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

Danilovic, Débora Lucia Seguro; Corrêa, Pedro Henrique Silveira; Costa, Elaine Maria Frade; Melo, Karla Fabiana Santana de; Mendonca, Berenice B.; Arnhold, Ivo Jorge Prado

doi:10.1007/s00198-006-0243-6

Cited by 93 publications

(79 citation statements)

References 35 publications

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“…The findings of greater BMD at the hip than at the spine in CAIS women in the present study are consistent with those observed by Danilovic et al in a study of complete and partial AIS women (22). The long-term effects of androgens on BMD in free-living subjects have not been demonstrated.…”

Section: Discussionsupporting

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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Section: Discussionsupporting

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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“…However, it has been established, at least in rodents, that androgen action on bone can be directly mediated by activation of AR in the absence of ER [30,31]. In addition, findings from individuals with androgen insensitivity syndrome suggest that androgens play an important role in normal male growth and maintenance of bone density which cannot be filled by estrogens [32,33].On the other hand, a recent clinical review concerning the impact of T therapy on bone health [34] concluded that the available trials do not provide convincing evidence for the efficacy of T in preventing and treating osteoporosis, and that further data on fractures need to be accumulated. As for the impact of 19-norandrogens on bone, MENT prevented the decreases in cortical and trabecular bone mineral density associated with orchidectomy in aged male rats [35], whereas effects of DMA and 11β-MNT on bone mineral density have yet to be assessed.…”

Section: Discussionmentioning

confidence: 99%

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17β-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11β-methyl-19-nortestosterone (11β-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) α and β in competitive binding assays (IC 50 's: 5−12 × 10 −9 M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E 2 ) (EC 50 's: 10 −12 to 10 −11 M). C19 androgens (T, 17α-methyltestosterone (17α-MT), androstenedione (AD), and 16α-hydroxyandrostenedione (16α-OHAD)), 19-norandrogens (DMA,, and 7α-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 μM with recombinant human aromatase for 10−180 min at 37 °C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16α-OHAD was linear for 40−60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11β-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11β position.

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“…Obesity is commonly reported, however, at rates that mimic the general population of women [10, 21]. Decreased bone mineral densities in the lumbar spine and hip regions occur both prior to gonadectomy in women with CAIS as well as in gonadectomized women receiving daily estrogen therapy [10, 21, 22].…”

Section: Androgen Insensitivity Syndromes (Aiss)mentioning

confidence: 99%

46,XY DSD with Female or Ambiguous External Genitalia at Birth due to Androgen Insensitivity Syndrome, 5α-Reductase-2 Deficiency, or 17β-Hydroxysteroid Dehydrogenase Deficiency: A Review of Quality of Life Outcomes

Wisniewski

Mazur

2009

International Journal of Pediatric Endocrinology

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Disorders of sex development refer to a collection of congenital conditions in which atypical development of chromosomal, gonadal, or anatomic sex occurs. Studies of 46,XY DSD have focused largely on gender identity, gender role, and sexual orientation. Few studies have focused on other domains, such as physical and mental health, that may contribute to a person's quality of life. The current review focuses on information published since 1955 pertaining to psychological well-being, cognition, general health, fertility, and sexual function in people affected by androgen insensitivity syndromes, 5-α reductase-2 deficiency, or 17β-hydroxysteroid dehydrogenase-3 deficiency—reared male or female. The complete form of androgen insensitivity syndrome has been the focus of the largest number of investigations in domains other than gender. Despite this, all of the conditions included in the current review are under-studied. Realms identified for further study include psychological well-being, cognitive abilities, general health, fertility, and sexual function. Such investigations would not only improve the quality of life for those affected by DSD but may also provide information for improving physical and mental health in the general population.

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

Abstract: 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.

Cited by 93 publications

References 35 publications

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

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

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

46,XY DSD with Female or Ambiguous External Genitalia at Birth due to Androgen Insensitivity Syndrome, 5α-Reductase-2 Deficiency, or 17β-Hydroxysteroid Dehydrogenase Deficiency: A Review of Quality of Life Outcomes

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