David A. Sullivan

Prevalence of dry eye syndrome among US women.

PURPOSE Dry eye syndrome (DES) is believed to be one of the most common ocular problems in the United States (US), particularly among older women. However, there are few studies describing the magnitude of the problem in women and how this may vary with demographic characteristics. DESIGN Cross-sectional prevalence survey. METHODS STUDY POPULATION we surveyed 39,876 US women participating in the Womens Health Study about a history of diagnosed DES and dry eye symptoms. MAIN OUTCOME MEASURE we defined DES as the presence of clinically diagnosed DES or severe symptoms (both dryness and irritation constantly or often). We calculated the age-specific prevalence of DES and adjusted the overall prevalence to the age distribution of women in the US population. We used logistic regression to examine associations between DES and other demographic factors. RESULTS The prevalence of DES increased with age, from 5.7% among women < 50 years old to 9.8% among women aged > or = 75 years old. The age-adjusted prevalence of DES was 7.8%, or 3.23 million women aged > or = 50 in the US. Compared with Whites, Hispanic (odds ratio [OR] = 1.81, confidence interval [CI] = 1.18-2.80) and Asian (OR = 1.77, CI = 1.17-2.69) women were more likely to report severe symptoms, but not clinically diagnosed DES. There were no significant differences by income (P([trend]) =.78), but more educated women were less likely to have DES (P([trend]) =.03). Women from the South had the highest prevalence of DES, though the magnitude of geographic differences was modest. CONCLUSIONS Dry eye syndrome leading to a clinical diagnosis or severe symptoms is prevalent, affecting over 3.2 million American women middle-aged and older. Although the condition is more prevalent among older women, it also affects many women in their 40s and 50s. Further research is needed to better understand DES and its impact on public health and quality of life.

The International Workshop on Meibomian Gland Dysfunction: Executive Summary

DOI:10.1167/iovs.10-6997a Investigative Ophthalmology & Visual Science, Special Issue 2011, Vol. 52, No. 4 Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc. 1922 ドライアイ疾患の原因としては、マイボーム腺機能不全 (MGD)がおそらく最も多い。この疾患によって数百万人 もの健康と幸福が損なわれているにもかかわらず、MGD の定 義、分類、診断、治療について世界的なコンセンサスはない。 そうしたコンセンサスに達する目的で、非営利団体である Tear Film and Ocular Surface Society( TFOS; http://www. tearfilm.org)が International Workshop on Meibomian Gland Dysfunction(国際マイボーム腺機能不全ワークショップ、 www.tearfilm.org/mgdworkshop/index.html)を起ち上げた。こ のワークショップの目的は以下の通りである:

The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland.

The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named. Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity. Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function. Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjogren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12 After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands.

Androgen Deficiency, Meibomian Gland Dysfunction, and Evaporative Dry Eye

Abstract: Objective. We have recently discovered that women with primary and secondary Sjögrens syndrome are androgen‐deficient. We hypothesize that this hormone insufficiency contributes to the meibomian gland dysfunction, tear film instability, and evaporative dry eye that are characteristic of this autoimmune disorder. If our hypothesis is correct, we predict: (1) that androgens regulate meibomian gland function, control the quality and/or quantity of lipids produced by this tissue, and promote the formation of the tear films lipid layer; and (2) that androgen deficiency, due to an attenuation in androgen synthesis (e.g., during Sjögrens syndrome, menopause, aging, complete androgen‐insensitivity syndrome [CAIS] and anti‐androgen use), will lead to meibomian gland dysfunction and evaporative dry eye. The following studies were designed to test these predictions. Methods. Experimental procedures included clinical studies, animal models, and histological, biochemical, molecular biological, and biomedical engineering techniques. Results. Our results demonstrate that: (1) androgens regulate the meibomian gland. This tissue contains androgen receptor mRNA, androgen receptor protein within acinar epithelial cell nuclei, and Types 1 and 2 5α‐reductase mRNAs. Moreover, androgens appear to modulate lipid production and gene expression in mouse and/or rabbit meibomian glands; and (2) androgen deficiency may lead to meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, tear film instability, and evaporative dry eye. Thus, we have found that anti‐androgen therapy in men is associated with meibomian gland disease, a decreased tear film breakup time, and functional dry eye. Furthermore, we have discovered that androgen receptor dysfunction in women with CAIS is associated with meibomian gland changes and a significant increase in the signs and symptoms of dry eye. Of interest, we have also found that androgen deficiency is associated with significant and striking alterations in the neutral and polar lipid patterns of human meibomian gland secretions. Conclusions. Our findings show that the meibomian gland is an androgen target organ and that androgen deficiency may promote meibomian gland dysfunction and evaporative dry eye. Overall, these results support our hypothesis that androgen deficiency may be an important etiologic factor in the pathogenesis of evaporative dry eye in women with Sjögrens syndrome.

Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2

European Vision and Eye Research Meeting (October, 2001, Alicante, Spain). 84. Krenzer KL, Dana MR, Ullman MD, Cermak JM, Tolls BD, Evans JE, Sullivan DA. Effect of androgen deficiency on the human meibomian gland and ocular surface. J Clin Endocr Metab. 2000; 85:4874-4882. 85. Sullivan BD, Evans JE, Krenzer KL, Dana MR, SulIivan DA. Impact of anti-androgen treatment on the fatty acid profile of neutral lipids in human meibomian gland secretions. J Clin Endocr Metab. 2000; 85:4866-4873. 86. Sullivan BD, Evans JE, Dana MR, SulIivan DA. Impact of androgen deficiency on the lipid profiles in human meibomian gland secretions. Adv Exp Med Bio!. 2001; in press. 87. Cermak JM, Krenzer KL, Dana MR, Sullivan DA. Do individuals with complete androgen insensitivity display the signs and symptoms of dry eye? Invest Ophthalmol Vis Sci. 1999; 40:S2836. 88. SulIivan BD, Evans JE, Krenzer KL, Dana MR, Sullivan DA. Complete androgen insensitivity syndrome: intluence on the polar and neutral lipid profiles of human meibomian gland secretions. Manuscript submitted, 2001. 89. Sullivan BD, Evans JE, Krenzer KL, Dana MR, SulIivan DA. Effect of aging on lipid patterns in human meibomian gland secretions. Manuscript submitted, 2001. 90. Zeligs MA, Gordon K. Dehydroepiandrosterone therapy for the treatment of dry eye disorders. Int Patent Application WO 94/04155, March, 1994. 91. Radn6t VM, Nemeth B. Wirkung der Testosteronpräparate auf die Tränendrüse. Ophthalmologica 1955; 129:376-380. 92. Radn6t M, Nemeth B. Testosteronkeszftmenyek hatisa a könnymirigyre. Orvosi Hetilap 1954; 95:580-581. 93. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and the prevalence of dry eye syndrome. Submitted, 200 1. 94. Schafer G, Krause W. The effect of estradiol on the sebaceous gland of the hamster ear and its antagonism by tamoxifen. Arch Dermatol Res. 1985; 277:230-234. Sex Steroids, the Meibomian Gland and Evaporative Dry Eye 95. Sweeney TM, Szarnicki RJ, Strauss JS, Pochi PE. The effect of estrogen and androgen on the sebaceous gland turnover time. J Invest Dermatol. 1969; 53:8-10. 399 96. Strauss JS, Kligman AM, Pochi PE. The effect of androgens and estrogens on human sebaceous glands. J luvest Dermatol. 1962; 39:139-155. 97. Sansone-Bazzano G, Reisner RM, Bazzano G. A possible mechanism of action of estrogen at the cellular level in a model sebaceous gland. J luvest Dermatol. 1972; 59:299-304. 98. Saihan EM, Burton JL. Sebaceous gland suppression in female acne patients by combined glucocortieoid-oestrogen therapy. Br J Dermatol. 1980; 103:139-142. 99. Poehi PE, Strauss JS. Sebaeeous gland inhibition from eombined glueocortieoid-estrogen treatment. Areh Dermatol. 1976; 112:1108-1109. 100. Smith E, Szego CM. Direct photomicroseopic evidenee for rapid nuclear penetration of lysosomal produets in steroid targets afterestrogen in vivo. Endoerinol. 1971; 88: Suppl XRA-151:AI51. 101. Gurwood AS, Gurwood I, Gubman DT, Brzeziek U. Idiosyneratie ocular symptoms associated with the estradiol transdermal estrogen replaeement patch system. Optom Vis Sei. 1995;72:29-33. 102. Verbeek B. Augenbefunde und stoffweehselverhalten bei einnahme von ovulationshemmern. Klin Mbl Augenheilk 1973; 162:612--621. 103. Christ T, Marquardt R, Stodtmeister R, Pillunat LE. Zur Beeinflussung der tränenfilmaufreibzeit dureh hormonale kontrazeptiva. Fortsehr Ophthalmol. 1986; 83: 108-111. 104. Brennan NA, Efron N. Symptomatology of HEMA eontaet lens wear. Optom Vis Sei. 1989;66:834-838. 105. Ruben M. Contaet lenses and oral eontraceptives. Brit Med J. 1966;1:1110. 106. Esmaeli B, Harvey JT, Hewlett B. Immunohistochemical evidence for estrogen receptors in meibomian glands. Ophthalmology 2000; 107: 180-184. 107. Suzuki T, Schaumberg DA, Sullivan BD, Liu M, Richards SM, Sullivan RM, Dana MR, Sullivan DA. Do estrogen and progesterone playa role in the dry eye of Sjögrens syndrome. Ann NY Acad Sei 200 I; in press. 108. Suzuki T, Sullivan BD, Liu M, Schirra F, Richards SM, Yamagami H, Sullivan DA. Estrogen and progesterone effects on the morphology of the mouse meibomian gland. Adv Exp Med Biol. 200 1; in press. 109. Sullivan BD, Evans JE, Sullivan RM, Sehaumberg DA, Dana MR, Sullivan DA. Impact of hormone replacement therapy on the lipid profile of meibomian gland secretions in postmenopausal women. Manuscript submitted, 2001. 110. Chew CKS, Hykin PG, Janswijer C, Dikstein S, Tiffany JM, Bron AI. The casuallevel of meibomian lipids in humans. Curr Eye Res. 1993;12:255-259. THE LIPID LA YER AND STABILITY OF TEARS IN HUMAN NEWBORNS Sherwin J. Isenberg, Madeline DeI Signore, Anthony Chen, and Jeffrey Wei Jules Stein Eye Institute and Harbor-UCLA Medical Center UCLA School of Medicine Los Angeles and Torrance, Califomia, USA

Epidemiology of Dry Eye Syndrome

Dry eye syndrome (DES) represents a heterogeneous group of conditions that share inadequate lubrication of the ocular surface as their common denominator. DES is characterized by symptoms of ocular dryness and discomfort due to insufficient tear quantity or quality caused by low tear production and/or excessive tear evaporation. Symptoms can be debilitating 1 and, when severe, may affect psychological health and ability to work. No cure exists for DES, which is one of the leading causes of patient visits to ophthalmologists and optometrists in the United States. Because of the presumed high prevalence of DES and the attendant health care burden, the National Eye Institute (NEI) has identified tear film and dry eye research as important areas in need of further study.

Androgens and Dry Eye in Sjögren's Syndromea

ABSTRACT: Sjögrens syndrome is an extremely complex and currently incurable autoimmune disorder, which occurs primarily in females, and is associated with lacrimal gland inflammation, meibomian gland dysfunction, and severe dry eye. We hypothesize that androgen deficiency, which reportedly occurs in primary and secondary Sjögrens syndrome (e.g., systemic lupus erythematosus, rheumatoid arthritis), is a critical etiologic factor in the pathogenesis of dry eye syndromes. We further hypothesize that androgen treatment to the ocular surface will promote both lacrimal and meibomian gland function and alleviate both “aqueous‐deficient” and “evaporative” dry eye. Our results demonstrate that androgens regulate both lacrimal and meibomian gland function, and suggest that topical androgen administration may serve as a safe and effective therapy for the treatment of dry eye in Sjögrens syndrome.

Proteomic analysis of human meibomian gland secretions

Background/aim: Human tears contain hundreds of proteins that may exert a significant influence on tear film stability, ocular surface integrity, and visual function. The authors hypothesise that many of these proteins originate from the meibomian gland. This study’s aim was to begin to develop the proteomic methodology to permit the testing of their hypothesis. Methods: Meibomian gland secretions were collected from the lower eyelids of adult volunteers and placed in a chloroform-methanol mixture. Samples were partitioned in a biphasic system and non-lipid phase materials were reduced, alkylated, and trypsin digested to obtain peptides for protein identification. This peptide mixture was separated by µ-capillary reverse phase chromatography and the effluent examined by nano-electrospray MS and data dependent MS/MS. SEQUEST software was used to identify proteins from the MS/MS spectra. Results: The methodological approach to date has permitted the identification of more than 90 proteins in human meibomian gland secretions. Proteins include the α2-macroglobulin receptor, IgA α chain, farnesoid X activated receptor, interferon regulatory factor 3, lacritin precursor, lactotransferrin, lipocalin 1, lysozyme C precursor, potential phospholipid transporting ATPase IK, seven transmembrane helix receptor (also termed somatostatin receptor type 4), testes development related NYD-SP21 (also termed high affinity IgE receptor β subunit), and TrkC tyrosine kinase. Conclusions: These findings indicate that the meibomian gland secretes a number of proteins into the tear film. It is quite possible that these proteins contribute to the dynamics of the tear film in both health and disease.

Influence of Gender, Sex Steroid Hormones, and the Hypothalamic-Pituitary Axis on the Structure and Function of the Lacrimal Gland

Throughout the twentieth century it has become increasingly apparent that males and females are different, and not just in terms of physical characteristics. Scientists have discovered that fundamental, gender-related differences exist in almost every cell, tissue and organ of the body, including those associated with respiration, digestion, metabolism, circulation, renal function, and neural and endocrine activity. Indeed, during a recent five year period, at least 8,159 scientific reports were published that addressed the basic and/or clinical influence of gender on health and disease (Table 1).

Is Complete Androgen Insensitivity Syndrome Associated with Alterations in the Meibomian Gland and Ocular Surface

Purpose. This studys purpose was to determine whether complete androgen insensitivity syndrome (CAIS) is associated with alterations in the meibomian gland and ocular surface. Methods. Individuals with CAIS, as well as age-matched female and male controls, completed questionnaires which assessed dry eye symptoms and underwent slit lamp evaluations of the tear film, tear meniscus, lids and lid margins and conjunctiva. The quality of meibomian gland secretions was also analyzed. Results. Our results demonstrate that CAIS is associated with meibomian gland alterations and a significant increase in dry eye signs and symptoms. Clinical assessment revealed that CAIS women, as compared to controls, had a significant increase in telangiectasia, keratinization, lid erythema and orifice metaplasia of the meibomian glands, and a significant decrease in the tear meniscus and quality of meibomian gland secretions. Questionnaire results showed that dry eye symptoms were increased over twofold in CAIS individuals, as compared to controls, including a significant increase in the sensations of dryness, pain and light sensitivity. Conclusion. Our results suggest that androgen insensitivity may promote meibomian gland dysfunction and an increase in the signs and symptoms of dry eye.