Androgens and male physiology—The syndrome of 5 alpha

Molecular and Cellular Endocrinology 198 (2002) 51 /59
www.elsevier.com/locate/mce
Androgens and male physiology the syndrome of 5a-reductase-2
deficiency
J. Imperato-McGinley *, Y.-S. Zhu
Division of Endocrinology, Diabetes and Metabolisms, Department of Medicine, Weill Medical College, Cornell University, 1300 York Avenue, Box 149,
Room F-260, New York, NY 10021, USA
Abstract
Dihydrotestosterone (DHT), a potent androgen, is converted from testosterone by 5a-reductase isozymes. There are two 5areductase isozymes, type 1 and type 2 in humans and animals. These two isozymes have differential biochemical and molecular
features. Mutations in type 2 isozyme cause male pseudohermaphroditism, and many mutations have been reported from various
ethnic groups. The affected 46XY individuals have high normal to elevated plasma testosterone levels with decreased DHT levels
and elevated testosterone/DHT ratios. They have ambiguous external genitalia at birth so that they are believed to be girls and are
often raised as such. However, Wolffian differentiation occurs normally and they have epididymides, vas deferens and seminal
vescles. Virilization occurs at puberty frequently with a gender role change. The prostate in adulthood is small and rudimentary, and
facial and body hair is absent or decreased. Balding has not been reported. Spermatogenesis is normal if the testes are descended.
The clinical, biochemical and molecular genetic analyses of 5a-reductase-2 deficiency highlight the significance of DHT in male
sexual differentiation and male pathophysiology.
# 2002 Published by Elsevier Science Ireland Ltd.
Keywords: 5a-Reductase; Androgen; Sexual development; Gender identity
1. Introduction
Male sexual development in the mammalian system
involves three sequential processes. The first step is
establishment of genetic sex by the presence of 46XY sex
chromosomes, a process completed at the time of
fertilization of the ovum. The second step is differentiation of the indifferent gonad to a testis. The process of
testicular differentiation involves the SRY gene located
on the Y chromosome as well as multiple genes located
on autosomal chromosomes. The third step is translation of the gonadal sex to phenotypic sex, i.e. the
formation of internal and external genitalia. Both
* Corresponding author. Tel.: /1-212-746-4745; fax: /1-212-7468922.
E-mail address: [email protected] (J. ImperatoMcGinley).
testosterone and its 5a reduced metabolite, DHT, play
critical roles in this process.
The importance of both androgens in male sexual
differentiation and development, and in determining
male gender identity will be discussed by reviewing the
clinical syndrome of 5a-reductase-2 deficiency.
2. 5a-Reductase isozymes
Steroid 5a-reductase isozymes are located in the
microsomes of the cell. These isozymes convert testosterone to DHT, a more potent androgen. They are
NADPH-dependent enzymes that reduce the double
bond at the four to five position in C19 steroids as well as
C21 steroids. Both testosterone and DHT bind to the
same intracellular androgen receptor, which is a member
of the nuclear steroid/thyroid hormone receptor superfamily, to regulate target gene expression (Beato, 1989).
0303-7207/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd.
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J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
Although testosterone and DHT produce distinct biological responses (Wilson, 1978), they interact with the
same androgen receptor. The molecular mechanism is
unclear. However, differences in receptor binding (Wilbert et al., 1983) and DNA interaction (Kovacs et al.,
1984) between testosterone and DHT have been reported.
It was theorized that multiple 5a-reductase isozymes
existed by (McGuire and Tomkins, 1960). Two different
pH optima for 5?-reductase activity in genital and
nongenital skin were detected in the 70’s (Moore and
Wilson, 1975, 1976). The major peak of 5a-reductase
activity with a narrow, acidic pH optimum of 5.5, was
found to be low in the genital skin of male pseudohermaphrodites with 5a-reductase deficiency. Another
broader peak of activity had a neutral to alkaline pH
(pH 7 /9), which was present in both genital and
nongenital skin. This activity was found to be normal
in the genital skin of male pseudohermaphrodites with
5a-reductase deficiency. Kinetic analysis of 5a-reductase
activity in the epithelium and stroma of the prostate also
suggested different 5a-reductase activities (Bruchovsky
et al., 1988; Hudson, 1987). Studies of specific 5areductase inhibitors further indicated that multiple 5areductase isozymes were present in human prostate
tissues (Jenkins et al., 1992).
Two genes encoding two 5a-reductase isozymes were
eventually identified: steroid 5a-reductase type 1 (gene
symbol: SRD5A1 ) and steroid 5a-reductase type 2 (gene
symbol: SRD5A2 ), were identified, using expression
cloning, in the early 90’s (Andersson et al., 1991;
Andersson and Russell, 1990; Labrie et al., 1992).
Male pseudohermaphroditism due to 5a-reductase deficiency was found to be due to mutations in the 5areductase-2 gene (Andersson et al., 1991) (see Table 1).
The human 5a-reductase-2 gene, located in the short
arm of chromosome 2 band 23 has five exons and four
introns. It encodes a 254 amino acid protein which is
highly hydrophobic with a molecular weight of approximately 28.4 kDa (Andersson et al., 1991; Russell and
Wilson, 1994), and has a much higher affinity for
testosterone (apparent Km /4/50 nM) than type 1
isozyme (Km /1 /5 mM). The apparent Km (3 /10 mM)
for the cofactor NADPH is similar for both isozymes.
The type-2 isozyme is sensitive to finasteride, a 5areductase-2 inhibitor, and is expressed in external genital
tissues early in gestation (Thigpen et al., 1993a). In
adulthood, its expression in prostate, genital skin,
epididymis, seminal vesicle and liver is relatively high,
while it is quite low in other tissues. This isozyme also
appears to be expressed in the ovary and hair follicles
(Eicheler et al., 1994, 1995).
The type 2 isozyme has an acidic pH optimum in the
enzymatic assays described (Andersson et al., 1991;
Moore and Wilson, 1975; Russell and Wilson, 1994).
However, studies with transfected Chinese hamster
ovary cells suggest that the type 2 isozyme may actually
have a neutral pH optimum in its native state, and that
the acidic optimum described may actually be an artifact
of cell lysis (Thigpen et al., 1993b). Additionally,
analyses using cell lysates, permeabilized cells and intact
cells suggest that the affinity of the type 2 isozyme for
steroid substrates is higher at a neutral pH than an
acidic pH (pH 5.0), suggesting that this isozyme acts at
neutral pH in the cell (Faller et al., 1993; Thigpen et al.,
1993b).
The functional domains of the type 2 isozyme have
been deduced from in vitro mutagenesis-transfection
analysis of natural mutations of the 5a-reductase-2
isozyme in cultured mammalian cells (Can et al., 1998;
Russell and Wilson, 1994; Wigley et al., 1994), and
mutagenesis analysis of the 5a-reductase-1 isozyme
(Thigpen and Russell, 1992). Mutations affecting
NADPH binding map to the last half of the type 2
isozyme, suggesting that the carboxyl-terminal of the
isozyme appears to be a cofactor-binding domain even
though consensus adenine dinucleotide-binding sequences are not identified. In contrast, the type 2
isozyme mutations that affect substrate (testosterone)
binding that appear to be located at both ends of the
protein. However, due to the fact that mutations affect
either substrate or cofactor binding, but not both
(Thigpen and Russell, 1992), the amino acid determinants of the substrate binding domain in the type 2
isozyme appear to be mainly located at the amino
terminal of the protein.
The 5a-reductase-1 gene is normal in male pseudohermaphrodites with 5a-reductase deficiency (Andersson et al., 1991) and maps to the short arm of
chromosome 5 band 15. It is composed of 5 exons and
4 introns and encodes a 259 highly hydrophobic amino
acid protein with a molecular weight approximately 29.5
kDa (Russell and Wilson, 1994). It has an approximately 50% homology to the type-2 isozyme in amino
acid composition, with a broad alkaline pH optimum, a
lower substrate affinity and a lower sensitivity to
finasteride inhibition (Russell and Wilson, 1994; Zhu
et al., 1998). At birth 5a-reductase-1 is detected in the
liver and nongenital skin, and is present throughout life.
Its expression in embryonic tissues, however, is quite
low. In adulthood, it is expressed in nongenital skin,
liver and certain brain regions; whereas, its presence in
the prostate, genital skin, epididymis, seminal vesicle,
testis, adrenal and kidney is low. The physiological
function of 5a-reductase-1 is still obscure, although it
may play a role in parturition (Mahendroo et al., 1996).
In the human prostate, both 5a-reductase isozymes
are present in epithelial cells and stromal cells, while 5areductase-2 is the predominant isozyme expressed in the
stromal cells (Russell and Wilson, 1994; Silver et al.,
1994; Thigpen et al., 1993a). Both isozymes are expressed in BPH and prostate cancer tissues, as well as in
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
prostate tumor cells including LNCaP cells (Delos et al.,
1998; Guillemette et al., 1996; Negri-Cesi et al., 1998;
Smith et al., 1994).
3. Clinical presentation
The clinical syndrome of 5a-reductase deficiency was
first described, clinically and biochemically, in studies of
24 affected subjects from a large Dominican kindred
(Imperato-McGinley et al., 1974), and in two siblings
from Dallas (Walsh et al., 1974). Subsequently a large
cohort in New Guinea (Imperato-McGinley et al., 1991)
and another in Turkey were described (Akgun et al.,
1986; Can et al., 1998; Imperato-McGinley et al., 1987)
as well as many other cases worldwide [see recent review
(Zhu and Imperato-McGinley, 2002)].
We have worked with affected subjects from the
Dominican kindred for 2/3 decades; this has enabled
us to obtain important information relevant to discerning the biology of testosterone and DHT in humans
(Fig. 1, Table 2).
Most affected subjects with 5a-reductase-2 deficiency
have striking ambiguity of the genitalia with a clitorallike phallus, severely bifid scrotum, pseudovaginal
perineoscrotal hypospadias and a rudimentary prostate
(Imperato-McGinley et al., 1974, 1979a; ImperatoMcGinley, 1992; Imperato-McGinley et al., 1992a;
Imperato-McGinley, 1996; Imperato-McGinley and Peterson, 1976; Peterson et al., 1977). More masculinized
subjects have been described; they either lack a separate
vaginal opening (Imperato-McGinley et al., 1980), or
have a blind vaginal pouch which opens into the urethra
(Imperato-McGinley et al., 1979a), penile hypospadias
53
(Carpenter et al., 1990) or even a penile urethra (Ng et
al., 1990).
Wolffian duct differentiation in affected subjects is
normal with seminal vesicles, vasa deferentia, epididymides and ejaculatory ducts; no Mullerian structures are
present. Cryptorchidism is frequently described though
it is not invariably present with testes occasionally
located in the abdomen but usually found in the inguinal
canal or scrotum.
Male pseudohermaphrodites with 5a-reductase-2 deficiency are clinical models for defining the actions of
testosterone and DHT during male sexual differentiation and development (Fig. 1). Testosterone acts on the
Wolffian ducts to cause differentiation to the vas
deferens, epididymis, and seminal vesicles. In contrast,
testosterone functions as a prehormone in the urogenital
sinus and urogenital tubercle, where it is converted to
DHT resulting in differentiation of the external genitalia
and prostate. Studies of the human fetus are supportive
of the human clinical model and demonstrate that at the
time of sexual differentiation 5a-reductase activity is
present in the urogenital sinus, urogenital tubercle and
urogenital swellings, but not in the Wolffian anlage until
sexual differentiation is completed (Siiteri and Wilson,
1974). Further supportive evidence is provided by
animal studies in the rat by using a 5a-reductase-2
inhibitor (Imperato-McGinley et al., 1992b; Spencer et
al., 1991). However, it is puzzling that the knockout of
5a-reductase-2 or 5a-reductase-2 plus 5a-reductase-1 in
mice had normal genitalia in male offsprings (Mahendroo et al., 2001).
In humans, with the onset of puberty, the affected
males have increased muscle mass and deepening of the
voice (Imperato-McGinley et al., 1974). The musculature is particularly prominent in Dominican, New
Fig. 1. A diagram illustrating the roles of testosterone and DHT in male sexual differentiation in utero.
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
54
Table 1
Comparison of human 5a-reductase isozymes
Type 1
Type 2
Gene structure
5 exons, 4 introns
Gene, chromosome location SRD5A1 , 5p15
Size
259 amino acids, Mr/29 462
Tissue distribution
Liver, nongenital skin, prostate, brain,
ovary, testis
Prostate level
Low
Activity in 5a-reductase de- Normal
ficiency
5 exons, 4 introns
SRD5A2 , 2p23
254 amino acids, Mr/28 398
Prostate, epididymis, seminal vesicle, genital skin, liver, uterus, breast, hair
follicle, placenta, testis
High
Mutated
Table 2
Androgen action at puberty
Testosterone
I
Anabolic actions
Muscle mass increased
Enlargement penis
Enlargement scrotum
Enlargement vocal cords
Skeletal maturation
Growth spurt
Epiphyseal closure
II Spermatogenesis
III Male sex drive, performance
IV Pituitary-gonadal feedback
DHT
Increased facial, body hair
Scalp hair recession
Prostate enlargement
Pituitary-gonadal feedback
Guinean and Turkish subjects (Akgun et al., 1986; Can
et al., 1998; Imperato-McGinley et al., 1974, 1987,
1991). Affected males in these kindreds are as tall as
their unaffected siblings (Imperato-McGinley et al.,
1979a, 1981; Peterson et al., 1977). The genitalia
enlarges with growth of the phallus as well as rugation
and hyperpigmentation of the scrotum. The inguinal
testes have been observed in some subjects to descend
into the scrotum at puberty (Imperato-McGinley et al.,
1979a, 1980, 1981). Libido is intact and affected men are
capable of erections (Fig. 2; Imperato-McGinley et al.,
1974; Imperato-McGinley and Peterson, 1979).
Although most subjects studied are generally oligo- or
azoospermic due to undescended testes; normal sperm
concentrations have been reported in subjects with
descended testes (Cai et al., 1994; Cantu et al., 1976;
Katz et al., 1997; Peterson et al., 1977). Men from the
Dominican kindred (Katz et al., 1997) and from Sweden
(Nordenskjold and Ivarsson, 1998) have been reported
to father children. These findings suggest that pubertal
events, including male sexual function and spermatogenesis, appear to be primarily testosterone mediated
(Table 2). The other possibility is that the amount of
DHT still present is enough for spermatogenesis.
On rectal examination (Imperato-McGinley et al.,
1974) the prostate in the affected male adults is
nonpalpable (Peterson et al., 1977) and is found to be
Fig. 2. A representative recording of nocturnal penile tumescence and
rigidity from penile base and tip in a 21-year-old subject with 5areductase-2 deficiency. It shows the presence of sleep-related erections.
rudimentary on transrectal ultrasound and MRI visualization (Imperato-McGinley et al., 1992a). Prostatic
volumes are much smaller than those of age-matched
normal controls and are the size of prepubertal boys.
Administration of DHT can result in enlargement of the
prostate (see Fig. 3) (Imperato-McGinley et al., 1992a;
Mendonca et al., 1996). These findings provide clinical
evidence that prostate differentiation and growth is
mediated largely by DHT (see Figs. 1 and 3, Table 2).
Prostate diseases such as prostate cancer and benign
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
55
Fig. 3. Representative sonograms showing the enlargement of prostate in a 5a-reductase-2 deficient patient pre DHT treatment (A) and post 2%
DHT cream (B) applied to the genital area for approximately 3 months. Note the crosses at the outer edges of the prostate.
prostate hyperplasia have not been reported in affected
males.
The facial and body hair is decreased, and male
pattern baldness has never been observed in genetic
males with this condition (Akgun et al., 1986; ImperatoMcGinley et al., 1974, 1991).
Sebum production is dependent on androgen action.
No demonstrable sebum is produced in 46XY subjects
with complete androgen insensitivity due to androgen
receptor mutation confirming its dependency (ImperatoMcGinley et al., 1993). However, the affected subjects
with 5a-reductase-2 deficiency have normal sebum
production, suggesting that sebum production is not
regulated by 5a-reductase-2 isozyme (Imperato-McGinley et al., 1993).
Homozygous females with a 5a-reductase-2 gene
mutation and decreased plasma DHT appear to have
decreased body hair and delayed menarche but normal
to enhanced fertility (Katz et al., 1995; Milewich et al.,
1995). Since 5a-reductase-2 is expressed in the ovary
(Eicheler et al., 1994), and our unpublished data] a
defect in this isozyme may decrease DHT production in
the ovary, resulting in an elevated estrogen to DHT
ratio, thereby, facilitating ovulation and infertility (Katz
et al., 1995).
4. Biochemical features of 5a-reductase-2 deficiency
Over the years, the biochemical features of this
syndrome have been well defined (see recent reviews
Imperato-McGinley, 1996; Zhu et al., 1998). These
include: (a) normal to elevated levels of plasma testosterone; (b) decreased levels of plasma DHT; (c) an
increased testosterone to DHT ratio at baseline and/or
following hCG stimulation; (d) decreased conversion of
testosterone to dihydrotestosterone (DHT) in vivo; (e)
normal metabolic clearance rates of testosterone and
DHT; (f) decreased production of urinary 5a-reduced
androgen metabolites with increased 5b/5a urinary
metabolite ratios; (g) decreased plasma and urinary
3a-androstanediol glucuronide, a major metabolite of
DHT; (h) a global defect in steroid 5a-reduction as
demonstrated by decreased urinary 5a-reduced metabolites of both C21 steroids and C19 steroids other than
testosterone, i.e. cortisol, corticosterone, 11b-hydroxyandrostenedione and androstenedione; (i) increased
plasma levels of LH and an increased LH pulse
amplitude with a normal LH frequency (Canovatchel
et al., 1994); (j) plasma FSH levels may be elevated.
5. Defects in the 5a-reductase-2 gene
The first identified genetic defect of 5a-reductase
deficiency was carried out in male pseudohermaphrodites from our New Guinean kindred (Andersson et al.,
1991). To date, over 33 mutations in the 5a-reductase-2
gene (Wilson et al., 1993; Nordenskjold et al., 1998;
Vilchis et al., 2000; Zhu et al., 1998 and our unpublished
data) have been identified, including mutations in the
three largest kindreds of male pseudohermaphrodites
with 5a-reductase-2 deficiency in the world */the Dominican, New Guinean and Turkish kindreds. A deletion of more than 20 kb in the 5a-reductase-2 gene was
found in the subjects from New Guinean kindred by
Southern blot analysis (Andersson et al., 1991). In the
Dominican kindred, a missense mutation was found in
exon 5 of the 5a-reductase-2 gene, substituting thymidine for cytosine and resulting in a substitution of the
non-polar amino acid tryptophan for the basic, polar
amino acid arginine at position 246 (R246W) of the
isozyme (Cai et al., 1996; Thigpen et al., 1992a). The
mutated isozyme has a decreased binding to the
cofactor, NADPH, an altered pH optimum and a
dramatic loss of enzymatic activity (Thigpen et al.,
56
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
1992a). Molecular genetic studies of the Turkish kindred
revealed a single base deletion in exon 5 of the 5areductase-2 gene resulting in a frame-shift at amino acid
position 251 with an addition of 23 amino acids at the
carboxyl-terminal of this 254 amino acid isozyme (Can
et al., 1998). The mutant isozyme had a complete loss of
enzymatic activity without an alteration in gene expression (Can et al., 1998).
Mutations in the 5a-reductase-2 gene have been
described in all five exons of the gene, and range from
a single point defect to a deletion of the entire gene
(Wilson et al., 1993; Zhu et al., 1998). These mutations
result in various enzymatic dysfunction and include a
complete loss of enzymatic activity; an impaired binding
of substrate and cofactor to the isozyme; a blocked
formation of a functional isozyme (deletion, nonsense
mutation, splice-junction alterations); and an unstable
isozyme (Can et al., 1998; Russell and Wilson, 1994;
Wigley et al., 1994). Correlation between the severity of
the syndrome and a particular gene defect has not been
observed.
5a-Reductase-2 deficiency is an inherited autosomal
recessive disease as evidenced by: pedigree analysis
(Imperato-McGinley et al., 1974, 1987); biochemical
analysis (Imperato-McGinley et al., 1974, 1985); and
molecular genetic analysis (Cai et al., 1996; Can et al.,
1998; Thigpen et al., 1992a). Heterozygotes males with a
defect in the 5a-reductase-2 gene have a normal male
phenotype. It should be noted that approximately 35
percent of subjects with 5a-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 due to the rarity of the disease phenotype
(Thigpen et al., 1992b).
6. Gender identity change
Gender identity change from female to male has been
demonstrated in subjects with 5a-reductase-2 deficiency
from different areas of the world (see recent review
Imperato-McGinley and Zhu, 2002). These subjects
demonstrate that exposure of the brain to androgen
(testosterone) in utero, during the early postnatal
period, and at puberty, appears to have a greater impact
in determining male gender identity than does sex of
rearing and sociocultural influences. Normally the sex of
rearing and androgen exposure of the brain act in
concert to determine the male gender. Subjects with
5a-reductase-2 deficiency demonstrate that in a laissezfaire environment, when the rearing (female) is discordant with the biological sex; the biologic sex will prevail
if normal activation of male puberty is permitted to
occur (Imperato-McGinley et al., 1979b; Zhu et al.,
1998). Studies of gender in subjects with 5a-reductase-2
deficiency underscore the importance of androgens,
which act as inducers and activators in evolution of
male gender identity in man.
It has been proposed that gender identity becomes
fixed by 18 months to 4 years of age, at the approximate
time of language development (Money et al., 1955b,a;
Money and Ogunro, 1974). During this time a child
becomes aware of his or her gender. Awareness of one’s
gender and being unalterably fixed in that gender appear
to be two separate issues. Subjects with 5a-reductase-2
deficiency who have undergone a gender change suggest
that gender identity in man is not fixed in childhood but
is continually evolving, becoming fixed with or following pubertal events.
In humans, androgens, and not just environmental or
sociocultural factors, make a strong and definite contribution to the formation of a male gender identity
(Imperato-McGinley et al., 1979b; Imperato-McGinley
and Zhu, 2002).
Our studies and those of others have demonstrated
that adult subjects who undergo a change in gender and
those raised from birth as males are psychosexual males.
They can function sexually as men and if the cryptorchidism is corrected soon after birth, fertility appears to be
possible (Imperato-McGinley and Zhu, 2002).
Genital correction of this condition in childhood is
difficult because of the severity of the genital ambiguity
and the small size of the phallus which is generally the
size of a clitoris. Topical application of DHT cream
results in phallic growth, facilitating surgical correction
of penoscrotal hypospadias (Carpenter et al., 1990;
Mendonca et al., 1996; Cantu, 1978; Imperato-McGinley, 1997). 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. Administration of
DHT after the critical period of sexual differentiation in
utero will stimulate phallic growth but will not correct
the genital defect, as sexual differentiation can occur
only during a critical period in utero.
The management of subjects who are raised as
females and diagnosed as having 5a-reductase-2 deficiency in the peripubertal period and postpubertal
period should be evaluated carefully. Long term evaluation is essential before gender decisions are made. Some
subjects with this condition who identify as male will
only reveal this fact after they determine how to deal
with the social pressures of family, friends, etc. (unpublished). Some subjects may admit their maleness but for
social reasons not change to a male gender role
(Imperato-McGinley, 1980). The occurrence of gender
role change in an individual with 5a-reductase-2 deficiency is obviously dependent upon a host of social and
cultural factors which might either consciously or
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
subconsciously suppress or foster the change. All these
factors must be considered by the subject’s physician, as
well as the psychiatrist working in concert with the
subject and the family (Imperato-McGinley, 1997).
Acknowledgements
The studies were supported in part by NIH Grant
M01-RR-00047 (General Clinical Research Center) and
HD-09421-15.
References
Akgun, S., Ertel, N., Imperato-McGinley, J., Sayli, B., Shackleton,
C.H.L., 1986. Familial male pseudohermaphroditism in a Turkish
village due to 5a-reductase deficiency. Am. J. Med. 81, 267 /274.
Andersson, S., Russell, D.W., 1990. Structural and biochemical
properties of cloned and expressed human and rat steroid 5areductases. Proc. Natl. Acad. Sci. USA 87, 3640 /3644.
Andersson, S., Berman, D.M., Jenkins, E.P., Russell, D.W., 1991.
Deletion of steroid 5a-reductase-2 gene in male pseudohermaphroditism. Nature 354, 159 /161.
Beato, M., 1989. Gene regulation by steroid hormones. Cell 56, 335 /
344.
Bruchovsky, N., Rennie, P.S., Batzold, F.H., Goldenberg, S.L.,
Fletcher, T., McLoughlin, M.G., 1988. Kinetic parameters of 5areductase activity in stroma and epithelium of normal, hyperplastic, and carcinomatous human prostates. J. Clin. Endocrinol.
Metab. 67, 806 /816.
Cai, L.-Q., Fratianni, C.M., Gautier, T., Imperato-McGinley, J., 1994.
Dihydrotestosterone regulation of semen in male pseudohermaphrodites with 5 alpha-reductase-2 deficiency. J. Clin. Endocrinol.
Metab. 79 (2), 409 /414.
Cai, L.-Q., Zhu, Y.S., Katz, M.D., Herrera, C., Baez, J., DeFilloRicart, M., Shackleton, C.H.L., Imperato-McGinley, J., 1996. 5aReductase-2 gene mutation in the Dominican Republic. J. Clin.
Endocrinol. Metab. 81, 1730 /1735.
Can, S., Zhu, Y.S., Cai, L.Q., Ling, Q., Katz, M.D., Akgun, S.,
Shackleton, C.H.L., Imperato-McGinley, J., 1998. The identification of 5a-reductase-2 and 17b -hydroxysteroid dehydrogenase-3
gene defects in male pseudohermaphrodites from a Turkish
kindred. J. Clin. Endocrinol. Metab. 83, 560 /569.
Canovatchel, W.J., Gautier, T., Volquez, D., et al., 1994. LH
pulsatility in subjects with 5a-reductase deficiency and decreased
DHT production. J. Clin. Endocrinol. Metab. 78 (4), 916 /921.
Cantu, J.M., 1978. Product replacement therapy in steroid 5areductase deficiency. Ann. Genet. 21, 120 /121.
Cantu, J.M., Hernandez-Montes, H., del Castillo, V., Cortés-Gallegos,
V., Sandoval, R., Armendares, S., Parra, A., 1976. Potential
fertility in incomplete male pseudohermaphroditism type 2. Rev.
Invest. Clin. 28, 177 /182.
Carpenter, T.O., Imperato-McGinley, J., Boulware, S.D., Weiss,
R.M., Shackleton, C.H.L., Wilson, J.D., 1990. Variable expression
of 5 alpha-reductase deficiency: presentation with male phenotype
in a child of Greek origin. J. Clin. Endocrinol. Metab. 71 (2), 318 /
322.
Delos, S., Carsol, J.L., Fina, F., Raynaud, J.P., Martin, P.M., 1998.
5alpha-reductase and 17beta-hydroxysteroid dehydrogenase expression in epithelial cells from hyperplastic and malignant human
prostate. Int. J. Cancer 75, 840 /846.
Eicheler, W., Tuohimaa, P., Vilja, P., Adermann, K., Forssmann,
W.G., Aumuller, G., 1994. Immunocytochemical localization of
57
human 5 alpha-reductase 2 with polyclonal antibodies in androgen
target and non-target human tissues. J. Histochem. Cytochem. 42,
667 /675.
Eicheler, W., Dreher, M., Hoffmann, R., Happle, R., Aumuller, G.,
1995. Immunohistochemical evidence for differential distribution
of 5 alpha-reductase isoenzymes in human skin. Br. J. Dermatol.
133, 371 /376.
Faller, B., Farley, D., Nick, H., 1993. Finasteride: a slow-binding 5
alpha-reductase inhibitor. Biochemistry 32, 5705 /5710.
Guillemette, C., Hum, D.W., Belanger, A., 1996. Evidence for a role of
glucuronosyltransferase in the regulation of androgen action in the
human prostatic cancer cell line LNCaP. J. Steroid Biochem. Mol.
Biol. 57, 225 /231.
Hudson, R.W., 1987. Comparison of nuclear 5 alpha-reductase
activities in the stromal and epithelial fractions of human prostatic
tissue. J. Steroid Biochem. 26, 349 /353.
Imperato-McGinley, J., 1992. Disorders of sexual differentiation. In:
Wyngaarden, J.B., Smith, L.H., Jr, Bennett, J.C. (Eds.), Cecil
Textbook of Medicine. W.B. Saunders, Philadelphia, pp. 1320 /
1332.
Imperato-McGinley, J., 1996. Male pseudohermaphroditism. In:
Adashi, E.Y., Rock, J.A., Rosenwaks, Z. (Eds.), Reproductive
Endocrinology, Surgery, and Technology. Lippincott-Raven Publishers, Philadephia, pp. 936 /955.
Imperato-McGinley, J., 1997. 5 alpha-reductase-2 deficiency. Curr.
Ther. Endocrinol. Metab. 6, 384 /387.
Imperato-McGinley, J., Peterson, R.E., 1976. Male pseudohermaphroditism: complexities of male sexual development. Am. J. Med.
61, 251 /272.
Imperato-McGinley, J., Peterson, R.E., 1979. Why does a pseudohermaphrodite want to be a man. New Engl. J. Med. 301, 840 /840.
Imperato-McGinley, J., Zhu, Y.S., 2002. Gender and behavior in
subjects with genetic defects in male sexual differentiation. In: Pfaff
et al. (eds.), Hormones, Brain, Behavior, 5 (92), 303 /345.
Imperato-McGinley, J., Guerrero, L., Gautier, T., Peterson, R.E.,
1974. Steroid 5a-reductase deficiency in man: an inherited form of
male pseudohermaphroditism. Science 186, 1213 /1216.
Imperato-McGinley, J., Peterson, R.E., Gautier, T., Sturla, E., 1979a.
Male pseudohermaphroditism secondary to 5a-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 /645.
Imperato-McGinley, J., Peterson, R.E., Gautier, T., Sturla, E., 1979b.
Androgens and the evolution of male-gender identity among male
pseudohermaphrodites with 5a-reductase deficiency. New Engl. J.
Med. 300, 1233 /1237.
Imperato-McGinley, J., Peterson, R.E., Leshin, M., Griffin, J.E.,
Cooper, G., Draghi, S., Berenyi, M., Wilson, J.D., 1980. Steroid
5a-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 /22.
Imperato-McGinley, J., Peterson, R.E., Gautier, T., Sturla, E., 1981.
The impact of androgens on the evolution of male gender identity.
In: Kogan, S.J., Hafez, E.S.E. (Eds.), Pediatric Andrology.
Martinus Nijhoff, The Hague, pp. 99 /108.
Imperato-McGinley, J., Peterson, R.E., Gautier, T., Shackleton,
C.H.L., Arthur, A., 1985. Decreased urinary C19 and C21 steroid
5a-metabolites in parents of male pseudohermaphrodites with 5areductase deficiency: detection of carriers. J. Clin. Endocrinol.
Metab. 60, 553 /558.
Imperato-McGinley, J., Akgun, S., Ertel, N.H., Sayli, B., Shackleton,
C.H.L., 1987. The coexistence of male pseudohermaphrodites with
17-ketosteroid reductase deficiency and 5a-reductase deficiency
within a Turkish kindred. Clin. Endocrinol. (Oxf.) 27, 135 /143.
Imperato-McGinley, J., Miller, M., Wilson, J.D., Peterson, R.E.,
Shackleton, C.H.L., Gajdusek, D.C., 1991. A cluster of male
58
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
pseudohermaphrodites with 5 alpha-reductase deficiency in Papua
New Guinea. Clin. Endocrinol. (Oxf.) 34, 293 /298.
Imperato-McGinley, J., Gautier, T., Zirinsky, K., Hom, T., Palomo,
O., Stein, E., Vaughan, E.D., Markisz, J., Ramirez de Arellano, E.,
Kazam, E., 1992a. Prostate visualization studies in males homozygous and heterozygous for 5a-reductase deficiency. J. Clin.
Endocrinol. Metab. 75, 1022 /1026.
Imperato-McGinley, J., Sanchez, R.S., Spencer, J.R., Yee, B.,
Vaughan, E.D., 1992b. Comparison of the effects of the 5areductase inhibitor finasteride and the antiandrogen flutamide on
prostate and genital differentiation: dose-response studies. Endocrinology 131, 1149 /1156.
Imperato-McGinley, J., Gautier, T., Yee, B., Cai, L.-Q., Epstein, J.,
Pochi, P., 1993. The androgen control of sebum production: studies
of subjects with dihydrotestosterone deficiency and complete
androgen insensitivity. J. Clin. Endocrinol. Metab. 76, 524 /533.
Jenkins, E.P., Andersson, S., Imperato-McGinley, J., Wilson, J.D.,
Russell, D.W., 1992. Genetic and pharmacological evidence for
more than one human steroid 5A-reductase. J. Clin. Invest. 89,
293 /300.
Katz, M.D., Cai, L.-Q., Zhu, Y.S., Herrera, C., DeFillo-Ricart, M.,
Shackleton, C.H.L., Imperato-McGinley, J., 1995. The biochemical
and phenotypic characterization of females homozygous for 5areductase-2 deficiency. J. Clin. Endocrinol. Metab. 80, 3160 /3167.
Katz, M.D., Kligman, I., Cai, L.Q., Zhu, Y.S., Fratianni, C.M.,
Zervoudakis, I., Rosenwaks, Z., Imperato-McGinley, J., 1997.
Paternity by intrauterine insemination with sperm from a man with
5alpha-reductase-2 deficiency. New Engl. J. Med. 336, 994 /997.
Kovacs, W.J., Griffin, J.E., Weaver, D.D., Carlson, B.R., Wilson,
J.D., 1984. 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 /1104.
Labrie, F., Sugimoto, Y., Luu-The, V., Simard, J., Lachance, Y.,
Bachvarov, D., Leblanc, G., Durocher, F., Paquet, N., 1992.
Structure of human type II 5 alpha-reductase gene. Endocrinology
131, 1571 /1573.
Mahendroo, M.S., Cala, K.M., Russell, D.W., 1996. 5a-reduced
androgens play a key role in murine parturition. Mol. Endocrinol.
10, 380 /392.
Mahendroo, M.S., Cala, K.M., Hess, D.L., Russell, D.W., 2001.
Unexpected virilization in male mice lacking steroid 5 alphareductase enzymes. Endocrinology 142, 4652 /4662.
McGuire, J.S., Tomkins, G.M., 1960. The heterogeneity of delta 4-3ketosteroid reductase (5a). J. Biol. Chem. 235, 1634 /1638.
Mendonca, B.B., Inacio, M., Costa, E.M., Arnhold, I.J., Silva, F.A.,
Nicolau, W., Bloise, W., Russel, D.W., Wilson, J.D., 1996. Male
pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency. diagnosis, psychological evaluation, and management.
Medicine (Baltimore) 75, 64 /76.
Milewich, L., Mendonca, B.B., Arnhold, I., Wallace, A.M., Donaldson, M.D., Wilson, J.D., Russell, D.W., 1995. Women with steroid
5 alpha-reductase 2 deficiency have normal concentrations of
plasma 5 alpha-dihydroprogesterone during the luteal phase. J.
Clin. Endocrinol. Metab. 80, 3136 /3139.
Money, J., Ogunro, C., 1974. Behavioral sexology: ten cases of genetic
male intersexuality with impaired prenatal and pubertal androgenization. Arch. Sex. Behav. 3, 181.
Money, J., Hampson, J.G., Hampson, J.L., 1955a. Hermaphroditism:
recommendations concerning assignment of sex, change of sex and
psychological management. Bull. Johns Hopkins Hosp. 97, 284 /
300.
Money, J., Hampson, J.G., Hampson, J.L., 1955b. An examination of
some basic sexual concepts: the evidence of human hermaphroditism. Bull. Johns Hopkins Hosp. 97, 301 /319.
Moore, R.J., Wilson, J.D., 1975. Diminished 5alpha-reductase activity
in extracts of fibroblasts cultured from patients with familial
incomplete male pseudohermaphroditism, type 2. J. Biol. Chem.
250, 7168 /7172.
Moore, R.J., Wilson, J.D., 1976. Steroid 5alpha-reductase in cultured
human fibroblasts. Biochemical and genetic evidence for two
distinct enzyme activities. J. Biol. Chem. 251, 5895 /5900.
Negri-Cesi, P., Poletti, A., Colciago, A., Magni, P., Martini, P., Motta,
M., 1998. Presence of 5a-reductase isozymes and aromatase in
human prostate cancer cells and in benign prostate hyperplastic
tissue. Prostate 34, 283 /291.
Ng, W.K., Taylor, N.F., Hughes, I.A., et al., 1990. 5a-reductase
deficiency without hypospadias. Arch. Dis. Child. 65, 1166 /1167.
Nordenskjold, A., Ivarsson, S.A., 1998. Molecular characterization of
5 alpha-reductase type 2 deficiency and fertility in a Swedish family.
J. Clin. Endocrinol. Metab. 83, 3236 /3238.
Nordenskjold, A., Magnus, O., Aagenaes, O., Knudtzon, J., 1998.
Homozygous mutation (A228T) in the 5alpha-reductase type 2
gene in a boy with 5alpha-reductase deficiency: genotype-phenotype correlations. Am. J. Med. Genet. 80, 269 /272.
Peterson, R.E., Imperato-McGinley, J., Gautier, T., Sturla, E., 1977.
Male pseudohermaphroditism due to steroid 5a-reductase deficiency. Am. J. Med. 62, 170 /191.
Russell, D.W., Wilson, J.D., 1994. Steroid 5 alpha-reductase: two
genes/two enzymes. Ann. Rev. Biochem. 63, 25 /61.
Siiteri, P., Wilson, J.D., 1974. Testosterone formation and metabolism
during male sexual differentiation in the human embryo. J. Clin.
Endocrinol. Metab. 38, 113 /125.
Silver, R.I., Wiley, E.L., Thigpen, A.E., Guileyardo, J.M., McConnell,
J.D., Russell, D.W., 1994. Cell type specific expression of steroid 5
alpha-reductase 2. J. Urol. 152, 438 /442.
Smith, C.M., Ballard, S.A., Wyllie, M.G., Masters, J.R., 1994.
Comparison of testosterone metabolism in benign prostatic hyperplasia and human prostate cancer cell lines in vitro. J. Steroid
Biochem. Mol. Biol. 50, 151 /159.
Spencer, J.R., Torrado, T., Sanchez, R.S., Vaughan, E.D., Jr,
Imperato-McGinley, J., 1991. Effects of flutamide and finasteride
on rat testicular descent. Endocrinology 129, 741 /748.
Thigpen, A.E., Russell, D.W., 1992. Four amino acid segments in
steroid 5a-reductase-1 confers insensitivity to finasteride, a competitive inhibitor. J. Biol. Chem. 267, 8577 /8577.
Thigpen, A.E., Davis, D.L., Gautier, T., Imperato-McGinley, J.,
Russell, D.W., 1992a. The molecular basis of steroid 5 alphareductase deficiency in a large Dominican kindred. New Engl. J.
Med. 327, 1216 /1219.
Thigpen, A.E., Davis, D.L., Milatovich, A., Mendonca, B.B., Imperato-McGinley, J., Francke, U., Wilson, J.D., Russell, D.W., 1992b.
The molecular genetics of steroid 5a-reductase 2 deficiency. J. Clin.
Invest. 90, 799 /809.
Thigpen, A.E., Silver, R.I., Guileyardo, J.M., Casey, M.L., McConnell, J.D., Russell, D.W., 1993a. Tissue distribution and ontogeny
of steroid 5a-reductase isozyme expression. J. Clin. Invest. 92,
903 /910.
Thigpen, A.E., Cala, K.M., Russell, D.W., 1993b. Characterization of
Chinese hamster ovary cell lines expressing human steroid 5 alphareductase isozymes. J. Biol. Chem. 268, 17404 /17412.
Vilchis, F., Mendez, J.P., Canto, P., Lieberman, E., Chavez, B., 2000.
Identification of missense mutations in the SRD5A2 gene from
patients with steroid 5alpha-reductase 2 deficiency. Clin. Endocrinol. (Oxf.) 52, 383 /387.
Walsh, P.C., Madden, J.D., Harrod, M.J., Goldstein, J.L., MacDonald, P.C., Wilson, J.D., 1974. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone
formation in pseudovaginal perineoscrotal hypospadias. New
Engl. J. Med. 291, 944 /949.
Wigley, W.C., Prihoda, J.S., Mowszowicz, I., Mendonca, B.B., New,
M.I., Wilson, J.D., Russell, D.W., 1994. Natural mutagenesis study
of the human steroid 5 alpha-reductase 2 isozyme. Biochemistry 33,
1265 /1270.
J. Imperato-McGinley, Y.-S. Zhu / Molecular and Cellular Endocrinology 198 (2002) 51 /59
Wilbert, D.M., Griffen, J.E., Wilson, J.D., 1983. Characterization of
the cytosol androgen receptor of the human prostate. J. Clin.
Endocrinol. Metab. 56, 113 /120.
Wilson, J.D., 1978. Sexual differentiation. Ann. Rev. Physiol. 40, 270 /
306.
Wilson, J.D., Griffin, J.E., Russell, D.W., 1993. Steroid 5a-reductase 2
deficiency. Endocr. Rev. 14, 577 /593.
59
Zhu, Y.S., Imperato-McGinley, J., 2002. Male pseudohermaphroditism due to 5alpha-reductase-2 deficiency. In: Sciarra, J.J. (Ed.),
Gynecology and Obstetrics. Lippincoft Williams & Wilkins, in
press.
Zhu, Y.S., Katz, M.D., Imperato-McGinley, J., 1998. Natural potent
androgens: lessons from human genetic models. Baillieres. Clin.
Endocrinol. Metab. 12, 83 /113.