Influence of Gender and Age on Gene Expression

PURPOSE:

Many epidemiologic studies indicate an increased incidence of certain vision threatening conditions in postmenopausal women. These data suggest that changes in sex steroid homeostasis may affect the physiology of the eye. To provide support to this hypothesis, the expression of estrogen receptor alpha (ER) in human eye tissues was investigated.

METHODS:

 Complementary studies including RNA analysis by reverse transcription polymerase chain reaction, western blot analysis, and immunocytochemistry were used to provide evidence of ER expression. Protein detection was carried out using a mouse monoclonal antibody raised against an epitope located in the ligand binding domain of the human receptor. Cellular localization was studied on formalin-fixed paraffin-embedded eye sections using conventional immunohistochemical techniques.

RESULTS:

 Gender and age differences in ER mRNA expression were observed in retina. The 65-kDa ER protein was detected in the retina and retinal pigment epithelium (RPE) of young female eyes but not in eye tissues dissected from men and postmenopausal women. Immunocytochemistry corroborated ER staining of a young female neurosensory retina and RPE. In addition, ER could be detected in the ciliary body, in the iris, and in the epithelium of the lens.

CONCLUSIONS:

 The presence of the ER in the human eye suggests that the sex steroid hormone axis may play a role in the pathogenesis of certain ocular diseases.

Significant gender-based differences in the incidence of many important ocular conditions raise the possibility that estrogens may have direct effects on the eye. Disorders such as age-related macular degeneration (AMD), idiopathic full-thickness macular hole, and cataract have been conclusively associated with gender and age in several epidemiologic studies. These investigations demonstrate an increased prevalence of high morbidity eye diseases in the elderly, and in postmenopausal women in particular.1 2 3 Furthermore, an elderly female population under estrogen replacement therapy has shown a reduced prevalence of nuclear cataract, indicating some beneficial effects of estrogens on lens physiology.4 Although other epidemiologic studies have suggested the prevalence of dry eye and glaucoma among the elderly, especially women, they involved different populations and different clinical end points and as such are inconclusive.5 6 7 Thus, the body of epidemiologic data points to an involvement of estrogens in the normal physiology of the human eye. A single study reported previously by Gans et al. failed to find estrogen and progesterone receptors in conjunctival human tissues.8

Estrogens are steroid hormones long known for their profound effects on both male and female reproductive systems. Estrogens regulate growth, differentiation, and function of diverse tissues both within and outside the reproductive system. The effects of estrogens are mediated by specific nuclear receptors, the estrogen receptor (ER) and ß types, that act as hormone-inducible transcription factors.9 10 11 Relatively recent findings demonstrate important roles of the steroid hormones in the cardiovascular system, in specific brain regions, in the liver, and in the maintenance of bone tissue. Despite the wide range of tissues influenced by estrogens and the broad transcriptional regulatory properties of the ligand-activated ERs, the literature contains limited evidence of these receptors in normal ocular tissues. This, and the large spectrum of physiological alterations occurring in women after the normal hormonal decline of menopause, or in males during andropause, motivated our studies. We report here that the type of estrogen receptor is normally present in the human eye and that gender and age differences may influence its expression.

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