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Relative hyperestrogenism in Klinefelter Syndrome: results from a meta-analysis

  • Daniele Santi
  • Sara De Vincentis
  • Sara Scaltriti
  • Vincenzo RochiraEmail author



Klinefelter Syndrome (KS) is classically described as characterized by hyperestrogenism, although solid evidence is lacking. This study aims to test the hypothesis that men with KS have higher serum estradiol than normal controls.


Meta-analysis of all studies extracted by MEDLINE from 1942 to 31 January 2018. All studies reporting serum estradiol measurement were considered, among them only case-control studies were included in the meta-analysis.


Meta-analysis was conducted according to the PRISMA statement using RevMan.


Out of 4120 articles, 23 case-control studies, 14 case series, and 19 case reports reported data on serum estradiol. A total of 707 KS and 1019 controls were included in the meta-analysis. Serum estradiol was slightly, but significantly higher in KS than controls (mean difference 4.25 pg/mL; CI: 0.41, 8.10 pg/mL; p = 0.030). This difference was lost considering only studies using estradiol assays with good accuracy (5.48 pg/mL, CI: −2.11, 13.07 pg/mL; p = 0.160). Serum testosterone and estradiol/testosterone ratio were significantly lower and higher in KS than controls, respectively. Data from KS case series and case reports confirmed that serum estradiol is within the normal ranges.


Serum estradiol is not increased in KS although slightly higher than controls. However, the meta-analysis that included only studies using a serum estradiol assay with good accuracy showed no difference in serum estradiol between KS and controls. The traditional belief that KS is associated with elevated serum estradiol should be reconsidered. This meta-analysis shows that men with KS have relative hyperestrogenism (increased estradiol/testosterone ratio) compared to controls.


XXY aneuploidy Estrogens Sex steroids Male Estrogen to testosterone ratio Testosterone 



Preliminary results of this work were presented at ENDO 2009 (Washington, DC, USA) in the Meet-the-Professor session on Clinical Issues in Management of Klinefelter’s Syndrome and summarized in the Meet-the-Professor and Case Management Forum Handouts.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

12020_2019_1850_MOESM1_ESM.docx (442 kb)
Supplementary Information


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Authors and Affiliations

  1. 1.Unit of Endocrinology, Department of Biomedical, Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly
  2. 2.Department of Medical Specialties, Azienda Ospedaliero-Universitaria di ModenaOspedale Civile di BaggiovaraModenaItaly

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