I've had a few questions lately from patients about using specific supplements for menopause symptoms. I wrote a blog post on supplements a few months ago, but there are always new marketing claims for new and old supplements so I will talk intermittently about ones that my patients are bringing to my attention.
An important thing to note about supplements is that there is minimal regulation of supplements in the United States. There are substantially more regulations on supplements in many other countries, including the European Union, Canada, and China. The FDA does not regulate supplements for efficacy or safety, but supplement companies are prohibited from selling products that are adulterated or misbranded. Unfortunately, however, there are many examples of ingredients being present in supplements that are not on the label and/or of contain ingredients at different dosages than the label. Between 2007 and 2016, the FDA identified 746 brands of supplements adulterated with pharmaceutical agents, including prescription medications, withdrawn medications, and unapproved drugs. One analysis concluded that while Americans likely have the same level of access to high-quality supplements as consumers abroad, Americans also have more access to low-quality and harmful supplements. It's difficult (to impossible) for consumers to know the difference.
Some supplements have undeniable benefit to human health, but all supplement companies would have you believe that their "natural" supplements are a healthy alternative to prescription drugs. Ironically, supplements may be less safe and less effective than prescription drugs, which are heavily regulated by the FDA and must be proven safe and effective before they can be sold. I promise you this...if I know of a supplement that is safe and effective for whatever ails you, I will recommend it. There is no conspiracy among doctors to withhold safe, useful products from patients. There is, however, a $71 billon supplement industry that would very much like for you to keep filling your cabinets with their products.
Update (11/14/2023): Dr. Jen Gunter, an OB/GYN who authored The Vagina Bible and The Menopause Manifesto wrote a post on alternative medicine/supplements that published the same day as this post. It's excellent and deserves your time and attention if you're interested in more information about alternative medicine, supplements, and other "natural" cures.
OK, let's get back to talking about whether the supplement DIM can help with peri-menopause symptoms. Some of my patients report having been told (by friends, family, the internet, or even a healthcare worker) that DIM can prevent the estrogen fluctuations that occur during peri-menopause that are responsible for the unwanted symptoms. When my patients brought it up, I didn't know much about DIM, but what I did know was that if there was a drug, supplement, food, lifestyle change, or witchcraft spell (I'm kidding) that had been shown to be effective at treating peri-menopause symptoms, medical organizations that focus on women's health like The Menopause Society and the American College of Obstetricians and Gynecologists (ACOG) would be talking about it. A quick internet search identified that many of the people who are touting the miraculous effects of DIM are also selling supplements and often, very expensive blood tests. Those are red flags for me, but I kept researching. As best as I can tell, the gist of the sales pitch is that DIM changes the metabolism of estrogen in women (there seems to be some data for this) which prevents estrogen fluctuations experienced in peri-menopause (there is no evidence of this) which reduces/eliminates symptoms (also no evidence of this, but there is mixed data about whether DIM can help with hot flashes in women undergoing breast cancer treatment.)
How in the world did folks jump straight to these unsupported conclusions? Besides an interest in selling DIM and/or estrogen metabolite blood tests, I have no idea. But let's look at the data that does exist.
3,3'-diindolylmethane (DIM) is a metabolite of a compound found in cruciferous vegetables like broccoli, brussel sprouts, and cauliflower. I found a few studies in the scientific literature that looked at the effects of eating cruciferous vegetables. One study analyzed data from 13 studies of almost 20,000 women and concluded that overall high intake of cruciferous vegetables was associated with a 15% lower risk of breast cancer. (Note that they found an association - they did not show that eating the vegetables actually caused the lower risk.) Another study suggested that eating cruciferous vegetables could decrease the risk of breast cancer recurrence. But one analysis calculated that you would need to eat more than 1.3 lbs per day of cruciferous vegetables to achieve any anticancer benefit. Other studies failed to find any link between cruciferous vegetables and breast cancer risk.
How about menopause symptoms? I found one study that examined high intake of cruciferous vegetables among women in medically-induced menopause. Researchers found that eating a diet high in cruciferous vegetables was correlated with fewer hot flashes. Again, correlated (or associated) and causative are very different things. Notably, these women ate the cruciferous vegetables because they believed it would help with their hot flashes - the researchers did not assign the diet to a random group of women. We know that in most studies looking at any intervention on hot flash frequency and severity, even the women getting placebo report as much as a 30% improvement so it's hard to quantify how much the vegetables actually helped.
What about DIM as a supplement? There are a fair number of scientific studies that examine the effect of DIM in vitro (i.e., outside of an organism - typically a group of cells or tissue) or in animals. Those studies suggest that DIM may be useful in prevention and treatment of cancers and for the treatment of a large number of other things, ranging from acne to weight loss to hot flashes to PMS. But there is a glaring lack of studies in humans, and you cannot make the leap from the test tube or an animal model to a human. Many more (and larger) clinical studies are needed.
For those who don't want to wade through the scientific explanation, skip ahead to the summary. If you want a longer explanation, keep reading...
But is it scientifically possible that DIM can reduce the estrogen fluctuations that occur in peri-menopausal women? Studies suggest that DIM likely impacts estrogen metabolism by enhancing the expression of genes (CYP) that make proteins that convert estrone to hydroxyestrones, including 2-hydroxyestrone. Time out. What the heck does that mean? I apologize in advance for the long background, but I promise to get to a point eventually. Estradiol is the most prevalent estrogen in reproductive age women, but there are others, like estrone, as well as a host of estrogen metabolites. In peri-menopausal women, estradiol levels fluctuate significantly for several years as the ovaries lose their ability to produce estradiol. Estradiol levels decrease significantly in menopausal women. Fat tissues continues to produce some estrogen (primarily estrone) throughout the post-menopausal years; however, levels remain consistently low. Circulating estrogens in women exist in a dynamic equilibrium. Transformations of estrogens take place mainly in the liver where estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major metabolite excreted in urine. Estrogens also recirculate by undergoing sulfate and glucuronide conjugation in the liver, biliary secretion into the intestine, and hydrolysis in the gut followed by reabsorption.
The metabolism of estradiol occurs mainly by chemical processes called 2-hydroxylation and 16-alpha-hydroxylation. The exact role of all of the estrogen metabolites in normal physiology and disease pathophysiology is not well understood. Since 16-alpha-hydroxyestrone (which has high potency at estrogen receptors) has been shown to initiate tumor development in some animal models, researchers since the 1980s have examined whether the ratio of 2-hydroxyestrone (a metabolite with less potency at estrogen receptors) to 16-alpha-hydroxyestrone impacts a woman's risk for breast cancer. To date, the studies in women have been small and have provided mixed results. The ratio of 2-hydroxyestrone to 16-alpha-hydroxyestrone appears to be altered in women who have a family history of breast cancer in addition to a specific genetic change in one of the proteins involved in estrogen metabolism. One study argued that the ratio cannot be used to predict a woman's breast cancer risk. Yet another study suggested that the ratio could be predictive. Scientists have also tried to find interventions that would change the ratio. Some studies suggest exercise may increase 2-hydroxyestrone, but higher body weight might favor 16-alpha-hydroxyestrone. MHT seems to increase 2-hydroxyestrone production more than 16-alpha-hydroxyestrone. Without more comprehensive research, it's not possible to say whether this ratio (and any changes in it) means anything at all or is just an interesting, but non-physiologically relevant, observation.
Despite the lack of conclusion about whether the ratio of estrogen metabolites has any physiologic implications, let's look at what DIM does to the ratio. In one study, DIM appeared to increase in the ratio of 2-hydroxyestrones to 16-alpha-hydroxyestrone. Another study looked at the effect of treatment with DIM for 4-6 weeks in 20 healthy women with a mutation in their BRCA1 gene. They found that DIM supplementation did not change the ratio of estrogen metabolites in urine, regardless of menopausal status. DIM also didn't increase or decrease the total amount of estrogens. On the other hand, a separate study in 19 post-menopausal women found that DIM supplementation resulted in a ratio favoring 2-hydroxyestrone. As in the previous study, DIM did not change the overall amount of estrogens. In short, the current scientific data does not provide a clear answer, and the studies are very small so interpretation of the findings is impossible at this time.
In summary, current evidence does not support use of DIM supplementation to prevent the estrogen fluctuations of peri-menopause or relieve hot flashes caused by decreased estradiol because DIM does not increase or decrease the total estrogens in the body, and the verdict is still out on whether DIM changes the ratio of estrogens and/or metabolites and, if it does, what, if anything, that means.
What about safety? DIM is not absorbed well by humans. The brand BioResponse has been the most studied DIM supplement since it appears to have 50% better bioavailability than others. Dose recommendations for DIM vary but typically fall within the 100-300 mg/day range. There are a few reports of people having nausea and other GI issues when taking 300 mg in one dose. Women taking tamoxifen shouldn't take DIM without talking to their doctor since DIM appears to disrupt tamoxifen metabolism and may reduce its effectiveness. Pregnant women should not use DIM since it appears to have an impact on estrogen metabolism, and the effects of those changes to the health of a fetus are unknown. No studies have been done to determine if DIM interferes with the effectiveness of hormonal birth control or MHT.
I recommend to my patients who are interested in using DIM that they instead increase their intake of cruciferous vegetables like arugula, kale, broccoli, brussel sprouts, and collard greens, since we know they contain healthy fiber, antioxidants, vitamins, and minerals and may be correlated (but evidence for a direct action is lacking) with a decreased risk of breast cancer. There are only a few studies on the effects of DIM on humans, and evidence supporting their effectiveness in preventing or treating symptoms of peri- and post-menopausal symptoms is lacking. There also aren't adequate studies about the safety of using DIM. Save your money, and buy some produce.
The supplement shelf or the produce aisle need not be the primary place you look for treatments for peri-menopausal symptoms We have many evidence-based treatments. Unwanted vaginal bleeding, common during peri-menopause can be managed with hormonal birth control, including IUDs. There are several FDA-approved non-hormonal medications to treat hot flashes and night sweats. Additionally, there are lifestyle changes, therapies, and other interventions that we know will help reduce severity and frequency of hot flashes. Mood disorders common to peri-menopause also can be treated with medication, therapy, and/or lifestyle changes. Many women experience sleep disturbances during peri-menopause; there are treatments and interventions that are not habit forming. If you're having unwanted symptoms as a result of peri-menopause or menopause, see your doctor. She can work with you to find solutions that are backed by science to be effective and safe. And particularly during the hormonal chaos of peri-menopause, eat a balanced diet filled with fruits, vegetables, and lean meats, exercise regularly, and find ways to reduce stress. Prioritizing care of yourself is more important than ever.