Indeed the primary TH crossing the adult blood–brain barrier (BBB) is believed to be T4; therefore, the adult brain may have access to sufficiently high levels of T4 to allow for direct binding to and transcriptional activation of TRs (
18,
19). In fact, we know that both T4 and T3 binding by TRs lead to very similar structural changes in the receptor (
12). Several reports have also shown that T4 exhibits non-genomic effects by interacting with integrin cell membrane receptors (
20). These studies suggest that T4 may exhibit a greater role in physiology than merely acting as a pro-hormone. Therefore, the precise role of T4 as a pro-hormone and whether T4 might function directly as an active hormone in the CNS, remain incompletely answered questions.