To recap from previous posts: The macular is the light sensitive area in the centre of the retina that controls visual field and the ability to see colours.  AMD is caused [...]]]> Age Related Macular Degeneration, or AMD, is the most common cause of blindness in people over the age of 50 in the UK.

To recap from previous posts: The macular is the light sensitive area in the centre of the retina that controls visual field and the ability to see colours.  AMD is caused by the deterioration of the macular.  As this happens the peripheral, outer, vision remains intact as the centre field of vision becomes slowly blurry, grey or filled with a large black spot.  Two forms of AMD exists: the dry form which develops slowly, accounting for 90% of all cases; and the wet form which causes rapid deterioration of central vision.

 
The exact causes of AMD are unknown although free radical damage, where unstable oxygen molecules damage the eye cells, is strongly implicated.  Tobacco smoke and sun exposure can increase the level of free radicals in the body and both are a risk for AMD.  High blood pressure and diabetes are also risk factors as these conditions can limit blood flow to the eyes.

New research (1) undertaken at Wilmer Eye Institute, Johns Hopkins School of Medicine USA has added to the evidence which suggests that a diet rich in omega 3 fats, naturally found in oily fish such as mackerel, sardines and salmon, can protect against advanced AMD.

High concentrations of omega-3 fatty acids are found in the retina of the eye and evidence has been mounting that the nutrient may be essential to eye health.  This newly published research (1) was part of the Salisbury Eye Evaluation (SEE) study.  The researchers wanted to determine the relationship between fish and shellfish consumption and age-related macular degeneration (AMD) status in study participants.  Over 2300 individuals aged between 65 and 84 years old were included in the study.   A validated food frequency questionnaire was used to estimate weekly fish/shellfish consumption for each participant. After dietary assessment was complete, participants were evaluated for AMD and the association between weekly fish/shellfish intake and risk of AMD was investigated.  1942 individuals had no AMD, 227 had early AMD, 153 had intermediate-stage disease, and 68 had advanced AMD. In the advanced AMD group, the macular area of the retina exhibited either neovascularization (abnormal blood vessel growth and bleeding) or a condition called geographic atrophy. Both conditions can result in blindness or severe vision loss.

The results data (1) found that there was a protective effect of fish and shellfish intake against advanced forms of AMD i.e. Those individuals with advanced AMD were significantly less likely to consume fish/shellfish high in omega-3 fatty acids.  In a press release Dr West, one of the study scientists said “Our study corroborates earlier findings that eating omega-3-rich fish and shellfish may protect against advanced AMD.” “While participants in all groups, including controls [those with no AMD], averaged at least one serving of fish or shellfish per week, those who had advanced AMD were significantly less likely to consume high omega-3 fish and seafood,”.

The study also looked at whether dietary zinc from crab and oyster consumption impacted advanced AMD risk, but no significant relationship was found. Zinc is also considered protective against AMD and is included in many eye-protection nutrient supplements.   Dr. West speculated that the current study found no effect because the levels of zinc obtained from seafood/fish were low compared to supplement levels (2).

This study was an association study and cannot prove that long chain omega 3 fats from oily fish can protect against AMD.  However, the results add to mounting data.  Omega 3 fatty acids are incredibly important for many aspects of health (and I have mentioned them throughout my blog postings).  Including at least two portions of oily fish per week is certainly recommended, however, many individuals in the UK do not achieve these intakes for various reasons.  A daily fish oil supplement may be something worth considering (for general health) but it is always best to check with your medical doctor prior to beginning any new supplement regimen. Available ‘eye health’ supplements often contain vitamins C, E, beta carotene and the mineral zinc in addition to lutein and zeaxanthin.  The rationale behind this comes from dietary association studies and some research evidence.  If you are considering supplements remember that they are not a substitute (more of a bonus) for nutritious daily meals!  A healthy diet, rich in a variety of vegetables and fruits, will provide an array of antioxidant nutrients to keep the whole body healthy, including the eyes.

(1)Swenor BK et al.  2010.  The Impact of Fish and Shellfish Consumption on Age-Related Macular Degeneration. Ophthalmology.    117:2395-2401 DOI: 10.1016/j.ophtha.2010.03.058

(2)Press release.  American Academy of Ophthalmology (2010, December 1). New evidence for eye-protective effects of omega-3-rich fish, shellfish. ScienceDaily. Retrieved December 2, 2010, from http://www.sciencedaily.com­ /releases/2010/12/101201123235.htm

Written by Ani Kowal

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1. More evidence suggests that eating oily fish might protect the eyes
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3. Long chain omega 3 fats shown again to be important for eye health

Age related macular degeneration (AMD) is the most common cause of blindness in people over the age of 50 in the UK.  I have previously written about this condition but to re-cap:  

The macular is the light sensitive area in the centre of the retina that controls visual field and the ability to [...]]]>

Age related macular degeneration (AMD) is the most common cause of blindness in people over the age of 50 in the UK.  I have previously written about this condition but to re-cap:  

The macular is the light sensitive area in the centre of the retina that controls visual field and the ability to see colours.  AMD is caused by the deterioration of the macular.  As this happens the peripheral, outer, vision remains intact as the centre field of vision becomes slowly blurry, grey or filled with a large black spot.  Two forms of AMD exists: the dry form which develops slowly, accounting for 90% of all cases; and the wet form which causes rapid deterioration of central vision. 

The exact causes of AMD are unknown although free radical damage, where unstable oxygen molecules damage the eye cells, is strongly implicated.  Tobacco smoke and sun exposure can increase the level of free radicals in the body and both are a risk for AMD.  High blood pressure and diabetes are also risk factors as these conditions can limit blood flow to the eyes.  For more information please visit Macular Disease Society website.  The Macular Disease Society aims to build confidence and independence for those with central vision impairment.  They are the only UK charity dedicated to helping people with macular degeneration and offer information, a helpline, counselling and emotional support among other resources.

Previously I have gone into detail as to why long chain omega 3 fatty acids may be important for eye health and written about various published studies.  A new paper (1) has just been published in the American Journal of Clinical Nutrition which adds further weight to the evidence.  The researchers of this study(1) wanted to investigate whether long chain omega 3 fatty acids, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), which are found in oily fish such as mackerel, trout, sardines and salmon, are associated with a reduced likelihood of developing AMD.  The study involved over 1800 people who were are risk of developing AMD,.  The individuals were followed from 1992 to 2005 and their diets were assessed vial a special validated questionnaire.  The results show that participants who reported the highest long chain omega 3 intakes were 30% less likely than their peers to develop AMD.  This study showed a strong association between omega 3 fatty acids and protection against AMD but further trials would be needed to prove cause and effect.  The authors conclude that “If these results are generalizable, they may guide the development of low-cost and easily implemented preventive interventions for progression to advanced AMD”

Long chain omega 3 fats certainly seems to be part of the story.  Antioxidants and other nutrients have also been implicated in the protection against eye disease.  Please read my previous posts on AMD and cataract for more information on how certain nutrients may be important for good eye health.  It is not yet recommended that omega 3 supplements be taken specifically for protection against AMD, however these fats are vital for health for a number of reasons, if you do not regularly (at least twice a week) eat oily fish you may wish to consider a fish oil supplement.  Vegetarians and vegans can take a flaxseed oil supplement (which provides short chain omega 3 fatty acids) or look into buying EPA/DHA supplements produced from algae, these supplements are becoming increasingly available.

(1)SanGiovanni JP et al.  2009.  omega–3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study.  Am J Clin Nutr 2009;90 1601-1607
Written by Ani Kowal

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1. Long chain omega 3 fatty acids may be helpful in treating depression
2. Study links fish and omega 3 fats to reduced risk of age-related macular degeneration in women
3. Omega 3 fats during pregnancy are important for memory function of children

Currently it is Save Your Vision Month in America, a campaign run by the American Optometric Association (1).  The role that diet plays in preserving our eyesight is highly important and certainly worth a loud mention.  In August last year I wrote about cataracts and age related macular degeneration (AMD) and mentioned how diet, [...]]]>

Currently it is Save Your Vision Month in America, a campaign run by the American Optometric Association (1).  The role that diet plays in preserving our eyesight is highly important and certainly worth a loud mention.  In August last year I wrote about cataracts and age related macular degeneration (AMD) and mentioned how diet, particularly omega 3 fatty acids from oily fish and antioxidants from vegetables and fruits, was important in preventing these conditions and preserving good eyesight.   In the UK Age-related Macular Degeneration (AMD) is the leading cause of blindness, with 45% of those registered as blind suffering from the disease.  For more info on AMD please read my previous blog post.

Very recently a paper was published (2) suggesting that B vitamins, particularly folic acid, vitamin B6 (also known as pyridoxine hydrochloride) and vitamin B12 (cyanocobalamin) may be particularly important for good eye health.  The study was conducted since previous research had indicated the links between homocysteine concentrations in the blood and the risk of age related macular degeneration (AMD).

I have previously written about homocysteine.  Most people are aware that high levels of homocysteine in the blood have been linked to an increased risk of heart problems.  Recently high homocystein levels have also been linked to poor bone health and other health problems.  To recap from my past blog posts: Homocysteine is produced when the amino acid (the building blocks of protein) methionine is broken down in the body.  Normal levels of homocysteine are important to help build and maintain body tissues, however elevated concentrations in the blood can be harmful and have been associated with an increased risk of many disorders.  At normal levels homocystein can be converted in the body into a harmless substance called cystanthionine.  The conversion of homocysteine into this harmless substance depends upon various B vitamins  (B6, B12 and folic acid).  Having good levels of these B vitamins appears to be a very good way of preventing high homocysteine levels and low levels of B vitamins have been associated with raised homocysteine levels.

The researchers of the eye health study (2) wanted to examine the incidence of AMD in a trial of combined folic acid, vitamin B6 and vitamin B12 therapy.  The trial was well designed and involved over 5000 women aged 40 or older with no diagnosis of AMD at the start of the trial.  These women received either a daily placebo supplement or a supplement containing 2.5mg folic acid, 50 mg vitamin B6, and 1g vitamin B12.  After around 7 years of treatment and follow-up it was found that the women receiving the supplement had a significantly reduced risk of AMD.   The women taking the multi-B vitamin supplement were around 35% less likely to develop AMD than those taking the placebo.

The research seems to support the idea that taking a multiple B vitamin supplements is useful for sight preservation.  It is not entirely clear whether the B vitamins worked to protect eyesight simply via lowering homocysteine levels.  These vitamins may have also been working via exerting antioxidant effects or by improving blood vessel function.  Further studies would be necessary to evaluate these ideas and strengthen data before strong recommendation for B vitamin supplementation can occur.

In the diet the B vitamins may be found in the following sources (vegetarians and vegans may wish to consider a multiple B vitamin supplement):
Vitamin B6 – Mainly found in meat, fish and eggs
Vitamin B12 – liver, meat, eggs, milk, yeast extract
Folic acid – liver, orange juice, green vegetables, nuts

Continuing with the theme of eye health.  Scientists at the University of Liverpool (3) have recently announced that the degeneration of sight caused by AMD could be reduced by up to 20% through dietary changes alone, specifically through the increase of vegetables, fruits and nuts in the diet.  Professor Ian Grierson, Head of Ophthalmology at the University of Liverpool, has produced a comprehensive cooking guide called ‘Fruit for Vision’, designed to add fruit and vegetables into everyday meals.  The recipes were formulated in order to help AMD sufferers slow down the degeneration process by increasing micronutrient, vitamin and antioxidant intake in the diet. Non-sufferers can also use the book to add fruit, nuts and vegetables into each meal to protect against the disease.

Professor Grierson said (3): “Poor eating habits have a huge impact on health in general and the health of your eyes is no exception. Eye problems such as AMD, cataract and even glaucoma can all be affected by what we eat. But a relatively minor change in diet – adding a little more fruit into our meals – can make a profound difference and can keep eye diseases like AMD at bay for up to 20% longer.  There are of course other risk factors related to AMD such as age, light exposure, smoking and being overweight. But if we can improve the kind of food that we eat, we could dramatically reduce the number of people who may suffer from eye diseases in the future.”

Fruit for Vision is published by Indigo Creative Marketing and the Macular Disease Society. It provides easy recipes that incorporate fruit and nuts in to the diet. The recipes suggest minor additions to what we already eat, rather than major dietary changes.

Over in America, the AOA has also released information (4) in order to highlight the importance that diet and nutrition play in eye health.  The AOA highlights six nutrients important for eyesight:
Lutein, Zeaxanthin, Essential fatty acids, Vitamins C, Vitamin E, Zinc  
 
In their press release the AOA mention the following food sources of these specific nutrients:
Lutein and zeaxanthin: Colorful fruits and vegetables such as broccoli, spinach, kale, corn, green beans, peas, oranges and tangerines
Essential fatty acids: Oily fish like trout, salmon, sardines, or herring, nuts and seeds, whole grain foods, chicken and eggs
Vitamin C: Fruits and vegetables, including oranges, grapefruit, strawberries, papaya, green peppers and tomatoes
Vitamin E: Vegetable oils, such as safflower or corn oil, almonds, pecans, sweet potatoes, and sunflower seeds
Zinc: Lean red meat, poultry, liver, shellfish, milk, baked beans, and whole grains

(1)American Optometric Association (AOA)
(2)William G. Christen, ScD et al.  2009.  Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women.   The Women’s Antioxidant and Folic Acid Cardiovascular Study.  Arch Intern Med.169(4):335-341.
(3)University of Liverpool – press release
(4) Open Your Eyes To Healthy Eating Habits – press release by the AOA

Written by Ani Kowal

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Sticking to the theme of eye health I wanted to briefly write about cataracts today.  Cataracts are cloudy areas that develop in the lens of the eye, the cloudiness reduces the amount of light transmitted to the retina and this causes poor vision.  In the UK about 1 in 3 people over the age [...]]]>

Sticking to the theme of eye health I wanted to briefly write about cataracts today.  Cataracts are cloudy areas that develop in the lens of the eye, the cloudiness reduces the amount of light transmitted to the retina and this causes poor vision.  In the UK about 1 in 3 people over the age of 65 develop a cataract, which gradually forms over many years.  Initially vision may only be very mildly affected and this may not progress, however, in some individuals the vision will get worse over time. 

Treatment is an option when a cataract becomes bad enough to interfere with normal life e.g. if vision starts to interfere with reading, driving, watching TV etc or stops an individual from doing anything that they would normally do.  Before making a decision about treatment it is recommended to make sure your glasses are giving you maximum benefit.  Treatment involves the removal of the cloudy lens and replacement with an artificial plastic lens (an intraocular implant).

Cataracts seem to occur due to the breakdown and subsequent clumping of proteins in the lens.  Obviously, prevention is always better than cure!  Lifestyle factors that may increase the risk of cataract development include a poor diet low in antioxidant nutrients (found in fruits and vegetables), smoking and prolonged sunlight exposure.  Again, as with AMD, free radicals appear to play a causal role and hence dietary antioxidants may be protective.

I would like to highlight three (1,2,3) very recent research studies.  The first study(1) looked at the association between cataracts and dietary lutein and zeaxanthin, caroteinoids found in spinach, collard greens and kale.  The study involved 1802 women aged 50 to 79 years.  Women with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of cataract compared to those with low levels.  Women with the highest dietary intakes or highest blood serum levels of lutein and zeaxanthin as compared with those with the lowest were 32% less likely to have cataract.  For more information on these carotenoids and potential supplements please refer to Monday’s post which looked at AMD.

The researchers involved in the second study(2) wanted to investigate the relationship between antioxidant nutrient intakes and incidence of age-related cataract over a 10 year period.  The study involved 2464 individuals (aged 49 or over at the start of the study) for 5-10 years.  Eye health was observed using lens photography and dietary intakes of various antioxidants, including zinc, beta carotene, vitamins A, C and E, was assessed.  Individuals with the highest total intake, from diet and supplements, of vitamin C had a 45% reduced risk of cataract.  An above average intake of combined antioxidants -vitamins C and E, beta-carotene, and zinc – was associated with a 49% reduced risk of cataract.  The authors of the study conclude that “Higher intakes of vitamin C or the combined intake of antioxidants had long-term protective associations against development of nuclear cataract in this older population”.

Both of these studies, as in the studies I highlighted in relation to eye health on Monday, re-iterate the importance of a diet rich in vegetables and fruits, which are fabulous sources of antioxidants.  As yet the role for supplementation in the prevention of cataract is unclear (and cannot, of course, substitute diet) but many individuals are taking multivitamin and mineral supplements to help keep their eyes, and bodies, healthy.  Future large supplementation trials are planned and I look forward to seeing the results.

The third study(3) involved around 2000 individuals aged 49 or over (at the start of a 5 year investigatory period).  The researchers found that higher dietary intakes of omega-3 polyunsaturated fatty acids were associated with a significantly reduced risk (42% compared to those with the lowest intakes) of developing cataract over 5 years.   For more information regarding omega 3 fatty acids and eye health please refer to the piece that I posted on Monday which looked at AMD.

(1)Moeller SM et al.  2008.  Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the carotenoids in the age related eye disease study, an ancillary study of the women’s health initiative.  Arch Opthalmol.  126:354-364
(2)Tan AG et al.  2008.  Antioxidant intake and the long-term incidence of age-related cataract: the blue mountains eye study.  Am J Clin Nutr.  87:1899-1905
(3)Townend BS et al.  2007.  Dietary macronutrient intake and five year incident cataract: the blue mountains eye study.  Am J Opthalmol.  143:932-939.

Written by Ani Kowal

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1. Healthy diet may protect against cataract development
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My eyesight is something that I value very highly.  Without my spec’s or contact lenses I have very limited vision.  Looking after my eyes, in order to prevent further long-sightedness in later life, is certainly high on my agenda.  Age Related Macular Degeneration (AMD) is the most common cause of blindness in people over [...]]]>

My eyesight is something that I value very highly.  Without my spec’s or contact lenses I have very limited vision.  Looking after my eyes, in order to prevent further long-sightedness in later life, is certainly high on my agenda.  Age Related Macular Degeneration (AMD) is the most common cause of blindness in people over the age of 50 in the UK and I feel that it deserves a little attention! 

The macular is the light sensitive area in the centre of the retina that controls visual field and the ability to see colours.  AMD is caused by the deterioration of the macular.  As this happens the peripheral, outer, vision remains intact as the centre field of vision becomes slowly blurry, grey or filled with a large black spot.  Two forms of AMD exists: the dry form which develops slowly, accounting for 90% of all cases; and the wet form which causes rapid deterioration of central vision.

The exact causes of AMD are unknown although free radical damage, where unstable oxygen molecules damage the eye cells, is strongly implicated.  Tobacco smoke and sun exposure can increase the level of free radicals in the body and both are a risk for AMD.  High blood pressure and diabetes are also risk factors as these conditions can limit blood flow to the eyes.

Evidence for diet and nutrition in the prevention, and to a certain extent treatment, of the condition is growing yearly.  The latest study was published in the August volume of the American Journal of Clinical Nutrition(1) and adds to the growing body of research(2,3,4,5,6,7,8) suggesting that oily fish and the long chain omega 3 fatty acids they provide, EPA and DHA (eicosapentaenoic acid and docosahexaenoic acid), may be preventative. 

This recent study(1) assessed the dietary intake data and photographic eye evidence of 105 individuals with AMD and compared it to 2170 control individuals (without any features of AMD).  All participants were aged 65 or over.  The researchers found that eating oily fish at least once per week compared with less than that was associated with a 50% reduced likelihood of having AMD.  There was no benefit from eating non-oily, white fish.  There was also a strong significant association between intake levels of DHA and EPA and AMD.  Individuals eating around 300mg or more of these fatty acids per day were 70% less likely to have AMD.  Two (75g) servings of oily fish, such as salmon, mackerel, sardines or trout, provides around 500mg of DHA and EPA 

The scientists are not yet recommending omega 3 supplements as the study did not investigate whether supplements would have the same benefit as dietary sources.  However, evidence for the potential benefits of fish oil (long chain omega 3 fatty acid) supplements is beginning to emerge, with one very recent study(5) finding that 800mg of DHA per day over 2-4 months was associated with beneficial changes in the macular. 

Omega 3 fatty acids are incredibly important for many aspects of health (and I have mentioned them throughout my blog postings).  Including at least two portions of oily fish per week is certainly recommended, however, many individuals in the UK do not achieve these intakes for various reasons.  A daily fish oil supplement providing around 250mg of EPA and 250mg DHA may be something worth considering (for general health).  For vegetarians and vegans a flaxseed oil supplement providing around 500-800mg of alpha-linolenic acid (a short chain omega 3 fatty acid which the body can convert to the longer chain forms) daily is a good way of ensuring a daily supply of these essential fats.

The other important nutrients worth discussing in relation to AMD prevention are the antioxidant carotenoids lutein and zeaxanthin, naturally found in foods such as spinach, collard greens and kale.  Research data(9,10,11,12) suggests that individuals with high dietary intakes of lutein and zeaxanthin, and high body levels of the carotenoids, have a reduced risk of developing AMD.  Supplements of these nutrients are now widely sold and targeted at eye health.  The supportive evidence for supplementation is not yet solid.  A small study(13) has shown benefit and paves the way for larger studies.  A very recent review(14) of the currently available evidence, published last month, concluded that “A definite association between lutein and zeaxanthin supplementation and clinical benefit has yet to be hown; however, it may still be an appropriate cautionary measure for patients at high risk for developing AMD”

Available ‘eye health’ supplements often contain vitamins C, E, beta carotene and the mineral zinc in addition to lutein and zeaxanthin.  The rationale behind this comes from dietary association studies and some research evidence.  If you are considering supplements remember that they are not a substitute (more of a bonus) for nutritious daily meals!  A healthy diet, rich in a variety of vegetables and fruits, will provide an array of antioxidant nutrients to keep the whole body healthy, including the eyes.

(1)Augood C et al.  2008.  Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoid acid intakes, and associations with neovascular age related macular degeneration.  American Journal of Clinical Nutrition.  88:398-406
(2)Chong EW et al.  2008.  Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis.  Arch Ophthalmol.  126:826-833.
(3)SanGiovanni JP et al.  2007.  The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20.  Arch Opthalmol.  125:671-679
(4)Seddon JM et al.  2006.  Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration.  Arch Opthalmol.  124:995-1001
(5)Johnson EJ et al.  2008.  The influence of supplemental lutein and docosahexaenoic acid on serum, lipoproteins, and macular pigmentation.  Am J Clin Nutr.  87:1521-1529
(6)Cho E et al.  2001.  Prospective study of dietary fat and the risk of age-related macular degeneration.  Am J Clin Nutr.  73:209-218
(7)Seddon JM et al.  2001.  Dietary fat and risk for advanced age related macular degeneration.  Arch Opthalmol.  119:1191-1199
(8)Smith W et al.  2000.  Dietary fat and fish intake and age related maculopathy.  Arch Opthalmol.  112:222-227
(9)Seddon JM et al.  1994.  Dietary carotenoids, vitamin A, C and E and advanced age-related macular degeneration.  JAMA.  272:1413-1420
(10)Bone RA et al.  2000.  Lutein and zeaxanthin in the eyesm serum and diet of human subjects.  Experimental Eye Research.  71:239-245
(11)Bone RA et al.  2001.  Macular pigment in donor eyes with and without AMD:A case-control study.  Invest Opthalmol Vis Sci.  42:234-240
(12)Gale CR et al.  2003.  Lutein and zeaxanthin status and risk of age-related macular degeneration.  Invest Opthalmol Vis Sci.  44:2661-2465
(13)Richer S et al.  2004.  Double-masked, placebo-controlled, randomised trial of lutein and antioxidant supplementation in the intervention of atropic age related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial).  Optometry.  75:216-230)
(14)Zhao L & Sweet BV.  2008.  Lutein and Zeaxanthin for macular degeneration.  Am J Health Syst Pharm.  65:1232-1238

Written by Ani Kowal

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1. Study links fish and omega 3 fats to reduced risk of age-related macular degeneration in women
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