View source for 5α-Reductase 2 deficiency

{{Infobox medical condition
 |name            =
 |synonyms        = 5-alpha reductase deficiency, Pseudovaginal perineoscrotal hypospadias<ref name="MedlinePlus">{{cite web | title=5-alpha reductase deficiency: MedlinePlus Genetics | website=MedlinePlus | date=April 1, 2017 | url=https://medlineplus.gov/genetics/condition/5-alpha-reductase-deficiency/ | access-date=December 11, 2023}}</ref> 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.<ref name="NORD">{{cite web | title=National Organization for Rare Disorders | website=National Organization for Rare Disorders | date=June 16, 2022 | url=https://rarediseases.org/gard-rare-disease/5-alpha-reductase-deficiency/ | access-date=December 11, 2023}}</ref>
 |image           = Test biosynth 5ARD2.jpg
 |caption         = [[Biochemistry]]; [[testosterone]] [[biosynthesis]], [[pathology]] in 5 alpha-reductase deficiency.
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 |specialty       = <!-- from Wikidata; can be overwritten -->
 |symptoms        =
 |complications   =
 |onset           =
 |duration        =
 |types           =
 |causes          = Mutations in the [[SRD5A2]] gene.<ref name="MedlinePlus"/>
 |risks           = <!-- or |risk= -->
 |diagnosis       =
 |differential    =
 |prevention      =
 |treatment       = <!-- or |management= -->
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 |frequency       = <!-- also |incidence= or |prevalence= -->
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}}

'''5α-Reductase 2 deficiency''' (5αR2D) is an [[autosomal recessive]] [[medical condition|condition]] caused by a [[genetic mutation|mutation]] in ''[[SRD5A2]]'', a [[gene]] encoding the [[enzyme]] [[5α-reductase type 2]] (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum.

5αR2 is expressed in specific tissues and catalyzes the transformation of [[testosterone]] (T) to [[5α-dihydrotestosterone]] (DHT). DHT plays a key role in the process of [[sexual differentiation]] in the external genitalia and [[prostate]] during the development of the male fetus. 5αR2D is a result of impaired 5αR2 activity resulting in decreased DHT levels. This defect results in a spectrum of [[phenotype]]s including overt genital ambiguity, [[hypospadias]], and [[micropenis]]. Affected males still develop typical masculine features at [[puberty]] (deep voice, facial hair, muscle bulk) since most aspects of pubertal [[virilization]] are driven by testosterone, not DHT.

Management of this condition in the context of [[sex assignment]] is a challenging and controversial area. Diagnostic availability, local laws, and parental anxiety all play roles in treatment decisions.

The investigation of 5αR2D as a disease has played a key role in the biochemical characterization of the SRD5A2 gene, the 5αR2 enzyme, and DHT in male sexual differentiation.

==Signs and symptoms==
Mutations in the [[SRD5A2]] gene can result in a [[Disorders of sex development|46,XY disorder of sex development]]<ref>{{cite journal |last1=Mendonca |first1=Berenice Bilharinho |last2=Domenice |first2=Sorahia |last3=Arnhold |first3=Ivo J. P. |last4=Costa |first4=Elaine M. F. |title=46,XY disorders of sex development (DSD): 46,XY disorders of sex development |journal=Clinical Endocrinology |date=February 2009 |volume=70 |issue=2 |pages=173–187 |doi=10.1111/j.1365-2265.2008.03392.x|pmid=18811725 |s2cid=31355974 }}</ref> (46,XY DSD) called 5α-reductase 2 deficiency (5αR2D). The mutations are inherited in an autosomal recessive pattern and can be either [[homozygous]] or, less frequently, [[compound heterozygous]] loss-of-function. Affected males exhibit a broad spectrum of presentation including atypical genitalia (ranging from female-appearing to underutilized male), [[hypospadias]], and isolated [[micropenis]]. The internal reproductive structures ([[vasa deferentia]], [[seminal vesicles]], [[epididymides]] and [[ejaculatory ducts]]) are normal but [[testes]] are usually undescended and [[prostate hypoplasia]] is common. Males with the same mutations in SRD5A2 can have different phenotypes suggesting additional factors that are involved in clinical presentation. Females with the same mutations in SRD5A2 as affected males (as seen in siblings) are unaffected and have normal female phenotypes and reproductive function.<ref name="Mendonca2016">{{cite journal |last1=Mendonca |first1=Berenice B. |last2=Batista |first2=Rafael Loch |last3=Domenice |first3=Sorahia |last4=Costa |first4=Elaine M.F. |last5=Arnhold |first5=Ivo J.P. |last6=Russell |first6=David W. |last7=Wilson |first7=Jean D. |title=Steroid 5α-reductase 2 deficiency |journal=The Journal of Steroid Biochemistry and Molecular Biology |date=October 2016 |volume=163 |pages=206–211 |doi=10.1016/j.jsbmb.2016.05.020|pmid=27224879 |s2cid=26748233 }}</ref><ref name="Imperato-McGinley2002">{{cite journal |last1=Imperato-McGinley |first1=J |last2=Zhu |first2=Y.-S |title=Androgens and male physiology the syndrome of 5α-reductase-2 deficiency |journal=Molecular and Cellular Endocrinology |date=December 2002 |volume=198 |issue=1–2 |pages=51–59 |doi=10.1016/s0303-7207(02)00368-4|pmid=12573814 |s2cid=54356569 }}</ref>

[[Virilization]] of genitalia with voice deepening, development of muscle mass occurs at puberty in affected males, and height is not impaired. [[Gynecomastia]] is uncommon and bone density is normal in contrast to 46,XY DSD from other causes such as [[partial androgen insensitivity syndrome]] and [[17β-hydroxysteroid dehydrogenase 3 deficiency]]. Hair on the face and body is reduced and [[male pattern baldness]] does not occur.<ref name="Mendonca2016"/>

==Genetics==
Two of three [[isozyme]]s of 5αR can catalyze the transformation of T to DHT, but it is only 5αR2D that causes 46XY, DSD. 5αR2 is encoded by the gene SRD5A2 which is located on the short arm of [[chromosome 2]] and contains five [[exon]]s and four [[intron]]s. 5αR2 consists of 254 [[amino acid]] residues with reported mutations at 67 of them with multiple different mutations at some residues.<ref name="Thigpen1992"/><ref name="Mendonca2016"/>

The first known mutation SRD5A2 was almost a complete [[deletion (genetics)|deletion]] that was discovered from an analysis of affected males in a Papua New Guinean tribe.<ref>{{cite journal |last1=Andersson |first1=Stefan |last2=Berman |first2=David M. |last3=Jenkins |first3=Elizabeth P. |last4=Russell |first4=David W. |title=Deletion of steroid 5α-reductase 2 gene in male pseudohermaphroditism |journal=Nature |date=November 1991 |volume=354 |issue=6349 |pages=159–161 |doi=10.1038/354159a0|pmid=1944596 |pmc=4451825 |bibcode=1991Natur.354..159A }}</ref> The majority of SRD5A2 mutations are [[missense mutation]]s, but small deletions, [[Splice site mutation|splice junction mutations]], and gross deletions were also observed.<ref name="Batista2020"/> Mutations result in a spectrum of activity effects ranging from destabilizing 5αR2 to complete loss of activity.<ref name="Mendonca2016"/>

SRD5A2 mutations are inherited in an autosomal recessive pattern. Homozygous defects are more common than compound heterozygous ones. A phenotype-genotype correlation is not known to exist for many of the most common mutations, and affected males with the same 5αR2 mutations have variable phenotypes suggesting other interacting genetic factors that determine phenotype.<ref>{{cite journal |last1=Avendaño |first1=Andrea |last2=Paradisi |first2=Irene |last3=Cammarata-Scalisi |first3=Francisco |last4=Callea |first4=Michele |title=5-α-Reductase type 2 deficiency: is there a genotype–phenotype correlation? A review |journal=Hormones |date=June 2018 |volume=17 |issue=2 |pages=197–204 |doi=10.1007/s42000-018-0013-9|pmid=29858846 |doi-access=free }}</ref>
==Mechanism==
[[5α-Reductase|5α-Reductase type 2]] (5αR2) is an [[enzyme]], encoded by the SRD5A2 gene, that is expressed in specific tissues in the male body from fetal development to adulthood.<ref name="Mendonca2016"/><ref>{{cite journal |last1=Levine |first1=A C |last2=Wang |first2=J P |last3=Ren |first3=M |last4=Eliashvili |first4=E |last5=Russell |first5=D W |last6=Kirschenbaum |first6=A |title=Immunohistochemical localization of steroid 5 alpha-reductase 2 in the human male fetal reproductive tract and adult prostate. |journal=The Journal of Clinical Endocrinology & Metabolism |date=January 1996 |volume=81 |issue=1 |pages=384–389 |doi=10.1210/jcem.81.1.8550782|pmid=8550782 |doi-access=free }}</ref><ref>{{cite journal |last1=Thigpen |first1=A E |last2=Silver |first2=R I |last3=Guileyardo |first3=J M |last4=Casey |first4=M L |last5=McConnell |first5=J D |last6=Russell |first6=D W |title=Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. |journal=Journal of Clinical Investigation |date=1 August 1993 |volume=92 |issue=2 |pages=903–910 |doi=10.1172/JCI116665|pmid=7688765 |pmc=294929 }}</ref> The enzyme catalyzes the transformation of [[testosterone]] (T) to [[5α-dihydrotestosterone]] (DHT) intracellularly. DHT is the most potent ligand to the [[androgen receptor]] (AR).<ref>{{cite journal |last1=Labrie |first1=F |last2=Sugimoto |first2=Y |last3=Luu-The |first3=V |last4=Simard |first4=J |last5=Lachance |first5=Y |last6=Bachvarov |first6=D |last7=Leblanc |first7=G |last8=Durocher |first8=F |last9=Paquet |first9=N |title=Structure of human type II 5 alpha-reductase gene. |journal=Endocrinology |date=September 1992 |volume=131 |issue=3 |pages=1571–1573 |doi=10.1210/endo.131.3.1505484|pmid=1505484 }}</ref> Upon binding, the DHT-AR complex translocates from cytoplasm to the nucleus and activates the androgen receptor-regulated genes involved in processes that include [[Sexual differentiation in humans|male sexual differentiation]].<ref name="Azzouni2012">{{cite journal |last1=Azzouni |first1=Faris |last2=Godoy |first2=Alejandro |last3=Li |first3=Yun |last4=Mohler |first4=James |title=The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases |journal=Advances in Urology |date=2012 |volume=2012 |page=530121 |doi=10.1155/2012/530121|pmid=22235201 |pmc=3253436 |doi-access=free }}</ref>

==Diagnosis==
Diagnosis is usually made between birth and puberty. Pseudovaginal perineoscrotal hypospadias presenting with female-appearing genitalia and pubertal virilization is the classical syndrome attributed to 5αR2D, but modern diagnostic methods can diagnose the deficiency shortly after birth and recognize the broad spectrum of presentation.<ref name="Mendonca2016"/>

The initial diagnosis of 46,XY DSD is indicated by overt genital abnormality. The objective clinical evaluation of dysmorphic features to diagnose 46,XY DSD for apparent female genitalia includes enlarged clitoris, posterior labial fusion, and inguinal/labial mass. For apparent male genitalia:  nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testis. Family history and prenatal history are also taken into account in the evaluation. [[karyotype|Karyotyping]] and [[SRY]] gene analysis on samples from peripheral [[leukocyte]]s will exclude [[sex chromosome]] abnormalities. With the determination of an XY karyotype and normal SRY, the differential diagnosis of 46,XY DSD is made with endocrinological measurements of T/DHT ratios<ref>{{cite journal |last1=Hiort |first1=Olaf |last2=Willenbring |first2=Holger |last3=Albers |first3=Norbert |last4=Hecker |first4=Wolfgang |last5=Engert |first5=Jürgen |last6=Dibbelt |first6=Leif |last7=Sinnecker |first7=Gernot H. G. |title=Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency |journal=European Journal of Pediatrics |date=June 1996 |volume=155 |issue=6 |pages=445–451 |doi=10.1007/BF01955179|pmid=8789759 |s2cid=24236741 }}</ref> (which indicate 5αR2 activity) and precise anatomical imaging since 5αR2D can be difficult to distinguish from other causes of 46,XY DSD (e.g., partial androgen insensitivity syndrome and 17β- hydroxysteroid dehydrogenase type 3 enzyme deficiencies).<ref name="Cheon2011">{{cite journal |last1=Cheon |first1=Chong Kun |title=Practical approach to steroid 5alpha-reductase type 2 deficiency |journal=European Journal of Pediatrics |date=January 2011 |volume=170 |issue=1 |pages=1–8 |doi=10.1007/s00431-010-1189-4|pmid=20349245 |s2cid=25945759 }}</ref>

The measurement of the serum DHT concentration is challenging since the concentrations are low and DHT has a high level of cross-reactivity. A high level of assay specificity is required to measure concentrations of DHT since serum T levels are generally 10-fold higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret since the normal ratio level varies according to age and severity of 5αR2 activity impairment. Affected young males of at least pubertal age with normal serum T levels demonstrate elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with [[human chorionic gonadotropin|human chorionic gonadotropin (hCG)]] (alternatively, [[testosterone enanthate]]) is required in prepubertal children (with stimulation and samples taken over several days) to increase serum testosterone levels for measurement. Interpreting T/DHT ratios in male newborns is especially challenging due to neonatal testosterone surge<ref>{{cite journal |last1=Clarkson |first1=Jenny |last2=Herbison |first2=Allan E. |title=Hypothalamic control of the male neonatal testosterone surge |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |date=19 February 2016 |volume=371 |issue=1688 |pages=20150115 |doi=10.1098/rstb.2015.0115|pmid=26833836 |pmc=4785901 }}</ref> and higher than normal 5a-reductase type 1 activity. SRD5A2 gene analysis is recommended for diagnosis in newborns.<ref>{{cite journal |last1=Achermann |first1=John C. |last2=Domenice |first2=Sorahia |last3=Bachega |first3=Tania A. S. S. |last4=Nishi |first4=Mirian Y. |last5=Mendonca |first5=Berenice B. |title=Disorders of sex development: effect of molecular diagnostics |journal=Nature Reviews Endocrinology |date=August 2015 |volume=11 |issue=8 |pages=478–488 |doi=10.1038/nrendo.2015.69|pmid=25942653 |s2cid=19704336 |url=https://discovery.ucl.ac.uk/id/eprint/1492403/ }}</ref><ref>{{cite journal |last1=Maimoun |first1=Laurent |last2=Philibert |first2=Pascal |last3=Cammas |first3=Benoit |last4=Audran |first4=Françoise |last5=Bouchard |first5=Philippe |last6=Fenichel |first6=Patrick |last7=Cartigny |first7=Maryse |last8=Pienkowski |first8=Catherine |last9=Polak |first9=Michel |last10=Skordis |first10=Nicos |last11=Mazen |first11=Inas |last12=Ocal |first12=Gonul |last13=Berberoglu |first13=Merih |last14=Reynaud |first14=Rachel |last15=Baumann |first15=Clarisse |last16=Cabrol |first16=Sylvie |last17=Simon |first17=Dominique |last18=Kayemba-Kay's |first18=Kabangu |last19=De Kerdanet |first19=Marc |last20=Kurtz |first20=François |last21=Leheup |first21=Bruno |last22=Heinrichs |first22=Claudine |last23=Tenoutasse |first23=Sylvie |last24=Van Vliet |first24=Guy |last25=Grüters |first25=Annette |last26=Eunice |first26=Marumudi |last27=Ammini |first27=Ariachery C. |last28=Hafez |first28=Mona |last29=Hochberg |first29=Ze'ev |last30=Einaudi |first30=Sylvia |last31=Al Mawlawi |first31=Horia |last32=del Valle Nuñez |first32=Cristóbal J. |last33=Servant |first33=Nadège |last34=Lumbroso |first34=Serge |last35=Paris |first35=Françoise |last36=Sultan |first36=Charles |title=Phenotypical, Biological, and Molecular Heterogeneity of 5α-Reductase Deficiency: An Extensive International Experience of 55 Patients |journal=The Journal of Clinical Endocrinology & Metabolism |date=February 2011 |volume=96 |issue=2 |pages=296–307 |doi=10.1210/jc.2010-1024|pmid=21147889 |doi-access= }}</ref> Broadly, 5αR2D is diagnosed with T/DHT ratios greater than 18 while ratios greater than 30 have been observed in severely affected individuals.<ref name="Mendonca2016"/> 5αR2D can also be indicated by low ratios of 5α- to 5ß- reduced steroids, as measured in urine measured via [[gas chromatography–mass spectrometry]].<ref>{{cite journal |last1=Chan |first1=Angel On Kei |last2=But |first2=Betty Wai Man |last3=Lee |first3=Ching Yin |last4=Lam |first4=Yuen Yu |last5=Ng |first5=Kwok Leung |last6=Tung |first6=Joanna Yuet Ling |last7=Kwan |first7=Elaine Yin Wah |last8=Chan |first8=Yuk Kit |last9=Tsui |first9=Teresa Kam Chi |last10=Lam |first10=Almen Lai Na |last11=Tse |first11=Wing Yee |last12=Cheung |first12=Pik To |last13=Shek |first13=Chi Chung |title=Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential? |journal=Clinical Chemistry |date=1 May 2013 |volume=59 |issue=5 |pages=798–806 |doi=10.1373/clinchem.2012.196501|pmid=23513070 |doi-access=free }}</ref>

[[Ultrasonography]] is the primary means for assessing internal reproductive organs for diagnosis while [[genitography]] and [[voiding cystourethrography]] are used to resolve structures such as urethral and vaginal tracts.<ref name="Chavhan2008">{{cite journal |last1=Chavhan |first1=Govind B. |last2=Parra |first2=Dimitri A. |last3=Oudjhane |first3=Kamaldine |last4=Miller |first4=Stephen F. |last5=Babyn |first5=Paul S. |last6=Pippi Salle |first6=Foao L. |title=Imaging of Ambiguous Genitalia: Classification and Diagnostic Approach |journal=RadioGraphics |date=November 2008 |volume=28 |issue=7 |pages=1891–1904 |doi=10.1148/rg.287085034|pmid=19001646 }}</ref><ref>{{cite journal |last1=Parisi |first1=Melissa A |last2=Ramsdell |first2=Linda A |last3=Burns |first3=Mark W |last4=Carr |first4=Michael C |last5=Grady |first5=Richard E |last6=Gunther |first6=Daniel F |last7=Kletter |first7=Gadi B |last8=McCauley |first8=Elizabeth |last9=Mitchell |first9=Michael E |last10=Opheim |first10=Kent E |last11=Pihoker |first11=Catherine |last12=Richards |first12=Gail E |last13=Soules |first13=Michael R |last14=Pagon |first14=Roberta A |title=A Gender Assessment Team: experience with 250 patients over a period of 25 years |journal=Genetics in Medicine |date=June 2007 |volume=9 |issue=6 |pages=348–357 |doi=10.1097/GIM.0b013e3180653c47|pmid=17575501 |s2cid=21141446 |doi-access=free }}</ref> The use of pelvic [[MRI]] for diagnostic imaging for 5αR2D remains controversial.<ref name="Chavhan2008"/>

==Management==
One of the most clinically challenging and controversial topics with 46,XY DSD is the practice of "sex assignment" or "sex of rearing".<ref name="Byers2017">{{cite journal |last1=Byers |first1=Heather M. |last2=Mohnach |first2=Lauren H. |last3=Fechner |first3=Patricia Y. |last4=Chen |first4=Ming |last5=Thomas |first5=Inas H. |last6=Ramsdell |first6=Linda A. |last7=Shnorhavorian |first7=Margarett |last8=McCauley |first8=Elizabeth A. |last9=Amies Oelschlager |first9=Anne-Marie E. |last10=Park |first10=John M. |last11=Sandberg |first11=David E. |last12=Adam |first12=Margaret P. |last13=Keegan |first13=Catherine E. |title=Unexpected ethical dilemmas in sex assignment in 46,XY DSD due to 5-alpha reductase type 2 deficiency |journal=American Journal of Medical Genetics Part C: Seminars in Medical Genetics |date=June 2017 |volume=175 |issue=2 |pages=260–267 |doi=10.1002/ajmg.c.31560|pmid=28544750 |pmc=5489130 }}</ref> This is especially so in 5αR2D, since most affected individuals have undervirilized genitalia at birth but virilize to varying degrees at puberty. Historically most 5αR2D individuals have been "raised as females",<ref>{{cite journal |last1=Kolesinska |first1=Z |last2=Ahmed |first2=SF |last3=Niedziela |first3=M |last4=Bryce |first4=J |last5=Molinska-Glura |first5=M |last6=Rodie |first6=M |last7=Jiang |first7=J |last8=Sinnott |first8=RO |last9=Hughes |first9=IA |last10=Darendeliler |first10=F |last11=Hiort |first11=O |last12=van der Zwan |first12=Y |last13=Cools |first13=M |last14=Guran |first14=T |last15=Holterhus |first15=PM |last16=Bertelloni |first16=S |last17=Lisa |first17=L |last18=Arlt |first18=W |last19=Krone |first19=N |last20=Ellaithi |first20=M |last21=Balsamo |first21=A |last22=Mazen |first22=I |last23=Nordenstrom |first23=A |last24=Lachlan |first24=K |last25=Alkhawari |first25=M |last26=Chatelain |first26=P |last27=Weintrob |first27=N |title=Changes over time in sex assignment for disorders of sex development. |journal=Pediatrics |date=September 2014 |volume=134 |issue=3 |pages=e710-5 |doi=10.1542/peds.2014-1088 |pmid=25092939|s2cid=9316947 }}</ref> but later reports show that over half of patients who underwent virilizing puberty adopted a male gender identity thus challenging historical practices.<ref>{{cite journal |last1=Cohen-Kettenis |first1=PT |title=Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. |journal=Archives of Sexual Behavior |date=August 2005 |volume=34 |issue=4 |pages=399–410 |doi=10.1007/s10508-005-4339-4 |pmid=16010463|s2cid=146495456 }}</ref><ref>{{cite journal |last1=Costa |first1=EM |last2=Domenice |first2=S |last3=Sircili |first3=MH |last4=Inacio |first4=M |last5=Mendonca |first5=BB |title=DSD due to 5α-reductase 2 deficiency&nbsp;— from diagnosis to long term outcome. |journal=Seminars in Reproductive Medicine |date=October 2012 |volume=30 |issue=5 |pages=427–31 |doi=10.1055/s-0032-1324727 |pmid=23044880|s2cid=5289961 }}</ref><ref>{{cite journal |last1=Maimoun |first1=L |last2=Philibert |first2=P |last3=Cammas |first3=B |last4=Audran |first4=F |last5=Bouchard |first5=P |last6=Fenichel |first6=P |last7=Cartigny |first7=M |last8=Pienkowski |first8=C |last9=Polak |first9=M |last10=Skordis |first10=N |last11=Mazen |first11=I |last12=Ocal |first12=G |last13=Berberoglu |first13=M |last14=Reynaud |first14=R |last15=Baumann |first15=C |last16=Cabrol |first16=S |last17=Simon |first17=D |last18=Kayemba-Kay's |first18=K |last19=De Kerdanet |first19=M |last20=Kurtz |first20=F |last21=Leheup |first21=B |last22=Heinrichs |first22=C |last23=Tenoutasse |first23=S |last24=Van Vliet |first24=G |last25=Grüters |first25=A |last26=Eunice |first26=M |last27=Ammini |first27=AC |last28=Hafez |first28=M |last29=Hochberg |first29=Z |last30=Einaudi |first30=S |last31=Al Mawlawi |first31=H |last32=Nuñez |first32=CJ |last33=Servant |first33=N |last34=Lumbroso |first34=S |last35=Paris |first35=F |last36=Sultan |first36=C |title=Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. |journal=The Journal of Clinical Endocrinology and Metabolism |date=February 2011 |volume=96 |issue=2 |pages=296–307 |doi=10.1210/jc.2010-1024 |pmid=21147889|doi-access= }}</ref>

The goal of sex assignment/rearing is to facilitate the greatest likelihood of concordant gender identity in the patient's adulthood. The factors that contribute to gender identity are complex and not easy to report but some factors that contribute include sex chromosomes, androgen exposure, psychosocial development, cultural expectations, family dynamics, and social situation.<ref name="Byers2017"/>

Female sex rearing in 5αR2D individuals involves surgical procedures such as childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty.<ref name="Cheon2011"/> Life-long hormonal treatments as also required for the development and maintenance of female secondary sex characteristics.<ref>{{cite journal |last1=Hughes |first1=IA |last2=Houk |first2=C |last3=Ahmed |first3=SF |last4=Lee |first4=PA |last5=Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology Consensus |first5=Group. |title=Consensus statement on management of intersex disorders. |journal=Journal of Pediatric Urology |date=June 2006 |volume=2 |issue=3 |pages=148–62 |doi=10.1016/j.jpurol.2006.03.004 |pmid=18947601}}</ref> Male sex of rearing avoids lifelong hormonal treatments and allows for the potential of fertility.<ref name="Byers2017"/>  [[Cryptorchidism]] and hypospadias must be addressed to prevent damage to the seminiferous tubules that are essential for spermatogenesis and fertility.<ref>{{cite journal |last1=Nordenskjöld |first1=A |last2=Ivarsson |first2=SA |title=Molecular characterization of 5 alpha-reductase type 2 deficiency and fertility in a Swedish family. |journal=The Journal of Clinical Endocrinology and Metabolism |date=September 1998 |volume=83 |issue=9 |pages=3236–8 |doi=10.1210/jcem.83.9.5125 |pmid=9745434|doi-access=free }}</ref> Some approaches encourage a diagnosis during infancy prior to any gender assignment or surgical interventions.<ref name="Cheon2011"/>

The intersection of the child's well-being, parental wishes, recommendations of the associated medical team, and local laws makes decision-making challenging in these cases. The necessity and ethics around consent and deception involved in administering such interventions have been seriously questioned.<ref>{{cite journal |last1=Dreger |first1=Alice Domurat |title="Ambiguous Sex": Or Ambivalent Medicine? Ethical Issues in the Treatment of Intersexuality |journal=The Hastings Center Report |date=May 1998 |volume=28 |issue=3 |pages=24–35 |doi=10.2307/3528648|jstor=3528648 |pmid=9669179 }}</ref>

===Fertility===
Spontaneous fertility in 5αR2D affected males is very unusual<ref name="Mendonca2016"/> (though has been observed<ref name="Recent Studies on the Mechanism of">{{cite journal |last1=Deykin |first1=Daniel |last2=Balko |first2=Christine |last3=Wilson |first3=Jean D. |title=Recent Studies on the Mechanism of Action of Testosterone |journal=New England Journal of Medicine |date=21 December 1972 |volume=287 |issue=25 |pages=1284–1291 |doi=10.1056/NEJM197212212872508|pmid=4119318 }}</ref>) due to semen abnormalities that include reduced sperm counts, high semen viscosity and, in some cases, lack of primary spermatocytes. This supports the notion that DHT has an important role in spermatocyte differentiation.<ref>{{cite journal |last1=Costa |first1=Elaine |last2=Domenice |first2=Sorahia |last3=Sircili |first3=Maria |last4=Inacio |first4=Marlene |last5=Mendonca |first5=Berenice |title=DSD Due to 5α-Reductase 2 Deficiency&nbsp;— from Diagnosis to Long Term Outcome |journal=Seminars in Reproductive Medicine |date=8 October 2012 |volume=30 |issue=5 |pages=427–431 |doi=10.1055/s-0032-1324727|pmid=23044880 |s2cid=5289961 }}</ref> The broad spectrum of presentation is consistent with highly varying sperm counts among affected males. Testicular function may also be impaired by incomplete descent as well as the genetic mutation itself.<ref name="Cheon2011"/>

Assisted reproduction methods involving sperm extraction and concentration for [[intrauterine insemination]],<ref>{{cite journal |last1=Katz |first1=Melissa D. |last2=Kligman |first2=Isaac |last3=Cai |first3=Li-Qun |last4=Zhu |first4=Yuan-Shan |last5=Fratianni |first5=Carmel M. |last6=Zervoudakis |first6=Ioannis |last7=Rosenwaks |first7=Zev |last8=Imperato-McGinley |first8=Julianne |title=Paternity by Intrauterine Insemination with Sperm from a Man with 5α-Reductase-2 Deficiency |journal=New England Journal of Medicine |date=3 April 1997 |volume=336 |issue=14 |pages=994–998 |doi=10.1056/NEJM199704033361404|pmid=9077378 |doi-access=free }}</ref> [[intracytoplasmic sperm injection]],<ref>{{cite journal |last1=Matsubara |first1=Keiko |last2=Iwamoto |first2=Hideki |last3=Yoshida |first3=Atsumi |last4=Ogata |first4=Tsutomu |title=Semen analysis and successful paternity by intracytoplasmic sperm injection in a man with steroid 5α-reductase-2 deficiency |journal=Fertility and Sterility |date=December 2010 |volume=94 |issue=7 |pages=2770.e7–2770.e10 |doi=10.1016/j.fertnstert.2010.04.013|pmid=20493473 |doi-access=free }}</ref> and [[in vitro fertilization]]<ref>{{cite journal |last1=Kang |first1=Hey-Joo |last2=Imperato-McGinley |first2=Julianne |last3=Zhu |first3=Yuan-Shan |last4=Cai |first4=Li-Qun |last5=Schlegel |first5=Peter |last6=Palermo |first6=Gianpiero |last7=Rosenwaks |first7=Zev |title=The first successful paternity through in vitro fertilization–intracytoplasmic sperm injection with a man homozygous for the 5α-reductase-2 gene mutation |journal=Fertility and Sterility |date=May 2011 |volume=95 |issue=6 |pages=2125.e5–2125.e8 |doi=10.1016/j.fertnstert.2011.01.121|pmid=21334614 |doi-access=free }}</ref> have all demonstrated successful outcomes for fertility in those with 5αR2D.

==Epidemiology==
5αR2D is a rare condition with a worldwide distribution. A 2020 study identified 434 cases of 5αR2D across 44 countries including Turkey (23%), China (17%), Italy (9%), and Brazil (7%). The same study also found that genitalia virilization influenced sex assignment while gender change was influenced by cultural aspects across the countries. Molecular diagnosis resulted in favoring male sex assignment in affected newborns.<ref name="Batista2020">{{cite journal |last1=Batista |first1=Rafael Loch |last2=Mendonca |first2=Berenice Bilharinho |title=Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide |journal=The Application of Clinical Genetics |date=14 April 2020 |volume=13 |pages=83–96 |doi=10.2147/TACG.S198178 |pmid=32346305 |pmc=7167369 |doi-access=free }}</ref>

Many SRD5A2 mutations come from areas with high coefficients of inbreeding,<ref name="Mendonca2016"/> including the [[Dominican Republic]] (where people with the condition are called [[güevedoces]]&nbsp;– "testes at twelve"),<ref>{{cite news |title=The extraordinary case of the Guevedoces |url=https://www.bbc.com/news/magazine-34290981 |work=BBC News |date=20 September 2015}}</ref> [[Papua New Guinea]] (where it is known as ''kwolu-aatmwol''&nbsp;– suggesting a person's transformation "into a male thing"),<ref name="AFS">{{cite book |last1=Fausto-Sterling |first1=Anne |title=Sexing the Body: Gender politics and the construction of sexuality |date=2000 |publisher=Basic Books |location=New York, NY |isbn=0465077145 |page=109 |edition=1st}}</ref> and [[Turkey]].<ref>{{cite journal |last1=Jong |first1=Diana Mettadewi |title=5-alpha-reductase deficiency: a case report |journal=Indonesian Pediatric Society |date=2016 |volume=43 |issue=6 |pages=234–240 |doi=10.14238/pi43.6.2003.234-40 |url=https://doaj.org/article/3fb6a62204aa4c05ad451b9629af1546 |access-date=24 October 2020|doi-access=free }}</ref>

In the Dominican Republic, güevedoces are regarded as a [[third gender]] and experience ambivalent [[Socialization#Gender socialization|gender socialisation]]. In adulthood, they most commonly [[Gender identity|self-identify]] as men, but are not necessarily completely treated as such by society.<ref name="AFS"/> 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= April 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 |s2cid= 84664559 }}</ref>

==History==
An autosomal recessive disorder of sex development, described as pseudovaginal perineoscrotal hypospadias (PPSH), was discovered in males in 1961.<ref>{{cite journal |last1=NOWAKOWSKI |first1=H |last2=LENZ |first2=W |title=Genetic aspects in male hypogonadism. |journal=Recent Progress in Hormone Research |date=1961 |volume=17 |pages=53–95 |pmid=13729828}}</ref> The main feature of this syndrome was a vulva with the presence of bilateral testes and male urogenital tracts in which the ejaculatory ducts terminate in a blind-ending vagina.<ref name="Mendonca2016"/> This disorder was consistent with 5αR2D as the underlying cause as observed in animal models.<ref name="Recent Studies on the Mechanism of"/> 5αR2D was confirmed as the cause in humans in 1974, when studies were done of 24 participants in the Dominican Republic<ref name="Imperato-McGinley1974">{{cite journal |last1=Imperato-McGinley |first1=J |last2=Guerrero |first2=L |last3=Gautier |first3=T |last4=Peterson |first4=RE |title=Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. |journal=Science |date=27 December 1974 |volume=186 |issue=4170 |pages=1213–5 |doi=10.1126/science.186.4170.1213 |pmid=4432067|bibcode=1974Sci...186.1213I |s2cid=36427689 }}</ref> and 2 in Dallas Texas, USA.<ref>{{cite journal |last1=Walsh |first1=PC |last2=Madden |first2=JD |last3=Harrod |first3=MJ |last4=Goldstein |first4=JL |last5=MacDonald |first5=PC |last6=Wilson |first6=JD |title=Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. |journal=The New England Journal of Medicine |date=31 October 1974 |volume=291 |issue=18 |pages=944–9 |doi=10.1056/NEJM197410312911806 |pmid=4413434}}</ref> One of the cases in Dallas began to virilize at puberty and underwent surgery to remove testes and "repair" the apparent [[clitoromegaly]]. During surgery, a normal male urogenital tract was observed as well as other features consistent with PPSH. DHT was almost undetectable in cultured fibroblasts from foreskin,<ref>{{cite journal|last1=Moore|first1=R J|last2=Griffin|first2=J E|last3=Wilson|first3=J D|date=September 1975|title=Diminished 5alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2.|journal=Journal of Biological Chemistry|volume=250|issue=18|pages=7168–7172|doi=10.1016/S0021-9258(19)40924-1|pmid=240819 |doi-access=free}}</ref> epididymis and the presumed "labia majora" whereas in normal males DHT is detected, suggesting impaired DHT formation.<ref name="Wilson1993">{{cite journal |last1=Wilson |first1=Jean D. |last2=Griffin |first2=James E. |last3=Russell |first3=David W. |title=Steroid 5α-Reductase 2 Deficiency* |journal=Endocrine Reviews |date=October 1993 |volume=14 |issue=5 |pages=577–593 |doi=10.1210/edrv-14-5-577|pmid=8262007 }}</ref> Similar conclusions were obtained for participants in a family in the Dominican Republic study, in whom high serum concentration ratios of T to DHT and low concentrations of urinary 5a-reduced androgens were observed. This disorder is now known to be due to homozygous or compound heterozygous loss-of-function mutations of the SRD5A2 gene.<ref name="Thigpen1992">{{cite journal |last1=Thigpen |first1=A E |last2=Davis |first2=D L |last3=Milatovich |first3=A |last4=Mendonca |first4=B B |last5=Imperato-McGinley |first5=J |last6=Griffin |first6=J E |last7=Francke |first7=U |last8=Wilson |first8=J D |last9=Russell |first9=D W |title=Molecular genetics of steroid 5 alpha-reductase 2 deficiency. |journal=Journal of Clinical Investigation |date=1 September 1992 |volume=90 |issue=3 |pages=799–809 |doi=10.1172/JCI115954|pmid=1522235 |pmc=329933 }}</ref>

==Society and culture==
===Sport===
In April 2014, the ''[[BMJ]]'' reported that four elite women athletes with 5-ARD were subjected to sterilization and "partial [[Clitoridectomy|clitoridectomies]]" in order to compete in [[women's 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|s2cid=2198650 }}</ref> Intersex advocates regard this intervention as "a clearly coercive process".<ref>{{cite web|url=https://ihra.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]]|access-date=2 February 2021|date=2014-09-11}}</ref>

===Popular culture===
In the ''[[Nip/Tuck]]'' season three episode "Quentin Costa", it is revealed that [[Quentin Costa]] had 5-ARD.<ref>{{cite book |last1=Steinhoff |first1=H. |title=Transforming Bodies: Makeovers and Monstrosities in American Culture |date=26 May 2015 |publisher=Springer |isbn=978-1-137-49379-8 |url=https://books.google.com/books?id=7xANCgAAQBAJ&pg=PA184 |language=en}}</ref>

[[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.<ref>{{cite journal |last1=Hsu |first1=Stephanie |title=Ethnicity and the Biopolitics of Intersex in Jeffrey Eugenides's 'Middlesex' |journal=MELUS |date=2011 |volume=36 |issue=3 |pages=87–110 |doi=10.1353/mel.2011.0045 |jstor=23035264 |s2cid=146517414 }}</ref><ref>{{cite news |title=Jeffrey Eugenides's Middlesex gave me the courage to take risks in my writing {{!}} Nadifa Mohamed |url=https://www.theguardian.com/commentisfree/2014/aug/25/middlesex-jeffrey-eugenides-intersex-book-changed-me |access-date=26 December 2021 |work=the Guardian |date=25 August 2014 |language=en}}</ref>

===Notable people===
* [[Caster Semenya]]<ref>{{Cite news |first=Sean |last=Ingle |url=http://www.theguardian.com/sport/2019/jun/18/caster-semenya-iaaf-athletics-guinea-pig|title=Caster Semenya accuses IAAF of using her as a 'guinea pig experiment' |date=June 18, 2019 |newspaper=[[The Guardian]] }}</ref><ref>{{Cite news |first=Matteo |last=Winkler |url=https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3805794|title=Of Athletes, Bodies and Rules: Making Sense of 'Caster Semenya' |date=18 Mar 2021 |newspaper=[[SSRN]] |ssrn=3805794 }}</ref>

==See also==
* [[Intersex]]
* [[Disorders of sexual development]], [[pseudohermaphroditism]], and [[ambiguous genitalia]]
* [[Inborn errors of steroid metabolism]]
* [[5α-Reductase]] ([[SRD5A1|I]], [[SRD5A2|II]])
* [[Androgen]] ([[testosterone]] and [[dihydrotestosterone]])
* [[Ambiguous genitalia]]
* [[Intersex surgery]]
* [[Androgen insensitivity syndrome]]
* [[Congenital adrenal hyperplasia]]

==References==
{{Reflist}}

==External links==
* [https://omim.org/entry/264600 OMIM article]
* {{EMedicine|article|924291|5-Alpha-Reductase Deficiency}}
{{Medical resources
| ICD11           = {{ICD11|LD2A.3}}
| ICD10           = {{ICD10|E29.1}}
| ICD10CM         = <!-- {{ICD10CM|Xxx.xxxx}} -->
| ICD9            = {{ICD9|257.2}}
| ICDO            =
| OMIM            = 264600
| MeshID          = C535830
| DiseasesDB      = 11
| SNOMED CT       = 57514000
| Curlie          =
| MedlinePlus     =
| eMedicineSubj   = ped
| eMedicineTopic  = 1980
| PatientUK       =
| NCI             =
| GeneReviewsNBK  =
| GeneReviewsName =
| NORD            =
| GARDNum         = 5680
| GARDName        = 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
| RP              =
| AO              =
| WO              =
| OrthoInfo       =
| Orphanet        = 753
| Scholia         = Q858426
| OB              =
}}

{{Defects of cholesterol and steroid metabolism}}
{{Congenital malformations of genital organs}}
{{Gonadal disorder}}
{{Auth}}

[[Category:Cholesterol and steroid metabolism disorders]]
[[Category:Endocrine gonad disorders]]
[[Category:Intersex variations]]