INTRODUCTION — Steroid 5-alpha-reductase 2 deficiency, a 46,XY disorder of sexual development (DSD), is an autosomal recessive condition in which 46,XY subjects with bilateral testes and normal testosterone production have impaired virilization during embryogenesis due to defective conversion of testosterone to dihydrotestosterone (DHT).

The clinical manifestations, pathogenesis, diagnosis, and treatment of 5-alpha-reductase deficiency are reviewed here. DSD due to defects in testosterone biosynthesis and in androgen receptor function are discussed elsewhere. (See "Pathogenesis and clinical features of disorders of androgen action" and "Diagnosis and treatment of disorders of the androgen receptor" and "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

EPIDEMIOLOGY — Steroid 5-alpha-reductase 2 deficiency was first reported in a pedigree of 24 families with 38 affected males in the Dominican Republic, an area where consanguineous marriages are common [1-3]. In a subsequent report of forty 46,XY infants born with ambiguous genitalia in the Dominican Republic over a 10-year period, five (13 percent) were diagnosed with steroid 5-alpha-reductase 2 deficiency [4]. One of the five patients was traced to the original kindred of 38 affected subjects.

Additional clusters of patients have also been reported in Turkey [5] and Papua New Guinea [6], but steroid 5-alpha-reductase 2 deficiency is otherwise thought to be rare. The prevalence in the general population is unknown [7]. However, patients with steroid 5-alpha-reductase 2 deficiency have now been reported from a variety of countries and ethnic backgrounds [8-10].

PATHOGENESIS — Individuals with steroid 5-alpha-reductase 2 deficiency are 46,XY with normal testosterone production but impaired virilization during embryogenesis, due to defective conversion of testosterone to dihydrotestosterone (DHT). The nature of the enzyme abnormality in this disorder was discovered when it was demonstrated that 5-alpha-reductase activity in cultured genital skin fibroblasts from affected subjects was reduced [11]. Cloning of the cDNAs that encode the enzymes revealed that there are two steroid 5-alpha-reductases, termed types 1 and 2, involved in human sex development [12].

●Steroid 5-alpha-reductase type 2 enzyme is defective in subjects with the disorder, whereas the type 1 enzyme is normal. Reduced DHT formation in androgen target tissues impairs virilization of the male urogenital tract in embryogenesis. The low but measurable serum concentrations of DHT in affected subjects could be due either to residual activity of the mutant enzyme or the normal type 1 isoenzyme. Studies in families in which the type 2 enzyme is believed to be absent suggest that the DHT in the serum of these subjects is predominantly derived from the type 1 enzyme [13].

●Virilization at the time of expected puberty in untreated subjects may be mediated by the increase in serum testosterone, which induces male-type body composition (muscle growth), or increase in DHT concentrations that occur at puberty through 5-alpha-reductase type 1.

●Testosterone and estrogen production are in the normal male range in 5-alpha-reductase 2 deficiency [14]. This explains why affected subjects do not develop permanent gynecomastia at the time of puberty. In contrast, gynecomastia at puberty is common in subjects with mutations of the androgen receptor (see 'Differential diagnosis' below and "Pathogenesis and clinical features of disorders of androgen action"). In addition, a steroid 5-alpha-reductase type 3 has been described, which does play a role in congenital disorders of glycosylation, but not in sex development or virilization [15,16].

Genetics — This disorder is due to autosomal recessive loss of function mutations in the gene that encodes steroid 5-alpha-reductase type 2 (SRD5A2). Mutations are distributed throughout the coding region. Over 50 different mutations have been described [13,17]. Point mutations are responsible for most cases. Approximately 40 percent of subjects carry homozygous mutations, in keeping with the finding of frequent consanguinity in the families; the remainder are compound heterozygotes [18].

The disorder has worldwide distribution. Identical mutations have been detected in different ethnic groups. The R227Q mutation, which is associated with retention of approximately 3 percent of normal enzymatic activity, appears to be relatively frequent in Asian populations and may cause micropenis rather than ambiguous genitalia [19]. In some instances, recurrent mutations are the consequence of a founder effect [20]. (See 'Epidemiology' above.)

CLINICAL MANIFESTATIONS

46,XY individuals — The typical clinical features in 46,XY males with 5-alpha-reductase 2 deficiency are those reported in the two originally recognized families as well as others [1,14,21].

●The external genitalia often are predominately female at birth; however, the range of undervirilization may be from almost complete male with isolated microphallus and varying degrees of hypospadias to completely female with clitoromegaly or normal female genital appearance [18,22]. Although the degree of virilization of the external genitalia is variable, masculinization of nongenital tissues, eg, muscle, at puberty is normal.

●The internal urogenital tract is male, consisting of epididymides, vasa deferentia, seminal vesicles, and ejaculatory ducts that empty into a blind-ending vagina. The absence of müllerian duct derivatives indicates that anti-müllerian hormone is produced and acts normally. (See "Typical sex development".)

●Gynecomastia, which is the hallmark of partial androgen insensitivity, is very rare in 5-alpha-reductase deficiency. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Partial androgen insensitivity (PAIS)'.)

A wide spectrum of phallic enlargement at birth was reported in a subsequent study of 55 patients with 5-alpha-reductase 2 deficiency [18]. The degree of phallic enlargement at birth can also be judged by observing that 40 of the patients (72 percent) were initially assigned to female gender. No enlargement (normal female) occurred in four (7.3 percent), a slight degree of enlargement (clitoromegaly) in 27 (49 percent), and a greater degree of enlargement but less than normal male (microphallus) in 18 patients (33 percent).

As adults, concentrations of serum testosterone and estradiol are similar to those in normal men. The level of serum luteinizing hormone (LH) is normal in approximately one-half of subjects and slightly elevated in the rest. Levels of serum follicle-stimulating hormone (FSH) may be elevated. Because of the defect in 5-alpha-reductase 2, the ratio of serum testosterone to dihydrotestosterone (DHT) is increased basally in adults and after administration of human chorionic gonadotropin (hCG) in childhood [23]. However, laboratory results may be nondiagnostic; therefore, molecular genetic analysis has been advocated for diagnosis [18,23].

In the initial descriptions, affected subjects were identified when they developed variable virilization at adolescence. Now that many affected families have been reported, it is apparent that the manifestations vary [13].

Approximately 55 percent of affected subjects have a blind-ending or pseudovagina in which the Wolffian ducts terminate in the upper vagina. In 40 percent, the Wolffian ducts terminate in the perineum on either side of the urethra. The remainder are considerably virilized, so that they have a predominantly male appearance at birth [24]. The testes are invariably outside the abdominal cavity either in the inguinal canals, labia majora, or scrotum, and spermatogenesis is often impaired.

One report of four individuals diagnosed as adults with intact testes found normal lumbar and hip bone mineral density in three individuals and mild lumbar osteopenia in the fourth [25]. In another study of 16 adult subjects with the disorder, hip bone mineral density was not significantly different than a reference male population [26].

Gender role change at puberty — In the past, when affected 46,XY children were raised initially as female, gender role behavior changed to male at the time of expected puberty in a variable percentage of patients. In a large extended kindred from the Dominican Republic, 18 of 19 subjects initially raised as females subsequently changed gender role behavior to male at the time of puberty [27]. Similar results were described in a report from China; almost all patients from 11 families changed from female to male gender after puberty [28]. In other reports, however, only 50 to 60 percent of affected individuals assigned female sex in infancy who then virilized in puberty changed their gender role behavior to male [7,29]. The percentage of patients changing gender role was much lower (12.5 percent) in one report from France [18].

The change in gender-role behavior is not unique to this disorder and has occurred in undervirilized 46,XY individuals with 17-beta-hydroxysteroid dehydrogenase 3 deficiency and other causes of impaired testosterone synthesis, and in subjects with mixed gonadal dysgenesis (45,X/46,XY disorder of sex development [DSD]) [30,31]. However, change in gender role behavior is rare in subjects with androgen-receptor disorders. (See "Pathogenesis and clinical features of disorders of androgen action".)

46,XX individuals — Women with 5-alpha-reductase 2 deficiency have also been described [32,33]. Three homozygous 46,XX women (siblings of the Dominican kindred described above) with 5-alpha-reductase 2 deficiency were identified based upon urinary steroid analyses and genotyping [33]. Biochemical features included elevated urinary testosterone levels and increased testosterone to DHT ratios. They had a normal female phenotype but they had absent arm or leg hair and a decrease in axillary and pubic hair (due to low DHT). They all experienced late menarche (ages 15 to 18 years) but then had normal menstrual function and fertility. These observations suggest that DHT plays an important role in the growth of normal body hair and pathogenesis of hirsutism in women. (See "Pathophysiology and causes of hirsutism".)

DIAGNOSIS — The diagnosis of 5-alpha-reductase 2 deficiency may be suspected in infants with ambiguous genitalia or in adolescents or young adults with the characteristic phenotype (see '46,XY individuals' above). Adolescents who are not diagnosed in infancy are typically individuals who were initially assigned to a female gender, but then present at the time of puberty with marked masculinization and phallic growth. Further evaluation then demonstrates a blind vaginal pouch; the absence of a uterus; and bilateral, usually inguinal, testes.

The diagnosis is supported by the biochemical findings of a normal male serum testosterone concentration, but an increased ratio of serum testosterone to dihydrotestosterone (DHT) (>20), as well as urinary excretion patterns of 5-alpha- to 5-beta-reduced steroids. Measurement of the urinary analytes is difficult and not widely available; also, measurement of DHT with immunoassays may be unspecific [34]. Because the biochemical determination of the diagnosis is difficult, we suggest making a definitive diagnosis with genotyping (analysis of the characteristic mutations in the SRD5A2 gene).

Laboratory assessment

Infants and prepubertal subjects — Measurement of basal serum concentrations of testosterone and DHT is not sufficient for diagnosis before the expected age of puberty, because available assays to measure the low levels of testosterone and DHT in infants and prepubertal children are inaccurate. To get reliable results in this age group, serum testosterone and DHT must be measured before and after multiple injections of human chorionic gonadotropin (hCG) [23,35,36] (see "Evaluation of the infant with atypical genital appearance (difference of sex development)"). However, we suggest genetic testing rather than hCG stimulation/biochemical testing for the definitive diagnosis [37].

Adolescents and adults — Measurement of basal concentrations of serum testosterone and DHT is usually sufficient for diagnosis after the expected age of puberty, because of the higher values of testosterone in this age group.

●The ratio of serum testosterone to DHT was >20 in affected subjects in the extended kindred from the Dominican Republic [3] and in another nine unrelated Brazilian families (figure 1) [36]. In the latter group, the ratio ranged from 35 to 84 in affected subjects as compared with 8 to 16 in normal subjects. In adults, measurement of the ratio of serum testosterone to DHT after administration of hCG or testosterone does not increase discrimination between affected and normal men (figure 1).

●Cultures of genital skin fibroblasts may be studied for enzyme characteristics, but these studies are invasive, costly, time-consuming, and in the time of molecular genetic diagnostics, not ethically appropriate.

●Definitive diagnosis of the mutation in the steroid 5-alpha-reductase 2 enzyme should be made by DNA analysis.

Differential diagnosis — Defects in testosterone biosynthesis and partial defects in androgen receptor function can cause phenotypes that are similar to those found in subjects with 5-alpha-reductase deficiency. (See "Pathogenesis and clinical features of disorders of androgen action" and "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

There are, however, important clinical differences among these disorders.

●17-beta-hydroxysteroid dehydrogenase 3 deficiency is a hereditary disorder of testosterone biosynthesis that results in a phenotype similar to 5-alpha-reductase deficiency but greater impairment in virilization of the external genitalia than of the internal urogenital tract. In this form of 46,XY disorder of sex development (DSD), serum testosterone concentrations are often in the lower normal male range, whereas serum concentrations of androstenedione, the precursor before the enzymatic block, are elevated several-fold [38,39]. Many different mutations can cause 17-beta-hydroxysteroid dehydrogenase 3 deficiency [40]. (See "Causes of differences of sex development", section on 'Disorders with abnormal androgen synthesis or response'.)

●Partial defects in androgen-receptor function can cause impaired external virilization and result in incomplete development of the male urogenital tract, including ambiguous genitalia. In contrast to 5-alpha-reductase deficiency, these disorders are usually associated with development of gynecomastia at the time of expected puberty. (See "Pathogenesis and clinical features of disorders of androgen action".)

Normal ratios of urinary 5-beta- to 5-alpha-reduced metabolites (measured in specialized laboratories) and testosterone to DHT in serum can be useful; however, only genetic analysis of the androgen receptor gene and the SRD5A2 gene can provide a definitive diagnosis [23]. (See "Pathogenesis and clinical features of disorders of androgen action" and "Diagnosis and treatment of disorders of the androgen receptor".)

MANAGEMENT — Management is primarily dependent upon the phenotypic findings and gender assignment at the time of diagnosis. As noted above, most affected newborns are now assigned the male gender at birth [24].

Initial gender assignment — The issue of gender assignment in the newborn in this condition is complex because historically ≥50 percent of individuals assigned the female gender have undergone a change in social gender (gender role behavior) later in life [30].

If the phenotype is predominantly male, the choice of male rearing is clear (see 'Gender role change at puberty' above). Some experts recommend that all infants diagnosed with steroid 5-alpha-reductase 2 deficiency be raised as males because affected subjects virilize to a variable extent later in life [41].

Given the complexity of gender assignment decisions in the newborn, we suggest that patients be treated in centers where multidisciplinary expertise in disorders of sex development (DSD) is available.

The issue of gender assignment is reviewed in detail separately. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on '46,XY 17-beta-HSD and 5-alpha-reductase deficiencies'.)

The situation is complex when the diagnosis is made later in childhood in individuals who were raised as female. On the one hand, such girls may be aware that their gender assignment was inappropriate from early childhood and may be ready to make a change in social gender [42]. On the other hand, other individuals are comfortable as females and do not wish to change social gender. The consequence is that when the diagnosis is made later in childhood or adolescence, surgical or endocrine intervention should only be done after careful psychological evaluation of the child and consultation with the parents [7,43,44]. The age of the subject, the sex of rearing, and the choice of social gender all influence subsequent management. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Psychosexual issues' and "Management of the infant with atypical genital appearance (difference of sex development)", section on '46,XY 17-beta-HSD and 5-alpha-reductase deficiencies'.)

Raised as female and maintained female gender role — In light of the frequent change in gender role from female to male (see above) [27], the decision to raise an individual as female should be made only after thorough psychologic assessment to confirm the presence of female gender identity. Once the decision has been made to maintain a female social role, management practices in many countries include:

●Gonadectomy is done before puberty to prevent or minimize virilization and to prevent development of tumors in inguinal or labial testes [45]. Clitoromegaly may be surgically corrected by an experienced surgeon to maintain the glans clitoris. If vaginal development is insufficient, vaginal depth should be enhanced by use of dilators at the appropriate age, and if this is unsuccessful, an artificial vagina should be created surgically [46]. This practice is still under debate, and any intervention depends upon social and medical standards, which vary by country. The approach may change once clearer practice guidelines become available.

●Estrogen therapy appropriate for inducing and maintaining feminization should be started at the time of usual pubertal maturation or immediately after gonadectomy is performed in an adult, similar to that for treatment of primary or secondary hypogonadism in women. Such therapy is critical to promote breast development and to prevent osteoporosis. Specific studies on hormonal management are lacking. (See "Approach to the patient with delayed puberty".)

Raised as males or changed gender role to male — Raising a subject as male requires complex decisions about the time and type of surgical and hormonal therapy. If patients are raised as males, surgical correction of the hypospadias and cryptorchidism (if present) should be performed by a surgeon experienced in these procedures at a time dictated by the degree of hypospadias and size of the phallus.

Supplemental testosterone — Since virilization is usually less than satisfactory, even when some phallic growth occurs after the time of sexual maturation, trials of supplemental androgen are sometimes undertaken [36,47]. Although pharmacologic doses of testosterone esters may raise serum dihydrotestosterone (DHT) concentrations to the normal range and cause acne and growth of facial and body hair, phallic growth is minimal in adults, and the long-term safety of this treatment is not established.

The results are different in prepubertal subjects. In one report, as an example, pharmacologic doses of testosterone (two intramuscular doses of testosterone ester 125 mg three weeks apart) led to more than a doubling of penis size [36]. An alternate approach is to administer DHT itself, either in the form of a transdermal cream [48] or an injectable ester [49]. Both modes of DHT administration raise serum DHT concentrations [48,49], but neither preparation is commercially available and an optimal regimen or an evidence-based guideline has not been established. Recent findings indicate that DHT treatment is not able to normalize stretched penile length [50].

Fertility — Sperm counts have been very low in most patients with 5-alpha-reductase 2 deficiency in whom sperm production has been measured. Sperm counts were within the low normal range in only one individual (of nine examined) from the Dominican Republic [51]. This man was able to achieve fertility with the use of intrauterine insemination [52].

Fertility has also been reported in men in whom 5-alpha-reductase deficiency caused isolated microphallus [53]. However, fertility in most affected men who have minimal detectable sperm production requires intrauterine insemination or in vitro fertilization with intracytoplasmic sperm injection [54]. (See "In vitro fertilization: Overview of clinical issues and questions" and "Intracytoplasmic sperm injection".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Differences of sex development".)

SUMMARY AND RECOMMENDATIONS — Steroid 5-alpha-reductase 2 deficiency is a rare, autosomal recessive disorder in which virilization of males during development is impaired because of inadequate conversion of testosterone to its more active intracellular metabolite dihydrotestosterone (DHT).

●The phenotype is striking because virilization of the external genitalia is impaired to varying degrees more severely than the virilization of the other parts of the male urogenital tract. As a consequence, most 46,XY persons were historically raised as females, a practice that is currently changing (see 'Clinical manifestations' above). 46,XX females with 5-alpha reductase deficiency have a normal female phenotype with the exception of late menarche. (See '46,XX individuals' above.)

●The diagnosis is suggested by the characteristic clinical features described above (see 'Clinical manifestations' above). It is further supported by an elevated ratio (>20) of plasma testosterone to DHT in 46,XY individuals after the age of puberty, or in infants and prepubertal subjects after administration of human chorionic gonadotropin (hCG). The urinary excretion ratio of 5-alpha- to 5-beta-reduced steroids has also been used in the diagnosis, but these assays are only available in specialized laboratories. However, definitive diagnosis requires sequencing the DNA of the gene that encodes steroid 5-alpha-reductase 2, termed SRD5A2. (See 'Diagnosis' above.)

●Sex assignment at birth – The fact that ≥50 to 60 percent of 46,XY individuals with this condition who are raised as females undergo change in gender role from female to male after the time of expected puberty complicates sex assignment in infants and small children (see 'Initial gender assignment' above). Careful psychological assessment should be performed prior to any irreversible interventions, most importantly surgery, to augment male or female development, particularly in children.

●Given the complexity of gender assignment decisions in the newborn, we suggest that patients be treated in centers where multidisciplinary expertise in disorders of sex development (DSD) is available. (See 'Initial gender assignment' above.)

The issues of sex assignment, psychosexual issues, and corrective genital surgery are reviewed in detail separately. (See "Management of the infant with atypical genital appearance (difference of sex development)".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge James Griffin, MD and Jean Wilson, MD, who contributed to earlier versions of this topic review.