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MINI REVIEW article

Front. Transplant.

Sec. Transplantation Immunology

This article is part of the Research TopicThe Impact of Biological Sex on Transplantation: From Bench to BedsideView all articles

The Role of Estrogen in Cardiac Transplantation: Mechanistic Insights and Effects on Clinical Outcomes

Provisionally accepted
Rosalie Wolff Von GudenbergRosalie Wolff Von Gudenberg1,2Constantin KupschConstantin Kupsch1,3Linda GillesLinda Gilles1,4Yao XiaoYao Xiao1Catalina OrtizCatalina Ortiz1Arjang RuhparwarArjang Ruhparwar2Hao ZhouHao Zhou1Stefan Guenther TulliusStefan Guenther Tullius1*
  • 1Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
  • 2Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
  • 3Department of General and Visceral Surgery, Medical Center-University of Freiburg, Freiburg Germany., Freiburg, Germany
  • 4Department of General, Visceral and Transplant Surgery, Charité, Berlin, Germany

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Sex hormones profoundly shape immune responses and influence outcomes after heart transplantation. Estrogen enhances allosensitization and is associated with a higher incidence of acute rejection in female recipients. Beyond its immunological effects, estrogen also modulates the pharmacokinetics and pharmacodynamics of calcineurin inhibitors—particularly cyclosporine A—thereby influencing immunosuppressive efficacy and early graft performance. Donor–recipient sex mismatch further modulates transplant outcomes. Female-to-male transplants in particular exhibit the poorest short- and long-term survival and show increased rates of primary graft failure and cardiac allograft vasculopathy. Mechanistic and experimental data provide a biological basis for these observations: estrogen protects the myocardium against ischemia–reperfusion injury and preserves vascular integrity through both nuclear estrogen receptors and GPER-mediated signaling. Abrupt withdrawal of this estrogen-mediated protection in male recipients of female donor hearts may therefore increase susceptibility to early graft dysfunction and chronic vasculopathy. Integrating sex and hormonal status into transplant medicine—through hormonal profiling, receptor-specific mechanistic studies, and sex-adapted immunosuppressive strategies—may pave the way toward more individualized and effective therapeutic approaches in heart transplantation.

Keywords: Cardiac allograft vasculopathy, Cardiac rejection, estrogen, Immunosuppression, Primary graft failure

Received: 28 Oct 2025; Accepted: 11 Dec 2025.

Copyright: © 2025 Wolff Von Gudenberg, Kupsch, Gilles, Xiao, Ortiz, Ruhparwar, Zhou and Tullius. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Stefan Guenther Tullius

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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