DHEA-S (Dehydroepiandrosterone sulfate or DHEA sulfate) is a steroid hormone produced primarily in the adrenal cortex. It is the sulfated version of the human steroid DHEA, and, like DHEA, it is secreted in response to ACTH.  DHEA-S been reported to have a diurnal rhythm, but the findings have varied, and some studies found no variation. (1)  DHEA-S in the blood stream has a longer half-life, slower clearance, and is more strongly bound to albumin than DHEA, which may affect synchronicity with the DHEA rhythm. (2,3,4)  DHEA-S appears to serve largely as a precursor molecule that is circulated to various target tissues in the body. In those locations, the sulfate is removed to yield DHEA, and the DHEA is then further metabolized into various estrogenic and androgenic compounds. This process allows androgens and estrogens to be delivered to the appropriate tissues without leakage of significant amounts into the circulation. (5,6)  DHEA-S is also synthesized directly in the central nervous system, where it is thought to help protect nervous tissues against harmful agents. (7,8)   DHEA-S has been investigated for relationships to mental and physical stress and psychological and behavioral disorders. ( 9,10,11,12,13) DHEA-S is a charged molecule, and it cannot diffuse through the neutral lipid membranes of the salivary cells like the other neutral steroids.  The exact mode of entry into saliva is not known.  Formerly, it was thought that DHEA-S enters saliva only by squeezing through the tight junctions between cells, and since it is too large to do this readily only small amounts would be present in saliva. (14)  More recent work has identified a large family of organic anion transport polypeptides (OATP) that actively transport molecules such as DHEA-S across membranes.  It is therefore seems likely that such a mode of entry occurs for DHEA-S into the saliva glands. (15,16)  Salivary levels of DHEA-S are quite low–less than 0.1 % of plasma levels in parotid saliva. (14) However, because levels of DHEA-S in blood are 250 and 500 times higher than DHEA in women and men, respectively, (2) the levels found in saliva are high enough to be measurable.  Due to the restrictive mode of entry for DHEA-S into saliva, its levels in saliva decrease as salivary flow rates increase. (14)  DHEA-S measurements in saliva must therefore be corrected for flow rate.  Because of the much higher levels of DHEA-S in blood, it is important to minimize the risk of blood contamination in the saliva samples. Salivary and plasma levels of DHEA-S show a significant positive correlation. (17)