SciELO - Scientific Electronic Library Online

vol.56 issue5Morphologic and morphometric evaluation of pancreatic islets in chronic Chagas' diseaseFriedreich's ataxia: clinical and molecular study of 25 Brazilian cases author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




Related links


Revista do Hospital das Clínicas

On-line version ISSN 1678-9903

Rev. Hosp. Clin. vol.56 no.5 São Paulo Sept./Oct. 2001 



Elaine Maria Frade Costa, Ivo Jorge Prado Arnhold, Marlene Inacio and Berenice Bilharinho Mendonca




COSTA EMF et al. - Normal bone density in male pseudohermaphroditism due to 5a-reductase 2 deficiency. Rev. Hosp. Clín. Fac. Med. S. Paulo 56(5):139-142, 2001.

Bone is an androgen-dependent tissue, but it is not clear whether the androgen action in bone depends on testosterone or on dihydrotestosterone. Patients with 5a-reductase 2 deficiency present normal levels of testosterone and low levels of dihydrotestosterone, providing an in vivo human model for the analysis of the effect of testosterone on bone.

OBJECTIVE: To analyze bone mineral density in 4 adult patients with male pseudohermaphroditism due to 5a-reductase 2 deficiency.

RESULTS: Three patients presented normal bone mineral density of the lumbar column (L1-L4) and femur neck, and the other patient presented a slight osteopenia in the lumbar column.

CONCLUSION: Patients with dihydrotestosterone deficiency present normal bone mineral density, suggesting that dihydrotestosterone is not the main androgen acting in bone.

DESCRIPTOR: Bone mineral density. Male pseudohermaphroditism. 5a-reductase type 2 deficiency.



It has been well documented in the literature that gonadal steroids regulate normal bone metabolism and that inadequate estrogen concentrations in females and androgen concentrations in males cause osteoporosis1-4. In males, hypogonadism is the main risk factor for the development of osteoporosis2, and therapy with androgens increases bone mineral density5. In females, androgen therapy associated with estrogens has proven to be more effective in the prevention of post-menopausal bone loss in comparison to estrogen therapy alone6.

Up to the end of the 1980s, the mechanism of action of steroid hormones on bone was unknown, until Eriksen et al.7 demonstrated the presence of estrogenic receptors in human osteoblasts, and Colvard et al.8 identified androgenic receptors in these cells, thus demonstrating that both androgens and estrogens act by a direct mechanism through their respective receptors. Carani et al.9, studying a patient with aromatase deficiency, demonstrated that estrogen therapy had a greater positive effect over bone maturation and skeletal growth than testosterone therapy. These data suggest that estrogen has a crucial effect on skeletal maturation in males.

It is still unclear in literature, however, if the tropic effect of androgens on bone is mediated by testosterone or by its metabolite, dihydrotestosterone (DHT), or even if the androgenic effects require aromatization into estrogens with subsequent activation of the estrogenic receptor. Although it has been speculated that DHT is the active androgen in bone10, the effect of DHT deficiency on bone has not yet been demonstrated.



We performed bone densitometry in 4 male pseudohermaphrodites with 5a-reductase 2 deficiency aged 25 to 40 years old. Diagnosis was confirmed through an elevated T/DHT ratio and the presence of mutations in the 5a-reductase 2 gene11. Patients 1, 2, and 3, who are siblings, are compound heterozygous for the Q126R/N193S mutations. Patient 4 is homozygous for the R227* mutation11. Basal TSH, free T4, PRL, LH, FSH, and cortisol were normal.

In order to increase penis size, patients were initially treated with 250 mg of mixed testosterone esters by intramuscular injections weekly from 2 to 8 months, and afterwards with 1.5 g of 2.5% DHT cream applied on the abdominal skin or thighs daily at night for 3 to 11 months. The chronological age at the time of treatment was 14 to 33 years old. Bone mineral density was measured through a dual energy x-ray bone densitometer (Hologic QDR 4500/A S/N – 45130) 7 to 9 years after completion of therapy. Bone mineral density values as determined by Hologic densitometry were compared with those of normal young men with the same weight and ethnic group.



The T/DHT ratio varied from 37 to 46 (normal values=14±5.2), and the molecular study demonstrated the presence of mutations in the 5a-reductase type 2 gene.

Three patients presented normal bone mineral density of the lumbar column (L1-L4) and femur neck, and patient 2 presented a slight osteopenia in the lumbar column (L1-L4) [Table 1].




The effect of androgen on hair follicles, prostate, and seminal vesicles depends on the local conversion of testosterone into DHT. In contrast, the effects of androgen on muscle mass, spermatogenesis, and libido are maintained by testosterone only12. Even though bone is an androgen-dependent tissue, it is still unknown if 5a-reductase type 2 activity is important for the androgenic action on bone cells. Previous studies demonstrated that the treatment of orchiectomized rats with DHT stimulates the development of endochondral bone13 and attenuates bone loss after orchiectomy14; furthermore, both testosterone and DHT increase the transcription of a1(I)-procollagen mRNA in osteoblast-like osteosarcoma cells15.

On the other hand, Rosen at al.16 demonstrated that rats treated with finasteride, which inhibits the action of 5a-reductase 2, had normal bone density, concluding that DHT deficiency was not deleterious for bone. Elderly men with benign prostate hyperplasia treated with finasteride did not show any effect on bone density or on bone and mineral metabolism17. Human and rat bone have 5a-reductase activity and can synthesize DHT in vitro10, but it is unclear which one of the two types of 5a-reductase (type 1 or type 2) acts predominantly on bone.

We studied 4 male pseudohermaphrodites with 5a-reductase 2 deficiency who were treated with DHT cream and testosterone esters for 3 to 11 months, 7 to 9 years before bone mass evaluation. One can speculate as to whether there was an effect of this short-period androgen therapy on the bone mass of our patients. However, our experience shows that this period of treatment is not enough to re-establish bone mass in men with hypogonadism. The same observation has been reported in men with isolated GnRH deficiency under gonadal steroid replacement therapy from 1 to 3 years whose bone density increased but failed to reach normal adult levels5. The importance of estrogen on bone maturation and mineralization has been recently demonstrated in 2 studies. Smith at al.18 reported an individual with estrogen-resistance syndrome who presented osteoporosis with increased bone resorption despite normal androgen concentrations. Another study demonstrated that the inhibition of androgen aromatization by vorozole (a non-steroid inhibitor of P450 aromatase) increases bone resorption, indicating the importance of estrogen on bone mineralization19.

Wiren et al.20 demonstrated that there is an up-regulation of the androgen receptor to androgen action (testosterone and DHT) in osteoblasts, which might increase the responsiveness of these cells to androgens.

Our results suggest that 5a-reductase 2 deficiency in humans does not have a significant effect on bone. Several assumptions can be made:

1) the enzyme involved in the 5a-reduction in bone is 5a-reductase 1, which is not responsible for male pseudohermaphroditism;

2) the small quantities of DHT produced by these patients might be enough to activate the androgenic receptor in bone cells;

3) testosterone, directly through the activation of its receptor, may be active in bone without converting into DHT;

4) testosterone is aromatized into estrogens that has a direct action on bone cells.

Further studies are required to determine the exact mechanism of androgen action in human bone. We conclude that patients with DHT deficiency present normal bone mineral density, suggesting that DHT is not the main androgen acting in bone.





COSTA EMF e col. - Pseudohermafroditas masculinos por deficiência de 5a-redutase 2 apresentam densidade óssea normal. Rev. Hosp. Clin. Fac. Med. S. Paulo 56(5):139-142, 2001.

O tecido ósseo é um tecido andrógeno-dependente porém não está claro se a ação androgênica depende da testosterona ou da diidrotestosterona. Os pacientes portadores de deficiência de 5a-redutase tipo 2, constituem um modelo natural para avaliar o efeito isolado da testosterona sobre a massa óssea.

OBJETIVO: Avaliar a densidade mineral óssea em quatro pacientes adultos portadores de pseudohermafroditismo masculino por deficiência da 5a-redutase tipo 2.

RESULTADOS: Três pacientes apresentaram densidade mineral óssea normal na coluna lombar e fêmur e o quarto paciente apresentou osteopenia leve em coluna lombar.

CONCLUSÃO: Pacientes com deficiência de diidrotestosterona apresentam densidade mineral óssea normal sugerindo que a diidrotestosterona não é o andrógeno que age sobre o osso.

DESCRITORES: Densidade mineral óssea. Pseudohermafroditismo masculino. Deficiência da 5a-redutase tipo 2.




1. RICHELSON LS, WAHNER HW, MELTON LJ et al. - Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984;311:1273-1275.         [ Links ]

2. SEEMAN E, MELTON LJ, JR O'FALLON WM et al. - Risks factors for spinal osteoporosis in men. Am J Med 1983;75:977-983.         [ Links ]

3. RIGGS BL & MELTON LJ - Involutional osteoporosis. N Engl J Med 1986;314:1676-1686.         [ Links ]

4. JACKSON JA, KLEEREKOPER M, PARFITT M et al. - Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis. J Clin Endocrinol Metabol 1987;65:53-58.         [ Links ]

5. FINKELSTEIN JS, KLIBANSKI A, NEER RM et al. - Increases in bone density during treatment of men with idiopatic hypogonadotropic hypogonadism. J Clin Endocrinol Metabol 1989;69(4):776-783.         [ Links ]

6. BUCHANAN JR, HOSPADAR P, MYERS C et al. - Effect of excess endogenous androgens on bone density in young women. J Clin Endocrinol Metab 1988;67:937-943.         [ Links ]

7. ERIKSEN EF, COLVARD DS, BERG NJ et al. - Evidence of estrogen receptors in normal human osteoblast-like cells. Science. 1988;241:84-86.         [ Links ]

8. COLVARD DS, ERIKSEN EF, KEETING PE et al. - Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci 1989;86:854-857.         [ Links ]

9. CARANI C, QIN K, SIMONI M et al. - Effect of testosterone and estradiol in man with aromatase deficiency. N Engl J Med 1997;337(2):91-95.         [ Links ]

10. SCHWEIKERT HU, RULF W, NIERDERLE N et al. - Testosterone metabolism in human bone. Acta Endocrinol (Copenh) 1980; 95:258-64.         [ Links ]

11. MENDONCA BB, INACIO M, COSTA EMF et al. - Male pseudohermaphroditism due to steroid 5a-reductase 2 deficiency: Diagnosis, psychological evaluation and management. Medicine 1996;75(2):64-76.         [ Links ]

12. RITTMASTER RS - Finasteride. N Engl J Med 1994;330:120-125.         [ Links ]

13. KAPUR SP & REDDI AH - Influence of testosterone and dihydrotestosterone on bone-matrix induced endochondral bone formation. Calcif Tissue Int 1989 44:108-113.         [ Links ]

14. VANDERSCHUEREN D, VAN HERCK E, SUIKER AM et al. - Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency. Endocrinology 1992; 130:2906-2916.         [ Links ]

15. BENZ DJ, HAUSSLER MR, THOMAS MA et al. - High-affinity androgen binding and androgenic regulation of a1(I)-procollagen and transforming growth factor-b steady state messenger ribonucleic acid levels in human osteoblast-like osteosarcoma cells. Endocrinol 1994;128:2723-2730.         [ Links ]

16. ROSEN HN, TOLLIN S, BALENA R et al. - Bone density is normal in male rats treated with finasteride. Endocrinol 1995; 136(4):1381-1387.         [ Links ]

17. MATZKIN H, CHEN J, WEISMAN Y et al. - Prolonged treatment with finasteride (a 5a- reductase inhibitor) does not affect bone density and metabolism. Clin Endocrinol 1992;37:432-436.         [ Links ]

18. SMITH EP, BOYD J, FRANK GR et al. - Estrogen resistance caused by a mutation in the estrogen-receptor gene in a men. N Engl J Med 1994;20:1056-1061.         [ Links ]

19. VANDERSCHUEREN D, VAN HERCK E, DECOSTER R et al. - Aromatization of androgens is important for skeletal maintenance of aged male rats. Calcif Tissue Int 1996;59:179-183.         [ Links ]

20. WIREN K, ZHANG CC & KEENAN E - Transcriptional up-regulation of the human androgen receptor by androgen in bone cells. Endocrinology 1997;138(6):2291-2300.         [ Links ]



Received for publication on January 15, 2001.



From the Division of Endocrinology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo.

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License