David Sullivan

Our laboratory has discovered that sex and sex steroid hormones are critical factors in the regulation of ocular surface tissues, as well as in the pathogenesis of dry eye syndromes.We have also discovered that androgens may suppress, and that estrogens may promote, aqueous-deficient and/or evaporative dry eye. More specifically:

• we have shown that sex and sex steroids, as well as neuropeptides and cytokines, regulate the secretory immune system of the eye. This system is designed to protect the ocular surface against bacterial colonization, viral adhesion, parasitic infestation and toxin-induced damage, thereby preserving corneal integrity and preventing severe visual impairment. Our results support our hypothesis that the endocrine, neural and immune systems govern ocular mucosal immunity. To help conduct these experiments we developed a defined culture system for the long term maintenance of responsive acinar epithelial cells from the lacrimal gland. This accomplishment was commended as one of the foremost achievements in ocular surface research by an NEI National Plan for Vision Research.

• we have shown that androgens reduce the inflammation in, and enhance the functional activity of, lacrimal glands in mouse models of Sjögren’s syndrome. These findings are extremely significant, given that no clinical therapy currently exists for this debilitating autoimmune disease, which occurs almost exclusively in women and is one of the leading causes of aqueous-deficient dry eye syndromes in the world. The mechanism(s) involved in this androgen-induced immunosuppression is unknown. However, our evidence indicates that this hormone action is a unique, tissue-specific effect, that is initiated through androgen binding to receptors in lacrimal gland epithelial cells. In addition, we hypothesize that this androgen interaction then causes the altered expression and/or activity of specific genes and proteins in lacrimal tissue, resulting in the reduction of immunopathological lesions and an improvement in glandular function. Our research has supported this hypothesis, which, if true, may lead to the development of unique, therapeutic strategies to safely and effectively treat this chronic and vision-threatening disease;

• we have shown that androgens regulate the meibomian gland, which is the primary tissue involved in maintaining tear film stability and preventing tear film evaporation. This finding is also very significant, given that almost no other information exists concerning the physiological control of this tissue, and that meibomian gland dysfunction is the major cause of evaporative dry eye syndromes throughout the world. Based upon our research, we hypothesize that: [a] androgens regulate meibomian gland function, improve the quality and/or quantity of lipids produced by this tissue and promote the formation of the tear film’s lipid layer; and [b] androgen deficiency, such as occurs during menopause, aging, Sjögren's syndrome, complete androgen insensitivity syndrome and the use of anti-androgen medications, leads to meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, decreased tear film stability and evaporative dry eye. Our data support these hypotheses, and have significantly increased our understanding of the physiological mechanisms controlling the meibomian gland in both health and disease;

• in collaboration with Drs. Debra A. Schaumberg, M. Reza Dana and Julie E. Buring, we have shown that dry eye syndromes occur predominantly in women and that estrogen replacement therapy increases the prevalence of dry eye signs and symptoms in postmenopausal women. This latter finding is extraordinary, given that many millions of women worldwide are prescribed estrogen to alleviate menopausal symptoms and are therefore at heightened risk of developing dry eye. The precise mechanism(s) underlying the sex-related difference in, and the estrogen effect on, dry eye prevalence is unclear. However, we hypothesize that: [a] androgen deficiency and estrogen use are key factors in the predominance of dry eye syndromes in women; and [b] sex, androgen and estrogen effects are mediated through the regulation of gene expression in the cornea and the lacrimal and meibomian glands. Our research supports these hypotheses, which, if correct, may be translated into new insights into how estrogens influence ocular tissues, and how these hormones may contribute to the etiology of dry eye syndromes.

In summary, our research has addressed the sex steroid regulation of the ocular surface and adnexa, as well as the interrelationships between sex, sex steroids and dry eye syndromes. Our studies have involved basic, clinical and epidemiological aspects, and have required the establishment of new and unique experimental approaches (e.g. lipid analytical, proteomic and molecular biological methods). Of particular interest, our research findings have led to the development of a topical androgen treatment that is currently in clinical trials and may serve as a potential therapy for both aqueousdeficient and evaporative dry eye syndromes.