Osteopenia as a feature of the androgen insensitivity syndrome

Soule, Steven; Conway, Gerard S.; Prelević, Gordana M.; Prentice, Malcolm; Ginsburg, Jean; Jacobs, Howard S.

doi:10.1111/j.1365-2265.1995.tb00533.x

Cited by 87 publications

(56 citation statements)

References 21 publications

(21 reference statements)

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“…In case reports describing genetic mutations, a man with defective aromatase activity [26] and another with nonfunctioning estrogen receptors [27] showed markedly reduced BMD despite normal or raised serum testosterone levels and normal androgen receptors. In both cases, BMD values were similar to those seen in the converse syndrome of genetic males with androgen insensitivity (androgen receptor defect but normal testosterone and estradiol levels) [28]. Perhaps the most convincing evidence is from another case report, in which a 28-year-old man with an inactivating mutation of his aromatase gene presented with infertility and was found to have a eunuchoid habitus with nonclosure of the epiphyses, below-average BMD, and bone age of 15 years.…”

supporting

confidence: 66%

“…It seems likely, on the basis of the somewhat limited evidence currently available, that both estrogens and androgens are required for the growth and maintenance of the adult male skeleton. In the presence of low levels of either class of sex hormone during growth there is failure of skeletal maturation and suboptimal peak bone mass [26][27][28][29], whereas low levels of hormone activity in later life are associated with rapid skeletal involution and osteoporotic fracture [30][31][32][33][34].…”

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confidence: 99%

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Sex Hormones and Osteoporosis in Men

et al. 1998

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Osteoporosis in men is a common disorder, the incidence of which is increasing. Bone is lost with advancing age in men as well as in women, leading to an increased risk of fracture after minimal trauma. Recent epidemiological data from North America suggests a lifetime risk of fracture of the hip, spine, or forearm of 13.1% in white men aged 50 [1]. Despite the considerable public health burden attributable to these fractures, our understanding of their pathogenesis is incomplete and there is no established treatment for osteoporosis in men.Androgen deficiency is thought to play an important role in many cases of male osteoporosis. Biochemical evidence of hypogonadism is found in about 20% of men with vertebral fractures [2] and up to 50% of men with hip fractures [3,4], often without other clinical features of gonadal failure. In cell culture studies using human osteoblastlike cells from both men and women [5][6][7], specific androgen receptors can be identified by nuclear and cytosolic binding assays (Table 1). Similarly, osteoblasts obtained from fresh femoral bone specimens can also metabolize the circulating androgen androstenedione to testosterone and 5␣-dihydrotestosterone (DHT) in both men and women [8] at rates dependent mainly on androstenedione concentration. Cells of osteoclast lineage may also have these properties, though this is less well established. Androgen receptors have also been directly demonstrated in osteoblasts and osteocytes around the growth plate [9]. Androgens may promote proliferation and differentiation of osteoblasts, inhibit osteoclast recruitment or affect osteoblast-to-osteoclast signaling.Animal studies have mostly been performed in orchiectomized (orch) male rats, though there are reservations about the appropriateness of this model because the rat skeleton grows throughout life. Replacement therapy with either testosterone or 5␣-DHT results in enhanced bone mass, though this remains lower than in control rats [10].In male humans, androgens have a marked effect on bone growth and peak bone mass via the growth hormone/ IGF-I axis; accordingly, androgen deficiency before puberty leads to lower bone mineral density (BMD) in both cortical and trabecular bone. Loss of androgens in later life is associated with increased bone resorption and loss of trabecular bone, but cortical bone mass is not greatly affected [11,12]. In a study of 12 men who had undergone judicial castration for ''sexual delinquency'' [13], bone turnover was increased and lumbar spine BMD fell significantly, with evidence of the most rapid loss in the first 5 years after castration. Rates of bone loss were as high as 7% per year, comparable to loss rates seen in early postmenopausal women. In this study, calcitonin therapy was effective in reducing bone loss, and low calcitonin levels have been reported in another group of young hypogonadal men who had not undergone surgery [14]. Others have found low plasma 1,25 dihydroxyvitamin D levels and impaired calcium absorption in hypogonadal men [15].This combination o...

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confidence: 66%

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confidence: 99%

Sex Hormones and Osteoporosis in Men

et al. 1998

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“…For AR, the testicular feminization (Tfm) male mice and the patients with the androgen-insensitive syndrome are the natural models for the study of the loss of androgen function in males (24).…”

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confidence: 99%

Generation and characterization of androgen receptor knockout (ARKO) mice: An in vivo model for the study of androgen functions in selective tissues

Yeh

Tsai

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

599

456

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By using a cre-lox conditional knockout strategy, we report here the generation of androgen receptor knockout (ARKO) mice. Phenotype analysis shows that ARKO male mice have a female-like appearance and body weight. Their testes are 80% smaller and serum testosterone concentrations are lower than in wild-type (wt) mice. Spermatogenesis is arrested at pachytene spermatocytes. The number and size of adipocytes are also different between the wt and ARKO mice. Cancellous bone volumes of ARKO male mice are reduced compared with wt littermates. In addition, we found the average number of pups per litter in homologous and heterozygous ARKO female mice is lower than in wt female mice, suggesting potential defects in female fertility and/or ovulation. The cre-lox ARKO mouse provides a much-needed in vivo animal model to study androgen functions in the selective androgen target tissues in female or male mice

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“…It is not clear whether low BMD in CAIS is influenced by inadequate oestrogen replacement or lack of androgen action on bone (10). This question cannot be explored by comparing a CAIS group with normal controls from whom they differ in three ways: the presence of a Y chromosome, oestrogen deficiency and androgen resistance.…”

Section: Introductionmentioning

confidence: 92%

Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis

Han¹,

Goswami²,

Trikudanathan³

et al. 2008

European Journal of Endocrinology

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Objectives: To compare bone mineral density (BMD) and body proportions between women with complete androgen insensitivity syndrome (CAIS) and with gonadal dysgenesis (GD). Setting: Adult Disorders of Sexual Development and Ovarian Failure Clinics at University College London Hospitals. Design: Retrospective cross-sectional study of three groups of women aged 17-58 years with varying degrees of exposure to sex hormones and different combinations of sex chromosomes. Forty-six subjects had CAIS, 18 had GD and 46,XY (GD(XY)), and 25 had GD and 46,XX (GD(XX)). In addition, body proportions of subgroups of these women were analysed. Outcome measures: Oestrogen therapy, karyotype, anthropometry and BMD. Results: Height differed between groups (F ratio 5.2, PZ0.007)), with GD(XX) women being the shortest (meanGS.D.: 1.66G0.10 m), GD(XY) women the tallest (1.74G0.09 m) and CAIS women were in-between (1.70G0.07 m). Delayed gonadectomy resulted in taller stature in CAIS women (PZ0.011). The ratio of lower to upper body length in GD(XY) women was significantly (PZ0.001) greater than that of CAIS women. Multivariate logistic regression analysis (adjusted for age and height) showed that among women with XY karyotype, GD(XY) women were 5.2 times (95% confidence interval (CI): 1.3-20.1, PZ0.018) more likely than CAIS women to have a low hip BMD. This difference was not evident among women with GD of different karyotypes (PZ0.938). Spinal BMD did not differ between subject groups. Further adjustment for oestrogen replacement did not alter these relationships. Conclusions: Taller stature in late gonadectomised CAIS women suggests an oestrogen deficiency in these women prior to gonadectomy. Increased lower to upper body ratio in GD(XY) women compared with the other groups implies that these subjects have the greatest degree of oestrogen deficiency in puberty. Androgen rather than sex chromosomes may play an important role in cortical bone mineralisation in CAIS women, probably via estrogen receptor-a either directly or via aromatisation during critical periods of growth prior to gonadectomy.

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Osteopenia as a feature of the androgen insensitivity syndrome

Cited by 87 publications

References 21 publications

Sex Hormones and Osteoporosis in Men

Sex Hormones and Osteoporosis in Men

Generation and characterization of androgen receptor knockout (ARKO) mice: An in vivo model for the study of androgen functions in selective tissues

Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis

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