The Hemp Connection:
metformin

One of the most difficult parts of working with PCOS is how hard it is to help cysters understand the widespread effects of their diagnosis. The tendency is to focus on the symptom causing the most distress in the moment, and to look for relief from that distress, even if it isn't helping the core issue.

So, for example, women who are focused on infertility, tend to be caught up in ways to have a child, and to not think about what it's going to take to keep that pregnancy, how to nurse the child, and how to stay healthy until that child grows up to produce grandchildren.

One very nice woman I worked with who had PCOS was only willing to work with me for one appointment. It seemed, as we worked through my assessment questions, that she was realizing that what was going to result from our time together, was that she would need to address her binge eating behavior in order to reduce her carbohydrate intake and manage her blood glucose. She politely told me that she had decided that she would be better off pursuing in vitro fertilization (IVF), and if she developed gestational diabetes, she would call me to schedule another appointment.

I felt very sad about this, because this woman was not young, and fertility was not something to take for granted. And it seemed to me that the bigger picture here was that if the binge eating was not addressed, she may never get to the point where she was pregnant and in need of my help! But I couldn't tell her that. My job is to accept my clients where they are at and maybe plant a seed or two that encourages seeing things in new and different ways.

Which brings me to my topic for today.

Serum C-reactive protein (CRP) is a blood marker of inflammation, a degenerative process that has been identified in women with PCOS.

In a study of 63 women receiving IVF, it was found that CRP increased in conjunction with this treatment. Even if the women were taking metformin.

There is such a mentality in our country that we are entitled to have access to medical treatments for whatever ails us, and that we should expect that these treatments are risk free. That simply isn't the case. IVF produces many beautiful babies, but that doesn't mean it isn't without its issues.

What isn't even considered here…is the effect of an active inflammatory process on the developing fetus who has no choice but to live in that environment for nine months?

Is it just me…or doesn't it seem that if you want a baby that badly, that this baby deserves the absolute best possible environment in which to live and thrive from day one in utero? Which means taking a serious inventory of all of the nutritional and lifestyle choices we make that interfere with that on behalf of the new life that we want to create? And making some sacrifices in that department?

Just a little something to think about.

Kjøtrød SB, Romundstad P, von Düring V, Sunde A, Carlsen SM. C-reactive protein levels are unaffected by metformin during pretreatment and an IVF cycle in women with polycystic ovary syndrome. Fertil Steril. 2008 Mar;89(3):635-41. Epub 2007 Jun 4.

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.

Dear Doctors,

I've been studying PCOS for about 10 years now. In that time, I've seen the standard dose of metformin double. As the dosage has slowly crept up, I have, more often, heard women complain that the side effects of metformin are so horrible that they stop taking it completely.

There are several ways you can look at this problem.

1. You can continue to prescribe the bigger dose of metformin because the lower dose isn't working, you have a limited amount of time to talk to your patient, and you want to feel like you did something. And you can continue to fail at adequately managing the process.

2. You can blame the problem on the patient. You can tell her she simply needs to hang in there for several months and be nauseous and miserable for 3 months while she waits for, with great hope, the side effects to subside.

I can't tell you what to do. But I can tell you, women who are not following their medication prescriptions are telling you something very important. That is, that increasing the dose of a medication they are not taking, is not the answer to the problem.

Have you considered what happens when your client does not eat in order to try to tolerate her medication without throwing up? She likely binge eats later in the day. There goes self-esteem, calorie control, and blood glucose management.

Have you considered what happens when she gives up on trying to follow your recommendations because she's too sick anymore to try? She stops coming in for checkups, providing ample opportunity for that inflammatory process to affect her brain, her nervous system, her ovaries, and her arteries, to name a few. She potentially shortens the duration, not to mention the quality of, her life.

Have you considered that when a woman takes a half a day off to sit in your office, waiting to see you, and patiently sits there even though you're running an hour behind, that the last thing she needs to hear from you is that she just needs to take her medicine, eat less, and exercise more? If that had worked, she would not have put herself out there like that in an effort to reach out for help that was going to work.

If you have not taken the time to refer your PCOS patient to a dietitian who can help normalize eating, reduce stress eating and binge eating, and identify other barriers to success that may help that patient succeed with you on a much lower dose of metformin, you may be missing the point. You may also be sending some of your business to someone who"gets it".

Please consider referring to one of our team. We're not trying to be argumentative by pointing this out in this blog post, just sending a friendly reminder that in our world of health care, the definition of insanity just might be prescribing larger and larger doses of a medication that didn't work the first time around…and expecting a different response.

We understand the health care system is set up to keep you from having a lot of time to talk to your patient about what's really going on, like how she's bingeing every time she has a negative pregnancy test, or looks in the mirror and sees new hair growth. We even understand that you're trained to look at numbers and not feelings. That's ok. That's why we started inCYST, so we could attend to the parts of the picture you cannot or do not wish to address. Please think of us as your support staff.

Thanks for hearing me out, and we look forward to helping guide you and your PCOS patients to treatment success.

Here's an interesting Cochrane Review hot off the presses, evaluating the effects of insulin-sensitizing agents on fertility.

A group of 31 studies that compared the effectiveness of these agents to a placebo were evaluated for what they said overall about the potential benefit for their use in women with PCOS who are trying to conceive. Of these, 27 were studies about metformin (likely because it is the most widely researched/used and more studies exist in the first place).

What the researchers concluded:

There is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene. However, metformin does improve ovulation and pregnancy rates. (Interpreted, this suggests that metformin does not help to prevent miscarriage.)

Metformin was also associated with a significantly higher incidence of gastrointestinal disturbance, but no serious adverse effects were reported. (I don't know about those of you reading this blog post who have tried metformin, but I would question the assertion that the gastrointestinal disturbance this medication causes is not a"serious adverse effect"!

IN THE WORDS OF THE AUTHORS:"In agreement with the previous review, metformin is still of benefit in improving clinical pregnancy and ovulation rates. However, there is no evidence that metformin improves live birth rates whether it is used alone or in combination with clomiphene, or when compared with clomiphene. Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited."

D-chiro-inositol was not even mentioned in the abstract, suggesting that the findings were not significant.

As with any information shared in this blog, only you and your provider can make the ultimate decision. I can tell you what went through my own mind--and heart--as I read this, was that this medication may create a lot of false hope and hurt for those who trust that it has more power than it actually does. I wouldn't wish a miscarriage on anyone.

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003053.

One of the main reasons women with PCOS are encouraged to take metformin is because it is widely believed that it can help to improve fertility and reduce the incidence of miscarriage.

A 2009 study challenges this belief. It comes from the Cochrane Collaboration, a not-for-profit organization that evaluates groupings of research independent of for-profit (read"drug company") funding. I like their studies because their sample sizes are large and their findings are evidence-based. It takes them a long time to adopt new ideas, but it is because they so heavily scrutinize the available information rather than jumping on any bandwagons.

In this study, authors searched several comprehensive medical databases for studies evaluating metformin used during in-vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI). They specifically looked at randomized, controlled trials containing a"no treatment" or placebo group to compare to a group receiving metformin. They evaluated several types of outcomes that metformin may have an opportunity to influence: live birth rate, pregnancy rate, miscarriage rate, incidence of ovarian hyperstimulation syndrome, patient-reported side effects, and several hormone levels (estradiol, androgen, fasting insulin and glucose).

This exhaustive review, under rigorous statistical analysis…

"found no evidence that metformin treatment before or during assisted reproductive technique (ART) cycles improved live birth or clinical pregnancy rates."

The one benefit of metformin appeared to be a reduced risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles.

I'm not a physician and therefore, I am not able to prescribe metformin. And I am ABSOLUTELY NOT ENCOURAGING ANYONE READING THIS TO DISCONTINUE USING MEDICATION THAT THEY HAVE BEEN PRESCRIBED. I do, however, see a tendency to hand this medication out without evaluating whether or not it is appropriate. It's important to discuss such issues with your physician and to be sure they are aware of the research supporting (or not supporting) their recommendation.

Here is the reference for anyone who wishes to share it with their personal provider.

Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006105.

If you're trying to conceive, you likely know that it's important to be getting enough folate in your diet in order to prevent neural tube defects.

Even if you're NOT trying to get pregnant, folate is important for women with PCOS.

Homocysteine is a compound found in the blood, which, in elevated amounts, indicates increased cardiovascular risk and inflammation. It tends to be elevated in women with PCOS.

Fifty patients with PCOS, were divided into two groups receiving two different treatments. The first group received 1700 mg of metformin per day, along with 400 mug folate. The second group received metformin without folate.

Homocysteine levels were significantly increased in both groups, but to a lesser degree when they also supplemented with folate.

I was heartened to see this study, since so much research on PCOS focuses on the part of PCOS we can SEE (i.e., weight), and seems to ignore that biochemistry can be altered regardless of weight. In fact, another study I ran across while looking for a blog topic this morning, focused on the fact that metformin improved biochemistry even without diet or exercise modifications. Yes, you can make a study say anything you wish if you correctly design it, but it is not fair to women with PCOS to do that and falsely lead them to believe that medication is the only answer. And, you've got to understand that even if your weight is normal with PCOS, you still have to pay attention to what is happening metabolically.

You've got to care about what's under the hood, not just how pretty the paint job is.

Palomba S, Falbo A, Giallauria F, Russo T, Tolino A, Zullo F, Colao A, Orio F. Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome. Diabetes Care. 2009 Nov 23. [Epub ahead of print]

Oppelt PG, Mueller A, Janetsch K, Kronawitter D, Reissmann C, Dittrich R, Beckmann MW, Cupisti S. The Effect of Metformin Treatment for 2 Years without Caloric Restriction on Endocrine and Metabolic Parameters in Women with Polycystic Ovary Syndrome. Exp Clin Endocrinol Diabetes. 2009 Dec 8. [Epub ahead of print]

Many of you already know you're insulin resistant, and are receiving medical attention for that. Here are the basic nutrition and lifestyle actions you can take to further help minimize the impact of that issue on your pregnancy success.

1. Move! I'm a distance runner. As much as I love running, however, I have a lot of other activities I love to do. Having a variety of activities to rotate through prevents boredom, and it involves different muscle groups in exercise. I learned to vary after a ski injury that sidelined my running for a year. You don't want that to happen, to become so dependent on one activity that you set yourself up to lose activity completely. These days I run, but I also walk, rollerblade, garden, hike, golf, swim and do yoga. (Ivonne recently talked me into trying a tango class. I think dancing is my new favorite!) Any little thing you can do that tells your body it needs to get better at moving glucose into muscle cells…is what you need to do.

2. Commit yourself to better sleeping habits. Poor sleep, either few hours or bad quality, interferes with insulin function. The clients I work with who prioritize better sleep are the ones who notice feeling better the soonest. It can be a hard one if you love the late night shows, easily get lost in the Internet, or don't set good boundaries with others. But good sleep is one of the most important things you can give yourself. If you search"sleep" in this blog there is a lot of information about how to achieve this.

3. Watch the caffeine. This goes hand in hand with #2. Caffeine in coffee, tea (it's in green tea, too, so be aware), chocolate…it all challenges healthy sleep. It's something you are best to live without during pregnancy anyway, so why not get used to decaffeinated life now if that's where you want to be?

4. Be aware of glycemic index. Foods with a low glycemic index are foods that don't challenge your insulin function as much as other foods. It's not that high glycemic foods are"bad", it's just that they should not be eaten as often. In order to make a MEAL lower-glycemic, be sure you have a good balance of carbs, fats, and proteins. People eating on the run tend to challenge glycemic function either by eating large quantities of fast food or nibbling all day long on carbs without making time for protein.

5. Pay attention to your fats. One reason I push the fish oil so much is that it really helps to improve insulin function."S" and"C" oils--safflower, sunflower, soybean, corn, cottonseed…tend to worsen glycemic function. They're found in processed foods, baked goods, and salad dressings. One reason I love teaching my classes at Whole Foods is that their entire deli uses only olive and canola (the only"C" exception) and you can literally choose what you want without ingredient anxiety.

6. Add a little cinnamon to your low-glycemic oatmeal. It has been found to improve insulin function…and it's tasty!

A word about metformin. Some women complain about digestive disturbances with this medication. A physician once shared that if you eat a lot of carbs (particularly sweets) while on the medication, it can cause diarrhea. So be forewarned, taking the medication is not a license to eat what you want, assuming metformin is going to do all the work. Metformin is most effective if you use it in conjunction with the guidelines in this post.

Next progesterone post we'll talk about poor nutrition. It is very important!

Two days ago a story made its way around the Internet, promoting the idea that 8 year old girls experiencing early puberty might benefit from metformin administration to delay the progression of PCOS. The argument was that these girls needed their fertility"protected". What the article neglected to acknowledge was that while metformin does appear to improve the rate of conception, it does not reduce the rate of miscarriage. I've written about this in a previous post.

I wrote an article with more detail about my feelings about this issue for my writing assignment as the Beverly Hills Women's Health writer for the Los Angeles Examiner. If you didn't know I also write over there, you can find all of my posts through the link I provided above.

With all due respect to the researchers so very excited to report this finding, I'm not impressed. Our little girls need to be treated as if they are more than just another profitable target market for a drug that has lost its patent and is looking for a new clinical indication/patent opportunity/way to keep sales going.

I mean, you'd think after spending 5 1/2 hours on this blog in the past year the researchers at Bristol Myers Squibb would've come up with something far more creative and helpful. So, BMS researchers, I would have told you this if you'd flat out asked, but since I don't have the money to build a research lab with anywhere near the capability of yours and just want someone to pursue the idea on behalf of helping 1 out of 10 women achieve better quality of life…I'll tell you what I would have told you had you been willing to admit you were even reading my stuff when I contacted you about it. Here is what I would do to get the patent and keep the revenue coming in so your reproductive scientists can keep their jobs.

Since the American public has now been conditioned to believe if it's not a prescription medication it can't possibly work, I propose you figure out a way to manufacture a metformin/fish oil combo pill. That way you get your money and the women who need the fish oil…actually take it.

There. You heard it here first. If you actually do something with this idea, sure would be nice to get some credit for it.

Oh and BMS, thanks for all the time on the blog. You've really helped our advertising rates, which helps us to research and advocate for non-medicinal answers to hormone problems. We'll never put you out of business…but we just might be able to give you a little bit of a run for your money.: )

Metformin, for many women, has been a miracle drug. It is the aspect of treatment that allowed them to finally conceive. Metformin is so popular it is almost expected as part of fertility treatment. So popular, in fact, that one client I referred to a reproductive practice here in Phoenix, before even being seen by her physician, was told by his receptionist…that she would be receiving a prescription for metformin on her visit.

That is not to say metformin is perfect, or that it is for everyone. A new article by a prominent PCOS researcher suggests that a"not so fast" approach to metformin use might be more appropriate. Dr. Dunaif at Northwestern University in Chicago writes that in her analysis of the data, metformin is no more effective than clomid in increasing pregnancy rates. She also writes that there is no evidence to support the use of metformin to prevent miscarriage or gestational diabetes.

She doesn't stop there. Mentioning the recent findings about increased cardiovascular risk with Avandia (rosiglitazone) and Actos (piaglitazone), she suggests that their use may not provide long-term health benefits.

Of course, I'm biased, being a dietitian and seeing our program work as well as it has, and I believe just a few simple dietary tweaks and diligent, consistent use of them…is incredibly important in the PCOS big picture. Whether or not you are pursuing conception.

If you're a woman considering or just beginning treatment for PCOS for infertility…or just PCOS in general, it might behoove you to bring this reference to your physician for review. These medications may still be appropriate in your individual case, but it is important to understand that no treatment is perfect or without risk. An informed decision based on input from both you and your physician will be sure that the best possible course of action was the one you decided on.

Dunaif A; Medscape. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome--a reappraisal. Nat Clin Pract Endocrinol Metab. 2008 May;4(5):272-83.