What is the diagnosis and treatment for 5-alpha (5α) reductase deficiency?

From the Guidelines

Individuals with 5-alpha reductase deficiency should receive psychological support and hormone therapy tailored to their gender identity, as this condition can lead to significant variations in sexual development and gender identity. The 5-alpha reductase deficiency is a rare genetic disorder that affects male sexual development, characterized by the inability to convert testosterone to dihydrotestosterone (DHT) due to a deficiency in the 5-alpha reductase type 2 enzyme 1. This condition typically results in individuals being born with ambiguous or female-appearing external genitalia despite having XY chromosomes and testes. At puberty, many affected individuals experience masculinization due to increased testosterone levels, including deepening voice, muscle development, and growth of facial hair.

Key Considerations

• The condition is inherited in an autosomal recessive pattern, and early diagnosis through genetic testing allows for appropriate management and support during development.
• Treatment depends on gender identity and may include hormone therapy, such as DHT cream or testosterone supplementation for those identifying as male, and estrogen therapy and anti-androgens for those identifying as female.
• Psychological support is essential, as individuals with 5-alpha reductase deficiency may experience gender dysphoria or uncertainty about their gender identity.
• The SRD5A2 gene on chromosome 2 provides instructions for making the 5-alpha reductase enzyme critical for male genital development during fetal life, and mutations in this gene are responsible for the condition 1.

Management and Support

• Genetic counseling is recommended for affected families to discuss the risks and implications of the condition.
• A multidisciplinary approach to care, including endocrinologists, psychologists, and surgeons, is necessary to provide comprehensive support and management for individuals with 5-alpha reductase deficiency.
• Regular follow-up and monitoring are crucial to address any physical or emotional changes that may occur during development and to provide timely interventions as needed.

From the Research

5a Reductase Deficiency

• 5α-reductase type 2 (5αRD2) deficiency is a 46,XY disorder of sex development caused by impaired conversion of testosterone (T) to dihydrotestosterone (DHT) 2.
• This disorder leads to undermasculinized external genitalia, such as severe micropenis, and penile enlargement therapy is important for male patients 2.
• High-dose T and percutaneous DHT replacement are reportedly efficacious for penile enlargement in patients with this disorder 2.

Treatment Options

• DHT therapy may be preferable to T replacement therapy for penile enlargement in patients with 5αRD2 deficiency during infancy 2.
• T replacement therapy can promote penile enlargement during and after puberty, possibly due to increased conversion of T to DHT via increased 5α-reductase type 1 activity 2.
• 5α-reductase inhibitors, such as finasteride and dutasteride, can have negative impacts on metabolic and sexual function in men by blocking the transformation of T to 5α-DHT 3.

Clinical Implications

• Androgen deficiency, including 5α-reductase deficiency, can have significant negative impacts on human health and quality of life, including reduced lean body mass, increased fat mass, and sexual dysfunction 3.
• The use of 5α-reductase inhibitors in transgender individuals is still a topic of debate and requires further research to determine their efficacy and safety 4.
• Testosterone replacement therapy can be an effective treatment option for hypogonadism, but its use should be individualized and monitored to maximize benefits and minimize risks 5.

Molecular Understanding

• The discovery of 5-alpha reductase deficiency has shed light on the crucial role of 5-alpha reductase, testosterone, and dihydrotestosterone in male sexual differentiation 6.
• Three different genes encoding for 5-alpha reductase have been identified, with 5-alpha reductase type 2 being implicated in disordered male sexual development 6.