Advertisement

Osteoporosis International

, Volume 18, Issue 3, pp 369–374 | Cite as

Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene

  • D. L. S. DanilovicEmail author
  • P. H. S. Correa
  • E. M. F. Costa
  • K. F. S. Melo
  • B. B. Mendonca
  • I. J. P. Arnhold
Original Article

Abstract

Introduction and hypothesis

Androgen insensitivity syndrome (AIS) constitutes a natural model to study effects of androgens and estrogens on growth and bone density. We evaluated height and bone density in patients with AIS with mutations in the androgen receptor (AR) gene.

Methods

A retrospective analysis was conducted of eight subjects with complete AIS (CAIS) and four with partial AIS (PAIS) submitted to gonadectomy followed by estrogen replacement, and three with PAIS who did not undergo gonadectomy. Standing height and bone mineral apparent density (BMAD) by DXA were measured and compared with male (z m) and female (z f) reference populations. The z-scores were compared with a value of zero using the one-sample t-test.

Results

Final heights of patients with CAIS and PAIS were intermediate between those predicted for females and males. BMAD of the lumbar spine in CAIS and PAIS after gonadectomy and estrogen replacement (z f = − 1.56 ± 1.04, P = 0.006, and z m = − 0.75 ± 0.89, P = 0.04) indicated vertebral bone deficit, whereas BMAD at the femoral neck was normal. No patient reported fractures.

Conclusion

Subjects with AIS had mean final height intermediate between mean normal male and female, and decreased bone mineral density in the lumbar spine. These data suggest an important role for androgens in normal male growth and bone density not replaced by estrogens.

Keywords

Androgen insensitivity syndrome Bone mineral density Height Mutations in androgen receptor gene 

References

  1. 1.
    Quigley CA, De Bellis A, Marschke KB et al (1995) Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 16:271–321PubMedCrossRefGoogle Scholar
  2. 2.
    Boehmer AL, Brinkmann O, Bruggenwirth H et al (2001) Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 86:4151–4160PubMedCrossRefGoogle Scholar
  3. 3.
    Melo KF, Mendonca BB, Billerbeck AE et al (2003) Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene. J Clin Endocrinol Metab 88:3241–3250PubMedCrossRefGoogle Scholar
  4. 4.
    Vanderschueren D, Vandenput L, Boonen S et al (2004) Androgens and bone. Endocr Rev 25:389–425PubMedCrossRefGoogle Scholar
  5. 5.
    Griffin J, Wilson JD (1989) The androgen resistance syndromes: 5a-reductase deficiency, testicular feminization, and related disorders. In: Scriver CR, Beaudet AL, Sly WS et al (eds) (1989) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 1919–1944Google Scholar
  6. 6.
    MacDonald PC, Madden JD, Brenner PF et al (1979) Origin of estrogen in normal men and in women with testicular feminization. J Clin Endocrinol Metab 49:905–916PubMedGoogle Scholar
  7. 7.
    Zachmann M, Prader A, Sobel EH et al (1986) Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls. J Pediatr 108:694–697PubMedCrossRefGoogle Scholar
  8. 8.
    Frank GR (2003) Role of estrogen and androgen in pubertal skeletal physiology. Med Pediatr Oncol 41:217–221PubMedCrossRefGoogle Scholar
  9. 9.
    Grumbach MM (2000) Estrogen, bone, growth and sex: a sea change in conventional wisdom. J Pediatr Endocrinol Metab 13:1439–1455PubMedGoogle Scholar
  10. 10.
    Carrascosa A, Audi L, Ferrandez MA et al (1990) Biological effects of androgens and identification of specific dihydrotestosterone-binding sites in cultured human fetal epiphyseal chondrocytes. J Clin Endocrinol Metab 70:134–140PubMedGoogle Scholar
  11. 11.
    Abu EO, Horner A, Kusec V et al (1997) The localization of androgen receptors in human bone. J Clin Endocrinol Metab 82:3493–3497PubMedCrossRefGoogle Scholar
  12. 12.
    Ben-Hur H, Thole HH, Mashiah A et al (1997) Estrogen, progesterone and testosterone receptors in human fetal cartilaginous tissue: immunohistochemical studies. Calcif Tissue Int 60:520–526PubMedCrossRefGoogle Scholar
  13. 13.
    Noble B, Routledge J, Stevens H et al (1999) Androgen receptors in bone-forming tissue. Horm Res 51:31–36PubMedCrossRefGoogle Scholar
  14. 14.
    van der Eerden BC, van Til NP, Brinkmann AO et al (2002) Gender differences in expression of androgen receptor in tibial growth plate and metaphyseal bone of the rat. Bone 30:891–896PubMedCrossRefGoogle Scholar
  15. 15.
    Munoz-Torres M, Jodar E, Quesada M et al (1995) Bone mass in androgen-insensitivity syndrome: response to hormonal replacement therapy. Calcif Tissue Int 57:94–96PubMedCrossRefGoogle Scholar
  16. 16.
    Bertelloni S, Baroncelli GI, Federico G et al (1998) Altered bone mineral density in patients with complete androgen insensitivity syndrome. Horm Res 50:309–314PubMedCrossRefGoogle Scholar
  17. 17.
    Marcus R, Leary D, Schneider DL et al (2000) The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. J Clin Endocrinol Metab 85:1032–1037PubMedCrossRefGoogle Scholar
  18. 18.
    Tanner JM, Whitehouse RH (1976) Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51:170–179PubMedCrossRefGoogle Scholar
  19. 19.
    Katzman DK, Bachrach LK, Carter DR et al (1991) Clinical and anthropometric correlates of bone mineral acquisition in healthy adolescent girls. J Clin Endocrinol Metab 73:1332–1339PubMedCrossRefGoogle Scholar
  20. 20.
    Bhudhikanok GS, Wang MC, Eckert K et al (1996) Differences in bone mineral in young Asian and Caucasian Americans may reflect differences in bone size. J Bone Miner Res 11:1545–1556PubMedGoogle Scholar
  21. 21.
    Bachrach LK, Hastie T, Wang MC et al (1999) Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab 84:4702–4712PubMedCrossRefGoogle Scholar
  22. 22.
    Carter DR, Bouxsein ML, Marcus R (1992) New approaches for interpreting projected bone densitometry data. J Bone Miner Res 7:137–145PubMedCrossRefGoogle Scholar
  23. 23.
    Smith DW, Marokus R, Graham JM Jr (1985) Tentative evidence of Y-linked statural gene(s). Growth in the testicular feminization syndrome. Clin Pediatr (Phila) 24:189–192Google Scholar
  24. 24.
    Sobel V, Schwartz B, Zhu YS et al (2006) Bone mineral density in the complete androgen insensitivity and 5(-reductase-2 deficiency syndromes. J Clin Endocrinol Metab 91:3017–3023PubMedCrossRefGoogle Scholar
  25. 25.
    Colvard DS, Eriksen EF, Keeting PE et al (1989) Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci USA 86:854–857PubMedCrossRefGoogle Scholar
  26. 26.
    Weinstein RS, Jilka RL, Parfitt AM et al (1997) The effects of androgen deficiency on murine bone remodeling and bone mineral density are mediated via cells of the osteoblastic lineage. Endocrinology 138:4013–4021PubMedCrossRefGoogle Scholar
  27. 27.
    Kousteni S, Bellido T, Plotkin LI et al (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730PubMedGoogle Scholar
  28. 28.
    Francis RM (1999) The effects of testosterone on osteoporosis in men. Clin Endocrinol (Oxf) 50:411–414CrossRefGoogle Scholar
  29. 29.
    Kiratli BJ, Srinivas S, Perkash I et al (2001) Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology 57:127–132PubMedCrossRefGoogle Scholar
  30. 30.
    Frost HM (1987) The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents. Bone Miner 2:73–85PubMedGoogle Scholar
  31. 31.
    Rauch F, Bailey DA, Baxter-Jones A et al (2004) The ‘muscle-bone unit’ during the pubertal growth spurt. Bone 34:771–775PubMedCrossRefGoogle Scholar
  32. 32.
    Saggese G, Baroncelli GI, Bertelloni S (2002) Puberty and bone development. Best Pract Res Clin Endocrinol Metab 16:53–64PubMedCrossRefGoogle Scholar
  33. 33.
    Schiessl H, Frost HM, Jee WS (1998) Estrogen and bone-muscle strength and mass relationships. Bone 22:1–6PubMedCrossRefGoogle Scholar
  34. 34.
    Frost HM, Schonau E (2000) The “muscle-bone unit” in children and adolescents: a 2000 overview. J Pediatr Endocrinol Metab 13:571–590PubMedGoogle Scholar
  35. 35.
    Schoenau E, Neu CM, Mokov E et al (2000) Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab 85:1095–1098PubMedCrossRefGoogle Scholar
  36. 36.
    Vered I, Kaiserman I, Sela BA et al (1997) Cross genotype sex hormone treatment in two cases of hypogonadal osteoporosis. J Clin Endocrinol Metab 82:576–578PubMedCrossRefGoogle Scholar
  37. 37.
    Mizunuma H, Soda M, Okano H et al (1998) Changes in bone mineral density after orchidectomy and hormone replacement therapy in individuals with androgen insensitivity syndrome. Hum Reprod 13:2816–2818PubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Authors and Affiliations

  • D. L. S. Danilovic
    • 1
    • 2
    Email author
  • P. H. S. Correa
    • 1
  • E. M. F. Costa
    • 1
  • K. F. S. Melo
    • 1
  • B. B. Mendonca
    • 1
  • I. J. P. Arnhold
    • 1
  1. 1.Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia e MetabologiaHospital das Clínicas da Faculdade de Medicina da Universidade de São PauloSão PauloBrazil
  2. 2.São PauloBrazil

Personalised recommendations