Androgen deficiency and defective intracrine processing of dehydroepiandrosterone in salivary glands in Sjögren's syndrome

Abstract

Objective. We hypothesized that in addition to dehydroepiandrosterone (DHEA) depletion, Sjögren's syndrome (SS) is characterized by local androgen deficiency in salivary glands and defects in local processing of DHEA. Methods. Sex steroid levels in serum and saliva were measured using enzyme immunoassays. Androgen effects on salivary gland cells were analyzed using the cysteine-rich secretory protein-3 (CRISP-3) androgen biomarker. Results. Serum and salivary concentrations of androgens were low in SS. Substrate to end-product ratios and correlations suggest that in SS salivary glands DHEA is effectively converted to testosterone, but that there are defects in converting testosterone further to dihydrotestosterone (DHT). In healthy controls no such phenomenon was seen, but testosterone is effectively converted to DHT. Salivary glands contained type I 5-α-reductase, and its inhibition with dutasteride completely blocked the upregulating effect of DHEA, but not of DHT, on CRISP-3 in human salivary gland acinar cells. Conclusion. DHEA and DHT upregulate CRISP-3, which is reportedly low in SS. The effect of DHEA on CRISP-3 is indirect and is inhibited by dutasteride, showing that there is intracrine processing of DHEA in salivary glands. In healthy glands, but not in SS, DHEA is effectively taken up and converted to DHT. Sex steroid concentrations in saliva in part reflect glandular uptake of DHEA-sulfate and local intracrine DHEA metabolism, which seem to be defective in SS. Our study demonstrates a prominent androgen deficiency and a defect in intracrine production of active androgens in SS salivary glands, also suggesting that salivary DHT cannot be maintained at a normal level in this female-dominant autoimmune exocrinopathy.