Impairment in the hypothalamic-pituitary-gonadal axis in males with medullary thyroid carcinoma treated with selpercatinib

Objectives: Erectile dysfunction (ED) is observed during treatment with the highly selective RET inhibitor selpercatinib. A pathogenic hypothesis is the impairment in the hypothalamic-pituitary-gonadal (HPG) axis. This study aims to analyze variations in the HPG axis in male patients with advanced medullary thyroid carcinoma (MTC) treated with selpercatinib. Methods: 19 male patients were evaluated for FSH, LH, Total Testosterone (TT), and Sex Hormone Binding Globulin (SHBG). Free Testosterone (FreeT) was estimated. In all patients (total group - T-Group), the HPG axis was evaluated before and after 12 months of selpercatinib initiation. In 7/19 (36.8%) cases (extended group - Ex-Group), data collection was extended beyond 24 months from the start of treatment. Semen analysis was performed in 6 (31.6%) patients. Results: 18/19 (94.7%) patients experienced ED: 2 (11.1%) had ED before, while 16 (88.9%) developed ED after starting selpercatinib. The median time to ED onset was 1 month. During the first year of treatment, a significant increase in FSH (p = 0.03) (+61.9%) was observed in the T-Group. In the Ex-Group, a significant increase in FSH (+60.6%), LH (+20.5%) (p < 0.01), and SHBG (+27.7%) (p = 0.04), and a decrease in TT (-20%) (p = 0.01) and FreeT (-12.5%) (p < 0.01) were observed. Five patients had azoospermia, and one severe oligospermia. Conclusions: ED shows high prevalence and early onset in males with MTC treated with selpercatinib. Impairment in the HPG axis and semen analysis can reflect damage to Sertoli and Leydig cells, leading to hypogonadism. Therefore, HPG axis evaluation and fertility counseling could be advisable mainly in childbearing males before starting selpercatinib.