Bone Mass in Subjects with Klinefelter Syndrome: Role of Testosterone Levels and Androgen Receptor Gene CAG Polymorphism

Ferlin, Alberto; Schipilliti, Mirko; Vinanzi, Cinzia; Garolla, Andrea; Mambro, Antonella Di; Selice, Riccardo; Lenzi, Andrea; Foresta, Carlo

doi:10.1210/jc.2010-1878

Cited by 65 publications

(48 citation statements)

References 37 publications

(41 reference statements)

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“…However, acute testosterone deprivation in healthy men leads to an increase in serum CCL2 levels, which is not reversed by restoration of physiological circulating concentrations of testosterone. Furthermore, the differences in the response to testosterone replacement therapy in KS could be dependent upon androgen receptor polymorphism (16,17,18). These results suggest that, in addition to hormonal factors, a genetic predisposition, possibly mediated through macrophage infiltration into adipose tissue, is involved in the development of MS in KS (15).…”

Section: Metabolic Syndromementioning

confidence: 88%

MANAGEMENT OF ENDOCRINE DISEASE: Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives

Salzano

Arcopinto

Marra

et al. 2016

European Journal of Endocrinology

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Klinefelter syndrome (KS) is the most frequently occurring sex chromosomal aberration in males, with an incidence of about 1 in 500 -700 newborns. Data acquired from large registry-based studies revealed an increase in mortality rates among KS patients when compared with mortality rates among the general population. Among all causes of death, metabolic, cardiovascular, and hemostatic complication seem to play a pivotal role. KS is associated, as are other chromosomal pathologies and genetic diseases, with cardiac congenital anomalies that contribute to the increase in mortality. The aim of the current study was to systematically review the relationships between KS and the cardiovascular system and hemostatic balance. In summary, patients with KS display an increased cardiovascular risk profile, characterized by increased prevalence of metabolic abnormalities including Diabetes mellitus (DM), dyslipidemia, and alterations in biomarkers of cardiovascular disease. KS does not, however, appear to be associated with arterial hypertension. Moreover, KS patients are characterized by subclinical abnormalities in left ventricular (LV) systolic and diastolic function and endothelial function, which, when associated with chronotropic incompetence may led to reduced cardiopulmonary performance. KS patients appear to be at a higher risk for cardiovascular disease, attributing to an increased risk of thromboembolic events with a high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism with higher risk of deep venous thrombosis or pulmonary embolism. It appears that cardiovascular involvement in KS is mainly due to chromosomal abnormalities rather than solely on low serum testosterone levels. On the basis of evidence acquisition and authors' own experience, a flowchart addressing the management of cardiovascular function and prognosis of KS patients has been developed for clinical use.

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Section: Metabolic Syndromementioning

confidence: 88%

MANAGEMENT OF ENDOCRINE DISEASE: Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives

Salzano

Arcopinto

Marra

et al. 2016

European Journal of Endocrinology

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“…[ Salbenblatt et al, 1985;Lanfranco et al, 2004;Ferlin et al, 2011b], whereas others found reduced E2 concentrations [Aksglaede et al, 2007a].…”

Section: Article American Journal Of Medical Genetics Part C (Seminarmentioning

confidence: 98%

“…Accordingly, adults with XXYoften present with decreased bone mineral density (BMD) [Horowitz et al, 1992;Bojesen et al, 2010;Aksglaede et al, 2011b;Ferlin et al, 2011b] In contrast to the studies on adults with XXY, normal lumbar BMD, and whole body bone mineral content (BMC) as evaluated by whole body DEXA scan in 24 boys and adolescents with XXY (4.3-18.6 years of age) has been shown, indicating that the risk of osteopenia/osteoporosis may not be present until after puberty [Aksglaede et al, 2008a].…”

Section: Bone Mineralizationmentioning

confidence: 99%

47,XXY Klinefelter syndrome: Clinical characteristics and age‐specific recommendations for medical management

Aksglæde

Link

Giwercman

et al. 2013

American J of Med Genetics Pt C

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47,XXY (Klinefelter syndrome) is the most frequent sex chromosomal disorder and affects approximately one in 660 newborn boys. The syndrome is characterized by varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportions. The phenotype is variable ranging from "near-normal" to a significantly affected individual. In addition, newborns with Klinefelter syndrome generally present with a normal male phenotype and the only consistent clinical finding in KS is small testes, that are most often not identified until after puberty. Decreased awareness of this syndrome among health professionals and a general perception that all patients with 47,XXY exhibit the classic textbook phenotype results in a highly under-diagnosed condition with up to 75% of the patients left undetected. Typically, diagnosis is delayed with the majority of patients identified during fertility workup in adulthood, and only 10% of patients diagnosed prior to puberty. Early detection of this syndrome is recommended in order to offer treatment and intervention at the appropriate ages and stages of development for the purpose of preventing osteopenia/osteoporosis, metabolic syndrome, and other medical conditions related to hypogonadism and to the XXY as well as minimizing potential learning and psychosocial problems. The aim of this review is to present the clinical aspects of XXY and the age-specific recommendations for medical management. © 2013 Wiley Periodicals, Inc.

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“…Our data in KS do not confirm this result. Although further studies are necessary to clarify these aspects, it has to be noted that the effect of testosterone on prostate growth and the role of CAG repeat length in modulating the effects of testosterone in KS are still controversial (17,19,36).…”

Section: Discussionmentioning

confidence: 99%

“…The AR gene is located on the X chromosome, and therefore in KS, it is present in double copy. The inactivation rate of the two X chromosomes, and the effective CAG repeat value in heterozygous KS men, was calculated as an X-weighted biallelic mean (19). This analysis was based on methylation-specific PCR at the human AR locus, with primers spanning the (CAG)n polymorphism region, as described previously (20).…”

Section: Patients and Clinical Analysismentioning

confidence: 99%

Prostate volume and growth during testosterone replacement therapy is related to visceral obesity in Klinefelter syndrome

Selice

Caretta

Mambro

et al. 2013

European Journal of Endocrinology

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Objective: Klinefelter syndrome (KS) is a chromosomal alteration characterized by increased risk of metabolic syndrome, mainly caused by visceral obesity. In the last years, obesity has been studied as a potential risk factor for prostate disease and recently a link has been demonstrated between visceral adiposity with prostate volume. The aim of this study was to analyze the relationship between obesity and prostate volume and growth during testosterone therapy in KS subjects. Design and methods: We evaluated reproductive hormones, metabolic parameters, anthropometric measures, PSA, and prostate volume in 121 naïve non-mosaic KS patients and 60 age-matched healthy male controls. Fifty-six KS hypogonadic subjects were treated with testosterone-gel 2% and reevaluated after 18 months of treatment. Results: Prostate volume in KS was positively related to waist circumference (WC). The KS group with WC R94 cm had significantly higher prostate volume, BMI, insulin plasma levels, homeostasis model assessment index, total cholesterol, triglycerides, and glycemia with respect to the KS group with WC !94 cm. After testosterone replacement therapy, only hypogonadic KS men with WC R94 cm had a statistically significant increase in prostate volume. Furthermore, in untreated KS subjects, prostate volume showed a statistically significant increase after 18 months of follow-up only in subjects with WC R94 cm. Conclusions: This study showed that visceral obesity, insulin resistance, and lipid and glucose metabolism alterations are associated with prostate volume and growth during testosterone replacement therapy in KS, independently from androgen or estrogen levels. These latter findings might provide the basis for a better management and follow-up of KS subjects.

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Bone Mass in Subjects with Klinefelter Syndrome: Role of Testosterone Levels and Androgen Receptor Gene CAG Polymorphism

Abstract: Testosterone levels and AR CAG polymorphism are not associated with bone mass phenotype in KS.

Cited by 65 publications

References 37 publications

MANAGEMENT OF ENDOCRINE DISEASE: Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives

MANAGEMENT OF ENDOCRINE DISEASE: Klinefelter syndrome, cardiovascular system, and thromboembolic disease: review of literature and clinical perspectives

47,XXY Klinefelter syndrome: Clinical characteristics and age‐specific recommendations for medical management

Prostate volume and growth during testosterone replacement therapy is related to visceral obesity in Klinefelter syndrome

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