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The hypothesis in the study was that androgens control meibomian gland function, regulate the quality and/or quantity of lipids produced by this tissue, and promote the formation of the tear film's lipid layer. To test this hypothesis, a study was conducted to determine whether androgen receptor protein exists in the epithelial cell nuclei of rat m...
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... The current study also reported reduced tear film stability in females compared to males, both in the DM group (í µí± < 0.01) and in the control group (í µí± = 0.06). A decrease in circulating androgens in postmenopausal women is believed to play an important role in affecting meibomian gland function, supporting female gender as a risk factor for dry eye disease [26]. In addition to a reduction in tear film stability, several studies have reported a diminished tear secretion in the diabetic eye [7] [11] [27], as observed in the present research. ...
Purpose:
To compare tear film metrics in patients with type 1 diabetes mellitus (DM) and healthy controls and investigate the association between peripheral neuropathy and ocular surface quality.
Methods:
Dry eye symptoms were quantified in 53 patients with type 1 DM and 40 age-matched controls. Ocular examination included tear film lipid layer thickness grading, tear film stability and quantity measurement, and retinal photography. DM individuals additionally underwent a detailed neuropathy assessment.
Results:
Neither mean age nor dry eye symptom scores differed significantly between the DM and control groups (P = 0.12 and P = 0.33, resp.). Tear lipid thickness (P = 0.02), stability (P < 0.0001), and quantity (P = 0.01) were significantly lower in the DM group. Corneal sensitivity was also reduced in the DM group (P < 0.001) and tear film stability was inversely associated with total neuropathy score (r = -0.29, P = 0.03).
Conclusion:
The DM group exhibited significantly reduced tear film stability, secretion, and lipid layer quality relative to the age-matched control group. The negative correlation between tear film parameters and total neuropathy score suggests that ocular surface abnormalities occur in parallel with diabetic peripheral neuropathy.
... Androgen receptors are expressed in sebocytes as well as meibocytes (Luderschmidt et al., 1983; Rocha et al., 2000). Androgens have been shown to regulate meibomian gland gene expression and lipid production (Krenzer et al., 2000; Schirra et al., 2005, 2006, 2007; Steagall et al., 2002; Sullivan et al., 2000). In particular, androgens stimulate genes in the lipid synthesis pathways in mouse meibomian gland (Schirra et al., 2005, 2007). ...
... During blinking, contraction of the orbicularis oculi and muscle of Riolan results in meibum being released onto the posterior lid margin [1-3]. Neuronal and hormonal control of the gland has previously been demonstrated [4,5]. ...
Lubricin is a principal boundary lubricating and anti-adhesion protein found in synovial fluid and several musculoskeletal tissues. This study investigates the presence of lubricin in the meibomian gland, lacrimal gland and ocular surface of healthy rabbits; prompted by the hypothesis that lubricin acts as boundary lubricant and anti-adhesive protein in the eye.
Thirty six eyelids were resected from ten cadaveric New Zealand White rabbits and two eyeballs and two lacrimal glands from two of them. Thirty two samples from 8 animals were processed for immunohistochemical localization of lubricin using a purified monoclonal antibody and quantification of the lubricin-containing meibocytes. Confirmatory western blot analysis was performed on four eyelids from 2 animals.
Lubricin-positive meibomian cells were seen in the glands in all eight animals evaluated immunohistochemically. The percentage of lubricin-positive cells ranged from was 8%-50% in the upper and 3%-50% in the lower eyelid, with no significant difference between the upper and lower eyelid. Western blot analysis confirmed the presence of lubricin ranging from 10 to 40 ng in four eyelids from the other two rabbits. Occasional staining was seen in the epithelium of the hair follicles of the eyelid. No lubricin was evident on the ocular surface or in the lacrimal gland.
Lubricin is secreted by the meibomian gland. The results provide a basis for the hypothesis that lubricin plays a role in boundary lubrication and in preventing adhesions in the eye, as well as in contributing to other functions of the meibomian gland. Moreover, if lubricin functions to decrease the friction between the eyelid and ocular surface, this study provides a rationale to supplement the amount of lubricin in cases of compromised meibomian gland function and other conditions.
... Results were obtained by comparing log-transformed data. The 17β-estradiol and progesterone data originated from other studies [42,43], for which the Association for Research in Vision and Ophthalmology is the copyright holder. ...
... Similarly, the meibomian gland is an androgen target organ, and androgens appear to regulate this tissue’s function (e.g. lipid production) [22-25,43-45]. Androgen deficiency, in turn, has been linked to lacrimal and meibomian gland dysfunction, and a corresponding aqueous tear deficiency and evaporative dry eye [22-26,28-30]. ...
We hypothesize that sex steroids induce sex-specific and/or opposite effects in the lacrimal and meibomian glands and that these actions may influence the prevalence of dry eye syndrome. The objective of this study was to begin to test this hypothesis.
Lacrimal and meibomian glands were obtained from ovariectomized mice that had been treated with testosterone or control vehicle for 14 days. Samples were processed for the isolation of RNA, and analyzed for differentially expressed mRNAs using CodeLink Bioarrays and quantitative real-time PCR (qPCR) techniques. Data were compared to those obtained following testosterone treatment of orchiectomized mice, as well as after the administration of 17beta-estradiol and/or progesterone to ovariectomized mice.
Our findings demonstrate that testosterone regulates the expression of thousands of genes in the lacrimal and meibomian glands of ovariectomized mice. The magnitude and extent of these hormonal effects, which encompassed numerous biological, molecular, and cellular ontologies, was tissue-dependent. Particularly notable was the androgen stimulation of meibomian gland genes related to lipid metabolic pathways, and the suppression of genes associated with keratinization. Many of the genes regulated by testosterone in female tissues were identical to those controlled by androgens in male lacrimal and meibomian glands. However, some genes were modulated in a sex-specific manner. In addition, a number of the androgen-regulated genes in female glands were altered in the opposite direction by 17beta-estradiol and/or progesterone.
Our results support our hypothesis that sex steroids may induce sex-specific and/or opposite effects in the lacrimal and meibomian glands. Whether these actions contribute to the prevalence of dry eye remains to be determined.
The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via the Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.
Meibum is a lipid-rich secretion that is produced by fully differentiated meibocytes in the holocrine Meibomian glands (MG) of humans and most mammals. The secretion is a part of a defense mechanism that protects the ocular surface from hazardous environmental factors, and from desiccation. Meibomian lipids that have been identified in meibum are very diverse and unique in nature. The lipid composition of meibum is different from virtually any other lipid pool found in the human body. In fact, meibum is quite different from sebum, which is the closest secretion that is produced by anatomically, physiologically, and biochemically related sebaceous glands. However, meibum of mice have been shown to closely resemble that of humans, implying similar biosynthetic mechanisms in MG of both species. By analyzing available genomic, immunohistochemical, and lipidomic data, we have envisioned a unifying network of enzymatic reactions that are responsible for biosynthesis of meibum, which we call meibogenesis. Our current theory is based on an assumption that most of the biosynthetic reactions of meibogenesis are catalyzed by known enzymes. However, the main features that make meibum unique – the ratio of identified classes of lipids, the extreme length of its components, extensive ω-hydroxylation of fatty acids and alcohols, iso- and anteiso-branching of meibomian lipids (e.g. waxes), and the presence of rather unique complex lipids with several ester bonds – make it possible that either the activity of known enzymes is altered in MG, or some unknown enzymes contribute to the processes of meibogenesis, or both. Studies are in progress to elucidate meibogenesis on molecular level.
Purpose:
To estimate the prevalence of Meibomian gland dysfunction (MGD) and determine the associated factors in the general population in Iran.
Methods:
This cross-sectional study is based on the data from the second phase of the Shahroud Eye Cohort Study conducted in 2014. Of the 4737 participants of the second phase, data was available for 4700 people; their mean age was 55.9±6.2 years and 2768 (58.9%) were women. Diagnosis of MGD was made based on the classification of the International Workshop on MGD as judged by the examining ophthalmologist. The prevalence of MGD was summarized as percentage and 95% confidence intervals (CI), and related factors were studied through simple and multiple logistic regressions.
Results:
The diagnosis of MGD in at least one eye was recorded for 1235 (26.3%) participants; the prevalence of unilateral and bilateral MGD was 26.3% (95% CI: 24.5-28.1) and 26.1% (95% CI: 24.3-27.9), respectively. In the multiple logistic regression analyses, MGD significantly correlated with pinguecula [odds ratio (OR)=1.3, 95% CI: 1.12-1.50], hypertension (OR=1.34, 95% CI: 1.11-1.61), high-density lipoprotein (HDL) level (OR=0.0992, 95% CI: 0.986-0.999), diabetes mellitus (OR=0.83, 95% CI: 0.71-0.97), and years of education (OR=0.98, 95% CI: 0.96-0.99).
Conclusions:
MGD prevalence in this study was lower than the rates reported in other studies on Asian populations. Besides HDL level, MGD is associated with another ocular surface disorder, namely pinguecula, as well as certain systemic diseases such as hypertension and diabetes mellitus. These associations should be taken into consideration when diagnosing MGD.
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.
Sjögren’s syndrome lacrimal keratoconjunctivitis is a chronic autoimmune disease that has a significant impact on the quality of patient’s lives throughout the world. Current evidence suggests that dysfunction of the complex lacrimal function unit (LFU: cornea, conjunctiva, lacrimal glands, and meibomian glands) results in unstable tear film and chronic inflammation. Inflammatory cell (e.g., CD4+ T cells) infiltration, elevated pro-inflammatory cytokine levels, increased epithelial cell apoptosis, and diminished goblet cell numbers within the LFU, coupled with decreased tear production, are hallmark features of Sjögren’s syndrome. The inability of lacrimal glands to adequately respond to signals of ocular surface dryness, an early feature of Sjögren’s syndrome, is hypothesized to perpetuate chronic inflammation. The cycle of autoimmunity during Sjögren’s syndrome is simplified into two main stages: (1) the afferent arm, in which desiccating stress on the ocular surface elicits the initial immune response and (2) an efferent arm, which describes activation and homing of autoreactive CD4+ T cells to the ocular surface that contribute to local tissue remodeling and destruction. Indeed, early inflammatory intervention can restore secretory function within the LFU; however, if left untreated, chronic inflammation may irreversibly impact the function of the lacrimal glands and/or conjunctival goblet cells. Current research is focused on gaining a better understanding of the mechanisms that contribute to the immunopathogenesis of Sjögren’s syndrome with the goals of developing sensitive diagnostics and superior therapeutics.
