1 Comparison Of Bone Mineral Density And Body Proportions Between ...
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Accepted Preprint first posted on 7 May 2008 as Manuscript EJE-08-0166
Comparison of bone mineral density and body proportions between women with
complete androgen insensitivity syndrome and women with gonadal dysgenesis
Han TS, Goswami D, Trikudanathan S, Creighton SM, Conway GS
Department of Endocrinology, University College London Hospitals
250 Euston Road, London, NW1 2PQ, UK
Correspondence:
Dr GS Conway
Department of Endocrinology
University College London Hospitals
250 Euston Road
London, NW1 2PQ
UK
Telephone: 020 7380 9101
Fax: 020 7380 9201
Email: g.conway@ucl.ac.uk
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ABSTRACT
Objectives: To compare bone mineral density (BMD) and body proportions between
women with complete androgen insensitivity syndrome (CAIS) and women with
gonadal dysgenesis.
Setting: Adult Disorders of Sexual Development and Ovarian Failure Clinics at
University College London Hospitals.
Design: Retrospective cross-sectional study of three groups of women aged 17-58
years with varying degrees of exposure to sex hormones and different combinations of
sex chromosomes. Forty-six subjects had complete androgen insensitivity syndrome,
18 had gonadal dysgenesis and 46,XY [GD(XY)], and 25 had gonadal dysgenesis and
46,XX [GD(XX)]. In addition, body proportions of subgroups of these women were
analysed.
Outcome measures: Oestrogen therapy, karyotype, anthropometry and BMD.
Results: Height differed between groups (F ratio 5.2, P = 0.007), with GD(XX)
women being shortest (mean ±SD: 1.66 ±0.10 m), GD(XY) women tallest (1.74 ±0.09
m) and in between were CAIS women (1.70 ±0.07 m). Delayed gonadectomy resulted
in taller stature in CAIS women (P = 0.011). The ratio of lower to upper body length
in GD(XY) women was significantly (P = 0.001) greater than that of CAIS women.
Multivariate logistic regression analysis (adjusted for age and height) showed that
among women with XY karyotype, GD(XY) women were 5.2 times (95% CI: 1.3 to
20.1, P = 0.018) more likely than CAIS women to have a low hip BMD. This
difference was not evident among women with gonadal dysgenesis of different
karyotypes (P = 0.938). Spinal BMD did not differ between subject groups. Further
adjustment for oestrogen replacement did not alter these relationships.
Conclusions: Taller stature in late gonadectomised CAIS women suggests oestrogen
deficiency in these women prior to gonadectomy. Increased lower body to upper body
ratio in GD(XY) women compared to the other groups implies that these subjects
have the greatest degree of oestrogen deficiency in puberty. Androgen rather than sex
chromosomes may play an important role in cortical bone mineralisation in CAIS
women, probably via ER- either directly or via aromatisation during critical periods
of growth prior to gonadectomy.
Keywords: body proportions, genetics, osteoporosis, stature, Swyer’s syndrome.
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INTRODUCTION
Complete androgen insensitivity syndrome (CAIS) is caused by loss of function
mutations of the androgen receptor (AR)1,2 and affects 1 in 20,000 - 90,000 births.3,4
Individuals with CAIS (46,XY karyotype) are phenotypically female with normal
pubertal development but lack Müllerian duct structures and androgen dependent
body hair. They typically present with inguinal hernia during infancy or with primary
amenorrhea in adolescence.5
In comparison, women with gonadal dysgenesis and 46,XY karyotype [GD(XY)]
(also known as Swyer’s syndrome) also present with primary amenorrhoea and are
characterised by streak gonads with normal uterine development after exposure to
oestrogen. Women with GD(XY) lack a gonadal source of androgen and oestrogen
but retain an adrenal androgen production and have intact AR function. Women with
CAIS and GD(XY) are taller than women with 46,XX karyotype.6,7 Tall stature in
these conditions may be contributed to both by a Y chromosome effect and by
oestrogen deficiency in puberty delaying closure of epiphysis.8,9 An ‘oestrogen effect’
can be explored by comparing exposure to exogenous estrogens with final height and
by comparing upper and lower body proportions. For most individuals with CAIS and
GD(XY), administration of oestrogens occurs soon after gonadectomy in those who
are at the age of puberty (11 years) or older.
Several studies have reported osteopenia in women with CAIS10,11 even after
adjusting for bone size using volumetric density.12 Oestrogen replacement has been
shown to improve bone mineral density (BMD) in women with CAIS.13,14 Bone
density in GD(XY) has not been studied.
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It is not clear whether low BMD in CAIS is influenced by inadequate oestrogen
replacement or lack of androgen action on bone.10 This question cannot be explored
by comparing a CAIS group with normal controls from whom they differ in three
ways: the presence of a Y chromosome, oestrogen deficiency and androgen resistance.
To address the effect of androgen on bone we have compared women with CAIS to
women with GD(XY) who share the Y chromosome and oestrogen deficiency but the
latter have normal sensitivity to androgens. In addition, women with gonadal
dysgenesis and 46XX karyotype [GD(XX)] were also included to determine the
effects of sex chromosomes on BMD by comparing them with GD(XY) women. The
present study also evaluated hormonal effects on stature and body proportions in these
three groups of women.
METHODS
Subjects and study design
This retrospective cross-sectional study of Caucasian women who attended the Adult
Adult Disorders of Sexual Development and Ovarian Failure Clinics at University
College Hospital, London comprised 46 women with CAIS and 18 women with
GD(XY), and 25 with GD(XX). The varying degrees of exposure to sex hormones
and various combinations of sex chromosomes in these women enabled the present
study to match them for XY karyotype and status of gonadal dysgenesis. Body
proportions of subgroups of 14 CAIS, seven GD(XY), and nine GD(XX) women were
also assessed. The study was approved by the Ethics Committee of University College
London Hospitals Trust.
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Diagnosis
The clinical diagnosis of women with CAIS was based on unambiguous female
phenotype, scant androgen dependent body hair, karyotype, testicular histology and
absent uterus.15 In adults who have been exposed to high circulating testosterone
concentrations, usually for some years, we consider this clinical diagnosis to be
secure. We have, wherever possible, sought congruity between classical endocrine
and gonad histology features of CAIS before accepting the diagnostic label although
in a tertiary adult setting every detail of previous work up is not uniform and so this
data is not presented here but this topic has been described previously.16 After
gonadectomy, the main competing diagnoses that can be reliably excluded are 5-K
reductase deficiency (SRD5A2) and forms of congenital adrenal hyperplasia (e.g.
P450 oxidoreductase deficiency) that can be detected using urinary steroid profiling -
this test has been completed in all cases. 17ዊ-hydroxysteroid dehydrogenase
deficiency was the only other competing diagnosis that has not been formally
excluded. Subjects with gonadal dysgenesis were diagnosed as unambiguous female
phenotype with streak gonads and intact Müllerian structures and were divided into
those with 46XY or 46XX karyotype.
Hormone replacement therapy (HRT)
Age of gonadectomy, age at starting oestrogen and cumulative oestrogen deficient
years were recorded. Cumulative oestrogen deficiency years were estimated from
non-compliance after initiation of oestrogen replacement therapy adding, in the case
of GD(XY) and GD(XX), the number of years after age 11 that the diagnosis was
delayed. Oestrogen replacement in this group was based on patient choice and the vast
majority received standard adult doses of oestradiol valerate 2 mg, conjugated equine
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oestrogens 0.625 mg, transdermal oestradiol 50 ዊg daily or oestradiol implant 50 mg
every six months. Those with a uterus and on the combined oral contraceptive pill had
a ‘Pill-free’ week every month. Most of CAIS women used unopposed oestrogens and
two of them chose to use testosterone replacement using mixed testosterone esters
(Sustanon) 250 mg every 4 weeks. The compliance for oestrogen was overall good in
our cohort of patients, being more than 80% in most of the cases.
Parameters which describe oestrogen usage over time are problematic as some are
influenced by age (e.g. the oestrogen index = years of HRT/age) and all are based on
recall in this age group. In addition, adult clinics receive cases from a variety of
paediatric centres in which the method and pace of induction of puberty vary. In
previous studies of oestrogen deficient young women we have found that ‘oestrogen
start age’ is a reliable parameter and that ‘cumulative years of oestrogen deficiency
after the age of 11’ (i.e. no HRT) is also reproducible.
Anthropometry and bone mineral density
Subjects’ weight, height and sitting height (upper body length) were measured by
standard balance and stadiometer. Body mass index (BMI) was calculated as weight
divided by height squared (kg/m2). Lower body length was calculated from the
difference between height and sitting height. From these parameters, ratios of lower
body to height or to upper body length were computed. Bone density measurements in
all subjects were made using a dual energy X-ray absorptiometer (DEXA) (Hologic
QDR 4500 fan beam, Hologic Inc, Waltham, MA, USA). Methods of BMD
measurements using the current DEXA have been essentially unchanged compared to
the previous DEXA (Hologic QDR 1000 fan beam) used at the same department
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described by Han et al.17 Total spinal BMD was obtained between lumbar levels 1 to
4 (L1-L4) and total hip BMD at femoral neck, trochanteric and intertrochanteric
regions. Results of BMD were provided in g/cm2 and T scores which expressed BMD
statistically in terms of number of standard deviations by which a result differed from
the mean young women.17
Statistical analysis
The present study used statistical package (SPSS v14, Chicago, IL, USA) for
analyses. Analysis of variance was used for assessing differences between groups and
generalised lineal model for calculating adjusted means. Multivariate logistic
regression analysis was employed using BMD T score as dependent variable, and
subject groups as independent variables. The relationships were analysed with
adjustments for potential confounding factors including age, height and oestrogen
therapy.
For the purpose of logistic regression analysis, continuous variables were converted to
binary variables. BMD at the hip and spine was categorised into high and low groups
using cut-offs corresponding to T score of -1 (reference groups had BMD above these
T scores). Height, age and oestrogen therapy were dichotomised at the group mean
values to create binary variables for analysis. Independent t-tests were used to
compare the differences in body proportions between groups.
RESULTS
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Subjects were between 18 to 58 years old with the mean age being higher in the CAIS
group (Table 1). Women with CAIS had gonadectomy and oestrogen replacement at
an earlier age than GD(XY) women and they also had the lowest duration of
oestrogen deficiency. There were no significant differences ( 2 = 0.245, P = 0.855) in
the proportions of women who did not take HRT (15.9% of CAIS women, 16.7% of
GDXY and 12% of GDXX women).
Height differed between groups (F ratio 5.2, P = 0.007), with GD(XX) group being
the shortest (mean 1.66 m ±SD 0.10), GD(XY) tallest (1.74 m ±0.09) and CAIS
intermediate in stature (1.70 m ±0.07). Sixteen women had AR mutations identified as
part of their previous workup. These 16 women did not differ by any measured
parameter from the 30 women with no genetic workup (Table 2). Figure 1 shows that
height relates to age of gonadectomy in a curvilinear fashion, explaining 20% of the
variance (P <0.05) in CAIS women and 11% of the variance (not significant) in
GD(XY) women. Oestrogen replacement was started soon after gonadectomy in
women who were at the age of puberty (age of 11 years) or older. In CAIS women,
height also correlated significantly with age of starting oestrogen replacement (r =
0.355, P = 0.02) but not with the duration of oestrogen deficiency. Partial correlations
controlling for oestrogen deficiency did not substantially change the relationships
between height and age of gonadectomy or age of starting oestrogen replacement. It
was calculated that height of CAIS women who underwent gonadectomy at puberty or
older (1.72 m) were in 6.3 cm (P = 0.011) taller than those who underwent
gonadectomy before puberty (1.65 m). There were no correlations between BMD at
the hip or the spine with gonadectomy age, age of starting oestrogen or duration of
oestrogen deficiency (results not shown).
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Tables 3 shows body proportions in different subject groups. GD(XY) women were
significantly taller than CAIS women and GD(XX) women. CAIS women and GD(XY)
women had almost identical mid-parental height. CAIS women achieved their expected adult
height based on mid-parental height whereas GD(XY) women had adult height exceeding
their expected height by 7 cm. There were significant correlations between adult height and
mid-parental height both in CAIS women (r = 0.63, P = 0.022) and GD(XY) women (r =
0.77, P = 0.041). All groups had similar upper body length, but GD(XY) women had greater
ratio of lower body length to height as well as ratio of lower body to upper body length than
CAIS women and GD(XX) women. Figure 2 shows a comparison of the lower body to
upper body length ratios of women in the present study to those from a reference
population of normal 21 year old Dutch men and women.18
In all groups the mean BMD T score at the hip was higher than at the spine (Table 3).
Both hip and spinal BMD differed between the three groups. In particular, CAIS
group had the highest values of BMD of the hip. Figure 3 shows that, as expected,
there was a substantial number of women with BMD in the range of osteopenia and
osteoporosis. Only 24% of women with CAIS had low hip BMD (T score below -1.0)
compared to 50% of women with GD(XY) and 55% of GD(XX) women (P <0.05).
Low spinal BMD was more prevalent in all subject groups but little difference
between CAIS and GD(XY) groups was observed.
Multivariate logistic regression analyses (Figure 4a & b) of the risk of low BMD
with adjustments for age and height showed that when women with 46XY
chromosomes were compared, using women with CAIS as reference group, women
with GD(XY) were 5.2 (95% CI: 1.3 to 20.1, P = 0.018) times more likely to have
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low BMD at the hip. When women with gonadal dysgenesis were compared, using
women with GD(XX) as reference group, women with GD(XY) did not have
significantly different BMD at the hip (OR 1.06, 95% CI: 0.3 to 4.4 P = 0.938). BMD
at the spine did not differ between subject groups. Controlling for each other’s group
did not change these relationships substantially. Further adjustments for the duration
of oestrogen deficiency and HRT status in multivariate logistic analyses did not alter
the differences in BMD between subject groups (results not shown).
DISCUSSION
The present study examined three groups of women with varying degrees of exposure
to sex hormones and various combinations of sex chromosomes, providing a unique
free-living human model for the evaluation of relative contribution of these factors on
the development of body proportions and bone. There was a significant increase in the
risk of low BMD in GD(XY) compared to CAIS whilst these differences were not
observed between the two gonadal dysgenesis groups of women of different
karyotypes suggest androgens rather than sex chromosomes may have a role in
protecting BMD in CAIS women.
In the present study, taller stature in CAIS women appeared to be determined by later
age of gonadectomy and introduction of oestrogen replacement, but not by the
duration of oestrogen deficiency. It has been shown previously that in comparison
with normal males, CAIS women with intact gonads have increased serum levels of
luteinising hormone, similar levels of testosterone and follicle stimulating hormone.15
Before gonadectomy, women with CAIS have been shown to have reduced circulating
concentrations of oestradiol which originated both from direct glandular secretion and
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from peripheral aromatization of androgen precursors.19 The present study provides
evidence for this oestrogen deficient state based on the association between
gonadectomy age and height suggesting that oestrogen levels sufficient to close the
epiphyses are achieved only with the exogenous source post gonadectomy. These
findings are consistent with data observed in CAIS women from previous studies -
adult stature of CAIS women with intact gonads was shown to approach their target
male adult height,20 whereas a CAIS woman who underwent gonadectomy and had
oestrogen replacement had reduced adult height.9 The oestrogen levels are, however,
sufficient for development of a normal external female phenotype to a greater degree
than that seen in the gonadal dysgenesis group.
The present study has shown that GD(XY) women had adult height exceeding their
mid-parental height by 7 cm whereas this difference was not observed in CAIS
women. GD(XY) women also had significantly greater ratios of lower body to height
or to upper body compared to CAIS women indicating that GD(XY) women are
probably less oestrogenised than CAIS women during periods prior to gonadectomy
since these two groups were well matched for oestrogen deficiency and age of
gonadectomy in the subgroup analysis. The difference in lower body to upper body
ratios between CAIS and GD(XY) women reflects hormonal influences on long bone
whereas the difference between GD(XY) and GD(XX) women reflects the influences
from Y chromosome. The latter observation is consistent with previous
observations.18,21 It is of interest that body proportions of women with GD(XY)
distinctly followed eunuchoid patterns with their ratios of lower body to upper body
being greater than 1.0 and they also had greater arm span than height by 5 cm (data
not presented). Their exceptionally high ratio could potentially be used as a screening
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tool for GD(XY) in women who first present with primary amenorrhoea. More
subjects are required for assessing its value in clinical practice.
The findings of greater BMD at the hip than at the spine in CAIS women in the
present study are consistent with those observed by Danilovic et al in a study of
complete and partial AIS women.22 The long-term effects of androgens on BMD in
free-living subjects have not been demonstrated. Results in the present study, using
groups of matched women who differed only in AR sensitivity, indicated that
androgens might have some direct action on cortical bone mineralisation based on two
accounts: firstly, women with CAIS are completely resistant to androgen at AR levels;
secondly, these women appeared to be oestrogen deficient as indicated by the
inhibitory effects on statural growth in those receiving early oestrogen replacement
(Figure 3). Androgens have been shown to have a direct stimulatory effect on ER of
osteoblasts,23,24,25 and may also act on the bone via AR as well as ER (particularly
ER- ) – either directly by testosterone per se or through aromatisation of androgen to
oestrogen.26 The lack of relationship between the age of gonadectomy or age of
introducing oestrogen replacement and BMD in CAIS (results not presented) suggests
that androgens probably exert their greatest effects on bone mineralisation in early
periods of life (prior to gonadectomy).
Study limitations
We have not been able to control for differences in the regimens for the induction of
puberty. In adult clinics, we inherit cases from a wide area (throughout the South of
England) and accept that every referring centre will have managed puberty
differently. Previously, we tried to collect a parameter that reflects the ‘ramping up’ of
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oestrogen dose after introduction but there is no easy way of accurately representing
this concept. It may be that women with 46XYGD had slower introduction of low
doses of HRT and women with CAIS will go straight on to average adult doses and
this would contribute to their greater oestrogen deficiency. Second, we have focussed
on the interplay between oestrogen and androgens but we could not control for the
difference in the administration of progesterone. Women with CAIS do not receive
progesterone while the other two groups do have exposure which may account for
some of the group differences. When oestrogen replacement therapy is considered, the
trade-off between the prevention of long-term bone loss and achieving an ‘ideal’ adult
height is crucial but there is no established consensus on the optimal age of oestrogen
replacement.
CONCLUSIONS
Taller stature in late gonadectomised CAIS women suggest oestrogen deficiency in
these women prior to gonadectomy. As well as Y chromosome, oestrogen deficiency
contributes considerably to tall stature in GD(XY) women. Increased lower body to
upper body ratio in women with GD(XY) compared to the other groups implies that
these subjects have the greatest degree of oestrogen deficiency in puberty. Androgen
rather than sex chromosomes may play an important role in cortical bone
mineralisation in women with CAIS, probably via ER- either directly or
aromatisation during critical periods of growth prior to gonadectomy. Based on our
observations, late gonadectomy may benefit BMD and the resulting tall stature may
be limited by introducing oestrogen replacement prior to gonadectomy as soon as the
diagnosis is made.
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DISCLOSURE
Fundings
Deepti Goswami was in receipt of Commonwealth Scholarship from the
Commonwealth Scholarship Commission, Association of Commonwealth
Universities, London, UK.
Conflicts of interest
We declare that there is no conflict of interest that would prejudice its impartiality.
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LEGENDS
Figure 1. Quadratic regression analysis to determine the relationships between height
and age of gonadectomy with r2 = 20% and P = 0.011 in CAIS women, r2 = 11% and
P = 0.421 in GD(XY) women, and r2 = 18% and P = 0.002 overall.
Figure 2. Comparing lower body length to upper body length (LB:UB) ratios in
different groups of women. Differences (95% CI) between GD(XY) minus CAIS
women = 0.10 (0.05 to 0.15), P = 0.001, and between GD(XY) minus GD(XX)
women = 0.08 (-0.01 to 0.17), P = 0.076. Lower body to upper body ratios of normal
21 year-old Dutch males (solid horizontal line) and 21 year-old Dutch females
(dashed horizontal line) are shown for comparison.18
Figure 3. Distribution of hip BMD (a) and spine BMD (b) in women with CAIS and
gonadal dysgenesis.
Figure 4. Age and height adjusted odds ratios and 95% CI to estimate the risk of low
BMD GD(XY) women with reference to AIS(XY) women (a), and GD(XX) women
with reference to GD(XY) women (b).
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Table 1. Characteristics of women with CAIS and women with gonadal dysgenesis.
Mean (SD)
CAIS
GD(XY)
GD(XX)
ANOVA
n = 46
n = 18
n = 25
F ratio
P
Age (y)
32.2 (10.7)
29.3 (8.5)
25.4 (7.3)
4.3
0.017
Weight (kg)
67.7 (12.3)
71.4 (14.0)
65.8 (21.3)
0.7
0.506
Height (m)
1.70 (0.07)
1.74 (0.09)
1.66 (0.10)
5.2
0.007
BMI (kg/m2)
23.5 (4.2)
23.5 (4.1)
23.8 (6.1)
0.0
0.964
Hip BMD (T score)
-0.58 (0.99)
-0.66 (1.24)
-1.14 (1.15)
3.7
0.030
Adjusted hip BMD (T score)*
-0.55 (1.07)
-0.67 (1.04)
-1.58 (1.26)
4.9
0.010
Spine BMD (T score)
-1.28 (1.19)
-0.88 (1.58)
-1.59 (1.15)
3.0
0.056
Adjusted spine BMD (T score)*
-1.29 (1.22)
-0.88 (1.10)
-1.78 (1.10)
2.2
0.124
Gonadectomy age (y)
15.9 (7.3)
20.3 (6.0)
_____
5.0
0.030
Age at start of oestrogen (y)
17.5 (5.3)
18.7 (4.2)
20.6 (4.3)
2.6
0.077
Oestrogen deficiency (y)
3.1 (5.2)
8.2 (4.6)
8.9 (4.8)
11.8
0.001
CAIS = complete androgen insensitive syndrome, GD = gonadal dysgenesis. ANOVA
= analysis of variance. *Adjusted means for age and height using general linear model
Page 22 of 27
Table 2. Characteristics of CAIS women without or with available AR mutation
information.
AR mutation information
Not available
Available
(n = 30)
(n = 16)
Mean (SD)
Mean (SD)
Difference
P
Height (m)
1.70 (0.07)
1.70 (0.8)
0.00
0.863
Weight (kg)
66.5 (10.0)
70.0 (15.9)
-3.5
0.368
BMI (kg/m2)
23.1 (3.3)
24.2 (5.6)
-1.2
0.383
Hip BMD (T score)
-0.62 (1.09)
-0.51 (0.79)
-0.11
0.729
Spinal BMD (T score)
-1.24 (1.27)
-1.34 (1.09)
0.10
0.780
Gonadectomy age (years)
16.2 (7.9)
15.6 (6.5)
0.6
0.798
Age at start of oestrogen (years)
17.1 (5.1)
18.3 (5.8)
-1.2
0.490
Oestrogen deficiency (years)
2.9 (5.9)
3.5 (4.0)
-0.6
0.738
Proportions not on HRT (%)
23.3
12.5
2 = 0.8
0.463
Page 23 of 27
Table 3. Body dimensions in subgroups of women.
Mean (SD)
CAIS
GD(XY)
GD(XX)
(n = 14)
(n = 7)
(n = 9)
Age (years)
42.1 (10.5)
36.7 (10.5)
27.9 (7.3)
Gonadectomy age (years)
21.3 (9.5)
22.1 (2.3)
___
Oestrogen deficiency (years)
8.2 (10.0)
7.8 (5.4)
5.7 (2.7)
Height (m)
1.69 (0.08)†
1.76 (0.07)
1.69 (0.09)*
Mid-parental height (m)
1.68 (0.04)
1.69 (0.06)
UB length (m)
0.88 (0.04)
0.87 (0.02)
0.87 (0.03)
LB length (m)
0.81 (0.05)
0.89 (0.06)
0.82 (0.08)
LB:height ratio
0.48 (0.01)
0.51 (0.02)
0.48 (0.03)
LB:UB ratio
0.92 (0.05)†
1.02 (0.07)
0.94 (0.10)*
CAIS = complete androgen insensitivity syndrome, GD = gonadal dysgenesis, UB =
upper body, LB = lower body. †P <0.01, *P <0.05 compared to GD(XY) group.
Page 24 of 27
Page 25 of 27
P = 0.001
P = 0.076
M
F
Page 26 of 27
AIS(XY) =24%
GD(XY) = 50%
GD(XX) = 55%
AIS(XY) = 63%
GD(XY) = 44%
GD(XX) = 80%
Page 27 of 27
AIS(XY) vs GD(XY)
1.3
5.2
20.1
GD(XY) vs GD(XX)
0.3 1.1 4.4
AIS(XY) vs GD(XY)
0.2
0.6
1.7
GD(XY) vs GD(XX)
0.1
0.4
1.8
