SEX HORMONE REGULATION OF LACRIMAL GLAND SECRETION

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DESCRIPTION (adapted from applicant's abstract): Dry eye disease is one of the most frequently encountered categories of ocular morbidity, and insufficient lacrimal gland fluid production is a frequent source of the problem. Lacrimal insufficiency results from autoimmune disease, most notably Sjogren's syndrome, and from other, poorly-understood etiologies. Most dry eye patients, and the vast majority of Sjogren's syndrome patients, are postmenopausal women. Additionally, many women who are pregnant or are taking oral contraceptives are unable to wear contact lenses due to decreased aqueous tear production. Thus, it appears that reproductive hormones modulate lacrimal secretory function and susceptibility to autoimmune disease. The goal of this study is to determine the hormonal factors regulating the secretory status of the female lacrimal gland. The specific aims are to test three hypotheses concerning interactions between androgens, estrogens, and prolactin: 1. Decreasing androgen and increasing estrogen levels result in lacrimal insufficiency. Because androgens as well as estrogens are lost after menopause, and because increasing estrogen levels decrease free androgens by increasing synthesis of sex hormone binding globulin, this hypothesis can account for the observation that lacrimal function is impaired both post-menopausally and in high-estrogen states. 2. Prolactin at optimal levels acts synergistically with androgens and estrogens in maintaining normal lacrimal gland function, while either insufficient or excess prolactin impairs function. 3. Prolactin synthesis in the lacrimal gland is decreased by androgens and circulating prolactin, and it is increased by estrogens. This hypothesis, to be tested with materials from the first two specific aims, is of interest because of the possibility that prolactin might act as an intracrine, or if released into the interstitium, an autocrine or paracrine mediator of lacrimal epithelial or lymphocytic activity. Rabbits will be ovariectomized, then treated with androgens, with and without estrogens, to test the first hypothesis. They will be treated with bromocriptine, prolactin, and sex steroids to test the second. Total membrane-associated Na,K-ATPase, muscarinic receptors, and beta-adrenergic receptors will be measured in initial surveys. The subcellular organization of these parameters, plus Na/H antiport, will be determined in final experiments, as will resting and cholinergically stimulated lacrimal gland fluid flow rates, lacrimal immunohistopathology, and acinar morphology. Prolactin mRNA abundance and immunoreactivity will be measured to test the third hypothesis. If the specific hypotheses are proven correct, the experimental results should inspire design of strategies for preventing or reversing hormonally-mediated lacrimal insufficiency.