Hypothalamic neurosecretory systems are fundamental regulatory circuits 
influenced by thyroid hormone. Monocarboxylate-transporter-8 (MCT8)-mediated 
uptake of thyroid hormone followed by type 3 deiodinase (D3)-catalyzed 
inactivation represent limiting regulatory factors of neuronal T3 availability. 
In the present study we addressed the localization and subcellular distribution 
of D3 and MCT8 in neurosecretory neurons and addressed D3 function in their 
axons. Intense D3-immunoreactivity was observed in axon varicosities in the 
external zone of the rat median eminence and the neurohaemal zone of the human 
infundibulum containing axon terminals of hypophysiotropic parvocellular 
neurons. Immuno-electronmicroscopy localized D3 to dense-core vesicles in 
hypophysiotropic axon varicosities. N-STORM-superresolution-microscopy detected 
the active center containing C-terminus of D3 at the outer surface of these 
organelles. Double-labeling immunofluorescent confocal microscopy revealed that 
D3 is present in the majority of GnRH, CRH and GHRH axons but only in a minority 
of TRH axons, while absent from somatostatin-containing neurons. 
Bimolecular-Fluorescence-Complementation identified D3 homodimers, a 
prerequisite for D3 activity, in processes of GT1-7 cells. Furthermore, 
T3-inducible D3 catalytic activity was detected in the rat median eminence. 
Triple-labeling immunofluorescence and immuno-electronmicroscopy revealed the 
presence of MCT8 on the surface of the vast majority of all types of 
hypophysiotropic terminals. The presence of MCT8 was also demonstrated on the 
axon terminals in the neurohaemal zone of the human infundibulum. The unexpected 
role of hypophysiotropic axons in fine-tuned regulation of T3 availability in 
these cells via MCT8-mediated transport and D3-catalyzed inactivation may 
represent a novel regulatory core mechanism for metabolism, growth, stress and 
reproduction in rodents and humans.