Morbidity in Klinefelter syndrome and the effect of testosterone treatment

Chang, Simon; Skakkebæk, Anne; Davis, Shanlee; Gravholt, Claus Højbjerg

doi:10.1002/ajmg.c.31798

Cited by 23 publications

(19 citation statements)

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“…Men with KS suffer from higher rates in various diseases and a higher mortality, which results in a shortened lifespan (about 2‐3 years) 8,41,135‐140 …”

Section: Clinical Pictures Diagnostic Steps and Therapymentioning

confidence: 99%

“…The resulting insulin resistance predisposes men with KS to a higher risk of developing type 2 diabetes mellitus 4,8,41,76,135,141 . The conditions named above can explain, at least partially, the increased cardiovascular mortality and morbidity observed in patients with KS 8,41,135‐140 . These comorbidities are strongly related to hypogonadism (Corona et al 2018).…”

Section: Clinical Pictures Diagnostic Steps and Therapymentioning

confidence: 99%

“…4,8,41,76,135,141 The conditions named above can explain, at least partially, the increased cardiovascular mortality and morbidity observed in patients with KS. 8,41,[135][136][137][138][139][140] These comorbidities are strongly related to hypogonadism (Corona et al 2018). However, the latter cannot entirely explain the increased CV risk and other factors (such as epigenetic mechanisms and AR functionality) are most likely involved.…”

Section: Evidencementioning

confidence: 99%

“…The risk of deep vein thrombosis and pulmonary embolism is elevated in KS, with an overall three-to six-fold increased risk as compared to the general population. 8,41,[135][136][137][138][139][140]144 The risk may be attributed to higher levels of the procoagulatory substance PAI-1, which is associated with the genetic setting in KS as well as with lower testosterone levels. 4 Testosterone treatment may reduce this risk, but evidence is still low.…”

Section: Evidencementioning

confidence: 99%

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European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

et al. 2020

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Background Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. Objective To create the first European Academy of Andrology (EAA) guidelines on KS. Methods An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Results Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone‐related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. Conclusion These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts.

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“…Men with KS suffer from higher rates in various diseases and a higher mortality, which results in a shortened lifespan (about 2‐3 years) 8,41,135‐140 …”

Section: Clinical Pictures Diagnostic Steps and Therapymentioning

confidence: 99%

Section: Clinical Pictures Diagnostic Steps and Therapymentioning

confidence: 99%

Section: Evidencementioning

confidence: 99%

Section: Evidencementioning

confidence: 99%

See 2 more Smart Citations

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

et al. 2020

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“…6,15,16 KS is associated with osteopenia, osteoporosis, and increased fracture risk. [17][18][19][20] Reduction of bone density in men with KS is associated with postpubertal testosterone deficiency and although histological change is related to serum testosterone, some individuals with KS develop low bone mineral density even with testosterone levels in the normal distribution. 6,19,21 This suggests a multifactorial etiology 21 with putative contributing factors including androgen receptor insensitivity 16,22,23 and/or hypovitaminosisD.…”

Section: Introductionmentioning

confidence: 99%

Klinefelters Syndrome: Change in T-Scores with Testosterone, Bisphosphonate, and Vitamin D Treatment Over 6 Years

Strange

König

Puttanna

et al. 2021

Androgens: Clinical Research and Therapeutics

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Background: Klinefelter's syndrome (KS) is characterized by extra X chromosomes and features of primary hypogonadism including osteopenia and osteoporosis. Testosterone therapy (TTh) is widely used to treat men with KS and low serum testosterone/hypogonadal symptoms, though studies on its efficacy in improving bone density show varied outcomes. Materials and Methods: We studied the effects of TTh, bisphosphonates, and vitamin D/calcium in 38 men with KS and low testosterone, hypogonadal symptoms, and T-scores consistent with osteoporosis. Our aim was to investigate at the end of follow-up (median: 87 months, range: 27-147 months), associations between age, baseline total testosterone, and T-scores, and change in T-scores after treatment. Results: At final assessment, all men had T-score values outside the osteoporotic range (À1.1 standard deviation [SD], À1.8 SD). Baseline age but not median baseline testosterone appeared associated with change in T-score and T-score at final assessment. All men had dual-energy X-ray absorptiometry every 6 months and demonstrated continued improvement in T-scores after 3 months and up to 72 months. Baseline age and T-scores (stratified by median) were associated with change in T-score at final assessment. Compared with men ‡51 years, those aged <51 years showed significantly greater improvement in T-scores between 6 and 30 months. Men with worse T-score values (<3.7 SD) showed significantly greater improvement at every time point up to 36 months. Our results indicate that TTh, bisphosphonates, and vitamin D/calcium improve osteoporosis although there is a need to better understand the effects of the individual therapies, age, and baseline T-score on treatment efficacy.

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Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

Davis,

Teerlink,

Lynch

et al. 2024

JAMA Netw Open

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ImportanceThe reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry.ObjectivesTo determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls.Design, Setting, and ParticipantsThis cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023.ExposureGenomic identification of an additional X or Y chromosomeMain Outcomes and MeasuresOutcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio.ResultsOf 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]).Conclusion and RelevanceIn this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.

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Morbidity in Klinefelter syndrome and the effect of testosterone treatment

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 23 publications

References 70 publications

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

Klinefelters Syndrome: Change in T-Scores with Testosterone, Bisphosphonate, and Vitamin D Treatment Over 6 Years

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort

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