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5α-Reductase 2 deficiency (5αR2D) is an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
condition caused by
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
impairing the function of ''
SRD5A2 The human gene ''SRD5A2'' encodes the 3-oxo-5α-steroid 4-dehydrogenase 2 enzyme, also known as 5α-reductase type 2 (5αR2), one of three isozymes of 5α-reductase. 5αR2 catalyzes the conversion of the male sex hormone testosterone into the m ...
'', a
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
located on chromosome 2 and encoding the
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
5α-reductase type 2 (5αR2). 5αR2 is expressed in specific tissues and catalyzes the transformation of
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
(T) to 5α-dihydrotestosterone (DHT). DHT plays a key role in the process of sexual differentiation. This rare deficiency causes atypical sex development in genetic males (people with a 46XY karyotype), with a broad spectrum of presentations most apparent in the
genitalia A sex organ, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...
. Many people with 5-alpha reductase deficiency are assigned female at birth based on their external genitalia. In other cases, affected infants are assigned male at birth based on their external genitalia, often an unusually small penis (
micropenis A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...
) and the urethra opening on the underside of the penis (
hypospadias Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...
). Still other affected infants may be assigned either female or male at birth as their external genitalia do not look clearly male or clearly female. During
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
, an increase in the levels of male sex hormones leads to the development of some secondary sex characteristics, such as increased muscle mass, deepening of the voice, development of pubic hair, and a growth spurt. The penis and scrotum may grow larger. People with 5-alpha reductase deficiency do not develop much facial or body hair.


Signs and symptoms

Affected individuals exhibit a broad spectrum of presentation including atypical genitalia (ranging from female-appearing to underutilized male),
hypospadias Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...
, and isolated
micropenis A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...
. The internal reproductive structures ( vasa deferentia, seminal vesicles,
epididymides The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...
and ejaculatory ducts) are normal but
testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...
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 Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...
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 Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ...
does not occur. Spontaneous fertility in 5αR2D affected individuals is very unusual (though has been observed) 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 SDR5A2, 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. Mutations in the
SRD5A2 The human gene ''SRD5A2'' encodes the 3-oxo-5α-steroid 4-dehydrogenase 2 enzyme, also known as 5α-reductase type 2 (5αR2), one of three isozymes of 5α-reductase. 5αR2 catalyzes the conversion of the male sex hormone testosterone into the m ...
gene can result in a 46,XY disorder of sex development(46,XY DSD) called 5α-reductase-2 deficiency. These mutations are more often observed in areas with a specific ethnic background and high coefficients of inbreeding. They generate proteins with various degrees of enzymatic activity ranging from an unstable isoenzyme to complete loss of enzymatic activity. Of the 254 amino acids in the 5a-reductase type 2 protein, mutations in codons specifying 67 different residues have been identified, with multiple mutations in the codons of several amino acids The first known mutation SRD5A2 was almost a complete deletion that was discovered from an analysis of affected individuals in a Papua New Guinean tribe. The majority of SRD5A2 mutations are
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
s, but small deletions, splice junction mutations, and gross deletions were also observed. Mutations result in a spectrum of activity effects ranging from destabilizing 5αR2 to complete loss of activity. 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 individuals with the same 5αR2 mutations have variable phenotypes suggesting other interacting genetic factors that determine phenotype.


Mechanism

5α-Reductase type 2 (5αR2) is an
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
, 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 Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
(T) to 5α-dihydrotestosterone (DHT) intracellularly. DHT is the most potent ligand to the
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...
(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. 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.
Karyotyping A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...
and SRY gene analysis on samples from peripheral
leukocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s will exclude
sex chromosome Sex chromosomes (also referred to as allosomes, heterotypical chromosome, gonosomes, heterochromosomes, or idiochromosomes) are chromosomes that carry the genes that determine the sex of an individual. The human sex chromosomes are a typical pair ...
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 (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. 5αR2D can also be indicated by low ratios of 5α- to 5ß- reduced steroids, as measured in urine measured via gas chromatography–mass spectrometry.
Ultrasonography Medical ultrasound includes diagnostic techniques (mainly imaging) using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, muscles, joints, ...
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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
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. Female sex rearing in 5αR2D individuals involves surgical procedures such as childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty. Life-long hormonal treatments as also required for the development and maintenance of female secondary sex characteristics. Male sex of rearing avoids lifelong hormonal treatments and allows for the potential of fertility. Cryptorchidism and hypospadias must be addressed to prevent damage to the seminiferous tubules that are essential for spermatogenesis and fertility. Some approaches encourage a diagnosis during infancy prior to any gender assignment or surgical interventions. 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. Assisted reproduction methods involving sperm extraction and concentration for intrauterine insemination, intracytoplasmic sperm injection, and
in vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation in which an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating the ovulatory process, then removing an ovum or ova (egg or eggs) from ...
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, including the
Dominican Republic The Dominican Republic is a country located on the island of Hispaniola in the Greater Antilles of the Caribbean Sea in the Atlantic Ocean, North Atlantic Ocean. It shares a Maritime boundary, maritime border with Puerto Rico to the east and ...
(where people with the condition are called güevedoces – "testes at twelve"),
Papua New Guinea Papua New Guinea, officially the Independent State of Papua New Guinea, is an island country in Oceania that comprises the eastern half of the island of New Guinea and offshore islands in Melanesia, a region of the southwestern Pacific Ocean n ...
(where it is known as ''kwolu-aatmwol'' – suggesting a person's transformation "into a male thing"), and
Turkey Turkey, officially the Republic of Türkiye, is a country mainly located in Anatolia in West Asia, with a relatively small part called East Thrace in Southeast Europe. It borders the Black Sea to the north; Georgia (country), Georgia, Armen ...
.


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. This disorder was consistent with 5αR2D as the underlying cause as observed in animal models. 5αR2D was confirmed as the cause in humans in 1974, when studies were done of 24 participants in the Dominican Republic 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 Third gender or third sex is an identity recognizing individuals categorized, either by themselves or by society, as neither a man nor a woman. Many gender systems around the world include three or more genders, deriving the concept either from ...
and experience ambivalent gender socialisation. In adulthood, they most commonly
self-identify Personal identity is the unique numerical identity of a person over time. Discussions regarding personal identity typically aim to determine the necessary and sufficient conditions under which a person at one time and a person at another time ...
as men, but are not necessarily completely treated as such by society.


Papua New Guinea

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.


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 Women and girls have participated in sports, physical Physical fitness, fitness, and exercise throughout history. However, the extent of their involvement has varied depending on factors such as country, time, geographical location, and level o ...
. 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 Middlesex (; abbreviation: Middx) is a Historic counties of England, former county in South East England, now mainly within Greater London. Its boundaries largely followed three rivers: the River Thames, Thames in the south, the River Lea, Le ...
'' 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 Caster Semenya Order of Ikhamanga, OIB (born 7 January 1991) is a South African middle-distance runner and winner of two Olympic medal, Olympic gold medals and three World Athletics Championships, World Championships in the women's 800 metres ...


See also

*
Intersex Intersex people are those born with any of several sex characteristics, including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical binar ...
* Disorders of sexual development,
pseudohermaphroditism Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism" (now known as ovotesticular syndrome), ...
, and
ambiguous genitalia Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...
* Inborn errors of steroid metabolism * 5α-Reductase ( I, II) *
Androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
(
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
and
dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...
) *
Ambiguous genitalia Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...
* Intersex surgery *
Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY (karyotype, karyotypically male) births. The condition result ...
*
Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...


References


External links


OMIM article
* {{Auth Cholesterol and steroid metabolism disorders Endocrine gonad disorders Intersex variations