5α-Reductase 2 deficiency

Affected individuals 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. Although people who are genetically female (with two X chromosomes in each cell) may inherit variants in both copies of the SRD5A2 gene, their sexual development is not affected. The development of female sex characteristics does not require DHT, so a lack of steroid 5-alpha reductase 2 activity does not cause physical changes in these individuals. Virilization of genitalia with voice deepening, development of muscle mass occurs at puberty in affected individuals, 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.) 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. The broad spectrum of presentation is consistent with highly varying sperm counts among affected individuals. Testicular function may also be impaired by incomplete descent as well as the genetic mutation itself. ==Genetics==

Two different genes, each with five exons and four introns, designated as SRD5A1 and SRD5A2, encode two different 5α-reductases. The human 5α-reductase-2 gene (SRD5A2) is located on the short arm of chromosome 2 at band 23 and encodes a 254 amino acid protein, called 5α-reductase type 2. The 5α-reductase-1 gene (SRD5A1) is located in band 15 on the short arm of chromosome 5 and encodes a 259 amino acid protein, called 5α-reductase type 1. The high amino acid sequence identity of their proteins (approximately 60%) indicates the possibility of a common precursor gene during evolution. But the role of 5α-reductase type 1 is not well defined. The majority of SRD5A2 mutations are missense mutations, but small deletions, splice junction mutations, and gross deletions were also observed. ==Mechanism==

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. The enzyme catalyzes the transformation of testosterone (T) to 5α-dihydrotestosterone (DHT) intracellularly. DHT is the most potent ligand to the androgen receptor (AR). Upon binding, the DHT-AR complex translocates from cytoplasm to the nucleus and activates the androgen receptor-regulated genes involved in processes that include male sexual differentiation. ==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. (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). 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 (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 and higher than normal 5a-reductase type 1 activity. SRD5A2 gene analysis is recommended for diagnosis in newborns. Broadly, 5αR2D is diagnosed with T/DHT ratios greater than 18 while ratios greater than 30 have been observed in severely affected individuals. 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. The use of pelvic MRI for diagnostic imaging for 5αR2D remains controversial. ==Management==

One of the most clinically challenging and controversial topics with 46,XY DSD is the practice of "sex assignment" or "sex of rearing". 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", but later reports show that over half of patients who underwent virilizing puberty adopted a male gender identity thus challenging historical practices. 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. Male sex of rearing avoids lifelong hormonal treatments and allows for the potential of fertility. Some approaches encourage a diagnosis during infancy prior to any gender assignment or surgical interventions. Assisted reproduction methods involving sperm extraction and concentration for intrauterine insemination, intracytoplasmic sperm injection, and in vitro fertilization 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. Many SRD5A2 mutations come from areas with high coefficients of inbreeding, Papua New Guinea (where it is known as kwolu-aatmwol – suggesting a person's transformation "into a male thing"), and Turkey. ==History==

An autosomal recessive disorder of sex development, described as pseudovaginal perineoscrotal hypospadias (PPSH), was discovered in males in 1961. 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. and 2 in Dallas Texas, USA. 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, epididymis and the presumed "labia majora" whereas in normal males DHT is detected, suggesting impaired DHT formation. 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. The frequency of the deficiency was found to be unusually high in Las Salinas, with occurrence ratio of 1 güevedoce to every 90 unaffected males. ==Society and culture==

Dominican Republic In the Dominican Republic, güevedoces are regarded as a third gender and experience ambivalent gender socialisation. In adulthood, they most commonly self-identify as men, but are not necessarily completely treated as such by society. Sport In April 2014, the BMJ reported that four elite athletes with 5-ARD were subjected to sterilization and "partial 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. Intersex advocates regard this intervention as "a clearly coercive process". 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 genetic sex, he transitions into Cal. Notable people • Caster Semenya ==See also==