0025-7974/00l7905-0299/0
MEDICINE9 79: 299-309, 2000
Copyright Q 2000 by Lippincott Williams & Wilkins, lnc.
Male Pseudohermaphroditism due to
1713-Hydrox ysteroid Dehydrogenase 3 Deficiency
Diagnosis, Psychological Evaluation, and Management
BERENICE B . MENDONCA, MARLENE lNACIO,
WALTER BLOISE, REGINA M.
MARTIN, FRANCISCO
STEFAN ANDERSSON, ANNIKA LINDQVIST, AND JEAN D. WILSO
Introduction
Impainnent of virilization in the male fetus (male
pseudohermaphroditism) can result either from de-
creased testosterone formation or from impaired
androgen metabolism or action (24). Defects in an-
drogen action are the most common cause and in-
clude mutations in genes that encode the androgen
receptor e40) or the steroid 5cx-reductase 2, which
converts testosterone to dihydrotestosterone in the
male urogenital tract (54). Defective androgen for-
mation is usually due to autosomal recessive muta-
tions that impair 1 of the enzymatic reactions
involved in the conversion of cholesterol to testos-
terone, including the side-chain cleavage reaction
(via impainnent of the steroid acute regulatory
protein), 3[3-hydroxysteroid dehydrogenas 2, 17cx-
hydroxylase/17-20 lyase, and 17[3-hydroxysteroid de-
hydrogenase 3 (l 7[3-HSD3) (25). The most common
of these disorders is 17[3-HSD3 deficiency (4), origi-
nally described by Saez and his colleagues (46, 47)
and subsequently reported from various parts of the
From Division of Endocrinology (BBM, MI, IJPA, EMFC, WB,
RMM) and Division ofUrology (FTD, FAQS), Hospital das Clinicas
of the University of So Paulo School of Medicine, So Paulo, SP,
Brazil; and the Departrnents of Obstetrics and Gynecology (SA,
AL) and Internai Medicine (JDW), The University ofTexas South-
western Medical Center, Dallas, Texas, USA.
Berenice B. Mendonca is supported by grant 301246195-5 from
CNPq, Brasil, and Stefan Andersson is supported by grant DK
52167 from the National lnstitutes ofHealth. Annika Llndqvist was
a fellow of the Emma Ekstrand, Hildur Tegger, and Jan Tegger
Foundation for the Advancement of Scientific Research.
Address reprint requests to: J ean D. Wilson, MD, Departrnent of
Internai Medicine, University ofTexas Southwestern Medical Cen-
ter, 5323 Harry Hines Boulevard, Dallas, TX 75235-8857. Fax: 214-
648-8917; e-mail: jwilsl@mednet.swmed.edu.
Abbreviations used in this article: l 7[3-HSD3, 17[3-hydroxys-
teroid dehydrogenase 3; FSH, follicle-stimulating hormone; GnRH,
gonadotropin-releasing hormone; hCG, human chorionic go-
nadotropin; LH, luteinizing hormone.
Vol. 79, No. 5
Prinled in U. S.A.
Ivo J. P. ARNHOLD, ELAINE M. F. COSTA,
T. DENES, FREDERICO A. Q. SILVA,
world (2, 3, 6, 7, 9, 10, 12-18, 20-23, 26, 28-31, 33, 35,
37-39, 41-45, 48, 50-53, 56, 57). The disorder is due
to mutations that impair function of the 17[3-HSD3
isoenzyme responsible for the conversion of an-
drostenedione to testosterone in the testes (3, 10, 20,
35, 45). Women with homozygous or compound het-
erozygous mutations of the sarne gene appear to be
normal (35, 45). Affected males usually have testes,
mal e epididymides, vasa deferentia, seminal vesicles,
and ejaculatory ducts, and ambiguous or female
externa! genitalia, and most are raised as females.
Occasionally, men with less severe defects in viril-
ization are raised as males (3). At the time of ex-
pected puberty, serum testosterone levels rise in all
affected males and may approximate the normal
adult male range. Serum testosterone in these men is
usually derived by extraglandular formation from cir-
culating androstenedione (3) but may be secreted by
the postpubertal testes when mutant enzymes retain
e
partial function 43). As a consequence of the rise in
plasma testosterone, most affected males virilize
during the teenage years, and some 46,XY individuals
raised as females change gender role behavior (so-
cial sex) from female to male after the time of ex-
pected puberty (2, 28, 42). As a consequence, the
appropriate management of infants with this disor-
der is among the most challenging problems in
endocrinology.
We report here clinica!, psychological, and thera-
peutic studies of 10 46,XY individuals from 7 Brazil-
ian families with 17[3-HSD3 deficiency. The 10
subjects were evaluated and followed in 1 clinic and
were assessed by the sarne psychologist. Anecdotal
evidence is also included about 2 affected males in
these families who underwent a change in social sex
from female to male but who refused to be studied.
The molecular defects in 5 of the families (3, 20), the
findings in the affected 46,XX sisters in 4 of the fam-
ilies (35), and the clinica! findings in Subjects 4 and 5
(6) have been reported previously.
299
300 MENDONCA ET AL
Subjects
Ali the subjects of this paper are 46,XY, but they
are referred to as either male or female depending on
the social sex.
Subject 1 (So Paulo 1 family)
Subject 1, the ninth of 11 children, carne to medical attention at
age 15 years because of failure of breast development and the ap-
pearance of facial hair, clitoral enlargement, and deepening of the
voice. The cricoid cartilage was male in character (Figure 1). She
had been raised as a female and had characteristic female behav-
ior, playing with dolls and helping with housework. Psychological
evaluation indicated that she had a female gender identity, and she
elected to maintain a female social sex. Bilateral gonadectomy and
clitoroplasty were perfom1ed (Figure 2), and the cricoid cartilage
was resected. She was begun on 0.625 mg/d of cor\jugated estro-
gens, and the breasts increased from Tanner stage 1 to Tanner
stage 3 within a year. At age 23 years breast development was still
Tanner stage 3, and she was changed to 2 mg/d of estradiol valer-
ate for 21 days a month and 5 mg/d of medroxyprogesterone ac-
etate for the last 10 days of the month. No change in breast size
was noted after 5 months. She was switched to oral contraceptives
and then to a 50 ,g estradiol transdermal patch twice a week, and
she now has Tanner stage 5 breast development. She began an ac-
tive sexual life at age 20 years and reported normal sexual inter-
course after the vagina was dilatated with vaginal molds (19). Her
first marriage temlinated in divorce after 2 years because of her in-
FIG. 1. The cricoid cartilage in 2 affected subjects before surgery. A. Subject 2; B. Subject 1.
fertility. She remarried 3 years !ater and again reports normal sex-
ual function.
Subject 2 (So Paulo 2 family)
Subject 2, the youngest of 7 sibs, was ascertained at age 21
years because of the absence of menses and failure of breast de-
velopment. Ambiguous gertalia had been noticed at birth but she
was raised as a female. Beginning at age 13 years she noticed an
increase in facial and chest hair and clitoral enlargement, and the
cricoid cartilage became masculine in character (see Figure lA).
After psychological evaluation confirmed female gender identity,
she underwent bilateral gonadectomy and clitoroplasty, and the
cricoid cartilage was resected. Treatment with cor\jugated estro-
gens was begun at age 21 years first ata dose of 0.625 mg/d and
then at a dose of 1.25 mg/d for 4 months. This regmen was
changed to 2 mg/d estradiol valerate for 21 days and 5 mg medrox-
yprogesterone acetate for the last 10 days of the month; after this
dose was doubled, breast size reached Tanner stage 4. At age 24
years she was changed to oral contraceptives (35 ,g of ethinyl
estradiol and 2 mg cyproterone acetate) with no additional en-
largement in breast size. The vagina was enlarged by the Frank
procedure (19). She is married and reports normal sexual activity.
Subject 3
Subject 3, the sixth sib of Subject 2, was also bom with am-
biguous gertalia and was raised as female. By age 12 years he be-
gan to exhibit male behavior, and psychological evaluation at age
 17[3-HYDROXYSTEROID DEHYDROGENASE
FIG. 2. The externai genitalia of Subject 1: A. Before surgery. B.
After surgery.
26 years revealed that he had male gender identity. He underwent
surgery for repair of hypospadias, began to date women, was mar-
ri ed for 5 years, and is now divorced. His sex life is unsatisfactory,
which he ai.tributes to the small size of his penis.
Subject 4 (So Paulo 3 family)
Subject 4, the sixth of 9 children of a rural family, carne to med-
ical attention at age 4 years because of arnbiguous genitalia, which
had been noticed at birth. Psychological evaluation indicated that
she had a femal.e gender identity, and she underwent a bilateral. or-
chidectomy and clitoroplasty. She was begun on estrogen therapy
(0.625 mg/d of coajugated estrogen) at age 12 years. By age 18
years breast development was only Tanner stage 3, and the dose
was increased to 1.25 rng/d. At age 19 years breast development
was Tanner 4, and she was treated with a vaginal mold (19). She
appears to be well adapted to the femal.e gender role but is not sex-
ually active.
Subject 5
Subject 5, an older sib of Subject 4, was raised as a femal.e and
underwent clitoroplasty without gonadectomy at age 8 years at an-
other hospital.. She was referred to us at age 10 years, and castra-
3 DEFICIENCY 301
tion was performed after psychological. exarnination established
that gender identity was femal.e. She was treated with coajugated
estrogens 0.625 mg/d daily and was reeval.uated at ages 20 and 26
years. Breast development is Tanner stage 3, and she appears to
be well adapted to the femal.e gender role. She is not sexually ac-
tive but dates men. Subjects 4 and 5 have been reported previously
(6).
Subject 6 (So Paulo 4 family)
Subject 6, the oldest of 5 children of a rural family, was noted
to have arnbiguous genitalia at birth but was raised as a femal.e.
Frorn an early age the child preferred mal.e activities and helped
the father in the fields, and by age 10 years he had begun to wear
mal.e clothing. At age 15 years he noted the appearance of facial
and chest hair, enlargement of the penis and testes, and develop-
ment of mal.e libido. Psychological. eval.uation confirrned mal.e sex
identification. He underwent hypospadias repair and formally
changed his social sex to mal.e. He is not married but reports an ac-
tive sexual life.
Subject 7
Subject 7 was brought to the hospital. at age 15 years by his sib,
Subject 6. He al.so had been bom with arnbiguous genitalia but was
registered and raised as a femal.e. At the time of eval.uation he wore
femal.e clothes but had had no breast development and had ab-
sence of menses. Psychological. eval.uation showed mal.e sex iden-
tification. He changed to mal.e social sex and underwent repair of
the hypospadias. He was treated with intrarnuscular testosterone
enanthate 250 mg every 2 weeks for 6 rnonths. However, the penis
size did not change, and the therapy was discontinued because he
was disturbed by an increase of body hair. AJthough satisfied with
a mal.e gender role, he finds it difficult to get ajob, worries about
the small size of his penis, and has difficulty in dating.
Subject 8 (So Paulo 5 family)
Subject 8, the fourth of 5 sibs, was exarnined at age 18 years at
another hospital. because of facial and body hair growth, clitoral.
enlargement, and facial and body acne. Menarche had not oc-
curred, and there was no breast development. No diagnosis was
made, and she was not treated. At the time of referrai. to another
unit at the Hospital. das Clinicas at age 34 years, she had Tanner
stage 1 breast development and was placed on 0.625 mg/d coaju-
gated estrogen. She was then referred to our clinic, at which time
breasts were Tanner 3. A 2.5-cm nodule under the right nipple
proved to be a ductal. carcinoma, stage m, and estrogen therapy
was discontinued. Subsequent whole body CT scans have been
negative. Psychological evaluation confirrned femal.e gender iden-
tity. She unde~ent clitoroplasty and bilateral. gonadectomy. She
is involved in a long-term relationship with a man.
Subject 9 (So Paulo 6 family)
Subject 9, the fourth of 5 children, was thought to be a normal
femal.e at birth and was raised as a girl. At 13 years of age she no-
ticed hair development on the face and chest. She described fe-
mal.e gender identity, married at age 15 years, and had normal
sexual activity for 3 years. However, she becarne increasingly vir-
ilized and was divorced by her husband. At age 23 years she carne
302 MENDONCA ET AL
to our clinic where psychological evaluation confinned female
gender identity. After clitoroplasty and bilateral gonadectomy she
was begun on 0.625 mg/d conjugated estrogen for breast develop-
ment and 50 mg/d cyproterone acetate for hirsutism. Within 6
months breast development was only Tanner stage 3, and the con-
jugated estrogen was changed to 2 mg/d estradiol valerate for 21
days and 5 mg/d medroxyprogesterone acetate for the last 10 days
of the month. At age 25 years breast development was Tanner
stage 4. She has remarried and describes regular sexual activity. ln
an attempt to enhance breast development she was given an oral
contraceptive (35 .g of ethinyl estradiol and 2 mg cyproterone ac-
etate/d) for 4 years, but breast development is still Tanner stage 4.
Subject 1 O (So Paulo 7 famy)
Subject 10, the oldest of 5 children, was thought to be a normal
female at birth and was raised as a girl. At 2 years of age, the
mother noticed bilateral nodules in the inguinal region, and by 12
years of age the subject began to develop deepening of the voice.
ln the ensuing years an increase in body and facial hair, appear-
ance of acne, enlargement of the clitoris, and mate pattem muscle
development were noted. At age 18 years the breasts were imma-
ture, and menarche had not occurred. Psychological evaluation re-
vealed female gender identity and female libido. Clitoroplasty and
bilateral gonadectomy were performed. She was begun on 1.25
mg/d conjugated estrogen, and 25 mg/d cyproterone acetate was
added to reduce facial hair. She now has Tanner stage 4 breast de-
velopment and is engaged to be married.
Methods
Laboratory evaluation
Serum luteinizing hormone (LII) and follicle-stimulating hor-
mone (FSH) were determined by commercial 12s1 double-antibody
radioimmunoassays in the first 3 subjects and by immunofluoro-
metric assays in the others (11). lnterassay variation was less than
10% for ali hormones. Serum androstenedione and testosterone
were determined by the method of Abraham (1) without prior
chromatography after establishing specificity of the antisera (34).
For' human chorionic gonadotropin (hCG) testing, the prepu-
bertal subjects (Subjects 4 and 5) were given 50-100 IU of hCG in-
tramuscularly every 4 days for 4 doses, and blood was sampled
before the fin)t dose and 48 and 72 hours after the Jast dose. The
sarne regmen was administered to 9 prepubertal boys (4.7 2.5 yr)
with unilateral or bilateral cryptorchidism and mate externai geni-
talia who were used as control subjects. Pubertal subjects (Sub-
jects 1-3 and 6-10) were given 6,000 IU ofhCG intramuscularly in
a single dose, and blood was collected before and 48 and 72 hours
after treatment. Eight control pubertal males were treated simi-
larly. To assess gonadotropin-releasing hormone (GnRH) respon-
siveness, blood was drawn in some subjects for measurement of
serum LH and FSH-15, O, 15, 30, 45, and 60 minutes after the intra-
venous administration of 100 .g of GnRH (gonadorelin).
Immediately after orchiectomy aliquots of the gonads were
fixed in Bouin solution and stained with hematoxylin-eosin for his-
tologic studies. To stimulate testosterone synthesis (6), 1,500 U of
hCG per day was given intramuscularly to the 2 prepubertal sub-
jects for 2 days before orchiectomy.
For analysis of the mutations in unreported subjects, the l 7~
HSD3 gene was sequenced as described (3).
Psychological evaluation
Nine of the subjects live in other states, and 1 resides in the rural
area of So Paulo state. Before and after surgery ali lived tem-
porarily in the city of So Paulo, either with relatives or accompa-
nied by parents. The sarne psychologist performed individual
evaluations in each subject during severa! interviews between 1983
and 1996, including free and directed anarnnesis. The personality
HTP (house, tree, person) tests, family and free drawings, the Forro
C Pierre Weil and Eva Nick nonverbal intelligence tests, and the
Szoundi test were applied, and devolutive interviews were con-
ducted with the subjects and with their family members (34). The
evaluations were designed to define the psychodynamic and be-
havioral features of the subjects, including evaluation of the social
and sexual attitudes of the subjects and of family members. After
the initial evaluation, the subjects were interviewed before and af-
ter surgery, and follow-up interviews were performed periodically.
Results and Discussion
Clinical features
Ali subjects had a 46,XY karyotype. Most were
bom at home under the care of a midwife. Sexual
ambiguity was noted at birth in 8 subjects, but all
were registered and raised as females because of in-
complete virilization of the externa! genitalia. Two
were diagnosed prepubertally, and the diagnosis was
made in the others between ages 15 and 34 years. The
physical features (Table 1) are similar to those previ-
ously described in this disorder (3, 10, 17, 46). At the
time of ascertainment, the externa! genitalia were
characterized by perineoscrotal hypospadias, a small
phallus (more than 2 standard deviations below the
age-matched normal range [49]), a bili.d scrotum, and
a blind-ending vaginal pouch. Eight subjects had sep-
arate urethral and vaginal openings, and 2 had a sin-
gle perineal opening with a short urogenital sinus. Ali
subjects had bilateral inguinal testes except Subject
1, whose right testis was intraabdominal. The testes
in the postpubertal subjects were normal or near nor-
mal in size. Ali subjects of postpubertal age had male
habitus, male pattem muscle development, male fa-
cial and chest hair, deep voice, and phallic enlarge-
ment. As illustrated in Figure 1, enlargement of the
cricoid cartilage was present in 2 subjects. Ali sub-
jects had normal heights for age, and bone age was
compatible with the chronologic age (data not
shown). ln 3 postpubertal subjects (and in a brother
and a first cousin not studied by us) , gender role
changed from female to male after the time of ex-
pected puberty; the other 7 affected 46,XY subjects
(including 2 who were castrated prepubertally) have
maintained a female social sex. ln the 3 subjects who
elected to change to male social sex, the penis ranged
from 5.0 to 6.8 cm in length (see Table 1). Gyneco-
mastia was not present in the postpubertal cases, in
keeping with our previous studies (3) but in contrast
 TABLE 1. Clinicai features in 10 46,XY individuais from 7 families with 1713-HSD3 deflciency
Anatomic Features
Consanquinity
EthnidSocial (Affected Age at Social Marital Vaginal Phallic Vaginal
Subject Family Mutation Testes
Background 46 XY and 46 XX Diagnosis/Last Sex Status and Size Depth ,_.
Fa.:ruiy Memb'e rs) Examination (yr) Location Size Urethral (cm) (cm) ....::J
(cm) Openings -v::i

1 Sao Paulo 1 Compound

heterozygote
White urban No
(46,XY 1)
15/30 Female Married X 2 Inguinal;
abdominal
4 X 2.5 Separate 6 1
~
::o
RSOQ/326-1, (46,XX2) o
G~C ~
2 Sao Paulo 2* Homozygous Black rural Yes 21/30 Female Married Inguinal 3 X 2; Separate 6.5 2 ~
t'l
A203V (46,XY3) 1.5 X 1
3 26/35 Female
~Male
Divorced Inguinal 4 X 2;
3 X2
Single 6 2 "'
o
8
4 Sao Paulo 3 Homozygous White rural No 4/20 Female Notmarried Inguinal 1.5 X; Separate 3 1 o
t'l

~
RSOQ (46,XY2) 1.5 X 1
(46,XX 1)
5 10/26 Female Notmarried Inguinal 1.5 X l;
1.5 X 1
Separate - 4
"'
o
ot'l
6 Sao Paulo 4 Homozygous White rural Yes 21/35 Female Notmarried Inguinal 5 X 3; Separate 6.8 2
E215D (46,XY2)
(46,XX2)
~Male 5 X3 ~
t'l
7 15129 Female Notmarried Inguinal 2.5 X 1.5; Separate 5 2 e.o
~Male 3 X 1.5 ot'l
8 Sao Paulo 5 Homozygous White rural Yes 34/37 Female Common-law Inguinal 4 X 2; Separate 7 5 ::;i
326-1, G~C (47,XY 1) marriage 4 X2 o
Eia
(46,XX2) z
9 Sao Paulo 6 Homozygous White rural Yes 23/25 Female Married X 2 Inguinal 5 X 2; Separate 6.5 7 ~
326-1, G~C (46,XY2) 2X1
10 Sao Paulo 7t Homozygous White urban Yes 18/23 Female Engaged to Inguinal 3.5 X 2; Single 4.5 5
A203V (46,XY2) be married 3.5 X 2
*Another sib in this family (not examined by us) was raised as a girl but underwent change to male behavior at age 17 years.
tAn affected cousin in this family (not examined by us) was raised as a girl but underwent change to male behavior at age 14 years.

e.o
o
e.o
304 MENDONCA ET AL

to the report offrequent gynecomastia in earlier stud-
ies (52).
Diagnosis
1713-HSD3 deficiency in postpubertal males is char-
acterized by higher levels of serum androstenedione
than of testosterone, which may be below or within the
range for normal adult men. lncreased androstene-
dione levels are due to deficiency of 1713-HSD3, which
catalyzes the conversion of androstenedione to testos-
terone in the testes. ln the present study basal serum
testosterone levels were low in 6 and normal in 2 sub-
jects of postpubertal age (Figure 3). The ratio of
serum androstenedione to testosterone was high in
the basal state in postpubertal subjects and after the
administration of hCG in all subjects. ln the 2 prepu-
bertal subjects, diagnosis required measurement of
serum androstenedione after hCG or of the ratio of
androstenedione to testosterone after hCG stimula-
tion (see Figure 3). Another nomogram that uses the
ratio of serum androstenedione to testosterone for
establishing the diagnosis has been published by
Boehmer et al (10).
The hypothalamic-pituitary-testicular axis was as-
sessed in 7 subjects (Table 2). Demonstration in post-
pubertal subjects of elevated levels of serum LH and
FSH in the basal state and after GnRH administration
indicates that the feedback regulatory control of the
pituitary by gonadal hormones is impaired. lncreases
in serum LH levels after the time of expected puberty
cause elevated androstenedione levels, and the ele-
vated androstenedione levels in tum allow formation
of some testosterone, either in extraglandular tissues
or by the testes (3). Elevation of FSH levels may be
due to damage to the spermatogenic tubules as a re-
sult of long-term cryptorchidism, a finding in keeping
with the histologic evidence of progressive testicular
damage with age (see Table 3). FSH levels have been
reported to be normal in some subjects (21, 45), but
the regulation of FSH secretion does not appear to
have been studied systematically in this disorder.

Androstenedione Testosterone AIT

(ng/dl) (ng/dl) / 2123
2000
1000 8

1500 750 6

1000 .
500




4
., .


,,,.
500 .

u

~
250 .; A

.
2

....
o :Q:
o o TI rn:
Basal After hCG Basal After hCG Basal After hCG

Prepubertal 46, XY subjects with 17~- HSD 3 deficiency

o Prepubertal 46, XY contrais, range
Postpubertal 46, XY subjects with 17~- HSD 3 deficiency
D Postpubertal 46, XY contrais, range

FIG. 3. Serurn leveis of androstenedione (A) and testosterone (T) and the ratios of serurn Aff before and after the aclministration of
human chorionic gonadotropin (hCG) in 46,XY subjects with 17(3-hydroxysteroid dehydrogenase 3 (17(3-HSD3) deficiency and in control
subjects.
 1713-HYDROXYSTEROID DEHYDROGENASE 3 DEF1CIENCY 305
TABLE 2. Basal and GnRH-stimulated LH and FSH
leveis before gonadectomy in subjects with male pseudohermaphroditism due to 17j3-HSD 3 deficiency
LH U/L FSH U/L
Subject Age (yr)
Basal Peak Basal Peak
l* 15 29 178 29 45
2* 21 28 109 29 56
3* 26 24 71 16 31
4t 4 5.4 4.9
5t 11 6.1 20 2.3 21
6t 21 27 202 64 189
7t 15 14 140 56 103
8t 34 35 38
9t 23 30 24
lOt 17 11 101 21 49
Raclioirrununoassay (ref. 36):j: 14 3.6 36 24 82 9.7 6.4
Fluoroirrununoassay (ref. ll):j: 3.9 1.8 20.l 5.7 2.7 2 4.9 2.0
Abbreviations: LH = luteinizing hormone; FSH = follicle-stimulation hormone; GnRH = gonadotropin-releasing hormone.
*Raclioirrununoassay.
t Fluoroirrununoassay.
+Normal adult male, mean SD.

Virilization is common in subjects with 1713-HSD3
deficiency at the time of e:xpected puberty, mani-
fested by phallic enlargement, development of male
pattem body hair and muscle development, and in
some by masculinization ofthe larynx (see Figure 1)
(3, 28, 47). This late virilization is a consequence of
the rise in plasma testosterone as a result of the con-
version of androstenedione to testosterone in ex-
tragonadal tissue (presumably 1713-HSD5) (3), and,
occasionally, of the secretion of testosterone by the
testes when levels of gonadotropins and of an-
drostenedione are high in subjects with some resid-
ual 1713-HSD3 function (43).
The discrepancy in this disorder between the failure
of intrauterine masculinization and the virilization at
the time of e:xpected puberty is poorly understood.
Aromatization of androstenedione by the placenta
might prevent the extragonadal conversion of an-
drostenedione to testosterone in the fetus (45, 46), but
female fetuses with congenital adrenal hyperplasia
due to deficiency of steroid 21-hyroXYlase or steroid
1113-hydroXYlase virilize when maternal plasma an-
drogen levels are elevated. Altematively, a limited ca-
pacity to convert androstenedione into testosterone in
extragonadal tissues in the embryo might e:xplain the
impairment of virilization of the extemal genitalia at
the time ofbirth (51).
Histowgic studies
The histologic features of the testes were assessed
in 8 subjects ranging in age from 4 to 34 years (Table
3). The most striking finding was that the testis from
the 4-year-old appeared to be normal but that pro-
found changes ensued with age. The Sertoli cells
changed from immature to mature to atrophic;
the spermatogonia changed from abundant to rare to
absent; and the Leydig cells changed from normal
to hyperplastic. Whether the apparent Leydig cell
hyperplasia is absolute or relative to the atrophy of
other elements is not clear, but it is common in the
testes of subjects with mutations of the androgen re-
ceptor and is probably dueto elevated levels ofplasma
LH (24). The basal membranes in the spermatogenic

TABLE 3. Histologic features of the testes in 8 subjects with 17j3-HSD3 deficiency

Histologic Finclings
Subj ect Age (yr)
Sertoli Cells Spermatogonia Leyclig Cells
Prepubertal
4 4 Immature Abundant Clusters in clifferent stages of development
5 11 Abundant Rare Many in clifferent stages of development
Pubertal
1 15 Mature Moderate Abundant
2 21 Abundant Rare Hyperplastic (Leyclig cell adenoma on right)
6 21 Abundant None identi.fied Normal
10 23 Reduced Decreased number with arrest Hyperplastic
at spermatocyte stage
9 23 Reduced Decreased number with arrest at Hyperplastic
spermatid 11 stage
8 34 Reduced Absent Hyperplastic
306 MENDONCA ET AL
tubules also becarne thicker with age, and some
tubules contained basophilic deposits suggestive of
calcification. The presence of atypical cells in the
testes of Subject 2 is disquieting because a metastatic
seminoma has been reported in a 30-year-old subject
who adopted the male social sex (28).
ln all instances examined here and in all reported
cases, m[uml]ullerian ducts were absent (indicating
normal synthesis of antim[uml]ullerian hormone by
the testes), and the epididymis and vas deferens were
mal e in character. The reason for the discrepancy be-
tween the virilization ofthe wolffian ducts in this dis-
order and the failure of virilization of the externa!
genitalia is not known. Androstenedione might be
converted to testosterone in the wolffian ducts by an
isoenzyme of 1713-HSD, or androstenedione in high
concentrations might be a more effective androgen
than has been recognized. A similar discrepancy be-
tween normal virilization of the wolffian ducts and
undervirilization ofthe externa! genitalia also occurs
in Leydig cell aplasia arising from mutations of the
LH receptor (5, 8) and in steroid 5u-reductase 2 defi-
ciency (24).
(]erietic sttui,ies
The autosomal recessive inheritance of this disor-
der was recognized initially e46, 47), and the fact that
consanguinity was present in 5 of the 7 families in the
current study emphasizes the rarity ofthe underlying
mutations. The diagnosis of 17(3-HSD3 deficiency
was confirmed in all 7 families by analysis of the mu-
tations, demonstrating compound heterozygous mu-
tations in 1 family and homozygous defects in 6 (1).
Phenotypically normal 46,XX sisters of affected men
from families 1, 3, 4, and 5 have the sarne homozy-
gous or compound heterozygous mutations (35).
Identical mutations recurred in apparently unrelated
families, narnely R80Q in 2 families, 326-1, G~C in
3 families, and A203V in 2 families. The R80Q muta-
tion was originally described in a Palestinian family
from the Gaza strip (20, 42-45), but we were unable
to document Palestinian ancestry in the Brazilian
families. The A203V, E215D, and 326-1, G~C muta-
tions appear to be unique to Brazil. Whether the ex-
istence of the sarne mutation in different families is
due to recurring new mutations or to a common an-
cestor is not known. Family 2 is black, whereas 1713-
HSD3 deficiency has rarely been described in blacks
(13).
(]ender ideritity!role behavior
A change in gender role from female to male in
male pseudohermaphrodites has been described oc-
casionally in the literature for many years and is now
known to be due in most instances to either of 2 au-
tosomal recessive disorders, steroid 5u-reductase 2
deficiency or l 7(3-HSD3 deficiency (reviewed in ref-
erence 55). The first known such instance in 1713-
HSD3 deficiency was a 14-year-old 46,XY subject
who was evaluated because of virilization and who
wished to change to male social sex (28). This indi-
vidual adapted successfully to the male sex and mar-
ried at age 25 years. A similar change in gender role
behavior has been described in additional individuals
with this disorder (2), including members of a large
consanguineous family in the Gaza strip (30, 42-45).
The mechanisms by which androgens influence
gender role behavior and, indeed, which androgens
or androgen metabolites exert this action are not
known. The imprinting of male behavior might be
mediated by direct action of androgen or by the con-
version of androgens into estrone or estradiol within
nervous tissue, but androgens probably mediate this
action directly because 46,XY women with the syn-
drome of testicular feminization due to mutations
that impair androgen receptor function have normal
extraglandular estrogen formation and unambiguous
female behavior, and because men with mutations
that impair estrogen formation or estrogen action
have male social behavior (27, 55). lt is also not
known whether the effect of androgen on gender role
behavior is mediated by hormonal effects in the cen-
tral nervous system or in peripheral tissues.
The present study provides insight into several as-
pects of this problem. First, the tearn performed psy-
chological assessment in 10 of 12 affected 46,XY
subjects, 7 of whom elected to maintain a female sex-
ual role and 3 of whom changed to social males. (Two
additional presumably affected males in these families
who were unavailable for study also changed social
sex to male, so the total number of such changes in
these families is 5.) Ifthese data are combined with the
various reports in the literature (reviewed in refer-
ences 3, 55), change in social sex in this disorder ap-
pears to be less common (less than 500;6) than in
fo-reductase 2 deficiency (about 75%) (55). The diffi-
culty in predicting whether change in social sex will
occur in a given subject is emphasized by the fact that
1 or more affected individuals in 2 families in the pres-
ent study changed to male role behavior whereas
other affected subjects maintained female social sex.
Two individuals with homozygous R80Q mutations
elected to remain female whereas most individuals
with the sarne mutation in the Gaza Strip change so-
cial sex to male (30, 42-45). There is no clear correla-
tion in this disorder or in steroid 5u-reductase 2
deficiency between the severity of the enzymatic de-
fect and the decision about social sex (55). These var-
ious findings indicate that unidentified factors-
biologic, social, or psychological-influence gender
role behavior in addition to androgens. Whatever the
frequency, the fact that in both steroid 5u-reductase 2
 17~-HYDROXYSTEROID DEHYDROGENASE
de:ficiency and 17~-HSD3 de:ficiency all affected
46,XY individuais do not change social sex compli-
cates the management of infants with the disorders.
Ali 10 individuais in the present study probably had
sexual arnbiguity at birth, but in 8 the diagnosis was
not made until after the age of expected puberty.
Consequently, it is not known whether the perfor-
mance of genital surgery that con:firmed the female
sexual assignment would have influenced the ulti-
mate choice of social sex (36). ln some individuais
with the disorder, sex assignment has been changed
from female to male in infancy (18), whereas in the
present series the majority of affected individuais
who were not ascertained until later in life chose a fe-
male social sex. Androgen therapy during infancy
has resulted in improvement in the degree of adult
virilization in steroid 5a-reductase 2 de:ficiency (34),
but whether it would doso in 17~-HSD3 de:ficiency or
whether it would confound gender identity/role be-
havior is not clear.
Management
Eight subjects carne from farm families, and 2
were from cities. Sexual arnbiguity was noted at birth
in 8, but workup and treatment were not pursued be-
cause of:financial and/or social constraints. Two sub-
jects are said to have had normal female externai
genitalia at birth but in retrospect also probably had
arnbiguity. Ali were registered as social females.
The 3 subjects who changed from female to male
social sex underwent surgical repair of the hypospa-
dias (in 2 or 3 stages) and orchiopexy. Complications
of surgery included 2 urethral :fistulas that were later
corrected and 1 instance of suppurative epididymitis
and orchitis followed by left testicular atrophy.
Testosterone therapy in Subject 7 did not cause an
increase in penis size, a failure of response previ-
ously reported in postpubertal men with 5a-reduc-
tase 2 de:ficiency (34).
The social females underwent surgical procedures
designed to feminize the externai genitalia. Bilateral
gonadectomy was performed through the prepuce in-
cision at the time of clitoroplasty to prevent an ab-
dominal scar. Labia minora were constructed with
phallus skin, and the vaginal introitus was expanded.
Before the initiation of sexual activity, the vagina was
enlarged by the Frank procedure (19). Ali the social
females were treated with estrogen for at Ieast 2
years, narnely 0.625 mg conjugated estrogen/d for 12
months followed by 1.25 mg/d for another 12 months,
in an attempt to increase breast size. However, breast
development remained subnormal, and they were
then treated with 30 .g/d of ethinyl estradiol and 0.15
mg levonorgestrel for 6 months without effect, fol-
lowed by a regimen of 2 mg estradiol valerate a day
for 21 days each month and 5 mg medroxyproges-
3 DEF1CIENCY 307
terone acetate during the last 10 days ofthe month for
6-12 months. After estrogen therapy, all of the social
females had Tanner stage 3-5 breast development.
Four of the social females with hirsutism were
treated (with limited success) with cyproterone ac-
etate (50 mg/10 days a month) to reduce facial hair.
Two of the social females aiso had masculine faces
and virilization ofthe cricoid cartilage (see Figure 1).
ln these 2 women the cricoid cartilage was reduced
at the time of genital surgery, and facial and chest
hair was treated by electrolysis.
Before surgery, all social females were shy and
somewhat withdrawn, possibly because of self-con-
sciousness about the absence of menses, poor breast
development, hirsutism, clitoromegaly, and masculin-
ization ofthe cricoid cartilage, and only 2 ofthem were
socially comfortable. All 10 subjects desired a normal
love life and a successful sexual relationship.
Following surgery and hormonal therapy all 10
subjects improved in regard to self-esteem and social
relationships, investing in their physical appearance,
dressing better, and taking care ofthemselves. Seven
subjects actively sought an affectionate relationship,
whereas the other 3 channeled their sexual and so-
cial fantasies to other areas, such as study and work.
Of the 7 social females, 3 are now married and appear
to be well adapted, 1 is involved in a long-term het-
erosexual relationship, 1 is engaged to be married,
and 2 (Subjects 4 and 5) are unmarried and not be-
lieved to be sexually active. Of the 3 social males, 1 is
divorced, and 2 have never married. (The sexual/mar-
ital status of the 2 unexamined individuais who
changed to male social sex is not known.) Nine sub-
jects had improved relationships with their families
after therapy, coming to terms with the problems ex-
perienced during childhood. ln summary, all 10 sub-
jects appear to be satis:fied with their assigned or
assumed gender role, and most of the social females
appear to be satis:fied with their social and sexual
outcomes.
Summary
Ten male pseudohermaphrodites with 17~-hy
droxysteroid dehydrogenase 3 (l 7~-HSD3) de:fi-
ciency were evaluated in 1 clinic with an average
follow-up of 10.1 years. The diagnoses were made by
demonstrating low to normal serum testosterone lev-
els, high androstenedione levels, and high ratios of
serum androstenedione to testosterone in the basal
state or after treatment with human chorionic go-
nadotropin. The molecular features of the underlying
mutations were identi:fied in all 7 families. Two addi-
tional males in the sarne families are believed to be
affected on the basis of history obtained from family
members.
308 MENDONCA ET AL
Ali of the 46,XY individuals in these families were
registered at birth and raised as females despite the e
presence of ambiguous genitalia in all or most), and
all virilized after the time of expected puberty due to
a rise in serum testosterone to or toward the normal
male range. The age at diagnosis varied from 4 to 37
years. Ten individual.S were studied by the sarne
psychologist, and change of gender role (social sex)
from female to male occurred in 3 subjects and in the
2 presumed affected subjects not studied. The indi-
vidual with the highest serum testosterone level
maintained female sexual identity, and in 2 families
some of the affected males changed gender role and
others did not. Thus, while androgen action plays a
role in the process, additional undefined psychologi-
cal, social, and/or biologic factors must be determi-
nants of gender identity/role behavior.
Management of the 7 individuals who chose to
maintain female sex roles included castration, clitoro-
plasty, vaginal enlargement procedures when appro-
priate, treatment of hirsutism, cricoid cartilage
reduction, and estrogen replacement. Three of the 7
are married (2 twice), 1 is involved in a long-term het-
erosexual relationship, 1 is engaged to be married, and
the other 2 are not married and not believed to be sex-
ually active. The 3 subjects who changed gender role
behavior to male underwent hypospadias repair, and
1 was given supplemental testosterone therapy. One
of these men is divorced, and the other 2 eaged 29 and
35 years) are unmarried. The diagnosis in 8 of these
subjects was made after the time of expected puberty;
it is unclear whether the functional and social out-
comes would have been different if the diagnosis had
been made and therapy begun earlier in life.
References
l. Abraham G. Raclioimmw10assay of steroids in biological materiais.
Acta Endoc1inol (Copenh) 75(Suppl 183): 1-42, 1974.
2. Akesode F, Meyer W, Migeon C. Male pseudohennaphroclitism with gy-
naecomastia due to testicular 17-ketosteroid reductase deficiency.
Clin Endocrinol 7: 443-52, 1977.
3. Andersson S, Geissler WM, Wu L, Davis DL, Grumbach MM, New MI,
Schwarz HP, Blethen SL, Mendonca BB, Bloise W, Witchel SF, Cutler
GB Jr, Griffin JE, Wilson JD, Russell DW. Molecul.a r genetics and
pathophysiology of 1713-hydroxysteroid dehydrogenase 3 deficiency. J
Clin Endocrinol Metab 81: 130--36, 1996.
4. Andersson S, Russell DW, Wilson JD. 1713-hydroxysteroid dehydroge-
nase 3 deficiency. Trends Endocrinol Metab 7: 121-26, 1996.
5. Arnhold LJP, Mendonca BB, Bisi H, Russo FO, Nicolau W, Bloise W,
Moreira-Filho CA. Normal expression of the serologically defined H-Y
antigen in Leyclig cell hypoplasia. J Urol 140: 1549-52, 1988.
6. Arnhold LJP, Mendonca BB, Diaz JAP, Nogueira C, Batista MC,
Madureira G, OliviraD, Nicolau W, Bloise W. Prepubertal male pseudo-
hennaphroclitism due to 17-ketosteroid reductase deficiency: Diag-
nostic value of a hCG test and lack of HLA association. J Endocrinol
lnvest 11: 319-22, 1988.
7. Balducci R, Toscano V, Wright F, Bozzalon F, cli Piero G, Maroder M,
Parei P, Sicarra F, Boscherini B. Familiai male pseudohermaphro-
clitis m with gynaecomastia due to 1713-hydroxysteroid dehydrogenase
deficiency. A report of 3 cases. Clin Endocrinol 23: 439-44, 1985.
8. Berthezene F, Forest MG, Grimaud JA, Claustrat B, Momex R. Leyclig-
cell agenesis. A cause of male pseudohennaphroclitism. N Eng! J Med
295: 969-72. 1976.
9. Bloise W. Deficiencia da 1713 ceto reductase no sexo masculino e fem-
inino ftl1esis]. Tese de Livre Docencia Apresentata a Faculdade de
Medicina da Universidade de Sao Paulo, Sao Paulo, Brasil, 1988.
10. Boehmer ALM, Blinkmann AO, Sandjuijl LA, Halley DJJ, Nienneijer
MF, Andersson S, de Jong FH, Kayserili H, de Vroede MA, Otten BJ,
Rouwe CW, Mendonca BB, Rodrugues C, Bode HH, de Ruiter, Dele-
marre-van der Waal HA, Drop SLS. 1713-hydroxysteroid dehyd.roge-
nase-3 deficiency: Diagnosis, phenotypic variability, population genet-
ics and worldwide d.istribution of ancient and de novo mutations. J
Clin Endocrinol Metab 84: 4713-21, 1999.
11. Brito VN, Batista MC, Borges MF, Latronico AC, Koher MBF, Thrirone
ACP, Jorge BH, Arnhold LJP, Mendonca BB. Diagnostic value of fluo-
rometric assays in the evaluation of precocious puberty. J Clin En-
docrinol Metab 84: 3539-44, 1999.
12. Can S, Zhu YS, Cai LQ, Ling Q, Karz MD, Akgun S, Shackleton CHL, Im-
perato-McGin!ey J. The identification of 5a-reductase-2 and 1713-hy-
droxysteroid dehydrogenase-3 gene defects in male pseudohennaphro-
dites from a Turkish kindred. J Clin E.ndocrinol Metab 83: 560-Q9, 1998.
13. Caufriez A. Male pseudohennaphroclitism dueto 17-ketoreductase de-
ficiency: Report of a case without gynecomastia and without vaginal
pouch. Am J Obstet Gynecot 154: 148-49, 1986.
14. David M, Calemard-Michel L, Morei Y, Forest MG. Di.fficulties in the cli-
agnosis of 1713-hydroxysteroid dehydrogenase (1713-HSD) deficiency,
mincking the androgen insensitivity syndrome (AIS) in early i.nfancy
fabstract] . Hom1 Res 48: Abstract 529, 1997.
15. Dumic M, Plavsic V, Fattorini I, Ille J . Absent spem1atogenesis despite
earty bilateral orchidopexy in 17-ketoreductase deficiency. Honn Res
22: 100-106, 1985.
16. Eckstein B, Cohen S, FarkasA, Rosler A. The nature ofthe defect in fa-
miliai male pseudohennaphroclitism in Arabs of Gaza J Clin En-
docrinol Metab 68: 477-85, 1989.
17. Forest M, de Peretti E, Campo-Paysaa A. Cas familiai de pseudo-her-
maphroclisme mascuJin par deficit en 17 ceto-reductase: Diagnostic
tardif chez a "tante" d'un sttjet porteur du meme deficit. Ann En-
docrinol (Paris) 40: 545-46, 1979.
18. Forest M, Nivelon J. 17-Ketoreductase deflciency (17-KRD) in an in-
fant: Differential cliagnosis with the androgen insensitivity syndrome
(AIS). Pecliatr Res 19: 624, 1984.
19. Frank RT. The fonnation of an artificial vagi.na without operation. Am
J Obstet Gynecot 35: 1053-55, 1938.
20. Geissler WM, Davis DL, Wu L, Bradshaw KD, Patel S, Mendonca BB,
Eliston KO, Wilson JD, Russell DW, Andersson S. Male pseudoher-
maphroclitism caused by mutations of testicular 1713-hydroxysteroid
dehydrogenase 3. Nat Genet 7: 34--39, 1994.
21. Givens JR, Wiser WL, Surnmitt RL, Kerber IJ, Andersen RN, Pittaway
AB, Fish SA. Fanlilial male pseudohennaphroclitism without gyneco-
mastia due to deficient testicular 17-ketosteroid reductase activity. N
Eng! J Med 291: 938-44, 1974.
22. Goebelsmann U, Horton R, Mestrnan JH, Arce JJ, Nagata Y, Nakamura
RM, Thomeycroft IH. Male pseudohennaphroditism due to testicular
17~-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol
Metab 36: 867-79, 1973.
23. Gregory JW, Aynsley-Green A, Evans BA, Hughes lA, Werder EA, Zach-
mann M. Deficiency of 17-ketoreductase presenti.ng before puberty.
Hom1 Res 40: 145-48, 1993.
24. Griffin JE, McPhaul MJ, Russell DW, Wilson JD. The androgen resis-
tance syndromes: Steroid 5a-reductase 2 deficiency, testicular femi-
nization, and related d.isorders. ln: Scriver CR, Beaudet AL, Sly WS,
Valle D, eds. The metabolic and molecular bases of inherited d.isease,
7th ed. New York: McGraw-Hill, (in press), 2000.
25. Griffin JE, Wilson JD. Disorders of sexual clifferentiation. ln: Walsh PC,
Resnilc AB, Stamey TA, Vaugl1an EDJ, eds. Campbell's textbook of
urology. Philadelphia: WB Saunders, pp 1509-42, 1992.
26. Gross DJ, Landau H, Kohn G, Farkas A, Elrayyes E, El-Shawwa R,
Lasch EF, Rosler A. Male pseudohennaphroditism dueto 1713-hydrox-
ysteroid dehydrogenase deficiency: Gender reassignment in early in-
fancy. Acta Endocrinol 112: 238-46, 1986.
27. Grumbach MM, Auchus RJ. Estrogen : Consequences and implications
of hun1an mutations in synthesis and action. J Clin Endocrinol Metab
84: 4677-94, 1999.
28. lmperato-McGinley J, Peterson RE, Stoller R, Goodwin WE. Male
pseudohermaphroclitism secondary to 1713-hydroxysteroid dehydroge-
nase deficiency: Gender role change witl1 puberty. J Clin Endocrinol
Metab 49: 391-95, 1979.
29. Knorr D, Bid.lingmaier F, Butenandt O, Engelliardt D. 1713-Hydroxys-
teroid-oxydoreduktase-mangel bei pseudohennaphroclitismus vom
typ des Reifenstein-syndroms. Klin Wochenschr 52: 537-43, 1974.
30. Kohn G, Lasch EE, El Shawwa R, Litvin Y, Rosler A. Male pseudoher-
maphroclitism due to l 7j}-hydroxysteroid dehydrogenase deficiency
 17[3-HYDROXYSTEROID DEHYDROGE ASE
(l 7J3-HSD) in a large Arab kinship. Studies on the natural history of the
defect. J Pediatr Endocrinol l: 29-37, 1985.
31. Lanes R, Brown TR, de Bustos EG, Valverde B, Pieretti RB, Bianco N, Or-
tega G, Migeon CJ. Sibship with 17-ketosteroid reductase (17-KSR) defi-
ciency and hypothyroidism. Lack of linkage of histocompatibility leuco-
cyte antigen and 17-KSR loci. J Clin Endocrinol Metab 57: 190-96, 1983.
32. Leinonen P, Dunkel L, Perheentupa J , Vihko R. Male pseudohermaph-
roditism dueto deficiency of testicular 17-ketosteroid reductase. Acta
Paediatr Scand 72: 211-14, 1983.
33. Levine LS, Lieber E, Pang S, New Ml. Male pseudoherrnaphroditism
due to 17-ketosteroid reductase deficiency diagnosed in the newbom
period [abstract]. Pediatr Res 14: 480, 1980.
34. Mendonca BB, Inacio M, Costa EMF, Arnhold lJP, Silva FAQ,
icolau W, Bloise W, Russell DW, Wilson JD. Male pseudohermaph-
roditism due to steroid 5a-reductase 2 deficiency: Diagnosis, psy-
chological evaluation, and management. Medicine (Baltimore) 75:
64-76, 1996.
35. Mendonca BB, Arnhold LJ, Bloise W, Andersson S, Russell DW, Wilson
JD. l 7J3-hydroxysteroid dehydrogenase deficiency in women. J Clin
Endocrinol Metab 84: 802-4, 1999.
36. Meyer-Bahlburg HFL. Gender assignrnent and reassignrnent in 46,XY
pseudohermaphroditism and related conditions. J Clin Endocrinol
Metab 84: 3455-58, 1999.
37. Millan M, Audi L, Martinez-Mora J, Martinez de Osaba MJ, Viguera J ,
Esmatjes E, Peig M, Vilardell E. 17-ketosteroid reductase deficiency in
an adult patient without gynaecomastia but with fernale psychosexual
orientation. Acta Endocrinol 102: 633-40, 1983.
38. Moghrabi N, Hughes IA, Dunaif A, Andersson S. Deleterious rnissense
mutations and silent polyrnorphism in the hurnan l 7J3-hydroxysteroid
dehydrogenase 3 gene (HSDl 7J33). J Clin Endocrinol Metab 83:
2855-60, 1998.
39. Nivelon JL, Forest MG, Nivelon-Chevallier A, Turc C, Dauvergne M,
Tenenbaurn D. Diagnostic prenatal dans une forme farniliale de
pseudohermaphrodisme masculin par deficit en 17-ceto reductase. J
Genet Hum 33: 179-86, 1985.
40. Quigley C, De Bellis A, Marschke K, El-Awady M, Wilson E, French F.
Androgen receptor defects: Historical, clinical, and molecular per-
spectives. Endocr Rev 16: 271-321, 1995.
41. Rogers DG, Chasalow Fl, Blethen SL. Partial deficiency in 17-ketosteroid
reductase presenting as gynecomastia Steroids 45: 19&--200, 1985.
42. Rosler A, Kohn G. Male pseudohermaphroditism due to 17 beta-hy-
droxysteroid dehydrogenase deficiency: Studies on the natural history
of the defect and effect of androgens on gender role. J Steroid Biochem
19: 663-74, 1983.
43. Rosler A, Belanger A, Labrie F. Mechanisrns of androgen production in
3 DEFICIENCY 309
male pseudohermaphroditism due to l 7J3-hydroxysteroid dehydroge-
nase deficiency. J Clin Endocrinol Metab 75: 773-78, 1992.
44. Rosler A. Steroid l 7j3-hydroxysteroid dehydrogenase deficiency in
rnan: An inherited form of male pseudohem1aphroditism. J Steroid
Biochem Mol Biol 43: 989-1002, 1992.
45. Rosler A, Silverstein S, Abeliovich D. A (RSOQ) mutation in 17 beta-hy-
droxysteroid dehydrogenase type 3 gene arnong Arabs of Israel is as-
sociated with pseudoherrnaphroditism in males and normal asyrnpto-
matic females. J Clin Endocrinol Metab 81: 1827-31, 1996.
46. Saez JM, De Peretti E, Morera AM, David M, Bertrand J. Farnilial rnale
pseudohermaphroditism with gynecomastia due to a testicular 17-ke-
tosteroid reductase defect !. Studies in vivo. J Clin Endocrinol Metab
32: 604-10, 1971.
47. Saez JM, Morera AM, De Peretti E, Bertrand J. Further in vivo studies
in male pseudohermaphroditism with gynecomastia dueto a testicular
17-ketosteroid reductase defect ( compared to a case of testicular fem-
inization). J Clin Endocrinol Metab 34: 598-600, 1972.
48. Schaison G, Sitruk LR. Male pseudohermaphroditism dueto testicular
17-ketosteroid reductase deficien'cy. Horm Metab Res 8: 307-10, 1976.
49. Schonfield WA, Beebe GW. Nomlal growth and variation in the rnale
genitaliafrom birth to maturity. J Urol 48: 759-77, 1942.
50. Tourniaire J, Laubie B, Saez J , Leung TK, Perrin J , Dutrieux L, Guinet
P. Pseudoherrnaphrodisme male farnilial par deficit testiculaire en 17-
cetosteroide-reductase. Ann Endocrinol (Paris) 34: 461-75, 1973.
51. Ulloa-Aguirre A, Bassol S, Poo J , Mendez JP, Mutchinick O, Robles C,
Perez-Palacios G. Endocrine and biochencal studies in a 46,XY phe-
notypically male infant with 17-ketosteroid reductase deficiency. J Clin
Endocrinol Metab 60: 639-43, 1985.
52. Virdis R, Saenger P, Senior B, New Ml. Endocrine studies in a pubertal
male pseudohermaphrodite with 17-ketosteroid reductase deficiency.
Acta Endocrinol 87: 212-24, 1978.
53. von Schnakenburg K, Bidlingrnaier F, Engelliardt D, Butenandt O, Un-
terburger P, Knorr D. 17-ketosteroid reductase deficiency-plasma
steroids and incubation studies with testicular tissue. Acta Endocrinol
94: 397-403, 1980.
54. Wilson JD, Griffin JE, Russell DW. Steroid 5a-reductase 2 deficiency.
Endocr Rev 14: 577-93, 1993.
55. Wilson JD. The role of androgens in male gender role behavior. Endocr
Rev 20: 726-37, 1999.
56. Wilson SC, Hodgins MB, Scott JS. Incomplete masculinization due to a
deficiency of l 7J3-hydroxysteroid dehydrogenase: Comparison of pre-
pubertal and peripubertal siblings. Clin Endocrinol 26: 459-69, 1987.
57. Wit JM, van Hooff CO, Thijssen JH, Van den Brande JL. In vivo and in
vitro studies in a 46,XY phenotypically female infant with 17-ketos-
teroid reductase deficiency. Horm Metab Res 20: 367-74, 1988.