Glaucoma - 11B-HSD and Cortisol

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In vivo evaluation of 11beta-hydroxysteroid dehydrogenase activity in the rabbit eye

            (Anderson, Carreiro et al. 2009) Download

PURPOSE: Steroids are used in a diverse range of conditions in clinical ophthalmology and one of the most significant complications is corticosteroid-induced glaucoma, which is characterized by an increase in intraocular pressure (IOP). 11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD1) is known to catalyze the interconversion of hormonally inactive cortisone to hormonally active cortisol and is widely expressed in the eye, particularly ciliary epithelium. Carbenoxolone (CBX), an 11beta-HSD1 inhibitor, has been shown to reduce IOP in healthy volunteers and patients with ocular hypertension (OHT). The purpose of this study was to: (1) develop an in vivo model for the assessment of cortisone to cortisol conversion in the eye, that is, 11beta-HSD1 activity and (2) assess the pharmacokinetic/pharmacodynamic relationship following topical treatment with 11beta-HSD1 inhibitors using an in vivo rabbit model. METHODS: Potent and selective 11beta-HSD1 inhibitors were topically administered to the rabbit eye and exogenous cortisone to endogenous cortisol conversion in the eye was assessed in rabbits. Tissues were then evaluated for cortisone, cortisol, and 11beta-HSD1 inhibitor levels by LC/MS/MS. Concomitantly cortisol activity in ocular tissue samples was determined using a secondary mechanistic pLuc-GRE assay. RESULTS: Topical treatment with potent and selective 11beta-HSD1 inhibitors resulted in complete inhibition in the conversion of cortisone to cortisol in the rabbit eye as well as decreased pLuc-GRE luciferase activity. The reduction of cortisone conversion was time- and dose-dependent as well as dependent on dosing volume (suggestive of increased spillover and washout with greater dosing volume). CONCLUSIONS: In conclusion, topical delivery of 11beta-HSD1 inhibitors can reduce or inhibit the conversion of cortisone to cortisol in the eye, indicating that the rabbit eye possesses an active enzyme for glucocorticoid synthesis. Dosing concentration and volume play an important role in the pharmacokinetic and pharmacodynamic effects of topically delivering an 11beta-HSD1 inhibitor. The rabbit model is useful for mechanistically assessing the conversion of cortisone to cortisol in the eye.

Basic sciences in clinical glaucoma: steroids, ocular hypertension, and glaucoma

            (Clark 1995) Download

Glucocorticoids (GC) can regulate aqueous humor outflow and have often been associated with primary open angle glaucoma (POAG). The ocular or systemic administration of glucocorticoids can cause the elevation of intraocular pressure by increasing aqueous humor outflow resistance via morphological and biochemical changes in the trabecular meshwork (TM). The ability of glucocorticoids to induce ocular hypertension is dependent on individual responsiveness, the potency of the glucocorticoid, the route of administration, and the duration of treatment. Glucocorticoid-induced ocular hypertension occurs not only in humans, but also in rabbits, cats, dogs, and nonhuman primates. Glucocorticoids have a multitude of effects on trabecular meshwork cells causing changes in TM protein expression, cytoskeletal organization, extracellular matrix deposition, cell shape, and cell function. Many of these changes in the TM may be responsible for the generation of glucocorticoid-induced ocular hypertension. There have been several reports of increased cortisol levels, altered cortisol metabolism, and differential glucocorticoid responsiveness in patients with ocular hypertension and POAG. However, there is as yet no clear evidence for a causal role between glucocorticoids and primary open angle glaucoma. Finally, there is evidence that a variety of steroids of differing pharmacological steroid classes can lower the elevated intraocular pressure (IOP) in glucocorticoid-induced ocular hypertension and/ or in glaucoma patients. Continued research in the coming years should (a) identify the molecular mechanisms responsible for glucocorticoid-induced ocular hypertension and glaucoma, (b) determine whether glucocorticoids play a role in the pathogenesis of primary open angle glaucoma, and (c) determine the therapeutic utility of anti-glaucoma steroids.

The role of steroids in outflow resistance

         (Clark and Wordinger 2009) Download

Glucocorticoid (GC)-induced ocular hypertension and secondary iatrogenic open-angle glaucoma are serious side effects of GC therapy. Its clinical presentation is similar in many ways to primary open-angle glaucoma, including increased aqueous outflow resistance and morphological and biochemical changes to the trabecular meshwork (TM). Therefore, a large number of studies have examined the effects of GCs on TM cells and tissues. GCs have diverse effects on the TM, altering TM cell functions, gene expression, extracellular matrix metabolism, and cytoskeletal structure. Some or all of these effects may be responsible for the increased outflow resistance associated with GC therapy. In contrast to GCs, several different classes of steroids appear to lower IOP. Additional research will help better define the molecular mechanisms responsible for GC-induced ocular hypertension and steroid-induced IOP lowering activity.

11beta-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

            (Draper and Stewart 2005) Download

Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2) catalyse the interconversion of hormonally active cortisol and inactive cortisone. The enzyme evolved from a metabolic pathway to a novel mechanism underpinning human disease with the elucidation of the role of the type 2 or 'kidney' isozyme and an inherited form of hypertension, 'apparent mineralocorticoid excess'. 'Cushing's disease of the kidney' arises because of a failure of 11beta-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid excess.Conversely, 11beta-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma). Here, the activation of cortisol from cortisone facilitates glucocorticoid hormone action at an autocrine level. The molecular basis for the putative human 11beta-HSD1 'knockout'--'cortisone reductase deficiency'--has recently been described, an observation that also answers a long standing conundrum relating to the set-point of 11beta-HSD1 activity. In each case, these clinical studies have been underpinned by studies in vitro and the manipulation of enzyme expression in vivo using recombinant mouse models.

Inhaled steroid use and glaucoma

            (Dreyer 1993) Download

Increased plasma noncortisol glucocorticoid activity in open-angle glaucoma

            (McCarty and Schwartz 1991) Download

Total biologic plasma glucocorticoid activity of normal, ocular hypertensive, and open-angle glaucoma patients was compared using a glucocorticoid receptor-based competitive binding assay. Multiple linear-regression analysis was used to adjust for the effects of significant ocular and nonocular variables, including therapy for glaucoma. The glaucoma patients had significantly greater plasma glucocorticoid activities than did normal subjects. A comparison of receptor-based assay values to values obtained with a cortisol radioimmunoassay showed that significant amounts of biologic glucocorticoid activity in the plasma of the glaucoma patients could not be explained by cortisol alone. In the normal and ocular hypertensive groups, however, virtually all of the plasma glucocorticoid activity could be accounted for by cortisol. These results suggest that in open-angle glaucoma patients, noncortisol glucocorticoids are responsible for elevating biologic plasma glucocorticoid activity. Thus, open-angle glaucoma may be associated with a disturbance of the hypothalamic-pituitary-adrenal axis that produces increased plasma levels of both cortisol and other noncortisol glucocorticoids.

Reduced plasma cortisol binding to albumin in ocular hypertension and primary open-angle glaucoma

            (McCarty and Schwartz 1999) Download

PURPOSE: To compare plasma cortisol binding as well as total plasma cortisol, free cortisol and percent free cortisol in normals, ocular hypertensives and primary high pressure open-angle glaucomas. METHODS: Blood samples were obtained on outpatient visits of 18 normals, 19 ocular hypertensives and 18 primary open-angle glaucomas. Plasma cortisol binding was determined after the endogenous steroids were removed by charcoal absorption. Scatchard analysis was used to determine both the affinity of binding and the cortisol binding capacity of corticosteroid binding globulin and albumin. Plasma total and free cortisol were measured by radioimmunoassay. RESULTS: Both the ocular hypertensive and the open-angle glaucomas in comparison to normals were found to have a highly significant reduced cortisol binding capacity to albumin (p = 0.006) with a borderline significantly increased binding affinity to plasma corticosteroid binding globulin (p = 0.0495) and no significant difference in binding affinity to albumin or cortisol binding capacity to plasma globulin. Both the ocular hypertensives and the open-angle glaucomas in comparison to normals were found to have significantly elevated levels of free cortisol (p = 0.012) and percent free cortisol (p = 0.003). Multivariate analyses showed that the reduced cortisol binding capacity to albumin was significantly associated with an increased percent free cortisol, with ocular hypertension and open-angle glaucoma and with male gender. CONCLUSION: Both ocular hypertension and primary open-angle glaucoma are associated with elevated levels of plasma free cortisol which are related to a reduced cortisol binding capacity to albumin.

Inhaled corticosteroids, family history, and risk of glaucoma

            (Mitchell, Cumming et al. 1999) Download

OBJECTIVE: Until recently, inhaled corticosteroids were not considered to cause elevated intraocular pressure (IOP), although topical and oral corticosteroids have been shown to do so in susceptible individuals. The authors aimed to (1) identify whether an association existed between inhaled corticosteroid use and elevated IOP or open-angle glaucoma and (2) determine whether this effect may have a genetic basis. DESIGN: Cross-sectional, population-based study of 3654 persons 49 to 97 years of age attending the Blue Mountains Eye Study, near Sydney, Australia. METHODS: A series of questions assessed use of inhaled and other corticosteroids as well as family history of glaucoma. Elevated IOP was assessed using applanation tonometry. Diagnosis of glaucoma was based on automated perimetry defects and optic disc signs but without reference to IOP. MAIN OUTCOME MEASURE: Statistical analysis of associations between inhaled corticosteroid use and elevated IOP or glaucoma, by family history, adjusting for other risk factors. RESULTS: Open-angle glaucoma was diagnosed in 108 subjects, and elevated IOP was found in 160 subjects. In persons with a glaucoma family history, there was a strong association between inhaled corticosteroid use and presence of either glaucoma or elevated IOP (odds ratio [OR], 2.6; 95% confidence interval, 1.2-5.8). The risk increased with higher doses (OR, 6.3; 95% CI, 1.0-38.6) for persons who used more than four puffs per day. These findings were not explained by concurrent use of oral or ocular corticosteroids. In persons without a family history of glaucoma, no association was found between use of inhaled corticosteroids and glaucoma or elevated IOP. CONCLUSIONS: These findings suggest an association between ever use of inhaled corticosteroids and a finding of elevated IOP or glaucoma in subjects with a glaucoma family history. Patients being treated with inhaled corticosteroids need review by an ophthalmologist if they report a glaucoma family history.

Type 1 11beta-hydroxysteroid dehydrogenase as universal drug target in metabolic diseases?

            (Oppermann 2006) Download

Glucocorticoid hormones play essential roles in adaptation to stress, regulation of metabolism and inflammatory responses. Their effects primarily depend on their binding to intracellular receptors leading to altered target gene transcription as well as on cell-type specific biotransformation between 11beta-hydroxy glucocorticoids and their 11-oxo metabolites. The latter effect is accomplished by two different 11beta-hydroxysteroid dehydrogenase isozymes, constituting a shuttle system between the receptor ligand cortisol and its non-binding precursor cortisone. Whereas the type 1 enzyme (11beta-HSD1) is in vitro a NADP(H)- dependent bidirectional enzyme, it reduces in most instances in vivo cortisone to active cortisol. The type 2 enzyme is an exclusive NAD+ dependent dehydrogenase of glucocorticoids, thus "protecting" the mineralocorticoid receptor against illicit occupation by cortisol. Inhibition of tissue-specific glucocorticoid activation by 11beta-HSD1 constitutes a promising target in the treatment of metabolic and cardiovascular diseases. Pharmacological inhibition leads in animal models to lowered hepatic glucose production and increased insulin sensitivity, the primary goals in therapy of diabetes mellitus. Importantly, 11beta-HSD1 activity appears to be intrinsically linked to all features of the metabolic syndrome, which could at least in animal experiments be modulated by use of synthetic selective inhibitors. Importantly, these features include not only insulin resistance but also dyslipidemia, obesity and arterial hypertension. Animal studies and pharmacological experiments suggest further unrelated target areas, for example improvement of cognitive function and treatment of glaucoma, due to the role of glucocorticoids and cellular activation by 11beta-HSD1 in these pathologies. The recent development of specific 11beta-HSD1 inhibitors coupled with advances on structural knowledge and regulation of the 11beta-HSD1 target has undoubtedly promoted the understanding of glucocorticoid control of metabolic regulation. Taken together, it appears that inhibitors against 11beta-HSD1 constitute a promising avenue for novel treatment strategies against the underlying causes of cardiovascular and other metabolic diseases.

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension

            (Rauz, Cheung et al. 2003) Download

BACKGROUND:Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes (11beta-HSD1 activating cortisol from cortisone, 11beta-HSD2 inactivating cortisol to cortisone). AIM: To analyse expression of 11beta-HSD in the human eye and investigate its putative role in AH formation. DESIGN: Multipart prospective study, including a randomized controlled clinical trial. METHODS: The expression of 11beta-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11beta-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11beta-HSD) on IOP. RESULTS: ISH defined expression of 11beta-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11beta-HSD1, with additional GR and MR, but not 11beta-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11beta-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p<0.0001). DISCUSSION: CBX lowers IOP in patients with ocular hypertension. Our data suggest that this is mediated through inhibition of 11beta-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11beta-HSD1 could provide a novel treatment for patients with glaucoma.

Steroid-Induced Iatrogenic Glaucoma

            (Razeghinejad and Katz 2011) Download

Steroids in susceptible individuals can cause a clinical condition similar to primary open-angle glaucoma. Five percent of the population are high steroid responders and develop an intraocular pressure (IOP) elevation of more than 15 mm Hg above baseline. IOP elevation may occur as early as 1 day to as late as 12 weeks after intravitreal triamcinolone in 20-65% of patients. On average, 75% of eyes with steroid implants require IOP-lowering therapy at some point within 3 years of follow-up. The exact mechanism of steroid-induced glaucoma is not totally understood, but decreased trabecular meshwork outflow is regarded as the main cause of IOP elevation. High-risk patients who receive steroids should be monitored closely and if they develop elevated IOP, steroids with lower potency or steroid-sparing agents should be used. The IOP usually returns to normal within 2-4 weeks after stopping the steroid. About 1-5% of patients do not respond to medical therapy and need surgery. Trabeculectomy, trabeculotomy, shunt surgery, and cyclodestructive procedures are among the methods employed. Removal of residual sub-Tenon or intravitreal steroids may help hasten the resolution of the steroid response. Early results with anecortave acetate, an analog of cortisol acetate with antiangiogenic activity, in controlling IOP have been promising.

Altered peripheral sensitivity to glucocorticoids in primary open-angle glaucoma

            (Stokes, Walker et al. 2003) Download

PURPOSE: Increased levels of glucocorticoids are associated with raised intraocular pressure (IOP). The activity of glucocorticoids is regulated at a prereceptor level by 11beta-hydroxysteroid dehydrogenases (11beta-HSD). This study was an investigation of the central and peripheral sensitivity to glucocorticoids in patients with POAG or ocular hypertension (OHT) and the differential metabolism of glucocorticoids by 11beta-HSDs. METHODS: Patients with POAG or OHT and normal control subjects were studied. Peripheral sensitivity to glucocorticoids was assessed as dermal blanching and central sensitivity by dexamethasone suppression testing. Daily production rates of glucocorticoids were determined by quantifying metabolites in 24-hour urine. Plasma cortisol levels were determined at baseline (9 AM) and after an overnight low-dose dexamethasone suppression test. In a separate study, plasma and aqueous humor cortisol levels were determined in patients with POAG and normal subjects. RESULTS: Patients with POAG exhibited a greater cutaneous vasoconstrictor response to glucocorticoids than patients with OHT and normal subjects (20.7 +/- 3.1 vs. 8.5 +/- 4.4 and 8.6 +/- 4.5 arbitrary units, respectively; P < 0.05 in each case). Total glucocorticoid production rates were not different between groups, nor were total circulating cortisol levels before or after suppression of the hypothalamic-pituitary-adrenal axis by dexamethasone or concentrations in aqueous humor. The ratio of urinary cortisol to cortisone metabolites was elevated in POAG versus normal control and OHT (1.74 +/- 0.13 vs. 1.34 +/- 0.11 and 1.32 +/- 0.14; P < 0.05 in each case), indicating a change in the balance of 11beta-HSDs, without a change in other metabolic pathways. CONCLUSIONS: Patients with POAG exhibit increased peripheral vascular sensitivity to glucocorticoids. Increased sensitivity of glucocorticoid receptors, may enhance local glucocorticoid action in the eye and exacerbate the adverse effects of glucocorticoids in this condition.

11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response

            (Tomlinson, Walker et al. 2004) Download

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

11Beta-hydroxysteroid dehydrogenase type 1 in human disease: a novel therapeutic target

            (Tomlinson 2005) Download

Patients with cortisol excess, Cushing's syndrome, develop a classical phenotype characterized by central obesity, hypertension, and increased cardiovascular mortality. Whilst this observation points to the importance of glucocorticoids, circulating cortisol excess is rare and does not explain the pathogenesis of many common conditions. At a tissue specific level, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) locally regenerates active cortisol from inactive cortisone amplifying glucocorticoid receptor activation in the context of normal circulating cortisol levels. Increased 11beta-HSD1 activity and expression have been implicated in the pathogenesis of many common conditions including, obesity, insulin resistance, the metabolic syndrome, polycystic ovarian syndrome, osteoporosis and glaucoma. Furthermore, selective 11beta-HSD1 inhibition has been proposed as a novel therapeutic strategy in many of these conditions. Here we review the role of 11beta-HSD1 in human disease and discuss the impact of selective 11beta-HSD1 inhibition.

11beta-hydroxysteroid dehydrogenase: unexpected connections

            (Walker and Stewart 2003) Download

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.

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.


Anderson, S., S. Carreiro, et al. (2009). "In vivo evaluation of 11beta-hydroxysteroid dehydrogenase activity in the rabbit eye." J Ocul Pharmacol Ther 25(3): 215-22.

Clark, A. F. (1995). "Basic sciences in clinical glaucoma: steroids, ocular hypertension, and glaucoma." J Glaucoma 4(5): 354-69.

Clark, A. F. and R. J. Wordinger (2009). "The role of steroids in outflow resistance." Exp Eye Res 88(4): 752-9.

Draper, N. and P. M. Stewart (2005). "11beta-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action." J Endocrinol 186(2): 251-71.

Dreyer, E. B. (1993). "Inhaled steroid use and glaucoma." N Engl J Med 329(24): 1822.

McCarty, G. R. and B. Schwartz (1991). "Increased plasma noncortisol glucocorticoid activity in open-angle glaucoma." Invest Ophthalmol Vis Sci 32(5): 1600-8.

McCarty, G. R. and B. Schwartz (1999). "Reduced plasma cortisol binding to albumin in ocular hypertension and primary open-angle glaucoma." Curr Eye Res 18(6): 467-76.

Mitchell, P., R. G. Cumming, et al. (1999). "Inhaled corticosteroids, family history, and risk of glaucoma." Ophthalmology 106(12): 2301-6.

Oppermann, U. (2006). "Type 1 11beta-hydroxysteroid dehydrogenase as universal drug target in metabolic diseases?" Endocr Metab Immune Disord Drug Targets 6(3): 259-69.

Rauz, S., C. M. Cheung, et al. (2003). "Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension." QJM 96(7): 481-90.

Razeghinejad, M. R. and L. J. Katz (2011). "Steroid-Induced Iatrogenic Glaucoma." Ophthalmic Res 47(2): 66-80.

Stokes, J., B. R. Walker, et al. (2003). "Altered peripheral sensitivity to glucocorticoids in primary open-angle glaucoma." Invest Ophthalmol Vis Sci 44(12): 5163-7.

Tomlinson, J. W. (2005). "11Beta-hydroxysteroid dehydrogenase type 1 in human disease: a novel therapeutic target." Minerva Endocrinol 30(1): 37-46.

Tomlinson, J. W., E. A. Walker, et al. (2004). "11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response." Endocr Rev 25(5): 831-66.

Walker, E. A. and P. M. Stewart (2003). "11beta-hydroxysteroid dehydrogenase: unexpected connections." Trends Endocrinol Metab 14(7): 334-9.

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