5-Alpha-Reductase Deficiency: Understanding Infertility in Ambiguous Genitalia

5-alpha-reductase deficiency is a condition that affects the male sexual development before birth and during puberty. One must understand the nature of 5-Alpha-Reductase Deficiency in order to Understand Infertility in Ambiguous Genitalia. Individuals with this condition are genetically male, possessing an X and a Y chromosome in each of their cells; they also have testes. However, their bodies produce inadequate amounts of the dihydrotestosterone (DHT) hormone.

The DHT hormone is crucial in male sexual development, and a shortage of this hormone disrupts the formation of the external sex organs before birth. 5-alpha-reductase deficiency is also congenital. Individuals born with this deficiency appear to be biologically female, but are genetically male and usually develop male genitals during puberty. 5-alpha-reductases are a group of enzymes that help regulate the sex hormones in the body, including estrogen and testosterone. The deficiency is considered a disorder of sexual differentiation and can be referred to as being intersex. Intersex is a situation where individuals possess reproductive organs and or external sexual characteristics that are both male and female.

What is the cause of 5-alpha-reductase deficiency?

The condition is a rare hereditary disorder caused by the mutation of the steroid 5-alpha-reductase 2 (SRD5A2). It is an autosomal recessive mutation; this means that an individual can only get it when both their parents pass on the gene mutation to them. There are more than 60 different mutations that can be responsible for this. Under normal circumstances, 5-alpha-reductase converts testosterone to DHT hormone, which is very critical in the male genitalia development prenatally. 

DHT is also responsible for the maturation of the penis and scrotum during puberty. It is also responsible for the growth of body and facial hair, increase in height, muscle mass development, deepening of voice, and the development of the prostate gland. The mutation of the SRD5A2 and the subsequent 5-alpha-reductase deficiency impairs the conversion of testosterone into DHT during fetal development. 

Only during the testosterone spike in puberty do the individual’s testes drop and the penis enlarge. The body will then develop secondary male sexual characteristics, a process called virilization. While this 5-alpha-reductase deficiency can occur in females, it does not affect their reproductive functions, their genitals, or their sexual characteristics.

How common is 5-alpha-reductase deficiency?

This condition is rare; the exact frequency is largely unknown. Large families with affected members have been found in several countries like Papua New Guinea, Egypt, Turkey, etc.

What are the symptoms of 5-alpha-reductase deficiency?

The symptoms of 5-alpha-reductase deficiency are often not recognized during infancy. Some babies will have a biologically female appearance with an apparent clitoris, vagina, and labia. Others will be more sexually ambiguous with an underdeveloped penis or genitals that do not clearly show their sex. Babies who lack the enzyme 5-alpha-reductase are born with bifid scrotums. This is because the structures that usually become the scrotum after they are exposed to testosterone in the womb are the same structures that become the labia when exposed to estrogen. 

While infants with 5-alpha-reductase deficiency possess testicles, they are usually buried within their abdomen or in the inguinal canal. It is only during puberty, with the increase in the levels of testosterone that secondary male sexual characteristics start to develop. The males with 5-alpha-reductase deficiency usually tend to have less facial and body hair than their peers and will also usually have infertility.

How is the condition diagnosed?

The diagnosis of this condition in infancy will depend on the appearance of the genitals. If the genitals are distinctly female, the condition may not be identified and diagnosed until puberty. However, if the genitals are more sexually ambiguous, 5-alpha-reductase deficiency is one of the first conditions that would be considered. In order to get a confirmation of the diagnosis, they may perform the following tests:

• Ultrasound – This is done on the abdomen and pelvic area to check for undescended testicles or the presence of a prostate gland
• Blood hormone analysis – This is done to examine the level of DHT in the blood of the individual.
• Chromosome analysis – This is done to see if the child has either male or female chromosomes, XY and XX, respectively.
• Gene sequencing – This is done to check for the presence of the SRD5A2 mutations.

What is the treatment for this condition?

The management or treatment of this condition is largely dependent on when it was discovered and diagnosed, either during infancy or at puberty. The main aim of the treatment is to reconcile the individual’s physical appearance with their gender. This usually involves hormonal and surgical therapy. These decisions may be more complicated when the condition is diagnosed at birth, especially around sex reassignment, and are usually decided on an individual case basis. Depending on the gender the individual chooses to identify they may be prescribed different hormones. If the individual chooses to be male, they may use DHT gel or testosterone injections. On the other hand, if they identify as female, they may take low doses of estrogen before puberty and continue taking estrogen throughout adulthood. 

Surgical treatment may involve the removal of the testes and a genital reconstruction to create a vaginal opening. They may also opt for a vaginoplasty as teenagers. Alternatively, surgery can be done for the treatment of the penis for hypospadias or chordee and the reconstruction of the urethra to help in the proper functioning of the penis. 

Psychotherapy will also be beneficial for the individuals and their families. This can help them understand their feelings and emotions, especially with their gender identity, and help them in avoiding experiencing gender dysphoria. 

What are the long-term effects of 5-alpha-reductase deficiency?

The long-term consequences of a 5-alpha-reductase deficiency depend on the severity of the illness and individual circumstances. Some of the most common side effects are ambiguous genitalia at birth, delayed or incomplete puberty, infertility, and a higher risk of some malignancies. Individuals with this deficit may also have irregular hair development, decreased muscle mass, and diminished bone density. It is critical to collaborate with a healthcare practitioner to manage and monitor the disease to avoid complications.

5-alpha-reductase deficiency and fertility 

Some research suggests that a person with 5-alpha-reductase deficiency may experience infertility because they have decreased sperm count and undescended testes. However, there have been some documented cases of natural conception from these individuals. 

Alternatively, they can employ assisted reproductive technology like in vitro fertilization, intrauterine insemination, and intra-cytoplasmic sperm injection to increase their chances of conception. They may also use surrogacy to achieve their aims. In cases where the technology is not advanced in their country of residence, they may choose to engage in overseas medical treatment. They can use medical travel agencies or meditour agencies in order to achieve this goal. This is also a form of health tourism and they may benefit from more sophisticated technology available in the other countries.