Exp Clin Endocrinol 100 (1992) 129-132
Experimental and Clinical Endocrinology
The Influence of Testosterone Substitution on Bone Mineral Density in Patients with Klinefelter's Syndrome A. Kübler, G. Schulz, U. Cordes, J. Beyer and U. Krause* Dept. of Internal Medicine, Endocrinology and Metabolism, Johannes Gutenberg-University, Mainz/Germany
Key words: Bone mineral density - Klinefelter's syndrome Testosterone substitution
Summary: The aim of this study was to clarify the extent of bone mineral deficiency in patients with Klinefelter's syndrome on the premise that testosterone substitution could prevent this
deficiency. Bone mineral density was measured by singlephoton absorptiometry in 42 patients with Klinefelter's syndrome, (21 patients wihout therapy. 10 with testosterone substitution before the age of 20 and 11 patients with testosterone substitution beginning after the age of 20). We found significantly lower bone mineral density in patients without therapy and
in patients when the therapy began later compared to normal individuals. Patients with early therapy showed a high proportion of normal values of bone mineral density. We found a positive correlation between bone mineral density and plasma testosterone and a negative correlation between plasma testosterone and age for patients without therapy. These findings suggest that low testosterone levels before or during puberty cause inadequate bone development and low hone mineral density in Klinefelter's syndrome. Only early testosterone substitution may prevent bone mineral deficiency. Later substitution no longer affects bone mineral density.
Introduction
Patients and Methods
Some characteristic bodily alterations can be seen in men with Klinefelter's syndrome. These comprise of
The diagnosis "primary hypogonadism with Klinefelter's syndrome" was verified by chromosome analysis in 42 hypogonadal men. Other diseases were excluded by detailed internal and endocrinological examinations. Twenty one patients had never had testosterone substitution.
increased stature, eunuchoid body proportions, small testes, testicular hyalinization with fibrosis and azoospermia (Klinefelter et al., 1942; Myhre et al., 1970). Previous publications have shown a deficiency of bone mineral density (BMD) and of cortical thickness in these patients,
but they could neither state the instance nor extent of bone mineral loss or the cause of it (Lauder et al., 1975;
Myhre et al., 1970; Ohsawa et al., 1971). The testosterone deficiency and the extra x-chromosome have been said to account for this.
The aim of this study was to explain the reasons for, time of and amount of bone mineral loss in Klinefelter's syndrome and in which instances testosterone substitution could prevent BMD deficiency. *) This work is dedicated to (J. Krause who died during the course of the work.
Ten received regular testosterone substitution, which was started before the age of 20, for a mean period of 5.7 ± 7.1 years (SD). The remaining Il patients received testosterone substitution after the age of 20, for a mean perïod of 5.4 ± 5.3 years (SD). Detailed information about age, height, weight and treatment duration are listed in Table I. Treated patients
received an intramuscular injection of 250 mg testosterone (Testoviron) at intervals of 4to 6 weeks dependent on individual well-being and plasma testosterone level which was measured every four weeks. Plasma testosterone levels are reported and analysed only in untreated patients, since in treated patients the testosterone level was dependent on the interval between injections.
For comparison of BMD a reference population of 133 healthy men ranging in age from 12 to 75 years was examined. They were selected from volunteers, hospital staff and students.
Downloaded by: Collections and Technical Services Department. Copyrighted material.
© 1992 Johann Ambrosius Barth
Exp Clin Endocrinol 100 (1992) 3
130
Information about age, height, weight, treatment duration and BMD % of reference population for all Klinefelter's patients Table. 1
age
no.
(years)
1
35
2
37
3 4
25 61
23 24 25 26 27 28 29 30 1
34 35 36 37 38 39 40
0 0
81
0 0
0 0 0 0
64.5
90
0
115.0
78
0
78.1
59 65
0
73.3
191
188
70
21
181
61
22 19 18 28 27
185 180
84 93 62
44 70 59 29
18
77 35 27
20 19
20 22, 21
17 38 16 57 49 37 33 46 49 39 46
26
181
195 175 179 177 179 187 185 182 187
0
0
0 0 0 0 0
0
75
10
96 67 80 57 97 67 74
16
.
21
2 1
1
4 2 1
1
184 178 185 190 184 180 188
90 70 74
182 176 185
14 16
4
91
1
92 72
9 6
.
2
80 85 73
4 2 2
1
1
i
therapy start
77.8 57.9 101.5 56.5
68 93 90 108 72
18
41
42
106 110 80
BMD in % of
0
10
19 20
164 174 186 176 205 187 179 189 185 178 174 194 175 182
treatment
duratïon (years) eference population
75
A44 12 13 14 15 16 17 18
(kg)
0
29
11
(cm) 163
73 98
28
¡ 9
height weight
BMD in patients without testosterone therapy was significantly lower (88.0%, compared with reference population, p < 0.0002) than in normal individuals (100.0%)
68.1 119.3
82.9 73.7 76.6 77.1 149,5
¡
77.1
106.6 86.3 91.3 107.6 105.9 82.0 73,7 144.6 119.5 121.5 111.0 106.5 92.7 88.9 109.4
30
20
10
40
50
60
80
70
age (years)
* ro '
.'
Fig. I Reference curves of bone mineral density and bone mineral density for patients with Klinefelter's syndrome. U Klinefelter's without therapy, A = Klinefelter's with therapy before the age of 20, = Klinefelter's with therapy after the age of 20. - reference curve (n = 133), borders of the 95 0/ confidence interval (SD) of the reference curve
92.1
85.3 88.9 111.1
56.8 98.5 75.0 76.9 63.4 76.4 111.0
8MO in % of reternce population
ft
a
20 100
80 60
reterenee population n
40
133
XXV with
XXV without therapy
n = 21
20
The controls had no previous history of bone metabolism disorder or any clinical symptoms or previous fractures of the forearm. The calculation and results of the reference curves are described in Kübler et al. (1991). In all patients and all members of the reference population,
BMD of radius and ulna was measured using a 251 singlephoton scanner (model nuclear data ND I tOOa). The principles
and reliability of this method can be found in Cameron and Sørensen (1963). Accuracy and long-term reproducibility were specified to be within 2% (Christiansen et al,, 1975). In every patient the nondominant arm was measured in order to minimize the influence of physical activity on BMD.
start of therapy before age 20 years
XXV with start of
n = 10
n=
therapy alter 20
il
o
- p
Experimental and Clinical Endocrinology
The Influence of Testosterone Substitution on Bone Mineral Density in Patients with Klinefelter's Syndrome A. Kübler, G. Schulz, U. Cordes, J. Beyer and U. Krause* Dept. of Internal Medicine, Endocrinology and Metabolism, Johannes Gutenberg-University, Mainz/Germany
Key words: Bone mineral density - Klinefelter's syndrome Testosterone substitution
Summary: The aim of this study was to clarify the extent of bone mineral deficiency in patients with Klinefelter's syndrome on the premise that testosterone substitution could prevent this
deficiency. Bone mineral density was measured by singlephoton absorptiometry in 42 patients with Klinefelter's syndrome, (21 patients wihout therapy. 10 with testosterone substitution before the age of 20 and 11 patients with testosterone substitution beginning after the age of 20). We found significantly lower bone mineral density in patients without therapy and
in patients when the therapy began later compared to normal individuals. Patients with early therapy showed a high proportion of normal values of bone mineral density. We found a positive correlation between bone mineral density and plasma testosterone and a negative correlation between plasma testosterone and age for patients without therapy. These findings suggest that low testosterone levels before or during puberty cause inadequate bone development and low hone mineral density in Klinefelter's syndrome. Only early testosterone substitution may prevent bone mineral deficiency. Later substitution no longer affects bone mineral density.
Introduction
Patients and Methods
Some characteristic bodily alterations can be seen in men with Klinefelter's syndrome. These comprise of
The diagnosis "primary hypogonadism with Klinefelter's syndrome" was verified by chromosome analysis in 42 hypogonadal men. Other diseases were excluded by detailed internal and endocrinological examinations. Twenty one patients had never had testosterone substitution.
increased stature, eunuchoid body proportions, small testes, testicular hyalinization with fibrosis and azoospermia (Klinefelter et al., 1942; Myhre et al., 1970). Previous publications have shown a deficiency of bone mineral density (BMD) and of cortical thickness in these patients,
but they could neither state the instance nor extent of bone mineral loss or the cause of it (Lauder et al., 1975;
Myhre et al., 1970; Ohsawa et al., 1971). The testosterone deficiency and the extra x-chromosome have been said to account for this.
The aim of this study was to explain the reasons for, time of and amount of bone mineral loss in Klinefelter's syndrome and in which instances testosterone substitution could prevent BMD deficiency. *) This work is dedicated to (J. Krause who died during the course of the work.
Ten received regular testosterone substitution, which was started before the age of 20, for a mean period of 5.7 ± 7.1 years (SD). The remaining Il patients received testosterone substitution after the age of 20, for a mean perïod of 5.4 ± 5.3 years (SD). Detailed information about age, height, weight and treatment duration are listed in Table I. Treated patients
received an intramuscular injection of 250 mg testosterone (Testoviron) at intervals of 4to 6 weeks dependent on individual well-being and plasma testosterone level which was measured every four weeks. Plasma testosterone levels are reported and analysed only in untreated patients, since in treated patients the testosterone level was dependent on the interval between injections.
For comparison of BMD a reference population of 133 healthy men ranging in age from 12 to 75 years was examined. They were selected from volunteers, hospital staff and students.
Downloaded by: Collections and Technical Services Department. Copyrighted material.
© 1992 Johann Ambrosius Barth
Exp Clin Endocrinol 100 (1992) 3
130
Information about age, height, weight, treatment duration and BMD % of reference population for all Klinefelter's patients Table. 1
age
no.
(years)
1
35
2
37
3 4
25 61
23 24 25 26 27 28 29 30 1
34 35 36 37 38 39 40
0 0
81
0 0
0 0 0 0
64.5
90
0
115.0
78
0
78.1
59 65
0
73.3
191
188
70
21
181
61
22 19 18 28 27
185 180
84 93 62
44 70 59 29
18
77 35 27
20 19
20 22, 21
17 38 16 57 49 37 33 46 49 39 46
26
181
195 175 179 177 179 187 185 182 187
0
0
0 0 0 0 0
0
75
10
96 67 80 57 97 67 74
16
.
21
2 1
1
4 2 1
1
184 178 185 190 184 180 188
90 70 74
182 176 185
14 16
4
91
1
92 72
9 6
.
2
80 85 73
4 2 2
1
1
i
therapy start
77.8 57.9 101.5 56.5
68 93 90 108 72
18
41
42
106 110 80
BMD in % of
0
10
19 20
164 174 186 176 205 187 179 189 185 178 174 194 175 182
treatment
duratïon (years) eference population
75
A44 12 13 14 15 16 17 18
(kg)
0
29
11
(cm) 163
73 98
28
¡ 9
height weight
BMD in patients without testosterone therapy was significantly lower (88.0%, compared with reference population, p < 0.0002) than in normal individuals (100.0%)
68.1 119.3
82.9 73.7 76.6 77.1 149,5
¡
77.1
106.6 86.3 91.3 107.6 105.9 82.0 73,7 144.6 119.5 121.5 111.0 106.5 92.7 88.9 109.4
30
20
10
40
50
60
80
70
age (years)
* ro '
.'
Fig. I Reference curves of bone mineral density and bone mineral density for patients with Klinefelter's syndrome. U Klinefelter's without therapy, A = Klinefelter's with therapy before the age of 20, = Klinefelter's with therapy after the age of 20. - reference curve (n = 133), borders of the 95 0/ confidence interval (SD) of the reference curve
92.1
85.3 88.9 111.1
56.8 98.5 75.0 76.9 63.4 76.4 111.0
8MO in % of reternce population
ft
a
20 100
80 60
reterenee population n
40
133
XXV with
XXV without therapy
n = 21
20
The controls had no previous history of bone metabolism disorder or any clinical symptoms or previous fractures of the forearm. The calculation and results of the reference curves are described in Kübler et al. (1991). In all patients and all members of the reference population,
BMD of radius and ulna was measured using a 251 singlephoton scanner (model nuclear data ND I tOOa). The principles
and reliability of this method can be found in Cameron and Sørensen (1963). Accuracy and long-term reproducibility were specified to be within 2% (Christiansen et al,, 1975). In every patient the nondominant arm was measured in order to minimize the influence of physical activity on BMD.
start of therapy before age 20 years
XXV with start of
n = 10
n=
therapy alter 20
il
o
- p
