Sex Characteristics & Genital Development

In many forms of Congenital Adrenal Hyperplasia (CAH), patients and parents are told to expect “virilization” (masculinization). However, because 3β-HSD deficiency affects both the adrenal glands and the gonads (the testes or ovaries), the effect on genital development is often the exact opposite of what is seen in more common types ^[1][2]. Understanding these physical differences is a key part of navigating care.

(Note on Terminology: Throughout this guide, the terms 46,XX and 46,XY refer to an individual’s chromosomal sex determined at conception, which dictates early gonadal development. These terms describe biology, not a person’s eventual gender identity.)

Why Genital Development is Affected

The HSD3B2 gene provides instructions for an enzyme that works in both the adrenal glands and the gonads ^[1]. Because this enzyme is missing or weakened, the body cannot produce high-potency androgens (like testosterone) during the critical windows of fetal development ^[2].

Genetic Males (46,XY)

In genetic males, the testes rely on the 3β-HSD enzyme to create the testosterone needed to masculinize the external genitalia before birth ^[2]. When this enzyme is deficient, the male fetus is frequently undervirilized ^[3].

• Physical Findings: Many genetic males with 3β-HSD deficiency are born with atypical genital development (often termed ambiguous genitalia) ^[4]. This may include hypospadias (where the opening of the urethra is on the underside of the penis), a smaller-than-average penis, or a divided scrotum ^[5][6].
• Puberty: Interestingly, some boys may experience spontaneous puberty and masculinization later in life because a different version of the enzyme (type 1) in the skin can convert some precursor hormones into testosterone ^[3][7].

Genetic Females (46,XX)

In genetic females, the ovaries do not need to produce high levels of androgens before birth. As a result, most girls with this condition are born with typical female genitalia ^[4].

• Physical Findings: In one clinical cohort, only a small percentage of girls showed signs of mild virilization at birth, such as a slightly enlarged clitoris ^[4]. This is generally much less pronounced than the changes seen in the 21-hydroxylase form of CAH ^[4].
• Long-term: In adolescence and adulthood, females may experience irregular periods, acne, or hyperandrogenism resulting in PCOS-like symptoms (Polycystic Ovary Syndrome-like changes) due to the hormone imbalances ^[4][3].

Your Multi-Disciplinary Care Team

Because 3β-HSD deficiency affects multiple systems and is classified under Differences of Sex Development (DSD), care should involve a specialized multi-disciplinary team ^[8].

• Endocrinologist: Manages the life-saving hormone replacements ^[1].
• Urologist/Surgeon: Evaluates the anatomy and discusses options for urinary and sexual function ^[8].
• Geneticist: Confirms the diagnosis and provides inheritance counseling ^[8].
• Clinical Psychologist: Provides essential emotional support, helping patients and parents navigate complex decisions and safeguard self-esteem ^[9].

Navigating Decisions About Surgery

If atypical genitalia are present, questions about surgery may arise. It is important to know that medical consensus on this has shifted significantly toward individualized, cautious care ^[10].

• Medical Necessity vs. Deferral: Unless there is a functional emergency (such as a urinary blockage), there is rarely a medical requirement for genital surgery in infancy ^[10][11].
• Comprehensive Evaluation: Decisions must involve a complete anatomic and gonadal evaluation, considering long-term urinary function, sexual sensation, fertility potential, complication risks, and the possible need for surgical revisions ^[12][13].
• Patient Autonomy: Current guidelines emphasize the importance of involving the child in these decisions as they mature (assent/consent) ^[14]. Decisions made by parents should be deeply considered, with full access to psychological support and awareness of applicable laws and safeguarding standards ^[15][16].

Regardless of the path chosen, the overarching goal of the DSD team is to support the individual’s physical health, sensory function, and long-term psychological well-being.