Age-related changes in 11β-hydroxyandrostenedione concentration in normal and osteoporotic women

J. SteroidBiochem. Molec. Biol. Vol.40, No. 4--6,pp. 731-733,1991

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AGE-RELATED

CHANGES

1 l fl-HYDROXYANDROSTENEDIONE NORMAL

AND

IN

CONCENTRATION

OSTEOPOROTIC

IN

WOMEN

R. SCHLAGHECKE,*D. BEUSCHER,H. K. KLEYand E. JULI Department of Endocrinologyand Rheumatology,Heinrich Heine UniversityDiisseldorf, Moorenstr. 5, 4000 Diisseldorf, Fed. Rep. Germany Summary--The secretion of dehydroepiandrosterone (DHEA) and its sulfate is known to decline gradually with advancing age. Furthermore DHEA is known to be significantly lower in osteoporotic subjects than in normals. Recently 1l~-hydroxyandrostenedione (11-OHA) has been proposed as an important indicator of the adrenal source of hormone excess in different hyperandrogenic states. In the present study we measured 11-OHA in 224 normal women aged 20-79 yr and 130 osteoporotic women aged 40-79 yr. RIA of 11-OHA was performed with highly specific antiserum raised in rabbits. The mean 1I-OHA serum concentration was 2.20 +__0.90 ng/ml in normal women and 1.75 ___0.58 ng/ml in osteoporotic women. In contrast to DHEA there was no age-related decrease in 1I-OHA serum concentrations in normal and osteoporotic women. Osteoporotic subjects showed statistically significantly lower l l-OHA serum concentrations than normal women. Therefore low serum 1I-OHA might represent a further risk factor for osteoporosis.

INTRODUCTION Sex steroid hormones play an important role in maintaining skeletal integrity. While the relationship of inadequate gonadal steroid production and declining bone mass is well established [1-6], little is known about the role of adrenal steroids in this context. Considerable evidence exists which suggest that the aging process involves not only the gonads but also the adrenal glands [7, 8]. Therefore a declining output of adrenal steroids might be a risk factor for developing osteoporosis. The adrenal androgen dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the circulation and is known to decline with advancing age. Its concentration is significantly lower in osteoporotic subjects than in normals [7, 9, 10]. Besides the 5-ene-androgen DHEAS, the 4-ene-androgen l lfl-hydroxyandrostenedione (OHA) is a specific marker of adrenal function[l l, 12]. In this study we measured 11-OHA in 224 normal women aged 20-79 yr and 130 osteoporotic women aged 40-79 yr. The aim of the study was to obtain further information about age-related changes Proceedings of the Vlllth International Congress on Hormonal Steroids, The Hague, The Netherlands, 16--21September

1990. *To whom correspondenceshould be addressed.

in adrenal androgens and to examine whether there is a correlation of 11-OHA concentrations with osteoporotic spine deformity.

SUBJECTS AND METHODS

Subjects

The study comprised 224 normal (20-79 yr, g54.1 _ 14.4) and 130 osteoporotic women (40-79yr, g63.1___10.0), presented to our osteoporosis ambulatory in 1986-1990. All subjects studied, were endocrinologically normal (based on normal serum assays for T4, T3, TSH, cortisol and PTH). Patients with osteomalacia, renal insufficiency, liver disease, or who had received long-term glucocorticoid therapy were excluded. The diagnosis of osteoporosis was made by X-ray (more than one wedged vertebrae, or one or more crushed vertebrae). L a b o r a t o r y analyses

The RIA system for 1 l~-hydroxyandrostenedione ( l l - O H A ) has been described previously[l 1]. Highly specific antiserum was raised in rabbits. The synthesis of labeled l l-OHA was performed by the method of Appleby and Norymberski[13] with [1,23H]cortisol as starting substance. Thin-layer

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R. SCHLAGHECKE et al. 11-OHA[ng/ml] 6 5.5 5 4.5 4 3.5 3 2.5

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Fig. 1. I I - O H A concentrations vs age in normal female subjects.

chromatography was performed before RIA procedure. Each 11-OHA value reflects the average of duplicate analyses. The intra-assay coefficient of variation was 6.8%. The inter-assay coefficient of variation was 8.9%. Blood was taken for 11-OHA measurement between 08.00 and 09.00 h in all subjects. D a t a were analyzed by 10-yr age groups (20-29, 30-39, 40-49, 50-59, 60-69 and 70-79).

Statistics H o r m o n e concentrations were given as the mean + standard deviation (~ + SD). Data were processed statistically using the Wilcoxon rank test. Pearson correlation coefficients were estimated in a linear regression analysis.

RESULTS

The results on 1 I - O H A concentration in normal female subjects are shown in Fig. 1. The mean serum concentration was found to be 2.17 ___0.90 ng/ml, range 0.5-4.0 ng/ml. There was no clear relationship between age and 11O H A serum concentration (r = 0.15). The resuits on l l - O H A serum concentration in osteoporotic females are shown in Fig. 2. The mean serum concentration was found to be 1.75 + 0.58 ng/ml, range 0.35-3.8 ng/ml. Again there was no clear relationship between age and 1 I - O H A serum concentration (r = 0.17). Osteoporotic subjects showed statistically significantly lower 11-OHA serum concentrations (P < 0.01) than normal subjects.

11"OHA [ng/ml] 4 I

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Fig. 2. 11-OHA concentrations vs age in osteoporotic female subjects.

1I-OHA in normal and osteoporotic women DISCUSSION C o n s i d e r a b l e evidence exists which suggests t h a t there is a progressive m o d u l a t i o n in a d r e n o c o r t i c a l f u n c t i o n with a d v a n c i n g age [14]. H o w e v e r , the v a r i a b i l i t y in the degree o f m o d u lation a m o n g species, strain a n d i n d i v i d u a l s is g r e a t [14]. T h e secretion o f a d r e n a l C 19 steroids, D H E A a n d its sulfate, has been k n o w n to decline g r a d u a l l y with a d v a n c i n g age, in contrast to t h a t o f cortisol, which is essentially unaffected by aging [7, 15]. In the present study we f o u n d no a g e - r e l a t e d changes in 1 1 - O H A serum c o n c e n t r a t i o n . T o g e t h e r with a b o v e ment i o n e d findings, the secretion o f 4-ene-adrenal steroids seems n o t to be affected by age, whereas the secretory c a p a c i t y o f 5-ene-adrenal steroids seems to be i m p a i r e d in elderly subjects. Therefore the site o f the defect is n o t a decline in overall a d r e n a l steroidogenesis as p r o p o s e d recently[16], b u t a r e d u c t i o n in the activity o f specific s t e r o i d o g e n i c enzymes has to be assumed. In p o s t m e n o p a u s a l w o m e n estrogens are k n o w n to be related to b o n e loss a n d risk o f fractures[17]. P o s t m e n o p a u s a l b o n e loss can be prevented by estrogen substitution t h e r a p y [18, 19]. A f t e r the m e n o p a u s e , when the o v a r i a n estrogen p r o d u c t i o n has ceased, a d r e n a l a n d r o g e n s are the m o s t i m p o r t a n t p r e c u r s o r s o f e n d o g e n o u s estrogen activity [20]. M o r e o v e r and r o g e n s m a y have a beneficial effect against o s t e o p o r o s i s in their o w n right [1]. In the present study, m e a n serum 1 1 - O H A c o n c e n t r a t i o n was f o u n d to be statistically significantly lower in o s t e o p o r o t i c t h a n in n o r m a l subjects. The difficulty to differentiate w o m e n with ost e o p o r o s i s f r o m those in c o n t r o l g r o u p s simply o n the basis o f steroid h o r m o n e levels is well k n o w n [ 2 , 2 1 ] . T h e r e f o r e o u r results c a n n o t p r o v e t h a t a d r e n a l a n d r o g e n s have an etiological basis in the d e v e l o p m e n t o f the o s t e o p o r o t i c process. Nevertheless the results o f o u r investig a t i o n e n c o u r a g e further study o f the influence o f e n d o g e n o u s a d r e n a l a n d r o g e n activity in relation to o s t e o p o r o s i s .

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