Results from clinical studies

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Horatio Perry
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1 Estrogen-induced changes in biomechanics of the cornea as possible reason for keratectasia E. Spoerl, F. Raiskup-Wolf, V. Zubaty Department of Ophthalmology Carl Gustav Carus University Hospital Dresden Germany Results from clinical studies Corneal thickness changes during pregnancy (Weinreb,1988) Women have 13.5 times higher risk of regression after PRK, if they take oral contraceptives (Corbett, 1996) After lasik women with HRT show a higher risk for refractive regression (O Doherty, 2006) Women have 9 times higher risk to develop a keratectasia after lasik (Randelman, 2003) Keratoconus starts after puberty.

$5 times higher risk of regression after PRK, if they take oral contraceptives (Corbett, 1996) After lasik women with HRT show a higher risk for refractive$

2 Consumer Drug Information Estrogen have been reported to produce keratoconus (steepening of corneal curvature) and intolerance to contact lenses. Diane 35 Consumer Drug Information Diane-35 Pharmacology: Cyproterone Acetate--Ethinyl Estradiol. Diane-35 is a combination antiandrogen-estrogen for use in the treatment of androgen-dependent dermatological conditions in females. Indications: For the treatment of women with severe acne, unresponsive to oral antibiotic and other available treatments, with associated symptoms of androgenization, including seborrhea and mild hirsutism. Precautions: Ocular Disease: Progressive astigmatic error, possibly leading to keratoconus, has been noted in some myopic women receiving drugs of the estrogen/progestogen class. In women who developed myopia at or near puberty, and in whom myopia stabilized in adult life, estrogen/progestogen combinations after some 6 months of use have increased the refractive error 2- to 3-fold. Women with a family history of myopic astigmatism or keratoconus who are using such therapy may experience rapid advancement of the ocular disorder.

Diane-35 is a combination antiandrogen-estrogen for use in the treatment of androgen-dependent dermatological conditions in females.

3 Keratectasia Development of regression or keratectasia is connected with a reduction of the stiffness of the cornea. Our hypothesis: - estrogen posseses a structure modulating effect. Problem? Until now there are no investigations about the influence of estrogen on the biomechanical behaviour of the cornea.

Our hypothesis: - estrogen posseses a structure modulating effect. Problem?

4 Material and Methods Two groups of 12 fresh porcine corneas each were incubated in culture medium for 7 days: control group: only culture medium (MEM, Sigma-Aldrich, E2257) without ß-estradiol estradiol group: with 10 µm ß-estradiol (Biochrom AD, Germany) Strips 10x5mm (superior-inferior) Thickness with ultrasonic pachymetry Stress-strain measurement in a biomaterial tester Calculation of stress stress σ = force F/ cross sectional area A σ = F/w t w = width t = thickness t before = thickness before incubation = thickness after incubation t after

(superior-inferior) Thickness with ultrasonic pachymetry Stress-strain measurement in a biomaterial tester Calculation of stress stress σ

5 Results: Thickness change During incubation the thickness increased in the control group by 5.9 % in the estradiol group by 12.0 % (P=0.006) A decrease of stress of about 6.1 % may be expected. Results: stress at 10 % strain Stress in 10³ N/m² P= control estradiol control estradiol calculated with corneal thickness before incubation after incubation P=0.002 Decrease of stress by 36 %

Results: stress at 10 % strain Stress in 10³ N/m² 140 120 100 80 60 40 20 0 123.5 P=0.012 88.3 120.1 76.

6 Discussion Significant influence of estrogen on the biomechanics of the cornea It is not only an effect of hydration Stiffness-reducing effect of estrogen does not play an important role in normal conditions but can be clearly seen in a biomechanically weakened cornea (after PRK, Lasik, KK) Explanation of the stiffeness-reducing effect of estrogen It was generally believed that the role of estrogen and testosterone was gender specific. This is an oversimplification. Keratocytes contain estrogen receptores (ER-α and ER-ß) Cornea is an estrogen-responsive tissue. Estrogen causes an increase of glycosaminoglycans combined with a higher water binding capacity. Estrogen stimulates expression of matrix metalloproteinases and the degradation of type I collagen.

the role of estrogen and testosterone was gender specific. This is an oversimplification. Keratocytes contain estrogen receptores (ER-α and ER-ß) Cornea is an estrogen-responsive tissue.

7 Results from other studies: elevated estrogen level Skin: increase of thickness combined with accumulation of water and synthesis of hyaluronic acide Biomechanical properties: distensibility increased Results from other studies: reduced estrogen level The level of glycosaminoglycans is significantly reduced in cartilage in case of estrogen deficiency and an increase of stiffness follows (Claassen, 2006) Blood vessels show an increase of stiffness with lower compliance after estrogen reduction (Takahashi, 2005, Wang 2004)

of glycosaminoglycans is significantly reduced in cartilage in case of estrogen deficiency and an increase of stiffness follows

8 Summary Estrogen is a modulating factor of the biomechanical properties of the cornea Influence of a hormone status on the biomechanical stability of the cornea and on the results after refractive surgery should not be underestimated Thank you very much for your attention! Striezelmarkt Xmas market in Dresden

$the cornea and on the results after refractive surgery should not be$

Corneal Collagen Cross-Linking (CXL) With Riboflavin

Dr. Paul J. Dubord, MD, FRCSC Clinical Professor Department of Ophthalmology and Visual Sciences University of British Columbia Patient Information Guide Corneal Collagen Cross-Linking (CXL) With Riboflavin