Context

Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1 , encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia ( P = 9 × 10^− 20).

Objective

To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.

Design

Retrospective cohort study.

Setting

Academic research.

Patients

Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.

Main outcome measures

DHEA, DHEA-S, and DHEA-S/DHEA ratio.

Results

Increased serum sulfate was associated with decreased DHEA-S ( P = 0.03) and DHEA-S/DHEA ratio ( P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate ( P = 9 × 10^{− 1 3} ), exhibited 14% lower DHEA levels ( P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers ( P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females ( P = 0.03).

Conclusions

Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.