5-alpha-reductase deficiency

5α-reductase deficiency

Classification and external resources
Specialty medical genetics
ICD-10 E29.1, Q56.3
ICD-9-CM 257.2, 752.7
OMIM 264600
DiseasesDB 11
eMedicine ped/1980

5α-Reductase deficiency (5-ARD) is an autosomal recessive intersex condition caused by a mutation of the 5α reductase type II gene.[1]

Normal function

5α-Reductase is an enzyme that converts testosterone to 5α-dihydrotestosterone (DHT) in peripheral tissues. These enzymes also participate in the creation of such neurosteroids as allopregnanolone and THDOC, convert progesterone into dihydroprogesterone (DHP), and convert deoxycorticosterone (DOC) into dihydrodeoxycorticosterone (DHDOC). 5-ARD is biochemically characterized by low to low-normal levels of testosterone and decreased levels of DHT, creating a higher testosterone/DHT ratio.

Biochemical effects of 5-ARD in testosterone biosynthesis. Levels of testosterone are elevated, while levels of DHT are significantly decreased, leading to male undervirilization.

DHT is a potent androgen, and is necessary for the development of male external genitalia in utero.


The condition affects only genetic males (that is, those with a Y-chromosome) because DHT has no known role in female development.[2]

Individuals with 5-ARD are born with male gonads, including testicles and Wolffian structures. They can have normal male external genitalia, ambiguous genitalia, or normal female genitalia, but usually tend towards a female appearance. As a consequence, they are often raised as girls, but usually have a male gender identity.[3][4] There is a tendency towards a macroclitoris or micropenis, and the urethra may attach to the phallus.

If the condition has not already been diagnosed, it usually becomes apparent at puberty around age twelve with primary amenorrhoea and virilization. This may include descending of the testes, hirsutism (facial/body hair considered normal in males - not to be confused with hypertrichosis), deepening of the voice, and enlargement of the clitoris. In adulthood, individuals do not experience male-pattern baldness.[1] As DHT is a far more potent androgen than testosterone alone, virilization in those lacking DHT may be absent or reduced compared to males with functional 5-AR. It is hypothesized that rising testosterone levels at the start of puberty are able to generate sufficient levels of DHT either by the action of 5α-reductase type I (active in the adult liver, non-genital skin and some brain areas) or through the expression of low levels of 5α-reductase type II in the testes.

5-ARD is associated with an increased risk of cryptorchidism and testicular cancer.


Although the external genitalia may be female, the vagina consists of only the lower two-thirds of a normal vagina, creating a blind-ending vaginal pouch. Due to the normal action of Müllerian inhibiting factor produced by the testes in utero, individuals with 5-ARD lack a uterus and Fallopian tubes. Thus, they are not able to carry a pregnancy, and, since they have testes and not ovaries, they are unable to create ova, which precludes such infertility treatments as surrogate motherhood.

In general, individuals with 5-ARD are capable of producing viable sperm. In individuals with feminized or ambiguous genitalia, the phallus may be capable of ejaculations as well as erections, but may be insufficient for intercourse. Fertility is further compromised by the underdevelopment of seminal vesicles and prostate.


The condition is extremely rare, with reported cases so far in the Dominican Republic, Papua New Guinea, and Turkey.

The cases of the condition reported in the Dominican Republic are of greatest interest due to its prevalence in the small remote village of Las Salinas, where 12 out of 13 families had one or more male family members that carried the genetic mutation, though not all the carriers of the mutation were affected. The overall incidence for the village was 1 in every 90 males were affected carriers, the remainder of the village genetic males were either non-carriers or non-affected carriers.[5]

It is thought that either a founder effect or a bottleneck effect (the villagers are interrelated and may have inherited the mutation from the same individual), in conjunction with a lack of geneflow (genes from outsiders) in the isolated geographic location of Las Salinas allowed the mutation to become amplified in the village. In the Dominican Republic, the Spanish term for a person with the condition is "güevedoce". This comes from the phrase "huevo/güevo a los doce" with the slang meaning of "ball[s]/penis at twelve [years of age]". Huevo in Spanish means "egg".[6]

It has been reported that in the cases seen in the Dominican Republic, locals celebrate when a child they previously believed to be a "girl" naturally transform into his male body upon reaching puberty and socially assumes his male gender role (in most cases, the gender identity had always been male even when the child was still socially a female). In the cases in Papua New Guinea, it has been said that the "girl" is shunned when she begins her natural transformation into a male body and socially assumes a male gender role.


In April 2014, the BMJ reported that four elite women athletes with 5-ARD were subjected to sterilization and "partial clitoridectomies" in order to compete in sport. The authors noted that "partial clitoridectomy" was "not medically indicated, does not relate to real or perceived athletic “advantage,"" relating to elevated androgen levels. The athletes were all from developing countries where lifetime access to hormone replacement may prove elusive.[7] Intersex advocates regard this intervention as "a clearly coercive process".[8]

Popular culture

In the Nip/Tuck season three episode "Quentin Costa", it is revealed that Quentin Costa had 5-ARD.

Jeffrey Eugenides' Pulitzer Prize-winning 2002 novel Middlesex is about a young man with 5-ARD. The character was originally born Calliope and raised as a girl, but upon realizing his true biological sex, he transitions into Cal.

See also


  1. 1 2 5-alpha reductase deficiency at GPnotebook
  2. eMedicine article on 5-ARD
  3. Praveen, EP; Praveen EP; Desai AK; Khurana ML; Philip J; Eunice M; Khadgawat R; Kulshreshtha B; Kucheria K; Gupta DK; Seith A; Ammini AC. (February 2008). "Gender identity of children and young adults with 5alpha-reductase deficiency.". J Pediatr Endocrinol Metab. (2nd ed.). 21 (2): 173–179. PMID 18422030.
  4. Imperato-Mcginley, Julianne; Julianne Imperato-McGinley, M.D.; Ralph E. Peterson, M.D.; Teofilo Gautier, M.D. & Erasmo Sturla, M.D. (May 31, 1979). "Androgens and the Evolution of Male-Gender Identity among Male Pseudohermaphrodites with 5α-Reductase Deficiency". New England Journal of Medicine. 300 (22): 1233–1237. doi:10.1056/NEJM197905313002201. PMID 431680.
  5. Imperato-McGinley, Julianne; Guerrero, Luis; Gautier, Teofilo; Peterson, Ralph Edward (December 1974). "Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism". Science. 186 (4170): 1213–1215. doi:10.1126/science.186.4170.1213. PMID 4432067.
  6. Mosley, Michael. "The extraordinary case of the Guevedoces". BBC News. BBC News. Retrieved 23 September 2015.
  7. Rebecca Jordan-Young; Peter Sonksen; Katrina Karkazis (2014). "Sex, health, and athletes". BMJ. 2014 (348): g2926. doi:10.1136/bmj.g2926. PMID 24776640.
  8. "UN Human Rights Council: resolution, statement and side event, "The time has come"". Organisation Intersex International Australia. Retrieved 28 September 2014.

External links

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