Causes of High DHEAS Levels
Elevated DHEAS levels most commonly result from adrenal androgen excess, which can be physiologic (adrenarche, PCOS), pathologic (adrenal tumors, congenital adrenal hyperplasia), or rarely due to genetic defects in steroid metabolism or transport. 1
Primary Adrenal Causes
Adrenal tumors are the most critical diagnosis to exclude when DHEAS is markedly elevated, as approximately 74% of DHEAS is produced by the adrenal glands and very high levels are typical for adrenal adenomas or carcinomas. 2 Imaging with ultrasound or MRI and dexamethasone suppression testing can help differentiate tumor from functional hypersecretion. 2, 3
Congenital adrenal hyperplasia (CAH), particularly 21-hydroxylase deficiency (both classic and non-classic forms), causes excess adrenal precursor androgen production and can result in a PCOS-like phenotype with elevated DHEAS. 1 However, inherited enzyme defects account for only a small fraction of women with hyperandrogenism. 1
Polycystic ovary syndrome (PCOS) is associated with elevated DHEAS in approximately 20-30% of affected women, reflecting a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation rather than overt hypothalamic-pituitary-adrenal axis dysfunction. 1 This appears to be inherited in nature. 1
Rare Genetic and Metabolic Causes
Steroid sulfatase (STS) deficiency or variants can theoretically impair DHEAS hydrolysis to DHEA, leading to accumulation, though heterozygous mutations alone are typically insufficient to cause clinically significant elevations. 2
Transporter protein defects, particularly variants in efflux transporters like breast cancer-resistance protein (BCRP) or uptake transporters (OATP, OAT carriers), may impair DHEAS cellular transport and excretion, potentially contributing to elevated serum levels when combined with other genetic factors. 2
Isolated functional adrenal DHEAS hypersecretion is a rare benign condition characterized by bilateral adrenal overproduction of DHEAS without other hormonal abnormalities, confirmed by selective renal vein catheterization and suppressibility with dexamethasone. 3
Context-Specific Considerations for Celiac Disease and IgA Deficiency
The combination of celiac disease and IgA deficiency in your patient is relevant because:
IgA deficiency occurs in 1-3% of celiac disease patients (compared to 1:500 in the general population), making this association well-established. 4, 5, 6 This high prevalence makes quantitative serum IgA measurement mandatory when screening for celiac disease. 4
However, neither celiac disease nor IgA deficiency directly causes elevated DHEAS. The guidelines and research provided do not establish a mechanistic link between these conditions and adrenal androgen excess. 4, 5, 6
Diagnostic Approach
Exclude adrenal tumor first with adrenal imaging (CT or MRI) and overnight dexamethasone suppression test (1 mg), particularly if DHEAS is >700 μg/dL or there are other concerning features. 2, 3
Evaluate for PCOS if the patient is female with clinical hyperandrogenism, menstrual irregularity, or polycystic ovarian morphology on ultrasound, as this accounts for the majority of moderate DHEAS elevations in reproductive-age women. 1
Consider 17-hydroxyprogesterone measurement to screen for non-classic CAH if DHEAS is elevated with other signs of androgen excess, though this is uncommon. 1
Assess for physiologic causes including obesity and insulin resistance, though these play a limited role in isolated DHEAS elevation. 1
Common Pitfalls
Do not assume the celiac disease or IgA deficiency is causally related to the DHEAS elevation—these are likely coincidental findings requiring separate evaluation. 4, 5, 6
Do not overlook adrenal imaging when DHEAS is significantly elevated, as missing an adrenal tumor has serious morbidity and mortality implications. 2, 3
Do not attribute all DHEAS elevations to PCOS without excluding other causes, particularly in patients without typical PCOS features. 1