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To determine if there is a difference in response to metyrapone, which blocks the conversion of 11-deoxycortisol to cortisol in the adrenal gland between normals and ocular hypertensives (OH) plus primary open-angle glaucomas (POAG) without pigmented angles.Intravenous metyrapone was given to 20 normals and 15 ocular hypertensives plus primary open-angle glaucomas without pigmented angles. Blood samples were obtained at 4, 6, and 8 hours after administration of intravenous metyrapone for analyses of 11-deoxycortisol and cortisol.The ocular hypertensives plus primary open-angle glaucoma group showed significantly lower cortisol values compared with the normal group at 6 hours (P = 0.002) but not at 4 or 8 hours. There were no significant differences between the two groups for 11-deoxycortisol values at 4, 6, or 8 hours. The percent decrease of plasma cortisol from baseline was significantly greater for the ocular hypertensives plus open-angle glaucoma group compared with the normals at 4 hours (P = 0.010) and 6 hours (P = 0.0004). Significant negative correlations were observed for the total group of subjects between levels of plasma cortisol at 6 hours and intraocular pressure, worse eye (P = 0.029), percent area of cupping, worse eye (P = 0.045), pallor, worse eye (P = 0.001), and visual field loss, worse eye (P = 0.048), so that the less the plasma cortisol, the greater the abnormality of the glaucomatous parameters. Multivariate analyses with the 6-hour plasma cortisol level as the dependent variable showed that the only significant (P = 0.0004) independent variable was the percent area of pallor, worse eye, associated with a smaller level of plasma cortisol at 6 hours. Similarly, the multiple regression models using the percent change from baseline of the 6-hour plasma cortisol value showed a significant association of larger percent decreases of plasma cortisol in the ocular hypertensives plus open-angle glaucoma compared with the normals.The ocular hypertensives plus primary open-angle glaucoma subjects show greater adrenal inhibition to metyrapone in the synthesis of cortisol from 11-deoxycortisol compared with normals. This observation suggests an adrenal abnormality in the ocular hypertensive plus primary open-angle glaucoma subjects.