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Thyroid Function and the Intraocular Pressure Response to Topical Corticosteroids
THYROID FUNCTION ANDT H E INTRAOCULAR PRESSURE RESPONSE T O TOPICAL CORTICOSTEROIDS THEODORE KRUPIN, M . D . , LAURENCE S. JACOBS, M . D . , S T E V E N M . P O D O S , M . D . , AND B E R N A R D B E C K E R , M . D . St. Louis,
An increased prevalence of thyroid dysfunction * and an increased ocular sensitivity to topically applied glucocorticoids * are associated with primary open-angle glaucoma. Patients with primary open-angle glaucoma exhibit suppression of plasma Cortisol levels after small oral doses of dexamethasone that are ineffective in normal subjects. It would b e desirable to know if this increased sensitivity to systemic glucocorticoids represents a phenomenon restricted to the hypothalamic-pituitary-adrenal system, if it represents only one facet of generalized hypersensitivity to glucocorticoids, or if increased sensitivity occurs in some selected tissues but not others. Thyrotropin ( T S H ) secretion is sensitive to d e x a m e t h a s o n e . Although it was presumed in the initial studies * that dexamethasone suppression of T S H was a hypothalamic event, subsequent studies have demonstrated that dexamethasone in an appropriate dosage and for an appropriate duration of exposure inhibits pituitary thyrotropic cell responses to administered TSH-releasing hormone 1
3
2
4
5
Missouri
( T R H ) . Suppression of the system at either locus could lower basal serum T S H and thyroid hormone levels. In the present study, we measured levels of T S H and thyroid hormones before and after administration of varying oral doses of dexamethasone in patients with primary open-angle glaucoma and in subjects demonstrating the previously described spectrum of intraocular pressure responses to topical corticosteroids. 3
M A T E R I A L AND M E T H O D S
E a c h individual patient was classified according to final intraocular pressure response by applanation tonometry, after six weeks of topical 0 . 1 % dexamethasone: NN ( < 2 0 mm Hg), N G (20 to 3 1 mm Hg), or G G ( > 3 1 mm Hg). All patients with primary open-angle glaucoma had glaucomatous field loss. Patients with angleclosure glaucoma were excluded. A history of physical or laboratory evidence of thyroid disease eliminated the patient from the study. None of the subjects were receiving oral contraceptives, diphenylhydantoin, or large doses of salicylates. We obtained baseline 8 AM fasting venous blood samples from 4 3 NN, 4 0 From the Glaucoma Center, Department of Oph- N G , and 2 1 G G subjects and 5 1 patients thalmology (Drs. Krupin, Podos, and Becker), and with primary open-angle glaucoma. Dexathe Metabolism Division and the Department of Medicine (Dr. Jacobs), Washington University methasone suppression of thyroid funcSchool of Medicine, St. Louis, Missouri. This study tion was studied in 2 7 NN subjects and in was supported in part by National Eye Institute 3 3 patients with primary open-angle glaugrant EY 00336; by a grant-in-aid from the National Society for the Prevention of Blindness, Inc. (Dr. coma. After we obtained baseline samples Krupin); by research grant 5 R 01-AM 05105; by for tetraiodothyronine ( T ) and triiodoDiabetes Center grant 5 P 30-AM 17904; and by thyronine ( T ) uptake tests and T S H dePublic Health Service research career development award 5 K 04-AM 70521 (Dr. Jacobs) from the terminations, subjects took 0 . 2 5 , 1, or 2 National Institute of Arthritis, Metabolism, and Di- mg of dexamethasone orally every five gestive Diseases. hours in four doses, beginning at 8 AM Reprint requests to Theodore Krupin, M.D., Department of Ophthalmology, 660 S. Euclid, St. and ending at 11 P M , for total doses of 1, Louis, MO 63110. 2, or 8 mg. Repeat blood samples were 6-12
6
7
8 - 1 2
4
3
643
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AMERICAN JOURNAL OF OPHTHALMOLOGY
obtained at 8 AM for the next two days for repeat analyses. Serum thyroxine and T resin uptake were determined by using a radioimmunoassay for T test and materials for T resin uptake measurements. Serum T S H was measured by radioimmunoassay. Iodination of T S H was carried out by the lactoperoxidase technique and tracer was repurified on columns of porous Polyacrylamide beads with an exclusion limit of 60,000 molecular weight on the day of use in order to minimize tracer aggregate and free iodide components. Preliminary experiments demonstrated that the system tolerated as much as 4 0 % serum without any change in blank, maximal binding, or concentration of T S H needed for 5 0 % or half inhibition of maximum binding. Data were obtained from assays in which 4 0 0 u.1 of serum was tested in a total incubation volume of 1 ml. T o attain maximal sensitivity, disequilibrium conditions were employed, with two days of incubation without tracer followed by four days with tracer. Bound and free hormones were separated by the double antibody method. T h e sensitivity of these assays was such that as little as 0.15 to 0.30 u,U/ml of T S H was detectable. Statistics were performed by using the Student's i-test.
MAY, 1977
in Table 1. There was no significant difference (P > .5) between the categories for T4, T3 resin uptake, or T S H tests. Baseline T S H for the combined NN-NG individuals was not significantly different from that of the combined group of G G subjects and patients with primary openangle glaucoma (P > .1). T h e distribution of the thyroid studies was also similar among the groups of patients. The systemic administration of dexamethasone resulted in a dose-dependent suppression of serum T S H . All three dexamethasone dosages were administered to five NN subjects and to five patients with primary open-angle glaucoma. T h e results in these ten patients were similar to those obtained in the entire group (Table 2). There was no significant difference in the T S H suppression between NN individuals and patients with primary openangle glaucoma. T h e 24-hour T S H rebound was also similar between these two groups. Dexamethasone administration did not cause any alteration of T or T resin uptake.
3
4
3
13
14
4
3
DISCUSSION
Becker, Kölker, and B a l l i n and M c L e nachan and Davies found low normal levels of protein bound iodine ( P B I ) and radioactive iodine ( I ) uptake measurements in patients with primary openangle glaucoma. All tests of thyroid function are limited and subject to interference by factors unrelated to the thyroid. 1
2
1 3 1
RESULTS
Baseline 8 AM thyroid functions for the four categories of patients are presented
TABLE 1 B A S E L I N E THYROID FUNCTIONS (MEAN ±
Category
No. of Patients
NN NC GG POAG*
43 40 21 51
Age, yrs 52.3 52.6 54.9 60.0
± ± ± ±
3.3 2.7 3.1 3.2
*POAG, primary open-angle glaucoma.
T (M-g/dl) 4
7.1 7.2 7.0 7.1
± ± ± ±
0.3 0.3 0.3 0.2
SEM)
T Uptake (%) 3
38.6 38.2 39.1 39.7
± ± ± ±
0.8 0.8 1.0 1.0
T S H (u-U/ml) 2.1 2.2 1.6 1.7
± ± ± ±
0.2 0.3 0.2 0.2
VOL. 83 NO. 5
THYROID FUNCTION AND INTRAOCULAR PRESSURE TABLE 2
TSH-DEXAMETHASONE SUPPRESSION (MEAN ±
Dexamethasone Dose, mg*
No. of Patients/ Group
1 2 8
10 8 16
SEM)
8 AM! / 8 AMot GlauNN coma 0.87 ± 0.1 0.45 ± 0.1 0.33 ± 0.06
0.95 ± 0.1 0.45 ± 0.1 0.26 ± 0.03
*Oral dexamethasone administration—total number of milligrams per 24-hour day. tBaseline TSH level (8 AM ) divided into TSH the day after dexamethasone administration (8 AM^. 0
T h e major drawback o f the P B I test is its lack of specificity in that it measures nonhormonal forms of iodine in the blood. A similar drawback of the I uptake measurement is its strong dependence on the iodide pool size. Competitive binding or radioimmunoassay measurements of thyroid hormones are not altered by iodide or nonhormonal organic iodine contamination. In the present study no difference in baseline thyroid function occurred between the various categories of patients classified according to their topical corticosteroid responsiveness. 1 3 1
Primary open-angle glaucoma is associated with an increased sensitivity o f intraocular pressure to glucocorticoids when applied topically, and of suppression of the hypothalamic-pituitary-adrenal axis when administered systemically. In addition, lymphocytes from patients with primary open-angle glaucoma exhibit increased sensitivity to glucocorticoid inhibition of phytohemagglutinin-induced blastogenesis. Patients with primary open-angle glaucoma did not, however, demonstrate an increased sensitivity of T S H suppression to administered glucocorticoids in this study. Since dexamethasone suppression to T S H occurs in part and perhaps primarily at the adenohypophysis, and since hypothalamic-pitui15
645
tary-adrenal suppression by dexamethasone may be largely hypothalamic, the thyrotropic cell of the adenohypophysis generally may be less sensitive to glucocorticoid effects than the hypothalamus, the eye, and the lymphocyte in primary open-angle glaucoma. SUMMARY
Baseline thyroxine, thyrotropin ( T S H ) , and triiodothyronine ( T ) resin uptake levels were measured in patients classified according to their topical intraocular response to corticosteroids. Results of thyroid studies were similar in patients with primary open-angle glaucoma and noncorticosteroid responsive (NN, intraocular pressure less than 2 0 m m H g after six weeks o f topical 0 . 1 % dexamethasone eyedrops) subjects. Primary openangle glaucoma was not associated with the increased prevalence of low thyroid function values. T h e T S H suppression induced by oral dexamethasone was similar in NN subjects and patients with primary open-angle glaucoma. Patients with primary open-angle glaucoma did not demonstrate an increased glucocorticoid sensitivity as related to thyroid function. T h u s , the adenohypophysial thyrotropic cell, the major site of dexamethasone inhibition o f T S H secretion, does not appear to share the enhanced corticosteroid sensitivity of the eye, the hypothalamus, and the lymphocyte in patients with primary open-angle glaucoma. 3
REFERENCES 1. Becker, B., Kölker, A. E . , and Ballin, N.: Thyroid function and glaucoma. Am. J. Ophthalmol. 61:997, 1966. 2. McLenachan, J., and Davies, D. M.: Glaucoma and the thyroid. Br. J. Ophthalmol. 49:441, 1965. 3. Becker, B.: Intraocular pressure response to topical corticosteroids. Invest. Ophthalmol. 4:198, 1965. 4. Armaly, M. F . : Effect of corticosteroids on intraocular pressure and fluid dynamics. Arch. Ophthalmol. 70:482, 1963. 5. Becker. B., Podos, S. M., Asseff, C. F., and
646
AMERICAN JOURNAL O F OPHTHALMOLOGY
Cooper, D. G.: Plasma Cortisol suppression in glaucoma. Am. J. Ophthalmol. 75:73, 1973. 6. Wilber, J. F., and Utiger, R. D.: The effect of glucocorticoids on thyrotropin secretion. J . Clin. Invest. 48:2096, 1969. 7. Nicoloff, J. T., Fisher, D. A., and Appleman, M. D., Jr.: The role of glucocorticoids in the regulation of thyroid function in man. J . Clin. Invest. 49:1922, 1970. 8. Otsuki, M., Dakoda, M., and Baba, S.: Influence of glucocorticoids on TRF-induced TSH response in man. J. Clin. Endocrinol. Metab. 36:95, 1973. 9. Faglia, G., Ferrari, C , Beck-Peccoz, P., Spada, A., Travaglini, P., and Ambrosi, B.: Reduced plasma thyrotropin response to thyrotropin releasing hormone after dexamethasone administration in normal subjects. Hormone Metab. Res. 5:289, 1973. 10. Polosa, P., Vigneri, R., Papalia, D., Squatrito, S., and Motta, L.: Inhibition by L-triiodothyronine
MAY, 1977
and dexamethasone of TSH response to thyrotropin releasing hormone in man. Ann. Endocrinol., 33: 593, 1972. 11. Tolis, G., Friesen, H. G., Bowers, C. Y., and McKenzie, J. M.: Glucocorticoids and thyrotropin releasing hormone (TRH) secretion. Neuroendocrinol. 15:245, 1974. 12. Dussault, J. H.: The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation. Can. Med. Assoc. J. 111:1195, 1974. 13. Utiger, R. D.: Radioimmunoassay of human plasma thyrotropin. J. Clin. Invest. 44:1277, 1965. 14. Thorell, J. I., and Johansson, B. G.: Enzymatic iodination of polypeptides with I to high specific activity. Biochim. Biophys. Acta 251:363, 1971. 15. Bigger, J. F., Palmberg, P. F., and Becker, B.: Increased cellular sensitivity to glucocorticoids in primary open-angle glaucoma. Invest. Ophthalmol. 11:832, 1972. J 2 !
OPHTHALMIC MINIATURE
Philip: What say'st thou, b o y ? L o o k in the lady's face. L e w i s : I do, my lord, and in her eye I find a wonder, or a wondrous miracle, the shadow of myself form'd in her eye, which, being but the shadow o f your son, becomes a sun and makes your son a shadow: I do protest I never lov'd myself till now infixed I beheld myself drawn in the flattering table o f her eye. The Life
William Shakespeare, and Death of King John
An increased prevalence of thyroid dysfunction * and an increased ocular sensitivity to topically applied glucocorticoids * are associated with primary open-angle glaucoma. Patients with primary open-angle glaucoma exhibit suppression of plasma Cortisol levels after small oral doses of dexamethasone that are ineffective in normal subjects. It would b e desirable to know if this increased sensitivity to systemic glucocorticoids represents a phenomenon restricted to the hypothalamic-pituitary-adrenal system, if it represents only one facet of generalized hypersensitivity to glucocorticoids, or if increased sensitivity occurs in some selected tissues but not others. Thyrotropin ( T S H ) secretion is sensitive to d e x a m e t h a s o n e . Although it was presumed in the initial studies * that dexamethasone suppression of T S H was a hypothalamic event, subsequent studies have demonstrated that dexamethasone in an appropriate dosage and for an appropriate duration of exposure inhibits pituitary thyrotropic cell responses to administered TSH-releasing hormone 1
3
2
4
5
Missouri
( T R H ) . Suppression of the system at either locus could lower basal serum T S H and thyroid hormone levels. In the present study, we measured levels of T S H and thyroid hormones before and after administration of varying oral doses of dexamethasone in patients with primary open-angle glaucoma and in subjects demonstrating the previously described spectrum of intraocular pressure responses to topical corticosteroids. 3
M A T E R I A L AND M E T H O D S
E a c h individual patient was classified according to final intraocular pressure response by applanation tonometry, after six weeks of topical 0 . 1 % dexamethasone: NN ( < 2 0 mm Hg), N G (20 to 3 1 mm Hg), or G G ( > 3 1 mm Hg). All patients with primary open-angle glaucoma had glaucomatous field loss. Patients with angleclosure glaucoma were excluded. A history of physical or laboratory evidence of thyroid disease eliminated the patient from the study. None of the subjects were receiving oral contraceptives, diphenylhydantoin, or large doses of salicylates. We obtained baseline 8 AM fasting venous blood samples from 4 3 NN, 4 0 From the Glaucoma Center, Department of Oph- N G , and 2 1 G G subjects and 5 1 patients thalmology (Drs. Krupin, Podos, and Becker), and with primary open-angle glaucoma. Dexathe Metabolism Division and the Department of Medicine (Dr. Jacobs), Washington University methasone suppression of thyroid funcSchool of Medicine, St. Louis, Missouri. This study tion was studied in 2 7 NN subjects and in was supported in part by National Eye Institute 3 3 patients with primary open-angle glaugrant EY 00336; by a grant-in-aid from the National Society for the Prevention of Blindness, Inc. (Dr. coma. After we obtained baseline samples Krupin); by research grant 5 R 01-AM 05105; by for tetraiodothyronine ( T ) and triiodoDiabetes Center grant 5 P 30-AM 17904; and by thyronine ( T ) uptake tests and T S H dePublic Health Service research career development award 5 K 04-AM 70521 (Dr. Jacobs) from the terminations, subjects took 0 . 2 5 , 1, or 2 National Institute of Arthritis, Metabolism, and Di- mg of dexamethasone orally every five gestive Diseases. hours in four doses, beginning at 8 AM Reprint requests to Theodore Krupin, M.D., Department of Ophthalmology, 660 S. Euclid, St. and ending at 11 P M , for total doses of 1, Louis, MO 63110. 2, or 8 mg. Repeat blood samples were 6-12
6
7
8 - 1 2
4
3
643
644
AMERICAN JOURNAL OF OPHTHALMOLOGY
obtained at 8 AM for the next two days for repeat analyses. Serum thyroxine and T resin uptake were determined by using a radioimmunoassay for T test and materials for T resin uptake measurements. Serum T S H was measured by radioimmunoassay. Iodination of T S H was carried out by the lactoperoxidase technique and tracer was repurified on columns of porous Polyacrylamide beads with an exclusion limit of 60,000 molecular weight on the day of use in order to minimize tracer aggregate and free iodide components. Preliminary experiments demonstrated that the system tolerated as much as 4 0 % serum without any change in blank, maximal binding, or concentration of T S H needed for 5 0 % or half inhibition of maximum binding. Data were obtained from assays in which 4 0 0 u.1 of serum was tested in a total incubation volume of 1 ml. T o attain maximal sensitivity, disequilibrium conditions were employed, with two days of incubation without tracer followed by four days with tracer. Bound and free hormones were separated by the double antibody method. T h e sensitivity of these assays was such that as little as 0.15 to 0.30 u,U/ml of T S H was detectable. Statistics were performed by using the Student's i-test.
MAY, 1977
in Table 1. There was no significant difference (P > .5) between the categories for T4, T3 resin uptake, or T S H tests. Baseline T S H for the combined NN-NG individuals was not significantly different from that of the combined group of G G subjects and patients with primary openangle glaucoma (P > .1). T h e distribution of the thyroid studies was also similar among the groups of patients. The systemic administration of dexamethasone resulted in a dose-dependent suppression of serum T S H . All three dexamethasone dosages were administered to five NN subjects and to five patients with primary open-angle glaucoma. T h e results in these ten patients were similar to those obtained in the entire group (Table 2). There was no significant difference in the T S H suppression between NN individuals and patients with primary openangle glaucoma. T h e 24-hour T S H rebound was also similar between these two groups. Dexamethasone administration did not cause any alteration of T or T resin uptake.
3
4
3
13
14
4
3
DISCUSSION
Becker, Kölker, and B a l l i n and M c L e nachan and Davies found low normal levels of protein bound iodine ( P B I ) and radioactive iodine ( I ) uptake measurements in patients with primary openangle glaucoma. All tests of thyroid function are limited and subject to interference by factors unrelated to the thyroid. 1
2
1 3 1
RESULTS
Baseline 8 AM thyroid functions for the four categories of patients are presented
TABLE 1 B A S E L I N E THYROID FUNCTIONS (MEAN ±
Category
No. of Patients
NN NC GG POAG*
43 40 21 51
Age, yrs 52.3 52.6 54.9 60.0
± ± ± ±
3.3 2.7 3.1 3.2
*POAG, primary open-angle glaucoma.
T (M-g/dl) 4
7.1 7.2 7.0 7.1
± ± ± ±
0.3 0.3 0.3 0.2
SEM)
T Uptake (%) 3
38.6 38.2 39.1 39.7
± ± ± ±
0.8 0.8 1.0 1.0
T S H (u-U/ml) 2.1 2.2 1.6 1.7
± ± ± ±
0.2 0.3 0.2 0.2
VOL. 83 NO. 5
THYROID FUNCTION AND INTRAOCULAR PRESSURE TABLE 2
TSH-DEXAMETHASONE SUPPRESSION (MEAN ±
Dexamethasone Dose, mg*
No. of Patients/ Group
1 2 8
10 8 16
SEM)
8 AM! / 8 AMot GlauNN coma 0.87 ± 0.1 0.45 ± 0.1 0.33 ± 0.06
0.95 ± 0.1 0.45 ± 0.1 0.26 ± 0.03
*Oral dexamethasone administration—total number of milligrams per 24-hour day. tBaseline TSH level (8 AM ) divided into TSH the day after dexamethasone administration (8 AM^. 0
T h e major drawback o f the P B I test is its lack of specificity in that it measures nonhormonal forms of iodine in the blood. A similar drawback of the I uptake measurement is its strong dependence on the iodide pool size. Competitive binding or radioimmunoassay measurements of thyroid hormones are not altered by iodide or nonhormonal organic iodine contamination. In the present study no difference in baseline thyroid function occurred between the various categories of patients classified according to their topical corticosteroid responsiveness. 1 3 1
Primary open-angle glaucoma is associated with an increased sensitivity o f intraocular pressure to glucocorticoids when applied topically, and of suppression of the hypothalamic-pituitary-adrenal axis when administered systemically. In addition, lymphocytes from patients with primary open-angle glaucoma exhibit increased sensitivity to glucocorticoid inhibition of phytohemagglutinin-induced blastogenesis. Patients with primary open-angle glaucoma did not, however, demonstrate an increased sensitivity of T S H suppression to administered glucocorticoids in this study. Since dexamethasone suppression to T S H occurs in part and perhaps primarily at the adenohypophysis, and since hypothalamic-pitui15
645
tary-adrenal suppression by dexamethasone may be largely hypothalamic, the thyrotropic cell of the adenohypophysis generally may be less sensitive to glucocorticoid effects than the hypothalamus, the eye, and the lymphocyte in primary open-angle glaucoma. SUMMARY
Baseline thyroxine, thyrotropin ( T S H ) , and triiodothyronine ( T ) resin uptake levels were measured in patients classified according to their topical intraocular response to corticosteroids. Results of thyroid studies were similar in patients with primary open-angle glaucoma and noncorticosteroid responsive (NN, intraocular pressure less than 2 0 m m H g after six weeks o f topical 0 . 1 % dexamethasone eyedrops) subjects. Primary openangle glaucoma was not associated with the increased prevalence of low thyroid function values. T h e T S H suppression induced by oral dexamethasone was similar in NN subjects and patients with primary open-angle glaucoma. Patients with primary open-angle glaucoma did not demonstrate an increased glucocorticoid sensitivity as related to thyroid function. T h u s , the adenohypophysial thyrotropic cell, the major site of dexamethasone inhibition o f T S H secretion, does not appear to share the enhanced corticosteroid sensitivity of the eye, the hypothalamus, and the lymphocyte in patients with primary open-angle glaucoma. 3
REFERENCES 1. Becker, B., Kölker, A. E . , and Ballin, N.: Thyroid function and glaucoma. Am. J. Ophthalmol. 61:997, 1966. 2. McLenachan, J., and Davies, D. M.: Glaucoma and the thyroid. Br. J. Ophthalmol. 49:441, 1965. 3. Becker, B.: Intraocular pressure response to topical corticosteroids. Invest. Ophthalmol. 4:198, 1965. 4. Armaly, M. F . : Effect of corticosteroids on intraocular pressure and fluid dynamics. Arch. Ophthalmol. 70:482, 1963. 5. Becker. B., Podos, S. M., Asseff, C. F., and
646
AMERICAN JOURNAL O F OPHTHALMOLOGY
Cooper, D. G.: Plasma Cortisol suppression in glaucoma. Am. J. Ophthalmol. 75:73, 1973. 6. Wilber, J. F., and Utiger, R. D.: The effect of glucocorticoids on thyrotropin secretion. J . Clin. Invest. 48:2096, 1969. 7. Nicoloff, J. T., Fisher, D. A., and Appleman, M. D., Jr.: The role of glucocorticoids in the regulation of thyroid function in man. J . Clin. Invest. 49:1922, 1970. 8. Otsuki, M., Dakoda, M., and Baba, S.: Influence of glucocorticoids on TRF-induced TSH response in man. J. Clin. Endocrinol. Metab. 36:95, 1973. 9. Faglia, G., Ferrari, C , Beck-Peccoz, P., Spada, A., Travaglini, P., and Ambrosi, B.: Reduced plasma thyrotropin response to thyrotropin releasing hormone after dexamethasone administration in normal subjects. Hormone Metab. Res. 5:289, 1973. 10. Polosa, P., Vigneri, R., Papalia, D., Squatrito, S., and Motta, L.: Inhibition by L-triiodothyronine
MAY, 1977
and dexamethasone of TSH response to thyrotropin releasing hormone in man. Ann. Endocrinol., 33: 593, 1972. 11. Tolis, G., Friesen, H. G., Bowers, C. Y., and McKenzie, J. M.: Glucocorticoids and thyrotropin releasing hormone (TRH) secretion. Neuroendocrinol. 15:245, 1974. 12. Dussault, J. H.: The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation. Can. Med. Assoc. J. 111:1195, 1974. 13. Utiger, R. D.: Radioimmunoassay of human plasma thyrotropin. J. Clin. Invest. 44:1277, 1965. 14. Thorell, J. I., and Johansson, B. G.: Enzymatic iodination of polypeptides with I to high specific activity. Biochim. Biophys. Acta 251:363, 1971. 15. Bigger, J. F., Palmberg, P. F., and Becker, B.: Increased cellular sensitivity to glucocorticoids in primary open-angle glaucoma. Invest. Ophthalmol. 11:832, 1972. J 2 !
OPHTHALMIC MINIATURE
Philip: What say'st thou, b o y ? L o o k in the lady's face. L e w i s : I do, my lord, and in her eye I find a wonder, or a wondrous miracle, the shadow of myself form'd in her eye, which, being but the shadow o f your son, becomes a sun and makes your son a shadow: I do protest I never lov'd myself till now infixed I beheld myself drawn in the flattering table o f her eye. The Life
William Shakespeare, and Death of King John