Background

Klinefelter syndrome (KF) is a genetic condition in which men have an extra X chromosome. Affecting between 1 in 500 and 1 in 1000 men, KF can cause differences in sex hormones that affect sexual function and fertility. In addition to these complications, KF may also cause metabolic syndrome, osteoporosis, hair and muscle mass loss, and breast enlargement.

Because of the hormonal imbalances, men with KF may also be affected by hypogonadism and may be at a higher risk of certain cancers. Notably, several studies have identified an increased risk of non-Hodgkin lymphoma, lung, breast, and mediastinal germ cell tumors (GCT).

Study Objectives

• To investigate risks of malignancy at a population level and to assess the impacts of hypogonadism (HG).
  • KF may be associated with similar malignancies. Controlling for HG might eliminate the risk of certain malignancies, which may be due to hormone-related mechanisms.

Methods

• Patient records of 25,115 males with and without KF between the ages of 3 and 42 years old were pulled from the Merative Marketscan database.
  • Age groups ranged from 14-41 years old and 1.5-3 years old.
• Records of those with KF were compared against those without in the same age group.
  • This was repeated with HG. Those with, compared to those without.
• Researchers also recorded any comorbidities related to cancers.

Key Results/Analysis

• Men with KF demonstrated an increased risk of breast cancer, testicular GCT, extragonadal GCT, and non-Hodgkin lymphoma.
  • Researchers believe this represents a potential hormone-related influence on cancer risk.
    • The risk of breast cancer may be related to different levels of estradiol and testosterone in men with KF than those without.
    • The risk of testicular GCT may be related to testicular atrophy and differing gonadotropin levels seen in men with KF than those without.
  • When compared against men without KF but with HG, men with KF demonstrated an increased risk of extragonadal GCT and a decreased risk of testicular GCT and prostate cancer.
    • Researchers believe this represents a potential genetic influence on cancer risk.
      • Previous studies have suggested extragonadal GCT may be related to abnormalities during fetal maturation, including incomplete germ cell migration from the yolk sac.
      • The decreased risk of prostate cancer in men with KF may be related to a decreased level of androgens, however this may be confounded by the fact that men with KF are usually treated with testosterone replacement.
    • Coronary artery disease (CAD) was the only comorbidity that increased risk of any cancer type for men with KF, unrelated to HG.
      • Researchers believe this may be related to CAD’s shared risk of cancer with metabolic syndrome, which is a common complication of KF.

Key Takeaways

• This was the first study to demonstrate a risk of certain cancers associated with KF on a population level.
  • Due to the allocation of data, this study may only be generalizable to the commercially insured.
• Researchers raise questions about the use of hormone replacement therapy and its effect on cancer risk in men with KF.
  • The difference in risk between the hypogonadal controls and the men with KF may be caused by the use of testosterone replacement on men with KF.
• Future studies should consider the effect of testosterone replacement therapy on cancer risk, as well as the connection between hormone levels and non-Hodgkin lymphoma in patients with KF.

Resources:

• Asanad, K., Davis, R., Horns, J. J., Samplaski, M. K., & Hotaling, J. M. (2026). Hypogonadism and cancer incidence in men with klinefelter syndrome. The Journal of Sexual Medicine, 23(1). https://doi.org/10.1093/jsxmed/qdaf360