Neurology
Volume 54 • Number 12 • June 27, 2000
Copyright © 2000 American Academy of Neurology
Articles
Brain
morphology in Klinefelter
syndrome
Extra X chromosome and testosterone
supplementation
A. J. Patwardhan MS, S. Eliez MD, B. Bender PhD, M. G. Linden MS, A. L. Reiss MD
From
the Stanford Psychiatry Neuroimaging Laboratory, Department of Psychiatry and
Behavioral Sciences (A.J. Patwardhan, and Drs. Eliez and Reiss), Stanford
University School of Medicine, CA; and the Department of Pediatrics (Dr.
Bender and M.G. Linden), National Jewish Medical and Research Center, Denver,
CO.
Received
September 29, 1999.
Accepted in
final form January 24,
2000.
Supported
by National Institutes of Health grants HD10032-22, MH01142, and HD31715; and
the David and Lucile Packard
Foundation.
Address
correspondence and reprint requests to Dr. Allan L. Reiss, Department of
Psychiatry and Behavioral Sciences, Stanford University School of Medicine,
401 Quarry Road, Stanford, CA
94305-5719.
Objective:
This
study focuses on variation in brain morphology associated with supernumerary X
chromosome and Klinefelter syndrome (KS). Using an unselected birth cohort of
KS subjects and high-resolution MRI, the authors investigated the
neuroanatomic consequences of the 47,XXY karyotype in the presence and absence
of exogenous testosterone
supplementation.
Methods:
Regional
brain volumes were measured in 10 subjects with KS and 10 age-matched control
men. Five of the KS subjects had received testosterone supplementation since
puberty (KS+T) and five had not
(KS-T).
Results:
KS
subjects showed significant (p
< 0.01) reduction in left
temporal lobe gray matter volumes compared with normal control subjects.
Differences in left temporal gray volumes were also significant between the
KS+T and KS-T groups (p
< 0.01). Verbal fluency
scores were significantly different between the KS+T and KS-T
groups as
well.
Conclusion:
Supernumerary
X chromosome material in men is associated with a reduction in left temporal
lobe gray matter, a finding that is consistent with the verbal and language
deficits associated with KS. Also, relative preservation of gray matter in the
left temporal region is associated with exposure to exogenous androgen during
development. A history of testosterone supplementation also appears to be
associated with increased verbal fluency scores in KS
patients.
Key
words: Brain morphology; Klinefelter
syndrome; Extra X chromosome; Testosterone
supplementation.
Introduction
Cognitive
and neurodevelopmental deficits associated with most forms of sex chromosome
aneuploidy are directly or indirectly related to the addition or absence of
X-chromosomal material. Most information on the neuroanatomic effects of sex
chromosome aneuploidy exists for Turner's syndrome and the 45,X
karyotype. Individuals with X monosomy and Turner's syndrome have
visual-spatial and executive function abnormalities associated with
morphologic anomalies of the parietal
lobe.
[1] [2] [3]
The
significant amount of data about X monosomy is in marked contrast to the lack
of information regarding the neuroanatomic basis of cognitive impairments in
Klinefelter syndrome (KS).
KS is a genetic disorder
caused by the addition of an extra X chromosome in phenotypic men occurring in
an estimated 1:600 live infants. Features of men with KS include a generally
normal appearance, slower growth rates, taller stature, smaller head
circumferences, increased incidence of gynocomastia, low basal testosterone
levels, small testes, and infertility. Many studies provide evidence that men
with KS perform normally on tests of nonverbal abilities and general
intelligence but are specifically impaired on measures of language skills.
These deficits seem to be most apparent in areas of verbal fluency and
expression
[4] [5]
and are
consistent with the high incidence of reading disabilities frequently
diagnosed in 47,XXY children.
[6]
Individual expression for the KS phenotype, however, is
variable.
The purpose of this study was to investigate
the neuroanatomic basis of the cognitive phenotype in an unselected population
with KS. The morphologic effects of extra X chromosomal material on the brain
in the presence and absence of exogenous testosterone supplementation also was
examined. We postulate that impaired verbal and language abilities in
unselected men with KS may be associated with decreased cortical gray matter
volumes, particularly in the areas of the temporal lobe and superior temporal
gyrus (STG).
Materials and
methods.
Patients.
Patients in the KS
sample were recruited from an unselected cohort of 40,000 consecutive newborns
screened for sex chromosome aneuploidy by X-chromatin examination between 1964
and 1974.
[7]
Of the 68 patients
with sex chromosome aneuploidy followed longitudinally, 13 had the 47,XXY
karyotype. Ten of these nonmosaic patients were involved in our present study,
including five who chose to receive testosterone supplementation (KS+T;
mean age at supplementation, 17.4 years; SD, 2.70) and five who received no
exogenous testosterone (KS-T). Cumulatively, the discontinuous intervals
of testosterone supplementation ranged from 2 to 10 years for each KS+T
patient.
The 10 propositi recruited by the National
Jewish Medical and Research Center underwent research MRI scans at University
Hospital in Denver, CO; they ranged in age from 24 to 32 years (mean, 27.32;
SD, 2.99) at the time of image acquisition. Ten individually age-matched
control men were recruited and scanned at both University Hospital in Denver
(n = 7) and at the Stanford University School of Medicine, Stanford, CA
(n = 3). Control subjects were matched within 2 years of age (mean,
26.81; SD, 3.28). Informed consent was obtained from all patients prior to
scanning and
testing.
Neuroimaging.
All
MR data were acquired using 1.5-tesla GE Signa scanners (Milwaukee, WI)
located at the two imaging centers. Coronal three-dimensional volumetric
spoiled gradient echo (SPGR) series were acquired with identical protocols in
both centers (repetition time [TR] = 35, echo time
[TE] = 6, flip angle = 45°; number of excitations
= 1, field of view = 24, matrix = 256 × 192; 124
1.5-mm-thick partitions with 0-mm gap) and were used for all
measurements and analysis. All raw formatted image data acquired in Colorado
were transferred via digital tape to the Stanford Psychiatry Neuroimaging
Laboratory for morphometric analysis.
The SPGR image
data were imported into the program BrainImage
© (Reiss,
1999) for semi-automated image processing, analysis, and quantification.
Volumetric assessment of segmented image data in
BrainImage©
[8]
requires a stepwise process of data importation, removal of nonbrain voxels,
correction of image nonuniformity, positional normalization, and fuzzy tissue
segmentation. Brain tissue was
isolated
[9]
and subdivided into
cerebral lobe, subcortical, cerebellum, and brainstem regions using a modified
Talairach stereotaxic
grid.
[10] [11]
Segmentation of whole tissue into white, gray, and CSF compartments relies on
a constrained fuzzy algorithm based on voxel intensity and tissue
boundaries.
[12]
Additionally, a
single rater manually circumscribed regions of the STG for the 10 KS patients
and 10 control subjects in coronal images oriented perpendicular to the
anterior commissure-posterior commissure plane according to a protocol
previously developed in our laboratory. The boundaries of the STG were defined
by the cortical surface and medially by a line connecting the deepest
extension of the superior temporal sulcus to the furthest extent of the
inferior ramus of the sylvian fissure. Anteriorly, the STG coincided with the
half-way point between the head of the putamen and the anterior commissure.
The most posterior slice of the STG was the first slice where the crus of the
fornix was clearly distinct from the pulvinar. Interrater reliability for this
procedure was previously established as 0.96 as measured by the intraclass
correlation
coefficient.
Neuropsychological
testing.
The relation between testosterone supplementation
and IQ for patients with KS was also examined to ensure that the five
KS+T patients had not been self-selected by receiving testosterone
supplementation. Wechsler Intelligence Scale for Children-Revised
(WISC-R) scores of performance IQ, verbal IQ, and full-scale IQ were gathered
for all KS patients prior to initial testosterone treatments (mean age, 8.5
years; SD, 2.38) and at comparative ages in the KS-T group (mean, 8.2
years; SD, 1.10).
Verbal abilities of adult KS men were
assessed within 3 years of the each patient's MRI scan. Standard scores
from the Memory for Sentences
subtest
[13]
of the
Woodcock-Johnson Language Battery were recorded to assess deficits in verbal
memory. Verbal fluency total scores were also gathered from the Controlled
Oral Word Association Test
(COWAT).
[14]
All testing was
done at the National Jewish Medical and Research Center in
Denver.
Statistics.
Total
brain volumes were distributed normally among the KS and control groups. Group
differences in regional volumes were assessed with analysis of variance
(ANOVA) that took diagnosis as a between-subject factor. Analysis of
covariance (ANCOVA) was also used to assess subregion comparisons after
adjusting for the effects of total (cerebral) or regional (temporal lobe)
compartmental volumes. Fisher's protected least significant difference
(PLSD) test for post hoc comparisons was used to further investigate multiple
comparisons between the control subjects and the KS+T and KS-T
groups for significantly different regions of interest. A two-sided
p
-value of 0.01 was the significance threshold for all
analyses.
Unpaired Student's
t
-tests were used to compare preadolescent IQ data between
the KS+T and KS-T groups. Student's t
-test
was also used to compare the standard Memory for Sentences subtest scores and
COWAT scores between the KS+T and KS-T groups. The association
between left temporal gray volumes and COWAT scores of KS patients was
measured using the Spearman rank correlation coefficient
(rho).
Results.
Control
subjects versus KS patients.
Whole-brain tissue (gray plus
white) volumes were roughly equivalent between the control and KS groups.
However, ANOVA revealed reductions (p
0.01) in total
temporal gray and left temporal gray volumes in KS patients compared with
control subjects (differences in right temporal gray volumes also approached
significance). These differences did not persist during ANCOVA after adjusting
for differences in total cerebral gray volumes between the KS and control
groups.
Total STG gray, right STG gray, left STG gray,
and right STG total tissue (gray + white) volumes were also reduced in
the KS patients compared with control subjects (p
0.01).
To assess the influence of the STG on reduced temporal lobe volumes, ANCOVA
was used to analyze total, right, and left STG gray measures using total right
or left temporal lobe gray volumes as covariates. None of these STG volumes
remained significantly reduced in the KS group after adjusting for reduced
total temporal lobe volumes
(table).
KS = Klinefelter
syndrome; KS+T = KS subjects with testosterone supplementation;
KS-T = KS subjects without testosterone supplementation; STG
= superior temporal
gyrus.
*
Analysis of variance (ANOVA) and Fisher's protected least significant
difference (PLSD) show significance compared to
controls.
ANOVA and Fisher's PLSD show significance compared to KS+T
group.
Analysis of covariance (ANCOVA) with total brain gray volume as a covariate.
Fisher's PLSD shows significance compared to control and KS+T
groups.
Other tissue
compartments of the cerebrum and posterior fossa did not differ between
groups. Differences were absent for ventricular CSF volumes, a region
previously reported to be significantly increased in KS patients when compared
with age-matched control
subjects.
[15]
Testosterone
effects in KS morphology.
Post hoc analyses revealed that
total and left temporal gray, total STG gray, right STG gray, left STG gray,
and right STG total tissue volumes were significantly reduced in the
KS-T group compared with the control group. KS+T volumes were not
significantly different from control subjects for any regions of interest.
Left temporal gray volume was significantly reduced in the KS-T compared
with the KS+T group ().
Figure
1. Left temporal lobe gray volumes
(cm
[3]
) for control subjects,
Klinefelter syndrome (KS) subjects with testosterone supplementation
(KS+T), and KS subjects without testosterone supplementation
(KS-T).
In
order to investigate whether temporal gray volume reductions in KS reflects
disproportionate regional volume loss in the brain, total temporal gray and
left temporal gray volumes were further analyzed using ANCOVA with total
cerebral gray volumes as the covariate. Post hoc analysis showed that
KS-T patients had significantly reduced left temporal gray volumes when
compared with both the control and KS+T groups. However, after covarying,
total temporal gray volumes (right plus left) were no longer significantly
reduced in the KS-T compared with KS+T
patients.
Testosterone effects in KS
cognition.
IQ scores taken prior to initial testosterone
treatment in KS+T patients and for comparative ages in KS-T
patients indicated that the groups had comparable cognitive abilities at the
time when five of the 10 KS patients received testosterone therapy. Unpaired
Student's t
-test revealed no significant differences
between the KS+T and KS-T groups for performance IQ, verbal IQ, and
full-scale IQ scores on the WISC-R.
Verbal abilities in
adult KS men were also examined in areas of verbal memory and verbal fluency
(figure 2). The groups
were not significantly different in scores of the Memory for Sentences subtest
for assessing verbal memory. For verbal fluency, however, the unpaired
Student's t
-tests revealed reduced COWAT scores
(p
0.01) for KS-T patients compared with KS+T
adults.
Figure
2. Verbal abilities in Klinefelter
syndrome (KS). Controlled Oral Word Association Test (COWAT) total scores
(verbal fluency) and Memory for Sentences Test standard scores (verbal memory)
for KS subjects with testosterone supplementation (KS+T) and without
testosterone supplementation (KS-T) in
adulthood.
The
association between left temporal gray volumes and COWAT scores was
investigated in the KS group (figure
3) using the Spearman rank correlation coefficient. A rho
of 0.542 was not significant indicating only a trend for increased COWAT
scores to be associated with increased left temporal gray volumes. However,
testosterone's distinguishing effect on the morphology and verbal
abilities of adults with KS is reflected in
, which
indicates both increased left temporal gray volumes and COWAT scores in
KS+T patients.
Figure
3. Left temporal lobe gray volumes and
verbal fluency in Klinefelter syndrome (KS). Controlled Oral Word Association
Test (COWAT) total scores (verbal fluency) versus left temporal gray volumes
in KS subjects with testosterone supplementation (
)
and
without testosterone supplementation
(
).
Discussion.
Limitations.
The results of this study are tempered by the potential selection
bias that is introduced when only five of the 10 patients with KS chose to
receive testosterone therapy. The cognitive, environmental (e.g.,
socioeconomic status), or physiologic variables occurring in KS may predispose
some individuals to seek testosterone supplementation more than others and may
contribute to the segregated KS+T versus KS-T results presented in
this paper. Scores of general intelligence were not significantly different
between KS+T and KS-T groups as assessed by the WISC-R administered
prior to puberty and testosterone supplementation. It appears, therefore, that
general intelligence was not a predictor for whether a patient received
testosterone treatment or not. As this is an indirect measure of intergroup
compatibility, however, other unassessed variables may be relevant in
selecting for testosterone-treated KS patients.
All of
the KS+T patients began supplementation 5 to 10 years prior to the MR
scan. However, the retrospective nature of this study makes it difficult to
precisely document the timing of testosterone usage. Although the effect of
testosterone supplementation is associated with preserved verbal fluency
scores and left temporal lobe volumes, the supplementation was discontinuous
and highly variable among these patients. Of the five KS+T patients, one
received testosterone supplementation continuously to date, one received
treatment sporadically, two received treatment continuously except for a
single 6 to 12 month interval, and one had had no supplementation 2 years
prior to the MRI. This variability may be a confounding factor in comparing
KS+T and KS-T patients and may blur the distinction between the two
groups.
Although volumetric measurements using the
Talairach coordinate system are sensitive to total lobar differences between
groups, they do not reflect differences that may occur in smaller subregions
of the brain. Specific areas of the frontal and parietal lobes may be
anomalous in KS and may correlate to deficits in phonologic processing, verbal
fluency, and reading that occur in men with KS. Our manual delineation was
limited to the STG--a structure thought to be integral in language
processing. Future investigations, however, should explore other neuroanatomic
areas that are of functional interest in KS but may not be assessed by the
Talairach
system.
Implications.
Our results
show evidence of significant variation in cortical gray volumes in the
temporal lobe of persons with KS, particularly on the left. For KS, reduced
performances on tests of retrieval, reading skill, verbal
IQ,
[16] [17]
and
auditory short-term
memory
[6] [18]
stand in
contrast to relatively preserved abilities on tests of visual-spatial and math
skills. It has been proposed that left-hemisphere-associated tasks such
as verbal fluency and auditory short-term memory are diminished in KS
individuals due to a reduction of the normal cerebral lateralization that
occurs in euploidic men.
[19]
In
normally developing men these skills are thought to be strongest in the left
hemisphere with lateralized verbal abilities occurring primarily in the
temporal lobe. Our finding of reduced left temporal lobe gray volumes in
patients with KS provides a potential structural basis for the observed
neuropsychological deficits. This result remains even after adjusting for the
slight differences in whole brain volumes between KS patients and control
subjects.
The high incidence of dyslexia in men with KS
also implicates functional abnormalities in areas of the brain thought to be
essential for reading. Reduced STG gray volumes in both hemispheres of the
brain are consistent with the bilateral reduction of gray matter within the
temporal lobe. However, ANCOVAs reveal that the STG does not specifically or
principally account for this temporal gray matter reduction in KS patients,
and that there may be more extensive loss of tissue within the entire lobe.
While the STG is thought to play an essential role in reading, it is possible
that the neuropathology associated with developmental reading disorders is
also distributed to areas of the temporal lobe not assessed in this
study.
Subgroup KS+T and KS-T comparisons
seem to indicate that androgen supplementation may affect KS morphology and
cognition. Temporal lobe gray and STG measures for the KS+T group were
not significantly reduced compared with control subjects, indicating a
preservation of temporal lobe gray matter bilaterally in this group.
Conversely, the untreated KS-T group illustrates the morphologic
consequences of KS in the absence of exogenous androgen supplementation
particularly in the left temporal lobe (see
figure
1).
Left temporal gray matter
preservation in KS+T patients may be related to a preservation of
cognitive abilities associated with this area. Memory for Sentences subtest
scores revealed no significant differences between KS+T and KS-T
groups, indicating relatively equivalent abilities in verbal memory. However,
the COWAT scores revealed higher abilities in verbal fluency among the
KS+T group (see figure
2) compared with the KS-T group. An association
between left temporal gray volumes and COWAT scores is difficult to assess
with such a small sample size. However, the relatively segregated distribution
between the KS+T and KS-T groups (see
figure 3) indicates
that testosterone supplementation was a potential influence on both COWAT
scores and left temporal lobe gray volumes. Given the phenotypic variability
that normally occurs among individuals with KS, the almost complete nonoverlap
between KS+T and KS-T groups for left temporal gray volumes and
COWAT scores may reflect a strong effect of exogenous
testosterone.
The cerebral cortex may retain plasticity
well into adulthood, allowing it to be continually modified by externally
supplemented and endogenous hormones. The ability to reverse right and left
patterns of cerebral asymmetry was previously demonstrated in gonadectomized
male and female adult rats. The original hemispheric patterns can be restored
in these animals with hormone
replacement.
[20]
Human
studies suggest a role for endogenous testosterone in determining spatial
abilities and functional lateralization in
children
[21]
and
adults.
[22]
Netley
[23]
showed a strong
correlation of verbal IQ with testosterone levels and early pubertal onset in
a birth cohort of KS patients measured during three intervals of sexual
maturation. Recent evidence also illustrates the cognitive effects of hormone
replacement therapy in surgically menopausal and healthy postmenopausal
women.
[24] [25]
Verbal
memory scores were shown to be preserved or increased in women receiving
estrogen replacement therapy after abdominal hysterectomy and bilateral
salpingo-oophorectomy when compared with preoperative scores and control
subjects who did not receive supplementation. With exogenous estrogen
administration, Sherwin and
Tulandi
[26]
demonstrated a
reversal of verbal memory deficits caused by decreased estrogen levels in
women treated with gonadotropin-releasing hormone agonists for uterine
myomas.
Although the language abilities of
testosterone-treated KS men have not previously been compared with those of
untreated KS men, other studies demonstrated the increased behavioral benefits
after supplementation, even in
adulthood.
[27] [28]
The
mechanism of testosterone's effectiveness, however, is not well
established, given the hormonal competition occurring in pituitary-gonadal
function in KS. Early pubertal boys with KS show increased estradiol levels
even when serum testosterone levels are relatively normal. These elevated
levels persist when testosterone levels drop off by
midpuberty.
[29]
Exogenous
testosterone may exert its influence in the brain through its competition with
serum free estrogen and other hormonal factors (follicle stimulating hormone,
luteinizing hormone), or may be mediated through the aromatization of
testosterone into estradiol
[30]
in specific areas of brain.
Men with KS show cognitive
deficits prior to puberty, even when basal testosterone levels are
comparatively normal.
[31]
The
putative role of testosterone as a primary predictor of cognitive functioning
in men, therefore, is doubtful. However, our investigation of this unselected
KS cohort suggests that testosterone supplementation is associated with
preserved left temporal gray tissue volume, even in postpubertal men with KS.
The small sample size makes it difficult to draw any conclusions about the
structural basis of the cognitive phenotype of KS; however, our results
support the left temporal lobe's role in diminished verbal fluency. With
a larger sample size and a randomized testosterone treatment condition, future
investigations using functional MRI should focus on the neurocognitive aspects
of KS and the neurodevelopmental effects of exogenous testosterone
supplementation.
References
1. Murphy DG, DeCarli C, Daly E, et al. X-chromosome effects on female brain: a magnetic resonance imaging study of
Turner's syndrome. Lancet 1993; 342: 1197-1200.
Abstract
2. Reiss AL, Freund L, Plotnick L, et al. The effects of X monosomy on brain
development: monozygotic twins discordant for
Turner's syndrome. Ann Neurol 1993; 34: 95-107.
Abstract
3. Reiss AL, Mazzocco MM, Greenlaw R, Freund LS, Ross JL. Neurodevelopmental
effects of X monosomy: a volumetric imaging study. Ann Neurol 1995; 38: 731-738.
Abstract
4. Netley C, Rovet J. Verbal deficits in
children with 47,XXY and 47,XXX karyotypes: a
descriptive and experimental study. Brain
Lang 1982; 17: 58-72.
Citation
5. Ratcliffe SG, Masera N, Pan H, McKie M. Head circumference and IQ
of children with sex chromosome abnormalities. Dev Med Child Neurol 1994; 36: 533-544.
Abstract
6. Bender BG, Puck MH, Salbenblatt JA, Robinson A. Dyslexia in 47,XXY boys
identified at birth. Behav Genet 1986; 16: 343-354.
Citation
7. Robinson A, Bender B, Borelli J, Puck M, Salbenblatt J, Webber ML. Sex chromosomal
abnormalities (SCA): a prospective and longitudinal
study of newborns identified in an unbiased manner. Birth Defects Orig Artic Ser 1982; 18: 7-39.
8. Reiss
A. BrainImage. Stanford, CA:
1999.
9. Subramaniam B, Naidu S, Reiss AL. Neuroanatomy in Rett
syndrome: cerebral cortex and posterior fossa. Neurology 1997; 48: 399-407.
Full Text
10. Kaplan DM, Liu AM, Abrams MT, et al. Application of an automated parcellation
method to the analysis of pediatric brain volumes. Psychiatry Res 1997; 76: 15-27.
Abstract
11. Andreasen NC, Rajarethinam R, Cizadlo T, et al. Automatic atlas-based volume estimation of
human brain regions from MR images. J Comput
Assist Tomogr 1996; 20: 98-106.
Abstract
12. Reiss AL, Hennessey JG, Rubin M, et al. Reliability and validity of an algorithm
for fuzzy tissue segmentation of MRI. J Comput
Assist Tomogr 1998; 22: 471-479.
Abstract
13. Thorndike RL HE, Sattler JM. Stanford-Binet
Intelligence Scale. 4th ed. Chicago: Riverside
Publishing; 1986.
14. Benton AL HK. Multilingual Aphasia
Examination. Iowa
City: AJA Associates; 1983.
15. Warwick MM, Doody GA, Lawrie SM, Kestelman JN, Best JJ, Johnstone EC. Volumetric magnetic
resonance imaging study of the brain in subjects with sex chromosome
aneuploidies. J Neurol Neurosurg Psychiatry 1999; 66: 628-632.
Abstract
16. Bender BG, Linden MG, Robinson A. Neuropsychological
impairment in 42 adolescents with sex chromosome abnormalities. Am J Med Genet 1993; 48: 169-173.
Abstract
17. Rovet J, Netley C, Keenan M, Bailey J, Stewart D. The psychoeducational
profile of boys with Klinefelter syndrome. J
Learn Disabil 1996; 29: 180-196.
Abstract
18. Graham JM Jr., Bashir AS, Stark RE, Silbert A, Walzer S. Oral and written language
abilities of XXY boys: implications for
anticipatory guidance. Pediatrics 1988; 81: 795-806.
Abstract
19. Netley C, Rovet J. Hemispheric
lateralization in 47,XXY Klinefelter's syndrome boys. Brain Cogn 1984; 3: 10-18.
Abstract
20. Pappas CT, Diamond MC, Johnson RE. Morphological changes in
the cerebral cortex of rats with altered levels of ovarian hormones. Behav Neural Biol 1979; 26: 298-310.
Citation
21. Grimshaw GM, Sitarenios G, Finegan JA. Mental rotation at 7
years: relations with prenatal testosterone levels
and spatial play experiences. Brain Cogn 1995; 29: 85-100.
Abstract
22. Hier DB, Crowley WF, Jr. Spatial
ability in androgen-deficient men. N Engl J Med 1982; 306: 1202-1205.
Abstract
23. Netley C. Time of pubertal onset,
testosterone levels and intelligence in 47,XXY males. Clin Genet 1992; 42: 31-34.
Abstract
24. Kampen DL, Sherwin BB. Estrogen use and verbal
memory in healthy postmenopausal women. Obstet
Gynecol 1994; 83: 979-983.
Abstract
25. Phillips SM, Sherwin BB. Effects of estrogen on
memory function in surgically menopausal women. Psychoneuroendocrinology 1992; 17: 485-495.
Abstract
26. Sherwin BB, Tulandi T. "Add-back"
estrogen reverses cognitive deficits induced by a gonadotropin-releasing
hormone agonist in women with leiomyomata uteri. J Clin Endocrinol Metab 1996; 81: 2545-2549.
Full Text
27. Nielsen J, Pelsen B, Sorensen K. Follow-up of 30
Klinefelter males treated with testosterone. Clin Genet 1988; 33: 262-269.
Abstract
28. Myhre SA, Ruvalcaba RH, Johnson HR, Thuline HC, Kelley VC. The effects of
testosterone treatment in Klinefelter's syndrome. J Pediatr 1970; 76: 267-276.
Citation
29. Salbenblatt JA, Bender BG, Puck MH, Robinson A, Faiman C, Winter JS. Pituitary-gonadal
function in Klinefelter syndrome before and during puberty. Pediatr Res 1985; 19: 82-86.
Abstract
30. Naftolin F, Ryan KJ. The metabolism of
androgens in central neuroendocrine tissues. J
Steroid Biochem 1975; 6: 993-997.
Citation
31. Stewart DA, Bailey JD, Netley CT, Rovet J, Park E. Growth and development
from early to midadolescence of children with X and Y chromosome aneuploidy: the Toronto Study. Birth Defects Orig Artic Ser 1986; 22: 119-182.
