More evidence supports link between dry eye and decreased serum androgen levels

Dry eye disease (DED) may be significantly associated with decreased levels of serum androgens, according to results of a study published in Ophthalmology, and adds to the increasing research linking androgens to ocular surface disease and DED.

“Given the many associations of DED with systemic and metabolic traits, this study aimed to explore the relationship between DED and serum metabolites using a hypothesis-free or non-targeted metabolomics approach in a large population-representative sample,” wrote these authors, led by Jelle Vehof, MD, PhD, Department of Ophthalmology and Department of Twin Research & Genetic Epidemiology, King's College London, St. Thomas' Hospital, London, UK.

They conducted this cross-sectional association study in 2,819 subjects (mean age: 57 years; 94.1% female) included in the TwinsUK cohort in the United Kingdom, and tested for associations between 222 known serum metabolites and DED.

Subjects first completed the Short Questionnaire for Dry EYE Syndrome (SQDES), which included two questions about the symptoms of dry eye and a third question about any previous DED diagnosis.

Researchers defined DED as a previous diagnosis of DED by a clinician or “often” or “constant” symptoms of dryness and irritation, and found a DED prevalence of 15.5%, a clinical diagnosis of dry eye in 13.2%, and dryness and irritation reported often or constantly by 6.5% of subjects.

These researchers then conducted a non-targeted metabolomics analysis of fasting plasma samples from subjects, using gas and liquid chromatography combined with mass spectrometry. Data were analyzed with linear mixed effect models including age, BMI, and sex as covariates.

Dr. Vehof and colleagues found a strong and metabolome-wide significant association between DED and decreased levels of androsterone sulfate (P=0.00030) and epiandrosterone sulfate (P=0.00036). The next most strongly associated metabolites included three involved in androgen metabolism: 4-androsten-3beta, 17beta-diol disulfate 1 and 2, and dehydroepiandrosterone sulfate, but these did not reach metabolome-wide significance.

Symptoms of dryness and irritation, as opposed to a clinical diagnosis, were strongly associated with decreased androgen steroid metabolites, all of which achieved metabolome-wide significance (androsterone sulfate, P=0.000000029; epiandrosterone sulfate, P=0.0000040; 4-androsten-3beta, 17beta-diol disulfate 1, P=0.000016; 4-androsten-3beta, 17beta-diol disulfate 2, P=0.000064; and dehydroepiandrosterone sulfate, P=0.00011).

Of these, epiandrosterone sulfate was most associated with a 2-year incidence of clinician-diagnosed DED (P=0.0076).

Finally, researchers also found an association between DED and decreased glycerophosphocholine, but this did not reach metabolome-wide significance.

“This study is the first hypothesis-free study that links androgens to DED, but not the first overall study that links them,” concluded these researchers. In addition, they noted that, based on this and other studies, reduced serum androgen levels are likely causative of DED.

“The exact relationship between serum androgens and tear film and ocular surface androgens remains to be elucidated,” they added. “Glucuronide and sulfate androgen metabolites in the serum, as measured by our metabolomics screen, have been shown to be the most valid and possibly only reliable estimate of the total androgen pool including the intracrine production in peripheral tissues, which is most likely the most important source in ocular surface tissues.”^1,2

References

1. Labrie F, Belanger A, Cusan L, et al. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metabol. 1997; 82: 2396–2402.
2. Labrie F, Belanger A, Cusan L, and Candas B. Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: Intracrinology. J Clin Endocrinol Metabol. 1997; 82: 2403–2409.