Dr Blanka Golebiowski
Research Fellow, School of Optometry and Vision Science, UNSW
Dry eye is a common and chronic problem, with a significant impact on quality of life due to its adverse effects on ocular comfort and vision. Dry eye is more common in women than men,1 especially in women after menopause. It is likely that alterations in the levels and balance of circulating sex hormones are involved; however, the mechanisms of how sex hormones regulate dry eye are not completely understood.
Whereas evidence suggests that circulating androgens are important in the maintenance of the tear film and ocular surface health, with an anti-inflammatory role in dry eye, our understanding of the role of oestrogens lacks consensus. The endocrine system influences homeostasis and pathophysiology of disease of the lacrimal glands, meibomian glands, and the corneal and conjunctival epithelia. Sex hormones appear to regulate the immune and secretory functions of these tissues. Receptors and receptor mRNA for androgens, oestrogens and progesterone as well as steroidogenic enzymes have been identified in several ocular tissues.2-7
There is considerable evidence supporting a positive influence of androgen on lacrimal gland secretion; it is also likely to have an anti-inflammatory role in that tissue.8-10 Androgens promote the production of lipids by the meibomian glands,11 and androgen deficiency may cause meibomian gland disease.8,12-15 Although administration of topical and systemic androgen therapy is reported to improve signs and symptoms of dry eye in patients with Sjögren’s syndrome and dry eye,8,16-20 this is yet to be confirmed in controlled trials.
To date, no prospective clinical intervention trials have been published that investigate effects of systemic or topical androgen treatment on the signs or symptoms of dry eye. Two retrospective case series describe improved dry eye symptoms after transdermal androgen patch therapy in women with low testosterone21 and following combined androgen and oestrogen therapy in post-menopausal women.20
Similarly, in a case report, treatment with testosterone cream applied to the eyelids appeared to normalise tear lipid layer thickness and stability.19 Conversely, systemic anti-androgen therapy appears to reduce tear stability and increase meibomian gland dysfunction.12 Trials of systemic supplementation with the androgen precursor DHEA have shown equivocal results in Sjögren’s patients, with no improvement in dry eye symptoms or tear function up to nine months of treatment.22-23
In contrast to androgen, the role of oestrogen in dry eye is not well-defined, with apparently contradictory effects in different tissues of the ocular surface and at different circulating oestrogen levels. Evidence from animal work and human in vitro studies suggests that oestrogen inhibits meibomian gland secretion,8 where it may also promote inflammation.24,25 The role of oestrogen in corneal epithelia and in regulation of the lacrimal gland is unclear; in both tissues it has been shown to have both a pro- and an anti-inflammatory effect. (See Truong et al 201431 for review).
The clinical evidence for the effect of oestrogen is similarly inconclusive. Higher blood oestrogen levels in post-menopausal women have been associated with reduced tear secretion,26 and the oestrogen peak in the menstrual cycle results in increased symptoms of dry eye.27
The relatively common use of hormone replacement therapy (HRT) in post-menopausal women has facilitated numerous studies into the effects of oestrogen and/or progesterone supplementation (Table 1).
Table 1. Summary of previously published controlled studies reporting the effects of oestrogen treatment on dry eye (reviewed in Truong et al 201438)
* Subjective symptoms are not reliable where study has not been placebo controlled
A large population-based study of post-menopausal women showed increased risk of dry eye for women using HRT, particularly with oestrogen-only therapy.28 The risk of dry eye was greater with longer duration of HRT use. These findings are supported by two smaller clinical studies that show oestrogen and/or progesterone intervention to worsen dry eye signs and possibly symptoms.29,30
Other clinical evidence indicates that HRT improves dry eye symptoms and tear function or that it has no effect (reviewed in Truong et al 201431). Of note, two studies of topical oestrogen applied to the ocular surface or ocular adnexa report an improvement in tear function and symptoms.
Oestrogen and/or progesterone supplementation in pre-menopausal women using the contraceptive pill has likewise not been found to negatively impact ocular symptoms or tear function.32-34
These contradictions may be explained by a differential action of oestrogen on different tissues of the ocular surface in which inflammatory mechanisms are mediated by distinct pathways (for example T- versus B-cell mediated responses)35,36 but this has yet to be shown in the eye.
A better understanding and clarification of the mechanism of action of sex hormones on the ocular surface is essential to enable development of hormone based therapeutic strategies for dry eye. In addition, publication of well-designed treatment studies is critical to confirm the impact of both oestrogen-based and androgen-based therapy in dry eye. Regardless, the literature as it stands indicates that treatment with androgen and/or oestrogen shows promise and may play an important role in dry eye management in the future.
- The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye Workshop. Ocul Surf 2007; 5: 93-107.
- Rocha EM, Wickham LA, Silveira d LA, Krenzer KL, Yu FS, Toda I, Sullivan BD, Sullivan DA. Identification of androgen receptor protein and 5alpha-reductase mRNA in human ocular tissues. Br J Ophthalmol 2000; 84: 76-84.
- Schirra F, Suzuki T, Dickinson DP, Townsend DJ, Gipson IK, Sullivan DA. Identification of steroidogenic enzyme mRNAs in the human lacrimal gland, meibomian gland, cornea, and conjunctiva. Cornea 2006; 25: 438-442.
- Wickham LA, Gao J, Toda I, Rocha EM, Ono M, Sullivan DA. Identification of androgen, estrogen and progesterone receptor mRNAs in the eye. Acta Ophthalmol Scand 2000; 78: 146-153.
- Sullivan DA, Edwards JA, Wickham LA, Pena JD, Gao J, Ono M, Kelleher RS. Identification and endocrine control of sex steroid binding sites in the lacrimal gland. Curr Eye Res 1996; 15: 279-291.
- Suzuki T, Kinoshita Y, Tachibana M, Matsushima Y, Kobayashi Y, Adachi W, Sotozono C, Kinoshita S. Expression of sex steroid hormone receptors in human cornea. Curr Eye Res 2001; 22: 28-33.
- Fuchsjäger-Mayrl G, Nepp J, Schneeberger C, Sator M, Dietrich W, Wedrich A, Huber J, Tschugguel W. Identification of estrogen and progesterone receptor mRNA expression in the conjunctiva of premenopausal women. Invest Ophthalmol Vis Sci 2002; 43: 2841-2844.
- Sullivan DA. Sex and sex steroid influence on dry eye syndromes. In: Pflugfelder S, Beuerman R, Stern ME, eds. Dry Eye and Ocular Surface Disease. New York City, NY: Marcel Dekker Inc, 2004. p 165-190.
- Sullivan DA, Kelleher RS, Vaerman JP, Hann LE. Androgen regulation of secretory component synthesis by lacrimal gland acinar cells in vitro. J Immunol 1990; 145: 4238-4244.
- Sato EH, Sullivan DA. Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjögren’s syndrome. Invest Ophthalmol Vis Sci 1994; 35: 2632-2642.
- Sullivan DA, Sullivan BD, Ullman MD, Rocha EM, Krenzer KL, Cermak JM, Toda I, Doane MG, Evans JE, Wickham LA. Androgen influence on the meibomian gland. Invest Ophthalmol Vis Sci 1994; 41: 3732-3742.
- Krenzer KL, Dana RM, Ullman MD, Cermak JM, Tolls DB, Evans JE, Sullivan DA. Effect of androgen deficiency on the human meibomian gland and ocular surface. J Clin Endocr Metab 2000; 85: 4874-4882.
- Cermak JM, Krenzer KL, Sullivan RM, Dana RM, Sullivan DA. Is complete androgen insensitivity syndrome associated with alterations in the meibomian gland and ocular surface? Cornea 2003; 22: 516-521.
- Sullivan DA, Sullivan BD, Evans JE, Schirra F, Yamagami H, Liu M, Richards SM, Suzuki T, Schaumberg DA, Sullivan RM, Dana RM. Androgen deficiency, meibomian gland dysfunction, and evaporative dry eye. Ann N Y Acad Sci 2002; 966: 211-222.
- Sullivan BD, Evans JE, Dana RM, Sullivan DA. Influence of aging on the polar and neutral lipid profiles in human meibomian gland secretions. Arch Ophthalmol 2006; 124: 1286-1292.
- Connor C, Karkkainen T. The efficacy of androgenic artificial tears in the treatment of dry eye. Optom Vis Sci 2001; Supplement: S123.
- Connor CG. Reduction in dry eye symptoms after treatment with transdermal sex hormone creams. Optom Vis Sci 2007; Supplement: S.
- Connor CG, Primo EJ. A weak androgenic artificial tear solution decreases the osmolarity of dry eye patients. Invest Ophthalmol Vis Sci 2001; 42: ARVO Abstract 170.
- Worda C, Nepp J, Huber JC, Sator MO. Treatment of keratoconjunctivitis sicca with topical androgen. Maturitas 2001; 37: 209-212.
- Scott G, Yiu SC, Wasilewski D, Song J, Smith RE. Combined esterified estrogen and methyltestosterone treatment for dry eye syndrome in postmenopausal women. Am J Ophthalmol 2005; 139: 1109-1110.
- Nanavaty AM, Long M., Malhotra R. Transdermal androgen patches in evaporative dry eye syndrome with androgen deficiency: a pilot study. Br J Ophthalmol 2014; 98: 567-569.
- Forsblad-d’Elia H, Carlsten H, Labrie F, Konttinen YT, Ohlsson C. Low serum levels of sex steroids are associated with disease characteristics in primary Sjögren’s syndrome; supplementation with dehydroepiandrosterone restores the concentrations. J Clin Endocr Metab 2009; 94: 2044-2051.
- Pillemer RS, Brennan TM, Sankar V, Leakan AR, Smith AJ, Grisius M, Ligier S, Radfar L, Kok RM, Kingman A, Fox CP. Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren’s syndrome. Arthritis Rheum 2004; 51: 601-604.
- Sullivan DA, Jensen RV, Suzuki T, Richards SM. Do sex steroids exert sex-specific and/or opposite effects on gene expression in lacrimal and meibomian glands? Mol Vis 2009; 15: 1553-1572.
- Suzuki T, Schirra F, Richards SM, Jensen RV, Sullivan DA. Estrogen and progesterone control of gene expression in the mouse meibomian gland. Invest Ophthalmol Vis Sci 2008; 49: 1797-1808.
- Mathers WD, Stovall D, Lane JA, Zimmerman MB, Johnson S. Menopause and tear function: the influence of prolactin and sex hormones on human tear production. Cornea 1998; 17: 353-358.
- Versura, P, Fresina, M, Campos, E.C. Ocular surface changes over the menstrual cycle in women with and without dry eye. Gynecol Endocrinol. 2007; 23(7):385-390.
- Schaumberg DA, Buring JE, Sullivan DA, Dana RM. Hormone replacement therapy and dry eye syndrome. JAMA 2001; 286: 2114-2119.
- Erde U, Ozdegirmenci O, Sobaci E, Sobaci G, Göktolga U, Dagli S. Dry eye in post-menopausal women using hormone replacement therapy. Maturitas 2007; 56: 257-262.
- Shaharuddin, B., Ismail-Mokhtar, S.F., Hussein, E. Dry eye in post-menopausal Asian women on hormone replacement therapy. Int J Ophthalmol 2008; 1: 158-160.
- Truong S, Cole N, Stapleton F, Golebiowski B. Sex hormones and the dry eye. Clin Exp Optom 2014; 97: 324-336.
- Chen SP, Massaro-Giordano G, Pistilli M, Schreiber CA, Bunya VY. Tear osmolarity and dry eye symptoms in women using oral contraception and contact lenses. Cornea 2013; 32: 423-428.
- Idu FK, Emina MO, Ubaru CO. Tear secretion and tear stability of women on hormonal contraceptives. J Optom 2013; 06: 45-50.
- Tomlinson A, Pearce IE, Simmons AP, Blades K. Effect of oral contraceptives on tear physiology. Ophthalmic Physiol Opt 2001; 21: 9-16.
- Lang JT. Estrogen as an immunomodulator. Clin Immunol 2004; 113: 224-230.
- Straub HR. The complex role of estrogens in inflammation. Endocr Rev 2007; 28: 521-574.