The relationship between Sex hormones and dry eye
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.
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.
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 . 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 . 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).
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).
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 . 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 . 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 . 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 , 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.
Having established the existence of a relationship between androgens and lacrimal and meibomian glands that are at the centre of dry eye pathogenesis, the mechanism through which these hormones influence either initiation or aggravation of the disease need to be looked into. According to Bhavsar et al (2011), androgens are involved in supporting the function of lacrimal gland as well as provide an anti-inflammatory condition within the gland to enable its normal activities. Meibomian glands have androgen receptors and hence are also targets of the hormone and offer a supportive role in the function of the gland. It has been noted that reduced levels of androgen allows inflammation of immune system and expression of inflammation genes results dry eye syndrome. This has been noted to occur mostly in women in the menopause age as they usually have decreased levels of circulating androgen. Such inflammations are the one that causes defects in the mucin components distribution on ocular thus aggravating the pathogenesis of dry eye (Bhavsar et al, 2011). Testosterone and prasterone have a protective role in pathophysiology of dry eye but when present in the right quantities in the circulation. Women have low quantity of testosterone than men as it is produced in large amount in the testes unlike prasterone that is produced in the brain of both male and female. Commonality in the genes regulated by the androgens can be attributed to the common hormone prasterone and the amount of testosterone produced in both sexes. The difference in the deficiency of testosterone especially in menopause women makes the difference in the prevalence of the dry eye between these women and men of their age.
Sjogern syndrome has previously been attributed to autoimmunity without clear triggers of the self-attacks by the body. The disease is characterised by immune cells, specifically lymphocytes, infiltration and presence of antibodies against autoantigens hence resulting to destruction of lacrimal glands as well as salivary glands (Tincani et al, 2012). The influence of sex hormones in the development of the disease was first noted by observing that the prevalence was higher in most post-menopausal women. This is due to the fact that sex hormones reduce with age and these hormones play a significant role in the physiology of most tissues of the body. Although not all post-menopausal women suffer from Sjogern syndrome, genetic predisposition to the disease aggravates the prevalence. Mostafa et al (2012) noted that apoptosis in the lacrimal gland was followed by lymphocytic infiltration and the situation was aggravated by the removal of sex hormones. The animal model study indicated that there is sufficient evidence to associate Sjogern syndrome and sex hormones. In their study, Mostafa et al noted that sex hormone replacement reduced the infiltration of the lymphocytes to the lacrimal gland even after apoptosis. This coupled with the fact that the disease mostly affects post-menopausal women led Mostafa to conclude that although the mechanism of infiltration of the lymphocytes after lacrimal cell apoptosis to the gland and their specific interaction with sex hormone was yet to be known, there exists a significance correlation (Mostafa et al, 2012). The mechanism through which sex hormones contribute to the development of the disease is through their impact on the initiation of autoimmunity. Stephen et al (2009) noted that defects in sex hormone receptors have a direct link to development and progression of various autoimmune disorders such as rheumatic arthritis and multiple sclerosis. In this context, it was noted that defects in androgen receptors, oestrogen receptor α and β are responsible for the development of autoimmune against lacrimal gland in Sjogren syndrome (Stephen et al, 2009). The role of oestrogen as a stimulator of inflammatory gene expression further cements the evidence. The many genes upregulated by the various sex hormones include some apoptotic genes that cause death of the cells in the lacrimal gland. It’s the death of the cells and the increased inflammation at the gland that initiates the lymphocyte infiltration as the cell fragments are turned into autoantigens. The body designs antibodies and cytokines against the antigens hence compromising the normal functioning of the gland leading to dry eye .
Menopause ids the age beyond which women can conceive as their ovulation is genetically programmed to stop at a particular age usually after 40 years . Sex hormones such as progesterone, oestrogen and androgen that are involved in the development of reproductive tissues at early age, regulation of menstruation, development of secondary sexual characteristics and maintenance of pregnancy during adulthood are no longer produced in enough quantities . The problem with the reduction in circulation of these hormones is that the numerous genes they used to regulate in various tissues such as the lacrimal and meibomian glands code for proteins required for normal functioning of non-reproductive organs and in this case, the eyes. Although dry eye disease is multifactorial, the influence of the hormones cannot be ignored as both Sjogren and non-Sjogren ADDE and EDE have been found to be more prevalent in women at their menopausal age . The sex hormones differ in how they impact the lacrimal and meibomian glands. Increased levels of oestrogen and progesterone result in dry eye while high levels of androgens have a protective role against dry eye syndrome. During menopause hormone replacement, the therapy is believed to be the best management of dry eye. However, the increased levels of the hormones may aggravate the condition or have no effect if the individual is genetically predisposed to dry eye . The role of sex hormones in the development of dry eye, however, has been noted by the reduced lacrimal secretions and when corticosteroids are administered, the symptoms are eliminated. This has been attributed to the role of the corticosteroids in regulation of gene expression in lacrimal and meibomian glands. The pro-inflammatory are down-regulated, while apoptotic genes are monitored to be expressed at normal rates. This ensures there is no unnecessary inflammation and epithelial cells do not die prematurely. This therapy also ensures that other genes such as those involved in lipid metabolism are expressed normally and the mucin components are in normal quality and quantity.
Dry eye disease was previously thought to occur due to old age or the autoimmune activity in the lacrimal and meibomian glands. The disease is characterised by inflammation of the ocular surface causing visual impairment and discomfort. The high prevalence of the disease in post-menopausal women provided a clue for further studies on the involvement of sex-difference in the pathogenesis of the disorder. Progesterone, oestrogen and androgens are the sex hormones that have been found to play a role in dry eye. Although they are usually used in reproductive process in both male and female, their influence on other tissues through regulation of gene expression is important. Reduced or increase amount of specific sex hormones alters the tear composition or the structure of the ocular, resulting to some or all of the symptoms seen in dry eye. Although Sjogren syndrome is an autoimmune disease, sex hormones play a significant role in its progression and severity. In women, sex hormones production decrease with age but the genes regulated by these hormones are still required for normal functioning of other organs. It is this phenomenon that causes the prevalence of dry eye to be more in post-menopausal women than young women or men of any age. From the evidence reviewed above, it is without doubt that there exists a significant correlation between dry eye and sex hormones.