Gender and Dry Eye

[Note: this is an older, but still potentially useful, article from the RPB archives.]

David A. Sullivan, Ph.D.
Associate Professor of Ophthalmology
Schepens Eye Research Institute
Harvard Medical School

Associates: L. Alexandra Wickham. B.A.. Ikuko Toda. M.D.. Eduardo M. Rocha. M.D.. Kathleen L. Krenzer. O.D.. Ph.D.. M. Reza Dana. M.D.. M.P.H.

SUMMARY AND SIGNIFICANCE

In Lewis Carroll's book, Alice's Adventures in Wonderland. the White Rabbit asked the King. "where shall I begin..., and the King responded: "begin at the beginning, and go on till you come to the end..." And so it is with medical research on dry eye syndromes, we must often begin at the beginning.

For years, it has been recognized that dry eye is one of the leading causes of patient visits to ophthalmologists. Indeed, current estimates indicate that over 10 million people in the United States have this problem. The incidence of this disorder is genderrelated and occurs most frequently in adult females. However, dry eye may also afflict children, adult males and the elderly, and has been likened to opening your eye and sticking it in the Sahara Desert. Dry eye is painful and extremely uncomfortable, Dry eye may significantly impair your vision. In fact, dry eye may also be devastating psychologically and interfere seriously with your job. A rheumatologist recently stated that he did not know whether he could continue to "see" patients because his dry eye condition was so severe. In fact. he was seriously considering ending his clinical practice. unless he could obtain a cure.

The problem, though, is that there is no cure for dry eve syndromes. The only way to minimize the sandy or gritty feeling in the eye is to use artificial tear substitutes, goggles or punctal plugs (i.e., devices that prevent the drainage of tears). which simply delay the pain but do not correct the problem. Why, then, is there no cue for dry eye syndromes? And what are they, anyway? And will our research at the Schepens Eve Research Institute (SERI) and Harvard Medical School lead to a safe and effective treatment?

To answer these questions, we would first like to explain something about the tear film and the causes of dry eye. We would then like to share with you some of our new, unique and exciting research findings, which may soon lead to a clinical therapy for the treatment, and potential cure, of dry eye syndromes.

Tears originate from several glands and form a film on the surface of the eye. This film consists of 3 layers: an underlying gel composed of compounds called mucins, a middle aqueous (i.e., watery) component that contains many critical substances required for the health of the eye, and an overlying oily layer made up of molecules called lipids. You might think of these lipids as something akin to the oils on your skin. These oils are very important in preventing your skin from becoming dry, just as tear lipids are essential for maintaining the tear film and preventing its evaporation.

The sources of these different layers of the tear film are cells on the eyelid and eye, which produce the underlying mucins: the lacrimal glands. which are situated above the eye and within the lids and secrete aqueous tears. such as when people cry for sadness or joy: and the meibomian glands, which are located behind the eyelashes and release the oily lipid layer.

Dry eye syndromes occur when one of these layers of the tear film is missing or deficient and, although dry eyes may be induced by many different diseases, there are only two major types: aqueous-deficient and evaporative. Aqueous-deficient dry eye, which is a very common form, is primarily due to a lack of tear secretion from the lacrimal gland. An example would be Sjdgren"s syndrome, an autoimmune disease wherein the body's immune system attacks and may eventually destroy the aqueous tear-producing cells (i.e.. epithelial) of the lacrimal gland. This disease occurs almost exclusively (>90%) in women and afflicts approximately 2 to 3 million Americans. There is no known cure. The second type of dry ere is called evaporative and is typically caused by meibomian gland dysfunction and lipid insufficiency. An example would be the problem of that rheumatologist, or perhaps the dry eye of peri-menopausal women or of elderly men and women. It has been estimated that meibomian gland disease, which also occurs in Sjogren's syndrome, may be a contributing factor in 60 to 80% of dry eye patients. Again, there is no cure ... and a major reason why there are no cures for these dry eve syndromes today is that we have only begun to understand the nature of gender's impact on the eye, as well as the processes that control the lacrimal and meibomian glands, in both health and disease.

Our laboratory has sought to advance the understanding of the mechanism by which gender influences and other factors (e.g., hormones) regulate. lacrimal and meibomian tissues, and with this information to develop strategies for the therapeutic treatment of dry eye syndromes. Our research has involved the fields of biochemistry, physiology. immunology, endocrinology, and molecular biology and has led to unique insights into the control of lacrimal and meibomian gland function. More importantly for the patient, though, our studies have indicated a new approach for the treatment of both aqueous deficient and evaporative dry eye syndromes. Thus, our research has begun to:

begun to unravel the mystery of why females are far more susceptible to certain types of dry eye syndromes;

shown that striking, gender-related differences exist in the structure and function of the lacrimal gland, and that man of these differences appear to be due to the effect of specific sex steroid hormones called androgens; other investigators have also drawn similar conclusions;

discovered that the administration of androgens not only stops the immune system from attacking the lacrimal gland in female animal models of Sjogren's syndrome, but that these hormones also suppress the inflammation within and increase the functional activity of lacrimal tissue in this disease;

discovered that the meibomian gland is an androgen target organ that androgens modulate lipid production within this tissue, and that androgen deficiency may cause meibomian gland dysfunction and dry eye.

Of particular importance, our results indicate that androgen action, or the lack thereof. may hold a key to understanding the sender-related incidence in the onset of. and the potential treatment for, dry eye syndromes.'' Thus, females have lower andro('ey levels than males, and conditions such as Sjogren's syndrome. menopause and aging all have in common a lower than normal concentration of serum androgens. Given these findings. we believe that topical (i.e. surface of the eye) androgen administration may serve as a safe and effective therapy for the treatment of various aqueous-deficient and evaporative dry eye syndromes. This belief will soon be tested in clinical trials by a major pharmaceutical firm. If our hypothesis is correct, then this hormone therapy may water the ocular desert, elicit a smile from dry eve patients and bring this research, which began at the beginning, to a meaningful end.

BACKGROUND AND RESULTS

Gender, Sex Steroids and the Eve-For centuries it has been recognized that males and females are different. and not just in terms of physical attributes. Fundamental. gender-associated differences exist in almost every cell, tissue and organ system of the body. including those related to circulation. respiration. digestion. renal function. metabolism. and neural and endocrine activity. Indeed. during a recent five-year period. over 8,150 scientific reports were published that addressed the basic and/or clinical influence of gender and many of these genderrelated differences were due, atleast in part, to the action of sex steroid hormones, androgens, estrogens, and progestins).

Given these observations, is it possible that gender and sex steroids also affect the eye" And, if so, do these effects have am relevance to ocular health.' The answer to both of these questions is yes. although much remains to be learned about the nature 'Lund extent of gender_ sex steroid and eye interactions.

In 190-, a book entitled "Ocular Troubles Originating from the Female Genital Tract" was published by Drs. E. Berger and R. Loewy in France. This hook summarized a series of clinical studies from the time of Hippocrates to the beginning of the 20th century and linked a variety of endocrine changes in females to alterations in the health of the eye. These ocular troubles. which were presumably due in part to
disruptions in sex steroid levels, included such conditions as conjunctivitis, eyelid edema. blepharospasm. keratitis, herpetic reactivation, corneal ulcer, cataract, iritis, glaucoma exacerbation. scotoma. amblyopia. optic neuritis. optic nerve atrophy and blindness. Indeed, in the late 1800's. European physicians had a society that was dedicated to understanding why genderrelated differences occur in the incidence of eye diseases. Their belief was that "males are by no means as prone to diseases of the eye from sexual causes as females.'"

Although this generalized statement may not receive much support today. it is true that numerous studies have been published since that time documenting the effects of gender and sex steroids on ocular tissues. For example: ( I ) gender-associated differences have been identified in. and/or androgens. estrogens or progestins have been proposed to act on. the lacrimal gland. meibomian gland. conjunctiva. goblet cells. cornea. anterior chamber. lens. vitreous and retina:- (2) androgen, estrogen and/or progesterone receptor messenger RNAs (mRNAs) and proteins are present in the lacrimal gland. meibomian gland. conjunctiva, cornea. iris/ciliarv body. lens and/or retina of humans. rats and/or rabbits. and the expression of these transcripts may vary according to gender* and (3) gender and sex hormones appear to modulate multiple structural and functional aspects of the eve. including tissue morphology, gene expression. protein synthesis. lipid production, mucous secretion. aqueous tear output. tear film stability, inmmunological activity. epithelial cell density. corneal thickness. curvature and sensitjvit\. wound healing. aqueous humor outflow. intraocular pressure. macular hole development and visual acuity. Thus. it would seem that gender and sex steroids may exert a significant impact on the health and well-being of the eve.

Gender. Sex Steroids and Aqueous-Deficient Dry Eve-Perhaps the best known example of genders influence on ocular disease is Sjogrey's syndrome. This syndrome is a complex autoimmune disorder that involves multiple systemic defects. occurs almost entirely in females. and has been reported to be one of the leading causes of keratoconjunctivitis sicca (dry eye) in the world. The primary reason for dry eye in Sjogren's syndrome appears to he reduced aqueous tear secretion from the inflamed main and accessory lacrimal glands. although inadequate mucin production (from conjunctival goblet and epithelial cells) and meibomian gland dysfunction may also play a role.' Clinically. Sjogren's syndrome may have a very severe impact on
ocular surface integrity and visual acuity: if unmanaged with artificial tear substitutes. for example. this disorder may lead to desiccation. ulceration and perforation of the cornea, an enhanced susceptibility to infectious disease, and potentially. significant visual loss and blindness. Unfortunately, there is no known cure.

The precise etiology of Sjogren's syndrome is unknown, but may involve the interplay of numerous factors, including those of endocrine, neural. genetic. viral and environmental origin.• Recently. considerable attention has been focused upon the role of sex steroids in disease pathogenesis." The rationale for this focus is that autoimmune disorders often. but not always. show a sexual dichotomy, with estrogens frequently augmenting disease severity in females and androgens commonly suppressing immunopathology in males. In support of this rationale. research has showy that estrogens may be involved in the etiology and progression of Sjogren's syndrome. In addition, studies have indicated that the serum concentrations of androgens are significantly reduced in this disease. This androgen reduction may well predispose to the gender-related incidence and overall development of Sjogren's syndrome.

It is noteworthy that the low levels of androgens in Sjogren's syndrome may also he a major contributing factor to the lacrimal gland dysfunction, decreased tear secretion and consequent dry eve encountered in this disorder. Significant, gender-related differences exist in the anatomy. biochemistry. physiology. immunology. molecular biology and/or disease susceptibility of the lacrimal gland in a variety of species (including humans). The mechanisms responsible for this sexual dimorphism have often been attributed. at least in part, to the impact of androgens.' These hormones influence the architecture of epithelial cells. the expression 01 specific genes. the synthesis of vary-ous proteins. the extent of certain secretory processes and the activity of the immune system in lacrimal tissue. In fact. the nature of these androgen effects appears to account for mane of the observed differences between males and females in lacrimal gland structure and function. Thus. the androgen deficit in Sjogren's syndrome may serve to lessen tissue function. as well as to promote the autoimmune process. in the lacrimal gland. Conversely. it is possible that the topical administration of androgens to the surface of the eve could theoretically correct the local hormonal imbalance and potentially provide a safe and effective treatment for lacrimal gland defects. and the associated dry eve. in Sjogren's syndrome.

In support of this hypothesis. our research has demonstrated that androgen (e.g., testosterone) therapy leads to a dramatic suppression of the inflammation in, and a significant increase in the functional activity of, lacrimal tissues in female animal models of Sjogren's syndrome.' Our studies have also shown that this androgen action is a unique, tissue-specific effect, that appears to be mediated through a hormone interaction with specific receptors in nuclei of epithelial cells, which then leads to alterations in the expression of pro- and anti-inflammatory cytokines (i.e., cellular signals), proto-oncogenes (i.e., genes involved in cell growth, regulation and death) and apoptotic factors (note: Apoptosis, also termed programmed cell death, is a normal process within the body to remove specific cells. This process may be altered in autoimmune disease, leading to the accumulation of lymphocytes in specific tissues and inflammation)."" These androgen actions result in the contraction of immunopathological lesions and an improvement in glandular function. Our findings seem to serve as a reasonable explanation for the success of earlier uncontrolled clinical studies which reported that systemic androgen administration might alleviate dry eye symptoms and augment tear flow in individuals with Sjogren's syndrome."-"

Given this information, we believe that the use of topical androgen therapy in patients with Sjogren's syndrome may:

decrease inflammation in adjacent lacrimal tissue and alleviate the immune-related damage to acinar and ductal epithelial cells;

allow accessory (situated in the lid) and palpebral (part of the main) lacrimal glands to secrete at least basal tear volumes:

make available regions of functional lacrimal tissue, that might respond to exogenous tear stimulants, to further increase aqueous tear production:

permit the use of very low concentrations of androgens (i.e., less than normally made daily by "healthy" women). thereby avoiding the dangerous side effects that typically preclude the oral or systemic use of these hormones in women, children and "healthy" men.

Androgens and Evaporative Dry Eye -Of particular importance, the potential benefit of topical androgen therapy may extend well beyond the treatment of aqueous-deficient dry eye syndromes (i.e., as in Sjogren's syndrome). Our recent research has indicated that topical androgen administration may also serve as a safe and effective treatment for evaporative dry eye disorders due to meibomian gland dysfunction.

The meibomian gland is a large sebaceous (i.e., oil-producing) gland, and androgens are known to regulate the development, differentiation and function of sebaceous glands throughout the body.'-1 More specifically, androgens appear to act primarily on acinar epithelial cells in sebaceous glands, and these cells contain both androgen receptor mRNA and protein (in their nuclei). These acinar cells respond to androgens by augmenting both the production and secretion of lipids. In addition, androgen action in many sebaceous glands is increased by, or dependent upon, the presence of an enzyme, called 5a-reductase, which converts testosterone into a more potent androgen. Of interest, sebaceous gland activity and secretion declines with age, and this aging-associated dysfunction has been correlated with both an atrophy (i.e., shrinkage) of acinar cells and a decrease in serum androgen levels. In fact, the age-related cellular shrinkage in certain sebaceous glands has been directly correlated with a decline in androgen content in the surrounding skin.

Given this background, we have hypothesized that androgens may also regulate meibomian gland function, enhance the quality and quantity of lipids produced by this tissue and stimulate the formation of the tear film's lipid layer. In addition, we have proposed that androgen deficiency, as occurs during menopause (decrease in ovarian and adrenal androgen secretion), aging in both sexes (decline in testicular androgen output in elderly males). autoimmune disease (e.g.. Sjogren's syndrome. systemic lupus erythematosus. rheumatoid arthritis) and the use of anti-androgen medications (e.g for prostatic hypertrophy or cancer) may lead to meibomian gland dysfunction and consequent evaporative dry eye.

In testing our hypotheses:

we have discovered that the human meibomian gland is an androgen target organ and contains androgen receptor mRNA. androgen receptor protein within the nuclei of its acinar epithelial cells and 5a-reductase mRNA;

we and others have found treatment of rabbits. dogs and/or humans with topical androgens influences the quality of meibomian gland secretions. stimulates the production and release of meibomian gland lipids, and prolongs the tear film breakup time (i.e., promotes tear film stability);

we have discovered that androgen deficiency in humans appears to be associated with meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, a decreased
tear film breakup time, and functional dry eye.'

Overall, these findings indicate that topical androgen application to the ocular surface may well serve as a possible therapy for meibomian gland dysfunction and its associated evaporative dry eye syndromes in androgen-deficient patients.

HUMAN INTEREST AND FUTURE DIRECTIONS

Dry eye syndromes are not only painful, they may also seriously impact one's quality of life. A woman with dry eye in Florida rarely leaves her house during the day because she is extremely sensitive to sunlight (photophobia). A woman with dry eye who lives along the East coast would love to stand on a boardwalk, watch the Atlantic surf crash on the beach and feel the ocean wind but she cannot. because even the smallest breeze hurts her eyes. A young woman, who was a financial planner in New York City, is now on the disabled list because her dry eyes prevent her from performing the necessary computer work. And a young man, who is a retinal surgeon in New Orleans. believes that he may soon have to seek another profession because his dry eyes seriously interfere with his ability to focus during surgery.

Although dry eye syndromes may occur in anyone. the majority of people with this problem are females. This gender-related prevalence is not surprising, given that individuals with primary and secondary (e.g., systemic lupus erythematosus. rheumatoid arthritis) Sjogren's syndrome are almost all women, and that these autoimmune disorders are among the most frequent causes of aqueous deficient dry eye. Moreover, the evaporative dry eye that may occur during menopause is a condition uniquely female.

Our belief is that the recognition of these gender-related differences in disease susceptibility, as well as the determination of their underlying basis, is extremely important. We also believe that such understanding may be translated into the development of new and unique therapeutic strategies to treat diverse ocular disorders. Our research results to date appear to give credence to these beliefs, and may soon lead to a novel, topical androgen treatment for both aqueous deficient and evaporative dry eye. Given that gender also influences the incidence of several blinding diseases, including certain types of glaucoma, macular holes and macular degeneration, it may be that future research into the nature and extent of this gender impact may result in new insight into the etiology, progression and treatment of these disorders.

REFERENCES

(1) Dartt DA. Physiology of tear production. In: Lemp MA, Marquardt R (eds): The Dry Eye. Berlin: SpringerVerlag. 1992:65-99. (2) Lemp MA. Report of the National Eye Institute/Industry Workshop on clinical trials in dry eyes. CLAO J 1995;21:221-232. (3) Homma M. Sugai S. Tojo T, Miyasaka N, Akizuki M (eds). Sjogren's Syndrome. State of the Art. Amsterdam: Kugler Press, 1994. (4) Driver PJ, Lemp MA. Meibomian gland dysfunction. Surv Ophthalmol 1996;40:343-367. (5) Sullivan DA, Wickham LA, Krenzer KL, Rocha EM. Toda I. Aqueous tear deficiency in Sjogren's syndrome: Possible causes and potential treatment. In: Pleyer U, Hartmann C and Sterry W (eds): Oculodermal Diseases-Immunology of Bullous Oculo-Muco-Cutaneous Disorders. Buren, The Netherlands: Aeolus Press, 1997:95-152. (6) Sullivan DA, Wickham LA, Rocha EM, Silveira LA, Toda 1. Influence of gender and sex steroid hormones on the structure and function of the lacrimal gland. Adv Exp Med Biol 1997; in press. (7) Wickham LA, Gao J, Toda 1. Rocha EM, Sullivan DA. Identification of androgen, estrogen and progesterone receptor mRNAs in rat, rabbit and human ocular tissues. Submitted for publication, 1997. (8) Rocha EM, Wickham LA, Silveira LA, Krenzer KL. Toda I, Sullivan DA. Identification of androgen receptor protein and 5a-reductase mRNA in human ocular tissues. Submitted for publication, 1997. (9) Sullivan DA, Krenzer KL, Ullman MD, Wickham LA. Toda I, Bazzinotti D. Dana MR. Androgen control of the meibomian gland. Submitted for publication, 1997. (10) Cavallero C. Relative effectiveness of various steroids in an androgen assay using the exorbital lacrimal gland of the castrated rat. Acta Endocrinol (Copenh) 1992:55:119-130. (11) Winderickx J, Vercaeren I. Verhoeven G, Heyns W. Androgen-dependent expression of cystatin-related protein (CRP) in the exorbital lacrimal gland of the rat. J Steroid Biochem Molec Biol 1994:48:165-170. (12) Mircheff AK. Understanding the causes of lacrimal insufficiency: implications for treatment and prevention of dry eye syndrome. In: Research to Prevent Blindness Science Writers Seminar. New York: Research to Prevent Blindness, 1993:51-54. (13) Xu G, Shang H, Zhu F. Measurement of serum testosterone level in female patients with dry eye. Proc Intl Congress Ophthalmol (Abstract) 1994. (14) Kollock CW. Diseases and functional disorders of the eye, produced by normal and abnormal conditions of the sexual organs. Trans South Carolina Med Assoc 1888: 97-102. (15) Ansar Ahmed S, Talal N. Sex hormones and the immune system-part 2. Animal data. Bailliere's Clin Rheum 1990: 4:13-31. (16) Sullivan DA. Sex hormones and Sjogren's syndrome. J Rheumatology Supplement. In: Parke AL. Tanzer JM. Donshik P (eds). Proceedings of the VI International Symposium on Sjogren's Syndrome (Connecticut, 10/97). 1997. in press. (17) Sullivan DA. Ocular mucosal immunity. In: Ogra PL. Mestecky J, Lamm ME. Strober W, McGhee J. Bienenstock J (eds): Handbook of Mucosal Immunology. 2nd Edition. Orlando. FL: Academic Press. 1997. in press. (18) Rocha EM, Wickham LA. Huang Z, Toda 1. Gao J, Silveira LA, Sullivan DA. Presence and testosterone influence on the levels of anti- and pro-inflammatory cytokines in lacrimal tissues of a mouse model of Sjogren's syndrome. Adv Exp Med Biol 1997: in press. (19) Toda 1, Wickham LA, Sullivan DA. Influence of gender and androgen treatment on the mRNA expression of proto-oncogenes and apoptotic factors in lacrimal and salivary tissues of the MRLJIpr mouse model of Sjogren's syndrome. Submitted for publication, 1997. (20) Toda I. Wickham LA, Sullivan DA. Gender and androgen-related influence on the expression of proto-oncogene and apoptotic factor mRNAs in lacrimal glands of autoimmune and non-autoimmune mice. Submitted for publication, 1997. (21) Br ickner R. Uber einem erfolgreich mit perandren behandelten fall von Sjogren'schem symptomen komplex. Ophthalmologica 1945:110:37-42. (22) Appelmans M. La Kerato-conjonctivite seche de Gougerot-Sjogren. Arch 'Ophralmologie 1948;81:577-588. (23) Bizzarro A, Valentine G, Di Marino G. Daponte A. De Bellis A, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter's syndrome. J Clin End Metab 1987;64:32-36. (24) Thody AJ, Shuster S. Control and function of sebaceous glands. Physiol Rev 1989:69:383-416. (25) Zeligs MA. Gordon K. Dehydroepiandrosterone therapy for the treatment of dry eye disorders. Int Patent Application WO 94/04155, March. 1994.

December 27, 2007