Biology of DSDs: 5-ARD
Description
5-alpha reductase deficiency, also known as 5-ARD, is a sex development condition which affects individuals with a 46,XY karyotype. Those with 5-ARD develop internal testes and a Wolffian structure, but a lack of dihydrotestosterone (DHT)--the sex hormone solely responsible for the development of male external genitalia in the womb--often causes the fetus to develop external genitalia that looks female-typical.
If you want to help improve medical research and psychological support for individuals with these conditions, you can donate to DSDFamilies (https://dsdfamilies.org/donate).
Sources
[1] NIH. (2020). 5-alpha reductase deficiency. Genetics Home Reference, National Library of Medicine.
[2] Isfort, A. (2016). 5-alpha reductase deficiency. Medscape.
[3] LOCAH. (2018). The intersex masterpost. Medium.
[4] Cheon, CK. (2011). Practical approach to steroid 5-ARD type 2 deficiency. Eur J Pediatr, 170(1).
[5] Kumar, G., Meca-Barboza, J. (2020). 5 Alpha Reductase Deficiency. StatPearls Publishing.
[6] Randall, V. (1994). Role of 5-ARD in health and disease. B Clinical Endocrinology & Metabolism, 8(2).
AIS support group:
https://www.aisdsd.org
Transcript
5-alpha reductase deficiency, also known as 5-ARD, is a sex development condition which affects individuals with a 46,XY karyotype. Those with 5-ARD develop internal testes and a Wolffian structure, but a lack of dihydrotestosterone (DHT)--the sex hormone solely responsible for the development of male external genitalia in the womb--causes the fetus to develop external genitalia that looks female-typical.
5-alpha reductase deficiency is among the rarest DSDs. In fact, the condition is so rare that there are no exact numbers. However, there is evidence that 5-ARD is more common in particular ethnic groups. For example, large families with affected members have been found in countries such as the Dominican Republic, Papua New Guinea, Turkey, and Egypt.
At conception, the chromosome set for 5-ARD begins with the typical 46,XY. Most cases are caused by an inherited mutation in the SRD5A2 gene located on chromosome 2. This gene provides instructions for making an enzyme called 5-alpha reductase 2. In typical circumstances, the enzyme converts the hormone testosterone into dihydrotestosterone (DHT). DHT plays a role in masculinizing the male's external genitalia during development, causing the testes to descend, forming the scrotum, and enlarging the penis. Without this enzyme, testosterone is not converted into DHT, and the masculinization of the external genitalia does not occur. Therefore, many people with 5-ARD are raised as girls. However, thanks to the functioning testes and androgen receptors, those with 5-ARD often experience male-typical levels of androgens during puberty, which leads to the development of increased muscle mass, deepening of the voice, and a masculinization of the external genitalia previously inhibited during fetal development. Affected individuals often adopt a male identity in adolescence or early adulthood, while others retain the female identity from which they were raised.
Around the 8th week after conception, the 46,XY fetus undergoes gonadal differentiation. The activation of the SRY gene on the Y chromosome causes the bipotential gonads to develop into testes. As the gonads differentiate into testes, they produce two hormones: anti-Mullerian hormone (AMH) and the androgen known as testosterone. Just like unaffected males, those with 5-ARD are fully exposed to AMH and testosterone in the womb but lack the super-testosterone DHT for the completion of the external male genitalia.
With the testes producing the anti-Mullerian hormone and testosterone necessary for male reproductive development, the Mullerian structure (which would have formed the fallopian tubes, uterus, cervix, and upper part of the vagina) disintegrates, and the Wolffian structure (which forms the epididymis, vas deferens, and seminal vesicle) develops. Because of a functioning SRY gene, anti-Mullerian hormone, and functioning androgen receptors, the fetus develops anatomy to support the production of small gametes.
Like other DSDs, newborns with 5-ARD can experience so-called 'ambiguous' genitalia, where it is not entirely certain whether the baby is a male with under-masculinized genitalia, or a female with over-masculinized genitalia. In such cases of so-called 'ambiguity,' sex can be determined through genetic analysis, hormone testing, and ultrasound. If the patient has a karyotype of 46,XY, has testes, a Wolffian structure, and functioning androgen receptors, but lacks the 5-alpha reductase 2 enzyme, then 5-ARD is a likely a cause. Further differential diagnosis and screening is necessary to narrow the diagnosis.
The treatments for 5-ARD depend on the specific characteristics of the affected patient. Hormone replacement therapy (HRT) is the most common. If it's desired by the patient, HRT with testosterone and dihydrotestosterone is highly effective during puberty to help promote and maintain male sex characteristics. Because individuals with 5-ARD develop internal testes and a complete Wolffian structure, fertility is common, and affected individuals can often produce viable sperm. Thus, fathering a child is possible.
In all, individuals with 5-ARD experience delayed male sex development due to a lack of DHT exposure in utero. Because they have functional androgen receptors, the testosterone produced from the testes during puberty usually results in full masculinization. With loving support from parents and peers, experts in psychology and counseling, and professional treatments with hormone replacement therapy, individuals with 5-ARD can live healthy lives and be secure in their bodies.
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