Primary thyroid dysfunction and changes in the gonadal axis and SHBG in adult men: a prospective cohort study

Objective Thyroid dysfunction modulates the hypothalamic-pituitary-gonadal axis in men, potentially altering sex hormone bioavailability. Prior studies relied on immunoassays for the measurement of sex steroids. We investigate the effect of primary thyroid dysfunction on testosterone (T) and estradiol (E2) in men, using high-specificity liquid chromatography–tandem mass spectrometry (LC-MS/MS). Methods In this prospective cohort study, adult men with newly diagnosed hyperthyroidism or hypothyroidism were evaluated at diagnosis and at first follow-up visit. Changes in serum markers of gonadal function were assessed: follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, sex hormone-binding globulin (SHBG), total and calculated free testosterone, total estradiol, and total testosterone:estradiol (T:E2) ratio. Results Sixteen men with hyperthyroidism and eleven with hypothyroidism were included. In the hyperthyroid cohort total T, total E2, and SHBG levels decreased during treatment (p=0.0131, p=0.0063, and p=0.0003), while free T remained unchanged, as well as total T:E2 ratio, FSH, LH, and prolactin. In the hypothyroid cohort, increased SHBG, LH, and FSH levels were observed during levothyroxine treatment (p=0.0014, p=0.0117, and p=0.0039), while total and free T, as well as total E2 and prolactin remained unchanged. In the subgroup with overt hypothyroidism, the total T:E2 ratio increased during levothyroxine treatment. Conclusion In hyperthyroid males during treatment, short-term changes on the gonadal axis are mainly mediated by reduced SHBG, without changes in free T, gonadotropins, or T:E2 ratio. In hypothyroid males, SHBG but also gonadotropins increased under levothyroxine supplementation. These findings highlight the importance of assessing SHBG when evaluating the male gonadal axis during thyroid dysfunction.