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BACKGROUND AND OBJECTIVES: Thyroid dysfunction has been claimed contributing to the spectrum of Klinefelter syndrome (KS); however, studies are scarce. In a retrospective longitudinal study, we aimed at describing the hypothalamus-pituitary-thyroid (HPT) axis and thyroid ultrasonographic (US) appearance in patients with KS throughout the life span. METHODS: 254 patients with KS (25.9±16.1 years) were classified according to their pubertal and gonadal status and compared with different groups of non-KS age-matched subjects with normal thyroid function, treated and untreated hypogonadism, or chronic lymphocytic thyroiditis. We assessed serum thyroid hormone levels, anti-thyroid antibodies, US thyroid parameters, in vitro pituitary type 2 deiodinase (D2) expression and activity. RESULTS: Thyroid autoimmunity was more prevalent among subjects with KS at all ages, although the Ab negative vs. positive cohorts were not different. Signs of thyroid dysfunction (reduced volume, lower echogenicity, and increased inhomogeneity) were more prominent in KS than in euthyroid controls. Free thyroid hormones were lower in pre-pubertal, pubertal, and adult subjects with KS, while TSH values were only lower in adults. Peripheral sensitivity to thyroid hormones was unaltered in KS, suggesting a dysfunctional HPT axis. Testosterone (T) was the only factor associated with thyroid function and appearance. In vitro testing demonstrated an inhibitory effect of T on pituitary D2 expression and activity, supporting enhanced central sensing of circulating thyroid hormones in hypogonadism. CONCLUSIONS: From infancy through adulthood, KS is characterized by increased morpho-functional abnormalities of the thyroid gland, combined with a central feedback dysregulation sustained by the effect of hypogonadism on D2 deiodinase.

Original publication




Journal article


J Clin Endocrinol Metab

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