Based on the long-term hormone follow-up of the patient in whom the disorder was originally described3, we here unveil two independent transcriptional effects of IGSF1 in pituitary physiology, stimulation of TRHR and repression of FSH synthesis, whose failure is mechanistically consistent with the hallmark features of human IGSF1 deficiency, central hypothyroidism and macroorchidism. This evidence concerns the gene TRHR and Central hypothyroidism.