Sex hormones can affect the ocular surface contributing to dry eye. This article will summarise these effects on different ocular tissues and provide practitioners with information of sex hormone synthesis outlining implications for the patient
Clinicians are all too familiar with the frequent complaint of dry eye from their patients. Major risk factors for developing dry eye include female sex and increasing age;1 the greater prevalence of dry eye in women suggests that sex hormones may play a role in this condition.
The effect of oestrogen on dry eye is by no means straightforward and the results from published studies are equivocal. During the follicular phase of the menstrual cycle, when oestrogen levels peak, impairment of tear stability and tear production as well as increased ocular surface dryness and inflammation have all been found to be higher.2 However, oestrogen has been shown to be beneficial in reducing symptoms of dry eye and increasing lacrimal secretion for post-menopausal women on hormone replacement therapy (HRT).3
As well as having an effect on ocular surface disease, sex steroid imbalance has also been shown to be related to onset and development of cardiovascular disease,4 osteoporosis,5 neurodegenerative disease,6 and obesity.7
The aim of this article is to summarise current findings into the effect of hormones on different ocular structures involved in dry eye.
Sex hormone biosynthesis
Sex hormones are steroids, produced mainly by the gonads and adrenal glands and secreted into circulation. Oestrogen is produced by the ovaries in females, and in a smaller amount by the testes in males and by the adrenals in both sexes. Conversely, androgens are produced mainly by the testes and in smaller amounts by the ovaries and adrenal glands. The ovaries, testes and adrenal glands are endocrine glands, using cholesterol as a precursor for androgen, oestrogen and progesterone production (see Figure 1: Endocrinology formation of hormones).
Sex hormones are also produced locally in tissues by intracrinology which is the transformation of inactive precursors DHEA and DHEA-S into active sex hormones (see Figure 2: Intracrinology hormone formation).8 Unlike endocrinology, during intracrinology the hormones exert their action and are inactivated all within the same tissue in which they were produced, avoiding release of active sex hormones into circulation.8 Intracrinology allows for local control of hormone levels, according to local requirements.9 Humans and other primates are unique in their ability to produce sex hormones by intracrinology by having target tissues equipped with the biomechanical machinery needed for intracrinology: high levels of DHEA-S and DHEA as well as the enzymes needed to convert them to active sex steroids.10 The human ocular tissues are among the target tissues equipped for intracrine synthesis and metabolism of oestrogens and androgens.11
Oestrogen production by intracrinology is estimated to be 75% pre-menopause, increasing to 100% post-menopause.8 In men, 50% of testosterone is produced by the testes, with the remaining 50% produced by the transformation of DHEA and DHEA-S into active androgens, testosterone and DHT, in the prostate.12
Menopause: evolution's protection
Post-menopausal women are a key patient group presenting in routine practice with dry eye symptoms. In a study involving over 25,000 men and almost 40,000 women, dry eye in the 50 years and over group was found to be 70% higher in women than men.13
Although menopause is often looked on negatively in relation to its associations with increased bone loss, hot flushes, fat accumulation, vulvovaginal atrophy, skin atrophy, type 2 diabetes and cognition problems,14 menopause is actually an evolutionary way to extend the lifespan of women.10 The cessation of oestrogen secretion at menopause results in circulating oestrogen levels being below biologically active levels which eliminates stimulation of the endometrium and the risk of endometrial hyperplasia and cancer.15 Oestrogen and androgen production needs to continue post-menopause as many tissues need oestrogen for normal function; for this, high levels of circulating DHEA are needed as well as possession by peripheral tissues of the enzymes required to convert DHEA into oestrogens and androgens.10 Intracrinology formation of oestrogens has been found in tissues throughout the body, including the brain, skin, bone and adipose tissue. In the endometrium there is an absence of the enzymes needed to transform DHEA to oestrogens,.6 thus intracrinology and the lack of it in the endometrium, protects from endometrial hyperplasia and cancer which would occur with non-opposed oestrogen stimulation. However, 75% of post-menopausal women have insufficient levels of DHEA and thus suffer from signs and symptoms of hormone deficiency.10
Recap of the tear film secretions
The inner hydrophobic mucin layer is mainly produced by the goblet cells of the conjunctiva, the middle aqueous layer is produced by the lacrimal glands (main and accessory) and the meibomian glands produce the outer lipid layer. Homeostasis is maintained via neural and hormonal regulation.
The higher prevalence of Sjögren’s syndrome in females than males has been accredited to hormones and their different effects on immune responses; 90% of Sjögren’s syndrome sufferers are women.16
Sjögren’s syndrome involves a change in the androgen-oestrogen ratio – without the anti-inflammatory effect of androgens in these androgen deficient patients, excessive amounts of inflammation occur. Patients suffering from the condition complain of severe dry eye. However, androgen deficiency without autoimmune disease, such as in men taking anti-androgen medication, is not related to lacrimal gland inflammation.
The meibomian gland is a target organ for androgens.17 A main function of the lipid produced by the meibomian glands is to impede tear evaporation. Other functions include: providing a smooth optical surface; improving tear stability and spreading; preventing tear film contamination; sealing the lid margins during sleep; and preventing tears spilling over the lid margin.18 Low androgen levels, such as in those who are androgen deficient or using androgen antagonists, can result in reduced quality and quantity of meibomian lipids which is seen clinically as increased tear film instability and reduced tear break-up time (TBUT).19 Since androgen levels are lower in women than men and decrease with age in both sexes, this could explain the increased prevalence of dry eye symptoms in women and with advancing age.10
Androgens upregulate expression of genes responsible for meibomian lipid production, whereas oestrogens suppress genes with these functions and upregulate genes which have the opposite effect.20 It is suggested that oestrogens do not have a direct effect on their receptors in meibomian glands, instead they antagonise androgen action.21 Consequently it may be the reduction of androgen action rather than the increased oestrogen action that is responsible for meibomian gland dysfunction and evaporative dry eye.22
The main function of the lacrimal glands is to secrete the aqueous component of the tear film, which as well as water also contains electrolytes and proteins. Inflammatory changes of the lacrimal gland in patients with androgen deficiencies in autoimmune disease such as Sjögren’s syndrome results in aqueous deficient dry eye.23 In contrast, studies with men taking anti-androgen medications have shown no change in tear secretion;24 this suggests androgen action on the lacrimal gland may be sex specific. Animal studies using rat lacrimal glands found androgen reduction led to the lacrimal gland becoming more like that of female rats. Conversely, testosterone treatment for female and castrated rats induced changes in appearance of the gland to that of intact male rats.20
The effect of oestrogens and progesterone on the lacrimal gland remains uncertain. Some studies found these hormones to have an anti-inflammatory effect, while others suggest that they have a pro-inflammatory role, such as in autoimmune disease, within the lacrimal gland, as reviewed by Sullivan.25
Genes involved in intracrine synthesis and metabolism of sex hormones have been found to be expressed in the human lacrimal and meibomian glands, as well as in corneal and conjunctival epithelial cells.11
The cornea and conjunctival epithelium are sensitive to changes over the course of the menstrual cycle. Since testosterone levels remain relatively stable over the menstrual cycle these structural and functional changes have been attributed to changes in oestrogen and progesterone levels.3 Corneal sensitivity is decreased during the oestrogen peak of the menstrual cycle.26 Elevated oestrogen levels, seen during the follicular phase of the menstrual cycle and with HRT post-menopause, corresponds with increased goblet cell density and maturation of conjunctival cells.27 Androgen levels have also been shown to affect the ocular surface with a study showing that women with complete androgen insufficiency syndrome (CAIS) had reduced mucin expression, perhaps due to compromised conjunctival goblet cell function.27 These changes demonstrate the effects of hormones on the ocular surface, which are important to consider when forming management plans with patients. The cornea has been shown to express oestrogen and progesterone receptors; these hormones may be available to the cornea via the tear film.28
The menstrual cycle allows monitoring of changes with the natural increase and decrease of hormones. In a normal menstrual cycle the follicular phase (day 1–14) sees a gradual increase in oestrogen levels with low progesterone levels; ovulation occurs mid cycle, with the oestrogen peak; the luteal phase sees an increase in progesterone levels and a shallower rise in oestrogen levels (see Figure 3: Menstrual cycle).
There are few studies that have evaluated ocular changes across the menstrual cycle and most have small sample sizes. The dichotomy of presenting signs and symptoms of dry eye during the menstrual cycle is demonstrated by a study which found symptoms to be increased in the luteal phase of the menstrual cycle, whereas TBUT and inflammation were worse in the follicular phase.2
Research into hormone replacement therapy is inconclusive. Some studies show hormone therapy to exacerbate symptoms, others show them to be beneficial in relieving symptoms, while some show no effect of oestrogen treatment on dry eye.22
Hormonal contraceptives, such as the oral contraceptive pill (OCP) work by keeping oestrogen and/or progesterone levels high, preventing ovulation with the lowest levels required to prevent ovulation used to limit systemic effects. Contraceptive use of synthetic oestrogen and/or progesterone does not appear to be related to increased symptoms or affect tear osmolarity,29 break up time or volume.30
In studies monitoring post-menopausal women, HRT administration was shown to promote dry eye symptoms in previously asymptomatic patients, with no symptom relief in dry eye patients.31 These negative findings of oestrogen on dry eye are supported by a large population study of over 25,000 women: HRT was associated with increased prevalence of dry eye (either severe symptoms or clinically diagnosed by an optometrist); longer duration of HRT use was also found to increase dry eye risk.32 In the same study, post-menopausal women who had never taken HRT were at the same risk of dry eye as pre-menopausal women. Oestrogen-only treatment showed greater risk for dry eye signs and symptoms than combined oestrogen-progesterone therapy.
On the other hand, there are studies which have found HRT to improve symptoms of dry eye and increase tear volume and improve symptoms,3 and also to improve TBUT and Schirmer’s test tear volume following the decrease associated with menopause.33
HRT was found to significantly reduce meibomian gland inflammation.34 Explanation for the conflicting results may be that HRT effect on dry eyes isn’t a one-size-fits-all conclusion with various factors affecting the influence including: age at onset of treatment; duration of treatment; type of treatment (oestrogen alone or combination); dose and duration; study design – use of control and masking.
Although not the main focus of this article, the posterior eye should be considered in order to give a sense of the widespread effects of sex hormones. Using animal and human studies, oestrogen, androgen and progesterone receptor mRNA have been found in various tissues of the eye with sex steroid hormone receptors isolated in the human cornea, lacrimal gland, meibomian gland, conjunctiva, lens, iris, ciliary body and retina.35 The presentation of these receptor mRNAs varies depending on sex and tissue involved.35
Primary open angle glaucoma in the under 50 age group has higher incidence in men than women; post-menopause the incidence levels in women reaches that in men; the influence of female sex hormones has been implicated as a reason for this change in incidence.36
Oestrogen may have direct effect upon the eye as seen by increased incidence of many ocular pathologies including: age-related cataract and dry eye are found to be higher in females than men; angle closure glaucoma is higher in women over 40 compared to age-matched men; idiopathic full thickness macular hole is found to be more prevalent in post-menopausal women than men or pre-menopausal women; central serous retinopathy is higher in pregnant women than men and non-pregnant women; and neovascular AMD is higher in menopausal women than age-matched men.35
The Beaver Dam Study found the use of HRT reduces the risk of severe nuclear sclerosis in post-menopausal women.37 Studies have found intraocular pressure (IOP) in post-menopausal women is higher than pre-menopause; they also found that treatment with HRT reduced the IOP back to pre-menopausal levels,33 which adds to the lack of uniformity in hormone therapy effect within the eye.
This article has shown that understanding hormones is not simple. Large population studies are needed as well as more sensitive hormone measurement. However, it is clear that hormones don’t have the same effect on each tissue and many effects are sex dependent.
Ocular disorders are treated the same in males and female patients, and consideration of the dimorphism is important for specific treatment. A large proportion of research into this area involves animal studies, so care needs to be taken when relating these findings to human models since these lower animal species do not synthesise hormones locally by intracrinology as humans do.
With there being so many dichotomies in the current research, it is impossible to come to a clear conclusion with advice we can give to our patients regarding the effect of hormones and therapy on dry eye disease: signs and symptoms of dry eye do not correlate; HRT is found to be beneficial or detrimental in different studies; oestrogen is both pro- and anti-inflammatory in different conditions. With increased life expectancy, women spend about 40% of their lives post-menopausal. Although we cannot give our patients definitive answers, in the future it may be possible to counteract the menopausal ocular effects of dry eye using hormone therapy. Rather than shying away from talks about OCP and HRT, as practitioners we should use these opportunities to discuss dry eye symptoms. A key point to remember is not to tell patients to stop taking any medication before consulting their medical practitioner.
About the authors
Emma Gibson is an optometrist who is currently undertaking a research doctorate at the University of New South Wales in Sydney, investigating whether oestrogen levels in tears affects evaporative dry eye. Professor Fiona Stapleton is the head of the School of Optometry and Vision Science at the University of New South Wales. Professor Stapleton graduated in optometry from Cardiff University and received her PhD from City University London and Moorfields Eye Hospital.
- Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol. 2009;3:405-412
- Versura P, Fresina M, Campos EC. Ocular surface changes over the menstrual cycle in women with and without dry eye. Gynecol Endocrinol. 2007;23(July):385-390. doi:10.1080/09513590701350390
- Affinito P, Di Spiezio Sardo A, Di Carlo C, et al. Effects of hormone replacement therapy on ocular function in postmenopause. Menopause. 2003;10(5):482-487. doi:10.1097/01.GME.0000063568.84134.35
- Traish AM, Kypreos KE. Testosterone and cardiovascular disease: An old idea with modern clinical implications. Atherosclerosis. 2011;214(2):244-248. doi:10.1016/j.atherosclerosis.2010.08.078
- Manolagas SC, Kousteni S, Jilka RL. Sex steroids and bone. Recent Prog Horm Res. 2002;57(1):385-409. doi:10.1210/rp.57.1.385
- Vest RS, Pike CJ. Gender, sex steroid hormones, and Alzheimer’s disease. Horm Behav. 2013;63(2):301-307. doi:10.1016/j.yhbeh.2012.04.006
- Lovejoy JC. The influence of sex hormones on obesity across the female life span. J Womens Health. 1998;7(10):1247-1256. doi:10.1089/jwh.1998.7.1247
- Labrie F. Intracrinology. Mol Cell Endocrinol. 1991;78:C113-C118. doi:10.1016/0303-7207(91)90116-A
- Labrie F, Bélanger A, Bélanger P, et al. Metabolism of DHEA in postmenopausal women following percutaneous administration. J Steroid Biochem Mol Biol. 2007;103:178-188. doi:10.1016/j.jsbmb.2006.09.034
- Labrie F, Labrie C. DHEA and intracrinology at menopause, a positive choice for evolution of the human species. Climacteric. 2013;16:205-213. doi:10.3109/13697137.2012.733983
- Schirra F, Suzuki T, Dickinson DP, Townsend DJ, Gipson IK, Sullivan D a. Identification of steroidogenic enzyme mRNAs in the human lacrimal gland, meibomian gland, cornea, and conjunctiva. Cornea. 2006;25(4):438-442. doi:10.1097/01.ico.0000183664.80004.44
- Labrie F. Adrenal androgens and intracrinology. Semin Reprod Med. 2004;22:299-309. doi:10.1055/s-2004-861547
- Schaumberg D a, Dana R, Buring JE, Sullivan D a. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 2009;127(6):763-768. doi:10.1001/archophthalmol.2009.103
- Labrie F. All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. J Steroid Biochem Mol Biol. 2014;145:133-138. doi:10.1016/j.jsbmb.2014.06.001
- Labrie F. DHEA, Important Source of Sex Steroids in Men and Even More in Women. Elsevier B.V.; 2010:97-148. doi:10.1016/S0079-6123(10)82004-7
- SSF. Dry Eye: A hallmark symtom of Sjogren’s syndrome. Sjogren’s Syndr Found. www.sjogrens.org/files/brochures/ssf_dryeye_brochure.pdf. Accessed October 20, 2015
- Sullivan D a., Sullivan BD, Ullman MD, et al. Androgen influence on the meibomian gland. Investig Ophthalmol Vis Sci. 2000;41(12):3732-3742
- Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocul Surf. 2003;1(3):107-126. doi:10.1016/S1542-0124(12)70139-8
- Krenzer KL, Dana MR, Ullman MD, et al. Effect of androgen deficiency on the human meibomian gland and ocular surface. J Clin Endocrinol Metab. 2000;85(12):4874-4882. doi:10.1210/jc.85.12.4874
- Sullivan D a, Jensen R V, 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(June):1553-1572
- Azzi L, El-Alfy M, Labrie F. Gender differences and effects of sex steroids and dehydroepiandrosterone on androgen and oestrogen alpha receptors in mouse sebaceous glands. Br J Dermatol. 2006;154(v):21-27. doi:10.1111/j.1365-2133.2005.06847.x
- Truong S, Cole N, Stapleton F, Golebiowski B. Sex hormones and dry eye. Clin Exp Optom. 2014;97:324-336
- Sullivan DA, Bélanger A, Cermak JM, et al. Are Women with Sjögren ’ s Syndrome Androgen- Deficient ? 2003;30(11)
- Sullivan D, Krenzer K, Sullivan B, Tolls D, Toda I, Dana M. Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency? Invest Ophthalmol Vis Sci X. 1999;40:1261-1265
- Sullivan D a. Tearful relationships? Sex, hormones, the lacrimal gland, and aqueous-deficient dry eye. Ocul Surf. 2004;2(2):92-123. doi:10.1016/S1542-0124(12)70147-7
- Guttridge NM. Changes in ocular and visual variables during the menstrual cycle. Ophthalmic Physiol Opt. 1994;14:38-48
- Bonini S, Mantelli F, Moretti C, Lambiase A, Bonini S, Micera A. Itchy-Dry Eye Associated with Polycystic Ovary Syndrome. Am J Ophthalmol. 2007;143. doi:10.1016/j.ajo.2007.01.030
- Suzuki T, Kinoshita Y, Tachibana M, et al. Expression of sex steroid hormone receptors in human cornea. Curr Eye Res. 2001;22(1):28-33. doi:10.1076/ceyr.18.104.22.16880
- Chen SP, Massaro-Giordano G, Pistilli M, Schreiber C a., Bunya VY. Tear Osmolarity and Dry Eye Symptoms in Women Using Oral Contraception and Contact Lenses. Cornea. 2012;32(4):423-428. doi:10.1097/ICO.0b013e3182662390
- Tomlinson a, Pearce EI, Simmons P a, Blades K. Effect of oral contraceptives on tear physiology. Ophthalmic Physiol Opt. 2001;21(1):9-16. doi:10.1046/j.1475-1313.2001.00544.x
- Erdem 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. doi:10.1016/j.maturitas.2006.08.007
- Schaumberg D a, Buring JE, Sullivan D a, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA. 2001;286(17):2114-2119. doi:10.1001/jama.286.17.2114.Text
- Altintaş Ö, Çaǧlar Y, Yüksel N, Demirci A, Karabaş L. The effects of menopause and hormone replacement therapy on quality and quantity of tear, intraocular pressure and ocular blood flow. Ophthalmologica. 2004;218:120-129. doi:10.1159/000076148
- Kuscu NK, Toprak AB, Vatansever S, Koyuncu FM, Guler C. Tear function changes of postmenopausal women in response to hormone replacement therapy. Maturitas. 2003;44:63-68. doi:10.1016/S0378-5122(02)00316-X
- Gupta PD, Johar K, Nagpal K, Vasavada a. R. Sex hormone receptors in the human eye. Surv Ophthalmol. 2005;50(3):274-284. doi:10.1016/j.survophthal.2005.02.005
- Meyer EJ, Leibowitz H, Christman EH, Niffenegger J a. Influence of norethynodrel with mestranol on intraocular pressure in glaucoma. Arch Ophthalmol. 1966;75:157-161. doi:10.1001/archopht.1966.00970050773011
- 37 Klein B, Klein R, Ritter L. Is there evidence of an estrogen effect on age-related lens opacities? The Beaver Dam Eye Study. Arch Ophth. Arch Ophthalmol. 1994;112:85-91