21-hydroxylase deficiency historical perspective

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

Congenital adrenal hyperplasia was first discovered by Luigi De Crecchio, an Italian anatomist.

Historical Perspective

• There are no difficulties assigning appropriate sex for most infants with congenital adrenal hyperplasia. Genetic males have normal male genitalia and gonads and simply need hormone replacement. Most virilized females are assigned and raised as girls even if their genitalia is ambiguous or look more male than female. They have normal ovaries and uterus and potential fertility with hormone replacement and surgery. However, the dilemmas surrounding sex assignment of the most severely virilized XX infants have helped shape our understanding of gender identity and sexual orientation, and continue to be a subject of debate.
• Until the 1950s, some virilized XX infants were assigned and raised as girls, and some as boys. Most developed gender identities congruent with their sex of rearing. In a few cases of male rearing, a sex reassignment was attempted in mid-childhood when newly discovered karyotyping revealed "female" chromosomes. These reassignments were rarely successful, leading John Money and other influential psychologists and physicians to conclude that gender identity was:

• Unrelated to chromosomes
• Primarily a result of social learning
• Could not be easily changed after infancy

• By the 1960s, congenital adrenal hyperplasia was well understood, karyotyping was routine, and standard management was to assign and raise all children with congenital adrenal hyperplasia according to their gonads and karyotypes, no matter how virilized. Markedly virilized girls were usually referred to a pediatric surgeon, often a pediatric urologist for a reconstructive vaginoplasty and clitoral reduction or recession—surgery to create or enlarge a vaginal opening and reduce the size or protrusion of the clitoris. This approach was designed to preserve fertility for both sexes and remains the standard management, but two aspects of this management have been challenged: assignment of completely virilized genetic females and the value and age of corrective surgery.

• The first questions about assignment were raised in the early 1980s, when Money and others reported an unexpectedly high rate of failure to achieve normal adult sexual relationships (i.e., heterosexual orientation, marriage, and children) in grown women with congenital adrenal hyperplasia (though all had female gender identities). However, the sample was small, and the results seemed interpretable in many ways: selection bias, early hormone effects on orientation, sexual dysfunction created by residual body abnormalities, or by the genital surgery itself. From a perspective two decades later, the report was one of the first pieces of evidence that the standard management paradigm was not always producing hoped-for outcomes.

• Despite these concerns, no significant opposition to standard management arose until the mid-1990s, when a confluence of evidence and opinion from several sources led to a re-examination of outcomes. Several intersex support and advocacy groups (e.g., Intersex Society of North America) began to publicly criticize infant genital surgery based on unsatisfactory outcomes of some adults who had been operated on as infants. Their complaints were that they had reduced ability to enjoy sexual relations or that they resented not having had the choice of gender assignment or surgical reconstruction left until they were old enough to participate.

• In 1997, influential articles by Reiner, Diamond, and Sigmundson advocated consideration of (1) male sex assignment in the unambiguously male XX infants (most of whom are considered male until the congenital adrenal hyperplasia is recognized at 1-2 weeks of age) and (2) delaying reconstructive surgery until the patient is old enough to participate in the decision.

• Although the standard management approach remains standard, more time and consideration are being given in many cases to explaining alternatives to parents and a small number of XX children with unambiguously male external genitalia are again being raised as boys.