Relationship between bone resorption and adrenal sex steroids and their derivatives in oophorectomized women

Transcription

1 FERTILITY AND STERILITY VOL. 82, NO. 6, DECEMBER 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Relationship between bone resorption and adrenal sex steroids and their derivatives in oophorectomized women M. Nozaki, M.D., K. Hashimoto, M.D., and H. Nakano, M.D. Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Objective: To clarify the role of adrenal sex steroids and their derivatives on bone resorption in oophorectomized women. Design: Cross-sectional study. Setting: Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University. Subject(s): Forty-eight women who were within one year of bilateral oophorectomy were recruited for this study. Intervention(s): None of the subjects were treated with the drugs affecting bone metabolism. Main Outcome Measure(s): Urinary deoxypyridinoline (Dpyr) as marker of bone resorption and serum DHEAS, androstenedione (A-dione), testosterone (T) and estrone (E 1 ) levels as adrenal sex steroids and their derivatives. Result(s): There was an inverse correlation between urinary Dpyr and serum concentrations of E 1, DHEAS, or A-dione. There was no significant relationship between urinary Dpyr and T. Conclusion(s): These results suggest that adrenal steroids and their derivatives may influence the bone resorption in oophorectomized women. (Fertil Steril 2004;82: by American Society for Reproductive Medicine.) Key Words: Adrenal steroids and their derivatives, oophorectomized women, bone resorption Received January 5, 2004; revised and accepted April 29, Reprint requests: M. Nozaki, M.D., Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka , Japan (FAX: ; E- mail: nozaki@med.kyushuu.ac.jp) /04/$30.00 doi: /j.fertnstert Estrogen deficiency after oophorectomy leads to an accelerated bone loss (1 3), which begins at an early phase after surgery and occurs predominantly in the trabecular bone at various skeletal sites. In these women, serum levels of androgen released from adrenal gland were also suggested to be another factor modulating bone density (4). The pathogenesis of an early rapid phase of bone loss in oophorectomized women is mainly thought to be due to an early increase of bone resorption, although the increase occurs at different rates between individuals. In oophorectomized women, circulating estrogen levels result from aromatization of adrenal androgens to estrogens in peripheral tissues (5). Although the aromatase enzyme is present in many tissues, including bone cells (6 7), most of the circulating estrogens in oophorectomized women are derived from aromatase activity in adipose tissue. Adrenal sex steroids and their derivatives, such as DHEAS, androstenedione (A), testosterone (T) and estrone (E 1 ) may affect this differential rate of bone resorption to some extent. Urinary deoxypyridinoline (Dpyr) is considered to be a reliable and reproducible biochemical indicator of bone resorption. It is important to know the individual variation of bone metabolism in the early phase of oophorectomy and to find out the fast loser of bone density. In the present study, the crosssectional relationship among those sex steroids and bone resorption in oophorectomized women was investigated. MATERIALS AND METHODS Forty-eight oophorectomized women who visited our Menopause Clinic at Kyushu University Hospital were examined. All of the women were Japanese residents in the city of Fukuoka. Their mean age was 43.2 years old, and mean body mass index was 22.6 kg/m 2, respectively. The patients selected for this 1556

2 TABLE 1 Patient characteristics. study had an oophorectomy for benign gynecologic diseases such as endometriosis or bilateral ovarian tumors and prior to the surgery had regular menstrual cycles. The patients were all within one year of the procedure. Patients were excluded from the study if they had a history of metabolic bone diseases or treatment with sex steroids, corticosteroids, or other drugs known to influence bone metabolism. Approval was obtained for this study from the institutional board of the hospital. All subjects gave informed consent to participate in the study. Blood and urine samples were obtained from all 48 subjects after an overnight fast and were collected between 0900 h and 1000 h to control for diurnal variation. Urinary Dpyr levels were measured by a high-pressure liquid chromatography assay as previously reported (6). Serum DHEAS levels were measured by the direct RIA method of Buster and Abraham (7), except that the radiolabeled ligand was [1,2-3 H]- instead of [7-3 H]DHEA. Coefficients of variation (CV) in inter- and intra-assay were 8.3% and 6.8%, respectively. Serum A-dione was measured by RIA using a kit from DPC Corporation (Tokyo, Japan). Inter- and intra-assay CV were 7.6% and 6.3%, respectively. Serum total T was measured by RIA using a kit from DPC Corporation. Inter- and intra-assay CV were 7.5% and 5.9%, respectively. Serum E 1 was measured by RIA using a kit from Diagnostic Biochemistry Canada (London, Ontario, Canada). Inter- and intra-assay CV were 8.2% and 7.8%, respectively. Relationships among variables were quantitated by using Pearson product-moment correlation. A value of P.05 was considered significant. All analyses were performed on the Statistical Analysis System software program (SAS Institute, Cary, NC) and BMDR 2R software (8). RESULTS Oophorectomized women (n 48) Age (y) BMI (kg/m 2 ) Days after oophorectomy (d) E 1 (pg/ml) A-dione (ng/ml) DHEAS ( g/ml) T (ng/ml) Note: Mean SD. BMI body mass index. The subjects characteristics and the hormone and bone resorption values are shown in Table 1. The urinary excretion of Dpyr-creatinine ratio (Dpyr/ creat.) is shown in Figure 1A. It can be seen that there is a good inverse relationship between Dpyr/creat. and the serum E 1 concentrations (r 0.63; P.001). The lower the amount of circulating E 1, the greater the Dpyr/creat. in urine. Figure 1B shows the relationship between urinary Dpyr/ creat. and the serum DHEAS concentrations. There is a loose, but significant, inverse relationship between Dpyr/ creat. and DHEAS levels (r 0.36; P.05). The lower the amount of circulating DHEAS, the greater the Dpyr/creat. in urine. Figure 1C shows the relationship between urinary Dpyr/ creat. and the serum A-dione concentrations. There is a loose, but significant, inverse relationship between Dpyr/ creat. and A-dione levels (r 0.33; P.05). The lower the amount of circulating A-dione, the greater the Dpyr/creat. in urine. Figure 1D shows the relationship between urinary Dpyr and the serum T concentrations. There was no relationship between Dpyr and T. DISCUSSION We found an inverse association between serum DHEAS, A-dione, and the level of bone resorption as indicated by urinary Dpyr. The correlation between serum E 1 and urinary Dpyr was modestly stronger. There was no relationship between bone resorption and T. DHEAS is the most abundant steroid in the circulation and arises primarily by secretion from the adrenal cortex (8). DHEAS increases during adrenarche, peaks between the ages of years in women, and mean values then decline until the seventh decade, falling to about one fifth of the maximum (9). In nonoophorectomized women, the majority of A-dione is derived from the ovaries and adrenal glands as compared to oophorectomized women where it is derived mainly from the adrenal glands. A recent study indicated that in late postmenopausal women even the low serum estrogen levels present exerted a restraining effect on bone resorption (9). Because the subjects in the present study are younger than late postmenopausal women, they have more abundant adrenal androgens and the derivatives that have much more effect on bone metabolism. In oophorectomized women, circulating levels of E 1 result from an aromatization of adrenocortical A-dione to E 1 in peripheral tissues, especially adipose tissue. Therefore, in our study, it is unclear whether DHEAS and A-dione have a direct effect on bone resorption or indirect effect through the sources of E 1. Although this study is lacking a control group of patients and a comparison between subjects pre- and postoperation, it is important to know about the individual variation of bone FERTILITY & STERILITY 1557

3 FIGURE 1 (A) The relationship between urinary Dpyr and the serum E 1 concentrations. Line fitted by method of least squares. (B) The relationship between urinary Dpyr and the serum DHEAS concentrations. Line fitted by method of least squares. metabolism in the early phase of oophorectomy and to find out the fast loser of bone density. The cross-sectional relationship among adrenal sex steroids and bone resorption in oophorectomized women was investigated in the present study; however, our findings would be more useful in the clinical practice if we set the control for a particular time frame for sample collection. In conclusion, these results suggest that E 1 may be the contributing factor to bone resorption and DHEAS and A Nozaki et al. Adrenal sex steroids and bone resorption Vol. 82, No. 6, December 2004

4 FIGURE 1 Continued. (C) The relationship between urinary Dpyr and the serum A-dione concentrations. Line fitted by method of least squares. (D) The relationship between urinary Dpyr and the serum T concentrations. Line fitted by method of least squares. dione might contribute to bone resorption to some extent in oophorectomized women. The variations in these steroid levels may contribute to differences in their rate of bone loss. Acknowledgment: The authors are grateful to Professor Brian Quinn for proofreading the manuscript. References 1. Genant HK, Cann CE, Ettinger B, Gordon GS. Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Inter Med 1982; 97: Horsman A, Simpson M, Kirby PA, Nordin BEC. Non-linear bone loss in oophorectomized women. Br J Radiol 1977;50: Hashimoto K, Nozaki M, Inoue Y, Sano M, Nakano H. The chronological change of vertebral bone loss following oophorectomy using dual energy x-ray absorptiometry; the correlation with specific markers of bone metabolism. Maturitas 1995;22: Nordin BEC, Robertson A, Seamark RF, Bridges A, Philcox JC, Need FERTILITY & STERILITY 1559

5 AG, et al. The relationship between calcium absorption, serum dehydroepiandrosterone, and vertebral mineral density in postmenopausal women. J Clin Endocrinol Metab 1985;60: Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 1994;15: Hashimoto K, Nozaki M, Yokoyama M, Sano M, Nakano H. Urinary excretion of pyridinium crosslinks of collagen as markers for bone resorption. Maturitas 1994;18: Buster JE, Abraham GE. Radioimmunoassay of plasma dehydroepiandrosterone sulfate. Anal Lett 1972;5: Dickson WJ, Jennrich R. Stepwise regression 2R. In: BMDP statistical software manual. Berkeley: University of California, 1990: Vande Wiele RL, Macdonald PC, Gurpide E, Lieberman S. Studies on the secretion and interconversion of the androgens. Recent Prog Horm Res 1963;19: Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59: Heshmati HM, Khosla S, Robins SP, O Fallon WM, Melton LJ III, Riggs BL. Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women. J Bone Miner Res 2002;17: Nozaki et al. Adrenal sex steroids and bone resorption Vol. 82, No. 6, December 2004