Calcified Tissue International

, Volume 59, Issue 3, pp 179–183

Aromatization of androgens is important for skeletal maintenance of aged male rats

  • D. Vanderschueren
  • E. Van Herck
  • R. De Coster
  • R. Bouillon
Laboratory Investigations


A nonsteroidal aromatase inhibitor vorozole (VOR) was administered to aged (12 months old) male Wistar rats and its effect was compared with the effect of androgen deficiency. The rats were either sham-operated (SHAM) or orchidectomized (ORCH) and treated with or without VOR. Thus, four experimental groups were created (SHAM, ORCH, SHAM + VOR, ORCH + VOR). The follow-up period was 4 months. At the end of the experimental period, bone mineral density (BMD) of the first four lumbar vertebrae and right femur was measured ex vivo with dualenergy X-ray absorptiometry, bone formation was evaluated by serum osteocalcin, and bone resorption by urinary excretion of (deoxy)pyridinoline. Orchidectomy increased bone resorption 2-to 3-fold whereas bone formation was only slightly increased. Treatment of intact male rats with VOR also increased bone resorption (+30% increase) whereas bone formation was not increased in this SHAM + VOR group. Their BMD was 7% lower in the femur (P < 0.01) and 6% lower in the lumbar vertebrae (P < 0.01) compared with the SHAM group that had not received VOR. Moreover, this decrease of bone mineral density was not significantly different from the expected decrease of bone density observed in the ORCH groups (6–10%). This was also reflected by a decrease of calcium content of the first four lumbar vertebrae of 15% (P < 0.001) in the SHAM + VOR group and 9–14% (P < 0.05) in the ORCH groups compared with the SHAM group, respectively. These data therefore suggest that inhibition of aromatization of androgens into estrogens increases bone resorption and bone loss similar to that observed after complete removal of androgens. Aromatization of androgens into estrogens may therefore, at least partly, explain the effects of androgens on skeletal maintenance.

Key words

Androgens Bone Vorozole Aromatase Osteoporosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Seeman E, Melton LJ III (1983) Risk factors for osteoporosis in men. Am J Med 75:977–983PubMedCrossRefGoogle Scholar
  2. 2.
    Stanley HL, Schmitt BP, Poses RM, Deiss WP (1991) Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men. J Am Geriatr Soc 39:766–771PubMedGoogle Scholar
  3. 3.
    Stepan JJ, Lachman M, Zverina J, Pacovscky V, Baylink DJ (1989) Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin Endocrinol Metab 69:523–527PubMedGoogle Scholar
  4. 4.
    Goldray D, Weisman Y, Jaccard N, Merdler C, Chen J, Matzin H (1993) Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist Decapeptyl. J Clin Endocrinol Metab 76:288–290PubMedCrossRefGoogle Scholar
  5. 5.
    Wakley GK, Schutte HD, Kathleen SH, Turner RT (1991) Androgen treatment prevents loss of cancellous bone in the orchidectomized rat. J Bone Miner Res 6:325–330PubMedGoogle Scholar
  6. 6.
    Vanderschueren D, Van Herck E, Suiker AMH, Visser WJ, Schot LPC, Bouillon R (1992) Bone and mineral metabolism in aged male rats: short- and long-term effects of androgen deficiency. Endocrinology 130:2906–2916PubMedCrossRefGoogle Scholar
  7. 7.
    Colvard DS, Eriksen EF, Keeting PE, Wilson EM, Lubahn DB, French FS, Riggs BL, Speisberg TC (1989) Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci USA 86:854–857PubMedCrossRefGoogle Scholar
  8. 8.
    Orwoll ES, Stribrska L, Ramsey EB, Keenan EJ (1991) Androgen receptors in osteoblast-like cells. Calcif Tissue Int 49: 183–188PubMedCrossRefGoogle Scholar
  9. 9.
    Kasperk C, Wergedal JE, Farley JR, Linkhart TA, Turner RT, Baylink D (1989) Androgens directly stimulate proliferation of bone cells in vitro. Endocrinology 124:1576–1579PubMedGoogle Scholar
  10. 10.
    Kasperk C, Fitzsimmons R, Strong D, Mohan S, Jennings J, Wergedal J, Baylink D (1990) Studies of the mechanism by which androgens enhance mitogenesis and differentiation in bone cells. J Clin Endocrinol Metab 71:1322–1329PubMedGoogle Scholar
  11. 11.
    Mooradian AD, Morley JE, Korenman SG (1987) Biological actions of androgens. Endocrinol Rev 8:1–27CrossRefGoogle Scholar
  12. 12.
    Tanaka S, Haji M, Nishi Y, Yanase T, Takayanagi R, Nawata H (1993) Aromatase activity in human osteoblast-like osteosarcoma cell. Calcif Tissue Int 52:107–109PubMedCrossRefGoogle Scholar
  13. 13.
    Purohit A, Flanagan AM, Reed MJ (1992) Estrogen synthesis by osteoblast cell lines. J Clin Endocrinol Metab 61:152–157Google Scholar
  14. 14.
    Vanderschueren D, Van Herck E, Suiker AMH, Visser WJ, Geusens P, Schot LPC, Bouillon R, Rush EB, Einhorn TA (1993) Bone and mineral metabolism in the androgen-resistant (testicular feminized) male rat. J Bone Miner Res 8:799–807Google Scholar
  15. 15.
    Vanderschueren D, Van Herck E, Geusens P, Bouillon R (1994) Androgen resistance and deficiency have different effects on the growing skeleton of the rat. Calcif Tissue Int 55:198–203PubMedCrossRefGoogle Scholar
  16. 16.
    Lips P, Asscheman H, Uitewaal P, Netenbos JC, Gooren L (1989) The effect of cross-gender hormonal treatment on bone metabolism in male to female transsexuals. J Bone Miner Res 4:657–662PubMedGoogle Scholar
  17. 17.
    Girasole G, Jilka RL, Passeri G, Scott B, Boder G, Williams DC, Manolagas SC (1992) Estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro. A potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 89:883–891PubMedCrossRefGoogle Scholar
  18. 18.
    Wouters W, Van Gunckel R, Krekels M, Bowden C, De Coster R (1993) Pharmacology of vorozole. J Steroid Biochem Mol Biol 44:617–621PubMedCrossRefGoogle Scholar
  19. 19.
    Balthazart J, Evrard L, Surlemont C (1990) Effects of the nonsteroidal inhibitor R 76713 on testosterone-induced sexual behavior in the Japanese quail. Horm Behav 24:510–531PubMedCrossRefGoogle Scholar
  20. 20.
    Verhaeghe J, Van Herck E, Van Bree R, Van Assche FA, Bouillon R (1989) Osteocalcin during the reproductive cycle in normal and diabetic rats. J Endocrinol 120:143–151PubMedCrossRefGoogle Scholar
  21. 21.
    Verhaeghe J, Van Herck E, Visser WJ, Suiker AMH, Thomasset M, Einhorn TA, (1990) Bone and mineral metabolism in BB rats with long-term diabetes. Decreased bone turnover and osteoporosis. Diabetes 39:477–482PubMedCrossRefGoogle Scholar
  22. 22.
    Verhoeven G, Koninckx P, De Moor P (1982) Androgen and progestogen production in cultured interstitial cells derived from immature rat testis. J Steroid Biochem 17:319–330PubMedCrossRefGoogle Scholar
  23. 23.
    Vanderschueren D, Jans I, Van Herck E, Moermans K, Verhaeghe J, Bouillon R (1994) Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats. Bone Miner 26:123–131PubMedCrossRefGoogle Scholar
  24. 24.
    Vanderschueren D, Van Herck E, Schot L, Rush E, Einhorn T, Geusens P, Bouillon R (1993) The aged male rat as a model for human osteoporosis: evaluation by nondestructive measurements and biomechanical testing. Calcif Tissue Int 53: 342–347PubMedCrossRefGoogle Scholar
  25. 25.
    Wouters W, De Coster R, Van Dun J, Krekels MDWG, Dillen A, Rayemaekers A, Freyne E, Van Gelder J, Ganz G, Venet M, Janssen M (1990) Comparative effects of the aromatase inhibitor R76713 and its enantiometers R 83839 and 83842 on steroid biosynthesis in vitro and in vivo J Steroid Biochem 37:1049–1054CrossRefGoogle Scholar
  26. 26.
    Folkerd EJ, James VHT (1983) Aromatization of steroids in peripheral tissues. J Steroid Biochem 19:687–690PubMedCrossRefGoogle Scholar
  27. 27.
    Schweikert HU, Rulf W, Niederle N, Schafer, Keck E, Kruck F (1980) Testosterone metabolism in human bone. Acta Endocrinol 95:258–264PubMedGoogle Scholar
  28. 28.
    Bruch HB, Wolf L, Budde R, Romalo G, Schweikert HU (1992) Androstenedione metabolism in cultured human osteoblast-like cells. J Clin Endocrinol Metab 75:101–105PubMedCrossRefGoogle Scholar
  29. 29.
    Turner RT, Bleriberg BB, Colvard DS, Keeting PE, Evans G, Spelsberg TC (1990) Failure of isolated rat tibial periosteal cells to 5 alfa-reduce testosterone to 5 alfa-dihydrotestosterone. J Bone Miner Res 5:775–779PubMedGoogle Scholar
  30. 30.
    Turner RT, Wakley GK, Hannon KS (1990) Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J Orthop Res 8:612–617PubMedCrossRefGoogle Scholar
  31. 31.
    Matzkin H, Chen J, Weisman Y, Goldray D, Pappas F, Jaccard N, Braf Z (1992) Prolonged treatment with finasteride (a 5α-reductase inhibitor) does not affect bone density and metabolism. Clin Endocrinol 37:432–436CrossRefGoogle Scholar
  32. 32.
    Rosen HN, Tollin S, Balena R, Middlebrooks VL, Moses AC, Yamamoto M, Zeind AJ, Greenspan SL (1995) Bone density is normal in male rats treated with finasteride. Endocrinology 136:1381–1387PubMedCrossRefGoogle Scholar
  33. 33.
    Kahn DN (1984) Evaluation of the pathogenesis of skeletal changes in the ovariectomized rat. Endocrinology 115:507–512CrossRefGoogle Scholar
  34. 34.
    Goulding A, Gold E (1993) Flutamide-mediated androgen blockade evokes osteopenia in the female rat. J Bone Miner Res 8:763–769PubMedCrossRefGoogle Scholar
  35. 35.
    De Coster R, Van Ginckel RF, Callens MJL, Goeminne NKG, Janssens BLE (1992) Antitumoral and endocrine effects of (+)-vorozole in rats bearing dimethylbenzanthracene-induced mammary tumors. Cancer Res 52:1240–1244PubMedGoogle Scholar
  36. 36.
    Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061PubMedCrossRefGoogle Scholar
  37. 37.
    Ke-nan Qjn, Fisher CR, Grumbach MM, Morshina A, Simpson ER (1995)Aromatase deficiency in a male subject: characterization of a mutation in the CYP 19 gene in an affected family (abstract) Endocrinol Soc, 77th annual meeting, p. 475 (abstracts P3-27)Google Scholar
  38. 38.
    Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90: 11162–11166PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • D. Vanderschueren
    • 1
  • E. Van Herck
    • 1
  • R. De Coster
    • 2
  • R. Bouillon
    • 1
  1. 1.Laboratorium voor Experimentele Geneeskunde en Endocrinologie (LEGENDO)LeuvenBelgium
  2. 2.Department of Endocrinology and ImmunopharmacologyJanssen Research FoundationBeerseBelgium

Personalised recommendations