • Hermaphroditism: True hermaphrodites have gonads possessing both ovarian and testicular elements. This condition includes the patients with mixed gonadal dysgenesis discussed above, in addition to those with the karyotype 46XX, and less commonly 46XY.
• Disorders of sexual phenotype:
  • Female pseudohermaphroditism: Masculinization of the female fetus is usually caused by androgens produced by the fetus or transferred across the placenta from the mother. The most common cause is CAH in which the fetal adrenal glands overproduce androgens in an attempt to correct cortisol deficiency.
  • Male pseudohermaphroditism: Incomplete masculinization of the male fetus can be caused by enzyme disorders of testosterone synthesis (e.g., CAH and 5α-reductase deficiency) or unresponsiveness to testosterone action (androgen resistance syndromes).

Sexual Ambiguity - DIAGNOSIS

Sexual Ambiguity - signs & symptoms

Ambiguous genitalia in the neonate should be treated as an emergency, and the diagnostic evaluation undertaken as soon as possible.

Sexual Ambiguity - history

Obtain a careful pregnancy and family history addressing:

• Drug ingestion
• Exposure to teratogens
• Infections during the pregnancy
• Androgenic changes in the mother
• Family history suggestive of CAH

Sexual Ambiguity - physical exam

Notable features:

• Palpable gonads: Imply the presence of Y-chromosome material
• Fusion of the labia
• Existence of a vagina
• Position of the urethra
• Length and diameter of the penis or clitoris
• Development of the scrotum
• Other dysmorphic features
• Hypertension is seen with 17α-hydroxylase and 11-hydroxylase deficiencies.
• Features of the classic disorders of adrenal steroidogenesis

Sexual Ambiguity - tests

Sexual Ambiguity - lab

• Specific tests:
  • Karyotype
  • Steroid levels: 17-hydroxyprogesterone, 17-hydroxypregnenolone, dehyrdoepiandrosterone (DHEA), testosterone, dihydrotestosterone (DHT), 11-deoxycortisol, androstenedione
• Nonspecific tests: Electrolytes: Hyponatremia, hyperkalemia, and metabolic acidosis are associated with several adrenal enzyme deficiencies.

Sexual Ambiguity - imaging

• Pelvic ultrasound
• Urethrogram

Sexual Ambiguity - differencial diagnosis

• Gonadal dysgenesis:
  • Partial dysgenesis of the gonads
  • Mixed gonadal dysgenesis
  • Hermaphroditism
• Female pseudohermaphroditism:
  • CAH: Inherited adrenal enzymatic defects, including 21-hydroxylase, 11-hydroxylase, and HSD3B2 deficiencies can cause virilization of females.
  • Maternal androgen exposure
  • Exogenous androgens or endogenous production (e.g., maternal virilizing tumor)
  • Multiple congenital anomalies
  • Ambiguous genitalia can be a part of a spectrum of congenital anomalies, especially those of the urologic system and rectum.
  • Idiopathic
• Male pseudohermaphroditism:
  • CAH: Deficiencies in HSD3B2, 17α-hydroxylase, StAR protein, and cholesterol desmolase result in insufficient androgen synthesis potentially causing undervirilization of boys.
• 5α-Reductase deficiency prevents the conversion of testosterone to DHT, which is necessary for the development of the male external genitalia.
• Syndromes of androgen resistance are due to abnormalities in androgen receptor or postreceptor defects. Patients with incomplete forms of androgen resistance may present with sexual ambiguity.
• Multiple congenital anomalies
• Idiopathic

Sexual Ambiguity - TREATMENT

Sexual Ambiguity - initial stabilization

• Gender assignment: The results of the diagnostic evaluation should be available within 48–72 hours, and gender assignment made by this time. A team approach with consultations from endocrinology, urology, and psychiatry is useful.
• Treatment of CAH:
  • Acute salt-wasting adrenal crisis
  • Volume resuscitation with 5% dextrose in normal saline (D5NS)
  • Stress hydrocortisone 25–50 mg IV immediately after the serum studies are drawn. This should be followed by 100 mg/m² per 24 hours of hydrocortisone intravenous divided q4h.
  • Hydrocortisone is gradually tapered over the next few days.
  • Fludrocortisone 0.05–0.3 mg/d when able to take PO

Sexual Ambiguity - general measures

• Treatment of CAH:
  • Acute salt-wasting adrenal crisis
  • Volume resuscitation with D5NS
  • Chronic management of CAH consists of cortisol replacement 12–25 mg/m² per 24 hours divided as q8h and fludrocortisone 0.05–0.3 mg/d.
• Counseling of families

Sexual Ambiguity - surgery

Surgery may be necessary so that the sexual phenotype and gonads are consistent with the gender assignment. Dysgenetic testes and ovotestes should be removed.

Sexual Ambiguity - FOLLOW UP

Sexual Ambiguity - prognosis

The cosmetic outcome from surgery is usually good. The potential for gender-appropriate sexual function is usually good with therapy. The potential for reproductive function depends on the diagnosis. Long-term studies of psychologic adjustment are underway.

Sexual Ambiguity - complications

• 21-Hydroxylase-, HSD3B2-, and StAR protein–deficient forms of CAH are associated with mineralocorticoid deficiency and consequent life-threatening salt-losing adrenal crises presenting in the 1st 2 weeks of life.
• CAH is also associated with cortisol deficiency, requiring emergent and chronic cortisol replacement.
• Dysgenetic testes and ovotestes have an increased risk of malignant degeneration and should be removed.
• An incorrect or hastily made sexual assignment can cause family members additional emotional stress.

Sexual Ambiguity - patient monitoring

• Hormone replacement therapy at puberty may be necessary.
• Long-term follow-up may involve monitoring hormone levels, linear growth, and sexual development.

Sexual Ambiguity - bibliography

1. Hyun G, Kolon TF. A practical approach to intersex in the newborn period. Urol Clin North Am. 2004;31:435–443.
2. Kohler B, Lumbroso S, Leger J, et al. Androgen insensitivity syndrome: Somatic mosaicism of the androgen receptor and consequences for sex assignment and genetic counseling. J Clin Endocrinol Metab. 2005;90:106–111.
3. MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004;350:367–378.
Moshang T, Thornton PS. Endocrine disorders. In: Avery GS, ed. Neonatology: Pathophysiology and Management. Philadelphia: JB Lippincott; 1999.
4. New MI. Inborn errors of adrenal steroidogenesis. Mol Cell Endocrinol. 2003;211:75–83.
5. New MI, Carlson A, Obeid J, et al. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab. 2001;86:5651–5657.
6. Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child. 2004;89:401–407.
7. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776–788.
8. Yong EL, Lim J, Qi W, et al. Molecular basis of androgen receptor diseases. Ann Med. 2000;32:15–22.

Sexual Ambiguity - CODES

Sexual Ambiguity - icd9

752.7 Indeterminate sex and pseudohermaphroditism

Sexual Ambiguity - FAQ

• Q: Should a child’s sex assignment be consistent with the karyotype?
• A: In the past, surgery was performed when the team decision focused on sexual function potential. Recently, there is a trend to raise the child consistent with the karyotype. This is a major decision that should involve the family and the treatment team.
• Q: What clues can the physical examination give to the timing of in utero events causing sexual ambiguity?
• A: In the virilized female, labioscrotal fusion results from androgen exposure prior to 12 weeks’ gestation. Thereafter, androgen exposure can cause only clitoromegaly.

Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.

More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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