Chapter 81
Male Pseudohermaphroditism From 5α-Reductase-2 Deficiency
Yuan-Shan Zhu and Julianne Imperato-McGinley
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Yuan-Shau Zhu, MD, PhD
Assistant Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Medical College of Cornell University, New York, New York (Vol 5, Chap 81)

Julianne Imperato-McGinley, MD
The Rochelle Belfer Professor of Medicine, Department of Medicine, Divisionof Endocrinology, Diabetes, and Metabolism, Weill Medical College of Cornell University, New York, New York (Vol 5, Chap 81)

 
INTRODUCTION
BIOCHEMISTRY AND MOLECULAR BIOLOGY OF 5α-REDUCTASE ISOENZYMES
CLINICAL SYNDROME OF MALE PSEUDOHERMAPHRODITISM FROM 5α-REDUCTASE-2 DEFICIENCY
BIOCHEMICAL FEATURES OF 5α-REDUCTASE-2 DEFICIENCY
MOLECULAR GENETICS OF 5α-REDUCTASE-2 DEFICIENCY
GENDER IDENTITY AND GENDER ROLE IN MALE PSEUDOHERMAPHRODITES WITH 5α-REDUCTASE-2 DEFICIENCY
DIAGNOSIS AND TREATMENT OF MALE PSEUDOHERMAPHRODITES WITH 5α-REDUCTASE-2 DEFICIENCY
SECONDARY CAUSES OF 5α-REDUCTASE DEFICIENCY
ACKNOWLEDGMENTS
REFERENCES

INTRODUCTION

A male pseudohermaphrodite is an incompletely masculinized individual with a 46,XY karyotype and testes. An inherited defect in 5α-reductase-2 isozyme results in male pseudohermaphroditism in affected 46,XY individuals.

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BIOCHEMISTRY AND MOLECULAR BIOLOGY OF 5α-REDUCTASE ISOENZYMES

Steroid 5α-reductase isozymes located in the microsomes of the cell are nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent proteins that reduce the double bond at the 4-5 position of a variety of c19 and c21 steroids. These isozymes convert testosterone to the more potent androgen, dihydrotestosterone (DHT). Testosterone and DHT bind to the intracellular androgen receptor (a member of the nuclear steroid/thyroid hormone receptor superfamily) and interact with a cognate androgen DNA response element to regulate target gene expression.1,2 Although testosterone and DHT interact with the same androgen receptor, they produce distinct biological responses in certain conditions.3 The molecular mechanism for this is unclear even though DHT has been reported to bind to the androgen receptor more avidly than testosterone,4 and the DHT-receptor complex is more efficiently transformed to the DNA-binding state than is the testosterone-receptor complex.5

In the early 1960s, it was theorized that multiple 5α-reductase isozymes existed.6 In 1975 and 1976, Moore and Wilson7,8 detected different pH optima for 5α-reductase activity in genital and nongenital skin. In the genital skin, the major enzymatic activity had a narrow, acidic pH optimum of 5.5,8 which was found to be low in the genital skin of male pseudohermaphrodites with 5α-reductase deficiency.7,9 Another enzymatic activity had a neutral to alkaline pH (pH 7 to 9), which was present in both normal genital and nongenital skin and was found to be normal in the genital skin of male pseudohermaphrodites with 5α-reductase deficiency. Kinetic analysis of 5α-reductase activity in the epithelium and stroma of the prostate also suggested that there were different 5α-reductase activities.10,11 Pharmacologic studies of specific 5α-reductase inhibitors provided further evidence of multiple 5α-reductase isozymes.12 Although many attempts were made to purify 5α-reductases, they were not successful because of the extreme insolubility of the protein.

In the early 1990s, two genes encoding two isozymes13,14,15,16 were cloned using expression cloning technology, steroid 5α-reductase type 1 (gene symbol:SRD5A1) and steroid 5α-reductase type 2 (gene symbol:SRD5A2). Mutations in the 5α-reductase-2 gene are responsible for male pseudohermaphrodi-tism from 5α-reductase deficiency.14,17 The characteristics of the two 5α-reductase isozymes are summarized in Table 1.

Table 1. Comparison of Human 5α-Reductase Isozymes


 

Type 1

Type 2

Gene structure

5 exons, 4 introns

5 exons, 4 introns

Gene, chromosome location

SRD5A1, 5p15

SRD5A2, 2p23

Size

259 amino acids

254 amino acids

 

Mr = 29,462

Mr = 28,398

Tissue distribution

Liver, nongenital skin,

Prostate, epididymis,

 

 prostate, brain, ovary, testis

 seminal vesicle, genital

 

 

 skin, liver, uterus, breast,

 

 

 hair follicle, placenta, testis

PH optima

Neutral to basic

Acidic or neutral

Prostate level

Low

High

Activity in 5α-reductase deficiency

Normal

Mutated

Finasteride inhibition

Ki 300 nM

Ki = 3–5 nM

The human 5α-reductase-2 gene has five exons and four introns, encodes a highly hydrophobic 254 amino acid protein with the molecular weight of approximately 28.4 kilodaltons (kd), and maps to the short arm of chromosome 2 band 23.14,16 The type 2 isozyme has a much higher affinity for testosterone (apparent Km = 4 to 50 nM) than type 1 isozyme (Km = 1 to 5 μM); however, the apparent Km (3 to 10 μM)for NADPH cofactor is similar in both isozymes. The type-2 isozyme is sensitive to finasteride, a 5α-reductase inhibitor. The type 2 isozyme has an acidic pH optimum in enzymatic assays7,14,16; however, it may work in a neutral pH optimum in its native state.18 The type 2 isozyme is expressed in the external genital tissues early in gestation.19 In adulthood, its expression in prostate, genital skin, epididymis, seminal vesicle, and liver is relatively high, whereas it is quite low in other tissues. Recently, it has been reported that this isozyme may also be expressed in the ovary and hair follicles.20,21

The 5α-reductase-1 gene is normal in male pseudohermaphrodites with 5α-reductase deficiency.14 It also has 5 exons and 4 introns and is located on the short arm of chromosome 5 band 15. This isozyme has 259 highly hydrophobic amino acids with a molecular weight approximately 29.5 kd.16 There is approximately 50% homology between human type-1 and type-2 isozymes in amino acid compositions. 5α-reductase-1 has a broad alkaline pH optimum, a lower substrate affinity, and a lower sensitivity to finasteride inhibition.16,17 This isozyme is expressed in nongenital skin, liver, and certain brain regions; however, its presence in the prostate, genital skin, epididymis, seminal vesicle, testis, adrenals, and kidney is low. Its expression is detected at birth in the liver and nongenital skin and is present throughout life, although its expression in embryonic tissues is low. The physiologic function of 5α-reductase-1 is still obscure. It may play a significant role in parturition.22

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CLINICAL SYNDROME OF MALE PSEUDOHERMAPHRODITISM FROM 5α-REDUCTASE-2 DEFICIENCY

An inherited defect in 5α-reductase-2 gene results in male pseudohermaphroditism. This syndrome was first described clinically and biochemically in 1974 in studies of 24 affected subjects from 13 families in a large Dominican kindred23 and in two siblings from Dallas.24 Since then, two other large cohorts in New Guinea25 and Turkey26,27,28 have been described. Since those original reports, many other cases have been described.17,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44

For the last 2 to 3 decades, we have had the unique opportunity of following some affected members of Dominican kindred, evaluating patients from childhood through adolescence and into adulthood. This has enabled us to make clinical observations that have provided information relevant to discerning the biology of testosterone and DHT in humans (Fig. 1 and Table 2).

Fig. 1. The specific roles of testosterone and DHT in male sexual differentiation in utero.

Table 2. Androgen Action at Puberty


Testosterone

Dihydrotestosterone

Anabolic Actions

Increased facial, body hair

  Muscle mass increased

Scalp hair recession

  Penis enlargement

 

  Scrotum enlargement

Prostate enlargement

  Vocal cord enlargement

 

  Skeletal maturation

Acne

   Growth spurt

 

   Epiphyseal closure

Pituitary-gonadal feedback

Spermatogenesis

 

Male sex drive, performance

 

Pituitary-gonadal feedback

 

Most males who are homozygous for 5α-reductase-2 deficiency have striking ambiguity of the genitalia with a clitoral-like phallus, severely bifid scrotum, pseudovaginal perineoscrotal hypospadias, and a rudimentary prostate.23,45,46,47,48,49,50 Consequently, many affected males are assigned a female gender at birth and are reared as girls. On occasion, more masculinized subjects have been described; they may lack a separate vaginal opening51 or have a blind vaginal pouch which opens into the urethra,47 penile hypospadias,37 or even a penile urethra.38 Wolffian duct differentiation is normal with seminal vesicles, vasa deferentia, epididymides, and ejaculatory ducts, although no müllerian structures. Cryptorchidism is frequently described, however, it is not invariably present. Testes may be located in the abdomen but are usually found in the inguinal canal or scrotum.

Male pseudohermaphrodites with 5α-reductase-2 deficiency are clinical models for defining the major actions of testosterone and DHT during male sexual differentiation and development (see Fig. 1). Both testosterone and DHT are necessary for complete male sexual differentiation and development. Testosterone secreted in utero by the testes acts directly on the wolffian ducts to cause differentiation to the vas deferens, epididymis, and seminal vesicles; but in the urogenital sinus and urogenital tubercle, testosterone functions as a prehormone, where its conversion to DHT results in differentiation of the external genitalia and prostate. This is consistent with the demonstration in human fetus that at the time of sexual differentiation, DHT formation occurs in the urogenital sinus, urogenital tubercle, and urogenital swellings, but does not occur in the wolffian anlage until sexual differentiation is completed.52 Animal studies by using specific 5α-reductase-2 inhibitor provide further evidence to support the differential roles of testosterone and DHT in male sexual differentiation.53,54

With the onset of puberty, the affected males have increased muscle mass and deepening of the voice.23 The musculature is particularly prominent in Dominican, New Guinean, and Turkish subjects.23,25,26,27,28 Affected males in these kindreds are as tall as their unaffected siblings, and there is no gynecomastia in adulthood.46,47,55 There is substantial growth of the phallus with rugation and hyperpigmentation of the scrotum. Inguinal testes descending into the scrotum at puberty have been observed in some patients.47,51,55 Libido is intact, and patients are capable of erections.23,56 Although patients are generally oligo- or azoospermic, normal sperm concentrations have been reported in patients with descended testes.29,46,57,58 Affected patients from the Dominican kindred58 and from Sweden59 have been reported to father children, suggesting that DHT does not play a major role in spermatogenesis and sperm function. These clinical findings suggest that pubertal events, including male sexual function and spermatogenesis, are primarily testosterone-mediated (see Table 2).

The prostate in the affected males is nonpalpable on rectal examination23,46 and is rudimentary on transrectal ultrasound and MRI visualization.49 Prostatic volumes are one-tenth the size of normal, age-matched controls.49 These findings have been confirmed by others,43 providing clinical evidence that prostate differentiation and growth is mediated largely by DHT (see Fig. 1 and Table 2). Prostate diseases such as prostate cancer and benign prostate hyperplasia have not been reported in male pseudohermaphrodites with 5α-reductase-2 deficiency. Consequently, 5α-reductase inhibition as a treatment for benign prostate hyperplasia evolved in part from the clinical observation that adult male pseudohermaphrodites with 5α-reductase-2 deficiency have rudimentary prostates caused by lifelong DHT deficiency.

The affected adult males have less facial and body hair than their unaffected male relatives, and male pattern baldness has never been observed in these affected males.23,25,26 The 5α-reductase-2 inhibitor, finasteride, has been used in the treatment of male pattern baldness.61,62

Androgens are involved in sebaceous gland secretion during puberty. Sebum production is dependent on androgen action as no demonstrable sebum is produced in 46,XY subjects with complete androgen insensitivity from androgen receptor mutation.63 Although the affected males with 5α-reductase-2 deficiency rarely have acne, they produce normal amounts of sebum, suggesting that sebum production is not regulated by 5α-reductase-2 isozyme.63

Homozygous females with a 5α-reductase-2 gene mutation have normal to elevatedplasma testosterone, with low DHT, and an elevated testosterone/DHT ratio. Urinary5β/5α C19 and C21 steroid metabolites are elevated and similarto the ratios of homozygous males. Despite the elevated testosterone, decreased body hair is found and no facial hair is present. Sebum production is normal.60 The diagnosis of homozygous females can be confirmed by molecular genetic analyses.

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BIOCHEMICAL FEATURES OF 5α-REDUCTASE-2 DEFICIENCY

The biochemical characteristics of 5α-reductase-2 deficiency have been well defined over the years.17,50 They include: (1) normal to elevated levels of plasma testosterone; (2) decreased levels of plasma DHT;(3) an increased testosterone to DHT ratio at baseline and/or following hCG stimulation; (4) decreased conversion of testosterone to DHT in vivo, with conversion ratios of testosterone to DHT of <1%; (5) reduced 5α-reductase activity in genital tissue and cultured fibroblasts; (6) normal metabolic clearance rates of testosterone and DHT; (7) decreased production of urinary 5α-reduced androgen metabolites with increased 5β/5α urinary metabolite ratios; (8) decreased plasma and urinary 3α-androstanediol glucuronide, a major metabolite of DHT64;(9) a global defect in steroid 5α-reduction as demonstrated by decreased urinary 5α-reduced metabolites of both c21 steroids and c19 steroids other than testosterone (e.g., cortisol, corticosterone, 11β-hydroxy-androstenedione, and androstenedione). Although the defect of 5α-reduction of steroids is generalized, only the defective reduction of testosterone appears to be of clinical significance.

The affected subjects have increased plasma levels of LH and an increased LH pulse amplitude with a normal LH frequency.65 The elevated mean LH occurs despite an elevated mean plasma testosterone, suggesting a role for DHT in the negative feedback control of LH.65 Plasma FSH levels may be elevated. Although some of the elevation in FSH is undoubtedly attributable to cryptorchidism and seminiferous tubular damage, a role for DHT in the feedback control of FSH cannot be ruled out.66

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MOLECULAR GENETICS OF 5α-REDUCTASE-2 DEFICIENCY

In the early 1990s, with the cloning of 5α-reductase isozyme genes, the genetic defect of 5α-reductase deficiency was defined. Our New Guinean kindred of male pseudohermaphrodites who were clinically and biochemically characterized as having 5α-reductase deficiency participated in the first genetic study.14,25 A deletion of more than 20 kb in the 5α-reductase-2 gene was found in these patients by Southern blot analysis,14 whereas the 5α-reductase-1 gene was normal. To date, more than 33 mutations in the 5α-reductase-2 gene (Fig. 2)17,30,31 (and our unpublished data) have been identified, including the three largest kindreds of male pseudohermaphrodites with 5α-reductase-2 deficiency in the world—the Dominican, New Guinean, and Turkish kindred. As stated above, patients in the New Guinean kindred have a large deletion of 5α-reductase-2 gene.14 In the Dominican kindred, a missense mutation is found in exon 5 of the 5α-reductase-2 gene, substituting thymidine for cytosine and resulting in a substitution of the nonpolar amino acid tryptophan for the basic, polar amino acid arginine at position 246 of the isozyme.67,68 This missense mutation causes a decrease in binding of the cofactor, NADPH, an altered pH optimum, and a dramatic loss of enzymatic activity.67 In male pseudohermaphrodites from the Turkish kindred, a single base deletion in exon 5 of the 5α-reductase-2 gene has been detected.28 This single-base deletion (adenine) results in a frame-shift at amino acid position 251 and an addition of 23 amino acids at the carboxyl-terminal of this 254 amino acid isozyme. This mutation in the isozyme results in a complete loss of enzymatic activity without an alteration in gene expression.28

Fig. 2. Mutations in the 5α-reductase-2 gene. A schematic diagram of the 5α-reductase-2 gene is shown in the middle with the exons ( boxes ), the introns ( dashed lines ), and the untranslated regions (filled boxes) on the 5'and 3' ends. The locations of 32 different mutations (right) and the corresponding ethnic groups for these mutations (left) are shown. A whole gene deletion of 5α-reductase-2 gene in New Guinea male pseudohermaphrodites is also shown (far left). Missense mutations are indicated by the single letter amino acid, and the first letter designates the normal amino acid, followed by the residue number and the mutant amino acid. The splice junction mutations indicated by the closest nucleotide in the exon + or - the number of nucleotides to the mutation. Deletion mutation is indicated by an Δ (e.g., 753 Δ A indicates a deletion of a single nucleotide, adenine, at position of 753 of cDNA). An asterisk indicates the termination codon (e.g., P212* designates a premature termination mutation at amino acid position 212 [proline] of the protein).

Mutations in the 5α-reductase-2 gene are found throughout all five exons of the gene and range from a single point defect to a deletion of the entire gene.17 These mutations result in various enzymatic dysfunction including impaired binding of substrate and cofactor to the isozyme; blocked formation of a functional isozyme (deletion, nonsense mutation, splice-junction alterations); and an unstable isozyme.16,41 Although various individual mutations have been characterized, no correlation between the severity of the syndrome and a particular gene defect has been observed.

5α-reductase-2 deficiency is an inherited autosomal recessive disease as evidenced by pedigree analysis,23,27 biochemical analysis,23,69 and molecular genetic analysis.28,67,68 Heterozygotes with 5α-reductase-2 defect have normal male phenotype. Approximately 35% of patients with 5α-reductase-2 deficiency from different families worldwide have been found to be either compound or inferred compound heterozygotes with mutations in two independent loci, resulting in the disease phenotype. This suggests that the carrier frequency of a single mutant allele is higher than previously suggested because of the rarity of the disease phenotype.39

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GENDER IDENTITY AND GENDER ROLE IN MALE PSEUDOHERMAPHRODITES WITH 5α-REDUCTASE-2 DEFICIENCY

Gender identity is the sense of being male or female, the awareness of knowing one's sex. Gender role is the expression of one's gender identity to the public. It is manifested by one's actions as either male or female.

Male pseudohermaphrodites with 5α-reductase-2 deficiency raised as females often change gender role during or after puberty, providing a clinical model for defining the role of testosterone in the evolution of male gender identity. Since our original report in the Dominican community,23,70,71 numerous groups have reported gender change in subjects with 5α-reductase-2 deficiency from many countries including individuals from the New Guinea, Turkey, Mexico, Cyprus, Algeria, Italy, Lebanon, Brazil, Pakistan, Saudi Arabia, UAE, Sweden, etc.17,25,26,35,40,43,51,72,73,74,75,76,77 It appears from these published observations that if puberty is permitted to occur spontaneously without surgical and hormonal reinforcement of the female sex of rearing, then a male gender identity, although discordant with the sex of rearing, will prevail. Under these circumstances, it appears that the extent of androgen (i.e., testosterone) exposure of the brain in utero, during the early postnatal period, and at puberty, has more of an effect in determining male gender identity than does sex of rearing and sociocultural influences.78

In the Dominican community, the female sex of rearing was never reinforced through castration and subsequent female hormone therapy. As such, at puberty a change in gender from female to male occurred in the vast majority of subjects from the older generation who were unambiguously reared as females.23,55,71 Psychosexual study in 18 subjects showed that 17 of them successfully changed gender identity from female to male. Between 7 and 12 years of age, patients who were raised as girls began to experience considerable anxiety over their lack of breast development and often began to be sexually attracted to girls. They became convinced of their male gender identity over the next several years and were masturbating and experiencing morning erections and nocturnal emissions. The change in gender role occurred on average at 16 years of age, with a range of 14 to 24 years. In three subjects, a gender role change did not occur until they were in their 20s. Admittedly, the fear of being stigmatized and anticipation of harassment by local villagers caused some subjects to hesitate at the prospect of changing gender roles, in some cases until they were confident of their ability to defend themselves. We have continued to observe the behavioral characteristics of these subjects for more than 20 years and have no doubts as to their male behavioral pattern in adulthood.

Normally, the sex of rearing and testosterone imprinting of the brain act in unison to determine the complete expression of the male gender; however, subjects with 5α-reductase-2 deficiency demonstrate that in a laissez-faire environment, when rearing (female) is discordant with the testosterone-mediated biological sex, the biological sex prevails if normal testosterone activation of puberty is permitted to occur. From the data, it appears that the extent of testosterone exposure of the brain in utero, in the early postnatal period and at puberty, has greater impact in determining the male gender identity than the female sex of rearing. This experiment of nature emphasizes the importance of androgens, which act as inducers and activators in evolution of male gender identity in man.78

It has been proposed that the gender identity becomes fixed by 18 months to 4 years of age, at the time of language development.79,80,81 At this time, a child becomes aware of his or her gender; however, being aware of one's gender and being unalterably fixed in that gender are two separate issues. The development of gender identity in man is continually evolving throughout childhood, becoming fixed with puberty.

The psychosexual studies in male pseudohermaphrodites with 5α-reductase-2 deficiency demonstrate that in humans, environmental or sociocultural factors are not solely responsible for the formation of a male gender identity, androgens make a strong and definite contribution. These data support the hormonal theory in the development of gender identity.17,71,78.

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DIAGNOSIS AND TREATMENT OF MALE PSEUDOHERMAPHRODITES WITH 5α-REDUCTASE-2 DEFICIENCY

5α-reductase-2 deficiency should be considered in 46,XY infants who are born with ambiguous external genitalia. Establishing the diagnosis of 5α-reductase-2 deficiency in infancy often requires that plasma testosterone/DHT ratios be determined following hCG administration.81a Measurement of urinary cortisol metabolite ratios, 5β-tetrahydrocortisol/5α-tetrahydrocortisol, is critical for the diagnosis of 5α-reductase-2 deficiency in infancy, because the amount of C19 androgen metabolites, etiocholanolone, and androsterone in the urine of neonates is insufficient for accurate measurement. In adult 46,XY subjects, an elevated testosterone/DHT ratio and markedly elevated urinary 5β/5α C19 androgen metabolites are essential to making the diagnosis. It should be noted that an elevation of the testosterone/DHT ratio can sometimes be found in subjects with androgen insensitivity. However, despite the elevated plasma testosterone/DHT ratio, the ratio of the urinary 5β/5α C19 androgen metabolites in androgen insensitivity are normal to slightly elevated.84 Molecular genetic analysis to identify a mutation of 5α-reductase-2 gene is used to confirm the diagnosis.

Once the diagnosis of male pseudohermaphroditism from 5α-reductase-2 deficiency has been made in the newborn, a decision concerning the sex of rearing must be made. From our observations of the natural history of this disorder for more than 2 decades that most affected subjects identify and behave as normal males in adulthood despite the trauma of having been raised in the wrong sex, we therefore believe that the most desirable situation is to raise children with 5α-reductase-2 deficiency as male, the gender compatible with their genetic and gonadal sex. They are psychosexually males and should be raised as male.71,78 This necessitates early diagnosis of the condition followed by surgical correction of the external genitalia and correction of cryptorchidism if present.

Adequate genital correction in childhood is difficult because of the severity of the genital ambiguity, and the phallus is generally only slightly larger than a clitoris. To enlarge the phallus and facilitate hypospadias repair, newborns with this condition can be treated by administering DHT cream.37,82,83 Topical application of 2% to 2.5% DHT cream results in good phallic growth, facilitating surgical correction of penoscrotal hypospadias.82 The rationale behind the treatment is replacement of the deficient hormone DHT to induce phallic growth that theoretically would have occurred in utero and in the postnatal period. Administering DHT after the critical period of sexual differentiation in utero will stimulate phallic growth but will not correct the genital defect, as sexual differentiation occurs during a critical period in utero.

Most patients described in the literature have perineoscrotal hypospadias, and therefore surgical correction is more difficult. Despite this concern, surgical correction of the genitalia is feasible and made easier if enlargement of the phallus can be accomplished with DHT cream administration. Pseudovaginal perineoscrotal hypospadias has also been successfully repaired in adulthood in patients with 5α-reductase-2 deficiency. The quality of surgery, however, is dependent on the expertise of the surgeon and should therefore be attempted only by an experienced surgeon. Early correction of cryptorchism in infancy or early childhood could preserve fertility.59

If genital repair is successful, (1) the child will have a male puberty with normal male psychosexual development; (2) he will be equal in height to the normal males in his family; (3) there will be growth of the genitalia at puberty with an increase in muscle mass and deepening of the voice; (4)gynecomastia will not be a concern; and (5) fertility in this condition has been reported.

The most serious debate involves the management of subjects who are raised as females and diagnosed as having 5α-reductase-2 deficiency in the peri- and postpubertal period. After careful psychiatric evaluation, often subjects will be found to identify as males and should be encouraged to take their place as males in society. Occasionally, a patient is found to be unable to admit51 or acknowledge maleness; then a change in gender role should not be discussed at that time, and long-term evaluation is essential before gender decisions are made. Some subjects with this condition, who identify as male, will change gender role with time if they can deal with the social pressures of family, friends, etc. (unpublished). Thus, whether or not a gender role change will occur in an individual with 5α-reductase-2 deficiency at this time is obviously dependent on a host of social and cultural factors that might either consciously or subconsciously suppress or foster the change. All these factors must be considered by the patient's physician, as well as the psychiatrist working in concert with the patient and the family.78,82

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SECONDARY CAUSES OF 5α-REDUCTASE DEFICIENCY

Secondary 5α-reductase deficiency has been described in subjects with androgen insensitivity from androgen receptor defect, indicating that the 5α-reductase isozymes are regulated by androgens. Androgen-insensitive subjects often have decreased plasma DHT with elevated plasma testosterone/DHT ratios, similar to subjects with primary 5α-reductase-2 gene defects.84,85 In contrast to the inherited 5α-reductase-2 deficiency in which a generalized severe defect of both hepatic and peripheral 5α-reductases is found, 5α-reductase activity in androgen insensitivity is preserved in the liver but deficient in the periphery. Thus, in androgen insensitivity syndrome, normal to minimally elevated urinary ratios of the 5β/5α metabolites of cortisol and corticosterone are found reflecting normal 5α-reduction metabolism in the liver, whereas increased ratios of the 5β/5αmetabolites of c19 androgens reflect impaired peripheral 5α-reduction. This distinct steroid metabolite pattern can help distinguish between the two clinical entities.84,85 Other clinical features can also help in the diagnosis such as complete androgen insensitivity syndrome usually has female phenotype of external genitalia and gynecomastia. Of course, molecular genetic identification of the gene defect will ultimately confirm the diagnosis.17,68,86

The defect in androgenic action from androgen receptor mutations may affect both type 1 and type 2 5α-reductase isozyme activity as animal studies have shown that DHT upregulated 5α-reductase activity and 5α-reductase type 1 and 2 mRNA levels in the rat prostate87,88,89 and in primary cultures of rat or human scrotal skin fibroblasts.90

Hepatic 5α-reductase activity has also been found to be decreased in other clinical situations such as in porphyria,91 Cushing's syndrome,46 hypothyroidism, and anorexia nervosa.92 The reason of secondary 5α-reductase deficiency in these clinical conditions is unclear.

Studies of male pseudohermaphrodites with 5α-reductase-2 deficiency over the last 2 to 3 decades has provided valuable information about male sexual development and has elucidated the roles of testosterone and DHT in human physiology and pathophysiology. Studies of subjects with this inherited condition has led to the development of specific 5α-reductase-2 inhibitors for the treatment of benign prostate hyperplasia and male pattern baldness.

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ACKNOWLEDGMENTS

Supported in part by NIH Grant M01-RR-00047 (General Clinical Research Center) and HD-09421-15.

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REFERENCES

1. Evans RM: The steroid and thyroid hormone receptor superfamily. Science 240: 889, 1988

2. Beato M: Gene regulation by steroid hormones. Cell 56: 335, 1989

3. Wilson JD: Sexual differentiation. Annu Rev Physiol 40: 270, 1978

4. Wilbert DM, Griffen JE, Wilson JD: Characterization of the cytosol androgen receptor of the human prostate. J Clin Endocrinol Metab 56: 113, 1983

5. Kovacs WJ, Griffin JE, Weaver DD et al: A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state. J Clin Invest 73: 1095, 1984

6. McGuire JS, Tomkins GM: The heterogeneity of delta 4-3-ketosteroid reductase (5α). J Biol Chem 235: 1634, 1960

7. Moore RJ, Wilson JD: Diminished 5 alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2. J Biol Chem 250: 7168, 1975

8. Moore RJ, Wilson JD: Steroid 5-alpha-reductase in cultured human fibroblasts: Biochemical and genetic evidence for two distinct enzyme activities. J Biol Chem 251: 5895, 1976

9. Wilson JD: Dihydrotestosterone formation in cultured human fibroblasts:Comparison of cells from normal subjects and patients with familial incomplete male pseudohermaphroditism, type 2. J Biol Chem 250: 3498, 1975

10. Bruchovsky N, Rennie PS, Batzold FH et al: Kinetic parameters of 5α-reductase activity in stroma and epithelium of normal, hyperplastic, and carcinomatous human prostates. J Clin Endocrinol Metab 67: 806, 1988

11. Hudson RW: Comparison of nuclear 5-alpha-reductase activities in the stromal and epithelial fractions of human prostatic tissue. J Steroid Biochem 26: 349, 1987

12. Jenkins EP, Andersson S, Imperato-McGinley J et al: Genetic and pharmacological evidence for more than one human steroid 5A-reductase. J Clin Invest 89: 293, 1992

13. Andersson S, Russell DW: Structural and biochemical properties of cloned and expressed human and rat steroid 5α-reductases. Proc Natl Acad Sci U S A 87: 3640, 1990

14. Andersson S, Berman DM, Jenkins EP et al: Deletion of steroid 5α-reductase-2 gene in male pseudohermaphroditism. Nature 354: 159, 1991

15. Labrie F, Sugimoto Y, Luu-The V et al: Structure of human type II 5-alpha-reductase gene. Endocrinology 131: 1571, 1992

16. Russell DW, Wilson JD: Steroid 5 alpha-reductase: Two genes/two enzymes. Annu Rev Biochem 63: 25, 1994

17. Zhu YS, Katz MD, Imperato-McGinley J: Natural potent androgens: Lessons from human genetic models. Baillieres Clin Endocrinol Metab 12: 83, 1998

18. Thigpen AE, Cala KM, Russell DW: Characterization of Chinese hamster ovary cell lines expressing human steroid 5-alpha-reductase isozymes. J Biol Chem 268: 17404, 1993

19. Thigpen AE, Silver RI, Guileyardo JM et al: Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression. J Clin Invest 92: 903, 1993

20. Eicheler W, Tuohimaa P, Vilja P et al: Immunocytochemical localization of human 5-alpha-reductase 2 with polyclonal antibodies in androgen target and non-target human tissues. J Histochem Cytochem 42: 667, 1994

21. Eicheler W, Dreher M, Hoffmann R et al: Immunohistochemical evidence for differential distribution of 5-alphareductase isoenzymes in human skin. Br J Dermatol 133: 371, 1995

22. Mahendroo MS, Cala KM, Russell DW: 5α-reduced androgens play a key role in murine parturition. Mol Endocrinol 10: 380, 1996

23. Imperato-McGinley J, Guerrero L, Gautier T et al: Steroid 5α-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 186: 1213, 1994

24. Walsh PC, Madden JD, Harrod MJ et al: Familial incomplete male pseudohermaphroditism, type 2: Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 291: 944, 1974

25. Imperato-McGinley J, Miller M, Wilson JD et al: A cluster of male pseudohermaphrodites with 5-alpha-reductase deficiency in Papua, New Guinea. Clin Endocrinol (Oxf) 34: 293, 1991

26. Akgun S, Ertel N, Imperato-McGinley J et al: Familial male pseudohermaphroditism in a Turkish village due to 5α-reductase deficiency. Am J Med 81: 267, 1986

27. Imperato-McGinley J, Akgun S, Ertel NH et al: The coexistence of male pseudohermaphrodites with 17-ketosteroid reductase deficiency and 5α-reductase deficiency within a Turkish kindred. Clin Endocrinol (Oxf)27:135, 1987

28. Can S, Zhu YS, Cai LQ et al: The identification of 5α-reductase-2 and 17α-hydroxysteroid dehydrogenase-3 gene defects in male pseudohermaphrodites from a Turkish kindred. J Clin Endocrinol Metab 83: 560, 1998

29. Cantu JM, Hernandez-Montes H, del Castillo V et al: Potential fertility in incomplete male pseudohermaphroditism type 2. Rev Invest Clin 28: 177, 1976

30. Nordenskjold A, Magnus O, Aagenaes O et al: Homozygous mutation (A228T)in the 5-alpha-reductase type 2 gene in a boy with 5-alpha-reductase deficiency: Genotype-phenotype correlations. Am J Med Genet 80: 269, 1998

31. Vilchis F, Mendez JP, Canto P et al: Identification of missense mutations in the SRD5A2 gene from patients with steroid 5-alpha-reductase-2 deficiency. Clin Endocrinol (Oxf) 52: 383, 2000

32. Saenger P, Goldman AS, Levine LS et al: Prepubertal diagnosis of steroid 5 alpha-reductase deficiency. J Clin Endocrinol Metab 46: 627, 1978

33. Fisher LK, Kogut MD, Moore RJ et al: Clinical, endocrinological, and enzymatic characterization of two patients with 5α-reductase deficiency: Evidence that a single enzyme is responsible for the 5α-reduction of cortisol and testosterone. J Clin Endocrinol Metab 47: 653, 1978

34. Kuttenn F, Mowszowicz I, Wright F et al: Male pseudohermaphroditism: A comparative study of one patient with 5-alpha-reductase deficiency and three patients with the complete form of testicular feminization. J Clin Endocrinol Metab 49: 861, 1979

35. Savage MO, Preece MA, Jeffcoate SL et al: Familial male pseudohermaphroditism due to deficiency of 5α- reductase. Clin Endocrinol (Oxf) 12: 397, 1980

36. Ivarsson SA, Nielsen MD, Lindberg T: Male pseudohermaphroditism due to 5-alpha-reductase deficiency in a Swedish family. Eur J Pediatr 147: 532, 1988

37. Carpenter TO, Imperato-McGinley J, Boulware SD et al: Variable expression of 5-alpha-reductase deficiency: Presentation with male phenotype in a child of Greek origin. J Clin Endocrinol Metab 71: 318, 1990

38. Ng WK, Taylor NF, Hughes IA et al: 5α-reductase deficiency without hypospadias. Arch Dis Child 65: 1166, 1990

39. Thigpen AE, Davis DL, Milatovich A et al: The molecular genetics of steroid 5α-reductase-2 deficiency. J Clin Invest 90: 799, 1992

40. Wilson JD, Griffin JE, Russell DW: Steroid 5α-reductase-2 deficiency. Endocr Rev 14: 577, 1993

41. Wigley WC, Prihoda JS, Mowszowicz I et al: Natural mutagenesis study of the human steroid 5-alpha-reductase-2 isozyme. Biochemistry 33: 1265, 1994

42. Forti G, Falchetti A, Santoro S et al: Steroid 5-alpha-reductase-2 deficiency: Virilization in early infancy may be due to partial function of mutant enzyme. Clin Endocrinol (Oxf) 44: 477, 1996

43. Mendonca BB, Inacio M, Costa EM et al: Male pseudohermaphroditism due to steroid 5-alpha-reductase-2 deficiency. diagnosis, psychological evaluation, and management. Medicine (Baltimore) 75: 64, 1996

44. Canto P, Vilchis F, Chavez B et al: Mutations of the 5 alpha-reductase type 2 gene in eight Mexican patients from six different pedigrees with 5 alpha-reductase-2 deficiency. Clin Endocrinol (Oxf) 46: 155, 1997

45. Imperato-McGinley J, Peterson RE: Male pseudohermaphroditism:Complexities of male sexual development. Am J Med 61: 251, 1976

46. Peterson RE, Imperato-McGinley J, Gautier T et al: Male pseudohermaphroditism due to steroid 5α-reductase deficiency. Am J Med 62: 170, 1977

47. Imperato-McGinley J, Peterson RE, Gautier T et al: Male pseudohermaphroditism secondary to 5α-reductase deficiency: A model for the role of androgens in both the development of the male phenotype and the evolution of a male gender identity. J Steroid Biochem Mol Biol 11: 637, 1979

48. Imperato-McGinley J: Disorders of sexual differentiation. In Wyngaarden JB, Smith LH Jr, Bennett JC (eds): Cecil Textbook of Medicine, pp1320–1332. Philadelphia, WB Saunders, 1992

49. Imperato-McGinley J, Gautier T, Zirinsky K et al: Prostate visualization studies in males homozygous and heterozygous for 5α-reductase deficiency. J Clin Endocrinol Metab 75: 1022, 1992

50. Imperato-McGinley J: Male pseudohermaphroditism. In Adashi EY, Rock JA, Rosenwaks Z (eds): Reproductive Endocrinology, Surgery, and Technology, pp 936–955. Philadelphia, Lippincott-Raven, 1996

51. Imperato-McGinley J, Peterson RE, Leshin M et al: Steroid 5α-reductase deficiency in a 65-year old male pseudohermaphrodite: The natural history, ultrastructure of the testes and evidence for inherited enzyme heterogeneity. J Clin Endocrinol Metab 50: 15, 1980

52. Siiteri P, Wilson JD: Testosterone formation and metabolism during male sexual differentiation in the human embryo. J Clin Endocrinol Metab 38: 113, 1974

53. Imperato-McGinley J, Sanchez RS, Spencer JR et al: Comparison of the effects of the 5α-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: Dose-response studies. Endocrinology 131: 1149, 1992

54. Spencer JR, Torrado T, Sanchez RS et al: Effects of flutamide and finasteride on rat testicular descent. Endocrinology 129: 741, 1991

55. Imperato-McGinley J, Peterson RE, Gautier T et al: The impact of androgens on the evolution of male gender identity. In Kogan SJ, Hafez ESE(eds): Pediatric Andrology, pp 99–108. The Hague, Martinus Nijhoff, 1981

56. Imperato-McGinley J, Peterson RE: Why does a pseudohermaphrodite want to be a man? N Engl J Med 301: 840, 1979

57. Cai L-Q, Fratianni CM, Gautier T et al: Dihydrotestosterone regulation of semen in male pseudohermaphrodites with 5-alpha-reductase-2 deficiency. J Clin Endocrinol Metab 79: 409, 1994

58. Katz MD, Kligman I, Cai LQ et al: Paternity by intrauterine insemination with sperm from a man with 5-alpha-reductase-2 deficiency. N Engl J Med 336: 994, 1997

59. Ivarsson SA: 5-alpha reductase deficient men are fertile [letter]. Eur J Pediatr 155: 425, 1996

60. Katz MD, Cai L-Q, Zhu YS et al: The biochemical and phenotypic characterization of females homozygous for 5α-reductase-2 deficiency. J Clin Endocrinol Metab 80: 3160, 1995

61. Kaufman KD, Olsen EA, Whiting D et al: Finasteride in the treatment of men with androgenetic alopecia: Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol 39: 578, 1998

62. Roberts JL, Fiedler V, Imperato-McGinley J et al: Clinical dose ranging studies with finasteride, a type-2 5-alpha-reductase inhibitor, in men with male pattern hair loss. J Am Acad Dermatol 41: 555, 1999

63. Imperato-McGinley J, Gautier T, Yee B et al: The androgen control of sebum production: Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab 76: 524, 1993

64. Ertel NH, Akgun S, Samojlik E et al: Decreased 3α-androstanediol glucuronide levels in plasma and random urines in male pseudohermaphroditism caused by 5α-reductase deficiency. Metabolism 38: 817, 1989

65. Canovatchel WJ, Gautier T, Volquez D et al: LH pulsatility in subjects with 5α-reductase deficiency and decreased DHT production. J Clin Endocrinol Metab 78: 916, 1994

66. Fratianni CM, Canovatchel WJ, Gautier T et al: FSH pulsatile secretion by RIA and IFMA in subjects with 5 alpha-reductase deficiency [abstract 398]. 75th Annual Meeting of Endocrine Society, Las Vegas, 1993

67. Thigpen AE, Davis DL, Gautier T et al: The molecular basis of steroid 5-alpha-reductase deficiency in a large Dominican kindred. N Engl J Med 327: 1216, 1992

68. Cai L-Q, Zhu YS, Katz MD et al: 5α-reductase-2 gene mutation in the Dominican Republic. J Clin Endocrinol Metab 81: 1730, 1996

69. Imperato-McGinley J, Peterson RE, Gautier T et al: Decreased urinary C19 and C21 steroid 5α-metabolites in parents of male pseudohermaphrodites with 5α-reductase deficiency: Detection of carriers. J Clin Endocrinol Metab 60: 553, 1985

70. Imperato-McGinley J, Peterson RE: Gender identity and hermaphroditism. Science 191: 872, 1976

71. Imperato-McGinley J, Peterson RE, Gautier T et al: Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5α-reductase deficiency. N Engl J Med 300: 1233, 1979

72. Gajdusek DC: Urgent opportunistic observations: The study of changing, transient and disappearing phenomena of medical interest in disrupted primitive human communities. In Health and Diseases in Tribal Societies, CIBA Symposium, pp 69–102. Amsterdam, North-Holland, Elsevier Excerpta Medica, 1977

73. Farquhar J, Gajdusek DC: Kuru: Early letters and field notes from the collection of D. Carleton Gajdusek. New York, Raven Press, 1981

74. Gajdusek DC: Journals 1957-1976: Eighteen volumes (with specific field data on Simbari male pseudohermaphrodites). Bethesda, MD, National Institutes of Health, 1989

75. Mulaisho C, Taha SA, Imperato-McGinley J: Male pseudohermaphroditism due to deficiency of steroid 5α-reductase enzyme. Saudi Med J 11: 71, 1990

76. Mendez JP, Ulloa-Aguirre A, Imperato-McGinley J et al: Male pseudohermaphroditism due to primary 5α-reductase deficiency: Variation in gender identity reversal in seven Mexican patients from five different pedigrees. J Endocrinol Invest 18: 205, 1995

77. Hochberg Z, Chayen R, Reiss N et al: Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5-alpha-reductase-2 deficiency. J Clin Endocrinol Metab 81: 2821, 1996

78. Imperato-McGinley J, Zhu YS: Gender and behavior in subjects with genetic defects in male sexual differentiation. In Pfaff DW(ed): Hormones, Brain, Behavior. San Diego, CA: Academic Press (in press)

79. Money J, Hampson JG, Hampson JL: Hermaphroditism: Recommendations concerning assignment of sex, change of sex and psychological management. Bull Johns Hopkins Hosp 97: 284, 1955

80. Money J, Hampson JG, Hampson JL: An examination of some basic sexual concepts: The evidence of human hermaphroditism. Bull Johns Hopkins Hosp 97: 301, 1955

81. Money J, Ogunro C: Behavioral sexology: Ten cases of genetic male intersexuality with impaired prenatal and pubertal androgenization. Arch Sex Behav 3: 181, 1974

81. Imperato-McGinley J, Gautier T, Pichardo M, Shackleton C: The diagnosis of 5α-reductase deficiency in infancy. J Clin Endocrinol Metab 63: 1313, 1986

82. Imperato-McGinley J: 5-alpha-reductase-2 deficiency. Curr Ther Endocrinol Metab 6: 384, 1997

83. Cantu JM: Product replacement therapy in steroid 5α-reductase deficiency. Ann Genet 21: 120, 1978

84. Imperato-McGinley J, Peterson RE, Gautier T et al: Hormonal evaluation of a large kindred with complete androgen insensitivity: Evidence for secondary 5α-reductase deficiency. J Clin Endocrinol Metab 54: 931, 1982

85. Jukier L, Kaufman M, Pinsky L et al: Partial androgen resistance associated with secondary 5 alpha-reductase deficiency: Identification of a novel qualitative androgen receptor defect and clinical implications. J Clin Endocrinol Metab 59: 679, 1984

86. Zhu YS, Cai LQ, Cordero JJ et al: A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred. J Clin Endocrinol Metab 84: 1590, 1999

87. George FW, Russell DW, Wilson JD: Feed-forward control of prostate growth: Dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase. Proc Natl Acad Sci U S A 88: 8044, 1991

88. Normington K, Russell DW: Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes: Evidence for distinct physiological functions. J Biol Chem 267: 19548, 1992

89. Andersson S, Bishop RW, Russell DW: Expression cloning and regulation of steroid 5 alpha-reductase, an enzyme essential for male sexual differentiation. J Biol Chem 264: 16249, 1989

90. Horton R, Pasupuletti V, Antonipillai I: Androgen induction of steroid 5 alpha-reductase may be mediated via insulin-like growth factor-I. Endocrinology 133: 447, 1993

91. Kappas A, Bradlow HL, Gillette PN et al: Studies in porphyria. I. A defect in the reductive transformation of natural steroid hormones in the hereditary liver disease, acute intermittent porphyria. J Exp Med 136: 1043, 1972

92. Bradlow HL, Boyar RM, O'Connor J et al: Hypothyroid-like alterations in testosterone metabolism in anorexia nervosa. J Clin Endocrinol Metab 43: 571, 1976

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