Androgens as biomarkers of Dry Eye Disease

pattismith

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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.
 

pattismith

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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.
 

pattismith

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Treatment of keratoconjunctivitis sicca with topical androgen.
2001

Abstract
OBJECTIVE:
Androgens have been reported to influence lipid production of sebaceous glands and even many ocular tissues. The effect of topical androgen therapy on a 54-year-old patient with keratoconjunctivitis sicca (KCS) and decreased lipid phase of the tear film is reported.
METHODS:
For assessment of the lipid phase of the tear film, break up time (BUT) and lipid layer thickness (LLT) were monitored during 6 months before treatment as well as 3 months while using a daily topical androgen therapy.
RESULTS:
During the topical androgen therapy the pathological lipid phase of the tear film was completely restored indicated by the normalisation of the values of BUT and LLT.
CONCLUSION:
These findings are consistent with animal experiments indicating that topical administered androgen can restore the decreased lipid phase of the tear film. This may open up new therapeutic strategies for KCS.

Androgen regulation of gene expression in human meibomian gland and conjunctival epithelial cells.
2012

Abstract
PURPOSE:
Androgens exert a significant influence on the structure, function and/or pathophysiology of the meibomian gland and conjunctiva. We sought to determine whether this hormone action involves the regulation of epithelial cell gene expression in these tissues.
METHODS:
Immortalized human meibomian gland and conjunctival epithelial cells were treated with placebo or dihydrotestosterone (DHT) and processed for molecular biologic procedures. Gene expression was evaluated with BeadChips and data were analyzed with bioinformatic and statistical software.
RESULTS:
Androgen treatment significantly influenced the expression of approximately 3,000 genes in immortalized human meibomian gland and conjunctival epithelial cells. The nature of DHT action on gene activity was predominantly cell-specific. Similarly, DHT exerted a significant, but primarily cell-specific, influence on many gene ontologies and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These included groups of genes related, for example, to lipid dynamics, innate immunity, cell cycle, Janus kinase (JAK)-signal transducer and activator of transcription (stat) cascades, oxidative phosphorylation, the proteasome, and mammalian target of rapamycin (mTOR), Wnt, and peroxisome proliferator-activated receptor (PPAR) signaling.
CONCLUSIONS:
Our findings support our hypothesis that androgens regulate gene expression in human meibomian gland and conjunctival epithelial cells. Our ongoing studies are designed to determine whether many of these genes are translated and play a role in the health and well being of the eye.
 
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Almost like hormones regulate all the areas that are seen to be dysfunctional in ME/CFS. @mariovitali shout out for PPAR, Wnt is one of the cilia signaling pathways, mTOR (which we’ve been talking about for the last couple years)handles muscle glucose uptake (mTORC2 mainly) and whole body energy homeostasis (closely linked to AMPK), oxidative phosphorylation and lipid dynamic dysfunction causes cellular stress, etc. It makes sense to target AR but we did see at the Australian symposium that there may be a low estrogen and a high estrogen group.
 
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Thinktank

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I suffer from DED and keratoconjunctivitis and can attest that androgens have a huge influence on teh severity of the disease.

1. My tearfilm improves whenever i abstain from sex for a few weeks. Tearfilm break up time improves by +/- 50% and tear volume increases. Free testosterone increases and is at its highest after 7 days.

2. When i used anabolic steroids (pre-ME) my dry eye syndrome completely vanished.

I have always known that my hormones are dysregulated but no doctor wants to delve into the subject because my total testosterone is normal to high, yet HSBG is high and certain androgen/estrogen metabolites tested in an extensive urine panel are way too low or too high. But because total testosteron is high they reason i have no androgenic problem and they don't want to take my urine panel results into account because it's "not a conventional diagnostic"....
It's appalling how even endrocronologists don't understand the biochemistry.
 

pattismith

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@mariovitali , I don't know the connection between DED and ME, but comorbidity has been found between DED and fibromyalgia, and testosterone therapy has been found useful both in DED subset and in fibro.

@Thinktank , did you had a blood DHEA test?

edit: also comorbidity between DES and CFS was found:


Dry eye syndrome and the subsequent risk of chronic fatigue syndrome—a prospective population-based study in Taiwan
Article (PDF Available)inOncotarget 9(55) · July 2018 


Abstract
Background and Aim The clinical association between dry eye syndrome (DES) and chronic fatigue syndrome (CFS) remain unclear with less evidences. We aimed to investigate the relationship between CFS and DES using a national insurance and prospective cohort study. Methods Data from the Longitudinal Health Insurance Database 2000 was applied to estimate the incidence of CFS among patients with DES, and their age- and sex-matched controls without DES over a long-term follow-up period. All participants were CFS free at baseline, before the interval (2005–2007), but were later diagnosed with CFS. DES patients and its relative matched controls were excluded prevalent CFS before the same interval. Results We identified 884 patients with DES and 3,536 matched controls in baseline and estimated the hazard ratios for incident CFS in the follow-up period. Patients with DES had a 2.08-fold considerably increasing risk of developing CFS, compared to non-DES group. An elevated risk of developing CFS remained (1.61-fold risk) even after adjusting for age, sex, and comorbidities. There was a presence of increasing risk in DES-related CFS when CFS-related comorbidities existing (adjusted hazard ratio, 1.98, 95% confidence interval, 1.19–3.29; p < 0.01). The subsequent risk for CFS between DES and non-DES patients was significant increased with three or more annual medical visits, the adjusted risk for CFS was 4.88-fold risk (95% CI, 2.26–10.58, p < 0.001). Conclusion We recommended that physicians should be aware of the increased risk of CFS among DES patients and adequately assess the health impacts among these patients.