Testosterone replacement therapy in Klinefelter syndrome - follow-up study associating hemostasis and RNA expression

Simon Chang; Jesper Just; Anne Skakkebæk; Emma B Johannsen; Jens Fedder; Claus H Gravholt; Anna-Marie B Münster

doi:10.1210/clinem/dgad658

Testosterone replacement therapy in Klinefelter syndrome - follow-up study associating hemostasis and RNA expression

Simon Chang^*, Jesper Just, Anne Skakkebæk, Emma B Johannsen, Jens Fedder, Claus H Gravholt, Anna-Marie B Münster

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

5 Citations (Scopus)

Abstract

Background: Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. Aim: To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. Methods: Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. Results: Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. Conclusion: KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.

Original language	English
Journal	The Journal of clinical endocrinology and metabolism
Volume	109
Issue	4
Pages (from-to)	978–991
Number of pages	14
ISSN	0021-972X
DOIs	https://doi.org/10.1210/clinem/dgad658
Publication status	Published - 1 Apr 2024

Keywords

Klinefelter syndrome
blood coagulation
fibrinolysis
genetic transcription
testosterone

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10.1210/clinem/dgad658

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@article{568d26620d4a4f6da05975d955b92101,

title = "Testosterone replacement therapy in Klinefelter syndrome - follow-up study associating hemostasis and RNA expression",

abstract = "Background: Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. Aim: To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. Methods: Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. Results: Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. Conclusion: KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.",

keywords = "Klinefelter syndrome, blood coagulation, fibrinolysis, genetic transcription, testosterone",

author = "Simon Chang and Jesper Just and Anne Skakkeb{\ae}k and Johannsen, {Emma B} and Jens Fedder and Gravholt, {Claus H} and M{\"u}nster, {Anna-Marie B}",

year = "2024",

month = apr,

day = "1",

doi = "10.1210/clinem/dgad658",

language = "English",

volume = "109",

pages = "978–991",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "4",

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Testosterone replacement therapy in Klinefelter syndrome - follow-up study associating hemostasis and RNA expression. / Chang, Simon ; Just, Jesper ; Skakkebæk, Anne et al.
In: The Journal of clinical endocrinology and metabolism, Vol. 109, No. 4, 01.04.2024, p. 978–991.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Testosterone replacement therapy in Klinefelter syndrome - follow-up study associating hemostasis and RNA expression

AU - Chang, Simon

AU - Just, Jesper

AU - Skakkebæk, Anne

AU - Johannsen, Emma B

AU - Fedder, Jens

AU - Gravholt, Claus H

AU - Münster, Anna-Marie B

PY - 2024/4/1

Y1 - 2024/4/1

N2 - Background: Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. Aim: To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. Methods: Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. Results: Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. Conclusion: KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.

AB - Background: Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. Aim: To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. Methods: Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. Results: Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. Conclusion: KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.

KW - Klinefelter syndrome

KW - blood coagulation

KW - fibrinolysis

KW - genetic transcription

KW - testosterone

UR - http://www.scopus.com/inward/record.url?scp=85194701230&partnerID=8YFLogxK

U2 - 10.1210/clinem/dgad658

DO - 10.1210/clinem/dgad658

M3 - Journal article

C2 - 37962976

SN - 0021-972X

VL - 109

SP - 978

EP - 991

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 4

ER -

Testosterone replacement therapy in Klinefelter syndrome - follow-up study associating hemostasis and RNA expression

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