Reversing

GLAUCOMA

©Thierry Hertoghe, MD, 13/11/2016

How do we see?

What

the ophthalmologist

may tell you ….

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First, capture of light rays:

Light rays reflected by subjects or

objects in the visual field reach the

cornea.

If the cornea is correctly curved,

these light rays are nicely bend while

passing it and reach the lens.

The lens converges the light rays

further during their passage on to

points situated on the retina.

The retina, at the back of the eye,

captures the light rays in specific

cells, called “cones” and “rods”,

named following their shape.

Then, information transfer to the brain

Photoreceptor cells in the retina transform the visual information into electric impulses, which are sent through the optic nerve to the visual cortex on the back of the brain (Brodmann areas 17, 18 and 19). There the information is processed and analyzed so that

what is seen is understood..

Glaucoma

Getting rid of the degeneration of the optic nerve and surrounding tissues,

and of the excessive eye tensionthat it often includes

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What is glaucoma?

Glaucoma is an eye disorder that is characterized by a progressive atrophy of the optic nerve, which brings the

information from the eye to the brain.

• As most cases of glaucoma have few or no early symptoms, about half of patients with glaucoma don't know they have it.

• Without an efficient treatment, the atrophy makes people lose vision, especially on the sides of the eyesight: peripheral vision loss. In severe cases, glaucoma results in complete blindness

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Eye pressure

Normal between 10-20 mm Hg

Mechanism

Healthy retina, choroid and optic

nerve

Eye pressure

Most cases (50-90%): the intraocular pressure exceeds what is

tolerable within the eye

Rarely (10-50%): normal or low eye pressure

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Healthy Glaucoma Eye pressure Eye pressure

Normal

between 10-20

mm Hg

Most cases (50-90%): the intraocular pressure exceeds what is tolerable within

the eye

Rarely (10-50%): normal or low eye pressure

Mechanism Mechanism

Healthy retina,

choroid and optic

nerve

High tension glaucoma: The excessive eye pressure compresses and atrophies

surrounding tissues:

o The choroid (the blood vessel network around the eye), reducing by this

mechanism the blood supply to the eye

o The retina (layer of specialized vision cells)

o The optic nerve at the back of the eye (which provides the nerve

connections between retina and brain).

Normal or low tension glaucoma: atherosclerosis or other causes reduces the

blood supply, causing atrophy of the retina and the optic nerve

Normal optic nerve (disk)

with small central cup

Irregular enlargement of the

central cup, due to a high degree

of (central) degeneration, atrophy

and loss of neural tissue

Healthy optic nerve (disk)

Glaucomatous optic nerve (disk

Glaucoma vision:

What does a patient

with severe glaucoma

see?

Subjects or objects situated on the periphery are not or imprecisely seen in the visual field

All subjects and objects situated in front

and on the periphery are well seen.

Glaucoma vision

Healthy vision

Glaucoma: Types

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Glaucoma can be classified following:

the intraocular pressure

the cause

the angle width between cornea and iris.

Glaucoma: Types

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Following the pressure within the eye globe, 3 types of glaucoma are distinguished:

• High–tension: the most frequent, starts at intraocular pressures above the 20 mmHg

• Normal–tension glaucoma

• Low-tension glaucoma: beneath the 10 mmHg.

Depending on the finding of a cause or not, 2 types of glaucoma are considered: primary or secondary

glaucoma.

• Primary glaucoma develops due to an unknown cause.

• Secondary glaucoma develops from a known cause, usually resulting from an eye injury.

Following the maintenance or not of an open angle between the cornea and iris, 2 types of glaucoma

can be characterized:

• Open-angle glaucoma

• Closed (or narrow)-angle glaucoma.

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Angle cornea/iris remains open Closed (anterior chamber closure)

Cause of high

tension

An obstruction in the trabecular

meshwork at the point of the angle

between cornea and iris, which

blocks drainage of the aqueous

material in the eye globe

Obstruction by the forward bowing of the

iris, which closes the anterior chamber

and blocks drainage of the aqueous

material in the eye globe

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Progression

Slow, so slow that often the

patient only notes that there is a

problem at an advanced stage.

Acute: angle-closure appears suddenly; is a medical

emergency. It can be triggered by sudden dilation of your

pupils in sensitive people with narrow drainage angles.

Chronic angle-closure appears slowly and gradually.

Frequency: Most common type: 90% of

glaucoma cases in the USA

Less than 10% of cases are closed-angle glaucoma in the

USA, but up to 50% of cases in some Asian countries.

Average & optimalintraocular pressures

• The average intraocular pressure in the population is around the 15 mmHg (reference

range from 10-21 mmHg), but this includes many elderly people whose eye pressure has

increased well above the better level they had at 25 years of age.

• An optimal eye pressure is possibly be slightly below the population average, possibly

around 13 mmHg.

The intraocular pressure is measured by tonometry, usually with an instrument that delivers a brief puff of air at the eye.

High intraocular pressures

• A high eye intraocular pressure (also called ocular hypertension) is above the 21 mmHg.

• Serious high-tension glaucoma is when the eye pressure gets at 23mmHg or above.

• Glaucoma becomes a medical emergency at eye pressures of 26-27 mmHg or above, which may request rapid surgical intervention to decompress the eye if no non-aggressive treatment quickly releases the eye pressure.x

Glaucoma: Frequency

Glaucoma frequency: Progressive increase in glaucoma incidence with age

Ocular hypertension, the major cause of glaucoma, affects 3-5% of individuals aged over 40; approximately one million people in England.

The researchers of the Ocular Hypertension Treatment Study found that 9% of untreated patients convert ocular hypertension to glaucoma over five years, a rate double that of treated patients (4.4%/5 years).

Patients at higher risk of converting more easily to glaucoma are

• older people

• individuals with the highest intraocular hypertension

• patients with a larger cup-to- optic disc ratio.x

Glaucoma frequency in age +40

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http://forecasting.preventblindness.org/disease-projections/glaucoma

Projected Glaucoma Population by Sex and Year

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http://forecasting.preventblindness.org/disease-projections/glaucoma

Consequences of glaucoma:

Poor vision up to the blindness

• The first risk is a reduced vision with spots of decreased light intensity or blind spots in the visual field, starting in the sides of the visual field (peripheral vision loss).

• The worse risk is of becoming blind. Following the a forementioned Singapore study blindness occurs in 8-15% of cases.

• The highest risks of blindness are for cases of secondary glaucoma, while the lowest for primary open angle glaucoma, whereas the risk of blindness for primary closed angle glaucoma is intermediate.

• In a follow-up study of the entire population of Peru above age 50, glaucoma was the second cause of blindness and caused 13.7% of blindness cases, far lower than cataract (58%) but above the frequency of age-related macular degeneration (11.5%).

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Glaucoma: Causes

Glaucoma: Causes

Aging, the number one trigger of glaucoma?

We saw earlier already that aging is a frequently associated with glaucoma development. Except aging, many other conditions may increase the likelihood of glaucoma. Most of these conditions are

preventable.

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Glaucoma: Causes

Genetic defects and presence of glaucoma in family members make you get easier glaucoma

Polymorphisms of the LOXL1 genes , which encode proteins essential to produce elastic and collagen tissue and capture oxidized cholesterol, may cause exfoliation glaucoma, also called

pseudo-exfolation glaucoma.

In this type of glaucoma, a flaky, dandruff-like material peels off the outer layer of the eye lens. The material accumulates in the angle between the cornea and the iris, tending to block the

drainage system of the eye, resulting in a build-up of eye pressure.

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Exfoliation glaucoma: what is it?x

12% of all glaucoma’s the USA population

are exfoliation glaucoma’s. This disorder is

also called pseudexfoliation glaucoma.

It is a systemic disorder in which a whitish-

grayish protein material accumulates - as it

is produced in unusual high concentrations

within the eye tissues - on the cornea, iris,

lens, ciliary bodies and trabecular

meshwork (that ensures drainage).

This material is insoluble and floats in theaqueous humor, which can reduce aqueoushumor outflow and increase intraocularpressure.

It typically presents unilaterally.

Risk factor: chronic exposure to intense heat.

Glaucoma: Causes

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Glaucoma genes Protein encoded by the genes Glaucoma risk Source

LOXL1 [RS2165241]

Lysyl Oxidase-Like 1, essential to the synthesis of

connective tissue = extracellular copper-

dependent amine oxidase that catalyzes the first

step in the formation of crosslinks in collagens

and elastin

3.4x

greater risk

Pasutto F, et al.

Invest

Ophthalmol

Vis Sci.

2008;49:1459LOX1 [RS3825942]

lectin-type oxidized LDL receptor 1, receptor

protein a which binds, internalizes and degrades

oxidized low-density lipoprotein

4.9x

greater risk

As glaucoma-promoting genes are inherited from parents who have inherited it from their parents, it is

not surprising that people with a family history of open-angle glaucoma in an African ethnicgroup (the

Mongo who live in Congo, Central Africa) with 4 times higher risk of glaucoma, for example, has been

reported to increases 18-fold the risk of glaucoma compared to individuals from families without a history of glaucoma!

In case of a high genetic predisposition to glaucoma, preventive lifestyle, nutritional and /or hormone

therapies can be applied to change the odds, as we will see below.

In the table below, are the two genotypes with 4 to 5-fiold risk increases.

Glaucoma: CausesDrinks: 1-2 coffee cups per day increase the intraocular pressure, but not alcohol

Among the drinks that should be avoided by people with glaucoma or people withpredisposition to glaucoma is coffee. Drinking daily one or 2 cups of normal coffee increasesthe intraocular pressure by an average of more than 2 mmHg (2.1 mmHg), but in somepeople up to 7 mmHg for 2 cups per day of coffee! As the average eye pressure of thepopulation is around the 15 mmHg, 2 cups of coffee per day may bring the eyes of a personwith an average intraocular pressure into the ocular hypertension range, the big promoter ofglaucoma!

However, the caffeine in the coffee does not seem to be the cause of increase in intraocularpressure as caffeine drops on the eyes do not seem to increase the intraocular pressure inpatients with ocular hypertension and primary open angle glaucoma. The increase in eyepressure in coffee drinkers is for this reason likely due to other coffee constituents. Amongpossible ocular hypertensive triggers are the pyrolytical by-products generated by high-temperature roasting from endogenous constituents of coffee beans.

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Glaucoma: Causes

Alcohol: no effect on glaucoma

It is worth noting that alcohol intake does not appear to be associated with an increase (or reduction) in glaucoma risk.

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Glaucoma: Causes

Rice, a risky food for glaucoma? What about a high cholesterol diet and food allergies?

Concern has been emitted about rice consumption. Regular rice eating has beenreported to increase 4 to 5 times the risk of open-angle glaucoma. The primaryrecommendation would then be not to eat rice to avoid glaucoma. Is rice rally sodangerous for the eyes? It might not be the rice itself, but the consumption of amonotonous diet where rice, very poor in any protective vitamin or trace element, iseaten almost every day, not supplying the body with a sufficient amount ofmicronutrients important for eye health. Any food, even rice, consumed too frequentlytriggers also food allergies. Food allergies have been repeatedly shown to increase theeye pressure.

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Glaucoma: Nutritional deficits as causes

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Lower magnesium levels may facilitate vasospasm and visual field defects in patients with

glaucoma

Magnesium deficiency may quickly affect the eye with temporarily vision defects by vasospasm, which is one of the factors that produces primary open angle glaucoma.

Lower vitamin B1 and C levels in glaucoma patients

A significantly lower serum vitamin B1 (thiamine) level is found in patients with open-angle glaucoma,

suggesting that the lack of this nerve-stimulating vitamin may facilitate atrophy of the optic nerve, and

thus glaucoma. In the same study vitamin C levels were normal, but in an investigation on patients with

normal-tension glaucoma, the serum vitamin C level was on average significantly -27% decreased,

while vitamin A and E, and folic acid levels were not significantly different from patients without normal-

tension glaucoma.

Lower vit. E, zinc, manganese; iron, omega-3 polyunsaturated fatty acids

Hormone deficits

that facilitate glaucoma

development

Hormone deficits that precipitate glaucoma

Thyroid deficiency may cause glaucoma

Thyroid deficiency or hypothyroidism sets the intraocular pressureapproximately 4 mmHg higher, a big change.

• In a study by Centanni et al., the intraocular pressure of both eyes of the 53hypothyroid patients were approximately 17.5 mmHg, while in the 24control subjects around the 13.5 mmHg.

• Research has reported that 16-22% of patients with chronic open angleglaucoma suffer from overt hypothyroidism.

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Glaucoma: the association with hypothyroidism in humans

• Becker B, Kolker AE, Bailin N. Thyroid function and glaucoma. Am J Ophthalmol

1966;61:997-999.

• Centanni M, Cesareo R, Verallo O, Brinelli M, Canettieri G, Viceconti N, Andreoli

M. Reversible increase of intraocular pressure in subclinical hypothyroid patients.

Eur J Endocrinol 1997;136: 595-598.(53 subjects (9 male and 44 female) aged

from 18 to 45 years (29 met the criteria of subclinical hypothyroidism and 24

euthyroid subjects) RESULTS: The hypothyroid patients showed a substantially

higher pressure in both eyes compared with control subjects (right eye = 17.52 +/-

4.74 vs 13.42 +/- 1.95 mmHg, P < 0.0001; left eye = 17.55 +/- 3.99 vs 13.71 +/-

1.55 mmHg, P < 0.0001). Indeed, the tonometric pressure exceeded 18 mmHg in

11 out of the 29 (38%) patients in the right eye and in 8 out of 29 (27%) patients in

the left eye. The outflow index was normal in all subjects except in two hypothyroid

patients.)

• McLenachan J, Davies DM. Glaucoma and the thyroid. Br J Ophthalmol

1965;49:441-444.

Mechanism to produce glaucoma

Hgher intraocular pressure in thyroid deficiency: likely due to the accumulation ofmucopolysaccharides, waste products around and within the eyes, and make thesetissues swell. The mucopolysaccharides that accumulate in the trabecularmeshwork that forms the drainage system of the aqueous humor of the eye globe(situated in the angle between the cornea and iris) hinder the evacuation of theaqueous liquid within the eye. The resulting excessive liquid in the eye, increasesfurther the intraocular pressure, which compresses, flattens and damages the opticnerve and its axons.

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In hypothyroidism , abundant deposits of blueish mucopolysaccharides(mucin), highlighted by an alcian blue periodic acid-Schiff stain, separated collage bundles in the papillary & reticular dermis

How many patients with glaucoma really suffer also from hypothyroidism?

The number of patients with open angle glaucoma who suffer from hypothyroidism, mightbe much greater than the 16-22% of patients presented by research, because manyhypothyroid patients with glaucoma who are not being diagnosed for hypothyroidism. Thereason of this underdiagnosis is the overreliance on solely laboratory tests for diagnosis ofthyroid deficiency among researchers. However, defining hypothyroidism solely as thepresence of a serum TSH level well above the upper reference limit, and/or of thyroidhormone levels below the lower reference limit is misleading as this restrictive definitionmake physicians miss the diagnosis of many more moderate and intermediate degrees ofhypothyroidism. These values concern only the most severe cases of hypothyroidism.Hypothyroidism can be also found in patients with low normal T3 and T4 levels and/or withhigh normal TSH levels within the reference ranges, who present numerous hypothyroidsigns and complaints patients. Overreliance on thyroid lab tests may lead to disregard anopportunity that prvide a thyroid treatment thatmight stop the progression of glaucoma oreven can reverse this condition. More explanations are provided in the chapter on glaucomatreatments. x

Glaucoma: Causes

Melatonin deficiency, risk factor for glaucoma

Melatonin deficiency may also contribute to glaucoma. The studies confirming

• the association of poor sleep with a higher glaucoma risk are suggestive of this (see above),

• melatonin treatment reduces the intraocular pressure. Melatonin deficiency might also predispose to glaucoma by another mechanism than an increase in intraocular pressure: increased free radical levels that may aggressively attack and damage the optic nerve.

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Melatonin protect against glaucoma

2 mechanisms:

• intraocular pressure

• free radical levels

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Glaucoma: Causes

The low female hormone levels of the menopause increase the risk of glaucoma

Woman who don’t take HRT (hormone replacement therapy) after menopause are 2 and half times more likely to develop glaucoma then women taking HRT since more than 5 years.

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19% of postmenopausal women (up to 60

years) not on HRT develop

glaucoma

only 7% of postmenopausal women taking HRT

get glaucoma

Glaucoma: the association with low female hormone levels such as in postmenopausal women never treated with female hormones

• Lang Y, Lang N, Ben-Ami M, Garzozi H. The effects of hormone replacement therapy (HRT) on the human eye : Harefuah. 2002 Mar;141(3):287-91 Dept. of Ophthalmology, Ha'EmekMedical Center, Afula.( This review presents the ever growing data accumulated over the past years concerning the beneficial effects of HRT on various eye pathologies. It was found that HRT may relieve dry eye symptoms in post-menopausal women, may decrease the intraocular pressure and may delay cataract formation in treated women)

• Wenderlein JM, Hensinger E. Hormone therapy for ophthalmoprophylaxis. Klin Monatsbl Augenheilkd. 2003 Oct;220(10):704-9. Universitatsfrauenklink Ulm (Women mainly aged over 70 suffering from age-related conditions such as glaucoma and cataract almost never had HRT. Thus in the following only women aged up to 60 have been of interest. 7 of 10 women being in the menopause for over 10 years with a visus higher than 0.7 received HRT. Only 1 of 10 women had a visual acuity less than 0.4. There was also a correlation between receiving HRT and intraocular pressure. In the group aged up to 60 without taking HRT 19 % had an intraocular pressure above 19. In women with HRT over 5 years this occurred in only 7 %.)

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Glaucoma: Causes

Growth hormone deficiency may facilitate the appearance of glaucoma:

3 to 4 mmHg higher intraocular pressure

The intraocular pressure in

• normal children: mean 14.6 mm Hg

• children with growth hormone deficiency is also higher : 18.2 mm Hg in

One of the reasons for the higher intraocular pressure might be the presence in growth hormone deficiency of a 11% thicker cornea that puts additional pressure on the eyes. This suggests that elderly people whose growth hormone levels have sometimes dramatically dropped, might also get easier a higher eye pressure because of their lower growth hormone production, and, thus, be at greater risk of developing high-tension glaucoma

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Child with growth

hormone deficiency:

+3.3 mmHg higher

intraocular pressure :

±18.2 mm Hg)

Adult with growth hormone deficiency:+3.3 mmHg higher intraocular pressure ?

Elevated intraocular pressure: the association with growth hormone deficiency in children

• Parentin F, Pensiero S. Central corneal thickness in children with growth hormone deficiency. Acta Ophthalmol. 2010 Sep;88(6):692-4. (“45 patients with growth defect treated with recombinant GH and 45 healthy children ..The average central corneal thickness (CCT) in the GH deficiency group was 570.6μm [standard deviation (SD) 37.4]. In the control group, it was 546.0 (SD 24.9). The average intraocular pressure (IOP) in the GH deficiency group was 18.2 mm Hg (SD 3.4). In the control group, it was 14.6 (SD 2.0). .. GH and insulin-like growth factor 1 are involved in ocular growth by influencing the synthesis of the extracellular matrix of the sclera. …A number of studies have demonstrated that central corneal thickness (CCT) in newborns is significantly greater than in adults; a decrease in CCT is closely correlated with an increase in corneal diameter. …herefore, we conclude that a greater central corneal thickness (CCT), can represent a sign of a delayed growth of the eye in patients with GH deficiency. .. the influence of corneal thickness on intraocular pressure (IOP) measures)

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Thinner nerve fiber layer thickness: the association with congenital isolated growth hormone deficiency

• Nalcacioglu-Yuksekkaya P, Sen E, Yilmaz S, Elgin U, Gunaydin S, Aycan Z. Decreased retinal nerve fiber layer thickness in patients with congenital isolated growth hormone deficiency. Eur J Ophthalmol. 2014 Nov-Dec;24(6):873-8. (32 eyes of 32 patients with congenital isolated GHD and 36 eyes of 36 healthy subjects. The topographic optic disc parameters (mean cup volume, rim volume, cup area, disc area, rim area, mean cup-to-disc ratio and cup depth, retinal nerve fiber layer thickness [RNFL]) were imaged in all subjects with Heidelberg retina tomograph (HRT)-III. … The mean retinal nerve fiber layer thickness [RNFL] thickness in children with congenital isolated GHD was found to be statistically significantly thinner than in healthy subjects (p&lt;0.05). However, no statistically significant differences were found between the mean cup volume, rim volume, cup area, disc area, rim area, mean cup-to-disc ratio and cup depth, and mean sectorial RNFL thickness (p&gt;0.05).) … congenital GHD may lead to thinner RNFL thickness when compared with healthy subjects. This indicates that GH has an important role in the development of the neural retina)

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Reduced retinal vascularization: the association with growth hormone deficiency in children

• Hellström A, Svensson E, Carlsson B, Niklasson A, Albertsson-Wikland K. Reduced retinal vascularization in children with growth hormone deficiency. J Clin Endocrinol Metab. 1999 Feb;84(2):795-8. 539 children (5 girls and 34 boys, aged 3.6-18.7 yr) with congenital GH deficiency, and it was compared to that of 100 healthy controls…. 20 children had received GH treatment (0.1 IU/kg daily). All children were born at term, and none of the children had any clinical signs of ocular disease or reduced vision. Children with GH insufficiencies, regardless of whether they were treated with GH, had a significantly lower number of vascular branching points than the reference group (P < 0.0001). 33% of the GH-insufficient individuals had a number of vascular branching points less than or equal to the fifth percentile of the reference group. The reduced retinal vascularization observed in children with congenital GH deficiency suggests that GH may be of importance for angiogenesis.)

Reduced retinal vascularization, increase of optic disc and cup size: the association with growth hormone deficiency in congenital lifetime

isolated growth hormone deficient-adults

• Pereira-Gurgel VM, Faro AC, Salvatori R, Chagas TA, Carvalho-Junior JF, Oliveira CR, Costa UM, Melo GB, Hellström A, Aguiar-Oliveira MH. Abnormal vascular and neural retinal morphology in congenital lifetime isolated growth hormone deficiency. Growth Horm IGF Res. 2016 Jul 27;30-31:11-15. (25 adult vascularization in untreated congenital IGHD (cIGHD) subjects) .. cIGHD subjects presented a more significant reduction of vascular branching points in comparison to controls (91% vs. 53% [p=0.049]). The percentage of moderate reduction was higher in cIGHD than in controls (p=0.01). The percentage of individuals with increased optic disc was higher in cIGHD subjects in comparison to controls (92.9% vs. 57.1%). The same occurred for cup size (92.9% vs. 66.7%), p<0.0001 in both cases. There was no difference in macula thickness.)

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Cortisol excess

= frequent cause of glaucoma and is in most cases due to unbalanced treatments with high-dosed

glucocorticoids (cortisol and its derivatives) - In the same way that cortisol increases the blood pressure by

increasing the salt and water content within arteries and by increasing the contraction of smooth muscles around

the arteries, excess cortisol might increase the intraocular pressure by increasing the salt and water content within the eye globe and by enhancing the

contraction of the muscles that surround the eye globe.

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Glaucoma: the association with increases in serum total cortisol, urinary free cortisol and 17-hydroxysteroids in patients with glaucoma

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1. Nowak M, Swietochowska E, Jochan K, Buntner B. Hormonal changes in male patients with

primary open angle glaucoma. Klin Oczna. 2000;102(2):103-8. (The serum concentration of TF

(UFF and 17-OHCS in urine was increased in 30 male patients, aged 55 +/- 13 years, treated

because of glaucoma for more than two years. compared with control group …elevated level of

cortisol, free cortisol and its metabolites is closely related to the POAG.

2. Janousková K, Tĕsínský P, Topolcan O. Hormonal changes in open-angle glaucoma. II. Levels of

cortisol and somatotropin in serum. Cesk Oftalmol. 1993 Jan;49(1):22-9. (102 glaucomatous

patients, a higher level of cortisol in plasma was detected in 40.2% of glaucomatous patients of

whom 31% had increased levels of cortisol together with IRI. In isolation the increased level of

cortisol occurred in 8.9%. The frequency of increased cortisol level in glaucomatous patients is

substantially lower (40.2%) than the frequency of abnormal insulin curves (78%). Increased

levels of growth hormone in the group of patients occurred in 9.3% of cases and these were

almost always associated with an abnormal immuno-reactive insulin curve (IRI curve).

Accordingly, it is evident that hormonal disorders are a major factor in the onset of both diabetes

and glaucoma.) Schwartz B, McCarty G, Rosner B. Increased plasma free cortisol in ocular hypertension and open angle glaucoma. Arch Ophthalmol. 1987 Aug;105(8):1060-5

Glaucoma: the induction by hydrocortisone treatment

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1. Li Voon Chong JS, Sen J, Johnson Z, Kyle G, MacFarlane IA. Hydrocortisone replacement dosage influences intraocular pressure in patients

with primary and secondary hypocortisolism. Clin Endocrinol (Oxf). 2001 Feb;54(2):267-71.( Seventeen patients (six Addison's disease, 11

hypopituitarism; seven males) aged 24-58 years mean 42.7 years and 20 control subjects (nine males) aged 20--59 years mean 38.7 years

were studied. On the first visit, the 17 patients had been taking HC replacement doses, 20 mg morning and 10 mg afternoon. Serum cortisol

and IOP in both eyes (Goldmann applanation tonometer) were measured at 0900, 1100, 1300, 1500, 1700 hours with HC 20 mg taken after the

0900 h assessment. The dose of HC was then reduced to 10 mg morning and 10 mg afternoon for 1 week and the measurements were

repeated in 16 patients, with HC 10 mg taken at 0900 h.

2. n the patients the peak serum cortisol occurred at 1100 h after the 0900 h HC dose. Cortisol levels were significantly higher at 1100, 1300, 1500

and 1700 h after taking 20 mg compared to 10 mg HC. The mean (SEM) IOP (mmHg) was significantly higher after 20 mg HC compared with

10 mg HC at 1300 h: 14.7(0.6) v 13.1(0.6) (P = 0.004) and at 1500 h: 14.4(0.6) v 13.1(0.5) (P = 0.04). The total mean (SEM) daily IOP score

was significantly higher after 20 mg HC compared with 10 mg HC: 14.5(0.3) v 13.5(0.3) (P = 0.0002). The total mean (SEM) daily IOP score

after the 20 mg HC dose compared with the control subjects was: 14.5(0.3) v 13.7(0.3) (P = 0.08)… Intraocular pressures during the day are

influenced by the morning hydrocortisone replacement dosage with significantly higher intraocular pressure levels in the early afternoon

following 20 mg compared with 10 mg. A morning hydrocortisone dose of 10 mg leads to a more physiological intraocular pressure profile during

the day)

3. Garbe E, LeLorier J, Boivin JF, Suissa S. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids.

Lancet. 1997 Oct 4;350(9083):979-82. (9793 patients with a new diagnosis of ocular hypertension or open-angle glaucoma, or on newly

prescribed treatment for these disorders (cases). 38,325 controls The adjusted odds ratio of ocular hypertension or open-angle glaucoma for

current users of oral glucocorticoids compared with non-users was 1.41 (95% CI 1.22-1.63). There was a dose-related increase in the adjusted

odds ratios for current users: 1.26 (1.01-1.56) for less than 40 mg per day of hydrocortisone, 1.37 (1.06-1.76) for patients on 40-79 mg per day,

and 1.88 (1.40-2.53) for patients on 80 mg or more per day. The odds ratios also increased with the duration of treatment over the first 11

months of exposure) Kimura R, Maekawa N. Effect of orally administered hydrocortisone on the ocular tension in primary open-angle glaucoma

subjects. Preliminary report. Acta Ophthalmol (Copenh). 1976 Aug;54(4):430-6. (diurnal ocular tension curve by peroral hydrocortisone in 16

eyes of 16 subjects with primary open-angle glaucoma. The baseline diurnal curve was determined by Schiotz tonometry six times daily starting

at 10 a.m. and repeated every four hours. The baseline curve showed a significant rise in the daytime with a fall during the night. On another

day, 20 mg hydrocortisone was given perorally at 5 p.m., for a repeat 24-h measurement period. A significant rise in ocular tension over the

baseline resulted in the following night-time tonometric readings, i.e. at 10 p.m. (P less than 0.01) and 2 a.m. (P less than 0.001). The results

seem to strongly indicate that plasma cortico-steroid levels dictate the pattern of diurnal variation of ocular tension.)

Glaucoma: the inductions by topical (gluco)steroid treatment on the eyelids

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1.Garrott HM, Walland MJ. Glaucoma from topical corticosteroids to the eyelids. Clin Experiment Ophthalmol. 2004 Apr;32(2):224-6.

Glaucoma: poor cortisol secretion in response to intramuscular ACTH in patients with ocular hypertensives and patients

with primary open-angle glaucoma’s

1. Schwartz B, Rabin PA, Wysocki A, Martin J. Decreased plasma cortisol in response to intramuscular ACTH in ocular

hypertensives and primary open-angle glaucomas. J Glaucoma. 2007 May;16(3):282-6. (patients with ocular hypertensives

(OHs) with primary open-angle glaucomas (POAGs)) showed lower cortisol/BMI values compared with the normal group at 4, 8,

and 24 hours with a significantly lower peak/BMI value (P=0.030). compared with normal)

2. Schwartz B, Wysocki A, Qi Y. Decreased response of plasma cortisol to intravenous metyrapone in ocular hypertension and

primary open-angle glaucoma. J Glaucoma. 2005 Dec;14(6):474-81 (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.)

Glaucoma: increased cutaneous vasoconstriction response to glucocorticoids in patients with primary open-angle

glaucoma

1. Stokes J, Walker BR, Campbell JC, Seckl JR, O'Brien C, Andrew R. Altered peripheral sensitivity to glucocorticoids in primary

open-angle glaucoma. Invest Ophthalmol Vis Sci. 2003 Dec;44(12):5163-7. (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)… Increased sensitivity of glucocorticoid receptors, may enhance local

glucocorticoid action in the eye and exacerbate the adverse effects of glucocorticoids in this condition.)

Glaucoma: the association with a low serum aldosterone level (but higher serum cortisol) in older (65-75 years old) males

and females

1. Dzhodzhua T, Sumbadze Ts. [Pituitary-adrenal axis system condition in patients with open angle glaucoma]. Georgian Med

News. 2005 Sep;(126):74-6. Russian (The level of serum cortisol was increased in all--I, II and III groups of males. Serum

aldosterone was decreased in III group of males and in I and III groups of females)

Hormonal risk factors for glaucoma

x

x

Nutritional risk factors for glaucoma

HORMONE

DEFICITPossible mechanism(s) causing optic nerve degeneration

Thyroid

deficiency

The optic nerve degenerates by

• Optic nerve compression due to • an increased in intraocular, itself due:

• increased external pressure on the eye globe by myxedematous (accumulation of waste products) swelling of surrounding tissues

• increased internal pressure due to iIncreased aqueous humor in the eye globe due to decreased evacuation of the liquid inside the eye globe by myxedema of the trabecular drainage system

• Increased intracranial pressure outside of the eye in the skull around the whole pathway of the optic nerve due to myxedematous swelling of the brain

• Reduced blood supply to the optic nerve on its whole trajectory due to myxedema and premature atherosclerosis of the arteries

Hormonal risk factors for glaucoma

x

x

Hormonal risk factors for glaucoma

HORMONE

DEFICITSPossible mechanism(s) causing optic nerve degeneration

Estrogen and

progesterone

deficiency

The retina and optic nerve degenerates by: • Optic nerve compression due to an increased in intraocular pressure,

resulting from the Increased aqueous liquid in the eye globe due to a decreased evacuation of the eye humor by failure of the trabecular drainage system

• Reduced blood supply to the optic nerve on its whole trajectory due to premature atherosclerosis of the arteries

Hormonal risk factors for glaucoma

x

x

Nutritional risk factors for glaucoma

HORMONE

DEFICITS OR

EXCESSES

Possible mechanism(s) causing optic nerve degeneration

Melatonin

deficiency?

The optic nerve degenerates by being damaged

Directly by the higher levels of free radicals, resulting from the loss of

melatonin’s potent antioxidant effect, and that aggress the neurons and

myelin sheaths that surround the axons of the neurons of the optic

nerve

Indirectly by compression due to the increased intraocular pressure due

to a loss in the relaxing effects of melatonin on eye muscles

Hormonal risk factors for glaucoma

x

x

Nutritional risk factors for glaucoma

HORMONE

DEFICITS OR

EXCESSES

Possible mechanism(s) causing optic nerve degeneration

Growth

hormone

deficiency

The retina and optic nerve degenerates by:

Optic nerve compression due to an increased in intraocular pressure

(+3.6 mm Hg), resulting from the Increased aqueous liquid in the eye

globe due to a reduced evacuation of the eye humor by failure of the

trabecular drainage system

Higher levels of free radicals, which are typical in growth hormone

deficiency, and that aggress the neurons and the myelin sheaths around

the axons of the optic nerve

Hormonal risk factors for glaucoma

x

x

Nutritional risk factors for glaucoma

HORMONE

DEFICITS OR

EXCESSES

Possible mechanism(s) causing optic nerve degeneration

Cortisol

excess

The optic nerve degenerates by

Compression because of increased intraocular pressure due to

o increased salt and water content within the eye globe due to

cortisol’s salt and water retaining

o increased muscle tension around the eye globe due to cortisol’s

muscle contracting actions

Excessive catabolism, which causes

o tissue atrophy, including optic nerve atrophy

Glaucoma: Treatmentsx

x

The aim of a glaucoma treatment is to reduce the intraocular pressure

below the 20-21 mmHg barrier. Ideal is even to get the intraocular

pressure back to the average of a normal population, which is around the

15mm Hg, or, even better, as discussed earlier, get to 12-13 mmHg of

intraocular pressure. A persistent pressure within the eye of 27-30 mmHg is

critical and may considerably and quickly damage the optic nerve and other

parts of the eye. Emergency surgery to release the pressure may have to

be done.

Nutritional therapies that may reverse glaucoma x

x

Magnesium reduces visual field defects due to poor circulation or aggressions in glaucoma

Magnesium is one of the 3 most important micronutrients for glaucoma prevention & treatment. Magnesium supplementation improves vision in patients with glaucoma, part. in the subjects with vasospasm in optic arteries. Vasospasm is typical for magnesium deficiency states – often to be suspected in individuals who easily present muscle spasms in the face, or muscle cramps in hands, feet and calves) .

How does magnesium work?

By 2 major mechanisms: an ocular blood flow & a protection of the (retinal) ganglion cells, which provide the electrical impulses that go to the optic nerve ganglion cell, against aggression and death. Magnesium improves the blood flow to the optic nerve and the (retinal) ganglion cells by reducing vasoconstriction induced by endothelin-1, a potent natural vasoconstricting peptide, and by increasing vasodilation by the vasodilator nitric oxide. Magnesium protects the neurons of the optic nerve and the (retinal) ganglion cells against oxidative stress and apoptosis, and by blocking both the penetration of calcium into these nerve cells (by binding to special sites on the ion channel protein NMDA - N-methyl-D-aspartate receptor) and inhibiting the release of neurotoxic glutamate.

Dettmann ES, Lüscher TF, Flammer J, Haefliger IO. Modulation of endothelin-1-induced contractions by magnesium/calcium in porcine ciliary arteries. Graefes Arch Clin Exp Ophthalmol. 1998 Jan;236(1):47-51.

Basralı F, Koçer G, Ülker Karadamar P, Nasırcılar Ülker S, Satı L, Özen N, Özyurt D, Şentürk ÜK. Effect of magnesium supplementation on blood pressure and vascular reactivity in nitric oxide synthase inhibition-induced hypertension model. Clin Exp Hypertens. 2015;37(8):633-

42.

Preventing glaucoma by taking folic acid supplements and increasing folic acid in the diet

Folic acid, the crucial vitamin to avoid neurological development disorders in unborn fetus, appears also to protects adults from optic nerve against degeneration and glaucoma. People with a high intake

(through intake of folic acid supplements and/or foods rich in folic acid) benefit from a -25% lower risk of exfoliation glaucoma, which is the most common type of secondary

glaucoma compared to people with a low intake (highest quintile of intake against the lowest quintile). Exfoliation glaucoma is characterized by the accumulation of microscopic granular amyloid-like protein fibers, which can block normal drainage of the eye fluid (the aqueous humor) and can cause, in turn, a buildup of pressure leading to glaucoma and loss of vision. It is more prevalent in persons past the age

of seventy.

Foods rich in folic acid are dark green leafy vegetables such raw spinach and lettuce, citrus fruits, and sprouted beans and peas on condition that they are eaten raw and not cooked, otherwise the fragile

folic acid molecule breaks down at high temperature cooking. Furthermore, to increase folic acid levels unsprouted beans and peas are not a solution as when they are eaten raw they are toxic for the

organism because of persistence of toxic molecules (phytic acid, galacoligosaccharides ad lectins) and ingested after cooking, which breaks down most toxic molecules, the fragile folic acid molecule has also

disappeared broken down by the high temperature of the cooking.

Kang JH, Loomis SJ, Wiggs JL, Willett WC, Pasquale LR. A prospective study of folate, vitamin B₆, and vitamin B₁₂ intake in relation to exfoliation glaucoma or suspected exfoliation glaucoma. JAMA Ophthalmol. 2014 May;132(5):549-59.

Vitamin E with or without other micronutrients (coQ10, vitamin B-complex, DHA) reduces the extent of damage in glaucoma

Another micronutrient may help glaucomatous patients too: vitamin E. Taking 300 to 600 mg/day of Vitamin E supplements through the oral route during 6 months has been shown to improve the

blood flow in the arteries of the eye (ophthalmic and posterior ciliary arteries) and also to reduce oxidative stress. oth actions reduce the glaucomatous damage to the optic nerve and the

ganglion cells.

However, it may be better to combine vitamin E with other micronutrients to potentialisebeneficial effects. An experiment where low doses of vitamin E (2 mg), the omega-3 fatty acid

docosahexaenoic acid or DHA (65 mg) and various vitamin B”s (0.2 mg B1, 0.3 mg B2, 3.9 mg B3, 0.4 µg B12) were orally taken during 3 months by glaucomatous patients showed that with this treatment the

eyesight improves for texts or objects situated on the periphery of the visual field. Text or color contrasts were also better seen.

The topical route may help too. Daily eye drops of vitamin E (at 0.5%) combined to coenzyme Q10 (0.1%) during 6-12 months also may improve the electroretinogram with consequent enhancement

of the visual cortical responses (visual-evoked potential improvement). in patients with open-angle glaucoma. The electroretinogram is an eye test used to detect abnormal function of the retina, the light-detecting portion of the eye). This test checks the activity o the light-sensitive cells of the eye, the rods

and cones, and their connecting ganglion cells in the retina are examined.

Parisi V, Centofanti M, Gandolfi S, Marangoni D, Rossetti L, Tanga L, Tardini M, Traina S, Ungaro N, Vetrugno M, Falsini B. Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma. J

Glaucoma. 2014 Aug;23(6):391-404.

Alpha-lipoic acid to reduce glaucoma damage Alpha-lipoic acid treatment has been shown to protect ganglion cells of the retina andtheir axons against dysfunction and death caused by glaucoma in mice.

The protective action of alpha-lipoic acid is mainly due to is potent anti-oxidant action,which neutralizes the many free radicals released in glaucoma disorders. This suggeststhat alpha-lipoic acid may be helpful for glaucoma patients too.

DBA/2J mouse model of glaucoma … with α-lipoic acid treatment … • does not affect intraocular pressure in DBA glaucoma mice …• preserves retinal ganglion cell soma and axon .. • 13 % more axons optic nerves; slightly higher density & 4 % more surface area. • The optic nerve degeneration grade (ON Grade) was also lower for the ALA group… • antioxidant gene and protein expression, increased protection of retinal ganglion cell

and improved retrograde transport compared to control. • oxidative stress: lipid peroxidation, protein nitrosylation, & DNA oxidation in

retina verified decreased)Inman DM, Lambert WS, Calkins DJ, Horner PJ. α-Lipoic acid antioxidant treatment limits glaucoma-related

retinal ganglion cell death and dysfunction. PLoS One. 2013 Jun 5;8(6):e65389.

Consume fish and linseed oil to reduce the clean the eyes, make them softer and reduce the eye pressure

Rats that were since birth raised on diets rich in omega-3polyunsaturated fatty acids benefit from a -13% decrease in intraocularpressure (this would mean a mean -2 mmHg in humans).

How do omega-3 fatty acids reduce the eye pressure? By

• the pressure on the eye from the outside by making the eye moreelastic (decreasing the eye rigidity by approximately -60%!)

• (>50%) the drainage (or outflow) of aqueous humor of the eye.Nguyen CT, Bui BV, Sinclair AJ, Vingrys AJ. Dietary omega 3 fatty acids decrease intraocular pressure with age by increasing

aqueous outflow. Invest Ophthalmol Vis Sci. 2007 Feb;48(2):756-62. (Rats raised on omega-3(+) diets had a 13% decrease in IOP at 40 weeks of age (13.48 +/- 0.32 mm Hg vs. 15.46 +/- 0.29 mm Hg; P < 0.01). When considered as a change in IOP relative to 5

weeks of age, the omega-3(+) group showed a 23% decrease (P < 0.001). This lower IOP in the omega-3(+) diet group was associated with a significant increase (+56%; P < 0.001) in outflow facility and a decrease in ocular rigidity (-59%; P < 0.001). The

omega-3(+) group showed a 3.3 times increase in ciliary body docosahexaenoic acid (P < 0.001)… Increasing dietary omega-3 reduces IOP with age because of increased outflow facility, likely resulting from an increase in docosanoids. “)

Flavonoids to see better in ocular hypertension and glaucoma

Flavonoids such as anthocyanins (abundant in blueberries), epicatechin 3-gallate (abundant in green tea) and genistein and

daidzein (soy) are another category of micronutrients that may help patient with ocular hypertension and glaucomatous patients to see better and slow the progression of visual field loss thanks to their

antioxidant action and other protective actions

Patel S, Mathan JJ, Vaghefi E, Braakhuis AJ. The effect of flavonoids on visual function in patients with glaucoma or ocular hypertension: a systematic review and meta-analysis. Graefes Arch Clin Exp Ophthalmol. 2015 Nov;253(11):1841-50. (analyses showed that flavonoids have a promising role in improving visual function in patients with glaucoma and ocular hypertension

(OHT), and appear to play a part in both improving and slowing the progression of visual field loss”)

Hormone therapies to reverse glaucomax

x

Thyroid treatment relieves hypothyroid eyes from compression and reduced aqueous humor outflow

As the intraocular pressure is higher in hypothyroid eyes, which are compressed by the myxedema, thyroid treatment makes the eye pressure drop in thyroid-

deficient patients by removing the unnecessary mucopolysaccharides, which form the myxedema, both in the tissues around and inside the eye. The disappearance

of the myxedema from the tissues surrounding the eye globe relieves the compression of the eye globe by these tissues. This results in a drop in intraocular pressure. This is the main mechanism by which thyroid treatment reverses ocular

hypertension. The elimination of mucopolysaccharides from the trabecular meshwork, which is situated in the angle between cornea and iris and forms the

drainage system that evacuates excessive aqueous humor of the eye globe, opens up this system, increasing and normalizing the outflow of aqueous humor,

resulting in a further reduction in intraocular pressure. This mechanism is of importance only for a fraction of persons with the highest intraocular pressure. The normalizing of the the intraocular pressure, relieves the optic nerve and the

x

Glaucoma: the improvement with oral thyroxine treatment in hypothyroid patients

x

x

1. Centanni M, Cesareo R, Verallo O, Brinelli M, Canettieri G, Viceconti N, Andreoli M. Reversible

increase of intraocular pressure in subclinical hypothyroid patients. Eur J Endocrinol 1997;136: 595-

598.(53 subjects (9 male and 44 female) aged from 18 to 45 years (29 met the criteria of subclinical

hypothyroidism and 24 euthyroid subjects) RESULTS: …After two months of L-thyroxine (L-T4)

replacement therapy, only one patient continued to show tonometric values above 18 mmHg and the

hypothyroid patients showed a significant reduction in mean IOP in both eyes compared with pre-

treatment values (right eye = 14.96 +/- 1.32 mmHg, P < 0.0097; left eye = 15.03 +/- 1.38 mmHg, P <

0.0018). Treatment did not lead to any change in the outflow indices; however, the C value (outflow

coefficient at the sclerocorneal corner) returned to normal in the two patients with increased pre-

treatment tonographic values….These findings indicate that the intraocular pressure is increased even in

subclinical hypothyroid patients and that, at this early stage, the impairment is fully reversible with L-T4 therapy.)

2. Tosini G, Iuvone M, Boatright JH. Is the melatonin receptor type 1 involved in the pathogenesis of

glaucoma? J Glaucoma. 2013 Jun-Jul;22 Suppl 5:S49-50.

3. Alcantara-Contreras S, Baba K, Tosini G. Removal of melatonin receptor type 1 increases intraocular

pressure and retinal ganglion cells death in the mouse. Neurosci Lett. 2011 Apr 20;494(1):61-4. ((Mice

lacking the melatonin receptor type 1 (MT1-/-) have demonstrated that MT1

-/- mice have higher

nocturnal IOP than wild type or melatonin receptor type 2 knock-out (MT2-/-) mice at 3 and 12 months

of age. … Administration of exogenous melatonin in wild-type, but not in MT1-/-, can significantly

reduce IOP)

Systemic or topical treatment with melatonin or its receptor agonists lowers intraocular pressure in mammals, including humans

Providing melatonin as a supplement helps undoubtedly to reduce the intraocular pressure and protect the optic nerve from degeneration.

Oral melatonin treatment, for example, reduces the intraocular pressure in

• healthy volunteers

• cataract patients.

Before cataract surgery: Acutely a high dose of 10 mg, melatonin

• reduces the intraocular pressure with approximately -4 mmHg (from a mean of 17.9 mmHg before the surgery to 13.8 mmHg during the surgery) in cataract patients.

• reduces the anxiety and pain scores allowing the anesthesiologist to use less painkillers (fentanyl) during the operation.

• Melatonin offers better operating conditions during cataract surgery under topical anesthesia. x

What about Melatonin’s effect on patients with glaucoma? At a pharmacological dose of 25 mg the melatonin agonist, agomelatine, has been shown to further

• significantly decrease the intraocular pressure in both eyes of all enrolled patients with primary open-angle glaucoma in whom multiple drug treatment with anti-glaucoma eye drops had no further effect.

Studies on rabbits have shown that

• daily adding melatonin and one of its agonist to brimonidine, a typical drug for reducing the intraocular pressure, further reduces the intraocular pressure by an additional 16%.

• Comparison of one of the melatonin agonist agomelatine to typical ocular hypotensive drugs on normal (normotensive ) eyes showed that agomelatine’s hypotensive effect on the eye comparable to latanoprost (40μl) and brimonidine (40μl), but not so effective as dorzolamide (40μl) or timolol (40μl°) . x

The reduction of intraocular pressure by melatonin and its analogue analogue, 5-

methoxycarbonylamino-N-acetyltryptamine

• is dependent on an intact sympathetic nervous system.

• After chemical sympathectomy by reserpine or 6-hydroxydopamine, the hypotensive effects of melatonin and its analogye are severely inhibited.

Melatonin’s effect in rabits and mice => eyes?

Melatonin also in rabbit studies has been reported to

• prevent and reverse the deleterious effect of ocular hypertension on the activity of the retina (assessed by electroretinography) and diminishes the vulnerability of retinal ganglion cells to these adverse effects.

Mice studies have shown that

• the hypotensive action of melatonin on the eyes occurs through the melatonin receptor type 1, not the type 2. In melatonin receptor type 1 knock-out mice, who have been made genetically deficient in melatonin receptor-1, the intraocular pressure increases, while it does not in both normal and melatonin receptor type 2 knock-out mice.

• Moreover, it is impossible to reduce the intraocular pressure with melatonin treatment inmelatonin receptor type 1 knock-out mice, while the pressure drops under melatonin in mice with normal melatonin receptor type 1 number.x

Melatonin receptor type 1

Melatonin receptor type 2

Hpotensive action of melatonin on the eyes

Melatonin’s protective effect on glaucoma => eyes: mechanisms?

The glaucoma protection by melatonin through the melatonin receptor type 1, not the type 2, may appear paradoxical because the melatonin receptor type 1 is not the one that is abundant in the retina, but the type 2, where it is believed to

express melatonin’s protective actions for the retina against light rays.

Melatonin receptor type 1 is mainly expressed in the pars tuberalis of the pituitary gland and the suprachiasmatic nuclei of the hypothalamus, indicative it is responsible for melatonin's circadian rhythm and reproductive involvements.

This involvement of melatonin receptors type 1 in circadian rhythm correction may explain part of their implication in glaucoma prevention, because glaucoma

is associated with dysregulation of circadian intraocular rhythms and sleep disorders.

x

Retinal cell loss and protection from AMPA-induced excitotoxicity: the improvement (antioxidant activity and damage reduction) with DHEA and DHEA sulfate treatments in rats

1. Kokona D, Charalampopoulos I, Pediaditakis I, Gravanis A, Thermos K. The neurosteroid dehydroepiandrosterone (DHEA) protects the retina from AMPA-induced excitotoxicity: NGF TrkA receptor involvement. Neuropharmacology. 2012 Apr;62(5-6):2106-17. (DHEA, administered intravitreally, protected the retina of rats from alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA -induced excitotoxicity in a dose-dependent manner)

Retinal cell death due to overdoses of pregnenolone sulfate induced excitotoxicity: the protection (antioxidant activity and damage reduction) with DHEA and DHEA sulfate treatments in vitro

1. Cascio C, Guarneri R, Russo D, De Leo G, Guarneri M, Piccoli F, Guarneri P. Pregnenolone sulfate, a naturally occurring excitotoxin involved in delayed retinal cell death. J Neurochem. 2000 Jun;74(6):2380-91. (brief pregnenolone sulfate (PS), pulse causes delayed retinal cell death due to acute excitotoxicity in a slowly evolving apoptotic fashion characterized by acycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset.

Retinal capillary pericytes in diabetic retinopathy: the protection with DHEA treatment in vitro (bovine cells)

1. Brignardello E, Beltramo E, Molinatti PA, Aragno M, Gatto V, Tamagno E, Danni O, Porta M, Boccuzzi G. Dehydroepiandrosterone protects bovine retinal capillary pericytes against glucose toxicity. J Endocrinol. 1998 Jul;158(1):21-6. (Pericyte loss is an early feature of diabetic retinopathy and represents a key step in the progression of this disease. This study aimed to evaluate the effect of dehydroepiandro-sterone (DHEA) on glucose toxicity in retinal capillary pericytes. Bovine retinal pericytes (BRP) were cultured in a high glucose concentration, with or without DHEA. After 4 days of incubation the number of BRP was significantly reduced by the high glucose concentration. The addition of DHEA to the medium reversed the adverse effect of high glucose: BRP proliferation partially recovered in the presence of 10 nmol/l DHEA, and completely recovered in the presence of DHEA at concentrations equal to or greater than 100 nmol/l. At physiological glucose concentrations, DHEA had no effect on BRP growth. Data show that DHEA, at concentrations similar to those found in human plasma, protects BRP against glucose toxicity. This effect seems specific for DHEA, since its metabolites, 5-en-androstene-3 beta, 17 beta-diol, dihydrotestosterone and estradiol did not alter BRP growth in normal or high glucose media. Various pieces of evidence link the antioxidant properties of DHEA to its protective effect on glucose-induced toxicity in BRP.)

x

Growth hormone

As the eye pressure in growth hormone-deficient children is increased, the finding of an ocular hypertension in growth hormone-deficient adults

suggests that the growth hormone deficit is at the origin of the increase in intraocular pressure and possibly the resulting glaucoma.

In this case, subcutaneous injections of growth hormone to may reduce the eye pressure by 1-4 mm Hg (if we rely on the previously mentioned

observations of growth hormone treatment to growth hormone-deficient children).

x

Glaucoma: treatment

Growth hormone treatment may sometimes dramatically

drop the eye pressure

x

Child with growth hormone deficiency:

+3.3 mmHg higher intraocular pressure :

±18.2 mm Hg)

Retinal ganglion cell death: the improvement (increase in survival) with growth hormone in vivo (chick embryos in ovo)

1. Sanders EJ, Lin WY, Parker E, Harvey S. Growth hormone promotes the survival of retinal cells in vivo. Gen Comp Endocrinol. 2011 May 15;172(1):140-50. (retinal GH has neuroprotective effects in retinal ganglion cells … The apoptotic cells induced by GH withdrawal were primarily located close to the optic fissure of the developing eye, and were distributed in clusters, suggesting that there are sub-populations of retinal cells that are particularly susceptible to apoptotic stimuliHarvey S, Baudet ML, Sanders EJ. Growth hormone-induced neuroprotection in the neural retina during chick embryogenesis. Ann N Y Acad Sci. 2009 Apr;1163:414-6.

2. Harvey S, Baudet ML, Sanders EJ. Growth hormone and cell survival in the neural retina: caspase dependence and independence. Neuroreport. 2006 Nov 6;17(16):1715-8.

Retinal ganglion cell death: the improvement (increase in survival) with growth hormone in vitro (embryonic chick neural retina)

1. Martínez-Moreno C, Andres A, Giterman D, Karpinski E, Harvey S. Growth hormone and retinal ganglion cell function: QNR/D cells as an experimental model. Gen Comp Endocrinol. 2014 Jan 1;195:183-9. (

2. Sanders EJ, Lin WY, Parker E, Harvey S. Growth hormone expression and neuroprotective activity in a quail neural retina cell line. Gen Comp Endocrinol.2010 Jan 1;165(1):111-9

3. Sanders EJ, Parker E, Harvey S. Endogenous growth hormone in human retinal ganglion cells correlates with cell survival. Mol Vis. 2009;15:920-6.

4. Sanders EJ, Parker E, Harvey S. Growth hormone-mediated survival of embryonic retinal ganglion cells: signaling mechanisms. Gen Comp Endocrinol. 2008 May 1;156(3):613-21

5. Sanders EJ, Parker E, Harvey S. Retinal ganglion cell survival in development: mechanisms of retinal growth hormone action. Exp Eye Res. 2006 Nov;83(5):1205-14.

6. Sanders EJ, Parker E, Arámburo C, Harvey S. Retinal growth hormone is an anti-apoptotic factor in embryonic retinal ganglion cell differentiation. Exp Eye Res. 2005 Nov;81(5):551-60 x

Retinal ganglion cells loss due to ocular hypertension: the protection (increased survival) with IGF-1 treatment (via transplantation of human neural progenitor cells expressing IGF-1) in vitro and in vivo in mice with glaucoma due to ocular hypertension

1. Ma J, Guo C, Guo C, Sun Y, Liao T, Beattie U, López FJ, Chen DF, Lashkari K. Transplantation of human neural progenitor cells expressing IGF-1 enhances Retinal ganglion cell survival. PLoS One. 2015 Apr 29;10(4):e0125695. (RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a mouse model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF-1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways.)

Retinal pigment epithelial cells loss due to toxin (sodium nitroprusside): the protection with IGF-1 treatment in vitro on isolated human retinal ganglion cells

1. Wang H, Liao S, Geng R, Zheng Y, Liao R, Yan F, Thrimawithana T, Little PJ, Feng ZP, Lazarovici P, Zheng W. IGF-1 signaling via the PI3K/Akt pathway confers neuroprotection in human retinal pigment epithelial cells exposed to sodium nitroprusside insult. J Mol Neurosci. 2015 Apr;55(4):931-40. (SNP, in a concentration-dependent fashion, increased the production of reactive oxygen species (ROS) and lipid peroxidation process causing cell death by apoptosis of D407 cells. IGF-1, in a time-and dose-dependent manner, conferred protection towards SNP-mediated insult. Both phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) were activated by IGF-1 in relation to the protective effect. Blockade of the PI3K/Akt pathway abolished the protective effect of IGF-1 whereas inhibition of the MAPK pathway was ineffective. SNP decreased the phosphorylation of Akt in the cells while IGF-1 reversed this inhibitory effect. These results indicate that the protective effect of IGF-1 on D407 exposed to SNP insult is mediated by the PI3K/Aktpathway.)

x

Retinal ganglion cell loss due to hypoxia: the protection with IGF-1 treatment in vitro on isolated retinal ganglion cell cultures

1. Yang X, Wei A, Liu Y, He G, Zhou Z, Yu Z. IGF-1 protects retinal ganglion cells from hypoxia-induced apoptosis by activating the Erk-1/2 and Akt pathways. Mol Vis. 2013 Sep 12;19:1901-12. (Purified RGC cultures were obtained from the retinas of neonatal rats .. . Hypoxia induces apoptosis in .. rat RGCs, as detected by caspase-3 expression and TUNEL and JC-1 staining assays, and that IGF-1 treatment could significantly reduce this effect in RGCs. Interestingly, pretreatment of RGCs with AG1024 (an IGF-1 inhibitor), U0126 (an Erk-1/2 inhibitor), and LY294002 (an Akt inhibitor) markedly attenuated the effects of IGF-1 treatment. … the Erk-1/2 and Akt signaling pathways play a role in the protective effects of IGF-1 on RGCs exposed to hypoxia.)

Retinal ganglion cell loss after optic nerve section: the protection with transcorneal electrical stimulation by increasing the level of IGF-1 production by Muller cells

1. Morimoto T, Miyoshi T, Matsuda S, Tano Y, Fujikado T, Fukuda Y. Transcorneal electrical stimulation rescues axotomized retinal ganglion cells by activating endogenous retinal IGF-1 system. Invest Ophthalmol Vis Sci. 2005 Jun;46(6):2147-55. (transcorneal electrical stimulation (TES) on the survival of axotomized RGCs … after optic nerve (ON) transection in rats … increased the survival of axotomized RGCs in vivo, and the degree of rescue depended on the strength of the electric charge. … gradual upregulation of intrinsic IGF-1 in the retina after TES. … IGF-1 immunoreactivity was localized initially in the endfeet of Muller cells and then diffused into the inner retina. … TES can rescue the axotomized RGCs by increasing the level of IGF-1 production by Muller cells.) x

Retinal cells (ganglion cells, pigmented epithelium cells, primitive rod- and cone-like photoreceptor cells, and primitive lens and corneal-like structure): the stimulation of their differentiation from human embryonic stem cells with IGF-1 treatment

1. Mellough CB, Collin J, Khazim M, White K, Sernagor E, Steel DH, Lako M. IGF-1 Signaling plays an important role in the formation of three-dimensional laminated neural retina and other ocular structures from human embryonic stem cells. Stem Cells. 2015 Aug;33(8):2416-30. (insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling.)

Human retinal pigment epithelial cells: the stimulation of proliferation with IGF-1 treatment

1. Weng CY, Kothary PC, Verkade AJ, Reed DM, Del Monte MA. MAP kinase pathway is involved in IGF-1-stimulated proliferation of human retinal pigment epithelial cells (hRPE). Curr Eye Res. 2009 Oct;34(10):867-76. (IGF-1 is a mitogen for hRPE cells and also stimulates production of the angiogenic factor, VEGF. Additionally, PD98059 inhibits the production of vascular endothelial growth factor (VEGF), suggesting that the MAP kinase pathway is involved in IGF-1-mediated angiogenesis.)

x

Female hormone treatment after the menopause prevents glaucoma

The intraocular pressure in postmenopausal women who since more than 5 years take HRT ((female) hormone replacement therapy) is lower than in women who do not take HRT. The

incidence of a higher intraocular tension above the 19 mmHg is 2 ½ times lower risk in women on HRT. Only 7 % of women aged up to 60 with HRT for more than 5 years suffer from this predisposing condition for glaucoma in comparison with the 19 % of women without HRT . These figures show the importance of female hormones treatments after

menopause in the prevention of glaucoma.

However, two studies have not confirmed these benefits of HRT on the intraocular pressure. This may be due to the use of oral estrogens, which reduce the action of other beneficial hormones such as thyroid and growth hormone by slowing down the release of these hormones in for their target cells in the eyes from the thyroid and growth hormone

(transporting) plasma binding proteins, which are overproduced by the liver due to an accumulation of estrogens in the liver.

One of the studies did show a slightly, but not significant, lower incidence of glaucoma in women on HRT (9% instead of 11%à.

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Intraocular pressure: the reduction with oral melatonin treatment in healthy people1. Samples JR, Krause G, Lewy AJ. Effect of melatonin on intraocular pressure. Curr Eye Res. 1988 Jul;7(7):649-53. (studied the

effect of orally administered melatonin on intraocular pressure in humans. We suppressed serum melatonin levels by exposing our subjects to bright light. Our experiments suggest that melatonin lowers intraocular pressure in man. This may prove to be a therapeutically useful agent since melatonin appears to be relatively free of side effects and is effective in small quantities.)

Glaucoma: the reduction in intraocular pressure with oral melatonin or melatonin agonist treatment in patients with cataract

1. Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg. 2009 Apr;108(4):1146-51. (40 patients undergoing cataract surgery under topical anesthesia were randomly assigned into two groups (20 patients each) to receive either melatonin 10 mg tablet (melatonin group) or placebo tablet (control group) as oral premedication 90 min before surgery. … Melatonin significantly reduced the anxiety scores (median, interquartile range) from 5, 3.5-6 to 3, 2-3 afterpremedication and to 3, 2-3.5 during surgery (P = 0.04 and P = 0.005 compared with the placebo group, respectively). Perioperative verbal pain scores were significantly lower in the melatonin group with less intraoperative fentanyl requirement (median, interquartile range) compared with the control group, 0, 0-32.5 vs 47.5, 30-65 µg, respectively, P = 0.007. Melatonin also decreased IOP (mean +/- sd) significantly from 17.9 +/- 0.9 to 14.2 +/- 1.0 mm Hg after premedication and to 13.8 +/- 1.1 mm Hg during surgery (P < 0.001). It also provided better quality of operative conditions.)

Glaucoma: the reduction in intraocular pressure with an oral melatonin agonist treatment in patients

1. Pescosolido N, Gatto V, Stefanucci A, Rusciano D. Oral treatment with the melatonin agonist agomelatine lowers the intraocular pressure of glaucoma patients. Ophthalmic Physiol Opt. 2015 Mar;35(2):201-5. (“The hypotonising effect of oral systemic agomelatine at 25 mg day(-1) was able to further decrease IOP in both eyes of all enrolled POAG patients in which multiple drug treatment with anti-glaucoma eye drops had no further effect.)

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Glaucoma: the reduction in retinal damage, but not in intraocular pressure, by treatments with oral melatonin or one of its analogues in rabbits

1. Belforte NA, Moreno MC, de Zavalía N, Sande PH, Chianelli MS, Keller Sarmiento MI, Rosenstein RE. Melatonin: a novel neuroprotectant for the treatment of glaucoma. J Pineal Res. 2010 May;48(4):353-64. (Melatonin, which did not affect intraocular pressure (IOP), prevented and reversed the effect of ocular hypertension on retinal function (assessed by electroretinography) and diminished the vulnerability of retinal ganglion cells to the deleterious effects of ocular hypertension.)

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Elevated intraocular pressure: the prevention with female hormone treatment in postmenopausal women

1. Lang Y, Lang N, Ben-Ami M, Garzozi H. The effects of hormone replacement therapy (HRT) on the human eye: Harefuah. 2002 Mar;141(3):287-91. (This review presents the ever growing data accumulated over the past years concerning the beneficial effects of HRT on various eye pathologies. It was found that HRT may relieve dry eye symptoms in post-menopausal women, may decrease the intraocular pressure and may delay cataract formation in treated women)

2. Wenderlein JM, Hensinger E. Hormone therapy for ophthalmoprophylaxis. Klin Monatsbl Augenheilkd. 2003 Oct;220(10):704-9. Universitatsfrauenklink Ulm (Women mainly aged over 70 suffering from age-related conditions such as glaucoma and cataract almost never had HRT. Thus in the following only women aged up to 60 have been of interest. 7 of 10 women being in the menopause for over 10 years with a visus higher than 0.7 received HRT. Only 1 of 10 women had a visual acuity less than 0.4. There was also a correlation between receiving HRT and intraocular pressure. In the group aged up to 60 without taking HRT 19 % had an intraocular pressure above 19. In women with HRT over 5 years this occurred in only 7 %.)

3. Abramov Y, Borik S, Yahalom C, Fatum M, Avgil G, Brzezinski A, Banin E. Does postmenopausal hormone replacement therapy affect intraocular pressure? J Glaucoma. 2005 Aug;14(4):271-5. (107 women aged 60 to 80 years receiving HRT and 107 controls who have never received HRT … The groups did not differ in mean IOP (15.3 versus 15.3 mm Hg), mean vertical (0.18 versus 0.21) and horizontal (0.17 versus 0.14) C/D ratios, and in prevalence of increased IOP (15% versus 14%), C/D ratio (7% versus 7%), or glaucoma (9% versus 11%).)

4. Toker E, Yenice O, Temel A. Influence of serum levels of sex hormones on intraocular pressure in menopausal women. J Glaucoma. 2003 Oct;12(5):436-40. (30 menopausal women on hormone replacement therapy and 32 menopausal women who had never received hormone replacement therapy (HRT) … Thirty menopausal women on hormone replacement therapy and 32 menopausal women who had never received hormone replacement therapy (HRT) … The mean IOP of postmenopausal women receiving HRT (13.29 +/- 2.28 mm Hg) was not significantly different from that of menopausal women not receiving HRT (13.56 +/- 2.5 mm Hg, P = 0.24).

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Retinal cell loss due to hyperoxia (prematurity): the protection (antioxidant effects and damage reduction) with estradiol treatment n neonatal rats

1. Zhang H, Wang X, Xu K, Wang Y, Wang Y, Liu X, Zhang X, Wang L, Li X. 17β-estradiol ameliorates oxygen-induced retinopathy in the early hyperoxic phase. Biochem Biophys Res Commun. 2015 Feb 20;457(4):700-5. (Retinopathy of prematurity (ROP) is a major and leading cause of blindness in premature infants. It .. large central capillary-free areas were induced in the retinas of pups exposed to hyperoxia on postnatal day 9 (P9), … The concentrations of malondiadehyde (MDA), an end-product of oxidative stress, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major enzyme producing free radicals, as well as the activity of NADPH oxidase were significantly elevated in the retinas of pups exposed to hyperoxia on P9 and postnatal day 13 (P13) compared to those in age matched pups exposed to normoxia. Treatment with 17β-E2 decreased not only the % of the central capillary-free area to total retina area but also the concentrations of MDA and NADPH oxidase as well as the activity of NADPH oxidase in a dose-dependent manner in pups exposed to hyperoxia on p9 and P13.)

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Retinal pigment cell damage and death due to toxins (which induce oxidative stress): the improvement (antioxidant effects and damage reduction) with estradiol treatment in vitro (rat cells)

1. Giddabasappa A, Bauler M, Yepuru M, Chaum E, Dalton JT, Eswaraka J. 17-β estradiol protects ARPE-19 cells from oxidative stress through estrogen receptor-β. Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5278-87

2. (retinal pigment epithelium (RPE) … Cultured ARPE-19 cells were subjected to oxidative stress with t-butyl hydroxide or hydrogen peroxide in the presence or absence of 17β-E(2). .. ARPE-19 cells expressed significant amounts of ERα and ERβ. Pretreatment with 17β-E2 protected ARPE-19 cells from oxidative stress and apoptosis. 17β-E(2) reduced the ROS levels and mitochondrial depolarization.)

Retinal macroglial (Muller) cell death due to hydrogen peroxide (H202): the protection with estradiol treatment in vitro (human cells)

1. Li C, Tang Y, Li F, Turner S, Li K, Zhou X, Centola M, Yan X, Cao W. 17-beta-estradiol (betaE2) protects human retinal Müller cell against oxidative stress in vitro: evaluation of its effects on gene expression by cDNA microarray. Glia. 2006 Mar;53(4):392-400. (Müller cells are the principal macroglia responsible for supporting retinal neuronal survival, information processing and removing metabolic waste. … betaE(2) protects cultured human Müller cells against H(2)O(2)-induced cell death through the inhibition of apoptosis. This protective effect may operate through regulation of genes, such as TSP1, MAP3K3, SOX11, TSP1, and PEDF, and may in turn exert an important role in protecting retinal neurons.)

Female hormone treatment after the menopause prevents glaucoma: mechanisms

Several mechanisms may explain why HRT may help to reduce the risk of glaucoma. They preventing thereby atrophy of retina and optic nerve by

• improving the blood supply to the retina,

• reducing the eye pressure via a better evacuation of any excess fluid from the eye globe.

• Reducing tge free radical load on the retina and optic nerve:

estradiol is a potent antioxidant. Estrogens have antioxidant properties, which are due to their ability to bind to estrogen receptors and to up-regulate the expression of antioxidant enzymes such as glutathione peroxidase.

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Protection against ocular hypertension and glaucoma by treatment with

DHEA, pregnenolone and aldosterone at physiological doses

DHEA treatment may protect the retina against excitotoxicity

DHEA, the abundant hormone n the serum as DHEA sulfate, also can protect the retina against cell death by (excito)toxins thanks to its antioxidant and anabolic activities. This is observed in

vivo in rats and in vitro on retinal cell cultures. DHEA also has been observed to help to preserve retinal capillary pericytes in diabetic retinopathy. Pericytes are contractile cells that

wrap around the endothelial cells of capillaries throughout the body.[ Pericytes regulate capillary blood flow, the clearance and phagocytosis of cellular debris, and the permeability of

the blood–brain barrier

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DHEA treatment protects the retina against excitotoxicityRetinal ces ll loss and protection from AMPA-induced excitotoxicity: the improvement (antioxidant activity and damage reduction) with DHEA and DHEA sulfate treatmentin rats

1. Kokona D, Charalampopoulos I, Pediaditakis I, Gravanis A, Thermos K. The neurosteroid dehydroepiandrosterone (DHEA) protects the retina from AMPA-induced excitotoxicity: NGF TrkA receptor involvement. Neuropharmacology. 2012 Apr;62(5-6):2106-17. (DHEA, administered intravitreally, protected the retina of rats from alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide(AMPA -induced excitotoxicity in a dose-dependent manner)

Retinal cell death due to overdoses of pregnenolone sulfate induced excitotoxicity: the protection (antioxidant activity and damage reduction) with DHEA and DHEA sulfate treatments in vitro

1. Cascio C, Guarneri R, Russo D, De Leo G, Guarneri M, Piccoli F, Guarneri P. Pregnenolone sulfate, a naturally occurring excitotoxin involved in delayed retinal cell death. J Neurochem. 2000 Jun;74(6):2380-91. (brief pregnenolone sulfate (PS), pulse causes delayed retinal cell death due to acute excitotoxicity in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset.

Retinal capillary pericytes in diabetic retinopathy: the protection with DHEA treatment in vitro (bovine cells)

1. Brignardello E, Beltramo E, Molinatti PA, Aragno M, Gatto V, Tamagno E, Danni O, Porta M, Boccuzzi G. Dehydroepiandrosterone protects bovine retinal capillary pericytes against glucose toxicity. J Endocrinol. 1998 Jul;158(1):21-6. (Pericyte loss is an early feature of diabetic retinopathy and represents a key step in the progression of this disease. This study aimed to evaluate the effect of dehydroepiandro-sterone (DHEA) on glucose toxicity in retinal capillary pericytes. Bovine retinal pericytes (BRP) were cultured in a high glucose concentration, with or without DHEA. After 4 days of incubation the number of BRP was significantly reduced by the high glucose concentration. The addition of DHEA to the medium reversed the adverse effect of high glucose: BRP proliferation partially recovered in the presence of 10 nmol/l DHEA, and completely recovered in the presence of DHEA at concentrations equal to or greater than 100 nmol/l. At physiological glucose concentrations, DHEA had no effect on BRP growth. Data show that DHEA, at concentrations similar tothose found in human plasma, protects BRP against glucose toxicity. This effect seems specific for DHEA, since its metabolites, 5-en-androstene-3 beta, 17 beta-diol, dihydrotestosterone and estradiol did not alter BRP growth in normal or high glucose media. Various pieces of evidence link the antioxidant properties of DHEA to its protective effect on glucose-induced toxicity in BRP.)

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Pregnenolone treatment may reduce the intraocular pressure & glaucomatous damage

When the episcleral veins, which drain aqueous humor, are blocked (occlusion) in rats, chronic ocular hypertension is induced and a progressive, time-dependent loss of ganglion cells & retinal thickness occurs. µ

Pregnenolone sulfate administration

• prevents the ganglion cell loss,

• protects the inner plexiform layer thickness of the retina

• increases the number of sigma receptors 1 (on which pregnenolone sulfate acts as an agonist) in these rats.

!! However, (very) high doses (over the 300 mg/day) may not be recommended as the excitatory neurotransmitter pregnenolone act then as an excitotoxin (toxin toxic for the nervous system and the otic nerve and ganglion cells) as observed in an in vitro study.

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Pregnenolone may reduce the intraocular pressure and glaucomatous damage

Ocular hypertension: the protection (reduction in intraocular pressure and damage reduction (ganglion cell loss and retinal atrophy of the retina)) with pregnenolone treatment in rats

1. Sun X, Cheng F, Meng B, Yang B, Song W, Yuan H. Pregnenolone sulfate decreases intraocular pressure and changes expression of sigma receptor in a model of chronic ocular hypertension. Mol Biol Rep. 2012 Jun;39(6):6607-14. (Sigma receptors are Ca(2+)-sensitive, ligand-operated receptor chaperones at the mitochondrion-associated endoplasmic reticulum membrane. This study describes the effect of the sigma receptor 1 agonist pregnenolone sulfate on intraocular pressure (IOP) and sigma receptor 1 expression in rat retinas after chronic ocular hypertension. Chronic ocular hypertension was induced by occlusion of episcleral veins. .. time-dependent loss of ganglion cells and retinal thickness occurred at elevated IOP. High IOP decreased sigma receptor 1 expression during the first week, but expression was increased at 8 weeks. Injected pregnenolone significantly decreased IOP, prevented ganglion cell loss, protected inner plexiform layer thickness, and increased sigma receptor 1 expression in episcleral vein-cauterized rats. Sigma receptors appear to be neuroprotective and potential targets for glaucoma therapeutics.)

Pregnenolone at pharmacological doses may reduce the intraocular pressure and glaucomatous damage

Retinal ganglion cell death due to toxin N-methyl-D-aspartate (NMDA): aggravation with pharmacological concentrations (≥ 1µM) of pregnenolone sulfate in vitro (serum pregnenolone sulfate levels in humans: 0.12-0.38 µM)

1. Guarneri P, Russo D, Cascio C, De Leo G, Piccoli T, Sciuto V, Piccoli F, Guarneri R. Pregnenolone sulfate modulates NMDA receptors, inducing and potentiating acute excitotoxicity in isolated retina. J Neurosci Res. 1998 Dec 15;54(6):787-97. (a 90-min exogenous application of Pregnenolone sulfate (PS) at 0.1-500 µM concentrations potentiated N-methyl-D-aspartate (NMDA) -induced cell death and at 50-500 µM concentrations caused cytotoxicity. their co-application resulted in a high degree of toxicity.)

Retinal ganglion cell death due to pharmacological doses of pregnenolone sulfate in vitro

1. Cascio C, Guarneri R, Russo D, De Leo G, Guarneri M, Piccoli F, Guarneri P. Pregnenolone sulfate, a naturally occurring excitotoxin involved in delayed retinal cell death. J Neurochem. 2000 Jun;74(6):2380-91. (brief pregnenolone sulfate (PS), pulse causes delayed retinal cell death due to acute excitotoxicity in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset.

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No increase of intraocular pressure with treatment with fludrocortisone, the synthetic derivative of the adrenal

hormone aldosterone

Patients with primary open-angle glaucoma patients who have low blood pressure due to aldosterone deficiency do not have to worry for their eyes. They

may receive the traditional treatment, fludrocortisone, to correct their deficit without having to worry about the intraocular pressure? It is not influenced by

intake of this hormone treatment.

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EPO treatment prevents retinal ganglion cell loss in ocular hypertension and glaucoma and protects peripheral

vision, without any effects on the intraocular pressure

• If the serum erythropoietin (EPO) level in the serum EPO concentrations of the eyes of glaucoma patients is usually not different to that in healthy people, the EPO level in the mean aqueous humor of glaucoma patients is usually higher than in cataract patients and in some studies than in healthy people.

• Luckily, because EPO (erythropoietin) is another hormone that protect the eyes against glaucomatous damage by neutralizing free radicals (antioxidant effects) and improving tissue oxygenation through an increase in the red blood cells, which transport oxygen in the blood cell.

• EPO receptors are found in the retinal ganglion cell layer in mice, suggesting a direct protective effect of EPO on these cells.

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EPO treatment glaucoma intraocular pressure

In chronic kidney failure patients, EPO’s preserves of the thickness of the retinal layer, where the nerve fibers (retinal nerve fiber layer) are found, is statistically significant mainly in the temporal (outer) quadrant) of the macula.

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In mice who are predisposed to glaucoma due to chronic intraocular hypertension, pharmacologically

high doses of EPO prevent significant retinal ganglion cell loss without any effect on intraocular

pressure.

• The EPO works mainly on the retinal ganglion cell bodies and not on their axons.

• When mice are subjected to optic nerve crush, EPO therapy dose-dependent protects the retinal

ganglion cell bodies, but is unable to prevent axonal degeneration.

• In chronic ocular hypertension rats, EPO treatment remarkably preserves the function of the retina on the electroretinogram (remarkable restoration of the amplitude of the b waves of the retina).

Glaucoma: the protection with EPO treatment in chronic renal failure patients1. Aktas Z, Unlu M, Uludag K, Erten Y, Hasanreisoglu B. The effect of systemic erythropoietin treatment on retinal nerve fiber layer parameters

in patients with chronic renal failure undergoing peritoneal dialysis. J Glaucoma. 2015 Mar;24(3):214-8. (The mean retinal nerve fiber layer thickness values in patients undergoing peritoneal dialysis were statistically lower than the control group at superior, inferior, nasal, and temporal quadrant, respectively (P=0.03, 0.04, 0.04, and 0.03). The effect of EPO on the retinal nerve fiber layer thickness values were statistically significant only in the temporal quadrant (P=0.02).)

Glaucoma: the protection with EPO treatment in mice1. Zhong L, Bradley J, Schubert W, Ahmed E, Adamis AP, Shima DT, Robinson GS, Ng YS. Erythropoietin promotes survival of retinal ganglion

cells in DBA/2J glaucoma mice. Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1212-8. (DBA/2J mouse model of glaucoma. Mice were intraperitoneally injected with control substances or various doses of EPO, starting at the age of 6 months and continuing for an additional 2, 4, or 6 months. … Treatment with EPO at doses of 3000, 6000, and 12,000 U/kg body weight per week all prevented significant RGC loss, compared with untreated DBA/2J control animals. EPO effects were similar to those of memantine, a known neuroprotective agent. IOP, in contrast, was unchanged by both EPO and memantine. Finally, EPOR was expressed in the RGC layer in both DBA/2J and C57BL/6J mice.

Optic nerve crush: the protection with EPO treatment in mice1. Sullivan TA, Geisert EE, Templeton JP, Rex TS. Dose-dependent treatment of optic nerve crush by exogenous systemic mutant

erythropoietin. Exp Eye Res. 2012 Mar;96(1):36-41. (Mice were subjected to optic nerve crush and analysis was performed thirty days later. EPO-R76E showed dose-dependent protection of the retinal ganglion cell bodies, but was unable to prevent axonal degeneration.)

Ocular hypertension: the protection with EPO treatment in rats

1. Gui DM, Yang Y, Li X, Gao DW. Effect of erythropoietin on the expression of HIF-1 and iNOS in retina in chronic ocular hypertension rats. Int J Ophthalmol. 2011;4(1):40-3. (In EPO drug treatment group, the amplitude of electroretinogram (ERG)-b wave of retina restored remarkably. There was significant difference between two groups (P<0.05). The expressions of HIF-1\iNOS (transcription factor hypoxia inducible factor-1 and its target inducible nitric oxide synthase ) mRNA and protein in EPO drug treatment group were weakened remarkably. It was statistically different compared with the non-drug treatment group... One of protect mechanisms of EPO to injured retina caused by chronic intraocular hypertension is through HIF-1\iNOS signal conduct path.

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Avoid high cortisol/low DHEA imbalancesTo avoid a chronic condition of excess glucocorticoids relative to DHEA that might be facilitating glaucoma, the first intervention is to check if a glucocorticoid, especially a synthetic derivative with prolonged action), is taken and if confirmed to check if the dose is excessive with development of overdose signs such as a swollen face, bruises, thinning of the skin. If excess signs are found the doseshould be reduced – usually by -25 up to -50%.

If there are physical cortisol overdose signs in the absence of a treatment, causes of the cortisol overproduction is in most cases a prolonged stressful condition that stimulates the release of important amounts of endogenous (internal) cortisol to cope with the situation. The first treatment is then aimed at a better stress management with mediation/relaxation sessions, job change, a vacation, and/or a better diet. The cortisol protective diet includes lots of vegetables and fruits and protein-rich foods as the amino acids of the protein prevent tissue-wasting effects (the more protein, the better the protection). Sweets and unsprouted grains should be avoided.

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x

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Dose RouteTime before

first effectsEfficacy

Thyroid

Desiccated thyroid 30-180 mg/day at wakeup

Oral 2-6 months ± to ++T3 andT4

combination

T3: 10-40 µg

per

dayT4: 50-200

Female hormones (HRT)

• estradiol 0.06

%: 0.75 to 2.25 mg/day upon waking from the 5th to 25th

day of cycle

Transdermal

2-6 months ± to +±

• Progesterone

100-200 mg at bedtime from the 15th to 25th day of menstrual cycle

Oral or vaginal

Melatonin • Melatonin0.1 0.5 mg/day Sublingual 1-48 hours 0 to +±?

0.5-3 mg/day Oral 1-48 hours 0 to +±?

Hormone therapies of Glaucoma

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Dose RouteTime for

first effectsEfficacy

Hormone

therapies

• DHEAMen: 20-50 mg/day

Men: 10-25 mg/dayOral

2-6 months0 to +

• Pregnenolone 25-50 mg/ay Oral2-6 months

0 to +

• Epo

(erythropoietin)100-1000 IU/day Subcutaneous inj. 2-6 months 0 to +

• Growth hormone 0.1-0.35 mg per day Subcutaneous inj. 2-6 months ± to +

Avoid Hormone excess

x

Dose Route

Time for

first

effects

Efficac

y

Hormone

therapies

Cortisol

excess

• Reduce the dose of any

glucocorticoid

• Counterbalance cortisol excess

with sufficient anabolic hormones

(DHEA, testosterone, estrogens,

GH, IGF-1, and melatonin)

Stop or reduce

the dose of

cortisol

treatment1-6 weeks ± to ++

Treatment of glaucoma by lifestyle & disease improvement

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Dose RouteTime for firsteffects

Efficacy

Lifestyle

• Regular physical exercise• 4-5x 30-45’/week: walking,

moderate jogging, bicycling2-48 hours ± to +

• Intensive sports in warmweather: Add salt

• 2-10 g/day depending on sweatintensity (not for patients withhypertension)

2-7 days ± to +

• Relax more, cut downyour worries

• 1-2x10-20’/day additionalrelaxation

2-48 hours ± to +±

• Sleep more• Add 30-60’/day of additional sleep

or rest2-48 hours ± to +±

• Stop smoking

• Smoke outdoors

• Drink >2L/day of water,

• Daily antioxidant supplements

if stopping isn’t felt as possible

2-6 months ± to +±

Disease • Improve diabetes• Metformin: ±2g/day for type 2

diabetesOral 2-6 months ± to +±

Treatment of glaucoma by diet improvement

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Treatment of glaucoma DoseTime for

first effectsEfficacy

• Drink more water • ≥ 2 L/day of still water 1-6 months± to

+±±

• Avoid coffee • Drink water, herbal tea, soup 2-48 hours ± to +±

• Consume fruits • ≥ 3 servings per day (300 g/day) 1-6 months ± to +±

• Eat vegetables, esp. green leafy

vegetables (rich in magnesium and

potassium)

• ≥ 3 servings per day 1-6 months ± to +±

• Eat more flavonoid-rich foods

• ≥ 3-4 servings per week ( 300-

400g) per week of berries, red

grapes or other flavonoid-rich

foods a

1-6 months 0 to +

x

x

Dose RouteTime for

first effectsEfficacy

LifestyleRegular physical

exercise

4-5x 30-45’/week:

walking, moderate

jogging, bicycling

2-48 hours ± to +

Nutritional

therapies

• Magnesium150-400 mg/day of

elemental magnesiumOral 1-7 days ± to +±

• Iron (only in iron-

deficient patients) (?)

20-80 mg/day of

elemental ironOral 2-6 months 0 to +?

• Manganese (?) 15-50 mg/day Oral, IM 2-6 months 0 to +?

• Zinc 25-100 mg per day Oral 2-6 months 0 to +

• Vitamin B-complex

≥ 0.2 mg B1, 0.3 mg B2,

3.9 mg B3, 0.4 µg

B12/day

Oral 2-6 months 0 to +

• Vitamin C 250-1000 mg/day Oral 2-6 months 0 to +

• Vitamin E 300-600 mg/day Oral 2-6 months 0 to +

Nutritional therapies of Glaucoma

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Dose RouteTime for

first effectsEfficacy

LifestyleRegular physical

exercise

4-5x 30-45’/week: walking,

moderate jogging, bicycling2-48 hours ± to +

Nutritional

therapies

Coenzyme Q10 30-150 mg/day Oral 2-6 months 0 to +

Eye

drops

Vitamin E 0.5% 1-2x1-2 drops/day on

each eyeOphtalmic 2-6 months 0 to +

Co Q10 0.1%

Alpha-lipoic acid 300-900 mg/day Oral 2-6 months 0 to +

Fish oil (containing at

least 350 mg /g of DHA)1-3 g/day Oral 1-6 months 0 to +

Borage oil (rich in

omega-6, esp. in GLA) (?)1-6 g/day Oral 2-6 months 0 to +?

Anthocyanides

(flavonoids)500 mg/day Oral 2-6 months 0 to +

Conclusion

People with glaucoma can apply the above-mentioned treatments to partially reverse it, or at least try to block any further glaucoma progression.Among these useful interventions let’s pinpoint two of them out that can very quickly reduce the eye pressure and stop the atrophy of the optic nerve of progressing any further: • Relax as much as possible to get rid of the nervous and muscle tension

brought by stress • Stop taking coffee. These 2 measures alone may drastically reduce the eye pressure in 24-48 hours’ time! Most other interventions such as nutritional and hormone therapies, except probably overdoses of melatonin take usually more time, 1- 2 months before noticing a substantial decrease in eye pressure.

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