Sex hormones and the dry eye.

C L I N I C A L

A N D

E X P E R I M E N T A L

OPTOMETRY REVIEW

Sex hormones and the dry eye Clin Exp Optom 2014 Susan Truong* BOptom hons BVisSci Nerida Cole*† PhD MSc BSc(hons) Fiona Stapleton* PhD MSc, BSc(Optom), MCOptom, DipCLP Blanka Golebiowski* PhD BOptom * The University of New South Wales, Kensington, New South Wales, Australia † University of Technology, Sydney, New South Wales, Australia E-mail: [email protected]

Submitted: 8 April 2013 Revised: 26 November 2013 Accepted for publication: 19 January 2014

DOI:10.1111/cxo.12147 The greater prevalence of dry eye in women compared to men suggests that sex hormones may have a role in this condition. This review aims to present evidence for how sex hormones may affect the ocular structures involved in the production, regulation and maintenance of the normal tear film. It is hypothesised that hormone changes alter the homeostasis of the ocular surface and contribute to dry eye. Androgens impact on the structure and function of the meibomian and lacrimal glands and therefore androgen deficiency is, at least in part, associated with the aetiology of dry eye. In contrast, reports of the effects of oestrogen and progesterone on these ocular structures and on the conjunctiva are contradictory and the mechanisms of action of these female-specific sex hormones in the eye are not well understood. The uncertainty of the effects of oestrogen and progesterone on dry eye symptoms is reflected in the controversial relationship between hormone replacement therapy and the signs and symptoms of dry eye. Current understanding of sex hormone influences on the immune system suggests that oestrogen may modulate a cascade of inflammatory events, which underlie dry eye.

Key words: androgen, dry eye, dry eye treatment, lacrimal gland, meibomian gland, ocular surface, oestrogen, progesterone, sex hormones, sex steroids, testosterone

A normal pre-ocular tear film is important for the protection of the ocular surface from infection and injury, acting both physically and immunologically to maintain a smooth refractive surface for optimum vision.1,2 Dry eye disease occurs where the tear film is compromised as a result of reduced aqueous tear production and/or excessive tear evaporation.3 Tear film function relies on the normal production of the constituents that comprise each of its three nominal layers. These constituents are produced by the ocular structures of the ‘lacrimal functional unit’: the inner hydrophilic mucin layer is produced mainly by conjunctival goblet cells and, to a lesser extent, conjunctival and corneal epithelial cells, the middle aqueous layer is produced by the main and accessory lacrimal glands and the outer lipid layer is secreted by the meibomian glands.4 Homeostasis is maintained through regulation by neuronal and hormonal mechanisms. Disruption to the functional unit, as a consequence of physiological or pathological local or systemic changes, and pharmacological or surgical interventions, can lead to a cycle of inflammatory events and the appearance of ocular surface disease, including dry eye.5

There is increasing evidence that dry eye is an immune-based inflammatory disease that affects the ocular surface and lacrimal glands.6–8 The ocular surface, that is, the tear film, corneal and conjunctival epithelia, conjunctival goblet cells and meibomian glands, together with the lacrimal glands (both main and accessory) and interconnecting neural reflex loops, act as an integrated ‘lacrimal functional unit’ to regulate tear production to maintain ocular surface wetting and integrity.5,9 Disturbance to any component of this unit compromises the neural feedback required to maintain tear film and ocular surface homeostasis.9,10 Loss of androgen support to the meibomian and lacrimal glands reduces the volume and/or stability of pre-ocular tears, decreasing the rate of tear turnover, increasing tear osmolarity and prolonging the exposure of the ocular surface to debris and microorganisms.5,11 Hyperosmolarity of the tear film stimulates synthesis and secretion of pro-inflammatory cytokines by the lacrimal gland and/or stressed ocular surface epithelia.12,13 The activation of inflammatory processes may subsequently impact neural function and disrupt the feedback mecha-

© 2014 The Authors Clinical and Experimental Optometry © 2014 Optometrists Association Australia

nism to the lacrimal gland, further impeding tear production and clearance. In contrast, oestrogens appear to promote such inflammatory processes in the meibomian gland,14–16 ocular surface epithelia17,18 and possibly the lacrimal gland;15,19,20 however, the role of oestrogen in dry eye is complex and remains unresolved. The most common treatments for dry eye aim to increase the amount of tears at the ocular surface by tear replacement with tear substitutes and lubricants or to improve tear retention by occlusion of the drainage system.21 However, such treatment is often palliative and inadequate in providing satisfactory relief from debilitating symptoms.21,22 Development of treatments directed at the underlying cause of dry eye is hampered by the difficulty in determining the exact pathophysiology of this multifactorial disease and the lack of standard diagnostic techniques. The inconsistencies in diagnostic criteria and definitions of dry eye are reflected in its reported prevalence, which varies from five to over 30 per cent.23–27 Common to most epidemiological findings is that dry eye becomes more frequent with age in both men and women and that Clinical and Experimental Optometry 2014

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Sex hormones and dry eye Truong, Cole, Stapleton and Golebiowski

ANDROGENS

DHEA-Sulphate (DHEA-S)

Cholesterol

PROGESTOGENS Pregnenolone

17α-Hydroxy pregnenolone

Dehydroepiandrosterone (DHEA)

17β-HSD

Androstenediol

Progesterone

17α-Hydroxy progesterone

Androstenedione

17β-HSD

Testosterone (testes >> ovaries)

Aromatase

Oestrone (E1)* (ovaries >> testes)

5α-reductase

Dihydrotestosterone (DHT)* (testes >> ovaries)

Aromatase

17β-HSD

Adrenal glands Gonads (ovaries or testes) OESTROGENS Adrenal glands and gonads *also produced in peripheral tissues by conversion of circulating steroid precursors 17β-HSD: 17β-hydroxysteroid dehydrongenase

Oestradiol (E2)* (ovaries >> testes)

Figure 1. Steroidogenesis in humans

women are at a higher risk of dry eye than men.23–28 The higher prevalence of signs and/or symptoms of dry eye in women has been associated with systemic conditions, such as Sjögren’s syndrome,29,30 complete androgen insensitivity syndrome,31,32 premature ovarian failure33,34 and polycystic ovary syndrome.35 Physiological changes with pregnancy, lactation, menstruation and menopause,36–41 use of medications such as contraceptives and hormone replacement therapy (HRT),42–44 as well as surgical procedures, including ovariectomy and hysterectomy, are also implicated.45 In men, anti-androgen therapy for prostatic indications is a sex-specific risk factor associated with dry eye.46,47 The significant contrast in the number of sex-specific risk factors between men and women suggests that the pathophysiological mechanisms that underlie dry eye disease may, at least in part, be due to sex-related differences in endocrine functions.15,48–51 This review aims to examine the evidence for a role of sex hormones in the aetiology of dry eye.

SEX HORMONES: SYNTHESIS AND TARGET TISSUES Sex hormones, namely androgens, oestrogens and progestogens, are steroid hormones, synthesised and secreted into the blood circulation primarily by the gonads (ovaries or testes) and the adrenal glands.48 The synthesis of sex hormones in endocrine glands involves biochemical pathways where Clinical and Experimental Optometry 2014

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cholesterol is a common precursor (Figure 1). Oestrogen is produced by the ovaries in females and to a lesser extent by the testes in males and the adrenal glands in both sexes. Androgens are produced mainly by the testes and, in smaller amounts, by the ovaries and adrenal glands. Sex steroids are also produced by conversion of steroid precursors in peripheral intracrine tissues such as the skin and adipose tissue.52 The production of androgen in the adrenal glands is limited to that of dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEA-S) and androstenedione. The release of these steroid precursors into the circulation allows for the production of half the active androgens in men and approximately threequarters of oestrogens in premenopausal women by the gonads and peripheral tissues.52 The gonads and peripheral intracrine tissues, in the presence of the 17 βhydroxysteroid dehydrogenase (17 β-HSD) enzyme, are capable of converting circulating adrenal and gonadal androstenedione into biologically active testosterone.53,54 Testosterone and androstenedione that are synthesised by the ovaries and, to a lesser extent, the testes and peripheral tissues, may subsequently be converted into oestradiol and oestrone, respectively, by the aromatase enzyme complex.53 Testosterone may undergo further conversions into a more potent androgen, dihydrotestosterone (DHT), by enzyme 5 α-reductase in peripheral tissues.53 In peripheral intracrine tissues, the level of expression and activity of steroidogenic enzymes determines the

amount of active sex hormones available in the tissue, allowing adjustments to be made according to local requirements.52,55,56 The human ocular surface and adnexa may be among the many peripheral target tissues, which contain the enzymatic machinery necessary for intracrine synthesis and metabolism of androgens and oestrogens.55,57,58 Although epithelial cells of the human lacrimal gland, meibomian gland, conjunctiva and cornea have been shown to contain messenger RNAs (mRNAs) for steroidogenic enzymes, such as 17 β-HSD, aromatase and 5 α-reductase,55,57,59 further studies are required to determine whether these mRNAs are subsequently translated into proteins that produce enzymes for the synthesis of sex hormones. Sex hormones produced within peripheral tissues exert their effects by binding to local hormone-specific receptors within the nucleus or cytoplasm of the target cell to initiate transcriptional regulation of target genes, also known as ‘classical’ genomic actions.56 Sex hormone receptor mRNAs in the lacrimal gland, meibomian gland, conjunctiva and cornea of humans and various animal species are translated into hormone receptor proteins.60,61 After the hormone binds to the receptor, the hormone-receptor complex interacts with a specific DNA sequence within the target cell nucleus and modulates gene transcription and expression.62–64 In ocular tissues, the number of genes influenced by exposure to sex hormones appears extensive and includes genes responsible for lipid secretion and wound repair.65 © 2014 The Authors

Clinical and Experimental Optometry © 2014 Optometrists Association Australia


SEX HORMONES AND THE MEIBOMIAN GLANDS The meibomian glands produce and secrete lipids to increase the surface tension and promote stability of the tear film to prevent evaporation of the underlying tear layers.66 Meibomian gland function is known to be regulated by sex hormones.47,67–69 Androgens enhance meibomian gland function and the quality and quantity of meibomian gland lipids.68,70 On the other hand, oestrogens and progesterones suppress sebaceous gland function and thus reduce lipid production.14,15

The effects of androgen on the meibomian glands The meibomian gland is an androgen target organ and its function is, at least in part, regulated by androgens.57,60,62,68 Low androgenic activity may result in meibomian gland dysfunction, compromised meibomian gland secretions and therefore, evaporative dry eye.29,31,32,46,47,71,72 Such changes are associated with gender and age, and are reported in individuals who are not responsive to androgen due to dysfunctional androgen receptors or use of androgen antagonists.31,32,46,47,71,72 Inherently lower levels of circulating androgens in women compared to men and the age-related reduction in gonadal androgen production in both sexes52,73 may contribute to increased risk of dry eye in these populations.71,72,74 Total androgen production in women under 30 years of age is approximately two-thirds of that found in men.73,75 Thereafter, adrenal secretion of precursor steroids markedly decreases in both sexes with only 30 per cent of peak levels remaining in women of menopausal age.73,75 The sex-related difference in serum androgen levels may account for the differences in lipid profiles of meibomian gland secretions between men and women;71 however, the basis for these differences is not fully understood. It is possible that gene expression is mediated by androgens in a way that is analogous to that in non-ocular sebaceous glands.76–79 Both men and women display structural and functional meibomian gland changes with advancing age. Atrophy of acinar cells and hyperkeratinisation of ductal epithelium result in significant alterations to chemical composition and lipid profiles of the gland secretions.80–82 More viscous and opaque meibomian gland secretions lead to

reduced gland expressibility and increased tear film instability.71,82–85 Signs and symptoms of dry eye caused by a reduction in quality and quantity of meibomian gland lipids may be exacerbated further by an accompanying increase in age-related eyelid and eyelid margin abnormalities seen with chronic blepharitis.71,80,86,87 The importance of androgens in the regulation of meibomian gland function is emphasised in individuals who do not respond to androgen due to androgen receptor mutations or use of androgen receptor antagonists. Women with dysfunctional androgen receptors due to complete androgen insensitivity syndrome and men using anti-androgen therapy for prostate cancer show signs of ocular surface abnormalities and significant meibomian gland dysfunction.31,32,46,47,72 Meibomian gland orifice metaplasia and compromised sebaceous gland activity in these patients are associated with alterations to the composition of meibomian gland lipids, increased tear film instability and low tear film break-up time (TBUT).31,32,46,47,72,82 The reduced quality and quantity of lipid may in turn lead to symptoms of dry eye, including pain, light sensitivity and blurred vision.31,47 In contrast, topical administration of the androgen precursor DHEA, in dry eye subjects can stimulate increased production and release of meibomian gland lipids, resulting in a longer TBUT.88,89 Androgen regulation of meibomian gland function, via its modulation of expression of numerous genes, is evident from animal studies.15,62,64 In particular, androgen stimulates the expression of genes associated with the activation of lipid metabolic pathways and the synthesis, transport and secretion of lipids.15,62–64,90,91 Androgen further enhances meibomian gland function through the suppression of genes related to keratinisation,15 which is believed to be the primary mechanism of meibomian gland dysfunction.82,92 Androgen deficiency in orchiectomised rabbits is associated with striking changes in lipid content within their meibomian glands.68 On the other hand, administration of 19-nortestosterone restores the changes in lipid content towards that found in intact male rabbits.68 Androgens also regulate in a sex-specific manner, genes that are identical in both male and female meibomian glands.15,62,90,91 Further research is required to determine the mechanisms of sex-related variations in gene expression and whether these variations contribute to the known


anatomical and physiological differences between male and female meibomian glands.93 Such knowledge will enhance understanding of sex-related differences in susceptibility to evaporative dry eye syndrome.

The effects of oestrogen and progesterone on the meibomian glands The presence of oestrogen and progesterone receptors in the meibomian glands of human and various animal species suggests that this tissue is predisposed to the influence of female sex hormones.60,94,95 The influence of oestrogen on the meibomian gland appears to antagonise the actions of androgen, with resultant effects on suppression of lipid synthesis and promotion of meibomian gland dysfunction and thus evaporative dry eye.15 The antagonistic effects of oestrogen may help to explain the exacerbation of signs and symptoms of dry eye in post-menopausal women using oestrogen replacement therapy; however, the direct influence of oestrogen and progesterone on the human meibomian gland is yet to be understood. The meibomian gland is a large sebaceous gland, and oestrogens have negative effects on the function and structure of sebaceous glands in other tissues of various species.15,76–78,96,97 Although the number of oestrogen receptors expressed in the human meibomian gland is similar in males and females,94,95 the number of oestrogen receptors is not strongly related to stability of the tear film lipid layer or to subjective symptoms of dry eye.95 The effects of oestrogen in sebaceous glands may not be exerted directly through interaction with their receptors but rather indirectly, through antagonising the action of androgen, attenuating testosterone uptake and/or interfering with the conversion of testosterone to the potent androgen, DHT, as shown in mice.16,97 It appears that androgens and oestrogens antagonise the regulation of binding sites that correspond to the opposing hormone in sebaceous glands.16 Thus, it may be the reduction in androgen action, rather than increased oestrogen action per se, that is responsible for the higher prevalence of dry eye in women. This provides a plausible explanation for the increased frequency of dry eye in postmenopausal women despite the cessation of ovarian oestradiol production. Clinical and Experimental Optometry 2014

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Upon binding to their respective receptors, oestrogen and progesterone, like androgens, modulate the expression of genes that alter biological processes, molecular functions and cellular components in the meibomian gland;14,98,99 however, oestradiol induces a pattern of gene expression in the meibomian gland that differs from that elicited by testosterone.100 In particular, testosterone upregulates the expression of genes that support meibomian lipid production, whereas oestradiol suppresses genes associated with these functions and upregulates genes, which have the opposite effect.14,15 Opposing effects also occur when androgens and progesterones act on the same processes,101 such as when progesterone downregulates expression of genes associated with immune processes.14 Much of the influence of progesterone is via downregulation of gene expression and its impact in the meibomian gland is much less than that of oestrogen;14 however, in contrast to androgens, oestrogen and progesterone make a relatively minor contribution to the sex-related differences in gene expression within the meibomian gland, at least in mice.93,99 It is unclear whether oestrogen or progesterone affect the morphology of the mouse meibomian gland.98,99 Thus, it may be the effects of androgen, rather than of oestrogen or progesterone,93 that are responsible for the mechanisms that underlie the sex-related differences in biological processes, molecular functions and cellular components in the meibomian gland.51,63,93 Further research is warranted to determine the definitive role of oestrogen and progesterone in evaporative dry eye.

SEX HORMONES AND THE LACRIMAL GLAND The primary function of the lacrimal glands is to synthesise and secrete proteins, electrolytes and water, which contributes to the aqueous layer of the tear film.102,103 The function and structure of the main lacrimal gland are, at least in part, mediated by sex hormones through the regulation of gene transcription.104–106 Recent findings suggest that the accessory lacrimal glands also expresses genes for androgen and oestrogen receptors.103 Androgens are partially accountable for sex-related variations in lacrimal gland characteristics and play an important role in modulating the morphology, biochemistry, molecular biology and Clinical and Experimental Optometry 2014

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secretory immune system of the tissue in various animal species.107,108 In contrast, the roles of oestrogens and progesterones in the lacrimal gland are unclear.18,20,109,110

The effects of androgen on the lacrimal gland The lacrimal gland, like the meibomian gland, is a target organ for androgens,104 which have a significant influence on the sex-related structural, functional and pathological characteristics of this tissue.50,105,107,111 A reduction in androgen influence with autoimmune disease such as Sjögren’s syndrome, results in inflammatory changes in the lacrimal gland, which leads to aqueousdeficient dry eye.30,112 Reduced serum androgen levels have been implicated in dry eye in women with altered endocrine states. Primary lacrimal gland deficiency has been observed in women after menopause or ovariectomy and during oral contraceptive use, despite their variable oestrogen levels.37,38,113 These observations contrast with those in men taking anti-androgen therapy, who do not show a change in their tear secretion,114 suggesting that androgen action may be sex-specific. Animal studies show that regulation of lacrimal gland integrity and secretory function depends for the most part on androgen action. Sex-related differences in androgen influence contribute to the sexual dimorphism of lacrimal gland characteristics observed in various animal species.50,111,115–117 Lacrimal glands of male rabbits are larger and contain a greater number of cells than those of females.118 Similarly, a reduction of endogenous androgen in castrated male rats induces a change in lacrimal gland appearance to resemble that of female rats.107,111 In contrast, testosterone treatment in female and castrated rats, stimulates a change in characteristics toward that of intact males.107,111 Acinar cells of intact male rats synthesise and secrete higher levels of immunoglobulin A and secretory component glycoprotein compared to female or castrated male rats;111 testosterone treatment of castrated rats likewise stimulates the lacrimal secretory immune system.111,115,117,119 Interestingly, lacrimal gland secretory function is not altered proportionately with androgen levels or the size of the lacrimal gland. Castration of male rats also induces an increase in tear volume, while ovariectomy in female animal species does not affect lacrimal secretion despite regression of lacrimal tissue.119–123 Con-

versely, the administration of androgen metabolites, DHT, or testosterone to restore tissue regression results in reduced lacrimal secretion.108,119–121 It appears that additional modulation of androgen levels, such as with pituitary gland removal, is required to produce a negative effect on tear volume in male rats.119,123 Sex- and species-related differences may exist in the influence of androgen on the lacrimal gland.50,107,119,120,123,124 The sex-related difference in androgen influence on the lacrimal gland is partially attributed to variations in gene expression.19,105,125–128 The number of binding sites and density of androgen receptor proteins, for example, are identical in the lacrimal gland of orchiectomised male and ovariectomised female rats50 but exist in far greater numbers in intact male than in intact female rats.104,112 The administration of testosterone to castrated rats restores the number of androgen receptors to that in intact male rats, suggesting that androgens may autoregulate their own binding sites.112,129 Disruption of androgen receptors with antagonists or mutations results in suppression of androgen action and inhibition of transcription and translation of genes.111,130,131 These findings indicate that androgen action on the lacrimal gland can be mediated through alterations in gene activity.105

The effects of oestrogen and progesterone on the lacrimal gland Although oestrogen and progesterone affect the biological processes, molecular functions and cellular components of the lacrimal gland,106 the nature and extent of the influence is controversial and yet to be fully understood. Some human and animal studies show that oestrogen and/or progesterone may have a role in the promotion of inflammation and autoimmune disease in the lacrimal gland,20,132 while others suggest that these hormones have significant antiinflammatory influences on the anatomy and physiology of the tissue.18,109,110 Yet others have found no effect of oestrogen treatment on the structure or function of lacrimal tissues in humans133 or rats.115,117,119,123,127,133–135 Some investigators have attributed dry eye syndrome in post-menopausal women to increased production of pro-inflammatory cytokines, diffuse fibrosis and atrophy of the lacrimal gland136 driven by diminishing levels of circulating oestrogen and progesterone.36 In animal studies, the significance © 2014 The Authors



of oestrogen to the maintenance of the structure and function of the lacrimal gland is demonstrated by the negative impact of oestrogen deficiency resulting from ovariectomy and anti-oestrogen treatment.106,108–110,121,132 The absence of oestrogenic influence in lacrimal glands of rabbit and mouse models of Sjögren’s syndrome leads to regressive, inflammatory changes in the tissue, while oestrogen administration prevents or reverses these changes and promotes lacrimal secretion.109,110,132 Consistent with these observations is the finding that oestrogen and/or progesterone influence expression of many immune-related genes, including upregulation of genes that inhibit the signalling of pro-inflammatory cytokines.106,137 These studies suggest that the effects of oestradiol on the lacrimal gland may be anti-inflammatory in nature. Other studies have proposed that oestrogen and/or progesterone have a role in the promotion of inflammatory and autoimmune diseases in the lacrimal gland. For example, one study found that oestrogen treatment of ovariectomised rabbits caused a significant increase in the activity, level and expression of proteolytic enzyme matrix metalloproteinases (MMPs) -2 and -9, which are involved in regulation of inflammatory processes.138 In addition, many genes expressed in the lacrimal gland in response to androgen stimulation are antagonised by oestrogen and/or progesterone;15 however, oestrogen and progesterone contribute relatively little to the sex-related differences in gene expression and sexual dimorphism of the lacrimal gland compared to androgen,19,105,106,118,133 and so may not be the underlying cause of aqueous tear deficiency in women. The contradictory findings may be due to differences in experimental design, animal models or the dosage and combinations of hormones used. Consequently, further studies are required to elucidate the effects of oestrogen and/or progesterone on the structure and function of the lacrimal gland, particularly in humans. SEX HORMONES AND THE OCULAR SURFACE In addition to the glands responsible for tear production and secretion, it is likely that sex hormones have a direct effect on the tissues of the ocular surface, including the cornea, conjunctiva and the tear film. Recent research has demonstrated the key

role of the mucin layer, derived primarily from the conjunctival goblet cells is to stabilise the tear film and thus lubricate, hydrate and protect the ocular surface.139–141 Patients with dry eye exhibit alterations in mucin distribution on the ocular surface, perhaps as a consequence of altered goblet cell density, which may have implications for tear film stability.142–148 Investigations of women with complete androgen insensitivity and polycystic ovary syndrome have shown that androgens are involved in the modulation of mucin production by conjunctival goblet cells.148,156 The cornea and conjunctiva are sensitive to the physiological changes in oestrogen and progesterone levels that occur in women during menstruation.39,149,150 Although high oestrogen levels are coincident with reduced corneal sensitivity and regulation of inflammation, oestrogen may also have a positive effect on the conjunctival epithelium by increasing epithelial cell maturation.41 The mechanisms by which the cornea and conjunctiva are affected by sex hormones remain to be fully determined. The current evidence for the effects of sex hormones on these tissues is reviewed below.

The effects of androgen on the ocular surface At least four of the 19 types of mucin identified in humans are present on the ocular surface.145,151,152 Secretory mucin MUC5A is a large gel-forming glycoprotein produced by conjunctival goblet cells.152,153 Membraneassociated mucins (MUCs 1, 4 and 16), on the other hand, are produced by conjunctival and corneal epithelial cells and form the inner hydrophilic glycocalyx portion of the tear film mucous layer.152–155 Few studies have investigated hormonal involvement in mucin production by the cornea and conjunctiva. One case study has shown that women with dry eye as a result of complete androgen insensitivity syndrome exhibit reduced MUC1 and MUC5AC protein expression in the tear film mucous layer.156 The reduction in MUC5AC expression with androgen deficiency has been attributed to compromised goblet cell function rather than a decline in goblet cell number.156,157 Interestingly, hyperandrogenism in women with polycystic ovary syndrome has also been associated with signs and symptoms of dry eye.35,148 The ocular surface of patients with polycystic ovary syndrome exhibits mucous hypersecretion and abnormal mucous filaments as a result of con-


junctival goblet cell hyperplasia.148 The conjunctival tissues of these patients have significantly reduced levels of MUC5AC mucins, despite an increase in the expression of MUC5AC mRNA compared with healthy subjects. Instead, these patients display increased levels of MUC5AC in their tears, which has been suggested to contribute to the pathogenesis of the condition as a result of abnormal mucous filaments on the ocular surface.148 Symptoms of dry eyes in polycystic ovary syndrome have been reported to be compounded by significant reductions in TBUT.148 Further, the authors reported that patients with hyperandrogenism who received anti-androgenic treatment demonstrated significantly longer TBUTs and reported improvements in ocular symptoms. These observations suggest that further research to determine if pharmacological manipulation of androgens aimed at effects on mucin production for treatment of dry eye symptoms in polycystic ovary syndrome is warranted. The repercussions of prolonged systemic antiandrogen therapy need to be considered.

The effects of oestrogen and progesterone on the ocular surface Corneal and conjunctival tissues are sensitive to changes in circulating hormone levels. Hormonal changes that occur with the menstrual cycle, contraceptive use, pregnancy, menopause and HRT have been associated with corneal alterations, including changes in sensitivity and therefore, changes in visual function and development of ocular symptoms.150,158–165 As testosterone levels remain relatively consistent throughout the cycle, structural and functional changes that occur in the cornea and conjunctiva during menstruation have been attributed to the effects of oestrogen and/or progesterone.39,149,150,164 As the cornea expresses receptors for both oestrogen and progesterone, it is probable that these hormones are available to the cornea from the tear film and aqueous humour.61 Reduced corneal sensitivity during phases of elevated oestrogen may disrupt the feedback mechanism to the lacrimal gland for normal tear production.161,164 These studies imply that sex hormones have a role in the regulation of corneal anatomy and physiology, although their direct effects on the cornea in dry eye are not yet known. The conjunctiva is an oestrogen-sensitive epithelium, as its cells display changes in Clinical and Experimental Optometry 2014

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levels of maturation and possibly mucin production that parallel the variation in hormone levels over the menstrual cycle.149 In the menstrual phase of the cycle, both oestrogen and progesterone levels are at their lowest and the conjunctival epithelium consists mainly of immature parabasal cells.40,162 Elevated levels of oestrogen in the follicular phase are coincident with maturation of parabasal cells to intermediate and superficial cells; while high progesterone levels in the luteal phase appear to oppose these proliferative effects.40,162 The relative proportions of parabasal, intermediate and mature superficial conjunctival cells correspond to the relative levels of oestrogens and/or progesterones in the menstrual, luteal and follicular phase, respectively.39,41 These maturational changes in the conjunctival epithelium are absent postmenopause.40,41 The conjunctiva of postmenopausal women is more susceptible to the development of squamous metaplasia and inflammation and exhibits a reduced number of goblet cells.142 The relationship of this with decreased oestrogen is consistent with the observation that increasing serum oestrogen levels with HRT induces maturation of conjunctival cells and an increase in the density of goblet cells.166,167 Interestingly, reports of other signs and symptoms of dry eye during the menstrual cycle vary between studies. Some studies have found that despite changes in the levels of oestrogen and progesterone, subjective symptoms and measurements of tear turnover, volume, osmolarity and stability remains unchanged.113,168 In contrast, one study found that signs and symptoms of dry eye vary during the menstrual cycle; however, the changes do not appear to correspond with the cellular changes observed in the conjunctival epithelium.39 In this study, ocular symptoms were reported to be significantly worse during the progesteronedominated luteal phase, while tear film instability and conjunctival dryness increased in the oestrogen-dominant follicular phase. There is evidence of an inflammatory component to the responses of the corneal and conjunctival epithelia to oestrogen. Studies in human corneal epithelial cells have shown that exposure to oestrogen results in upregulation of both proinflammatory cytokines and MMPs.17 In Sjögren’s syndrome, patients with such inflammatory events have been reported to both induce increased and decreased Clinical and Experimental Optometry 2014

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mucin expression, further emphasising the complexity of hormonal regulation of these tissues.169–172 The complexity of mucin regulation by oestrogen and progesterone is confirmed by animal studies, where increases in oestrogen and/or progesterone in ocular surface tissues of ovariectomised mice did not alter distribution or expression of mucins,153 while in rabbits, physiologically occurring higher oestrogen levels resulted in increased goblet cell secretions, whereas increased progesterone did not.173 SEX HORMONES AND INFLAMMATION IN DRY EYE Inflammation is a common factor that underlies many causes of dry eye. Inflammation may occur as a result of changes to the androgen-to-oestrogen/progesterone ratio in the circulatory system, such as occurs in Sjögren’s syndrome. This syndrome is associated with extensive inflammation of the lacrimal gland and with dry eye. It occurs primarily in women. The higher incidence of Sjögren’s syndrome in females has been attributed partially to the differential actions of sex hormones on the immune system.174– 176 Increases in inflammatory molecules have been reported in patients with Sjögren’s syndrome177–179 and dry eye.180–182 The number of genes reported to be influenced by sex hormone levels in ocular tissues is extensive and includes genes responsible for inflammatory mediators such as interleukin (IL)-1, tumor necrosis factor (TNF)-α, IL-6 and vascular endothelial growth factor (VEGF);177–179 however, the exact relationships between hormones and these mediators are yet to be fully understood. While oestrogens are implicated in the pathogenesis and progression of autoimmune disorders,174,183,184 androgens can attenuate the disease and its deficiency is a critical factor in Sjögren’s syndrome.29,30 The anti-inflammatory properties of androgen treatment have been demonstrated in a mouse model of Sjögren’s syndrome20 and have been further confirmed in humans by a clinical study, where systemic androgen treatment in patients with Sjögren’s syndrome can stimulate tear flow and alleviate signs and symptoms of dry eye.185 In contrast, oestradiol treatment in mouse models of Sjögren’s syndrome results in significant decline in tear volume and increase in lymphocyte infiltration within the lacrimal glands.20

In the absence of autoimmune disease, androgen insufficiency alone does not appear to elicit the generation of inflammatory changes in the lacrimal gland. Androgen deficiency in testicular feminised mouse models show no signs of lacrimal gland inflammation, while men using antiandrogen therapy has no effect on tear secretion.114,186 Similarly, there is no evidence of lymphocytic accumulation within the lacrimal glands of various animal species after castration or interruption to their hypothalamic-pituitary axis.114 In the absence of inflammatory changes, a reduction in androgen influence from ovariectomy or hypophysectomy may trigger lacrimal gland atrophy associated with acinar cell degeneration.108,120 Current evidence shows oestrogen influences the expression of pro-inflammatory cytokines in human corneal epithelial cells. However, findings between studies are contradictory. Some show that 17 β-oestradiol increases expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-8) and thus MMPs (-2, -7 and -9) in human corneal epithelial cells and therefore proposed that oestrogen has a role in the pathogenesis of inflammatory dry eye.17,187 On the other hand, a more recent study, demonstrated that 17 β-oestradiol treatment suppresses expression and production of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) in human corneal epithelial cells, implying that oestrogen may protect against hyperosmolarityinduced ocular surface inflammation in dry eye.188 As immortalised cells were used in these studies, the effects of oestrogen on pro-inflammatory cytokine expression in corneal epithelial cells in vivo remains to be determined. Further, cytokines, particularly IL-6, can exhibit both pro- and antiinflammatory actions depending on the inflammatory milieu.189 In the eye, where responses to both hormones and inflammatory mediators differ between individual tissues, further research is required to understand the complex interplay of these mediators and derive appropriate pharmacological interventions. HORMONE TREATMENT AND DRY EYE

Androgen treatment No clinical trials have been published which investigate the effects of systemic or topical androgen treatment on the signs or symptoms of dry eye. In a case report, treatment © 2014 The Authors



with testosterone cream applied to the eyelids for three months was shown to normalise tear lipid layer thickness and break-up time.89 Similarly, a retrospective uncontrolled case series of 11 postmenopausal women reported an improvement in dry eye symptoms with combined androgen and oestrogen systemic therapy.190 Conversely, systemic anti-androgen therapy results in reduced tear stability, increased meibomian gland dysfunction and greater corneal and conjunctival staining;47 however, trials of supplementation with the androgen precursor DHEA in Sjögren’s syndrome patients have shown equivocal results, with no changes in dry eye symptoms or tear function up to nine months of systemic treatment.191,192 The paucity of published clinical investigations is interesting in light of numerous patent applications listed in this area. Publication of well-controlled and appropriately designed studies is critical to confirm the impact of androgen therapy in dry eye.

Oestrogen and progesterone treatment Hormonal replacement therapies are commonly prescribed for women with climacteric symptoms after hysterectomy/ ovariectomy, menopause or due to premature ovarian failure. As such, this ‘convenient’ sample has resulted in numerous studies into the effects of oestrogen and/or progesterone supplementation on dry eye in this group; however, the findings of these studies remain inconclusive. Some studies report the exacerbation of dry eye with oestrogen replacement therapy, others suggest that dry eye symptoms may be alleviated with treatment and yet others report no effect (Table 1). In pre-menopausal women, exogenous synthetic oestrogen and/or progesterone for contraceptive use, have not been found to affect ocular symptoms, tear volume, break-up time or osmolarity.113,168,193 Observations that dry eye may be associated with oestrogen supplementation are supported by a number of studies. In one report, asymptomatic post-menopausal women developed dry eye symptoms after three months of oestrogen/progesterone replacement therapy, while symptomatic women were not relieved of dry eye by hormone replacement therapy.42 Another study showed a decline in tear production in women using oestrogen/progesterone therapy for 12 months, with a greater effect

in those on oestrogen-only treatment.44 A cross-sectional study comparing women on oestrogen/progesterone and oestrogenonly hormone replacement therapy with untreated women reported more dry eye signs in the women on hormone replacement therapy.194 These findings are supported by a large population-based study of 25,665 post-menopausal women, which found a higher risk of clinically diagnosed dry eye in women using HRT, particularly for women using oestrogen-only therapy.43 Duration of hormone replacement therapy in this study was associated with an elevated risk of dry eye. Interestingly, postmenopausal women who had never used HRT were found to have a risk of dry eye comparable to that in pre-menopausal women.43 These studies imply that addition of progesterone to the HRT regimen may have a beneficial role in attenuating the signs and symptoms of dry eye.194 Contrary to these investigations, other clinical evidence appear to suggest that postmenopausal women with dry eye may benefit from HRT. An improvement in ocular symptoms has been reported with oral and transdermal supplementation with oestrogen and oestrogen/progesterone,159,195–198 as well as a positive impact on tear volume and stability.159,166,195,197,199–201 Topically applied oestrogen drops and ointment may also improve symptoms and tear function.202,203 Unfortunately, the evidence for the effects of hormone treatment on dry eye from this body of work is limited, as only one placebocontrolled (pilot) study has been published 203 and many are not controlled. The conflicting results reported by studies investigating the effect of HRT on the signs and symptoms of dry eye may be accounted for by several factors, including inconsistencies in drug composition, route of administration, treatment dose and length of treatment. Furthermore, it is probable that dry eye syndrome in post-menopausal women is attributed to the relative levels of androgen, oestrogen and progesterone in the circulatory system, irrespective of HRT use. Therefore, patient characteristics as well as differences in study design and diagnostic tests used may also contribute to the difficulties in drawing conclusions. Collectively, these studies do not provide clear evidence to support the clinical use of HRT as a treatment option for dry eye. Placebo-controlled, randomised, doubleblind studies involving larger study popula-


tions are required to more clearly define the relationship between HRT and dry eye. SUMMARY Epidemiological data, along with the presence of sex hormone receptor mRNAs and proteins in the lacrimal gland, meibomian gland, conjunctiva and cornea suggest that these ocular tissues are susceptible to the action of sex hormones. The specific and often-opposing influence of sex hormones on gene expression may account for the sex-related differences in structural and functional characteristics of these ocular tissues. An extensive number of genes in ocular tissues is reported to be influenced by exposure to hormones and includes genes responsible for lipid secretion and wound repair. Changes in gene expression influenced by hormone ratios are believed to contribute to the increased prevalence of dry eye observed in women. Dry eye is recognised as an inflammatory disease and sex hormones have profound effects on the immune system. Dry eye in women has been attributed to their relatively low levels of serum androgen, which has antiinflammatory effects on the ocular surface. The effects of androgen deficiency on dry eye in women may be exaggerated in sexspecific physiological and pathological conditions, which impact on the endocrine system. Although oestrogens may be proinflammatory in nature, the effects of these hormones remain unclear as dry eye occurs in women under endocrine states that are characterised by both high and low serum oestrogen levels. It has been suggested that oestrogens and progesterones act indirectly through mechanisms that antagonise the effects of androgens, although the exact nature and extent of oestrogen and/or progesterone influence on the ocular tissues remains controversial. The difficulty in elucidating the precise mechanisms that underlie the effects of sex hormones on ocular tissues may be attributed to the presence of other influences on the regulation of tear production, such as from the autonomic nervous system and pituitary hormones. Current evidence indicates that it may be an imbalance of relative levels of androgens, oestrogens and progesterones in the circulation that triggers (or once triggered, alters the outcome of) inflammatory processes within the ocular structures of the lacrimal functional unit and forms the basis for the pathogenesis of dry eye. It remains unclear Clinical and Experimental Optometry 2014

7

8

O (n = 42)

O (n = 10)

O+P (n = 4)

Sator et al 1998202

Evans et al 2002196

Vavilis et al 1997167

Clinical and Experimental Optometry 2014

HRT (n = 60)

O+P (n = 25)

Taner et al 2004206

Tibolone (n = 40)

HRT (various, n = 15,681)

Population study

Cross-sectional study

Various

Not stated

Oral

Untreated comparison group


Topical tear supplement

No control


Untreated

Untreated

Placebo

No control

No control

Untreated

No control

No control

Untreated

No control

Untreated

Untreated

No control

Untreated

No Δ

↑

no Δ

↑ (Tibolone group)

No Δ

no Δ

worst in O group

↓ (12 m)

no difference

↑ (Tibolone group)

No Δ

No Δ

No difference

no Δ

No Δ

no Δ

↑ (6, 12 m)

no difference

No Δ

↑

↑

↑

↓

↓

↑

↑

↑

no Δ

↑

↑

↑ (topical group)

↑

Schirmer test

↑

↑

TBUT

↓

↓

↓

↓ (topical group)

No difference

Symptoms

Table 1. Previously published intervention studies reporting oestrogen and progesterone supplementation.

TBUT, tear film break-up time; O, oestrogen; P, progesterone; MG, meibomian gland; MGD, meibomian gland dysfunction; m, months; Δ, change; HRT, hormone replacement therapy

Schaumberg et al 200143

O (n = 11)

O+P (n = 19)

Shaharuddin et al 2008194

3 months

oral

O+P (n = 40)

Tibolone (n = 12)

Oral

Oral

Oral

Oral

Transdermal+oral

Oral

Oral

Various

Oral

Oral

Oral

Oral

Oral

Transdermal

Transdermal

Transdermal+oral

Transdermal or implant

Placebo Oral o ± artificial tears

Topical ointment

Control

Oral ± topical drops

Route of administration

transdermal

6, 12 months


6 months

6 months

3 months

6 months

3, 6, 12 months


6 months

1, 3 months

2 months

3 months

12 months

3, 6 months

4 months


4 months

4 weeks

Duration

O (n = 5)

O+P (n = 19)

HRT (various, n = 38)

Erdem et al 200742

Uncu et al 200644

NEGATIVE EFFECT

Lekskul et al 2004208

Verit et al 2007207

O+P (n = 21)

Piwkumsribonruang et al 2010205

Tibolone (n = 29)

O+P (n = 10)

Kuscu et al 2003204

EQUIVOCAL

Okon et al 2001201

O+P (n = 36)

O+P (n = 34)

O+P (n = 15)

Altintas et al 2004199

Moon et al 2010197

HRT (various, n = 25)

O+P (n = 17)

Pelit et al 2003166

Jensen et al 2000198

O+P (n = 40)

Guaschino et al 2003200

Coksuer et al 2011195

O+P (n = 25)

Affinito et al 2003159

O (n = 7)

O (n = 10)

Akramian et al 1998203

POSITIVE EFFECT

Treatment

↑ prevalence of dry eye with HRT, worse with O only

↑ frequency of dry eye signs in treated group

↑ ? MGD

no Δ in conjunctival cytology

↓ MG inflammation, ↑tear IgA, no Δ in tear lysozyme

↑ conjunctival goblet cell density

Improvement in conjunctival epithelium maturational changes

no difference in tear osmolarity

Other parameters


© 2014 The Authors



as to how the different sex hormones interact to regulate the functional activity of ocular tissues to provide homeostasis of the ocular surface. As much of the evidence in this area is derived from animal studies, caution needs to be exercised when applying these findings to human models, as for example, rodent animal species do not synthesise sex hormones in local tissues, as is the case in humans. Nevertheless, as it stands, the literature indicates that the development of therapeutic strategies to target the pathogenesis of dry eye disease may be possible through the alleviation of endocrine imbalances.

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13

Sex-steroid imbalance in females and dry eye.

Regarding the influence of sex and aging on dry eye disease.

Dry eye and mental health.

Sex, sex hormones and chronic liver diseases.

Sex differences in the effect of aging on dry eye disease.

Sex Hormones and Blood Pressure.

Hepatocellular carcinoma and sex hormones.

Sex hormones and immune dimorphism.

Sex hormones and pancreatic cancer.

Sex hormones and macronutrient metabolism.

[Conservative treatment of dry eye].

Lacrimal Gland, Ocular Surface, and Dry Eye.

Dry eye and ocular surface disease.

Evaluation of treatment for dry eye with 2-hydroxyestradiol using a dry eye rat model.

Relation of accommodative microfluctuation with dry eye symptoms in short tear break-up time dry eye.

Review: The Lacrimal Gland and Its Role in Dry Eye.

Angiogenin for the Diagnosis and Grading of Dry Eye Syndrome.

Diagnostic tests for dry eye disease in normals and dry eye patients with and without Sjögren's syndrome.

Sex hormones in the cardiovascular system.

The impact of conjunctivochalasis on dry eye symptoms and signs.

Smoking and the risk of dry eye: a Meta-analysis.

Sex hormones in breast disease.

Sex steroid hormones and circulating IgE levels.

Female sex hormones and thrombosis. Epidemiological aspects.