Sex, sex steroids & dry eye syndromes: The impact of androgen deficiency

Sex steroid deficiency has been linked to the development and/or progression of a wide variety of clinical disorders, including cardiovascular disease, osteoporosis, obesity, insulin resistance and certain cancers. We hypothesize that sex steroid deficiency specifically that of androgens, may also be a critical pathogenetic factor in the etiology of dry eye syndromes. Dry eye syndromes are a leading cause of patient visits to eye care practitioners and are classified into two major types: aqueous-deficient and evaporative. Aqueous-deficient dry eye is due to a lack of aqueous tear secretion by lacrimal tissue. An example is Sjögren's syndrome, an autoimmune disorder that afflicts predominantly women. This syndrome is associated with extensive inflammation in lacrimal glands, an immune-mediated dysfunction and/or destruction of acinar and ductal epithelial cells, and a significant decline in aqueous tear output. Sjögren's syndrome may be either primary (i.e. no associated connective tissue disease) or secondary (e.g. people with systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]). The second type of dry eye is termed evaporative and is most often caused by meibomian gland dysfunction and lipid insufficiency, thereby promoting increased evaporation and decreased stability of the tear film. This form of dry eye is also found in Sjögren's syndrome, as well as during menopause and aging. Researchers have estimated that meibomian gland disease may be a contributing factor in over 67% of all dry eye patients. The rationale for our hypothesis linking androgen deficiency with dry eye syndromes is twofold. First, androgens control numerous aspects of the lacrimal gland, including epithelial cell morphology, gene expression, protein synthesis, secretory processes and immune function. Indeed, androgen action appears to account for many of the sex-related differences that exist in the anatomy, physiology, molecular biology and immunology of this tissue. However, women with Sjögren's syndrome have an androgen deficiency, and this hormone deficit may predispose to lacrimal gland dysfunction, attenuated tear secretion and aqueous-deficient dry eye. Consistent with this hypothesis is the observation that androgen treatment of female mouse models of Sjögren's syndrome causes a dramatic suppression of the inflammation in, and a significant increase in the functional activity of, lacrimal glands. Similarly, androgen therapy has been reported to alleviate dry eye signs and symptoms, and stimulate tear flow, in patients with Sjögren's syndrome. The mechanism by which androgens suppress lacrimal gland autoimmune disease seems to involve hormone binding to nuclear receptors within epithelial cells and a consequent alteration in the activity …