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| {{Infobox medical condition (new)
| | #REDIRECT [[5α-Reductase 2 deficiency]] |
| | synonyms = 5-ARD
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| | name = 5α-Reductase deficiency
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| |image=Autosomal recessive - en.svg
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| | caption =Pseudovaginal perineoscrotal hypospadias is inherited in an autosomal recessive manner
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| '''5α-Reductase deficiency''' is an [[autosomal recessive]] [[intersexuality|intersex]] [[medical condition|condition]] caused by a [[genetic mutation|mutation]] in ''[[SRD5A2]]'', a [[gene]] encoding the [[enzyme]] [[5α-reductase type 2]].<ref name="Gpnotebook">{{Cite GPnotebook|852492298|5-alpha reductase deficiency}}</ref> The [[phenotype]] this usually causes is '''pseudovaginal perineoscrotal hypospadias''', a configuration of the external [[genitalia]] of an infant.<ref name="pmid16098368">{{cite journal |vauthors=Bahceci M, Ersay AR, Tuzcu A, Hiort O, Richter-Unruh A, Gokalp D |title=A novel missense mutation of 5-alpha reductase type 2 gene (SRD5A2) leads to severe male pseudohermaphroditism in a Turkish family |journal=Urology |volume=66 |issue=2 |pages=407–10 |year=2005 |pmid=16098368 |doi=10.1016/j.urology.2005.02.021}}</ref><ref name="NieschlagBehre2009">{{cite book|author1=Eberhard Nieschlag|author2=Hermann M. Behre|author3=Susan Nieschlag|title=Andrology: Male Reproductive Health and Dysfunction|url=https://books.google.com/books?id=mEgckDNkonUC&pg=PA328|accessdate=2 January 2011|date=July 2009|publisher=Springer|isbn=978-3-540-78354-1|pages=328–}}</ref> In a sense, this configuration is roughly midway between [[phenotypical]] human male genitalia, and phenotypical human female genitalia, in structure and appearance. It is a relatively common form of [[ambiguous genitalia|genital ambiguity]] caused by [[undervirilization]] of genetic males due to several different [[intersex]] conditions.
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| ==Signs and symptoms==
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| Individuals with 5-ARD are born with [[male]] [[gonad]]s, 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.{{citation needed|date=August 2020}}
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| The development of the [[genital tubercle]] tissue (which by week 9 of a [[fetus]]' gestation becomes either a [[clitoris]] or a [[penis]]) tends towards a size qualifying it as an ambiguous [[clitoromegaly|macroclitoris]]/[[micropenis]] (large clitoris/small penis), and the [[urethra]] may attach to the phallus.{{citation needed|date=August 2020}}
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| 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 into what would then be classed as a penis.{{citation needed|date=August 2020}}
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| In adulthood, individuals do not experience male-pattern baldness.<ref name="Gpnotebook" /> As [[dihydrotestosterone]] (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 [[Reductase|5α-reductase]] type II in the testes.5-ARD is associated with an increased risk of [[cryptorchidism]] and [[testicular cancer]].{{Citation needed|date=June 2018}}
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| ===PPSH===
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| PPSH usually consists of:{{citation needed|date=August 2020}}
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| *a [[phallus]] midway in size between [[penis]] and [[clitoris]],
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| *a [[chordee]] tethering it to the [[perineum]],
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| *a [[urethra]]l opening usually on the perineum (the [[hypospadias]]),
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| *and an incompletely closed urogenital opening, which resembles a small and shallow [[vagina]].
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| [[Testes]] are often palpable in the [[scrotum]] or [[inguinal canal]]s, and the [[karyotype]] is XY. In most cases there are no internal female structures such as a [[uterus]] or other [[Müllerian duct]] derivatives.
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| ===Fertility===
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| Since the [[gonad]] tissue develops into [[testes]] rather than [[ovaries]], they are thus unable to create ova but may be able to create sperm. Male fertility can still be possible if viable sperm is present in the testes and is able to be extracted. In general, individuals with 5-ARD are capable of producing viable [[sperm]].{{citation needed|date=August 2020}}
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| Although the external genitalia can sometimes be completely female, the vagina consists of only the lower two-thirds of a normal vagina, creating a blind-ending vaginal pouch. Because of normal action of [[Anti-müllerian hormone|Müllerian inhibiting factor]] produced by the [[testes]] in utero, individuals with 5-ARD lack a [[uterus]] and [[Fallopian tube]]s. Thus, they would not physically be able to carry a pregnancy in any event. Even with treatments such as surrogate motherhood, female infertility is caused by the lack of any ova to implant in a surrogate mother.{{citation needed|date=August 2020}}
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| In individuals with an ambiguous genital resulting in a macroclitoris/micropenis, the genital may be capable of ejaculations as well as erections, but may be of insufficient size for penetrative [[sexual intercourse]].{{citation needed|date=August 2020}}
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| Fertility is further compromised by the underdevelopment of seminal vesicles and prostate.{{citation needed|date=August 2020}}
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| ==Cause==
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| The condition affects only those with a [[Y chromosome|Y-chromosome]] because DHT has no known role in development of XX fetuses.<ref>[http://www.emedicine.com/ped/topic1980.htm eMedicine article on 5-ARD]</ref>
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| ==Mechanism==
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| [[5α-Reductase]] is an [[enzyme]] that converts [[testosterone]] to [[5α-dihydrotestosterone]] (DHT) in peripheral tissues. These enzymes also participate in the creation of such [[neurosteroid]]s as [[allopregnanolone]] and [[Tetrahydrodeoxycorticosterone|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.{{citation needed|date=August 2020}}
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| [[Image:Test biosynth 5ARD2.jpg|thumb|center|600px| Biochemical effects of 5-ARD in testosterone biosynthesis. Levels of testosterone are elevated, while levels of DHT are significantly decreased, leading to male [[undervirilization]].]]
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| DHT is a potent [[androgen]], and is necessary for the development of male external [[genitalia]] in utero.
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| ==Diagnosis==
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| {{Empty section|date=January 2019}}
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| ==Management==
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| Until recently, reconstruction of children's genitals was often undertaken to "normalize" their appearance in accordance with a binary model of anatomical sex. Parents often request and/or authorize the reconstructive surgery with the hope of sparing their child the shame and embarrassment which is often associated with being visibly "different" than the child's peers in situations such as school locker rooms etc.. The practice is being met with increasing resistance from the medical community, since an actual medical need for such interventions is often not given. Furthermore, social advocates are working to increase awareness, understanding and acceptance of non-binary sexual anatomy, which is reducing the potential for stigma and shame for people born with intersex or indeterminate anatomy.{{citation needed|date=August 2020}}
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| ==Epidemiology==
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| The condition is rare, with areas of greater incidence known in regions of the [[Dominican Republic]], [[Papua New Guinea]], and [[Turkey]].{{citation needed|date=August 2020}}
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| 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.<ref name="sci001">{{cite journal | last1 = Imperato-McGinley | first1 = Julianne | last2 = Guerrero | first2 = Luis | last3 = Gautier | first3 = Teofilo | last4 = Peterson | first4 = Ralph Edward | title = Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism | journal = Science | volume = 186 | issue = 4170 | pages = 1213–1215 |date=December 1974 | doi = 10.1126/science.186.4170.1213 | pmid = 4432067| bibcode = 1974Sci...186.1213I }}</ref>
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| It is thought that either a [[founder effect]] or a [[Population bottleneck|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 colloquial [[Spanish language|Spanish]] term for a person with the condition is ''[[güevedoce]]'', a contraction in the local dialect of the phrase "huevos a los doce", meaning "eggs at twelve".<ref>{{Cite news|url=http://almomento.net/los-guevedoces-los-ninos-de-rd-a-los-que-el-pene-les-empieza-a-crecer-a-los-12-anos/138245|title=BARAHONA: Enfermedad genética hace que niños RD nazcan sin pene|last=AlMomento.net|work=AlMomento.net|access-date=2017-03-08|language=es-ES}}</ref> ''Huevo'' or ''güevo'' literally means ''egg'', but is also slang for ''testicle'', so the meaning is "testicles at age twelve".{{citation needed|date=August 2020}}
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| 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).<ref name="BBC News">{{cite news|last1=Mosley|first1=Michael|title=The extraordinary case of the Guevedoces|url=https://www.bbc.com/news/magazine-34290981|website=BBC News|publisher=BBC News|accessdate=23 September 2015|date=2015-09-20}}</ref> In the cases in Papua New Guinea, it has been said that the "girl" is shunned when he begins his natural transformation into a male body and socially assumes a male gender role.<ref>{{cite journal |vauthors = Imperato-McGinley J, Miller M, Wilson JD, Peterson RE, Shackleton C, Gajdusek DC |date= Apr 1991 |title= A cluster of male pseudohermaphrodites with 5 alpha-reductase deficiency in Papua New Guinea |journal= Clin Endocrinol |volume= 34 |issue= 4 |pages= 293–8 |doi= 10.1111/j.1365-2265.1991.tb03769.x |pmid= 1831738 }}</ref>
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| ==Society and culture==
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| ===Sport===
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| 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.<ref>{{cite journal |author=Rebecca Jordan-Young |author-link=Rebecca Jordan-Young |author2=Peter Sonksen |author3=Katrina Karkazis |author3-link=Katrina Karkazis|title= Sex, health, and athletes |journal=[[BMJ]]|volume=348|pages=g2926|year=2014 |doi=10.1136/bmj.g2926|url=http://www.bmj.com/content/348/bmj.g2926 |pmid=24776640}}</ref> Intersex advocates regard this intervention as "a clearly coercive process".<ref>{{cite web|url=http://oii.org.au/27745/un-human-rights-council-side-event-the-time-has-come/|title=UN Human Rights Council: resolution, statement and side event, "The time has come"|publisher=[[Organisation Intersex International Australia]]|accessdate=28 September 2014|date=2014-09-11}}</ref>
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| ===Popular culture===
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| In the ''[[Nip/Tuck]]'' season three episode "Quentin Costa", it is revealed that [[Quentin Costa]] had 5-ARD.
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| [[Jeffrey Eugenides]]' Pulitzer Prize-winning 2002 novel ''[[Middlesex (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 genetic sex, he transitions into Cal.
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| ==See also==
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| *[[Intersex]]
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| *[[Disorders of sexual development]], [[pseudohermaphroditism]], and [[ambiguous genitalia]]
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| *[[Inborn errors of steroid metabolism]]
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| *[[5α-Reductase]] ([[SRD5A1|I]], [[SRD5A2|II]])
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| *[[Androgen]] ([[testosterone]] and [[dihydrotestosterone]])
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| *[[Ambiguous genitalia]]
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| *[[Intersex surgery]]
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| *[[Androgen insensitivity syndrome]]
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| ==References==
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| {{Reflist}}
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| ==External links==
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| *[http://omim.org/entry/264600 OMIM article]
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| *[http://www.emedicine.com/ped/topic1980.htm 5α-Reductase Deficiency at eMedicine]
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| {{Medical resources
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| | DiseasesDB = 11
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| | ICD10 = {{ICD10|E|29|1|e|20}}, {{ICD10|Q|56|3|q|50}}, {{ICD10|Q|56|1|q|50}}
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| | ICD9 = {{ICD9|257.2}}, {{ICD9|752.7}}
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| | ICDO =
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| | OMIM = 264600
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| | MedlinePlus =
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| | eMedicineSubj = ped
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| | eMedicineTopic = 1980
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| | Orphanet = 753
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| }}
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| {{Defects of cholesterol and steroid metabolism}}
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| {{Congenital malformations of genital organs}}
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| {{Gonadal disorder}}
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| [[Category:Cholesterol and steroid metabolism disorders]]
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| [[Category:Endocrine gonad disorders]]
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| [[Category:Intersex variations]]
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