Glaucoma - Dihydrocortisol Abstracts 1

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Altered cortisol metabolism in cells cultured from trabecular meshwork specimens obtained from patients with primary open-angle glaucoma

            (Southren, Gordon et al. 1983) Download

Cells cultured from trabecular meshwork specimens obtained from patients with primary open angle glaucoma (TMPOAG cells) exhibited two major differences in cortisol-metabolizing enzymes when compared with similar cells from nonglaucomatous patients. One is a marked increase (greater than 100-fold) in delta 4-reductase activity and the other is a decrease (4-fold) in 3-oxidoreductase activity. Peripheral lymphocytes from one of these patients as well as from five additional patients with POAG, did not show these abnormalities, indicating that the defects are not found in all cortisol-metabolizing cells. The abnormal metabolism of cortisol by TMPOAG cells may be of significance in the pathogenesis of POAG.

5 beta-Dihydrocortisol: possible mediator of the ocular hypertension in glaucoma

            (Southren, Gordon et al. 1985) Download

5 beta-dihydrocortisol potentiates the action of topically applied dexamethasone in raising the intraocular pressure (IOP) in young rabbits. Dexamethasone (0.06%) plus 5 beta-dihydrocortisol (0.1 and 1.0%) elevated the IOP 7-10 mmHg within 18 days of treatment. By contrast, 0.06% dexamethasone alone raised the IOP 3 to 4 mmHg in a similar period of time. Since 5 beta-dihydrocortisol accumulates abnormally in cultured cells derived from the outflow region of the eye from patients with primary open angle glaucoma (POAG), a similar potentiation in man may account for the sensitivity of these patients to the IOP raising effect of glucocorticoids. Further, this metabolite may potentiate endogenous glucocorticoids resulting in the ocular hypertension characteristic of POAG.

Potentiation of collagen synthesis in explants of the rabbit eye by 5 beta-dihydrocortisol

            (Southren, Hernandez et al. 1986) Download

The biologic effect of 5 beta-dihydrocortisol on collagen synthesis was evaluated. The metabolite was found to potentiate subthreshold levels of dexamethasone in increasing 3H-proline incorporation in cells of the outflow region of the rabbit. Digestion of the tissue with highly purified collagenase indicated that the 3H-proline was incorporated into collagen type protein. This study demonstrates another biologic activity of 5 beta-dihydrocortisol, a metabolite found to accumulate in cells cultured from trabeculectomy specimens from patients with primary open angle glaucoma.

Intraocular hypotensive effect of a topically applied cortisol metabolite: 3 alpha, 5 beta-tetrahydrocortisol

            (Southren, l'Hommedieu et al. 1987) Download

3 alpha, 5 beta-tetrahydrocortisol, previously considered an inactive metabolite of cortisol, was found to lower significantly the intraocular pressure (IOP) of rabbits made ocular hypertensive with dexamethasone alone or with threshold levels of dexamethasone plus 5 beta-dihydrocortisol. The ocular hypotensive effect appeared within 3-7 days after the metabolite was started and persisted through the duration of the experiments. The metabolite did not lower the IOP of ocular normotensive untreated animals. Thus, 3 alpha,5 beta-tetrahydrocortisol is a naturally occurring steroid antagonist, which may be of use in the treatment of primary open-angle glaucoma.

Potentiation of glucocorticoid activity by 5 beta-dihydrocortisol: its role in glaucoma

            (Weinstein, Gordon et al. 1983) Download

5 beta-Dihydrocortisol potentiated the threshold level (the smallest dose producing a measurable effect) of topically applied cortisol (0.02 percent) and dexamethasone (0.003 percent) in causing nuclear translocation of the cytosolic glucocorticoid receptor in rabbit iris-ciliary body tissue. 5 beta-Dihydrocortisol accumulates in cells cultured from trabecular meshwork specimens from patients with primary open-angle glaucoma, but not in similar cells derived from nonglaucomatous patients. In view of the sensitivity of patients with primary open-angle glaucoma to the effects of glucocorticoids in raising intraocular pressure, this potentiation may be responsible for the steroid sensitivity and for the ocular hypertension seen in this disorder.

Defects in cortisol-metabolizing enzymes in primary open-angle glaucoma

            (Weinstein, Munnangi et al. 1985) Download

Assays of cortisol-metabolizing enzymes in homogenates of human trabecular meshwork cells under optimal conditions revealed two defects in primary open-angle glaucoma (POAG): one is a marked increase in delta 4-reductase and the other is a decrease in 3-oxidoreductase. Experiments indicated that the differences in enzyme activities seen between POAG and nonPOAG trabecular meshwork derived cell homogenates were due to altered amounts of enzymes rather than to alterations in cofactor availability, pH, or endogenous activators or inhibitors. This clearly demonstrates an enzymatic defect(s) in POAG which may be the basis for the ocular hypertension and sensitivity to exogenous glucocorticoids seen in this disorder.

5 alpha-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro

            (Weinstein, Kandalaft et al. 1991) Download

Glucocorticoids have long been implicated in the etiology of primary open-angle glaucoma (POAG) and cataract. Cortisol metabolites have biologic activity and may affect aqueous humor dynamics. This study was done to determine whether these metabolites are found in human aqueous humor and can be produced by ocular tissues. Radioimmunoassays (RIA) were developed for 5 alpha-dihydrocortisol (5 alpha-DHF) and 5 beta-dihydrocortisol (5 beta-DHF). These assays, as well as a cortisol RIA, were used to quantify these three steroids in 20 surgically derived aqueous humor specimens from patients with and without POAG. The mean concentrations of cortisol and 5 alpha-DHF were 2.5 and 1.3 ng/ml, respectively. In the small group studied, there was no statistically significant difference between the aqueous humor steroid levels in patients with and without POAG. The amount of 5 beta-DHF was at the lower limits of detection of the assay system and could not be uniquivocally shown. Human lenses metabolized cortisol in vitro to 5 alpha-DHF and 3 alpha,5 alpha-tetrahydrocortisol (3 alpha,5 alpha-THF). There was no 5 beta-DHF or cortisone formed. The 5 alpha-DHF and 3 alpha,5 alpha-THF were identified by their positions on thin-layer chromatography, their retention times on high-performance liquid chromatography, and recrystallization with authentic standards to constant specific activity. The data suggest that the lens is the source of 5 alpha-DHF in aqueous humor.

Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma

            (Weinstein, Iyer et al. 1996) Download

The purpose of the present study was to determine whether peripheral blood lymphocytes (PBL) from primary open angle glaucoma (POAG) patients have reduced 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity as was previously found in POAG-derived cultured trabecular meshwork cells. The availability of PBL from both POAG and control patients makes this a useful system for studying the association of decreased 3 alpha-HSD activity with POAG. PBL were isolated from the venous blood of 17 POAG patients and 22 non-glaucoma controls and assayed for 3 alpha-HSD activity with tritiated 5 beta-dihydrocortisol as a substrate. The mean 3 alpha-HSD activity +/- S.E.M., expressed in comparable units of specific activity, of the POAG derived PBL was 13.8 +/- 1.3 U as compared to 32.8 +/- 2.0 U for control cells. This reduction (> 50%) was statistically significant (P < 0.001). Quantitative immunoblot analysis of PBL indicated that the POAG and control cells, despite their difference in 3 alpha-HSD activity, had nearly identical amounts of 3 alpha-HSD protein. The molecular weight of PBL 3 alpha-HSD from both groups of patients was 38,000, the same as previously reported for human liver. The results of this study show an association of decreased PBL 3 alpha-HSD activity and POAG which was not related to antiglaucoma therapy. The reduced levels of 3 alpha-HSD activity in the readily obtainable PBL may serve as a marker for POAG or those at risk for developing the disease.


References

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Iyer, R. B., J. M. Binstock, et al. (1990). "Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase(s)." Steroids 55(11): 495-500.

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Rivero-Marabe, J. J., J. I. Maynar-Marino, et al. (2001). "Determination of natural corticosteroids in urine samples from sportsmen." J Chromatogr B Biomed Sci Appl 761(1): 77-84.

Schoneshofer, M., B. Weber, et al. (1983). "Increased urinary excretion of free 20 alpha- and 20 beta-dihydrocortisol in a hypercortisolemic but hypocortisoluric patient with Cushing's disease." Clin Chem 29(2): 385-9.

Schoneshofer, M., B. Weber, et al. (1986). "Measurement of urinary free 20 alpha-dihydrocortisol in biochemical diagnosis of chronic hypercorticoidism." Clin Chem 32(5): 808-10.

Southren, A. L., G. G. Gordon, et al. (1985). "5 beta-Dihydrocortisol: possible mediator of the ocular hypertension in glaucoma." Invest Ophthalmol Vis Sci 26(3): 393-5.

Southren, A. L., G. G. Gordon, et al. (1983). "Altered cortisol metabolism in cells cultured from trabecular meshwork specimens obtained from patients with primary open-angle glaucoma." Invest Ophthalmol Vis Sci 24(10): 1413-7.

Southren, A. L., M. R. Hernandez, et al. (1986). "Potentiation of collagen synthesis in explants of the rabbit eye by 5 beta-dihydrocortisol." Invest Ophthalmol Vis Sci 27(12): 1757-60.

Southren, A. L., D. l'Hommedieu, et al. (1987). "Intraocular hypotensive effect of a topically applied cortisol metabolite: 3 alpha, 5 beta-tetrahydrocortisol." Invest Ophthalmol Vis Sci 28(5): 901-3.

Walker, B. R., D. I. Phillips, et al. (1998). "Increased glucocorticoid activity in men with cardiovascular risk factors." Hypertension 31(4): 891-5.

Weinstein, B. I., G. G. Gordon, et al. (1983). "Potentiation of glucocorticoid activity by 5 beta-dihydrocortisol: its role in glaucoma." Science 222(4620): 172-3.

Weinstein, B. I., R. B. Iyer, et al. (1996). "Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma." Exp Eye Res 62(1): 39-45.

Weinstein, B. I., N. Kandalaft, et al. (1991). "5 alpha-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro." Invest Ophthalmol Vis Sci 32(7): 2130-5.

Weinstein, B. I., P. Munnangi, et al. (1985). "Defects in cortisol-metabolizing enzymes in primary open-angle glaucoma." Invest Ophthalmol Vis Sci 26(6): 890-3.