PCOS and Endometrial Cancer Risk: The Dilemma of Weight Loss and Weight Cycling

September is Polycystic Ovarian Syndrome (PCOS) Awareness Month. As part of our ongoing series on PCOS, today we are going to talk about endometrial cancer.

PCOS is a hormonal disorder usually characterized by very strong insulin resistance. This insulin resistance causes many problems in the body, including irregular menstrual cycles, strong susceptibility towards weight gain, unwanted hair growth on the face and body (hirsutism), hair loss on the head (alopecia), cystic acne, body tags, a strong tendency towards diabetes, infertility, and many other symptoms.

Among other risks, PCOS is associated with a high risk for endometrial cancer (cancer in the lining of the uterus). Because PCOS tends to cause an irregular menstrual cycle, a woman's uterine lining may not get sloughed off each month. Some women with PCOS have extra long cycles (35 or more days), while others go months or even years without a menstrual cycle. This causes the lining of the uterus (the endometrium) to build up excessively; in time, atypical cells may develop. This is called endometrial hyperplasia, or overgrowth of the uterine lining. This hyperplasia can eventually turn into endometrial cancer.

This is why it is so important that women with PCOS get treatment. They need to have regular periods so that this overgrowth does not occur. There are many options for this, including progesterone treatments; birth control pills; insulin sensitizers like metformin, TZDs, or inositols; and androgen blockers.

However, most doctors' first recommendation is weight loss.

The Weight Loss Dilemma

The majority of women with PCOS have an "overweight" or "obese" BMI. Because of the very significant insulin resistance with PCOS, these women have a strong tendency towards weight gain over time.

Women of size with PCOS face a difficult dilemma in how they approach their weight. Care providers push them to lose weight, often telling them weight loss can "cure" PCOS or get rid of most of their symptoms. Weight loss is considered by many to be the first line of therapy for PCOS.

It's true that some short-term research does seem to suggest benefits from weight loss for women with PCOS, especially in shocking the system into ovulation. But this research is almost always based on fairly short follow-ups because most weight comes back within a few years after a significant weight loss. The very loss that leads to short-term benefits may backfire later into weight gain and worsened insulin resistance.

The critical question is whether women are better off in the long term trying to lose weight, or whether the high potential for weight cycling overcomes the possible benefit of weight loss. In particular, we need to know how weight loss and weight cycling affects the chances of getting endometrial cancer.

Here are two studies that demonstrate this weight loss dilemma. One study (Luo 2017) looked at intentional weight loss in "obese" women and how that affected their risk for endometrial cancer. (The study did not look specifically at women with PCOS but weight and PCOS are so tightly tied together that weight is a pretty fair proxy for presumed PCOS when discussing endometrial cancer.)

In the study, those women who intentionally lost weight lowered their chances for endometrial cancer. The effect was particularly strong in obese women who intentionally lost weight. So if  you can lose weight and keep it off, it looks like there might be some benefit.

However, remember that the majority of women who lose weight gain it back, and often end up at a higher weight than they started. In the Luo study, women who gained weight were at increased risk for endometrial cancer. So you take a calculated risk; if you lose weight and keep it off, you might significantly reduce your risk for endometrial cancer. However, if you regain that weight and end up heavier than you started, you probably have increased your risk for endometrial cancer.

Weight fluctuations up and down the scale may also have its own independent effect. The second study (Welti 2017) found that weight cycling 4-6 times was associated with an increase in risk for endometrial cancer. Many women of size cycle far more times than that; how increased is their risk?

Summary

High BMI women with PCOS face a difficult dilemma when deciding what to do to lessen their risk for endometrial cancer.

Intentional weight loss ─ if they can keep it off ─ might lower their risk for endometrial cancer. On the other hand, if the weight loss attempt leads to weight cycling and/or overall weight gain ─ as it does for so many ─ then that weight loss attempt probably actually increases their risk. 

In other words, high BMI women with PCOS are faced with a game of Russian Roulette when it comes to weight loss and endometrial cancer.  

There are no easy answers here. Each individual woman gets to make her own choices about weight loss as a treatment for PCOS, taking into account her own personal weight history and habits.

Although most doctors don't acknowledge it, it is a perfectly reasonable choice not to pursue weight loss as a treatment for PCOS. That doesn't mean that lifestyle is irrelevant. One can choose to emphasize sensible nutrition and exercise as a treatment for PCOS without measuring the worth of those treatments by weight loss. A Health At Every Size® approach can work for PCOS.

Care providers need to recognize that their constant pressure on patients to lose weight may actually backfire and create more risk rather than less. They need to recognize the right of the patient to choose whether or not to pursue weight loss, that it is possible to emphasize healthy lifestyle without tying that to weight loss, and to acknowledge the need for multiple tools beyond weight loss to address the unique needs of their PCOS patients.



References

Cancer Epidemiol Biomarkers Prev. 2017 May;26(5):779-786. doi: 10.1158/1055-9965.EPI-16-0611. Epub 2017 Jan 9. Weight Fluctuation and Cancer Risk in Postmenopausal Women: The Women's Health Initiative. Welti LM, Beavers DP, Caan BJ, Sangi-Haghpeykar H, Vitolins MZ, Beavers KM. PMID: 28069684

BACKGROUND: Weight cycling, defined by an intentional weight loss and subsequent regain, commonly occurs in overweight and obese women and is associated with some negative health outcomes. We examined the role of various weight-change patterns during early to mid-adulthood and associated risk of highly prevalent, obesity-related cancers (breast, endometrial, and colorectal) in postmenopausal women. METHODS: A total of 80,943 postmenopausal women (age, 63.4 ± 7.4 years) in the Women's Health Initiative Observational Study were categorized by self-reported weight change (weight stable; weight gain; lost weight; weight cycled [1-3, 4-6, 7-10, >10 times]) during early to mid-adulthood (18-50 years). Three site-specific associations were investigated using Cox proportional hazard models [age, race/ethnicity, income, education, smoking, alcohol, physical activity, hormone therapy, diet, and body mass index (BMI)]. RESULTS: A total of 7,464 (breast = 5,564; endometrial = 788; and colorectal = 1,290) incident cancer cases were identified between September 1994 and August 2014. Compared with weight stability, weight gain was significantly associated with risk of breast cancer [hazard ratio (HR), 1.11; 1.03-1.20] after adjustment for BMI. Similarly, weight cycling was significantly associated with risk of endometrial cancer (HR = 1.23; 1.01-1.49). Weight cycling "4 to 6 times" was most consistently associated with cancer risk, showing a 38% increased risk for endometrial cancer [95% confidence interval (CI), 1.08-1.76] compared with weight stable women.  CONCLUSIONS: Weight gain and weight cycling were positively associated with risk of breast and endometrial cancer, respectively. IMPACT: These data suggest weight cycling and weight gain increase risk of prevalent cancers in postmenopausal women. Adopting ideal body-weight maintenance practices before and after weight loss should be encouraged to reduce risk of incident breast and endometrial cancers. 

J Clin Oncol. 2017 Apr 10;35(11):1189-1193. doi: 10.1200/JCO.2016.70.5822. Epub 2017 Feb 6. Intentional Weight Loss and Endometrial Cancer Risk. Luo J, Chlebowski RT, Hendryx M, Rohan T, Wactawski-Wende J, Thomson CA, Felix AS, Chen C, Barrington W, Coday M, Stefanick M, LeBlanc E, Margolis KL. PMID: 28165909

PURPOSE: Although obesity is an established endometrial cancer risk factor, information about the influence of weight loss on endometrial cancer risk in postmenopausal women is limited. Therefore, we evaluated associations among weight change by intentionality with endometrial cancer in the Women's Health Initiative (WHI) observational study. PATIENTS AND METHODS: Postmenopausal women (N = 36,794) ages 50 to 79 years at WHI enrollment had their body weights measured and body mass indices calculated at baseline and at year 3. Weight change during that period was categorized as follows: stable (change within ± 5%), loss (change ≥ 5%), and gain (change ≥ 5%). Weight loss intentionality was assessed via self-report at year 3; change was characterized as intentional or unintentional. During the subsequent 11.4 years (mean) of follow-up, 566 incident endometrial cancer occurrences were confirmed by medical record review. Multivariable Cox proportional hazards regression models were used to evaluate relationships (hazard ratios [HRs] and 95% CIs) between weight change and endometrial cancer incidence. RESULTS: In multivariable analyses, compared with women who had stable weight (± 5%), women with weight loss had a significantly lower endometrial cancer risk (HR, 0.71; 95% CI, 0.54 to 0.95). The association was strongest among obese women with intentional weight loss (HR, 0.44; 95% CI, 0.25 to 0.78). Weight gain (≥ 10 pounds) was associated with a higher endometrial cancer risk than was stable weight, especially among women who had never used hormones. CONCLUSION: Intentional weight loss in postmenopausal women is associated with a lower endometrial cancer risk, especially among women with obesity. These findings should motivate programs for weight loss in obese postmenopausal women.

Mammograms: Getting Called Back for Additional Testing

At some point in a woman's life, she should start having regular mammograms. When she should do this is a matter of some controversy, but sooner or later, most women will have regular mammograms every year or two.

But what happens when you get a call back after your mammogram telling you that you need further imaging? What can you expect, and how likely is it that you will be diagnosed with breast cancer? How can you handle the anxiety while waiting for further results? Where can you get further support and information?

Earlier this year, this happened to me. I had my regular mammogram and got a call back telling me they had found two suspicious areas and I needed further testing. It was very unsettling. Even though intellectually you understand it's not an actual diagnosis of cancer, it feels like a sentence of doom. Your anxiety levels go through the roof.

Statistically, only a few women who get called back for additional testing after an "abnormal" mammogram result actually have cancer. Most are just fine, but many of those called back have fears about what additional testing entails.

Let's talk about what diagnostic mammograms are, what additional testing may be used, what to expect during the appointment, how to handle the waiting, and the latest screening guidelines. Then I'll share with you my diagnostic testing experience.

First Step: Don't Panic

Although it's deeply unnerving to get "the call" telling you to get more testing, the first step is to stay calm. Don't panic and start mentally going to worst-case scenarios. As one resource notes (my emphasis):

If doctors find something suspicious, they’ll call you back – usually within just 5 days – to take new pictures or get other tests. Getting that call can be scary, but a suspicious finding does not mean you have cancer. In fact, less than 10% of women called back for more tests are found to have breast cancer.

Although your mind will tend to automatically assume the worst, take a deep breath. Remind yourself that even when extra testing is required, you have a 90%+ chance of not having cancer. 

It's normal to cycle in and out of various "what-if" scenarios in the time before your diagnostic test, but the important thing is to focus as much as possible on the other business of your life. There's no need to panic when you don't know if there's something to actually panic over.

It's understandable to do some worrying, but don't let it consume you. Hard as it is, try not to focus on the uncertainty; let the future take care of itself. Focus instead on the everyday tasks of your life.

Screening vs. Diagnostic Mammograms

An important aid in avoiding panic is to remember that there is a major difference between a screening test and a diagnostic test.

A diagnostic test tells you for sure whether or not you have a certain condition. To get that kind of certainty, diagnostic tests are very involved, expensive, and time-consuming. Because of the time and expense, it simply does not make sense to order them for everyone.

Therefore, a simpler and less-expensive test is used on everyone ─ a screening test. Screening tests are designed to test a wide variety of asymptomatic individuals to look for problems that might need a closer look. These tests are slanted towards what's called "sensitivity" ─ a high chance of finding any existing problems ─ so as not to miss any potential disease. The trade-off is that many people (including many who don't have the disease) will require additional diagnostic testing, and that testing process can be unnerving.

Diagnostic testing looks specifically for disease or a high suspicion of disease. It is geared towards "specificity" ─ accuracy in ruling out disease. If something pops up on the screening test that is unusual or statistically outside of the norm, that person is called back in for further testing. [Of course, anyone with a distinct symptom of a disease goes straight to diagnostic testing.]

This arrangement of starting with a screening test and only going to a diagnostic test for a few people is a smart way to save time and money in an era of limited medical resources. But because most of the public doesn't understand the difference between a screening and diagnostic tests, many people automatically assume that a call-back means they likely have cancer. It doesn't.

Handling the Anxiety of Waiting

Even for people who understand screening vs. diagnostic testing, call-backs can still feel quite alarming. Human nature makes us emotionally jump to worst-case scenarios. That's why you have to keep reminding yourself not to panic. The best thing to do is simply to focus as much of your attention as possible on the tasks of everyday living and not dwell on the fear. Find ways to redirect your anxiety.

Of course, just telling yourself not to worry may be counterproductive; it may be easier instead to let yourself worry but to limit the amount of time spent on it. If you find yourself being taken over with worry, try writing down your worries, putting them into an envelope (physical or mental), and taking them out to indulge the worry only at specified times. When you do indulge the worries, let yourself do it in depth. Think of every worst-case scenario you can, weep and wail, write your good-bye letters, plan your funeral, etc. But then at the end of the specified time, stop and put those fears away until next time. By indulging your fears periodically, you lessen their emotional dominance the rest of the time. It's the rigidly suppressed fear that tends to multiply. Let yourself express your worries but it may help to put some limits on that expression.

Another thing that can help is to journal about why you are so worried. Do some stream-of-consciousness writing to explore your fears. Often the answers seem simple when you start, but the writing process helps uncover more subtle reasons that can give you insight. Journaling won't make the worry go away but understanding the true source of the anxiety may help diffuse its power so it is less emotionally overwhelming.

It's only natural to worry, but try to keep the worry in perspective, try to understand it, and find ways to deal with it that keep it from taking over your life. Soon you will have the answers that you need and can either relax or start developing a positive plan of action. If you need additional support, don't forget that many cancer organizations have 24 hour free phone lines for information and support.

Follow-Up Testing: What to Expect

When you return for follow-up testing, what can you expect?

Basically, plan to devote about half a day to the appointment, give or take. Remember not to wear any powder or lotions to the appointment. Bring a book to help occupy yourself while waiting. The appointment will take several hours and quite a bit of this will be waiting.

You will start by having a longer and more in-depth mammogram. More images will be taken, using more angles, so they can really focus in on the area in question. Although longer than a normal mammogram, this process is usually less than an hour. Don't be afraid to ask questions about the process; technicians are limited in what they can say (and obviously can't give a diagnosis), but often can offer insight into what is being looked at and why.

Next comes the ultrasound. Although not mandatory, most mammography centers also do an ultrasound of the breast during follow-up testing. This process is also around an hour and will examine closely any areas of concern on the breast as well as lymph nodes underneath the arm.

Sometimes an MRI is also done. This is not considered standard-of-care and may not be covered by insurance so it is not part of most routine follow-up testing at this time.

You will be asked to wait on site while a radiologist reviews the results. This can take an hour or two more, so be prepared to wait, but you should get the results that day. The results are usually one of the following:

• The suspicious area turned out to be nothing to worry about and you can return to your regular mammogram schedule
• The area is probably nothing to worry about, but you should have your next mammogram sooner than normal – usually in 4 to 6 months – to make sure it doesn’t change over time
• Cancer was not ruled out and a biopsy is needed to tell for sure

Remember, even if a biopsy is recommended, chances are you still don't have cancer. Often biopsy results are benign. This is hard to remember when you are told you need a biopsy but it's important to keep reminding yourself of this fact.

There are different types of biopsies. Most are done with a needle but some need a small incision. Biopsy results have to be sent away for analysis, which can take anywhere from a few days to a week or two. The wait is difficult. Find some emotional support but don't forget to keep your focus on normalcy during daily life.

If your biopsy results are benign, ask the doctor whether any follow-up is needed and when your next mammogram should be. Get the results and recommendations in writing for future reference.

If your biopsy results show cancer, then it is time to consult a breast specialist. People often report difficulty in recalling the information given at these consultations, so take a knowledgeable and supportive friend or relative with you to the appointment. Ask to record the appointment so you can refer back to it later. Take notes (or have your support person take notes) and ask for correct spellings of any words you don't know so you can research it further. You can find a list of questions to ask here.

Don't be afraid to ask for a second opinion about your options. You can you get completely different advice from another care provider so it really is worthwhile to get a second (or even third) opinion. You can also call the American Cancer Society for information and support at 1-800-227-2345. Many additional online resources for support also exist; don't be afraid to reach out to them. Many women find it helpful to be paired with someone who has been through breast cancer themselves and is trained in offering support to newly-diagnosed patients.

Reminder of Screening Guidelines

With all the anxiety that a positive screening test can generate, it's no surprise that many women opt out of yearly mammograms. They simply don't want to deal with the anxiety it produces. Others are concerned about over-treatment for non-aggressive cancers, false-positives, and the cumulative effect of the radiation from many mammograms.

Yet we know that statistically, mammograms save lives, especially as women age. So when should women start getting mammograms?

Unfortunately, even the experts can't agree on how often women should have mammograms. Some organizations suggest regular screening start at 40, some suggest 45, some suggest waiting till 50.

Once you do start regular screening, some suggest that every 2 years is enough, while others strongly push yearly screening. It's hard to know what to do.

From cancer.net, Dr. Connie Lehmen gives a summary of the controversy over screening guidelines:

At an absolute minimum, women should begin screening mammography no later than age 50 and get a mammogram every 1 to 2 years until at least age 74. All medical organizations agree with these minimum recommendations for screening...The areas of disagreement, and reasons for differences in the recommendations from different groups, center around the age to begin screening (40, 45, or 50) and the interval of screening (every year or every 2 years). These variations are due to different groups of people who interpret clinical trial data differently.

Bottom line, when you start and how often you screen really depends on your risk factors. Recommendations will vary from woman to woman.

How does "obesity" figure into recommendations? That's harder because it's not always clear. We do know that high-BMI women are less likely to get regular mammograms or follow-ups after abnormal mammograms, which may partially explain why we tend to be diagnosed at more advanced stages of cancer. Yet there is only limited research and recommendations specifically on the trade-off of benefits and risks of screening in obese women at different ages.

As women of size, it is clear that we are at increased risk for post-menopausal cancer ─ but authorities often neglect to mention that we are generally at decreased risk for pre-menopausal breast cancer (except triple negative breast cancer). But when does that initially decreased risk cross over to increased risk? Is it a hard and fast conversion right at menopause, or a gradual increase of risk as you approach menopause? I don't think anyone really knows for sure.

That means it's particularly hard to know what mammogram schedule a woman of size should follow during that in-between time in the 40s when women are peri-menopausal.

The short version is that mammogram decisions then really seem to boil down to your other risk factors (especially family history, breast density, and blood sugar status) and becomes a personal choice you decide in consultation with your healthcare provider.

Personally, not having access to much family medical history and having had a lot of fibrocystic lumps, I had a number of mammograms in my 20s and 30s. In retrospect, I think we did too much. After a lot of research, I opted out of yearly mammograms in my 40s, but did have a couple to establish a baseline. Now that I am past 50 I think it sensible to get regular mammograms (about every year or two) because high-BMI women really are at increased risk for post-menopausal breast cancer.

I still don't love mammograms but have found a center where the care is more sensitive and gentle than I've experienced in the past. It's still anxiety-producing but regular mammograms seem a sensible precaution at my age.

But that's just my choice, based on my own circumstances. Yours may be completely different.

My Experience with Call-Back Testing

Needing a follow-up diagnostic mammogram really threw me. It just goes to show that having intellectual knowledge about a subject doesn't always have a lot to do with how you react to unsettling news.

Even though intellectually I knew that I probably didn't have cancer, I'm very good at "catastrophizing." It took quite a bit of effort to reel back my tendency to immediately go to the worst-case scenarios. Reading up about screening vs. diagnostic testing helped me scale back some of my fears. Education can be a powerful counter to fear.

When the anxiety elevated despite my reading, I made an effort to explore it. Obviously I was deeply concerned about leaving my children motherless, especially because I still have a young one at home. But upon further reflection, I realized that my fear was made worse by the fact that my husband had just been laid off. My big concern was that if I did have breast cancer, we'd run out of health insurance and I'd bankrupt the family and cause us to lose our house. We also have two kids in college, another in high school heading off to college soon, and the young one in private school; I was worried that my medical bills would derail their educations.

For me, handling the anxiety proactively while waiting needed multiple approaches. Research helped reassure my rational mind that I had a 90% chance of not having cancer. Emotionally, taking the time to explore why the fear was persistent helped me understand and diffuse a lot of its power. I was then better able to just focus on the everyday tasks instead of spending my days in constant fear.

In the end, I didn't have cancer, just some "asymmetrical lymph nodes" that the radiologist initially flagged but ultimately considered normal. I don't even have to go back for more frequent testing, just the normal screening.

Whew, what a relief! But oh, how difficult that waiting period is. Especially coming during a job layoff and time of great stress at my own work.

Sadly, there are no magical answers to getting through it; for me doing research and exploring my fears was vital in staying sane. In the end, though, it really boiled down to gritting my teeth and focusing on everyday tasks so I didn't go crazy.

It's totally normal to be anxious while waiting. But if that anxiety gets overwhelming, consider what is effective for you to deal with the worry. Consider developing some additional tools to help.

Has anyone else gone through a similar experience? What helped you get through the waiting period?


Resources

• http://www.cancer.org/cancer/news/features/if-youre-called-back-after-a-mammogram
• http://www.breastcancer.org/symptoms/testing 
• http://ww5.komen.org/BreastCancer/SupportGroups.html 
• http://www.webmd.com/breast-cancer/guide/breast-cancer-support-resources
• https://www2.breastcare.org/national-breast-cancer-resources/

PCOS Treatment: Metformin

graphic from www.1-in-10.org  

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. Today, let's discuss the use of metformin in the treatment of PCOS.

So far we've talked about the definition and symptoms of PCOS, how it presents, its testing and diagnosis, and its possible causes.

Now we are discussing common treatment protocols for the metabolic issues of PCOS, and the pros and cons of each treatment option. (Fertility treatment will be covered in a different set of posts.)

Today, we discuss metformin (Glucophage).

Disclaimer: While the following information is based on my best understanding of the research, I am not a medical health-care professional and no medical advice should be inferred. Always do your own research and consult your healthcare provider.  

Trigger Warning: Remember that the purpose of these posts is to provide a basic introduction to PCOS with a size acceptance approach that is rare on PCOS websites. However, there will be some occasional mention of weight loss in some posts because this is part of the traditional approach to treating PCOS and fair coverage demands exploring the pros and cons of all treatments. This approach has been approved by the fatosphere monitors. In this post, there is a brief mention of the weight loss properties associated with metformin in some people.  

Insulin-Sensitizing Agent Overview

Because insulin resistance (IR) is a strong part of the PCOS profile, because IR may be an integral part of its mechanism, and because decompensation of glucose tolerance due to IR is a big part of the long-term health impact of PCOS, treatment with insulin-sensitizing agents is considered a vitally important part of PCOS treatment by most clinicians.

Insulin-sensitizing agents help the body to use its own insulin more effectively, so less insulin has to be produced. It can improve blood sugar because the insulin already present is used better, and the glucose uptake in peripheral tissues is improved. It helps improve other symptoms because there is less excess insulin running amok in your body, creating side effects.

Unlike metformin, sulfonylureas (another common type of blood sugar medication for diabetics) work by forcing the body to produce more insulin. This can improve blood sugar in the short run, but in the long run it often exhausts the ability of the pancreas to produce insulin at all, and of course, more insulin in the body creates more negative side effects.

So insulin-sensitizing medications like metformin were a big step forward in treatment for people with blood sugar and insulin-resistance issues. They didn't add more insulin into the body, they just helped the body use its own insulin better. In the long run, this preserves pancreatic function longer, lessens symptoms, and probably delays (or perhaps even prevents) the development of diabetes.

For these reasons, insulin-sensitizing agents are an extremely important part of PCOS care.

Types of Insulin-Sensitizing Agents 

There are two main types of insulin-sensitizing agents, the group of drugs known as biguanides and the thiazolidinediones. From one website on insulin resistance:

• Biguanides. Biguanides are drugs that improve the body's sensitivity to insulin by lowering the absorption of glucose in the small intestine, decreasing the liver's production of glucose, and increasing the uptake of glucose in muscle and fatty tissues...
• Thiazolidinediones. These drugs stimulate glucose uptake in the muscles and fatty tissues by activating specific receptors in the cell nucleus. They also lower blood insulin levels in patients with hyperinsulinemia. The thiazolidinediones include pioglitazone (Actos) and rosiglitazone (Avandia).

Of the biguanides, metformin hydrochloride (brand name: Glucophage) is the only drug still left in use. Although its sister drugs went out of use due to safety concerns, metformin has a much better safety profile. It's been in use for a very long time and has a more complete safety profile than any other insulin-resistance drug on the market. It was approved in the USA by the FDA in the mid-1990s but was in use in Europe for many years before that.

Thiazolidinediones (also known as glitazones or TZDs) were all the rage for a while because they seemed even more effective than metformin against IR and PCOS symptoms. However, safety concerns arose over the years and two TZDs (Rezulin and Avandia) were pulled from the market or restricted, while a third (Actos) remains available but under fire.

There are other insulin-sensitizing drugs that are not in common usage yet. The inositols (related to B vitamins, but not technically a vitamin), including myo-inositol and d-chiro-inositol, also show some promise in improving insulin sensitivity in women with PCOS.

In addition, there are new medications available that help improve both glucose and insulin levels for those in whom diabetes has already been diagnosed.

Today, however, we discuss only metformin. TZDs, inositols, and other medications will be discussed in separate posts.

Metformin: General Information

Metformin is the most common drug used to treat glucose/insulin resistance (IR) issues.

It is now considered the first-line choice for treatment of diabetes, and is often used with PCOS as well, although there is less research into its use with PCOS.

Metformin works in the following ways:

Metformin improves hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis)...The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. 

Metformin activates AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells... 

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by phosphorylating GLUT-4 enhancer factor), increases fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. 

By decreasing glucose production in the liver, increasing insulin sensitivity, and improving the uptake of glucose in the GI tract and all over the body, metformin lowers blood sugar, decreases insulin resistance, and may prevent or delay the progression of insulin resistance to diabetes.

This is very important for folks with IR/diabetes, and probably also for folks with PCOS.

History 

Originally derived from the herb, Goat's Rue (a.k.a. French Lilac), metformin has been around for a long time:

First synthesized and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to insulin and other antidiabetic drugs. Interest in metformin was rekindled in the late 1940s after several reports that it could reduce blood sugar levels in people, and in 1957, French physician Jean Sterne published the first clinical trial of metformin as a treatment for diabetes. It was introduced to the United Kingdom in 1958, Canada in 1972, and the United States in 1995.

This long history of use gives it a tremendous advantage over other more recent anti-diabetes drugs, which don't have as long a track record of safety.

Dosage

The most beneficial dosage for metformin use is controversial. Many clinicians use a low dose in normoglycemic women with PCOS, wanting to reserve a higher dose for later, should diabetes develop. However, therapeutic benefit in PCOS is usually not seen until at least 1500 mg.

Many PCOS specialists feel that these low doses (500-1000 mg) are not optimal, and that women with PCOS only start to see benefit when dosages reach 1500 mg or more. Some women report only seeing a benefit at doses of 2000 mg or more. It can also take at least 6 months on the drug to see a significant benefit, so it's important not to give up on it too soon.

From the INCIID FAQ on PCOS:

The maximum recommended dose of metformin is 2550 mg per day (3 x 850 mg pills). The usual dose in diabetics is 1000 mg twice daily. Studies with metformin for patients with PCOS usually use 500 mg three times a day or 850 mg twice daily.

The optimal dose for women with PCOS will depend on her degree of insulin resistance, but doses of at least 1500 mg seem to be the standard among providers with PCOS expertise. More severe cases usually need higher doses, and may also need the addition of secondary drugs.

It can be difficult to get some providers to prescribe metformin to women with PCOS who are not diabetic or pre-diabetic. They may view it only as a blood sugar drug, instead of recognizing that insulin resistance is at the heart of many of the problems of PCOS and may benefit from treatment even when blood sugar is still normal.

Even when doctors do prescribe metformin, many will only prescribe it at low dosages of 500-1000 mg instead of at the higher dosages that seem to be more effective for women with PCOS. Again, this hearkens back to viewing it as a blood sugar drug instead of a treatment for the severe insulin resistance that is a big part of the metabolic issues of many women with PCOS.

Metformin for Diabetics

Outside of PCOS, metformin has clearly been shown to be beneficial in diabetics.

It decreases blood sugar readings, whether fasting, post-meals or average blood sugars over time (as reflected by the HbA1c or "glycosylated hemoglobin" test). This is important because chronically high blood sugar damages the body and is thought to cause many of the long-term health risks associated with diabetes (blindness, kidney failure, blood vessel disease, heart disease, etc.). Decreasing blood sugar should help to prevent or delay these.

Metformin has also been shown to modestly lower total cholesterol and LDL cholesterol without adversely affecting other lipid levels. Unlike many other diabetes medications, metformin does not cause an increase in low blood sugar incidents (hypoglycemia), which is another important benefit.

Metformin does not cause weight gain, a side effect common to many other diabetes medications. In fact, some people who take metformin lose a few pounds with its use. However, its weight loss abilities tend to be overestimated by many care providers.

Some people who use it experience small amounts of weight loss if they consistently take the medication, but not all do. Others experience a little weight loss at first, but this weight loss does not continue and may rebound. So on the whole, while it can be effective for weight loss for some, don't count on metformin for weight loss. Its inconsistent effect on weight is incidental to other, more important benefits.

The most important benefit of metformin use is that it seems to improve long-term outcomes and end-points, not just short-term lab results of risk factors.

For example, some research shows that metformin use in diabetics lowers the risk for heart attacks and cardiovascular mortality. Recent research suggests that it decreases the risk for blood clots, which may be how it lowers cardiovascular risk. It also lowers the risk for common diabetes complications like liver disease.

By decreasing hyperinsulinemia, researchers speculate that metformin may also decrease the chance of cancer. In diabetics, it has recently been shown to decrease the occurrence of colorectal, liver, and pancreatic cancers, and decrease the occurrence of breast cancer. It has also been shown to lower the rate of mortality after cancer incidence compared to other diabetes treatments.

This research on long-term outcomes for metformin is HUGE.  Most drugs only have data on reduction of risk factors or short-term end-points, like reducing blood sugar or cholesterol. Doctors assume that reducing risk factors will lead to improved outcomes, but this is not always true. There are drugs that reduce risk factors yet increase the risk for some long-term end-point outcomes like heart attacks, cancer, or mortality.

So the fact that research shows that metformin reduces the risk for long-term outcomes like heart attacks, some types of cancer, and even mortality is VERY important.

However, it should be cautioned that many of these results were from observational studies; the results of randomized controlled trials have been less clear. Still, overall the results from metformin trials are quite encouraging.

Metformin for Women with PCOS

There is no question that metformin is beneficial for diabetics, and the Diabetes Prevention Program has shown that metformin is helpful for preventing or delaying diabetes in those who are pre-diabetic.

The $64,000 question is whether metformin is as beneficial for normoglycemic women with PCOS as it is for diabetics and pre-diabetics.

In other words, should metformin be used as a first-line therapy for normoglycemic women with PCOS to improve menstrual regularity, improve fertility, and prevent long-term progression to diabetes and cardiovascular disease?

From http://www.fertilitycommunity.com/fertility/hyperinsulinemia-not-ovaries-at-core-of-pcos.html:

The most exciting development in PCOS therapy involves pharmacologic reversal of the primary defect: hyperinsulinemia. Metformin is the best-studied drug. Studies to date are small but generally show metformin cuts fasting insulin, LH, and free testosterone levels by half. The drug also restores menstrual cyclicity and fertility, reverses hirsutism, and reduces body mass index.

Since women with PCOS typically have too much insulin in their bodies already, it benefits them to have a drug that increases their sensitivity to it, so their bodies don't have to produce so much. This may preserve pancreatic function longer, thus preventing or at least postponing a PCOS woman's progression over time to diabetes. In addition, it may decrease androgenic side effects from the insulin.

However, not all authorities agree that hyperinsulinemia is at the heart of PCOS. Some women with PCOS do not seem to have hyperinsulinemia. Thus, some authorities argue that metformin should not be used routinely in all patients with PCOS.

On the other hand, some research suggests that even PCOS women who do not seem to be insulin-resistant benefit from metformin treatment. Thus, the controversy of whether or not to routinely prescribe metformin for all women with PCOS is ongoing.

What Does the Research on Metformin and PCOS Say?

Benefits of treatment with metformin in PCOS
TG = Triglycerides, TC = Total Cholesterol
LDL = "bad" cholesterol, HDL = "good" cholesterol
Image from Ther Adv Endocrinol Metab 2012

Research suggests that short-term and long-term (3 years) treatment with metformin modestly improves HDL cholesterol, BMI and blood pressure in women with PCOS, and may also lower androgen levels, insulin resistance, lipids, and improve menstrual regularity.

However, longer-term data is needed, especially of metformin's effects on cardiovascular disease and mortality in women with PCOS. We know it improves long-term outcomes in diabetics; now we need to know whether it improves long-term endpoints in women with PCOS too.

Non-Alcoholic Fatty Liver Disease (NAFLD) is another co-morbidity associated with PCOS.  Some research suggests that metformin treatment may improve liver function, as well as decreasing development of the Metabolic Syndrome.

This decrease in Metabolic Syndrome points to another potential benefit of metformin use in women with PCOS ─ it might help delay or prevent the progression to diabetes. Research has shown that prediabetic people treated with metformin lowered their risk for diabetes by about a third. Since women with PCOS are also at high risk for diabetes, might routine use of metformin have a similar benefit in this group?

Alas, we only have small studies on this so far, but what we do have suggests that metformin use might have a strong protective effect against progression to impaired glucose tolerance or diabetes in women with PCOS. More research is needed to confirm this.

Limitations of the Data

One difficulty with PCOS and metformin studies is that researchers often couple weight loss, lifestyle intervention (carb moderation and increased exercise), and metformin treatment in studies. Therefore it can be difficult to untangle the effect of each on clinical outcomes. More studies are needed that examine the role of each treatment choice individually (and long-term).

This is especially important for those of us who choose not to pursue weight-loss regimens; we need to know what individual effects increased exercise, carb moderation, or metformin use might have on our PCOS symptoms, even if we don't lose weight with these interventions.

Encouragingly, several small studies have found that metformin use alone (without caloric restriction) still improved insulin resistance, menstrual regularity, cholesterol levels, blood pressure, androgen levels, and hirsutism in women with PCOS.

Hopefully, researchers will do more studies that distinguish between the influences of each intervention separately in the future.

All in all, metformin seems to be a promising first-line treatment for PCOS, even in women who are still normoglycemic. However, not all authorities agree that metformin should be a first-line therapy in non-diabetic women with PCOS.

More complete and longer-term data is needed. We particularly need to know that metformin use impacts clinically significant end-points like mortality or development of heart disease in women with PCOS, as it does in diabetics.

Side Effects and Risks of Metformin

Many people have a love/hate relationship with metformin. They find it very effective at lowering their blood sugar and improving their insulin resistance and PCOS symptoms, but some find the side effects intolerable. Others are troubled by the potential risks.

Therefore, despite its impressive safety profile and research results, some women with PCOS decide against taking metformin.

Women with PCOS should educate themselves thoroughly about the pros and cons of metformin so they can make their decision from an informed place.

Side Effects

The main disadvantage of metformin is its gastrointestinal side-effects.  About 1 in 3 people who take metformin experience significant incidents of diarrhea, gas, nausea, vomiting, or bloating.

Because it can be difficult to predict when these distressing side effects will occur, this can have a major negative impact on a person's quality of life.

These unpredictable GI side effects cause many people to discontinue metformin. On the other hand, many people use metformin without significant GI issues, so its effect really varies from person to person.

To lessen the occurrence of GI side effects, metformin is started at lower doses and gradually increased, the "start low and go slow" approach. GI side effects are supposed to disappear within 4-8 weeks once a final dosage is established, but most people find that they recur periodically anyhow. Those prone to IBS (Irritable Bowel Syndrome) issues seem particularly sensitive.

GI issues are lessened if metformin is taken with a meal (especially dinner), and GI incidents are significantly reduced with the extended release version of metformin.

Those who have had a bad experience with the short-term generic form of metformin often do much better when using the extended-release version.

Some women find that GI incidents are reduced if they avoid foods high in carbs or fat. Others find that they have certain trigger foods that provoke a GI incident. Still others find that taking acidopholus ("good" bacteria) concurrently with metformin lessens GI problems significantly.

Anecdotally, many women with PCOS report sensitivity to gluten. Theoretically, women who have significant GI issues with metformin may be better able to tolerate it when gluten is eliminated from the diet, but this is purely conjectural at this point.

Still, those who have significant G.I. distress with metformin may want to experiment with taking gluten out of their diet before giving up on metformin.

Risks

Although metformin has a very good safety profile, like all medications it does have some risks.

Metformin can result in vitamin B12 deficiencies. It may also affect folate levels. The longer you have taken metformin and the higher the dosage, the stronger the effect. This can particularly impact memory and cognitive function if the deficiency gets too severe.

Therefore, if you take metformin, it is important to have your B12 and folate levels monitored periodically, especially if you plan to get pregnant. Unfortunately, studies show that many care providers fail to routinely check these levels, even in patients with long-term, high-dosage metformin use.

It is not clear at this time whether taking additional B vitamins can help lessen this effect or improve outcomes (and if so, what dosage and method is most optimal), but it seems to be an option worth exploring. Some limited research suggests that taking additional calcium may help improve B12 status as well.

Another recently-discovered side effect of metformin is that it can lower TSH (thyroid stimulating hormone) test results, without a corresponding effect on T4 levels. This may cause unneeded dosage change recommendations, or result in a patient's hypothyroidism being undertreated. Therefore, it's important for care providers to test all the thyroid levels (Free T3 and Free T4) as well as the patient's TSH levels.

Metformin can affect the kidneys negatively in some people, so kidney function (via creatinine tests) should be monitored yearly while on metformin. People with severe liver or kidney disease should probably not be placed on metformin, nor should those who indulge in significant binge drinking. Many doctors also will not place patients with mild liver or kidney issues on metformin. However, other researchers feel that those with mild liver or kidney disease may still benefit from metformin; research is ongoing into this question.

One potential serious side effect of metformin is lactic acidosis. According to pharmacologists,

Lactic acidosis occurs in one out of every 30,000 patients and is fatal in 50% of cases. The symptoms of lactic acidosis are weakness, trouble breathing, abnormal heartbeats, unusual muscle pain, stomach discomfort, light-headedness and feeling cold. Patients at risk for lactic acidosis include those with reduced function of the kidneys or liver, congestive heart failure, severe acute illnesses, and dehydration...

Lactic acidosis is more likely to occur in patients who have certain medical conditions, including kidney or liver disease, recent surgery, a serious infection, conditions that may cause a low level of oxygen in the blood or poor circulation (such as congestive heart failure, recent heart attack, recent stroke), heavy alcohol use, a severe loss of body fluids (dehydration), or X-ray or scanning procedures that require an injectable iodinated contrast drug.

You can drink alcohol while on metformin, but it's not generally recommended. The effects are felt sooner, it's easier to get intoxicated, you are more prone to hypoglycemia (low blood sugar), and, as noted, it may make you more prone to lactic acidosis. Usually this only occurs with a lot of alcohol, but it can act synergistically with other factors, so great caution is warranted.

Metformin should also be temporarily discontinued under certain circumstances, such as radiologic studies involving intravascular iodinated contrast drugs, before surgery, and in people experiencing shock, heart attack, congestive heart failure, or other chronic low-oxygen states.

Some providers also recommend a temporary discontinuation when the patient may become dehydrated, such as when they are extremely ill, have a serious infection, are unable to eat or drink adequately, have significant vomiting or diarrhea, have a significant fever, or are subject to strenuous exercise without enough caloric or fluid intake.

Lactic acidosis is a significant potential risk of metformin and must be taken seriously, but it should be pointed out that most cases occur in people with pre-existing disease or other risk factors (like dehydration, illness, drinking, etc.). For those without risk factors who take metformin carefully, the risk of lactic acidosis is probably lower. And some research disputes whether metformin increases the risk of lactic acidosis at all.

Metformin Combination Drugs

Metformin is often used in conjunction with other drugs, mostly for diabetes treatment. Some are available as fixed-dose combinations in order to lower the number of pills being taken and to make administration simpler and more convenient.

Generally speaking, monotherapy with metformin is the first choice, with additional drugs only being added if metformin alone is not effective enough.  

Metformin plus a TZD is often used in people with severe PCOS or long-term diabetes. In the U.S., metformin plus pioglitazone (Actoplus Met) is available. Metformin plus Avandia (rosiglitazone) is sold as Avandamet. This was taken off the market in 2005 because of problems in the manufacturing process, but has since been returned to the market.

For diabetics, metformin plus sulfonylureas are also available, usually metformin plus glipizide (trade name Metaglip) and metformin plus glyburide (trade name Glucovance). Generic forms of these combo drugs are available now too.

In addition, metformin plus the dipeptidyl peptidase-4 inhibitor sitagliptin is available (sold under the trade name Janumet), as is metformin plus a meglitinide (called PrandiMet).

Again, metformin plus other drugs is not the usual course of therapy for normoglycemic women recently diagnosed with PCOS or those with relatively mild cases. It's only for those with very severe cases that do not respond to metformin alone, or for those with diabetes that is difficult to control.

[More information about these other types of diabetes drugs is forthcoming in another PCOS Treatment Post.]

Summary

Because of its good safety profile and its excellent efficacy, metformin is considered the first-line therapy for diabetes nowadays. For many diabetics, it has been a miracle drug.

Research indicates that not only does metformin improve blood sugar and lessen insulin resistance, it also lessens clinical endpoints like heart disease and mortality. Many diabetes drugs improve blood sugar, but not all improve clinical endpoints, and some even worsen them.

Therefore, metformin's importance as first-line therapy for diabetics cannot be understated.  

The problem is that most metformin research has been done on people with type 2 diabetes, not on women with PCOS. So while metformin is shown to help improve future health in diabetics, the question is whether it should be prescribed for non-diabetic women with PCOS.

In women with PCOS, metformin does seem promising for improving some short-term issues like insulin resistance, reducing androgens, and improving blood sugar and cholesterol. On that basis alone, it probably has a role to play in the treatment of most women with PCOS.

Metformin has also been shown to help improve fertility in women with PCOS, especially when combined with Clomid. Although its effect on the live birth rate is less clear, it probably does have a role to play in the fertility treatment of many women with PCOS as well.

The question is whether metformin's benefits for long-term health in women with PCOS will outweigh its potential risks. So far the data is promising, but only time and more research will tell.

References

*Trigger warnings for weight loss talk always apply to PCOS research.

General Information on Insulin-Sensitizing Agents

• http://www.inciid.org/faq.php?cat=complementarymed&id=2#106 - INCIID FAQ on PCOS
• http://www.drugs.com/pro/metformin.html - FDA pharmacology information on metformin
• http://en.wikipedia.org/wiki/Metformin - Wikipedia entry on metformin
• http://en.wikipedia.org/wiki/Thiazolidinedione - Wikipedia entry on TZDs

General Information on Metformin

• http://www.endo-society.org/endo_news/tri_point/2004/upload/3-Perspectives-on-PCOS.pdf - debate between several doctors about the use of metformin for PCOS treatment
• http://healthlifeandstuff.com/2009/09/metformin-effects-benefits-and-problems/ - general information about metformin and its use
• http://www.medscape.com/viewarticle/440689 - metformin and PCOS, dosages, etc. 
• http://www.ncbi.nlm.nih.gov/pubmed/22775758 - comparison of metformin and extended release metformin on side effects like GI disturbances
• http://www.ncbi.nlm.nih.gov/pubmed/21521311 - documents that metformin use can lower TSH readings in thyroid tests, despite not affecting other thyroid levels

Metformin and Diabetes

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002966. Metformin monotherapy for type 2 diabetes mellitus. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. PMID: 16034881

...MAIN RESULTS: We included for analysis 29 trials with 37 arms (5259 participants)...Obese patients allocated to intensive blood glucose control with metformin showed a greater benefit than chlorpropamide, glibenclamide, or insulin for any diabetes-related outcomes (P = 0.009), and for all-cause mortality (P = 0.03). Obese participants assigned to intensive blood glucose control with metformin showed a greater benefit than overweight patients on conventional treatment for any diabetes-related outcomes (P = 0.004), diabetes-related death (P = 0.03), all-cause mortality (P = 0.01), and myocardial infarction (P = 0.02). Patients assigned to metformin monotherapy showed a significant benefit for glycaemia control, weight, dyslipidaemia, and diastolic blood pressure. Metformin presents a strong benefit for HbA1c when compared with placebo and diet; and a moderated benefit for: glycaemia control, LDL cholesterol, and BMI or weight when compared with sulphonylureas. AUTHORS' CONCLUSIONS: Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.

Metformin for PCOS, pro and con

Clin Endocrinol (Oxf). 2011 Feb;74(2):148-51. doi: 10.1111/j.1365-2265.2010.03934.x. When should an insulin sensitizing agent be used in the treatment of polycystic ovary syndrome? Franks S. PMID: 21121941

...There seems an obvious place for insulin sensitizing agents in management of both reproductive and metabolic disturbances. Of the available agents affecting insulin sensitivity, metformin has been the most widely used but despite an enormous literature reporting beneficial effects on reproductive, cutaneous and metabolic manifestations of PCOS, its efficacy is unproven apart from in those subjects with impaired glucose tolerance or frank diabetes. Metformin at least has an assured safety record whereas both efficacy and safety of other insulin sensitizing agents in women of reproductive age, such as thiazolidinediones and glucagon-like peptide analogues, remains to be established.

Cochrane Database Syst Rev. 2012 May 16;5:CD003053. doi:10.1002/14651858.CD003053.pub5. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. PMID: 22592687

...OBJECTIVES: To assess the effectiveness of insulin-sensitising drugs in improving reproductive outcomes and metabolic parameters for women with PCOS.  MAIN RESULTS: Forty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women. ...AUTHORS' CONCLUSIONS: In agreement with the previous review, metformin was associated with improved clinical pregnancy but there was 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 role of metformin in improving reproductive outcomes in women with PCOS appears to be limited.

Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005552. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N.  PMID: 17253562

...MAIN RESULTS: Six trials were included for analysis, four of which compared metformin versus OCP (104 participants) and two of which compared OCP combined with metformin versus OCP alone (70 participants)...AUTHORS' CONCLUSIONS: Up to 12-months treatment with the OCP is associated with an improvement in menstrual pattern and serum androgen levels compared with metformin; but metformin treatment results in a reduction in fasting insulin and lower triglyceride levels than with the OCP. Side-effect profiles differ between the two drugs. There is either extremely limited or no data on important clinical outcomes such as the development of diabetes, cardiovascular disease, or endometrial cancer. There are no data comparing ISDs other than metformin (that is rosiglitazone, pioglitazone, and D-chiro-inositol) versus OCPs (alone or in combination).

Endocr Pract. 2007 Jul-Aug;13(4):373-9. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Sharma ST, Wickham EP 3rd, Nestler JE. PMID: 17669713

OBJECTIVE: To determine whether treatment with metformin would prevent progression to glucose intolerance and type 2 diabetes in women with polycystic ovary syndrome (PCOS). METHODS: We conducted a retrospective review of medical records of women treated for PCOS during a 5-year period...Fifty women with PCOS fulfilled the eligibility criteria. RESULTS: At baseline, 11 women (22%) had impaired glucose tolerance (IGT), and 39 (78%) had normal glucose tolerance (NGT). After treatment with metformin, IGT persisted in 5 (45%) of the 11 women who had IGT at baseline, whereas 6 (55%) had reversion to NGT. During a mean treatment period of 43.3 months, 2 (5%) of the 39 women with baseline NGT had conversion to IGT, resulting in an annual conversion rate from NGT to IGT of 1.4%. In comparison with the 16% to 19% annual conversion rate reported in the literature, metformin treatment in this study resulted in an 11-fold decrease in the annual conversion rate from NGT to IGT (P = 0.01). None of the 50 women developed diabetes. CONCLUSION: The findings of this retrospective study suggest that long-term treatment with metformin delays or prevents the development of IGT and type 2 diabetes in women with PCOS.

Diabet Med. 2011 Sep 26. doi: 10.1111/j.1464-5491.2011.03460.x. Current perspectives of insulin resistance and polycystic ovary syndrome. Pauli JM, Raja-Khan N, Wu X, Legro RS.  PMID: 21950959

Insulin resistance likely plays a central pathogenic role in polycystic ovary syndrome and may explain the pleiotropic presentation and involvement of multiple organ systems. Insulin resistance in the skeletal muscle of women with polycystic ovary syndrome involves both intrinsic and acquired defects in insulin signalling. The cellular insulin resistance in polycystic ovary syndrome has been further shown to involve a novel post-binding defect in insulin signal transduction. Treatment of insulin resistance through lifestyle therapy or with a diabetes drug has become mainstream therapy in women with polycystic ovary syndrome. However, effects with current pharmacologic treatment with metformin tend to be modest, with limited benefit as an agent to treat infertility... CONCLUSIONS: Insulin resistance is linked to polycystic ovary syndrome. Further study of lifestyle and pharmacologic interventions that reduce insulin resistance, such as metformin, are needed to demonstrate that they are effective in reducing the risk of diabetes, endometrial abnormalities and cardiovascular disease events in women with polycystic ovary syndrome.

Ann Endocrinol (Paris). 2010 Feb;71(1):25-7. Epub 2010 Jan 15. Should physicians prescribe metformin to women with polycystic ovary syndrome PCOS? Duranteau L, et al.  PMID: 20079483

"1. Metformin is not efficient enough in order to regulate menstrual cycles. 2. Metformin is not efficient enough in order to treat hyperandrogenism. 3. Metformin should not be used as a first-line treatment in order to treat infertility. Clomiphene citrate (CC) is the reference treatment. 4. Metformin in addition to CC is not recommended as a second line treatment, after the failure of CC alone. 5. Metformin should not be used during pregnancy in non diabetic women with PCOS, in order to prevent the risk of gestational diabetes. 6. Metformin should be prescribed to PCOS women when they are diabetic, in order to prevent their cardiovascular risk, after lifestyle modification. 7. Metformin should not be used in PCOS non diabetic women in order to lose weight. Metformin should not be used in order to treat dyslipidemia in women with PCOS. 8. In PCOS women, without diabetes, but with fasting hyperglycemia or carbohydrate intolerance, metformin should be prescribed if: BMI greater than 35."

Obstet Gynecol. 2008 Apr;111(4):959-68. Use of metformin in polycystic ovary syndrome: a meta-analysis. Creanga AA, et al. PMID: 18378757

...Metformin improved the odds of ovulation in women with polycystic ovary syndrome when compared with placebo (odds ratio [OR] 2.94; 95% confidence interval [CI] 1.43-6.02; number-needed-to-treat 4.0) and appears more effective for non-clomiphene-resistant women. Metformin and clomiphene increased the likelihood of ovulation (OR 4.39; 95% CI 1.94-9.96; number-needed-to-treat 3.7) and pregnancy (OR 2.67; 95% CI 1.45-4.94; number-needed-to-treat 4.6) when compared with clomiphene alone, especially in clomiphene-resistant and obese women with polycystic ovary syndrome. These treatment effects were greater for trials with shorter follow-up. CONCLUSION:  Using all available evidence, this meta-analysis suggests that metformin increases the likelihood of ovulation and, in combination with clomiphene, increases the odds of both ovulation and pregnancy in women with polycystic ovary syndrome.

Hum Reprod. 2007 Nov;22(11):2967-73. Epub 2007 Aug 31. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Trolle B, et al. PMID: 17766923

...Our aim was to assess the effects of metformin on menstrual frequency, fasting plasma glucose (FPG), insulin resistance assessed as HOMA-index, weight, waist/hip ratio, blood pressure (BP), serum lipids, and testosterone levels in women with polycystic ovary syndrome (PCOS) METHODS: In a randomized, controlled, double-blinded setup, 56 women aged 18-45 with PCOS were treated with either metformin 850 mg or placebo twice daily for 6 months. After a wash-out period of 3 months participants received the alternate treatment for 6 months. The changes in the measured parameters were analysed by intention-to-treat and per protocol...CONCLUSIONS: Metformin treatment lowered weight and systolic blood pressure and increased HDL in women with PCOS. In post-hoc analysis it increased insulin sensitivity and lowered testosterone in obese women. Non-obese women did not benefit from metformin.

Fertil Steril. 2012 January; 97(1): 18–22. doi: 10.1016/j.fertnstert.2011.11.036. All women with PCOS should be treated for insulin resistance. Marshall, JC and Dunaif, A.  Complete text available for free at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277302/

Kmom note: Excellent summary of a pro and con debate of whether metformin and other insulin-sensitizing medications should be used in all women with PCOS.  

Metabolism. 2005 Jan;54(1):113-21. Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance. Goldenberg N, et al.  PMID: 15562389

...We prospectively assessed whether metabolic and menstrual benefits of metformin-diet were equally realized in women with polycystic ovary syndrome (PCOS), categorized by pretreatment top (n = 32) and bottom (n = 35) quintile homeostasis model assessment insulin resistance (IR). Effects of metformin (2.55 g/d) and diet (1500-2000 cal/d, 26% protein, 44% carbohydrate) were prospectively assessed for 12 months....Metformin-diet metabolic effects were much more marked in women in the top vs the bottom quintile for IR. Women with PCOS in the bottom insulin-resistant quintile, conventionally thought not to respond optimally to metformin-diet, nevertheless experience significant metabolic and menstrual benefits. Metformin-diet should benefit most women with PCOS, even those with normal serum insulin, without IR.

Metformin Efficacy Without Concurrent Weight Loss Intervention

J Clin Endocrinol Metab. 2000 Jan;85(1):139-46. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M.  PMID: 10634377 

...In the present study, 23 PCOS subjects...were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits...Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities...In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.

Exp Clin Endocrinol Diabetes. 2010 Oct;118(9):633-7. The effect of metformin treatment for 2 years without caloric restriction on endocrine and metabolic parameters in women with polycystic ovary syndrome.  Oppelt PG, et al.   PMID: 19998243

...MATERIALS AND METHODS: Twenty-six obese women with PCOS were treated with metformin over 2 years without caloric restriction. Clinical, metabolic and endocrine parameters and the body mass index were measured and an oral glucose tolerance test was carried out to calculate insulin resistance indices at the beginning and at the follow-up after 2 years...CONCLUSIONS: Long-term treatment with metformin in women with PCOS appears to reduce androgen excess due to increased SHBG and decreased [Total Testosterone] levels resulting in improvement of hirsutism as a clinical sign of androgen excess. Furthermore a significant decrease in fasting and 2-h insulin levels and slightly improved insulin resistance indices were observed.

Saudi Med J. 2007 Nov;28(11):1694-9. Dietary intervention versus metformin to improve the reproductive outcome in women with polycystic ovary syndrome. A prospective comparative study. Qublan HS, et al. PMID: 17965792

...Forty-six patients with PCOS were studied prospectively in Prince Rashed Hospital, Irbid, Jordan, between January 2003 and April 2005. The women were randomly divided into 2 groups: Group 1 (n=24) was prescribed with 1200-1400 kcal/day diet (25% proteins, 25% fat, and 50% carbohydrates plus 25-30 gm of fiber per week). Group 2 (n=22) was assigned to take 850 mg of metformin twice in a continuous manner. Both treatments continued for 6 months...Both groups had a significant improvement after treatment in the menstrual cyclicity (66.7% and 68.2% versus 12.5% and 18.2%) and significant reduction in BMI (mean of 27.4 and 27.8 versus 32.2 and 31.9), luteinizing hormone levels (7.9+/-1.7 and 6.9+/-1.8 versus 11.8+/-2.2 and 11.5+/-1.8), and androgen (testosterone, androstenedione, dehydroepiandrosterone sulfate) concentration. The clinical, biochemical, and reproductive outcome including menstrual cycle pattern, ovulation, and pregnancy rates were similar in both groups after treatment. CONCLUSION:  Amelioration of hyperinsulinemia and hyperandrogenemia with dietary intervention or metformin treatment improves significantly the clinical features and reproductive function in overweight PCOS women.

Diab Vasc Dis Res. 2009 Apr;6(2):110-9. Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Cheang KI, et al. PMID: 20368201

...In this study, we evaluated the long-term effect of metformin on metabolic parameters in women with PCOS during routine care without a controlled diet. We performed a retrospective medical chart review of 70 women with PCOS receiving metformin from an academic endocrine clinic...After a mean follow-up of 36.1 months with metformin treatment, improvements were observed for BMI, diastolic blood pressure, and HDL cholesterol. The prevalence of metabolic syndrome decreased from 34.3% at baseline to 21.4%...In conclusion,metformin improved the metabolic profile of women with PCOS over 36.1 months, particularly in HDL cholesterol, diastolic blood pressure and BMI.

Gynecol Endocrinol. 2012 Mar;28(3):182-5. doi: 10.3109/09513590.2011.583957. Epub 2012 Feb 6. Metformin versus lifestyle changes in treating women with polycystic ovary syndrome. Curi DD, Fonseca AM, Marcondes JA, Almeida JA, Bagnoli VR, Soares JM Jr, Baracat EC. PMID: 22309675

...DESIGN: Prospective, randomized clinical trial of 40 women with PCOS to analyze the effects of metformin and lifestyle intervention treatments on menstrual pattern and hormone and metabolic profile. The duration of treatment was 6 months... RESULTS: Fifteen women in the metformin group and 12 in the lifestyle changes group completed the study. The menstrual pattern improved by ~67% in both groups. There was a significant decrease in waist circumference in the lifestyle changes group (101.8 ± 3.9 and 95.1 ± 3.6, at baseline and at 6 months of treatment, respectively; p < 0.001) and in body mass index (BMI) in both groups. The predictor of menstrual pattern improvement was BMI. CONCLUSIONS: Both metformin and lifestyle changes may increase the number of menstrual cycles in PCOS. This effect was related to a decrease in BMI.

Metformin and Vitamin Deficiencies

J Diabetes Complications. 2007 Mar-Apr;21(2):118-23. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. Sahin M, et al. PMID: 17331860

...We investigated whether 6 weeks' treatment with metformin or rosiglitazone affects serum concentrations of Hcy [homocysteine], folate, or vitamin B(12) in subjects with newly diagnosed type 2 diabetes compared with controls. We examined 165 patients with type 2 diabetes...In patients with type 2 diabetes, metformin reduces levels of folate and vitamin B(12) and increases Hcy...The clinical significance of these findings remains to be investigated.

BMJ. 2010 May 20;340:c2181.0  Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. de Jager J et al.  PMID: 20488910

...Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered.

Arch Intern Med. 2006 Oct 9;166(18):1975-9. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Ting RZ et al. PMID: 17030830

...Our results indicate an increased risk of vitamin B(12) deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.

J Intern Med. 2003 Nov;254(5):455-63. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. Wulffelé MG, et al.  PMID: 14535967

...We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin...Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. CONCLUSION: In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.

Metformin and Risk for Cancer

Diabetologia. 2009 Sep;52(9):1766-77. Epub 2009 Jul 2. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Currie CJ, Poole CD, Gale EA.  PMID: 19572116

...This was a retrospective cohort study of people treated in UK general practices...A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin...Metformin monotherapy carried the lowest risk of cancer...Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer.

Diabetes Care. 2010 Feb;33(2):322-6.  Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16.  Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. PMID: 19918015

...CONCLUSION: In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality.

BMC Cancer. 2011 Jan 18;11:20. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. Lee MS, et al. PMID: 21241523

...We examined the possible metformin effect on total, esophageal, gastric, colorectal (CRC), hepatocellular (HCC) and pancreatic cancers in a Taiwanese cohort...With diabetes but no anti-hyperglycemic medication, cancer incidence density increased at least 2-fold for total, CRC and HCC. On metformin, total, CRC and HCC incidences decreased to near non-diabetic levels but to varying degrees depending on gender and cancer type (CRC in women, liver in men)...Metformin can reduce the incidences of several gastroenterological cancers in treated diabetes.

J Clin Oncol. 2012 Jun 11. Diabetes, Metformin, and Breast Cancer in Postmenopausal Women. Chlebowski RT, et al.   PMID: 22689798

...PATIENTS AND METHODS: In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. ...RESULTS: Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04)...women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2. CONCLUSION: Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.

Diabetes Care. 2011 Oct;34(10):2323-8. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Zhang ZJ, et al.  PMID: 21949223

OBJECTIVE: Both in vitro and in vivo studies indicate that metformin inhibits cancer cell growth and reduces cancer risk. Recent epidemiological studies suggest that metformin therapy may reduce the risks of cancer and overall cancer mortality among patients with type 2 diabetes. However, data on its effect on colorectal cancer are limited and inconsistent. We therefore pooled data currently available to examine the association between metformin therapy and colorectal cancer among patients with type 2 diabetes. ...RESULTS: The analysis included five studies comprising 108,161 patients with type 2 diabetes. Metformin treatment was associated with a significantly lower risk of colorectal neoplasm (relative risk [RR] 0.63 [95% CI 0.50-0.79]; P < 0.001)... CONCLUSIONS: From observational studies, metformin therapy appears to be associated with a significantly lower risk of colorectal cancer in patients with type 2 diabetes. Further investigation is warranted.

J Clin Endocrinol Metab. 2012 Jul;97(7):2347-53. Epub 2012 Apr 20. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. Zhang ZJ, et al.  PMID: 22523334 

...The objective of this study was to review the evidence currently available to examine the potential role of metformin in chemoprevention for liver cancer in patients with type 2 diabetes...DATA SYNTHESIS: A database was developed on the basis of five studies consisting of approximately 105,495 patients with type 2 diabetes. In meta-analyses, metformin was associated with an estimated 62% reduction in the risk of liver cancer among patients with type 2 diabetes (odds ratio 0.38, 95% confidence interval 0.24, 0.59; P < 0.001)...CONCLUSIONS: Metformin appears to be associated with a lower risk of liver cancer in patients with type 2 diabetes. Further investigation, including mechanistic studies, well-designed cohort studies, and possibly controlled trials, is needed.

Metformin and Long-Term Health

Lancet. 1998 Sep 12;352(9131):854-65. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.  PMID: 9742977

...Median glycated haemoglobin (HbA1c) was 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011)...Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.

Ginekol Pol. 2011 Apr;82(4):259-64. Effects of metformin therapy on markers of coagulation disorders in hyperinsulinemic women with polycystic ovary syndrome. Serdyńska-Szuster M et al. PMID: 21735693

The objective of this study was to prospectively assess the effects of a 6-month metformin therapy on body mass index (BMI), insulin sensitivity and coagulation/fibrinolysis markers in hyperinsulinemic women with PCOS...Metformin administration decreases the circulating PAI-1 concentration and simultaneously improves insulin sensitivity and BMI in PCOS women with hyperinsulinemia. Long-term metformin administration may be a new prophylactic measure for the prevention of cardiovascular disorders in such patients.

Clin Endocrinol (Oxf). 2011 Oct;75(4):520-7. doi: 10.1111/j.1365-2265.2011.04093.x. Long-term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight patients with polycystic ovarian syndrome. Gangale MF, et al. PMID: 21569072

The objective of this study is to determine the ability of metformin treatment in reducing the prevalence of metabolic syndrome (MS) and its hepatic involvement [Non-Alcoholic Fatty Liver Disease, NAFLD] in young hyperinsulinaemic overweight patients with polycystic ovarian syndrome (PCOS)...Treatment with metformin is indicated in all hyperinsulinaemic overweight patients with PCOS, especially in those with NAFLD. These data appear even more interesting considering their increased risk to develop metabolic and hepatic complications.

BMJ Open. 2012 Jul 13;2(4). pii: e001076. doi: 10.1136/bmjopen-2012-001076. Print 2012. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. Ekström N, et al.  PMID: 22798258

OBJECTIVE: To evaluate the effectiveness and safety of metformin use in clinical practice in a large sample of pharmacologically treated patients with type 2 diabetes and different levels of renal function. DESIGN: Observational study between July 2004 and December 2010, mean follow-up 3.9 years. SETTING: Hospital outpatient clinics and primary care in Sweden. PARTICIPANTS: 51 675 men and women with type 2 diabetes, registered in the Swedish National Diabetes Register, and on continuous glucose-lowering treatment with oral hypoglycaemic agents (OHAs) or insulin...CONCLUSIONS:
Metformin showed lower risk than insulin for CVD and all-cause mortality and slightly lower risk for all-cause mortality compared with other OHA, in these 51 675 patients followed for 4 years. Patients with renal impairment showed no increased risk of CVD, all-cause mortality or acidosis/serious infection. In clinical practice, the benefits of metformin use clearly outbalance the risk of severe side effects.