Androgens as biomarkers of Dry Eye Disease

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A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers

2017

Purpose
To test the association between serum metabolites and dry eye disease (DED) using a hypothesis-free metabolomics approach.
Design
Cross-sectional association study.
Participants
A total of 2819 subjects from the population-representative TwinsUK cohort in the United Kingdom, with a mean age of 57 years (range, 17–82 years).
Methods
We tested associations between 222 known serum metabolites and DED. All subjects underwent nontargeted metabolomic analysis of plasma samples using gas and liquid chromatography in combination with mass spectrometry (Metabolon Inc., Durham, NC). Dry eye disease was defined from the validated Short Questionnaire for Dry Eye Syndrome (SQDES) as a previous diagnosis of DED by a clinician or “often” or “constant” symptoms of dryness and irritation. Analyses were performed with linear mixed effect models that included age, BMI, and sex as covariates, corrected for multiple testing.
Main Outcome Measures
Primary outcome was DED as defined by the SQDES, and secondary outcomes were symptom score of DED and a clinical diagnosis of DED.

Results
Prevalence of DED as defined by the SQDES was 15.5% (n = 436). A strong and metabolome-wide significant association with DED was found with decreased levels of the metabolites androsterone sulfate (P = 0.00030) and epiandrosterone sulfate (P = 0.00036). Three other metabolites involved in androgen metabolism, 4-androsten-3beta,17beta-diol disulfate 1 and 2, and dehydroepiandrosterone sulfate, were the next most strongly associated of the 222 metabolites, but did not reach metabolome-wide significance.

Dryness and irritation symptoms, as opposed to a clinical diagnosis, were particularly strongly associated with decreased androgen steroid metabolites, with all reaching 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 5 androgens, epiandrosterone sulfate (P = 0.0076) was most associated with 2-year incidence of clinician-diagnosed DED.


In addition, we found decreased glycerophosphocholines to be associated with DED, although not at metabolome-wide significance.


Conclusions
This hypothesis-free metabolomic approach found decreased serum androgens to be highly associated with DED and adds important evidence to the growing body of research that links androgens to ocular surface disease and DED.
 
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Sex hormons and androgens are for a long time suspected for involvement in Dry Eyes.

This review article is from 2014:


Sex hormones and the dry eye
Susan Truong BOptom hons BVisSci
The University of New South Wales, Kensington, New South Wales, Australia



Abstract

The greater prevalence of dry eye in women compared to men suggests that sex hormones may have a role in this condition.
This review aims to present evidence for how sex hormones may affect the ocular structures involved in the production, regulation and maintenance of the normal tear film.
It is hypothesised that hormone changes alter the homeostasis of the ocular surface and contribute to dry eye.

Androgens impact on the structure and function of the meibomian and lacrimal glands and therefore androgen deficiency is, at least in part, associated with the aetiology of dry eye. In contrast, reports of the effects of oestrogen and progesterone on these ocular structures and on the conjunctiva are contradictory and the mechanisms of action of these female‐specific sex hormones in the eye are not well understood. The uncertainty of the effects of oestrogen and progesterone on dry eye symptoms is reflected in the controversial relationship between hormone replacement therapy and the signs and symptoms of dry eye. Current understanding of sex hormone influences on the immune system suggests that oestrogen may modulate a cascade of inflammatory events, which underlie dry eye.
A normal pre‐ocular tear film is important for the protection of the ocular surface from infection and injury, acting both physically and immunologically to maintain a smooth refractive surface for optimum vision.1, 2 Dry eye disease occurs where the tear film is compromised as a result of reduced aqueous tear production and/or excessive tear evaporation.3 Tear film function relies on the normal production of the constituents that comprise each of its three nominal layers. These constituents are produced by the ocular structures of the ‘lacrimal functional unit’: the inner hydrophilic mucin layer is produced mainly by conjunctival goblet cells and, to a lesser extent, conjunctival and corneal epithelial cells, the middle aqueous layer is produced by the main and accessory lacrimal glands and the outer lipid layer is secreted by the meibomian glands.4 Homeostasis is maintained through regulation by neuronal and hormonal mechanisms. Disruption to the functional unit, as a consequence of physiological or pathological local or systemic changes, and pharmacological or surgical interventions, can lead to a cycle of inflammatory events and the appearance of ocular surface disease, including dry eye.5
There is increasing evidence that dry eye is an immune‐based inflammatory disease that affects the ocular surface and lacrimal glands.6-8 The ocular surface, that is, the tear film, corneal and conjunctival epithelia, conjunctival goblet cells and meibomian glands, together with the lacrimal glands (both main and accessory) and interconnecting neural reflex loops, act as an integrated ‘lacrimal functional unit’ to regulate tear production to maintain ocular surface wetting and integrity.5, 9 Disturbance to any component of this unit compromises the neural feedback required to maintain tear film and ocular surface homeostasis.9, 10
Loss of androgen support to the meibomian and lacrimal glands reduces the volume and/or stability of pre‐ocular tears, decreasing the rate of tear turnover, increasing tear osmolarity and prolonging the exposure of the ocular surface to debris and microorganisms.5, 11 Hyperosmolarity of the tear film stimulates synthesis and secretion of pro‐inflammatory cytokines by the lacrimal gland and/or stressed ocular surface epithelia.12, 13 The activation of inflammatory processes may subsequently impact neural function and disrupt the feedback mechanism to the lacrimal gland, further impeding tear production and clearance. In contrast, oestrogens appear to promote such inflammatory processes in the meibomian gland,14-16 ocular surface epithelia17, 18 and possibly the lacrimal gland;15, 19, 20 however, the role of oestrogen in dry eye is complex and remains unresolved.
The most common treatments for dry eye aim to increase the amount of tears at the ocular surface by tear replacement with tear substitutes and lubricants or to improve tear retention by occlusion of the drainage system.21 However, such treatment is often palliative and inadequate in providing satisfactory relief from debilitating symptoms.21, 22 Development of treatments directed at the underlying cause of dry eye is hampered by the difficulty in determining the exact pathophysiology of this multifactorial disease and the lack of standard diagnostic techniques. The inconsistencies in diagnostic criteria and definitions of dry eye are reflected in its reported prevalence, which varies from five to over 30 per cent.23-27
Common to most epidemiological findings is that dry eye becomes more frequent with age in both men and women and that women are at a higher risk of dry eye than men.23-28 The higher prevalence of signs and/or symptoms of dry eye in women has been associated with systemic conditions, such as Sjögren's syndrome,29, 30 complete androgen insensitivity syndrome,31, 32 premature ovarian failure33, 34 and polycystic ovary syndrome.35 Physiological changes with pregnancy, lactation, menstruation and menopause,36-41 use of medications such as contraceptives and hormone replacement therapy (HRT),42-44 as well as surgical procedures, including ovariectomy and hysterectomy, are also implicated.45 In men, anti‐androgen therapy for prostatic indications is a sex‐specific risk factor associated with dry eye.46, 47 The significant contrast in the number of sex‐specific risk factors between men and women suggests that the pathophysiological mechanisms that underlie dry eye disease may, at least in part, be due to sex‐related differences in endocrine functions.15, 48-51 This review aims to examine the evidence for a role of sex hormones in the aetiology of dry eye.