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Search Results for: statistics
Evidence based medicine is a term we use (or more correctly, throw around) when we are trying to assure the validity that what medicine we are giving has been proven by science to work. Actually this is a definition I just made up as a summary of best explanation I can find to describe this term. I don’t think there is a definite definition for it as it depends who you are talking to and what they are trying to prove. I tend to think since science is constantly learning, claiming evidence based can be a tenuous term but a valuable one nonetheless when used correctly – that evidence shows it works.
The overall judge of this is statistical analysis, a gift really, that allows us to state in one sentence if the results we are looking at mean anything. Statistical analysis is an elementary type of math that allows you to determine easily if what you saw in an experiment can be applied to everyone. It is fascinating to see in action. In other words, the sample of people you drew for the experiment from everyone on the planet gives a result. It is statistic’s job to evaluate whether or not the results you have observed have a small enough range in values based on your sample size to be representative of the larger population. This range in values is referred to as Standard Deviation and gives a measure of how far from the mean all of your readings deviate. This is why an experiment with a large number of study subjects giving results close to the same reading gives a more robust ability to come to a conclusion that it represents the entire population. Conversely, readings all over the board may mean statistically you cannot come to a firm conclusion, and a small sample size in the experiment means you really need to be on your game and have vary little deviation in results to arrive at a strong conclusion.
Observe the above graph that outlines a typical bell curve in readings in an experiment. The goal is to keep all readings as close to the mean as possible to claim that there is a statistical effect. Outside of this range of SD+-1 readings happen that broaden the SD to +-2 and can reduce the certainty of your results. Note the word certainty, we can narrow down the certainty that the conclusion is true but we can’t prove beyond a shadow of a doubt that it is. The biggest beef with self described strict evidence based only medicine subscribers is that a Type 1 error or false positive will result: we have claimed a difference between placebo and drug when in fact there isn’t one. They really don’t care about the Type 2 errors or false negatives when a small study claims there is no difference when in fact there is one because that rarely leads to the therapy being used.
So a larger sample size should have the power to detect smaller differences that are statistically significant between placebo and drug group. When we are looking for a benefit like pain relief with topically applied medication, small differences are not what we are looking for so a big difference is not too difficult to find with a small sample size. Increasing the sample size will help to increase the power of the test and make it more sensitive meaning we avoid type 2 errors more. We make all tests stronger when we repeat the experiment and find similar results, even if that test has a small number of test subjects. Going back to the pain relief in cancer patients, where placebo effect might be there (the palliative care Doctor says if the placebo effect does that then we should bottle that and sell it), a sizeable improvement in pain relief with a small sample size (N of 1) is required to really show the pain creams work, and repeated application of the cream with the same results backs this up.
So what about those patients that fall on the outside of this bell curve. Those in the centre seem to respond well to the drug where as a population sample drawn on the left or right of this graph seems to have non-responders or low responders. How do we treat them? Perhaps the geographical area where the study was done had a result that the larger population didn’t. Small sample size studies are more able to find subtle changes in a medication’s response to a population group that may be lost in a large sample size.
Overall, evidence based medicine is the gold standard and small studies are quite unique in contributing to our overall understanding of the puzzle when applied correctly, just as any large study needs to be evaluated for its strength in arriving at the conclusion it did.
Should Pharmacists be blasted for selling what some call alternative therapies or products that are not “evidence based”? These criticisms can blindside unsuspecting Pharmacists trying to do what they can for their patients regardless of the fact that they are making a profit from it or not. What makes it more difficult is the way in which these criticisms are delivered, especially when delivered in an offensive type of online statement like most opinions are delivered today. It makes one grow thick skin if they wish to continue. As a pharmacist myself, I can reflect on the strong personal feelings we have towards our patients, especially in small community pharmacies. Not that many other health care professionals don’t have this deep feeling of ownership in their patient’s heath, it’s just that as pharmacists, the frequency we see these people is just so much higher, either in person or on the phone. We are one of the most if not the most accessible in their health care team and we answer a lot of questions from them, gladly.
Not only are we seeing these people regularly for health related concerns, but we also see them in passing when they need milk or a greeting card. In short, they feel and we feel like we see them more than some of our own family members sometimes. Couple this with the utter vastness of concerns this patient has and relies on us for.
Quite often these questions fall within the 80% of questions we hear every day. Prescription medications, interactions, side effects, screening what should go on to the doctor and what doesn’t need to, and OTC issues like supplements, cough and cold, pain relief, skin ailments, self treatable infections of all kinds, preventative measures, weight loss advice, and many more. During Med Review interviews, we uncover medical issues not being addressed fully or at all. There are medical issues that are treated in ways that the patient would prefer were treated a different way, either due to current side effects, potential side effects, interactions, or for the simple reason that they just want to be on fewer medications.
Now some may consider this an environment that sets up a scenario for a trap of giving the patient something that hasn’t been proven with studies of thousands and thousands of test subjects in randomized controlled trials. There has been no drug rep with glossy handouts showing graphs and impressive relative change overshadowing a less impressive absolute change in results. Perhaps the pharmacist has no idea of any studies that might exist for anything at their OTC disposal, no numbers needed to treat are at their fingertips (however unimpressive even Rx values for NNT are).
The truth is, a lot of these OTC treatments, even though we are taught them in Pharmacy school as recommended treatments, don’t have all that much in the way of studies to prove they work as I pointed out in a previous blog . This starts the slippery slope of evidence based to non evidence based medicine. This is a continuum rather than a conscious switch. As pharmacists who see the direct results of these recommendations daily, we begin to realize what the term “evidence based” means. It includes the evidence they see every day. Some refer only to large centre, many subject, randomized controlled trials for their definition of this term. Of course this is the basis of our scientific and medical knowledge and has extended lifespan many years. These people however may also recommend some things in what is known as off label use of some medications where the evidence is less plentiful. This is outlined in a recent blog: https://stonespharmasave.com/blog/?p=796 . The statistical method is a gift that helps us weed out chance encounters from truth (https://stonespharmasave.com/blog/?s=statistics ) . Anecdotal evidence can be notoriously prone to incorrect conclusions as it sidesteps statistics in its conclusions. Sometimes we just don’t have these studies available to us and must rely on smaller studies or a physiological basis for a recommendation.
I see this with topical pain compounding all the time. Repeated successful results with a scientific basis and numerous small studies and numerous anecdotal reports drive more recommendations and more feedback. This spreads to physicians that may be skeptical on how these products work. With one patient with a favourable results they become more comfortable in writing again. If a patient tries a prescription medication and it doesn’t work is the Doctor a quack? Of course not. Evidence based becomes what you see before you in your little world, regardless of what online bullies think, as long as your first priority is to keep the patient safe.
Graham MacKenzie Ph.C.
When I am asked to “prove” something by showing a study, it reminds me of how backwards we can be when it comes to stacking studies against each other to make a point. We come up with rebuttals like, “the patient size was too small”, “the study is too old” and “the study wasn’t double blinded”. In fact, virtually every study that has ever been done can be debated for some reason or other. As well, it is safe to say that not much has ever been proven of any value or consequence by just one study alone.
Let’s say that a colleague and myself have a disagreement on whether or not chromium has the ability to prevent hypoglycemia. This can start out with a quick exchange of some handpicked positive and negative outcome studies that may be well designed or not or maybe had the power to determine the outcome or not. Maybe a study hid some of the data or the statistical analysis was done improperly. Maybe my colleague had 10 times as many studies compared to mine. Is that what decides the outcome of all of these scientific studies? That one person can scrounge up more studies than someone else? How does that person explain a well-designed study that doesn’t back up his or her argument? Do they quietly pass off the study as a fluke or placebo effect or do they start to see what scientific study is for us – many studies that create a whole picture much like individual pieces of a puzzle make a picture.
Let’s say we have a puzzle. It is a puzzle of a field of green grass on a sunny day with blue sky and some white clouds. It turns out that this picture is a picture of a rabbit sitting in the field, only a very small part of the picture, less than one percent is taken up with the rabbit. This translates into just 2 pieces of the 500 piece puzzle. Let’s say my colleague and I divide the puzzle in two and each take half of the puzzle home with us. We separately lay out the pieces and get a vague idea about what the picture shows. It turns out I have both pieces that make up the rabbit, statistically not what we would expect but it happened. I call my colleague and tell him about the picture we are looking at and how it appears to be one with a rabbit in the field. He says, “that’s crazy, there’s no rabbit in this picture”. He said he’s looked at all of his pieces and no evidence of any rabbit.
So who is correct? Well based on what is in front of each of us, we are both correct. When we both meet to put the puzzle together on one table, the entire picture becomes clear. The puzzle changes from a field on a sunny day to a rabbit on a sunny day. Each piece of the puzzle is a scientific study.
This exercise shows us what the power of a study means, or an analysis of many studies can show. For an infrequent result, the amount of pieces that are required to find the rabbit are large. My colleague arrived at what would be called a negative result and mine was a positive result. In a book called Statistics Done Wrong, (Alex Reinhart) it is described that in a review of studies between 1975 and 1990 in prestigious medical journals, almost a third of these studies yielded negative results. A full 64% of these studies didn’t have the power to determine a 50% difference in the primary outcome they were looking for between treatment groups. When a 25% difference was present, a full 84% of studies didn’t have the power to find this.
As always, I believe that scientific studies are the best thing we have to unlock what we do not know. One study however, can be deceiving when taken as a single data point on a graph. Scientific studies are a group effort.
As a pharmacist I see the alarming rate that antidepressant medication is used, especially in young people. Along with this use, anti-anxiety and sleep medication are also one of the most commonly used medications that leave my pharmacy. Statistics tell us that the number of patients diagnosed with depression increases by approximately 20% per year, that roughly 10% of us experience depression like symptoms at some point in our lives and that 80% of those with these symptoms never receive any specific treatment for their condition. (Healthline). More alarming is the decreasing age of onset of diagnosed depression in our young population. It is common for me to see parents of teenagers that are suffering from depression and anxiety.
When we look at a map of the world that shows the global distribution of depression, it looks much like a lot of other global distribution maps for diseases like cancer and obesity. The “Western” type societies stand out. Western refers to many things but for this purpose it refers to what is introduced into our bodies in the way of our diet. The increase in the omega 6 in our foods over the last 60 years and certainly since the introduction of farming has taken our roughly 1:1 omega 6 : omega 3 ratio to something closer to 16:1. This increase of omega 6 into the food chain via the way we feed our farm animals has drastically changed our once anti-inflammatory food to an inflammatory type diet that our DNA was not designed to function with in a healthy manner. Added to this is the introduction of vegetable oils and omega 6 based oils that don’t spoil as easily as their omega 3 counterparts. This leads to easier distribution of the food to its destination. These two fatty acids compete for the same enzyme systems in the body with opposite effects. There is virtually no omega 3 in safflower, sunflower, corn, cottonseed, sesame and peanut oils. Flax has more three than six and walnut, canola and soybean at least show some omega 3.
Consumption of omega 3 oils and fish in the diet has been correlated with a lower rate of depression as well as post partum depression, bipolar disorder, seasonal affective disorder as well as suicidal ideation. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC533861/ . More specifically, Krill oil, with naturally occurring phospholipids and a higher concentration of EPA/DHA omega 3 fatty acids has shown even better results. Epidemiological, lab and clinical evidence shows a positive result in numerous studies. A number of different mechanisms have been postulated for this effect, and an increase of distribution of food from the affected countries to worldwide destinations threatens the mental state of those countries as well. http://www.ncbi.nlm.nih.gov/pubmed/12442909
Although fish is often thought of as a common source of omega 3, there are plant sources available. Quite often these plant sources supply alpha linolenic acid (ALA), the parent compound of EPA and DHA. This conversion from ALA to EPA/DHA is inefficient in the human body however so it is more desirable to get the EPA/DHA supplement. (Rebecca Long, Omega-3 Fatty Acid Deficiencies: How Our Modern Diet Has Made Us Unhappy)
Getting back to your kids and our young population that are experiencing depression more often. Although I always recommend GI repair and probiotics to increase serotonin and improve mood in these patients, a key ingredient to any mental health protocol should always consider a measure of omega 3 and 6 via a simple blood spot test and corresponding supplementation with omega 3, and then a retest. Personally, 4 g daily for a month of EPA/DHA increased my omega 3 markers in the blood positively but even with this higher dose there was still room for improvement in the omega 3 score in the blood. It is important to remember that you are not suffering depression because of a physiological deficiency in an antidepressant and this disorder and anxiety do not occur randomly for no reason. I sell antidepressants daily as prescriptions, I see the side effects they produce and I regularly steer patients towards omega 3 and probiotics for depression. It’s important to not change your prescription therapy without discussing it with your doctor. Those on blood thinners may need to use extra caution when using omega 3 supplementation.
You are what you eat
The World Health Organization has released statistics that relate the most common causes of death in relation to overall income for a country. Believe it or not, HIV/AIDS is the second leading cause of death among low income countries. Also in these countries, almost 1/2 of the deaths in children under the age of five occurred within the first 28 days of birth. Causes of death for these infants are taken for granted in western societies, diarrhea, pneumonia and malaria are major causes of death in parts of the world with the lowest income. And let’s not forget tuberculosis, a disease that is making a comeback due to the length of time required to treat, not to mention the cost. Fully 1/3 of all deaths in low income countries are from these above mentioned causes. To add to these deaths is the increased percentage of maternal deaths – moms that pass away during childbirth, because of pregnancy related medical issues or medical problems related to the birth of their child after birth. Premature births are also a major contributor to death in this population.
However, in contrast to the infectious diseases mentioned above, the higher income countries death rates showed that 87% of deaths were non infectious disease related deaths. 70% of people in high income countries die at the age of 70 or higher in contrast to 20% in low income countries. What are we dying from in higher income countries? Ischemic Heart Disease and Stroke, collectively known as cardiovascular disease. Only 1 in 100 deaths is among the age group of 15 years old and younger in western societies, compared to 4 in 10 for lower income countries.
What does this all tell us? Well people in these low income countries still die of heart disease and stroke. We just live longer in higher income countries because of the healthcare and medications available that allow us to fight these diseases. Certainly medications have drastically lowered the main causes of death here that are common for the low income countries like communicable diseases and childhood deaths. We may die of accidental causes more in western type societies. As a pharmacist I can tell you if I take away the number of prescriptions that are for infection, cardiovascular disease medications amount for a significant proportion of medications. Psychoactive meds perhaps second, acid lowering meds close behind (which brings to light the issue of gastric cancer in western societies as compared to lower income countries). As I have blogged before, the medications are only a small part of it, as is evidenced in the difference in life expectancy between the US and Canada. Life expectancy in Canada is notably higher than the US even though we have the same medications available, just different healthcare models. Healthcare in Canada is free for the most part except for medications. I think the main reason is diet, as many states have similar life expectancy to Canada except for the Southern states, which have quite a different diet than the rest of the country and skew that country’s total life expectancy to a lower number.
So how long can we expect to live as humans? Absolutely one of the greatest achievements of the 20th century was the increase in lifespan for those on the planet. We have extended lifespan by nearly 40% in the last century. Definitely getting a human past the age of 15 is a huge hurdle in extending this timeline. In the next 50 years, the percent growth in our population is expected to be exponential in the 85 and older group compared to those that are younger. All of the above mentioned factors of medication, research, healthcare models, and so on have certainly helped and perhaps knowledge of nutrition, but food has been the downfall of how we die. Not only cancer but other obesity related issues can be chalked up to our diet in some way or another. Exposure to other toxins daily due to our lifestyle has drastically changed in the last 60 years as well. Our lifespan has increased but our disease state that ends our life has changed. Seemingly, when someone moves from Rural China to North America, the reason for dying changes within a generation or two.
The timing of our decline and ultimate death is encoded deep in our genes. I am always quick to argue that your genes can be controlled to prevent disease but ultimately there is something more powerful going on that we can’t yet override. There seems to be a clock or sensor in our genes that says, “time to wind down”, or “you are no longer able to contribute to the reproduction of the species”. These genes are interfered with less in lower income countries with less availability to medication or healthcare. Diet, exercise and lifestyle are free to impose their natural forces on DNA unhindered by medicine. Even if we avoid disease, if that is possible, we still can’t live forever. Why is that?
The telomere theory of agin does a good job to explain this. Telomeres are located at the end of our DNA strands. As our cells divide, the DNA replicates so each new cell has its own DNA. Telomeres are disposable caps at the DNA strands. As DNA divides there is always a point where the division of DNA occurs before the actual end of the DNA strand. Small amounts get clipped at the end with each cell division. Telomeres are the buffers that contain “throw away” pieces with each cell division. Now imagine how much of this finite buffer is left when you are 80 compared to 20 years old. At that point we start clipping useable pieces of DNA with each cell division after using up the telomere buffer during your lifetime. At that point we actually have defences to stop division of that cell so mutant cells or cancer won’t develop. The bad side is that we don’t duplicate a cell like that anymore and it dies. Antiaging medicine has focused on keeping the length of these telomers as lengthy as possible to maintain healthy cell division.
This is an over simplified method of aging. How do we prevent the shortening of telomeres and therefore heart disease, cartilage loss? Antioxidant support, astralgus, B,D and C vitamin and mineral support, a good diet, organic food, lack of stress, and as much a we hear that multivitamins are useless, a study has shown that telomeres are on average 5% longer in those that take multivitamins as opposed to those that don’t. Dropping inflammation with omega 3 is also helpful and green tea, curcumin, quercetin, resveratrol, mixed tocopherols (vitamin E mix) also have shown promise.
So we can debate the effect of money on cause of death for a given country, but in the end, even if we prevent disease, we aren’t living forever. Keeping the degradation of telomeres at bay not only prevents longterm disease, but extends lifespan even more. Don’t agree with these nutrition recommendations? Just start by eating better and exercise more.
There is no point giving statistics anymore on the incidence of obesity, the effects of obesity, the millions of dollars spent to eliminate obesity, or the cost obesity has on everyone. These statistics are merely valuable for trivia at best and really don’t result in anyone becoming fearful for their lives and going off to lose weight. The fact is that each generation finds it easier to put on weight than the last. It is common to tell someone they are overweight simply because they eat more than they burn off; that someone is overweight because they are lazy. Hmmmm….logic would lead us to believe then that laziness is a relatively new human trait that progressively becomes worse with each generation, leading to more overweight people.
Of course this type of thinking only results in people incorrectly thinking that their weight problem happened 100% because of their fault. True, weight loss occurs in humans when we change what and how much we eat and increase our activity level – it is pretty difficult to disprove that. If you live a healthier lifestyle you should lose weight and keep a healthy weight. But why is it easier now to put pounds back on when we lose our focus for just a few days? Is this what happened say, 2000 years ago? 10,000 years ago? Were we all sitting around the TV watching weight loss programs back then scratching our heads as to how we got so big? Obesity is not new to us, but the prevalence of it has never been higher. It becomes clear that it is nothing short of cruel to make a person believe that all of us would be the same weight if we all ate the same and exercised the same and that the reason they are overweight is negligence on their behalf.
So what is the difference today compared to back then?
ENDOCRINE DISRUPTORS One thing that we are constantly exposed to from conception onward in this part of the world are insults in the environment that have adverse effects on our hormones. Thyroid, estrogens and androgens. One of the biggest increases in this category is from bisphenol A (BPA). This chemical is found everywhere in our daily lives. From the lining of metal cans, to your plastic containers containing your drinking water, the plastic tea bag holding your healthy dose of herbal tea, food storage containers (that you microwave), even the air you are breathing – all contain this chemical. It has been proven that exposure to BPA causes obesity. It is a potent imitator of estrogen in the body and alters glucose and lipid metabolism.
FOOD SENSITIVITIES Certainly one thing around today that wasn’t around thousands of years ago is the type of food available. It was postulated in the first half of the last century that food sensitivity was responsible for obesity. We now know the exact mechanism that happens when we eat an inflammatory food and how it results in fat cells increasing in both size and number. Genetically modified food that the body was not evolved to recognize is one source. The reliance we have in this part of the world on this type of food is staggering. Because of the dominance in the market with this type of thinking from a handful of companies, we consume more and more of this kind of food. To ad insult to injury, the same foods we are allergic to cause an addiction to the same food and cravings occur for the food that increases weight. Not many of us have an addiction to say kale, or carrots. We do though often have addictions to carbs, which when ingested create substances in the body that are related to opiods. This includes wheat gluten and milk protein (also a relatively new introduction to humans) as well as refined sugar.
REFINED SUGAR Another new addition to our diets as humans is this much hated and loved set of molecules. Consuming these causes a spike in insulin levels to deal with the sugar load in your blood. Hopefully this spike will drop the blood sugar level quickly. Unfortunately the resulting dive in blood sugar and the overcompensation of insulin dumped into the blood causes a low sugar level in the blood that you are chasing all day. You eat more sugar, you get more insulin, your sugar drops… do you see a pattern. This helps to contribute to insulin sensitivity. It is like a wave on the ocean that you can’t stop. Fructose is one of these sugars. Although this sugar doesn’t result in the up and down levels in the blood just described, it does get metabolized into lipids and results in abdominal weight gain.
STRESS Anyone out there with no stress in their lives, please stand up. Now that we are all sitting down, you are at least comforted by the fact that you are not alone. You have bills, you have relationships, you have deaths of loved ones, you have job issues, you have traffic, you have kids, you have stress. True, stress has always been there with humans, it’s just the constant nature of stress we deal with that is different. So is the type of stress. Cavemen and women had stress when they left the cave to get food and not get eaten themselves. They weren’t late for work, checking their visa bills on their iPhone at 2:00 AM, breaking down on the freeway taking their kids to soccer, or paying for their college education. Stress increases cortisol, and constant stress keeps cortisol elevated more than it should, cortisol stores your fat.
Other things we have the ability to chose but are so prevalent in our world are trans fatty acids, lack of dietary fiber, artificial sweeteners, lack of breast feeding, high caloric diets, lack of frequent small meals, grazing, late bedtimes, lack of sleep, prevalence of acid lowering drugs that prevent digestion from fully occurring, lack of exercise, all contribute to weight gain.
It’s not totally your fault you crept up a few pounds year by year, it’s not your fault it takes more work to lose weight than your friend of the same age, but it is still up to you to decide if you want to remain overweight or not. We know how to lose weight, it’s just harder for some more than others. Your genes are different than your friend’s. It means they have blonde hair and you have brown, is can also mean you lose weight with more effort than them. But you can still do it.
According to Canada’s Movember, the following statistics show alarming facts about Prostate health
1 in 7 men will develop prostate cancer during his lifetime and 1 in 28 will die of it.
A man dies from prostate cancer every 15.6 minutes.
In 2013, 26,500 new cases of the disease will be diagnosed and 4,000 men will die of prostate cancer.
Prostate cancer is the most frequently diagnosed cancer in men after skin cancer.
The incidence rates are nearly double for in African American men.
If detected and treated early, prostate cancer has a 95 percent success rate.
While there are cases of prostate cancer showing up in younger men, it is recommended that men begin an annual screening at age 50 and at age 40 if there is a family history.
The older you get the better the chance of Prostate Cancer occurring. The prostate is notoriously slow the act and react to its surroundings in a good or bad way. Therefore your prostate health is as much preventative as it is treatment based. This means there are things you should be doing now at any age rather than wait for prostatic hypertrophy (enlarged prostate), prostatitis, or prostate cancer to occur.
Testosterone can change to DHT via an enzyme called 5-alpha-reductase or to estrogen via aromatase. Most men believe that it is the excess of testosterone that causes the problem, but it is more the conversion of testosterone to these metabolites that results in hypertrophy (enlarged prostate). Estrogen dominance is not only a common problem in women but also in men due to diet, environmental factors, and being overweight (aromatase works in fat tissue in abundance in men and women). Some supplements you can take to help reduce this include:
- Zinc – which helps stop the conversion of testosterone to harmful metabolites.
- Prostaglandins in the prostate decrease with age. It is believed that these substances help to control the growth of the prostate from hormonal factors. Essential Fatty Acids are precursors to these substances and can help reduce the prostatic hypertrophy
- Saw Plametto inhibits the 5-alpha-reductase enzyme and reduces the DHT produced and has other actions that help to reduce the size of the prostate. It is well studied in prostatic health.
- Pumpkin seed , Pygeum Africanum (an endagered species), Saw Palmetto and stinging nettle contain phytosterols that have been studied extensively for prostatic hypertrophy and shown to have beneficial effects.
- Prostatitis, which is an inflammation or infection of the prostate can be aided with zinc due to it’s antibacterial effects, and Quercetin (a natural anti-inflammatory flavanoid). Also, we here from our patients all the time how diet affects their prostatitis.
Ask us more on doses and sources of these supplements and which foods to avoid and other proactive things you can do to avoid this condition. Estrogen metabolism is just as important in men and we can help you funnel estrogen down to favourable metabolites and decrease your estrogen dominance.
Gaby, Alan R. Nutritional Medicine – A Textbook, chapter 210