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We now welcome Dr Shirine Boardman. She is a graduate from the University of Malaya and has worked in the UK since 1991 in Leicester’s and Nottingham’s teaching hospitals. She moved to the Diabetes Research Laboratories at the University of Oxford in 1994 where she worked on the prevention of diabetes. Her specialist training in endocrinology and diabetes was completed at the Radcliffe Infirmary. In 2000 she was appointed a Consultant in endocrinology and diabetes at Warwick hospital and became an Honorary Senior Lecturer at the University of Warwick working closely with the Department of Obesity and Metabolic Research. She is a Committee Member of the Association of British Consultant Diabetologists (ABCD) and the British Endocrine Society (BES). Her current research interests include weight management in a variety of metabolic disorders including PCOS and insulin pump therapy. In addition, Shirine has been instrumental in setting up a local support group for patients at Warwick hospital which you may have read about in the last issue of In Touch. So, ‘Managing Insulin Resistance and the Hormonal Imbalances of PCOS’ – welcome Dr Shirine Boardman. Thank you for inviting me here today. My support groups were set up for women with PCOS with the understanding that drugs that are currently used in the treatment of diabetes were actually very useful for the treatment of PCOS. All of a sudden, we found that gynaecologists and dermatologists were sending patients to us and it was a very distressing syndrome, and I found that spending just 10 minutes in clinic with these women was just not enough time to deal with all the issues and questions that they had and so we applied for funding and managed to get a pharmaceutical funding to have a nurse-led service, which is supported by myself and since then the service has grown. It is incredibly popular and people travel in from other parts of the country to see us. We have a large support group for these women and we are about to start developing a website to enable women from other areas to access information about PCOS. Today, I am going to focus on the kind of women who present to an Endocrinologist. Many women with PCO will present to the gynaecologist, some will present to the skin specialist and some will come to us. The kind of women that I tend to be referred, tend to be the ones that have a weight problem or find that they are extremely hormonal. They will have read about metformin and need some information to find out whether it will work or not. I know that some of you will be on metformin and for some of you, it will not have worked for you and maybe some of you have never been offered it. I am going to give you some facts about metformin, (and there is a leaflet) so that you are ‘armed’ next time you visit your GP. I have here a picture showing the first lady with PCOS that was described in medical literature. It is quite a horrific picture and must have been before the days of beauty salons! This is a woman who had seven babies, so she didn’t have a problem with fertility, but certainly had a problem with all the other aspects of the syndrome. At the age of 37, she had a beard. For those of you who wondered what the classical picture of PCO might be and what the ovaries look like – they are rather big, with lots of cysts inside and they tend to be on the edges of the ovary. However, we know now from all the research that is emerging that the classical picture is not necessarily required to be diagnosed with the syndrome and that 1:4 women will actually have ovaries with cysts but not have the syndrome. If that doesn’t complicate matters, I don’t know what will! It is no wonder women and GP’s are confused. The latest classification that is coming out of Europe and America is that you don’t need to have the cysts to make the diagnosis. If you have the symptoms and the blood test, then you could have PCOS. Ovulation may not occur, there may be acne and hairiness and blood tests may show continuous elevated male hormone levels. By that, I don’t just mean testosterone. Some doctors may just measure this. Just be aware that testosterone is only one of the male hormones that your body makes. They are produced from the ovary and the adrenal gland. If it was just about the ovaries, then just removing the ovaries would ‘save’ you from PCOS! Unfortunately, this is not true. Even if you had a hysterectomy, PCOS does not go away. There is a new understanding about this syndrome in that there is actually more to this syndrome than just abnormal ovaries and that the abnormal ovaries are probably just a symptom of something else that is happening in the body that is not right. The reason for not including the need for cysts in the ovaries to make the diagnosis is because about 24% of normal women will have these cysts. 5-

10% of women of the reproductive age group will have this syndrome. I wonder if you are aware that so many young women suffer with the syndrome! More that more than 70% of ovulatory infertility is caused by PCOS and by the age of 40, women with PCO have a 40% risk of going onto impaired glucose intolerance, or diabetes. This is a huge and real health risk that hasn’t been recognised before. An American college has realised that PCOS needs to be treated seriously and that more research is needed. The big question today in the diabetes world is whether PCOS is another manifestation of the metabolic syndrome. This is syndrome X – the insulin resistant syndrome, which is a very ‘hip’ word amongst diabetologists and heart specialists, as it is well recognised that heart attacks and strokes are related to the insulin resistant syndrome. Insulin resistance in itself seems to predispose to diabetes, sugar problems, high cholesterol, blood pressure problems and PCOS. As a result of this, discussions are taking place to decide whether PCOS is actually a precursor to what is being seen in the diabetic clinic or the heart clinic. There is also a similar syndrome which is slowly being recognised suggesting that men who do not have enough male hormones seem to suffer a similar syndrome as women who have too much male hormone. It is quite interesting – too much in women is bad and too little in men is bad! Insulin is a hormone made by the pancreas and it lowers blood sugar levels. It also allows fat to be made from sugar, so any excess sugar will be converted into fat. It is an anabolic hormone, which builds up your body. Resistance to its action in the liverine muscle is known as insulin resistance and if you have high levels of insulin resistance, then you will have high levels of insulin in your blood, which makes the body a very efficient fat maker! The trick is to keep the insulin level down, which will help the metabolism. Again, I must emphasise that this is a general rule and that some of you may not be insulin resistant or may be at the other end of the norm, in which case, the insulin resistance does not play such a big role. Most of women with PCOS are insulin resistant, but as you are probably aware, there is a wide spectrum. If you are insulin resistant, it will affect your ovaries. It prevents the eggs you are producing from coming out of the ovaries and going down the tubes. Every month, an egg will be released from the ovaries, down the tubes and into the uterus. If you have high insulin levels, it locks all the eggs into the ovary. These trapped eggs can then go on to make cysts. The ovary goes into overdrive with the high insulin level and it makes lots of extra male hormones. You probably thought that the ovaries only produced oestrogen, but this is not the case. If testosterone is not present in our bodies, we would feel dreadful. We would have no libido! It is important for a woman’s wellbeing to have male hormones, but with the insulin resistance, there is too much. Then, as a result of the high insulin levels, the pancreas makes too much when it is not supposed to and the blood sugars start to go up and down, which also affects your moods. When your blood sugars drop, you may not feel hungry, but you will feel dreadful, and need a ‘sugar fix’ to fix the mood problem and the more sugar fixes you have, the worse the problem becomes. The more insulin you will have to make to counter react the rise in blood sugar, and the more insulin you make, the bigger the drop in blood sugar level shortly after! The blood sugar rise will make you feel better, but this will dip soon after – your brain will feel like it is not functioning correctly, you will feel fuzzy. The brain does not like these yoyo effects at all. It is a very powerful chemical imbalance. Eating the right foods regularly will maintain a balanced level. It causes mood swings and it is the refined carbohydrates that are notorious for this and we tend to use low glycaemic index diets for our women and this makes them feel so much better. The Atkins diet works to keep blood sugar levels low but has a high fat content, which is not good. It is increasingly being recognised that people with insulin resistance that any of the low glycaemic index diets which are low in refined carbohydrates are probably going to help with moods, hunger pangs and ability to lose weight. There is a lot of research currently being done in this area. Insulin resistance also increases the risk of premature diabetes, diabetes at an earlier age and furring of the arteries. A lot of research of insulin resistance in PCOS which suggests that a lot of what we are looking at in PCO is very similar to what we see in diabetes, so there is a belief that PCO is probably a precursor to type 2 diabetes. For me, it was a chance to do something for these women before they turned up in the diabetic clinic, when the pancreas had packed up.

My message to women with PCOS is to reduce insulin resistance, as this is the key to making many of the symptoms better. If the insulin resistance reduces, theoretically, the hair should get better, the acne should get better, periods and fertility should get better, your moods will get better and you will never become diabetic. The key to reducing insulin resistance is weight loss. This is not easy; both women and men with insulin resistance find it notoriously difficult to lose weight. The insulin resistance feeds the system. I can’t emphasise how important exercise is because the insulin resistance is, to a large degree, determined by the muscles in the body. That is where the insulin resistance is, in the liver and the muscles. If you do not exercise, the muscles become incredibly insulin resistant. While running these support groups for women, I have been amazed at how women have managed to find time to do exercise in their normal busy day. I used to be very lazy, but do now do 20 minutes exercise every morning. It is important to find time. Set small targets, do it in little steps. It needs to become a ‘part’ of our lives, like brushing your teeth each morning. One lady I know, does her ironing upstairs but keeps her ironing downstairs, so each time she irons something, she runs down to get it and then upstairs to iron it – she has just lost her fourth stone! The support groups are excellent for sharing ideas of how to incorporate exercise into daily life. It is important to use the low glycaemic index (GI) diets for weight loss. A small reduction in weight will improve all the features of the syndrome. Fertility will improve with weight loss. If any of you have GPs that are not happy to prescribe metformin, please do refer them to this British Medical Journal paper that was published last year which states that women who cannot ovulate, that metformin is probably the first line drug that should be tried. This paper can be accessed via the internet. Metformin is an insulin sensitising drug, which reduces insulin levels. Glitazones are other insulin sensitising drugs but I do not use these much as I prefer metformin, which seems to help with weight loss, whereas glitazones may cause weight gain. There are many drugs in research stage. I take women off the pill, particularly dianette, which may cause weight gain. Sibutramine is a slimming agent also used at the clinic, which makes you feel full, not interested in food, so it helps the lifestyle changes necessary to lose weight. It also increases the metabolic weight. Patients concerned with their weight were taken off dianette and treated with metformin and sibutramine, which after an audit carried out at our clinic, appears to be a good combination with significant results in weight loss. Looking at period abnormalities in these women, we found that although only 8 patients had completely regular periods to start with, at the end of the follow up period, 17 patients had completely regular periods and the number of patients who had no periods at all, decreased from 5 to 1. It is a very effective treatment. With regard to the hair, results appear mixed. Half the studies say it makes the hair problems better and half say it doesn’t. That is exactly the results we found at the clinic. About 42% of patients said there was no change using metformin and sibutramine when they lost weight, although others did say that their skin got better. In general, I have found that additional drugs are needed to deal with the hair side of things. Metformin and weight loss alone is not enough. There are side effects with both drugs but in general, most women were so delighted that they were losing so much weight that they didn’t mind! They can cause constipation and sometimes headaches and it can cause sleeplessness although these get better the longer the drugs are taken. It is important to monitor blood pressure with sibutramine. The low carb diet seemed to help too. The results from this audit have now been passed to the journals reporting that patients on the slimming agent with PCO lost an average of 8 kilos over 6 months and all our patients lost weight. Prior to combination therapy, all our women had a BMI of over 27 and after 6 months on the treatment, on average 20% of them had a BMI less than 27 and in our clinic now, we have many size 8 and size10 patients. Finally, to summarise, the combination appears to be well tolerated and effective in improving menstrual irregularities and it may well improve hairiness. Further weight loss may be possible with

longer follow up times on these women and further research will establish the role of these agents as first line agents for the treatment of PCO, if we think that weight loss is key with women who have a weight problem with PCO. Back in Warwick, we are doing a large prospective study now where the women are offered this type of treatment and we are looking to see how much weight they lose, what else happens to them and how much better they get. There is another paper that came out since we found this in our clinic and it suggests that sibutramine may help women with PCOS and I think this was published in one of your earlier newsletters. With the success we were finding in our clinics and wanting to achieve even greater weight loss, we felt that a support group was necessary as we could spend more time with women. We managed to get funding for free gym spaces in group attendances, although this was not taken up as the women were too busy to get there at 5pm! We scrapped that. We offered behaviour therapy, which is vital, as women with PCOS suffer horrendously with binge eating, comfort eating and stress eating, due to the blood sugar levels being up and down. I felt we need a psychologist, someone who understood how the brain worked and eating and how the chemicals worked in relation to eating. Many of us eat when we are not hungry. We eat because we are bored or stressed. We do have a consultant who is a specialist in eating disorders and he does offer women simple techniques to deal with this and these are issues that we discuss regularly in our clinic. Once the weight has been lost, it is important to maintain this. Apart from metformin, which will help to maintain this, exercise is key. The insulin resistance and getting those muscles working is something we emphasise again and again in the clinic. After a year, sibutramine may be offered in pulses, to maintain their weight loss. Do visit the Warwick Hospital website which informs you about the lecture we are doing for the month. In October, our skin specialist talked about the management of acne and I talked about hormonal treatments for excess hairiness. Three days ago, our eating orders consultant talked about dealing with binge eating and next month it is about staying slim through Christmas with a low GI diet. Last month we were finalists in the Health Service awards and we went to London to present the service we set up in Warwick and there were 16 categories. We were short listed in the patientcentred care category and I am pleased to say that we did get support from Verity in the form of a statement in support of similar services around the country and we ended up being highly commended and made first runner up. We are hopeful to raise the profile of this distressing syndrome that affects 10% of women out there and that can lead to diabetes in the long term and that on a national level, we can fight this condition and with more research, help more women lose weight and prevent diabetes in the long term. I would like to end by making the statement ‘Men are from Mars and Women are from Venus’. Unfortunately, it is very easy for men. They have testosterone, which doesn’t go up and down; they don’t have periods – they will never understand how a woman feels at different times of the month and sometimes it can be very difficult to get through to your doctor, but don’t give up – there is treatment out there and if you are not too far, you are welcome to come to us. Alternatively, we are developing our website and all the lectures from all our specialists will be made available for you to access. Thank you. Questions I have been on sibutramine and metformin for approx 6 months and lost a stone. I had a bit of a hiccup as I was also on another treatment involving progesterone, which upset me, and half has gone back on! I need now to get back to doing the exercise.

Yes, exercise is vital. These drugs should be used to help make the lifestyle changes needed for a healthy lifestyle. It does help, but you must make the changes! I think support groups are vital too – you need support. I did find that once the side effects of sibutramine had worn off that the appetite was increased – is that common? Some people do report this. It is also raising your metabolic rate. If you don’t lose weight and you are doing all you can, there is usually a reason for not losing weight. I sometimes find that there maybe nutritional reasons, or thyroid problems. I have been on metformin for 14 months and so far have lost 4 stone but I am now 3 months pregnant and have been taking metformin up to now, as I understand that metformin can also help to prevent the risk of miscarriage and I have had a miscarriage before. What is the current advice regarding continuing to use metformin throughout the pregnancy, as I am concerned that if I stop taking it, that the risk of diabetes will be increased? This is a difficult question to answer as there are no proper randomised controlled trials. There are reports that it may decrease the risk of miscarriage, and I have a lady in clinic who continued to take metformin through her pregnancy. She continued to lose weight and had a healthy baby. Once the baby was born however, she started to gain weight, which is odd. There is a publication that has stated that metformin is completely safe during pregnancy but there is also a subsequent publication that states that there are problems that can be expected as with any drug that is taken in pregnancy. The more recent works, particularly in PCO, which is not a randomised controlled trial, so it cannot be assumed that it is true, does suggest that it may have benefits in reducing miscarriage rates. The current advice would have to be that it is still not best to take a drug during pregnancy. I could not advise it until more data is available. I start IVF in January and I asked my consultant if I could go on metformin. He said he didn’t want my hormones being ‘messed’ around. Is this good advice? It depends if you have PCO and you are not ovulating? I have PCO and I bleed all the time You bleed all the time? Yes It is difficult if you are bleeding all the time. The anovulatory infertility that the paper in the BMJ discusses, tends to be about women who have less periods rather than women who have continuous periods, so if you gynaecologist knows about how beneficial metformin is and still feels that it is not the answer, then you should go with what they think. For those of you who are not ovulating, there is evidence out there that says that metformin does work quite well and in fact there is now data showing that the combination of metformin and clomiphene is more effective than clomiphene on its own. If you have tried clomiphene and not got pregnant, you do not need to go down the route of having IVF without first trying this combination, as this is more likely to result in success. What about women who do not want to conceive? You mentioned you took women off dianette – can you still take dianette and sibutramine? Yes, there is no reason why you cannot take the two together. Dianette is very good for excess hair but recent advice from the Committee of Safety of Drugs does suggest that you should not take dianette for any length of time. At the end of the day, it depends on how distressed you are by the excess of hair. Previous teaching said that if you stopped taking the drug, it all came back. I have to say that I see women and it all goes away too. The testosterone goes away from years of being on the pill. For some women, the oestrogen, which is contained in the dianette, does make all the fat cells start to grow and they put on weight. The women I look after have a weight problem, therefore I take them off it – if you do not have a weight problem, it is fine to take both together. Are there any other drugs you recommend? In America, dianette is not even licensed for the use of treating hair problems – it is not even licensed as a drug. In America, they use a drug called spiralactone which is a water tablet. It is not a contraceptive and may mess up your periods, but it is effective too. Other drugs are flutamadin, finasteride which we use in clinic and a cream called Vaniqa. The laser treatment is still a very good

treatment for excess hair and remember that some of the mini pills, the progesterone only formulations, may make the hair problem worse. I have been tested for diabetes and insulin resistance and come back negative for both. That was 5 years ago, how often do you recommend I should retest? If you have PCOS, and particularly if there is a family history of diabetes, I think it is reasonable to be checked every 3 years or so, particularly with the data now coming available that suggests that 1:3 women may have glucose intolerance.

I am on the pill, not dianette, and suffer from thinning hair on my head. Are there any drugs that would stabilise this? Hair loss on the head is much more difficult to treat. Just to be aware, thyroid problems, which can go with PCO may cause women to lose hair, so that should be treated if it is an issue. Similarly, iron deficiency or any nutritional disorder needs to be addressed. Once these aspects have been dealt with and you know it is not one of these, then it is likely to be the male hormone. Strangely, the excess of male hormone causes excess hair growth where you don’t want it but is causes it to thin in a male pattern of baldness and thin on the head. It is difficult to treat but there are some anti male hormone drugs which are supposed to be quite effective, such as flutamide, dianette, finasteride. These are all anti male hormone drugs. It is vital that a specialist deals with this, not your GP. Dianette may be prescribed by the GP but not the newer drugs. There is another treatment called ‘Regain’ which can be bought off the counter, which is applied to the scalp. It helps between 30-40% of women with hair loss. Is it possible to achieve weight loss without the use of drugs? Yes. There are many women out there who have PCO and do not have a weight problem. (Victoria Beckham!). They may have other aspects of the PCO. Similarly, there are lots of slim women out there that have PCO and I do not know if they are slim because they have lost weight and manage it, or if they are slim due to a different genetic makeup. Just keep to a low GI diet and exercise. I do find that some women lose a huge amount of weight with just metformin and a low GI diet and exercise. People tell me that metformin helps with their moods, they feel more positive about life. Try this route and if not, go back to your doctor and ask him to prescribe. Do you still find that GPs are reluctant to prescribe metformin because it is not actually licensed for PCOS? Yes, but hopefully this situation is changing in the near future. When diagnosed with PCOS, should you automatically be referred to a gynaecologist or endocrinologist to support you with your syndrome, not just left with your GP? That is a million pound question! In the past, women were probably not sent to anyone unless there was a specific issue. If it was about fertility, then they may see a gynaecologist; if you had hair problems you may have been sent to the skin specialist. There is no real guidance out there and these risks with the health of these women is just now becoming obvious. The fact that they may be pre diabetic and harbour all these additional risks. It seems crazy not to do something about it at this stage rather than wait until they need the diabetic clinic. At the programme we ran using the gym and offering free sessions, it took over 8 months to get this for women with PCO to exercise as a group. Meeting after meeting occurred and I was told that WHEN they get diagnosed with diabetes, then they can come for free. They asked if they had high blood pressure or high cholesterol – not yet! I argued that they needed to do this exercise and lose weight BEFORE these symptoms occurred! They were happy to oblige if they HAD a health problem but not willing to help in PREVENTING this! The whole Health Service needs to rethink its strategy. Once you are diagnosed with diabetes you cost the tax payer hundreds of pounds. We need proactive medicine, not reactive medicine. This was part of our case when we submitted our case to The Department of Health, that Verity could save the Health Service a lot of money in the long run because we are hopefully helping women to

become educated about the right type of diet and exercise that will help to prevent them getting diabetes, or at least delay the onset. Is an under active thyroid and PCOS linked? The gynaecologists say it is not, but it is not just about the ovaries. There is something far more profound going on with the physiology in women with PCO and we do measure things like a slightly raised prolactin, a slightly raised TSH, which is linked to the hypothalamus. The adrenals are not functioning normally either. A lot of work is now going on. Gerry Conway runs a famous clinic in London and he is specifically looking at the adrenal gland and how it functions. The pituitary is also not innocent. It is much more complex than it was ever thought to be. Gynaecologists only understand ovaries and fertility; skin specialists are only interested in the skin; the diabetologist has arrived quite late on and we are seeing the consequences in the clinics, so we have a special interest in going back to look at what exactly what is driving this syndrome and whether it can be reversed before the damage is done. There are links, but whether treating that will make a difference on the rest of the syndrome is another area that has currently not yet been addressed. Watch this space! Thank you. Shirine has done copies of her slides, so please, if you are interested, take a copy with you.


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