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The Journal of Clinical Endocrinology & Metabolism 87(11):5119 –5124
Copyright © 2002 by The Endocrine Society
doi: 10.1210/jc.2001-011531
Sex-Typed Toy Play Behavior Correlates with the Degree
of Prenatal Androgen Exposure Assessed by CYP21
Genotype in Girls with Congenital Adrenal Hyperplasia
ANNA NORDENSTRÖM, ANNA SERVIN, GUNILLA BOHLIN, AGNE LARSSON,
AND
ANNA WEDELL
Department of Pediatrics, Karolinska Institute, Huddinge University Hospital (A.N., A.L.), S-141 86 Stockholm, Sweden;
Department of Psychology, University of Uppsala (A.S., G.B.), S-751 42 Uppsala, Sweden; and Department of Molecular
Medicine, Karolinska Institute, Karolinska Hospital (A.W.), S-171 76 Stockholm, Sweden
Previous studies have shown that girls with congenital adrenal hyperplasia (CAH), a syndrome resulting in overproduction of adrenal androgens from early fetal life, are behaviorally masculinized. We studied play with toys in a structured
play situation and correlated the results with disease severity,
assessed by CYP21 genotyping, and age at diagnosis. Girls
with CAH played more with masculine toys than controls
when playing alone. In addition, we could demonstrate a doseresponse relationship between disease severity (i.e. degree of
B
EHAVIORAL STUDIES in children with congenital adrenal hyperplasia (CAH) are important for several reasons. They provide information that is important for the
management and follow-up of patients. In addition, the influence of prenatal and neonatal hormonal factors on sex
differences in behavior can be studied in girls with CAH, as
these children have been exposed to elevated levels of androgens from early fetal development.
In the 1960s, Money and Ehrhardt (1) reported that girls
with CAH often preferred boys’ toys and outdoor sports.
Since then, several studies have shown that girls with CAH
are behaviorally masculinized (2– 4). Girls with CAH reached
higher scores than their sisters in some cognitive parameters,
such as three-dimensional rotational spatial ability, a pattern
similar to that seen in comparisons of normal boys and girls
(5, 6). Women with CAH showed a typical male pattern for
measures of personality traits (7). In direct observational
studies of toy play Berenbaum et al. (8, 9) showed that girls
with CAH played more with boys’ toys and less with girls’
toys than their unaffected sisters. The results regarding the
correlation of disease severity with degree of masculinization
of behavior have been somewhat contradictory (2, 3, 8, 10).
Berenbaum et al. (11) and our group (Servin, A., A. Nordenström, A. Larsson, and G. Bohlin, submitted for publication)
have shown that childhood boy-typical interest was strongly
associated with the degree of virilization of the genitalia, an
indicator of prenatal androgen exposure. It has been argued
that the behavioral changes in girls with CAH are the results
of the parental treatment triggered by the virilization of
genitalia at birth (13). On the other hand, the persistence of
sex-atypical interests, activities, and careers in adolescent
girls with CAH suggests that they result from the direct
Abbreviation: CAH, Congenital adrenal hyperplasia.
fetal androgen exposure) and degree of masculinization of
behavior. The presence of a parent did not influence the CAH
girls to play in a more masculine fashion. Four CAH girls with
late diagnosis are also described. Three of the four girls played
exclusively with one of the masculine toys, a constructional
toy. Our results support the view that prenatal androgen exposure has a direct organizational effect on the human brain
to determine certain aspects of sex-typed behavior. (J Clin
Endocrinol Metab 87: 5119 –5124, 2002)
effects of androgens on the developing brain rather than
social responses, because these girls were brought up as
females (14). The vast majority of girls with CAH have a
typical female gender identity (15).
CAH constitutes a family of defects in the synthesis of
steroid hormones in the adrenal cortex. In more than 90% of
the cases it is caused by a defect in the 21-hydroxylase gene
(CYP21) (16, 17). The enzyme deficiency results in impaired
synthesis of cortisol and aldosterone. The low cortisol level
results in increased production of ACTH by the pituitary,
which causes hyperplasia of the adrenal glands and increased synthesis of steroid precursors, resulting in high
androgen levels. The androgen excess is present from early
embryogenesis and results in varying degrees of virilization
of the external genitalia in girls depending on the degree of
enzyme deficiency. In severe forms, the virilization may result in uncertainty in gender assignment at birth, and the sex
of some girls is initially designated as male.
The molecular genetics of 21-hydroxylase deficiency have
been studied extensively. More than 95% of the patients are
homozygous or compound heterozygotes for any of nine
different point mutations or deletion of the CYP21 gene. With
very few exceptions there is a good correlation between the
CYP21 genotype and disease severity (18 –20). Deletions or
mutations that completely abolish enzyme activity are referred to as null mutations. Patients who are homozygous for
null mutations have the most severe form of the disease, with
salt loss in the neonatal period and severe prenatal virilization of external genitalia in girls. The I2 splice mutation is
slightly less severe; some homozygous patients are not affected by salt loss. The I172N mutation is associated with
varying degrees of virilization of external genitalia, but only
about 10% of patients with this genotype show signs of salt
loss. The V281L mutation is even milder and is associated
5119
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J Clin Endocrinol Metab, November 2002, 87(11):5119 –5124
Nordenström et al. • Toy Play Correlates with CYP21 Genotype in CAH
with nonclassical CAH without virilization of external genitalia at birth. Untreated, these patients develop symptoms of
androgen excess later in life, such as accelerated growth rate,
hirsutism, or infertility. At birth, most children with CAH are
diagnosed either because of clinical signs or in neonatal
screening programs. The treatment consists of glucocorticoid
and mineralocorticoid substitution that decreases/normalizes ACTH levels and thereby androgen production. Corrective surgery on the external genitalia is performed when
needed (17).
In this study we wanted to investigate further the possible
influence of disease severity, i.e. the degree of fetal androgen
exposure, on toy play and toy preference in girls with CAH.
For this purpose we took advantage of the possibility of
determining the degree of 21-hydroxylase deficiency by
CYP21 genotyping. There is a good genotype-phenotype correlation (18 –20), and genotyping is also a more objective way
to measure disease severity compared with other methods,
such as Prader score or classification according to salt loss.
Furthermore, we have previously shown that at birth the
level of one of the hormones preceding the enzyme block,
17-hydroxyprogesterone, is correlated to the CYP21 genotype (21). This indicates that the androgen level, to which the
fetus is exposed, during intrauterine life is related to the
genotype. We measured sex-typed play behavior in a structured play situation. To assess parental influence, toy play
was studied when the child was playing alone as well as
when a parent was present. A possible influence of postnatal
androgen exposure on toy preference was studied in four
children with late diagnosis who had been untreated until
3– 6 yr of age.
Subjects and Methods
Study population
All families in Sweden with girls with CAH between 1 and 10 yr of
age were contacted during 1997–2000 and asked to participate. Five
families did not agree to participate. A total of 40 girls with CAH in 35
families were included in the study. CYP21 mutation analysis was performed in 39 of these children. The 4 girls who had been diagnosed
prenatally and treated with dexamethasone in utero until term were
excluded from this study. Four girls had been missed by the screening
and were diagnosed late, at 3– 6 yr of age. Healthy girls matched for age
⫾2 months on a case by case basis were used as controls.
Mutation analysis
CYP21 mutation analysis was carried out using allele-specific PCR
from genomic DNA prepared from venous blood samples (22). This
detects the 95% of alleles that carry any of the common pseudogenederived mutations. Additional rare alleles were characterized by direct
DNA sequencing (23). The genotypes were divided into four groups
with respect to the severity of the mutation of the allele with the mildest
mutation: null, I2 splice, I172N, and V281L (see Tables 1 and 2). We were
able to obtain a sample for CYP21 mutation analysis from all but one
child.
Toy play
In a structured toy play situation, 10 different toys that had previously
been defined as masculine, feminine, or neutral for children in the
presently employed ages were used (9, 24 –27). Feminine toys included
a doll with a blanket and feeding bottle, Barbie and Ken dolls, a teapot
with four cups, and a female doll’s head with brush, comb, and mirror.
TABLE 1. CYP21 genotypes of the 31 girls with CAH diagnosed in the neonatal period
Toy play, seconds, median (range)
Genotype group
No.
Age at study
yr (mean)
Masculine
Feminine
Neutral
Prader score
(mean)
SW/SV
Nulla
12Splice
10
9
5.3
6.3
394 (273–598)
340 (39 – 478)
25 (0 –144)
0 (0 –275)
0 (0 – 65)
0 (0 –346)
3.8
3.4
10/0
9/0
1172N
9
6.2
25 (0 – 420)
16 (0 –322)
0 (0 –386)
2.0
V28IL
3
4.4
353 (104 –386)
60 (0 –103)
81 (0 –180)
0.7
Control
31
5.8
231 (0 – 420)
18 (0 – 420)
43 (0 – 420)
Genotypes included
in the group
Null/null
12Splice/null
12Splice/12Splice
12Splice/null or
12Splice/12Splice
1172N/null
1172N/12Splice
1172N/1172N
V28IL/null
V281L/12Splice
4/4b
c
No.
10
6
2
1
2
4
3
2
1
The mean Prader score and classification with respect to salt-wasting (SW) or simple virilizing (SV) form of CAH as well as the number of
seconds that the girls in the different genotype groups played with the different types of toys are also listed.
a
Null mutations were CYP21 deletion, V281L⫹L307insT (two mutations in the same allele), L307insT⫹Q318X, I172N⫹
ClusterE6⫹V281L⫹L307insT⫹Q318X⫹R356W (six point mutations in the same allele), Q318X, and W405X.
b
For one patient, who was adopted, the classification was not available.
c
The patients in the V281L genotype group were nonclassical.
TABLE 2. CYP21 genotypes of the four girls with CAH diagnosed later in childhood
Toy play, seconds
Genotype
Age at diagnosis
(yr)
Age at study
(yr)
Masculine
Feminine
Neutral
I172N/I172N
I172N/null
V281L/I172N
V281L/I172N
3
3
6
6
9
9
10
8
420
420
420
246
0
0
0
131
0
0
0
10
Patients with late diagnosis.
Toy kept
Doll
Doll
Ball
Doll
Nordenström et al. • Toy Play Correlates with CYP21 Genotype in CAH
J Clin Endocrinol Metab, November 2002, 87(11):5119 –5124 5121
Masculine toys were a bus, a garage with four cars, a constructional toy
(Lincoln logs), and two fighting figures. Neutral toys were a sketchbook
and a deck of cards. The toys were arranged in a standard order in a
semicircle on the floor in the homes of the children, with every other toy
being masculine and feminine and the neutral toys in between. The child
was asked to sit in the middle of the semicircle and was videotaped for
7 min when playing alone and for 7 min when playing with her parent.
The play order, alone vs. with a parent, was alternated. The families with
a girl with CAH could choose whether the mother or the father would
participate (two fathers participated). The control families were matched
for these factors. The tapes were then scored for the number of seconds
that the child played with the different types of toys. Play was defined
as the child touching the toy. The person who scored the tapes was blind
to the status of the child on the tape. At the end of the visit the children
were given a toy to keep as a present. They were able to choose between
a doll (feminine), a car (masculine), and a ball (neutral).
Statistical analysis
The girls with CAH, regardless of disease severity, and the controls
were compared with respect to toy play using the Mann-Whitney U test.
The relationship between toy play and genotype was analyzed by means
of the Spearman rank order correlation coefficient. The groups were
graded according to enzyme activity, with the null genotype group
being the lowest and the controls the highest. The girls with late diagnosis were compared with respect to toy play with other girls of the same
age, both controls and girls with CAH and early diagnosis, using the
Kruskal-Wallis and Mann-Whitney U tests. Intraindividual comparison
of toy play with and without a parent was analyzed using Wilcoxon’s
signed ranks test. Fisher’s exact test was used to compare the choice of
toy to keep as a present. The choice of doll vs. one of the other toys and
the choice of car vs. one of the other toys was tested for the CAH girls
with early diagnosis (as a group) compared with the controls. The choice
of doll vs. one of the other toys was tested for the CAH girls with late
diagnosis compared with girls with CAH and early diagnosis of the
same age as well as with girls with the same mutations and early
diagnosis regardless of age. SPSS computer program 10.1 (SPSS, Inc.,
Chicago, IL) was used for all the statistical analyses. The ␣ level was set
at 0.05.
The study was approved by the ethical committee of the Karolinska
Institute (Stockholm, Sweden). Informed consent was obtained from all
participants.
Results
The 31 girls with early diagnosis and start of treatment in
the neonatal period were divided into 4 genotype groups
(Table 1). Three of the groups were of equal size, and 1 was
smaller, comprising only 3 children. The mean Prader scores
for the different genotype groups are also listed in Table 1.
In addition, there were 4 girls with late diagnosis and treatment (Table 2). Two of them belonged to the I172N genotype
group and had started treatment at 3 yr of age. The other 2
belonged to the V281L genotype group and had been treated
since 6 yr of age (Table 2).
We compared toy play for CAH and control girls when the
children were playing alone. As expected, there was a significant difference in toy play for masculine toys between the
girls with CAH as a group and the controls (P ⫽ 0.017). In
addition, we found a significant correlation between the degree of disease severity as measured by CYP21 genotypes
and the amount of time the CAH girls spent playing with
masculine toys (r ⫽ ⫺0.39; P ⫽ 0.002; Fig. 1A). The correlation
was also significant when the controls were excluded (r ⫽
⫺0.41; P ⫽ 0.024). For play with neutral toys the correlation
was significant, but less striking (r ⫽ 0.27; P ⫽ 0.036), and the
coefficient when the controls were excluded was r ⫽ 0.34; P ⫽
0.064 (Fig. 1C). The correlation was not significant for play
FIG. 1. Amount of time (seconds) that the CAH girls played with
masculine toys (A), feminine toys (B), and neutral toys (C) in relation
to the CYP21 genotype groups. The box plot shows the median values
and the 10th, 25th, 75th, and 90th percentiles. The extreme values are
denoted with an asterisk, and the outliers are denoted with a circle.
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J Clin Endocrinol Metab, November 2002, 87(11):5119 –5124
with the feminine toys (Fig. 1B; r ⫽ 0.20; P ⫽ 0.129 with the
controls included and r ⫽ 0.12; P ⫽ 0.53 with the controls
excluded from the calculation). In conclusion, the milder the
disease, i.e. the higher the enzyme activity and therefore
the lower the androgen level, the less time was spent with the
masculine toys, whereas neutral toys were increasingly preferred. As shown in Fig. 1, the girls with CAH in all of the
genotype groups played more with the masculine than with
the feminine or neutral toys. The control girls also played
more with the masculine toys than with the feminine ones
(Fig. 1 and Table 1).
Figure 2 shows the difference in the amount of time that
the girls with early diagnosis in the different genotype
groups spent playing with the different types of toys alone
compared with when a parent was present. Positive values
thus represent time spent with the toys when the child was
alone, whereas negative values indicate toys that were chosen more often when the parent was present. For the control
girls the influence of the parents was negligible, the median
difference with or without a parent was 10 sec for masculine
toys. As a group, the CAH girls played somewhat less with
the masculine toys when the parent was present (the median
difference was 39 sec), but this difference was not significant
(P ⫽ 0.12). When considering the different genotype groups
separately, the girls seemed to be increasingly diverted from
masculine toys by the parents with decreasing disease
severity.
The results of the study of choice of toy to keep as a present
are shown in Fig. 3. The girls in the null group chose a car
more often than a ball, whereas the girls with I2 splice chose
a car or a ball equally often. Some of the girls with I172N
chose a doll. None of the three girls with V281L and two of
the control girls chose a car. The observed difference between
FIG. 2. The mean difference in the amount of time that the girls in
the different genotype groups played with the different types of toys
when they played alone compared with when they played with a
parent (bars represent time playing alone minus time playing with
parent). Positive values thus represent preference for toys when the
child was alone, whereas negative values indicate toys that were
chosen more often when the parent was present.
Nordenström et al. • Toy Play Correlates with CYP21 Genotype in CAH
girls with CAH and controls in choice of car and choice of doll
was significant (P ⫽ 0.001).
There were four girls in this study with late diagnosis
(Table 2). The two girls diagnosed at 3 yr of age with the
I172N mutation played more with the masculine toys than
the girls with the same mutation but early diagnosis and
treatment, as shown in Fig. 1A and Tables 1 and 2. They both
played exclusively with the constructional toy. In the mildest
group, mutation V281L, the two girls with late diagnosis (at
age 6 yr) showed different toy play patterns. One girl, studied
at 8 yr of age, played in a way similar to that of the girls with
the same mutation treated early on. The other girl, studied
at age 10 yr, played with the constructional toy the whole
time when she played alone. To substantiate these observations, the four girls with a late diagnosis were compared with
girls of the same age, 8 –10 yr, both controls (n ⫽ 12) and girls
with CAH diagnosed in the neonatal period, including the
severe forms (n ⫽ 8). Play with the constructional toy was
analyzed separately. The girls with late diagnosis played
significantly more with the constructional toy (median, 420
sec; range, 64 – 420 sec) than control girls of the same age
(median, 13 sec; range, 0 –316 sec; P ⫽ 0.01). There was a
statistical trend that the girls with late diagnosis played more
with the constructional toy than the other girls with CAH of
the same age (median, 420 sec; range, 64 – 420 sec vs. median,
218 sec; range, 0 – 420 sec; P ⫽ 0.1). In addition, we compared
the choice of toy to keep as a present between the different
groups of girls of this age. Three of the girls with late diagnosis chose a doll, and the fourth chose a ball. The controls
were more likely to choose a ball (car, n ⫽ 1; ball, n ⫽ 10; doll,
n ⫽ 1). The CAH girls with early diagnosis chose a car and
a ball equally often (car, n ⫽ 4; ball, n ⫽ 4). The difference
in choice of doll between the patients with late and early
diagnosis was significant (P ⫽ 0.018). The choice of doll as
a toy to keep as a present was also compared for the patients
with the I172N or V281L mutations regardless of age or late
(n ⫽ 4) vs. early diagnosis (n ⫽ 12). The girls with late
diagnosis chose a doll more often (P ⫽ 0.052).
FIG. 3. Choice of toy to keep as a present in the different genotype
groups.
Nordenström et al. • Toy Play Correlates with CYP21 Genotype in CAH
Discussion
We found that girls with CAH played more with masculine toys than controls, which is in line with the findings of
previous studies (9, 3, 28). In addition, this study is the first
to correlate behavior to CYP21 genotype, which is known to
reflect the degree of disease severity and thus the degree of
fetal androgen exposure. We found a dose-response relationship between disease severity (i.e. degree of fetal androgen exposure) and degree of masculinization of toy play and
preference. This finding supports a biological basis for the
differences in play behavior between CAH girls and unaffected girls. It has been argued that the masculinization of
play behavior that has been seen in girls with CAH can be
attributed to parental influence due to expectations of a more
masculine behavior in these girls triggered by the virilization
of external genitalia at birth (13). Our results do not support
this view. When a parent was present, there was no difference in toy play for the girls with the most severe form of
CAH, and the girls with less severe forms of CAH played
less, rather than more, with masculine toys.
The possible effects of prenatal vs. postnatal androgen
exposure on behavior have been discussed. Hormones are
considered to affect behavior in different ways (29), namely
by having an early organizational effect that takes place
during certain critical periods of development and/or a later
activational effect, for instance during puberty. Maze learning in rodents, for example, is dependent on organizational
influences of androgens (29). In this study the results in girls
with CAH diagnosed and treated at an early age favor a
prenatal, organizational effect of androgens during the development of the central nervous system. On the other hand,
even though there are few observations, our results for the
girls with CAH diagnosed late indicate that postnatal androgens may have effects as well. The girls with late diagnosis all had less severe forms of CAH and can be assumed
to have been exposed to lower levels of androgens in utero.
They were diagnosed at 3 or 6 yr of age and therefore had
an overproduction of androgens during the first years of life.
Three of these girls played with the Lincoln logs the whole
time when they played alone. This result was significantly
different from the result for the controls in the same age
group. In addition, there was a statistical trend that the girls
with late diagnosis played more with the constructional toy
compared with CAH girls of the same age but with early
diagnosis (P ⫽ 0.1). These results are intriguing because they
contrast with the results in the choice of toy to keep as a
present. It was striking that 3 of the CAH girls with late
diagnosis preferred the doll, and only 1 chose the ball to keep,
while among the girls with the same mutations, I172N or
V281L, and early diagnosis 2 of 12 chose a doll. This raises
questions concerning the possibility that prenatal and postnatal androgen exposure may affect different aspects of cognitive development.
In a study by Berenbaum et al. (11) a much less marked
effect of postnatal than prenatal androgen exposure in masculinizing play behavior was shown. This is in agreement
with the results of our studies. However, in their study the
effect on spatial ability or play with constructional toys was
not studied specifically. The possibility of a postnatal effect
J Clin Endocrinol Metab, November 2002, 87(11):5119 –5124 5123
of androgens on central nervous system development has
implications for treatment during the first years of life. It has
been argued that the glucocorticoid dose should be kept low
during the first 1–2 yr to minimize the negative effects on
growth, as no effect of androgens on growth or skeletal
maturation has been observed during this period (30). However, if elevated androgen levels have an effect on the developing brain, perhaps this regimen should only be used in
boys with CAH.
We recognize that additional factors, such as upbringing
and cultural influences, play vital roles in such complex
human characteristics as behavior. We believe, however, that
girls with CAH will benefit from an increased understanding
and acceptance of their preferences as well as from the acknowledgment that parental expectations, if anything, tend
to counteract them.
In conclusion, we have found evidence supporting the
idea that prenatal androgen exposure has a direct organizational effect on the human brain so as to determine certain
aspects of sex-typed behavior. In addition, our data raise
questions concerning possible postnatal effects of androgens.
Further studies are needed on this subject to clarify the possible sensitive periods and levels of androgens mediating
these effects.
Acknowledgments
We gratefully acknowledge Sheri Berenbaum for her valuable contribution in planning this study. We are grateful to the children and their
families for their cooperation.
Received September 21, 2001. Accepted July 30, 2002.
Address all correspondence and requests for reprints to: Dr. Anna
Nordenström, Department of Pediatrics, Karolinska Institute, Huddinge University Hospital, S-141 86 Stockholm, Sweden. E-mail:
[email protected].
This work was supported by the Swedish Medical Research Council,
Grants 4792 and 12198, the Novo Nordisk Foundation, the Märta and
Gunnar Philipson Foundation, the Samariten Foundation, and the
Frimurare Barnhuset Foundation.
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