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139 Normal Bone Density in Male SEPTEMBER-OCTOBER REV. HOSP. CLÍN. FAC. MED. S. PAULO 56(5):139-142, 2001 NORMAL BONE DENSITY IN MALE PSEUDOHERMAPHRODITISM DUE TO 5α- REDUCTASE 2 DEFICIENCY Elaine Maria Frade Costa, Ivo Jorge Prado Arnhold, Marlene Inacio and Berenice Bilharinho Mendonca RHCFAP/3050 COSTA EMF et al. - Normal bone density in male pseudohermaphroditism due to 5α-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 5α-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 5α-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. 5α-reductase type 2 deficiency. It has been well documented in the fied androgenic receptors in these cells, fects require aromatization into estro- literature that gonadal steroids regulate thus demonstrating that both androgens gens with subsequent activation of the normal bone metabolism and that in- and estrogens act by a direct mecha- estrogenic receptor. Although it has adequate estrogen concentrations in fe- nism through their respective receptors. been speculated that DHT is the active males and androgen concentrations in Carani et al.9, studying a patient with androgen in bone10, the effect of DHT males cause osteoporosis1-4. In males, aromatase deficiency, demonstrated deficiency on bone has not yet been hypogonadism is the main risk factor that estrogen therapy had a greater demonstrated. for the development of osteoporosis2, positive effect over bone maturation and therapy with androgens increases and skeletal growth than testosterone bone mineral density5. In females, an- therapy. These data suggest that estro- PATIENTS AND METHODS drogen therapy associated with estro- gen has a crucial effect on skeletal gens has proven to be more effective maturation in males. We performed bone densitometry in in the prevention of post-menopausal It is still unclear in literature, how- 4 male pseudohermaphrodites with 5α- bone loss in comparison to estrogen ever, if the tropic effect of androgens reductase 2 deficiency aged 25 to 40 therapy alone6. on bone is mediated by testosterone or years old. Diagnosis was confirmed Up to the end of the 1980s, the by its metabolite, dihydrotestosterone through an elevated T/DHT ratio and the mechanism of action of steroid hor- (DHT), or even if the androgenic ef- presence of mutations in the 5α-reduc- mones on bone was unknown, until tase 2 gene11. Patients 1, 2, and 3, who 7 Eriksen et al. demonstrated the pres- From the Division of Endocrinology, Hospital are siblings, are compound heterozygous ence of estrogenic receptors in human das Clínicas, Faculty of Medicine, University for the Q126R/N193S mutations. Patient osteoblasts, and Colvard et al.8 identi- of São Paulo. 4 is homozygous for the R227* mutation 139 REV. HOSP. CLÍN. FAC. MED. S. PAULO 56(5):139-142, 2001 SEPTEMBER-OCTOBER 11. Basal TSH, free T4, PRL, LH, FSH, bone13 and attenuates bone loss after or- with estrogen-resistance syndrome and cortisol were normal. chiectomy14; furthermore, both testoster- who presented osteoporosis with in- In order to increase penis size, pa- one and DHT increase the transcription creased bone resorption despite normal tients were initially treated with 250 of a1(I)-procollagen mRNA in osteo- androgen concentrations. Another mg of mixed testosterone esters by in- blast-like osteosarcoma cells15. study demonstrated that the inhibition tramuscular injections weekly from 2 On the other hand, Rosen at al.16 of androgen aromatization by vorozole to 8 months, and afterwards with 1.5 demonstrated that rats treated with (a non-steroid inhibitor of P450 g of 2.5% DHT cream applied on the finasteride, which inhibits the action of aromatase) increases bone resorption, abdominal skin or thighs daily at night 5α-reductase 2, had normal bone den- indicating the importance of estrogen for 3 to 11 months. The chronological sity, concluding that DHT deficiency on bone mineralization19. age at the time of treatment was 14 to was not deleterious for bone. Elderly Wiren et al.20 demonstrated that 33 years old. Bone mineral density was men with benign prostate hyperplasia there is an up-regulation of the andro- measured through a dual energy x-ray treated with finasteride did not show gen receptor to androgen action (test- bone densitometer (Hologic QDR any effect on bone density or on bone osterone and DHT) in osteoblasts, 4500/A S/N – 45130) 7 to 9 years af- and mineral metabolism17. Human and which might increase the responsive- ter completion of therapy. Bone min- rat bone have 5α-reductase activity and ness of these cells to androgens. eral density values as determined by can synthesize DHT in vitro10, but it is Our results suggest that 5α-reduc- Hologic densitometry were compared unclear which one of the two types of tase 2 deficiency in humans does not with those of normal young men with 5α-reductase (type 1 or type 2) acts have a significant effect on bone. Sev- the same weight and ethnic group. predominantly on bone. eral assumptions can be made: We studied 4 male pseudoherma- 1) the enzyme involved in the 5α-re- phrodites with 5α-reductase 2 defi- duction in bone is 5α-reductase 1, RESULTS ciency who were treated with DHT which is not responsible for male cream and testosterone esters for 3 to pseudohermaphroditism; The T/DHT ratio varied from 37 to 11 months, 7 to 9 years before bone 2) the small quantities of DHT pro- 46 (normal values=14±5.2), and the mass evaluation. One can speculate as duced by these patients might be molecular study demonstrated the pres- to whether there was an effect of this enough to activate the androgenic ence of mutations in the 5α-reductase short-period androgen therapy on the receptor in bone cells; type 2 gene. bone mass of our patients. However, 3) testosterone, directly through the Three patients presented normal our experience shows that this period activation of its receptor, may be bone mineral density of the lumbar col- of treatment is not enough to re-estab- active in bone without converting umn (L1-L4) and femur neck, and pa- lish bone mass in men with hypogo- into DHT; tient 2 presented a slight osteopenia in nadism. The same observation has 4) testosterone is aromatized into es- the lumbar column (L1-L4) [Table 1]. been reported in men with isolated trogens that has a direct action on GnRH deficiency under gonadal ste- bone cells. roid replacement therapy from 1 to 3 Further studies are required to de- DISCUSSION years whose bone density increased but termine the exact mechanism of andro- failed to reach normal adult levels5. gen action in human bone. We con- The effect of androgen on hair fol- The importance of estrogen on bone clude that patients with DHT defi- licles, prostate, and seminal vesicles de- maturation and mineralization has been ciency present normal bone mineral pends on the local conversion of test- recently demonstrated in 2 studies. density, suggesting that DHT is not the osterone into DHT. In contrast, the ef- Smith at al.18 reported an individual main androgen acting in bone. fects of androgen on muscle mass, sper- matogenesis, and libido are maintained Table 1 - Bone mineral density (BMD) of the lumbar column (L1-L4) and femur neck in 4 male α by testosterone only12. Even though pseudohermaphrodites with 5 -RD2 deficiency. bone is an androgen-dependent tissue, Patients L1-L4 Femur Neck 2 2 it is still unknown if 5α-reductase type BMD (g/cm ) T score* BMD (g/cm ) T score* 2 activity is important for the andro- 1 1.141 +0.46 0.987 +0.07 2 0.920 -1.55 1.115 +1.24 genic action on bone cells. Previous 3 0.990 -0.92 1.170 +1.74 studies demonstrated that the treatment 4 1.014 -0.70 1.107 +1.16 of orchiectomized rats with DHT stimu- Normal Lower Range 0.8 -1 0.6 lates the development of endochondral *T score compared with the mean standard deviation for BMD of normal young adults. 140 SEPTEMBER-OCTOBER REV. HOSP. CLÍN. FAC. MED. S. PAULO 56(5):139-142, 2001 RESUMO RHCFAP/3050 COSTA EMF e col. - Pseudo- de 5α-redutase tipo 2, constituem um quarto paciente apresentou osteopenia hermafroditas masculinos por defi- modelo natural para avaliar o efeito leve em coluna lombar. ciência de 5α-redutase 2 apresen- isolado da testosterona sobre a massa Conclusão: Pacientes com defici- tam densidade óssea normal. Rev. óssea. ência de diidrotestosterona apresentam Hosp. Clin. Fac. Med. S. Paulo Objetivo: Avaliar a densidade mi- densidade mineral óssea normal suge- 56(5):139-142, 2001. neral óssea em quatro pacientes adul- rindo que a diidrotestosterona não é o tos portadores de pseudohermafro- andrógeno que age sobre o osso. O tecido ósseo é um tecido ditismo masculino por deficiência da andrógeno-dependente porém não está 5α-redutase tipo 2. DESCRITORES: Densidade mine- claro se a ação androgênica depende da Resultados: Três pacientes apre- ral óssea. Pseudohermafroditismo testosterona ou da diidrotestosterona. sentaram densidade mineral óssea nor- masculino. Deficiência da 5α- Os pacientes portadores de deficiência mal na coluna lombar e fêmur e o redutase tipo 2.
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