5-alpha-reductase deficiency

Chapters:

Watch video only

Introduction0:00–1:05

5α- reductase deficiency is a genetic disorder in which a protein called 5α reductase is defective or absent. 5α- reductase is an enzyme that converts the male hormone testosterone to its more potent form, called dihydrotestosterone.
One of the most important roles of dihydrotestosterone is to help male external genitalia develop in a male fetus. Alright, so, normally, very early on in fetal life, male and female internal sex organs and external genitalia are undifferentiated and look identical.
Within the first few months of development, testes develop in the male fetus. The testes start producing testosterone which is a male steroid hormone that belongs to a class of hormones called androgens.
The testosterone gets released into the blood and a tiny fraction of it gets converted to dihydrotestosterone by 5α- reductase, which is mainly made in the skin of the genital area.
Over time, dihydrotestosterone levels start rising and it affects undifferentiated genital structures. Looking closely at these structures, at the top there’s the genital tubercle, which is a small projection.

Embryology1:05–2:30

Just below that, there's the urethral groove, which is the external opening of the urogenital sinus or the future urethra and bladder and that’s surrounded by the urethral folds and the labioscrotal swellings.
Now, once dihydrotestosterone reaches these structures, it makes the genital tubercle elongate into the phallus which will eventually be the penis.
The elongating genital tubercle pulls up the urethral folds which fuse in the midline, forming the spongy or penile urethra.
The tips of the urethral folds remain unfused and that forms the external urethral opening at the distal tip of the penis.
The labioscrotal swellings also fuse proximally to form the scrotum, which eventually houses the testes. In females, the gonads develop into ovaries, which produce very low levels of androgens, so the genital tubercle remains small, forming the clitoris and the urethral folds and labioscrotal swellings remain unfused or separate, surrounding the opening of the vagina.
This process is usually complete by month four of fetal development. In 5α- reductase deficiency there’s a mutation in the gene SRD5A2 and that reduces the amount of 5α- reductase enzyme that’s made.

Pathophysiology2:30–4:30

The condition is inherited in an autosomal recessive but sex-limited pattern. This means that for the disease to appear, both copies of the gene have to be mutated and the individual has to be genetically male, with one X and one Y chromosome in each cell, since dihydrotestosterone has no role in the development of genetically female individuals, with two X chromosomes in each cell.
So the problem arises in a male fetus where the testes produce testosterone, but it isn’t converted to dihydrotestosterone because the 5α- reductase enzyme is missing.
As a result, while there are male internal sex organs, the external genitalia follow more of a female path of development.
Specifically, the phallus doesn’t fully elongate, resembling something in between a clitoris and a penis, the scrotum often remains split in two which is also called a bifid scrotum, and the urethral opening remains on the underside of the penis, which is called hypospadias.
The external genitalia doesn’t look clearly male or female and is sometimes called ambiguous genitalia. When these individuals reach puberty, though, there’s a huge increase in the levels of testosterone.
Even though it can’t be converted to dihydrotestosterone, there’s so much testosterone around that the phallus and scrotum grow larger and start having more of a male appearance.
In addition, the high levels of testosterone will usually lead to deepening of the voice, muscle growth and development of facial and body hair.
Some individuals with 5α- reductase deficiency adopt a male gender role, while others adopt a female gender role. Most individuals with 5α- reductase deficiency also struggle with infertility.

Diagnosis4:30–4:57

Diagnosis of 5α- reductase deficiency is usually suspected in newborns with ambiguous genitalia. A karyotype can be used to visualize the sex chromosomes X and Y and ensure that the individual is genetically male.
Lab studies usually show a normal serum testosterone level, low dihydrotestosterone levels, and therefore a high testosterone to dihydrotestosterone ratio.

Treatment4:57–5:22

Treatment of 5α- reductase deficiency focuses on hormone replacement therapy. That means giving male or female sex hormones, according to the gender role adopted by the individual.
Surgical procedures can also be done to help restore external genitalia to a non-ambiguous appearance. For those struggling with infertility, assisted reproduction techniques are useful, too.
All right, as a quick recap, 5α- reductase deficiency results in a male fetus being unable convert testosterone to its more active form, dihydrotestosterone.

Review5:22–6:33

This leads to male internal organs and ambiguous external genitalia. Both sex hormones and surgery can be done to help align the external genitalia with the gender identity adopted by the individual.