The relationship between Sex hormones and dry eye

The relationship between Sex hormones and dry eye

Abstract

            There has been no conclusive evidence as to the relationship between dry eyes and sex hormones. Although one of the known conditions, Sjogren syndrome, is said to be due to autoimmunity, the influence of sex hormones have been controversial. This paper reviews the existing evidence for or against the existence of the relationship between sex hormones and dry eyes. The mechanisms of how these hormones influence the development of progression of the disease will be reviewed.

Introduction

            Dry eye syndrome has been associated with various causes and abstractly to hormonal changes especially in women. The disorder is characterized by reduced ocular surface lubrication due to tear-film instability due to dysfunction of meibomian gland, deficient tear-film layer or reduced tear production by the lacrimal gland. Oestrogen and progesterone fluctuations have for long been associated with dry eyes in women. The levels of the hormones in women who have reached menopause were the major factor associated with dry eye syndrome. Recently, androgens (testosterone and prasterone) have been found to play a role in the development of the disorder. The involvement of androgens thus includes men in the category of those patients whose dry eyes are as a result of sex hormones. Sex hormones influence on the eyes has been controversial, where their relationship was first thought to exist without much evidence being presented. This resulted in other factors being considered the main causes of dry-eye syndrome excluding the hormonal influence. This review will seek to establish the existence or lack thereof of a relationship between sex hormones and dry eye by analysing the most recent findings from studies that have been carried out. The degree with which the relationship will be found to be significant or not will be determined. The use of hormone replacement therapy at menopause will be assessed and analysed against the evidenced that is available. Sjogren syndrome will be reviewed and its pathophysiology analysed in the context of sex hormone functions or influence.        

Sex hormones

            Progesterone is found in both male and female and is produced as a precursor of other steroid hormones in the cortex of the adrenal gland [6]. The hormone is predominantly found in females, where it is produced in the ovaries and in the placenta during pregnancy. Testicles produce small quantities of progesterone and in both male and female, the hormone is produced in the brain [10]. The role of the hormone in females is to prepare the uterus for pregnancy during menstrual cycle by transforming the mucus membrane into secretion state from proliferative state. It is also involved in pregnancy maintenance during the first few weeks after implantation. About 3% of the circulating progesterone is not protein-bound, while the other fraction is bound to corticoid binding globulin and albumin (Kubli-Garfias et al, 2013). In males, progesterone has been found to influence spermiogenesis, testosterone biosynthesis and acrosome reaction. Secretion of the hormone in the brain helps in blocking secretion of gonadotropin, effects on immune system, respiratory system and kidney function (Shinohara et al, 2013).

            Oestrogen is a female sex hormone produced primarily by the ovaries and placenta (during pregnancy) (Hickey et al, 2013). Production of the hormone in the ovaries is stimulated by follical stimulating hormone. Oestrogen is then produced by granulosa cells of the corpora lutea and follicles (Hickey et al, 2013). Other secondary sources of oestrogen include the breast, adrenal gland and the liver. These sources have been said to be very crucial for postmenopausal women (Sandeep et al, 2013). Oestrogen is also found in men but at a lower quantity compared to female. In female, the hormone binds to oestrogen receptor and the hormone-receptor complex binds to specific encoding regins of DNA to initiate transcription (Hickey et al, 2013). The major roles of the hormone in female include development of secondary sexual traits such as breast development, menstrual cycle regulation and thickening of the endometrium; while in males, oestrogen is involved in sperm maturation (Sample et al, 2012). Oestrogen is also involved in lipid levels regulation and fluid balance (Sharma et al, 2012).   

            Testosterone is predominantly a male hormone although found in low quantities in females. The hormone is produced by the testes in large quantities in males and ovaries and adrenal cortex in females in smaller quantities (Sharma et al, 2012). Testosterone is a derivative of cholesterol and it is transported to the action site bound to sex hormone binding globulin and plasma protein. Its effects are through activation of oestrogen and androgen receptors. The hormone-receptor complex initiates transcription of genes after binding to hormone response elements in the chromosomal DNA, producing the traits observed in individuals. The main functions of the hormone in males include development of reproductive tissues in males such as prostate and testis, secondary sexual traits development and increasing bone density (Kubli-Garfias et al, 2013). The levels of testosterone decrease with age in both sexes.    

            Prasterone is produced in the brain, adrenal gland and the gonads and it is the most abundant in both males and females (Kocis, 2009). Like testosterone, Prasterone is derived from cholesterol and acts as a precursor for other androgens such as testosterone. It is also involved in androgenic activity such as being an agonist of androgen receptor due to low affinity for androgen receptor (Sánchez-Guerrero et al, 2009). It is involved in regulation of proteins through transcription regulation such as biosynthesis of cortisol (Marder et al, 2010).

Dry eyes

            The tear film was previously thought to be made up of three layers; innermost, intermediate and outermost layers.

The innermost layer is the mucin layer that covers the conjunctival and corneal epithelium, the intermediate is the aqueous layer produced by the lacrimal gland, while the outermost is the lipid layer produced by the meibomian glands (Bhavsar et al, 2011).

This concept has been currently elucidated and the tear film is said to consist of an aqueous gel that has a mucin component decreasing gradually towards the under surface of the outermost layer from the ocular surface.

The structure of the outermost layer associates with aqueous layer that has a mucin component, contributing to stability of tear film and reducing evaporative loss of aqueous tear between blinks (Bhavsar et al, 2011).

Formation of a tear film is through blinking, where tears are distributed over the surface of the ocular. After a blink, the film thins evenly leaving an aqueous cover and the thickness is replaced by distribution of another tear film in the subsequent blink. The mucins components in the aqueous layer are of three types; transmembrane, gel-forming and soluble mucins (Schirra et al, 2009). Transmembrane mucin is produced by the conjunctival and corneal cells and supports the surface structure of the epithelial cells, where it associates with the gel-forming mucin from the conjunctival globlet cell and soluble mucin from the lacrimal gland to cleanse the ocular surface and stabilize the tear film. The interaction between lipid and mucin maintains a stable tear film between the blinks (Schirra et al, 2009).  

Dry eye has multifactorial causes and affects the ocular surface and tears. It is characterised by visual disturbance, tear film instability and discomfort that may lead to ocular surface damage. These symptoms are usually accompanied by inflammation of the ocular surface and increased tear film osmolarity (Bhavsar et al, 2011).

The disease is a common chronic problem affecting mostly the elderly with approximately 50% of adult population reporting to have one of the above symptoms (Schirra et al, 2009). The causes of the disease are said to be unknown, but it is suggested it could be due to activation of nociceptive nerve endings on the surface of cornea. Hyperosmolarity of the surface stimulates the nerve endings resulting in tear break up. Inflammations is then caused by increased shear force due to reduced mucins and tear volume at the surface of the ocular resulting in nerve endings hypersensitivity. Two types of dry-eye syndrome have been noted to be aqueous deficiency dry eye (ADDE) and evaporative dry eye (EDE) (Reed, 2013). ADDE is where the lacrimal gland is defective such that it does not produce soluble mucin in enough quantities or does not produce at all.

Evaporative dry eye results from meibomian gland inflammation that is responsible for production of gel-forming mucin or the lipid layer, which reduces the rate of tear evaporation and stabilizes the tear film (Bhavsar et al, 2011).

Sjogren syndrome

            The disorder was first described by Sjogern and thus named after him. It is characterized by the attack of the salivary and lacrimal glands by the autoimmune system (Moerman et al, 2013). T-cells infiltrate the glands causing reduced secretion of tears and saliva as well as death of ductular and acinar cells. The effect of the inflammation on the glands results from expression of autoantigens on the epithelial cell surface as well as presence of CD8 and CD4 T-cells specific to the glands. Reduction in secretion of the tears and saliva is aggravated by presence of circulating antibodies and inflammatory cytokines released locally that cause a neurosecretory block (Reed, 2013). The disease is classified into primary and secondary Sjogren Syndrome. The primary type is characterised by ADDE and dry mouth while the secondary Sjogren Syndrome is characterised by ADDE, dry mouth and other autoimmune diseases such as systemic lupus erythematosis or rheumatoid arthiritis (Marder et al, 2010). Although the cause of the disease has been noted as autoimmune effects and inflammation, the triggers of the autoimmune response remain unknown. However, risk factors have been noted and include androgen status, genetic profile, viral infection and nutritional deficiency in unsaturated fatty acids and vitamin C (Marder et al, 2010). Dry eye is caused by defective lipid layer of tear film from the inflammation resulting in increased evaporation.       

Relationship between sex hormones and dry eye

            Sex hormones have been implicated in the development of dry eye syndrome through their effect on gene expression and then influences the physiology of tissues involved in normal eye physiology (Rocha et al, 2013). Several studies have been conducted to determine the relationship of sex hormones and dry eye and the findings are to the affirmative although some reservations are made as to how the hormones affect the eyes. One such study was conducted by Sullivan et al (2009), who sought to investigate existence of sex-specific effects of steroids on expression of genes in meibomian and lacrimal glands. In their study, the mRNA in lacrimal and meibomian glands was assayed after administration of androgens, progesterone and oestrogen to both male and female mice. The result indicated regulation of numerous genes by the sex hormones in the two glands, where testosterone had the highest number of genes it regulated that are involved in a number of biological and molecular functions. Androgens were involved in initiation of genes in the meibomian gland that are involved in lipid metabolism and suppression of genes involved in keratinisation. Although similar genes regulated by androgens were similar in both male and female mice, oestrogen and progesterone showed opposite effect in the expression of androgen genes in both glands in female. Sullivan et al (2009) noted that although the effects of the sex hormones in glands involved in eye physiology have been identified, their contribution to dry eye was not determined. Recent evidence has shown how the sex hormones are involved in the pathophysiology of dry eye. According to Bajwa et al (2012), the anatomical, developmental and physiological ocular aspects differ between sexes. They noted that sex hormones; androgen, oestrogen and progesterone, are related to ocular pathologies through their action on the hormones receptors. Seamon et al (2009) reported that hormonal studies have shown that sex hormones have an effect on ocular surface conditions. The effect of these hormones on conjunctival globlet cell density, meibomian gland function and tear secretion has been associated with their influence on dry eye. The relationship between sex hormone and dry eye is further evidenced by its increasing occurrence in pregnant and lactating mothers. Furthermore, there has been noted that some women bleed through ocular tissue an occurrence that is said to account for 1% of extragonadal sites of vicarious menstruation (Sullivan et al, 2009). During menstrual period, pregnancy and lactation, corneal thickness and curvature has been observed and results in impaired vision which further strengthen the relationship between dry eye and sex hormones (Sullivan et al, 2009). Gender related difference that include hormones have been found to be responsible for regulation of genes that are involved in apoptosis in different ocular tissues (Bajwa et al, 2012). This adds to the existing evidence on the influence of specific sex hormones directly or indirectly in the pathophysiology of dry eye.  

            Oestrogen role in the dry eye is said to be through known and yet to be elucidated mechanisms. Of the known, the hormone is responsible prevention of ocular changes through gene regulation and other physiological effects. This is evidenced by the increased occurrence of macular degeneration in women past the menopause age (Barabino et al, 2012). While the above maybe true, other findings such as those by Barabino et al (2012) indicate that oestrogen is involved in stimulation of expression of inflammatory genes in the epithelial cells of the cornea such as IL-1β, IL-8 and IL-6. This complexity of the specific role of oestrogen in inflammation was also noted by Wang [31]. Wang noted that the hormone has both anti- and pro-inflammatory effects but it is rarely involved in disease pathogenesis. Receptors for oestrogen are expressed in leukocytes and ocular tissues, where they have a pro-inflammatory influence. Animal model has demonstrated that oestrogen negatively regulates epithelial wound healing in the eye as well as healing of the lipid layer in the cornea. This has been found to occur through down-regulation of epithelial gene expression such as 15-LOX involved in cell regeneration [31]. Inflammation of the epithelial cells of the cornea results to cell death and hence a wound is created. Oestrogen is involved in the initiation of this inflammation and latter down-regulated expression of essential genes and intrinsic lipid circuit that aid in the healing process of the epithelial wound [31]. Although most studies report that the mechanism through which oestrogen affects dry eye is unknown, this seems the most probable way in which the pathogenesis of the disease in influence by the hormone.             

            Progesterone has close association with dry eye as evidenced in the occurrence of the disease in females during pregnancy and menstrual period. It has been noted that the mechanism of action in the dry eye syndrome is through gene regulation; genes that are involved in proper functioning of glands involved in secretion of all components of tears and the structural part of the ocular (Sullivan et al, 2009). To demonstrate the role of the influence of progesterone in dry eye, various studies have been conducted and one of them sought to investigate the influence of the hormone in regulation of expression of various genes within the tissues involved in normal eye physiology. Sullivan et al (2009) measured the levels of mRNA in meibomian and lacrimal glands mice that had been treated with various sex hormones. Progesterone was found to influence the expression of numerous genes in both meibomian and lacrimal glands. The genes affected were hormone-specific; combination of hormones in the mouse model resulted in alteration of more gene expression as each hormone acts specifically on genes. Having noted that progesterone alters gene expression, the relationship of the altered genes and dry eye have to be elucidated. According to Grant & Hughes [10], progesterone is involved in autoimmune development. This is the most plausible mechanism through which the hormone influences the dry eye syndrome. Autoimmune disease is where the immune system of the body attacks its own receptors that it recognizes as antigens. When this occurs, inflammation is eminent and the result is wound in the epithelial layer of the cornea. This is followed by increased expression of inflammatory genes through the influence of progesterone results to more damage to the lacrimal and meibomian glands. Normal quantities and quality of tears are not produced and the structure of the ocular is altered resulting in dry eye syndrome.     

            According to Sullivan et al (2009), androgen suppresses ADDE and EDE. By using real-time quantitative PCR, mRNA were measured in lacrimal and meibomian gland in mouse treated with androgens.

The results indicated the extent in which androgens influence gene expression in both male and female subjects in both glands. 768 genes were up-regulated, while 1350 gens were down-regulated in the lacrimal gland. Testosterone increased the expression of 726 genes and inhibited the regulation of 283 genes in the meibomian gland.

Androgens were found to significantly influence cell cycle, chromosomes and transferase activities in the lacrimal gland and protein transport, mitochondria and oxidoreductase activity in the meibomian glands. Translation, protein activity and immune response, plasma membrane and receptor binding were found to be suppressed significantly by testosterone in lacrimal and meibomian glands respectively (Sullivan et al, 2009). Among the genes that are influenced by androgens, lipid metabolism genes in meibomian tissue were significantly impacted as well as suppression of apoptotic and keratinisation genes. It has been noted that the effect of androgens on the lacrimal and meibomian glands is almost similar in both male and female. However, due to differences in the genetic make-up and hence the hormone influence, a number of genes regulated by the hormones were found to differ which explains the higher prevalence of dry eye in female than males. Sullivan et al (2009) noted that administration of testosterone resulted in reduced expression of 4 genes in female, but their expression remain normal in males in the lacrimal gland.

Furthermore, 2 genes were down-regulated in females but up-regulated in male in the meibomian gland. The influence of androgens also resulted in expression difference in 13 genes of the meibomian gland where the direction of expression differed between female and male.