Sex steroid hormone metabolism takes place in human ocular cells

Department of Ophthalmology and Visual Science, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06510, USA.
The Journal of Steroid Biochemistry and Molecular Biology (Impact Factor: 3.63). 08/2003; 86(2):207-16. DOI: 10.1016/j.jsbmb.2003.08.001
Source: PubMed


Steroids are potentially important mediators in the pathophysiology of ocular diseases. In this study, we report on the gene expression in the human eye of a group of enzymes, the 17beta-hydroxysteroid dehydrogenases (17HSDs), involved in the biosynthesis and inactivation of sex steroid hormones. In the eye, the ciliary epithelium, a neuroendocrine secretory epithelium, co-expresses the highest levels of 17HSD2 and 5 mRNAs, and in lesser level 17HSD7 mRNA. The regulation of gene expression of these enzymes was investigated in vitro in cell lines, ODM-C4 and chronic open glaucoma (GCE), used as cell models of the human ciliary epithelium. The estrogen, 17beta-estradiol (10(-7) M) and androgen agonist, R1881 (10(-8) M) elicited in ODM-C4 and GCE cells over a 24 h time course a robust up-regulation of 17HSD7 mRNA expression. 17HSD2 was up-regulated by estradiol in ODM-C4 cells, but not in GCE cells. Under steady-state conditions, ODM-C4 cells exhibited a predominant 17HSD2 oxidative enzymatic activity. In contrast, 17HSD2 activity was low or absent in GCE cells. Our collective data suggest that cultured human ciliary epithelial cells are able to metabolize estrogen, androgen and progesterone, and that 17HSD2 and 7 in these cells are sex steroid hormone-responsive genes and 17HSD7 is responsible to keep on intra/paracrine estrogenic milieu.

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Available from: Julio Escribano, Oct 10, 2015
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    • "It was observed that 17β estradiol is present in ocular cells (HTM and RPE), which was further supported by the expression of the enzymes required to synthesize estrogen from cholesterol in these cells. Previous studies have demonstrated presence of estradiol synthesizing enzymes in human ocular surface and adnexal tissues (lacrimal and meibomian glands, corneal and conjunctival epithelium, ciliary epithelium etc.) [24], [25]. Expression of sex steroid hormone receptors were also found in multiple ocular tissues (cornea, conjunctiva, ciliary body, retina, RPE etc.) in different animals [26]. "
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    ABSTRACT: CYP1B1 has been implicated in primary congenital glaucoma with autosomal recessive mode of inheritance. Mutations in CYP1B1 have also been reported in primary open angle glaucoma (POAG) cases and suggested to act as a modifier of the disease along with Myocilin (MYOC). Earlier reports suggest that over-expression of myocilin leads to POAG pathogenesis. Taken together, we propose a functional interaction between CYP1B1 and myocilin where 17β estradiol acts as a mediator. Therefore, we hypothesize that 17β estradiol can induce MYOC expression through the putative estrogen responsive elements (EREs) located in its promoter and CYP1B1 could manipulate MYOC expression by metabolizing 17β estradiol to 4-hydroxy estradiol, thus preventing it from binding to MYOC promoter. Hence any mutation in CYP1B1 that reduces its 17β estradiol metabolizing activity might lead to MYOC upregulation, which in turn might play a role in glaucoma pathogenesis. It was observed that 17β estradiol is present in Human Trabecular Meshwork cells (HTM) and Retinal Pigment Epithelial cells (RPE) by immunoflouresence and ELISA. Also, the expression of enzymes related to estrogen biosynthesis pathway was observed in both cell lines by RT-PCR. Subsequent evaluation of the EREs in the MYOC promoter by luciferase assay, with dose and time dependent treatment of 17β estradiol, showed that the EREs are indeed active. This observation was further validated by direct binding of estrogen receptors (ER) on EREs in MYOC promoter and subsequent upregulation in MYOC level in HTM cells on 17β estradiol treatment. Interestingly, CYP1B1 mutants with less than 10% enzymatic activity were found to increase the level of endogenous myocilin in HTM cells. Thus the experimental observations are consistent with our proposed hypothesis that mutant CYP1B1, lacking the 17β estradiol metabolizing activity, can cause MYOC upregulation, which might have a potential implication in glaucoma pathogenesis.
    PLoS ONE 09/2012; 7(9):e45077. DOI:10.1371/journal.pone.0045077 · 3.23 Impact Factor
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    • "ERs have also been detected in the neuroendocrine secretory and metabolic ciliary epithelium. 17β-hydroxysteroid dehydrogenases (17HSDs), involved in the biosynthesis and inactivation for sex steroids, were shown to be under direct paracrine influence of 17β-estradiol, evidence of estrogen modulating its own fate within the eye [28]. The presence of estrogen receptors and metabolic machinery within the eye suggest that estrogens play more than a passive role in the retina. "
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    ABSTRACT: Estrogens play a critical role in the normal growth and development of humans and in recent years our understanding of their effects in the central nervous system (CNS) have been advancing rapidly. It is now known that estrogens influence synaptic plasticity, brain development, and memory. In addition, estrogens have been shown to be neuroprotective in degenerative disorders. The understanding of the influences of estrogens in the retina, as a component of the CNS, has not kept pace with the advances in understanding of the brain. Studies that have addressed the effects of estrogens on the retina, specifically those focusing on glaucoma, are examined here in the hope that estrogen therapy may be a viable option for treating retinal dystrophies and optic neuropathies.
    Molecular vision 02/2008; 14:1480-6. · 1.99 Impact Factor
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    ABSTRACT: Tear fluid plays a vital role in protecting the ocular surface and maintaining conditions optimal for ocular health and vision. Tear fluid may also potentially have a role as a diagnostic fluid, in a similar manner to the way in which saliva has increasingly been utilized for diagnostic tests. This study aimed to determine if tear fluid analysis could distinguish subjects classed as stressed, based on their scores on a validated psychological questionnaire, from non-stressed subjects. The levels of a number of molecules known to be involved in the stress response were investigated in tear fluid.Two of these stress mediators, cortisol and dehydroepiandrosterone (DHEA), were reported for the first time in tear fluid, while the remaining molecules, serotonin, secretory immunoglobulin A (sIgA) and the cytokines interleukin (IL)-1, IL-6, IL-8, IL-10, IL- 12p70 and TNF-, had already been reported in tears but not in relation to stress levels.After preliminary investigation of chromatographic methods, enzyme immunoassays were used to detect and quantitate all the molecules except for the cytokines, which were analysed on a flow cytometer using a cytometric bead array assay.The levels of tear cortisol, DHEA and the molar ratio of these two, [C/D], were significantly different between stressed and non-stressed groups, with cortisol being lower, DHEA higher and [C/D] lower in the stressed group. Further extensive investigation is required before the reliability of these potential biomarkers is confirmed. However, preliminary studies showed that tear cortisol and DHEA concentrations exhibited a diurnal variation, and while they showed considerable variation between individuals, the tear [C/D] showed a lower ratio of within-subject variance to between-subject variance than the saliva [C/D] or serum [C/D].Of the other molecules investigated, tear sIgA concentration normalised for tear protein concentration, as well as the levels of the cytokines IL-12p70 and IL-8, had some relationship to the stress level of the study’s subjects. However, further studies with larger subject groups are required before making firm conclusions on these markers.
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