Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004
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8
Sex and Sex Steroid Influences on Dry Eye Syndrome
David A. Sullivan
Harvard Medical School, Boston, Massachusetts, U.S.A.
Recent research on the regulation of the lacrimal and meibomian glands has led to the hypothesis that sex and sex steroid hormones are critical factors in the control of these tissues, as well as in the pathogenesis of aqueous-deficient and evaporative dry eye syndromes. Experimental findings also support the hypothesis that androgens suppress and estrogens may promote dry eye syndromes. The rationale for these hypotheses is reviewed in this chapter.
I.SEX AND DRY EYE SYNDROMES
A majority of individuals with dry eye syndrome are women [1–8]. This sexrelated prevalence of dry eye is not surprising, because significant sex-related differences exist in the lacrimal and meibomian glands. Lacrimal gland differences, which are found in multiple species, include variations in the structural profile, functional capacity, secretory activity and disease susceptibility of this tissue (Table 1). Additionally, over 90% of patients with Sjögren’s syndrome, one of the most common causes of aqueous-deficient dry eye, are women [65–67]. Sex-associated differences are also found in the output of the human meibomian gland. Casual levels of meibomian gland lipids on the lid margin are higher in males than females from puberty until 50 years of age [68]. Meibomian gland dysfunction and evaporative dry eye frequently occur during menopause and aging [69–71]. The sex-associated differences in the prevalence of dry eye syndrome are hypothesized to be due, in part, to androgen deficiency and to the influence of endogenous or exogenous estrogens.
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Table 1 Sex-Related Differences in the Lacrimal Gland |
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Male |
Female |
Morphological appearance |
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Large, irregular acini with wide lumina Acinar cell borders indistinct or not evident
Epithelial cells with cloudy, light granular and basophilic cytoplasm
Centrally located nucleus varying considerably in size and shape
Distinct nuclear polymorphism
Increased number of polyploid nuclei; nuclei frequently contain prominent nucleoli
Basal vacuoles and enhanced quantity of intranuclear inclusions in acinar cells
Sparse intercellular channels Specialized structure of Golgi fields Capillary endothelia display few pores
Increased labeling index of epithelial cells; suggesting decreased cell turnover during aging
Greater extent of harderianization Marked sexual dimorphism during aging More frequent lobular fibrosis and focal
atrophy in elderly
Small, regular acini with narrow lumina Acinar cell borders clear and lobulated; acinar cell contours more conspicuous
Epithelial cells with clearer and less structured cytoplasm with heavy basophilic staining around nucleus (lighter toward periphery)
Basally situated nucleus showing more regularity in size and shape
Numerous, large cytoplasmic vesicles
Frequent intercellular channels
Capillary endothelia typically show pores
More frequent diffuse fibrosis and diffuse atrophy in elderly
Molecular, physiological, and immune characteristics
Higher levels of many mRNAs (e.g.,2u-globulin, secretory component, cystatin-related protein, TGF- 1, Fas antigen, and mouse urinary protein mRNAs)
Greater synthesis of various proteins (e.g., androgen receptor and secretory component)
Higher number and affinity of -adrenergic binding sites and total quantity of-adrenergic receptors
Greater activity of hydroxyindole-o- methyltransferase and carbonic anhydrase
Higher levels of many mRNAs (e.g., bcl-2, c-myc, c-myb, p53, androgen receptor, IL-1 , TNF- , and pancreatic lipase mRNAs; some differences are strain-dependent)
Greater synthesis of various proteins (e.g., melatonin, 20-kDa protein and N-acetyltransferase, as well as leucine aminopeptidase after puberty)
Higher specific activity of Na , K -ATPase, cholinergic receptors, acid and alkaline phosphatase, and galactosyltransferase
Greater peroxidase activity
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Table 1 Continued |
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Male |
Female |
Increased number of IgA-containing cells after puberty
Higher susceptibility to cytomegalovirus invasion and/or replication
Greater incidence of focal adenitis (particularly in females 45 years old)
Higher incidence of autoimmune disease
Secretory activity and tear film attributes
Higher secretion and tear levels of various proteins (e.g., SC, IgA, cystatin-related protein, 42-kDa and 46-kDa proteins)
Greater phenylephrine-induced secretion of peroxidase and total protein in vitro
Greater amounts of EGF, TGF- , and gender-specific tear protein
Higher tear osmolality ( 41 years old)
Higher secretion and tear levels of various proteins (e.g., 90-kDa and 20-kDa proteins)
Lower noninvasive tear breakup time and increased tear osmolality during aging
Higher prevalence of aqueous tear deficiency
Greater prevalence of dry eye syndromes
This table was compiled from Refs. 9–64, and was modified from Ref. 177.
II.SEX, SEX STEROIDS, AND AQUEOUS-DEFICIENT DRY EYE IN SJÖGREN’S SYNDROME
The sex-related prevalence of Sjögren’s syndrome has been linked to two general factors: significant sex-associated differences in the immune system and differential effects of sex steroids on the immune system. Women have a more potent, vigorous, and competent systemic immune capability than men [72–78]. They have higher serum immunoglobulin levels, stronger primary and secondary humoral responses to many antigens, and superior resistance to a number of bacterial and parasitic infections. Women exhibit greater cell-mediated immunity, increased resistance to the induction of immunological tolerance, and a greater ability to reject allografts and to elicit tumor regression. This augmented immune activity is believed to contribute to the much greater prevalence and severity of many autoimmune diseases in females [79].
Sex steroids have differential effects on the immune systems of women and men. Androgens, estrogens, and progestins affect both innate and adaptive
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immunity [9,72–77,79–88]. For example, these hormones have been demonstrated to modulate the maturation, proliferation, migration, rescue, and/or function of pluripotent stem cells, B cells, autoreactive B cells, T-helper cells, T-suppressor cells, natural killer cells, monocytes, and macrophages. Sex steroids also control the synthesis, appearance, secretion, and/or action of antibodies, cytokines, growth factors, adhesion molecules, proto-oncogenes, thymic factors, and immunosuppressive agents. They regulate the density of lymphocyte and immune factor receptors, the expression of autoantigens, the generation of autoantibodies, and the formation of immune complexes. Sex steroids influence the immune response to, and clearance of, various foreign antigens and infectious organisms. These hormones also modify the induction of tolerance, the rejection of allografts, the extent of graft-versus-host disease, and the magnitude of inflammation. Additionally, estrogens have been implicated in the pathogenesis and/or progression of many autoimmune disorders, whereas androgens have been shown to often decrease autoimmune sequelae [9,72–81,84,86–88]. In fact, androgen therapy has been used to reduce autoimmune expression in animal models of systemic lupus erythematosus, thyroiditis, polyarthritis, autoimmune hemolytic anemia, and myasthenia gravis, and to ameliorate various signs and symptoms in humans with systemic lupus erythematosus and rheumatoid arthritis [9,66,73–78,89–93].
A similar situation appears to occur in Sjögren’s syndrome. Thus, estrogens appear to play a major role in the etiology and perpetuation of Sjögren’s syndrome [94,95]. Estrogens enhance polyclonal B-cell activation, autoantibody formation, and tissue abnormalities found in this disorder [94–96]. These hormones also increase serum prolactin levels, which may further enhance immune activity and potentially exacerbate this autoimmune disease [97–100]. Estrogen action may contribute to the development of hyperprolactinemia, which is encountered in a number of Sjögren’s patients [101]. In contrast, androgens seem to provide a protective influence and to suppress various immunopathologies in Sjögren’s syndrome [72,89,90,92,96,102–106].
The relative levels of androgens and estrogens appear to be quite important in determining the progression of both primary and secondary Sjögren’s syndrome [72–76,78,107]. Serum concentrations of androgens in Sjögren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis are significantly reduced [76,108–123]. Conversely, female patients with systemic lupus erythematosus have altered metabolism of sex steroids. Both the oxidation of testosterone and the 16α-hydroxylation of estrone are elevated, leading to attenuated plasma testosterone levels, a decreased testosterone/estrogen ratio, and increased levels of circulating and potent estrogen metabolites [73–76,78,107,124,125]. Further changes in sex steroid metabolism may be induced by pro-inflammatory cytokines, such as IL–1, TNF-α, and/or IL–6, whose concentrations are increased in exocrine tissues in Sjögren’s syndrome [72,126–134]. Pro-inflammatory alterations include an
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increase of aromatase activity (i.e., conversion of androstenedione to estrone, testosterone to 17β-estradiol) and stimulation of a reductive 17β-hydroxysteroid dehydrogenase pathway (estrone to more active 17β-estradiol), which cause additional reduction in the testosterone/estrogen ratio [135–138]. The proinflammatory cytokines may reduce expression of androgen receptor mRNA [139], interfere with certain androgen effects [140], and promote corticosteroidogenesis. This last action may potentiate the aromatization of adrenal or testicular androgens, leading to decreased testosterone and heightened estrogen levels [73,75]. The latter effect may be very important during stress (increased in Sjögren’s syndrome), when circulating IL–1 concentrations are elevated, resulting in enhanced cortisol and depressed testosterone serum concentrations [73,75].
Overall, this reduction in androgen levels may predispose individuals to the development of Sjögren’s syndrome, and specifically lacrimal gland dysfunction, decreased tear secretion, and resulting dry eye. Consistent with this hypothesis are observations that androgens typically exert a significant and positive effect on the epithelial architecture, gene expression, protein synthesis, immune activity, and secretory processes in the lacrimal gland (Table 2). Androgen action also appears to account for many sex-related differences that occur in the anatomy, molecular biology, physiology, and immunology of this tissue [177]. Thus, the androgen deficit in Sjögren’s syndrome may serve to decrease tissue function and promote (but not cause) the autoimmune process in the lacrimal gland [9,177,178]. As additional considerations, androgen treatment of female mouse models of Sjögren’s syndrome [i.e., MRL/Mp-lpr/lpr (MRL/lpr) and NZB/NZW F1 (F1)] suppresses inflammation in lacrimal glands, and increases their functional activity [9,96,102–106]. Furthermore, investigators have reported that androgen treatment alleviates dry eye signs and symptoms and stimulates tear flow in Sjögren’s syndrome patients [89,90,92,179].
These findings support the hypothesis that androgen deficiency is a critical etiological factor in the pathogenesis of aqueous-deficient dry eye in Sjögren’s syndrome. They also suggest that correction of the androgen deficit in Sjögren’s syndrome may be therapeutic for the lacrimal gland. The precise mechanism(s) by which androgens suppress lacrimal gland autoimmune disease has yet to be determined. However, evidence indicates that this hormone action is initiated through androgen interaction with saturable, high-affinity and steroid-specific binding sites within epithelial cell nuclei [170,180]; these receptors are members of the steroid/thyroid hormone/retinoic acid family of ligand-activated transcription factors [181,182]. It is hypothesized that this androgen interaction then causes a change in the expression of specific genes and proteins in lacrimal tissue [10,11,126,183–185], leading to the reduction of immunopathological lesions and an improvement in glandular function.
In contrast to these findings with androgens, estrogen’s role in the etiology of lacrimal gland inflammation and aqueous-deficient dry eye in Sjögren’s syndrome