Our Chicago network member Lesli Bitel-Koskela sent me this great article about myoinositol, a nutrition supplement that was recently studied in comparison to metformin for its effect on anovulation and infertility.
In a study with 120 women who were required to have both a PCOS diagnosis and confirmed 14 to 16 months infertility prior to starting the research protocol, half were randomly assigned to a regimen of 1,500 mg metformin daily, while the rest were assigned a combination regimen of 4 grams myoinositol and 400 mcg folic acid. Here's how their stories played out.
Metformin 50% restored spontaneous ovulation, and 18.3% of those who did, achieved pregnancy. Total pregnancies for the 60 women: 5.
Myoinositol 65% restored spontaneous ovulation, and 30% of those who did, achieved pregnancy. Total pregnancies for the 60 women: 12.
My thoughts:
1. Myoinositol is a metabolic intermediate, and it's relatively inexpensive (looks like about 78 cents per 4 g dose as described above).
2. It certainly makes sense to try this first before moving into metformin.
3. If it doesn't succeed in achieving ovulation and pregnancy on its own, it certainly wouldn't hurt to use it in conjunction with metformin, hopefully achieving more effects with metformin on lower doses less likely to cause the horrible side effects our readers consistently complain about.
4. If you choose to try this regimen, be sure to include both the myoinositol and the folic acid, as it was not clarified which of the two is the most active one, or whether they work in conjunction.
5. This is a different compound from d-chiro-inositol, a popular supplement with women who have PCOS. Both appear to have benefit, as research evolves, we'll understand the particulars.
Lesli, I can guarantee you made a lot of readers happy by sharing this!
Readers, if you do experience success with this, please come back and share with us so those coming along behind you can benefit.
If you're REALLY interested in this, over the weekend I'll talk about where you can find myoinositol in food.
Raffone E, Rizzo P, Benedetto V. Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women. Gynecol Endocrinol. 2010;26(4)275-280.
I've been writing this blog long enough to know that as soon as I recommend a supplement, the post is circulated, reposted, retweeted, ad nauseum. If I talk about changing food choices, it sits there like a bump on a log.
I posted the information about myoinositol supplementation because I knew that many of you are having such a hard time with the side effects of metformin, that it might be helpful to try this compound as an adjunct.
In the process of researching the topic, however, I came to understand that part of the reason many of you have a problem with your myoinositol levels in the first place…is that your dietary choices may have backed you into a corner.
Myoinositol isn't new news, really. Back in 1980 a physician and a dietitian wrote a very nice review article and developed some recommendations for increasing dietary inositol that I'm going to summarize here. In a nutshell, it's a dietary intermediate that is found in high quantities in nerve cells. If your nerves are working harder than they were designed to, as is the case when you don't manage your stress, don't attend to good sleep hygiene, overexercise, and eat a poorly varied diet, there is a really good chance you're going to deplete your myoinositol levels more quickly than you can replete them. That is a consequence for ANYONE not taking good care of themselves, it's not a unique feature of PCOS.
For anyone struggling with medical issues related to hyperexcitable brains, including migraines, epilepsy, anxiety disorder, OCD, PTSD, bipolar disorder, etc., it's highly possible that your daily myoinositol needs are simply higher than average. Everything you see us write about on this blog, from omega-3's to antioxidants, is designed to reduce that hyperexcitability and make it easier for your brain to function as it should. It certainly is not going to hurt to take a supplement, and if you've been asking your brain to run on nutritional empty for a long time, or if you've been working hard to turn your PCOS around with good habits and just don't seem to be getting over the hump with it, supplementing may be a great tool to add to your already good habits.
There is some thought that people with insulin function problems may have alterations in myoinositol function, which could also increase the daily needed dose.
I must iterate, however, that a myoinositol supplement is NOT a substitute for a healthy diet. There is no such thing as a donut for breakfast, a Snickers for lunch, and a binge for dinner…cancelled out by a few pills in a bottle. So my guess is that those of you who are making good changes diet and stress management-wise in conjunction with the supplement are the most likely to achieve the benefit of the supplement. That is just how biochemistry works!
The study I recently quoted (focusing on neuropathy, not ovulation) used a myoinositol dose of 4 grams. The study I quote today found an effective response from a highest dose of 1,500 mg. It doesn't mean that these are the doses recommended for each particular diagnosis, or type of inositol, pill or food…it simply means those are the doses the reseachers decided to study.
However, since that is the dose reported in the ovulation study, and more of you reading this are interested in conception than nerve pain, I'll post the values of the highest myoinositol containing foods and let you figure out what your best food/supplement combination is to achieve that dose (4000 mg or 4 g daily).
I'm going to tell you, what I was thinking as I compiled this list was that if you're only concentrating on carb/protein/fat content, you're cutting out all your myoinositol sources. It looks like Mother Nature makes sure that when we eat carbohydrate as it appears in nature, that it comes packaged with a nutrient important for metabolizing it. It's when we refine that sugar and eat it out of context, as with sodas, candy, baked goods, etc…that we dig a hole for our nervous systems.
We just can't outsmart her, can we?
The complete list can be found at this link.
Myoinositol Containing Foods with more than 100 mg/serving 1/2 cup grapefruit juice 456 1/2 cup canned great northern beans 440 1/4 fresh cantelope 355 1 fresh orange 307 1 slice stone ground wheat bread 288 1/2 cup rutabaga 252 1/2 cup kidney beans 249 1/2 cup orange juice 245 1/2 cup canned oranges 240 1/2 cup canned peas 235 1/2 fresh grapefruit 199 1 fresh lime 194 1/2 cup canned blackberries 173 1/2 cup mandarin oranges 149 1/2 cup canned lima beans 146 1/2 cup kiwi fruit 136 1 cup split peas 128 2 T. creamy peanut butter 122 1 fresh nectarine 118 1/2 cup canned black-eyed peas 117 1/2 cup grapefruit sections, canned 117 Rex S. Clements, Jr., M.D. and Betty Darnell, M.S., RD. Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J Clin Nutr September 1980 vol. 33 no. 9, 1954-1967.
OK. Today's the day. There was finally a quiet morning to read the research about d-chiro inositol. Ever since I posted a link to Sasha Ottey's interview on the topic on her PCOS Challenge radio show, traffic linking to us with that keyword has been very high. I've known we needed a blog post, but I just wanted to be sure it was scientifically accurate and presented information in a way that was beneficial, not hurtful.
What is inositol? It is a chemical that is necessary for several body functions, including: cell structure, insulin function, nerve function, fat breakdown, and maintenance of healthy cholesterol levels.
Inositol comes in nine different forms. Two of those types of inositol, myo-inositol and d-chiro-inositol, have been found to have therapeutic value. Myo-inositol supplementation has been found to alleviate symptoms of bulimia, panic disorder, obsessive-compulsive disorder, agoraphobia, depression, and bipolar disorder. d-chiro-inositol supplementation has been found to be useful for symptoms associated with insulin, high androgen levels, and menstrual irregularity. It is also reported that myoinositol can help prevent hair loss.
Both categories of symptoms are common in PCOS, so it appears that inositol levels and metabolism may be problematic with a high percentage of readers of this blog.
One thing you can do to help improve your levels of both myo- and d-chiro-inositol is to know their dietary sources. Myo-inositol is found in brewer's yeast, liver, milk, whole grains, brown rice, oats, nuts, citrus fruits, molasses, legumes, raisins, and bananas. The best sources of d-chiro-inositol are buckwheat and garbanzo beans (hummous, anyone?)
The theory is, that women with PCOS have trouble converting myo-inositol into d-chiro-inositol. So they need to bypass that metabolic bottleneck with a supplement.
I haven't had the opportunity to use d-chiro-inositol with my clients yet. I haven't wanted to recommend anything unless I'd researched it. But I had a client once, with severe OCD, who responded well to myo-inositol in a way medication and behavioral therapy never achieved. The only issue she had with the supplement was the large dose she needed to take (10 grams per day) in order to see benefit.
Fast forward to today, I've been wondering for awhile if maybe the symptoms attributed to myoinositol deficiency weren't actually myoinositol issues at all, but d-chiro-inositol issues, and the large dose needed was because the conversion in this population is so low.
So here's the best way I would think it would work to determine if d-chiro-inositol deficiency is your problem.
1. Be sure to include all the foods I mentioned above in your diet on a regular basis.
2. Try d-chiro-inositol. Give it three months of regular use to see if it helps. --If it helps with your insulin levels, androgen levels, and menstrual cycles, then by all means continue using it! --If it helps with the above, but doesn't help with binge eating, mood, or obsessive thinking, then consider adding some myoinositol to the mix.
3. And please, check back with us. I'm really curious to know what happens. If d-chiro-inositol also helps with mood, etc., that's very important information.
Recommended doses of each: myo-inositol 12-30 grams per day d-chiro-inositol 100 mg, twice per day
I know, I know, if you're obsessive, you're going to want to take the higher dose of myo-inositol, or even double the dose I've listed.: ) I strongly encourage you to resist the temptation and start low and titrate up as you need to.
I spent quite a bit of time in the supplement department at Whole Foods, to get an idea of what readers would find if they went to buy inositol. As you can see at this link, the options on amazon.com, as they are in most health food stores, are primarily myoinositol.
If you'd like to purchase d-chiro-inositol, the most popular source for women with PCOS appears to be www.chiralbalance.com.
d-Chiro inositol is an extremely popular supplement with women with PCOS. I've heard some fantastic stories about it helping when nothing else seemed to make a difference.
That being said…
…I ran across a very interesting study published this past summer. It has to do with myo-inositol, another member of the same family that does not convert well to the d-chiro form in women with PCOS.
In this study, two groups of women undergoing in-vitro fertilization (IVF) were evaluated for pregnancy outcome with two different supplement protocols. One group received myo-inositol plus folic acid, the other received these two supplements as well as melatonin. Each group produced a similar number of eggs, but the women receiving the melatonin had a greater percentage of mature vs. immature eggs (i.e., better egg quality). Though the fertilization rate was equal in both groups, actual pregnancy rates tended to be better in the women receiving melatonin.
********BEFORE YOU RUN OUT AND BUY YET ANOTHER SUPPLEMENT!!!********* Take a look at your sleep hygiene! Are you keeping regular sleep hours? Or are you up late at night reading, watching TV, surfing the Internet?
Melatonin is the sleep hormone. There are many aspects of PCOS that are associated with not sleeping well, including insulin resistance and weight gain.
Supplements do their best work in a well-balanced environment. One that is balanced nutritionally, emotionally, physically (with exercise), and with regards to sleep.
Create your own melatonin naturally, with more attention to sleep and rest. As with some of our success stories, you might be surprised at what happens when you focus on the little things rather than on the name of the supplement.
Rizzo P, Raffone E, Benedetto V. Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles. A prospective, clinical trial. Eur Rev Med Pharmacol Sci. 2010 Jun;14(6):555-61.
I'm guessing the title of this post conjures up the story of the tortoise and the hare for many of you. Though it likely pertains, I would like to tell another reptilian story that this week's series of posts brought to mind.
Many moons ago, I traveled to Costa Rica with a couple of friends. It was egg laying season for the leatherback turtles, and one of the most important things we wanted to do while there, was to see this in action. So one night, in the middle of the night, Micki and Ginger and I took off for Playa Ocotal, where the locals told us we should go.
Soon after we arrived, a huge leatherback mama pulled herself out of the ocean, groaned and labored over dry sand for about 15 yards, dug a hole about 3' x 3' x 3' and deposited about 100 golf ball-sized eggs. It happened to be a full moon that night, and I will never forget watching this…midway through the event, mama released a tear that fully reflected the moonlight.
The Costa Ricans, famous for how they value and protect their natural wonders, had set up a protective net that kept us a safe distance from the action. It seems that turtle mamas sense the vibration of the waves crashing against the sand, and they use that to navigate their way in and out of the water. Too much foot action disorients them and interferes with the process.
The docents that evening were from a local Boy Scout troop, and they taught us more than I ever thought I would know about turtle babies. Years before, once scientists noted that babies hatching during the daytime almost never survived because they were easy prey for flying birds, they tried to help them out of that dilemma by standing watch for hatchlings. Only the babies that were manually picked up, walked to the water's edge, and deposited into the water, didn't survive, either.
From THAT experience, scientists learned that when the babies hatch, their shell bellies are not fully developed. It is the process of crawling across the sand, on their own, and some kind of interaction between shell and sand, that closes up that shell and renders the baby flotatious enough to survive. In bypassing this important process, the scientists were inadvertently drowning the creatures they so wanted to help.
So they learned, that the best that they could do, was protect, as much as possible, the environment and conditions that best supported reproduction and survival, so that the turtles could best do what they had done for eons.
Here is the little guy who appeared right between my feet while I was listening to the docents! Isn't he just precious?
I didn't even realize it at the time, but it was my first reminder that Mother Nature guards her complicated recipe for reproduction more closely than Cadbury guards its chocolate making. Mess with even one ingredient, and it may not turn out at all.
I hadn't thought of this night in a long time, but the research about myoinositol that I've been writing about brought it to mind.
Like the leatherback turtles, there are many, many steps in the process of bring babies to life and releasing them. And each of those steps, no matter how insignificant to the bystander it may seem, has an important purpose. Alter it, try to jump over it, try to convince the system that it's not necessary, and the chance of failure increases.
Every one of you seeking fertility is where you are at for a unique and different reason. It could be one step in the chain, several…your stories are as unique and varied as the pathways that go from brain to fertilized egg. It is clear, since more than 60% of in-vitro fertilization (IVF) procedures do NOT result in a successful pregnancy, that ignoring all of the steps between your brain and fertilization and focusing on the endpoint, results in tremendous emotional, physical, and financial stress for a lot of anxious couples. It is important that attention be focused on how to maximize all of the processes occurring between brain and ovary, in order to enhance the success rate of IVF.
Some of it is lifestyle. Some of it is supplementation. None of it is a magic bullet that allows you to ignore any step along the way. Myoinositol will help those for whom myoinositol deficiency is an issue…but it won't help others with other reasons for being infertile. Removing that cluster of cases from the mix, however, will give reproductive scientists the next great step to discover and enhance.
The information I presented all last week was illuminating, but it still didn't generate a 100% success rate. We still have many questions to answer. I am excited about the new findings, and hope to be able to use the new Research Institute to help clarify the route to fertility that is best for each individual situation. As well as to gain better insight into who is most likely to benefit from myoinositol supplementation.
It's going to take a little more time to find these answers than it took to find Playa Ocotal, and it's going to require more than a roadmap and a flashlight! For that reason, I encourage all of you to do your very best to maximize the information we share about lifestyle (diet, stress management, activity), rather than waiting for science to find a miracle, or waiting for a supplement to become available in your country. It can't hurt, it might help, and your effort and the information it elucidates may generate observations important to solving the problem.
ADDENDUM: By sheer coincidence, as I was working on this post, CNN did a wonderful story on a special leatherback turtle. I know we have a lot of animal lovers reading this blog, so I'm including the link if you'd like to learn more about Clover and her very loving and unique method of assisted reproduction!
Yesterday I reported on research suggesting that myoinositol was effective in creating more viable eggs than d-chiro-inositol, but qualified that the study was performed on women with PCOS whose insulin function was normal. Guess what…myoinositol does that too!
Again, this experiment was conducted in conjunction with the administration of folate, so realistically re-creating this in your own home laboratory may require both.
Forty-two women with PCOS were treated in a double-blind trial with myoinositol plus folic acid or folic acid alone by itself. The myoinositol group, at the end of the study, experienced lower serum total testosterone, serum free testosterone, plasma triglycerides, systolic blood pressure, diastolic blood pressure, and area under the plasma insulin curve after oral administration of glucose. And insulin sensitivity increased. 16 out of 23 women given myoinositol group ovulated, compared to 4 out of 19 in placebo group.
When this information is combined with the information I wrote about yesterday, what it seems to say is that myoinositol creates an environment where a pregnancy is not only more likely to occur and but also to sustain itself. One of the frustrations I have expressed here before is that while metormin helps to increase ovulation rate, it doesn't transfer to babies at the end of the path. I don't have to tell you how frustrating it is to know you've got half the system up and running and nothing you try seems to make the other half cooperate.
Costantino D, Minozzi G, Minozzi E, Guaraldi C. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. Eur Rev Med Pharmacol Sci. 2009 Mar-Apr;13(2):105-10.
Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol. 2008 Mar;24(3):139-44.
Yesterday I shared some great news from an Italian research group about myoinositol for improving fertility. In the process of corresponding, they sent me a series of articles from their lab. One of their most recent investigated the combination of myoinositol and melatonin in fertility treatment.
Here's how it looks like the story goes.
Ovulation is an inflammatory process Yes, the process of releasing an egg, and giving life, is pro-inflammatory. It takes a lot of energy to do this, and as that energy is metabolized, it's oxidizing tissue around it.
Melatonin is one of the most powerful antioxidants we have You know, if you think about this the way Mother Nature does, it makes sense that we'd want to roll over and sleep all cuddled up after sex. It is her way of protecting that fragile egg from all of the stresses of the day.
The research I read yesterday was about INOFOLIC PLUS, an Italian proprietary blend of inositol, folic acid, and melatonin. Forty-six women who had previously undergone in-vitro fertilization (IVF) and failed, used this supplement daily for 3 months before undergoing another IVF procedure. They also continued to take INOFOLIC throughout the entire IVF cycle. This study, by the way, did NOT focus on women with PCOS, merely women who had failed IVF.
Here are some of the results of the second IVF in which the supplement was used: --Higher number of embryo transfers --Higher embryo quality --Where all of the subjects had failed with their first IVF the first time, 13 (28%) became pregnant during the study, 4 miscarried.
What is remarkable about this study is that the average age of these women was 39 years, an age where fertility is starting to become difficult even without a diagnosis of infertility.
The supplement is not perfect, but it shows promise for helping women for whom other strategies have failed. It seems to be a great combination of compounds for peeling off the layers of inflammatory/oxidative damage have inflicted on reproductive systems…talking your ovaries down out of the tree, so to speak. What it seems to do, is both create a higher quality egg and then protect it from the ravages of oxidation long enough for it to meet a sperm, conceive, and create an embryo.
Ahhhhhh…just love the power we have within ourselves to create healing solutions!
As I mentioned yesterday, unfortunately, INOFOLIC is not available in the United States. However, there is an important bottom line message here that cannot be ignored.
When you're not eating enough antioxidants, not delegating, working too hard, not sleeping well, not managing your stress, the melatonin Mother Nature given you to protect your eggs, may likely be channeled into fighting other damages those lifestyle choices have promoted.
Not trying to shake the eFinger at you here, it's just becoming apparent from listening to so many of your stories that when we don't take good care of ourselves, the effects can stick around for a very long time. And when we do things in an effort to eat well but don't do our homework first (such as eating vegan but not making sure all nutrients are still adequate in the diet or panicking and going on a crash diet in order to get pregnant, or overexercising as the only way to manage stress), they can hurt us in the long run.
If you start to think about your choices as"What can I do to not unnecessarily use my own antioxidant power so it can be there for that egg?"…perhaps making some of those choices you've been reluctant to take on, might become easier to embrace.
Unfer V, Raffone E, Rizzo P, Buffo S. Effect of a supplementation with myo-inositol plus melatonin on oocyte quality in women who failed to conceive in previous in vitro fertilization cycles for poor oocyte quality: a prospective, longitudinal, cohort study. Gynecol Endocrinol. 2011 Apr 5. [Epub ahead of print]
D-chiro-inositol, supplement popular with women with PCOS, has a lesser known cousin, myoinositol, that is beginning to gain some attention in PCOS world. An Italian research laboratory has started to report findings from studies suggesting that with regard to fertility, at least, myoinositol may be the inositol of choice.
Eighty-four women at the AGUNCO Obstetrics and Gynecology Centre in Rome, Italy, were treated either with two grams of myoinositol twice a day, or 0.6 grams d-chiro-inositol twice a day. Eggs from both groups of subjects were then retrieved for use in intracytoplasmic sperm injection (ICSI) as part of in-vitro fertilization (IVF). The inositol supplement is a proprietary blend of myoinositol and folate, INOFOLIC, that currently is not available in the United States.
Researchers were able to harvest an equal number of eggs from each group. However, in the myoinositol-supplemented women, the quality of the eggs was better (more mature). This group also had more successful IVF outcomes than the d-chiroinositol-supplemented women.
Because there is such a preference for using d-chiro-inositol in the audience reading this blog, I contacted the researchers conducting these studies for clarification. It turns out, they recently had a letter just accepted for publication in Fertility and Sterility in which they discuss why they believe myoinositol works in a way that d-chiro-inositol does not.
In this letter, the researchers discuss that both myoinositol and d-chiro-inositol are involved in insulin function. In fact, a normal metabolic process is the conversion of into d-chiro-inositol. In most tissues, supplementing with d-chiro-inositol helps to maintain levels of this compound; this is why insulin resistance improves when supplementing with this particular compound.
However, ovaries do not develop insulin resistance. In a nutshell, that means that supplementing with d-chiro-inositol does not help them. The only way they can maintain healthy d-chiro-inositol levels, is to improve conversion of myoinositol to d-chiro-inositol. Eventually, that enhanced conversion process depletes myoinositol levels…and there is not enough d-chiro-inositol available to maintain normal ovarian function. Ironically, the only way to achieve healthy d-chiro-inositol levels in ovaries…seems to be to supplement with myoinositol. D-chiro-inositol supplementation does not appear to have the same effect.
A special thanks to Drs. Gianfranco Carmagno, PhD, and Vittorio Unfer, MD, and their Florida colleague Scott Roseff, MD, for dedicating so much time to pursuing this issue, and for taking the time to help me put this blog post together.
Unfer V, Carlomagno G, Rizzon P, Raffone E, Roseff S. Myo-inositol rather than D-chiro-inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Eur Rev Med Pharmacol Sci 2011 Apr;15(4):452-7.
Papaleo E, Unfer V, Baillargeon JP, Fusi F, Occhi F, and DeSantis L. Myo-inositol rather than D-chiroinositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Fertil Steril 91:5; 1750-1754.
