What to know about 5-alpha reductase deficiency

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5-αRD is a rare inherited condition that may affect male sexual development before birth and during puberty. People with this condition are genetically male, with one X and one Y chromosome, and male gonads, or testes. However, due to a genetic variation, they do not produce enough of a hormone known as dihydrotestosterone (DHT).

The body produces DHT by converting testosterone. DHT is a potent androgenic hormone that stimulates the development of certain male characteristics. A shortage of DHT may disrupt the formation of external sex organs before birth and affect secondary sex characteristics during puberty, such as facial or body hair development.

While people with 5-αRD may be male-assigned at birth, many caregivers may raise children as females. During adolescence or early adulthood, people can choose to identify as whatever gender they feel most comfortable with.

5-αRD is rare, and researchers do not know the exact incidence. However, evidence suggests that it is rare in white people, and there is a higher prevalence of the condition in certain countries, including the Dominican Republic, Papua New Guinea, Turkey, and Egypt.

Some healthcare professionals may use the term disorders of sex development to refer to conditions such as 5-αRD. This term describes differences in sex characteristics that do not fit the binary idea of male or female. This can include differences in genitalia, hormones, chromosomes, or internal anatomy. However, it is important to note that many people do not identify with this term and prefer intersex.

It can be challenging to distinguish some of these conditions from each other. For example, 5-αRD may present with similar symptoms to androgen insensitivity syndrome (AIS). This condition occurs when the body does not respond to sex hormones called androgens. However, the main difference is that a person with AIS still produces DHT.

5-αRD occurs due to a genetic variation that a person inherits in an autosomal recessive pattern. This means a person must inherit two copies of the variation, one from each parent, to have the condition. The alteration occurs in the steroid 5 alpha-reductase 2, or SRD5A2 gene.

This gene is present on chromosome 2 and provides instructions for making an enzyme called steroid 5-alpha reductase 2. This enzyme is responsible for catalyzing the conversion of testosterone into the more active DHT. Alterations in this gene prevent the enzyme from effectively converting testosterone to DHT in the developing reproductive tissues.

Both testosterone and DHT are essential for the development of male sex characteristics. Before birth, testosterone is responsible for the formation of internal male genitalia, while DHT directs the development of the external genitalia. During puberty, both hormones play an important role in developing secondary male sex characteristics.

As such, insufficient levels of DHT may result in undervirilization of the external genitalia at birth but pronounced masculinization at puberty. This is because puberty typically relies more on testosterone levels rather than DHT.

The defining symptom of 5-αRD is the effect it may have on the external genitalia. Many individuals with the condition are born with external genitalia that appear female. In some cases, a person may have genitalia that appear predominantly male, but are small, known as micropenis, or has the urethra opening on the underside of the penis, known as hypospadias.

In other cases, a person may have external genitalia that does not look clearly male or female. In these circumstances, a healthcare professional may use the term ambiguous genitalia to refer to the genitals.

If a child presents with symptoms that indicate 5-αRD, a doctor may request some tests to confirm the diagnosis. This may include:

Biochemical assays

This test estimates the ratio between testosterone and DHT after stimulation with human chorionic gonadotropin (hCG). Those with 5-αRD will have an increase in the ratio of testosterone to DHT. However, it is important to note that if the ratio does not increase after hCG administration, it does not rule out 5-αRD. This test is not very reliable as many different factors can affect results.

Gene analysis

As 5-αRD occurs due to an alteration in the SRD5A2 gene, a healthcare professional can test for a variation in this gene. Evidence notes there are at least 54 different types of alterations involving this gene, which can vary in severity of the condition.

Management will depend on when a doctor diagnoses 5-αRD, either during infancy or adolescence.

The primary goal of treatment is to align a person’s physical appearance with their gender. This typically involves hormonal and surgical treatment options. However, when diagnosed at birth, decisions around sex assignment may be complicated and are decided on a case-by-case basis.

Depending on a person’s gender identity, they may consider using hormones. For example, those who identify as male may use testosterone injections or DHT gel. Those who identify as female may take low dosages of estrogen before puberty and may continue taking estrogen throughout adulthood.

Surgery can involve removal of the testes and genital reconstruction to create a vaginal opening. When the child becomes a teenager, they may choose to have a vaginoplasty. Alternatively, surgery can involve treating the penis for hypospadias or chordee and reconstructing the urethra to help with the functioning of the penis.

Additionally, some people and their families may also benefit from psychotherapy. This can help them understand their feelings and emotions, particularly with gender identity, and can help prevent them from experiencing gender dysphoria.

There is a lack of research exploring the outlook of those living with 5-αRD. However, an academic overview of the condition suggests that the outlook is positive, with individuals able to live healthy lives.

Some research suggests that a person with 5-αRD may experience infertility due to decreased sperm count and undescended testes. However, evidence notes there are cases of natural conception. Alternatively, people can use assisted reproductive technology, such as in vitro fertilization (IVF) and intrauterine insemination, to increase the chance of conceiving.

It is not uncommon for caregivers to raise children with 5-αRD as females. Following adolescence or early adulthood, a person with 5-αRD can choose to adopt whichever gender they identify with most.

5-alpha reductase deficiency describes a rare genetic condition that can affect male genital development. It occurs due to a variation in the SRD5A2 gene, which plays an important role in the development of external genitalia before birth.

A person with 5-αRD may have what a clinician might describe as ambiguous genitalia. To confirm a diagnosis of 5-αRD, a healthcare professional can use genetic testing. Treatment for 5-αRD typically involves aligning a person’s physical appearance with their chosen gender.