Benjamin Cordner

1129275

“Are there benefits from omega-3 fatty acids in the treatment of women with polycystic ovary syndrome?”

Project Unit - BHS012-3

Dissertation

University of Bedfordshire

Department of Life Sciences

Contents:

Content Page

Abstract 3

Introduction 4-8

Analysis of Six Key Research Papers on PCOS: 9-17

i. Oner, G. Muderris, I. (2013) 9-10

ii. Mohammadi, E. et al (2012) 10-11

iii. Phelan, N. et al (2011) 11-12

iv. Vargas, M. et al (2011) 12-13

v. Ouladsahebmadarek, E. et al (2013) 14-15

vi. Kalgaonkar, S. et al (2011) 15-17

Discussion 18-20

Conclusion 21

References 22-23

2

Abstract:

The objective of this research was to find evidence that omega-3 fatty acids were beneficial

in the treatment of women with polycystic ovary syndrome. This was done by in depth

reviews of six previous studies involving omega-3 and PCOS. It was found that omega-3

reduced most symptoms of PCOS by acting on various receptors and enzymes including the

decrease of insulin resistance which is a major problem in women with PCOS and can lead to

diabetes and other medical conditions. There are also problems with testosterone and other

adiponectin levels that can lead to acne, hirsutism and oily skin but omega-3 has been shown

to reduce these levels and therefore improve the symptoms. In conclusion omega-3s should

be used by women with PCOS due to its major benefits. More research is needed as these

studies are not reliable enough due to factors such as using small subject group and also need

to be done over longer time periods. There must also be research done into the differences

between each omega-3 when used on women with PCOS as some have shown less beneficial

effects.

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Introduction:

Polycystic ovarian syndrome (PCOS) is a common disease affecting up to 20% of women in

the UK (between approximately 12 to 45 years of age). can cause distressing symptoms and

is linked to infertility and life-threatening diseases. PCOS itself is not life-threatening

however there are some important health consequences such as cardiovascular disease and

diabetes due to insulin resistance and hyperlipidamia. There is also a risk of endometrial

cancer as the endometrium may proliferate due to oestrogen being unopposed by

progesterone in PCOS. For this reason it is important to research into effective treatments and

this study will examine the research on omega-3, which can be introduced into the diet.

PCOS is defined as symptomatic women with a FSH:LH ratio of at least 1:3, and the

appearance of multiple small bilateral ovarian cysts on ultrasound scan. It can often be

undiagnosed, misdiagnosed or even dismissed by the medical profession (Raisbeck, 2009).

One of the reasons for these issues when undertaking a diagnosis is that there are many

variations in the presentation and indeed 20% of women who have polycystic ovaries on

ultrasound scan do not have the syndrome. There is some indication that PCOS could be

genetically based and recent studies have been looking into ways of detecting and treating

symptomatic women. The familial link could explain why some women are affected and not

others, although this is not fully understood. There are also influences from racial origins

which influence the expression of the condition such as the Asian population having less

hirsutism than Eastern and Mediterranean women (Chandrika, 2013).

PCOS causes a multitude of symptoms, physical, hormonal and psychological, which usually

begin during a women’s adolescence. The extent of the women’s signs and symptoms depend

on the amount of testosterone and other androgens that are released from the adrenal and

ovarian glands. Although all women produce both male and female hormones women with

PCOS have higher levels of androgen than normal, which being predominately masculine

hormones cause various changes when in women. High levels cause an increase in ovarian

follicle atresia, a degeneration and resorption before reaching maturity, leading to further

androgens and oestrogen. This causes hyperplasia of the ovary allowing the syndrome to

perpetuate itself. As androgens regulate bodily hair growth, sebum production and also

influence musculature, the higher levels can cause a variety of symptoms including hair loss

or hirsutism, which is an abnormal excess of hairiness and can cause distress as it follows a

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male pattern on the sides of the face, lip, chin and lower abdomen with dark coarser hair.

Acne especially over the face, back and chest is another androgenic effect.

Amenorrhoea/oligomenorrhoea in PCOS is postulated to be caused by some of the androgens

produced from the adrenal gland being converted into oestrogens in fatty tissue. This causes

feedback to the pituitary gland, as oestrogens are present in post-ovulatory levels, making it

believe that ovulation has taken place. This alters the production of gonadotrophins so

ovulation may not occur and progesterone production decreases. This affects the normal

feedback between the ovary and pituitary gland causing absent or erratic menses and sub-

fertility due to a lack of normal cyclical control. Obesity is also a common symptom but not a

universal one and is worsened by those who are already overweight as adipose tissue is also a

site for conversion of androgens and oestrogen. One of the major symptoms is that some

women can develop insulin resistance causing a high level of insulin and tissues that are

unresponsive to this level. This hyperinsulinaemia affects follicle development in the ovary

through the alteration of gonadotrophin and androgen levels. It is also linked to

hyperlipidaemia which carries with it and increased risk of atherosclerosis, heart disease and

morality rate.

A variety of treatments have been developed for PCOS including prescribed medicines and

other non-medical treatments. None of these are in any way “curative” but rather provide for

some measure of symptom control. Potent artificial oestrogen’s have an anti-androgen effect

which thereby suppresses LH and in turn down regulates androgen receptors making the body

less responsive to androgens and helping correct both hirsutism and oligomenorrhoea.

Cyproterone (Dianette) is a specific anti-androgen which is used both for PCOS and acne

treatment. Metformin is an anti-diabetic drug that may be used to treat PCOS by affecting

insulin resistance and helping with weight gain. Spironolactone is a diuretic which also helps

with symptom control. Non-medical treatments are varied and often employ a conservative

approach including lifestyle modifications such as weight loss, exercise and low carbohydrate

diets, though these are often difficult to maintain in women with PCOS. The best diet is

thought to be a low glycaemic index (low GI) which differentiates foods that are slowly

absorbed keeping blood sugar levels steady. Other treatments include hair remove and facial

treatment for acne.

Omega-3 fatty acids are a relatively new postulated treatment that may be a means of

balancing cholesterol level and reducing insulin resistance in women with PCOS. These

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essential long chain fatty acids, which cannot be synthesized by the human body, are

biologically active (n-3) poly-unsaturated fatty acids. The n-3 references the site of the first

carbon double bond (C=C) within the structure of the molecule. The molecule itself is a chain

of variable length carbon atoms of single and double bonds with a methyl group (CH3; n-1)

at one end and a carboxylic acid (-COOH) at the other, as shown in Figure. 1.

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Figure.1. Structures of some of the omega 3 fatty acids.

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Several varieties exist with alpha-linolenic acid being the simplest. This can then be

metabolised, often in the liver in humans, and converted by a process of desaturation and

elongation reactions into the more biologically active eicosapentaenoic acid (EPA) and

docosahexaenoic acid (DHA), with a variable number of molecules in between. These longer

21 and 22 chain carbon fatty acids have a wide variety of biological and physiological actions

relating to cell membrane structure and function, on both intracellular and extracellular

membranes. They have a major influence on the patterns of gene expression and also

membrane receptor signalling mechanisms. As these molecules are actually incorporated into

cell membranes, it appears availability may have an influence. Westernised diets are usually

richer in n-6 PUFA’s such as linolenic and arachidonic acid found in corn and peanut oil,

whereas diets richer in nuts, fish and green leaves are rich in n-3. N-6 PUFA’s are

metabolised to Eicosanoids which have an oxidative action and have been implicated in

pathophysiological roles. Whereas Eicosanoids produced from EPA have differing and

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beneficial properties. N-3 PUFA’s also give rise to proteins called resolvins and protectins

which appear to have potent beneficial effects. There is a competitive effect between n-6 and

n-3 FA’s in the enzymatic elongation reaction in conversion from the shorter chain linolenic

(n-6) and α-linolenic (n-3) acid to more potent longer chain versions, and the concentrations

of each at the outset may have a function on the end product. The balance of n-6:n-3 as they

are incorporated into cell membranes influences the function of the cell and its receptor

responses, thus the dietary balance of these ingested oils may have a part to play.

A wide range of physiological roles has been attributed to n-3 PUFA’s with influence on

many systems in the human body. See Table 1, reproduced from a study by Calder (2012).

Much research has looked at cardiovascular affects and the beneficial reduction of risk. N-3’s

appear to have affects platelet reactivity and thrombosis, triglyceride and HDL levels, blood

pressure, arrythmia’s and inflammation. There may be protective effects in inflammatory

conditions such as Rheumatoid, Inflammatory Bowel Disease and even Asthma. They have

also been linked to cognition in both early development of the brain and the aging process.

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The studies explored here have looked at the affects of PUVA’s on women suffering from

PCOS. The purpose of this research was to provide evidence that there are certain benefits, or

limitations, for women with polycystic ovary syndrome taking omega-3 fatty acids. This

research aims to address several issues. It will look at the possible reduction of some

symptoms of PCOS such as hirsutism, oligo or amenorrhoea, and infertility. It will also

explore the affects on a variety of biochemical markers such as FSH/LH, glucose,

testosterone and adiponectin levels. Another area is the affect on lipid profile including

triglycerides, cholesterol [including the beneficial HDL and toxic LDL] and subsequent

cardiovascular risk. This research will also suggest evidence that omega-3 can prevent some

diseases exacerbated by PCOS such as diabetes due to increasing insulin resistance, and the

often subsequent weight gain. It will address the issue of the balance of n-6:n-3 fatty acids

and how this may affect health markers in women with PCOS. Another consideration is how

the origin of the ingested omega3 FA’s may have an affect on PCOS, IE: fish oil versus flax

oil. The studies in this research will answer these questions with reliable evidence to suggest

omega-3 is beneficial for women with PCOS. It is important for these questions to be

answered as it could lead to more women taking the correct omega-3 and more people,

especially medical professionals, suggesting that omega-3 be taken as a treatment for PCOS

and a prevention of complications caused by PCOS.

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Analysis of Six Key Research Papers on PCOS:

This section of the study will focus on setting out and analysing six different studies that have

contributed to the field of PCOS research. These research papers have been chosen for the

different ways in which they study the interaction between omega-3 and PCOS. In the

conclusion to each of the subsections below there will be an analysis of the importance of the

study and a consideration of how it may be repeated in future investigations by eliminating

errors within the experiments and dependent on the data that is evaluated by this research

paper.

i. Oner, G. Muderris, I. (2013) Efficacy of omega-3 in the treatment of polycystic ovary syndrome.

This study by Oner et al(2013) shows important data on the metabolic, clinical and endocrine

effects of Omega-3 in patients with PCOS. This study focused on the clinical, hormonal,

TNF-alpha and resistin levels in women with PCOS by various treatments. These included

measuring body mass index (BMI), hirsutism score, fasting glucose and insulin levels. 45

non-obese women were treated daily with 1500mg of oral omega-3 for 6 months. The

average BMI of the subjects significantly changed during the treatment period falling by

0.6kg/m2. Hirsutism, as measured using the Ferriman-Gallwey (F-G) scoring system, showed

a significant reduction in scores. Insulin levels also showed a significant decrease during

treatment but glucose levels did not change. HOMA was used to assess insulin resistance by

using fasting serum concentration of insulin and glucose, the results showed a significant

decrease. Serum follicle-stimulating hormone (FSH), dehydroepiandrosterone-sulphate

(DHEAS) and thyroid stimulating hormone (TSH) levels did not change after the treatment.

Serum luteinising hormone (LH), total testosterone (T), free T and androgen (A) levels

decreased significantly. The sex hormone-binding globulin (SHBG) levels increased

significantly after the 6 months. Resistin levels did not show any difference during the

therapy. Hence this study confirmed beneficial effects in symptom control with omega-3

giving a reduction in hirsutism and in weight.

Biochemical effects included reduced insulin levels but not, interestingly, glucose. LH

stabilised and this could positively the effect menstrual rhythm. Testosterone levels

significantly decreased, hence the reduction in androgenic effects. The data in this study also

shows omega-3 has a function in decreasing insulin resistance. A main aim for the treatment

of women with PCOS is to prevent hyperinsulinaemia by decreasing insulin resistance and

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previous studies have also shown that omega-3 fatty acids may cause a decrease in insulin

resistance (Lopez, Klunder, Azcarate and Huerta 2013).

Although there were only a limited number of subjects used in the study it shows a number of

benefits towards the use of omega-3 in women with PCOS, including a positive outcome for

a decrease in hirsutism, insulin resistance, BMI and androgen hormones such as testosterone

with no change of endocrine profile. Clinical effects were shown in contrast with the other

studies, but this is likely as the time scale was longer at 6 months.

ii. Mohammadi, E. et al (2012). Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome.

Mohammadi et al (2012) performed a study to investigate the effects that omega-3 had on

serum adiponectin levels and some metabolic risk factors in PCOS patients. This study shows

that treatment with omega-3 fatty acids appears to increase the baseline level. The study was

performed on 64 overweight or obese PCOS patients aged between 20-35. Half of the women

were given daily omega-3 fatty acids the other half were given a placebo over an eight week

period. Adipose tissue itself produces several modulators called adipocytokines of which

adiponectin is the most abundant. This hormone has been shown to improve insulin

sensitivity and to have anti-atherogenic and anti-inflammatory effects. The study was

complete by 61 of the women; three were excluded due to personal reasons. There were no

significant differences between or within the groups at baseline weight, BMI, WC or WHR

after the eight week intervention. Daily dietary intakes were taken and there was no

significant difference in any of the results except cholesterol, which had a significant

difference between the omega-3 and placebo groups at the beginning of the study. At baseline

there were also no significant differences between the groups in terms of glucose, insulin,

serum adiponectin, HOMA-IR, lipids and high sensitivity creative protein (hs-CRP) levels.

At the end of the study there were no significant differences in weight, BMI, WC or WHR.

After the eight weeks the results showed there were statistically significant differences

between the two groups in respect of glucose, insulin, serum adiponectin, HOMA-IR, total

cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and lipids. In the omega-3

fatty acid group the serum levels of adiponectin were raised after the eight weeks, however

the serum levels of glucose, HOMA-IR, TC, insulin and LDL-C showed a significant

decrease in the omega-3 fatty acid group when compared over the eight weeks to the baseline

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values. There were no significant changes in serum TG, HDL-C and hs-CRP. These results

suggest that the omega-3 fatty acid group had a reduced level of glucose, insulin, HOMA-IR,

TC and LDL-C, when placed in comparison to the placebo group. This could be due to an

increased level of adiponectin.

No demonstratable effects regarding physical symptom reduction were seen in this study

though some were postulated. Several beneficial biochemical effects were noted including

those which could positively influence CVD risk and a reduction in insulin resistance. This

study shows that treatment with omega-3 fatty acids appears to increase the baseline level of

adiponectin in all the study subjects. It is postulated that one of the effects of omega-3s is the

stimulation of the adiponectin gene leading to increased production. There may be a

relationship between improved insulin sensitivity and the elevated levels of the adiponectin.

Adiponectin appears to increase glucose sensitivity though the activation of ANP-activated

protein kinase and it also suppresses gluconeogenesis in the liver. This study also

demonstrated that supplementation of omega-3 fatty acids led to a significant reduction in

serum lipids (with reduced LDL and increased HDL) this may be because omega-3s are

natural ligands for metabolic nuclear receptors which down regulate the genes that stimulate

lipid synthesis. This study concludes that there appears to be a beneficial effect on serum

adiponectin levels, lipid profile and insulin resistance when treating PCOS women with

omega-3 fatty acids and this may contribute to an improvement in their metabolic

complications.

iii. Phelan, N. et al (2011). Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomised, placebo-controlled crossover trail.

Phelan et al, published an interesting cross-sectional study used a cohort of 104 women with

PCOS to examine a baseline of plasma fatty acid profiles and the effect of LC n-3 PUFA’s

(omega 3’s) on this versus n-6 PUFA (olive oil). It also looked at the direct effect of these 2

PUFA’s on steroidogenesis in primary bovine cells. The baseline cross-sectional data

revealed that a higher circulating ratio of n−6:n−3 PUFA’s were associated with higher

circulating androgens, and that plasma LC n−3 PUFA status was associated with a less

atherogenic lipid profile, that is lower levels of LDL and higher levels of HDL.

Supplementation with Omega-3 also reduced plasma testosterone and this was shown to be

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greatest in subjects with the greatest reduction in n−6:n−3 ratio’s. The treatment of bovine

theca cells with n−6 showed an increase in the levels of androstenedione but there was no

observed change with n−3 PUFAs over placebo, suggesting that n-3 may competitively bind

with the cell membrane and thus proportionately reduce steroidogenesis. The androgenic

effect demonstrated in both the higher n-6:n-3 ratio and the Bovine cell study may be an

indirect functional effect caused by mutations of enzyme pathways in women with PCOS and

be maximised by a diet rich in n-6 PUFA’s. This does confer the idea that further dietary

manipulation, with a healthy balance of n-6 to n-3 PUFA’s may produce an optimizing effect

on the health of sufferers.

The positive effects of n-3 PUFA’s on metabolic aberrations is well recognised, including

inflammatory reactions, adiposity, and dyslipidaemias especially post-prandial lipid balance

control. The baseline FA analysis confirmed this finding with higher baseline n-3 levels

reflected on lower triacylglycerol concentrations. However the addition of n-3 PUFA

supplements failed to demonstrate reduced triacylglycerol levels. This is possibly due to

limitation of size of the trial or reduced specificity, as significant reductions in triacylglycerol

concentrations have been observed in a more target profile of women with a more adverse

metabolic profile. Also of note there was no stratification at the outset of the study on

variability within the condition PCOS itself. It is known that many women with demonstrable

polycystic ovaries on ultrasound scan, do not in-fact have any clinical symptoms and that the

symptoms themselves can be varied and influenced widely by subjective feelings. Thus

targeting the more severely symptomatic within the spectrum may allow for a more

consistent result. This study contributes to the developing knowledge regarding the

interaction of omega 3 fatty acids on the treatment of PCOS but is limited in both size and

scope. A larger cohort would allow for a better standardisation of data, and a longer treatment

period may give a clearer view of the metabolic and androgenic effects. Despite this it is clear

that this study suggests an omega 3 rich diet confers clear health benefits on PCOS sufferers.

iv. Vargas, M. et al (2011). Metabolic and endocrine effects of long-chain versus essential omega-3 polyunsaturated fatty acids in polycystic ovary syndrome.

This study by Vargas (2011) was to compare the effects of long-chain vs essential omega-3

fatty polyunsaturated fatty acids (PUFAs) in PCOS. This study was completed by 51 women

with PCOS over a 6 weeks period. 17 of these women were given flaxseed oil as a source of

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essential n-3 PUFA ALA; 17 were given fish oil as a rich source of long-chain n-3 PUFAs

(eicosapentaenoic acid[EPA] and docosahexaenoic acid [DHA]); 17 were given soybean oil

as a placebo. This study was performed as there has been research to show that n-3 PUFAs

help with symptoms of PCOS but there has been no comparative data to show the possible

positive and negative differences between n-3 PUFAs vs long-chain n-3 PUFAs EPA and

DHA. This could be important to know because there is a competitive agonist/antagonist

relationship between essential and long-chain n-3 PUFA which is very inefficient.

The baseline data had no significant differences in any of the intervention groups. The

micronutrient intake, weight, BMI, waist circumference and fat mass showed no significant

change during the study. There was no change in any intervention group of fasting glucose,

insulin, adiponectin, leptin and HOMA. Glucose was measured using an oral glucose test

with blood samples every 30 minutes for 2 hours. When comparing baseline results to post

results, within groups, it showed that there was an increase in serum glucose after 120

minutes and insulin after 60 minutes from fish oil. Flaxseed oil showed an increase after 30

minutes but did not show an increase in insulin. Soybean oil also increases glucose at 30

minutes with the insulin increasing at 90 minutes. When comparing serum levels of lipids pre

and post intervention both fish and flaxseed oil decreased significantly, soybean had no

significant change. Fish and flaxseed oil also increased LDL-C and soybean would decrease

it. It was also found that soybean oils reduced testosterone significantly, where fish and

flaxseed oil did not affect it. Fish and soybean oil are shown to have similar effects on

glucose homeostasis but differ from flaxseed oil. Fish and flaxseed are shown to have similar

effects on lipid metabolism but differ from soybean.

To conclude the findings specify that essential vs long-chain n-3 PUFA-rich oils from plant

vs marine sources perform specific effects on glucose homeostasis in women with PCOS.

Both n-6 PUFA-rich soybean oil and long-chain n-3 PUFA-rich fish oil supplements can

impair glucose tolerance, increase hyperinsulinemia and decrease early insulin secretion.

Essential n-3 flaxseed oil will have no adverse effect. This gives evidence that it is important

to monitor blood glucose in women with PCOS after they start and PUFA supplementation.

The importance of this study is how it suggests different responses to different sources of oils

and the how these can be measured. This would suggest ways that future research could be

carried out to find effective relieve for symptomatic women.

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v. Ouladsahebmadarek, E. et al (2013). Hormonal and metabolic effects of polyunsaturated fatty acids (omega-3) on polycystic ovary syndrome induced rat under diet.

A recent study submitted by Ouladsahebmadarek et al (2013) focuses specifically looks on

the biochemical effects of a combination of Omega 3 with a low CHO diet. This is the only

study not to be undertaken in human subjects and as such is an important part of this research

paper as it shows how non-human research can deliver different forms of results and can be

carried out in a space that is less effected by environmental factors (a point that will be

looked at in more depth in the discussion section). This study appears to confirm that the

introduction of omega3 along with carbohydrate reduction [by 10%] with oestrogen

stimulated PCOS appears to have a beneficial effect on antioxidant levels [SOD,GPX] as well

reducing both testosterone and glucose levels. This supports finding demonstrated in some of

the studies discussed in human subjects.

Forty female rats were allocated to control and test groups [G1,G2,G3], with 10 in each. G1,

received omega-3; G2 and G3 groups were induced PCO by single injection of estradiol. G3

in addition received omega-3 and low carbohydrate feeding for 60 days; Then a 5ml blood

sample and ovarian tissue of all rats in the group were removed and prepared for biochemical

and hormonal analysis. Groups that received omega-3 showed higher levels of Catalase, GPX

(Glutathione peroxidase), SOD (Superoxide dismutase); all having antioxidant effects. MDA

(malondialdehyde), which is a biomarker for oxidative stress, was significantly decreased in

the omega 3 group in comparison with other experimental groups. FSH (follicle stimulating

hormone) was decreased, but the level of testosterone was significantly increased in PCO

group, in comparison with control and omega-3 administered groups.

Antioxidants are known to have a protective role to reproductive health and are closely

associated with oocyte maturation. The depleted antioxidant level as demonstrated in the

PCOS group may have an implication on the infertility commonly seen in PCOS patients.

Omega 3’s are bioactive substances that positively impact signalling pathways via

adiponectin that are involved in the improvement of cardiovascular disease risk including

major risk factors of metabolic syndrome, especially adiposity, dyslipidaemia, insulin

resistance, diabetes, hypertension, oxidative stress, and possibly inflammation.

PCOS can be seen to cause a decrease in the level of follicle stimulating hormone (FSH) but

increase the level of luteinizing hormone (LH) usually with a ratio of 1:3 which is part of the

diagnostic criteria. FSH is the hormone that is responsible for stimulating the growth of

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follicles thus maturing eggs in ovaries. A lack of FSH for a long time results in immaturation

the follicles which results in infertility. This study showed an increase in FSH in the PCOS

rats treated with omega3 and thus there may be potential knock-on implications in treating

humans. In addition testosterone levels were also significantly reduced in the omega3 treated

PCOS rats, and high testosterone levels are known to influence both the menstrual cycle and

hirsutism. This again may implicate a possible benefit for human treatment.

Unfortunately this study did not differentiate between treatment with omega3’s and

carbohydrate reduction. This introduces a fallacy in the papers findings as it is impossible to

define if the beneficial effect seen in the omega3 treated group of PCOS rats is due to either

omega 3, CHO reduction, or a combination of both. Thus although this study reflects the

beneficial biochemical and hormonal profiles generated by omega 3 ingestion in rats, it goes

little way to an implication in women besides postulating theoretical benefits. However as

further research by Ouladsahebmadarek has indicated the use of non-human subjects can

enable the monitoring of variations such as water intake, exact food size and type, exercise

and other environmental factors which can help to decrease inaccurate fluctuations in the

results. In addition in his 2013 study on the fat and carbohydrate relationship, “Nutrition with

Polyunsaturated fatty acid and lower carbohydrate diet has controlled poly cystic ovarian

syndrome, on poly cystic ovarian (PCO) induced rats”, Ouladsahebmadarek et al noted how

habitual diet can condition a body to create a metabolic response which requires a lengthy

period of readjustment in order to give more accurate results; this is easier to eliminated using

laboratory rats. For this reason such research is important when considering the dietary

benefits of omega-3 on PCOS.

vi. Kalgaonkar, S. et al (2011) Differential effects of walnuts vs almonds on improving metabolic and endocrine parameters in PCOS.

Kalgaonkar et al published a study in the European journal of clinical nutrition (2011) which

involves comparing the effects of mono-unsaturated fatty acids [MUFA]-rich and almonds

versus n-3/n-6 PUFA-rich walnuts on the metabolic and endocrine parameters of PCOS. This

is interesting as it differentiated between the long chain fatty acids with almonds being richer

in the MUFA and n-6 PUFA with no n-3; and walnuts in the n-6 and n-3 (omega 3) PUFA

with a n-3:n-6 ratio of 1:4. Therefore this study, as was seen earlier, demonstrates the

differences of using a variety of omega-3 sources. The importance of this study is due to the

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contrasting biological effects of n-3 vs n-6. Theses n-3 PUFA are anti-inflammatory, anti-

coagulant, and increase insulin sensitivity which reduces insulin levels; n-6 PUFA are pro-

inflammatory, pro-coagulant and may stimulate insulin secretion.

Thirty-one women with PCOS randomly received either walnut or almonds, both contained

31g of fat and taken daily for 6 weeks. There was no change in weight from either group and

the 7-day food record demonstrated that the percent of overall fat intake did not change. Both

groups did show significantly different linoleic acid [LA] and α-linoleic acid [ALA] intakes,

walnuts increased ALA and LA, while almonds decreased saturated fat intake and increase

MUFA. Almonds also increased arachidonic acid (AA) and oleic acid, while walnuts

decreased both. Plasma phosolipids were measured at the end of the study and walnuts

significantly increased both LA and ALA in membranes, but did not appear to have an effect

on EPA and DHA. Neither almonds or walnuts changed fasting glucose, insulin or

homeostatic model assessment, mostly likely due to the short time frame of the study. Both

treatments increased adiponectin and walnuts increased leptin. Almonds increased SHBG

which can decrease the free fraction of androgens. Almonds increased the MUFA intake by

33% and decreased saturated fat by 25% without altering n-3 or n-6 PUFA. In contrast to this

walnuts increased n-3 PUFA and n-6 PUFA without affecting MUFA or saturated fat intake.

Both the almonds and the walnuts decreased cholesterol, although changes were most

significant in walnuts, which could be due to a smaller population size in the almond group. It

was also demonstrated that walnuts increased insulin response during OGTT. Other studies

have also shown that walnuts increase fasting insulin in type 2 diabetic patients as well. This

could be due to walnuts stimulating insulin secretion from the pancreas directly. Some animal

and cell culture studies have shown major PUFA in walnuts stimulating secretion directly.

Walnuts increased SHBG, which is lowered by insulin resistance in women with PCOS and

causes a higher testosterone level leading to excess hair growth and acne. As the insulin

resistance did not change in the study SHBG must be directly affected. Almonds decrease

free androgen index by increasing SHBG and decreasing testosterone. Both of the nuts

therefore have a favourable effect on the circulating androgens.

This study was limited by the lack of a non-treatment PCOS arm or a non-PCOS control

group, having only given treatment over 6 weeks and a relatively small population. Despite

these the results support inclusion of nuts in the diet of women with PCOS due to their

beneficial effects on lipids, androgens and possibly inflammatory markers. Thus this study

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confirms the importance of the constitution of foods containing FA’s. Even nuts, often

attributed as health foods, have a widely variable balance of nutrients and we see that walnuts

for example are much more rich in the beneficial n-3 PUFA’s and almonds, and this

favourably affects the phospholipid profile found in serum. This study did not reflect

symptomatic changes, and the effects on biochemical markers were variable, though

testosterone did appear to be reduced in both nuts which could potentially have a therapeutic

effect. Both nuts positively influenced lipid profiles, with walnuts particularly lowering LDL,

which could have a potential positive effect on reducing CVD risk. Again there appeared to

be a favourable influence on diabetes prevention with walnuts reducing insulin resistance.

This is important as other studies such as those by Jakubowicz et al (2013) suggest a link

between diabetes and PCOS. Their study also points to the genetic aspect as it discovers a

microRNA defect in fat cells of PCOS and insulin resistant women. This could have

consequences for future research and in helping to both define and treat both syndromes.

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Discussion:

All of these studies support the use of omega-3 FA’s in the treatment of women with

polycystic ovarian syndrome and suggest that there are overall benefits. Confirmation of

physical symptoms reduction was shown in Omer et al (2013) which established a reduction

in hirsutism and weight. Although none of the other studies showed this, it this could be due

to their restricted timescale. Many other studies including Mohammadi et al, Kalgaonkar et al

and Ouladsadebmadarek et al, postulated benefits of hirsutism reduction through biochemical

benefits of reduced androgens but failed to produce any measurable data. Most studies

analysed biochemical markers which showed positive benefits. Oner et al, Phelan et al and

Ouladsadebmadarek et al, confirmed reduced levels of testosterone and FSH. Mohammadi et

al also found benefits for glucose, insulin and CRP reduction. Although these have theoretical

benefits this was not assessed clinically and further studies are needed.

A postulative benefit for CVD reduction was shown in several studies through LDL

reduction, reduced inflammatory markers and TG stabilisation. These include Mohammadi et

al via TC, LDL and adiponectin reductions; Phelan et al demonstrating reduced LDL and

increased HDL; Vargas gave equivocal results on LDl levels; and Kalgaonkar et al also noted

a positive lipid profile with walnuts. However these results only bear a postulative benefit for

CVD risk reduction as it would take many years for a study to show such a reduction in

human populations. Effects on insulin resistance was demonstrated in the studies by Oner et

al, Mohammadi et al and Kalgaonkar et al using walnuts. Vargas et al again gave equivocal

results. However the consensus would appear to show that there may be a beneficial effect for

diabetes prevention, but again for full confirmation on a human population this would take

several years. The proportion of n-6:n-3 was assessed in 2 studies. Phelan did demonstrate

positive biochemical changes in the markers in young PCOS sufferers, but the analysis in

vivo bovine cells failed to show reliable results. Kalgaonkar et al demonstrated the variability

of the specific FA content within nuts and how this can alter the biochemical markers in

serum with possible affects on CVD risk and insulin resistance. Vargas et al looked

specifically at flax oil higher in shorter chain PUFA’s and fish oils higher in long chain FA’s

specifically EPA and DHA. Some positive effects were seen on LDL but did not appear to be

consistent. Insulin resistance was also affected with fish oil giving a more beneficial effect.

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The interesting combination of length and techniques used in these studies allows for

comparisons to suggest ways of improving future studies. It is important to use control group

during studies to compare differences that may have changed over the time period of the

study, however some of these studies only compared the result of the subjects before and

after the treatment. Without the use of a control group it makes the results less valid as there

can be no comparison to women with PCOS that are not taking omega-3 over the course of

the study. Most studies were performed using human volunteers and some studies were

performed for as little as six weeks, others up to six months. Other studies such as

Oulandsahebmadarek (2013) focused on omega-3 under invasive laboratory conditions such

as the hormonal and metabolic effect on rats with induces PCOS. There are also studies such

as Phelan (2011) that also focus on laboratory studies using bovine ovaries, Phelan also used

other data collected during human studies to help show correlations and reliability in their

research.

During the last 10 years Omega-3 fatty acids were advised by the National Institute for health

and Care Excellence (NICE) guidance and by medical professionals as initial data seemed to

show health benefits for reduced cardiovascular risk of the basis of initial studies. It was used

for the secondary prevention by promoting a more beneficial lipogenic profile. However

subsequence studies failed to correlate to this, therefore NICE withdrew recommendation for

omega 3 which are now not recommended (NICE, 2015). In view of this data it is important

to continue research into omega-3 to suggest other possible benefits and limitations, it is also

important to provide studies that are over a longer time period as even a 6 month study is not

long enough to reliably suggest some of the results such as if reduced insulin resistance is

going to continue after the 6 months. Most of the test groups in these studies were also too

small to give a reliable result and they did not take into account the possible racial,

environmental or geographical differences of women with PCOS. An example of

environmental is obesity and overweight subjects. Some of these studies such as Oner(2013)

use women who are not overweight or obese, while other studies will use women who are

obese and overweight

A major benefit to omega-3 over other treatments of PCOS is that the overall cost for omega-

3 is much lower and can even be included in a person’s daily diet. Another benefit is that

omega-3 has much fewer side-effects when compared with other PCOS treatments. As

women with PCOS symptoms may be suffering from a loss of confidence or even depression,

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due to symptoms, the reduced lack of side effects as well as treatment of symptoms could be

very beneficial. As omega 3 is an existing substance and not a new drug, drug companies are

not willing to perform studies. This means that the only studies performed on omega-3 are

done by universities which only have small funding when compared to drug companies as

they will not make a large profit from omega 3 when compared to other drugs they could be

researching. This means that it is difficult to perform the types of studies that need to be done

to give the best results to suggest women with PCOS should be taking omega-3.

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Conclusion:

Further research should be done into the benefits of omega-3 to treat women with PCOS as it

has been shown to improve most major symptoms of PCOS and other health aspects. There is

also a need for more research to be done into the types of omega-3s that should be taken by

women with PCOS and research into which omega-3s should not be taken together due to

competition or adverse effects. When comparing most of these studies you see that the data

shows a small benefit when using omega-3 in the areas that need improved for women with

PCOS, but if the research was completed over a longer time period the data could possibly

give more beneficial results.

Not only should we be looking at omega-3 but other fatty acids that could improve the

symptoms. It is also important to consider omega-3 present in foods such as nuts and fish that

could give similar fatty acids to benefit lifestyle. This should including research using foods

with omega-3 rather than supplements.

There was not enough negative data on the effects of omega-3 or other omega on the body

and how it affected women with PCOS. The research in this paper could have been improved

if further research was done into any possible negative impacts of omega.

Even without further research the correlating evidence suggests that women with PCOS

should be taking omega-3 and even people without PCOS could benefit by increasing omega-

3 levels in their diet, especially women at risk of developing PCOS.

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