Our goal was to evaluate the association between androgen levels and symptoms and signs of DES in an older male population. We found that patients with severe DES had increased levels of SHBG and decreased levels of A compared to those with minimal or no DES. Furthermore, several weak associations were seen between worse global, lipid, and aqueous tear parameters and lower A levels. Interestingly, we found that this association was mostly driven by the presence of ATD, perhaps because of a synergistic relationship between low androgens and low tear production on TBUT. Of note, a similar relationship between A and DES was previously described in SS patients (
n = 23), a group known to have low tear production. In that study, a moderate association was reported between low A and symptoms (
r s = −0.55,
P < 0.05).
43 Similar to the lack of correlation between DES symptoms and signs reported in a previous study,
34 we did not find a relationship between symptoms and androgen levels in our study.
With regard to androgens, it remains controversial which measured androgens most closely reflect the total androgen pool and therefore should be studied in DES. Tamer et al.
44 found significantly lower levels of BioT (
P = 0.002), DHEA (
P = 0.009), and DHEAS (
P = 0.001) in a group of nonautoimmune DES males with MG dysfunction (
n = 32) compared to nonautoimmune DES males without MG dysfunction (
n = 32) and age-matched controls (
n = 32). Our study, however, did not replicate these findings. Similar to our study, the investigation by Tamer et al.
44 did not show significant differences in total T between the groups. This has biologic plausibility, as 50% of the total T and DHT in males is peripherally produced by adrenal precursors like DHEA and DHEAS.
44–46 Intracellular levels of T and DHT therefore do not parallel serum levels of T and DHT.
24 While T and DHT are more potent androgens, other androgens likely provide a stronger correlation with total androgen pool and therefore diseases such as MG dysfunction.
Conjugated DHT metabolites (such as 3α-diolG) represent the total peripheral production and metabolism of androgens and may therefore be more reliable measures of the total androgen pool.
24,45,46 One study measuring 3α-diolG reported lower levels of this androgen in women with SS.
47 Our data on 3α-diolG are more difficult to interpret as we found a U-shaped curve for this androgen, with highest 3α-diolG levels seen in those with intermediate disease.
It is biologically plausible that androgens may affect MG function and DES in humans, as several animal models have demonstrated an effect of androgen replacement on MG output. In MGs of orchiectomized rabbits, topical T administration affected the expression of 58 mRNAs
48 while topical or systemic administration of 19-nortestosterone normalized lipids patterns.
49 Also, systemic T administration affected the expression of over 1000 genes in MGs of both orchiectomized
50 and ovariectomized
51 mice.
Similarly, androgens may also affect lacrimal gland function. Androgen binding sites have been found in lacrimal tissues of male and female rats, and androgen receptor mRNA has been found in the lacrimal glands of various species, including humans.
52 Furthermore, T-containing pellets enhanced lacrimal gland function, and systemic administration suppressed lacrimal gland inflammation in mouse models of SS.
53,54 Dihydrotestosterone administration also affected lacrimal gland health with improved fluid secretion in ovariectomized rabbits.
55
The unanswered question is whether there is a role for local and/or systemic androgen replacement in men with low androgens and unhealthy tear parameters. Unfortunately, sparse data are available to answer this question. One study treated male and female LTD patients with either 0.03% T (
n = 46) or vehicle (
n = 42) and found that after 6 months, those with T treatment had a higher percentage of normal-viscosity MG secretions (65% vs. 36%,
P = 0.045) and decreased ocular discomfort (30% vs. 8%;
P = 0.06) (Schiffman RM, et al.
IOVS 2006;47:ARVO E-Abstract 5608). While not peer reviewed, a news report highlighted Allan Panzer's success using topical T to treat hundreds of male and female DES patients.
56 Results of systemic treatment are less clear; one study in females with SS (
n = 23) failed to show a benefit of oral DHEA treatment on ocular sicca symptoms,
43 while a separate study in females with LTD and low T (
n = 14) found that a transdermal androgen patch improved TBUT and Schirmer tests (
P < 0.03) and Ocular Surface Disease Index symptoms scores (
P < 0.01).
57 Considering the various results of these studies with variable methods of androgen administration, it is clear that more clinical trials are needed to study the effects of topical and/or systemic androgens in the treatment of DES in the aging male population.
As with all studies, our findings must be interpreted in light of our study limitations. First, our study population consisted of older male veterans seeking treatment for ocular disorders, and as such, it is possible that our findings may not generalize to other US male populations. Second, there are potential confounders (such as dietary information and environmental exposures) that were not captured. Third, our findings are specific to the metrics tested, and it is possible that different scales (e.g., Ocular Surface Disease Index) or measurements (other conjugated metabolites such as androsterone glucuronide) may have displayed different relationships. Finally, it is important to remember that as with all statistical methodologies, LCA is based on assumptions that need to be considered when interpreting the results. For example, LCA makes the assumption of local independence (i.e., once a certain class is assigned, the measurements within that class are assumed statistically independent). However, the effect of this latter assumption was evaluated in our original paper.
41 As the correlations among the measured parameters were low, assignment to latent classes had little effect on the observed correlations (data not shown).
To conclude, we found that individuals with lower levels of A had less healthy tear film parameters, and that this finding was more prominent in the ATD group. No meaningful correlations between androgen levels and DES symptoms were found. More research is needed on the role of androgens in tear function in males, as this avenue may be of potential preventive and therapeutic use in DES.